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Magnetic resonance therapy for knee osteoarthritis
|
Magnetic resonance therapy for knee osteoarthritis
Evidence-based recommendations on magnetic resonance therapy for knee osteoarthritis in adults. This involves placing a magnetic resonance device over the knee to stimulate cartilage to heal and relieve the symptoms of osteoarthritis.
# Recommendations
Evidence on the safety of magnetic resonance therapy for knee osteoarthritis shows no major safety concerns. Evidence on efficacy is inadequate in quality and quantity and shows no benefit over placebo. Therefore, this procedure should not be used unless it is part of a research study. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should be in the form of appropriately powered randomised controlled trials comparing the procedure with placebo. It should report patient selection and treatment protocols, including the number of sessions and magnetic field strength.# The condition, current treatments and procedure
# The condition
Osteoarthritis of the knee is the result of progressive deterioration of the articular cartilage and menisci of the joint, usually because of trauma and wear and tear. This leads to exposure of the bone surface. Symptoms include pain, stiffness, swelling and difficulty walking. Acute exacerbations of pain are common and usually self‑limiting after 14 days. Only a small number of patients develop progressive symptoms needing treatment.
# Current treatments
Treatment depends on the severity of the symptoms. Conservative treatments include analgesics and corticosteroid injections to relieve pain and inflammation, and physiotherapy and prescribed exercise to improve function and mobility. When symptoms are severe, surgery may be indicated: options include upper tibial osteotomy and unicompartmental or total knee replacement.
# The procedure
Magnetic resonance therapy (MRT) for osteoarthritis is a non-invasive procedure that uses a special device to administer electromagnetic energy to an osteoarthritic joint. A range of devices with different physical designs are available. The aim is to relieve the symptoms and to improve the osteoarthritis by stimulating the cartilage cells.
MRT is done in an outpatient setting. During the procedure, the patient lies on the couch and a section of the MRT device slides over the knee. The device generates electromagnetic fields which are targeted to the cartilaginous tissue in the affected joint. The aim is to promote joint repair and relieve the symptoms of osteoarthritis. Each treatment lasts 60 minutes. Depending on the severity of the disease and MRT therapy device, a course of treatment typically consists of 5 to 10 treatment sessions on consecutive days.
|
{'Recommendations': 'Evidence on the safety of magnetic resonance therapy for knee osteoarthritis shows no major safety concerns. Evidence on efficacy is inadequate in quality and quantity and shows no benefit over placebo. Therefore, this procedure should not be used unless it is part of a research study. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should be in the form of appropriately powered randomised controlled trials comparing the procedure with placebo. It should report patient selection and treatment protocols, including the number of sessions and magnetic field strength.', 'The condition, current treatments and procedure': '# The condition\n\nOsteoarthritis of the knee is the result of progressive deterioration of the articular cartilage and menisci of the joint, usually because of trauma and wear and tear. This leads to exposure of the bone surface. Symptoms include pain, stiffness, swelling and difficulty walking. Acute exacerbations of pain are common and usually self‑limiting after 14\xa0days. Only a small number of patients develop progressive symptoms needing treatment.\n\n# Current treatments\n\nTreatment depends on the severity of the symptoms. Conservative treatments include analgesics and corticosteroid injections to relieve pain and inflammation, and physiotherapy and prescribed exercise to improve function and mobility. When symptoms are severe, surgery may be indicated: options include upper tibial osteotomy and unicompartmental or total knee replacement.\n\n# The procedure\n\nMagnetic resonance therapy (MRT) for osteoarthritis is a non-invasive procedure that uses a special device to administer electromagnetic energy to an osteoarthritic joint. A range of devices with different physical designs are available. The aim is to relieve the symptoms and to improve the osteoarthritis by stimulating the cartilage cells.\n\nMRT is done in an outpatient setting. During the procedure, the patient lies on the couch and a section of the MRT device slides over the knee. The device generates electromagnetic fields which are targeted to the cartilaginous tissue in the affected joint. The aim is to promote joint repair and relieve the symptoms of osteoarthritis. Each treatment lasts 60\xa0minutes. Depending on the severity of the disease and MRT therapy device, a course of treatment typically consists of 5 to 10\xa0treatment sessions on consecutive days.'}
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https://www.nice.org.uk/guidance/ipg702
|
Evidence-based recommendations on magnetic resonance therapy for knee osteoarthritis in adults. This involves placing a magnetic resonance device over the knee to stimulate cartilage to heal and relieve the symptoms of osteoarthritis.
|
1eb94cfd8840a782c7db2b4ca45f113ddf8c4a80
|
nice
|
Laparoscopic removal of uterine fibroids with power morcellation
|
Laparoscopic removal of uterine fibroids with power morcellation
Evidence-based recommendations on laparoscopic removal of uterine fibroids with power morcellation in adults. This involves cutting the fibroids into small pieces to remove them.
# Recommendations
Evidence on the safety of laparoscopic removal of uterine fibroids with power morcellation shows potentially serious complications. In particular there is a risk of spreading undiagnosed malignant tissue, which has higher prevalence in people who are postmenopausal or over 50. Evidence on the procedure's efficacy is limited in quantity. Therefore:
For people who are postmenopausal or over 50, this procedure should not be used. Find out why NICE recommends not to use some procedures on the NICE interventional procedures guidance page.
For people who are premenopausal or 50 or under, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Further research should report details of patient selection, surgical technique (including any containment system used) and long-term outcomes.
Clinicians wishing to do laparoscopic removal of uterine fibroids with power morcellation in people who are premenopausal or 50 or under should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Also see the Royal College of Obstetricians and Gynaecologists' advice on obtaining consent from women having this procedure.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Also see the Royal College of Obstetricians and Gynaecologists' information for patients who may be considering this procedure.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedures outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
This procedure should only be done by a surgeon with specific training in laparoscopic surgery. When an in-bag technique is needed, the surgeon should also have specific training in using containment systems.# The condition, current treatments and procedure
# The condition
Uterine fibroids (also known as uterine leiomyomas or myomas) are benign tumours of the uterus. They can be asymptomatic or can cause symptoms including heavy periods or intermenstrual bleeding. They can be associated with fertility problems and miscarriage.
# Current treatments
Treatment depends on whether the fibroids cause symptoms, and if the person would like to become pregnant in the future. For symptomatic fibroids, treatment options include medication, interventional radiology and surgery. Interventional radiology treatments include uterine artery embolisation and MRI‑guided focused ultrasound. Surgery includes hysterectomy, myomectomy, endometrial ablation techniques and myolysis.
# The procedure
Laparoscopic surgery with power morcellation allows uterine fibroids to be cut into smaller pieces so they can be removed laparoscopically and without the need for a laparotomy. The procedure aims to reduce symptoms caused by fibroids.
Laparoscopic removal of uterine fibroids with power morcellation is done with the patient under general anaesthesia. During laparoscopic surgery and under direct visualisation an electrosurgical morcellator is introduced through a small incision into the abdomen and used to cut the uterine fibroid into smaller pieces. If a hysterectomy is planned, morcellation can be used to also remove part or all of the uterus. The fragments are removed through the morcellation cannula. The removed tissue should be sent for histological analysis. To reduce the risk of disseminating benign and malignant uterine tissue, the tissue can be contained in an insufflated sterile bag while being morcellated within the abdomen.
|
{'Recommendations': "Evidence on the safety of laparoscopic removal of uterine fibroids with power morcellation shows potentially serious complications. In particular there is a risk of spreading undiagnosed malignant tissue, which has higher prevalence in people who are postmenopausal or over\xa050. Evidence on the procedure's efficacy is limited in quantity. Therefore:\n\nFor people who are postmenopausal or over\xa050, this procedure should not be used. Find out why NICE recommends not to use some procedures on the NICE interventional procedures guidance page.\n\nFor people who are premenopausal or 50\xa0or under, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFurther research should report details of patient selection, surgical technique (including any containment system used) and long-term outcomes.\n\nClinicians wishing to do laparoscopic removal of uterine fibroids with power morcellation in people who are premenopausal or 50\xa0or under should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Also see the Royal College of Obstetricians and Gynaecologists' advice on obtaining consent from women having this procedure.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Also see the Royal College of Obstetricians and Gynaecologists' information for patients who may be considering this procedure.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedures outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThis procedure should only be done by a surgeon with specific training in laparoscopic surgery. When an in-bag technique is needed, the surgeon should also have specific training in using containment systems.", 'The condition, current treatments and procedure': '# The condition\n\nUterine fibroids (also known as uterine leiomyomas or myomas) are benign tumours of the uterus. They can be asymptomatic or can cause symptoms including heavy periods or intermenstrual bleeding. They can be associated with fertility problems and miscarriage.\n\n# Current treatments\n\nTreatment depends on whether the fibroids cause symptoms, and if the person would like to become pregnant in the future. For symptomatic fibroids, treatment options include medication, interventional radiology and surgery. Interventional radiology treatments include uterine artery embolisation and MRI‑guided focused ultrasound. Surgery includes hysterectomy, myomectomy, endometrial ablation techniques and myolysis.\n\n# The procedure\n\nLaparoscopic surgery with power morcellation allows uterine fibroids to be cut into smaller pieces so they can be removed laparoscopically and without the need for a laparotomy. The procedure aims to reduce symptoms caused by fibroids.\n\nLaparoscopic removal of uterine fibroids with power morcellation is done with the patient under general anaesthesia. During laparoscopic surgery and under direct visualisation an electrosurgical morcellator is introduced through a small incision into the abdomen and used to cut the uterine fibroid into smaller pieces. If a hysterectomy is planned, morcellation can be used to also remove part or all of the uterus. The fragments are removed through the morcellation cannula. The removed tissue should be sent for histological analysis. To reduce the risk of disseminating benign and malignant uterine tissue, the tissue can be contained in an insufflated sterile bag while being morcellated within the abdomen.'}
|
https://www.nice.org.uk/guidance/ipg703
|
Evidence-based recommendations on laparoscopic removal of uterine fibroids with power morcellation in adults. This involves cutting the fibroids into small pieces to remove them.
|
bfaa33232d8d65f8b19c6c6ced5bc9687ebff031
|
nice
|
Hysteroscopic mechanical tissue removal (hysteroscopic morcellation) for uterine fibroids
|
Hysteroscopic mechanical tissue removal (hysteroscopic morcellation) for uterine fibroids
Evidence-based recommendations on hysteroscopic mechanical tissue removal (hysteroscopic morcellation) for uterine fibroids in adults. This involves cutting the fibroids into small pieces to remove them.
# Recommendations
Evidence on the safety of hysteroscopic mechanical tissue removal (hysteroscopic morcellation) for uterine fibroids shows there are well recognised, infrequent but potentially serious side-effects. Evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do hysteroscopic mechanical tissue removal (hysteroscopic morcellation) for uterine fibroids should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
The procedure should only be done by clinicians with specific training in this technique, including fluid management.
Further research should report details of patient selection and patient reported outcomes, particularly symptom relief.# The condition, current treatments and procedure
# The condition
Uterine fibroids (also known as uterine leiomyomas or myomas) are benign tumours of the uterus. They can be asymptomatic or cause symptoms including heavy periods or bleeding between periods. They can be associated with fertility problems and miscarriage.
# Current treatments
Treatment depends on whether the fibroids cause symptoms, and if the person would like to become pregnant in the future. For symptomatic fibroids, treatment options include medication, interventional radiology and surgery. Interventional radiology treatments include uterine artery embolisation and MRI-guided focused ultrasound. Surgery includes hysterectomy, myomectomy, endometrial ablation techniques and myolysis.
This procedure is used for submucosal fibroids, which develop in the muscle layer beneath the inner lining of the uterus and grow into the uterine cavity. This includes pedunculated fibroids, which are attached to the uterus with a narrow stalk of tissue.
# The procedure
Hysteroscopic mechanical tissue removal (hysteroscopic morcellation) aims to remove submucosal uterine fibroids under visual guidance using a hysteroscope inserted into the uterus through the cervix. It is intended to reduce the risk of traumatic injury to the uterus associated with traditional procedures. An intended advantage of the procedure over thermal ablation techniques is avoiding the risk of thermal injury.
The procedure may be done under local, regional, or general anaesthesia, typically as a day-case procedure. A hysteroscope is inserted into the uterus through the cervix and saline is pumped thorough a small channel in the hysteroscope to distend the uterus. A morcellator is passed through the hysteroscope and used to cut and simultaneously aspirate the morcellated fibroid tissue. The aspirated tissue can be collected for histological analysis.
Different devices are available for this procedure.
|
{'Recommendations': "Evidence on the safety of hysteroscopic mechanical tissue removal (hysteroscopic morcellation) for uterine fibroids shows there are well recognised, infrequent but potentially serious side-effects. Evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do hysteroscopic mechanical tissue removal (hysteroscopic morcellation) for uterine fibroids should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThe procedure should only be done by clinicians with specific training in this technique, including fluid management.\n\nFurther research should report details of patient selection and patient reported outcomes, particularly symptom relief.", 'The condition, current treatments and procedure': '# The condition\n\nUterine fibroids (also known as uterine leiomyomas or myomas) are benign tumours of the uterus. They can be asymptomatic or cause symptoms including heavy periods or bleeding between periods. They can be associated with fertility problems and miscarriage.\n\n# Current treatments\n\nTreatment depends on whether the fibroids cause symptoms, and if the person would like to become pregnant in the future. For symptomatic fibroids, treatment options include medication, interventional radiology and surgery. Interventional radiology treatments include uterine artery embolisation and MRI-guided focused ultrasound. Surgery includes hysterectomy, myomectomy, endometrial ablation techniques and myolysis.\n\nThis procedure is used for submucosal fibroids, which develop in the muscle layer beneath the inner lining of the uterus and grow into the uterine cavity. This includes pedunculated fibroids, which are attached to the uterus with a narrow stalk of tissue.\n\n# The procedure\n\nHysteroscopic mechanical tissue removal (hysteroscopic morcellation) aims to remove submucosal uterine fibroids under visual guidance using a hysteroscope inserted into the uterus through the cervix. It is intended to reduce the risk of traumatic injury to the uterus associated with traditional procedures. An intended advantage of the procedure over thermal ablation techniques is avoiding the risk of thermal injury.\n\nThe procedure may be done under local, regional, or general anaesthesia, typically as a day-case procedure. A hysteroscope is inserted into the uterus through the cervix and saline is pumped thorough a small channel in the hysteroscope to distend the uterus. A morcellator is passed through the hysteroscope and used to cut and simultaneously aspirate the morcellated fibroid tissue. The aspirated tissue can be collected for histological analysis.\n\nDifferent devices are available for this procedure.'}
|
https://www.nice.org.uk/guidance/ipg704
|
Evidence-based recommendations on hysteroscopic mechanical tissue removal (hysteroscopic morcellation) for uterine fibroids in adults. This involves cutting the fibroids into small pieces to remove them.
|
5393c6d6c50e5551d8774a44490402fd149d8ab6
|
nice
|
Babies, children and young people's experience of healthcare
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Babies, children and young people's experience of healthcare
This guideline describes good patient experience for babies, children and young people, and makes recommendations on how it can be delivered. It aims to make sure that all babies, children and young people using NHS services have the best possible experience of care. It is recognised that parents and carers play a key role, and where appropriate, we took their views into account when developing the recommendations.
# Introduction from the young people involved in the development of this guideline
When babies, children and young people access healthcare, it is important that their experience is as positive as possible. This guideline has been written with children and young people who know what it's like to be a patient. It has been an opportunity to share what has and has not worked, and hopefully improve the healthcare experience of many babies, children and young people in the future.
Adults often see children and young people as passive recipients of healthcare. This can lead to children and young people not being listened to, having a lack of understanding of their own condition and may lead to problems that can affect future care (for example, finding it difficult to trust healthcare professionals or feeling very anxious before procedures). However, having a positive experience can make a child or young person feel confident, empowered and supported to manage decisions about their own health and healthcare, and can improve their perception of their diagnosis and treatment. This positive experience should also ensure that babies, children and young people are treated as individuals with a life outside healthcare, and not just as their condition or diagnosis.
This guideline aims to improve the healthcare experience of babies, children and young people with the hope that this can improve their health outcomes and their wellbeing.# Context
Optimising patient experience has long been recognised as an integral part of effective healthcare for adults. The healthcare experience of babies, children and young people has received less attention in the past, despite the legal rights of children to participate in decisions that affect them. Unfamiliar environments, and having to meet and interact with a range of healthcare professionals, can be particularly unsettling for babies, children and young people, and may lead to anxiety and distress.
Many NHS providers of healthcare services for children and young people currently carry out user surveys directly with children and young people as well as with their parents or carers, and some run focus groups to obtain feedback from children and young people and their parents or carers, with a view to improving the provision of services and the experience of healthcare. However, surveys of children and young people's healthcare experiences have identified that feedback from children themselves is generally less positive than their parents' responses, with a third of children in 1 survey reporting that they did not always understand what staff said, and over half feeling they were not involved enough in making decisions about their care or treatment.
Although there are some examples of good practice and initiatives to improve babies, children and young people's experience of healthcare, there is variation in practice across the country.
This guideline covers babies, children and young people (aged 17 and under) accessing NHS physical or mental health services, or local authority-commissioned healthcare services. Babies, children and young people are entitled to always receive the same high-quality healthcare experience, and so the recommendations in this guideline apply to all healthcare experiences and settings. For some babies, children and young people, interaction with healthcare services may be limited to visits to a dentist or GP, whereas other babies, children and young people may have medical conditions that need frequent interactions, inpatient stays and an ongoing healthcare relationship with professionals, so a personalised approach to implementation is needed.
The guideline provides evidence-based information for healthcare professionals, children, young people and their parents or carers about communication, information, support, the healthcare environment, access and continuity of care. It also provides guidance on maintaining usual activities because babies, children and young people need the opportunity to grow, learn and develop alongside their peers, despite their healthcare needs.# Recommendations
Healthcare professionals should involve children and young people in decisions about their healthcare in ways that are appropriate to their maturity and understanding. Some children and young people will be able to give informed consent themselves, some will be able to contribute to the discussion, and others may not be able to be involved at all. For more information, see NICE's information on making decisions about your care.
A parent or carer, who has parental responsibility for a child (as defined by the Children's Act 1989), will have a key role to play in planning and making decisions about their child's health and care, particularly when they are young. As children grow older and develop the maturity and understanding to make decisions for themselves, that role will diminish, particularly if the child wants it to. Where relevant, parents and carers should be given information and support to enable them to do this, as set out in the NHS Constitution and summarised in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding that should be used alongside this guidance.
# Overarching principles
## Safeguarding
Adhere to all relevant legislation and follow all national and local safeguarding policies and professional guidelines when implementing these recommendations and when planning and delivering healthcare services for all babies, children and young people, in any setting. See further guidance in the NICE advice on safeguarding and the Children's Act 1989 (and subsequent updates).
## Disabilities
Adhere to all relevant legislation relating to the rights of disabled babies, children and young people to access healthcare, and make reasonable adjustments as required by legislation to enable this access. See the Equality Act 2010.
## Competence
Involve all children and young people in decisions about their healthcare, unless they do not wish (or are unable) to be involved (see recommendations 1.1.4 to 1.1.7). Recognise that:
Young people aged 16 or 17 years with mental capacity to make decisions about their healthcare are entitled to do so, and to consent to treatment. There is a presumption that a person above the age of 16 has capacity unless and until assessed otherwise.
Children and young people under 16 years can make decisions about their healthcare and consent to treatment if they are assessed by a healthcare professional to be Gillick competent. The conclusion that a child or young person is competent relates to that specific healthcare decision.
## Age- and developmentally appropriate care
Ensure that all methods of communication, information and discussions are tailored for the age, developmental stage and level of understanding of the baby, child or young person.
Recognise that needs and preferences may change as children mature, and that it is necessary to revisit these needs and preferences on a regular basis and to adapt support, information and complexity of discussions accordingly.
## Changes in needs and preferences
Recognise that children and young people's needs, preferences and engagement with healthcare professionals and healthcare services (for example, how much they would like to be involved in decision making or how much support they need) may vary from day to day, at different encounters or may be affected by other factors (for example, how unwell they are feeling).
Ensure that previously expressed needs, preferences or engagement levels are revisited, and give additional or alternative opportunities for discussions or decisions, particularly if personal or clinical circumstances have changed.
## Digital access
Recognise that not all children and young people, or the parents or carers of babies and young children, are able to access digital resources (for example, online information, messaging or video-calling, apps or other digital tools).
Ensure that non-digital methods of attending appointments, communicating, and providing information are available, and provide an equal level of service, for anyone who cannot access (or prefers not to use) digital methods.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on overarching principles .
Full details of the evidence and the committee's discussion are in:
evidence review A: planning healthcare and making shared decisions
evidence review C: consent privacy and confidentiality
evidence review D: providing information
evidence review E: understanding the risks and benefits of healthcare decisions
evidence review F: involving parents or carers in healthcare and healthcare decisions
evidence review G: support from healthcare staff
evidence review M: healthcare environment.
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# Communication and information
## Communication by healthcare staff
Ensure that children and young people, and their parents or carers have a positive experience by:
introducing yourself and anyone else present
asking them how they wish to be addressed (for example, their preferred name and pronouns)
putting the child or young person and their parents or carers at ease by being friendly and welcoming (for example smiling, saying hello, using eye contact)
building a rapport to develop trust
encouraging children, young people and the parents and carers of babies and young children to contribute to, and be active participants in, discussions and decisions about their care. See also the section on support from healthcare staff.
Communicate with children and young people and their parents or carers with:
kindness, compassion and respect
cultural sensitivity
a non-judgemental attitude.
When communicating with babies, children and young people, particularly those with ongoing health needs, develop an understanding of them as individuals, not only based on their health condition or diagnosis (for example, referring to the baby, child or young person by name, asking them what is important to them in their healthcare).
Take time to listen to and address the concerns and fears of children and young people, and of the parents or carers of babies and young children and:
treat their concerns and feelings (such as fear and embarrassment) with empathy and understanding
give reassurance that these concerns are very common and are nothing to feel embarrassed or upset about (for example, by saying 'it's OK to be scared').
Identify who is the most appropriate person to communicate with a child or young person, or the parent or carer of a baby or young child (for example, this could be a healthcare professional or other member of the multidisciplinary team, or another professional such as a youth worker or social worker). When deciding on the person, take into account:
the clinical circumstances
the subjects to be discussed
the preferences of the child or young person.
Identify the child or young person's preferred forms of communication and use these when communicating with them. Ask their advice, or ask their parents or carers what these are. Take into account that:
English may not be their first language
these may be non-verbal (for example, sign language, Makaton)
identification of a 'yes' or 'no' response (which might be non-verbal) can allow a direct conversation between a child or young person and a healthcare professional
these might need additional resources (for example, foreign language or sign language interpreters, picture boards, computer-based systems)
individuals with additional communication needs might need more time and specialist support for alternative forms of communication (for example, augmentative and alternative communication).
Be aware that parents or carers may have communication preferences and needs of their own that may affect their ability to discuss their baby or child's care.
Use developmentally appropriate creative and interactive tools to help effective communications with babies, children and young people (for example, play dough, pictures, diagrams and writing).
Help engage babies, children and young people in communication by:
using both verbal and non-verbal methods (for example, sitting at the same level as them, using body language to show attentive listening, reassuring babies by positive touch or containment holding before or during procedures)
pausing and allowing time for responses.
When communicating with children and young people, always check they have taken the information in and understood it (for example, by asking children or young people to explain back to you in their own words).
If a child or young person is uncomfortable or having difficulty communicating, try alternatives that may help. This may include:
trying again at a different time
trying again in a different, quieter or more private setting (see recommendations 1.4.8 and 1.4.9)
seeing them without their parents or carers
involving a different person (for example, another healthcare professional or an adult trusted by the child or young person)
using a different means of communication.
Respect times when children and young people do not wish to communicate, and be aware that their wish to communicate may vary at different times.
In urgent or emergency situations when time may be limited, give children and young people opportunities to communicate whenever possible, and the opportunity to discuss afterwards.
Be aware that babies, children and young people may not communicate pain, distress or anxiety verbally so you may need to:
ask parents or carers what is usual behaviour for their child or young person
be alert to physical cues (for example, lack of or abnormal movements to reduce pain) or behavioural cues (for example, crying, refusing to speak or pushing away, or behaviour that appears aggressive such as anger, defiance or biting).
All staff involved in providing healthcare services to babies, children and young people should have skills and competencies in relevant communication skills.
For guidance on communicating with children with life-limiting conditions, see the NICE guideline on end of life care for infants, children and young people with life-limiting conditions.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on communication by healthcare staff .
Full details of the evidence and the committee's discussion are in evidence review B: communication by healthcare staff.
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## Providing information
Ask children and young people, and the parents or carers of babies and young children, about the quantity and type of information they wish to receive, and how they wish to receive it. This should include, but not be limited to, details of:
their condition and any treatment options and issues related to these (including diagnosis, possible side effects, long-term outcomes, and symptoms they may experience)
any preventative action or lifestyle changes they can make
where they will be seen
likely timescales and waiting times for their treatment, including keeping them informed about waits or delays at appointments
who will be involved in providing their healthcare
what will happen at key points in their care (for example, on transfer from one healthcare setting to another, when being referred to a different healthcare team). Follow the recommendations on age and developmentally appropriate care and the recommendations on changes in needs and preferences.
When giving information to the child or young person, or the parents or carers of babies and young children:
use their preferred method whenever possible; this may be in person face-to-face or other methods (for example email, phone call, text message or video call)
take into account that the child or young person's preferences for, and ability to access, digital resources may differ from those of their parents and carers
provide written and digital information to back up and supplement face-to-face contact, telephone calls or video calls and to refer to later.
Ensure information for children and young people is provided privately when appropriate, for example:
without their parents or carers present if this is what they would prefer
by telephoning or texting them directly
by addressing letters to children or young people themselves, and not their parents or carers.
Discuss with children and young people if there is information that should be provided to their parents or carers, to help their parents or carers support them or look after them (for example, dietary information, post-operative care, or symptoms to look out for).
Provide information for children and young people or the parents or carers of babies and young children that is:
in simple, clear language that is easy to understand, avoiding jargon and explaining any medical terms used
evidence based
appropriate for their individual needs
culturally sensitive
not judgemental
presented in accessible formats and language that can be understood by them (for example, through an interpreter, translated into another language, or as an easy-read version using pictures and symbols)
given consistently by all members of the healthcare team
in line with the NHS Accessible Information Standard.
Provide written or digital information (for example leaflets, websites, apps) for children and young people that is:
created in partnership with children and young people
engaging for children and young people (for example, containing appealing images, video, audio or animations).
Provide information at a suitable time, place and pace, for example:
when possible, at regular, predictable times such as during ward rounds or clinic reviews
in stages if necessary, so children, young people, parents or carers are not overloaded with too much information at one time.
When children, young people, parents or carers have had time to absorb and reflect on information they are given:
check they have understood it, and how it applies to them (see recommendation 1.2.10)
allow time to discuss the information again
actively encourage them to ask questions
make sure they know what to do if they do not understand, or have questions about their healthcare that come up later on.
When giving information to children and young people about their care, take into account:
the possible emotional impact of any information provided (for example, children and young people may be upset by what they have been told)
that support might be needed to help them think about and process the information
that they may feel intimidated by the healthcare professional providing information (if they feel that individual is in a position of authority), and might need reassurance and support.
Warn children and young people, parents or carers that some of the medical information available which they have not been directed to by the healthcare team (for example, online, on social media or from friends) may be inaccurate or have a limited evidence base.
Support children and young people to identify reliable sources of information related to their care or condition, and ensure that recommended sources are:
up to date
professional, credible and evidence based (for example, NHS resources, charities and support groups).
Advise children and young people to check the validity of information with their healthcare professional if they are unsure about its accuracy.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on providing information .
Full details of the evidence and the committee's discussion are in evidence review D: providing information.
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# Planning healthcare
## Shared decision making
Respect and support the right of children and young people to be involved in making decisions about their healthcare. This should include:
ensuring early and ongoing involvement in discussions about their healthcare
providing opportunities for them to share their opinions
supporting them to make decisions independently
taking into account previous discussions or decisions, and checking if their decisions have changed
including them in any decisions when there is a choice of options, including where there is no impact on health or treatment outcomes (for example, what colour plaster cast they would prefer, whether they prefer their medicine as liquid or tablets).
When involving children and young people in decision making, take into account that:
the extent and level of their involvement may vary, between individuals and on different occasions; follow the recommendations on changes in needs and preferences
-n occasions, some children and young people might not wish to be involved in shared decision making, and that this choice should be respected
they might wish to have help from their parents or carers, or another person or advocate, for support, to help understand information or to help make decisions
they might need time to think about decisions, so planning discussions in advance to allow for this might be helpful.
When discussing and making decisions about treatment options with children and young people:
follow the recommendations on communication by healthcare staff and the recommendations on providing information
clearly articulate the options, and adapt the description of the treatment options so they are understood by the child or young person you are talking to
use alternative methods for discussions and decisions if necessary (for example, children and young people might prefer to write down or pre-record questions or opinions if they are not comfortable talking about them)
consider using decision aids to support complex decisions, or if children and young people are having difficulty making a decision.
Involve parents or carers in discussions and decisions relating to the care of their baby or young child (for example, for inpatient care, by allowing parents to be present at ward rounds when their baby or child's care is discussed whenever possible). Follow the same principles as shown in recommendations 1.3.1 to 1.3.3.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on shared decision making .
Full details of the evidence and the committee's discussion are in evidence review A: planning healthcare and making shared decisions.
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## Risks and benefits
Offer children, young people and the parents or carers of babies and young children information about the potential risks and benefits of healthcare options to allow them to make informed decisions. Follow the recommendations on communication by healthcare staff and the recommendations on providing information.
Ensure this information is:
provided in a way they can understand, and they can see how it applies to them
relevant to their individual needs and personal circumstances (for example, health setting, health status, age and developmental stage).
Discuss with children and young people how much information they would like about risks and benefits, and take this into consideration. Recognise that some children and young people:
might not want to know more about the risks than is needed for informed consent
might not want to know about risks on a particular occasion
might need additional opportunities to think about and discuss risks and benefits
might benefit from alternative methods of communicating risks and benefits
might need to take a break when discussing risk, and to come back to the topic later
might want to discuss the risks and benefits without their parents or carers present.
When discussing the risks and benefits of healthcare options with the child or young person, parent or carer:
check their understanding of what the risks mean to them and what the benefits to them would be (see recommendation 1.2.10)
ask them if they have any particular concerns or worries they would like to talk about (for example, fear about procedures such as injections, or children may want to ask about the risk of death, however unlikely this may be)
answer any questions they may have and address any concerns.
Reconfirm understanding of risks and benefits on an ongoing basis. Follow the recommendations on changes in needs and preferences.
Explore, acknowledge and respond to any concerns that children and young people or their parents or carers have about risk, and provide opportunities to discuss concerns and what will be done to reduce risk.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on risks and benefits .
Full details of the evidence and the committee's discussion are in evidence review E: understanding the risks and benefits of healthcare decisions.
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# Consent, privacy and confidentiality
Discuss consent, assent, privacy and confidentiality directly with children and young people if:
they are able to understand what these concepts mean (with appropriate explanation)
they can relate them to their own situation.
When discussing consent, assent, privacy and confidentiality:
ensure that children and young people, and parents or carers, understand their rights and responsibilities
explain when parents or carers might have to make decisions on behalf of children and young people.
For detailed advice on best practice around consent, privacy and confidentiality, refer to relevant professional guidance (for example, the General Medical Council's ethical guidance for doctors on decision making and consent and the 0–18 years: guidance for all doctors, the Nursing and Midwifery Council's Code and the guidance on consent in the General Dental Council's standards for the dental team).
## Consent
Support children and young people to make informed decisions to assent to, consent to or refuse treatment, taking into account their individual capacity or competence (which may be different for different decisions).
Provide children and young people with clear explanations about why treatment in their best interests had to go ahead if it is not possible to obtain their consent or assent before treatment (for example, in an emergency situation).
If there is a difference of opinion about consent, assent or refusal for a procedure (for example, if the views of the child or young person are different from those of their parents or carers, or the views of the child, young person or parent or carer are different from those of healthcare professionals):
recognise that all discussions and decisions should focus on what is in the best interests of the baby, child or young person
consider involving others, such as another member of the multidisciplinary team, another healthcare professional, an independent advocate, or a named or designated professional for child protection
discuss with the child, young person and their parent or carer that you would like to involve other people
ensure that the child, young person and parent or carer are offered support.
Reconfirm a child or young person's understanding and consent decisions on an ongoing basis. Follow the recommendations on changes in needs and preferences.
## Privacy and confidentiality
Maintain privacy and dignity during discussions, examinations and care. Take into account individual preferences, circumstances and cultural sensitivities whenever possible.
Discuss potentially sensitive topics in places where they are less likely to be overheard, when possible, for example, in a clinic room or side room rather than behind bed space curtains.
When using digital or virtual methods for consultations or discussions:
ask if the child or young person is able to speak without being overheard to discuss potentially sensitive topics
confirm with them that they are able to talk freely, or if they would prefer an alternative time or method of communication.
Be aware that information sharing, privacy and confidentiality laws also apply to babies, children and young people. Only share their information:
with their consent for the purposes of care and treatment or
when in the baby, child or young person's best interests to do so or
when otherwise required to do so by law.
Offer children and young people the opportunity to see and talk to a healthcare professional without the presence or involvement of their parent or carer, and explain that this discussion will be confidential.
If children and young people who usually rely on their parents or carers for help communicating want to have private conversations with healthcare professionals without the presence or involvement of their parent or carer, ensure additional support is provided (for example, by determining mechanisms to enable children and young people to express a 'yes' and 'no' response (which may be non-verbal), or including other people in conversations and meetings). See recommendation 1.2.6.
Explain to children and young people that it may be necessary to share confidential information without their consent in certain circumstances (for example, if they or others may be in danger).
For a short explanation of why the committee made these recommendations, see the rationale and impact section on consent, privacy and confidentiality .
Full details of the evidence and the committee's discussion are in evidence review C: consent, privacy and confidentiality.
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# Advocacy and support
## Involvement of parents or carers
Involve parents or carers in discussions and decisions about the care of babies and young children, and recognise that parents or carers will be their principal caregivers and advocates.
Give all children and young people opportunities to express their opinions about their health needs independently, including:
asking them about the extent to which they want their parent or carer to be involved in their healthcare
-ffering to see them separately from their parents or carers for part of the consultation.
Be aware that their wish for parental involvement may depend on the circumstances (for example, what the appointment is about, if they have to have any procedures) or may vary. Follow the recommendations on changes in needs and preferences.
Encourage children and young people to develop their confidence in making decisions for themselves (for example, by giving them opportunities to do this), and encourage their parents or carers to support them with this.
Encourage parents and carers to talk to their child or young person about how they will be involved in decisions about their healthcare. This might include:
finding out whether the child or young person would like to know more about what will happen at appointments (for example, what healthcare procedures might take place), even if the parent or carer might feel they should leave out details so as not to worry them
the parent or carer reassuring their child or young person that they can have part or all of an appointment without them being present if they would prefer that
regularly confirming with their child or young person that they can change their mind at any time about how involved they want them to be.
Ensure that children or young people who do not have a parent or carer to support them, or whose parents or carers are not able to support them, are offered other sources of support (for example, a family member, advocate, social worker, youth worker, nurse or play specialist). Young people may wish to be supported by a friend or partner.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on involvement of parents or carers .
Full details of the evidence and the committee's discussion are in evidence review F: involving parents or carers in healthcare and healthcare decisions.
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## Support from healthcare staff
All staff involved in providing healthcare services to babies, children and young people should uphold children's rights in accordance with the United Nations Convention on the Rights of the Child.
Advise children and young people about how they can be supported by healthcare staff in a specific setting and encourage them to express their preferences about the support they would find helpful.
Be aware that some children and young people may need more support from healthcare staff than others and that this support may change over time. Follow the recommendations on changes in needs and preferences.
When building a healthcare relationship with children and young people:
introduce yourself, explain your role and how you can help support them
listen to and be seen to believe their experiences (for example, symptoms such as discomfort, how they are feeling)
reassure them that you will take their concerns seriously
provide calm and positive emotional support and encouraging words
discuss with them how you will act on what they have said.
Help children and young people to speak up about things that matter to them, and their views and preferences by:
advocating for them and upholding their preferences if they are unable or unwilling to do this themselves
acting as a trusted person for them to talk to when they feel their concerns are not being listened to.
Encourage children and young people to ask for the support they need to help with their healthcare experiences or encourage them to use coping techniques they have already developed. These could include:
their parent or carer to be with them or someone's hand to hold
music to listen to, a soft toy to cuddle, playing a game on a phone or tablet, a support animal or pet to stroke
individual coping techniques. Ask them if these techniques help or if they would like to try other techniques.
Provide advice about and access to other forms of support available (for example, from the education or voluntary sector).
For a short explanation of why the committee made these recommendations, see the rationale and impact section on support from healthcare staff .
Full details of the evidence and the committee's discussion are in evidence review G: support from healthcare staff.
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## Self-advocacy
Facilitate self-advocacy in children and young people. This may include:
allowing enough time in consultations and appointments
providing confidential and private spaces
providing information on their rights to advocate for themselves
establishing and using the child or young person's preferred method of communication, paying particular attention to those who do not communicate verbally (see recommendation 1.2.6 and recommendation 1.4.13).
Assume that all children and young people have views and opinions about their own healthcare, and actively encourage them to express what matters to them. In particular:
do not make assumptions that certain groups of children or young people will not want or will not be able to advocate for themselves
recognise that children and young people from different backgrounds may have different levels of confidence or skills to advocate for themselves.
Empower children and young people to advocate for themselves by:
providing information so they can develop an understanding of their own condition and health needs
making them central to discussions about their healthcare
agreeing with them when and how they would like their parents or carers included in discussions and decision making, and ensure this agreement is followed
working collaboratively with them to discuss healthcare needs and treatment options and include them in decisions about their care
taking into account their own culture, experiences, needs, wishes and feedback
considering the use of age- and developmentally appropriate healthcare-management applications, such as smartphone apps; apps should meet the criteria specified in the NICE evidence standards framework for digital health technologies; see the NHS Apps library for details of NHS approved apps.
Support children and young people to develop skills in advocating for themselves by offering opportunities to be involved in feedback, service design or improvement or other engagement activities (see recommendations 1.7.1 to 1.7.9).
For a short explanation of why the committee made these recommendations, see the rationale and impact section on self-advocacy .
Full details of the evidence and the committee's discussion are in evidence review H: empowering children and young people to advocate for themselves.
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## Independent advocates
Children and young people must have access to an independent advocate in line with statutory requirements. This includes the Mental Health Act 2007, the Care Act 2014 and the Mental Capacity Act 2005.
Where children and young people are eligible, inform them that, they can have another person, known as an independent advocate, present with them when speaking to healthcare professionals, rather than their parent or carer. See also recommendation 1.3.2 about support from other people for shared decision making.
Provide children and young people who are eligible for support from an independent advocate with information about independent advocates. Include:
the role of an independent advocate (including confidentiality and independence from the healthcare team)
the option to express a preference for an advocate of a particular gender, or how to change advocate.
Support eligible children and young people to meet with an independent advocate (for example, by providing a private space and time to meet).
Independent advocates should work with eligible children and young people to support and empower them in discussions and decisions about their healthcare. This should include:
identifying and using the child or young person's preferred method of communication and using additional support to communicate if necessary (see recommendation 1.2.6)
building a trusting relationship, ensuring continuity where possible
ensuring confidentiality
providing guidance on healthcare systems, pathways and processes, where necessary
providing explanations of medical information and terminology, where necessary
empowering children and young people to make their own decisions.
Independent advocates should provide a mechanism for children or young people to give feedback on the advocacy service and to check that the relationship is working effectively for the benefit of the child or young person.
Commissioners should consider expanding the availability of independent advocates services to support children or young people who are not eligible under legislation, but who are not adequately represented by their parents or carers or other professionals.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on independent advocates .
Full details of the evidence and the committee's discussion are in evidence review I: independent advocacy in healthcare for children and young people.
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# Improving healthcare experience
## Food
Ensure babies, children and young people who are inpatients have access to food that meets their needs. This should include:
a balanced healthy diet that will help with their recovery
a choice of food options at every meal that are culturally and dietetically appropriate and will appeal to a range of tastes
flexibility in availability of food, for example access to snacks outside meal times
food choices and menus that have been developed in conjunction with children and young people. For babies who are breast or bottle fed, ensure there are suitable facilities to support this.
## Pain-related anxiety
Reduce the fear and anxiety about pain that may be experienced by babies, children and young people during healthcare interventions by:
preparing them with information about interventions or procedures (for example, blood tests and injections)
being honest about possible pain and what will be done to alleviate pain
using therapeutic play and distraction techniques and creating a calm environment before, during and after interventions or procedures that are likely to be painful
upholding children and young people's experiences of pain, showing them they are believed, and avoiding language that minimises the child or young person's experience of pain (for example, do not say a procedure they found painful "didn't really hurt").
Ensure adequate pain assessments are carried out and acted on. See NICE guidelines for the management of pain in specific conditions, such as the NICE guideline on cerebral palsy for under 25s for advice on assessing pain in verbal and non-verbal children and young people, the NICE guideline on end of life care for infants, children and young people with life-limiting conditions and the NICE guideline on sickle cell disease.
## Staff uniforms and healthcare clothing
Ensure children and young people, and parents or carers of babies and young children can easily identify members of staff. This could include:
visible name badges with easy to understand job roles or titles
recognisable uniforms, particularly if they help differentiate between professions.
Be aware that healthcare clothing (for example gowns, masks or visors) can be frightening for babies, children and young people and they may be unable to recognise staff or see their facial expressions or smiles. This is particularly important for children who rely on lip reading or facial cues for communication.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on improving healthcare experience .
Full details of the evidence and the committee's discussion are in evidence review J: improving experience of healthcare.
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# Involvement in improving healthcare experience
## Design of healthcare services
When designing services that will be used by babies, children and young people:
involve children and young people and obtain their views, or for babies and young children, involve their parents or carers
actively seek out children and young people (or the parents or carers of babies and young children) from under-represented groups (for example, black, Asian and minority ethnic groups, people with physical, sensory or learning disabilities, people from a disadvantaged background, LGBT+ people, people who have not been able to, or have chosen not to, use the services before, looked-after children).
Assume that all children and young people have relevant opinions on services they use and their care, and will give them if asked in a suitable way.
Make it as simple as possible for children and young people to contribute to service design by:
using appropriate methods to engage them, capture their views and enable them to contribute (for example, internet surveys, social media, forums and groups)
addressing any practical issues that could be barriers to involvement (for example, transport, timing, language, travel costs, disabilities or communication difficulties).
Ensure that feedback about the design of services from children, young people and parents or carers is shared and used. Explain how their input has shaped design of services (for example, using social media or posters to describe methods such as 'Ask Listen Do' and 'You Said We Did').
For a short explanation of why the committee made these recommendations, see the rationale and impact section on design of healthcare services .
Full details of the evidence and the committee's discussion are in evidence review K: design of healthcare services.
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## Measuring experience
Collect feedback (for example, using questionnaires or surveys) directly from children and young people at different points in their healthcare experience. Collect feedback for babies and young children from their parents or carers.
Actively seek out feedback from children and young people (or the parents or carers of babies and young children) from under-represented groups (for example, black, Asian and minority ethnic groups, people with physical, sensory or learning disabilities, people from a disadvantaged background, LGBT+ people, people who have not been able to, or have chosen not to, use the services before, looked-after children).
Make it easier for people to give meaningful feedback by using tools that:
have been co-produced with the appropriate age group
are appropriate for, and selected together with, the intended group (including taking into account any disabilities or communication preferences)
are provided at a convenient time and place, and by a convenient method, for respondents (for example, voting systems in a healthcare setting, or an online survey to be completed at home).
Ensure that the feedback on healthcare experiences from children, young people and parents or carers is shared and used. Explain how their input has been used to improve healthcare experiences (for example, using social media or posters to describe methods such as 'Ask Listen Do', 'You Said We Did').
Inform children and young people, and the parents or carers of babies and young children, of their right to complain. Ensure that it is easy for children and young people to make a complaint if they need to.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on measuring experience .
Full details of the evidence and the committee's discussion are in evidence review L: measuring experience.
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# Healthcare environment
Care for babies, children and young people in an environment that:
meets their clinical and personal needs
takes into account their preferences about their place of care (or the preferences of parents or carers for babies or young children)
is appropriate for their age and developmental stage, is physically accessible and has adaptations available, if needed.
Provide a healthcare environment that supports:
privacy and dignity
confidence in healthcare delivery (for example, equipment is available when needed)
family-centred care for inpatients (for example, the option for a parent or carer to stay and sleep, including in non-paediatric areas)
parents or carers to give developmentally appropriate care to their children (for example, changing their baby's nappy, helping children wash and dress)
-ther family members, siblings, or those important to the child or young person to be present (if this is what they would like)
easily accessible, age-appropriate play and recreation for children and young people, including to reduce boredom and anxiety while waiting for appointments or interventions
children and young people who are inpatients to mix with friends, peers or partners (for example, flexible visiting times, access to social media, spaces away from clinical areas to meet)
a feeling of safety (for example, easy access to call bells or other means of summoning help, knowing that someone is around to help).
Provide a healthcare environment that:
is clean, comfortable and feels homely
is calm, with as little disturbance from background noise as possible
separates treatment areas from those for play and recreation
is designed and decorated in a suitable way for the age group it is for (including use of colours, layout, lighting and clear signs)
in an inpatient setting is quiet enough for rest and sleep, particularly at night.
Provide children and young people who are inpatients with information about the facilities and routine on the ward (for example, where the bathrooms are located, what times meals are served, where play and recreation facilities are located and how they can be accessed, where there are quiet areas), and answer any questions they may have.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on healthcare environment .
Full details of the evidence and the committee's discussion are in evidence review M: healthcare environment.
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# Maintaining usual activities
Give children and young people ongoing opportunities to identify aspects of their lives that are important to them (for example, physical, social and recreational activities, schooling and education, their developmental, cultural and emotional needs).
Discuss with children and young people, particularly those with ongoing health needs:
how their health condition and their healthcare will impact on their ability to engage in usual activities
what their expectations and goals may be for their future involvement in usual activities, and how they can be helped achieve them.
Ensure that babies, children and young people are able to continue with their usual activities of daily life with minimal disruption while receiving healthcare and, when clinically appropriate, make reasonable adjustments to their environment to support this (for example, providing a quiet space for studying).
In an inpatient setting, ensure free internet access over Wi-Fi, and that any Wi-Fi codes or passwords are freely available so that children and young people can maintain their usual contacts and networks.
Advise children and young people that use of social media or technology (for example, phones, noisy computer games) must not compromise the privacy or the environment of other people.
Recognise that the wishes and needs of each baby, child and young person to engage in the activities they have identified as important to them will vary between individuals and over time. Integrate these needs into the delivery of healthcare.
Make sure that the baby, child or young person's usual support networks (for example, parents and carers, siblings, partners and friends) can be involved in maintaining activities of daily living (for example, changing nappies, washing, getting dressed, eating) and other usual activities.
Ensure coordination between healthcare, education and social care to maintain an individual's usual activities, including education and learning. This could include education support roles, Early Help or making adjustments such as scheduling treatment appointments around school commitments.
Help children and young people to use cultural, spiritual or religious beliefs that they find helpful in their lives as a source of support if they wish. This could include facilitating religious activities such as prayer time, or letting them know about chaplaincy services or other religious support available.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on maintaining usual activities .
Full details of the evidence and the committee's discussion are in:
evidence reviews N: supporting participation in usual activities
evidence review J: improving experience of healthcare.
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# Accessibility, continuity and coordination
## Accessing healthcare
Provide children and young people with targeted information about:
when an illness or condition means they should seek medical help
what services are available (for example, using the NHSGo app)
when and how they can access services. Follow the recommendations on providing information.
Reassure children and young people that:
healthcare services are there to help them
feeling afraid or embarrassed about asking for help is normal but healthcare professionals will understand and provide support.
Develop information about healthcare and healthcare services with input from children and young people themselves, and in collaboration with healthcare professionals (for example, play specialists, child psychologists) and other sectors (for example, education, social care, the voluntary sector).
Provide information for parents and carers to support them in accessing healthcare services for their baby or child (for example, the eRedbook app).
Actively seek out groups of parents or carers who may face barriers accessing healthcare services for their children (for example, those who would benefit from translated materials or those who may have limited internet access), to ensure they have accessible information about what care their children can receive, and are encouraged to use those services.
Provide information to children and young people on:
what services they can access with or without their parents or carers
whether their parents or carers will need to be told if they access services.
Take into account the views of children and young people, and for babies and young children the views of their parents and carers, when designing or redesigning healthcare services. Include:
personal factors, such as the age range, gender and developmental stages of the children and young people using the service
social factors, such as the religious, cultural or social background of the children and young people using the service. See recommendations 1.7.1 to 1.7.4 on involving children and young people in design of healthcare services.
Provide children and young people with support and help to access the healthcare system. Ensure additional support, such as one-to-one support from a named healthcare or social care professional, is available for those who need it (for example, children with learning disabilities, looked-after children, children in institutional care, care leavers).
Take into account access needs specific to children and young people. This might include:
accommodating preferences about the gender of the healthcare professional who they see
-ffering flexible appointments that meet an individual's and family's needs, for example minimising regular appointments during school hours
providing services in locations that are easier for children and young people to access, or co-locating with other services that children and young people access (for example, youth centres and schools).
Use flexible methods where clinically appropriate, agreed with the child or young person to deliver healthcare services (for example, telephone or video calls, digital media such as websites and apps) as alternatives to in person face-to-face services to help overcome access difficulties, such as travelling to appointments or relying on parents for transport.
Use feedback from children and young people to improve the accessibility of healthcare services. See recommendations 1.7.5 to 1.7.9 on measuring experience of care.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on accessing healthcare .
Full details of the evidence and the committee's discussion are in evidence review O: accessing healthcare.
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## Continuity and coordination of care
Maintain continuity of care by providing healthcare from the same professionals or teams when clinically appropriate.
Ensure clear and timely exchange of relevant patient information:
between healthcare professionals and children and young people or the parents or carers of babies and young children
between healthcare professionals
between healthcare, education and social care professionals.
Pay particular attention to communication between healthcare professionals and services and the coordination of ongoing care:
at key points in care (for example, on transfer from one healthcare setting to another, or when being referred to a different healthcare team)
for children and young people who might need additional support (for example, children with learning disabilities, looked-after children, care leavers, young people who are homeless). For advice on transition to adult services, see the NICE guideline on transition from children's to adults' services.
Ensure systems are in place so that children and young people and the parents or carers of babies and young children do not need to unnecessarily repeat their healthcare history when being seen by different healthcare professionals (for example, by using health passports or digital health records).
Ensure children and young people and the parents or carers of babies and young children have access to their healthcare records. Access must meet the requirements of the Access to Health Records Act 1990.
Provide contact information so that children and young people know how to obtain advice from the same service or team in the future.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on continuity and coordination of care .
Full details of the evidence and the committee's discussion are in evidence review P: continuity of care.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary.
## Accessible
Something (for example, a service or information format) designed in a way so that people who have a disability or impairment are able to use it with a similar level of time, effort and skill needed as someone who does not.
## Assent
Agreement given by a child or young person to a course of action or procedure, when they are not legally empowered to give consent.
## Consent
Agreement (which can be verbal, non-verbal or written) to a course of action or procedure, after a discussion of the risks and benefits, when they are legally empowered to give consent.
## Containment holding
Placing both hands firmly but gently on a baby and holding the position very still, to provide reassurance and comfort.
## Cultural sensitivity
Knowledge, awareness and respect for other people's cultural background, identity and differences, without making assumptions about them.
## Focus and reference groups
A series of focus and reference groups with children and young people were held to obtain their views and opinions. These views and opinions were considered by the committee as part of their review of the evidence.
## Gillick competent
Children under the age of 16 can consent to their own treatment if they're believed to have enough intelligence, competence and understanding to fully appreciate what's involved in their treatment. Also see the NHS website on consent to treatment – children and young people.
## National surveys
A review of recent national surveys of children and young people's views on healthcare was carried out. The findings of these surveys were considered by the committee as part of their review of the evidence.
## Non-judgemental
Not criticising or demonstrating a negative attitude about another person's feelings or actions, based on personal opinions or personal biases.
## Parents or carers
Parents or carers refers to the primary caregivers for a baby or child at any given time. This can include birth or adoptive parents with parental responsibility, other members of the extended family who provide care such as siblings, grandparents, aunts and uncles, others nominated by the parents, or legal guardians. For looked-after children or those who lack mental capacity, it can also include those acting instead of parents such as a social worker, key worker, foster carers or guardians. It does not refer to nurses, healthcare assistants or other healthcare professionals who are acting in their professional capacity.
## Positive touch
Human touch that aims to give babies the experience of touch that is not for a clinical purpose, but is given tenderly, lovingly and gently, and that which responds to and does not ignore their behaviour.
## Usual activities
Activities that form part of a baby, child or young person's daily life and which may be disrupted by illness or the need to access healthcare services. This may include activities of daily living (bathing, showering, eating), interactions with family and friends, social and emotional development, education and schooling, sports, hobbies and interests, social activities and use of social media.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Risks and benefits
What decision aids are the most cost effective and acceptable when explaining the risks and benefits of healthcare interventions to children and young people?
For a short explanation of why the committee made this research recommendation, see the rationale section on risks and benefits .
Full details of the evidence and the committee's discussion are in evidence review E: understanding the risks and benefits of healthcare decisions.
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## Independent advocacy
How can the views of babies, children and young people be best represented by independent advocates?
For a short explanation of why the committee made this research recommendation, see the rationale section on independent advocates .
Full details of the evidence and the committee's discussion are in evidence review I: independent advocacy in healthcare for children and young people.
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## Improving healthcare experience
What elements of healthcare matter most to babies, children and young people to create positive experiences of healthcare?
For a short explanation of why the committee made this research recommendation, see the rationale section on improving healthcare experience .
Full details of the evidence and the committee's discussion are in evidence review J: improving experience of healthcare.
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## Measuring experience
How can the experience of babies, children and young people be measured so as to improve their experience of healthcare?
For a short explanation of why the committee made this research recommendation, see the rationale section on measuring experience .
Full details of the evidence and the committee's discussion are in evidence review L: measuring experience.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Overarching principles
Recommendations 1.1.1 to 1.1.9
## Why the committee made the recommendations
The committee were aware, based on their own knowledge and experience, that safeguarding is an important consideration that applies to all aspects of healthcare services, and so made an overarching recommendation to state this. Similarly, the committee were aware that it is necessary for all services to make reasonable adjustments as required by legislation in order to meet the needs of disabled babies, children and young people, and so made an overarching recommendation to state this.
Based on stakeholder feedback, the committee added an overarching recommendation to clarify the rights of children and young people to make decisions about their healthcare and to consent to treatment.
There was evidence from a number of reviews: that all discussion, support and information need to be suitable for the age, developmental stage and level of understanding for an individual child or young person; that, as children develop and mature, their healthcare needs and preferences change; and that determining needs and preferences is not a static one-off decision.
As a number of recommendations throughout the guideline relate to the use of digital resources, the committee clarified that alternative methods should be available as access to these digital resources is not universal.
## How the recommendations might affect practice
The recommendations are in line with current practice and should have little impact on resources, but may mean extra time is needed to revisit needs and preferences on a regular basis, or to provide alternatives to online information.
Return to recommendations
# Communication by healthcare staff
Recommendations 1.2.1 to 1.2.16
## Why the committee made the recommendations
There was good evidence that children and young people like healthcare professionals to communicate in a friendly, compassionate and respectful manner, reading behavioural cues, giving them sufficient time, listening to them and getting to know them on a personal level.
There was good evidence that different methods of communication should be used when appropriate, and this includes using verbal and non-verbal communication, and identifying the best way to communicate for individuals, particularly those who have additional communication needs.
The committee were also aware of the need for healthcare professionals to ensure that different methods of communication are used if necessary to meet the requirement of the Mental Capacity Act 2005 that a person is not to be treated as unable to make a decision unless all practicable steps to help them to do so have been tried.
## How the recommendations might affect practice
Healthcare professionals might need more time to communicate with children and young people and this could mean some consultation times are longer, which would create a resource impact for the NHS. Additional help to communicate may be needed (for example, use of foreign language or sign language interpreters) and that may also have a resource impact for the NHS.
Ensuring that all staff are competent to communicate effectively might also need additional time and resources for training and skill development.
Return to recommendations
# Providing information
Recommendations 1.2.17 to 1.2.28
## Why the committee made the recommendations
There was good evidence from the systematic literature review on the preferred sources of information, with in person face-to-face information provided by a healthcare professional one of the preferred and most trusted forms of information. The evidence showed that healthcare professionals should provide information clearly in a way that is easy for children and young people to understand, and that it is important that healthcare professionals consider when and how to deliver information, as sufficient information needs to be provided, but this should not be overwhelming. The evidence also showed that children and young people, and the parents of babies and young children, want information in a variety of formats, including written materials, websites and smartphone applications and any other digital sources, and that these sources should be clear and easy to understand and relevant.
There was evidence that children and young people would want their parents or carers to have information tailored to their condition and needs in order to provide support and look after them.
There was evidence that whatever the format, information should be age- and developmentally appropriate, and should be available in different versions (for example, easy-read versions) and languages to allow as many people to access it as possible.
The evidence from the focus and reference groups and some limited evidence from the national surveys reinforced the systematic literature review evidence, showing that the quantity of information should not be overwhelming, and that there is a need for clear, understandable verbal and written information.
## How the recommendations might affect practice
The recommendations may mean additional time and resources are needed to deliver and produce information in suitable formats (for example leaflets, websites, apps) in partnership with children and young people. However, it was acknowledged that many services are already using a variety of alternative ways of proving information to children or young people and the overall resource impact in this area will be modest.
Return to recommendations
# Shared decision making
Recommendations 1.3.1 to 1.3.4
## Why the committee made the recommendations
There was evidence from the systematic literature review, focus and reference groups and from the national surveys that most children and young people want to be involved in making shared decisions about their healthcare, but that the level of preferred involvement may vary between different children, on different occasions and may change as children get older.
The committee were also aware of the requirement of the Mental Capacity Act 2005 that a person is not to be treated as unable to make a decision unless all practicable steps to help them to do so have been taken without success. Healthcare professionals therefore need to tailor their approach to discussions (with advice from other specialists or those who know the person well if necessary) to ensure this.
There was some evidence on children and young people's preferences for how the shared decision-making process should be undertaken, for example by starting discussions as soon as possible, making sure information is presented clearly, tailoring its complexity, providing it at a suitable pace and using decision aids if they are available.
The committee also used their knowledge and experience to make additional recommendations to adhere to these principles when making shared decisions with parents and carers on behalf of babies and young children.
## How the recommendations might affect practice
Additional time may be needed to carry out meaningful discussions around shared decision making. Ensuring that all staff are competent to implement shared decision making effectively might also need additional time and resources for training and skill development.
Return to recommendations
# Risks and benefits
Recommendations 1.3.5 to 1.3.10
## Why the committee made the recommendations
There was limited evidence that decision aids improve knowledge about risks and benefits and reduce decisional conflict, but as there was insufficient evidence to allow the committee to give advice on their use, a research recommendation was made on this topic (see research recommendation 1). There was some evidence from the focus and reference groups that children and young people vary in their views about how much information they like to receive on risks. Based on this evidence, and on their knowledge and experience, the committee made recommendations on the best ways to discuss risk and benefits with children and young people, including pacing this information, having discussions without parents and carers, and ensuring understanding.
## How the recommendations might affect practice
The recommendations might mean additional time and resources are needed to help children, young people and the parents or carers of babies and young children understand the risks and benefits of healthcare decisions. Ensuring that all staff are competent to discuss risks and benefits effectively might also need additional time and resources for training and skill development.
Return to recommendations
# Consent, privacy and confidentiality
Recommendations 1.4.1 to 1.4.14
## Why the committee made the recommendations
No evidence relating to consent was found, but the committee discussed that children and young people have the legal right to consent to, or refuse, treatment as set out in UK law and the UN Convention on the Rights of the Child. These rights are dependent on their age and competence and as the committee agreed it was such an important principle, they included these details in an overarching recommendation at the beginning of the guideline.
The committee used their experience and expertise to make recommendations on how children and young people could be best supported to make decisions on consent. The committee also used their knowledge and experience of how differences of opinion over consent, assent or refusal of treatment should be approached. This could include involving other healthcare professionals, but the committee also recognised that the child, young person, parents or carers should be offered support so that they did not feel outnumbered in discussions.
There was some low-quality evidence on privacy and confidentiality, which showed that children are aware of the risks to anonymity and privacy with digital information applications, but that they also recognised that in some cases, it was valuable to share information (for example, with parents, or to allow peer-to-peer support). The committee therefore also used their experience and expertise on best practice at maintaining privacy (particularly when using digital or virtual methods for consultations, or with children or young people who needed additional support to communicate without their parents or carers), discussing private and confidential information with children and young people, and the sharing of information with parents or carers.
## How the recommendations might affect practice
There are already examples of good practice across the NHS concerning consent, privacy and confidentiality, and these recommendations are designed to increase consistency throughout the NHS. Implementing these recommendations might mean extra time is needed for healthcare professionals to discuss and explain issues surrounding consent, privacy and confidentiality with children and young people. There may also be a need to consider the environment in which healthcare is delivered to provide privacy and ensure confidentiality.
Return to recommendations
# Involvement of parents or carers
Recommendations 1.5.1 to 1.5.6
## Why the committee made the recommendations
There was evidence that children and young people want to be able to express their opinions independently from their parents, but they also value their parent or carers' presence or support. There was evidence that the extent of support they want varies depending on the circumstances and the child or young person, and that it should be discussed between parents or carers and their children. The committee were aware from their knowledge and experience that certain groups of children and young people did not have parents or carers to support them, and that it is particularly important that these children and young people should be offered alternative support.
## How the recommendations might affect practice
The recommendations are in line with current practice and should have little impact on resources, but may need extra time to have these discussions, and to see children with their parents or carers and separately.
Return to recommendations
# Support from healthcare staff
Recommendations 1.5.7 to 1.5.13
## Why the committee made the recommendations
There was evidence that children and young people have differing preferences for the support they wish to receive from healthcare professionals, so this should be personalised based on their preferences at any time (as these preferences can change depending on different factors). There was also evidence around needing to build a trusting relationship. Based on their knowledge and experience, the committee agreed that it was essential that healthcare professionals support children and young people's rights and advocate for them where necessary. There was also evidence that children and young people appreciate support to identify and use coping techniques, and to be advised on other sources of support.
## How the recommendations might affect practice
Additional time may be needed to build trust, discuss and provide the support according to the preferences and needs of children and young people.
Return to recommendations
# Self-advocacy
Recommendations 1.5.14 to 1.5.17
## Why the committee made the recommendations
There was evidence from the systematic literature review and the focus and reference groups for strategies that would enable children and young people to advocate for themselves with respect to their healthcare and related decisions. This includes providing time, space and adequate information.
There was evidence that some children and young people felt as though healthcare professionals have a preconceived idea of their ability and motivation to engage with healthcare decisions. This often results in missed opportunities to encourage vulnerable children and young people to engage in their care and advocate for their choices.
The evidence also showed that engaging children and young people in feedback, service design and other activities could improve and facilitate their self-advocacy skills.
Based on the evidence and their knowledge and experience, the committee identified approaches to empower children to advocate for themselves.
## How the recommendations might affect practice
Additional time may be needed to discuss and provide the adequate support to children and young people so they can be empowered to advocate for themselves.
Return to recommendations
# Independent advocates
Recommendations 1.5.18 to 1.5.24
## Why the committee made the recommendations
The recommendations reflect current UK legislation in respect of access to independent advocates in certain situations for children and young people. Based on their knowledge and experience, the committee recognised the potential benefits to children and young people of independent advocacy in wider healthcare situations, not currently covered by the legislation. These benefits include support to understand healthcare processes and procedures, to express views and opinions, and with decision making.
There was evidence from an expert witness and the focus and reference groups that eligible children and young people may have limited knowledge about independent advocacy services. Therefore, they should be provided with this information and supported throughout the process.
There was evidence from the expert witness and the focus and reference groups about the role of independent advocates, which involves supporting children and young people in decisions about their healthcare and that, in order to be most effective, independent advocates should take time to build a trusting and confidential relationship with children and young people.
As there was no evidence from the systematic review of the literature for this review, the committee made research recommendation 2.
## How the recommendations might affect practice
The recommendations on access to an independent advocate are in line with current UK legislation, with little additional impact on resources. However, the suggested expansion of this service to children and young people who are not adequately represented by parent and carers may lead to an increase in the number of independent advocates needed by NHS services, which will need an increased level of funding. There may be an increased amount of time for healthcare professionals to facilitate this use of independent advocates.
Return to recommendations
# Improving healthcare experience
Recommendations 1.6.1 to 1.6.5
## Why the committee made the recommendations
The qualitative and quantitative evidence identified 4 aspects of healthcare that were important to children and young people but which were not covered in other evidence reviews. These were food, pain-related anxiety, staff uniforms and healthcare clothing, and religious, cultural and spiritual support. Based on their expertise and experience, the committee made additional recommendations on these topics. The committee agreed that the recommendations on religious support related to maintaining usual activities, and therefore they placed this recommendation in that section of the guideline.
As there was limited quantitative evidence on the elements of healthcare that matter most to babies, children and young people to create a positive experience of healthcare, the committee made research recommendation 3.
## How the recommendations might affect practice
The recommendations reflect best practice and may reduce variation in practice.
Return to recommendations
# Design of healthcare services
Recommendations 1.7.1 to 1.7.4
## Why the committee made the recommendations
There was some evidence that children and young people are keen to contribute to the design of healthcare services, and appreciate the opportunity to do so. There was also evidence that the children and young people recognise there could be practical difficulties with involvement (for example, time, travel, number of events, and content not being age- or developmentally appropriate). There was evidence that ways to obtain feedback should be age- and developmentally appropriate. There was evidence that children and young people want their views to be taken seriously, and that they appreciate being told how their input had changed practice.
The committee and stakeholders identified that there may be particular groups who may be less likely to be involved in the design of healthcare services and so recommended that the views of these groups should be actively sought. However, the list is not exhaustive and other groups may be identified according to local circumstances or demographics.
## How the recommendations might affect practice
There are already examples of good practice across the NHS, but practice is inconsistent. These recommendations aim to standardise how children, young people, parents and carers should be involved in the design of services, to encourage more consistent practice across the whole NHS.
Implementing this across the NHS might mean increased resources are needed to develop the tools, identify participants, aid involvement, and evaluate and feedback the results.
Return to recommendations
# Measuring experience
Recommendations 1.7.5 to 1.7.9
## Why the committee made the recommendations
There was some evidence from the focus and reference groups that children and young people are keen to provide feedback, that they are willing to use a variety of methods to do this, and that surveys should be quick and easy to complete. The evidence also showed that children and young people prefer giving their feedback at or towards the end of treatment but based on their knowledge and experience, the committee agreed this should be at various points in treatment. There was a very small amount of evidence from the national surveys on the problems children and young people had had using complaints systems. The committee also used their own knowledge and experience on helping people give feedback to optimise responses.
The committee and stakeholders identified that there may be particular groups who may be less likely to be involved in providing feedback on healthcare services and so recommended that the views of these groups should be actively sought. However, the list is not exhaustive and other groups may be identified according to local circumstances or demographics.
As there was very limited evidence from the systematic review of the literature on measuring children and young people's experience, the committee made research recommendation 4.
## How the recommendations might affect practice
Experience may already be measured in a number of different ways across the NHS and these recommendations will increase measurement of experience, reinforce best practice and make practice more consistent.
Implementing this across the NHS might mean more resources are needed to co-produce the tools, identify participants, aid involvement and evaluate and feedback the results.
Return to recommendations
# Healthcare environment
Recommendations 1.8.1 to 1.8.4
## Why the committee made the recommendations
There was some evidence from young people about their preferences, and from parents of babies in neonatal units, and the committee agreed that all babies and young children (represented by their parents), children and young people, should be able to express views about the preferences for place of care. The committee used this and their own knowledge and experience to agree how settings should be appropriate, comfortable, welcoming and acceptable to the people who need to use them. There was evidence that young people prefer their care environment to be age-appropriate, and that they may feel uncomfortable in paediatric settings aimed at young children. There was also evidence that they like to be able to meet visitors in an appropriate space, to have areas for recreation facilities, to have adequate signs, and for there not to be too much noise. They also expressed wanting to feel safe in healthcare environments.
There was evidence from parents or carers of babies about the need for privacy, comfortable furniture and furnishings, and facilities so they have the option to stay with their babies. Although there was no evidence about privacy for children and young people, the committee agreed that offering privacy is important, based on their knowledge and experience.
## How the recommendations might affect practice
The recommendations aim to make best practice more consistent across the NHS. Some changes to improve the healthcare environment might be easy to make, but changing or redesigning healthcare environments can be an expensive process, and some of the recommendations could need considerable resources to implement.
Return to recommendations
# Maintaining usual activities
Recommendations 1.9.1 to 1.9.9
## Why the committee made the recommendations
Based on their knowledge and experience, the committee made recommendations on the importance of determining what usual activities were important to children and young people, and making adjustments to allow these to continue. The committee agreed that providing support to continue with usual activities would need to be personalised to account for different needs, preferences and developmental stages. The committee recognised the benefits to the wellbeing of children and young people of continuing with usual activities, which may include a reduction in boredom, anxiety and distress. There was evidence that some children prefer to receive help with personal care from their family, as would happen if the child were at home. There was also evidence that children and young people want to continue with social activities and keeping in touch with their friends. There was no evidence from the systematic literature review specifically about Wi-Fi access but the committee agreed that the ability to instantly contact friends was a part of everyday life for most children and young people and this was reinforced by evidence from the focus and reference groups and the national surveys.
The evidence on educational support reinforced the committee's experience that maintaining educational provision and liaison with education services is very important.
There was evidence that some children and young people found religious or spiritual support or beliefs helpful when they were unwell. Other aspects from this evidence are reflected in the recommendations on improving healthcare experience, where this evidence is described in more detail.
## How the recommendations might affect practice
The recommendations aim to reduce variation in practice across the NHS, and might mean extra staff time or changes in practice are needed to implement them.
Return to recommendations
# Accessing healthcare
Recommendations 1.10.1 to 1.10.11
## Why the committee made the recommendations
There was evidence from the systematic review of the literature about factors that could be barriers for children and young people to access health services. This included factors relating to practical aspects of accessing healthcare such as location and timing of appointments, as well as trust and relationships with healthcare professionals and lack of knowledge about when to access healthcare, and what services to access. The focus and reference groups also provided evidence about the perceived barriers and these included fear and embarrassment, being too busy to access healthcare or not wanting to miss out on school or social activities, and being aware of the capacity issues within the NHS. The committee then used this evidence to make recommendations designed to overcome these barriers. The evidence from the national surveys also identified that certain groups of children and young people may need additional help and support to access and navigate the health system.
## How the recommendations might affect practice
Additional resources may be needed to promote and deliver accessible and flexible services.
Return to recommendations
# Continuity and coordination of care
Recommendations 1.10.12 to 1.10.17
## Why the committee made the recommendations
There was good evidence that children and young people prefer to see the same healthcare professionals whenever possible, and that this promotes improved engagement and continuity of care. The committee were aware that children and young people prefer to be able to contact their healthcare professionals or teams directly.
There was good evidence that children and young people do not want to have to repeat their healthcare history on multiple occasions, and that good and timely communication between healthcare professionals, services, and children and young people and the parents or carers of babies and young children could help with this. There was also some evidence for the use of different methods to help improve communication and continuity of care, and in particular the use of electronic health records.
## How the recommendations might affect practice
There are some electronic and paper methods to improve communication already in use, including electronic health records. Implementing more integrated systems to share information with and between healthcare professionals, other services and children and young people or the parents and carers of babies and young children will have resource implications for the NHS. In addition, there may be a need for improved administration support to help with the sharing of information, which will also have some resource implications.
Return to recommendations
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{'Introduction from the young people involved in the development of this guideline': "When babies, children and young people access healthcare, it is important that their experience is as positive as possible. This guideline has been written with children and young people who know what it's like to be a patient. It has been an opportunity to share what has and has not worked, and hopefully improve the healthcare experience of many babies, children and young people in the future.\n\nAdults often see children and young people as passive recipients of healthcare. This can lead to children and young people not being listened to, having a lack of understanding of their own condition and may lead to problems that can affect future care (for example, finding it difficult to trust healthcare professionals or feeling very anxious before procedures). However, having a positive experience can make a child or young person feel confident, empowered and supported to manage decisions about their own health and healthcare, and can improve their perception of their diagnosis and treatment. This positive experience should also ensure that babies, children and young people are treated as individuals with a life outside healthcare, and not just as their condition or diagnosis.\n\nThis guideline aims to improve the healthcare experience of babies, children and young people with the hope that this can improve their health outcomes and their wellbeing.", 'Context': "Optimising patient experience has long been recognised as an integral part of effective healthcare for adults. The healthcare experience of babies, children and young people has received less attention in the past, despite the legal rights of children to participate in decisions that affect them. Unfamiliar environments, and having to meet and interact with a range of healthcare professionals, can be particularly unsettling for babies, children and young people, and may lead to anxiety and distress.\n\nMany NHS providers of healthcare services for children and young people currently carry out user surveys directly with children and young people as well as with their parents or carers, and some run focus groups to obtain feedback from children and young people and their parents or carers, with a view to improving the provision of services and the experience of healthcare. However, surveys of children and young people's healthcare experiences have identified that feedback from children themselves is generally less positive than their parents' responses, with a third of children in 1\xa0survey reporting that they did not always understand what staff said, and over half feeling they were not involved enough in making decisions about their care or treatment.\n\nAlthough there are some examples of good practice and initiatives to improve babies, children and young people's experience of healthcare, there is variation in practice across the country.\n\nThis guideline covers babies, children and young people (aged 17 and under) accessing NHS physical or mental health services, or local authority-commissioned healthcare services. Babies, children and young people are entitled to always receive the same high-quality healthcare experience, and so the recommendations in this guideline apply to all healthcare experiences and settings. For some babies, children and young people, interaction with healthcare services may be limited to visits to a dentist or GP, whereas other babies, children and young people may have medical conditions that need frequent interactions, inpatient stays and an ongoing healthcare relationship with professionals, so a personalised approach to implementation is needed.\n\nThe guideline provides evidence-based information for healthcare professionals, children, young people and their parents or carers about communication, information, support, the healthcare environment, access and continuity of care. It also provides guidance on maintaining usual activities because babies, children and young people need the opportunity to grow, learn and develop alongside their peers, despite their healthcare needs.", 'Recommendations': 'Healthcare professionals should involve children and young people in decisions about their healthcare in ways that are appropriate to their maturity and understanding. Some children and young people will be able to give informed consent themselves, some will be able to contribute to the discussion, and others may not be able to be involved at all. For more information, see NICE\'s information on making decisions about your care.\n\nA parent or carer, who has parental responsibility for a child (as defined by the Children\'s Act 1989), will have a key role to play in planning and making decisions about their child\'s health and care, particularly when they are young. As children grow older and develop the maturity and understanding to make decisions for themselves, that role will diminish, particularly if the child wants it to. Where relevant, parents and carers should be given information and support to enable them to do this, as set out in the NHS Constitution and summarised in NICE\'s information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding that should be used alongside this guidance.\n\n# Overarching principles\n\n## Safeguarding\n\nAdhere to all relevant legislation and follow all national and local safeguarding policies and professional guidelines when implementing these recommendations and when planning and delivering healthcare services for all babies, children and young people, in any setting. See further guidance in the NICE advice on safeguarding and the Children\'s Act 1989 (and subsequent updates).\n\n## Disabilities\n\nAdhere to all relevant legislation relating to the rights of disabled babies, children and young people to access healthcare, and make reasonable adjustments as required by legislation to enable this access. See the Equality Act 2010.\n\n## Competence\n\nInvolve all children and young people in decisions about their healthcare, unless they do not wish (or are unable) to be involved (see recommendations 1.1.4 to 1.1.7). Recognise that:\n\nYoung people aged 16\xa0or 17\xa0years with mental capacity to make decisions about their healthcare are entitled to do so, and to consent to treatment. There is a presumption that a person above the age of\xa016 has capacity unless and until assessed otherwise.\n\nChildren and young people under 16\xa0years can make decisions about their healthcare and consent to treatment if they are assessed by a healthcare professional to be Gillick competent. The conclusion that a child or young person is competent relates to that specific healthcare decision.\n\n## Age- and developmentally appropriate care\n\nEnsure that all methods of communication, information and discussions are tailored for the age, developmental stage and level of understanding of the baby, child or young person.\n\nRecognise that needs and preferences may change as children mature, and that it is necessary to revisit these needs and preferences on a regular basis and to adapt support, information and complexity of discussions accordingly.\n\n## Changes in needs and preferences\n\nRecognise that children and young people\'s needs, preferences and engagement with healthcare professionals and healthcare services (for example, how much they would like to be involved in decision making or how much support they need) may vary from day to day, at different encounters or may be affected by other factors (for example, how unwell they are feeling).\n\nEnsure that previously expressed needs, preferences or engagement levels are revisited, and give additional or alternative opportunities for discussions or decisions, particularly if personal or clinical circumstances have changed.\n\n## Digital access\n\nRecognise that not all children and young people, or the parents or carers of babies and young children, are able to access digital resources (for example, online information, messaging or video-calling, apps or other digital tools).\n\nEnsure that non-digital methods of attending appointments, communicating, and providing information are available, and provide an equal level of service, for anyone who cannot access (or prefers not to use) digital methods.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on overarching principles\xa0.\n\nFull details of the evidence and the committee\'s discussion are in:\n\nevidence review A: planning healthcare and making shared decisions\n\nevidence review C: consent privacy and confidentiality\n\nevidence review D: providing information\n\nevidence review E: understanding the risks and benefits of healthcare decisions\n\nevidence review F: involving parents or carers in healthcare and healthcare decisions\n\nevidence review G: support from healthcare staff\n\nevidence review M: healthcare environment.\n\nLoading. Please wait.\n\n# Communication and information\n\n## Communication by healthcare staff\n\nEnsure that children and young people, and their parents or carers have a positive experience by:\n\nintroducing yourself and anyone else present\n\nasking them how they wish to be addressed (for example, their preferred name and pronouns)\n\nputting the child or young person and their parents or carers at ease by being friendly and welcoming (for example smiling, saying hello, using eye contact)\n\nbuilding a rapport to develop trust\n\nencouraging children, young people and the parents and carers of babies and young children to contribute to, and be active participants in, discussions and decisions about their care. See also the section on support from healthcare staff.\n\nCommunicate with children and young people and their parents or carers with:\n\nkindness, compassion and respect\n\ncultural sensitivity\n\na non-judgemental attitude.\n\nWhen communicating with babies, children and young people, particularly those with ongoing health needs, develop an understanding of them as individuals, not only based on their health condition or diagnosis (for example, referring to the baby, child or young person by name, asking them what is important to them in their healthcare).\n\nTake time to listen to and address the concerns and fears of children and young people, and of the parents or carers of babies and young children and:\n\ntreat their concerns and feelings (such as fear and embarrassment) with empathy and understanding\n\ngive reassurance that these concerns are very common and are nothing to feel embarrassed or upset about (for example, by saying \'it\'s OK to be scared\').\n\nIdentify who is the most appropriate person to communicate with a child or young person, or the parent or carer of a baby or young child (for example, this could be a healthcare professional or other member of the multidisciplinary team, or another professional such as a youth worker or social worker). When deciding on the person, take into account:\n\nthe clinical circumstances\n\nthe subjects to be discussed\n\nthe preferences of the child or young person.\n\nIdentify the child or young person\'s preferred forms of communication and use these when communicating with them. Ask their advice, or ask their parents or carers what these are. Take into account that:\n\nEnglish may not be their first language\n\nthese may be non-verbal (for example, sign language, Makaton)\n\nidentification of a \'yes\' or \'no\' response (which might be non-verbal) can allow a direct conversation between a child or young person and a healthcare professional\n\nthese might need additional resources (for example, foreign language or sign language interpreters, picture boards, computer-based systems)\n\nindividuals with additional communication needs might need more time and specialist support for alternative forms of communication (for example, augmentative and alternative communication).\n\nBe aware that parents or carers may have communication preferences and needs of their own that may affect their ability to discuss their baby or child\'s care.\n\nUse developmentally appropriate creative and interactive tools to help effective communications with babies, children and young people (for example, play dough, pictures, diagrams and writing).\n\nHelp engage babies, children and young people in communication by:\n\nusing both verbal and non-verbal methods (for example, sitting at the same level as them, using body language to show attentive listening, reassuring babies by positive touch or containment holding before or during procedures)\n\npausing and allowing time for responses.\n\nWhen communicating with children and young people, always check they have taken the information in and understood it (for example, by asking children or young people to explain back to you in their own words).\n\nIf a child or young person is uncomfortable or having difficulty communicating, try alternatives that may help. This may include:\n\ntrying again at a different time\n\ntrying again in a different, quieter or more private setting (see recommendations 1.4.8 and 1.4.9)\n\nseeing them without their parents or carers\n\ninvolving a different person (for example, another healthcare professional or an adult trusted by the child or young person)\n\nusing a different means of communication.\n\nRespect times when children and young people do not wish to communicate, and be aware that their wish to communicate may vary at different times.\n\nIn urgent or emergency situations when time may be limited, give children and young people opportunities to communicate whenever possible, and the opportunity to discuss afterwards.\n\nBe aware that babies, children and young people may not communicate pain, distress or anxiety verbally so you may need to:\n\nask parents or carers what is usual behaviour for their child or young person\n\nbe alert to physical cues (for example, lack of or abnormal movements to reduce pain) or behavioural cues (for example, crying, refusing to speak or pushing away, or behaviour that appears aggressive such as anger, defiance or biting).\n\nAll staff involved in providing healthcare services to babies, children and young people should have skills and competencies in relevant communication skills.\n\nFor guidance on communicating with children with life-limiting conditions, see the NICE guideline on end of life care for infants, children and young people with life-limiting conditions.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on communication by healthcare staff\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review B: communication by healthcare staff.\n\nLoading. Please wait.\n\n## Providing information\n\nAsk children and young people, and the parents or carers of babies and young children, about the quantity and type of information they wish to receive, and how they wish to receive it. This should include, but not be limited to, details of:\n\ntheir condition and any treatment options and issues related to these (including diagnosis, possible side effects, long-term outcomes, and symptoms they may experience)\n\nany preventative action or lifestyle changes they can make\n\nwhere they will be seen\n\nlikely timescales and waiting times for their treatment, including keeping them informed about waits or delays at appointments\n\nwho will be involved in providing their healthcare\n\nwhat will happen at key points in their care (for example, on transfer from one healthcare setting to another, when being referred to a different healthcare team). Follow the recommendations on age and developmentally appropriate care and the recommendations on changes in needs and preferences.\n\nWhen giving information to the child or young person, or the parents or carers of babies and young children:\n\nuse their preferred method whenever possible; this may be in person face-to-face or other methods (for example email, phone call, text message or video call)\n\ntake into account that the child or young person\'s preferences for, and ability to access, digital resources may differ from those of their parents and carers\n\nprovide written and digital information to back up and supplement face-to-face contact, telephone calls or video calls and to refer to later.\n\nEnsure information for children and young people is provided privately when appropriate, for example:\n\nwithout their parents or carers present if this is what they would prefer\n\nby telephoning or texting them directly\n\nby addressing letters to children or young people themselves, and not their parents or carers.\n\nDiscuss with children and young people if there is information that should be provided to their parents or carers, to help their parents or carers support them or look after them (for example, dietary information, post-operative care, or symptoms to look out for).\n\nProvide information for children and young people or the parents or carers of babies and young children that is:\n\nin simple, clear language that is easy to understand, avoiding jargon and explaining any medical terms used\n\nevidence based\n\nappropriate for their individual needs\n\nculturally sensitive\n\nnot judgemental\n\npresented in accessible formats and language that can be understood by them (for example, through an interpreter, translated into another language, or as an easy-read version using pictures and symbols)\n\ngiven consistently by all members of the healthcare team\n\nin line with the NHS Accessible Information Standard.\n\nProvide written or digital information (for example leaflets, websites, apps) for children and young people that is:\n\ncreated in partnership with children and young people\n\nengaging for children and young people (for example, containing appealing images, video, audio or animations).\n\nProvide information at a suitable time, place and pace, for example:\n\nwhen possible, at regular, predictable times such as during ward rounds or clinic reviews\n\nin stages if necessary, so children, young people, parents or carers are not overloaded with too much information at one time.\n\nWhen children, young people, parents or carers have had time to absorb and reflect on information they are given:\n\ncheck they have understood it, and how it applies to them (see recommendation 1.2.10)\n\nallow time to discuss the information again\n\nactively encourage them to ask questions\n\nmake sure they know what to do if they do not understand, or have questions about their healthcare that come up later on.\n\nWhen giving information to children and young people about their care, take into account:\n\nthe possible emotional impact of any information provided (for example, children and young people may be upset by what they have been told)\n\nthat support might be needed to help them think about and process the information\n\nthat they may feel intimidated by the healthcare professional providing information (if they feel that individual is in a position of authority), and might need reassurance and support.\n\nWarn children and young people, parents or carers that some of the medical information available which they have not been directed to by the healthcare team (for example, online, on social media or from friends) may be inaccurate or have a limited evidence base.\n\nSupport children and young people to identify reliable sources of information related to their care or condition, and ensure that recommended sources are:\n\nup to date\n\nprofessional, credible and evidence based (for example, NHS resources, charities and support groups).\n\nAdvise children and young people to check the validity of information with their healthcare professional if they are unsure about its accuracy.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on providing information\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review D: providing information.\n\nLoading. Please wait.\n\n# Planning healthcare\n\n## Shared decision making\n\nRespect and support the right of children and young people to be involved in making decisions about their healthcare. This should include:\n\nensuring early and ongoing involvement in discussions about their healthcare\n\nproviding opportunities for them to share their opinions\n\nsupporting them to make decisions independently\n\ntaking into account previous discussions or decisions, and checking if their decisions have changed\n\nincluding them in any decisions when there is a choice of options, including where there is no impact on health or treatment outcomes (for example, what colour plaster cast they would prefer, whether they prefer their medicine as liquid or tablets).\n\nWhen involving children and young people in decision making, take into account that:\n\nthe extent and level of their involvement may vary, between individuals and on different occasions; follow the recommendations on changes in needs and preferences\n\non occasions, some children and young people might not wish to be involved in shared decision making, and that this choice should be respected\n\nthey might wish to have help from their parents or carers, or another person or advocate, for support, to help understand information or to help make decisions\n\nthey might need time to think about decisions, so planning discussions in advance to allow for this might be helpful.\n\nWhen discussing and making decisions about treatment options with children and young people:\n\nfollow the recommendations on communication by healthcare staff and the recommendations on providing information\n\nclearly articulate the options, and adapt the description of the treatment options so they are understood by the child or young person you are talking to\n\nuse alternative methods for discussions and decisions if necessary (for example, children and young people might prefer to write down or pre-record questions or opinions if they are not comfortable talking about them)\n\nconsider using decision aids to support complex decisions, or if children and young people are having difficulty making a decision.\n\nInvolve parents or carers in discussions and decisions relating to the care of their baby or young child (for example, for inpatient care, by allowing parents to be present at ward rounds when their baby or child\'s care is discussed whenever possible). Follow the same principles as shown in recommendations 1.3.1 to 1.3.3.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on shared decision making\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review A: planning healthcare and making shared decisions.\n\nLoading. Please wait.\n\n## Risks and benefits\n\nOffer children, young people and the parents or carers of babies and young children information about the potential risks and benefits of healthcare options to allow them to make informed decisions. Follow the recommendations on communication by healthcare staff and the recommendations on providing information.\n\nEnsure this information is:\n\nprovided in a way they can understand, and they can see how it applies to them\n\nrelevant to their individual needs and personal circumstances (for example, health setting, health status, age and developmental stage).\n\nDiscuss with children and young people how much information they would like about risks and benefits, and take this into consideration. Recognise that some children and young people:\n\nmight not want to know more about the risks than is needed for informed consent\n\nmight not want to know about risks on a particular occasion\n\nmight need additional opportunities to think about and discuss risks and benefits\n\nmight benefit from alternative methods of communicating risks and benefits\n\nmight need to take a break when discussing risk, and to come back to the topic later\n\nmight want to discuss the risks and benefits without their parents or carers present.\n\nWhen discussing the risks and benefits of healthcare options with the child or young person, parent or carer:\n\ncheck their understanding of what the risks mean to them and what the benefits to them would be (see recommendation 1.2.10)\n\nask them if they have any particular concerns or worries they would like to talk about (for example, fear about procedures such as injections, or children may want to ask about the risk of death, however unlikely this may be)\n\nanswer any questions they may have and address any concerns.\n\nReconfirm understanding of risks and benefits on an ongoing basis. Follow the recommendations on changes in needs and preferences.\n\nExplore, acknowledge and respond to any concerns that children and young people or their parents or carers have about risk, and provide opportunities to discuss concerns and what will be done to reduce risk.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on risks and benefits\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review E: understanding the risks and benefits of healthcare decisions.\n\nLoading. Please wait.\n\n# Consent, privacy and confidentiality\n\nDiscuss consent, assent, privacy and confidentiality directly with children and young people if:\n\nthey are able to understand what these concepts mean (with appropriate explanation)\n\nthey can relate them to their own situation.\n\nWhen discussing consent, assent, privacy and confidentiality:\n\nensure that children and young people, and parents or carers, understand their rights and responsibilities\n\nexplain when parents or carers might have to make decisions on behalf of children and young people.\n\nFor detailed advice on best practice around consent, privacy and confidentiality, refer to relevant professional guidance (for example, the General Medical Council\'s ethical guidance for doctors on decision making and consent and the 0–18 years: guidance for all doctors, the Nursing and Midwifery Council\'s Code and the guidance on consent in the General Dental Council\'s standards for the dental team).\n\n## Consent\n\nSupport children and young people to make informed decisions to assent to, consent to or refuse treatment, taking into account their individual capacity or competence (which may be different for different decisions).\n\nProvide children and young people with clear explanations about why treatment in their best interests had to go ahead if it is not possible to obtain their consent or assent before treatment (for example, in an emergency situation).\n\nIf there is a difference of opinion about consent, assent or refusal for a procedure (for example, if the views of the child or young person are different from those of their parents or carers, or the views of the child, young person or parent or carer are different from those of healthcare professionals):\n\nrecognise that all discussions and decisions should focus on what is in the best interests of the baby, child or young person\n\nconsider involving others, such as another member of the multidisciplinary team, another healthcare professional, an independent advocate, or a named or designated professional for child protection\n\ndiscuss with the child, young person and their parent or carer that you would like to involve other people\n\nensure that the child, young person and parent or carer are offered support.\n\nReconfirm a child or young person\'s understanding and consent decisions on an ongoing basis. Follow the recommendations on changes in needs and preferences.\n\n## Privacy and confidentiality\n\nMaintain privacy and dignity during discussions, examinations and care. Take into account individual preferences, circumstances and cultural sensitivities whenever possible.\n\nDiscuss potentially sensitive topics in places where they are less likely to be overheard, when possible, for example, in a clinic room or side room rather than behind bed space curtains.\n\nWhen using digital or virtual methods for consultations or discussions:\n\nask if the child or young person is able to speak without being overheard to discuss potentially sensitive topics\n\nconfirm with them that they are able to talk freely, or if they would prefer an alternative time or method of communication.\n\nBe aware that information sharing, privacy and confidentiality laws also apply to babies, children and young people. Only share their information:\n\nwith their consent for the purposes of care and treatment or\n\nwhen in the baby, child or young person\'s best interests to do so or\n\nwhen otherwise required to do so by law.\n\nOffer children and young people the opportunity to see and talk to a healthcare professional without the presence or involvement of their parent or carer, and explain that this discussion will be confidential.\n\nIf children and young people who usually rely on their parents or carers for help communicating want to have private conversations with healthcare professionals without the presence or involvement of their parent or carer, ensure additional support is provided (for example, by determining mechanisms to enable children and young people to express a \'yes\' and \'no\' response (which may be non-verbal), or including other people in conversations and meetings). See recommendation 1.2.6.\n\nExplain to children and young people that it may be necessary to share confidential information without their consent in certain circumstances (for example, if they or others may be in danger).\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on consent, privacy and confidentiality\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review C: consent, privacy and confidentiality.\n\nLoading. Please wait.\n\n# Advocacy and support\n\n## Involvement of parents or carers\n\nInvolve parents or carers in discussions and decisions about the care of babies and young children, and recognise that parents or carers will be their principal caregivers and advocates.\n\nGive all children and young people opportunities to express their opinions about their health needs independently, including:\n\nasking them about the extent to which they want their parent or carer to be involved in their healthcare\n\noffering to see them separately from their parents or carers for part of the consultation.\n\nBe aware that their wish for parental involvement may depend on the circumstances (for example, what the appointment is about, if they have to have any procedures) or may vary. Follow the recommendations on changes in needs and preferences.\n\nEncourage children and young people to develop their confidence in making decisions for themselves (for example, by giving them opportunities to do this), and encourage their parents or carers to support them with this.\n\nEncourage parents and carers to talk to their child or young person about how they will be involved in decisions about their healthcare. This might include:\n\nfinding out whether the child or young person would like to know more about what will happen at appointments (for example, what healthcare procedures might take place), even if the parent or carer might feel they should leave out details so as not to worry them\n\nthe parent or carer reassuring their child or young person that they can have part or all of an appointment without them being present if they would prefer that\n\nregularly confirming with their child or young person that they can change their mind at any time about how involved they want them to be.\n\nEnsure that children or young people who do not have a parent or carer to support them, or whose parents or carers are not able to support them, are offered other sources of support (for example, a family member, advocate, social worker, youth worker, nurse or play specialist). Young people may wish to be supported by a friend or partner.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on involvement of parents or carers\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review F: involving parents or carers in healthcare and healthcare decisions.\n\nLoading. Please wait.\n\n## Support from healthcare staff\n\nAll staff involved in providing healthcare services to babies, children and young people should uphold children\'s rights in accordance with the United Nations Convention on the Rights of the Child.\n\nAdvise children and young people about how they can be supported by healthcare staff in a specific setting and encourage them to express their preferences about the support they would find helpful.\n\nBe aware that some children and young people may need more support from healthcare staff than others and that this support may change over time. Follow the recommendations on changes in needs and preferences.\n\nWhen building a healthcare relationship with children and young people:\n\nintroduce yourself, explain your role and how you can help support them\n\nlisten to and be seen to believe their experiences (for example, symptoms such as discomfort, how they are feeling)\n\nreassure them that you will take their concerns seriously\n\nprovide calm and positive emotional support and encouraging words\n\ndiscuss with them how you will act on what they have said.\n\nHelp children and young people to speak up about things that matter to them, and their views and preferences by:\n\nadvocating for them and upholding their preferences if they are unable or unwilling to do this themselves\n\nacting as a trusted person for them to talk to when they feel their concerns are not being listened to.\n\nEncourage children and young people to ask for the support they need to help with their healthcare experiences or encourage them to use coping techniques they have already developed. These could include:\n\ntheir parent or carer to be with them or someone\'s hand to hold\n\nmusic to listen to, a soft toy to cuddle, playing a game on a phone or tablet, a support animal or pet to stroke\n\nindividual coping techniques. Ask them if these techniques help or if they would like to try other techniques.\n\nProvide advice about and access to other forms of support available (for example, from the education or voluntary sector).\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on support from healthcare staff\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review G: support from healthcare staff.\n\nLoading. Please wait.\n\n## Self-advocacy\n\nFacilitate self-advocacy in children and young people. This may include:\n\nallowing enough time in consultations and appointments\n\nproviding confidential and private spaces\n\nproviding information on their rights to advocate for themselves\n\nestablishing and using the child or young person\'s preferred method of communication, paying particular attention to those who do not communicate verbally (see recommendation 1.2.6 and recommendation 1.4.13).\n\nAssume that all children and young people have views and opinions about their own healthcare, and actively encourage them to express what matters to them. In particular:\n\ndo not make assumptions that certain groups of children or young people will not want or will not be able to advocate for themselves\n\nrecognise that children and young people from different backgrounds may have different levels of confidence or skills to advocate for themselves.\n\nEmpower children and young people to advocate for themselves by:\n\nproviding information so they can develop an understanding of their own condition and health needs\n\nmaking them central to discussions about their healthcare\n\nagreeing with them when and how they would like their parents or carers included in discussions and decision making, and ensure this agreement is followed\n\nworking collaboratively with them to discuss healthcare needs and treatment options and include them in decisions about their care\n\ntaking into account their own culture, experiences, needs, wishes and feedback\n\nconsidering the use of age- and developmentally appropriate healthcare-management applications, such as smartphone apps; apps should meet the criteria specified in the NICE evidence standards framework for digital health technologies; see the NHS Apps library for details of NHS approved apps.\n\nSupport children and young people to develop skills in advocating for themselves by offering opportunities to be involved in feedback, service design or improvement or other engagement activities (see recommendations 1.7.1 to 1.7.9).\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on self-advocacy\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review H: empowering children and young people to advocate for themselves.\n\nLoading. Please wait.\n\n## Independent advocates\n\nChildren and young people must have access to an independent advocate in line with statutory requirements. This includes the Mental Health Act 2007, the Care Act 2014 and the Mental Capacity Act 2005.\n\nWhere children and young people are eligible, inform them that, they can have another person, known as an independent advocate, present with them when speaking to healthcare professionals, rather than their parent or carer. See also recommendation 1.3.2 about support from other people for shared decision making.\n\nProvide children and young people who are eligible for support from an independent advocate with information about independent advocates. Include:\n\nthe role of an independent advocate (including confidentiality and independence from the healthcare team)\n\nthe option to express a preference for an advocate of a particular gender, or how to change advocate.\n\nSupport eligible children and young people to meet with an independent advocate (for example, by providing a private space and time to meet).\n\nIndependent advocates should work with eligible children and young people to support and empower them in discussions and decisions about their healthcare. This should include:\n\nidentifying and using the child or young person\'s preferred method of communication and using additional support to communicate if necessary (see recommendation 1.2.6)\n\nbuilding a trusting relationship, ensuring continuity where possible\n\nensuring confidentiality\n\nproviding guidance on healthcare systems, pathways and processes, where necessary\n\nproviding explanations of medical information and terminology, where necessary\n\nempowering children and young people to make their own decisions.\n\nIndependent advocates should provide a mechanism for children or young people to give feedback on the advocacy service and to check that the relationship is working effectively for the benefit of the child or young person.\n\nCommissioners should consider expanding the availability of independent advocates services to support children or young people who are not eligible under legislation, but who are not adequately represented by their parents or carers or other professionals.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on independent advocates\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review I: independent advocacy in healthcare for children and young people.\n\nLoading. Please wait.\n\n# Improving healthcare experience\n\n## Food\n\nEnsure babies, children and young people who are inpatients have access to food that meets their needs. This should include:\n\na balanced healthy diet that will help with their recovery\n\na choice of food options at every meal that are culturally and dietetically appropriate and will appeal to a range of tastes\n\nflexibility in availability of food, for example access to snacks outside meal times\n\nfood choices and menus that have been developed in conjunction with children and young people. For babies who are breast or bottle fed, ensure there are suitable facilities to support this.\n\n## Pain-related anxiety\n\nReduce the fear and anxiety about pain that may be experienced by babies, children and young people during healthcare interventions by:\n\npreparing them with information about interventions or procedures (for example, blood tests and injections)\n\nbeing honest about possible pain and what will be done to alleviate pain\n\nusing therapeutic play and distraction techniques and creating a calm environment before, during and after interventions or procedures that are likely to be painful\n\nupholding children and young people\'s experiences of pain, showing them they are believed, and avoiding language that minimises the child or young person\'s experience of pain (for example, do not say a procedure they found painful "didn\'t really hurt").\n\nEnsure adequate pain assessments are carried out and acted on. See NICE guidelines for the management of pain in specific conditions, such as the NICE guideline on cerebral palsy for under\xa025s for advice on assessing pain in verbal and non-verbal children and young people, the NICE guideline on end of life care for infants, children and young people with life-limiting conditions and the NICE guideline on sickle cell disease.\n\n## Staff uniforms and healthcare clothing\n\nEnsure children and young people, and parents or carers of babies and young children can easily identify members of staff. This could include:\n\nvisible name badges with easy to understand job roles or titles\n\nrecognisable uniforms, particularly if they help differentiate between professions.\n\nBe aware that healthcare clothing (for example gowns, masks or visors) can be frightening for babies, children and young people and they may be unable to recognise staff or see their facial expressions or smiles. This is particularly important for children who rely on lip reading or facial cues for communication.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on improving healthcare experience\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review J: improving experience of healthcare.\n\nLoading. Please wait.\n\n# Involvement in improving healthcare experience\n\n## Design of healthcare services\n\nWhen designing services that will be used by babies, children and young people:\n\ninvolve children and young people and obtain their views, or for babies and young children, involve their parents or carers\n\nactively seek out children and young people (or the parents or carers of babies and young children) from under-represented groups (for example, black, Asian and minority ethnic groups, people with physical, sensory or learning disabilities, people from a disadvantaged background, LGBT+ people, people who have not been able to, or have chosen not to, use the services before, looked-after children).\n\nAssume that all children and young people have relevant opinions on services they use and their care, and will give them if asked in a suitable way.\n\nMake it as simple as possible for children and young people to contribute to service design by:\n\nusing appropriate methods to engage them, capture their views and enable them to contribute (for example, internet surveys, social media, forums and groups)\n\naddressing any practical issues that could be barriers to involvement (for example, transport, timing, language, travel costs, disabilities or communication difficulties).\n\nEnsure that feedback about the design of services from children, young people and parents or carers is shared and used. Explain how their input has shaped design of services (for example, using social media or posters to describe methods such as \'Ask Listen Do\' and \'You Said We Did\').\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on design of healthcare services\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review K: design of healthcare services.\n\nLoading. Please wait.\n\n## Measuring experience\n\nCollect feedback (for example, using questionnaires or surveys) directly from children and young people at different points in their healthcare experience. Collect feedback for babies and young children from their parents or carers.\n\nActively seek out feedback from children and young people (or the parents or carers of babies and young children) from under-represented groups (for example, black, Asian and minority ethnic groups, people with physical, sensory or learning disabilities, people from a disadvantaged background, LGBT+ people, people who have not been able to, or have chosen not to, use the services before, looked-after children).\n\nMake it easier for people to give meaningful feedback by using tools that:\n\nhave been co-produced with the appropriate age group\n\nare appropriate for, and selected together with, the intended group (including taking into account any disabilities or communication preferences)\n\nare provided at a convenient time and place, and by a convenient method, for respondents (for example, voting systems in a healthcare setting, or an online survey to be completed at home).\n\nEnsure that the feedback on healthcare experiences from children, young people and parents or carers is shared and used. Explain how their input has been used to improve healthcare experiences (for example, using social media or posters to describe methods such as \'Ask Listen Do\', \'You Said We Did\').\n\nInform children and young people, and the parents or carers of babies and young children, of their right to complain. Ensure that it is easy for children and young people to make a complaint if they need to.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on measuring experience\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review L: measuring experience.\n\nLoading. Please wait.\n\n# Healthcare environment\n\nCare for babies, children and young people in an environment that:\n\nmeets their clinical and personal needs\n\ntakes into account their preferences about their place of care (or the preferences of parents or carers for babies or young children)\n\nis appropriate for their age and developmental stage, is physically accessible and has adaptations available, if needed.\n\nProvide a healthcare environment that supports:\n\nprivacy and dignity\n\nconfidence in healthcare delivery (for example, equipment is available when needed)\n\nfamily-centred care for inpatients (for example, the option for a parent or carer to stay and sleep, including in non-paediatric areas)\n\nparents or carers to give developmentally appropriate care to their children (for example, changing their baby\'s nappy, helping children wash and dress)\n\nother family members, siblings, or those important to the child or young person to be present (if this is what they would like)\n\neasily accessible, age-appropriate play and recreation for children and young people, including to reduce boredom and anxiety while waiting for appointments or interventions\n\nchildren and young people who are inpatients to mix with friends, peers or partners (for example, flexible visiting times, access to social media, spaces away from clinical areas to meet)\n\na feeling of safety (for example, easy access to call bells or other means of summoning help, knowing that someone is around to help).\n\nProvide a healthcare environment that:\n\nis clean, comfortable and feels homely\n\nis calm, with as little disturbance from background noise as possible\n\nseparates treatment areas from those for play and recreation\n\nis designed and decorated in a suitable way for the age group it is for (including use of colours, layout, lighting and clear signs)\n\nin an inpatient setting is quiet enough for rest and sleep, particularly at night.\n\nProvide children and young people who are inpatients with information about the facilities and routine on the ward (for example, where the bathrooms are located, what times meals are served, where play and recreation facilities are located and how they can be accessed, where there are quiet areas), and answer any questions they may have.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on healthcare environment\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review M: healthcare environment.\n\nLoading. Please wait.\n\n# Maintaining usual activities\n\nGive children and young people ongoing opportunities to identify aspects of their lives that are important to them (for example, physical, social and recreational activities, schooling and education, their developmental, cultural and emotional needs).\n\nDiscuss with children and young people, particularly those with ongoing health needs:\n\nhow their health condition and their healthcare will impact on their ability to engage in usual activities\n\nwhat their expectations and goals may be for their future involvement in usual activities, and how they can be helped achieve them.\n\nEnsure that babies, children and young people are able to continue with their usual activities of daily life with minimal disruption while receiving healthcare and, when clinically appropriate, make reasonable adjustments to their environment to support this (for example, providing a quiet space for studying).\n\nIn an inpatient setting, ensure free internet access over Wi-Fi, and that any Wi-Fi codes or passwords are freely available so that children and young people can maintain their usual contacts and networks.\n\nAdvise children and young people that use of social media or technology (for example, phones, noisy computer games) must not compromise the privacy or the environment of other people.\n\nRecognise that the wishes and needs of each baby, child and young person to engage in the activities they have identified as important to them will vary between individuals and over time. Integrate these needs into the delivery of healthcare.\n\nMake sure that the baby, child or young person\'s usual support networks (for example, parents and carers, siblings, partners and friends) can be involved in maintaining activities of daily living (for example, changing nappies, washing, getting dressed, eating) and other usual activities.\n\nEnsure coordination between healthcare, education and social care to maintain an individual\'s usual activities, including education and learning. This could include education support roles, Early Help or making adjustments such as scheduling treatment appointments around school commitments.\n\nHelp children and young people to use cultural, spiritual or religious beliefs that they find helpful in their lives as a source of support if they wish. This could include facilitating religious activities such as prayer time, or letting them know about chaplaincy services or other religious support available.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on maintaining usual activities\xa0.\n\nFull details of the evidence and the committee\'s discussion are in:\n\nevidence reviews N: supporting participation in usual activities\n\nevidence review J: improving experience of healthcare.\n\nLoading. Please wait.\n\n# Accessibility, continuity and coordination\n\n## Accessing healthcare\n\nProvide children and young people with targeted information about:\n\nwhen an illness or condition means they should seek medical help\n\nwhat services are available (for example, using the NHSGo app)\n\nwhen and how they can access services. Follow the recommendations on providing information.\n\nReassure children and young people that:\n\nhealthcare services are there to help them\n\nfeeling afraid or embarrassed about asking for help is normal but healthcare professionals will understand and provide support.\n\nDevelop information about healthcare and healthcare services with input from children and young people themselves, and in collaboration with healthcare professionals (for example, play specialists, child psychologists) and other sectors (for example, education, social care, the voluntary sector).\n\nProvide information for parents and carers to support them in accessing healthcare services for their baby or child (for example, the eRedbook app).\n\nActively seek out groups of parents or carers who may face barriers accessing healthcare services for their children (for example, those who would benefit from translated materials or those who may have limited internet access), to ensure they have accessible information about what care their children can receive, and are encouraged to use those services.\n\nProvide information to children and young people on:\n\nwhat services they can access with or without their parents or carers\n\nwhether their parents or carers will need to be told if they access services.\n\nTake into account the views of children and young people, and for babies and young children the views of their parents and carers, when designing or redesigning healthcare services. Include:\n\npersonal factors, such as the age range, gender and developmental stages of the children and young people using the service\n\nsocial factors, such as the religious, cultural or social background of the children and young people using the service. See recommendations 1.7.1 to 1.7.4 on involving children and young people in design of healthcare services.\n\nProvide children and young people with support and help to access the healthcare system. Ensure additional support, such as one-to-one support from a named healthcare or social care professional, is available for those who need it (for example, children with learning disabilities, looked-after children, children in institutional care, care leavers).\n\nTake into account access needs specific to children and young people. This might include:\n\naccommodating preferences about the gender of the healthcare professional who they see\n\noffering flexible appointments that meet an individual\'s and family\'s needs, for example minimising regular appointments during school hours\n\nproviding services in locations that are easier for children and young people to access, or co-locating with other services that children and young people access (for example, youth centres and schools).\n\nUse flexible methods where clinically appropriate, agreed with the child or young person to deliver healthcare services (for example, telephone or video calls, digital media such as websites and apps) as alternatives to in person face-to-face services to help overcome access difficulties, such as travelling to appointments or relying on parents for transport.\n\nUse feedback from children and young people to improve the accessibility of healthcare services. See recommendations 1.7.5 to 1.7.9 on measuring experience of care.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on accessing healthcare\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review O: accessing healthcare.\n\nLoading. Please wait.\n\n## Continuity and coordination of care\n\nMaintain continuity of care by providing healthcare from the same professionals or teams when clinically appropriate.\n\nEnsure clear and timely exchange of relevant patient information:\n\nbetween healthcare professionals and children and young people or the parents or carers of babies and young children\n\nbetween healthcare professionals\n\nbetween healthcare, education and social care professionals.\n\nPay particular attention to communication between healthcare professionals and services and the coordination of ongoing care:\n\nat key points in care (for example, on transfer from one healthcare setting to another, or when being referred to a different healthcare team)\n\nfor children and young people who might need additional support (for example, children with learning disabilities, looked-after children, care leavers, young people who are homeless). For advice on transition to adult services, see the NICE guideline on transition from children\'s to adults\' services.\n\nEnsure systems are in place so that children and young people and the parents or carers of babies and young children do not need to unnecessarily repeat their healthcare history when being seen by different healthcare professionals (for example, by using health passports or digital health records).\n\nEnsure children and young people and the parents or carers of babies and young children have access to their healthcare records. Access must meet the requirements of the Access to Health Records Act 1990.\n\nProvide contact information so that children and young people know how to obtain advice from the same service or team in the future.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on continuity and coordination of care\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review P: continuity of care.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary.\n\n## Accessible\n\nSomething (for example, a service or information format) designed in a way so that people who have a disability or impairment are able to use it with a similar level of time, effort and skill needed as someone who does not.\n\n## Assent\n\nAgreement given by a child or young person to a course of action or procedure, when they are not legally empowered to give consent.\n\n## Consent\n\nAgreement (which can be verbal, non-verbal or written) to a course of action or procedure, after a discussion of the risks and benefits, when they are legally empowered to give consent.\n\n## Containment holding\n\nPlacing both hands firmly but gently on a baby and holding the position very still, to provide reassurance and comfort.\n\n## Cultural sensitivity\n\nKnowledge, awareness and respect for other people\'s cultural background, identity and differences, without making assumptions about them.\n\n## Focus and reference groups\n\nA series of focus and reference groups with children and young people were held to obtain their views and opinions. These views and opinions were considered by the committee as part of their review of the evidence.\n\n## Gillick competent\n\nChildren under the age of 16 can consent to their own treatment if they\'re believed to have enough intelligence, competence and understanding to fully appreciate what\'s involved in their treatment. Also see the NHS website on consent to treatment – children and young people.\n\n## National surveys\n\nA review of recent national surveys of children and young people\'s views on healthcare was carried out. The findings of these surveys were considered by the committee as part of their review of the evidence.\n\n## Non-judgemental\n\nNot criticising or demonstrating a negative attitude about another person\'s feelings or actions, based on personal opinions or personal biases.\n\n## Parents or carers\n\nParents or carers refers to the primary caregivers for a baby or child at any given time. This can include birth or adoptive parents with parental responsibility, other members of the extended family who provide care such as siblings, grandparents, aunts and uncles, others nominated by the parents, or legal guardians. For looked-after children or those who lack mental capacity, it can also include those acting instead of parents such as a social worker, key worker, foster carers or guardians. It does not refer to nurses, healthcare assistants or other healthcare professionals who are acting in their professional capacity.\n\n## Positive touch\n\nHuman touch that aims to give babies the experience of touch that is not for a clinical purpose, but is given tenderly, lovingly and gently, and that which responds to and does not ignore their behaviour.\n\n## Usual activities\n\nActivities that form part of a baby, child or young person\'s daily life and which may be disrupted by illness or the need to access healthcare services. This may include activities of daily living (bathing, showering, eating), interactions with family and friends, social and emotional development, education and schooling, sports, hobbies and interests, social activities and use of social media.', 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Risks and benefits\n\nWhat decision aids are the most cost effective and acceptable when explaining the risks and benefits of healthcare interventions to children and young people?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on risks and benefits\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: understanding the risks and benefits of healthcare decisions.\n\nLoading. Please wait.\n\n## Independent advocacy\n\nHow can the views of babies, children and young people be best represented by independent advocates?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on independent advocates\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: independent advocacy in healthcare for children and young people.\n\nLoading. Please wait.\n\n## Improving healthcare experience\n\nWhat elements of healthcare matter most to babies, children and young people to create positive experiences of healthcare?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on improving healthcare experience\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: improving experience of healthcare.\n\nLoading. Please wait.\n\n## Measuring experience\n\nHow can the experience of babies, children and young people be measured so as to improve their experience of healthcare?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on measuring experience\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: measuring experience.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Overarching principles\n\nRecommendations 1.1.1 to 1.1.9\n\n## Why the committee made the recommendations\n\nThe committee were aware, based on their own knowledge and experience, that safeguarding is an important consideration that applies to all aspects of healthcare services, and so made an overarching recommendation to state this. Similarly, the committee were aware that it is necessary for all services to make reasonable adjustments as required by legislation in order to meet the needs of disabled babies, children and young people, and so made an overarching recommendation to state this.\n\nBased on stakeholder feedback, the committee added an overarching recommendation to clarify the rights of children and young people to make decisions about their healthcare and to consent to treatment.\n\nThere was evidence from a number of reviews: that all discussion, support and information need to be suitable for the age, developmental stage and level of understanding for an individual child or young person; that, as children develop and mature, their healthcare needs and preferences change; and that determining needs and preferences is not a static one-off decision.\n\nAs a number of recommendations throughout the guideline relate to the use of digital resources, the committee clarified that alternative methods should be available as access to these digital resources is not universal.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice and should have little impact on resources, but may mean extra time is needed to revisit needs and preferences on a regular basis, or to provide alternatives to online information.\n\nReturn to recommendations\n\n# Communication by healthcare staff\n\nRecommendations 1.2.1 to 1.2.16\n\n## Why the committee made the recommendations\n\nThere was good evidence that children and young people like healthcare professionals to communicate in a friendly, compassionate and respectful manner, reading behavioural cues, giving them sufficient time, listening to them and getting to know them on a personal level.\n\nThere was good evidence that different methods of communication should be used when appropriate, and this includes using verbal and non-verbal communication, and identifying the best way to communicate for individuals, particularly those who have additional communication needs.\n\nThe committee were also aware of the need for healthcare professionals to ensure that different methods of communication are used if necessary to meet the requirement of the Mental Capacity Act 2005 that a person is not to be treated as unable to make a decision unless all practicable steps to help them to do so have been tried.\n\n## How the recommendations might affect practice\n\nHealthcare professionals might need more time to communicate with children and young people and this could mean some consultation times are longer, which would create a resource impact for the NHS. Additional help to communicate may be needed (for example, use of foreign language or sign language interpreters) and that may also have a resource impact for the NHS.\n\nEnsuring that all staff are competent to communicate effectively might also need additional time and resources for training and skill development.\n\nReturn to recommendations\n\n# Providing information\n\nRecommendations 1.2.17 to 1.2.28\n\n## Why the committee made the recommendations\n\nThere was good evidence from the systematic literature review on the preferred sources of information, with in person face-to-face information provided by a healthcare professional one of the preferred and most trusted forms of information. The evidence showed that healthcare professionals should provide information clearly in a way that is easy for children and young people to understand, and that it is important that healthcare professionals consider when and how to deliver information, as sufficient information needs to be provided, but this should not be overwhelming. The evidence also showed that children and young people, and the parents of babies and young children, want information in a variety of formats, including written materials, websites and smartphone applications and any other digital sources, and that these sources should be clear and easy to understand and relevant.\n\nThere was evidence that children and young people would want their parents or carers to have information tailored to their condition and needs in order to provide support and look after them.\n\nThere was evidence that whatever the format, information should be age- and developmentally appropriate, and should be available in different versions (for example, easy-read versions) and languages to allow as many people to access it as possible.\n\nThe evidence from the focus and reference groups and some limited evidence from the national surveys reinforced the systematic literature review evidence, showing that the quantity of information should not be overwhelming, and that there is a need for clear, understandable verbal and written information.\n\n## How the recommendations might affect practice\n\nThe recommendations may mean additional time and resources are needed to deliver and produce information in suitable formats (for example leaflets, websites, apps) in partnership with children and young people. However, it was acknowledged that many services are already using a variety of alternative ways of proving information to children or young people and the overall resource impact in this area will be modest.\n\nReturn to recommendations\n\n# Shared decision making\n\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations\n\nThere was evidence from the systematic literature review, focus and reference groups and from the national surveys that most children and young people want to be involved in making shared decisions about their healthcare, but that the level of preferred involvement may vary between different children, on different occasions and may change as children get older.\n\nThe committee were also aware of the requirement of the Mental Capacity Act 2005 that a person is not to be treated as unable to make a decision unless all practicable steps to help them to do so have been taken without success. Healthcare professionals therefore need to tailor their approach to discussions (with advice from other specialists or those who know the person well if necessary) to ensure this.\n\nThere was some evidence on children and young people's preferences for how the shared decision-making process should be undertaken, for example by starting discussions as soon as possible, making sure information is presented clearly, tailoring its complexity, providing it at a suitable pace and using decision aids if they are available.\n\nThe committee also used their knowledge and experience to make additional recommendations to adhere to these principles when making shared decisions with parents and carers on behalf of babies and young children.\n\n## How the recommendations might affect practice\n\nAdditional time may be needed to carry out meaningful discussions around shared decision making. Ensuring that all staff are competent to implement shared decision making effectively might also need additional time and resources for training and skill development.\n\nReturn to recommendations\n\n# Risks and benefits\n\nRecommendations 1.3.5 to 1.3.10\n\n## Why the committee made the recommendations\n\nThere was limited evidence that decision aids improve knowledge about risks and benefits and reduce decisional conflict, but as there was insufficient evidence to allow the committee to give advice on their use, a research recommendation was made on this topic (see research recommendation 1). There was some evidence from the focus and reference groups that children and young people vary in their views about how much information they like to receive on risks. Based on this evidence, and on their knowledge and experience, the committee made recommendations on the best ways to discuss risk and benefits with children and young people, including pacing this information, having discussions without parents and carers, and ensuring understanding.\n\n## How the recommendations might affect practice\n\nThe recommendations might mean additional time and resources are needed to help children, young people and the parents or carers of babies and young children understand the risks and benefits of healthcare decisions. Ensuring that all staff are competent to discuss risks and benefits effectively might also need additional time and resources for training and skill development.\n\nReturn to recommendations\n\n# Consent, privacy and confidentiality\n\nRecommendations 1.4.1 to 1.4.14\n\n## Why the committee made the recommendations\n\nNo evidence relating to consent was found, but the committee discussed that children and young people have the legal right to consent to, or refuse, treatment as set out in UK law and the UN Convention on the Rights of the Child. These rights are dependent on their age and competence and as the committee agreed it was such an important principle, they included these details in an overarching recommendation at the beginning of the guideline.\n\nThe committee used their experience and expertise to make recommendations on how children and young people could be best supported to make decisions on consent. The committee also used their knowledge and experience of how differences of opinion over consent, assent or refusal of treatment should be approached. This could include involving other healthcare professionals, but the committee also recognised that the child, young person, parents or carers should be offered support so that they did not feel outnumbered in discussions.\n\nThere was some low-quality evidence on privacy and confidentiality, which showed that children are aware of the risks to anonymity and privacy with digital information applications, but that they also recognised that in some cases, it was valuable to share information (for example, with parents, or to allow peer-to-peer support). The committee therefore also used their experience and expertise on best practice at maintaining privacy (particularly when using digital or virtual methods for consultations, or with children or young people who needed additional support to communicate without their parents or carers), discussing private and confidential information with children and young people, and the sharing of information with parents or carers.\n\n## How the recommendations might affect practice\n\nThere are already examples of good practice across the NHS concerning consent, privacy and confidentiality, and these recommendations are designed to increase consistency throughout the NHS. Implementing these recommendations might mean extra time is needed for healthcare professionals to discuss and explain issues surrounding consent, privacy and confidentiality with children and young people. There may also be a need to consider the environment in which healthcare is delivered to provide privacy and ensure confidentiality.\n\nReturn to recommendations\n\n# Involvement of parents or carers\n\nRecommendations 1.5.1 to 1.5.6\n\n## Why the committee made the recommendations\n\nThere was evidence that children and young people want to be able to express their opinions independently from their parents, but they also value their parent or carers' presence or support. There was evidence that the extent of support they want varies depending on the circumstances and the child or young person, and that it should be discussed between parents or carers and their children. The committee were aware from their knowledge and experience that certain groups of children and young people did not have parents or carers to support them, and that it is particularly important that these children and young people should be offered alternative support.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice and should have little impact on resources, but may need extra time to have these discussions, and to see children with their parents or carers and separately.\n\nReturn to recommendations\n\n# Support from healthcare staff\n\nRecommendations 1.5.7 to 1.5.13\n\n## Why the committee made the recommendations\n\nThere was evidence that children and young people have differing preferences for the support they wish to receive from healthcare professionals, so this should be personalised based on their preferences at any time (as these preferences can change depending on different factors). There was also evidence around needing to build a trusting relationship. Based on their knowledge and experience, the committee agreed that it was essential that healthcare professionals support children and young people's rights and advocate for them where necessary. There was also evidence that children and young people appreciate support to identify and use coping techniques, and to be advised on other sources of support.\n\n## How the recommendations might affect practice\n\nAdditional time may be needed to build trust, discuss and provide the support according to the preferences and needs of children and young people.\n\nReturn to recommendations\n\n# Self-advocacy\n\nRecommendations 1.5.14 to 1.5.17\n\n## Why the committee made the recommendations\n\nThere was evidence from the systematic literature review and the focus and reference groups for strategies that would enable children and young people to advocate for themselves with respect to their healthcare and related decisions. This includes providing time, space and adequate information.\n\nThere was evidence that some children and young people felt as though healthcare professionals have a preconceived idea of their ability and motivation to engage with healthcare decisions. This often results in missed opportunities to encourage vulnerable children and young people to engage in their care and advocate for their choices.\n\nThe evidence also showed that engaging children and young people in feedback, service design and other activities could improve and facilitate their self-advocacy skills.\n\nBased on the evidence and their knowledge and experience, the committee identified approaches to empower children to advocate for themselves.\n\n## How the recommendations might affect practice\n\nAdditional time may be needed to discuss and provide the adequate support to children and young people so they can be empowered to advocate for themselves.\n\nReturn to recommendations\n\n# Independent advocates\n\nRecommendations 1.5.18 to 1.5.24\n\n## Why the committee made the recommendations\n\nThe recommendations reflect current UK legislation in respect of access to independent advocates in certain situations for children and young people. Based on their knowledge and experience, the committee recognised the potential benefits to children and young people of independent advocacy in wider healthcare situations, not currently covered by the legislation. These benefits include support to understand healthcare processes and procedures, to express views and opinions, and with decision making.\n\nThere was evidence from an expert witness and the focus and reference groups that eligible children and young people may have limited knowledge about independent advocacy services. Therefore, they should be provided with this information and supported throughout the process.\n\nThere was evidence from the expert witness and the focus and reference groups about the role of independent advocates, which involves supporting children and young people in decisions about their healthcare and that, in order to be most effective, independent advocates should take time to build a trusting and confidential relationship with children and young people.\n\nAs there was no evidence from the systematic review of the literature for this review, the committee made research recommendation 2.\n\n## How the recommendations might affect practice\n\nThe recommendations on access to an independent advocate are in line with current UK legislation, with little additional impact on resources. However, the suggested expansion of this service to children and young people who are not adequately represented by parent and carers may lead to an increase in the number of independent advocates needed by NHS services, which will need an increased level of funding. There may be an increased amount of time for healthcare professionals to facilitate this use of independent advocates.\n\nReturn to recommendations\n\n# Improving healthcare experience\n\nRecommendations 1.6.1 to 1.6.5\n\n## Why the committee made the recommendations\n\nThe qualitative and quantitative evidence identified 4 aspects of healthcare that were important to children and young people but which were not covered in other evidence reviews. These were food, pain-related anxiety, staff uniforms and healthcare clothing, and religious, cultural and spiritual support. Based on their expertise and experience, the committee made additional recommendations on these topics. The committee agreed that the recommendations on religious support related to maintaining usual activities, and therefore they placed this recommendation in that section of the guideline.\n\nAs there was limited quantitative evidence on the elements of healthcare that matter most to babies, children and young people to create a positive experience of healthcare, the committee made research recommendation 3.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect best practice and may reduce variation in practice.\n\nReturn to recommendations\n\n# Design of healthcare services\n\nRecommendations 1.7.1 to 1.7.4\n\n## Why the committee made the recommendations\n\nThere was some evidence that children and young people are keen to contribute to the design of healthcare services, and appreciate the opportunity to do so. There was also evidence that the children and young people recognise there could be practical difficulties with involvement (for example, time, travel, number of events, and content not being age- or developmentally appropriate). There was evidence that ways to obtain feedback should be age- and developmentally appropriate. There was evidence that children and young people want their views to be taken seriously, and that they appreciate being told how their input had changed practice.\n\nThe committee and stakeholders identified that there may be particular groups who may be less likely to be involved in the design of healthcare services and so recommended that the views of these groups should be actively sought. However, the list is not exhaustive and other groups may be identified according to local circumstances or demographics.\n\n## How the recommendations might affect practice\n\nThere are already examples of good practice across the NHS, but practice is inconsistent. These recommendations aim to standardise how children, young people, parents and carers should be involved in the design of services, to encourage more consistent practice across the whole NHS.\n\nImplementing this across the NHS might mean increased resources are needed to develop the tools, identify participants, aid involvement, and evaluate and feedback the results.\n\nReturn to recommendations\n\n# Measuring experience\n\nRecommendations 1.7.5 to 1.7.9\n\n## Why the committee made the recommendations\n\nThere was some evidence from the focus and reference groups that children and young people are keen to provide feedback, that they are willing to use a variety of methods to do this, and that surveys should be quick and easy to complete. The evidence also showed that children and young people prefer giving their feedback at or towards the end of treatment but based on their knowledge and experience, the committee agreed this should be at various points in treatment. There was a very small amount of evidence from the national surveys on the problems children and young people had had using complaints systems. The committee also used their own knowledge and experience on helping people give feedback to optimise responses.\n\nThe committee and stakeholders identified that there may be particular groups who may be less likely to be involved in providing feedback on healthcare services and so recommended that the views of these groups should be actively sought. However, the list is not exhaustive and other groups may be identified according to local circumstances or demographics.\n\nAs there was very limited evidence from the systematic review of the literature on measuring children and young people's experience, the committee made research recommendation 4.\n\n## How the recommendations might affect practice\n\nExperience may already be measured in a number of different ways across the NHS and these recommendations will increase measurement of experience, reinforce best practice and make practice more consistent.\n\nImplementing this across the NHS might mean more resources are needed to co-produce the tools, identify participants, aid involvement and evaluate and feedback the results.\n\nReturn to recommendations\n\n# Healthcare environment\n\nRecommendations 1.8.1 to 1.8.4\n\n## Why the committee made the recommendations\n\nThere was some evidence from young people about their preferences, and from parents of babies in neonatal units, and the committee agreed that all babies and young children (represented by their parents), children and young people, should be able to express views about the preferences for place of care. The committee used this and their own knowledge and experience to agree how settings should be appropriate, comfortable, welcoming and acceptable to the people who need to use them. There was evidence that young people prefer their care environment to be age-appropriate, and that they may feel uncomfortable in paediatric settings aimed at young children. There was also evidence that they like to be able to meet visitors in an appropriate space, to have areas for recreation facilities, to have adequate signs, and for there not to be too much noise. They also expressed wanting to feel safe in healthcare environments.\n\nThere was evidence from parents or carers of babies about the need for privacy, comfortable furniture and furnishings, and facilities so they have the option to stay with their babies. Although there was no evidence about privacy for children and young people, the committee agreed that offering privacy is important, based on their knowledge and experience.\n\n## How the recommendations might affect practice\n\nThe recommendations aim to make best practice more consistent across the NHS. Some changes to improve the healthcare environment might be easy to make, but changing or redesigning healthcare environments can be an expensive process, and some of the recommendations could need considerable resources to implement.\n\nReturn to recommendations\n\n# Maintaining usual activities\n\nRecommendations 1.9.1 to 1.9.9\n\n## Why the committee made the recommendations\n\nBased on their knowledge and experience, the committee made recommendations on the importance of determining what usual activities were important to children and young people, and making adjustments to allow these to continue. The committee agreed that providing support to continue with usual activities would need to be personalised to account for different needs, preferences and developmental stages. The committee recognised the benefits to the wellbeing of children and young people of continuing with usual activities, which may include a reduction in boredom, anxiety and distress. There was evidence that some children prefer to receive help with personal care from their family, as would happen if the child were at home. There was also evidence that children and young people want to continue with social activities and keeping in touch with their friends. There was no evidence from the systematic literature review specifically about Wi-Fi access but the committee agreed that the ability to instantly contact friends was a part of everyday life for most children and young people and this was reinforced by evidence from the focus and reference groups and the national surveys.\n\nThe evidence on educational support reinforced the committee's experience that maintaining educational provision and liaison with education services is very important.\n\nThere was evidence that some children and young people found religious or spiritual support or beliefs helpful when they were unwell. Other aspects from this evidence are reflected in the recommendations on improving healthcare experience, where this evidence is described in more detail.\n\n## How the recommendations might affect practice\n\nThe recommendations aim to reduce variation in practice across the NHS, and might mean extra staff time or changes in practice are needed to implement them.\n\nReturn to recommendations\n\n# Accessing healthcare\n\nRecommendations 1.10.1 to 1.10.11\n\n## Why the committee made the recommendations\n\nThere was evidence from the systematic review of the literature about factors that could be barriers for children and young people to access health services. This included factors relating to practical aspects of accessing healthcare such as location and timing of appointments, as well as trust and relationships with healthcare professionals and lack of knowledge about when to access healthcare, and what services to access. The focus and reference groups also provided evidence about the perceived barriers and these included fear and embarrassment, being too busy to access healthcare or not wanting to miss out on school or social activities, and being aware of the capacity issues within the NHS. The committee then used this evidence to make recommendations designed to overcome these barriers. The evidence from the national surveys also identified that certain groups of children and young people may need additional help and support to access and navigate the health system.\n\n## How the recommendations might affect practice\n\nAdditional resources may be needed to promote and deliver accessible and flexible services.\n\nReturn to recommendations\n\n# Continuity and coordination of care\n\nRecommendations 1.10.12 to 1.10.17\n\n## Why the committee made the recommendations\n\nThere was good evidence that children and young people prefer to see the same healthcare professionals whenever possible, and that this promotes improved engagement and continuity of care. The committee were aware that children and young people prefer to be able to contact their healthcare professionals or teams directly.\n\nThere was good evidence that children and young people do not want to have to repeat their healthcare history on multiple occasions, and that good and timely communication between healthcare professionals, services, and children and young people and the parents or carers of babies and young children could help with this. There was also some evidence for the use of different methods to help improve communication and continuity of care, and in particular the use of electronic health records.\n\n## How the recommendations might affect practice\n\nThere are some electronic and paper methods to improve communication already in use, including electronic health records. Implementing more integrated systems to share information with and between healthcare professionals, other services and children and young people or the parents and carers of babies and young children will have resource implications for the NHS. In addition, there may be a need for improved administration support to help with the sharing of information, which will also have some resource implications.\n\nReturn to recommendations"}
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https://www.nice.org.uk/guidance/ng204
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This guideline describes good patient experience for babies, children and young people, and makes recommendations on how it can be delivered. It aims to make sure that all babies, children and young people using NHS services have the best possible experience of care. It is recognised that parents and carers play a key role, and where appropriate, we took their views into account when developing the recommendations.
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7e104a28c22deb848d959dd17da38af45242d998
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nice
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Pemigatinib for treating relapsed or refractory advanced cholangiocarcinoma with FGFR2 fusion or rearrangement
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Pemigatinib for treating relapsed or refractory advanced cholangiocarcinoma with FGFR2 fusion or rearrangement
Evidence-based recommendations on pemigatinib (Pemaryze) for relapsed or refractory advanced cholangiocarcinoma with FGFR2 fusion or rearrangement in adults.
# Recommendations
Pemigatinib is recommended, within its marketing authorisation, as an option for treating locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that has progressed after systemic therapy in adults. It is recommended only if the company provides pemigatinib according to the commercial arrangement.
Why the committee made these recommendations
Current treatment for advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement that has progressed after systemic therapy is symptom control, with or without modified folinic acid, 5‑fluorouracil and oxaliplatin (mFOLFOX) chemotherapy.
Clinical evidence from 1 study suggests that pemigatinib may be more effective than current treatments. This is uncertain because the study did not directly compare pemigatinib with symptom control or mFOLFOX. But the cancer is rare. This means the number of people who could take part in a study is small, making it difficult to collect robust comparative data. So, the uncertainty is considered acceptable.
Pemigatinib meets NICE's criteria for a life-extending treatment at the end of life. The cost-effectiveness estimates are uncertain but are likely to be within the range that NICE considers a cost-effective use of NHS resources. So, pemigatinib is recommended.# Information about pemigatinib
# Marketing authorisation indication
Pemigatinib (Pemaryze, Incyte Corporation) has a conditional marketing authorisation for 'the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of pemigatinib 13.5 mg tablets is £7,159.04 for a pack of 14 (company submission), which is an annual cost of £124,430. The company has a commercial arrangement. This makes pemigatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Incyte Corporation, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway and comparator
## There is an unmet need for a disease-modifying treatment for advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement after systemic therapy
Cholangiocarcinoma is a rare cancer that develops from the epithelial lining of the bile ducts. It is classified as intrahepatic or extrahepatic based on the location of the primary tumour. Fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement may lead to the tumours forming. The clinical experts advised that the aim of treatment for advanced cholangiocarcinoma with FGFR2 fusion or rearrangement that is refractory to chemotherapy is to improve symptoms, delay tumour progression and extend survival. There are no licensed, targeted or disease-modifying therapies currently available in the NHS to treat this condition. The clinical and patient experts highlighted that treatment for the condition has not improved in over a decade. Therefore, current treatment is further chemotherapy containing modified folinic acid, 5‑fluorouracil and oxaliplatin, plus active symptom control (mFOLFOX+ASC). If further chemotherapy is not suitable, ASC alone is offered. The patient and clinical experts emphasised the aggressive nature of this cancer and its poor prognosis. The patient experts described the difficulty of being diagnosed with a cancer for which there are very few treatment options and of being told of the poor prognosis often while feeling well. They also highlighted difficulty accessing experts in this condition. There is a lack of effective treatment options. Also, chemotherapy may or may not extend life at the expense of debilitating side effects, which may have a significant effect on quality of life. The committee concluded that there is an urgent unmet need for people with advanced cholangiocarcinoma with FGFR2 fusion or rearrangement after systemic therapy. It agreed that people with this condition would welcome a disease-modifying treatment option like pemigatinib.
## mFOLFOX+ASC and ASC alone are the most appropriate comparators
The company submission compared pemigatinib with mFOLFOX+ASC and ASC alone in people with advanced cholangiocarcinoma with FGFR2 fusion or rearrangement after systemic therapy. The ERG noted uncertainty in clinical guidelines and an absence of real-world prescribing data. It highlighted that clinical advice to the company suggested that capecitabine with oxaliplatin may be preferred to mFOLFOX for some people. It advised that it is likely that other chemotherapy agents are also given in routine NHS practice. The clinical experts advised that the relevant comparators currently used in routine clinical practice include mFOLFOX+ASC and ASC alone. The committee concluded that these are the most appropriate comparators for this appraisal.
# Clinical-effectiveness evidence
## The clinical evidence for pemigatinib is from a single-arm non-randomised study
The clinical evidence for pemigatinib came from FIGHT‑202. This was a phase 2, single-arm, non-randomised, open-label study in people with advanced or surgically unresectable cholangiocarcinoma that had not responded to previous therapy. Only cohort A of FIGHT‑202, which included people with FGFR2 fusion or rearrangement, was relevant to this appraisal. The clinical evidence from the latest data cut is considered confidential by the company so cannot be reported here. In an earlier data cut (March 2019), the median progression-free survival was 6.9 months and the median overall survival was 21.1 months. The committee noted that, because FIGHT‑202 was a single-arm study, it did not provide evidence of the relative effectiveness of pemigatinib compared with current treatment options. But it acknowledged that doing studies for advanced chemorefractory cholangiocarcinoma is difficult because of the rarity of this cancer. It concluded that, in the absence of direct evidence, indirect comparisons were needed to assess the relative effectiveness of pemigatinib compared with the comparators.
## The population in cohort A of FIGHT‑202 is appropriate for decision making
The ERG highlighted that cohort A of FIGHT‑202 was a subset of the population in the marketing authorisation. It highlighted that 98% of people in cohort A had intrahepatic disease. However, the marketing authorisation and the NICE scope include people with non-intrahepatic disease. The company stated that there is no biological reason that pemigatinib would not provide benefit to people with non-intrahepatic cholangiocarcinoma with FGFR2 fusion or rearrangement. The clinical experts advised that about 40% of people with advanced cholangiocarcinoma have intrahepatic disease. However, they explained that, in advanced cancer, it is difficult to differentiate intrahepatic disease from other subtypes. They advised that FGFR2 fusion or rearrangement can be present in non-intrahepatic disease but it is uncommon. To be eligible for pemigatinib, people will be identified by the presence of an FGFR2 fusion or rearrangement and not by the disease subtype. The committee concluded that the population in cohort A of FIGHT‑202 was appropriate for decision making.
# Comparative evidence
## The comparative evidence from ABC‑06 is appropriate for decision making but has limitations
No studies directly compared pemigatinib with treatments currently used in the NHS. The main comparative evidence was from ABC‑06. This was a phase 3, randomised, open-label study of mFOLFOX+ASC or ASC alone for people with locally advanced or metastatic biliary tract cancers previously treated with gemcitabine plus cisplatin chemotherapy. The committee noted that ABC‑06 was done in a different population to FIGHT‑202 and did not report FGFR2 mutation status in either treatment group. It understood that FGFR2 mutation status appears to be an important prognostic indicator, and that not knowing the FGFR2 mutation status in the ABC‑06 population was a significant limitation. However, at the second committee meeting, the company described new evidence suggesting that the FGFR2 mutation is not a significant predictor of overall survival. So, the committee considered that the prognostic value of FGFR2 mutation status is uncertain. The clinical experts explained that, because of the rarity of this cancer it is difficult to do comparative studies in the relevant subpopulation. The committee acknowledged that because of the rarity of the cancer, the data on the comparators from ABC‑06 were the best available evidence. Despite the limitations, it concluded that the comparative efficacy and safety data from ABC‑06 were the most appropriate evidence for decision making.
## Pemigatinib is likely to be more effective than the comparators
In the absence of direct comparative evidence, the estimate of the relative treatment effect of pemigatinib compared with mFOLFOX+ASC and ASC alone was based on an unanchored matching adjusted indirect comparison of patient-level data from FIGHT‑202 and data from ABC‑06. The weightings were derived using a propensity score logistic regression model adjusted for selected prognostic factors. The weighted hazard ratios for overall survival and progression-free survival are considered confidential by the company and exact results cannot be reported here. In general, the results were more favourable for pemigatinib. The hazard ratio for overall survival was lower for pemigatinib compared with mFOLFOX+ASC and ASC alone. The hazard ratio for progression-free survival was also lower for pemigatinib compared with mFOLFOX+ASC. Progression-free survival data were not available for the ASC-alone arm from ABC‑06. So, the company assumed that the progression-free survival hazard ratio for pemigatinib compared with ASC alone was the same as the progression-free survival hazard ratio for pemigatinib compared with mFOLFOX+ASC. The ERG advised that the estimate of comparative treatment effect was highly uncertain and likely to be biased because the matching adjusted indirect comparison was done between mismatched study populations (see section 3.5). The committee noted the lack of direct comparative evidence (see section 3.3) and the limitations of using a matching adjusted indirect comparison to compare the efficacy of pemigatinib with the comparators. However, it recognised the rarity of the cancer and limitations in the available evidence for the comparators. It concluded that the matching adjusted indirect comparison suggests pemigatinib was more effective than the comparators, but that this was uncertain.
## Comparative safety evidence is likely to have little effect on the cost-effectiveness estimates
The company did not do a matching adjusted indirect comparison for the safety of pemigatinib compared with the comparators. Instead, it used unadjusted adverse-event rates for pemigatinib from FIGHT‑202 and for mFOLFOX+ASC and ASC alone from ABC‑06. The ERG advised that no conclusions could be drawn about the safety of pemigatinib, relative to mFOLFOX+ASC and ASC alone, in the specified population, without comparative safety evidence. It noted that there was little value in doing a matching adjusted indirect comparison with poor quality evidence. During technical engagement, the company provided additional analyses that varied the modelled adverse events rates for the comparator to extreme values. These showed that the cost-effectiveness estimates were not sensitive to comparative safety data. The committee concluded that there was a lack of comparative safety evidence for pemigatinib and its comparators, but that this was unlikely to have much effect on the cost-effectiveness estimates.
# Economic model
## The company's economic model is appropriate for decision making
The company's partitioned survival model used parametric survival models to predict outcomes including time-on-treatment, progression-free survival and overall survival. The model included people in both the progression-free and post-progression health states, either on or off treatment. It used a life-time horizon with a cycle length of 1 week. An annual discount rate of 3.5% was applied to costs and outcomes. The committee concluded the company's economic model was appropriate for decision making.
# Survival analysis
## Independently fitted models are appropriate
In the company's base-case analysis, long-term survival with pemigatinib was estimated by fitting parametric survival models to unadjusted overall-survival data from cohort A of FIGHT‑202. Long-term survival for the comparators was estimated by applying the inverse of the relative treatment effect from the matching adjusted indirect comparison (see section 3.6). The company preferred the log-logistic model to extrapolate overall survival from FIGHT‑202 and the log-logistic model to extrapolate overall survival from both arms of ABC‑06 for its base case. The committee considered that applying the hazard ratio to the treatment arm to generate parametric curves for comparator survival may be inappropriate. It noted that applying the hazard ratios from the indirect comparison requires the assumption of proportional hazards. The committee also noted that the company's selected log-logistic parametric curves were not proportional-hazards models. In response to the appraisal consultation document, the company provided log-cumulative hazard plots for overall survival with pemigatinib derived from the matching adjusted indirect comparison. These suggested that the proportional-hazards assumption was reasonable. The company also provided new scenarios in which FIGHT‑202 and ABC‑06 data were extrapolated independently using the April 2020 data cut, but it did not agree that independent models provide more robust or clinically plausible outcomes. However, the committee concluded that it was more appropriate to fit independent curves to each arm instead of applying the assumption of proportional hazards to non-proportional hazard models.
## The log-logistic parametric curve is the most plausible
At the first appraisal committee meeting, the committee stated that there was a lack of clear justification for the selected parametric curve. It agreed that it would like to have seen clearer clinical expectations of survival in the treatment and comparator arms over time. In response to the appraisal consultation document, the company's clinical experts suggested a probability of overall survival at 5 years of about 0.1% for people having mFOLFOX+ASC and of close to 0% for those having ASC alone. The company's clinical experts struggled to choose the most plausible curve for the pemigatinib survival extrapolation. After appraisal consultation, the clinical experts predicted survival at 5 years of between 10% and 13% for people who have pemigatinib, based on evidence from the maximum follow up of 3 years from FIGHT‑202. The committee noted that a recent publication of data from ABC‑06 may be informative. The company submitted this after consultation but it did not include additional follow-up data. The company also provided external data from ClarlDHy, a phase 3 randomised study, to validate the estimated survival for the comparator groups. When adjusted for crossover, the ClarlDHy placebo arm was consistent with outcomes from ABC‑06. The committee noted that ClarlDHy was for a different molecular population, the iDH1 mutation, and that similarities between the iDH1 and FGFR2 mutation populations did not necessarily equate to similar survival characteristics in people with FGFR2 mutations. The company preferred the log-logistic curve to extrapolate overall survival with pemigatinib because the company's clinical experts agreed that a declining hazard function over time was plausible, it was a good visual and statistical fit, and it was clinically plausible. The company also explored the generalised gamma curve in scenario analysis, which the committee agreed also predicted a declining hazard function and was clinically plausible. The committee noted that the generalised gamma curve predicted a lower 5‑year survival compared with the log-logistic curve for the extrapolated FIGHT‑202 data and both arms of ABC‑06. It considered that the log-logistic model was a statistically better fit than the generalised gamma model. Also, the 5‑year survival predicted by the log-logistic curve was within the clinical expert's estimated range. The committee considered that both the log-logistic and generalised gamma curves could be reasonable, but concluded that it would base its decision making on the log-logistic curve.
# Additional costs
## NHS England's genetic testing costs are included in the cost-effectiveness analysis
At the first appraisal committee meeting, the clinical experts advised that FGFR2 testing is not done as part of routine clinical practice in the UK. The committee noted that the 2020/21 National Genomic Test Directory does not include FGFR2 mutation testing for people with cholangiocarcinoma. The Cancer Drugs Fund clinical lead advised that there is already a multitarget panel test for people with cholangiocarcinoma to assess eligibility for other treatments. The prevalence of FGFR2 fusion or rearrangement is about 10% across all types of cholangiocarcinoma. So, adding FGFR2 as a target would incur an additional cost of £34, which would be applicable if pemigatinib is recommended for routine use in NHS practice. This gives a preferred cost of £340 for each additional person identified who is FGFR2-positive. The committee concluded that NHS England's genetic testing costs and the prevalence of FGFR2 fusion or rearrangement should have been included in the cost-effectiveness analysis. After consultation, the company included the costs of FGFR2 genetic testing in its base-case analysis.
## Costs of optical coherence tomography are included in the cost-effectiveness analysis
Pemigatinib treatment can sometimes cause retinal pigment epithelial detachment. At the first appraisal committee meeting, the Cancer Drugs Fund clinical lead advised that ophthalmological examination using optical coherence tomography would be needed before and after starting treatment with pemigatinib in the NHS. The company confirmed that this is detailed in the summary of product characteristics. The committee concluded that the costs of optical coherence tomography should be included in the economic analysis. After consultation, the company included the cost of optical coherence tomography in its analysis.
# End of life criteria
## Pemigatinib is considered to be a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. For the short life-expectancy criterion, the company's base-case model estimated a mean undiscounted life expectancy of 8.0 months for mFOLFOX+ASC and 7.3 months for ASC alone. For the life-extension criterion, the company's base-case model estimated an undiscounted mean incremental life expectancy with pemigatinib of 25.6 months compared with mFOLFOX+ASC and 26.4 months compared with ASC alone. The ERG advised that these estimates were highly uncertain given the uncertainty in the results from the matching adjusted indirect comparison and the approach used to estimate health outcomes in the company's economic model. The clinical experts confirmed that people with relapsed or refractory cholangiocarcinoma with FGFR2 fusion or rearrangement have a life expectancy of between 4.7 and 10 months with current treatment. The committee was satisfied that pemigatinib meets the short life-expectancy criterion with current care. It acknowledged that the extension-to-life criterion with pemigatinib was less certain because of limitations in the survival analysis (see sections 3.9 and 3.10). However, it considered that the risk of the extension-to-life criterion not being met was relatively small, given that the estimates were substantially greater than 3 months. The committee concluded that pemigatinib could be considered a life-extending treatment at the end of life.
# Cost-effectiveness estimates
## The most plausible incremental cost-effectiveness ratios are below £50,000 per quality-adjusted life year gained
NICE's guide to the methods of technology appraisal highlights that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratios (ICERs). It states that the committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically about the matching adjusted indirect comparison (see section 3.6). But it acknowledged that the company had identified all the available data to validate the survival estimates, given the rarity of the cancer. For a life-extending treatment at the end of life, the upper limit of the range usually considered to represent a cost-effective use of NHS resources is £50,000 per quality-adjusted life year (QALY) gained. The committee noted that the company's new base-case ICERs for pemigatinib, including an updated patient access scheme, were £42,076 per QALY gained compared with mFOLFOX+ASC, and £45,029 per QALY gained compared with ASC alone. The committee's preferred assumptions for decision making at the second appraisal committee meeting were to use:
independently fitted models (see section 3.9)
the log-logistic curve to extrapolate long-term overall survival with pemigatinib (see section 3.10).Using these preferred assumptions, the ICER was between £45,051 and £45,808 per QALY gained compared with mFOLFOX+ASC, and between £44,354 and £45,010 per QALY gained compared with ASC alone. The ICER value depended on whether the FIGHT‑202 data were adjusted for the mFOLFOX+ASC or ASC‑alone data from ABC‑06. Other scenarios, including using the generalised gamma curve to extrapolate long-term survival with pemigatinib, resulted in higher ICERs. The committee considered the uncertainty in the clinical evidence but noted the rarity of the cancer being appraised. It concluded that the cost-effectiveness estimates for pemigatinib suggest it is an acceptable use of NHS resources for a life-extending treatment at the end of life. So pemigatinib was recommended for routine use in the NHS.
# Innovation
## Pemigatinib is an innovative treatment for advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement
The company considered pemigatinib to be innovative because there are no other licensed or targeted disease-modifying treatment options for advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement. The patient and clinical experts emphasised the importance of improving debilitating symptoms and health-related quality of life, and of extending life, and the potential benefit from pemigatinib in achieving this. The committee noted the potential benefits of pemigatinib for people with advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement. But it concluded that it had not been presented with evidence of any additional benefits that had not been captured in the QALY calculations.
# Equalities considerations
## There are no equalities issues relevant to the recommendation
No equalities issues were raised during scoping and technical engagement. No potential equality issues were identified in the company submission. The committee concluded that there were no equalities issues relevant to the recommendation.
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{'Recommendations': "Pemigatinib is recommended, within its marketing authorisation, as an option for treating locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor\xa02 (FGFR2) fusion or rearrangement that has progressed after systemic therapy in adults. It is recommended only if the company provides pemigatinib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement that has progressed after systemic therapy is symptom control, with or without modified folinic acid, 5‑fluorouracil and oxaliplatin (mFOLFOX) chemotherapy.\n\nClinical evidence from 1\xa0study suggests that pemigatinib may be more effective than current treatments. This is uncertain because the study did not directly compare pemigatinib with symptom control or mFOLFOX. But the cancer is rare. This means the number of people who could take part in a study is small, making it difficult to collect robust comparative data. So, the uncertainty is considered acceptable.\n\nPemigatinib meets NICE's criteria for a life-extending treatment at the end of life. The cost-effectiveness estimates are uncertain but are likely to be within the range that NICE considers a cost-effective use of NHS resources. So, pemigatinib is recommended.", 'Information about pemigatinib': "# Marketing authorisation indication\n\nPemigatinib (Pemaryze, Incyte Corporation) has a conditional marketing authorisation for 'the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor\xa02 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of pemigatinib 13.5\xa0mg tablets is £7,159.04 for a pack of 14 (company submission), which is an annual cost of £124,430. The company has a commercial arrangement. This makes pemigatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Incyte Corporation, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway and comparator\n\n## There is an unmet need for a disease-modifying treatment for advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement after systemic therapy\n\nCholangiocarcinoma is a rare cancer that develops from the epithelial lining of the bile ducts. It is classified as intrahepatic or extrahepatic based on the location of the primary tumour. Fibroblast growth factor receptor\xa02 (FGFR2) fusion or rearrangement may lead to the tumours forming. The clinical experts advised that the aim of treatment for advanced cholangiocarcinoma with FGFR2 fusion or rearrangement that is refractory to chemotherapy is to improve symptoms, delay tumour progression and extend survival. There are no licensed, targeted or disease-modifying therapies currently available in the NHS to treat this condition. The clinical and patient experts highlighted that treatment for the condition has not improved in over a decade. Therefore, current treatment is further chemotherapy containing modified folinic acid, 5‑fluorouracil and oxaliplatin, plus active symptom control (mFOLFOX+ASC). If further chemotherapy is not suitable, ASC alone is offered. The patient and clinical experts emphasised the aggressive nature of this cancer and its poor prognosis. The patient experts described the difficulty of being diagnosed with a cancer for which there are very few treatment options and of being told of the poor prognosis often while feeling well. They also highlighted difficulty accessing experts in this condition. There is a lack of effective treatment options. Also, chemotherapy may or may not extend life at the expense of debilitating side effects, which may have a significant effect on quality of life. The committee concluded that there is an urgent unmet need for people with advanced cholangiocarcinoma with FGFR2 fusion or rearrangement after systemic therapy. It agreed that people with this condition would welcome a disease-modifying treatment option like pemigatinib.\n\n## mFOLFOX+ASC and ASC alone are the most appropriate comparators\n\nThe company submission compared pemigatinib with mFOLFOX+ASC and ASC alone in people with advanced cholangiocarcinoma with FGFR2 fusion or rearrangement after systemic therapy. The ERG noted uncertainty in clinical guidelines and an absence of real-world prescribing data. It highlighted that clinical advice to the company suggested that capecitabine with oxaliplatin may be preferred to mFOLFOX for some people. It advised that it is likely that other chemotherapy agents are also given in routine NHS practice. The clinical experts advised that the relevant comparators currently used in routine clinical practice include mFOLFOX+ASC and ASC alone. The committee concluded that these are the most appropriate comparators for this appraisal.\n\n# Clinical-effectiveness evidence\n\n## The clinical evidence for pemigatinib is from a single-arm non-randomised study\n\nThe clinical evidence for pemigatinib came from FIGHT‑202. This was a phase\xa02, single-arm, non-randomised, open-label study in people with advanced or surgically unresectable cholangiocarcinoma that had not responded to previous therapy. Only cohort\xa0A of FIGHT‑202, which included people with FGFR2 fusion or rearrangement, was relevant to this appraisal. The clinical evidence from the latest data cut is considered confidential by the company so cannot be reported here. In an earlier data cut (March\xa02019), the median progression-free survival was 6.9\xa0months and the median overall survival was 21.1\xa0months. The committee noted that, because FIGHT‑202 was a single-arm study, it did not provide evidence of the relative effectiveness of pemigatinib compared with current treatment options. But it acknowledged that doing studies for advanced chemorefractory cholangiocarcinoma is difficult because of the rarity of this cancer. It concluded that, in the absence of direct evidence, indirect comparisons were needed to assess the relative effectiveness of pemigatinib compared with the comparators.\n\n## The population in cohort\xa0A of FIGHT‑202 is appropriate for decision making\n\nThe ERG highlighted that cohort\xa0A of FIGHT‑202 was a subset of the population in the marketing authorisation. It highlighted that 98% of people in cohort\xa0A had intrahepatic disease. However, the marketing authorisation and the NICE scope include people with non-intrahepatic disease. The company stated that there is no biological reason that pemigatinib would not provide benefit to people with non-intrahepatic cholangiocarcinoma with FGFR2 fusion or rearrangement. The clinical experts advised that about 40% of people with advanced cholangiocarcinoma have intrahepatic disease. However, they explained that, in advanced cancer, it is difficult to differentiate intrahepatic disease from other subtypes. They advised that FGFR2 fusion or rearrangement can be present in non-intrahepatic disease but it is uncommon. To be eligible for pemigatinib, people will be identified by the presence of an FGFR2 fusion or rearrangement and not by the disease subtype. The committee concluded that the population in cohort\xa0A of FIGHT‑202 was appropriate for decision making.\n\n# Comparative evidence\n\n## The comparative evidence from ABC‑06 is appropriate for decision making but has limitations\n\nNo studies directly compared pemigatinib with treatments currently used in the NHS. The main comparative evidence was from ABC‑06. This was a phase\xa03, randomised, open-label study of mFOLFOX+ASC or ASC alone for people with locally advanced or metastatic biliary tract cancers previously treated with gemcitabine plus cisplatin chemotherapy. The committee noted that ABC‑06 was done in a different population to FIGHT‑202 and did not report FGFR2 mutation status in either treatment group. It understood that FGFR2 mutation status appears to be an important prognostic indicator, and that not knowing the FGFR2 mutation status in the ABC‑06 population was a significant limitation. However, at the second committee meeting, the company described new evidence suggesting that the FGFR2 mutation is not a significant predictor of overall survival. So, the committee considered that the prognostic value of FGFR2 mutation status is uncertain. The clinical experts explained that, because of the rarity of this cancer it is difficult to do comparative studies in the relevant subpopulation. The committee acknowledged that because of the rarity of the cancer, the data on the comparators from ABC‑06 were the best available evidence. Despite the limitations, it concluded that the comparative efficacy and safety data from ABC‑06 were the most appropriate evidence for decision making.\n\n## Pemigatinib is likely to be more effective than the comparators\n\nIn the absence of direct comparative evidence, the estimate of the relative treatment effect of pemigatinib compared with mFOLFOX+ASC and ASC alone was based on an unanchored matching adjusted indirect comparison of patient-level data from FIGHT‑202 and data from ABC‑06. The weightings were derived using a propensity score logistic regression model adjusted for selected prognostic factors. The weighted hazard ratios for overall survival and progression-free survival are considered confidential by the company and exact results cannot be reported here. In general, the results were more favourable for pemigatinib. The hazard ratio for overall survival was lower for pemigatinib compared with mFOLFOX+ASC and ASC alone. The hazard ratio for progression-free survival was also lower for pemigatinib compared with mFOLFOX+ASC. Progression-free survival data were not available for the ASC-alone arm from ABC‑06. So, the company assumed that the progression-free survival hazard ratio for pemigatinib compared with ASC alone was the same as the progression-free survival hazard ratio for pemigatinib compared with mFOLFOX+ASC. The ERG advised that the estimate of comparative treatment effect was highly uncertain and likely to be biased because the matching adjusted indirect comparison was done between mismatched study populations (see section\xa03.5). The committee noted the lack of direct comparative evidence (see section\xa03.3) and the limitations of using a matching adjusted indirect comparison to compare the efficacy of pemigatinib with the comparators. However, it recognised the rarity of the cancer and limitations in the available evidence for the comparators. It concluded that the matching adjusted indirect comparison suggests pemigatinib was more effective than the comparators, but that this was uncertain.\n\n## Comparative safety evidence is likely to have little effect on the cost-effectiveness estimates\n\nThe company did not do a matching adjusted indirect comparison for the safety of pemigatinib compared with the comparators. Instead, it used unadjusted adverse-event rates for pemigatinib from FIGHT‑202 and for mFOLFOX+ASC and ASC alone from ABC‑06. The ERG advised that no conclusions could be drawn about the safety of pemigatinib, relative to mFOLFOX+ASC and ASC alone, in the specified population, without comparative safety evidence. It noted that there was little value in doing a matching adjusted indirect comparison with poor quality evidence. During technical engagement, the company provided additional analyses that varied the modelled adverse events rates for the comparator to extreme values. These showed that the cost-effectiveness estimates were not sensitive to comparative safety data. The committee concluded that there was a lack of comparative safety evidence for pemigatinib and its comparators, but that this was unlikely to have much effect on the cost-effectiveness estimates.\n\n# Economic model\n\n## The company's economic model is appropriate for decision making\n\nThe company's partitioned survival model used parametric survival models to predict outcomes including time-on-treatment, progression-free survival and overall survival. The model included people in both the progression-free and post-progression health states, either on or off treatment. It used a life-time horizon with a cycle length of 1\xa0week. An annual discount rate of 3.5% was applied to costs and outcomes. The committee concluded the company's economic model was appropriate for decision making.\n\n# Survival analysis\n\n## Independently fitted models are appropriate\n\nIn the company's base-case analysis, long-term survival with pemigatinib was estimated by fitting parametric survival models to unadjusted overall-survival data from cohort\xa0A of FIGHT‑202. Long-term survival for the comparators was estimated by applying the inverse of the relative treatment effect from the matching adjusted indirect comparison (see section\xa03.6). The company preferred the log-logistic model to extrapolate overall survival from FIGHT‑202 and the log-logistic model to extrapolate overall survival from both arms of ABC‑06 for its base case. The committee considered that applying the hazard ratio to the treatment arm to generate parametric curves for comparator survival may be inappropriate. It noted that applying the hazard ratios from the indirect comparison requires the assumption of proportional hazards. The committee also noted that the company's selected log-logistic parametric curves were not proportional-hazards models. In response to the appraisal consultation document, the company provided log-cumulative hazard plots for overall survival with pemigatinib derived from the matching adjusted indirect comparison. These suggested that the proportional-hazards assumption was reasonable. The company also provided new scenarios in which FIGHT‑202 and ABC‑06 data were extrapolated independently using the April\xa02020 data cut, but it did not agree that independent models provide more robust or clinically plausible outcomes. However, the committee concluded that it was more appropriate to fit independent curves to each arm instead of applying the assumption of proportional hazards to non-proportional hazard models.\n\n## The log-logistic parametric curve is the most plausible\n\nAt the first appraisal committee meeting, the committee stated that there was a lack of clear justification for the selected parametric curve. It agreed that it would like to have seen clearer clinical expectations of survival in the treatment and comparator arms over time. In response to the appraisal consultation document, the company's clinical experts suggested a probability of overall survival at 5\xa0years of about 0.1% for people having mFOLFOX+ASC and of close to 0% for those having ASC alone. The company's clinical experts struggled to choose the most plausible curve for the pemigatinib survival extrapolation. After appraisal consultation, the clinical experts predicted survival at 5\xa0years of between 10% and 13% for people who have pemigatinib, based on evidence from the maximum follow up of 3\xa0years from FIGHT‑202. The committee noted that a recent publication of data from ABC‑06 may be informative. The company submitted this after consultation but it did not include additional follow-up data. The company also provided external data from ClarlDHy, a phase\xa03 randomised study, to validate the estimated survival for the comparator groups. When adjusted for crossover, the ClarlDHy placebo arm was consistent with outcomes from ABC‑06. The committee noted that ClarlDHy was for a different molecular population, the iDH1 mutation, and that similarities between the iDH1 and FGFR2 mutation populations did not necessarily equate to similar survival characteristics in people with FGFR2 mutations. The company preferred the log-logistic curve to extrapolate overall survival with pemigatinib because the company's clinical experts agreed that a declining hazard function over time was plausible, it was a good visual and statistical fit, and it was clinically plausible. The company also explored the generalised gamma curve in scenario analysis, which the committee agreed also predicted a declining hazard function and was clinically plausible. The committee noted that the generalised gamma curve predicted a lower 5‑year survival compared with the log-logistic curve for the extrapolated FIGHT‑202 data and both arms of ABC‑06. It considered that the log-logistic model was a statistically better fit than the generalised gamma model. Also, the 5‑year survival predicted by the log-logistic curve was within the clinical expert's estimated range. The committee considered that both the log-logistic and generalised gamma curves could be reasonable, but concluded that it would base its decision making on the log-logistic curve.\n\n# Additional costs\n\n## NHS England's genetic testing costs are included in the cost-effectiveness analysis\n\nAt the first appraisal committee meeting, the clinical experts advised that FGFR2 testing is not done as part of routine clinical practice in the UK. The committee noted that the 2020/21 National Genomic Test Directory does not include FGFR2 mutation testing for people with cholangiocarcinoma. The Cancer Drugs Fund clinical lead advised that there is already a multitarget panel test for people with cholangiocarcinoma to assess eligibility for other treatments. The prevalence of FGFR2 fusion or rearrangement is about 10% across all types of cholangiocarcinoma. So, adding FGFR2 as a target would incur an additional cost of £34, which would be applicable if pemigatinib is recommended for routine use in NHS practice. This gives a preferred cost of £340 for each additional person identified who is FGFR2-positive. The committee concluded that NHS England's genetic testing costs and the prevalence of FGFR2 fusion or rearrangement should have been included in the cost-effectiveness analysis. After consultation, the company included the costs of FGFR2 genetic testing in its base-case analysis.\n\n## Costs of optical coherence tomography are included in the cost-effectiveness analysis\n\nPemigatinib treatment can sometimes cause retinal pigment epithelial detachment. At the first appraisal committee meeting, the Cancer Drugs Fund clinical lead advised that ophthalmological examination using optical coherence tomography would be needed before and after starting treatment with pemigatinib in the NHS. The company confirmed that this is detailed in the summary of product characteristics. The committee concluded that the costs of optical coherence tomography should be included in the economic analysis. After consultation, the company included the cost of optical coherence tomography in its analysis.\n\n# End of life criteria\n\n## Pemigatinib is considered to be a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. For the short life-expectancy criterion, the company's base-case model estimated a mean undiscounted life expectancy of 8.0\xa0months for mFOLFOX+ASC and 7.3\xa0months for ASC alone. For the life-extension criterion, the company's base-case model estimated an undiscounted mean incremental life expectancy with pemigatinib of 25.6\xa0months compared with mFOLFOX+ASC and 26.4\xa0months compared with ASC alone. The ERG advised that these estimates were highly uncertain given the uncertainty in the results from the matching adjusted indirect comparison and the approach used to estimate health outcomes in the company's economic model. The clinical experts confirmed that people with relapsed or refractory cholangiocarcinoma with FGFR2 fusion or rearrangement have a life expectancy of between 4.7\xa0and\xa010\xa0months with current treatment. The committee was satisfied that pemigatinib meets the short life-expectancy criterion with current care. It acknowledged that the extension-to-life criterion with pemigatinib was less certain because of limitations in the survival analysis (see sections\xa03.9 and\xa03.10). However, it considered that the risk of the extension-to-life criterion not being met was relatively small, given that the estimates were substantially greater than 3\xa0months. The committee concluded that pemigatinib could be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness estimates\n\n## The most plausible incremental cost-effectiveness ratios are below £50,000 per quality-adjusted life year gained\n\nNICE's guide to the methods of technology appraisal highlights that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratios (ICERs). It states that the committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically about the matching adjusted indirect comparison (see section\xa03.6). But it acknowledged that the company had identified all the available data to validate the survival estimates, given the rarity of the cancer. For a life-extending treatment at the end of life, the upper limit of the range usually considered to represent a cost-effective use of NHS resources is £50,000 per quality-adjusted life year (QALY) gained. The committee noted that the company's new base-case ICERs for pemigatinib, including an updated patient access scheme, were £42,076 per QALY gained compared with mFOLFOX+ASC, and £45,029 per QALY gained compared with ASC alone. The committee's preferred assumptions for decision making at the second appraisal committee meeting were to use:\n\nindependently fitted models (see section\xa03.9)\n\nthe log-logistic curve to extrapolate long-term overall survival with pemigatinib (see section\xa03.10).Using these preferred assumptions, the ICER was between £45,051 and £45,808 per QALY gained compared with mFOLFOX+ASC, and between £44,354 and £45,010 per QALY gained compared with ASC alone. The ICER value depended on whether the FIGHT‑202 data were adjusted for the mFOLFOX+ASC or ASC‑alone data from ABC‑06. Other scenarios, including using the generalised gamma curve to extrapolate long-term survival with pemigatinib, resulted in higher ICERs. The committee considered the uncertainty in the clinical evidence but noted the rarity of the cancer being appraised. It concluded that the cost-effectiveness estimates for pemigatinib suggest it is an acceptable use of NHS resources for a life-extending treatment at the end of life. So pemigatinib was recommended for routine use in the NHS.\n\n# Innovation\n\n## Pemigatinib is an innovative treatment for advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement\n\nThe company considered pemigatinib to be innovative because there are no other licensed or targeted disease-modifying treatment options for advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement. The patient and clinical experts emphasised the importance of improving debilitating symptoms and health-related quality of life, and of extending life, and the potential benefit from pemigatinib in achieving this. The committee noted the potential benefits of pemigatinib for people with advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement. But it concluded that it had not been presented with evidence of any additional benefits that had not been captured in the QALY calculations.\n\n# Equalities considerations\n\n## There are no equalities issues relevant to the recommendation\n\nNo equalities issues were raised during scoping and technical engagement. No potential equality issues were identified in the company submission. The committee concluded that there were no equalities issues relevant to the recommendation."}
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https://www.nice.org.uk/guidance/ta722
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Evidence-based recommendations on pemigatinib (Pemaryze) for relapsed or refractory advanced cholangiocarcinoma with FGFR2 fusion or rearrangement in adults.
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54feeb61e8763b5affb4a1488143bb5c89ae741f
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nice
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Continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome
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Continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome
Evidence-based recommendations on continuous positive airway pressure for treating obstructive sleep apnoea/hypopnoea syndrome in adults.
# Guidance
Continuous positive airway pressure (CPAP) is recommended as a treatment option for adults with moderate or severe symptomatic obstructive sleep apnoea/hypopnoea syndrome (OSAHS).
This recommendation has been updated and replaced by recommendation 1.5.2 on continuous positive airway pressure for mild OSAHS in the NICE guideline on obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in over 16s.
The diagnosis and treatment of OSAHS, and the monitoring of the response, should be carried out by a specialist service with appropriately trained medical and support staff.# Clinical need and practice
Apnoea is defined as a temporary absence or cessation of breathing. OSAHS is a condition in which a person experiences repeated episodes of apnoea because of a narrowing or closure of the pharyngeal airway during sleep. This is caused by a decrease in the tone of the muscles supporting the airway during sleep. Complete closure (obstruction) stops airflow (apnoea) whereas partial obstruction decreases airflow (hypopnoea). OSAHS results in episodes of brief awakening from sleep to restore normal breathing.
Moderate to severe OSAHS can be diagnosed from patient history and a sleep study using oximetry or other monitoring devices carried out in the person's home. In some cases, further studies that monitor additional physiological variables in a sleep laboratory or at home may be required, especially when alternative diagnoses are being considered. The severity of OSAHS is usually assessed on the basis of both severity of symptoms (particularly the degree of sleepiness) and the sleep study, by using either the apnoea/hypopnoea index (AHI) or the oxygen desaturation index. OSAHS is considered mild when the AHI is 5 to 14 in a sleep study, moderate when the AHI is 15 to 30, and severe when the AHI is over 30. In addition to the AHI, the severity of symptoms is also important.
The symptoms of OSAHS include impaired alertness, cognitive impairment, excessive daytime sleepiness, snoring, nocturia, morning headaches and sexual dysfunction. The sleep quality of partners may also be affected. Excessive daytime sleepiness can adversely affect cognitive function, mood and quality of life. OSAHS is associated with high blood pressure, which increases the risk of cardiovascular disease and stroke. OSAHS has also been associated with an increased risk of road traffic accidents.
Major risk factors for developing OSAHS are increasing age, obesity and being male. OSAHS is also associated with certain specific craniofacial characteristics (such as retrognathia), enlarged tonsils and enlarged tongue. Use of alcohol or sedatives can also increase the risk or severity of the condition. OSAHS has been reported to affect up to 4% of middle-aged men and 2% of middle-aged women in the UK. It is estimated that 1% of men in the UK may have severe OSAHS.
Treatments aim to reduce daytime sleepiness by reducing the number of episodes of apnoea/hypopnoea experienced during sleep. The alternatives to CPAP are lifestyle management, dental devices and surgery. Lifestyle management involves helping people to lose weight, stop smoking and/or decrease alcohol consumption. Dental devices are designed to keep the upper airway open during sleep. The efficacy of dental devices has been established in clinical trials, but these devices are traditionally viewed as a treatment option only for mild and moderate OSAHS. Surgery involves resection of the uvula and redundant retrolingual soft tissue. However, there is a lack of evidence of clinical effectiveness, and surgery is not routinely used in clinical practice.# The technology
A CPAP device consists of a unit that generates airflow, which is directed to the airway via a mask. Positive pressure is generated by the airflow, which prevents upper airway collapse. For CPAP treatment to be effective the person must always wear their device when they go to sleep.
Reasons for not adhering to CPAP treatment include poor mask fit, pressure intolerance and, more commonly, upper airway symptoms such as nasal dryness, nasal bleeding and throat irritation. Humidification devices are now commonly used in conjunction with CPAP devices in order to reduce these side effects. Masks should be replaced at least annually, and long-term follow-up of patients is critical to ensure adherence.
There are two types of CPAP devices. Fixed CPAP devices deliver air at constant pressure throughout the night, and the person will continue to receive this pressure until a further titration study is performed to determine whether the set pressure is still appropriate. Auto-titrating CPAP devices continually adjust the pressure delivered throughout the night, with the aim of improving comfort and thus adherence.
CPAP devices available in the UK are the SleepStyle 230 and 600 series (Fisher & Paykel Healthcare), the S8 series (ResMed (UK)), the RPM BiLevel 9055, RPM 9054, AutoAdjust and Horizon range (Sunrise Medical – DeVilbiss), the GoodKnight 420 series (Tyco Healthcare), the Breas range (Vital Signs) and the REMstar series (Respironics UK).
The price of CPAP devices ranges from £250 to £550 (pricing information obtained from manufacturers' submissions or NCCHTA briefing notes). Costs may vary in different settings because of negotiated procurement discounts. The lifespan of a CPAP device has been reported to be approximately 7 years. The lifespan of a mask is 6 to 12 months.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
The assessment report included 48 randomised controlled trials (RCTs) that compared the efficacy of CPAP with placebo or usual care or dental devices. Submissions were obtained from three manufacturers. Fisher & Paykel Healthcare included one RCT that compared CPAP with placebo. This study was excluded by the Assessment Group on the grounds of study quality. Respironics UK did not carry out a review of clinical effectiveness, and ResMed (UK) presented the findings of a Cochrane systematic review carried out in 2006.
The Assessment Group identified 23 RCTS that compared CPAP with placebo or usual care using the Epworth Sleepiness Scale (ESS). A meta-analysis of these studies identified a statistically significantly greater reduction in daytime sleepiness with CPAP compared with placebo or usual care (weighted mean difference in ESS score −2.7; 95% confidence interval −3.5 to −2.0).
The Assessment Group undertook a series of meta-analyses that compared the effect of CPAP on levels of daytime sleepiness in different populations. This showed a statistically significantly greater reduction in daytime sleepiness with CPAP compared with placebo for moderate and severe categories of OSAHS. For mild OSAHS (meta-analysis of 3 studies; AHI=5 to 14 episodes per hour) a weighted mean difference in ESS score of −1.5 (95% CI −3.4 to 0.4) was found. For moderate OSAHS (meta-analysis of 7 studies; AHI=15 to 30 episodes per hour) a weighted mean difference in ESS score of −2.0 (95% CI −3.0 to −1.1) was found. For severe OSAHS (meta-analysis of 13 studies; AHI=over 30 episodes per hour) a weighted mean difference in ESS score of −3.4 (95% CI −4.6 to −2.3) was found.
The Cochrane systematic review submitted by ResMed (UK) included 36 RCTs. A meta-analysis of the parallel-group studies found a statistically significantly greater reduction in daytime sleepiness with CPAP compared with placebo or usual care (weighted mean difference in ESS score −3.8; 95% CI −4.6 to −3.1). A meta-analysis of the crossover studies showed a statistically significantly greater reduction in daytime sleepiness with CPAP compared with placebo or usual care (weighted mean difference in ESS score −1.9; 95% CI −2.6 to −1.3). The RCT included by Fisher & Paykel Healthcare compared CPAP with placebo, and reported improvements in sleepiness (measured by the ESS, a subjective measure) and in wakefulness (measured by the 'modified maintenance of wakefulness' test, an objective measure) with CPAP.
The Assessment Group identified six RCTs that compared the effects on daytime sleepiness (ESS score) of CPAP and dental devices. A meta-analysis of these studies did not identify a statistically significant difference between the two treatments (weighted mean difference in ESS score −0.9; 95% CI −2.1 to 0.4). The Assessment Group also found that removing individual trials from the analysis, use of a fixed-effect model or conducting subgroup analysis by study design (parallel group or crossover) did not reveal any statistically significant differences in daytime sleepiness between CPAP and dental devices.
A meta-analysis from the Cochrane systematic review identified statistically significant improvements in the AHI and in minimum oxygen saturation during sleep in favour of CPAP compared with dental devices.
The Assessment Group identified six RCTs that measured daytime mean arterial blood pressure. A meta-analysis of these RCTs found that CPAP was associated with a reduction in arterial blood pressure compared with placebo or usual care (mean difference −2.1 mmHg; 95% CI −4.3 to 0.0 mmHg). However, when these RCTs were analysed by severity of OSAHS classified by baseline ESS score, a statistically significant treatment effect in favour of CPAP was identified only for severe OSAHS (mean difference −4.2 mmHg; 95% CI −6.4 to −2.0 mmHg), but not for mild (mean difference 1.1 mmHg; 95% CI −2.9 to 5.1 mmHg) or moderate (mean difference −3.4 mmHg; 95% CI −7.9 to 1.2 mmHg) OSAHS.
The Assessment Group identified six RCTs that evaluated the effect of CPAP treatment on driving ability, using the Steerclear computerised driving simulator program. A meta-analysis of the four studies that reported the number of obstacles hit did not identify a statistically significant difference between CPAP treatment and placebo (weighted mean difference −5.74; 95% CI −14.75 to 3.27). A meta-analysis of the two RCTs that reported percentage of obstacles hit did not show a statistically significant difference in favour of CPAP (weighted mean difference 0.00; 95% CI −3.35 to 3.35).
The Assessment Group identified one trial that used a computerised simulated driving program that assessed night-time driving ability. CPAP resulted in statistically significant improvements in standard deviation of position on the road (p = 0.03), minutes spent driving accurately (p = 0.02) and deterioration in driving ability (p = 0.007) compared with placebo.
The Assessment Group identified two studies that estimated the impact of CPAP on the rate of road traffic accidents. The first study (a meta-analysis of eight before-and-after studies) estimated that use of CPAP reduced the odds of a road traffic accident by 85% (odds ratio 0.15). The second study showed reduced odds of a road traffic accident with CPAP treatment (odds ratio 0.33). A meta-analysis of these two studies identified an 83% reduction in road traffic accidents (odds ratio 0.17). The ResMed (UK) submission reported the findings of a 3-year case–control study that estimated the annual number of road traffic accidents among 640 people with OSAHS as 0.18 per year before and as 0.06 per year after initiation of CPAP therapy.
The Assessment Group found that there were not enough studies for meta-analyses to be performed for most of the quality-of-life outcome measures reported. Six studies were identified that used the SF-36 instrument for measuring health-related quality of life. Meta-analyses of these studies did not find a statistically significant difference between CPAP and placebo or usual care for any of the subscales, but there was a trend towards an improvement in favour of CPAP in the subscales for vitality and physical role. Individual studies showed statistically significant improvements in the subscales for bodily pain, emotional role, mental health, general health, physical function, social function and vitality. Four studies were identified that used the Functional Outcomes of Sleep Questionnaire. A statistically significant benefit in favour of CPAP was identified for the activity level and social outcome subscales, but not for the general productivity, intimacy and sexual activity or vigilance subscales, or total scores. Only two studies reported the Sleep Apnoea Quality of Life Index total score: one reported a significant benefit with CPAP compared with placebo, but in the other study there was no statistically significant difference.
There was no statistically significant difference between CPAP and dental devices when the results from two studies reporting scores on the Functional Outcomes of Sleep Questionnaire and two studies reporting the Sleep Apnoea Quality of Life Index were pooled. Three studies used the SF-36 instrument to compare CPAP with dental devices, but the findings were not consistent. One of these studies reported a benefit with CPAP compared with dental devices in both the physical and mental component summary scores, one study reported no difference in the total SF-36 score, and the remaining study identified a statistically significant benefit in favour of CPAP only for the bodily pain subscale.
The ResMed (UK) submission identified seven studies that reported short- and longer-term rates of adherence with CPAP therapy. The mean rate of adherence across the studies was 71% (range 64–83%) up to 12 months and 79% (range 68–90%) at 12 months or more. The Assessment Group reported on one of these studies, which was an observational study carried out over 6 years in a Scottish cohort. The adherence rates were 84% at 1 year, 74% at 2 years, 73% at 3 years and 68% after 4 years.
Statements from the patient experts and clinical specialists asserted that there are enough trained medical staff in secondary care to investigate the expected numbers of patients with likely OSAHS, but further training of support staff for CPAP provision will be necessary over the coming years. There are currently insufficient resources and training in primary care for the continued supervision of patients being treated with CPAP for OSAHS.
# Cost effectiveness
Four published economic evaluations were identified by the Assessment Group, all of which compared CPAP with a 'do nothing' alternative. The resulting incremental cost-effectiveness ratios (ICERs) were: (1) US $3354 (approximately £1688; currency conversions were calculated in August 2007) per quality-adjusted life year (QALY) gained from a third-party payer perspective and US $314 (£158) per QALY gained from a societal perspective; (2) €7861 (£5348) per QALY gained over a 5-year time horizon and €4938 (£3359) per QALY gained for a lifetime time horizon; (3) £8300 per QALY gained at 1 year and £5200 per QALY gained at 2 years; (4) Can $9809 (£4654) per QALY gained for the high‑cost estimate and Can $3523 (£1672) per QALY gained for the low-cost estimate.
Fisher & Paykel Healthcare and Respironics UK did not submit its own cost-effectiveness analyses. The Assessment Group therefore evaluated only the economic model submitted by ResMed (UK).
ResMed (UK) submitted an economic model comparing fixed and auto-titrating CPAP devices with a 'do nothing' alternative. The model included people with severe OSAHS with the following health states: event free, cardiovascular event, stroke and road traffic accident. People remained in one of the four health states for 1 year before moving to another state. People who had a cardiovascular event or road traffic accident in 1 year could have a stroke, cardiovascular event or road traffic accident in a later year. People who had experienced a stroke were considered unable to drive and therefore could not experience a subsequent road traffic accident, but they could experience a subsequent stroke or cardiovascular event. There was no limit to the total number of events each person could undergo in subsequent years. No complications or symptoms were included, and the model had a 14-year time horizon and was from a UK NHS perspective. Utility estimates were obtained from a published study reporting EQ-5D data. The results of the ResMed (UK) model showed that both fixed and auto-titrating CPAP devices dominated 'non-treatment' after a minimum of 2 years of treatment (that is, CPAP was associated with more QALYs and lower costs than 'non-treatment').
The Assessment Group provided an economic model comparing CPAP with dental devices and with lifestyle management. The base-case model included people with moderate OSAHS and included the following health states: OSAHS, OSAHS post-coronary heart disease (CHD), OSAHS post-stroke, and death. People remained in one of the health states for 1 year, and could remain in the initial OSAHS state until death or until they experienced a road traffic accident, stroke or CHD event, which could result in disability. The OSAHS post-CHD and OSAHS post-stroke states incorporated the increased mortality and morbidity associated with having these events. People could remain in the post-stroke or post-CHD state until death. No complications or symptoms were included, and the model had a lifetime time horizon and was from a UK NHS perspective.
Health effects in the model included decreased utility associated with ESS score, cardiovascular events, stroke and road traffic accidents, and effects on mortality associated with cardiovascular events, stroke and road traffic accidents. The Assessment Group developed its own mapping algorithm to transform ESS data into utility scores. For this, the Assessment Group used three sets of individual patient data that measured ESS score and SF-36 and/or EQ-5D profile in the same people. A simple linear regression model was fitted to predict absolute utility scores from absolute ESS scores, controlling for baseline utility and ESS scores. This utility mapping was then applied to data on mean difference in ESS score between CPAP and placebo (23 studies) and between CPAP and dental devices (6 studies).
The base-case ICERs for men were £2000 per QALY gained for dental devices compared with lifestyle management, and £3899 per QALY gained for CPAP compared with dental devices. The ICERs for women were similar. The Assessment Group undertook a series of subgroup analyses based on baseline severity of OSAHS as measured by the ESS. This analysis excluded road traffic accidents and cardiovascular events. The resulting ICERs for CPAP compared with lifestyle management were £20,585 per QALY gained for mild OSAHS, £9391 per QALY gained for moderate OSAHS and £4413 per QALY gained for severe OSAHS. Dental devices were extendedly dominated by CPAP for moderate OSAHS, and there were no data for comparisons of dental devices with CPAP for mild or severe OSAHS.
Only two of the Assessment Group's subgroup and scenario analyses resulted in pronounced changes to the base-case ICERs. When the lifespan of the device was changed from 7 to 5 years and an auto-titrating device plus humidifier was used instead of a fixed-pressure device, the ICER was £16,362 per QALY gained. When cardiovascular events and road traffic accidents were excluded in the analysis for the total population (all severities of OHAHS), the ICER was approximately £8000 per QALY gained.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of CPAP, having considered evidence on the nature of the condition and the value placed on the benefits of CPAP by people with OSAHS, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
The Committee sought the opinion of the clinical specialists and patient experts on the impact of OSAHS on people's lives and on the experience of using CPAP devices. The Committee heard that OSAHS can be a debilitating condition that affects both the individual and their immediate family. It can also have a wider impact through the increased risk of road traffic accidents caused by people with untreated or undiagnosed OSAHS.
The Committee considered the alternative treatment options available for people with OSAHS, namely lifestyle advice, dental devices and surgery. The Committee heard that advice to lose weight is often not effective, partly because people with severe OSAHS lack the energy to engage in weight loss activities. The experts stated that dental devices can be uncomfortable and of limited effectiveness for most people, even those with mild OSAHS. The Committee also discussed the use of surgical procedures to correct craniofacial features associated with OSAHS, and understood that such forms of surgery were not usually considered to be viable treatment options because of lack of efficacy.
The Committee noted that the clinical effectiveness of CPAP was usually assessed in RCTs by measuring the ESS score (self-reported episodes of daytime sleep or dozing). The Committee heard from the clinical specialists that the ESS score does not cover all effects of OSAHS, and may underestimate the effectiveness of CPAP. However, the Committee was persuaded, on the basis of the RCT evidence and statements from the clinical specialists and patient experts that CPAP treatment is associated with considerable reductions in daytime sleepiness compared with placebo or lifestyle management. The Committee noted that most of the available RCT evidence did not identify a statistically significant reduction in daytime sleepiness for CPAP compared with dental devices. It heard from the clinical specialists that the reason for this could be that dental devices are not normally used for treating severe OSAHS, so such comparisons were likely to be weighted towards the less severe end of the condition, where generally the treatment effects are smaller. The Committee noted that the absolute effect of CPAP increased with increasing severity of OSAHS.
The Committee reviewed the evidence on the impact of CPAP on quality of life. The Committee noted that most of the available evidence did not identify a statistically significant difference in favour of CPAP. However, the Committee noted that studies that included dimensions specifically related to sleepiness found evidence of improvements in quality of life with CPAP therapy.
The Committee discussed the variable levels of adherence to CPAP therapy. It heard that adherence or under-use can be monitored and that it is routine practice for those under-using a CPAP device to be asked to return it, so that it can be used for another person.
The Committee reviewed the available evidence on the cost effectiveness of CPAP for the treatment of severe OSAHS, namely the analyses from one of the manufacturers (ResMed (UK)) and from the Assessment Group, and noted that the base-case ICERs in both analyses were below £5000 per QALY gained.
The Committee reviewed the results of the sensitivity analyses available. It understood that there was a lack of conclusive evidence for a beneficial effect of CPAP on blood pressure across all severity grades, and that the effect on cardiovascular events was inferred in the economic model via this effect of lowering of blood pressure. However, the Committee noted that excluding the effect of CPAP on cardiovascular events in the model did not lead to significant changes in the ICER.
The Committee noted that there was a lack of evidence on which to base the lifespan of the device, and that reducing the lifespan of the device from 7 to 5 years increased the ICER considerably in both economic models. However, the Committee was persuaded by the clinical specialists and patient experts that the assumed 7-year lifespan is plausible.
The Committee considered the regression mapping to predict utility values from ESS scores used in the Assessment Group model. The Committee was concerned that the utility values were not based on clinical trial evidence and also, given the reservations about the ESS, that these utility values were associated with some degree of uncertainty. However, the Committee agreed that in the absence of other plausible utility values, the approach taken by the Assessment Group was appropriate.
The Committee noted that the data on the likely beneficial effect of CPAP treatment on the rate of road traffic accidents came from observational studies and were not consistently supported by the RCT evidence on driving performance. Furthermore, it heard from the clinical specialists that people diagnosed with OSAHS but not yet successfully treated are not permitted to drive by the UK Driver and Vehicle Licensing Authority. Therefore, the Committee agreed that it was important also to take into account the sensitivity analyses that excluded road traffic accidents.
The Committee considered the findings of the subgroup analysis for different severity grades of OSAHS. This subgroup analysis was only available excluding cardiovascular events and road traffic accidents. The Committee noted that the ICERs for moderate and severe OSAHS were below £10,000 per QALY gained, even when road traffic accidents were excluded from the economic modelling. It therefore agreed that, for people with moderate or severe OSAHS, CPAP would be an appropriate use of NHS resources and should be recommended as a treatment option. The Committee further agreed that the diagnosis, treatment and monitoring of OSAHS should be carried out by specialists with experience in the management of sleep disorders.
The Committee noted that for people with mild OSAHS, the utility gains from using CPAP were lower than for those with moderate or severe OSAHS. The only analysis available for this subgroup excluded road traffic accidents and resulted in an ICER of £20,585 per QALY gained. The Committee heard from the clinical specialists that usually CPAP was considered not to be appropriate for people with mild symptomatic CPAP, because the inconvenience associated with use of the device would outweigh the benefits in reduction of OSAHS symptoms. Therefore the Committee concluded that other options, such as providing advice and support on lifestyle management, including helping people to lose weight, stop smoking and/or decrease alcohol consumption, should be considered first for this group. However, the Committee also heard that there may be people with mild severity grading who have considerable OSAHS symptoms that affect their quality of life and ability to go about their daily activities, and therefore could benefit from CPAP treatment. It agreed that, based on the ICER of £20,585 per QALY gained, CPAP should only be available as a treatment option for people with mild symptomatic OSAHS if lifestyle advice and other relevant treatment options have been unsuccessful or are considered inappropriate.
The Committee discussed the use of CPAP therapy for children and adolescents with OSAHS. The Committee heard that OSAHS is less common among children than in adults and that the clinical issues and aetiology in children are different from those encountered in adults. The Committee concluded that the recommendations for CPAP should apply only to adults with OSAHS.
The Committee discussed whether there are important differences between models and makes of CPAP devices, for example between fixed and auto-titrating devices or between those with and without a humidifier. The Committee heard from the clinical specialists and patient experts that the available CPAP devices are broadly similar, and that there is no robust evidence on patient preferences. The Committee therefore concluded that decisions on the make and type of CPAP device to be used should be made on the basis of the requirements of the individual.# Related NICE guidance
NICE interventional procedure guidance on radiofrequency ablation of the soft palate for snoring.
NICE interventional procedure guidance on soft-palate implants for obstructive sleep apnoea.
NICE interventional procedure guidance soft-palate implants for simple snoring.
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{'Guidance': 'Continuous positive airway pressure (CPAP) is recommended as a treatment option for adults with moderate or severe symptomatic obstructive sleep apnoea/hypopnoea syndrome (OSAHS).\n\nThis recommendation has been updated and replaced by recommendation 1.5.2 on continuous positive airway pressure for mild OSAHS in the NICE guideline on obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in over 16s. \n\nThe diagnosis and treatment of OSAHS, and the monitoring of the response, should be carried out by a specialist service with appropriately trained medical and support staff.', 'Clinical need and practice': "Apnoea is defined as a temporary absence or cessation of breathing. OSAHS is a condition in which a person experiences repeated episodes of apnoea because of a narrowing or closure of the pharyngeal airway during sleep. This is caused by a decrease in the tone of the muscles supporting the airway during sleep. Complete closure (obstruction) stops airflow (apnoea) whereas partial obstruction decreases airflow (hypopnoea). OSAHS results in episodes of brief awakening from sleep to restore normal breathing.\n\nModerate to severe OSAHS can be diagnosed from patient history and a sleep study using oximetry or other monitoring devices carried out in the person's home. In some cases, further studies that monitor additional physiological variables in a sleep laboratory or at home may be required, especially when alternative diagnoses are being considered. The severity of OSAHS is usually assessed on the basis of both severity of symptoms (particularly the degree of sleepiness) and the sleep study, by using either the apnoea/hypopnoea index (AHI) or the oxygen desaturation index. OSAHS is considered mild when the AHI is 5\xa0to\xa014 in a sleep study, moderate when the AHI is 15\xa0to\xa030, and severe when the AHI is over 30. In addition to the AHI, the severity of symptoms is also important.\n\nThe symptoms of OSAHS include impaired alertness, cognitive impairment, excessive daytime sleepiness, snoring, nocturia, morning headaches and sexual dysfunction. The sleep quality of partners may also be affected. Excessive daytime sleepiness can adversely affect cognitive function, mood and quality of life. OSAHS is associated with high blood pressure, which increases the risk of cardiovascular disease and stroke. OSAHS has also been associated with an increased risk of road traffic accidents.\n\nMajor risk factors for developing OSAHS are increasing age, obesity and being male. OSAHS is also associated with certain specific craniofacial characteristics (such as retrognathia), enlarged tonsils and enlarged tongue. Use of alcohol or sedatives can also increase the risk or severity of the condition. OSAHS has been reported to affect up to 4% of middle-aged men and 2% of middle-aged women in the UK. It is estimated that 1% of men in the UK may have severe OSAHS.\n\nTreatments aim to reduce daytime sleepiness by reducing the number of episodes of apnoea/hypopnoea experienced during sleep. The alternatives to CPAP are lifestyle management, dental devices and surgery. Lifestyle management involves helping people to lose weight, stop smoking and/or decrease alcohol consumption. Dental devices are designed to keep the upper airway open during sleep. The efficacy of dental devices has been established in clinical trials, but these devices are traditionally viewed as a treatment option only for mild and moderate OSAHS. Surgery involves resection of the uvula and redundant retrolingual soft tissue. However, there is a lack of evidence of clinical effectiveness, and surgery is not routinely used in clinical practice.", 'The technology ': "A CPAP device consists of a unit that generates airflow, which is directed to the airway via a mask. Positive pressure is generated by the airflow, which prevents upper airway collapse. For CPAP treatment to be effective the person must always wear their device when they go to sleep.\n\nReasons for not adhering to CPAP treatment include poor mask fit, pressure intolerance and, more commonly, upper airway symptoms such as nasal dryness, nasal bleeding and throat irritation. Humidification devices are now commonly used in conjunction with CPAP devices in order to reduce these side effects. Masks should be replaced at least annually, and long-term follow-up of patients is critical to ensure adherence.\n\nThere are two types of CPAP devices. Fixed CPAP devices deliver air at constant pressure throughout the night, and the person will continue to receive this pressure until a further titration study is performed to determine whether the set pressure is still appropriate. Auto-titrating CPAP devices continually adjust the pressure delivered throughout the night, with the aim of improving comfort and thus adherence.\n\nCPAP devices available in the UK are the SleepStyle 230 and 600 series (Fisher & Paykel Healthcare), the S8 series (ResMed (UK)), the RPM BiLevel 9055, RPM 9054, AutoAdjust and Horizon range (Sunrise Medical – DeVilbiss), the GoodKnight 420 series (Tyco Healthcare), the Breas range (Vital Signs) and the REMstar series (Respironics UK).\n\nThe price of CPAP devices ranges from £250 to £550 (pricing information obtained from manufacturers' submissions or NCCHTA briefing notes). Costs may vary in different settings because of negotiated procurement discounts. The lifespan of a CPAP device has been reported to be approximately 7\xa0years. The lifespan of a mask is 6\xa0to 12\xa0months.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe assessment report included 48\xa0randomised controlled trials (RCTs) that compared the efficacy of CPAP with placebo or usual care or dental devices. Submissions were obtained from three manufacturers. Fisher & Paykel Healthcare included one RCT that compared CPAP with placebo. This study was excluded by the Assessment Group on the grounds of study quality. Respironics UK did not carry out a review of clinical effectiveness, and ResMed (UK) presented the findings of a Cochrane systematic review carried out in 2006.\n\nThe Assessment Group identified 23\xa0RCTS that compared CPAP with placebo or usual care using the Epworth Sleepiness Scale (ESS). A meta-analysis of these studies identified a statistically significantly greater reduction in daytime sleepiness with CPAP compared with placebo or usual care (weighted mean difference in ESS score −2.7; 95% confidence interval [CI] −3.5 to −2.0).\n\nThe Assessment Group undertook a series of meta-analyses that compared the effect of CPAP on levels of daytime sleepiness in different populations. This showed a statistically significantly greater reduction in daytime sleepiness with CPAP compared with placebo for moderate and severe categories of OSAHS. For mild OSAHS (meta-analysis of 3\xa0studies; AHI=5 to 14\xa0episodes per hour) a weighted mean difference in ESS score of −1.5 (95% CI −3.4 to 0.4) was found. For moderate OSAHS (meta-analysis of 7 studies; AHI=15\xa0to 30\xa0episodes per hour) a weighted mean difference in ESS score of −2.0 (95% CI −3.0 to −1.1) was found. For severe OSAHS (meta-analysis of 13 studies; AHI=over 30\xa0episodes per hour) a weighted mean difference in ESS score of −3.4 (95% CI −4.6 to −2.3) was found.\n\nThe Cochrane systematic review submitted by ResMed (UK) included 36 RCTs. A meta-analysis of the parallel-group studies found a statistically significantly greater reduction in daytime sleepiness with CPAP compared with placebo or usual care (weighted mean difference in ESS score −3.8; 95% CI −4.6 to −3.1). A meta-analysis of the crossover studies showed a statistically significantly greater reduction in daytime sleepiness with CPAP compared with placebo or usual care (weighted mean difference in ESS score −1.9; 95% CI −2.6 to −1.3). The RCT included by Fisher & Paykel Healthcare compared CPAP with placebo, and reported improvements in sleepiness (measured by the ESS, a subjective measure) and in wakefulness (measured by the 'modified maintenance of wakefulness' test, an objective measure) with CPAP.\n\nThe Assessment Group identified six RCTs that compared the effects on daytime sleepiness (ESS score) of CPAP and dental devices. A meta-analysis of these studies did not identify a statistically significant difference between the two treatments (weighted mean difference in ESS score −0.9; 95% CI −2.1 to 0.4). The Assessment Group also found that removing individual trials from the analysis, use of a fixed-effect model or conducting subgroup analysis by study design (parallel group or crossover) did not reveal any statistically significant differences in daytime sleepiness between CPAP and dental devices.\n\nA meta-analysis from the Cochrane systematic review identified statistically significant improvements in the AHI and in minimum oxygen saturation during sleep in favour of CPAP compared with dental devices.\n\nThe Assessment Group identified six RCTs that measured daytime mean arterial blood pressure. A meta-analysis of these RCTs found that CPAP was associated with a reduction in arterial blood pressure compared with placebo or usual care (mean difference −2.1\xa0mmHg; 95% CI −4.3 to 0.0\xa0mmHg). However, when these RCTs were analysed by severity of OSAHS classified by baseline ESS score, a statistically significant treatment effect in favour of CPAP was identified only for severe OSAHS (mean difference −4.2\xa0mmHg; 95% CI −6.4 to −2.0\xa0mmHg), but not for mild (mean difference 1.1\xa0mmHg; 95% CI −2.9 to 5.1\xa0mmHg) or moderate (mean difference −3.4\xa0mmHg; 95% CI −7.9 to 1.2\xa0mmHg) OSAHS.\n\nThe Assessment Group identified six RCTs that evaluated the effect of CPAP treatment on driving ability, using the Steerclear computerised driving simulator program. A meta-analysis of the four studies that reported the number of obstacles hit did not identify a statistically significant difference between CPAP treatment and placebo (weighted mean difference −5.74; 95% CI −14.75 to 3.27). A meta-analysis of the two RCTs that reported percentage of obstacles hit did not show a statistically significant difference in favour of CPAP (weighted mean difference 0.00; 95% CI −3.35 to 3.35).\n\nThe Assessment Group identified one trial that used a computerised simulated driving program that assessed night-time driving ability. CPAP resulted in statistically significant improvements in standard deviation of position on the road (p\xa0=\xa00.03), minutes spent driving accurately (p\xa0=\xa00.02) and deterioration in driving ability (p\xa0=\xa00.007) compared with placebo.\n\nThe Assessment Group identified two studies that estimated the impact of CPAP on the rate of road traffic accidents. The first study (a meta-analysis of eight before-and-after studies) estimated that use of CPAP reduced the odds of a road traffic accident by 85% (odds ratio 0.15). The second study showed reduced odds of a road traffic accident with CPAP treatment (odds ratio 0.33). A meta-analysis of these two studies identified an 83% reduction in road traffic accidents (odds ratio 0.17). The ResMed (UK) submission reported the findings of a 3-year case–control study that estimated the annual number of road traffic accidents among 640 people with OSAHS as 0.18\xa0per year before and as 0.06\xa0per year after initiation of CPAP therapy.\n\nThe Assessment Group found that there were not enough studies for meta-analyses to be performed for most of the quality-of-life outcome measures reported. Six studies were identified that used the SF-36 instrument for measuring health-related quality of life. Meta-analyses of these studies did not find a statistically significant difference between CPAP and placebo or usual care for any of the subscales, but there was a trend towards an improvement in favour of CPAP in the subscales for vitality and physical role. Individual studies showed statistically significant improvements in the subscales for bodily pain, emotional role, mental health, general health, physical function, social function and vitality. Four studies were identified that used the Functional Outcomes of Sleep Questionnaire. A statistically significant benefit in favour of CPAP was identified for the activity level and social outcome subscales, but not for the general productivity, intimacy and sexual activity or vigilance subscales, or total scores. Only two studies reported the Sleep Apnoea Quality of Life Index total score: one reported a significant benefit with CPAP compared with placebo, but in the other study there was no statistically significant difference.\n\nThere was no statistically significant difference between CPAP and dental devices when the results from two studies reporting scores on the Functional Outcomes of Sleep Questionnaire and two studies reporting the Sleep Apnoea Quality of Life Index were pooled. Three studies used the SF-36 instrument to compare CPAP with dental devices, but the findings were not consistent. One of these studies reported a benefit with CPAP compared with dental devices in both the physical and mental component summary scores, one study reported no difference in the total SF-36 score, and the remaining study identified a statistically significant benefit in favour of CPAP only for the bodily pain subscale.\n\nThe ResMed (UK) submission identified seven studies that reported short- and longer-term rates of adherence with CPAP therapy. The mean rate of adherence across the studies was 71% (range 64–83%) up to 12\xa0months and 79% (range 68–90%) at 12\xa0months or more. The Assessment Group reported on one of these studies, which was an observational study carried out over 6\xa0years in a Scottish cohort. The adherence rates were 84% at 1\xa0year, 74% at 2\xa0years, 73% at 3\xa0years and 68% after 4\xa0years.\n\nStatements from the patient experts and clinical specialists asserted that there are enough trained medical staff in secondary care to investigate the expected numbers of patients with likely OSAHS, but further training of support staff for CPAP provision will be necessary over the coming years. There are currently insufficient resources and training in primary care for the continued supervision of patients being treated with CPAP for OSAHS.\n\n# Cost effectiveness\n\nFour published economic evaluations were identified by the Assessment Group, all of which compared CPAP with a 'do nothing' alternative. The resulting incremental cost-effectiveness ratios (ICERs) were: (1) US $3354 (approximately £1688; currency conversions were calculated in August 2007) per quality-adjusted life year (QALY) gained from a third-party payer perspective and US $314 (£158) per QALY gained from a societal perspective; (2) €7861 (£5348) per QALY gained over a 5-year time horizon and €4938 (£3359) per QALY gained for a lifetime time horizon; (3) £8300 per QALY gained at 1\xa0year and £5200 per QALY gained at 2\xa0years; (4) Can $9809 (£4654) per QALY gained for the high‑cost estimate and Can $3523 (£1672) per QALY gained for the low-cost estimate.\n\nFisher & Paykel Healthcare and Respironics UK did not submit its own cost-effectiveness analyses. The Assessment Group therefore evaluated only the economic model submitted by ResMed (UK).\n\nResMed (UK) submitted an economic model comparing fixed and auto-titrating CPAP devices with a 'do nothing' alternative. The model included people with severe OSAHS with the following health states: event free, cardiovascular event, stroke and road traffic accident. People remained in one of the four health states for 1\xa0year before moving to another state. People who had a cardiovascular event or road traffic accident in 1\xa0year could have a stroke, cardiovascular event or road traffic accident in a later year. People who had experienced a stroke were considered unable to drive and therefore could not experience a subsequent road traffic accident, but they could experience a subsequent stroke or cardiovascular event. There was no limit to the total number of events each person could undergo in subsequent years. No complications or symptoms were included, and the model had a 14-year time horizon and was from a UK NHS perspective. Utility estimates were obtained from a published study reporting EQ-5D data. The results of the ResMed (UK) model showed that both fixed and auto-titrating CPAP devices dominated 'non-treatment' after a minimum of 2\xa0years of treatment (that is, CPAP was associated with more QALYs and lower costs than 'non-treatment').\n\nThe Assessment Group provided an economic model comparing CPAP with dental devices and with lifestyle management. The base-case model included people with moderate OSAHS and included the following health states: OSAHS, OSAHS post-coronary heart disease (CHD), OSAHS post-stroke, and death. People remained in one of the health states for 1\xa0year, and could remain in the initial OSAHS state until death or until they experienced a road traffic accident, stroke or CHD event, which could result in disability. The OSAHS post-CHD and OSAHS post-stroke states incorporated the increased mortality and morbidity associated with having these events. People could remain in the post-stroke or post-CHD state until death. No complications or symptoms were included, and the model had a lifetime time horizon and was from a UK NHS perspective.\n\nHealth effects in the model included decreased utility associated with ESS score, cardiovascular events, stroke and road traffic accidents, and effects on mortality associated with cardiovascular events, stroke and road traffic accidents. The Assessment Group developed its own mapping algorithm to transform ESS data into utility scores. For this, the Assessment Group used three sets of individual patient data that measured ESS score and SF-36 and/or EQ-5D profile in the same people. A simple linear regression model was fitted to predict absolute utility scores from absolute ESS scores, controlling for baseline utility and ESS scores. This utility mapping was then applied to data on mean difference in ESS score between CPAP and placebo (23 studies) and between CPAP and dental devices (6 studies).\n\nThe base-case ICERs for men were £2000 per QALY gained for dental devices compared with lifestyle management, and £3899 per QALY gained for CPAP compared with dental devices. The ICERs for women were similar. The Assessment Group undertook a series of subgroup analyses based on baseline severity of OSAHS as measured by the ESS. This analysis excluded road traffic accidents and cardiovascular events. The resulting ICERs for CPAP compared with lifestyle management were £20,585 per QALY gained for mild OSAHS, £9391 per QALY gained for moderate OSAHS and £4413 per QALY gained for severe OSAHS. Dental devices were extendedly dominated by CPAP for moderate OSAHS, and there were no data for comparisons of dental devices with CPAP for mild or severe OSAHS.\n\nOnly two of the Assessment Group's subgroup and scenario analyses resulted in pronounced changes to the base-case ICERs. When the lifespan of the device was changed from 7 to 5\xa0years and an auto-titrating device plus humidifier was used instead of a fixed-pressure device, the ICER was £16,362 per QALY gained. When cardiovascular events and road traffic accidents were excluded in the analysis for the total population (all severities of OHAHS), the ICER was approximately £8000 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of CPAP, having considered evidence on the nature of the condition and the value placed on the benefits of CPAP by people with OSAHS, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee sought the opinion of the clinical specialists and patient experts on the impact of OSAHS on people's lives and on the experience of using CPAP devices. The Committee heard that OSAHS can be a debilitating condition that affects both the individual and their immediate family. It can also have a wider impact through the increased risk of road traffic accidents caused by people with untreated or undiagnosed OSAHS.\n\nThe Committee considered the alternative treatment options available for people with OSAHS, namely lifestyle advice, dental devices and surgery. The Committee heard that advice to lose weight is often not effective, partly because people with severe OSAHS lack the energy to engage in weight loss activities. The experts stated that dental devices can be uncomfortable and of limited effectiveness for most people, even those with mild OSAHS. The Committee also discussed the use of surgical procedures to correct craniofacial features associated with OSAHS, and understood that such forms of surgery were not usually considered to be viable treatment options because of lack of efficacy.\n\nThe Committee noted that the clinical effectiveness of CPAP was usually assessed in RCTs by measuring the ESS score (self-reported episodes of daytime sleep or dozing). The Committee heard from the clinical specialists that the ESS score does not cover all effects of OSAHS, and may underestimate the effectiveness of CPAP. However, the Committee was persuaded, on the basis of the RCT evidence and statements from the clinical specialists and patient experts that CPAP treatment is associated with considerable reductions in daytime sleepiness compared with placebo or lifestyle management. The Committee noted that most of the available RCT evidence did not identify a statistically significant reduction in daytime sleepiness for CPAP compared with dental devices. It heard from the clinical specialists that the reason for this could be that dental devices are not normally used for treating severe OSAHS, so such comparisons were likely to be weighted towards the less severe end of the condition, where generally the treatment effects are smaller. The Committee noted that the absolute effect of CPAP increased with increasing severity of OSAHS.\n\nThe Committee reviewed the evidence on the impact of CPAP on quality of life. The Committee noted that most of the available evidence did not identify a statistically significant difference in favour of CPAP. However, the Committee noted that studies that included dimensions specifically related to sleepiness found evidence of improvements in quality of life with CPAP therapy.\n\nThe Committee discussed the variable levels of adherence to CPAP therapy. It heard that adherence or under-use can be monitored and that it is routine practice for those under-using a CPAP device to be asked to return it, so that it can be used for another person.\n\nThe Committee reviewed the available evidence on the cost effectiveness of CPAP for the treatment of severe OSAHS, namely the analyses from one of the manufacturers (ResMed (UK)) and from the Assessment Group, and noted that the base-case ICERs in both analyses were below £5000 per QALY gained.\n\nThe Committee reviewed the results of the sensitivity analyses available. It understood that there was a lack of conclusive evidence for a beneficial effect of CPAP on blood pressure across all severity grades, and that the effect on cardiovascular events was inferred in the economic model via this effect of lowering of blood pressure. However, the Committee noted that excluding the effect of CPAP on cardiovascular events in the model did not lead to significant changes in the ICER.\n\nThe Committee noted that there was a lack of evidence on which to base the lifespan of the device, and that reducing the lifespan of the device from 7 to 5\xa0years increased the ICER considerably in both economic models. However, the Committee was persuaded by the clinical specialists and patient experts that the assumed 7-year lifespan is plausible.\n\nThe Committee considered the regression mapping to predict utility values from ESS scores used in the Assessment Group model. The Committee was concerned that the utility values were not based on clinical trial evidence and also, given the reservations about the ESS, that these utility values were associated with some degree of uncertainty. However, the Committee agreed that in the absence of other plausible utility values, the approach taken by the Assessment Group was appropriate.\n\nThe Committee noted that the data on the likely beneficial effect of CPAP treatment on the rate of road traffic accidents came from observational studies and were not consistently supported by the RCT evidence on driving performance. Furthermore, it heard from the clinical specialists that people diagnosed with OSAHS but not yet successfully treated are not permitted to drive by the UK Driver and Vehicle Licensing Authority. Therefore, the Committee agreed that it was important also to take into account the sensitivity analyses that excluded road traffic accidents.\n\nThe Committee considered the findings of the subgroup analysis for different severity grades of OSAHS. This subgroup analysis was only available excluding cardiovascular events and road traffic accidents. The Committee noted that the ICERs for moderate and severe OSAHS were below £10,000 per QALY gained, even when road traffic accidents were excluded from the economic modelling. It therefore agreed that, for people with moderate or severe OSAHS, CPAP would be an appropriate use of NHS resources and should be recommended as a treatment option. The Committee further agreed that the diagnosis, treatment and monitoring of OSAHS should be carried out by specialists with experience in the management of sleep disorders.\n\nThe Committee noted that for people with mild OSAHS, the utility gains from using CPAP were lower than for those with moderate or severe OSAHS. The only analysis available for this subgroup excluded road traffic accidents and resulted in an ICER of £20,585 per QALY gained. The Committee heard from the clinical specialists that usually CPAP was considered not to be appropriate for people with mild symptomatic CPAP, because the inconvenience associated with use of the device would outweigh the benefits in reduction of OSAHS symptoms. Therefore the Committee concluded that other options, such as providing advice and support on lifestyle management, including helping people to lose weight, stop smoking and/or decrease alcohol consumption, should be considered first for this group. However, the Committee also heard that there may be people with mild severity grading who have considerable OSAHS symptoms that affect their quality of life and ability to go about their daily activities, and therefore could benefit from CPAP treatment. It agreed that, based on the ICER of £20,585 per QALY gained, CPAP should only be available as a treatment option for people with mild symptomatic OSAHS if lifestyle advice and other relevant treatment options have been unsuccessful or are considered inappropriate.\n\nThe Committee discussed the use of CPAP therapy for children and adolescents with OSAHS. The Committee heard that OSAHS is less common among children than in adults and that the clinical issues and aetiology in children are different from those encountered in adults. The Committee concluded that the recommendations for CPAP should apply only to adults with OSAHS.\n\nThe Committee discussed whether there are important differences between models and makes of CPAP devices, for example between fixed and auto-titrating devices or between those with and without a humidifier. The Committee heard from the clinical specialists and patient experts that the available CPAP devices are broadly similar, and that there is no robust evidence on patient preferences. The Committee therefore concluded that decisions on the make and type of CPAP device to be used should be made on the basis of the requirements of the individual.", 'Related NICE guidance': 'NICE interventional procedure guidance on radiofrequency ablation of the soft palate for snoring.\n\nNICE interventional procedure guidance on soft-palate implants for obstructive sleep apnoea.\n\nNICE interventional procedure guidance soft-palate implants for simple snoring.'}
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https://www.nice.org.uk/guidance/ta139
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Evidence-based recommendations on continuous positive airway pressure for treating obstructive sleep apnoea/hypopnoea syndrome in adults.
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099920ca55fdaedd590bd16954fa9d1b58575758
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Obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in over 16s
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Obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in over 16s
This guideline covers the diagnosis and management of obstructive sleep apnoea/hypopnoea syndrome (OSAHS), obesity hypoventilation syndrome (OHS) and chronic obstructive pulmonary disease with OSAHS (COPD–OSAHS overlap syndrome) in people over 16. It aims to improve recognition, investigation and treatment of these related conditions.
# Obstructive sleep apnoea/hypopnoea syndrome
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Please note that the following guidance from the Driver and Vehicle Licensing Agency (DVLA) and the UK government is relevant to these recommendations:
DVLA guidance on assessing fitness to drive: a guide for medical professionals
DVLA guidance on excessive sleepiness and driving
UK government guidance on COVID-19: infection prevention and control.
Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a condition in which the upper airway is narrowed or closes during sleep when muscles relax, causing under breathing (hypopnoea) or stopping breathing (apnoea). The person wakes or lightens sleep to stop these episodes, which can lead to disrupted sleep and potentially excessive sleepiness.
# Initial assessment for OSAHS
## When to suspect OSAHS
Take a sleep history and assess people for OSAHS if they have 2 or more of the following features:
snoring
witnessed apnoeas
unrefreshing sleep
waking headaches
unexplained excessive sleepiness, tiredness or fatigue
nocturia (waking from sleep to urinate)
choking during sleep
sleep fragmentation or insomnia
cognitive dysfunction or memory impairment.
Be aware that there is a higher prevalence of OSAHS in people with any of the following conditions:
-besity or overweight
-besity or overweight in pregnancy
treatment-resistant hypertension
type 2 diabetes
cardiac arrythmia, particularly atrial fibrillation
stroke or transient ischaemic attack
chronic heart failure
moderate or severe asthma
polycystic ovary syndrome
Down's syndrome
non-arteritic anterior ischaemic optic neuropathy (sudden loss of vision in 1 eye due to decreased blood flow to the optic nerve)
hypothyroidism
acromegaly.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on when to suspect OSAHS .
Full details of the evidence and the committee's discussion are in evidence review A: when to suspect OSAHS, OHS and COPD–OSAHS overlap syndrome.
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## Assessment scales for suspected OSAHS
When assessing people with suspected OSAHS:
Use the Epworth Sleepiness Scale in the preliminary assessment of sleepiness.
Consider using the STOP-Bang Questionnaire as well as the Epworth Sleepiness Scale.
Do not use the Epworth Sleepiness Scale alone to determine if referral is needed, because not all people with OSAHS have excessive sleepiness.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment scales for suspected OSAHS .
Full details of the evidence and the committee's discussion are in evidence review B: assessment tools for people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.
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# Prioritising people for rapid assessment by a sleep service
See also recommendation 4.1.1 on providing information for people with suspected OSAHS who are being referred to a sleep service.
When referring people with suspected OSAHS to a sleep service, include the following information in the referral letter to facilitate rapid assessment:
results of the person's assessment scores
how sleepiness affects the person
comorbidities
-ccupational risk
-xygen saturation and blood gas values, if available.
Within the sleep service, prioritise people with suspected OSAHS for rapid assessment if any of the following apply:
they have a vocational driving job
they have a job for which vigilance is critical for safety
they have unstable cardiovascular disease, for example, poorly controlled arrhythmia, nocturnal angina or treatment-resistant hypertension
they are pregnant
they are undergoing preoperative assessment for major surgery
they have non-arteritic anterior ischaemic optic neuropathy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prioritising people for rapid assessment by a sleep service .
Full details of the evidence and the committee's discussion are in evidence review C: prioritisation for rapid assessment at a sleep centre of people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.
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# Diagnostic tests for OSAHS
See also section 4 on providing information for people who have been diagnosed with OSAHS.
Offer home respiratory polygraphy to people with suspected OSAHS.
If access to home respiratory polygraphy is limited, consider home oximetry for people with suspected OSAHS. Take into account that oximetry alone may be inaccurate for differentiating between OSAHS and other causes of hypoxaemia in people with heart failure or chronic lung diseases.
Consider respiratory polygraphy or polysomnography if oximetry results are negative but the person has significant symptoms.
Consider hospital respiratory polygraphy for people with suspected OSAHS if home respiratory polygraphy and home oximetry are impractical or additional monitoring is needed.
Consider polysomnography if respiratory polygraphy results are negative but symptoms continue.
Use the results of the sleep study to diagnose OSAHS and determine the severity of OSAHS (mild, moderate or severe).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnostic tests for OSAHS .
Full details of the evidence and the committee's discussion are in evidence review D: diagnostic tests for OSAHS, OHS and COPD–OSAHS overlap syndrome.
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# Lifestyle advice for all severities of OSAHS
Discuss appropriate lifestyle changes with all people with OSAHS. Provide support and information on losing weight, stopping smoking, reducing alcohol intake and improving sleep hygiene, tailored to the person's needs and in line with the NICE guidelines on:
stop smoking interventions and services
preventing excess weight gain
-besity: identification, assessment and management (in particular, the section on lifestyle interventions)
alcohol-use disorders: prevention (in particular, recommendations on screening, brief advice and extended brief interventions for adults).
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on lifestyle advice for all severities of OSAHS .
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# Treatments for mild OSAHS
See also section 4 on providing information for people starting treatment for OSAHS.
## Lifestyle advice alone for mild OSAHS
Explain to people with mild OSAHS who have no symptoms or with symptoms that do not affect usual daytime activities that:
treatment is not usually needed and
changes to lifestyle and sleep habits (see recommendation 1.4.1 on lifestyle advice) can help to prevent OSAHS from worsening.
## Continuous positive airway pressure for mild OSAHS
Recommendation 1.5.2 updates recommendation 1.2 in NICE's technology appraisal guidance on continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome.
For people with mild OSAHS who have symptoms that affect their quality of life and usual daytime activities, offer fixed-level continuous positive airway pressure (CPAP):
at the same time as lifestyle advice if they have any of the priority factors listed in recommendation 1.2.2 or
if lifestyle advice alone has been unsuccessful or is considered inappropriate.
For people with mild OSAHS having CPAP:
Offer telemonitoring with CPAP for up to 12 months.
Consider using telemonitoring beyond 12 months.
Consider auto‑CPAP as an alternative to fixed-level CPAP in people with mild OSAHS if:
high pressure is needed only for certain times during sleep or
they are unable to tolerate fixed-level CPAP or
telemonitoring cannot be used for technological reasons or
auto‑CPAP is available at the same or lower cost than fixed-level CPAP, and this price is guaranteed for an extended period of time.
Consider heated humidification for people with mild OSAHS having CPAP who have upper airway side effects, such as nasal and mouth dryness, and CPAP-induced rhinitis.
Be aware that CPAP is an aerosol-generating procedure and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. These may include setting up the device at home by video consultation or with precautions in hospital.For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.
## Mandibular advancement splints for mild OSAHS
If a person with mild OSAHS and symptoms that affect their usual daytime activities is unable to tolerate or declines to try CPAP, consider a customised or semi-customised mandibular advancement splint as an alternative to CPAP if they:
are aged 18 and over and
have optimal dental and periodontal health.
Be aware that semi-customised mandibular advancement splints may be inappropriate for people with:
active periodontal disease or untreated dental decay
few or no teeth
generalised tonic-clonic seizures.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatments for mild OSAHS .
Full details of the evidence and the committee's discussion are in:
evidence review E: CPAP devices for the treatment of mild OSAHS
evidence review F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome
evidence review G: oral devices.
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# Treatments for moderate and severe OSAHS
See also section 4 on providing information for people starting treatment for OSAHS.
## CPAP for moderate and severe OSAHS
CPAP is recommended as a treatment option for adults with moderate or severe symptomatic OSAHS in NICE's technology appraisal guidance on continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome.
Offer fixed-level CPAP, in addition to lifestyle advice, to people with moderate or severe OSAHS.
For people with moderate or severe OSAHS having CPAP:
Offer telemonitoring with CPAP for up to 12 months.
Consider using telemonitoring beyond 12 months.
Consider auto‑CPAP as an alternative to fixed-level CPAP in people with moderate or severe OSAHS if:
high pressure is needed only for certain times during sleep or
they are unable to tolerate fixed-level CPAP or
telemonitoring cannot be used for technological reasons or
auto‑CPAP is available at the same or lower cost than fixed-level CPAP, and this price is guaranteed for an extended period of time.
Consider heated humidification for people with moderate or severe OSAHS having CPAP who have upper airway side effects such as nasal and mouth dryness, and CPAP-induced rhinitis.
Be aware that CPAP is an aerosol-generating procedure and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. These may include setting up the device at home by video consultation or with precautions in hospital. For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.
## Mandibular advancement splints for moderate and severe OSAHS
If a person with moderate or severe OSAHS is unable to tolerate or declines to try CPAP, consider a customised or semi-customised mandibular advancement splint as an alternative to CPAP if they:
are aged 18 and over and
have optimal dental and periodontal health.
Be aware that semi-customised mandibular advancement splints may be inappropriate for people with:
active periodontal disease or untreated dental decay
few or no teeth
generalised tonic-clonic seizures.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatments for moderate and severe OSAHS .
Full details of the evidence and the committee's discussion are in evidence review F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome and evidence review G: oral devices.
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# Further treatment options for OSAHS
## Positional modifiers for OSAHS
Consider a positional modifier for people with mild or moderate positional OSAHS if other treatments are unsuitable or not tolerated.
Be aware that positional modifiers are unlikely to be effective in severe OSAHS.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on positional modifiers for OSAHS .
Full details of the evidence and the committee's discussion are in evidence review H: positional modifiers.
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## Surgery for OSAHS
Consider tonsillectomy for people with OSAHS who have large obstructive tonsils and a body mass index (BMI) of less than 35 kg/m2.
Consider referral for assessment for oropharyngeal surgery in people with severe OSAHS who have been unable to tolerate CPAP and a customised mandibular advancement splint despite medically supervised attempts.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgery for OSAHS .
Full details of the evidence and the committee's discussion are in evidence review J: surgery.
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# Managing rhinitis in people with OSAHS
Assess people with nasal congestion and OSAHS for underlying allergic or vasomotor rhinitis.
If rhinitis is diagnosed in people with OSAHS, offer initial treatment with:
topical nasal corticosteroids or antihistamines for allergic rhinitis or
topical nasal corticosteroids for vasomotor rhinitis.
For people with OSAHS and persistent rhinitis, consider referral to an ear, nose and throat specialist if:
symptoms do not improve with initial treatment or
anatomical obstruction is suspected.
Be aware that:
rhinitis can affect people's tolerance to CPAP but changing from a nasal to an orofacial mask and adding humidification can help (see recommendation 1.5.5 on heated humidification for mild OSAHS and recommendation 1.6.4 on heated humidification for moderate and severe OSAHS)
CPAP can worsen or cause rhinitis and nasal congestion.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing rhinitis in people with OSAHS .
Full details of the evidence and the committee's discussion are in evidence review K: rhinitis.
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# Follow-up and monitoring for people with OSAHS
Tailor follow-up to the person's overall treatment plan, which may include lifestyle changes and treating comorbidities. See the recommendations on tailoring healthcare services for each patient in the NICE guideline on patient experience in adult NHS services.
## Follow-up for people using CPAP
Offer face-to-face, video or phone consultations, including review of telemonitoring data (if available), to people with OSAHS having CPAP. This should include:
an initial consultation within 1 month and
subsequent follow-up according to the person's needs and until optimal control of symptoms and apnoea–hypopnoea index (AHI) or oxygen desaturation index (ODI) is achieved.
Once CPAP is optimised, consider annual follow-up for people with OSAHS.
Offer people with OSAHS having CPAP access to a sleep service for advice, support and equipment between follow-up appointments.
## Follow-up for people using mandibular advancement splints
Offer face-to-face, video or phone consultations, including review of downloads from the device (if available), to people with OSAHS using a mandibular advancement splint. This should include:
initial follow-up to review adjustment of the device and symptom improvement at 3 months and
subsequent follow-up according to the person's needs and until optimal control of symptoms and AHI or ODI is achieved.
## Follow-up for people using positional modifiers
Offer face-to-face, video or phone consultations, including review of downloads from the device (if available), to people with OSAHS using a positional modifier. This should include:
an initial consultation within 3 months and
subsequent follow-up according to the person's needs until optimal control of symptoms and AHI or ODI is achieved.
## Follow-up for people who have had surgery
Offer people with OSAHS who have had surgery:
an initial follow-up consultation with respiratory polygraphy within 3 months of the operation and
subsequent follow-up according to the person's needs.
## Follow-up for drivers with excessive sleepiness
Ensure follow-up is in line with Driver and Vehicle Licensing Agency guidance on assessing fitness to drive.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up for people with OSAHS .
Full details of the evidence and the committee's discussion are in evidence review L: monitoring.
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## Monitoring treatment efficacy
Assess the effectiveness of treatment with CPAP, mandibular advancement splints and positional modifiers in people with OSAHS by reviewing the following:
OSAHS symptoms, including the Epworth Sleepiness Scale and vigilance, for example, when driving
severity of OSAHS, using AHI or ODI
adherence to therapy
telemonitoring data or download information from the device (if available).
Explore with people using CPAP their understanding and experience of treatment, and review the following:
mask type and fit, including checking for leaks
nasal or mouth dryness, and the need for humidification
-ther factors affecting sleep disturbance such as insomnia, restless legs and shift work
sleep hygiene
cleaning and maintenance of equipment.
Consider stopping treatment if OSAHS may have resolved, for example, with significant weight loss. After at least 2 weeks without treatment:
re-evaluate any return of symptoms and
consider a sleep study.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring treatment efficacy in people with OSAHS .
Full details of the evidence and the committee's discussion are in evidence review M: demonstration of efficacy.
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# Supporting adherence to treatment for OSAHS
Offer people with OSAHS educational or supportive interventions, or a combination of these, tailored to the person's needs and preferences, to improve adherence to CPAP, mandibular advancement splints and positional modifiers.
Interventions to support adherence to treatment for OSAHS should be given by trained specialist staff when treatment is started and as needed at follow-up.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting adherence to treatment for OSAHS .
Full details of the evidence and the committee's discussion are in evidence review N: adherence.
Loading. Please wait.# Obesity hypoventilation syndrome
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Please note that the following guidance from the Driver and Vehicle Licensing Agency (DVLA) and the UK government is relevant to these recommendations:
DVLA guidance on assessing fitness to drive: a guide for medical professionals
DVLA guidance on excessive sleepiness and driving
UK government guidance on COVID-19: infection prevention and control.
Obesity hypoventilation syndrome (OHS) is defined as the combination of obesity (body mass index of 30 kg/m2 or more), raised arterial or arterialised capillary carbon dioxide (CO2) level when awake, and breathing abnormalities during sleep, which may consist of obstructive apnoeas and hypopnoeas, or hypoventilation, or a combination of both. OHS is a specific form of chronic ventilatory failure.
# Initial assessment for OHS
## When to suspect OHS
Take a sleep history and assess people for OHS if they have a BMI of 30 kg/m2 or more with:
features of obstructive sleep apnoea/hypopnoea syndrome (OSAHS; see recommendation 1.1.1) or
features of nocturnal hypoventilation such as:
waking headaches
peripheral oedema
hypoxaemia (arterial oxygen saturation less than 94% on air)
unexplained polycythaemia.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on when to suspect OHS .
Full details of the evidence and the committee's discussion are in evidence review A: when to suspect OSAHS, OHS and COPD–OSAHS overlap syndrome.
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## Assessment scales for suspected OHS
Use the Epworth Sleepiness Scale in the preliminary assessment of sleepiness in people with suspected OHS.
Do not use the Epworth Sleepiness Scale alone to determine if referral is needed, because not all people with OHS have excessive sleepiness.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment scales for suspected OHS .
Full details of the evidence and the committee's discussion are in evidence review B: assessment tools for people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.
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# Prioritising people for rapid assessment by a sleep service
See also recommendation 4.1.1 on providing information for people with suspected OHS who are being referred to a sleep service.
When referring people with suspected OHS to a sleep service, include the following information in the referral letter to facilitate rapid assessment:
results of the person's sleepiness score
how sleepiness affects the person
BMI
comorbidities
-ccupational risk
-xygen saturation and blood gas values, if available
any history of emergency admissions and acute non-invasive ventilation.
Within the sleep service, prioritise people with suspected OHS for rapid assessment if any of the following apply:
they have severe hypercapnia (PaCO2 over 7.0 kPa when awake)
they have hypoxaemia (arterial oxygen saturation less than 94% on air)
they have acute ventilatory failure
they have a vocational driving job
they have a job for which vigilance is critical for safety
they are pregnant
they have unstable cardiovascular disease, for example, poorly controlled arrhythmia, nocturnal angina, heart failure or treatment-resistant hypertension
they are undergoing preoperative assessment for major surgery
they have non-arteritic anterior ischaemic optic neuropathy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prioritising people for rapid assessment by a sleep service .
Full details of the evidence and the committee's discussion are in evidence review C: prioritisation for rapid assessment at a sleep centre of people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.
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# Diagnostic tests for OHS
See also section 4 on providing information for people who have been diagnosed with OHS.
## Diagnosing OHS and assessing ventilatory failure
Consider measuring serum venous bicarbonate as a preliminary test if the pre-test probability of OHS is low. If bicarbonate levels are below 27 mmol/litre, OHS is unlikely.
Measure arterial or arterialised capillary blood gases when the person with suspected OHS is awake, to diagnose OHS and assess the extent of chronic ventilatory failure.
Do not delay treatment for acute ventilatory failure to carry out further investigations for OHS.
## Diagnosing the presence of OSAHS or nocturnal hypoventilation in people with OHS
Offer respiratory polygraphy, either in hospital or at home, to determine the presence of OSAHS in people with suspected OHS.
Consider adding transcutaneous CO2 monitoring during sleep to respiratory polygraphy in people with suspected OHS to determine the extent of nocturnal hypoventilation and provide additional information to guide treatment.
Do not use oximetry alone to determine the presence of OSAHS in people with OHS.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnostic tests for OHS .
Full details of the evidence and the committee's discussion are in evidence review D: diagnostic tests for OSAHS, OHS and COPD–OSAHS overlap syndrome.
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# Lifestyle advice for OHS
Discuss appropriate lifestyle changes with all people with OHS. Provide support and information on losing weight, stopping smoking, reducing alcohol intake and improving sleep hygiene tailored to the person's needs and in line with the NICE guidelines on:
stop smoking interventions and services
-besity: identification, assessment and management (in particular, the section on lifestyle interventions)
alcohol-use disorders: prevention (in particular, recommendations on screening, brief advice and extended brief interventions for adults).
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on lifestyle advice for OHS .
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# Treatments for OHS
See also section 4 on providing information for people starting treatment for OHS.
## CPAP and non-invasive ventilation
Offer continuous positive airway pressure (CPAP) to people with OHS and severe OSAHS as first-line treatment.
Offer non-invasive ventilation as an alternative to CPAP for people with OHS and severe OSAHS if symptoms do not improve, hypercapnia persists, apnoea–hypopnoea index (AHI) or oxygen desaturation index (ODI) are not sufficiently reduced or CPAP is poorly tolerated.
Consider non-invasive ventilation for people with OHS and nocturnal hypoventilation who do not have OSAHS, or in whom OSAHS is not severe.
Consider heated humidification in addition to CPAP for people with OHS and OSAHS and upper airway side effects such as nasal and mouth dryness, and CPAP-induced rhinitis.
Offer non-invasive ventilation to people with OHS with acute ventilatory failure:
If hypercapnia persists, consider continuing and further optimising non-invasive ventilation.
If hypercapnia resolves, consider stopping non-invasive ventilation and monitoring the response.
After a person with OHS and acute ventilatory failure has been stabilised on non-invasive ventilation with control of hypercapnia, consider:
stopping non-invasive ventilation and carrying out respiratory polygraphy and
a trial of CPAP in people with frequent episodes of obstructive apnoea and minimal hypoventilation. If the person decompensates after stopping non-invasive ventilation, offer to restart non-invasive ventilation.
Be aware that CPAP and non-invasive ventilation are aerosol-generating procedures and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. These may include setting up the device at home by video consultation or with precautions in hospital. For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.
## Oxygen therapy
Consider supplemental oxygen therapy with CPAP or non-invasive ventilation for people with OHS who remain hypoxaemic despite optimal control of nocturnal hypoventilation and AHI on CPAP or non-invasive ventilation, and address any additional underlying causes of hypoxaemia where possible.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatments for OHS .
Full details of the evidence and the committee's discussion are in evidence review F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome and evidence review I: oxygen therapy.
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# Managing rhinitis in people with OHS
Assess people with nasal congestion and OHS for underlying allergic or vasomotor rhinitis.
If rhinitis is diagnosed in people with OHS, offer initial treatment with:
topical nasal corticosteroids or antihistamines for allergic rhinitis or
topical nasal corticosteroids for vasomotor rhinitis.
For people with OHS and persistent rhinitis, consider referral to an ear, nose and throat specialist if:
symptoms do not improve with initial treatment or
anatomical obstruction is suspected.
Be aware that:
rhinitis can affect people's tolerance to CPAP and non-invasive ventilation but changing from a nasal to an orofacial mask and adding humidification can help (see recommendation 2.5.4 on heated humidification for OHS and OSAHS)
CPAP and non-invasive ventilation can worsen or cause rhinitis and nasal congestion.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing rhinitis in people with OHS .
Full details of the evidence and the committee's discussion are in evidence review K: rhinitis.
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# Follow-up and monitoring for people with OHS
Tailor follow-up to the person's overall treatment plan, which may include lifestyle changes and treating comorbidities. See the recommendations on tailoring healthcare services for each patient in the NICE guideline on patient experience in adult NHS services.
## Follow-up for people using CPAP or non-invasive ventilation
Offer face-to-face, video or phone consultations, including review of telemonitoring data (if available), to people with OHS having non-invasive ventilation or CPAP. This should include:
an initial consultation within 1 month and
subsequent follow-up according to the person's needs and until optimal control of symptoms, AHI or ODI, oxygenation and hypercapnia is achieved.
When non-invasive ventilation or CPAP (with or without oxygen therapy) has been optimised for people with OHS and their symptoms are controlled, consider 6‑monthly to annual follow-up according to the person's needs.
Offer people with OHS having non-invasive ventilation or CPAP access to a sleep and ventilation service for advice, support and equipment between follow-up appointments.
## Follow-up for drivers with excessive sleepiness
Ensure follow-up is in line with Driver and Vehicle Licensing Agency guidance on assessing fitness to drive.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up for people with OHS .
Full details of the evidence and the committee's discussion are in evidence review L: monitoring.
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## Monitoring treatment efficacy for people with OHS
Assess the effectiveness of treatment with CPAP or non-invasive ventilation in people with OHS by reviewing the following:
OHS symptoms, including the Epworth Sleepiness Scale and vigilance, for example, when driving
severity of OSAHS, using AHI or ODI
improvement in oxygenation and hypercapnia while awake and asleep
adherence to therapy
telemonitoring or download information from the device (if available).
Explore with the person their understanding and experience of treatment, and review the following:
mask type and fit, including checking for leaks
nasal and mouth dryness, and the need for humidification
-ther factors affecting sleep disturbance such as insomnia, restless legs and shift work
sleep hygiene
cleaning and maintenance of equipment.
For people with OHS having supplemental oxygen therapy, review whether this is still needed after treatment with non-invasive ventilation or CPAP has been optimised.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring treatment efficacy for people with OHS .
Full details of the evidence and the committee's discussion are in evidence review M: demonstration of efficacy.
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# Supporting adherence to treatment for OHS
Offer people with OHS educational or supportive interventions, or a combination of these, tailored to the person's needs and preferences, to improve adherence to CPAP and non-invasive ventilation.
Interventions to support adherence to treatment for OHS should be given by trained specialist staff when treatment is started and as needed at follow-up.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting adherence to treatment for OHS .
Full details of the evidence and the committee's discussion are in evidence review N: adherence.
Loading. Please wait.# COPD–OSAHS overlap syndrome
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Please note that the following guidance from the Driver and Vehicle Licensing Agency (DVLA) and the UK government is relevant to these recommendations:
DVLA guidance on assessing fitness to drive: a guide for medical professionals
DVLA guidance on excessive sleepiness and driving
UK government guidance on COVID-19: infection prevention and control.
COPD–OSAHS overlap syndrome occurs in people who have both chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea/hypopnoea syndrome (OSAHS). The combined effect of these conditions on ventilatory load, gas exchange, comorbidities and quality of life is greater than either condition alone.
Recommendations in this guideline cover assessment and treatment of OSAHS in people with COPD. For recommendations on the diagnosis and management of COPD, see the NICE guidelines on chronic obstructive pulmonary disease in over 16s and chronic obstructive pulmonary disease (acute exacerbation): antimicrobial prescribing. See also NICE's guideline on community-based care of patients with COPD during the COVID-19 pandemic.
# Initial assessment for COPD–OSAHS overlap syndrome
## When to suspect COPD–OSAHS overlap syndrome
Take a sleep history and assess people for COPD–OSAHS overlap syndrome if they have confirmed COPD with:
features of OSAHS (see recommendation 1.1.1) or
features of nocturnal hypoventilation such as:
waking headaches
peripheral oedema
hypoxaemia (arterial oxygen saturation less than 94% on air)
unexplained polycythaemia.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on when to suspect COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review A: when to suspect OSAHS, OHS and COPD–OSAHS overlap syndrome.
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## Assessment scales and tests for suspected COPD–OSAHS overlap syndrome
When assessing people with suspected COPD–OSAHS overlap syndrome:
Use the Epworth Sleepiness Scale in the preliminary assessment of sleepiness.
Consider using the STOP-Bang Questionnaire, as well as the Epworth Sleepiness Scale.
Do not use the Epworth Sleepiness Scale alone to determine if referral is needed, because not all people with COPD–OSAHS overlap syndrome have excessive sleepiness.
Offer spirometry to assess the severity of COPD in people with suspected COPD–OSAHS overlap syndrome (see the recommendations on spirometry in NICE's guideline on chronic obstructive pulmonary disease in over 16s).
Be aware that spirometry is an aerosol-generating procedure and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment scales and tests for suspected COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review B: assessment assessment tools for people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.
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# Prioritising people for rapid assessment by a sleep service
See also recommendation 4.1.1 on providing information for people with suspected COPD–OSAHS overlap syndrome who are being referred to a sleep service.
When referring people with suspected COPD–OSAHS overlap syndrome to a sleep service, include the following information in the referral letter to facilitate rapid assessment:
results of the person's sleepiness score
how sleepiness affects the person
body mass index (BMI)
severity and frequency of exacerbations of COPD
use of oxygen therapy at home
comorbidities
-ccupational risk
-xygen saturation and blood gas values, if available
any history of acute non-invasive ventilation.
Within the sleep service, prioritise people with suspected COPD–OSAHS overlap syndrome for rapid assessment if any of the following apply:
they have severe hypercapnia (PaCO2 over 7.0 kPa when awake)
they have hypoxaemia (arterial oxygen saturation less than 94% on air)
they have acute ventilatory failure
they have a vocational driving job
they have a job for which vigilance is critical for safety
they are pregnant
they have unstable cardiovascular disease, for example, poorly controlled arrhythmia, nocturnal angina, heart failure or treatment-resistant hypertension
they are undergoing preoperative assessment for major surgery
they have non-arteritic anterior ischaemic optic neuropathy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prioritising people for rapid assessment by a sleep service .
Full details of the evidence and the committee's discussion are in evidence review C: prioritisation for rapid assessment at a sleep centre of people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.
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# Diagnostic tests for COPD–OSAHS overlap syndrome
See also section 4 on providing information for people who have been diagnosed with COPD–OSAHS overlap syndrome.
## Diagnosing ventilatory failure
Measure arterial or arterialised capillary blood gas when the person with suspected COPD–OSAHS overlap syndrome is awake, to assess for ventilatory failure.
Do not delay treatment for acute ventilatory failure to carry out further investigations for COPD–OSAHS overlap syndrome.
## Diagnosing OSAHS or nocturnal hypoventilation in people with suspected COPD–OSAHS overlap syndrome
Offer respiratory polygraphy, either in hospital or at home, to diagnose OSAHS in people with suspected COPD–OSAHS overlap syndrome.
Consider adding transcutaneous carbon dioxide (CO2) monitoring during sleep to respiratory polygraphy to provide additional information to guide treatment.
Do not use oximetry alone to diagnose OSAHS or nocturnal hypoventilation in people with suspected COPD–OSAHS overlap syndrome.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnostic tests for COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review D: diagnostic tests for OSAHS, OHS and COPD–OSAHS overlap syndrome.
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# Lifestyle advice for COPD–OSAHS overlap syndrome
For people with COPD–OSAHS overlap syndrome, follow recommendation 1.4.1 on lifestyle advice for people with OSAHS. Prioritise advice on stopping smoking and follow the recommendations on smoking cessation in NICE's guideline on chronic obstructive pulmonary disease in over 16s.
# Treatments for COPD–OSAHS overlap syndrome
See also section 4 on providing information for people starting treatment for COPD–OSAHS overlap syndrome.
## CPAP and non-invasive ventilation
Consider continuous positive airway pressure (CPAP) as first-line treatment for people with COPD–OSAHS overlap syndrome if they do not have severe hypercapnia (PaCO2 of 7.0 kPa or less).
Consider non-invasive ventilation instead of CPAP for people with COPD–OSAHS overlap syndrome with nocturnal hypoventilation if they have severe hypercapnia (PaCO2 greater than 7.0 kPa).
Consider heated humidification in addition to CPAP for people with COPD–OSAHS overlap syndrome and upper airway side effects such as nasal and mouth dryness, and CPAP-induced rhinitis.
Be aware that CPAP and non-invasive ventilation are aerosol-generating procedures and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. These may include setting up the device at home by video consultation or with precautions in hospital.For more information, see NICE's guideline on community-based care of patients with COPD during the COVID-19 pandemic, the UK government guidance on COVID-19: infection prevention and control and local guidance.
## Oxygen therapy
Consider supplemental oxygen for people with COPD–OSAHS overlap syndrome if hypoxaemia persists once control of apnoea and nocturnal hypoventilation has been optimised by CPAP or non-invasive ventilation, and address any additional underlying causes of hypoxaemia where possible.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatments for COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome and evidence review I: oxygen therapy.
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# Managing rhinitis in people with COPD–OSAHS overlap syndrome
For people with COPD–OSAHS overlap syndrome, follow the recommendations on managing rhinitis in people with OSAHS.
# Follow-up and monitoring for people with COPD–OSAHS overlap syndrome
Tailor follow-up to the person's overall treatment plan, which may include lifestyle changes and treating comorbidities. It may also include discussions about care planning (for example, COPD exacerbation action plan and advance care planning) for those with severe COPD. See the recommendations on self-management in the NICE guideline on chronic obstructive pulmonary disease in over 16s and tailoring healthcare services for each patient in the NICE guideline on patient experience in adult NHS services.
## Follow-up for people using CPAP or non-invasive ventilation
Offer face-to-face, video or phone consultations, including review of telemonitoring data (if available), to people with COPD–OSAHS overlap syndrome having non-invasive ventilation or CPAP. This should include:
an initial consultation within 1 month and
subsequent follow-up according to the person's needs and until optimal control of symptoms, apnoea–hypopnoea index (AHI) or oxygen desaturation index (ODI), oxygenation and hypercapnia is achieved.
When non-invasive ventilation or CPAP (with or without oxygen therapy) has been optimised for people with COPD–OSAHS overlap syndrome and their symptoms are controlled, consider 6‑monthly to annual follow-up according to the person's needs.
Offer people with COPD–OSAHS overlap syndrome having non-invasive ventilation or CPAP access to a sleep and ventilation service for advice, support and equipment between follow-up appointments.
## Follow-up for drivers with excessive sleepiness
Ensure follow-up is in line with Driver and Vehicle Licensing Agency guidance on assessing fitness to drive.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up for people with COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review L: monitoring.
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## Monitoring treatment efficacy for people with COPD–OSAHS overlap syndrome
Assess the effectiveness of treatment with CPAP or non-invasive ventilation in people with COPD–OSAHS overlap syndrome by reviewing the following:
symptoms of OSAHS and nocturnal hypoventilation, including the Epworth Sleepiness Scale and vigilance, for example, when driving
severity of OSAHS, using AHI or ODI
improvement in oxygenation and hypercapnia while awake and asleep
adherence to therapy
telemonitoring or download information from the device (if available).
Explore with the person their understanding and experience of treatment, and review the following:
mask type and fit, including checking for leaks
nasal and mouth dryness, and need for humidification
-ther factors affecting sleep disturbance such as insomnia, restless legs and shift work
sleep hygiene
cleaning and maintenance of equipment.
Be aware that some symptoms associated with COPD such as cough and wheeze, and certain medications such as theophyllines, may adversely affect sleep quality.
For people with COPD–OSAHS overlap syndrome having supplemental oxygen therapy, review whether this is still needed after treatment with non-invasive ventilation or CPAP has been optimised.
Consider stopping CPAP or non-invasive ventilation and using a symptom-management approach for people with COPD–OSAHS overlap syndrome who have severe COPD if, despite treatment optimisation, CPAP or non-invasive ventilation does not improve their symptoms or quality of life, or adds to the burden of therapy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring treatment efficacy for people with COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review M: demonstration of efficacy.
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# Supporting adherence to treatment for COPD–OSAHS overlap syndrome
Offer people with COPD–OSAHS overlap syndrome educational or supportive interventions, or a combination of these, tailored to the person's needs and preferences, to improve adherence to CPAP and non-invasive ventilation.
Interventions to support adherence to treatment for COPD–OSAHS overlap syndrome should be given by trained specialist staff when treatment is started and as needed at follow-up.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting adherence to treatment for COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review N: adherence.
Loading. Please wait.# Information for people with OSAHS, OHS or COPD–OSAHS overlap syndrome
When providing information, follow the recommendations on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services and putting shared decision making into practice in NICE's guideline on shared decision making.
For people with suspected obstructive sleep apnoea/hypopnoea syndrome (OSAHS), obesity hypoventilation syndrome (OHS) or chronic obstructive pulmonary disease–obstructive sleep apnoea/hypopnoea syndrome (COPD–OSAHS) overlap syndrome who are being referred to a sleep service, provide information on:
the underlying causes of their condition
what sleep studies involve
why treatment is important
what treatments are available
the impact of excessive sleepiness on safe driving and occupational risk
the Driver and Vehicle Licensing Agency (DVLA) guidance on excessive sleepiness and driving and when there is a legal requirement for the person to notify the DVLA of their condition
lifestyle changes, including weight loss, increasing physical activity, and avoiding alcohol excess and sedatives before sleep
-ther sources of patient support.
For people who have been diagnosed with OSAHS, OHS or COPD–OSAHS overlap syndrome, repeat the information provided at referral (see recommendation 4.1.1) and give additional information on:
choosing the best treatment for the person
the practicalities of travel.
For people starting treatment with continuous positive airway pressure (CPAP) or non-invasive ventilation, provide information on:
why it is used and how it works
the benefits of continuing with treatment and advice on encouraging adherence
how to get support for technical and clinical problems, including side effects, and obtain replacement masks and other parts
different masks or other interface options, humidification and how to manage problems with masks
how often to expect follow-up appointments
how to clean and maintain the equipment
taking short breaks from treatment
making arrangements for travelling with CPAP or non-invasive ventilation.
Advise people using CPAP and non-invasive ventilation that these are aerosol-generating procedures and they should take appropriate precautions if there is a risk that they may have an airborne infection such as COVID‑19. For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.
For people starting treatment with a mandibular advancement splint, provide information on:
why they are used and how they work
the benefits of continuing with treatment, and advice on encouraging adherence
possible short-term side effects, such as mild discomfort, hypersalivation and altered bite
possible long-term side effects, such as problems with dental occlusion
adjusting the device to ensure maximum benefit
how to clean and maintain the device
maintaining good oral health
who to contact for help with problems, for example, if the device breaks or the fit becomes poor
how often to expect follow-up appointments.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information for people with OSAHS, OHS and COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review O: information and support.
Loading. Please wait.# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
# Apnoea
A complete pause in breathing, defined as lasting 10 seconds or more on a sleep study. An obstructive apnoea is caused by blockage of the upper airway, whereas a central apnoea occurs when there is no respiratory effort.
# Apnoea–hypopnoea index (AHI)
The number of apnoeas and hypopnoeas per hour, measured during a multi-channel sleep study.
# Hypopnoea
A reduction in breathing, defined as lasting for 10 seconds or more on a sleep study. An obstructive hypopnoea is caused by partial obstruction of the upper airway.
# Mandibular advancement splint
An oral device used to treat sleep-related breathing disorders. It is worn over the upper and lower teeth, and holds the lower jaw forward, thereby increasing space at the back of the mouth and decreasing snoring and sleep apnoea. A custom-made mandibular advancement splint is formed from a dental impression taken by a dentist, which is used to make the splint in a laboratory. It is then fitted by a suitably trained general dental practitioner. A semi-customised mandibular advancement splint is formed using a dental impression taken by the patient, which they send to the manufacturer to make the splint.
# Nocturnal hypoventilation
Decreased breathing or under breathing during sleep, which can lead to varying severities of ventilatory failure (low oxygen levels and raised carbon dioxide). It can be caused by obesity, underlying lung disease, neuromuscular weakness and some medications such as opiates. Severe hypercapnia can be caused by nocturnal hypoventilation.
# Oxygen desaturation index (ODI)
The ODI is defined as the number of episodes of oxygen desaturation per hour of sleep.
# Positional modifier
An intervention to encourage patients not to sleep on their backs. There are several devices available such as the tennis ball technique, lumbar or abdominal binders, semi-rigid backpacks, full-length pillows and electronic sleep position trainers.
# Positional OSAHS
A type of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) that is affected by the person's sleep position. People with positional OSAHS have an apnoea–hypopnoea index (AHI) at least twice as high when lying face up (supine) as lying on their side (laterally).
# Severity of OSAHS
This is determined using the AHI value, as follows:
Mild OSAHS: AHI of 5 or more to less than 15
Moderate OSAHS: AHI of 15 or more to less than 30
Severe OSAHS: AHI of 30 or more.
# Sleep study
A test used to diagnose sleep disorders by recording multiple channels during sleep, such as brain activity, breathing rate, blood oxygen level, heart rate, and eye and leg movements. There are several different types of sleep study:
-ximetry measures arterial oxygen saturation and heart rate while the person is asleep
respiratory polygraphy includes at least 4 channels such as oximetry, breathing rate, apnoeas and hypopnoeas, snoring and body position
polysomnography, which is more detailed and includes respiratory polygraphy measures combined with assessment of sleep quality and duration using additional brain activity, eye movement and muscle tone signals.
# Telemonitoring
The use of information and communication technologies to monitor patients remotely and transmit data related to their health. It is used to provide information including respiratory events, pressure requirements, mask leak and adherence.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Auto- versus fixed-level CPAP for OSAHS
What is the clinical and cost effectiveness of auto- and fixed-level continuous positive airway pressure (CPAP) for managing mild obstructive sleep apnoea/hypopnoea syndrome (OSAHS)?
For a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for mild OSAHS .
Full details of the evidence and the committee's discussion are in evidence review F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome.
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What is the clinical and cost effectiveness of auto- and fixed-level continuous positive airway pressure (CPAP) for managing moderate and severe OSAHS?
For a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for moderate and severe OSAHS .
Full details of the evidence and the committee's discussion are in evidence review F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome.
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## Interventions to improve CPAP adherence
Which interventions, including behavioural interventions, are most clinically and cost effective to improve adherence to CPAP in people with OSAHS, obesity hypoventilation syndrome (OHS) and COPD–OSAHS (chronic obstructive pulmonary disease–OSAHS) overlap syndrome who have difficulty using CPAP?
For a short explanation of why the committee made the recommendation for research, see the rationale section on supporting adherence to treatment for OSAHS .
Full details of the evidence and the committee's discussion are in evidence review N: adherence.
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## Mandibular advancement splints for mild symptomatic OSAHS and moderate OSAHS
In mild symptomatic OSAHS, which clinical and physiological phenotypes predict treatment response to customised mandibular advancement splints?
For a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for mild OSAHS .
Full details of the evidence and the committee's discussion are in evidence review G: oral devices.
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In moderate OSAHS, which clinical and physiological phenotypes predict treatment response to customised mandibular advancement splints?
For a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for moderate and severe OSAHS .
Full details of the evidence and the committee's discussion are in evidence review G: oral devices.
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## Mandibular advancement splints for severe OSAHS
What is the clinical and cost effectiveness of mandibular advancement splints for managing severe OSAHS?
For a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for moderate and severe OSAHS .
Full details of the evidence and the committee's discussion are in evidence review G: oral devices.
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## Treatment for people with COPD–OSAHS overlap syndrome
What is the optimal treatment for people with COPD–OSAHS overlap syndrome: non-invasive ventilation or CPAP?
For a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for COPD–OSAHS overlap syndrome .
Full details of the evidence and the committee's discussion are in evidence review F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome.
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# Other recommendations for research
## Upper airway surgery in people unable to tolerate or adhere to CPAP
What is the clinical and cost effectiveness of upper airway surgical interventions for people with OSAHS who are unable to tolerate or adhere to CPAP?
For a short explanation of why the committee made the recommendation for research, see the rationale section on surgery for OSAHS .
Full details of the evidence and the committee's discussion are in evidence review J: surgery.
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## Oxygen therapy for OSAHS
What is the clinical and cost effectiveness of nocturnal oxygen compared with placebo in people with OSAHS who are unable to tolerate CPAP?
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale section on oxygen therapy for OSAHS .
Full details of the evidence and the committee's discussion are in evidence review I: oxygen therapy.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# When to suspect OSAHS
Recommendations 1.1.1 and 1.1.2
## Why the committee made the recommendations
There was limited evidence for identifying who to assess for obstructive sleep apnoea/hypopnoea syndrome (OSAHS), so the committee also used their clinical knowledge and experience to make the recommendations.
The committee agreed that, after taking a sleep history, further assessment for OSAHS should be carried out in people presenting with common symptoms and features of OSAHS, such as unexplained excessive sleepiness, snoring, apnoeas observed during sleep and choking during sleep, but that a broader range of symptoms should also be recognised, such as sleep fragmentation, insomnia, and fatigue in people without excessive sleepiness. The committee agreed that a single symptom alone, such as snoring, is not sufficient for further investigation and that 2 or more features should be identified to warrant assessment. Based on evidence and experience, the committee listed conditions associated with OSAHS that should alert healthcare professionals to the possibility of OSAHS.
## How the recommendations might affect practice
The recommendations aim to raise awareness of symptoms and associated conditions that should raise suspicion of OSAHS, as well as prompting assessment. This could increase the number of people being assessed and referred to sleep services.
Return to recommendations
# Assessment scales for suspected OSAHS
Recommendations 1.1.3 and 1.1.4
## Why the committee made the recommendations
The Epworth Sleepiness Scale is intended to assess for sleepiness rather than to diagnose OSAHS, and the limited evidence reflected this, showing that it performed poorly both for sensitivity and specificity in diagnosing OSAHS. The committee noted that some people with OSAHS do not have excessive sleepiness and that not all healthcare professionals are aware of this. However, they agreed that it has a useful role in assessment and monitoring, and noted that when healthcare professionals are requested by the Driver and Vehicle Licensing Agency (DVLA) to complete assessment of a driver with OSAHS, this includes the Epworth Sleepiness Scale. They therefore agreed that it should be used, but not as the sole means of assessing the presence of OSAHS or as the sole basis for referral.
Limited evidence showed that the STOP-Bang Questionnaire had high sensitivity and low specificity for diagnosing OSAHS. Sensitivity is a priority for questionnaires used for initial assessment. The committee had some concerns about its accuracy in people with less common presentations and in women, but agreed that it could have a role in assessment alongside the Epworth Sleepiness Scale to inform the preliminary understanding of the person's symptoms and concerns. The Epworth questionnaire is used to assess only sleepiness whereas the STOP-Bang Questionnaire is used to assess risk of having OSAHS and includes parameters such as snoring, tiredness, history of high blood pressure, body mass index (BMI), age, neck size and gender. With this in mind, the committee agreed that the Epworth questionnaire should be used and the STOP-Bang Questionnaire could also be considered for initial assessment.
## How the recommendations might affect practice
The recommended questionnaires are widely used in current practice, so the recommendations are not expected to involve a change in practice.
Return to recommendations
# Prioritising people for rapid assessment by a sleep service
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendations
There was limited evidence available on who to prioritise for assessment in a sleep service, and the committee noted that service provision and waiting times vary across sleep services and regions in England. Therefore, the committee used their knowledge and experience to identify groups that would benefit most from prompt assessment and treatment.
The committee agreed that sleep services should prioritise access to a sleep study and treatment for people in whom vigilance and alertness are vital to occupational safety, particularly those with problematic sleepiness, and to people with pre-existing conditions who are at increased risk of adverse events. They agreed that sleep services should aim to fast-track priority groups to be seen as soon as possible.
The committee discussed the effect of OSAHS on work performance and safety, and how it could increase the risk of work accidents in safety-sensitive occupations. People with a wide range of jobs or activities could be affected, for example, drivers, train drivers, pilots, heavy machinery operators, surgeons and people caring for vulnerable children or adults. The committee noted that DVLA guidance on assessing fitness to drive recommends that drivers with suspected or confirmed OSAHS and excessive sleepiness having, or likely to have, an adverse impact on driving must not drive until there is satisfactory symptom control. Control of symptoms is likely to need assessment and treatment from a sleep specialist.
The committee noted that untreated OSAHS is recognised as a risk factor for treatment-resistant hypertension and recurrence of atrial flutter in people who have had treatment with ablative therapy. Therefore, it was agreed that people with unstable cardiovascular disease should be prioritised because of the risks of worsening cardiovascular disease or adverse events.
The committee agreed that priority should be given to pregnant women because OSAHS in pregnancy is associated with increased risks for the mother and baby.
The committee agreed that people with a high probability of OSAHS who need major surgery should be prioritised to avoid delaying surgery.
The committee also agreed that the risk of sudden blindness in patients with non-arteritic anterior ischaemic optic neuropathy warrants priority assessment because of its possible association with OSAHS.
To ensure that people are prioritised appropriately by sleep services and to allow fast-tracking directly to a sleep study, the committee agreed on key details, based on their experience, that should be included in referral letters.
## How the recommendations might affect practice
In current practice, specific groups are not always prioritised for assessment, so there is likely to be a change in practice for some providers. There is increasing pressure on sleep services, and offering higher priority to some groups may delay sleep studies for other people. Planning for and providing rapid-access sleep studies may help to reduce the pressure on services, with triage of referrals allowing people to be fast-tracked directly to a diagnostic study.
Return to recommendations
# Diagnostic tests for OSAHS
Recommendations 1.3.1 to 1.3.6
## Why the committee made the recommendations
The evidence on diagnostic tests for OSAHS was not consistent. The studies reviewed looked at diagnostic devices with a variety of monitoring channels and included different patient groups. The committee also noted that diagnostic equipment has evolved and improved over time. The committee used their clinical knowledge and experience supported by the published evidence and by the economic model developed for this guideline to make the recommendations.
Home respiratory polygraphy was more cost effective than both hospital (inpatient) respiratory polygraphy and home oximetry. The committee noted that respiratory polygraphy has the added benefit of aiding the diagnosis of other conditions such as central sleep apnoea and nocturnal hypoventilation and it is better than oximetry alone in identifying artefacts in the recordings.
The use of oximetry alone, or oximetry followed by home respiratory polygraphy if initial oximetry is negative, was less cost effective than initial home respiratory polygraphy. However, diagnostic strategies incorporating oximetry are still used in practice, for example, by services with limited availability of home polygraphy equipment, and the committee recognised that it might take time and significant resources to change practice. They noted that when suspicion of OSAHS is low, a normal oximetry result can provide further evidence to rule out diagnosis. The committee agreed that oximetry could still be an option and that this would help to avoid unacceptable delays in diagnosis where there is a lack of access to home respiratory polygraphy.
The committee also highlighted the potential problems of relying on oximetry for diagnosis. Oximetry may be particularly inaccurate in people with conditions such as heart failure or chronic lung disease, which can result in desaturation without the presence of OSAHS, although they agreed that a negative test result is still useful. In addition, oximetry cannot reliably distinguish between obstructive or central apnoeas and nocturnal hypoventilation, which is important to help determine treatment.
The option to do the sleep study in hospital was also considered important by the committee. Hospital polygraphy may sometimes be needed when investigating alternative diagnoses alongside OSAHS, because extra monitoring channels can be used. It might also be an option if home respiratory polygraphy or home oximetry are impractical, for example, for people who need help with the monitoring equipment, or who need to travel long distances to pick up and return devices, or when a number of inpatient investigations need to be combined.
The committee agreed that further investigation with polysomnography, which is more accurate and more expensive than respiratory polygraphy, should be an option to provide more detail on sleep fragmentation and respiratory events for people with symptoms of OSAHS who have a negative respiratory polygraphy or oximetry result but continue to have suggestive symptoms. This may help distinguish between OSAHS and other disorders such as narcolepsy, rapid eye movement sleep behaviour disorder, periodic limb movement disorders, idiopathic hypersomnolence or parasomnias, which are suspected as a more likely diagnosis for the person's symptoms; or help diagnose these disorders when they are suspected in addition to OSAHS.
## How the recommendations might affect practice
Current practice is variable, with some sleep services offering oximetry as the first-line test and others offering home respiratory polygraphy. The recommendations will reduce this variation by encouraging the use of home respiratory polygraphy over home oximetry. Some services will need to provide more home respiratory polygraphy equipment and fewer home oximetry devices, but improved testing should lead to fewer repeat tests and optimal treatment. The option to use home oximetry as an alternative to respiratory polygraphy will lessen the impact on resources as practice changes.
The use of polysomnography for those who still have symptoms despite negative respiratory polygraphy results reflects current practice for this small population.
Return to recommendations
# Lifestyle advice for all severities of OSAHS
Recommendation 1.4.1
## Why the committee made the recommendation
Evidence for lifestyle advice was not reviewed because it is covered by other NICE guidelines.
The committee agreed that all people with OSAHS should discuss lifestyle changes with their healthcare professional. This should be tailored to the person's needs and the chosen treatment method. It may include advice on weight loss, preventing excess weight gain, stopping smoking and reducing alcohol intake, as appropriate.
Lifestyle changes are important because obesity increases the prevalence and severity of OSAHS, smoking causes upper airway inflammation (which can exacerbate symptoms), and excess alcohol before sleep reduces upper airway tone (increasing apnoeas) and reduces sleep quality. Advice on sleep hygiene may include ensuring adequate sleep time, avoiding caffeine and stimulants that interfere with sleep before bedtime, exercising regularly, having a quiet, comfortable, darkened bedroom, and winding down before sleep.
## How the recommendation might affect practice
Lifestyle advice is widely used in current practice, so the recommendations are not expected to involve a change in practice.
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# Treatments for mild OSAHS
Recommendations 1.5.1 to 1.5.8
## Why the committee made the recommendations
From their experience, the committee agreed that for many people with mild OSAHS who have no symptoms or symptoms that do not affect usual daytime activities, lifestyle changes alone can prevent OSAHS worsening and improve their quality of life. Lifestyle and sleep hygiene advice should be tailored to the person's circumstances. The committee noted that people without symptoms may come to the attention of a specialist because their partner has witnessed apnoeas and overt snoring.
For people with mild OSAHS whose symptoms affect their quality of life and usual daytime activities, the evidence suggested that CPAP was more clinically and cost effective than conservative management (including lifestyle changes and sleep hygiene). However, the quality of the evidence means that there is some uncertainty about the cost effectiveness. CPAP was found to be beneficial in improving sleepiness, fatigue, vitality and quality of life, which confirmed the committee's experience that there are benefits to giving CPAP to people with symptomatic mild OSAHS. Although some people could try lifestyle modification first, they noted that these changes take time to work and may not always be effective.
Delaying offering CPAP to people with any of the priority factors for rapid referral (listed in recommendation 1.2.1) could adversely affect quality of life, associated medical conditions or the person's ability to carry out their work, by failing to control their symptoms. The committee agreed that, in their experience, offering CPAP to these groups helped control their symptoms and reduced the risks described in the rationale section for prioritising people for rapid assessment by a sleep service. Therefore, the committee agreed that, for these people, CPAP should be offered as a first-line treatment alongside lifestyle changes, as soon as mild OSAHS is diagnosed. They also agreed that CPAP would be beneficial to control symptoms in people for whom lifestyle changes alone are unsuccessful or are not appropriate.
The committee also discussed the benefits of telemonitoring, described in more detail in the rationale section on follow-up for people with OSAHS. They agreed that the costs varied between sleep centres and, in the committee's experience, telemonitoring is included in the price of the machine for 12 months. Based on this, the committee recommended it should be offered alongside CPAP for up to 12 months, and considered beyond 12 months if optimal control of symptoms and apnoea–hypopnoea index (AHI) has not been achieved, or to help with solving problems that people with OSAHS might experience.
Telemonitoring has allowed remote assessment of patients during the coronavirus pandemic and has become a standard follow-up option in most sleep services. This use is likely to continue long term, because it is convenient for patients, enables them to assess progress themselves and allows access to efficacy and adherence data whenever needed, for example, for problem solving, routine follow-up and to complete DVLA reports.
The evidence showed fixed-level CPAP and auto‑CPAP to be equally effective, and auto‑CPAP to be more costly. Therefore, the committee agreed to recommend fixed-level CPAP as the first-choice treatment. However, some people, particularly those in whom high pressures are only needed part of the time, find auto‑CPAP more comfortable and effective than fixed-level CPAP. For others, telemonitoring may not be possible because of technological constraints such as the lack of availability of internet or poor internet connection. The committee agreed that auto‑CPAP should be an option in these cases. The committee were also aware that some hospitals get significant discounts on auto‑CPAP devices, which might make them more cost effective. Therefore, the committee agreed that if auto‑CPAP can be purchased and administered at the same or lower cost than fixed-level CPAP, auto‑CPAP could be considered. Given the uncertainty about the cost-effectiveness between auto- and fixed-level CPAP the committee made a research recommendation to help inform future guidelines.
Based on their experience of current practice, the committee agreed that using humidification with CPAP in people with nasal symptoms can reduce side effects associated with upper airway dryness and this may improve adherence and treatment effectiveness.
There was very little evidence for non-customised oral devices in people with mild OSAHS. Most of the evidence was for customised mandibular advancement splints and no evidence was found for tongue-retaining devices or tongue-stabilising devices. One study showed little benefit of mandibular advancement splints compared with no treatment in people with mild symptomatic OSAHS, but the committee agreed that the duration of the study was not sufficient for the true benefit to be assessed. Indirect evidence from studies in people with moderate OSAHS did show clinical benefit compared with placebo, and also showed better ease of use and patient preference scores than for CPAP.
An economic analysis showed that CPAP was slightly more cost effective than customised mandibular advancement splints, but the committee agreed the difference was small and they did not want to exclude these devices as an option, bearing in mind that some people find CPAP unacceptable. Based on this and their experience, the committee agreed that mandibular advancement splints should be considered as a treatment for people with mild OSAHS who have symptoms that affect their usual daytime activities if they are unable to tolerate or decline to try CPAP.
The evidence was unclear about the best type of mandibular advancement splint, but from their experience, the committee agreed that devices that are custom made and fitted by a suitably trained dentist are superior to semi-customised and ready-made (also called 'boil and bite') splints. Despite higher initial costs to make and fit, customised devices are more durable and longer lasting than the other devices. They are also preferred by patients. Semi-customised devices also last longer than ready-made devices and are cheaper than customised devices. Both customised and semi-customised devices were shown to be more cost effective than ready-made devices.
Semi-customised devices may be inappropriate for people with active periodontal disease or untreated dental decay, few or no teeth and for people with generalised tonic-clonic seizures. Experienced specialist care is needed to use these devices in people with few or no teeth. Mandibular advancement splints are not suitable for people under 18 because they may adversely affect development of dentition.
The committee observed that careful patient selection is vital and further research is needed to determine which patients with mild OSAHS would benefit most from mandibular advancement splint therapy. They developed a research recommendation on treating mild OSAHS with a mandibular advancement splint to inform future guidance.
## How the recommendations might affect practice
Some people with mild OSAHS currently use CPAP, for example, people with symptoms that affect their ability to do daily activities, and when other treatment options and lifestyle advice have been unsuccessful or are considered inappropriate. It is expected that there will be increased uptake of CPAP for mild OSAHS, and therefore a resource increase to the NHS from this recommendation, especially as the estimate of prevalence of mild OSAHS has increased, and more people are referred and diagnosed. Some sleep services currently using auto‑CPAP may switch to fixed-level CPAP for new patients starting CPAP, which is likely to be cost saving.
Some people with mild OSAHS currently use mandibular advancement splints. Many of these will be less effective ready-made devices that people have bought themselves. It is expected that there will be increased uptake of semi-customised and customised mandibular advancement splints and therefore a resource increase from this recommendation. NHS provision of dental services producing mandibular advancement splints is currently limited. Mandibular advancement splints need replacing at regular intervals and people using them need follow-up to assess efficacy.
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# Treatments for moderate and severe OSAHS
Recommendations 1.6.1 to 1.6.7
## Why the committee made the recommendations
The NICE technology appraisal guidance on continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome recommends CPAP as a treatment option for moderate and severe OSAHS.
The committee discussed the benefits of telemonitoring, described in more detail in the rationale section on follow-up for people with OSAHS. They agreed that the costs varied between sleep centres and, in the committee's experience, telemonitoring is included in the price of the machine for 12 months. Based on this, they recommend it should be offered alongside CPAP for up to 12 months, and considered beyond 12 months if optimal control of symptoms and AHI has not been achieved, or to help with solving problems that people with OSAHS might experience.
Telemonitoring has allowed remote assessment of patients during the coronavirus pandemic and has become a standard follow-up option in most sleep services. This use is likely to continue long term, because it is convenient for patients, enables them to assess progress themselves and allows access to efficacy and adherence data whenever needed, for example, for problem solving, routine follow-up and to complete DVLA reports.
The evidence showed fixed-level CPAP and auto‑CPAP to be equally effective, and auto‑CPAP to be more costly. Therefore, the committee agreed to recommend fixed-level CPAP as the first-choice treatment. However, some people, particularly those in whom high pressures are only needed part of the time, find auto‑CPAP more comfortable and effective than fixed-level CPAP. For others, telemonitoring may not be possible because of technological constraints such as the lack of availability of internet or poor internet connection. The committee agreed that auto‑CPAP should be an option in these cases. The committee were also aware that some hospitals get significant discounts on auto‑CPAP devices, which might make them more cost effective. Therefore, the committee agreed that if auto‑CPAP can be purchased and administered at the same or lower cost than fixed-level CPAP, auto‑CPAP could be considered. Given the uncertainty about the cost-effectiveness between auto- and fixed-level CPAP the committee made a research recommendation to help inform future guidelines.
Based on its experience of current practice, the committee agreed that using humidification with CPAP may reduce side effects causing upper airway symptoms and subsequently improve adherence and treatment effectiveness.
Although CPAP is the treatment of choice for people with moderate and or severe OSAHS, some people are unable to tolerate it in any form. The evidence showed that mandibular advancement splints are of benefit to people with moderate OSAHS and the committee agreed that they should be considered as an alternative treatment if CPAP is not tolerated or people decide not to try it. In the absence of evidence for severe OSAHS, the committee agreed that the evidence for moderate OSAHS could be extrapolated to this population. The committee also made a research recommendation on mandibular advancement splints for severe OSAHS.
The evidence was unclear about the best type of mandibular advancement splint, but from their experience, the committee agreed that devices that are custom made and fitted by a suitably trained dentist are superior to semi-customised and ready-made (also called 'boil and bite') splints. Despite higher initial costs to make and fit, customised devices are more durable and longer lasting than the other devices. They are also preferred by patients. Semi-customised devices also last longer than ready-made devices and are cheaper than customised devices. Both customised and semi-customised devices were shown to be more cost effective than ready-made devices.
Semi-customised devices may be inappropriate for people with active periodontal disease or untreated dental decay, few or no teeth and for people with generalised tonic-clonic seizures. Experienced specialist care is needed to manage these devices in people with few or no teeth. Mandibular advancement splints are not suitable for children and young people under 18 because they may adversely affect development of dentition.
## How the recommendations might affect practice
The recommendations for CPAP reflect current practice in most sleep services. Some sleep services currently using auto‑CPAP may switch to fixed-level CPAP for new patients starting CPAP, which is likely to be cost saving.
It is expected that there will be increased uptake of customised and semi-customised mandibular advancement splints and therefore a resource increase from this recommendation. NHS provision of dental services producing mandibular advancement splints is currently limited. Mandibular advancement splints need replacing at regular intervals and people using them need follow-up to assess efficacy and dentition.
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# Positional modifiers for OSAHS
Recommendations 1.7.1 and 1.7.2
## Why the committee made the recommendations
There was limited evidence on positional modifiers to treat OSAHS and the available studies were small with limited follow-up. The committee agreed that the evidence did not support their use as a first-choice treatment over CPAP and mandibular advancement splints in patients with mild or moderate positional OSAHS. However, there was some evidence of a reduction of OSAHS severity in supine sleep and an associated fall in the number of apnoeas compared with no treatment, with no evidence of adverse effects, so the committee agreed that they could be an option if other treatments were unsuccessful or not tolerated. It is estimated that more than half of people with OSAHS have positional OSAHS, so this recommendation will give more choice and offer an alternative option for the many people who find CPAP and mandibular advancement splints difficult to tolerate or unsuitable.
The committee did not support the use of positional modifiers in people with severe OSAHS, because these people usually continue to have obstructive events even when lying on their side. The committee were also aware of evidence that suggested an increase in the number of apnoeas with the use of positional modifiers in this population.
The studies looked at a variety of different positional modifiers, including the tennis ball technique and an electronic sleep position trainer, but the committee noted that that they did not include other devices such as lumbar or abdominal binders, semi-rigid backpacks and full-length pillows. The committee agreed that the evidence for different types of positional modifiers was insufficient to recommend a specific device.
The committee did not make a research recommendation because it was aware of several relevant research trials already in progress.
## How the recommendations might affect practice
Positional modifiers are not used commonly in current practice so the recommendation would involve a change in practice by most providers. Currently people tend to buy their own positional devices, often after not tolerating CPAP or mandibular advancement splints. However, it is only an option if CPAP and mandibular advancement splints are unsuccessful, so increased uptake of these devices and resource impact is likely to be small.
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# Surgery for OSAHS
Recommendations 1.7.3 and 1.7.4
## Why the committee made the recommendations
The evidence showed that oropharyngeal surgery (including tonsillectomy) was effective in some people with moderate or severe OSAHS.
Based on their knowledge and experience, the committee agreed that tonsillectomy should be prioritised in people with large obstructive tonsils, and that people with a BMI of 35 kg/m2 or above are less likely to benefit from surgery because they are more likely to have multi-level upper airway obstruction. There was no direct evidence for people with mild OSAHS, but the committee agreed that tonsillectomy should be applicable to all severities when tonsils are clearly causing obstruction.
Based on the evidence and their knowledge and experience, the committee agreed that other types of oropharyngeal surgery could be an option for some people with severe OSAHS who have been unable to tolerate CPAP and a customised mandibular advancement splint. Although the evidence included people with moderate or severe OSAHS, most were in the severe category and the committee agreed that benefit was more likely in this group. There are no other treatment options for people with severe OSAHS who cannot tolerate CPAP and mandibular advancement splints, and the committee agreed that surgery for the right people would improve their quality of life. They noted that the economic analysis showed that this surgery could be cost effective if the treatment effects are maintained for 2.4 years or more. On that basis, the committee agreed that referral for oropharyngeal surgery is cost effective for carefully selected people with severe OSAHS who have been unable to tolerate other treatments.
The committee stressed that, before considering referral for surgery, people should have fully explored other treatment options under medical supervision for a sufficient period of time. The committee also noted the potential risks of surgical intervention in people with severe OSAHS, and stressed that a personalised approach to patient selection is needed. This includes an assessment of anaesthetic risk and of the type and extent of surgery, which is critical because the outcome will depend on the anatomical and physiological phenotype of OSAHS. They therefore made a recommendation for referral for surgical consideration rather than surgery itself, acknowledging that precise individual assessment by the surgical team would be needed.
Because of a lack of sufficient evidence, the committee did not make any recommendations for nasal or skeletal framework surgery. They made a research recommendation on upper airway surgical interventions for people with OSAHS who are unable to tolerate or adhere to CPAP, because there was limited evidence for the applicability of this approach.
## How the recommendations might affect practice
The recommendation for tonsillectomy is broadly in line with current practice.
People who are unable to tolerate or adhere to CPAP and mandibular advancement splints are not usually referred for oropharyngeal surgery, so there is likely to be a change in practice for some providers. This recommendation is likely to only affect a small minority of people with severe OSAHS that is not helped by other treatments, have few comorbidities and for whom surgery is a suitable option.
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# Oxygen therapy for OSAHS
There was no evidence for oxygen therapy as an adjunct to CPAP for people with OSAHS.
There was also a lack of convincing evidence in favour of oxygen therapy alone for people with moderate OSAHS and no evidence for people with mild and severe OSAHS. Therefore, the committee decided that because there is a cost associated with this treatment and no evidence of benefit, they could not make a consensus recommendation for oxygen therapy for anyone with OSAHS. They agreed that a research recommendation on oxygen therapy, specifically looking at the clinical effectiveness of oxygen therapy compared with a placebo in people with OSAHS unable to tolerate CPAP would help to inform future guidance.
# Managing rhinitis in people with OSAHS
Recommendations 1.8.1 to 1.8.4
## Why the committee made the recommendations
There was limited evidence to demonstrate the benefits of treating rhinitis. However, the committee agreed, based on their knowledge and experience, that treating rhinitis and other causes of nasal obstruction is important and may help people use CPAP more comfortably, and has a positive impact on sleep disorders. Changing the interface from a nasal to an orofacial mask and adding humidification can also help. The committee advised that current practice should be followed for initial treatment, and that referral to an ear, nose and throat specialist may be needed for further assessment of persistent symptoms.
## How the recommendations might affect practice
The recommendations reflect current practice in most NHS centres, so there is likely to be little change in practice.
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# Follow-up for people with OSAHS
Recommendations 1.9.1 to 1.9.8
## Why the committee made the recommendations
There was limited evidence on follow-up, so the committee also used their clinical knowledge and experience to make the recommendations.
The committee noted that CPAP is just one aspect of treatment for OSAHS, and that follow-up should be tailored to the person's overall treatment plan. This may include lifestyle changes (such as weight management, modifying use of sedative drugs and alcohol, and stopping smoking) and treating underlying lung disease and other comorbidities.
CPAP adherence patterns are usually established in the first week of therapy. Therefore the committee agreed that early assessment of CPAP (within 1 month) is helpful to check adherence, for initial problem solving and to provide support. There was no evidence to suggest a difference between face-to-face, phone and video consultations, so the committee agreed that these could all be options for follow-up. The evidence also suggested that consultations with telemonitoring were as effective as those without telemonitoring. However, there was some evidence available for people with severe OSAHS that suggested adherence is improved by including telemonitoring and the committee agreed that the data could be extrapolated to people with mild and moderate OSAHS.
The committee agreed that although the available evidence did not show much benefit, in their experience telemonitoring offers significant advantages over not using telemonitoring to both the clinician and the person using CPAP. These include early night-by-night access to data, which can lead to early detection of problems such as mask leaks or persistent respiratory events of sleep apnoea, and the ability to monitor control of OSAHS and adherence to therapy.
Telemonitoring makes managing a person's OSAHS more efficient for healthcare professionals because they have ready access to the person's data when needed, for example, to help identify a problem (such as, mask leak or inadequate pressure) and take action without a scheduled appointment.
The committee agreed that video and phone consultations along with telemonitoring are also advantageous in reducing the number of in-person visits needed to the sleep service. This can be particularly beneficial to people who have difficulty getting to clinics, for example, those who live in remote areas or have poor mobility. The reduction in the number of face-to-face consultations will also help reduce the risk of infection during the COVID‑19 pandemic. Based on their experience, the committee agreed that subsequent follow-up should be personalised until effective CPAP treatment is established.
The committee discussed the benefits of longer-term follow-up comparing annual with a 2‑yearly follow-up interval once CPAP is established. They agreed that annual follow-up should be considered because it allows the opportunity to review progress and symptom control, assess adherence and effectiveness, and review the need to continue therapy. The committee also agreed that support between appointments was important in case of problems, and for providing advice, equipment and consumables.
No evidence was identified on monitoring for people using mandibular advancement splints. Based on experience, the committee agreed that early face-to-face follow-up, or video or phone consultation is advisable for people using a mandibular advancement splint to review symptom improvement and make further adjustments to the device. Subsequent follow-up should be personalised and include assessment of side effects and the impact on dentition and bite.
There was no evidence on monitoring for people using positional devices, but the committee also agreed that early face-to-face follow-up, video or phone consultation is beneficial to assess symptom control and determine whether respiratory events are controlled.
For people who have had surgery for OSAHS, the committee agreed that follow-up should happen within 3 months and include respiratory polygraphy. Wound healing and any early inflammation should be resolved before this is considered.
The committee noted that an annual review is required by the DVLA for Group 2 licence holders (lorry and bus drivers) with moderate or severe OSAHS and excessive sleepiness at diagnosis. For Group 1 licence holders (car and motorcycle drivers) with OSAHS and excessive sleepiness, review is required at least every 3 years. For more information, see the DVLA guidance on assessing fitness to drive.
## How the recommendations might affect practice
Current practice includes a mixture of face-to-face, phone and video consultations and telemonitoring. The increasing number of people being offered CPAP means that providing regular outpatient follow-up has become increasingly difficult. The use of telemonitoring may increase, which is likely to reduce the need for face-to-face consultations and may reduce pressure on outpatient clinics. Increasing web- and app-based access to telemonitoring data will allow patients to access their own results and will encourage self-management.
The committee noted that there has been a significant move to video and phone consultations to reduce the risk of infection during the COVID‑19 pandemic, and this shift in practice is likely to persist.
The committee stressed that telemonitoring crucially involves feedback to patients, and time should be available for sleep service staff to review data, act on this and share with the person using CPAP. Current practice already includes ready access to advice and CPAP equipment from sleep services.
Recommendations on monitoring for positional modifiers, mandibular advancement splints and surgery are considered to be current practice in many areas and are not expected to lead to major changes in practice.
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# Monitoring treatment efficacy in people with OSAHS
Recommendations 1.9.9 to 1.9.11
## Why the committee made the recommendations
No evidence was available on the efficacy of treatment for OSAHS, so the recommendations are based on the committee's knowledge and experience.
The effectiveness of treatment can be confirmed by control of symptoms and AHI or oxygen desaturation index (ODI), and uptake and adherence to therapy. The committee identified several factors that commonly cause problems with CPAP that should be routinely reviewed if treatment is not working. As well as assessing sleepiness, the committee agreed that vigilance should be assessed by discussing the person's alertness and ability to concentrate on tasks. This is particularly important for drivers.
OSAHS may sometimes resolve, for example, because of weight loss or other lifestyle changes. The committee agreed that stopping treatment should be considered if this is suspected. If symptoms return, these will need to be re‑evaluated. A sleep study may be needed to confirm whether OSAHS has resolved.
## How the recommendations might affect practice
These recommendations reflect current practice and are not expected to lead to a change in practice.
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# Supporting adherence to treatment for OSAHS
Recommendations 1.10.1 and 1.10.2
## Why the committee made the recommendations
The committee considered behavioural, supportive and educational interventions and made recommendations based on the evidence and their experience.
The evidence suggested that all types of interventions to support adherence (educational, behavioural, supportive and mixed) increased CPAP use in people starting CPAP for the first time with moderate or severe OSAHS. There was no evidence available for people with mild OSAHS, but the committee agreed that these recommendations would be applicable to all people having treatment for OSAHS. The committee agreed that educational or supportive interventions, or a combination of these, provided by specialist staff, would help to improve adherence to CPAP.
Educational interventions include providing information about OSAHS, its treatment and outcomes, which can be delivered using a variety of different sessions and formats. Supportive interventions involve additional clinical follow-up (for example, extra clinic visits, video or teleconsultations or use of telemonitoring) to provide support. The nature of behavioural interventions varied widely, making it difficult to identify the most effective components. Therefore, the committee could not recommend any specific behavioural interventions.
Optimal adherence to CPAP therapy is conventionally considered to be 4 hours or more per night or using CPAP for an average of more than 4 hours per night for 70% or more nights. Early adherence studies focused on control of sleepiness but there is evidence that increased CPAP use of more than 5 hours a night in OSAHS benefits other aspects of health such as control of blood pressure and cardiovascular risk. However, it is recognised that people can gain some benefit from a shorter period of use, and individual response is variable. People should be encouraged to maximise their CPAP use to achieve optimal control of their symptoms, underlying conditions, sleep quality and quality of life.
There was no evidence available for improving adherence to mandibular advancement splint and positional modifiers in OSAHS. However, the committee agreed that evidence for improving adherence for CPAP could be applied to other treatments.
Because there was no evidence for people who have difficulty using CPAP, the committee made a research recommendation on interventions to improve CPAP adherence to inform future guidance.
## How the recommendations might affect practice
The recommendations reflect best practice, but current provision varies across NHS settings. Therefore, the recommendations will involve a change of practice for some providers.
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# When to suspect OHS
Recommendation 2.1.1
## Why the committee made the recommendation
No evidence was available on identifying who to assess for obesity hypoventilation syndrome (OHS), so the recommendation is based on the committee's knowledge and experience.
The committee agreed that further assessment for OHS should be carried out in people with obesity together with symptoms of OSAHS or features of nocturnal hypoventilation. These criteria were chosen because some people with OHS have OSAHS, some have nocturnal hypoventilation alone, and others have both. A low arterial oxygen saturation value or polycythaemia may be indicative of OHS, but raised PaCO2 (partial pressure of carbon dioxide) is needed for diagnosis (for more information, see the rationale and impact section on diagnostic tests for OHS ).
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## How the recommendation might affect practice
In current practice, not all people with the listed symptoms and features are considered for further assessment for OHS, so this recommendation may result in a change of practice for most providers, leading to more testing and treatment. This will be magnified by the rising prevalence of obesity in the general population.
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# Assessment scales for suspected OHS
Recommendations 2.1.2 and 2.1.3
## Why the committee made the recommendations
No evidence was found on assessment tools for suspected OHS, so the committee based the recommendation on their knowledge and experience. They agreed that the Epworth Sleepiness Scale has a useful role in monitoring and assessment of sleepiness in people with OHS. However, they noted that not all people with OHS have excessive sleepiness and that healthcare professionals may not always be aware of this.
The evidence for the STOP-Bang Questionnaire was limited to OSAHS only and there was no validation for its use in OHS. The committee agreed that the STOP-Bang Questionnaire is not used in practice for OHS, so they did not make a recommendation for this.
## How the recommendations might affect practice
The Epworth Sleepiness Scale is widely used in current practice, so the recommendations are not expected to involve a change in practice.
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# Prioritising people for rapid assessment by a sleep service
Recommendations 2.2.1 and 2.2.2
## Why the committee made the recommendations
No evidence was available for prioritising people with OHS for assessment in a sleep service, so the committee used their knowledge and experience to identify groups that would benefit most from prompt assessment and treatment.
The committee noted that people with a BMI over 30 kg/m2 and severe hypercapnia or hypoxaemia should be prioritised because they have chronic ventilatory failure and are at risk of acute decompensated ventilatory failure, both of which carry a poor prognosis.
The committee agreed that sleep services should prioritise access to a sleep study and treatment for people in whom vigilance and alertness are vital to occupational safety, particularly those with problematic sleepiness, and to people with pre-existing conditions who are at increased risk of adverse events. They agreed that services should aim to fast-track priority groups to be seen as soon as possible.
The committee discussed the effect on work performance and safety for people with suspected OHS who also have OSAHS and how it could increase the risk of work accidents in safety-sensitive occupations. People with a wide range of jobs or activities could be affected, for example, drivers, train drivers, pilots, heavy machinery operators, surgeons and people caring for vulnerable children or adults. They noted that DVLA guidance on assessing fitness to drive recommends that drivers with suspected or confirmed OSAHS and excessive sleepiness having, or likely to have, an adverse impact on driving must not drive until there is satisfactory symptom control. Control of symptoms is likely to need assessment and treatment from a sleep specialist.
The committee agreed that priority should be given to pregnant women, because uncontrolled OHS may adversely affect both the mother and baby.
The committee agreed that people with unstable cardiovascular disease should be offered early investigation and treatment, because cardiovascular complications are a major cause of mortality and morbidity in people with OHS.
The committee agreed that people with a high probability of OHS who need major surgery should be prioritised to avoid delaying surgery.
The committee also agreed that the risk of sudden blindness in patients with non-arteritic anterior ischaemic optic neuropathy warrants priority assessment because of its possible association with OHS.
To ensure that people are prioritised appropriately by sleep services, and to allow fast-tracking directly to a sleep study, the committee agreed on key details, based on their experience, that should be included in referral letters.
## How the recommendations might affect practice
In current practice, specific groups are not always prioritised for assessment, so there is likely to be a change in practice for some providers. There is increasing pressure on sleep services, and offering higher priority to some groups may delay studies for other people. Planning for and providing rapid-access sleep studies may help to reduce the pressure on services, with triage of referrals allowing people to be fast-tracked directly to a diagnostic study.
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# Diagnostic tests for OHS
Recommendations 2.3.1 to 2.3.6
## Why the committee made the recommendations
The committee noted that OHS is defined by the presence of PaCO2 greater than 6.0 kPa while awake in people with a BMI of 30 kg/m2 or more. There was no evidence for diagnostic tests to identify the presence of OSAHS or nocturnal hypoventilation in people with suspected OHS, so the committee also used their clinical knowledge and experience to make the recommendations.
OHS is a specific form of chronic ventilatory failure and, by definition, a measurement of PaCO2 from arterial or arterialised capillary blood gas, taken while the person with suspected OHS is awake, is needed to establish the diagnosis and to assess the extent of chronic ventilatory failure. It is current practice to measure these and, although they are invasive tests, obtaining the samples is generally straightforward.
Serum venous bicarbonate indirectly reflects medium- and long-term PaCO2 levels. It is a simpler test to perform, and a normal level is helpful in ruling out OHS if the pre-test probability of the diagnosis is low. The committee therefore agreed that it could be recommended in such cases, but noted that this alone will not completely rule out OHS and that other tests are needed when clinical suspicion is high.
People with any form of chronic ventilatory failure can readily develop acute ventilatory failure if, for example, they have an intercurrent respiratory tract infection. Acute ventilatory failure is a medical emergency needing urgent treatment, and the committee agreed it is important to state that this should take priority over full investigation of any underlying chronic disease.
Diagnosis of coexisting OSAHS is needed to ensure optimal choice of treatment, and the committee agreed that this should be with either hospital or home respiratory polygraphy, based on their experience and the evidence for diagnosis of OSAHS in people without OHS (see the rationale section on diagnostic tests for OSAHS). The committee agreed that transcutaneous CO2 monitoring with respiratory polygraphy should also be considered at the same time, to help establish the severity of nocturnal hypoventilation. A markedly raised CO2 level suggests non-invasive ventilation may be the treatment of choice rather than CPAP.
Home or hospital respiratory polygraphy are recommended equally because diagnosing the presence of OSAHS in OHS is more complex than diagnosing OSAHS alone; it is important to be able to distinguish between OSAHS and nocturnal hypoventilation. The committee also discussed that CO2 monitoring is quite hard to do at home.
Oximetry alone is insufficient for diagnosis because it does not clearly distinguish between obstructive apnoeas and nocturnal hypoventilation.
## How the recommendations might affect practice
The recommendations reflect current practice and would therefore not be expected to increase NHS cost.
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# Lifestyle advice for OHS
Recommendation 2.4.1
## Why the committee made the recommendation
Evidence for lifestyle advice was not reviewed because it is covered by other NICE guidelines.
The committee agreed that all people with OHS should discuss lifestyle changes with their healthcare professional. This should focus on weight loss and be tailored to the person's needs and the chosen treatment method.
Lifestyle changes are important because obesity increases the prevalence and severity of OHS, smoking causes upper airway inflammation (which can exacerbate symptoms), and excess alcohol before sleep reduces upper airway tone (increasing apnoeas) and reduces sleep quality. Advice on sleep hygiene may include ensuring adequate sleep time, avoiding caffeine and stimulants that interfere with sleep before bedtime, exercising regularly, having a quiet, comfortable, darkened bedroom, and winding down before sleep.
## How the recommendation might affect practice
Lifestyle advice is widely used in current practice, so the recommendations are not expected to involve a change in practice.
Return to recommendations
# Treatments for OHS
Recommendations 2.5.1 to 2.5.8
## Why the committee made the recommendations
The evidence was limited to people with OHS and severe OSAHS without acute ventilatory failure. It showed that both CPAP and non-invasive ventilation are beneficial compared with lifestyle changes, and that there is little difference in effectiveness between these treatments. There was no evidence for people with acute ventilatory failure.
Based on evidence and their experience, the committee agreed that CPAP should be offered as a first-line treatment for people with OHS and severe OSAHS who do not have acute ventilatory failure because it is more cost effective, simpler to set up and may be better tolerated than non-invasive ventilation. If symptoms do not improve, severe hypercapnia persists, AHI or ODI are not sufficiently reduced, or CPAP is poorly tolerated, the committee agreed that treatment should be changed to non-invasive ventilation to control nocturnal hypoventilation.
In line with current practice, the committee agreed that non-invasive ventilation should be considered as first-line treatment for people with OHS in the absence of severe OSAHS.
Although there was no direct evidence available, the committee were clear that non-invasive ventilation should be the first-line treatment for people with OHS and acute ventilatory failure because rapid improvement in hypercapnia is a priority. A trial without non-invasive ventilation may be suitable for people in whom hypercapnia resolves. In this instance, they should remain under review in case hypercapnia recurs and be restarted on non-invasive ventilation, if necessary. Assessment with respiratory polygraphy on recovery should be carried out to determine if long-term treatment with CPAP or non-invasive ventilation is needed. The committee agreed that people with residual OSAHS but minimal hypoventilation when stable can be switched to CPAP.
No evidence was available for oxygen therapy in people with OHS. The committee agreed that, although optimal CPAP or non-invasive ventilation will usually be sufficient to correct ventilatory failure, some people with OHS may remain hypoxaemic during sleep despite control of AHI and nocturnal hypercapnia on CPAP or non-invasive ventilation. This would be shown on oximetry measures or on arterial blood gas during sleep. Addition of supplemental oxygen therapy to the CPAP or non-invasive ventilation during sleep may be needed to correct this hypoxia and any additional underlying causes of hypoxaemia should be addressed where possible. Usually only a low flow rate such as 1 to 2 litres/minute would be needed. Repeating oximetry or arterial blood gas would allow the response to this oxygen therapy to be evaluated and any further adjustments to oxygen prescription to be made.
## How the recommendations might affect practice
The use of CPAP for people with OHS is a change in practice that is likely to result in less non-invasive ventilation use.
The recommendations on oxygen therapy reflect current practice in most NHS centres, so there is likely to be little impact on practice.
Return to recommendations
# Managing rhinitis in people with OHS
Recommendations 2.6.1 to 2.6.4
## Why the committee made the recommendations
No evidence was available on managing rhinitis for people with OHS. The committee agreed that recommendations for OSAHS are applicable to people with OHS as well. They agreed, based on their knowledge and experience, that treating rhinitis and other causes of nasal obstruction is important and may help people use CPAP more comfortably, and have a positive impact on sleep disorders. Changing the interface from a nasal to an orofacial mask and adding humidification can also help. The committee advised that current practice should be followed for initial treatment, and that referral to an ear, nose and throat specialist may be needed for further assessment of persistent symptoms.
## How the recommendations might affect practice
The recommendations reflect current practice in most NHS centres, so there is likely to be little change in practice.
Return to recommendations
# Follow-up for people with OHS
Recommendations 2.7.1 to 2.7.5
## Why the committee made the recommendations
The committee noted that CPAP and non-invasive ventilation are just part of treatment for OHS, and that follow-up should be tailored to the person's overall treatment plan. This should also include lifestyle changes (such as weight management, modifying use of sedative drugs and alcohol, and stopping smoking) and treating underlying lung disease and other comorbidities.
Based on their knowledge and experience, the committee agreed that for people with OHS starting CPAP or non-invasive ventilation, early follow-up at 1 month is advisable to review control of symptoms, sleep-disordered breathing and adherence. Problem solving can be achieved by face-to-face, video or phone consultations, and can include review of telemonitoring data if available. The committee also agreed that although most studies of telemonitoring are in patients with OSAHS, and that there is not yet the ability to assess hypercapnia through telemonitoring, it is still of value for monitoring in people with OHS who also have OSAHS.
In addition to annual review, people with OSAHS and OHS having CPAP or non-invasive ventilation therapy need to be able to access a sleep service for advice and provision of consumables such as masks, circuitry and filters.
The committee noted that an annual review is required by the DVLA for Group 2 licence holders (lorry and bus drivers) with moderate or severe OSAHS and excessive sleepiness at diagnosis. For Group 1 licence holders (car and motorcycle drivers) with OSAHS and excessive sleepiness, review is required at least every 3 years. For more information, see the DVLA guidance on assessing fitness to drive.
## How the recommendations might affect practice
Current practice includes a mixture of face-to-face, phone and video consultations and telemonitoring. The increasing number of people being offered CPAP means that providing regular outpatient follow-up has become increasingly difficult. In addition, a more personalised approach enables attention to be focused on people with problems adapting to therapy. Telemonitoring is included in the overall cost of CPAP devices by some manufacturers for variable periods, and is increasingly available for non-invasive ventilators. The committee discussed that routine use of telemonitoring should reduce the need for face-to-face consultations, and reduce pressure on outpatient clinics, but feedback and discussion with patients is still needed. Increasing web- and app-based access to telemonitoring data will allow patients to access their own results and encourage self-management.
The committee noted that there has been a significant move to video and phone consultations to reduce the risk of infection during the COVID‑19 pandemic, and this shift in practice is likely to persist.
Return to recommendations
# Monitoring treatment efficacy for people with OHS
Recommendations 2.7.6 to 2.7.8
## Why the committee made the recommendations
No evidence was available for demonstrating efficacy of treatment for OHS, so the recommendations are based on the committee's knowledge and experience.
In OHS, control of nocturnal hypoventilation is demonstrated by improvement of symptoms, hypercapnia when awake and asleep, and oxygenation. It is important to optimise these to improve wellbeing and prognosis, and to reduce the risk of hospital admission.
The committee agreed that clinical effectiveness of CPAP and non-invasive ventilation in people with OHS should be assessed by reviewing symptoms of OSAHS and nocturnal hypoventilation including Epworth Sleepiness Scale score, AHI or ODI, adherence to therapy, improvement in oxygenation and hypercapnia while awake and asleep, and telemonitoring or download information from the CPAP or non-invasive ventilation device. As well as assessing sleepiness, the committee agreed that vigilance should be assessed by discussing the person's alertness and ability to concentrate on tasks. This is particularly important for drivers.
The committee agreed that the understanding and experience of people having CPAP or non-invasive ventilation should be explored, and factors that commonly cause problems should be reviewed.
The committee highlighted that in people with OHS, the need for oxygen therapy and adherence to this should be reviewed after treatment with non-invasive ventilation or CPAP has been optimised.
## How the recommendations might affect practice
These recommendations reflect current practice and are not expected to lead to major changes in practice.
Return to recommendations
# Supporting adherence to treatment for OHS
Recommendations 2.8.1 and 2.8.2
## Why the committee made the recommendations
There was no evidence available for people with OHS. The committee agreed that the evidence reviewed for supporting adherence to CPAP in people with OSAHS could be extrapolated to treatments in people with OHS.
## How the recommendations might affect practice
The recommendations reflect best practice but are currently implemented to varying degrees across NHS settings and will involve a change of practice for some providers.
Return to recommendations
# When to suspect COPD–OSAHS overlap syndrome
Recommendation 3.1.1
## Why the committee made the recommendation
No evidence was available for when to suspect chronic obstructive pulmonary disease–obstructive sleep apnoea/hypopnoea syndrome (COPD–OSAHS) overlap syndrome, so the recommendations are based on the committee's knowledge and experience.
COPD–OSAHS overlap syndrome describes the combination of COPD and OSAHS. These are 2 of the most prevalent pulmonary conditions and therefore the combination is likely to be common. Hypoxaemia due to COPD is exacerbated during sleep by OSAHS, which may worsen prognosis and symptom burden. The committee agreed that a sleep history should be taken and further assessment for OSAHS carried out in people with COPD presenting with common symptoms and features of either OSAHS or nocturnal hypoventilation. The type of symptoms, nature of sleep-disordered breathing and outcome will be affected by the relative severity of COPD and OSAHS.
## How the recommendation might affect practice
It is estimated that COPD–OSAHS overlap syndrome has a prevalence of approximately 1% and is currently under recognised. In current practice, not all people with the symptoms and features of OSAHS listed in the recommendation are considered for further assessment for COPD–OSAHS overlap syndrome, hence implementation of these recommendations may change practice for most providers. A growth in referrals for sleep study is anticipated with an increased understanding of the impact of COPD–OSAHS overlap syndrome. As a result of increased diagnosis, CPAP and non-invasive ventilation use may increase. Treatment in turn may reduce acute admissions and long-term complications.
Return to recommendations
# Assessment scales and tests for suspected COPD–OSAHS overlap syndrome
Recommendations 3.1.2 to 3.1.5
## Why the committee made the recommendations
There was limited evidence on assessment tools for suspected COPD–OSAHS overlap syndrome, so the committee also used their knowledge and collective experience to make the recommendations.
The Epworth Sleepiness Scale is intended to assess for sleepiness and the limited evidence reflected this, showing that it had moderate sensitivity and low specificity for diagnosing COPD–OSAHS overlap syndrome. The committee noted that some people with this syndrome do not have excessive sleepiness and that not all healthcare professionals are aware of this. However, they agreed that it has a useful role in assessment and monitoring, and noted that when healthcare professionals are requested by the DVLA to complete assessment of a driver with OSAHS (which will include those with COPD–OSAHS overlap syndrome), this includes the Epworth Sleepiness Scale.
Limited evidence showed that the STOP-Bang Questionnaire had high sensitivity and low specificity for diagnosing COPD–OSAHS overlap syndrome. Sensitivity is a priority for questionnaires used for initial assessment. The committee had some concerns about its accuracy in people with less common presentations and in women, but agreed that it could have a role in assessment, alongside the Epworth Sleepiness Scale, to inform the preliminary understanding of the person's symptoms and concerns. The Epworth questionnaire is used to assess only sleepiness whereas the STOP-Bang Questionnaire is used to assess risk of having OSAHS and includes parameters such as snoring, tiredness, history of high blood pressure, BMI, age, neck size and gender. With this in mind, the committee agreed that the Epworth questionnaire should be used, and the STOP-Bang Questionnaire could also be considered for initial assessment.
Spirometry is routinely measured in clinical practice to assess the severity of COPD, and it aids the understanding of the relative contribution of COPD and OSAHS to symptom load and pathophysiology.
## How the recommendations might affect practice
The Epworth Sleepiness Scale and the STOP-Bang Questionnaire are widely used in current practice, and spirometry is routinely used to assess COPD, so the recommendations are not expected to involve a change in practice.
Return to recommendations
# Prioritising people for rapid assessment by a sleep service
Recommendations 3.2.1 and 3.2.2
## Why the committee made the recommendations
No evidence was available for prioritising people with COPD–OSAHS overlap syndrome for assessment in a sleep service, so the committee used their knowledge and experience to identify groups that would benefit most from prompt assessment and treatment.
The committee noted that people with suspected COPD–OSAHS overlap syndrome who have severe hypercapnia or hypoxaemia should be prioritised for assessment because they have chronic ventilatory failure, and are at risk of acute decompensated ventilatory failure, both of which carry a poor prognosis.
The committee agreed that sleep services should prioritise access to a sleep study and treatment for people in whom vigilance and alertness are vital to occupational safety, particularly those with problematic sleepiness, and to people with pre-existing conditions who are at increased risk of adverse events. They agreed that services should aim to fast-track priority groups to be seen as soon as possible.
The committee discussed the effect of OSAHS on work performance and safety, and how it could increase the risk of work accidents in safety-sensitive occupations. People with a wide range of jobs or activities could be affected, for example, drivers, train drivers, pilots, heavy machinery operators, surgeons and people caring for vulnerable children or adults. The committee noted that DVLA guidance on assessing fitness to drive recommends that drivers with suspected or confirmed OSAHS and excessive sleepiness having, or likely to have, an adverse impact on driving must not drive until there is satisfactory symptom control. Control of symptoms is likely to need assessment and treatment from a sleep specialist.
The committee agreed that priority should be given to pregnant women, because COPD–OSAHS overlap syndrome may be associated with poor outcomes for mothers and babies.
People with suspected COPD–OSAHS overlap syndrome and unstable cardiovascular disease need early investigation and treatment, because cardiovascular complications may be a major cause of mortality and morbidity in overlap syndrome.
The committee agreed that people with a high probability of COPD–OSAHS overlap syndrome who need major surgery should be prioritised to avoid delaying surgery.
The committee also agreed that the risk of sudden blindness in patients with non-arteritic anterior ischaemic optic neuropathy warrants priority assessment because of its possible association with COPD–OSAHS overlap syndrome.
To ensure that patients are prioritised appropriately by sleep services and to allow fast-tracking directly to a sleep study, the committee agreed on key details, based on their experience, that should be included in referral letters.
## How the recommendations might affect practice
In current practice, specific groups are not always prioritised for assessment, so there is likely to be a change in practice for some providers. There is increasing pressure on sleep services, and offering higher priority to some groups may delay studies for other people. Planning for and providing rapid-access sleep studies may help to reduce the pressure on services, with triage of referrals allowing people to be fast-tracked directly to a diagnostic study.
Return to recommendations
# Diagnostic tests for COPD–OSAHS overlap syndrome
Recommendations 3.3.1 to 3.3.5
## Why the committee made the recommendations
There was little evidence for diagnostic tests in people with COPD–OSAHS overlap syndrome, so the committee used their clinical knowledge and experience, and the evidence on testing for OSAHS, to make the recommendations.
The committee agreed that arterial or arterialised capillary blood gas measurement is needed to assess for ventilatory failure. People with any form of chronic ventilatory failure can readily develop acute ventilatory failure if, for example, they have an intercurrent respiratory tract infection. Acute ventilatory failure is a medical emergency needing urgent treatment, and the committee agreed it important to state that this should take priority over full investigation of any underlying chronic disease.
The committee agreed that arterial blood gas and arterialised capillary blood gas measurements give precise information about oxygen and carbon dioxide levels and information about acid–base balance at the point in time they are taken. It is current practice to use them, and they are generally straightforward to measure.
Respiratory polygraphy (either in hospital or at home) is recommended to establish the presence and severity of OSAHS and nocturnal hypoventilation, and to help determine the most suitable treatment (such as non-invasive ventilation or CPAP). The committee agreed that transcutaneous CO2 monitoring with respiratory polygraphy should also be considered to help confirm nocturnal hypoventilation and severity of hypercapnia. Adding transcutaneous CO2 monitoring with respiratory polygraphy may also help to define the relative contributions of COPD and OSAHS and therefore guide treatment choices and titration of settings. The person needs to have stable COPD, without recent exacerbations, before a clear diagnosis can be established.
Home or hospital respiratory polygraphy are recommended equally because diagnosing the presence of OSAHS in COPD–OSAHS overlap syndrome is more complex than diagnosing OSAHS alone. The hospital setting may be better for distinguishing between OSAHS and nocturnal hypoventilation, and determining whether to offer CPAP or non-invasive ventilation to a person with COPD on long-term oxygen therapy. The committee also discussed that CO2 monitoring is quite hard to do at home.
Oximetry alone should not be used to diagnose OSAHS in this population because people with COPD are more likely to have a degree of hypoxaemia when awake, and therefore more easily exhibit falls in oxygen saturation level during sleep, making identification of apnoea episodes more difficult.
## How the recommendations might affect practice
The recommendations reflect current practice.
Return to recommendations
# Treatments for COPD–OSAHS overlap syndrome
Recommendations 3.5.1 to 3.5.5
## Why the committee made the recommendations
No evidence was identified for CPAP or non-invasive ventilation for people with COPD–OSAHS overlap syndrome, so the recommendations are based on the committee's knowledge and experience.
The committee agreed that treatment for this population depends on the level of hypercapnia when awake and asleep. People with more severe hypercapnia when awake (PaCO2 greater than 7 kPa) caused by nocturnal hypoventilation, are likely to need non-invasive ventilation. This is based on extrapolation from data, not reviewed for this guideline but known to the committee, on people with COPD without OSAHS. In these people, definite benefit of non-invasive ventilation has not been demonstrated when hypercapnia is modest (PaCO2 between 6 kPa and 7 kPa, and not associated with exacerbation of COPD). The committee therefore recommended that CPAP should be considered in people with COPD–OSAHS overlap syndrome if they have confirmed OSAHS from a sleep study and if their PaCO2 is less than or equal to 7.0 kPa, and non-invasive ventilation should be considered if the PaCO2 is higher.
The committee also made a research recommendation on the optimal treatment for people with COPD–OSAHS overlap syndrome to inform future guidance.
Based on their experience of current practice, the committee agreed that using humidification with CPAP for people with COPD–OSAHS overlap syndrome who have nasal symptoms may reduce side effects associated with upper airway dryness and this may improve adherence and treatment effectiveness.
For all treatments, the committee highlighted the importance of assessing response to treatment (see recommendations 3.7.6 to 3.7.10).
No evidence was available for oxygen therapy in people with COPD–OSAHS overlap syndrome. Some people will be established users of long-term oxygen therapy, in which case their supplemental oxygen can be given by CPAP or non-invasive ventilation while sleeping, with oxygen flow rate and non-invasive ventilation or CPAP settings titrated during respiratory polygraphy, according to individual need.
People with COPD–OSAHS overlap syndrome are subject to greater falls in oxygen saturation while sleeping than those with COPD alone, and the committee therefore agreed that people with COPD–OSAHS overlap syndrome who do not fulfil the criteria for long-term oxygen therapy may need supplemental oxygen therapy during sleep if they remain hypoxaemic despite control of AHI and nocturnal hypercapnia on CPAP or non-invasive ventilation, and any additional underlying causes of hypoxaemia should be addressed where possible.
## Why the committee did not make recommendations
There was no evidence for the use of mandibular advancement splints in people with COPD–OSAHS overlap syndrome. The committee discussed whether evidence from people with OSAHS could be used for people with COPD–OSAHS overlap syndrome, but they agreed that the differences between these 2 groups are too great to allow them to make a consensus recommendation based on this evidence.
The committee were also aware of the potential risks of the long-term use of mandibular advancement splints. People with COPD–OSAHS overlap syndrome are generally older and have poorer dentition which makes mandibular advancement splints less likely to be effective. They also agreed that people with COPD–OSAHS overlap syndrome are at risk of or have ventilatory failure, and mandibular advancements splints are not appropriate in those circumstances.
## How the recommendations might affect practice
The recommendations reflect current practice.
Return to recommendations
# Follow-up for people with COPD–OSAHS overlap syndrome
Recommendations 3.7.1 to 3.7.5
## Why the committee made the recommendations
The committee noted that CPAP and non-invasive ventilation are just part of treatment for COPD–OSAHS overlap syndrome, and that follow-up should be tailored to the person's overall treatment plan. This should also include lifestyle changes (such as weight management, modifying use of sedative drugs and alcohol, and stopping smoking) and treating underlying lung disease and other comorbidities. For some people, it may also include discussions about care planning (for example, COPD exacerbation action plan and advance care planning) for those with severe COPD.
Based on their knowledge and experience, the committee agreed that for people with COPD–OSAHS overlap syndrome starting CPAP or non-invasive ventilation, early follow-up is advisable to review control of symptoms, sleep-disordered breathing and adherence. Problem solving can be achieved by face-to-face consultations, or video or phone consultations, and include review of telemonitoring data if available. The committee also agreed that although most studies of telemonitoring are in people with OSAHS, and that there is not yet the ability to assess hypercapnia through telemonitoring, it is still of value for monitoring in people with COPD–OSAHS overlap syndrome.
In addition to their 6‑monthly or annual review, people with COPD–OSAHS overlap syndrome having CPAP or non-invasive ventilation need to be able to access a sleep service for advice, and provision of consumables such as masks, circuitry and filters.
The committee noted that annual review is required by the DVLA for Group 2 licence holders (lorry and bus drivers) with moderate or severe OSAHS and excessive sleepiness at diagnosis. For Group 1 licence holders (car and motorcycle drivers) with OSAHS and excessive sleepiness, review is required at least every 3 years. For more information, see the DVLA guidance on assessing fitness to drive.
## How the recommendations might affect practice
Current practice includes a mixture of face-to-face, phone, video consultations and telemonitoring. The increasing number of people being offered CPAP and non-invasive ventilation means that regular outpatient follow-up becomes difficult for sleep services to provide. In addition, a more personalised approach enables attention to be focused on people with problems adapting to therapy. Telemonitoring is included in the overall cost of CPAP devices by some manufacturers for variable periods. The committee discussed that routine use of telemonitoring should reduce the need for face-to-face consultations, and reduce pressure on outpatient clinics, but feedback and discussion with patients is still needed. Increasing web- and app-based access to telemonitoring data will allow patients to access their own results and encourage self-management.
The committee noted that there has been a significant move to video and phone consultations to reduce the risk of infection during the COVID‑19 pandemic, and this shift in practice is likely to persist.
Return to recommendations
# Monitoring treatment efficacy for people with COPD–OSAHS overlap syndrome
Recommendations 3.7.6 to 3.7.10
## Why the committee made the recommendations
No evidence was available on efficacy of treatment for COPD–OSAHS overlap syndrome, so the recommendations are based on the committee's knowledge and experience.
In COPD–OSAHS overlap syndrome, control of nocturnal hypoventilation is demonstrated by normalisation of oxygenation and hypercapnia when awake and asleep; this is important to improve prognosis.
The committee agreed that clinical effectiveness of CPAP and non-invasive ventilation in people with COPD–OSAHS overlap syndrome should be assessed by reviewing symptoms of OSAHS and nocturnal hypoventilation including Epworth Sleepiness Scale score, AHI or ODI, adherence to therapy, improvement in oxygenation and hypercapnia (if present) while awake and asleep, and telemonitoring or download information from CPAP or non-invasive ventilation device. As well as assessing sleepiness, the committee agreed that vigilance should be assessed by discussing the person's alertness and ability to concentrate on tasks. This is particularly important for drivers. The committee agreed that the understanding and experience of people having CPAP and non-invasive ventilation should be explored, and factors that commonly cause problems should be reviewed. They noted that sleep quality may be poor in COPD patients, with disruption from cough, wheeze, restless legs and medication.
The committee highlighted that in people with COPD–OSAHS overlap syndrome who are already having supplemental oxygen therapy, the need for oxygen therapy should be reviewed after treatment with non-invasive ventilation or CPAP has been optimised. Effective treatment with CPAP or non-invasive ventilation may improve the person's condition to the extent that they no longer fulfil the criteria for supplemental oxygen.
In some patients with severe COPD and COPD–OSAHS overlap syndrome, optimised treatment of the OSAHS may produce an objective improvement in indices such as the AHI or oxygen desaturation during sleep, but fail to improve symptoms or quality of life for the person. This would usually be because the severity of the person's COPD has the overriding influence on quality of life. Because use of non-invasive ventilation or CPAP equipment adds to the burden of therapy, consideration should be given to stopping these and using a symptom-management approach. This needs careful discussion with the person and their family or carers, including considering what they would like to do for COPD exacerbations and advance care planning when appropriate.
## How the recommendations might affect practice
These recommendations reflect current practice and are not expected to lead to major changes in practice.
Return to recommendations
# Supporting adherence to treatment for people with COPD–OSAHS overlap syndrome
Recommendations 3.8.1 and 3.8.2
## Why the committee made the recommendations
There was no evidence available for people with COPD–OSAHS overlap syndrome. The committee agreed that the evidence reviewed for supporting adherence to CPAP in people with OSAHS could be extrapolated to treatments in people with COPD–OSAHS overlap syndrome.
## How the recommendations might affect practice
The recommendations reflect best practice but are currently implemented to varying degrees across NHS settings and will involve a change of practice for some providers.
Return to recommendations
# Information for people with OSAHS, OHS and COPD–OSAHS overlap syndrome
Recommendations 4.1.1 to 4.1.5
## Why the committee made the recommendations
There was limited evidence from clinical studies on the information and support needs of people with OSAHS, and no evidence for people with OHS and COPD–OSAHS overlap syndrome, so the committee also used their clinical knowledge and experience to make the recommendations.
The committee discussed that providing appropriate information for people with OSAHS, OHS and COPD–OSAHS overlap syndrome is essential to help them understand their condition and access support and treatment. Attendance for sleep investigation, such as respiratory polygraphy, is likely to be higher if patients understand why these are being performed and what they entail.
The committee agreed that giving information about all aspects of treatment is likely to increase uptake and therefore effectiveness.
The committee noted that different sleep services provide their own information and were aware of useful resources produced by a number of organisations providing support to patients.
## How the recommendations might affect practice
The recommendations reflect current best practice.
Return to recommendations# Context
This guideline covers obstructive sleep apnoea/hypopnoea syndrome (OSAHS), obesity hypoventilation syndrome (OHS), and chronic obstructive pulmonary disease (COPD) with OSAHS overlap syndrome, providing advice on investigating and managing these related conditions.
OSAHS is a common, but frequently unrecognised cause of serious disability that has important health and social consequences. It is characterised by recurrent episodes of complete or partial upper airway obstruction during sleep resulting in dips in oxygen level, autonomic dysfunction and sleep fragmentation. There are a number of clinical and physiological variants (phenotypes) of the condition, which may influence treatment response.
OHS occurs when people who are obese are unable to breathe rapidly or deeply enough, resulting in low oxygen levels and high blood carbon dioxide levels. It is usually associated with OSAHS or nocturnal hypoventilation, and people with OHS often have cardiovascular complications and other comorbidities.
COPD–OSAHS overlap syndrome is the coexistence of OSAHS and COPD, which combined can cause a greater degree of oxygen deficiency, and increased morbidity, compared with either condition alone.
These conditions can have a profound impact on people's lives, causing excessive sleepiness or sleep disturbance that affects social activities, work performance, the ability to drive safely and quality of life. Undiagnosed, these conditions are closely associated with serious health problems, including hypertension, diabetes, stroke and heart disease, and can shorten life expectancy.
High numbers of the population are affected by these conditions, and they are often undiagnosed; it is estimated that 5% of adults in the UK have undiagnosed OSAHS. Both COPD and OSAHS are common conditions and are estimated to coexist, as overlap syndrome, in about 1% of the adult UK population. OHS is of particular concern because of rising obesity; it is already estimated to affect 0.3% to 0.4% of the UK population, with prevalence likely to grow.
The availability of services for investigation and management is variable. Failure to treat these conditions can result in an increased use of services and may leave people with a reduced quality of life. Highly effective treatment, in the form of continuous positive airway pressure (CPAP), is available. But approaches to CPAP therapy differ and there is a lack of guidance on when other forms of treatment, such as non-invasive ventilation, oral devices, lifestyle changes and surgery are effective. Adherence to therapy is known to be low, so advice on interventions to help with adherence is also a priority for this guideline.
This guideline is needed to improve recognition and management of OSAHS, OHS and COPD–OSAHS overlap syndrome, and ensure consistent provision of care. It gives advice to healthcare professionals on when and how to investigate, and how to manage each of these conditions. It also gives guidance on supporting people to adhere to treatment and providing follow-up.
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{'Obstructive sleep apnoea/hypopnoea syndrome': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nPlease note that the following guidance from the Driver and Vehicle Licensing Agency (DVLA) and the UK government is relevant to these recommendations:\n\nDVLA guidance on assessing fitness to drive: a guide for medical professionals\n\nDVLA guidance on excessive sleepiness and driving\n\nUK government guidance on COVID-19: infection prevention and control.\n\nObstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a condition in which the upper airway is narrowed or closes during sleep when muscles relax, causing under breathing (hypopnoea) or stopping breathing (apnoea). The person wakes or lightens sleep to stop these episodes, which can lead to disrupted sleep and potentially excessive sleepiness.\n\n# Initial assessment for OSAHS\n\n## When to suspect OSAHS\n\nTake a sleep history and assess people for OSAHS if they have 2\xa0or more of the following features:\n\nsnoring\n\nwitnessed apnoeas\n\nunrefreshing sleep\n\nwaking headaches\n\nunexplained excessive sleepiness, tiredness or fatigue\n\nnocturia (waking from sleep to urinate)\n\nchoking during sleep\n\nsleep fragmentation or insomnia\n\ncognitive dysfunction or memory impairment.\n\nBe aware that there is a higher prevalence of OSAHS in people with any of the following conditions:\n\nobesity or overweight\n\nobesity or overweight in pregnancy\n\ntreatment-resistant hypertension\n\ntype\xa02 diabetes\n\ncardiac arrythmia, particularly atrial fibrillation\n\nstroke or transient ischaemic attack\n\nchronic heart failure\n\nmoderate or severe asthma\n\npolycystic ovary syndrome\n\nDown's syndrome\n\nnon-arteritic anterior ischaemic optic neuropathy (sudden loss of vision in 1\xa0eye due to decreased blood flow to the optic nerve)\n\nhypothyroidism\n\nacromegaly.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on when to suspect OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: when to suspect OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n## Assessment scales for suspected OSAHS\n\nWhen assessing people with suspected OSAHS:\n\nUse the Epworth Sleepiness Scale in the preliminary assessment of sleepiness.\n\nConsider using the STOP-Bang Questionnaire as well as the Epworth Sleepiness Scale.\n\nDo not use the Epworth Sleepiness Scale alone to determine if referral is needed, because not all people with OSAHS have excessive sleepiness.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment scales for suspected OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: assessment tools for people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Prioritising people for rapid assessment by a sleep service\n\nSee also recommendation 4.1.1 on providing information for people with suspected OSAHS who are being referred to a sleep service.\n\nWhen referring people with suspected OSAHS to a sleep service, include the following information in the referral letter to facilitate rapid assessment:\n\nresults of the person's assessment scores\n\nhow sleepiness affects the person\n\ncomorbidities\n\noccupational risk\n\noxygen saturation and blood gas values, if available.\n\nWithin the sleep service, prioritise people with suspected OSAHS for rapid assessment if any of the following apply:\n\nthey have a vocational driving job\n\nthey have a job for which vigilance is critical for safety\n\nthey have unstable cardiovascular disease, for example, poorly controlled arrhythmia, nocturnal angina or treatment-resistant hypertension\n\nthey are pregnant\n\nthey are undergoing preoperative assessment for major surgery\n\nthey have non-arteritic anterior ischaemic optic neuropathy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prioritising people for rapid assessment by a sleep service\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: prioritisation for rapid assessment at a sleep centre of people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Diagnostic tests for OSAHS\n\nSee also section 4 on providing information for people who have been diagnosed with OSAHS.\n\nOffer home respiratory polygraphy to people with suspected OSAHS.\n\nIf access to home respiratory polygraphy is limited, consider home oximetry for people with suspected OSAHS. Take into account that oximetry alone may be inaccurate for differentiating between OSAHS and other causes of hypoxaemia in people with heart failure or chronic lung diseases.\n\nConsider respiratory polygraphy or polysomnography if oximetry results are negative but the person has significant symptoms.\n\nConsider hospital respiratory polygraphy for people with suspected OSAHS if home respiratory polygraphy and home oximetry are impractical or additional monitoring is needed.\n\nConsider polysomnography if respiratory polygraphy results are negative but symptoms continue.\n\nUse the results of the sleep study to diagnose OSAHS and determine the severity of OSAHS (mild, moderate or severe).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnostic tests for OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: diagnostic tests for OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Lifestyle advice for all severities of OSAHS\n\nDiscuss appropriate lifestyle changes with all people with OSAHS. Provide support and information on losing weight, stopping smoking, reducing alcohol intake and improving sleep hygiene, tailored to the person's needs and in line with the NICE guidelines on:\n\nstop smoking interventions and services\n\npreventing excess weight gain\n\nobesity: identification, assessment and management (in particular, the section on lifestyle interventions)\n\nalcohol-use disorders: prevention (in particular, recommendations on screening, brief advice and extended brief interventions for adults).\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on lifestyle advice for all severities of OSAHS\xa0.\n\nLoading. Please wait.\n\n# Treatments for mild OSAHS\n\nSee also section 4 on providing information for people starting treatment for OSAHS.\n\n## Lifestyle advice alone for mild OSAHS\n\nExplain to people with mild OSAHS who have no symptoms or with symptoms that do not affect usual daytime activities that:\n\ntreatment is not usually needed and\n\nchanges to lifestyle and sleep habits (see recommendation\xa01.4.1 on lifestyle advice) can help to prevent OSAHS from worsening.\n\n## Continuous positive airway pressure for mild OSAHS\n\nRecommendation 1.5.2 updates recommendation 1.2 in NICE's technology appraisal guidance on continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome.\n\nFor people with mild OSAHS who have symptoms that affect their quality of life and usual daytime activities, offer fixed-level continuous positive airway pressure (CPAP):\n\nat the same time as lifestyle advice if they have any of the priority factors listed in recommendation 1.2.2\xa0or\n\nif lifestyle advice alone has been unsuccessful or is considered inappropriate.\n\nFor people with mild OSAHS having CPAP:\n\nOffer telemonitoring with CPAP for up to 12\xa0months.\n\nConsider using telemonitoring beyond 12\xa0months.\n\nConsider auto‑CPAP as an alternative to fixed-level CPAP in people with mild OSAHS if:\n\nhigh pressure is needed only for certain times during sleep or\n\nthey are unable to tolerate fixed-level CPAP or\n\ntelemonitoring cannot be used for technological reasons or\n\nauto‑CPAP is available at the same or lower cost than fixed-level CPAP, and this price is guaranteed for an extended period of time.\n\nConsider heated humidification for people with mild OSAHS having CPAP who have upper airway side effects, such as nasal and mouth dryness, and CPAP-induced rhinitis.\n\nBe aware that CPAP is an aerosol-generating procedure and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. These may include setting up the device at home by video consultation or with precautions in hospital.For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.\n\n## Mandibular advancement splints for mild OSAHS\n\nIf a person with mild OSAHS and symptoms that affect their usual daytime activities is unable to tolerate or declines to try CPAP, consider a customised or semi-customised mandibular advancement splint as an alternative to CPAP if they:\n\nare aged\xa018 and over and\n\nhave optimal dental and periodontal health.\n\nBe aware that semi-customised mandibular advancement splints may be inappropriate for people with:\n\nactive periodontal disease or untreated dental decay\n\nfew or no teeth\n\ngeneralised tonic-clonic seizures.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatments for mild OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E: CPAP devices for the treatment of mild OSAHS\n\nevidence review\xa0F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome\n\nevidence review\xa0G: oral devices.\n\nLoading. Please wait.\n\n# Treatments for moderate and severe OSAHS\n\nSee also section 4 on providing information for people starting treatment for OSAHS.\n\n## CPAP for moderate and severe OSAHS\n\nCPAP is recommended as a treatment option for adults with moderate or severe symptomatic OSAHS in NICE's technology appraisal guidance on continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome.\n\nOffer fixed-level CPAP, in addition to lifestyle advice, to people with moderate or severe OSAHS.\n\nFor people with moderate or severe OSAHS having CPAP:\n\nOffer telemonitoring with CPAP for up to 12\xa0months.\n\nConsider using telemonitoring beyond 12\xa0months.\n\nConsider auto‑CPAP as an alternative to fixed-level CPAP in people with moderate or severe OSAHS if:\n\nhigh pressure is needed only for certain times during sleep or\n\nthey are unable to tolerate fixed-level CPAP or\n\ntelemonitoring cannot be used for technological reasons or\n\nauto‑CPAP is available at the same or lower cost than fixed-level CPAP, and this price is guaranteed for an extended period of time.\n\nConsider heated humidification for people with moderate or severe OSAHS having CPAP who have upper airway side effects such as nasal and mouth dryness, and CPAP-induced rhinitis.\n\nBe aware that CPAP is an aerosol-generating procedure and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. These may include setting up the device at home by video consultation or with precautions in hospital. For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.\n\n## Mandibular advancement splints for moderate and severe OSAHS\n\nIf a person with moderate or severe OSAHS is unable to tolerate or declines to try CPAP, consider a customised or semi-customised mandibular advancement splint as an alternative to CPAP if they:\n\nare aged\xa018 and over and\n\nhave optimal dental and periodontal health.\n\nBe aware that semi-customised mandibular advancement splints may be inappropriate for people with:\n\nactive periodontal disease or untreated dental decay\n\nfew or no teeth\n\ngeneralised tonic-clonic seizures.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatments for moderate and severe OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome and evidence review\xa0G: oral devices.\n\nLoading. Please wait.\n\n# Further treatment options for OSAHS\n\n## Positional modifiers for OSAHS\n\nConsider a positional modifier for people with mild or moderate positional OSAHS if other treatments are unsuitable or not tolerated.\n\nBe aware that positional modifiers are unlikely to be effective in severe OSAHS.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on positional modifiers for OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: positional modifiers.\n\nLoading. Please wait.\n\n## Surgery for OSAHS\n\nConsider tonsillectomy for people with OSAHS who have large obstructive tonsils and a body mass index (BMI) of less than 35\xa0kg/m2.\n\nConsider referral for assessment for oropharyngeal surgery in people with severe OSAHS who have been unable to tolerate CPAP and a customised mandibular advancement splint despite medically supervised attempts.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgery for OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: surgery.\n\nLoading. Please wait.\n\n# Managing rhinitis in people with OSAHS\n\nAssess people with nasal congestion and OSAHS for underlying allergic or vasomotor rhinitis.\n\nIf rhinitis is diagnosed in people with OSAHS, offer initial treatment with:\n\ntopical nasal corticosteroids or antihistamines for allergic rhinitis or\n\ntopical nasal corticosteroids for vasomotor rhinitis.\n\nFor people with OSAHS and persistent rhinitis, consider referral to an ear, nose and throat specialist if:\n\nsymptoms do not improve with initial treatment or\n\nanatomical obstruction is suspected.\n\nBe aware that:\n\nrhinitis can affect people's tolerance to CPAP but changing from a nasal to an orofacial mask and adding humidification can help (see recommendation 1.5.5 on heated humidification for mild OSAHS and recommendation 1.6.4 on heated humidification for moderate and severe OSAHS)\n\nCPAP can worsen or cause rhinitis and nasal congestion.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing rhinitis in people with OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: rhinitis.\n\nLoading. Please wait.\n\n# Follow-up and monitoring for people with OSAHS\n\nTailor follow-up to the person's overall treatment plan, which may include lifestyle changes and treating comorbidities. See the recommendations on tailoring healthcare services for each patient in the NICE guideline on patient experience in adult NHS services.\n\n## Follow-up for people using CPAP\n\nOffer face-to-face, video or phone consultations, including review of telemonitoring data (if available), to people with OSAHS having CPAP. This should include:\n\nan initial consultation within 1\xa0month and\n\nsubsequent follow-up according to the person's needs and until optimal control of symptoms and apnoea–hypopnoea index (AHI) or oxygen desaturation index (ODI) is achieved.\n\nOnce CPAP is optimised, consider annual follow-up for people with OSAHS.\n\nOffer people with OSAHS having CPAP access to a sleep service for advice, support and equipment between follow-up appointments.\n\n## Follow-up for people using mandibular advancement splints\n\nOffer face-to-face, video or phone consultations, including review of downloads from the device (if available), to people with OSAHS using a mandibular advancement splint. This should include:\n\ninitial follow-up to review adjustment of the device and symptom improvement at 3\xa0months and\n\nsubsequent follow-up according to the person's needs and until optimal control of symptoms and AHI or ODI is achieved.\n\n## Follow-up for people using positional modifiers\n\nOffer face-to-face, video or phone consultations, including review of downloads from the device (if available), to people with OSAHS using a positional modifier. This should include:\n\nan initial consultation within 3\xa0months and\n\nsubsequent follow-up according to the person's needs until optimal control of symptoms and AHI or ODI is achieved.\n\n## Follow-up for people who have had surgery\n\nOffer people with OSAHS who have had surgery:\n\nan initial follow-up consultation with respiratory polygraphy within 3\xa0months of the operation and\n\nsubsequent follow-up according to the person's needs.\n\n## Follow-up for drivers with excessive sleepiness\n\nEnsure follow-up is in line with Driver and Vehicle Licensing Agency guidance on assessing fitness to drive.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up for people with OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: monitoring.\n\nLoading. Please wait.\n\n## Monitoring treatment efficacy\n\nAssess the effectiveness of treatment with CPAP, mandibular advancement splints and positional modifiers in people with OSAHS by reviewing the following:\n\nOSAHS symptoms, including the Epworth Sleepiness Scale and vigilance, for example, when driving\n\nseverity of OSAHS, using AHI or ODI\n\nadherence to therapy\n\ntelemonitoring data or download information from the device (if available).\n\nExplore with people using CPAP their understanding and experience of treatment, and review the following:\n\nmask type and fit, including checking for leaks\n\nnasal or mouth dryness, and the need for humidification\n\nother factors affecting sleep disturbance such as insomnia, restless legs and shift work\n\nsleep hygiene\n\ncleaning and maintenance of equipment.\n\nConsider stopping treatment if OSAHS may have resolved, for example, with significant weight loss. After at least 2\xa0weeks without treatment:\n\nre-evaluate any return of symptoms and\n\nconsider a sleep study.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring treatment efficacy in people with OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: demonstration of efficacy.\n\nLoading. Please wait.\n\n# Supporting adherence to treatment for OSAHS\n\nOffer people with OSAHS educational or supportive interventions, or a combination of these, tailored to the person's needs and preferences, to improve adherence to CPAP, mandibular advancement splints and positional modifiers.\n\nInterventions to support adherence to treatment for OSAHS should be given by trained specialist staff when treatment is started and as needed at follow-up.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting adherence to treatment for OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review N: adherence.\n\nLoading. Please wait.", 'Obesity hypoventilation syndrome': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nPlease note that the following guidance from the Driver and Vehicle Licensing Agency (DVLA) and the UK government is relevant to these recommendations:\n\nDVLA guidance on assessing fitness to drive: a guide for medical professionals\n\nDVLA guidance on excessive sleepiness and driving\n\nUK government guidance on COVID-19: infection prevention and control.\n\nObesity hypoventilation syndrome (OHS) is defined as the combination of obesity (body mass index [BMI] of 30\xa0kg/m2 or more), raised arterial or arterialised capillary carbon dioxide (CO2) level when awake, and breathing abnormalities during sleep, which may consist of obstructive apnoeas and hypopnoeas, or hypoventilation, or a combination of both. OHS is a specific form of chronic ventilatory failure.\n\n# Initial assessment for OHS\n\n## When to suspect OHS\n\nTake a sleep history and assess people for OHS if they have a BMI of 30\xa0kg/m2 or more with:\n\nfeatures of obstructive sleep apnoea/hypopnoea syndrome (OSAHS; see recommendation 1.1.1) or\n\nfeatures of nocturnal hypoventilation such as:\n\n\n\nwaking headaches\n\nperipheral oedema\n\nhypoxaemia (arterial oxygen saturation less than 94% on air)\n\nunexplained polycythaemia.\n\n\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on when to suspect OHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: when to suspect OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n## Assessment scales for suspected OHS\n\nUse the Epworth Sleepiness Scale in the preliminary assessment of sleepiness in people with suspected OHS.\n\nDo not use the Epworth Sleepiness Scale alone to determine if referral is needed, because not all people with OHS have excessive sleepiness.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment scales for suspected OHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: assessment tools for people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Prioritising people for rapid assessment by a sleep service\n\nSee also recommendation 4.1.1 on providing information for people with suspected OHS who are being referred to a sleep service.\n\nWhen referring people with suspected OHS to a sleep service, include the following information in the referral letter to facilitate rapid assessment:\n\nresults of the person's sleepiness score\n\nhow sleepiness affects the person\n\nBMI\n\ncomorbidities\n\noccupational risk\n\noxygen saturation and blood gas values, if available\n\nany history of emergency admissions and acute non-invasive ventilation.\n\nWithin the sleep service, prioritise people with suspected OHS for rapid assessment if any of the following apply:\n\nthey have severe hypercapnia (PaCO2 [partial pressure of carbon dioxide] over 7.0\xa0kPa when awake)\n\nthey have hypoxaemia (arterial oxygen saturation less than 94% on air)\n\nthey have acute ventilatory failure\n\nthey have a vocational driving job\n\nthey have a job for which vigilance is critical for safety\n\nthey are pregnant\n\nthey have unstable cardiovascular disease, for example, poorly controlled arrhythmia, nocturnal angina, heart failure or treatment-resistant hypertension\n\nthey are undergoing preoperative assessment for major surgery\n\nthey have non-arteritic anterior ischaemic optic neuropathy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prioritising people for rapid assessment by a sleep service\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: prioritisation for rapid assessment at a sleep centre of people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Diagnostic tests for OHS\n\nSee also section 4 on providing information for people who have been diagnosed with OHS.\n\n## Diagnosing OHS and assessing ventilatory failure\n\nConsider measuring serum venous bicarbonate as a preliminary test if the pre-test probability of OHS is low. If bicarbonate levels are below 27\xa0mmol/litre, OHS is unlikely.\n\nMeasure arterial or arterialised capillary blood gases when the person with suspected OHS is awake, to diagnose OHS and assess the extent of chronic ventilatory failure.\n\nDo not delay treatment for acute ventilatory failure to carry out further investigations for OHS.\n\n## Diagnosing the presence of OSAHS or nocturnal hypoventilation in people with OHS\n\nOffer respiratory polygraphy, either in hospital or at home, to determine the presence of OSAHS in people with suspected OHS.\n\nConsider adding transcutaneous CO2 monitoring during sleep to respiratory polygraphy in people with suspected OHS to determine the extent of nocturnal hypoventilation and provide additional information to guide treatment.\n\nDo not use oximetry alone to determine the presence of OSAHS in people with OHS.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnostic tests for OHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: diagnostic tests for OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Lifestyle advice for OHS\n\nDiscuss appropriate lifestyle changes with all people with OHS. Provide support and information on losing weight, stopping smoking, reducing alcohol intake and improving sleep hygiene tailored to the person's needs and in line with the NICE guidelines on:\n\nstop smoking interventions and services\n\nobesity: identification, assessment and management (in particular, the section on lifestyle interventions)\n\nalcohol-use disorders: prevention (in particular, recommendations on screening, brief advice and extended brief interventions for adults).\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on lifestyle advice for OHS\xa0.\n\nLoading. Please wait.\n\n# Treatments for OHS\n\nSee also section 4 on providing information for people starting treatment for OHS.\n\n## CPAP and non-invasive ventilation\n\nOffer continuous positive airway pressure (CPAP) to people with OHS and severe OSAHS as first-line treatment.\n\nOffer non-invasive ventilation as an alternative to CPAP for people with OHS and severe OSAHS if symptoms do not improve, hypercapnia persists, apnoea–hypopnoea index (AHI) or oxygen desaturation index (ODI) are not sufficiently reduced or CPAP is poorly tolerated.\n\nConsider non-invasive ventilation for people with OHS and nocturnal hypoventilation who do not have OSAHS, or in whom OSAHS is not severe.\n\nConsider heated humidification in addition to CPAP for people with OHS and OSAHS and upper airway side effects such as nasal and mouth dryness, and CPAP-induced rhinitis.\n\nOffer non-invasive ventilation to people with OHS with acute ventilatory failure:\n\nIf hypercapnia persists, consider continuing and further optimising non-invasive ventilation.\n\nIf hypercapnia resolves, consider stopping non-invasive ventilation and monitoring the response.\n\nAfter a person with OHS and acute ventilatory failure has been stabilised on non-invasive ventilation with control of hypercapnia, consider:\n\nstopping non-invasive ventilation and carrying out respiratory polygraphy and\n\na trial of CPAP in people with frequent episodes of obstructive apnoea and minimal hypoventilation. If the person decompensates after stopping non-invasive ventilation, offer to restart non-invasive ventilation.\n\nBe aware that CPAP and non-invasive ventilation are aerosol-generating procedures and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. These may include setting up the device at home by video consultation or with precautions in hospital. For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.\n\n## Oxygen therapy\n\nConsider supplemental oxygen therapy with CPAP or non-invasive ventilation for people with OHS who remain hypoxaemic despite optimal control of nocturnal hypoventilation and AHI on CPAP or non-invasive ventilation, and address any additional underlying causes of hypoxaemia where possible.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatments for OHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome and evidence review\xa0I: oxygen therapy.\n\nLoading. Please wait.\n\n# Managing rhinitis in people with OHS\n\nAssess people with nasal congestion and OHS for underlying allergic or vasomotor rhinitis.\n\nIf rhinitis is diagnosed in people with OHS, offer initial treatment with:\n\ntopical nasal corticosteroids or antihistamines for allergic rhinitis or\n\ntopical nasal corticosteroids for vasomotor rhinitis.\n\nFor people with OHS and persistent rhinitis, consider referral to an ear, nose and throat specialist if:\n\nsymptoms do not improve with initial treatment or\n\nanatomical obstruction is suspected.\n\nBe aware that:\n\nrhinitis can affect people's tolerance to CPAP and non-invasive ventilation but changing from a nasal to an orofacial mask and adding humidification can help (see recommendation 2.5.4 on heated humidification for OHS and OSAHS)\n\nCPAP and non-invasive ventilation can worsen or cause rhinitis and nasal congestion.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing rhinitis in people with OHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: rhinitis.\n\nLoading. Please wait.\n\n# Follow-up and monitoring for people with OHS\n\nTailor follow-up to the person's overall treatment plan, which may include lifestyle changes and treating comorbidities. See the recommendations on tailoring healthcare services for each patient in the NICE guideline on patient experience in adult NHS services.\n\n## Follow-up for people using CPAP or non-invasive ventilation\n\nOffer face-to-face, video or phone consultations, including review of telemonitoring data (if available), to people with OHS having non-invasive ventilation or CPAP. This should include:\n\nan initial consultation within 1\xa0month and\n\nsubsequent follow-up according to the person's needs and until optimal control of symptoms, AHI or ODI, oxygenation and hypercapnia is achieved.\n\nWhen non-invasive ventilation or CPAP (with or without oxygen therapy) has been optimised for people with OHS and their symptoms are controlled, consider 6‑monthly to annual follow-up according to the person's needs.\n\nOffer people with OHS having non-invasive ventilation or CPAP access to a sleep and ventilation service for advice, support and equipment between follow-up appointments.\n\n## Follow-up for drivers with excessive sleepiness\n\nEnsure follow-up is in line with Driver and Vehicle Licensing Agency guidance on assessing fitness to drive.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up for people with OHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: monitoring.\n\nLoading. Please wait.\n\n## Monitoring treatment efficacy for people with OHS\n\nAssess the effectiveness of treatment with CPAP or non-invasive ventilation in people with OHS by reviewing the following:\n\nOHS symptoms, including the Epworth Sleepiness Scale and vigilance, for example, when driving\n\nseverity of OSAHS, using AHI or ODI\n\nimprovement in oxygenation and hypercapnia while awake and asleep\n\nadherence to therapy\n\ntelemonitoring or download information from the device (if available).\n\nExplore with the person their understanding and experience of treatment, and review the following:\n\nmask type and fit, including checking for leaks\n\nnasal and mouth dryness, and the need for humidification\n\nother factors affecting sleep disturbance such as insomnia, restless legs and shift work\n\nsleep hygiene\n\ncleaning and maintenance of equipment.\n\nFor people with OHS having supplemental oxygen therapy, review whether this is still needed after treatment with non-invasive ventilation or CPAP has been optimised.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring treatment efficacy for people with OHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: demonstration of efficacy.\n\nLoading. Please wait.\n\n# Supporting adherence to treatment for OHS\n\nOffer people with OHS educational or supportive interventions, or a combination of these, tailored to the person's needs and preferences, to improve adherence to CPAP and non-invasive ventilation.\n\nInterventions to support adherence to treatment for OHS should be given by trained specialist staff when treatment is started and as needed at follow-up.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting adherence to treatment for OHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: adherence.\n\nLoading. Please wait.", 'COPD–OSAHS overlap syndrome': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nPlease note that the following guidance from the Driver and Vehicle Licensing Agency (DVLA) and the UK government is relevant to these recommendations:\n\nDVLA guidance on assessing fitness to drive: a guide for medical professionals\n\nDVLA guidance on excessive sleepiness and driving\n\nUK government guidance on COVID-19: infection prevention and control.\n\nCOPD–OSAHS overlap syndrome occurs in people who have both chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea/hypopnoea syndrome (OSAHS). The combined effect of these conditions on ventilatory load, gas exchange, comorbidities and quality of life is greater than either condition alone.\n\nRecommendations in this guideline cover assessment and treatment of OSAHS in people with COPD. For recommendations on the diagnosis and management of COPD, see the NICE guidelines on chronic obstructive pulmonary disease in over\xa016s and chronic obstructive pulmonary disease (acute exacerbation): antimicrobial prescribing. See also NICE's guideline on community-based care of patients with COPD during the COVID-19 pandemic.\n\n# Initial assessment for COPD–OSAHS overlap syndrome\n\n## When to suspect COPD–OSAHS overlap syndrome\n\nTake a sleep history and assess people for COPD–OSAHS overlap syndrome if they have confirmed COPD with:\n\nfeatures of OSAHS (see recommendation 1.1.1) or\n\nfeatures of nocturnal hypoventilation such as:\n\n\n\nwaking headaches\n\nperipheral oedema\n\nhypoxaemia (arterial oxygen saturation less than 94% on air)\n\nunexplained polycythaemia.\n\n\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on when to suspect COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: when to suspect OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n## Assessment scales and tests for suspected COPD–OSAHS overlap syndrome\n\nWhen assessing people with suspected COPD–OSAHS overlap syndrome:\n\nUse the Epworth Sleepiness Scale in the preliminary assessment of sleepiness.\n\nConsider using the STOP-Bang Questionnaire, as well as the Epworth Sleepiness Scale.\n\nDo not use the Epworth Sleepiness Scale alone to determine if referral is needed, because not all people with COPD–OSAHS overlap syndrome have excessive sleepiness.\n\nOffer spirometry to assess the severity of COPD in people with suspected COPD–OSAHS overlap syndrome (see the recommendations on spirometry in NICE's guideline on chronic obstructive pulmonary disease in over\xa016s).\n\nBe aware that spirometry is an aerosol-generating procedure and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment scales and tests for suspected COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: assessment assessment tools for people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Prioritising people for rapid assessment by a sleep service\n\nSee also recommendation 4.1.1 on providing information for people with suspected COPD–OSAHS overlap syndrome who are being referred to a sleep service.\n\nWhen referring people with suspected COPD–OSAHS overlap syndrome to a sleep service, include the following information in the referral letter to facilitate rapid assessment:\n\nresults of the person's sleepiness score\n\nhow sleepiness affects the person\n\nbody mass index (BMI)\n\nseverity and frequency of exacerbations of COPD\n\nuse of oxygen therapy at home\n\ncomorbidities\n\noccupational risk\n\noxygen saturation and blood gas values, if available\n\nany history of acute non-invasive ventilation.\n\nWithin the sleep service, prioritise people with suspected COPD–OSAHS overlap syndrome for rapid assessment if any of the following apply:\n\nthey have severe hypercapnia (PaCO2 [partial pressure of carbon dioxide] over 7.0\xa0kPa when awake)\n\nthey have hypoxaemia (arterial oxygen saturation less than 94% on air)\n\nthey have acute ventilatory failure\n\nthey have a vocational driving job\n\nthey have a job for which vigilance is critical for safety\n\nthey are pregnant\n\nthey have unstable cardiovascular disease, for example, poorly controlled arrhythmia, nocturnal angina, heart failure or treatment-resistant hypertension\n\nthey are undergoing preoperative assessment for major surgery\n\nthey have non-arteritic anterior ischaemic optic neuropathy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prioritising people for rapid assessment by a sleep service\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: prioritisation for rapid assessment at a sleep centre of people with suspected OSAHS, OHS or COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Diagnostic tests for COPD–OSAHS overlap syndrome\n\nSee also section 4 on providing information for people who have been diagnosed with COPD–OSAHS overlap syndrome.\n\n## Diagnosing ventilatory failure\n\nMeasure arterial or arterialised capillary blood gas when the person with suspected COPD–OSAHS overlap syndrome is awake, to assess for ventilatory failure.\n\nDo not delay treatment for acute ventilatory failure to carry out further investigations for COPD–OSAHS overlap syndrome.\n\n## Diagnosing OSAHS or nocturnal hypoventilation in people with suspected COPD–OSAHS overlap syndrome\n\nOffer respiratory polygraphy, either in hospital or at home, to diagnose OSAHS in people with suspected COPD–OSAHS overlap syndrome.\n\nConsider adding transcutaneous carbon dioxide (CO2) monitoring during sleep to respiratory polygraphy to provide additional information to guide treatment.\n\nDo not use oximetry alone to diagnose OSAHS or nocturnal hypoventilation in people with suspected COPD–OSAHS overlap syndrome.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnostic tests for COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: diagnostic tests for OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Lifestyle advice for COPD–OSAHS overlap syndrome\n\nFor people with COPD–OSAHS overlap syndrome, follow recommendation 1.4.1 on lifestyle advice for people with OSAHS. Prioritise advice on stopping smoking and follow the recommendations on smoking cessation in NICE's guideline on chronic obstructive pulmonary disease in over\xa016s.\n\n# Treatments for COPD–OSAHS overlap syndrome\n\nSee also section 4 on providing information for people starting treatment for COPD–OSAHS overlap syndrome.\n\n## CPAP and non-invasive ventilation\n\nConsider continuous positive airway pressure (CPAP) as first-line treatment for people with COPD–OSAHS overlap syndrome if they do not have severe hypercapnia (PaCO2 of 7.0\xa0kPa or less).\n\nConsider non-invasive ventilation instead of CPAP for people with COPD–OSAHS overlap syndrome with nocturnal hypoventilation if they have severe hypercapnia (PaCO2 greater than 7.0\xa0kPa).\n\nConsider heated humidification in addition to CPAP for people with COPD–OSAHS overlap syndrome and upper airway side effects such as nasal and mouth dryness, and CPAP-induced rhinitis.\n\nBe aware that CPAP and non-invasive ventilation are aerosol-generating procedures and, if there is a risk of airborne infection, such as COVID‑19, appropriate infection control precautions should be taken. These may include setting up the device at home by video consultation or with precautions in hospital.For more information, see NICE's guideline on community-based care of patients with COPD during the COVID-19 pandemic, the UK government guidance on COVID-19: infection prevention and control and local guidance.\n\n## Oxygen therapy\n\nConsider supplemental oxygen for people with COPD–OSAHS overlap syndrome if hypoxaemia persists once control of apnoea and nocturnal hypoventilation has been optimised by CPAP or non-invasive ventilation, and address any additional underlying causes of hypoxaemia where possible.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatments for COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome and evidence review\xa0I: oxygen therapy.\n\nLoading. Please wait.\n\n# Managing rhinitis in people with COPD–OSAHS overlap syndrome\n\nFor people with COPD–OSAHS overlap syndrome, follow the recommendations on managing rhinitis in people with OSAHS.\n\n# Follow-up and monitoring for people with COPD–OSAHS overlap syndrome\n\nTailor follow-up to the person's overall treatment plan, which may include lifestyle changes and treating comorbidities. It may also include discussions about care planning (for example, COPD exacerbation action plan and advance care planning) for those with severe COPD. See the recommendations on self-management in the NICE guideline on chronic obstructive pulmonary disease in over\xa016s and tailoring healthcare services for each patient in the NICE guideline on patient experience in adult NHS services.\n\n## Follow-up for people using CPAP or non-invasive ventilation\n\nOffer face-to-face, video or phone consultations, including review of telemonitoring data (if available), to people with COPD–OSAHS overlap syndrome having non-invasive ventilation or CPAP. This should include:\n\nan initial consultation within 1\xa0month and\n\nsubsequent follow-up according to the person's needs and until optimal control of symptoms, apnoea–hypopnoea index (AHI) or oxygen desaturation index (ODI), oxygenation and hypercapnia is achieved.\n\nWhen non-invasive ventilation or CPAP (with or without oxygen therapy) has been optimised for people with COPD–OSAHS overlap syndrome and their symptoms are controlled, consider 6‑monthly to annual follow-up according to the person's needs.\n\nOffer people with COPD–OSAHS overlap syndrome having non-invasive ventilation or CPAP access to a sleep and ventilation service for advice, support and equipment between follow-up appointments.\n\n## Follow-up for drivers with excessive sleepiness\n\nEnsure follow-up is in line with Driver and Vehicle Licensing Agency guidance on assessing fitness to drive.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up for people with COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: monitoring.\n\nLoading. Please wait.\n\n## Monitoring treatment efficacy for people with COPD–OSAHS overlap syndrome\n\nAssess the effectiveness of treatment with CPAP or non-invasive ventilation in people with COPD–OSAHS overlap syndrome by reviewing the following:\n\nsymptoms of OSAHS and nocturnal hypoventilation, including the Epworth Sleepiness Scale and vigilance, for example, when driving\n\nseverity of OSAHS, using AHI or ODI\n\nimprovement in oxygenation and hypercapnia while awake and asleep\n\nadherence to therapy\n\ntelemonitoring or download information from the device (if available).\n\nExplore with the person their understanding and experience of treatment, and review the following:\n\nmask type and fit, including checking for leaks\n\nnasal and mouth dryness, and need for humidification\n\nother factors affecting sleep disturbance such as insomnia, restless legs and shift work\n\nsleep hygiene\n\ncleaning and maintenance of equipment.\n\nBe aware that some symptoms associated with COPD such as cough and wheeze, and certain medications such as theophyllines, may adversely affect sleep quality.\n\nFor people with COPD–OSAHS overlap syndrome having supplemental oxygen therapy, review whether this is still needed after treatment with non-invasive ventilation or CPAP has been optimised.\n\nConsider stopping CPAP or non-invasive ventilation and using a symptom-management approach for people with COPD–OSAHS overlap syndrome who have severe COPD if, despite treatment optimisation, CPAP or non-invasive ventilation does not improve their symptoms or quality of life, or adds to the burden of therapy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring treatment efficacy for people with COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: demonstration of efficacy.\n\nLoading. Please wait.\n\n# Supporting adherence to treatment for COPD–OSAHS overlap syndrome\n\nOffer people with COPD–OSAHS overlap syndrome educational or supportive interventions, or a combination of these, tailored to the person's needs and preferences, to improve adherence to CPAP and non-invasive ventilation.\n\nInterventions to support adherence to treatment for COPD–OSAHS overlap syndrome should be given by trained specialist staff when treatment is started and as needed at follow-up.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting adherence to treatment for COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: adherence.\n\nLoading. Please wait.", 'Information for people with OSAHS, OHS or COPD–OSAHS overlap syndrome': "When providing information, follow the recommendations on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services and putting shared decision making into practice in NICE's guideline on shared decision making.\n\nFor people with suspected obstructive sleep apnoea/hypopnoea syndrome (OSAHS), obesity hypoventilation syndrome (OHS) or chronic obstructive pulmonary disease–obstructive sleep apnoea/hypopnoea syndrome (COPD–OSAHS) overlap syndrome who are being referred to a sleep service, provide information on:\n\nthe underlying causes of their condition\n\nwhat sleep studies involve\n\nwhy treatment is important\n\nwhat treatments are available\n\nthe impact of excessive sleepiness on safe driving and occupational risk\n\nthe Driver and Vehicle Licensing Agency (DVLA) guidance on excessive sleepiness and driving and when there is a legal requirement for the person to notify the DVLA of their condition\n\nlifestyle changes, including weight loss, increasing physical activity, and avoiding alcohol excess and sedatives before sleep\n\nother sources of patient support.\n\nFor people who have been diagnosed with OSAHS, OHS or COPD–OSAHS overlap syndrome, repeat the information provided at referral (see recommendation 4.1.1) and give additional information on:\n\nchoosing the best treatment for the person\n\nthe practicalities of travel.\n\nFor people starting treatment with continuous positive airway pressure (CPAP) or non-invasive ventilation, provide information on:\n\nwhy it is used and how it works\n\nthe benefits of continuing with treatment and advice on encouraging adherence\n\nhow to get support for technical and clinical problems, including side effects, and obtain replacement masks and other parts\n\ndifferent masks or other interface options, humidification and how to manage problems with masks\n\nhow often to expect follow-up appointments\n\nhow to clean and maintain the equipment\n\ntaking short breaks from treatment\n\nmaking arrangements for travelling with CPAP or non-invasive ventilation.\n\nAdvise people using CPAP and non-invasive ventilation that these are aerosol-generating procedures and they should take appropriate precautions if there is a risk that they may have an airborne infection such as COVID‑19. For more information, see the UK government guidance on COVID-19: infection prevention and control and local guidance.\n\nFor people starting treatment with a mandibular advancement splint, provide information on:\n\nwhy they are used and how they work\n\nthe benefits of continuing with treatment, and advice on encouraging adherence\n\npossible short-term side effects, such as mild discomfort, hypersalivation and altered bite\n\npossible long-term side effects, such as problems with dental occlusion\n\nadjusting the device to ensure maximum benefit\n\nhow to clean and maintain the device\n\nmaintaining good oral health\n\nwho to contact for help with problems, for example, if the device breaks or the fit becomes poor\n\nhow often to expect follow-up appointments.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information for people with OSAHS, OHS and COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: information and support.\n\nLoading. Please wait.", 'Terms used in this guideline': "This section defines terms that have been used in a particular way for this guideline.\n\n# Apnoea\n\nA complete pause in breathing, defined as lasting 10\xa0seconds or more on a sleep study. An obstructive apnoea is caused by blockage of the upper airway, whereas a central apnoea occurs when there is no respiratory effort.\n\n# Apnoea–hypopnoea index (AHI)\n\nThe number of apnoeas and hypopnoeas per hour, measured during a multi-channel sleep study.\n\n# Hypopnoea\n\nA reduction in breathing, defined as lasting for 10\xa0seconds or more on a sleep study. An obstructive hypopnoea is caused by partial obstruction of the upper airway.\n\n# Mandibular advancement splint\n\nAn oral device used to treat sleep-related breathing disorders. It is worn over the upper and lower teeth, and holds the lower jaw forward, thereby increasing space at the back of the mouth and decreasing snoring and sleep apnoea. A custom-made mandibular advancement splint is formed from a dental impression taken by a dentist, which is used to make the splint in a laboratory. It is then fitted by a suitably trained general dental practitioner. A semi-customised mandibular advancement splint is formed using a dental impression taken by the patient, which they send to the manufacturer to make the splint.\n\n# Nocturnal hypoventilation\n\nDecreased breathing or under breathing during sleep, which can lead to varying severities of ventilatory failure (low oxygen levels and raised carbon dioxide). It can be caused by obesity, underlying lung disease, neuromuscular weakness and some medications such as opiates. Severe hypercapnia can be caused by nocturnal hypoventilation.\n\n# Oxygen desaturation index (ODI)\n\nThe ODI is defined as the number of episodes of oxygen desaturation per hour of sleep.\n\n# Positional modifier\n\nAn intervention to encourage patients not to sleep on their backs. There are several devices available such as the tennis ball technique, lumbar or abdominal binders, semi-rigid backpacks, full-length pillows and electronic sleep position trainers.\n\n# Positional OSAHS\n\nA type of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) that is affected by the person's sleep position. People with positional OSAHS have an apnoea–hypopnoea index (AHI) at least twice as high when lying face up (supine) as lying on their side (laterally).\n\n# Severity of OSAHS\n\nThis is determined using the AHI value, as follows:\n\nMild OSAHS: AHI of 5\xa0or more to less than\xa015\n\nModerate OSAHS: AHI of 15\xa0or more to less than\xa030\n\nSevere OSAHS: AHI of 30\xa0or more.\n\n# Sleep study\n\nA test used to diagnose sleep disorders by recording multiple channels during sleep, such as brain activity, breathing rate, blood oxygen level, heart rate, and eye and leg movements. There are several different types of sleep study:\n\noximetry measures arterial oxygen saturation and heart rate while the person is asleep\n\nrespiratory polygraphy includes at least 4\xa0channels such as oximetry, breathing rate, apnoeas and hypopnoeas, snoring and body position\n\npolysomnography, which is more detailed and includes respiratory polygraphy measures combined with assessment of sleep quality and duration using additional brain activity, eye movement and muscle tone signals.\n\n# Telemonitoring\n\nThe use of information and communication technologies to monitor patients remotely and transmit data related to their health. It is used to provide information including respiratory events, pressure requirements, mask leak and adherence.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Auto- versus fixed-level CPAP for OSAHS\n\nWhat is the clinical and cost effectiveness of auto- and fixed-level continuous positive airway pressure (CPAP) for managing mild obstructive sleep apnoea/hypopnoea syndrome (OSAHS)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for mild OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\nWhat is the clinical and cost effectiveness of auto- and fixed-level continuous positive airway pressure (CPAP) for managing moderate and severe OSAHS?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for moderate and severe OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n## Interventions to improve CPAP adherence\n\nWhich interventions, including behavioural interventions, are most clinically and cost effective to improve adherence to CPAP in people with OSAHS, obesity hypoventilation syndrome (OHS) and COPD–OSAHS (chronic obstructive pulmonary disease–OSAHS) overlap syndrome who have difficulty using CPAP?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on supporting adherence to treatment for OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: adherence.\n\nLoading. Please wait.\n\n## Mandibular advancement splints for mild symptomatic OSAHS and moderate OSAHS\n\nIn mild symptomatic OSAHS, which clinical and physiological phenotypes predict treatment response to customised mandibular advancement splints?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for mild OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: oral devices.\n\nLoading. Please wait.\n\nIn moderate OSAHS, which clinical and physiological phenotypes predict treatment response to customised mandibular advancement splints?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for moderate and severe OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: oral devices.\n\nLoading. Please wait.\n\n## Mandibular advancement splints for severe OSAHS\n\nWhat is the clinical and cost effectiveness of mandibular advancement splints for managing severe OSAHS?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for moderate and severe OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: oral devices.\n\nLoading. Please wait.\n\n## Treatment for people with COPD–OSAHS overlap syndrome\n\nWhat is the optimal treatment for people with COPD–OSAHS overlap syndrome: non-invasive ventilation or CPAP?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on treatments for COPD–OSAHS overlap syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: positive airway pressure therapy variants for OSAHS, OHS and COPD–OSAHS overlap syndrome.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Upper airway surgery in people unable to tolerate or adhere to CPAP\n\nWhat is the clinical and cost effectiveness of upper airway surgical interventions for people with OSAHS who are unable to tolerate or adhere to CPAP?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on surgery for OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: surgery.\n\nLoading. Please wait.\n\n## Oxygen therapy for OSAHS\n\nWhat is the clinical and cost effectiveness of nocturnal oxygen compared with placebo in people with OSAHS who are unable to tolerate CPAP?\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale section on oxygen therapy for OSAHS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: oxygen therapy.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# When to suspect OSAHS\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\nThere was limited evidence for identifying who to assess for obstructive sleep apnoea/hypopnoea syndrome (OSAHS), so the committee also used their clinical knowledge and experience to make the recommendations.\n\nThe committee agreed that, after taking a sleep history, further assessment for OSAHS should be carried out in people presenting with common symptoms and features of OSAHS, such as unexplained excessive sleepiness, snoring, apnoeas observed during sleep and choking during sleep, but that a broader range of symptoms should also be recognised, such as sleep fragmentation, insomnia, and fatigue in people without excessive sleepiness. The committee agreed that a single symptom alone, such as snoring, is not sufficient for further investigation and that 2\xa0or more features should be identified to warrant assessment. Based on evidence and experience, the committee listed conditions associated with OSAHS that should alert healthcare professionals to the possibility of OSAHS.\n\n## How the recommendations might affect practice\n\nThe recommendations aim to raise awareness of symptoms and associated conditions that should raise suspicion of OSAHS, as well as prompting assessment. This could increase the number of people being assessed and referred to sleep services.\n\nReturn to recommendations\n\n# Assessment scales for suspected OSAHS\n\nRecommendations 1.1.3 and 1.1.4\n\n## Why the committee made the recommendations\n\nThe Epworth Sleepiness Scale is intended to assess for sleepiness rather than to diagnose OSAHS, and the limited evidence reflected this, showing that it performed poorly both for sensitivity and specificity in diagnosing OSAHS. The committee noted that some people with OSAHS do not have excessive sleepiness and that not all healthcare professionals are aware of this. However, they agreed that it has a useful role in assessment and monitoring, and noted that when healthcare professionals are requested by the Driver and Vehicle Licensing Agency (DVLA) to complete assessment of a driver with OSAHS, this includes the Epworth Sleepiness Scale. They therefore agreed that it should be used, but not as the sole means of assessing the presence of OSAHS or as the sole basis for referral.\n\nLimited evidence showed that the STOP-Bang Questionnaire had high sensitivity and low specificity for diagnosing OSAHS. Sensitivity is a priority for questionnaires used for initial assessment. The committee had some concerns about its accuracy in people with less common presentations and in women, but agreed that it could have a role in assessment alongside the Epworth Sleepiness Scale to inform the preliminary understanding of the person's symptoms and concerns. The Epworth questionnaire is used to assess only sleepiness whereas the STOP-Bang Questionnaire is used to assess risk of having OSAHS and includes parameters such as snoring, tiredness, history of high blood pressure, body mass index (BMI), age, neck size and gender. With this in mind, the committee agreed that the Epworth questionnaire should be used and the STOP-Bang Questionnaire could also be considered for initial assessment.\n\n## How the recommendations might affect practice\n\nThe recommended questionnaires are widely used in current practice, so the recommendations are not expected to involve a change in practice.\n\nReturn to recommendations\n\n# Prioritising people for rapid assessment by a sleep service\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nThere was limited evidence available on who to prioritise for assessment in a sleep service, and the committee noted that service provision and waiting times vary across sleep services and regions in England. Therefore, the committee used their knowledge and experience to identify groups that would benefit most from prompt assessment and treatment.\n\nThe committee agreed that sleep services should prioritise access to a sleep study and treatment for people in whom vigilance and alertness are vital to occupational safety, particularly those with problematic sleepiness, and to people with pre-existing conditions who are at increased risk of adverse events. They agreed that sleep services should aim to fast-track priority groups to be seen as soon as possible.\n\nThe committee discussed the effect of OSAHS on work performance and safety, and how it could increase the risk of work accidents in safety-sensitive occupations. People with a wide range of jobs or activities could be affected, for example, drivers, train drivers, pilots, heavy machinery operators, surgeons and people caring for vulnerable children or adults. The committee noted that DVLA guidance on assessing fitness to drive recommends that drivers with suspected or confirmed OSAHS and excessive sleepiness having, or likely to have, an adverse impact on driving must not drive until there is satisfactory symptom control. Control of symptoms is likely to need assessment and treatment from a sleep specialist.\n\nThe committee noted that untreated OSAHS is recognised as a risk factor for treatment-resistant hypertension and recurrence of atrial flutter in people who have had treatment with ablative therapy. Therefore, it was agreed that people with unstable cardiovascular disease should be prioritised because of the risks of worsening cardiovascular disease or adverse events.\n\nThe committee agreed that priority should be given to pregnant women because OSAHS in pregnancy is associated with increased risks for the mother and baby.\n\nThe committee agreed that people with a high probability of OSAHS who need major surgery should be prioritised to avoid delaying surgery.\n\nThe committee also agreed that the risk of sudden blindness in patients with non-arteritic anterior ischaemic optic neuropathy warrants priority assessment because of its possible association with OSAHS.\n\nTo ensure that people are prioritised appropriately by sleep services and to allow fast-tracking directly to a sleep study, the committee agreed on key details, based on their experience, that should be included in referral letters.\n\n## How the recommendations might affect practice\n\nIn current practice, specific groups are not always prioritised for assessment, so there is likely to be a change in practice for some providers. There is increasing pressure on sleep services, and offering higher priority to some groups may delay sleep studies for other people. Planning for and providing rapid-access sleep studies may help to reduce the pressure on services, with triage of referrals allowing people to be fast-tracked directly to a diagnostic study.\n\nReturn to recommendations\n\n# Diagnostic tests for OSAHS\n\nRecommendations 1.3.1 to 1.3.6\n\n## Why the committee made the recommendations\n\nThe evidence on diagnostic tests for OSAHS was not consistent. The studies reviewed looked at diagnostic devices with a variety of monitoring channels and included different patient groups. The committee also noted that diagnostic equipment has evolved and improved over time. The committee used their clinical knowledge and experience supported by the published evidence and by the economic model developed for this guideline to make the recommendations.\n\nHome respiratory polygraphy was more cost effective than both hospital (inpatient) respiratory polygraphy and home oximetry. The committee noted that respiratory polygraphy has the added benefit of aiding the diagnosis of other conditions such as central sleep apnoea and nocturnal hypoventilation and it is better than oximetry alone in identifying artefacts in the recordings.\n\nThe use of oximetry alone, or oximetry followed by home respiratory polygraphy if initial oximetry is negative, was less cost effective than initial home respiratory polygraphy. However, diagnostic strategies incorporating oximetry are still used in practice, for example, by services with limited availability of home polygraphy equipment, and the committee recognised that it might take time and significant resources to change practice. They noted that when suspicion of OSAHS is low, a normal oximetry result can provide further evidence to rule out diagnosis. The committee agreed that oximetry could still be an option and that this would help to avoid unacceptable delays in diagnosis where there is a lack of access to home respiratory polygraphy.\n\nThe committee also highlighted the potential problems of relying on oximetry for diagnosis. Oximetry may be particularly inaccurate in people with conditions such as heart failure or chronic lung disease, which can result in desaturation without the presence of OSAHS, although they agreed that a negative test result is still useful. In addition, oximetry cannot reliably distinguish between obstructive or central apnoeas and nocturnal hypoventilation, which is important to help determine treatment.\n\nThe option to do the sleep study in hospital was also considered important by the committee. Hospital polygraphy may sometimes be needed when investigating alternative diagnoses alongside OSAHS, because extra monitoring channels can be used. It might also be an option if home respiratory polygraphy or home oximetry are impractical, for example, for people who need help with the monitoring equipment, or who need to travel long distances to pick up and return devices, or when a number of inpatient investigations need to be combined.\n\nThe committee agreed that further investigation with polysomnography, which is more accurate and more expensive than respiratory polygraphy, should be an option to provide more detail on sleep fragmentation and respiratory events for people with symptoms of OSAHS who have a negative respiratory polygraphy or oximetry result but continue to have suggestive symptoms. This may help distinguish between OSAHS and other disorders such as narcolepsy, rapid eye movement sleep behaviour disorder, periodic limb movement disorders, idiopathic hypersomnolence or parasomnias, which are suspected as a more likely diagnosis for the person's symptoms; or help diagnose these disorders when they are suspected in addition to OSAHS.\n\n## How the recommendations might affect practice\n\nCurrent practice is variable, with some sleep services offering oximetry as the first-line test and others offering home respiratory polygraphy. The recommendations will reduce this variation by encouraging the use of home respiratory polygraphy over home oximetry. Some services will need to provide more home respiratory polygraphy equipment and fewer home oximetry devices, but improved testing should lead to fewer repeat tests and optimal treatment. The option to use home oximetry as an alternative to respiratory polygraphy will lessen the impact on resources as practice changes.\n\nThe use of polysomnography for those who still have symptoms despite negative respiratory polygraphy results reflects current practice for this small population.\n\nReturn to recommendations\n\n# Lifestyle advice for all severities of OSAHS\n\nRecommendation 1.4.1\n\n## Why the committee made the recommendation\n\nEvidence for lifestyle advice was not reviewed because it is covered by other NICE guidelines.\n\nThe committee agreed that all people with OSAHS should discuss lifestyle changes with their healthcare professional. This should be tailored to the person's needs and the chosen treatment method. It may include advice on weight loss, preventing excess weight gain, stopping smoking and reducing alcohol intake, as appropriate.\n\nLifestyle changes are important because obesity increases the prevalence and severity of OSAHS, smoking causes upper airway inflammation (which can exacerbate symptoms), and excess alcohol before sleep reduces upper airway tone (increasing apnoeas) and reduces sleep quality. Advice on sleep hygiene may include ensuring adequate sleep time, avoiding caffeine and stimulants that interfere with sleep before bedtime, exercising regularly, having a quiet, comfortable, darkened bedroom, and winding down before sleep.\n\n## How the recommendation might affect practice\n\nLifestyle advice is widely used in current practice, so the recommendations are not expected to involve a change in practice.\n\nReturn to recommendations\n\n# Treatments for mild OSAHS\n\nRecommendations 1.5.1 to 1.5.8\n\n## Why the committee made the recommendations\n\nFrom their experience, the committee agreed that for many people with mild OSAHS who have no symptoms or symptoms that do not affect usual daytime activities, lifestyle changes alone can prevent OSAHS worsening and improve their quality of life. Lifestyle and sleep hygiene advice should be tailored to the person's circumstances. The committee noted that people without symptoms may come to the attention of a specialist because their partner has witnessed apnoeas and overt snoring.\n\nFor people with mild OSAHS whose symptoms affect their quality of life and usual daytime activities, the evidence suggested that CPAP was more clinically and cost effective than conservative management (including lifestyle changes and sleep hygiene). However, the quality of the evidence means that there is some uncertainty about the cost effectiveness. CPAP was found to be beneficial in improving sleepiness, fatigue, vitality and quality of life, which confirmed the committee's experience that there are benefits to giving CPAP to people with symptomatic mild OSAHS. Although some people could try lifestyle modification first, they noted that these changes take time to work and may not always be effective.\n\nDelaying offering CPAP to people with any of the priority factors for rapid referral (listed in recommendation 1.2.1) could adversely affect quality of life, associated medical conditions or the person's ability to carry out their work, by failing to control their symptoms. The committee agreed that, in their experience, offering CPAP to these groups helped control their symptoms and reduced the risks described in the rationale section for prioritising people for rapid assessment by a sleep service. Therefore, the committee agreed that, for these people, CPAP should be offered as a first-line treatment alongside lifestyle changes, as soon as mild OSAHS is diagnosed. They also agreed that CPAP would be beneficial to control symptoms in people for whom lifestyle changes alone are unsuccessful or are not appropriate.\n\nThe committee also discussed the benefits of telemonitoring, described in more detail in the rationale section on follow-up for people with OSAHS. They agreed that the costs varied between sleep centres and, in the committee's experience, telemonitoring is included in the price of the machine for 12\xa0months. Based on this, the committee recommended it should be offered alongside CPAP for up to 12\xa0months, and considered beyond 12\xa0months if optimal control of symptoms and apnoea–hypopnoea index (AHI) has not been achieved, or to help with solving problems that people with OSAHS might experience.\n\nTelemonitoring has allowed remote assessment of patients during the coronavirus pandemic and has become a standard follow-up option in most sleep services. This use is likely to continue long term, because it is convenient for patients, enables them to assess progress themselves and allows access to efficacy and adherence data whenever needed, for example, for problem solving, routine follow-up and to complete DVLA reports.\n\nThe evidence showed fixed-level CPAP and auto‑CPAP to be equally effective, and auto‑CPAP to be more costly. Therefore, the committee agreed to recommend fixed-level CPAP as the first-choice treatment. However, some people, particularly those in whom high pressures are only needed part of the time, find auto‑CPAP more comfortable and effective than fixed-level CPAP. For others, telemonitoring may not be possible because of technological constraints such as the lack of availability of internet or poor internet connection. The committee agreed that auto‑CPAP should be an option in these cases. The committee were also aware that some hospitals get significant discounts on auto‑CPAP devices, which might make them more cost effective. Therefore, the committee agreed that if auto‑CPAP can be purchased and administered at the same or lower cost than fixed-level CPAP, auto‑CPAP could be considered. Given the uncertainty about the cost-effectiveness between auto- and fixed-level CPAP the committee made a research recommendation to help inform future guidelines.\n\nBased on their experience of current practice, the committee agreed that using humidification with CPAP in people with nasal symptoms can reduce side effects associated with upper airway dryness and this may improve adherence and treatment effectiveness.\n\nThere was very little evidence for non-customised oral devices in people with mild OSAHS. Most of the evidence was for customised mandibular advancement splints and no evidence was found for tongue-retaining devices or tongue-stabilising devices. One study showed little benefit of mandibular advancement splints compared with no treatment in people with mild symptomatic OSAHS, but the committee agreed that the duration of the study was not sufficient for the true benefit to be assessed. Indirect evidence from studies in people with moderate OSAHS did show clinical benefit compared with placebo, and also showed better ease of use and patient preference scores than for CPAP.\n\nAn economic analysis showed that CPAP was slightly more cost effective than customised mandibular advancement splints, but the committee agreed the difference was small and they did not want to exclude these devices as an option, bearing in mind that some people find CPAP unacceptable. Based on this and their experience, the committee agreed that mandibular advancement splints should be considered as a treatment for people with mild OSAHS who have symptoms that affect their usual daytime activities if they are unable to tolerate or decline to try CPAP.\n\nThe evidence was unclear about the best type of mandibular advancement splint, but from their experience, the committee agreed that devices that are custom made and fitted by a suitably trained dentist are superior to semi-customised and ready-made (also called 'boil and bite') splints. Despite higher initial costs to make and fit, customised devices are more durable and longer lasting than the other devices. They are also preferred by patients. Semi-customised devices also last longer than ready-made devices and are cheaper than customised devices. Both customised and semi-customised devices were shown to be more cost effective than ready-made devices.\n\nSemi-customised devices may be inappropriate for people with active periodontal disease or untreated dental decay, few or no teeth and for people with generalised tonic-clonic seizures. Experienced specialist care is needed to use these devices in people with few or no teeth. Mandibular advancement splints are not suitable for people under\xa018 because they may adversely affect development of dentition.\n\nThe committee observed that careful patient selection is vital and further research is needed to determine which patients with mild OSAHS would benefit most from mandibular advancement splint therapy. They developed a research recommendation on treating mild OSAHS with a mandibular advancement splint to inform future guidance.\n\n## How the recommendations might affect practice\n\nSome people with mild OSAHS currently use CPAP, for example, people with symptoms that affect their ability to do daily activities, and when other treatment options and lifestyle advice have been unsuccessful or are considered inappropriate. It is expected that there will be increased uptake of CPAP for mild OSAHS, and therefore a resource increase to the NHS from this recommendation, especially as the estimate of prevalence of mild OSAHS has increased, and more people are referred and diagnosed. Some sleep services currently using auto‑CPAP may switch to fixed-level CPAP for new patients starting CPAP, which is likely to be cost saving.\n\nSome people with mild OSAHS currently use mandibular advancement splints. Many of these will be less effective ready-made devices that people have bought themselves. It is expected that there will be increased uptake of semi-customised and customised mandibular advancement splints and therefore a resource increase from this recommendation. NHS provision of dental services producing mandibular advancement splints is currently limited. Mandibular advancement splints need replacing at regular intervals and people using them need follow-up to assess efficacy.\n\nReturn to recommendations\n\n# Treatments for moderate and severe OSAHS\n\nRecommendations 1.6.1 to 1.6.7\n\n## Why the committee made the recommendations\n\nThe NICE technology appraisal guidance on continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome recommends CPAP as a treatment option for moderate and severe OSAHS.\n\nThe committee discussed the benefits of telemonitoring, described in more detail in the rationale section on follow-up for people with OSAHS. They agreed that the costs varied between sleep centres and, in the committee's experience, telemonitoring is included in the price of the machine for 12\xa0months. Based on this, they recommend it should be offered alongside CPAP for up to 12\xa0months, and considered beyond 12\xa0months if optimal control of symptoms and AHI has not been achieved, or to help with solving problems that people with OSAHS might experience.\n\nTelemonitoring has allowed remote assessment of patients during the coronavirus pandemic and has become a standard follow-up option in most sleep services. This use is likely to continue long term, because it is convenient for patients, enables them to assess progress themselves and allows access to efficacy and adherence data whenever needed, for example, for problem solving, routine follow-up and to complete DVLA reports.\n\nThe evidence showed fixed-level CPAP and auto‑CPAP to be equally effective, and auto‑CPAP to be more costly. Therefore, the committee agreed to recommend fixed-level CPAP as the first-choice treatment. However, some people, particularly those in whom high pressures are only needed part of the time, find auto‑CPAP more comfortable and effective than fixed-level CPAP. For others, telemonitoring may not be possible because of technological constraints such as the lack of availability of internet or poor internet connection. The committee agreed that auto‑CPAP should be an option in these cases. The committee were also aware that some hospitals get significant discounts on auto‑CPAP devices, which might make them more cost effective. Therefore, the committee agreed that if auto‑CPAP can be purchased and administered at the same or lower cost than fixed-level CPAP, auto‑CPAP could be considered. Given the uncertainty about the cost-effectiveness between auto- and fixed-level CPAP the committee made a research recommendation to help inform future guidelines.\n\nBased on its experience of current practice, the committee agreed that using humidification with CPAP may reduce side effects causing upper airway symptoms and subsequently improve adherence and treatment effectiveness.\n\nAlthough CPAP is the treatment of choice for people with moderate and or severe OSAHS, some people are unable to tolerate it in any form. The evidence showed that mandibular advancement splints are of benefit to people with moderate OSAHS and the committee agreed that they should be considered as an alternative treatment if CPAP is not tolerated or people decide not to try it. In the absence of evidence for severe OSAHS, the committee agreed that the evidence for moderate OSAHS could be extrapolated to this population. The committee also made a research recommendation on mandibular advancement splints for severe OSAHS.\n\nThe evidence was unclear about the best type of mandibular advancement splint, but from their experience, the committee agreed that devices that are custom made and fitted by a suitably trained dentist are superior to semi-customised and ready-made (also called 'boil and bite') splints. Despite higher initial costs to make and fit, customised devices are more durable and longer lasting than the other devices. They are also preferred by patients. Semi-customised devices also last longer than ready-made devices and are cheaper than customised devices. Both customised and semi-customised devices were shown to be more cost effective than ready-made devices.\n\nSemi-customised devices may be inappropriate for people with active periodontal disease or untreated dental decay, few or no teeth and for people with generalised tonic-clonic seizures. Experienced specialist care is needed to manage these devices in people with few or no teeth. Mandibular advancement splints are not suitable for children and young people under\xa018 because they may adversely affect development of dentition.\n\n## How the recommendations might affect practice\n\nThe recommendations for CPAP reflect current practice in most sleep services. Some sleep services currently using auto‑CPAP may switch to fixed-level CPAP for new patients starting CPAP, which is likely to be cost saving.\n\nIt is expected that there will be increased uptake of customised and semi-customised mandibular advancement splints and therefore a resource increase from this recommendation. NHS provision of dental services producing mandibular advancement splints is currently limited. Mandibular advancement splints need replacing at regular intervals and people using them need follow-up to assess efficacy and dentition.\n\nReturn to recommendations\n\n# Positional modifiers for OSAHS\n\nRecommendations 1.7.1 and 1.7.2\n\n## Why the committee made the recommendations\n\nThere was limited evidence on positional modifiers to treat OSAHS and the available studies were small with limited follow-up. The committee agreed that the evidence did not support their use as a first-choice treatment over CPAP and mandibular advancement splints in patients with mild or moderate positional OSAHS. However, there was some evidence of a reduction of OSAHS severity in supine sleep and an associated fall in the number of apnoeas compared with no treatment, with no evidence of adverse effects, so the committee agreed that they could be an option if other treatments were unsuccessful or not tolerated. It is estimated that more than half of people with OSAHS have positional OSAHS, so this recommendation will give more choice and offer an alternative option for the many people who find CPAP and mandibular advancement splints difficult to tolerate or unsuitable.\n\nThe committee did not support the use of positional modifiers in people with severe OSAHS, because these people usually continue to have obstructive events even when lying on their side. The committee were also aware of evidence that suggested an increase in the number of apnoeas with the use of positional modifiers in this population.\n\nThe studies looked at a variety of different positional modifiers, including the tennis ball technique and an electronic sleep position trainer, but the committee noted that that they did not include other devices such as lumbar or abdominal binders, semi-rigid backpacks and full-length pillows. The committee agreed that the evidence for different types of positional modifiers was insufficient to recommend a specific device.\n\nThe committee did not make a research recommendation because it was aware of several relevant research trials already in progress.\n\n## How the recommendations might affect practice\n\nPositional modifiers are not used commonly in current practice so the recommendation would involve a change in practice by most providers. Currently people tend to buy their own positional devices, often after not tolerating CPAP or mandibular advancement splints. However, it is only an option if CPAP and mandibular advancement splints are unsuccessful, so increased uptake of these devices and resource impact is likely to be small.\n\nReturn to recommendations\n\n# Surgery for OSAHS\n\nRecommendations 1.7.3 and 1.7.4\n\n## Why the committee made the recommendations\n\nThe evidence showed that oropharyngeal surgery (including tonsillectomy) was effective in some people with moderate or severe OSAHS.\n\nBased on their knowledge and experience, the committee agreed that tonsillectomy should be prioritised in people with large obstructive tonsils, and that people with a BMI of 35\xa0kg/m2 or above are less likely to benefit from surgery because they are more likely to have multi-level upper airway obstruction. There was no direct evidence for people with mild OSAHS, but the committee agreed that tonsillectomy should be applicable to all severities when tonsils are clearly causing obstruction.\n\nBased on the evidence and their knowledge and experience, the committee agreed that other types of oropharyngeal surgery could be an option for some people with severe OSAHS who have been unable to tolerate CPAP and a customised mandibular advancement splint. Although the evidence included people with moderate or severe OSAHS, most were in the severe category and the committee agreed that benefit was more likely in this group. There are no other treatment options for people with severe OSAHS who cannot tolerate CPAP and mandibular advancement splints, and the committee agreed that surgery for the right people would improve their quality of life. They noted that the economic analysis showed that this surgery could be cost effective if the treatment effects are maintained for 2.4\xa0years or more. On that basis, the committee agreed that referral for oropharyngeal surgery is cost effective for carefully selected people with severe OSAHS who have been unable to tolerate other treatments.\n\nThe committee stressed that, before considering referral for surgery, people should have fully explored other treatment options under medical supervision for a sufficient period of time. The committee also noted the potential risks of surgical intervention in people with severe OSAHS, and stressed that a personalised approach to patient selection is needed. This includes an assessment of anaesthetic risk and of the type and extent of surgery, which is critical because the outcome will depend on the anatomical and physiological phenotype of OSAHS. They therefore made a recommendation for referral for surgical consideration rather than surgery itself, acknowledging that precise individual assessment by the surgical team would be needed.\n\nBecause of a lack of sufficient evidence, the committee did not make any recommendations for nasal or skeletal framework surgery. They made a research recommendation on upper airway surgical interventions for people with OSAHS who are unable to tolerate or adhere to CPAP, because there was limited evidence for the applicability of this approach.\n\n## How the recommendations might affect practice\n\nThe recommendation for tonsillectomy is broadly in line with current practice.\n\nPeople who are unable to tolerate or adhere to CPAP and mandibular advancement splints are not usually referred for oropharyngeal surgery, so there is likely to be a change in practice for some providers. This recommendation is likely to only affect a small minority of people with severe OSAHS that is not helped by other treatments, have few comorbidities and for whom surgery is a suitable option.\n\nReturn to recommendations\n\n# Oxygen therapy for OSAHS\n\nThere was no evidence for oxygen therapy as an adjunct to CPAP for people with OSAHS.\n\nThere was also a lack of convincing evidence in favour of oxygen therapy alone for people with moderate OSAHS and no evidence for people with mild and severe OSAHS. Therefore, the committee decided that because there is a cost associated with this treatment and no evidence of benefit, they could not make a consensus recommendation for oxygen therapy for anyone with OSAHS. They agreed that a research recommendation on oxygen therapy, specifically looking at the clinical effectiveness of oxygen therapy compared with a placebo in people with OSAHS unable to tolerate CPAP would help to inform future guidance.\n\n# Managing rhinitis in people with OSAHS\n\nRecommendations 1.8.1 to 1.8.4\n\n## Why the committee made the recommendations\n\nThere was limited evidence to demonstrate the benefits of treating rhinitis. However, the committee agreed, based on their knowledge and experience, that treating rhinitis and other causes of nasal obstruction is important and may help people use CPAP more comfortably, and has a positive impact on sleep disorders. Changing the interface from a nasal to an orofacial mask and adding humidification can also help. The committee advised that current practice should be followed for initial treatment, and that referral to an ear, nose and throat specialist may be needed for further assessment of persistent symptoms.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice in most NHS centres, so there is likely to be little change in practice.\n\nReturn to recommendations\n\n# Follow-up for people with OSAHS\n\nRecommendations 1.9.1 to 1.9.8\n\n## Why the committee made the recommendations\n\nThere was limited evidence on follow-up, so the committee also used their clinical knowledge and experience to make the recommendations.\n\nThe committee noted that CPAP is just one aspect of treatment for OSAHS, and that follow-up should be tailored to the person's overall treatment plan. This may include lifestyle changes (such as weight management, modifying use of sedative drugs and alcohol, and stopping smoking) and treating underlying lung disease and other comorbidities.\n\nCPAP adherence patterns are usually established in the first week of therapy. Therefore the committee agreed that early assessment of CPAP (within 1\xa0month) is helpful to check adherence, for initial problem solving and to provide support. There was no evidence to suggest a difference between face-to-face, phone and video consultations, so the committee agreed that these could all be options for follow-up. The evidence also suggested that consultations with telemonitoring were as effective as those without telemonitoring. However, there was some evidence available for people with severe OSAHS that suggested adherence is improved by including telemonitoring and the committee agreed that the data could be extrapolated to people with mild and moderate OSAHS.\n\nThe committee agreed that although the available evidence did not show much benefit, in their experience telemonitoring offers significant advantages over not using telemonitoring to both the clinician and the person using CPAP. These include early night-by-night access to data, which can lead to early detection of problems such as mask leaks or persistent respiratory events of sleep apnoea, and the ability to monitor control of OSAHS and adherence to therapy.\n\nTelemonitoring makes managing a person's OSAHS more efficient for healthcare professionals because they have ready access to the person's data when needed, for example, to help identify a problem (such as, mask leak or inadequate pressure) and take action without a scheduled appointment.\n\nThe committee agreed that video and phone consultations along with telemonitoring are also advantageous in reducing the number of in-person visits needed to the sleep service. This can be particularly beneficial to people who have difficulty getting to clinics, for example, those who live in remote areas or have poor mobility. The reduction in the number of face-to-face consultations will also help reduce the risk of infection during the COVID‑19 pandemic. Based on their experience, the committee agreed that subsequent follow-up should be personalised until effective CPAP treatment is established.\n\nThe committee discussed the benefits of longer-term follow-up comparing annual with a 2‑yearly follow-up interval once CPAP is established. They agreed that annual follow-up should be considered because it allows the opportunity to review progress and symptom control, assess adherence and effectiveness, and review the need to continue therapy. The committee also agreed that support between appointments was important in case of problems, and for providing advice, equipment and consumables.\n\nNo evidence was identified on monitoring for people using mandibular advancement splints. Based on experience, the committee agreed that early face-to-face follow-up, or video or phone consultation is advisable for people using a mandibular advancement splint to review symptom improvement and make further adjustments to the device. Subsequent follow-up should be personalised and include assessment of side effects and the impact on dentition and bite.\n\nThere was no evidence on monitoring for people using positional devices, but the committee also agreed that early face-to-face follow-up, video or phone consultation is beneficial to assess symptom control and determine whether respiratory events are controlled.\n\nFor people who have had surgery for OSAHS, the committee agreed that follow-up should happen within 3\xa0months and include respiratory polygraphy. Wound healing and any early inflammation should be resolved before this is considered.\n\nThe committee noted that an annual review is required by the DVLA for Group\xa02 licence holders (lorry and bus drivers) with moderate or severe OSAHS and excessive sleepiness at diagnosis. For Group\xa01 licence holders (car and motorcycle drivers) with OSAHS and excessive sleepiness, review is required at least every 3\xa0years. For more information, see the DVLA guidance on assessing fitness to drive.\n\n## How the recommendations might affect practice\n\nCurrent practice includes a mixture of face-to-face, phone and video consultations and telemonitoring. The increasing number of people being offered CPAP means that providing regular outpatient follow-up has become increasingly difficult. The use of telemonitoring may increase, which is likely to reduce the need for face-to-face consultations and may reduce pressure on outpatient clinics. Increasing web- and app-based access to telemonitoring data will allow patients to access their own results and will encourage self-management.\n\nThe committee noted that there has been a significant move to video and phone consultations to reduce the risk of infection during the COVID‑19 pandemic, and this shift in practice is likely to persist.\n\nThe committee stressed that telemonitoring crucially involves feedback to patients, and time should be available for sleep service staff to review data, act on this and share with the person using CPAP. Current practice already includes ready access to advice and CPAP equipment from sleep services.\n\nRecommendations on monitoring for positional modifiers, mandibular advancement splints and surgery are considered to be current practice in many areas and are not expected to lead to major changes in practice.\n\nReturn to recommendations\n\n# Monitoring treatment efficacy in people with OSAHS\n\nRecommendations 1.9.9 to 1.9.11\n\n## Why the committee made the recommendations\n\nNo evidence was available on the efficacy of treatment for OSAHS, so the recommendations are based on the committee's knowledge and experience.\n\nThe effectiveness of treatment can be confirmed by control of symptoms and AHI or oxygen desaturation index (ODI), and uptake and adherence to therapy. The committee identified several factors that commonly cause problems with CPAP that should be routinely reviewed if treatment is not working. As well as assessing sleepiness, the committee agreed that vigilance should be assessed by discussing the person's alertness and ability to concentrate on tasks. This is particularly important for drivers.\n\nOSAHS may sometimes resolve, for example, because of weight loss or other lifestyle changes. The committee agreed that stopping treatment should be considered if this is suspected. If symptoms return, these will need to be re‑evaluated. A sleep study may be needed to confirm whether OSAHS has resolved.\n\n## How the recommendations might affect practice\n\nThese recommendations reflect current practice and are not expected to lead to a change in practice.\n\nReturn to recommendations\n\n# Supporting adherence to treatment for OSAHS\n\nRecommendations 1.10.1 and 1.10.2\n\n## Why the committee made the recommendations\n\nThe committee considered behavioural, supportive and educational interventions and made recommendations based on the evidence and their experience.\n\nThe evidence suggested that all types of interventions to support adherence (educational, behavioural, supportive and mixed) increased CPAP use in people starting CPAP for the first time with moderate or severe OSAHS. There was no evidence available for people with mild OSAHS, but the committee agreed that these recommendations would be applicable to all people having treatment for OSAHS. The committee agreed that educational or supportive interventions, or a combination of these, provided by specialist staff, would help to improve adherence to CPAP.\n\nEducational interventions include providing information about OSAHS, its treatment and outcomes, which can be delivered using a variety of different sessions and formats. Supportive interventions involve additional clinical follow-up (for example, extra clinic visits, video or teleconsultations or use of telemonitoring) to provide support. The nature of behavioural interventions varied widely, making it difficult to identify the most effective components. Therefore, the committee could not recommend any specific behavioural interventions.\n\nOptimal adherence to CPAP therapy is conventionally considered to be 4\xa0hours or more per night or using CPAP for an average of more than 4\xa0hours per night for 70% or more nights. Early adherence studies focused on control of sleepiness but there is evidence that increased CPAP use of more than 5\xa0hours a night in OSAHS benefits other aspects of health such as control of blood pressure and cardiovascular risk. However, it is recognised that people can gain some benefit from a shorter period of use, and individual response is variable. People should be encouraged to maximise their CPAP use to achieve optimal control of their symptoms, underlying conditions, sleep quality and quality of life.\n\nThere was no evidence available for improving adherence to mandibular advancement splint and positional modifiers in OSAHS. However, the committee agreed that evidence for improving adherence for CPAP could be applied to other treatments.\n\nBecause there was no evidence for people who have difficulty using CPAP, the committee made a research recommendation on interventions to improve CPAP adherence to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect best practice, but current provision varies across NHS settings. Therefore, the recommendations will involve a change of practice for some providers.\n\nReturn to recommendations\n\n# When to suspect OHS\n\nRecommendation 2.1.1\n\n## Why the committee made the recommendation\n\nNo evidence was available on identifying who to assess for obesity hypoventilation syndrome (OHS), so the recommendation is based on the committee's knowledge and experience.\n\nThe committee agreed that further assessment for OHS should be carried out in people with obesity together with symptoms of OSAHS or features of nocturnal hypoventilation. These criteria were chosen because some people with OHS have OSAHS, some have nocturnal hypoventilation alone, and others have both. A low arterial oxygen saturation value or polycythaemia may be indicative of OHS, but raised PaCO2 (partial pressure of carbon dioxide) is needed for diagnosis (for more information, see the rationale and impact section on diagnostic tests for OHS\xa0).\n\nLoading. Please wait.\n\n## How the recommendation might affect practice\n\nIn current practice, not all people with the listed symptoms and features are considered for further assessment for OHS, so this recommendation may result in a change of practice for most providers, leading to more testing and treatment. This will be magnified by the rising prevalence of obesity in the general population.\n\nReturn to recommendations\n\n# Assessment scales for suspected OHS\n\nRecommendations 2.1.2 and 2.1.3\n\n## Why the committee made the recommendations\n\nNo evidence was found on assessment tools for suspected OHS, so the committee based the recommendation on their knowledge and experience. They agreed that the Epworth Sleepiness Scale has a useful role in monitoring and assessment of sleepiness in people with OHS. However, they noted that not all people with OHS have excessive sleepiness and that healthcare professionals may not always be aware of this.\n\nThe evidence for the STOP-Bang Questionnaire was limited to OSAHS only and there was no validation for its use in OHS. The committee agreed that the STOP-Bang Questionnaire is not used in practice for OHS, so they did not make a recommendation for this.\n\n## How the recommendations might affect practice\n\nThe Epworth Sleepiness Scale is widely used in current practice, so the recommendations are not expected to involve a change in practice.\n\nReturn to recommendations\n\n# Prioritising people for rapid assessment by a sleep service\n\nRecommendations 2.2.1 and 2.2.2\n\n## Why the committee made the recommendations\n\nNo evidence was available for prioritising people with OHS for assessment in a sleep service, so the committee used their knowledge and experience to identify groups that would benefit most from prompt assessment and treatment.\n\nThe committee noted that people with a BMI over 30\xa0kg/m2 and severe hypercapnia or hypoxaemia should be prioritised because they have chronic ventilatory failure and are at risk of acute decompensated ventilatory failure, both of which carry a poor prognosis.\n\nThe committee agreed that sleep services should prioritise access to a sleep study and treatment for people in whom vigilance and alertness are vital to occupational safety, particularly those with problematic sleepiness, and to people with pre-existing conditions who are at increased risk of adverse events. They agreed that services should aim to fast-track priority groups to be seen as soon as possible.\n\nThe committee discussed the effect on work performance and safety for people with suspected OHS who also have OSAHS and how it could increase the risk of work accidents in safety-sensitive occupations. People with a wide range of jobs or activities could be affected, for example, drivers, train drivers, pilots, heavy machinery operators, surgeons and people caring for vulnerable children or adults. They noted that DVLA guidance on assessing fitness to drive recommends that drivers with suspected or confirmed OSAHS and excessive sleepiness having, or likely to have, an adverse impact on driving must not drive until there is satisfactory symptom control. Control of symptoms is likely to need assessment and treatment from a sleep specialist.\n\nThe committee agreed that priority should be given to pregnant women, because uncontrolled OHS may adversely affect both the mother and baby.\n\nThe committee agreed that people with unstable cardiovascular disease should be offered early investigation and treatment, because cardiovascular complications are a major cause of mortality and morbidity in people with OHS.\n\nThe committee agreed that people with a high probability of OHS who need major surgery should be prioritised to avoid delaying surgery.\n\nThe committee also agreed that the risk of sudden blindness in patients with non-arteritic anterior ischaemic optic neuropathy warrants priority assessment because of its possible association with OHS.\n\nTo ensure that people are prioritised appropriately by sleep services, and to allow fast-tracking directly to a sleep study, the committee agreed on key details, based on their experience, that should be included in referral letters.\n\n## How the recommendations might affect practice\n\nIn current practice, specific groups are not always prioritised for assessment, so there is likely to be a change in practice for some providers. There is increasing pressure on sleep services, and offering higher priority to some groups may delay studies for other people. Planning for and providing rapid-access sleep studies may help to reduce the pressure on services, with triage of referrals allowing people to be fast-tracked directly to a diagnostic study.\n\nReturn to recommendations\n\n# Diagnostic tests for OHS\n\nRecommendations 2.3.1 to 2.3.6\n\n## Why the committee made the recommendations\n\nThe committee noted that OHS is defined by the presence of PaCO2 greater than 6.0\xa0kPa while awake in people with a BMI of 30\xa0kg/m2 or more. There was no evidence for diagnostic tests to identify the presence of OSAHS or nocturnal hypoventilation in people with suspected OHS, so the committee also used their clinical knowledge and experience to make the recommendations.\n\nOHS is a specific form of chronic ventilatory failure and, by definition, a measurement of PaCO2 from arterial or arterialised capillary blood gas, taken while the person with suspected OHS is awake, is needed to establish the diagnosis and to assess the extent of chronic ventilatory failure. It is current practice to measure these and, although they are invasive tests, obtaining the samples is generally straightforward.\n\nSerum venous bicarbonate indirectly reflects medium- and long-term PaCO2 levels. It is a simpler test to perform, and a normal level is helpful in ruling out OHS if the pre-test probability of the diagnosis is low. The committee therefore agreed that it could be recommended in such cases, but noted that this alone will not completely rule out OHS and that other tests are needed when clinical suspicion is high.\n\nPeople with any form of chronic ventilatory failure can readily develop acute ventilatory failure if, for example, they have an intercurrent respiratory tract infection. Acute ventilatory failure is a medical emergency needing urgent treatment, and the committee agreed it is important to state that this should take priority over full investigation of any underlying chronic disease.\n\nDiagnosis of coexisting OSAHS is needed to ensure optimal choice of treatment, and the committee agreed that this should be with either hospital or home respiratory polygraphy, based on their experience and the evidence for diagnosis of OSAHS in people without OHS (see the rationale section on diagnostic tests for OSAHS). The committee agreed that transcutaneous CO2 monitoring with respiratory polygraphy should also be considered at the same time, to help establish the severity of nocturnal hypoventilation. A markedly raised CO2 level suggests non-invasive ventilation may be the treatment of choice rather than CPAP.\n\nHome or hospital respiratory polygraphy are recommended equally because diagnosing the presence of OSAHS in OHS is more complex than diagnosing OSAHS alone; it is important to be able to distinguish between OSAHS and nocturnal hypoventilation. The committee also discussed that CO2 monitoring is quite hard to do at home.\n\nOximetry alone is insufficient for diagnosis because it does not clearly distinguish between obstructive apnoeas and nocturnal hypoventilation.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice and would therefore not be expected to increase NHS cost.\n\nReturn to recommendations\n\n# Lifestyle advice for OHS\n\nRecommendation 2.4.1\n\n## Why the committee made the recommendation\n\nEvidence for lifestyle advice was not reviewed because it is covered by other NICE guidelines.\n\nThe committee agreed that all people with OHS should discuss lifestyle changes with their healthcare professional. This should focus on weight loss and be tailored to the person's needs and the chosen treatment method.\n\nLifestyle changes are important because obesity increases the prevalence and severity of OHS, smoking causes upper airway inflammation (which can exacerbate symptoms), and excess alcohol before sleep reduces upper airway tone (increasing apnoeas) and reduces sleep quality. Advice on sleep hygiene may include ensuring adequate sleep time, avoiding caffeine and stimulants that interfere with sleep before bedtime, exercising regularly, having a quiet, comfortable, darkened bedroom, and winding down before sleep.\n\n## How the recommendation might affect practice\n\nLifestyle advice is widely used in current practice, so the recommendations are not expected to involve a change in practice.\n\nReturn to recommendations\n\n# Treatments for OHS\n\nRecommendations 2.5.1 to 2.5.8\n\n## Why the committee made the recommendations\n\nThe evidence was limited to people with OHS and severe OSAHS without acute ventilatory failure. It showed that both CPAP and non-invasive ventilation are beneficial compared with lifestyle changes, and that there is little difference in effectiveness between these treatments. There was no evidence for people with acute ventilatory failure.\n\nBased on evidence and their experience, the committee agreed that CPAP should be offered as a first-line treatment for people with OHS and severe OSAHS who do not have acute ventilatory failure because it is more cost effective, simpler to set up and may be better tolerated than non-invasive ventilation. If symptoms do not improve, severe hypercapnia persists, AHI or ODI are not sufficiently reduced, or CPAP is poorly tolerated, the committee agreed that treatment should be changed to non-invasive ventilation to control nocturnal hypoventilation.\n\nIn line with current practice, the committee agreed that non-invasive ventilation should be considered as first-line treatment for people with OHS in the absence of severe OSAHS.\n\nAlthough there was no direct evidence available, the committee were clear that non-invasive ventilation should be the first-line treatment for people with OHS and acute ventilatory failure because rapid improvement in hypercapnia is a priority. A trial without non-invasive ventilation may be suitable for people in whom hypercapnia resolves. In this instance, they should remain under review in case hypercapnia recurs and be restarted on non-invasive ventilation, if necessary. Assessment with respiratory polygraphy on recovery should be carried out to determine if long-term treatment with CPAP or non-invasive ventilation is needed. The committee agreed that people with residual OSAHS but minimal hypoventilation when stable can be switched to CPAP.\n\nNo evidence was available for oxygen therapy in people with OHS. The committee agreed that, although optimal CPAP or non-invasive ventilation will usually be sufficient to correct ventilatory failure, some people with OHS may remain hypoxaemic during sleep despite control of AHI and nocturnal hypercapnia on CPAP or non-invasive ventilation. This would be shown on oximetry measures or on arterial blood gas during sleep. Addition of supplemental oxygen therapy to the CPAP or non-invasive ventilation during sleep may be needed to correct this hypoxia and any additional underlying causes of hypoxaemia should be addressed where possible. Usually only a low flow rate such as 1\xa0to 2\xa0litres/minute would be needed. Repeating oximetry or arterial blood gas would allow the response to this oxygen therapy to be evaluated and any further adjustments to oxygen prescription to be made.\n\n## How the recommendations might affect practice\n\nThe use of CPAP for people with OHS is a change in practice that is likely to result in less non-invasive ventilation use.\n\nThe recommendations on oxygen therapy reflect current practice in most NHS centres, so there is likely to be little impact on practice.\n\nReturn to recommendations\n\n# Managing rhinitis in people with OHS\n\nRecommendations 2.6.1 to 2.6.4\n\n## Why the committee made the recommendations\n\nNo evidence was available on managing rhinitis for people with OHS. The committee agreed that recommendations for OSAHS are applicable to people with OHS as well. They agreed, based on their knowledge and experience, that treating rhinitis and other causes of nasal obstruction is important and may help people use CPAP more comfortably, and have a positive impact on sleep disorders. Changing the interface from a nasal to an orofacial mask and adding humidification can also help. The committee advised that current practice should be followed for initial treatment, and that referral to an ear, nose and throat specialist may be needed for further assessment of persistent symptoms.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice in most NHS centres, so there is likely to be little change in practice.\n\nReturn to recommendations\n\n# Follow-up for people with OHS\n\nRecommendations 2.7.1 to 2.7.5\n\n## Why the committee made the recommendations\n\nThe committee noted that CPAP and non-invasive ventilation are just part of treatment for OHS, and that follow-up should be tailored to the person's overall treatment plan. This should also include lifestyle changes (such as weight management, modifying use of sedative drugs and alcohol, and stopping smoking) and treating underlying lung disease and other comorbidities.\n\nBased on their knowledge and experience, the committee agreed that for people with OHS starting CPAP or non-invasive ventilation, early follow-up at 1\xa0month is advisable to review control of symptoms, sleep-disordered breathing and adherence. Problem solving can be achieved by face-to-face, video or phone consultations, and can include review of telemonitoring data if available. The committee also agreed that although most studies of telemonitoring are in patients with OSAHS, and that there is not yet the ability to assess hypercapnia through telemonitoring, it is still of value for monitoring in people with OHS who also have OSAHS.\n\nIn addition to annual review, people with OSAHS and OHS having CPAP or non-invasive ventilation therapy need to be able to access a sleep service for advice and provision of consumables such as masks, circuitry and filters.\n\nThe committee noted that an annual review is required by the DVLA for Group\xa02 licence holders (lorry and bus drivers) with moderate or severe OSAHS and excessive sleepiness at diagnosis. For Group\xa01 licence holders (car and motorcycle drivers) with OSAHS and excessive sleepiness, review is required at least every 3\xa0years. For more information, see the DVLA guidance on assessing fitness to drive.\n\n## How the recommendations might affect practice\n\nCurrent practice includes a mixture of face-to-face, phone and video consultations and telemonitoring. The increasing number of people being offered CPAP means that providing regular outpatient follow-up has become increasingly difficult. In addition, a more personalised approach enables attention to be focused on people with problems adapting to therapy. Telemonitoring is included in the overall cost of CPAP devices by some manufacturers for variable periods, and is increasingly available for non-invasive ventilators. The committee discussed that routine use of telemonitoring should reduce the need for face-to-face consultations, and reduce pressure on outpatient clinics, but feedback and discussion with patients is still needed. Increasing web- and app-based access to telemonitoring data will allow patients to access their own results and encourage self-management.\n\nThe committee noted that there has been a significant move to video and phone consultations to reduce the risk of infection during the COVID‑19 pandemic, and this shift in practice is likely to persist.\n\nReturn to recommendations\n\n# Monitoring treatment efficacy for people with OHS\n\nRecommendations 2.7.6 to 2.7.8\n\n## Why the committee made the recommendations\n\nNo evidence was available for demonstrating efficacy of treatment for OHS, so the recommendations are based on the committee's knowledge and experience.\n\nIn OHS, control of nocturnal hypoventilation is demonstrated by improvement of symptoms, hypercapnia when awake and asleep, and oxygenation. It is important to optimise these to improve wellbeing and prognosis, and to reduce the risk of hospital admission.\n\nThe committee agreed that clinical effectiveness of CPAP and non-invasive ventilation in people with OHS should be assessed by reviewing symptoms of OSAHS and nocturnal hypoventilation including Epworth Sleepiness Scale score, AHI or ODI, adherence to therapy, improvement in oxygenation and hypercapnia while awake and asleep, and telemonitoring or download information from the CPAP or non-invasive ventilation device. As well as assessing sleepiness, the committee agreed that vigilance should be assessed by discussing the person's alertness and ability to concentrate on tasks. This is particularly important for drivers.\n\nThe committee agreed that the understanding and experience of people having CPAP or non-invasive ventilation should be explored, and factors that commonly cause problems should be reviewed.\n\nThe committee highlighted that in people with OHS, the need for oxygen therapy and adherence to this should be reviewed after treatment with non-invasive ventilation or CPAP has been optimised.\n\n## How the recommendations might affect practice\n\nThese recommendations reflect current practice and are not expected to lead to major changes in practice.\n\nReturn to recommendations\n\n# Supporting adherence to treatment for OHS\n\nRecommendations 2.8.1 and 2.8.2\n\n## Why the committee made the recommendations\n\nThere was no evidence available for people with OHS. The committee agreed that the evidence reviewed for supporting adherence to CPAP in people with OSAHS could be extrapolated to treatments in people with OHS.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect best practice but are currently implemented to varying degrees across NHS settings and will involve a change of practice for some providers.\n\nReturn to recommendations\n\n# When to suspect COPD–OSAHS overlap syndrome\n\nRecommendation 3.1.1\n\n## Why the committee made the recommendation\n\nNo evidence was available for when to suspect chronic obstructive pulmonary disease–obstructive sleep apnoea/hypopnoea syndrome (COPD–OSAHS) overlap syndrome, so the recommendations are based on the committee's knowledge and experience.\n\nCOPD–OSAHS overlap syndrome describes the combination of COPD and OSAHS. These are 2\xa0of the most prevalent pulmonary conditions and therefore the combination is likely to be common. Hypoxaemia due to COPD is exacerbated during sleep by OSAHS, which may worsen prognosis and symptom burden. The committee agreed that a sleep history should be taken and further assessment for OSAHS carried out in people with COPD presenting with common symptoms and features of either OSAHS or nocturnal hypoventilation. The type of symptoms, nature of sleep-disordered breathing and outcome will be affected by the relative severity of COPD and OSAHS.\n\n## How the recommendation might affect practice\n\nIt is estimated that COPD–OSAHS overlap syndrome has a prevalence of approximately 1% and is currently under recognised. In current practice, not all people with the symptoms and features of OSAHS listed in the recommendation are considered for further assessment for COPD–OSAHS overlap syndrome, hence implementation of these recommendations may change practice for most providers. A growth in referrals for sleep study is anticipated with an increased understanding of the impact of COPD–OSAHS overlap syndrome. As a result of increased diagnosis, CPAP and non-invasive ventilation use may increase. Treatment in turn may reduce acute admissions and long-term complications.\n\nReturn to recommendations\n\n# Assessment scales and tests for suspected COPD–OSAHS overlap syndrome\n\nRecommendations 3.1.2 to 3.1.5\n\n## Why the committee made the recommendations\n\nThere was limited evidence on assessment tools for suspected COPD–OSAHS overlap syndrome, so the committee also used their knowledge and collective experience to make the recommendations.\n\nThe Epworth Sleepiness Scale is intended to assess for sleepiness and the limited evidence reflected this, showing that it had moderate sensitivity and low specificity for diagnosing COPD–OSAHS overlap syndrome. The committee noted that some people with this syndrome do not have excessive sleepiness and that not all healthcare professionals are aware of this. However, they agreed that it has a useful role in assessment and monitoring, and noted that when healthcare professionals are requested by the DVLA to complete assessment of a driver with OSAHS (which will include those with COPD–OSAHS overlap syndrome), this includes the Epworth Sleepiness Scale.\n\nLimited evidence showed that the STOP-Bang Questionnaire had high sensitivity and low specificity for diagnosing COPD–OSAHS overlap syndrome. Sensitivity is a priority for questionnaires used for initial assessment. The committee had some concerns about its accuracy in people with less common presentations and in women, but agreed that it could have a role in assessment, alongside the Epworth Sleepiness Scale, to inform the preliminary understanding of the person's symptoms and concerns. The Epworth questionnaire is used to assess only sleepiness whereas the STOP-Bang Questionnaire is used to assess risk of having OSAHS and includes parameters such as snoring, tiredness, history of high blood pressure, BMI, age, neck size and gender. With this in mind, the committee agreed that the Epworth questionnaire should be used, and the STOP-Bang Questionnaire could also be considered for initial assessment.\n\nSpirometry is routinely measured in clinical practice to assess the severity of COPD, and it aids the understanding of the relative contribution of COPD and OSAHS to symptom load and pathophysiology.\n\n## How the recommendations might affect practice\n\nThe Epworth Sleepiness Scale and the STOP-Bang Questionnaire are widely used in current practice, and spirometry is routinely used to assess COPD, so the recommendations are not expected to involve a change in practice.\n\nReturn to recommendations\n\n# Prioritising people for rapid assessment by a sleep service\n\nRecommendations 3.2.1 and 3.2.2\n\n## Why the committee made the recommendations\n\nNo evidence was available for prioritising people with COPD–OSAHS overlap syndrome for assessment in a sleep service, so the committee used their knowledge and experience to identify groups that would benefit most from prompt assessment and treatment.\n\nThe committee noted that people with suspected COPD–OSAHS overlap syndrome who have severe hypercapnia or hypoxaemia should be prioritised for assessment because they have chronic ventilatory failure, and are at risk of acute decompensated ventilatory failure, both of which carry a poor prognosis.\n\nThe committee agreed that sleep services should prioritise access to a sleep study and treatment for people in whom vigilance and alertness are vital to occupational safety, particularly those with problematic sleepiness, and to people with pre-existing conditions who are at increased risk of adverse events. They agreed that services should aim to fast-track priority groups to be seen as soon as possible.\n\nThe committee discussed the effect of OSAHS on work performance and safety, and how it could increase the risk of work accidents in safety-sensitive occupations. People with a wide range of jobs or activities could be affected, for example, drivers, train drivers, pilots, heavy machinery operators, surgeons and people caring for vulnerable children or adults. The committee noted that DVLA guidance on assessing fitness to drive recommends that drivers with suspected or confirmed OSAHS and excessive sleepiness having, or likely to have, an adverse impact on driving must not drive until there is satisfactory symptom control. Control of symptoms is likely to need assessment and treatment from a sleep specialist.\n\nThe committee agreed that priority should be given to pregnant women, because COPD–OSAHS overlap syndrome may be associated with poor outcomes for mothers and babies.\n\nPeople with suspected COPD–OSAHS overlap syndrome and unstable cardiovascular disease need early investigation and treatment, because cardiovascular complications may be a major cause of mortality and morbidity in overlap syndrome.\n\nThe committee agreed that people with a high probability of COPD–OSAHS overlap syndrome who need major surgery should be prioritised to avoid delaying surgery.\n\nThe committee also agreed that the risk of sudden blindness in patients with non-arteritic anterior ischaemic optic neuropathy warrants priority assessment because of its possible association with COPD–OSAHS overlap syndrome.\n\nTo ensure that patients are prioritised appropriately by sleep services and to allow fast-tracking directly to a sleep study, the committee agreed on key details, based on their experience, that should be included in referral letters.\n\n## How the recommendations might affect practice\n\nIn current practice, specific groups are not always prioritised for assessment, so there is likely to be a change in practice for some providers. There is increasing pressure on sleep services, and offering higher priority to some groups may delay studies for other people. Planning for and providing rapid-access sleep studies may help to reduce the pressure on services, with triage of referrals allowing people to be fast-tracked directly to a diagnostic study.\n\nReturn to recommendations\n\n# Diagnostic tests for COPD–OSAHS overlap syndrome\n\nRecommendations 3.3.1 to 3.3.5\n\n## Why the committee made the recommendations\n\nThere was little evidence for diagnostic tests in people with COPD–OSAHS overlap syndrome, so the committee used their clinical knowledge and experience, and the evidence on testing for OSAHS, to make the recommendations.\n\nThe committee agreed that arterial or arterialised capillary blood gas measurement is needed to assess for ventilatory failure. People with any form of chronic ventilatory failure can readily develop acute ventilatory failure if, for example, they have an intercurrent respiratory tract infection. Acute ventilatory failure is a medical emergency needing urgent treatment, and the committee agreed it important to state that this should take priority over full investigation of any underlying chronic disease.\n\nThe committee agreed that arterial blood gas and arterialised capillary blood gas measurements give precise information about oxygen and carbon dioxide levels and information about acid–base balance at the point in time they are taken. It is current practice to use them, and they are generally straightforward to measure.\n\nRespiratory polygraphy (either in hospital or at home) is recommended to establish the presence and severity of OSAHS and nocturnal hypoventilation, and to help determine the most suitable treatment (such as non-invasive ventilation or CPAP). The committee agreed that transcutaneous CO2 monitoring with respiratory polygraphy should also be considered to help confirm nocturnal hypoventilation and severity of hypercapnia. Adding transcutaneous CO2 monitoring with respiratory polygraphy may also help to define the relative contributions of COPD and OSAHS and therefore guide treatment choices and titration of settings. The person needs to have stable COPD, without recent exacerbations, before a clear diagnosis can be established.\n\nHome or hospital respiratory polygraphy are recommended equally because diagnosing the presence of OSAHS in COPD–OSAHS overlap syndrome is more complex than diagnosing OSAHS alone. The hospital setting may be better for distinguishing between OSAHS and nocturnal hypoventilation, and determining whether to offer CPAP or non-invasive ventilation to a person with COPD on long-term oxygen therapy. The committee also discussed that CO2 monitoring is quite hard to do at home.\n\nOximetry alone should not be used to diagnose OSAHS in this population because people with COPD are more likely to have a degree of hypoxaemia when awake, and therefore more easily exhibit falls in oxygen saturation level during sleep, making identification of apnoea episodes more difficult.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nReturn to recommendations\n\n# Treatments for COPD–OSAHS overlap syndrome\n\nRecommendations 3.5.1 to 3.5.5\n\n## Why the committee made the recommendations\n\nNo evidence was identified for CPAP or non-invasive ventilation for people with COPD–OSAHS overlap syndrome, so the recommendations are based on the committee's knowledge and experience.\n\nThe committee agreed that treatment for this population depends on the level of hypercapnia when awake and asleep.\xa0People with more severe hypercapnia when awake (PaCO2 greater than 7\xa0kPa) caused by nocturnal hypoventilation, are likely to need non-invasive ventilation. This is based on extrapolation from data, not reviewed for this guideline but known to the committee, on people with COPD without OSAHS. In these people, definite benefit of non-invasive ventilation has not been demonstrated when hypercapnia is modest (PaCO2 between 6\xa0kPa\xa0and 7\xa0kPa, and not associated with exacerbation of COPD). The committee therefore recommended that CPAP should be considered in people with COPD–OSAHS overlap syndrome if they have confirmed OSAHS from a sleep study and if their PaCO2 is less than or equal to 7.0\xa0kPa, and non-invasive ventilation should be considered if the PaCO2 is higher.\n\nThe committee also made a research recommendation on the optimal treatment for people with COPD–OSAHS overlap syndrome to inform future guidance.\n\nBased on their experience of current practice, the committee agreed that using humidification with CPAP for people with COPD–OSAHS overlap syndrome who have nasal symptoms may reduce side effects associated with upper airway dryness and this may improve adherence and treatment effectiveness.\n\nFor all treatments, the committee highlighted the importance of assessing response to treatment (see recommendations 3.7.6 to 3.7.10).\n\nNo evidence was available for oxygen therapy in people with COPD–OSAHS overlap syndrome. Some people will be established users of long-term oxygen therapy, in which case their supplemental oxygen can be given by CPAP or non-invasive ventilation while sleeping, with oxygen flow rate and non-invasive ventilation or CPAP settings titrated during respiratory polygraphy, according to individual need.\n\nPeople with COPD–OSAHS overlap syndrome are subject to greater falls in oxygen saturation while sleeping than those with COPD alone, and the committee therefore agreed that people with COPD–OSAHS overlap syndrome who do not fulfil the criteria for long-term oxygen therapy may need supplemental oxygen therapy during sleep if they remain hypoxaemic despite control of AHI and nocturnal hypercapnia on CPAP or non-invasive ventilation, and any additional underlying causes of hypoxaemia should be addressed where possible.\n\n## Why the committee did not make recommendations\n\nThere was no evidence for the use of mandibular advancement splints in people with COPD–OSAHS overlap syndrome. The committee discussed whether evidence from people with OSAHS could be used for people with COPD–OSAHS overlap syndrome, but they agreed that the differences between these 2\xa0groups are too great to allow them to make a consensus recommendation based on this evidence.\n\nThe committee were also aware of the potential risks of the long-term use of mandibular advancement splints. People with COPD–OSAHS overlap syndrome are generally older and have poorer dentition which makes mandibular advancement splints less likely to be effective. They also agreed that people with COPD–OSAHS overlap syndrome are at risk of or have ventilatory failure, and mandibular advancements splints are not appropriate in those circumstances.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nReturn to recommendations\n\n# Follow-up for people with COPD–OSAHS overlap syndrome\n\nRecommendations 3.7.1 to 3.7.5\n\n## Why the committee made the recommendations\n\nThe committee noted that CPAP and non-invasive ventilation are just part of treatment for COPD–OSAHS overlap syndrome, and that follow-up should be tailored to the person's overall treatment plan. This should also include lifestyle changes (such as weight management, modifying use of sedative drugs and alcohol, and stopping smoking) and treating underlying lung disease and other comorbidities. For some people, it may also include discussions about care planning (for example, COPD exacerbation action plan and advance care planning) for those with severe COPD.\n\nBased on their knowledge and experience, the committee agreed that for people with COPD–OSAHS overlap syndrome starting CPAP or non-invasive ventilation, early follow-up is advisable to review control of symptoms, sleep-disordered breathing and adherence. Problem solving can be achieved by face-to-face consultations, or video or phone consultations, and include review of telemonitoring data if available. The committee also agreed that although most studies of telemonitoring are in people with OSAHS, and that there is not yet the ability to assess hypercapnia through telemonitoring, it is still of value for monitoring in people with COPD–OSAHS overlap syndrome.\n\nIn addition to their 6‑monthly or annual review, people with COPD–OSAHS overlap syndrome having CPAP or non-invasive ventilation need to be able to access a sleep service for advice, and provision of consumables such as masks, circuitry and filters.\n\nThe committee noted that annual review is required by the DVLA for Group\xa02 licence holders (lorry and bus drivers) with moderate or severe OSAHS and excessive sleepiness at diagnosis. For Group\xa01 licence holders (car and motorcycle drivers) with OSAHS and excessive sleepiness, review is required at least every 3\xa0years. For more information, see the DVLA guidance on assessing fitness to drive.\n\n## How the recommendations might affect practice\n\nCurrent practice includes a mixture of face-to-face, phone, video consultations and telemonitoring. The increasing number of people being offered CPAP and non-invasive ventilation means that regular outpatient follow-up becomes difficult for sleep services to provide. In addition, a more personalised approach enables attention to be focused on people with problems adapting to therapy. Telemonitoring is included in the overall cost of CPAP devices by some manufacturers for variable periods. The committee discussed that routine use of telemonitoring should reduce the need for face-to-face consultations, and reduce pressure on outpatient clinics, but feedback and discussion with patients is still needed. Increasing web- and app-based access to telemonitoring data will allow patients to access their own results and encourage self-management.\n\nThe committee noted that there has been a significant move to video and phone consultations to reduce the risk of infection during the COVID‑19 pandemic, and this shift in practice is likely to persist.\n\nReturn to recommendations\n\n# Monitoring treatment efficacy for people with COPD–OSAHS overlap syndrome\n\nRecommendations 3.7.6 to 3.7.10\n\n## Why the committee made the recommendations\n\nNo evidence was available on efficacy of treatment for COPD–OSAHS overlap syndrome, so the recommendations are based on the committee's knowledge and experience.\n\nIn COPD–OSAHS overlap syndrome, control of nocturnal hypoventilation is demonstrated by normalisation of oxygenation and hypercapnia when awake and asleep; this is important to improve prognosis.\n\nThe committee agreed that clinical effectiveness of CPAP and non-invasive ventilation in people with COPD–OSAHS overlap syndrome should be assessed by reviewing symptoms of OSAHS and nocturnal hypoventilation including Epworth Sleepiness Scale score, AHI or ODI, adherence to therapy, improvement in oxygenation and hypercapnia (if present) while awake and asleep, and telemonitoring or download information from CPAP or non-invasive ventilation device. As well as assessing sleepiness, the committee agreed that vigilance should be assessed by discussing the person's alertness and ability to concentrate on tasks. This is particularly important for drivers. The committee agreed that the understanding and experience of people having CPAP and non-invasive ventilation should be explored, and factors that commonly cause problems should be reviewed. They noted that sleep quality may be poor in COPD patients, with disruption from cough, wheeze, restless legs and medication.\n\nThe committee highlighted that in people with COPD–OSAHS overlap syndrome who are already having supplemental oxygen therapy, the need for oxygen therapy should be reviewed after treatment with non-invasive ventilation or CPAP has been optimised. Effective treatment with CPAP or non-invasive ventilation may improve the person's condition to the extent that they no longer fulfil the criteria for supplemental oxygen.\n\nIn some patients with severe COPD and COPD–OSAHS overlap syndrome, optimised treatment of the OSAHS may produce an objective improvement in indices such as the AHI or oxygen desaturation during sleep, but fail to improve symptoms or quality of life for the person. This would usually be because the severity of the person's COPD has the overriding influence on quality of life. Because use of non-invasive ventilation or CPAP equipment adds to the burden of therapy, consideration should be given to stopping these and using a symptom-management approach. This needs careful discussion with the person and their family or carers, including considering what they would like to do for COPD exacerbations and advance care planning when appropriate.\n\n## How the recommendations might affect practice\n\nThese recommendations reflect current practice and are not expected to lead to major changes in practice.\n\nReturn to recommendations\n\n# Supporting adherence to treatment for people with COPD–OSAHS overlap syndrome\n\nRecommendations 3.8.1 and 3.8.2\n\n## Why the committee made the recommendations\n\nThere was no evidence available for people with COPD–OSAHS overlap syndrome. The committee agreed that the evidence reviewed for supporting adherence to CPAP in people with OSAHS could be extrapolated to treatments in people with COPD–OSAHS overlap syndrome.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect best practice but are currently implemented to varying degrees across NHS settings and will involve a change of practice for some providers.\n\nReturn to recommendations\n\n# Information for people with OSAHS, OHS and COPD–OSAHS overlap syndrome\n\nRecommendations 4.1.1 to 4.1.5\n\n## Why the committee made the recommendations\n\nThere was limited evidence from clinical studies on the information and support needs of people with OSAHS, and no evidence for people with OHS and COPD–OSAHS overlap syndrome, so the committee also used their clinical knowledge and experience to make the recommendations.\n\nThe committee discussed that providing appropriate information for people with OSAHS, OHS and COPD–OSAHS overlap syndrome is essential to help them understand their condition and access support and treatment. Attendance for sleep investigation, such as respiratory polygraphy, is likely to be higher if patients understand why these are being performed and what they entail.\n\nThe committee agreed that giving information about all aspects of treatment is likely to increase uptake and therefore effectiveness.\n\nThe committee noted that different sleep services provide their own information and were aware of useful resources produced by a number of organisations providing support to patients.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current best practice.\n\nReturn to recommendations", 'Context': "This guideline covers obstructive sleep apnoea/hypopnoea syndrome (OSAHS), obesity hypoventilation syndrome (OHS), and chronic obstructive pulmonary disease (COPD) with OSAHS overlap syndrome, providing advice on investigating and managing these related conditions.\n\nOSAHS is a common, but frequently unrecognised cause of serious disability that has important health and social consequences. It is characterised by recurrent episodes of complete or partial upper airway obstruction during sleep resulting in dips in oxygen level, autonomic dysfunction and sleep fragmentation. There are a number of clinical and physiological variants (phenotypes) of the condition, which may influence treatment response.\n\nOHS occurs when people who are obese are unable to breathe rapidly or deeply enough, resulting in low oxygen levels and high blood carbon dioxide levels. It is usually associated with OSAHS or nocturnal hypoventilation, and people with OHS often have cardiovascular complications and other comorbidities.\n\nCOPD–OSAHS overlap syndrome is the coexistence of OSAHS and COPD, which combined can cause a greater degree of oxygen deficiency, and increased morbidity, compared with either condition alone.\n\nThese conditions can have a profound impact on people's lives, causing excessive sleepiness or sleep disturbance that affects social activities, work performance, the ability to drive safely and quality of life. Undiagnosed, these conditions are closely associated with serious health problems, including hypertension, diabetes, stroke and heart disease, and can shorten life expectancy.\n\nHigh numbers of the population are affected by these conditions, and they are often undiagnosed; it is estimated that 5% of adults in the UK have undiagnosed OSAHS. Both COPD and OSAHS are common conditions and are estimated to coexist, as overlap syndrome, in about 1% of the adult UK population. OHS is of particular concern because of rising obesity; it is already estimated to affect 0.3% to 0.4% of the UK population, with prevalence likely to grow.\n\nThe availability of services for investigation and management is variable. Failure to treat these conditions can result in an increased use of services and may leave people with a reduced quality of life. Highly effective treatment, in the form of continuous positive airway pressure (CPAP), is available. But approaches to CPAP therapy differ and there is a lack of guidance on when other forms of treatment, such as non-invasive ventilation, oral devices, lifestyle changes and surgery are effective. Adherence to therapy is known to be low, so advice on interventions to help with adherence is also a priority for this guideline.\n\nThis guideline is needed to improve recognition and management of OSAHS, OHS and COPD–OSAHS overlap syndrome, and ensure consistent provision of care. It gives advice to healthcare professionals on when and how to investigate, and how to manage each of these conditions. It also gives guidance on supporting people to adhere to treatment and providing follow-up."}
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https://www.nice.org.uk/guidance/ng202
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This guideline covers the diagnosis and management of obstructive sleep apnoea/hypopnoea syndrome (OSAHS), obesity hypoventilation syndrome (OHS) and chronic obstructive pulmonary disease with OSAHS (COPD–OSAHS overlap syndrome) in people over 16. It aims to improve recognition, investigation and treatment of these related conditions.
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b8703a640a18ad9f824ebc75b85bda4d6dc3196e
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nice
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Antenatal care
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Antenatal care
This guideline covers the routine antenatal care that women and their babies should receive. It aims to ensure that pregnant women are offered regular check‑ups, information and support. We have also published a guideline on postnatal care, which covers the topics of emotional attachment and baby feeding.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Supporting women to make decisions about their care is important during pregnancy. Healthcare professionals should ensure that women have the information they need to make decisions and to give consent in line with General Medical Council (GMC) guidance, the Nursing and Midwifery Council (NMC) Code and the 2015 Montgomery ruling.
Please note that the Royal College of Obstetricians and Gynaecologists has produced guidance on COVID-19 and pregnancy for all midwifery and obstetric services.
# Organisation and delivery of antenatal care
## Starting antenatal care
Ensure that antenatal care can be started in a variety of straightforward ways, depending on women's needs and circumstances, for example, by self-referral, referral by a GP, midwife or another healthcare professional, or through a school nurse, community centre or refugee hostel.
At the point of antenatal care referral:
Provide an easy-to-complete referral form.
Offer early pregnancy health and wellbeing information before the booking appointment. This should include information about modifiable factors that may affect the pregnancy, including stopping smoking, avoiding alcohol, taking supplements, and eating healthily. See also recommendation 1.3.9 and the NICE guidelines on maternal and child nutrition, vitamin D, and smoking: stopping in pregnancy and after childbirth.
Ensure that the materials are available in different languages or formats such as digital, printed, braille or Easy Read.
The referral form for women to start antenatal care should:
enable healthcare professionals to identify women with:
specific health and social care needs
risk factors, including those that can potentially be addressed before the booking appointment, for example, smoking
include contact details about the woman's GP.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on starting antenatal care .
Full details of the evidence and the committee's discussion are in evidence review F: accessing antenatal care.
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## Antenatal appointments
Offer a first antenatal (booking) appointment with a midwife to take place by 10+0 weeks of pregnancy.
If women contact or are referred to maternity services later than 9+0 weeks of pregnancy, offer a first antenatal (booking) appointment to take place within 2 weeks if possible.
If a woman books late in pregnancy, ask about the reasons for the late booking because it may reveal social, psychological or medical issues that need to be addressed.
Plan 10 routine antenatal appointments with a midwife or doctor for nulliparous women. (See schedule of appointments.)
Plan 7 routine antenatal appointments with a midwife or doctor for parous women. (See schedule of appointments.)
Also see the NICE guideline on pregnancy and complex social factors for:
women who misuse substances
recent migrants, asylum seekers or refugees, or women who have difficulty reading or speaking English
young women aged under 20
women who experience domestic abuse.
Offer additional or longer antenatal appointments if needed, depending on the woman's medical, social and emotional needs. Also see the NICE guidelines on pregnancy and complex social factors, intrapartum care for women with existing medical conditions or obstetric complications and their babies, hypertension in pregnancy, diabetes in pregnancy and twin and triplet pregnancy.
Ensure that reliable interpreting services are available when needed, including British Sign Language. Interpreters should be independent of the woman rather than using a family member or friend.
Those responsible for planning and delivering antenatal services should aim to provide continuity of carer.
Ensure that there is effective and prompt communication between healthcare professionals who are involved in the woman's care during pregnancy.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on antenatal appointments .
Full details of the evidence and the committee's discussion are in:
evidence review H: timing of first antenatal appointment
evidence review I: number of antenatal appointments
evidence review J: referral and delivery of antenatal care.
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## Involving partners
A woman can be supported by a partner during her pregnancy so healthcare professionals should:
involve partners according to the woman's wishes and
inform the woman that she is welcome to bring a partner to antenatal appointments and classes.
Consider arranging the timing of antenatal classes so that the pregnant woman's partner can attend, if the woman wishes.
When planning and delivering antenatal services, ensure that the environment is welcoming for partners as well as pregnant women by, for example:
providing information about how partners can be involved in supporting the woman during and after pregnancy
providing information about pregnancy for partners as well as pregnant women
displaying positive images of partner involvement (for example, on notice boards and in waiting areas)
providing seating in consultation rooms for both the woman and her partner
considering providing opportunities for partners to attend appointments remotely as appropriate.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on involving partners .
Full details of the evidence and the committee's discussion are in evidence review C: involving partners and evidence review B: approaches to information provision.
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# Routine antenatal clinical care
## Taking and recording the woman's history
At the first antenatal (booking) appointment, ask the woman about:
her medical history, obstetric history and family history (of both biological parents)
previous or current mental health concerns such as depression, anxiety, severe mental illness, psychological trauma or psychiatric treatment, to identify possible mental health problems in line with the section on recognising mental health problems in pregnancy and the postnatal period and referral in the NICE guideline on antenatal and postnatal mental health
current and recent medicines, including over-the-counter medicines, health supplements and herbal remedies
allergies
her occupation, discussing any risks and concerns
her family and home situation, available support network and any health or other issues affecting her partner or family members that may be significant for her health and wellbeing
-ther people who may be involved in the care of the baby
contact details for her partner and her next of kin
factors such as nutrition and diet, physical activity, smoking and tobacco use, alcohol consumption and recreational drug use (see also recommendations 1.3.8 and 1.3.9).
Consider reviewing the woman's previous medical records if needed, including records held by other healthcare providers.
Be aware that, according to the 2020 MBRRACE-UK reports on maternal and perinatal mortality, women and babies from some minority ethnic backgrounds and those who live in deprived areas have an increased risk of death and may need closer monitoring and additional support. The reports showed that:
compared with white women (8/100,000), the risk of maternal death during pregnancy and up to 6 weeks after birth is:
times higher in black women (34/100,000)
times higher in women with mixed ethnic background (25/100,000)
times higher in Asian women (15/100,000; does not include Chinese women)
compared with white babies (34/10,000), the stillbirth rate is
more than twice as high in black babies (74/10,000)
around 50% higher in Asian babies (53/10,000)
women living in the most deprived areas (15/100,000) are more than 2.5 times more likely to die compared with women living in the least deprived areas (6/100,000)
the stillbirth rate increases according to the level of deprivation in the area the mother lives in, with almost twice as many stillbirths for women living in the most deprived areas (47/10,000) compared with the least deprived areas (26/10,000).
If the woman or her partner smokes or has stopped smoking within the past 2 weeks, offer a referral to NHS Stop Smoking Services in line with the NICE guideline on smoking: stopping in pregnancy and after childbirth. Also see the NICE guideline on smokeless tobacco: South Asian communities.
Ask the woman about domestic abuse in a kind, sensitive manner at the first antenatal (booking) appointment, or at the earliest opportunity when she is alone. Ensure that there is an opportunity to have a private, one‑to‑one discussion. Also see the NICE guideline on domestic violence and abuse and the section on pregnant women who experience domestic abuse in the NICE guideline on pregnancy and complex social factors.
Assess the woman's risk of and, if appropriate, discuss female genital mutilation (FGM) in a kind, sensitive manner. Take appropriate action in line with UK government guidance on safeguarding women and girls at risk of FGM.
Refer the woman for a clinical assessment by a doctor to detect cardiac conditions if there is a concern based on the pregnant woman's personal or family history. See also the section on heart disease in the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies.
Refer the woman to an obstetrician or other relevant doctor if there are any medical concerns or if review of current long-term medicines is needed.
After discussion with and agreement from the woman, contact the woman's GP to share information about the pregnancy and potential concerns or complications during pregnancy.
At every antenatal appointment, carry out a risk assessment as follows:
ask the woman about her general health and wellbeing
ask the woman (and her partner, if present) if there are any concerns they would like to discuss
provide a safe environment and opportunities for the woman to discuss topics such as concerns at home, domestic abuse, concerns about the birth (for example, if she previously had a traumatic birth) or mental health concerns
review and reassess the plan of care for the pregnancy
identify women who need additional care.
At every antenatal contact, update the woman's antenatal records to include details of history, test results, examination findings, medicines and discussions.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on taking and recording the woman's history .
Full details of the evidence and the committee's discussion are in evidence review G: content of antenatal appointments.
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## Examinations and investigations
At the first face-to-face antenatal appointment:
-ffer to measure the woman's height and weight and calculate body mass index
-ffer a blood test to check full blood count, blood group and rhesus D status.
At the first antenatal (booking) appointment, discuss and share information about, and then offer, the following screening programmes:
NHS infectious diseases in pregnancy screening programme (HIV, syphilis and hepatitis B)
NHS sickle cell and thalassaemia screening programme
NHS fetal anomaly screening programme.Inform the woman that she can accept or decline any part of any of the screening programmes offered.
Offer pregnant women an ultrasound scan to take place between 11+2 weeks and 14+1 weeks to:
determine gestational age
detect multiple pregnancy
and if opted for, screen for Down's syndrome, Edwards' syndrome and Patau's syndrome (see the NHS fetal anomaly screening programme).
Offer pregnant women an ultrasound scan to take place between 18+0 weeks and 20+6 weeks to:
screen for fetal anomalies (see the NHS fetal anomaly screening programme)
determine placental location.
At the antenatal appointment at 28 weeks, offer:
anti-D prophylaxis to rhesus-negative women in line with NICE's technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative (see also NICE's diagnostics guidance on high-throughput non-invasive prenatal testing for fetal RHD genotype)
a blood test to check full blood count, blood group and antibodies.
If there are any unexpected results from examinations or investigations, offer referral according to local pathways and ensure appropriate information provision and support.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on examinations and investigations .
Full details of the evidence and the committee's discussion are in evidence review G: content of antenatal appointments.
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## Venous thromboembolism
Assess the woman's risk factors for venous thromboembolism at the first antenatal (booking) appointment, and after any hospital admission or significant health event during pregnancy. Consider using guidance by an appropriate professional body, for example, the Royal College of Obstetricians and Gynaecologists' guideline on reducing the risk of venous thromboembolism during pregnancy.
For pregnant women who are admitted to a hospital or a midwife-led unit, see the section on interventions for pregnant women and women who gave birth or had a miscarriage or termination of pregnancy in the past 6 weeks in the NICE guideline on venous thromboembolism in over 16s.
For women at risk of venous thromboembolism, offer referral to an obstetrician for further management.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on venous thromboembolism .
Full details of the evidence and the committee's discussion are in evidence review N: risk factors for venous thromboembolism in pregnancy.
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## Gestational diabetes
At the first antenatal (booking) appointment, assess the woman's risk factors for gestational diabetes in line with the recommendations on gestational diabetes risk assessment in the NICE guideline on diabetes in pregnancy.
If a woman is at risk of gestational diabetes, offer referral for an oral glucose tolerance test to take place between 24+0 weeks and 28+0 weeks in line with the recommendations on gestational diabetes risk assessment and the recommendations on gestational diabetes testing in the NICE guideline on diabetes in pregnancy.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on gestational diabetes .
Full details of the evidence and the committee's discussion are in evidence review G: content of antenatal appointments.
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## Pre-eclampsia and hypertension in pregnancy
At the first antenatal (booking) appointment and again in the second trimester, assess the woman's risk factors for pre-eclampsia, and advise those at risk to take aspirin in line with the section on antiplatelet agents in the NICE guideline on hypertension in pregnancy.
Measure and record the woman's blood pressure at every routine face-to-face antenatal appointment using a device validated for use in pregnancy, and following the recommendations on measuring blood pressure in the NICE guideline on hypertension in adults.
For women under 20+0 weeks with hypertension, follow the recommendations on the management of chronic hypertension in pregnancy in the NICE guideline on hypertension in pregnancy.
Refer women over 20+0 weeks with a first episode of hypertension (blood pressure of 140/90 mmHg or higher) to secondary care to be seen within 24 hours. See the recommendations on diagnosing hypertension in the NICE guideline on hypertension in adults.
Urgently refer women with severe hypertension (blood pressure of 160/110 mmHg or higher) to secondary care to be seen on the same day. The urgency of the referral should be determined by an overall clinical assessment.
Offer a urine dipstick test for proteinuria at every routine face-to-face antenatal appointment.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on pre-eclampsia and hypertension in pregnancy .
Full details of the evidence and the committee's discussion are in evidence review K: identification of hypertension in pregnancy and evidence review G: content of antenatal appointments.
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## Monitoring fetal growth and wellbeing
Offer a risk assessment for fetal growth restriction at the first antenatal (booking) appointment, and again in the second trimester. Consider using guidance by an appropriate professional or national body, for example, the Royal College of Obstetricians and Gynaecologists' guideline on the investigation and management of the small-for-gestational-age fetus or the NHS saving babies' lives care bundle version 2.
Offer symphysis fundal height measurement at each antenatal appointment after 24+0 weeks (but no more frequently than every 2 weeks) for women with a singleton pregnancy unless the woman is having regular growth scans. Plot the measurement onto a growth chart in line with the NHS saving babies' lives care bundle version 2.
If there are concerns that the symphysis fundal height is large for gestational age, consider an ultrasound scan for fetal growth and wellbeing.
If there are concerns that the symphysis fundal height is small for gestational age, offer an ultrasound scan for fetal growth and wellbeing, the urgency of which may depend on additional clinical findings, for example, reduced fetal movements or raised maternal blood pressure.
Do not routinely offer ultrasound scans after 28 weeks for uncomplicated singleton pregnancies.
Discuss the topic of babies' movements with the woman after 24+0 weeks, and:
ask if she has any concerns about her baby's movements at each antenatal contact after 24+0 weeks
advise her to contact maternity services at any time of day or night if she has any concerns about her baby's movements or she notices reduced fetal movements after 24+0 weeks
assess the woman and baby if there are any concerns about the baby's movements.
Service providers should recognise that the use of structured fetal movement awareness packages, such as the one studied in the AFFIRM trial, has not been shown to reduce stillbirth rates.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on monitoring fetal growth and wellbeing .
Full details of the evidence and the committee's discussion are in:
evidence review O: monitoring fetal growth
evidence review P: fetal movement monitoring
evidence review Q: routine third trimester ultrasound for fetal growth.
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## Breech presentation
Offer abdominal palpation at all appointments after 36+0 weeks to identify possible breech presentation for women with a singleton pregnancy.
If breech presentation is suspected on abdominal palpation, offer an ultrasound scan to determine the presentation.
For women with an uncomplicated singleton pregnancy with breech presentation confirmed after 36+0 weeks:
discuss the different options available and their benefits, risks and implications, including:
external cephalic version (to turn the baby from bottom to head down)
breech vaginal birth
elective caesarean birth
for women who prefer cephalic (head-down) vaginal birth, offer external cephalic version.Also see the recommendations on breech presentation in the NICE guideline on caesarean birth, and the recommendations on breech presenting in labour in the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on breech presentation .
Full details of the evidence and the committee's discussion are in evidence review L: identification of breech presentation and evidence review M: management of breech presentation.
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# Information and support for pregnant women and their partners
## Communication – key principles
When caring for a pregnant woman, listen to her and be responsive to her needs and preferences. Also see the NICE guideline on patient experience in adult NHS services, in particular the sections on communication and information, and the NICE guideline on shared decision making.
Ensure that when offering any assessment, intervention or procedure, the risks, benefits and implications are discussed with the woman and she is aware that she has a right to decline.
Women's decisions should be respected, even when this is contrary to the views of the healthcare professional.
When giving women (and their partners) information about antenatal care, use clear language, and tailor the timing, content and delivery of information to the needs and preferences of the woman and her stage of pregnancy. Information should support shared decision making between the woman and her healthcare team, and be:
-ffered on a one-to-one or couple basis
supplemented by group discussions (women only or women and partners)
supplemented by written information in a suitable format, for example, digital, printed, braille or Easy Read
-ffered throughout the woman's care
individualised and sensitive
supportive and respectful
evidence-based and consistent
translated into other languages if needed.For more guidance on communication, providing information (including different formats and languages), and shared decision making, see the NICE guideline on patient experience in adult NHS services and the NHS Accessible Information Standard.
Explore the knowledge and understanding that the woman (and her partner) has about each topic to individualise the discussion.
Check that the woman (and her partner) understands the information that has been given, and how it relates to them. Provide regular opportunities to ask questions, and set aside enough time to discuss any concerns.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on communication – key principles .
Full details of the evidence and the committee's discussion are in:
evidence review B: approaches to information provision
evidence review A: information provision
evidence review J: referral and delivery of antenatal care.
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## Information about antenatal care
At the first antenatal (booking) appointment, discuss antenatal care with the woman (and her partner) and provide her schedule of antenatal appointments.
At the first antenatal (booking) appointment (and later if appropriate), discuss and give information on:
what antenatal care involves and why it is important
the planned number of antenatal appointments
where antenatal appointments will take place
which healthcare professionals will be involved in antenatal appointments
how to contact the midwifery team for non-urgent advice
how to contact the maternity service about urgent concerns, such as pain and bleeding
screening programmes: what blood tests and ultrasound scans are offered and why
how the baby develops during pregnancy
what to expect at each stage of the pregnancy
physical and emotional changes during the pregnancy
mental health during the pregnancy
relationship changes during the pregnancy
how the woman and her partner can support each other
immunisation for flu, pertussis (whooping cough) and other infections (for example, COVID‑19) during pregnancy, in line with the NICE guideline on flu vaccination and the Public Health England Green Book on immunisation against infectious disease
infections that can impact on the baby in pregnancy or during birth (such as group B streptococcus, herpes simplex and cytomegalovirus)
reducing the risk of infections, for example, encouraging hand washing
safe use of medicines, health supplements and herbal remedies during pregnancy
resources and support for expectant and new parents
how to get in touch with local or national peer support services.
At the first antenatal (booking) appointment, and later if appropriate, discuss and give information about nutrition and diet, physical activity, smoking cessation and recreational drug use in a non-judgemental, compassionate and personalised way. See the NICE guidelines on maternal and child nutrition, vitamin D, weight management before, during and after pregnancy, smoking: stopping in pregnancy and after childbirth, and the section on pregnant women who misuse substances (alcohol and/or drugs) in the NICE guideline on pregnancy and complex social factors.
At the first antenatal (booking) appointment, and later if appropriate, discuss alcohol consumption and follow the UK Chief Medical Officers' low-risk drinking guidelines. Explain that:
there is no known safe level of alcohol consumption during pregnancy
drinking alcohol during the pregnancy can lead to long-term harm to the baby
the safest approach is to avoid alcohol altogether to minimise risks to the baby.
Throughout the pregnancy, discuss and give information on:
physical and emotional changes during the pregnancy
relationship changes during the pregnancy
how the woman and her partner can support each other
resources and support for expectant and new parents
how the parents can bond with their baby and the importance of emotional attachment (also see the section on promoting emotional attachment in the NICE guideline on postnatal care)
the results of any blood or screening tests from previous appointments.
See the NICE guideline on pelvic floor dysfunction for guidance on:
providing information about pelvic floor dysfunction (recommendation 1.1.6)
pelvic floor muscle training during and after pregnancy.
After 24 weeks, discuss babies' movements (see also recommendation 1.2.34).
Before 28 weeks, start talking with the woman about her birth preferences and the implications, benefits and risks of different options (see the section on choosing planned place of birth in the NICE guideline on intrapartum care for healthy women and babies and the section on planning mode of birth in the NICE guideline on caesarean birth).
After 28 weeks, discuss and give information on:
preparing for labour and birth, including information about coping in labour and creating a birth plan
recognising active labour
the postnatal period, including:
care of the new baby
the baby's feeding
vitamin K prophylaxis
newborn screening
postnatal self-care, including pelvic floor exercises
awareness of mood changes and postnatal mental health.Also see the NICE guideline on postnatal care.
From 28 weeks onwards, as appropriate, continue the discussions and confirm the woman's birth preferences, discussing the implications, benefits and risks of all the options.
From 38 weeks, discuss prolonged pregnancy and options on how to manage this, in line with the NICE guideline on inducing labour.
See the NICE guideline on preterm labour and birth for women at increased risk of, or with symptoms and signs of, preterm labour (before 37 weeks), and women having a planned preterm birth.
Provide appropriate information and support for women whose baby is considered to be at an increased risk of neonatal admission.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information about antenatal care .
Full details of the evidence and the committee's discussion are in:
evidence review A: information provision
evidence review B: approaches to information provision
evidence review C: involving partners
evidence review D: peer support
evidence review G: content of antenatal appointments
evidence review J: referral and delivery of antenatal care
evidence review P: fetal movement monitoring.
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## Antenatal classes
Offer nulliparous women (and their partners) antenatal classes that include topics such as:
preparing for labour and birth
supporting each other throughout the pregnancy and after birth
common events in labour and birth
how to care for the baby
how the parents can bond with their baby and the importance of emotional attachment (also see the section on promoting emotional attachment in the NICE guideline on postnatal care)
planning and managing their baby's feeding (also see the section on planning and supporting babies' feeding in the NICE guideline on postnatal care).
Consider antenatal classes for multiparous women (and their partners) if they could benefit from attending (for example, if they have had a long gap between pregnancies, or have never attended antenatal classes before).
Ensure that antenatal classes are welcoming, accessible and adapted to meet the needs of local communities. Also see the section on young pregnant women aged under 20 in the NICE guideline on pregnancy and complex social factors.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on antenatal classes .
Full details of the evidence and the committee's discussion are in evidence review E: antenatal classes and evidence review B: approaches to information provision.
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## Peer support
Discuss the potential benefits of peer support with pregnant women (and their partners), and explain how it may:
provide practical support
help to build confidence
reduce feelings of isolation.
Offer pregnant women (and their partners) information about how to access local and national peer support services.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on peer support .
Full details of the evidence and the committee's discussion are in evidence review D: peer support.
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## Sleep position
Advise women to avoid going to sleep on their back after 28 weeks of pregnancy and to consider using pillows, for example, to maintain their position while sleeping.
Explain to the woman that there may be a link between going to sleep on her back and stillbirth in late pregnancy (after 28 weeks).
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on sleep position .
Full details of the evidence and the committee's discussion are in evidence review W: maternal sleep position during pregnancy.
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# Interventions for common problems during pregnancy
## Nausea and vomiting
Reassure women that mild to moderate nausea and vomiting are common in pregnancy, and are likely to resolve before 16 to 20 weeks.
Recognise that by the time women seek advice from healthcare professionals about nausea and vomiting in pregnancy, they may have already tried a number of different interventions.
For pregnant women with mild‑to‑moderate nausea and vomiting who prefer a non-pharmacological option, suggest that they try ginger.
When considering pharmacological treatments for nausea and vomiting in pregnancy, discuss the advantages and disadvantages of different antiemetics with the woman. Take into account her preferences and her experience with treatments in previous pregnancies. See table 1 on the advantages and disadvantages of different pharmacological treatments for nausea and vomiting in pregnancy to support shared decision making.
For pregnant women with nausea and vomiting who choose a pharmacological treatment, offer an antiemetic (see table 1 on the advantages and disadvantages of different pharmacological treatments for nausea and vomiting in pregnancy).
For pregnant women with moderate‑to‑severe nausea and vomiting:
consider intravenous fluids, ideally on an outpatient basis
consider acupressure as an adjunct treatment.
Consider inpatient care if vomiting is severe and not responding to primary care or outpatient management. This will include women with hyperemesis gravidarum. Also see the section on venous thromboembolism.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on nausea and vomiting .
Full details of the evidence and the committee's discussion are in evidence review R: management of nausea and vomiting in pregnancy.
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## Heartburn
Give information about lifestyle and dietary changes to pregnant women with heartburn in line with the section on common elements of care in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults.
Consider a trial of an antacid or alginate for pregnant women with heartburn.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on heartburn .
Full details of the evidence and the committee's discussion are in evidence review S: management of heartburn in pregnancy.
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## Symptomatic vaginal discharge
Advise pregnant women who have vaginal discharge that this is common during pregnancy, but if it is accompanied by symptoms such as itching, soreness, an unpleasant smell or pain on passing urine, there may be an infection that needs to be investigated and treated.
Consider carrying out a vaginal swab for pregnant women with symptomatic vaginal discharge if there is doubt about the cause.
If a sexually transmitted infection is suspected, consider arranging appropriate investigations.
Offer vaginal imidazole (such as clotrimazole or econazole) to treat vaginal candidiasis in pregnant women.
Consider oral or vaginal antibiotics to treat bacterial vaginosis in pregnant women in line with the NICE guideline on antimicrobial stewardship.
For a short explanation of why the committee made the recommendations and how they might practice, see the rationale and impact section on symptomatic vaginal discharge .
Full details of the evidence and the committee's discussion are in evidence review T: management of symptomatic vaginal discharge in pregnancy.
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## Pelvic girdle pain
For women with pregnancy-related pelvic girdle pain, consider referral to physiotherapy services for:
exercise advice and/or
a non-rigid lumbopelvic belt.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on pelvic girdle pain .
Full details of the evidence and the committee's discussion are in evidence review U: management of pelvic girdle pain in pregnancy.
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## Unexplained vaginal bleeding after 13 weeks
Offer anti-D immunoglobulin to women who present with vaginal bleeding after 13 weeks of pregnancy if they are:
rhesus D-negative and
at risk of isoimmunisation.
Refer pregnant women with unexplained vaginal bleeding after 13 weeks to secondary care for a review.
For pregnant women with unexplained vaginal bleeding after 13 weeks, assess whether to admit them to hospital, taking into account:
the risk of placental abruption
the risk of preterm delivery
the extent of vaginal bleeding
the woman's ability to attend secondary care in an emergency.
For pregnant women who present with unexplained vaginal bleeding, offer to carry out placental localisation by ultrasound if the placental site is not known.
For pregnant women with unexplained vaginal bleeding who are admitted to hospital, consider corticosteroids for fetal lung maturation if there is an increased risk of preterm birth within 48 hours. Take into account gestational age (see the section on maternal corticosteroids in the NICE guideline on preterm labour and birth).
Consider discussing the increased risk of preterm birth with women who have unexplained vaginal bleeding.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on unexplained vaginal bleeding after 13 weeks .
Full details of the evidence and the committee's discussion are in evidence review V: management of unexplained vaginal bleeding in pregnancy.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
## Bonding and emotional attachment
Bonding is the positive emotional and psychological connection that the parent develops with the baby.
Emotional attachment refers to the relationship between the baby and parent, driven by innate behaviour and which ensures the baby's proximity to the parent and safety. Its development is a complex and dynamic process that is dependent on sensitive and emotionally attuned parent interactions supporting healthy infant psychological and social development and a secure attachment. Babies form attachments with a variety of caregivers but the first, and usually most significant of these, will be with the mother and/or father.
## Continuity of carer
Having continuity of carer means that a trusting relationship can be developed between the woman and the healthcare professional who cares for her. Better Births, a report by the National Maternity Review, defines continuity of carer as consistency in the midwifery team (between 4 and 8 individuals) that provides care for the woman and her baby throughout pregnancy, labour and the postnatal period. A named midwife coordinates the care and takes responsibility for ensuring that the needs of the woman and her baby are met throughout the antenatal, intrapartum and postnatal periods.
For the purpose of this guideline, definition of continuity of carer in the Better Births report has been adapted to include not just the midwifery team but any healthcare team involved in the care of the woman and her baby. It emphasises the importance of effective information transfer between the individuals within the team. For more information, see the NHS Implementing Better Births: continuity of carer.
## Partner
Partner refers to the woman's chosen supporter. This could be the baby's father, the woman's partner, family member or friend, or anyone who the woman feels supported by and wishes to involve in her antenatal care.
## Shared decision making
Shared decision making is a collaborative process that involves a person and their healthcare professional working together to reach a joint decision about care. It could be care the person needs straightaway or care in the future, for example, through advance care planning. See the full definition in the NICE guideline on shared decision making. In line with NHS England's personalised care and support planning guidance: guidance for local maternity systems, in maternity services, this may be referred to as 'informed decision making'.
## Structured fetal movement awareness packages
The structured fetal movement awareness package described in the Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM) trial consisted of:
an e-learning education package for all clinical staff about the importance of a recent change in the frequency of fetal movements and how to manage reduced fetal movements
a leaflet given to pregnant women at 20 weeks of pregnancy to raise awareness of the importance of monitoring fetal movements and reporting reduced movements
a structured management plan for hospitals following reporting of reduction in fetal movement including cardiotocography, measurement of liquor volume and a growth scan (umbilical artery doppler was encouraged if available).# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Hospitalisation of pregnant women with unexplained vaginal bleeding
What is the clinical and cost effectiveness of hospitalisation compared with outpatient management for pregnant women with unexplained vaginal bleeding?
For a short explanation of why the committee made this research recommendation, see the rationale section on unexplained vaginal bleeding .
Full details of the research recommendation are in evidence review V: management of unexplained vaginal bleeding in pregnancy.
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## Medications for mild to moderate nausea and vomiting in pregnancy
What is the clinical and cost effectiveness of medication for women with nausea and vomiting in pregnancy?
For a short explanation of why the committee made this research recommendation, see the rationale section on nausea and vomiting .
Full details of the research recommendation are in evidence review R: management of nausea and vomiting in pregnancy.
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## Models of antenatal care
What is the clinical and cost effectiveness of different models of antenatal care with varying numbers and times of appointment, and should different models be used for groups at risk of worse outcomes?
For a short explanation of why the committee made this research recommendation, see the rationale section on starting antenatal care .
Full details of the research recommendation are in evidence review F: accessing antenatal care.
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What is the clinical and cost effectiveness of different models of antenatal care with varying numbers and times of appointment, and should different models be used for groups at risk of worse outcomes?
For a short explanation of why the committee made this research recommendation, see the rationale section on antenatal appointments .
Full details of the research recommendation are in evidence review F: accessing antenatal care.
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## Identification of breech presentation
What is the clinical and cost effectiveness of routine ultrasound from 36+0 weeks compared with selective ultrasound in identifying breech presentation?
For a short explanation of why the committee made this research recommendation, see the rationale section on breech presentation .
Full details of the research recommendation are in evidence review L: identification of breech presentation.
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## Management of severe nausea and vomiting
What is the clinical and cost effectiveness of corticosteroids for women with severe nausea and vomiting in pregnancy?
For a short explanation of why the committee made this research recommendation, see the rationale section on nausea and vomiting .
Full details of the research recommendation are in evidence review R: management of nausea and vomiting in pregnancy.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Starting antenatal care
Recommendations 1.1.1 to 1.1.3
## Why the committee made the recommendations
No relevant evidence was identified and so the committee made the recommendations based on their knowledge and experience, and also made a research recommendation about how to start antenatal care. The committee discussed the ways in which women should be able to access antenatal care, but agreed that the configuration details would depend on local arrangements.
The committee agreed that antenatal service planning should take into account women's needs and circumstances, and should not discriminate against, for example, a limited ability to use and access online services, limited skills in English language or in literacy, or not being registered with a GP surgery. The committee were aware that for some women in vulnerable situations or with limited English language skills, there may be a delay in accessing and starting antenatal care.
The booking appointment should occur by 10 weeks of pregnancy but the initial contact and referral might have happened several weeks earlier, so the committee agreed that the referral contact should include provision of early pregnancy information, for example, public health messages for the woman about folic acid supplementation or stopping smoking. It is also important to identify women with specific needs or risk factors early on so that appropriate care can be provided from the beginning.
The committee agreed that it is important to have the contact details for the woman's GP to ensure that information can be shared between primary care and maternity services so that care is provided according to the woman's individual needs, and to identify potential safeguarding issues.
## How the recommendations might affect practice
There is variation in current practice in how women access antenatal care and the time between women's first contact with a healthcare professional and subsequent steps. Enabling women to start their antenatal care through various routes, including through school nurses, community centres or refugee hostels, may have some implications on resources; however, these should be outweighed by the benefits of timely antenatal care. The recommendations should improve timely access to antenatal care for women in various situations, and improve early recognition of specific needs and risk factors so that care can be planned.
Return to recommendations
# Antenatal appointments
Recommendations 1.1.4 to 1.1.13
## Why the committee made the recommendations
There was no new evidence to support changing from the existing recommended practice of women having their first antenatal (booking) appointment by 10+0 weeks.
Some women only contact, or are referred to, maternity services after 9+0 weeks. This 'late booking' may be particularly common among some socially vulnerable women or women with limited English language skills. Based on their knowledge and experience, the committee agreed that women who contact, or are referred to, maternity services after 9+0 weeks should have a booking appointment ideally within 2 weeks so that early pregnancy care, including information provision and screenings, can happen within the right timeframe. The committee agreed that it would be helpful to identify any underlying factors that may have led to the 'late booking' so that the woman's need for potential additional support or care can be considered and that any potential inequality and accessibility issues can be addressed.
There was no new evidence that led the committee to change from the existing recommended practice of arranging 10 appointments for nulliparous women and 7 appointments for parous women. Instead, the committee made a research recommendation about the ideal number and timing of antenatal appointments, including consideration for groups at higher risk of adverse outcomes.
The evidence on women's experience and satisfaction in relation to the number of antenatal appointments was mixed, but the committee agreed the importance of being flexible to meet women's needs.
There was evidence that women who needed to use interpreters found the service to be unreliable and inconsistent, so the committee made a specific recommendation highlighting that interpreters should always be available when needed (including, for example, at scan appointments) and that they should be independent of the woman and not, for example, a family member or a friend.
There was good evidence that women value having the same midwife throughout their antenatal care, although the review did not look at the benefits and harms of continuity of carer in relation to clinical- and cost-effectiveness outcomes. The NHS England's report Better Births: improving outcomes of maternity services in England – a five year forward view for maternity care recommends continuity of carer by 1 midwife who is part of a small team of midwives based in the community, so that they can get to know the woman and provide support to her throughout pregnancy all the way to the postnatal period.
Various health professionals or providers may be involved throughout the pregnancy, and the committee emphasised the need for good communication between different health professionals and providers.
## How the recommendations might affect practice
The timing of the booking appointment and the number of appointments reflects current clinical practice. The recommendation about women who do not have a booking appointment arranged by 9+0 weeks may lead to more women attending booking appointments before 11 weeks and it may also reduce how long it takes to secure a booking appointment. However, this may also be challenging for services to organise.
The recommendation about offering additional or longer antenatal appointments depending on need may lead to a small increase in the number of antenatal appointments, but this is likely to be negligible and potentially have benefits later on.
The recommendation on the use of interpreters is not new but is not well implemented in all units, so may involve a change in practice.
In current practice, providing continuity of carer can be difficult to achieve and there can be significant resource implications; however, the recommendation reflects NHS England's recommendations.
The committee agreed that the recommendations would not result in a major change in practice but should reduce variation in practice and improve care for women.
Return to recommendations
# Involving partners
Recommendations 1.1.14 to 1.1.16
## Why the committee made the recommendations
The committee recognised that women's home and family circumstances vary, and it is up to the woman to decide who she may want to involve in her antenatal care. Involving partners is an important part of antenatal care, and the World Health Organization has emphasised the importance of engaging with partners during pregnancy, childbirth and postnatally. The committee discussed the impact that a partner's support, lack of support, or their wellbeing can have on the wellbeing of the pregnant woman. The committee recognised that the woman's partner is often also an expectant parent and being involved in the antenatal care, if the woman so wishes, can provide information and support for them as well.
The committee discussed that partners can face many types of barriers when engaging with antenatal services. There was good quality evidence on partners' views and experiences of antenatal care that showed that women appreciate being able to involve their partners in antenatal care, but that this can be difficult, for example, because of the partner's work patterns. Therefore, the committee agreed that the services should consider adapting when to offer antenatal classes (for example, in the evenings or at the weekends) to enable partners to be involved if the woman wishes.
Evidence showed that partners can feel like bystanders in appointments if, for example, there is no space for them to sit with their partner. The committee agreed ways that antenatal services could promote partner involvement. The committee agreed that partners are not always given information, including on how partners can support the woman during and after pregnancy, and the general pregnancy information that women receive.
Increased use of virtual platforms for appointments may also improve partners' involvement in antenatal care. For example, this could enable the partner to attend remotely if the woman has a face-to-face appointment, or for the couple to attend together if she has a video appointment. However, the committee recognised that evidence on video consultations and appointments was not reviewed for this guideline, and the benefits, harms and experiences related to them is important to consider when planning services. The committee also agreed that it is important to carefully assess any potential inequalities issues that could be associated with video appointments, for example, among people with sensory impairments or language barriers, minority groups, or in relation to access to devices or internet connection.
## How the recommendations might affect practice
The committee agreed that the recommendations may increase and promote the involvement of partners, while respecting the woman's decisions. The recommendations are not expected to have a large resource impact or be difficult to implement although there may be some organisational changes needed to support making the timing of antenatal classes more flexible.
Return to recommendations
# Taking and recording the woman's history
Recommendations 1.2.1 to 1.2.11
## Why the committee made the recommendations
The recommendations were not developed by the usual NICE guideline systematic review process. A new evidence review was not considered necessary because the issues are covered by other NICE guidelines, or there is no clinical uncertainty or significant resource impact. Where there might be a potential limited resource impact, this could be justifiably offset by improved outcomes, avoidance of serious adverse outcomes or addressing inequalities. The recommendations were based on committee consensus on what is best practice, as well as other existing NICE guidelines.
Asking the woman about her past and present conditions and experiences in relation to her physical, obstetric, psychological, emotional and social health enables potential risk factors to be identified and managed. The committee used their knowledge and experience to list the factors that should be discussed so that appropriate action can be taken, and care tailored to the woman's needs. For example, it is important to note which pharmacological and non-pharmacological remedies the woman uses so that current medication can be reviewed in light of pregnancy. It is important that women do not automatically stop using their regular medication without consultation. This discussion also allows for individualised advice on safe medicine use during pregnancy and can help with identifying any health issues that may have otherwise not come up.
The committee also agreed that it is important to discuss the woman's home and family situation and the available support she has. There may be issues that can impact on her wellbeing, for example, lack of support, illness in the family or a partner's substance use issues.
Sometimes there may be a reason to review the woman's previous medical records, for example, when her previous maternity care has been in a different organisation, she cannot recall details of a potentially significant issue, or the discussion somehow triggers a concern.
The committee agreed that healthcare professionals should be aware of the disproportionate maternal mortality and stillbirth rates among women and babies from black and Asian backgrounds and those living in deprived areas, as highlighted by the 2020 MBRRACE-UK reports on maternal mortality and perinatal mortality. This increased risk of death indicates that interventions to improve engagement, support and closer monitoring need to be explored. Future research could help understand the mechanisms underlying these disparities and what interventions could improve the outcomes. In general, action on the wider determinants of health, including different social, economic and environmental factors, is also needed to overcome such inequalities.
The committee agreed that domestic abuse puts both the woman and her baby at risk of harm, so it is important that all pregnant women are asked about it in a kind, sensitive way. Pregnancy can sometimes be a trigger for domestic abuse or existing domestic abuse can continue or worsen during pregnancy, so it is important that women feel that they can disclose it safely so that they can be supported, and interventions put in place if needed. Although partner involvement in antenatal care is welcome, it is also important to ensure that there is an opportunity to discuss domestic issues privately with the woman.
The committee recognised the need to identify women who have undergone female genital mutilation (FGM) or whose unborn baby girl might be at risk of FGM so that appropriate safeguarding can take place. In the context of this guideline, this could be the pregnant woman, or the unborn baby when there is a family history or tradition of FGM. There is a mandatory duty to report suspected or known FGM in under 18s. The Department of Health and Social Care has produced a quick guide for healthcare professionals on FGM safeguarding and risk assessment, which includes information about countries where FGM is practised, and practical advice on how to start the conversation.
Identifying underlying cardiac problems is important because cardiovascular disease is the leading cause of death among women in the UK during and after pregnancy, according to the 2019 report MBRRACE-UK: Saving lives, improving mothers' care – lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2016–18. Some women are at a higher risk of undiagnosed structural cardiac problems, such as women with a family history of cardiac abnormalities or women who were brought up in a country with a high incidence of rheumatic fever. Clinical assessment cannot identify all cardiac problems that cause maternal mortality, but it might pick up structural heart disease or concerns that warrant further investigations. Early identification of underlying cardiac conditions allows these women to receive appropriate care during their pregnancy, childbirth and postnatal period, and potentially avoid poor outcomes.
The committee also agreed the importance of information sharing between the maternity unit and the GP, and agreeing this with the woman. This is particularly important if the woman has self-referred (because the GP may be unaware of her pregnancy), and if women have a complex medical, psychological or social history (because different agencies may need to be involved in her and her baby's care).
Antenatal appointments are opportunities for continued monitoring and risk assessment on the health and wellbeing of the woman and her baby. They also allow for regular reassessments of women's antenatal care needs and plans.
## How the recommendations might affect practice
The recommendations largely reflect current best practice. Clinical assessment for cardiac conditions is not always done for women who may be at an increased risk so this recommendation may change practice to some extent. The number of women this recommendation applies to is relatively small and the potentially life-saving benefit of this simple examination outweighs the potential cost and resource implications.
Return to recommendations
# Examinations and investigations
Recommendations 1.2.12 to 1.2.17
## Why the committee made the recommendations
Most of the issues are covered by national screening programmes or other NICE guidance, so no new evidence review was needed. The committee agreed, by consensus, any other recommendations where there is no clinical uncertainty or significant resource impact.
The timing of the ultrasound scans aligns with the NHS fetal anomaly screening programme.
It is important that women understand the potential implications of each of the tests being offered so that they have the opportunity to accept or decline.
## How the recommendations might affect practice
The recommendations reflect current practice and no change in practice is expected.
Return to recommendations
# Venous thromboembolism
Recommendations 1.2.18 to 1.2.20
## Why the committee made the recommendations
The committee based the recommendations on the evidence on independent risk factors for venous thromboembolism in pregnancy, their knowledge and experience, and the NICE guideline on venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. The evidence on independent risk factors for venous thromboembolism during pregnancy did not assess the accuracy of tools used to measure the risk, so the committee recommended that tools should meet certain quality criteria. They agreed that an example of a tool that might be used is the risk assessment tool in the Royal College of Obstetricians and Gynaecologists' green-top guideline on reducing the risk of venous thromboembolism during pregnancy (2015), which is commonly used in practice.
The committee highlighted some risk factors in the evidence review (blood type A or B, miscarriage after 10 weeks in the current pregnancy and history of previous blood transfusion) that are not always incorporated into commonly used venous thromboembolism tools. However, they agreed not to include them specifically in the recommendations because it could give a false impression that these factors were more important than others or lead to overtreatment.
The committee agreed that women assessed as being at an increased risk of venous thromboembolism should be offered referral to an obstetrician so that a risk management plan can be made, for example, starting thromboprophylaxis.
## How the recommendation might affect practice
The recommendation reflects current practice and no change in practice is expected.
Return to recommendations
# Gestational diabetes
Recommendations 1.2.21 and 1.2.22
## Why the committee made the recommendations
Guidance on risk assessment for and identification of gestational diabetes is covered by the NICE guideline on diabetes in pregnancy.
## How the recommendations might affect practice
The recommendation reflects current practice and no change in practice is expected.
Return to recommendations
# Pre-eclampsia and hypertension in pregnancy
Recommendations 1.2.23 to 1.2.28
## Why the committee made the recommendations
Guidance on risk assessment and risk reduction for pre-eclampsia is covered by the NICE guideline on hypertension in pregnancy. Although the guideline implies that pregnant women will be routinely tested for proteinuria, it does not explicitly recommend this. Therefore, the committee agreed that, in line with current practice, urine testing for proteinuria should be offered at every routine face-to-face appointment.
There was little evidence on the setting and technique for monitoring blood pressure during pregnancy, so the committee made the recommendations based on their knowledge and experience and existing NICE guidance. The committee were aware that the British and Irish Hypertension Society lists blood pressure measurement devices validated for use in pregnancy. This has also been noted in the NICE guideline on hypertension in adults.
The committee agreed that monitoring blood pressure and testing for proteinuria at every routine face-to-face antenatal appointment enables hypertension and pre‑eclampsia to be identified and treated early, which is important because they can have severe consequences.
Guidance on care for pregnant women with gestational or chronic hypertension is covered by the NICE guideline on hypertension in pregnancy.
## How the recommendations might affect practice
The recommendation reflects current practice and no change in practice is expected.
Return to recommendations
# Monitoring fetal growth and wellbeing
Recommendations 1.2.29 to 1.2.35
## Why the committee made the recommendations
Risk assessment starting in early pregnancy enables increased monitoring of babies who are at an increased risk of fetal growth restriction, which is associated with fetal morbidity and mortality. The committee were aware of available risk assessment tools, such as those in the Royal College of Obstetricians and Gynaecologists' guideline on the investigation and management of the small-for-gestational-age fetus or the NHS saving babies' lives care bundle version 2.
Evidence showed that ultrasound scans and symphysis fundal height measurement do not accurately predict a baby being born small or large for gestational age. However, the committee agreed that the current routine practice of using symphysis fundal height measurement to monitor fetal growth should be used, because it is a simple and low-cost intervention and can alert to further investigations when concerns arise about the baby being either larger or smaller than expected for gestational age. When the symphysis fundal height measurement is large for gestational age, ultrasound scans could be used to assess the size of the baby and the volume of amniotic fluid. Small-for-gestational-age babies are at an increased risk of perinatal mortality and morbidity; therefore, when this is suspected, further investigations should be done to monitor the growth and wellbeing of the baby, taking into consideration the full clinical picture.
The committee were aware that many women may request routine ultrasound scans in late pregnancy, but available evidence showed no benefit from routine ultrasound in late pregnancy (from 28 weeks) for uncomplicated singleton pregnancies. However, the absence of effect found in the evidence does not mean that there is definitely no effect. There was also no evidence on maternal anxiety in relation to routine ultrasound scanning. The committee were in favour of research on this in the future; however, a research recommendation was not prioritised because there is a good amount of evidence on other key outcomes.
The committee were aware that cases of stillbirth have been linked to reduced fetal movements. Therefore, structured fetal movement awareness packages have been trialled. Evidence on the use of a structured fetal movement awareness package, such as the one described in the UK trial Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM), did not detect a reduction in stillbirths or perinatal mortality but did find that there were more interventions at birth, including more caesarean births and inductions of labour, and fewer spontaneous vaginal births. Another study from Sweden compared giving a leaflet to pregnant women teaching them a method of being aware of fetal movements, with usual care. No clinically important benefits or harms were detected, including no difference in perinatal mortality, although there was a small, but statistically significant, reduction in births after 41+6 weeks and fewer caesarean births. Health economic evaluation did not establish cost effectiveness for either of these structured awareness packages.
Although the available evidence did not support the use of structured packages, the committee agreed that fetal movements should be discussed routinely and women's concerns should be taken seriously. The committee agreed that there is no agreed definition of normal fetal movements. Discussing the topic of babies' movements in the womb and how they change throughout the pregnancy can help women recognise changes to their own baby's movement patterns. When there are concerns, an assessment of the woman's wellbeing and the baby's wellbeing and size should be done.
## How the recommendations might affect practice
The recommendations on fetal growth monitoring largely reflect current practice, although in some maternity units it is common to offer women with uncomplicated singleton pregnancies ultrasound scans after 28 weeks to monitor the baby, so there might be a change of practice for these units and some potential cost savings. On the other hand, there may be some more scans due to suspected large for gestational age.
Current practice for managing reduced fetal movements is to follow the NHS saving babies' lives care bundle version 2. The recommendations in this guideline similarly emphasise the importance of recognising and reporting concerns on fetal movements and acting on those concerns by assessing the woman and the baby.
Return to recommendations
# Breech presentation
Recommendations 1.2.36 to 1.2.38
## Why the committee made the recommendations
There was not enough evidence to support routine ultrasound at 36+0 weeks to 39+0 weeks to identify breech presentation, so the committee did not change the current standard practice of offering abdominal palpation with selective ultrasound when breech is suspected.
Because of the lack of evidence, the committee made a research recommendation to compare routine ultrasound scans from 36+0 weeks with selective ultrasound scans.
In the case of breech presentation, the committee agreed that a discussion about the different options and their potential benefits, harms and implications is needed to ensure an informed decision. External cephalic version is standard practice for managing breech presentation in uncomplicated singleton pregnancies at or after 36+0 weeks. Head-down vaginal birth is preferred by many women and the evidence suggests that external cephalic version is an effective way to achieve this.
## How the recommendations might affect practice
The recommendations reflect current clinical practice and no change in practice is expected.
Return to recommendations
# Communication – key principles
Recommendations 1.3.1 to 1.3.6
## Why the committee made the recommendations
The committee agreed that the key principles of care in the antenatal period are to listen to women and be responsive to their needs, in line with the findings of the Ockenden report on maternity services at the Shrewsbury and Telford hospital NHS trust, and to enable women to make informed decisions about their care, in line with the Montgomery ruling. The committee emphasised that women should be supported in their decision making even when their preferences and values differ from those of the healthcare professionals.
The evidence did not show a particular benefit from any one specific approach to giving information, although 1 study found that supplementing information provided face-to-face with online information increased knowledge. The committee based the recommendations on their knowledge and experience.
The committee agreed that information should meet the needs of the woman, for example, taking into account any language barriers, learning disabilities or other needs. Most antenatal care information is given in a one-to-one or couple discussion. Offering other formats to supplement this can help improve understanding and engagement, including written materials and group discussions in antenatal classes or, in some cases, group antenatal appointments.
There was evidence that women value information that is relevant to their own circumstances. The committee agreed that healthcare professionals should explore the level and accuracy of the woman's (and her partner's) existing knowledge and understanding of the topic. The committee discussed the importance of allowing sufficient time for discussions.
## How the recommendations might affect practice
The recommendations largely reflect current practice.
Return to recommendations
# Information about antenatal care
Recommendations 1.3.7 to 1.3.19
## Why the committee made the recommendations
The committee agreed, based on the evidence and their knowledge and experience, that if women are given information about antenatal care, their schedule of appointments and what happens at different appointments and stages of pregnancy, they are more likely to be engaged, follow advice and share their concerns with healthcare professionals.
There was no evidence identified to inform the timing of information provision, but the committee agreed that it is important to have a staged approach and cover topics relevant to each stage of pregnancy.
The first antenatal (booking) appointment is an opportunity to discuss and share information about various practical issues related to pregnancy and antenatal care so that the woman knows what to expect and how to get support. The evidence showed that partners also value practical information throughout the pregnancy. For example, in relation to safe use of medicines in pregnancy, the committee were aware of the UK Teratology Information Service's information resources on best use of medicines in pregnancy (bumps).
The evidence suggested that women want information on how behavioural factors, such as smoking, alcohol, diet and physical activity may affect them and their baby's health. The evidence also highlighted how emotional these topics could be for women and that women may feel judged or patronised. The committee agreed that it is important to have these discussions in a sensitive manner that supports individual women. Guidance on all these issues is covered by other NICE guidelines or government documents.
The committee recognised that pregnant women and their partners often look for information and support from various sources, such as websites, and not all of them are necessarily evidence-based, so signposting to trusted resources may be helpful.
There was some evidence that women and their partners valued information and discussion around the transition to parenthood, and the changes that pregnancy and becoming a parent will bring to their life and relationship. The committee were aware of various available resources that could be helpful for parents, particularly new parents.
The evidence showed that women want information on their options for giving birth. The committee agreed that these discussions should start, at the latest, around the start of the third trimester, depending on the woman's preferences and circumstances. The committee agreed, in line with the Montgomery ruling, that discussing the implications, benefits and risks is fundamental to making shared and informed decisions. Guidance on making decisions about place of birth, mode of birth and prolonged pregnancy are also covered by other NICE guidelines.
Considering the amount of new information given at the beginning of antenatal care, discussions around practical aspects related to labour, childbirth and postnatal care are often more appropriate later on in pregnancy. There was some evidence that healthcare professionals thought that providing information on emotional attachment and bonding could improve women's confidence and increase their preparedness for birth. Further recommendations about promoting emotional attachment and bonding, as well as planning and managing infant feeding, are covered by the NICE guideline on postnatal care.
## How the recommendations might affect practice
The recommendations will improve consistency of care and reinforce best practice.
Return to recommendations
# Antenatal classes
Recommendations 1.3.19 to 1.3.21
## Why the committee made the recommendations
Evidence among nulliparous women showed that women who went to antenatal classes were more likely to have their cervix dilated by 3 cm or more on admission to labour. A dilated cervix on admission may reduce the need for interventions. This may indicate that women who attended antenatal classes have better coping strategies and the confidence to deal with pain at home in the early stages of labour. There was no evidence about the most effective content for antenatal classes, so the committee made the recommendations based on their experience.
The committee recognised that there may be multiparous women who could also particularly benefit from antenatal classes, so providing them for these women should be considered.
The committee recognised that some groups of women may be less likely to attend antenatal classes (for example, some women from low income or disadvantaged backgrounds or minority ethnic groups, or those for whom English is not their first language). The committee agreed that in order to increase engagement with antenatal classes, service providers should ensure that classes are accessible, welcoming and adapted to meet the needs of local communities.
## How the recommendations might affect practice
The recommendations reflect current practice. However, adapting classes to the needs of the local communities might involve some reorganising of practices.
Return to recommendations
# Peer support
Recommendations 1.3.22 and 1.3.23
## Why the committee made the recommendations
The evidence showed that peer support could offer helpful and valuable care and guidance during the antenatal period. There was evidence among women from particular subpopulations, such as migrant women, women of lower socioeconomic status, women with intellectual disabilities, or younger women, and the committee agreed that peer support groups among women in similar circumstances might be particularly helpful.
The committee discussed that peer support, including group peer support, volunteer peer support, doula support and online support, is usually provided through 'third sector' services, and they agreed that healthcare professionals should give women information about how to contact local and national services. Although there was little evidence on partners' experiences of peer support, in the committee's experience, some partners find peer support services for partners helpful.
## How the recommendations might affect practice
The recommendations reflect current best practice.
Return to recommendations
# Sleep position
Recommendations 1.3.24 and 1.3.25
## Why the committee made the recommendations
The evidence suggested that there is an increased risk of stillbirth and babies being born small for gestational age after 28 weeks if women fall asleep on their backs. The committee agreed that there is some uncertainty about this risk because the evidence was from relatively small studies whose design made it difficult to assume that sleep position caused the adverse outcomes. The committee recognised that further research is unlikely because conducting sufficiently powered prospective cohort studies is not feasible given the relatively low incidence of stillbirth (1 in every 244 births in England and Wales according to 2018 Office for National Statistics data). The committee also noted that not all the included studies used the same definition of stillbirth and that only 1 study reported data according to whether the stillbirth occurred at term or at preterm. On balance, the committee agreed that the evidence was strong enough to advise women to try to avoid going to sleep on their back after 28 weeks.
The committee knew from their experience that providing practical advice about risk reduction is extremely important for pregnant women. They discussed reassuring women about sleep positions, aids that could make it easier for pregnant women not to go to sleep on their backs and maintain this position when sleeping, for example, by using pillows.
The committee also agreed that the reason for this advice should be explained, and they recognised the potential anxiety and feelings of guilt that women may experience, for example, if they wake up on their backs.
## How the recommendations might affect practice
Healthcare professionals may need to spend more time talking to women about sleep position in pregnancy, but the recommendations are not expected to have a significant cost or resource impact.
Return to recommendations
# Nausea and vomiting
Recommendations 1.4.1 to 1.4.7
## Why the committee made the recommendations
Nausea and vomiting in pregnancy can affect daily functioning and quality of life, and can cause significant worry and upset. Based on their knowledge and experience, the committee agreed that it is important to reassure pregnant women who experience mild‑to‑moderate nausea and vomiting that these are common symptoms in early pregnancy and will usually settle later in the second trimester.
However, the committee recognised that many pregnant women expect nausea and vomiting in pregnancy and might even tolerate significant symptoms and try various self-help approaches before seeking medical advice. It is therefore important to take it seriously when women do seek help.
Some women prefer to use non-pharmacological treatments whereas others may prefer pharmacological treatments, so both options are recommended.
There was some evidence that ginger is effective in treating mild‑to‑moderate nausea and vomiting in pregnancy compared with placebo, and this may be an option particularly for women who want to try a non-pharmacological option.
There was evidence on a wide variety of pharmacological treatments, many of which are commonly used in current practice. The evidence on the medicines varied in quality and for some medicines, no evidence was found. Metoclopramide hydrochloride was supported by good quality evidence showing that it was effective in improving symptoms. Ondansetron was also found to be effective in improving symptoms. A combination drug with pyridoxine and doxylamine is currently the only drug licensed for this indication, but the evidence is very old and of low quality and did not show a convincing effect on symptom improvement. Evidence on histamine H1 receptor antagonists was of very low quality and not particularly convincing. Studies on pyridoxine hydrochloride showed differing results, with larger trials showing no improvement in symptoms. No evidence was identified on the effectiveness of cyclizine hydrochloride alone in pregnant women, so the committee made a research recommendation on the effectiveness of medication for women with nausea and vomiting in pregnancy.
The treatment options have different advantages and disadvantages, including effectiveness in relieving symptoms, safety and other considerations, which have been summarised in a table to help with decision making. The committee used information available from the British National Formulary (BNF), the UK Teratology Information Service monographs and patient information leaflets, and the manufacturers' summaries of product characteristics to inform women about the potential effects on the baby. The committee recognised that women are often concerned about the possible adverse effects of medicines on the baby and that these should be discussed in the context of understanding the small risk of adverse outcomes unrelated to medicine use.
The evidence for treating the more severe form of nausea and vomiting in pregnancy did not generally support any different treatment options from those used for mild and moderate nausea and vomiting in pregnancy. An exception was for acupressure combined with standard care where the evidence showed benefits in relieving symptoms in women with moderate‑to‑severe nausea and vomiting in pregnancy, which was not shown for women with mild and moderate nausea and vomiting. Therefore, the committee recommended that acupressure could be considered for women with moderate‑to‑severe nausea and vomiting as an additional treatment.
No recommendation was made on the use of corticosteroids as a treatment for severe nausea and vomiting in pregnant women because, despite research in this area, no evidence was found to support its use. The committee discussed that although corticosteroids have well-known harms, the benefits can outweigh them so that some units use corticosteroids in severe cases of nausea and vomiting in pregnancy, and so a research recommendation on the effectiveness of corticosteroids for women with severe nausea and vomiting in pregnancy was made.
Some women with moderate‑to‑severe nausea and vomiting in pregnancy might need intravenous fluids. The evidence showed no difference in most outcomes between offering intravenous fluids in an inpatient or outpatient setting. Offering them to an outpatient is less expensive, reduces time spent in hospital and, in the committee's experience, is generally preferred by women. Inpatient care may be needed when severe nausea and vomiting persists despite treatment. Hyperemesis gravidarum can have serious harmful consequences, and treatment and care in hospital may be needed. It should be noted that this guideline only covers treatments to manage nausea and vomiting in pregnancy and comprehensive management of hyperemesis gravidarum, which may include nutritional interventions, is not covered by this guideline on routine antenatal care.
## How the recommendations might affect practice
The treatment options are all used in current practice but there may be a change in practice in encouraging shared decision making for different options. This may mean that those prescribing medicines may need to spend more time discussing the options with the woman.
An increase in giving intravenous fluids as an outpatient service instead of an inpatient service could bring cost savings.
Return to recommendations
# Heartburn
Recommendations 1.4.8 and 1.4.9
## Why the committee made the recommendations
There was no evidence on whether giving lifestyle and diet information to pregnant women with heartburn is effective, but the committee agreed, based on their own knowledge and experience, that it may help. This is supported by guidance for the general adult population in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia.
The committee recommended considering either antacid or alginate therapy for women with heartburn in pregnancy because there is evidence that they are equally effective. These medicines are available over the counter. Because the studies examined various antacid and alginate remedies, the committee agreed that they could not make a more specific recommendation.
The committee did not make any recommendations about acupuncture or proton pump inhibitors (PPIs) because, although there was some evidence that acupuncture is effective in alleviating heartburn and that PPI use in the first trimester is not harmful to the baby, it was of very low quality and not good enough to support recommending them to be used routinely. In addition, there was no evidence on H2 receptor antagonist (H2RA) therapy to treat heartburn in pregnancy.
## How the recommendations might affect practice
The recommendations reflect current clinical practice.
Return to recommendations
# Symptomatic vaginal discharge
Recommendations 1.4.10 to 1.4.14
## Why the committee made the recommendations
There was limited evidence on the effectiveness of treatments for symptomatic vaginal discharge in pregnant women, so the committee used their knowledge and clinical experience to make the recommendations. The committee agreed that some women can find an increase in vaginal discharge distressing or uncomfortable, so it is important to reassure women that it is a normal feature of pregnancy. However, women should also be made aware of the symptoms and signs of infection that may need further action, because there is a small chance that some infections could lead to complications.
Candidiasis (thrush) is often an easily identifiable cause of symptomatic vaginal discharge and may not need a formal investigation. However, if there is doubt about the cause, a vaginal swab could be used. It is important that possible sexually transmitted infections are appropriately investigated so that they can be treated, because they could have an impact on the baby.
The evidence on antifungal treatment to treat symptomatic vaginal discharge because of vaginal candidiasis was very limited, imidazole being the only drug class being studied. However, imidazole (for example, clotrimazole or econazole) was consistently shown to be effective.
The evidence on the benefits and harms of antibiotics to treat symptomatic vaginal discharge due to bacterial vaginosis was also very limited. There was only evidence on oral amoxicillin (which is not commonly prescribed in current practice for this indication) and oral metronidazole. The committee were aware of evidence among asymptomatic populations that antibiotics are effective in treating the underlying infection, but the committee agreed that it cannot be assumed that they would be effective in relieving symptomatic vaginal discharge. The committee noted that it is common practice to prescribe vaginal rather than oral antibiotics for this indication – in particular, clindamycin or metronidazole. Combining this with their knowledge and experience, they recommended that either oral or vaginal antibiotics could be considered. The NICE guideline on antimicrobial stewardship gives guidance on good practice in prescribing antimicrobials.
No evidence was identified on the effectiveness of metronidazole to treat symptomatic vaginal discharge because of vaginal trichomoniasis, therefore no recommendations were made.
## How the recommendations might affect practice
The committee agreed that the recommendations will reinforce current best practice and standardise care.
Return to recommendations
# Pelvic girdle pain
Recommendation 1 4.15
## Why the committee made the recommendation
There was evidence of varying quality from several randomised controlled trials that exercise advice from a physiotherapist may reduce pain intensity and pelvic-related functional disability. The committee recommended referral to physiotherapy services rather than to a physiotherapist because, in some cases, information and advice could be given over the telephone or in an email or letter rather than in a face-to-face appointment.
Moderate quality evidence from 1 randomised controlled trial showed that a non-rigid lumbopelvic belt together with general information about anatomy, body posture and ergonomic advice reduced pelvic girdle pain intensity, compared with exercise advice and information, and information only. However, it did not have an impact on functional status in daily activities. No evidence was identified about adverse effects of using a lumbopelvic belt. Providing a non-rigid lumbopelvic belt was also found to be cost effective based on an economic evaluation, but because the clinical evidence base was limited, the committee agreed not to make a strong recommendation.
The committee agreed that there was not enough evidence to show that manual therapy alone had any benefits for women with pelvic girdle pain, so did not make a recommendation. The committee agreed that the evidence for acupuncture to treat pelvic girdle pain was mixed, of poor quality and therefore not adequate enough to justify a recommendation that would have a substantial resource impact.
## How the recommendation might affect practice
Current practice for pregnancy-related pelvic girdle pain is to offer analgesics (for example, paracetamol) and provide information about lifestyle and health changes. Some hospitals also have access to physiotherapy services. Providing a lumbopelvic belt is not current practice in all units, so the committee recognised that the recommendation may have cost implications. However, health economic modelling showed that it is cost effective even if women are referred for physiotherapy. The recommendation may increase the number of pregnant women seeking referral to physiotherapy services.
Return to recommendation
# Unexplained vaginal bleeding after 13 weeks
Recommendations 1.4.16 to 1.4.21
## Why the committee made the recommendations
There was very little evidence, so the committee used their knowledge and experience to make recommendations. They took into account the risks associated with a delay in assessing and treating unexplained vaginal bleeding in pregnancy, the possibility that anti‑D injections may be needed for women who are rhesus D‑negative, the need to exclude a low-lying placenta (placenta praevia) and that corticosteroids may be needed if there is a risk of preterm birth.
The committee agreed that a review in secondary care is needed when unexplained vaginal bleeding occurs after 13 weeks of pregnancy. Evidence on the effectiveness of hospitalisation was limited, with only 1 retrospective study that showed no difference in the number of fetal deaths whether women were admitted to hospital or discharged on the day they presented. Because of limited evidence, the committee made a research recommendation on the effectiveness of hospitalisation compared with outpatient management for pregnant women with unexplained vaginal bleeding.
The committee agreed that hospitalisation should be considered for monitoring, administering corticosteroids and neonatal unit care if the baby is born preterm. Discussion with the woman about the possibility of preterm birth may also be helpful.
## How the recommendations might affect practice
The recommendations reflect current practice.
Return to recommendations# Context
Around 660,000 women give birth in England and Wales each year. The antenatal period is an excellent opportunity to not only provide support and information to women (and their families) about pregnancy, birth and the postnatal period, but also to assess their risk of complications. Even in fit and healthy women, concerns and complications can still arise, and good quality antenatal care is vital to identify and deal with potential problems and reduce the chance of poor outcomes for both the woman and the baby.
Antenatal service delivery and provision of care have changed over time and this guideline updates and replaces the version of the NICE guideline on antenatal care (first published in 2008).
This guideline covers routine antenatal care for all women. However, it does not cover specialised care for women with underlying medical conditions or obstetric complications (once diagnosed) but refers to other NICE guidelines.
This guideline covers the organisation and delivery of antenatal care, in particular, how to initially access antenatal care and antenatal appointments, and the involvement of partners in antenatal care. Routine care and monitoring during pregnancy is covered and the guideline makes references to other guidance on risk assessment and screening. This guideline also covers providing information and support during antenatal care, and managing some of the common problems during pregnancy.
Throughout the development of this guideline, the committee has considered how antenatal care could be made accessible, fair and high quality for all women, regardless of their background or situation.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nSupporting women to make decisions about their care is important during pregnancy. Healthcare professionals should ensure that women have the information they need to make decisions and to give consent in line with General Medical Council (GMC) guidance, the Nursing and Midwifery Council (NMC) Code and the 2015 Montgomery ruling.\n\nPlease note that the Royal College of Obstetricians and Gynaecologists has produced guidance on COVID-19 and pregnancy for all midwifery and obstetric services.\n\n# Organisation and delivery of antenatal care\n\n## Starting antenatal care\n\nEnsure that antenatal care can be started in a variety of straightforward ways, depending on women's needs and circumstances, for example, by self-referral, referral by a GP, midwife or another healthcare professional, or through a school nurse, community centre or refugee hostel.\n\nAt the point of antenatal care referral:\n\nProvide an easy-to-complete referral form.\n\nOffer early pregnancy health and wellbeing information before the booking appointment. This should include information about modifiable factors that may affect the pregnancy, including stopping smoking, avoiding alcohol, taking supplements, and eating healthily. See also recommendation 1.3.9 and the NICE guidelines on maternal and child nutrition, vitamin\xa0D, and smoking: stopping in pregnancy and after childbirth.\n\nEnsure that the materials are available in different languages or formats such as digital, printed, braille or Easy Read.\n\nThe referral form for women to start antenatal care should:\n\nenable healthcare professionals to identify women with:\n\n\n\nspecific health and social care needs\n\nrisk factors, including those that can potentially be addressed before the booking appointment, for example, smoking\n\n\n\ninclude contact details about the woman's GP.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on starting antenatal care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: accessing antenatal care.\n\nLoading. Please wait.\n\n## Antenatal appointments\n\nOffer a first antenatal (booking) appointment with a midwife to take place by 10+0\xa0weeks of pregnancy.\n\nIf women contact or are referred to maternity services later than 9+0\xa0weeks of pregnancy, offer a first antenatal (booking) appointment to take place within 2\xa0weeks if possible.\n\nIf a woman books late in pregnancy, ask about the reasons for the late booking because it may reveal social, psychological or medical issues that need to be addressed.\n\nPlan 10\xa0routine antenatal appointments with a midwife or doctor for nulliparous women. (See schedule of appointments.)\n\nPlan 7\xa0routine antenatal appointments with a midwife or doctor for parous women. (See schedule of appointments.)\n\nAlso see the NICE guideline on pregnancy and complex social factors for:\n\nwomen who misuse substances\n\nrecent migrants, asylum seekers or refugees, or women who have difficulty reading or speaking English\n\nyoung women aged under\xa020\n\nwomen who experience domestic abuse.\n\nOffer additional or longer antenatal appointments if needed, depending on the woman's medical, social and emotional needs. Also see the NICE guidelines on pregnancy and complex social factors, intrapartum care for women with existing medical conditions or obstetric complications and their babies, hypertension in pregnancy, diabetes in pregnancy and twin and triplet pregnancy.\n\nEnsure that reliable interpreting services are available when needed, including British Sign Language. Interpreters should be independent of the woman rather than using a family member or friend.\n\nThose responsible for planning and delivering antenatal services should aim to provide continuity of carer.\n\nEnsure that there is effective and prompt communication between healthcare professionals who are involved in the woman's care during pregnancy.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on antenatal appointments\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0H: timing of first antenatal appointment\n\nevidence review\xa0I: number of antenatal appointments\n\nevidence review\xa0J: referral and delivery of antenatal care.\n\nLoading. Please wait.\n\n## Involving partners\n\nA woman can be supported by a partner during her pregnancy so healthcare professionals should:\n\ninvolve partners according to the woman's wishes and\n\ninform the woman that she is welcome to bring a partner to antenatal appointments and classes.\n\nConsider arranging the timing of antenatal classes so that the pregnant woman's partner can attend, if the woman wishes.\n\nWhen planning and delivering antenatal services, ensure that the environment is welcoming for partners as well as pregnant women by, for example:\n\nproviding information about how partners can be involved in supporting the woman during and after pregnancy\n\nproviding information about pregnancy for partners as well as pregnant women\n\ndisplaying positive images of partner involvement (for example, on notice boards and in waiting areas)\n\nproviding seating in consultation rooms for both the woman and her partner\n\nconsidering providing opportunities for partners to attend appointments remotely as appropriate.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on involving partners\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: involving partners and evidence review\xa0B: approaches to information provision.\n\nLoading. Please wait.\n\n# Routine antenatal clinical care\n\n## Taking and recording the woman's history\n\nAt the first antenatal (booking) appointment, ask the woman about:\n\nher medical history, obstetric history and family history (of both biological parents)\n\nprevious or current mental health concerns such as depression, anxiety, severe mental illness, psychological trauma or psychiatric treatment, to identify possible mental health problems in line with the section on recognising mental health problems in pregnancy and the postnatal period and referral in the NICE guideline on antenatal and postnatal mental health\n\ncurrent and recent medicines, including over-the-counter medicines, health supplements and herbal remedies\n\nallergies\n\nher occupation, discussing any risks and concerns\n\nher family and home situation, available support network and any health or other issues affecting her partner or family members that may be significant for her health and wellbeing\n\nother people who may be involved in the care of the baby\n\ncontact details for her partner and her next of kin\n\nfactors such as nutrition and diet, physical activity, smoking and tobacco use, alcohol consumption and recreational drug use (see also recommendations 1.3.8 and 1.3.9).\n\nConsider reviewing the woman's previous medical records if needed, including records held by other healthcare providers.\n\nBe aware that, according to the 2020 MBRRACE-UK reports on maternal and perinatal mortality, women and babies from some minority ethnic backgrounds and those who live in deprived areas have an increased risk of death and may need closer monitoring and additional support. The reports showed that:\n\ncompared with white women (8/100,000), the risk of maternal death during pregnancy and up to 6 weeks after birth is:\n\n\n\ntimes higher in black women (34/100,000)\n\ntimes higher in women with mixed ethnic background (25/100,000)\n\ntimes higher in Asian women (15/100,000; does not include Chinese women)\n\n\n\ncompared with white babies (34/10,000), the stillbirth rate is\n\n\n\nmore than twice as high in black babies (74/10,000)\n\naround 50% higher in Asian babies (53/10,000)\n\n\n\nwomen living in the most deprived areas (15/100,000) are more than 2.5\xa0times more likely to die compared with women living in the least deprived areas (6/100,000)\n\nthe stillbirth rate increases according to the level of deprivation in the area the mother lives in, with almost twice as many stillbirths for women living in the most deprived areas (47/10,000) compared with the least deprived areas (26/10,000).\n\nIf the woman or her partner smokes or has stopped smoking within the past 2\xa0weeks, offer a referral to NHS Stop Smoking Services in line with the NICE guideline on smoking: stopping in pregnancy and after childbirth. Also see the NICE guideline on smokeless tobacco: South Asian communities.\n\nAsk the woman about domestic abuse in a kind, sensitive manner at the first antenatal (booking) appointment, or at the earliest opportunity when she is alone. Ensure that there is an opportunity to have a private, one‑to‑one discussion. Also see the NICE guideline on domestic violence and abuse and the section on pregnant women who experience domestic abuse in the NICE guideline on pregnancy and complex social factors.\n\nAssess the woman's risk of and, if appropriate, discuss female genital mutilation (FGM) in a kind, sensitive manner. Take appropriate action in line with UK government guidance on safeguarding women and girls at risk of FGM.\n\nRefer the woman for a clinical assessment by a doctor to detect cardiac conditions if there is a concern based on the pregnant woman's personal or family history. See also the section on heart disease in the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies.\n\nRefer the woman to an obstetrician or other relevant doctor if there are any medical concerns or if review of current long-term medicines is needed.\n\nAfter discussion with and agreement from the woman, contact the woman's GP to share information about the pregnancy and potential concerns or complications during pregnancy.\n\nAt every antenatal appointment, carry out a risk assessment as follows:\n\nask the woman about her general health and wellbeing\n\nask the woman (and her partner, if present) if there are any concerns they would like to discuss\n\nprovide a safe environment and opportunities for the woman to discuss topics such as concerns at home, domestic abuse, concerns about the birth (for example, if she previously had a traumatic birth) or mental health concerns\n\nreview and reassess the plan of care for the pregnancy\n\nidentify women who need additional care.\n\nAt every antenatal contact, update the woman's antenatal records to include details of history, test results, examination findings, medicines and discussions.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on taking and recording the woman's history\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: content of antenatal appointments.\n\nLoading. Please wait.\n\n## Examinations and investigations\n\nAt the first face-to-face antenatal appointment:\n\noffer to measure the woman's height and weight and calculate body mass index\n\noffer a blood test to check full blood count, blood group and rhesus\xa0D status.\n\nAt the first antenatal (booking) appointment, discuss and share information about, and then offer, the following screening programmes:\n\nNHS infectious diseases in pregnancy screening programme (HIV, syphilis and hepatitis\xa0B)\n\nNHS sickle cell and thalassaemia screening programme\n\nNHS fetal anomaly screening programme.Inform the woman that she can accept or decline any part of any of the screening programmes offered.\n\nOffer pregnant women an ultrasound scan to take place between 11+2\xa0weeks and 14+1\xa0weeks to:\n\ndetermine gestational age\n\ndetect multiple pregnancy\n\nand if opted for, screen for Down's syndrome, Edwards' syndrome and Patau's syndrome (see the NHS fetal anomaly screening programme).\n\nOffer pregnant women an ultrasound scan to take place between 18+0\xa0weeks and 20+6\xa0weeks to:\n\nscreen for fetal anomalies (see the NHS fetal anomaly screening programme)\n\ndetermine placental location.\n\nAt the antenatal appointment at 28\xa0weeks, offer:\n\nanti-D prophylaxis to rhesus-negative women in line with NICE's technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus\xa0D negative (see also NICE's diagnostics guidance on high-throughput non-invasive prenatal testing for fetal RHD genotype)\n\na blood test to check full blood count, blood group and antibodies.\n\nIf there are any unexpected results from examinations or investigations, offer referral according to local pathways and ensure appropriate information provision and support.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on examinations and investigations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: content of antenatal appointments.\n\nLoading. Please wait.\n\n## Venous thromboembolism\n\nAssess the woman's risk factors for venous thromboembolism at the first antenatal (booking) appointment, and after any hospital admission or significant health event during pregnancy. Consider using guidance by an appropriate professional body, for example, the Royal College of Obstetricians and Gynaecologists' guideline on reducing the risk of venous thromboembolism during pregnancy.\n\nFor pregnant women who are admitted to a hospital or a midwife-led unit, see the section on interventions for pregnant women and women who gave birth or had a miscarriage or termination of pregnancy in the past 6\xa0weeks in the NICE guideline on venous thromboembolism in over\xa016s.\n\nFor women at risk of venous thromboembolism, offer referral to an obstetrician for further management.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on venous thromboembolism\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: risk factors for venous thromboembolism in pregnancy.\n\nLoading. Please wait.\n\n## Gestational diabetes\n\nAt the first antenatal (booking) appointment, assess the woman's risk factors for gestational diabetes in line with the recommendations on gestational diabetes risk assessment in the NICE guideline on diabetes in pregnancy.\n\nIf a woman is at risk of gestational diabetes, offer referral for an oral glucose tolerance test to take place between 24+0\xa0weeks and 28+0\xa0weeks in line with the recommendations on gestational diabetes risk assessment and the recommendations on gestational diabetes testing in the NICE guideline on diabetes in pregnancy.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on gestational diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: content of antenatal appointments.\n\nLoading. Please wait.\n\n## Pre-eclampsia and hypertension in pregnancy\n\nAt the first antenatal (booking) appointment and again in the second trimester, assess the woman's risk factors for pre-eclampsia, and advise those at risk to take aspirin in line with the section on antiplatelet agents in the NICE guideline on hypertension in pregnancy.\n\nMeasure and record the woman's blood pressure at every routine face-to-face antenatal appointment using a device validated for use in pregnancy, and following the recommendations on measuring blood pressure in the NICE guideline on hypertension in adults.\n\nFor women under 20+0\xa0weeks with hypertension, follow the recommendations on the management of chronic hypertension in pregnancy in the NICE guideline on hypertension in pregnancy.\n\nRefer women over 20+0\xa0weeks with a first episode of hypertension (blood pressure of 140/90\xa0mmHg or higher) to secondary care to be seen within 24\xa0hours. See the recommendations on diagnosing hypertension in the NICE guideline on hypertension in adults.\n\nUrgently refer women with severe hypertension (blood pressure of 160/110\xa0mmHg or higher) to secondary care to be seen on the same day. The urgency of the referral should be determined by an overall clinical assessment.\n\nOffer a urine dipstick test for proteinuria at every routine face-to-face antenatal appointment.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on pre-eclampsia and hypertension in pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: identification of hypertension in pregnancy and evidence review\xa0G: content of antenatal appointments.\n\nLoading. Please wait.\n\n## Monitoring fetal growth and wellbeing\n\nOffer a risk assessment for fetal growth restriction at the first antenatal (booking) appointment, and again in the second trimester. Consider using guidance by an appropriate professional or national body, for example, the Royal College of Obstetricians and Gynaecologists' guideline on the investigation and management of the small-for-gestational-age fetus or the NHS saving babies' lives care bundle version\xa02.\n\nOffer symphysis fundal height measurement at each antenatal appointment after 24+0\xa0weeks (but no more frequently than every 2\xa0weeks) for women with a singleton pregnancy unless the woman is having regular growth scans. Plot the measurement onto a growth chart in line with the NHS saving babies' lives care bundle version\xa02.\n\nIf there are concerns that the symphysis fundal height is large for gestational age, consider an ultrasound scan for fetal growth and wellbeing.\n\nIf there are concerns that the symphysis fundal height is small for gestational age, offer an ultrasound scan for fetal growth and wellbeing, the urgency of which may depend on additional clinical findings, for example, reduced fetal movements or raised maternal blood pressure.\n\nDo not routinely offer ultrasound scans after 28\xa0weeks for uncomplicated singleton pregnancies.\n\nDiscuss the topic of babies' movements with the woman after 24+0\xa0weeks, and:\n\nask if she has any concerns about her baby's movements at each antenatal contact after 24+0\xa0weeks\n\nadvise her to contact maternity services at any time of day or night if she has any concerns about her baby's movements or she notices reduced fetal movements after 24+0\xa0weeks\n\nassess the woman and baby if there are any concerns about the baby's movements.\n\nService providers should recognise that the use of structured fetal movement awareness packages, such as the one studied in the AFFIRM trial, has not been shown to reduce stillbirth rates.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on monitoring fetal growth and wellbeing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0O: monitoring fetal growth\n\nevidence review\xa0P: fetal movement monitoring\n\nevidence review\xa0Q: routine third trimester ultrasound for fetal growth.\n\nLoading. Please wait.\n\n## Breech presentation\n\nOffer abdominal palpation at all appointments after 36+0\xa0weeks to identify possible breech presentation for women with a singleton pregnancy.\n\nIf breech presentation is suspected on abdominal palpation, offer an ultrasound scan to determine the presentation.\n\nFor women with an uncomplicated singleton pregnancy with breech presentation confirmed after 36+0\xa0weeks:\n\ndiscuss the different options available and their benefits, risks and implications, including:\n\n\n\nexternal cephalic version (to turn the baby from bottom to head down)\n\nbreech vaginal birth\n\nelective caesarean birth\n\n\n\nfor women who prefer cephalic (head-down) vaginal birth, offer external cephalic version.Also see the recommendations on breech presentation in the NICE guideline on caesarean birth, and the recommendations on breech presenting in labour in the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on breech presentation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: identification of breech presentation and evidence review\xa0M: management of breech presentation.\n\nLoading. Please wait.\n\n# Information and support for pregnant women and their partners\n\n## Communication – key principles\n\nWhen caring for a pregnant woman, listen to her and be responsive to her needs and preferences. Also see the NICE guideline on patient experience in adult NHS services, in particular the sections on communication and information, and the NICE guideline on shared decision making.\n\nEnsure that when offering any assessment, intervention or procedure, the risks, benefits and implications are discussed with the woman and she is aware that she has a right to decline.\n\nWomen's decisions should be respected, even when this is contrary to the views of the healthcare professional.\n\nWhen giving women (and their partners) information about antenatal care, use clear language, and tailor the timing, content and delivery of information to the needs and preferences of the woman and her stage of pregnancy. Information should support shared decision making between the woman and her healthcare team, and be:\n\noffered on a one-to-one or couple basis\n\nsupplemented by group discussions (women only or women and partners)\n\nsupplemented by written information in a suitable format, for example, digital, printed, braille or Easy Read\n\noffered throughout the woman's care\n\nindividualised and sensitive\n\nsupportive and respectful\n\nevidence-based and consistent\n\ntranslated into other languages if needed.For more guidance on communication, providing information (including different formats and languages), and shared decision making, see the NICE guideline on patient experience in adult NHS services and the NHS Accessible Information Standard.\n\nExplore the knowledge and understanding that the woman (and her partner) has about each topic to individualise the discussion.\n\nCheck that the woman (and her partner) understands the information that has been given, and how it relates to them. Provide regular opportunities to ask questions, and set aside enough time to discuss any concerns.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on communication – key principles\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0B: approaches to information provision\n\nevidence review A: information provision\n\nevidence review J: referral and delivery of antenatal care.\n\nLoading. Please wait.\n\n## Information about antenatal care\n\nAt the first antenatal (booking) appointment, discuss antenatal care with the woman (and her partner) and provide her schedule of antenatal appointments.\n\nAt the first antenatal (booking) appointment (and later if appropriate), discuss and give information on:\n\nwhat antenatal care involves and why it is important\n\nthe planned number of antenatal appointments\n\nwhere antenatal appointments will take place\n\nwhich healthcare professionals will be involved in antenatal appointments\n\nhow to contact the midwifery team for non-urgent advice\n\nhow to contact the maternity service about urgent concerns, such as pain and bleeding\n\nscreening programmes: what blood tests and ultrasound scans are offered and why\n\nhow the baby develops during pregnancy\n\nwhat to expect at each stage of the pregnancy\n\nphysical and emotional changes during the pregnancy\n\nmental health during the pregnancy\n\nrelationship changes during the pregnancy\n\nhow the woman and her partner can support each other\n\nimmunisation for flu, pertussis (whooping cough) and other infections (for example, COVID‑19) during pregnancy, in line with the NICE guideline on flu vaccination and the Public Health England Green Book on immunisation against infectious disease\n\ninfections that can impact on the baby in pregnancy or during birth (such as group\xa0B streptococcus, herpes simplex and cytomegalovirus)\n\nreducing the risk of infections, for example, encouraging hand washing\n\nsafe use of medicines, health supplements and herbal remedies during pregnancy\n\nresources and support for expectant and new parents\n\nhow to get in touch with local or national peer support services.\n\nAt the first antenatal (booking) appointment, and later if appropriate, discuss and give information about nutrition and diet, physical activity, smoking cessation and recreational drug use in a non-judgemental, compassionate and personalised way. See the NICE guidelines on maternal and child nutrition, vitamin\xa0D, weight management before, during and after pregnancy, smoking: stopping in pregnancy and after childbirth, and the section on pregnant women who misuse substances (alcohol and/or drugs) in the NICE guideline on pregnancy and complex social factors.\n\nAt the first antenatal (booking) appointment, and later if appropriate, discuss alcohol consumption and follow the UK Chief Medical Officers' low-risk drinking guidelines. Explain that:\n\nthere is no known safe level of alcohol consumption during pregnancy\n\ndrinking alcohol during the pregnancy can lead to long-term harm to the baby\n\nthe safest approach is to avoid alcohol altogether to minimise risks to the baby.\n\nThroughout the pregnancy, discuss and give information on:\n\nphysical and emotional changes during the pregnancy\n\nrelationship changes during the pregnancy\n\nhow the woman and her partner can support each other\n\nresources and support for expectant and new parents\n\nhow the parents can bond with their baby and the importance of emotional attachment (also see the section on promoting emotional attachment in the NICE guideline on postnatal care)\n\nthe results of any blood or screening tests from previous appointments.\n\nSee the NICE guideline on pelvic floor dysfunction for guidance on:\n\nproviding information about pelvic floor dysfunction (recommendation 1.1.6)\n\npelvic floor muscle training during and after pregnancy.\n\nAfter 24 weeks, discuss babies' movements (see also recommendation 1.2.34).\n\nBefore 28\xa0weeks, start talking with the woman about her birth preferences and the implications, benefits and risks of different options (see the section on choosing planned place of birth in the NICE guideline on intrapartum care for healthy women and babies and the section on planning mode of birth in the NICE guideline on caesarean birth).\n\nAfter 28\xa0weeks, discuss and give information on:\n\npreparing for labour and birth, including information about coping in labour and creating a birth plan\n\nrecognising active labour\n\nthe postnatal period, including:\n\n\n\ncare of the new baby\n\nthe baby's feeding\n\nvitamin K prophylaxis\n\nnewborn screening\n\npostnatal self-care, including pelvic floor exercises\n\nawareness of mood changes and postnatal mental health.Also see the NICE guideline on postnatal care.\n\n\n\nFrom 28\xa0weeks onwards, as appropriate, continue the discussions and confirm the woman's birth preferences, discussing the implications, benefits and risks of all the options.\n\nFrom 38\xa0weeks, discuss prolonged pregnancy and options on how to manage this, in line with the NICE guideline on inducing labour.\n\nSee the NICE guideline on preterm labour and birth for women at increased risk of, or with symptoms and signs of, preterm labour (before 37\xa0weeks), and women having a planned preterm birth.\n\nProvide appropriate information and support for women whose baby is considered to be at an increased risk of neonatal admission.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information about antenatal care\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: information provision\n\nevidence review B: approaches to information provision\n\nevidence review\xa0C: involving partners\n\nevidence review\xa0D: peer support\n\nevidence review\xa0G: content of antenatal appointments\n\nevidence review\xa0J: referral and delivery of antenatal care\n\nevidence review P: fetal movement monitoring.\n\nLoading. Please wait.\n\n## Antenatal classes\n\nOffer nulliparous women (and their partners) antenatal classes that include topics such as:\n\npreparing for labour and birth\n\nsupporting each other throughout the pregnancy and after birth\n\ncommon events in labour and birth\n\nhow to care for the baby\n\nhow the parents can bond with their baby and the importance of emotional attachment (also see the section on promoting emotional attachment in the NICE guideline on postnatal care)\n\nplanning and managing their baby's feeding (also see the section on planning and supporting babies' feeding in the NICE guideline on postnatal care).\n\nConsider antenatal classes for multiparous women (and their partners) if they could benefit from attending (for example, if they have had a long gap between pregnancies, or have never attended antenatal classes before).\n\nEnsure that antenatal classes are welcoming, accessible and adapted to meet the needs of local communities. Also see the section on young pregnant women aged under\xa020 in the NICE guideline on pregnancy and complex social factors.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on antenatal classes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: antenatal classes and evidence review\xa0B: approaches to information provision.\n\nLoading. Please wait.\n\n## Peer support\n\nDiscuss the potential benefits of peer support with pregnant women (and their partners), and explain how it may:\n\nprovide practical support\n\nhelp to build confidence\n\nreduce feelings of isolation.\n\nOffer pregnant women (and their partners) information about how to access local and national peer support services.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on peer support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: peer support.\n\nLoading. Please wait.\n\n## Sleep position\n\nAdvise women to avoid going to sleep on their back after 28\xa0weeks of pregnancy and to consider using pillows, for example, to maintain their position while sleeping.\n\nExplain to the woman that there may be a link between going to sleep on her back and stillbirth in late pregnancy (after 28\xa0weeks).\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on sleep position\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0W: maternal sleep position during pregnancy.\n\nLoading. Please wait.\n\n# Interventions for common problems during pregnancy\n\n## Nausea and vomiting\n\nReassure women that mild to moderate nausea and vomiting are common in pregnancy, and are likely to resolve before 16\xa0to 20\xa0weeks.\n\nRecognise that by the time women seek advice from healthcare professionals about nausea and vomiting in pregnancy, they may have already tried a number of different interventions.\n\nFor pregnant women with mild‑to‑moderate nausea and vomiting who prefer a non-pharmacological option, suggest that they try ginger.\n\nWhen considering pharmacological treatments for nausea and vomiting in pregnancy, discuss the advantages and disadvantages of different antiemetics with the woman. Take into account her preferences and her experience with treatments in previous pregnancies. See table\xa01 on the advantages and disadvantages of different pharmacological treatments for nausea and vomiting in pregnancy to support shared decision making.\n\nFor pregnant women with nausea and vomiting who choose a pharmacological treatment, offer an antiemetic (see table\xa01 on the advantages and disadvantages of different pharmacological treatments for nausea and vomiting in pregnancy).\n\nFor pregnant women with moderate‑to‑severe nausea and vomiting:\n\nconsider intravenous fluids, ideally on an outpatient basis\n\nconsider acupressure as an adjunct treatment.\n\nConsider inpatient care if vomiting is severe and not responding to primary care or outpatient management. This will include women with hyperemesis gravidarum. Also see the section on venous thromboembolism.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on nausea and vomiting\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: management of nausea and vomiting in pregnancy.\n\nLoading. Please wait.\n\n## Heartburn\n\nGive information about lifestyle and dietary changes to pregnant women with heartburn in line with the section on common elements of care in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults.\n\nConsider a trial of an antacid or alginate for pregnant women with heartburn.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on heartburn\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0S: management of heartburn in pregnancy.\n\nLoading. Please wait.\n\n## Symptomatic vaginal discharge\n\nAdvise pregnant women who have vaginal discharge that this is common during pregnancy, but if it is accompanied by symptoms such as itching, soreness, an unpleasant smell or pain on passing urine, there may be an infection that needs to be investigated and treated.\n\nConsider carrying out a vaginal swab for pregnant women with symptomatic vaginal discharge if there is doubt about the cause.\n\nIf a sexually transmitted infection is suspected, consider arranging appropriate investigations.\n\nOffer vaginal imidazole (such as clotrimazole or econazole) to treat vaginal candidiasis in pregnant women.\n\nConsider oral or vaginal antibiotics to treat bacterial vaginosis in pregnant women in line with the NICE guideline on antimicrobial stewardship.\n\nFor a short explanation of why the committee made the recommendations and how they might practice, see the rationale and impact section on symptomatic vaginal discharge\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0T: management of symptomatic vaginal discharge in pregnancy.\n\nLoading. Please wait.\n\n## Pelvic girdle pain\n\nFor women with pregnancy-related pelvic girdle pain, consider referral to physiotherapy services for:\n\nexercise advice and/or\n\na non-rigid lumbopelvic belt.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on pelvic girdle pain\xa0.\n\nFull details of the evidence and the committee's discussion are in\xa0evidence review\xa0U: management of pelvic girdle pain in pregnancy.\n\nLoading. Please wait.\n\n## Unexplained vaginal bleeding after 13\xa0weeks\n\nOffer anti-D immunoglobulin to women who present with vaginal bleeding after 13\xa0weeks of pregnancy if they are:\n\nrhesus D-negative and\n\nat risk of isoimmunisation.\n\nRefer pregnant women with unexplained vaginal bleeding after 13\xa0weeks to secondary care for a review.\n\nFor pregnant women with unexplained vaginal bleeding after 13\xa0weeks, assess whether to admit them to hospital, taking into account:\n\nthe risk of placental abruption\n\nthe risk of preterm delivery\n\nthe extent of vaginal bleeding\n\nthe woman's ability to attend secondary care in an emergency.\n\nFor pregnant women who present with unexplained vaginal bleeding, offer to carry out placental localisation by ultrasound if the placental site is not known.\n\nFor pregnant women with unexplained vaginal bleeding who are admitted to hospital, consider corticosteroids for fetal lung maturation if there is an increased risk of preterm birth within 48\xa0hours. Take into account gestational age (see the section on maternal corticosteroids in the NICE guideline on preterm labour and birth).\n\nConsider discussing the increased risk of preterm birth with women who have unexplained vaginal bleeding.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on unexplained vaginal bleeding after 13\xa0weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0V: management of unexplained vaginal bleeding in pregnancy.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Bonding and emotional attachment\n\nBonding is the positive emotional and psychological connection that the parent develops with the baby.\n\nEmotional attachment refers to the relationship between the baby and parent, driven by innate behaviour and which ensures the baby's proximity to the parent and safety. Its development is a complex and dynamic process that is dependent on sensitive and emotionally attuned parent interactions supporting healthy infant psychological and social development and a secure attachment. Babies form attachments with a variety of caregivers but the first, and usually most significant of these, will be with the mother and/or father.\n\n## Continuity of carer\n\nHaving continuity of carer means that a trusting relationship can be developed between the woman and the healthcare professional who cares for her. Better Births, a report by the National Maternity Review, defines continuity of carer as consistency in the midwifery team (between 4\xa0and 8\xa0individuals) that provides care for the woman and her baby throughout pregnancy, labour and the postnatal period. A named midwife coordinates the care and takes responsibility for ensuring that the needs of the woman and her baby are met throughout the antenatal, intrapartum and postnatal periods.\n\nFor the purpose of this guideline, definition of continuity of carer in the Better Births report has been adapted to include not just the midwifery team but any healthcare team involved in the care of the woman and her baby. It emphasises the importance of effective information transfer between the individuals within the team. For more information, see the NHS Implementing Better Births: continuity of carer.\n\n## Partner\n\nPartner refers to the woman's chosen supporter. This could be the baby's father, the woman's partner, family member or friend, or anyone who the woman feels supported by and wishes to involve in her antenatal care.\n\n## Shared decision making\n\nShared decision making is a collaborative process that involves a person and their healthcare professional working together to reach a joint decision about care. It could be care the person needs straightaway or care in the future, for example, through advance care planning. See the full definition in the\xa0NICE guideline on shared decision making. In line with\xa0NHS England's personalised care and support planning guidance: guidance for local maternity systems, in maternity services, this may be referred to as 'informed decision making'.\n\n## Structured fetal movement awareness packages\n\nThe structured fetal movement awareness package described in the Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM) trial consisted of:\n\nan e-learning education package for all clinical staff about the importance of a recent change in the frequency of fetal movements and how to manage reduced fetal movements\n\na leaflet given to pregnant women at 20\xa0weeks of pregnancy to raise awareness of the importance of monitoring fetal movements and reporting reduced movements\n\na structured management plan for hospitals following reporting of reduction in fetal movement including cardiotocography, measurement of liquor volume and a growth scan (umbilical artery doppler was encouraged if available).", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Hospitalisation of pregnant women with unexplained vaginal bleeding\n\nWhat is the clinical and cost effectiveness of hospitalisation compared with outpatient management for pregnant women with unexplained vaginal bleeding?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on unexplained vaginal bleeding\xa0.\n\nFull details of the research recommendation are in evidence review\xa0V: management of unexplained vaginal bleeding in pregnancy.\n\nLoading. Please wait.\n\n## Medications for mild to moderate nausea and vomiting in pregnancy\n\nWhat is the clinical and cost effectiveness of medication for women with nausea and vomiting in pregnancy?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on nausea and vomiting\xa0.\n\nFull details of the research recommendation are in evidence review\xa0R: management of nausea and vomiting in pregnancy.\n\nLoading. Please wait.\n\n## Models of antenatal care\n\nWhat is the clinical and cost effectiveness of different models of antenatal care with varying numbers and times of appointment, and should different models be used for groups at risk of worse outcomes?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on starting antenatal care\xa0.\n\nFull details of the research recommendation are in evidence review\xa0F: accessing antenatal care.\n\nLoading. Please wait.\n\nWhat is the clinical and cost effectiveness of different models of antenatal care with varying numbers and times of appointment, and should different models be used for groups at risk of worse outcomes?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on antenatal appointments\xa0.\n\nFull details of the research recommendation are in evidence review\xa0F: accessing antenatal care.\n\nLoading. Please wait.\n\n## Identification of breech presentation\n\nWhat is the clinical and cost effectiveness of routine ultrasound from 36+0\xa0weeks compared with selective ultrasound in identifying breech presentation?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on breech presentation\xa0.\n\nFull details of the research recommendation are in evidence review\xa0L: identification of breech presentation.\n\nLoading. Please wait.\n\n## Management of severe nausea and vomiting\n\nWhat is the clinical and cost effectiveness of corticosteroids for women with severe nausea and vomiting in pregnancy?\n\nFor a short explanation of why the committee made this research recommendation, see the rationale section on nausea and vomiting\xa0.\n\nFull details of the research recommendation are in evidence review\xa0R: management of nausea and vomiting in pregnancy.\n\nLoading. Please wait.', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Starting antenatal care\n\nRecommendations 1.1.1 to 1.1.3\n\n## Why the committee made the recommendations\n\nNo relevant evidence was identified and so the committee made the recommendations based on their knowledge and experience, and also made a research recommendation about how to start antenatal care. The committee discussed the ways in which women should be able to access antenatal care, but agreed that the configuration details would depend on local arrangements.\n\nThe committee agreed that antenatal service planning should take into account women's needs and circumstances, and should not discriminate against, for example, a limited ability to use and access online services, limited skills in English language or in literacy, or not being registered with a GP surgery. The committee were aware that for some women in vulnerable situations or with limited English language skills, there may be a delay in accessing and starting antenatal care.\n\nThe booking appointment should occur by 10\xa0weeks of pregnancy but the initial contact and referral might have happened several weeks earlier, so the committee agreed that the referral contact should include provision of early pregnancy information, for example, public health messages for the woman about folic acid supplementation or stopping smoking. It is also important to identify women with specific needs or risk factors early on so that appropriate care can be provided from the beginning.\n\nThe committee agreed that it is important to have the contact details for the woman's GP to ensure that information can be shared between primary care and maternity services so that care is provided according to the woman's individual needs, and to identify potential safeguarding issues.\n\n## How the recommendations might affect practice\n\nThere is variation in current practice in how women access antenatal care and the time between women's first contact with a healthcare professional and subsequent steps. Enabling women to start their antenatal care through various routes, including through school nurses, community centres or refugee hostels, may have some implications on resources; however, these should be outweighed by the benefits of timely antenatal care. The recommendations should improve timely access to antenatal care for women in various situations, and improve early recognition of specific needs and risk factors so that care can be planned.\n\nReturn to recommendations\n\n# Antenatal appointments\n\nRecommendations 1.1.4 to 1.1.13\n\n## Why the committee made the recommendations\n\nThere was no new evidence to support changing from the existing recommended practice of women having their first antenatal (booking) appointment by 10+0\xa0weeks.\n\nSome women only contact, or are referred to, maternity services after 9+0\xa0weeks. This 'late booking' may be particularly common among some socially vulnerable women or women with limited English language skills. Based on their knowledge and experience, the committee agreed that women who contact, or are referred to, maternity services after 9+0\xa0weeks should have a booking appointment ideally within 2\xa0weeks so that early pregnancy care, including information provision and screenings, can happen within the right timeframe. The committee agreed that it would be helpful to identify any underlying factors that may have led to the 'late booking' so that the woman's need for potential additional support or care can be considered and that any potential inequality and accessibility issues can be addressed.\n\nThere was no new evidence that led the committee to change from the existing recommended practice of arranging 10\xa0appointments for nulliparous women and 7\xa0appointments for parous women. Instead, the committee made a research recommendation about the ideal number and timing of antenatal appointments, including consideration for groups at higher risk of adverse outcomes.\n\nThe evidence on women's experience and satisfaction in relation to the number of antenatal appointments was mixed, but the committee agreed the importance of being flexible to meet women's needs.\n\nThere was evidence that women who needed to use interpreters found the service to be unreliable and inconsistent, so the committee made a specific recommendation highlighting that interpreters should always be available when needed (including, for example, at scan appointments) and that they should be independent of the woman and not, for example, a family member or a friend.\n\nThere was good evidence that women value having the same midwife throughout their antenatal care, although the review did not look at the benefits and harms of continuity of carer in relation to clinical- and cost-effectiveness outcomes. The NHS England's report Better Births: improving outcomes of maternity services in England – a five year forward view for maternity care recommends continuity of carer by 1\xa0midwife who is part of a small team of midwives based in the community, so that they can get to know the woman and provide support to her throughout pregnancy all the way to the postnatal period.\n\nVarious health professionals or providers may be involved throughout the pregnancy, and the committee emphasised the need for good communication between different health professionals and providers.\n\n## How the recommendations might affect practice\n\nThe timing of the booking appointment and the number of appointments reflects current clinical practice. The recommendation about women who do not have a booking appointment arranged by 9+0\xa0weeks may lead to more women attending booking appointments before 11\xa0weeks and it may also reduce how long it takes to secure a booking appointment. However, this may also be challenging for services to organise.\n\nThe recommendation about offering additional or longer antenatal appointments depending on need may lead to a small increase in the number of antenatal appointments, but this is likely to be negligible and potentially have benefits later on.\n\nThe recommendation on the use of interpreters is not new but is not well implemented in all units, so may involve a change in practice.\n\nIn current practice, providing continuity of carer can be difficult to achieve and there can be significant resource implications; however, the recommendation reflects NHS England's recommendations.\n\nThe committee agreed that the recommendations would not result in a major change in practice but should reduce variation in practice and improve care for women.\n\nReturn to recommendations\n\n# Involving partners\n\nRecommendations 1.1.14 to 1.1.16\n\n## Why the committee made the recommendations\n\nThe committee recognised that women's home and family circumstances vary, and it is up to the woman to decide who she may want to involve in her antenatal care. Involving partners is an important part of antenatal care, and the World Health Organization has emphasised the importance of engaging with partners during pregnancy, childbirth and postnatally. The committee discussed the impact that a partner's support, lack of support, or their wellbeing can have on the wellbeing of the pregnant woman. The committee recognised that the woman's partner is often also an expectant parent and being involved in the antenatal care, if the woman so wishes, can provide information and support for them as well.\n\nThe committee discussed that partners can face many types of barriers when engaging with antenatal services. There was good quality evidence on partners' views and experiences of antenatal care that showed that women appreciate being able to involve their partners in antenatal care, but that this can be difficult, for example, because of the partner's work patterns. Therefore, the committee agreed that the services should consider adapting when to offer antenatal classes (for example, in the evenings or at the weekends) to enable partners to be involved if the woman wishes.\n\nEvidence showed that partners can feel like bystanders in appointments if, for example, there is no space for them to sit with their partner. The committee agreed ways that antenatal services could promote partner involvement. The committee agreed that partners are not always given information, including on how partners can support the woman during and after pregnancy, and the general pregnancy information that women receive.\n\nIncreased use of virtual platforms for appointments may also improve partners' involvement in antenatal care. For example, this could enable the partner to attend remotely if the woman has a face-to-face appointment, or for the couple to attend together if she has a video appointment. However, the committee recognised that evidence on video consultations and appointments was not reviewed for this guideline, and the benefits, harms and experiences related to them is important to consider when planning services. The committee also agreed that it is important to carefully assess any potential inequalities issues that could be associated with video appointments, for example, among people with sensory impairments or language barriers, minority groups, or in relation to access to devices or internet connection.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations may increase and promote the involvement of partners, while respecting the woman's decisions. The recommendations are not expected to have a large resource impact or be difficult to implement although there may be some organisational changes needed to support making the timing of antenatal classes more flexible.\n\nReturn to recommendations\n\n# Taking and recording the woman's history\n\nRecommendations 1.2.1 to 1.2.11\n\n## Why the committee made the recommendations\n\nThe recommendations were not developed by the usual NICE guideline systematic review process. A new evidence review was not considered necessary because the issues are covered by other NICE guidelines, or there is no clinical uncertainty or significant resource impact. Where there might be a potential limited resource impact, this could be justifiably offset by improved outcomes, avoidance of serious adverse outcomes or addressing inequalities. The recommendations were based on committee consensus on what is best practice, as well as other existing NICE guidelines.\n\nAsking the woman about her past and present conditions and experiences in relation to her physical, obstetric, psychological, emotional and social health enables potential risk factors to be identified and managed. The committee used their knowledge and experience to list the factors that should be discussed so that appropriate action can be taken, and care tailored to the woman's needs. For example, it is important to note which pharmacological and non-pharmacological remedies the woman uses so that current medication can be reviewed in light of pregnancy. It is important that women do not automatically stop using their regular medication without consultation. This discussion also allows for individualised advice on safe medicine use during pregnancy and can help with identifying any health issues that may have otherwise not come up.\n\nThe committee also agreed that it is important to discuss the woman's home and family situation and the available support she has. There may be issues that can impact on her wellbeing, for example, lack of support, illness in the family or a partner's substance use issues.\n\nSometimes there may be a reason to review the woman's previous medical records, for example, when her previous maternity care has been in a different organisation, she cannot recall details of a potentially significant issue, or the discussion somehow triggers a concern.\n\nThe committee agreed that healthcare professionals should be aware of the disproportionate maternal mortality and stillbirth rates among women and babies from black and Asian backgrounds and those living in deprived areas, as highlighted by the 2020 MBRRACE-UK reports on maternal mortality and perinatal mortality. This increased risk of death indicates that interventions to improve engagement, support and closer monitoring need to be explored. Future research could help understand the mechanisms underlying these disparities and what interventions could improve the outcomes. In general, action on the wider determinants of health, including different social, economic and environmental factors, is also needed to overcome such inequalities.\n\nThe committee agreed that domestic abuse puts both the woman and her baby at risk of harm, so it is important that all pregnant women are asked about it in a kind, sensitive way. Pregnancy can sometimes be a trigger for domestic abuse or existing domestic abuse can continue or worsen during pregnancy, so it is important that women feel that they can disclose it safely so that they can be supported, and interventions put in place if needed. Although partner involvement in antenatal care is welcome, it is also important to ensure that there is an opportunity to discuss domestic issues privately with the woman.\n\nThe committee recognised the need to identify women who have undergone female genital mutilation (FGM) or whose unborn baby girl might be at risk of FGM so that appropriate safeguarding can take place. In the context of this guideline, this could be the pregnant woman, or the unborn baby when there is a family history or tradition of FGM. There is a mandatory duty to report suspected or known FGM in under\xa018s. The Department of Health and Social Care has produced a quick guide for healthcare professionals on FGM safeguarding and risk assessment, which includes information about countries where FGM is practised, and practical advice on how to start the conversation.\n\nIdentifying underlying cardiac problems is important because cardiovascular disease is the leading cause of death among women in the UK during and after pregnancy, according to the 2019 report MBRRACE-UK: Saving lives, improving mothers' care – lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2016–18. Some women are at a higher risk of undiagnosed structural cardiac problems, such as women with a family history of cardiac abnormalities or women who were brought up in a country with a high incidence of rheumatic fever. Clinical assessment cannot identify all cardiac problems that cause maternal mortality, but it might pick up structural heart disease or concerns that warrant further investigations. Early identification of underlying cardiac conditions allows these women to receive appropriate care during their pregnancy, childbirth and postnatal period, and potentially avoid poor outcomes.\n\nThe committee also agreed the importance of information sharing between the maternity unit and the GP, and agreeing this with the woman. This is particularly important if the woman has self-referred (because the GP may be unaware of her pregnancy), and if women have a complex medical, psychological or social history (because different agencies may need to be involved in her and her baby's care).\n\nAntenatal appointments are opportunities for continued monitoring and risk assessment on the health and wellbeing of the woman and her baby. They also allow for regular reassessments of women's antenatal care needs and plans.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current best practice. Clinical assessment for cardiac conditions is not always done for women who may be at an increased risk so this recommendation may change practice to some extent. The number of women this recommendation applies to is relatively small and the potentially life-saving benefit of this simple examination outweighs the potential cost and resource implications.\n\nReturn to recommendations\n\n# Examinations and investigations\n\nRecommendations 1.2.12 to 1.2.17\n\n## Why the committee made the recommendations\n\nMost of the issues are covered by national screening programmes or other NICE guidance, so no new evidence review was needed. The committee agreed, by consensus, any other recommendations where there is no clinical uncertainty or significant resource impact.\n\nThe timing of the ultrasound scans aligns with the NHS fetal anomaly screening programme.\n\nIt is important that women understand the potential implications of each of the tests being offered so that they have the opportunity to accept or decline.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice and no change in practice is expected.\n\nReturn to recommendations\n\n# Venous thromboembolism\n\nRecommendations 1.2.18 to 1.2.20\n\n## Why the committee made the recommendations\n\nThe committee based the recommendations on the evidence on independent risk factors for venous thromboembolism in pregnancy, their knowledge and experience, and the NICE guideline on venous thromboembolism in over\xa016s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. The evidence on independent risk factors for venous thromboembolism during pregnancy did not assess the accuracy of tools used to measure the risk, so the committee recommended that tools should meet certain quality criteria. They agreed that an example of a tool that might be used is the risk assessment tool in the Royal College of Obstetricians and Gynaecologists' green-top guideline on reducing the risk of venous thromboembolism during pregnancy (2015), which is commonly used in practice.\n\nThe committee highlighted some risk factors in the evidence review (blood type\xa0A or\xa0B, miscarriage after 10\xa0weeks in the current pregnancy and history of previous blood transfusion) that are not always incorporated into commonly used venous thromboembolism tools. However, they agreed not to include them specifically in the recommendations because it could give a false impression that these factors were more important than others or lead to overtreatment.\n\nThe committee agreed that women assessed as being at an increased risk of venous thromboembolism should be offered referral to an obstetrician so that a risk management plan can be made, for example, starting thromboprophylaxis.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice and no change in practice is expected.\n\nReturn to recommendations\n\n# Gestational diabetes\n\nRecommendations 1.2.21 and 1.2.22\n\n## Why the committee made the recommendations\n\nGuidance on risk assessment for and identification of gestational diabetes is covered by the NICE guideline on diabetes in pregnancy.\n\n## How the recommendations might affect practice\n\nThe recommendation reflects current practice and no change in practice is expected.\n\nReturn to recommendations\n\n# Pre-eclampsia and hypertension in pregnancy\n\nRecommendations 1.2.23 to 1.2.28\n\n## Why the committee made the recommendations\n\nGuidance on risk assessment and risk reduction for pre-eclampsia is covered by the NICE guideline on hypertension in pregnancy. Although the guideline implies that pregnant women will be routinely tested for proteinuria, it does not explicitly recommend this. Therefore, the committee agreed that, in line with current practice, urine testing for proteinuria should be offered at every routine face-to-face appointment.\n\nThere was little evidence on the setting and technique for monitoring blood pressure during pregnancy, so the committee made the recommendations based on their knowledge and experience and existing NICE guidance. The committee were aware that the British and Irish Hypertension Society lists blood pressure measurement devices validated for use in pregnancy. This has also been noted in the NICE guideline on hypertension in adults.\n\nThe committee agreed that monitoring blood pressure and testing for proteinuria at every routine face-to-face antenatal appointment enables hypertension and pre‑eclampsia to be identified and treated early, which is important because they can have severe consequences.\n\nGuidance on care for pregnant women with gestational or chronic hypertension is covered by the NICE guideline on hypertension in pregnancy.\n\n## How the recommendations might affect practice\n\nThe recommendation reflects current practice and no change in practice is expected.\n\nReturn to recommendations\n\n# Monitoring fetal growth and wellbeing\n\nRecommendations 1.2.29 to 1.2.35\n\n## Why the committee made the recommendations\n\nRisk assessment starting in early pregnancy enables increased monitoring of babies who are at an increased risk of fetal growth restriction, which is associated with fetal morbidity and mortality. The committee were aware of available risk assessment tools, such as those in the Royal College of Obstetricians and Gynaecologists' guideline on the investigation and management of the small-for-gestational-age fetus or the NHS saving babies' lives care bundle version\xa02.\n\nEvidence showed that ultrasound scans and symphysis fundal height measurement do not accurately predict a baby being born small or large for gestational age. However, the committee agreed that the current routine practice of using symphysis fundal height measurement to monitor fetal growth should be used, because it is a simple and low-cost intervention and can alert to further investigations when concerns arise about the baby being either larger or smaller than expected for gestational age. When the symphysis fundal height measurement is large for gestational age, ultrasound scans could be used to assess the size of the baby and the volume of amniotic fluid. Small-for-gestational-age babies are at an increased risk of perinatal mortality and morbidity; therefore, when this is suspected, further investigations should be done to monitor the growth and wellbeing of the baby, taking into consideration the full clinical picture.\n\nThe committee were aware that many women may request routine ultrasound scans in late pregnancy, but available evidence showed no benefit from routine ultrasound in late pregnancy (from 28\xa0weeks) for uncomplicated singleton pregnancies. However, the absence of effect found in the evidence does not mean that there is definitely no effect. There was also no evidence on maternal anxiety in relation to routine ultrasound scanning. The committee were in favour of research on this in the future; however, a research recommendation was not prioritised because there is a good amount of evidence on other key outcomes.\n\nThe committee were aware that cases of stillbirth have been linked to reduced fetal movements. Therefore, structured fetal movement awareness packages have been trialled. Evidence on the use of a structured fetal movement awareness package, such as the one described in the UK trial Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM), did not detect a reduction in stillbirths or perinatal mortality but did find that there were more interventions at birth, including more caesarean births and inductions of labour, and fewer spontaneous vaginal births. Another study from Sweden compared giving a leaflet to pregnant women teaching them a method of being aware of fetal movements, with usual care. No clinically important benefits or harms were detected, including no difference in perinatal mortality, although there was a small, but statistically significant, reduction in births after 41+6\xa0weeks and fewer caesarean births. Health economic evaluation did not establish cost effectiveness for either of these structured awareness packages.\n\nAlthough the available evidence did not support the use of structured packages, the committee agreed that fetal movements should be discussed routinely and women's concerns should be taken seriously. The committee agreed that there is no agreed definition of normal fetal movements. Discussing the topic of babies' movements in the womb and how they change throughout the pregnancy can help women recognise changes to their own baby's movement patterns. When there are concerns, an assessment of the woman's wellbeing and the baby's wellbeing and size should be done.\n\n## How the recommendations might affect practice\n\nThe recommendations on fetal growth monitoring largely reflect current practice, although in some maternity units it is common to offer women with uncomplicated singleton pregnancies ultrasound scans after 28\xa0weeks to monitor the baby, so there might be a change of practice for these units and some potential cost savings. On the other hand, there may be some more scans due to suspected large for gestational age.\n\nCurrent practice for managing reduced fetal movements is to follow the NHS saving babies' lives care bundle version\xa02. The recommendations in this guideline similarly emphasise the importance of recognising and reporting concerns on fetal movements and acting on those concerns by assessing the woman and the baby.\n\nReturn to recommendations\n\n# Breech presentation\n\nRecommendations 1.2.36 to 1.2.38\n\n## Why the committee made the recommendations\n\nThere was not enough evidence to support routine ultrasound at 36+0\xa0weeks to 39+0\xa0weeks to identify breech presentation, so the committee did not change the current standard practice of offering abdominal palpation with selective ultrasound when breech is suspected.\n\nBecause of the lack of evidence, the committee made a research recommendation to compare routine ultrasound scans from 36+0\xa0weeks with selective ultrasound scans.\n\nIn the case of breech presentation, the committee agreed that a discussion about the different options and their potential benefits, harms and implications is needed to ensure an informed decision. External cephalic version is standard practice for managing breech presentation in uncomplicated singleton pregnancies at or after 36+0\xa0weeks. Head-down vaginal birth is preferred by many women and the evidence suggests that external cephalic version is an effective way to achieve this.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current clinical practice and no change in practice is expected.\n\nReturn to recommendations\n\n# Communication – key principles\n\nRecommendations 1.3.1 to 1.3.6\n\n## Why the committee made the recommendations\n\nThe committee agreed that the key principles of care in the antenatal period are to listen to women and be responsive to their needs, in line with the findings of the Ockenden report on maternity services at the Shrewsbury and Telford hospital NHS trust, and to enable women to make informed decisions about their care, in line with the Montgomery ruling. The committee emphasised that women should be supported in their decision making even when their preferences and values differ from those of the healthcare professionals.\n\nThe evidence did not show a particular benefit from any one specific approach to giving information, although 1\xa0study found that supplementing information provided face-to-face with online information increased knowledge. The committee based the recommendations on their knowledge and experience.\n\nThe committee agreed that information should meet the needs of the woman, for example, taking into account any language barriers, learning disabilities or other needs. Most antenatal care information is given in a one-to-one or couple discussion. Offering other formats to supplement this can help improve understanding and engagement, including written materials and group discussions in antenatal classes or, in some cases, group antenatal appointments.\n\nThere was evidence that women value information that is relevant to their own circumstances. The committee agreed that healthcare professionals should explore the level and accuracy of the woman's (and her partner's) existing knowledge and understanding of the topic. The committee discussed the importance of allowing sufficient time for discussions.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current practice.\n\nReturn to recommendations\n\n# Information about antenatal care\n\nRecommendations 1.3.7 to 1.3.19\n\n## Why the committee made the recommendations\n\nThe committee agreed, based on the evidence and their knowledge and experience, that if women are given information about antenatal care, their schedule of appointments and what happens at different appointments and stages of pregnancy, they are more likely to be engaged, follow advice and share their concerns with healthcare professionals.\n\nThere was no evidence identified to inform the timing of information provision, but the committee agreed that it is important to have a staged approach and cover topics relevant to each stage of pregnancy.\n\nThe first antenatal (booking) appointment is an opportunity to discuss and share information about various practical issues related to pregnancy and antenatal care so that the woman knows what to expect and how to get support. The evidence showed that partners also value practical information throughout the pregnancy. For example, in relation to safe use of medicines in pregnancy, the committee were aware of the UK Teratology Information Service's information resources on best use of medicines in pregnancy (bumps).\n\nThe evidence suggested that women want information on how behavioural factors, such as smoking, alcohol, diet and physical activity may affect them and their baby's health. The evidence also highlighted how emotional these topics could be for women and that women may feel judged or patronised. The committee agreed that it is important to have these discussions in a sensitive manner that supports individual women. Guidance on all these issues is covered by other NICE guidelines or government documents.\n\nThe committee recognised that pregnant women and their partners often look for information and support from various sources, such as websites, and not all of them are necessarily evidence-based, so signposting to trusted resources may be helpful.\n\nThere was some evidence that women and their partners valued information and discussion around the transition to parenthood, and the changes that pregnancy and becoming a parent will bring to their life and relationship. The committee were aware of various available resources that could be helpful for parents, particularly new parents.\n\nThe evidence showed that women want information on their options for giving birth. The committee agreed that these discussions should start, at the latest, around the start of the third trimester, depending on the woman's preferences and circumstances. The committee agreed, in line with the Montgomery ruling, that discussing the implications, benefits and risks is fundamental to making shared and informed decisions. Guidance on making decisions about place of birth, mode of birth and prolonged pregnancy are also covered by other NICE guidelines.\n\nConsidering the amount of new information given at the beginning of antenatal care, discussions around practical aspects related to labour, childbirth and postnatal care are often more appropriate later on in pregnancy. There was some evidence that healthcare professionals thought that providing information on emotional attachment and bonding could improve women's confidence and increase their preparedness for birth. Further recommendations about promoting emotional attachment and bonding, as well as planning and managing infant feeding, are covered by the NICE guideline on postnatal care.\n\n## How the recommendations might affect practice\n\nThe recommendations will improve consistency of care and reinforce best practice.\n\nReturn to recommendations\n\n# Antenatal classes\n\nRecommendations 1.3.19 to 1.3.21\n\n## Why the committee made the recommendations\n\nEvidence among nulliparous women showed that women who went to antenatal classes were more likely to have their cervix dilated by 3\xa0cm or more on admission to labour. A dilated cervix on admission may reduce the need for interventions. This may indicate that women who attended antenatal classes have better coping strategies and the confidence to deal with pain at home in the early stages of labour. There was no evidence about the most effective content for antenatal classes, so the committee made the recommendations based on their experience.\n\nThe committee recognised that there may be multiparous women who could also particularly benefit from antenatal classes, so providing them for these women should be considered.\n\nThe committee recognised that some groups of women may be less likely to attend antenatal classes (for example, some women from low income or disadvantaged backgrounds or minority ethnic groups, or those for whom English is not their first language). The committee agreed that in order to increase engagement with antenatal classes, service providers should ensure that classes are accessible, welcoming and adapted to meet the needs of local communities.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice. However, adapting classes to the needs of the local communities might involve some reorganising of practices.\n\nReturn to recommendations\n\n# Peer support\n\nRecommendations 1.3.22 and 1.3.23\n\n## Why the committee made the recommendations\n\nThe evidence showed that peer support could offer helpful and valuable care and guidance during the antenatal period. There was evidence among women from particular subpopulations, such as migrant women, women of lower socioeconomic status, women with intellectual disabilities, or younger women, and the committee agreed that peer support groups among women in similar circumstances might be particularly helpful.\n\nThe committee discussed that peer support, including group peer support, volunteer peer support, doula support and online support, is usually provided through 'third sector' services, and they agreed that healthcare professionals should give women information about how to contact local and national services. Although there was little evidence on partners' experiences of peer support, in the committee's experience, some partners find peer support services for partners helpful.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current best practice.\n\nReturn to recommendations\n\n# Sleep position\n\nRecommendations 1.3.24 and 1.3.25\n\n## Why the committee made the recommendations\n\nThe evidence suggested that there is an increased risk of stillbirth and babies being born small for gestational age after 28\xa0weeks if women fall asleep on their backs. The committee agreed that there is some uncertainty about this risk because the evidence was from relatively small studies whose design made it difficult to assume that sleep position caused the adverse outcomes. The committee recognised that further research is unlikely because conducting sufficiently powered prospective cohort studies is not feasible given the relatively low incidence of stillbirth (1\xa0in every 244\xa0births in England and Wales according to 2018 Office for National Statistics [ONS] data). The committee also noted that not all the included studies used the same definition of stillbirth and that only 1\xa0study reported data according to whether the stillbirth occurred at term or at preterm. On balance, the committee agreed that the evidence was strong enough to advise women to try to avoid going to sleep on their back after 28\xa0weeks.\n\nThe committee knew from their experience that providing practical advice about risk reduction is extremely important for pregnant women. They discussed reassuring women about sleep positions, aids that could make it easier for pregnant women not to go to sleep on their backs and maintain this position when sleeping, for example, by using pillows.\n\nThe committee also agreed that the reason for this advice should be explained, and they recognised the potential anxiety and feelings of guilt that women may experience, for example, if they wake up on their backs.\n\n## How the recommendations might affect practice\n\nHealthcare professionals may need to spend more time talking to women about sleep position in pregnancy, but the recommendations are not expected to have a significant cost or resource impact.\n\nReturn to recommendations\n\n# Nausea and vomiting\n\nRecommendations 1.4.1 to 1.4.7\n\n## Why the committee made the recommendations\n\nNausea and vomiting in pregnancy can affect daily functioning and quality of life, and can cause significant worry and upset. Based on their knowledge and experience, the committee agreed that it is important to reassure pregnant women who experience mild‑to‑moderate nausea and vomiting that these are common symptoms in early pregnancy and will usually settle later in the second trimester.\n\nHowever, the committee recognised that many pregnant women expect nausea and vomiting in pregnancy and might even tolerate significant symptoms and try various self-help approaches before seeking medical advice. It is therefore important to take it seriously when women do seek help.\n\nSome women prefer to use non-pharmacological treatments whereas others may prefer pharmacological treatments, so both options are recommended.\n\nThere was some evidence that ginger is effective in treating mild‑to‑moderate nausea and vomiting in pregnancy compared with placebo, and this may be an option particularly for women who want to try a non-pharmacological option.\n\nThere was evidence on a wide variety of pharmacological treatments, many of which are commonly used in current practice. The evidence on the medicines varied in quality and for some medicines, no evidence was found. Metoclopramide hydrochloride was supported by good quality evidence showing that it was effective in improving symptoms. Ondansetron was also found to be effective in improving symptoms. A combination drug with pyridoxine and doxylamine is currently the only drug licensed for this indication, but the evidence is very old and of low quality and did not show a convincing effect on symptom improvement. Evidence on histamine H1 receptor antagonists was of very low quality and not particularly convincing. Studies on pyridoxine hydrochloride showed differing results, with larger trials showing no improvement in symptoms. No evidence was identified on the effectiveness of cyclizine hydrochloride alone in pregnant women, so the committee made a research recommendation on the effectiveness of medication for women with nausea and vomiting in pregnancy.\n\nThe treatment options have different advantages and disadvantages, including effectiveness in relieving symptoms, safety and other considerations, which have been summarised in a table to help with decision making. The committee used information available from the British National Formulary (BNF), the UK Teratology Information Service monographs and patient information leaflets, and the manufacturers' summaries of product characteristics to inform women about the potential effects on the baby. The committee recognised that women are often concerned about the possible adverse effects of medicines on the baby and that these should be discussed in the context of understanding the small risk of adverse outcomes unrelated to medicine use.\n\nThe evidence for treating the more severe form of nausea and vomiting in pregnancy did not generally support any different treatment options from those used for mild and moderate nausea and vomiting in pregnancy. An exception was for acupressure combined with standard care where the evidence showed benefits in relieving symptoms in women with moderate‑to‑severe nausea and vomiting in pregnancy, which was not shown for women with mild and moderate nausea and vomiting. Therefore, the committee recommended that acupressure could be considered for women with moderate‑to‑severe nausea and vomiting as an additional treatment.\n\nNo recommendation was made on the use of corticosteroids as a treatment for severe nausea and vomiting in pregnant women because, despite research in this area, no evidence was found to support its use. The committee discussed that although corticosteroids have well-known harms, the benefits can outweigh them so that some units use corticosteroids in severe cases of nausea and vomiting in pregnancy, and so a research recommendation on the effectiveness of corticosteroids for women with severe nausea and vomiting in pregnancy was made.\n\nSome women with moderate‑to‑severe nausea and vomiting in pregnancy might need intravenous fluids. The evidence showed no difference in most outcomes between offering intravenous fluids in an inpatient or outpatient setting. Offering them to an outpatient is less expensive, reduces time spent in hospital and, in the committee's experience, is generally preferred by women. Inpatient care may be needed when severe nausea and vomiting persists despite treatment. Hyperemesis gravidarum can have serious harmful consequences, and treatment and care in hospital may be needed. It should be noted that this guideline only covers treatments to manage nausea and vomiting in pregnancy and comprehensive management of hyperemesis gravidarum, which may include nutritional interventions, is not covered by this guideline on routine antenatal care.\n\n## How the recommendations might affect practice\n\nThe treatment options are all used in current practice but there may be a change in practice in encouraging shared decision making for different options. This may mean that those prescribing medicines may need to spend more time discussing the options with the woman.\n\nAn increase in giving intravenous fluids as an outpatient service instead of an inpatient service could bring cost savings.\n\nReturn to recommendations\n\n# Heartburn\n\nRecommendations 1.4.8 and 1.4.9\n\n## Why the committee made the recommendations\n\nThere was no evidence on whether giving lifestyle and diet information to pregnant women with heartburn is effective, but the committee agreed, based on their own knowledge and experience, that it may help. This is supported by guidance for the general adult population in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia.\n\nThe committee recommended considering either antacid or alginate therapy for women with heartburn in pregnancy because there is evidence that they are equally effective. These medicines are available over the counter. Because the studies examined various antacid and alginate remedies, the committee agreed that they could not make a more specific recommendation.\n\nThe committee did not make any recommendations about acupuncture or proton pump inhibitors (PPIs) because, although there was some evidence that acupuncture is effective in alleviating heartburn and that PPI use in the first trimester is not harmful to the baby, it was of very low quality and not good enough to support recommending them to be used routinely. In addition, there was no evidence on H2\xa0receptor antagonist (H2RA) therapy to treat heartburn in pregnancy.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current clinical practice.\n\nReturn to recommendations\n\n# Symptomatic vaginal discharge\n\nRecommendations 1.4.10 to 1.4.14\n\n## Why the committee made the recommendations\n\nThere was limited evidence on the effectiveness of treatments for symptomatic vaginal discharge in pregnant women, so the committee used their knowledge and clinical experience to make the recommendations. The committee agreed that some women can find an increase in vaginal discharge distressing or uncomfortable, so it is important to reassure women that it is a normal feature of pregnancy. However, women should also be made aware of the symptoms and signs of infection that may need further action, because there is a small chance that some infections could lead to complications.\n\nCandidiasis (thrush) is often an easily identifiable cause of symptomatic vaginal discharge and may not need a formal investigation. However, if there is doubt about the cause, a vaginal swab could be used. It is important that possible sexually transmitted infections are appropriately investigated so that they can be treated, because they could have an impact on the baby.\n\nThe evidence on antifungal treatment to treat symptomatic vaginal discharge because of vaginal candidiasis was very limited, imidazole being the only drug class being studied. However, imidazole (for example, clotrimazole or econazole) was consistently shown to be effective.\n\nThe evidence on the benefits and harms of antibiotics to treat symptomatic vaginal discharge due to bacterial vaginosis was also very limited. There was only evidence on oral amoxicillin (which is not commonly prescribed in current practice for this indication) and oral metronidazole. The committee were aware of evidence among asymptomatic populations that antibiotics are effective in treating the underlying infection, but the committee agreed that it cannot be assumed that they would be effective in relieving symptomatic vaginal discharge. The committee noted that it is common practice to prescribe vaginal rather than oral antibiotics for this indication – in particular, clindamycin or metronidazole. Combining this with their knowledge and experience, they recommended that either oral or vaginal antibiotics could be considered. The NICE guideline on antimicrobial stewardship gives guidance on good practice in prescribing antimicrobials.\n\nNo evidence was identified on the effectiveness of metronidazole to treat symptomatic vaginal discharge because of vaginal trichomoniasis, therefore no recommendations were made.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations will reinforce current best practice and standardise care.\n\nReturn to recommendations\n\n# Pelvic girdle pain\n\nRecommendation 1 4.15\n\n## Why the committee made the recommendation\n\nThere was evidence of varying quality from several randomised controlled trials that exercise advice from a physiotherapist may reduce pain intensity and pelvic-related functional disability. The committee recommended referral to physiotherapy services rather than to a physiotherapist because, in some cases, information and advice could be given over the telephone or in an email or letter rather than in a face-to-face appointment.\n\nModerate quality evidence from 1 randomised controlled trial showed that a non-rigid lumbopelvic belt together with general information about anatomy, body posture and ergonomic advice reduced pelvic girdle pain intensity, compared with exercise advice and information, and information only. However, it did not have an impact on functional status in daily activities. No evidence was identified about adverse effects of using a lumbopelvic belt. Providing a non-rigid lumbopelvic belt was also found to be cost effective based on an economic evaluation, but because the clinical evidence base was limited, the committee agreed not to make a strong recommendation.\n\nThe committee agreed that there was not enough evidence to show that manual therapy alone had any benefits for women with pelvic girdle pain, so did not make a recommendation. The committee agreed that the evidence for acupuncture to treat pelvic girdle pain was mixed, of poor quality and therefore not adequate enough to justify a recommendation that would have a substantial resource impact.\n\n## How the recommendation might affect practice\n\nCurrent practice for pregnancy-related pelvic girdle pain is to offer analgesics (for example, paracetamol) and provide information about lifestyle and health changes. Some hospitals also have access to physiotherapy services. Providing a lumbopelvic belt is not current practice in all units, so the committee recognised that the recommendation may have cost implications. However, health economic modelling showed that it is cost effective even if women are referred for physiotherapy. The recommendation may increase the number of pregnant women seeking referral to physiotherapy services.\n\nReturn to recommendation\n\n# Unexplained vaginal bleeding after 13\xa0weeks\n\nRecommendations 1.4.16 to 1.4.21\n\n## Why the committee made the recommendations\n\nThere was very little evidence, so the committee used their knowledge and experience to make recommendations. They took into account the risks associated with a delay in assessing and treating unexplained vaginal bleeding in pregnancy, the possibility that anti‑D injections may be needed for women who are rhesus\xa0D‑negative, the need to exclude a low-lying placenta (placenta praevia) and that corticosteroids may be needed if there is a risk of preterm birth.\n\nThe committee agreed that a review in secondary care is needed when unexplained vaginal bleeding occurs after 13\xa0weeks of pregnancy. Evidence on the effectiveness of hospitalisation was limited, with only 1\xa0retrospective study that showed no difference in the number of fetal deaths whether women were admitted to hospital or discharged on the day they presented. Because of limited evidence, the committee made a research recommendation on the effectiveness of hospitalisation compared with outpatient management for pregnant women with unexplained vaginal bleeding.\n\nThe committee agreed that hospitalisation should be considered for monitoring, administering corticosteroids and neonatal unit care if the baby is born preterm. Discussion with the woman about the possibility of preterm birth may also be helpful.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nReturn to recommendations", 'Context': 'Around 660,000 women give birth in England and Wales each year. The antenatal period is an excellent opportunity to not only provide support and information to women (and their families) about pregnancy, birth and the postnatal period, but also to assess their risk of complications. Even in fit and healthy women, concerns and complications can still arise, and good quality antenatal care is vital to identify and deal with potential problems and reduce the chance of poor outcomes for both the woman and the baby.\n\nAntenatal service delivery and provision of care have changed over time and this guideline updates and replaces the version of the NICE guideline on antenatal care (first published in\xa02008).\n\nThis guideline covers routine antenatal care for all women. However, it does not cover specialised care for women with underlying medical conditions or obstetric complications (once diagnosed) but refers to other NICE guidelines.\n\nThis guideline covers the organisation and delivery of antenatal care, in particular, how to initially access antenatal care and antenatal appointments, and the involvement of partners in antenatal care. Routine care and monitoring during pregnancy is covered and the guideline makes references to other guidance on risk assessment and screening. This guideline also covers providing information and support during antenatal care, and managing some of the common problems during pregnancy.\n\nThroughout the development of this guideline, the committee has considered how antenatal care could be made accessible, fair and high quality for all women, regardless of their background or situation.'}
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https://www.nice.org.uk/guidance/ng201
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This guideline covers the routine antenatal care that women and their babies should receive. It aims to ensure that pregnant women are offered regular check‑ups, information and support. We have also published a guideline on postnatal care, which covers the topics of emotional attachment and baby feeding.
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8f0a4f3241d331693b5ca122f74f5fd4f53c5a36
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nice
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Chlormethine gel for treating mycosis fungoides-type cutaneous T-cell lymphoma
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Chlormethine gel for treating mycosis fungoides-type cutaneous T-cell lymphoma
Evidence-based recommendations on chlormethine gel (Ledaga) for treating early-stage mycosis fungoides-type cutaneous T-cell lymphoma in adults.
# Recommendations
Chlormethine gel is recommended as an option for treating early stage (stage 1A, 1B, and 2A) mycosis fungoides-type cutaneous T‑cell lymphoma (MF‑CTCL) in adults, only if the company provides chlormethine gel according to the commercial arrangement.
This recommendation is not intended to affect treatment with chlormethine gel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Most treatments for early stage MF‑CTCL aim to relieve the skin symptoms. Options depend on the extent of the skin affected, but include treatments applied to the skin, such as topical steroids, phototherapy (light therapy) and radiotherapy. Systemic treatment that targets the whole body, such as oral bexarotene, can also be used to relieve skin symptoms if those treatments do not work, no longer work, or become unsuitable.
Clinical evidence shows that chlormethine gel improves skin disease. It may particularly benefit people who have skin disease over a limited area of the body or for whom whole body phototherapy is unsuitable. However, there is no robust evidence for its effectiveness compared with other treatments or showing if it is more effective for people with limited skin disease.
Some things are still uncertain, including the true effectiveness of phototherapy, which was used as a comparator in the model, and the average amount of chlormethine gel used per day.
But the cost-effectiveness estimates for chlormethine gel in early stage disease, using the preferred assumptions and the company's updated patient access scheme, are within the range NICE considers cost effective. Therefore, chlormethine gel is recommended in early stage disease.# Information about chlormethine gel
# Marketing authorisation indication
Chlormethine gel (Ledaga, Recordati Rare Diseases and Helsinn Healthcare) is indicated for 'the topical treatment of mycosis fungoides-type cutaneous T‑cell lymphoma (MF‑type CTCL) in adult patients'.
# Dosing in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for chlormethine gel is £1,000 per 60 g tube (excluding VAT; BNF online accessed 17 July 2020).
The company has a commercial arrangement. This makes chlormethine gel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Recordati Rare Diseases and Helsinn Healthcare, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
Phototherapy (PUVA and UVB bundled) is an appropriate comparator for chlormethine gel in the model.
The company's estimate for phototherapy administration costs is acceptable for use in the model. Costs were derived from the mean of dermatology and oncology costs for consultant-led outpatient clinic cost of phototherapy and photochemotherapy (sourced from NHS reference costs 2017/18). The company and the ERG agreed that the PROCLIPI registry is an appropriate source of evidence to derive the distributions of PUVA and UVB phototherapy for the model.
The Kim 2003 study is an acceptable data source to estimate time to progression to systemic treatment after a complete skin symptom response on chlormethine gel in the model. Study 201 is the current best available evidence for estimating complete and partial response rates in the chlormethine gel arm of the model. The company agreed with the ERG to use Phan et al. (2019) as the data source for complete and partial response rates in the phototherapy arm of the model.
# Clinical need
## There is a clinical need for chlormethine gel as an alternative treatment option for people with MF-CTCL, particularly in people with low skin burden
The patient expert explained in their written statement that mycosis fungoides-type cutaneous T‑cell lymphoma (MF‑CTCL) negatively affects many aspects of life including employment, leisure activities, relationships and day-to-day living. Symptoms include itching, pain and fever, can be distressing, and are associated with fatigue, anxiety and depression. There is often a delay in being diagnosed with MF‑CTCL, and people may already have tried several treatments to relieve their skin symptoms before their eventual diagnosis. Consultation responses noted that there is no gold standard treatment and that initial treatment depends on various factors including burden or stage of skin disease, availability of therapy, clinician speciality, location, personal experience, and personal preference. The effects of existing skin-directed treatments, including phototherapy and sometimes radiotherapy, are not long lasting and people often cycle between treatments. This means that people must travel for repeated hospital appointments and their quality of life may be affected. A new option which could be used at home would be welcomed. People with early disease (which consists of patches or plaques on the skin but no disease elsewhere in the body) have a particular unmet need because existing skin-directed treatments are limited, and systemic treatments are onerous and associated with side effects. Clinical experts noted that they may be offered topical steroids or emollients, but these only relieve the symptoms of itchiness and redness and do not reduce the patches or plaques. The only options for treating the patches are localised radiotherapy, which is not ideal for younger people, and phototherapy. There is a particular disadvantage of phototherapy for people with limited skin disease (disease covering less than 10% of the skin surface), because the whole skin is exposed to the UV radiation, which carries a long-term risk of inducing skin cancer. These people would prefer an effective topical treatment applied only to the disease area. The committee also recognised the need for an alternative treatment option that may be more convenient and could be particularly useful during the COVID‑19 pandemic. It concluded that chlormethine gel would be particularly useful for people who have limited skin disease who want to avoid whole body phototherapy, or people for whom phototherapy is not effective or who have exceeded the maximum safe UV exposure for phototherapy. It could also be helpful for those who find it difficult to attend hospital for courses of phototherapy.
# Treatment pathway
## Chlormethine gel relieves skin symptoms but is not a cure
Clinical experts explained that, in practice, the impact of chlormethine gel would be assessed after the first 4 to 6 months. Treatment would stop if the skin disease resolved because there would be no remaining patches to treat. For people with a partial response, treatment would be expected to stop after a year, although if there was clear benefit it might be continued for longer. People could have further courses of treatment with chlormethine gel, or move onto other skin-directed treatments, such as phototherapy, if the chlormethine gel was not effective or the skin disease recurred. Clinical experts also explained that, like the other skin-directed treatments available for MF‑CTCL, chlormethine gel is not a cure, and does not affect the spread of the disease to other organs in the body or mortality from the disease. However, if the skin disease cannot be controlled, people are offered systemic therapy even if the disease has not spread to other areas, so effective skin-directed therapies are important because systemic treatments are expensive and toxic. If another skin-directed therapy were available, it could keep the skin disease under control for longer, which could improve people's quality of life. The clinical experts explained that there was a previous similar version of this treatment in the form of a nitrogen mustard ointment. The committee understood that people had benefited from treatment with nitrogen mustard, and that up until recently it was still being used in parts of the UK. Therefore, clinicians have experience with using similar topical treatments. The clinical experts explained that, although it is uncommon for skin symptoms to completely resolve, therapies can relieve skin symptoms and improve people's quality of life. The committee concluded that chlormethine gel is not a disease-modifying treatment, but it relieves skin symptoms and improves quality of life.
## People with early stage MF-CTCL have multiple treatments
Clinical experts explained that skin-directed therapy decisions for MF‑CTCL are based on the extent of the skin involvement, not just the overall stage of disease. As noted in section 3.1, people with early stage disease and a low skin burden (less than 10%; typically stage 1A but other stages may also have a low skin burden) have a particular unmet need because of the disadvantages of whole body phototherapy when the extent of the disease is limited. Clinical experts explained that some people with stage 1B disease may have a skin burden greater than 10% but it still may be relatively limited (around 15% to 17%) so topical treatments may be preferable to whole body treatments. People with early stage disease and more extensive skin burden (a proportion of patients with stage 1B or 2A may also have a high skin burden) are usually offered topical treatments, phototherapy or localised radiotherapy. The clinical experts also explained that people with early stage MF‑CTCL, whose disease is confined to the skin, cycle through available treatments with periods of active monitoring (watch and wait) between therapies, with the sequence depending on the response in skin symptoms. Because individual treatments are typically not long lasting, multiple courses of treatment are usually necessary, although the number of courses of phototherapy is limited by the cumulative UV dose. It is therefore likely that repeated courses of chlormethine gel would be offered, and in practice phototherapy could be followed by chlormethine gel or vice versa. If the skin disease becomes refractory to skin-directed treatments, or the maximum safe UV exposure has been reached, or if the condition progresses to an advanced stage, then systemic therapies such as oral bexarotene and peginterferon alfa are offered. The committee concluded that treatment in clinical practice depends on the level of skin burden and the extent of the underlying disease. But, in practice, people with early MF‑CTCL have multiple treatments in different sequences until symptoms no longer respond or the disease spreads beyond the skin.
# Clinical evidence
## The main trial shows chlormethine gel improves the skin symptoms of early stage MF-CTCL but compares it with a treatment that is no longer used
The main trial, Study 201, was a non-inferiority trial (a trial showing that a new treatment is not substantially worse than another treatment) comparing chlormethine gel with chlormethine ointment in 260 people with early stage MF‑CTCL (stage 1A to 2A). People with advanced stage disease were not included in the trial. Skin symptom response rate was scored on the Composite Assessment of Index Lesion Severity (CAILS) and the modified Severity Weighted Assessment Tool (mSWAT). The overall response rate for chlormethine gel was 58.5% using CAILS and 46.9% using mSWAT. Using CAILS, 13.8% of people had a complete response in skin symptoms and 44.6% of people had a partial response in skin symptoms. The complete and partial response rates measured using mSWAT are confidential and cannot be reported. The committee understood that Study 201 shows that chlormethine gel improves the skin symptoms of early stage MF‑CTCL. However, because the comparator ointment is no longer used in clinical practice, the committee concluded that Study 201 does not show how effective chlormethine gel is compared with current alternative treatments.
## The clinical effectiveness of chlormethine gel compared with phototherapy is not known
The company compared phototherapy with chlormethine gel in its submission. However, there was no evidence directly comparing chlormethine gel with phototherapy, and no connected network for an indirect comparison could be formed. Therefore, the company did an unadjusted naive comparison. However, most of the studies available to provide estimates of phototherapy's effectiveness are of low quality and there was considerable debate about the most appropriate source to use. The company initially used overall response rates from the weighted average estimates of 7 phototherapy studies. But it then used results from a systematic review on the clinical effectiveness of phototherapies (Phan et al. 2019) identified by the ERG in its base case after technical engagement. The response rates in the 7 studies identified by the company and in the systematic review were higher for phototherapy than the response rates for chlormethine gel in Study 201. Complete skin symptom response was also higher for phototherapy than partial skin symptom response (73.2% and 20.8% respectively, as reported in the 7 phototherapy studies), but the reverse was the case for chlormethine gel (13.8% and 44.6% respectively, using CAILS). The clinical experts said that the reason the response rates in Study 201 appeared lower than the phototherapy trials is that Study 201 used clear criteria for assessing response (CAILS and mSWAT), whereas most of the phototherapy trials were based on less reliable assessments by clinicians. Responses to consultation noted that the early studies of chlormethine in ointment form, which are all retrospective studies, had response rates comparable to those from the phototherapy studies. They suggested that the lower response rates in Study 201 may be because many patients (39%) in the trial had already had phototherapy. The committee understood that most studies included in Phan et al. (2019) were retrospective and at risk of bias. It also noted the ERG's concern that there was substantial heterogeneity across the included studies, including differences in how complete and partial response in skin symptoms were defined and measured. The committee concluded that the true clinical effectiveness of chlormethine gel compared with phototherapy is not known, given the high uncertainty associated with the unadjusted naive comparison.
# Cost effectiveness
## Clinical practice is better represented in the company's revised model
The company updated its model substantially in response to the first consultation, and then again after the second consultation, to better reflect the treatment pathway for people with MF‑CTCL in clinical practice. After the first consultation, the company introduced a skin-directed therapy state for people whose symptoms were refractory to chlormethine gel or for people whose skin symptoms relapse after responding to treatment. The ERG considered that when people whose condition is refractory to chlormethine gel go to the skin-directed therapy state but people whose condition is refractory to phototherapy go straight to systemic therapy, chlormethine gel has an unfair advantage. In response to the second consultation, the company amended its base case model to reflect the ERG and the committee's preferred assumptions. These were that people with disease refractory to chlormethine gel or phototherapy move to systemic treatment but those in the chlormethine arm have 1 course of phototherapy first. The company noted however that, although it had incorporated the committee's preferences into its base case, it did not agree that this better reflects clinical practice. The company considered it an oversimplification because it does not allow for more than 1 course of phototherapy and does not capture the range of responses to phototherapy. The clinical experts consulted by the company had noted that the number of courses of phototherapy may differ depending on the type of phototherapy and duration of response to initial courses of treatment. The company also did not agree with the ERG that delaying transition to the systemic therapy state for people whose condition was refractory to chlormethine gel gave an unfair advantage to chlormethine gel. However, it acknowledged that the health state utility in the skin-directed therapy state might differ for relapsed compared with refractory disease and so presented several scenarios with different utilities. The committee concluded that the company's revised model better reflected clinical practice and incorporated the committee's preferred assumptions.
## Models based on skin burden are preferred but the company's updated models for stage 1A and early stage disease are suitable for decision making
At the second meeting, the committee noted that the company's model, which included early and late-stage disease, resulted in uncertainty in costs. This was because of the variability in costs within the model, with people who have different levels of skin disease using different amounts of gel, and because people at different skin stages may start costly subsequent systemic treatments at different times. The committee had concluded that the company's model did not reflect who may benefit the most from chlormethine gel (people with a low skin burden, see section 3.1). In response to the second appraisal consultation, the company changed its approach, and excluded people with advanced disease (stage 2B and later). Instead, it presented 2 models: one for stage 1A disease and another for early stage disease (stages 1A, 1B, and 2A). The company explained that it was unable to model by skin burden alone because of the way the previous model was developed. The ERG agreed that the company's model was difficult to amend to represent low skin burden because of its structure and the difficulty in populating the required transition probabilities. The ERG noted that a decision based on disease stage is the most robust, given the model structure. The committee considered that a model based on skin burden would be more appropriate but concluded that the company's models based on disease stage were suitable for decision making.
## Phototherapy's effectiveness may be overestimated in the model
The committee noted that the high levels of uncertainty about the true clinical effectiveness of phototherapy (see section 3.5) made the benefits of chlormethine gel compared with phototherapy in the model uncertain. However, the committee concluded at the second meeting that, while it did not consider that any data source was robust, it preferred the ERG's approach of using one data source for all outcome measures because it ensured the same consistent source of data for response rates and duration, reducing potential bias. The company preferred Whittaker et al. (2012), which reports lower response rates than Phan et al. (2019) and is a controlled, prospective study that used an objective scoring system. The ERG was concerned about the quality of all sources of data for the effectiveness of phototherapy. It was particularly concerned about the company's use of Whittaker et al. (2012) because it had a small sample size and excluded people with stage 1A disease. The ERG preferred to use Phan et al. (2019), despite its limitations (see section 3.5), because of the availability of data for all outcome measures and because it separates outcomes by type of phototherapy and stage of disease. The company considered that the estimates from Phan et al. (2019) overestimate the effectiveness of phototherapy, resulting in a 'worst case' for chlormethine gel. But, in response to consultation, it used Phan et al. (2019) in its base case for complete response, partial response, progressed disease and duration response, as preferred by the committee and the ERG. The committee acknowledged the uncertainty around capturing the effectiveness of phototherapy in the model, given the poor data available. It concluded that the true clinical effectiveness of phototherapy was not known and that the parameters used in the model could mean that the model may have overestimated the effectiveness of phototherapy.
## The mean daily dose of chlormethine gel is uncertain
The clinical experts explained that the amount of gel used depends on skin burden, not disease stage. The committee noted that the population included in the trial had mixed skin burdens, which made it difficult to accurately estimate gel usage. Dose estimates from the clinical experts, the company model, and the ERG were all different. The ERG used a mean daily dose of 2.8 g in the original model. It sourced this information from the summary of product characteristics for Valchlor (the US brand name of chlormethine gel) from Study 201. The company used a lower mean daily dose in its original model, which was taken from individual patient data based on the number of returned empty tubes per follow-up visit from Study 201. The clinical experts estimated that people with limited disease need at least 6 tubes a year (1 every 2 months) because of the shelf-life of the product. But they said it was not uncommon for people to use 1 tube every month with a mean daily dose of approximately 1 g, up to 2 g. They added that usage was difficult to predict and relates to the body surface area affected. However, it was unlikely that people with more extensive skin burden (needing more than 2 tubes a month) would want to take the time to put this on their whole body. They may use it for exposed areas like the hands and face, which could have a big impact on their quality of life. In the company's revised models, the company used the ERG's estimate of 2.8 g but noted that it was likely to be a substantial overestimate of gel used. The committee concluded that the average daily dose of chlormethine gel, and therefore the costs, were uncertain but preferred the ERG's estimate of 2.8 g.
## The committee would have preferred utility values derived from patient-reported outcomes
The company generated utility values from a de novo vignette study and used EQ‑5D‑5L responses from clinicians, mapped to EQ‑5D‑3L and valued using the UK general population time-trade off tariffs. The committee understood that chlormethine gel does not aim to cure, but to relieve the skin symptoms of people and improve quality of life. The committee considered patient-reported outcomes to be important in assessing quality-of-life benefits. The committee concluded that it would have preferred patient-reported outcomes to responses from clinicians to be used for deriving health state utility values.
## The early stage disease model is most appropriate to decision making
The company's stage 1A model represents a population with low skin burden but excludes a proportion of people who have stage 2A disease with low skin burden. The company's early stage model represents both low and high skin burden. The ERG noted that, while the early stage model applies to people with both low and high skin burden, the combined state of stage 1B/2A assumes that all have high skin burden. The company considered the early stage model to be conservative because it includes people with a higher skin burden who would use more gel and therefore have higher costs. The ERG noted that, because the differential treatment effect of low compared with high skin burden is unknown, it is not clear if the early stage model is conservative. The company explained that it preferred the early stage model over the stage 1A model because it includes people with low skin burden in stages other than stage 1A and because skin burden is not the only factor influencing disease stage. The ERG noted that there was no evidence to suggest that the results from the stage 1A model could be applied to low skin burden in other stages. Clinical experts noted that there are difficulties with accurately staging disease, particularly in differentiating between stage 1A and stage 1B. The committee noted that the evidence base for this disease was poor and that splitting the data down into substages within early stage disease increases the uncertainty in the modelling. The committee also considered the difficulties in differentiating between stages and the difficulty there would be in implementing a recommendation only for stage 1A. It concluded that the early stage disease model was most appropriate for decision-making.
# Cost-effectiveness estimates and conclusion
## Chlormethine gel is cost effective for early stage MF-CTCL and therefore recommended
There are updated patient access schemes for chlormethine gel (agreed in response to the second consultation) and a patient access scheme for the subsequent treatment, bexarotene. Therefore, all costs and incremental cost-effectiveness ratios (ICERs) are confidential and cannot be presented. The cost-effectiveness estimates for early stage disease are uncertain but below what NICE normally considers an acceptable use of NHS resources. The committee was aware of the uncertainty associated with the effectiveness estimates of phototherapy and dosage used. However, it agreed that the most plausible ICER is unlikely to be above what NICE normally considers an acceptable use of NHS resources. It therefore recommended chlormethine gel as an option for treating adults with early stage (stage 1A, 1B, and 2A) MF‑CTCL.
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{'Recommendations': "Chlormethine gel is recommended as an option for treating early stage (stage 1A, 1B, and 2A) mycosis fungoides-type cutaneous T‑cell lymphoma (MF‑CTCL) in adults, only if the company provides chlormethine gel according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with chlormethine gel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nMost treatments for early stage MF‑CTCL aim to relieve the skin symptoms. Options depend on the extent of the skin affected, but include treatments applied to the skin, such as topical steroids, phototherapy (light therapy) and radiotherapy. Systemic treatment that targets the whole body, such as oral bexarotene, can also be used to relieve skin symptoms if those treatments do not work, no longer work, or become unsuitable.\n\nClinical evidence shows that chlormethine gel improves skin disease. It may particularly benefit people who have skin disease over a limited area of the body or for whom whole body phototherapy is unsuitable. However, there is no robust evidence for its effectiveness compared with other treatments or showing if it is more effective for people with limited skin disease.\n\nSome things are still uncertain, including the true effectiveness of phototherapy, which was used as a comparator in the model, and the average amount of chlormethine gel used per day.\n\nBut the cost-effectiveness estimates for chlormethine gel in early stage disease, using the preferred assumptions and the company's updated patient access scheme, are within the range NICE considers cost effective. Therefore, chlormethine gel is recommended in early stage disease.", 'Information about chlormethine gel': "# Marketing authorisation indication\n\nChlormethine gel (Ledaga, Recordati Rare Diseases and Helsinn Healthcare) is indicated for 'the topical treatment of mycosis fungoides-type cutaneous T‑cell lymphoma (MF‑type CTCL) in adult patients'.\n\n# Dosing in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for chlormethine gel is £1,000 per 60\xa0g tube (excluding VAT; BNF online accessed 17\xa0July\xa02020).\n\nThe company has a commercial arrangement. This makes chlormethine gel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Recordati Rare Diseases and Helsinn Healthcare, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nPhototherapy (PUVA [psoralens and UVA] and UVB bundled) is an appropriate comparator for chlormethine gel in the model.\n\nThe company's estimate for phototherapy administration costs is acceptable for use in the model. Costs were derived from the mean of dermatology and oncology costs for consultant-led outpatient clinic cost of phototherapy and photochemotherapy (sourced from NHS reference costs 2017/18). The company and the ERG agreed that the PROCLIPI registry is an appropriate source of evidence to derive the distributions of PUVA and UVB phototherapy for the model.\n\nThe Kim 2003 study is an acceptable data source to estimate time to progression to systemic treatment after a complete skin symptom response on chlormethine gel in the model. Study\xa0201 is the current best available evidence for estimating complete and partial response rates in the chlormethine gel arm of the model. The company agreed with the ERG to use Phan et al. (2019) as the data source for complete and partial response rates in the phototherapy arm of the model.\n\n# Clinical need\n\n## There is a clinical need for chlormethine gel as an alternative treatment option for people with MF-CTCL, particularly in people with low skin burden\n\nThe patient expert explained in their written statement that mycosis fungoides-type cutaneous T‑cell lymphoma (MF‑CTCL) negatively affects many aspects of life including employment, leisure activities, relationships and day-to-day living. Symptoms include itching, pain and fever, can be distressing, and are associated with fatigue, anxiety and depression. There is often a delay in being diagnosed with MF‑CTCL, and people may already have tried several treatments to relieve their skin symptoms before their eventual diagnosis. Consultation responses noted that there is no gold standard treatment and that initial treatment depends on various factors including burden or stage of skin disease, availability of therapy, clinician speciality, location, personal experience, and personal preference. The effects of existing skin-directed treatments, including phototherapy and sometimes radiotherapy, are not long lasting and people often cycle between treatments. This means that people must travel for repeated hospital appointments and their quality of life may be affected. A new option which could be used at home would be welcomed. People with early disease (which consists of patches or plaques on the skin but no disease elsewhere in the body) have a particular unmet need because existing skin-directed treatments are limited, and systemic treatments are onerous and associated with side effects. Clinical experts noted that they may be offered topical steroids or emollients, but these only relieve the symptoms of itchiness and redness and do not reduce the patches or plaques. The only options for treating the patches are localised radiotherapy, which is not ideal for younger people, and phototherapy. There is a particular disadvantage of phototherapy for people with limited skin disease (disease covering less than 10% of the skin surface), because the whole skin is exposed to the UV radiation, which carries a long-term risk of inducing skin cancer. These people would prefer an effective topical treatment applied only to the disease area. The committee also recognised the need for an alternative treatment option that may be more convenient and could be particularly useful during the COVID‑19 pandemic. It concluded that chlormethine gel would be particularly useful for people who have limited skin disease who want to avoid whole body phototherapy, or people for whom phototherapy is not effective or who have exceeded the maximum safe UV exposure for phototherapy. It could also be helpful for those who find it difficult to attend hospital for courses of phototherapy.\n\n# Treatment pathway\n\n## Chlormethine gel relieves skin symptoms but is not a cure\n\nClinical experts explained that, in practice, the impact of chlormethine gel would be assessed after the first 4 to 6\xa0months. Treatment would stop if the skin disease resolved because there would be no remaining patches to treat. For people with a partial response, treatment would be expected to stop after a year, although if there was clear benefit it might be continued for longer. People could have further courses of treatment with chlormethine gel, or move onto other skin-directed treatments, such as phototherapy, if the chlormethine gel was not effective or the skin disease recurred. Clinical experts also explained that, like the other skin-directed treatments available for MF‑CTCL, chlormethine gel is not a cure, and does not affect the spread of the disease to other organs in the body or mortality from the disease. However, if the skin disease cannot be controlled, people are offered systemic therapy even if the disease has not spread to other areas, so effective skin-directed therapies are important because systemic treatments are expensive and toxic. If another skin-directed therapy were available, it could keep the skin disease under control for longer, which could improve people's quality of life. The clinical experts explained that there was a previous similar version of this treatment in the form of a nitrogen mustard ointment. The committee understood that people had benefited from treatment with nitrogen mustard, and that up until recently it was still being used in parts of the UK. Therefore, clinicians have experience with using similar topical treatments. The clinical experts explained that, although it is uncommon for skin symptoms to completely resolve, therapies can relieve skin symptoms and improve people's quality of life. The committee concluded that chlormethine gel is not a disease-modifying treatment, but it relieves skin symptoms and improves quality of life.\n\n## People with early stage MF-CTCL have multiple treatments\n\nClinical experts explained that skin-directed therapy decisions for MF‑CTCL are based on the extent of the skin involvement, not just the overall stage of disease. As noted in section 3.1, people with early stage disease and a low skin burden (less than 10%; typically stage\xa01A but other stages may also have a low skin burden) have a particular unmet need because of the disadvantages of whole body phototherapy when the extent of the disease is limited. Clinical experts explained that some people with stage 1B disease may have a skin burden greater than 10% but it still may be relatively limited (around 15% to 17%) so topical treatments may be preferable to whole body treatments. People with early stage disease and more extensive skin burden (a proportion of patients with stage\xa01B or 2A may also have a high skin burden) are usually offered topical treatments, phototherapy or localised radiotherapy. The clinical experts also explained that people with early stage MF‑CTCL, whose disease is confined to the skin, cycle through available treatments with periods of active monitoring (watch and wait) between therapies, with the sequence depending on the response in skin symptoms. Because individual treatments are typically not long lasting, multiple courses of treatment are usually necessary, although the number of courses of phototherapy is limited by the cumulative UV dose. It is therefore likely that repeated courses of chlormethine gel would be offered, and in practice phototherapy could be followed by chlormethine gel or vice versa. If the skin disease becomes refractory to skin-directed treatments, or the maximum safe UV exposure has been reached, or if the condition progresses to an advanced stage, then systemic therapies such as oral bexarotene and peginterferon alfa are offered. The committee concluded that treatment in clinical practice depends on the level of skin burden and the extent of the underlying disease. But, in practice, people with early MF‑CTCL have multiple treatments in different sequences until symptoms no longer respond or the disease spreads beyond the skin.\n\n# Clinical evidence\n\n## The main trial shows chlormethine gel improves the skin symptoms of early stage MF-CTCL but compares it with a treatment that is no longer used\n\nThe main trial, Study\xa0201, was a non-inferiority trial (a trial showing that a new treatment is not substantially worse than another treatment) comparing chlormethine gel with chlormethine ointment in 260\xa0people with early stage MF‑CTCL (stage\xa01A to 2A). People with advanced stage disease were not included in the trial. Skin symptom response rate was scored on the Composite Assessment of Index Lesion Severity (CAILS) and the modified Severity Weighted Assessment Tool (mSWAT). The overall response rate for chlormethine gel was 58.5% using CAILS and 46.9% using mSWAT. Using CAILS, 13.8% of people had a complete response in skin symptoms and 44.6% of people had a partial response in skin symptoms. The complete and partial response rates measured using mSWAT are confidential and cannot be reported. The committee understood that Study\xa0201 shows that chlormethine gel improves the skin symptoms of early stage MF‑CTCL. However, because the comparator ointment is no longer used in clinical practice, the committee concluded that Study\xa0201 does not show how effective chlormethine gel is compared with current alternative treatments.\n\n## The clinical effectiveness of chlormethine gel compared with phototherapy is not known\n\nThe company compared phototherapy with chlormethine gel in its submission. However, there was no evidence directly comparing chlormethine gel with phototherapy, and no connected network for an indirect comparison could be formed. Therefore, the company did an unadjusted naive comparison. However, most of the studies available to provide estimates of phototherapy's effectiveness are of low quality and there was considerable debate about the most appropriate source to use. The company initially used overall response rates from the weighted average estimates of 7\xa0phototherapy studies. But it then used results from a systematic review on the clinical effectiveness of phototherapies (Phan et al. 2019) identified by the ERG in its base case after technical engagement. The response rates in the 7\xa0studies identified by the company and in the systematic review were higher for phototherapy than the response rates for chlormethine gel in Study\xa0201. Complete skin symptom response was also higher for phototherapy than partial skin symptom response (73.2% and 20.8% respectively, as reported in the 7\xa0phototherapy studies), but the reverse was the case for chlormethine gel (13.8% and 44.6% respectively, using CAILS). The clinical experts said that the reason the response rates in Study\xa0201 appeared lower than the phototherapy trials is that Study\xa0201 used clear criteria for assessing response (CAILS and mSWAT), whereas most of the phototherapy trials were based on less reliable assessments by clinicians. Responses to consultation noted that the early studies of chlormethine in ointment form, which are all retrospective studies, had response rates comparable to those from the phototherapy studies. They suggested that the lower response rates in Study\xa0201 may be because many patients (39%) in the trial had already had phototherapy. The committee understood that most studies included in Phan et al. (2019) were retrospective and at risk of bias. It also noted the ERG's concern that there was substantial heterogeneity across the included studies, including differences in how complete and partial response in skin symptoms were defined and measured. The committee concluded that the true clinical effectiveness of chlormethine gel compared with phototherapy is not known, given the high uncertainty associated with the unadjusted naive comparison.\n\n# Cost effectiveness\n\n## Clinical practice is better represented in the company's revised model\n\nThe company updated its model substantially in response to the first consultation, and then again after the second consultation, to better reflect the treatment pathway for people with MF‑CTCL in clinical practice. After the first consultation, the company introduced a skin-directed therapy state for people whose symptoms were refractory to chlormethine gel or for people whose skin symptoms relapse after responding to treatment. The ERG considered that when people whose condition is refractory to chlormethine gel go to the skin-directed therapy state but people whose condition is refractory to phototherapy go straight to systemic therapy, chlormethine gel has an unfair advantage. In response to the second consultation, the company amended its base case model to reflect the ERG and the committee's preferred assumptions. These were that people with disease refractory to chlormethine gel or phototherapy move to systemic treatment but those in the chlormethine arm have 1\xa0course of phototherapy first. The company noted however that, although it had incorporated the committee's preferences into its base case, it did not agree that this better reflects clinical practice. The company considered it an oversimplification because it does not allow for more than 1\xa0course of phototherapy and does not capture the range of responses to phototherapy. The clinical experts consulted by the company had noted that the number of courses of phototherapy may differ depending on the type of phototherapy and duration of response to initial courses of treatment. The company also did not agree with the ERG that delaying transition to the systemic therapy state for people whose condition was refractory to chlormethine gel gave an unfair advantage to chlormethine gel. However, it acknowledged that the health state utility in the skin-directed therapy state might differ for relapsed compared with refractory disease and so presented several scenarios with different utilities. The committee concluded that the company's revised model better reflected clinical practice and incorporated the committee's preferred assumptions.\n\n## Models based on skin burden are preferred but the company's updated models for stage 1A and early stage disease are suitable for decision making\n\nAt the second meeting, the committee noted that the company's model, which included early and late-stage disease, resulted in uncertainty in costs. This was because of the variability in costs within the model, with people who have different levels of skin disease using different amounts of gel, and because people at different skin stages may start costly subsequent systemic treatments at different times. The committee had concluded that the company's model did not reflect who may benefit the most from chlormethine gel (people with a low skin burden, see section 3.1). In response to the second appraisal consultation, the company changed its approach, and excluded people with advanced disease (stage 2B and later). Instead, it presented 2\xa0models: one for stage 1A disease and another for early stage disease (stages 1A, 1B, and 2A). The company explained that it was unable to model by skin burden alone because of the way the previous model was developed. The ERG agreed that the company's model was difficult to amend to represent low skin burden because of its structure and the difficulty in populating the required transition probabilities. The ERG noted that a decision based on disease stage is the most robust, given the model structure. The committee considered that a model based on skin burden would be more appropriate but concluded that the company's models based on disease stage were suitable for decision making.\n\n## Phototherapy's effectiveness may be overestimated in the model\n\nThe committee noted that the high levels of uncertainty about the true clinical effectiveness of phototherapy (see section 3.5) made the benefits of chlormethine gel compared with phototherapy in the model uncertain. However, the committee concluded at the second meeting that, while it did not consider that any data source was robust, it preferred the ERG's approach of using one data source for all outcome measures because it ensured the same consistent source of data for response rates and duration, reducing potential bias. The company preferred Whittaker et al. (2012), which reports lower response rates than Phan et al. (2019) and is a controlled, prospective study that used an objective scoring system. The ERG was concerned about the quality of all sources of data for the effectiveness of phototherapy. It was particularly concerned about the company's use of Whittaker et al. (2012) because it had a small sample size and excluded people with stage\xa01A disease. The ERG preferred to use Phan et al. (2019), despite its limitations (see section 3.5), because of the availability of data for all outcome measures and because it separates outcomes by type of phototherapy and stage of disease. The company considered that the estimates from Phan et al. (2019) overestimate the effectiveness of phototherapy, resulting in a 'worst case' for chlormethine gel. But, in response to consultation, it used Phan et al. (2019) in its base case for complete response, partial response, progressed disease and duration response, as preferred by the committee and the ERG. The committee acknowledged the uncertainty around capturing the effectiveness of phototherapy in the model, given the poor data available. It concluded that the true clinical effectiveness of phototherapy was not known and that the parameters used in the model could mean that the model may have overestimated the effectiveness of phototherapy.\n\n## The mean daily dose of chlormethine gel is uncertain\n\nThe clinical experts explained that the amount of gel used depends on skin burden, not disease stage. The committee noted that the population included in the trial had mixed skin burdens, which made it difficult to accurately estimate gel usage. Dose estimates from the clinical experts, the company model, and the ERG were all different. The ERG used a mean daily dose of 2.8\xa0g in the original model. It sourced this information from the summary of product characteristics for Valchlor (the US brand name of chlormethine gel) from Study\xa0201. The company used a lower mean daily dose in its original model, which was taken from individual patient data based on the number of returned empty tubes per follow-up visit from Study\xa0201. The clinical experts estimated that people with limited disease need at least 6\xa0tubes a year (1 every 2\xa0months) because of the shelf-life of the product. But they said it was not uncommon for people to use 1\xa0tube every month with a mean daily dose of approximately 1\xa0g, up to 2\xa0g. They added that usage was difficult to predict and relates to the body surface area affected. However, it was unlikely that people with more extensive skin burden (needing more than 2\xa0tubes a month) would want to take the time to put this on their whole body. They may use it for exposed areas like the hands and face, which could have a big impact on their quality of life. In the company's revised models, the company used the ERG's estimate of 2.8\xa0g but noted that it was likely to be a substantial overestimate of gel used. The committee concluded that the average daily dose of chlormethine gel, and therefore the costs, were uncertain but preferred the ERG's estimate of 2.8\xa0g.\n\n## The committee would have preferred utility values derived from patient-reported outcomes\n\nThe company generated utility values from a de novo vignette study and used EQ‑5D‑5L responses from clinicians, mapped to EQ‑5D‑3L and valued using the UK general population time-trade off tariffs. The committee understood that chlormethine gel does not aim to cure, but to relieve the skin symptoms of people and improve quality of life. The committee considered patient-reported outcomes to be important in assessing quality-of-life benefits. The committee concluded that it would have preferred patient-reported outcomes to responses from clinicians to be used for deriving health state utility values.\n\n## The early stage disease model is most appropriate to decision making\n\nThe company's stage 1A model represents a population with low skin burden but excludes a proportion of people who have stage 2A disease with low skin burden. The company's early stage model represents both low and high skin burden. The ERG noted that, while the early stage model applies to people with both low and high skin burden, the combined state of stage 1B/2A assumes that all have high skin burden. The company considered the early stage model to be conservative because it includes people with a higher skin burden who would use more gel and therefore have higher costs. The ERG noted that, because the differential treatment effect of low compared with high skin burden is unknown, it is not clear if the early stage model is conservative. The company explained that it preferred the early stage model over the stage 1A model because it includes people with low skin burden in stages other than stage 1A and because skin burden is not the only factor influencing disease stage. The ERG noted that there was no evidence to suggest that the results from the stage 1A model could be applied to low skin burden in other stages. Clinical experts noted that there are difficulties with accurately staging disease, particularly in differentiating between stage 1A and stage 1B. The committee noted that the evidence base for this disease was poor and that splitting the data down into substages within early stage disease increases the uncertainty in the modelling. The committee also considered the difficulties in differentiating between stages and the difficulty there would be in implementing a recommendation only for stage\xa01A. It concluded that the early stage disease model was most appropriate for decision-making.\n\n# Cost-effectiveness estimates and conclusion\n\n## Chlormethine gel is cost effective for early stage MF-CTCL and therefore recommended\n\nThere are updated patient access schemes for chlormethine gel (agreed in response to the second consultation) and a patient access scheme for the subsequent treatment, bexarotene. Therefore, all costs and incremental cost-effectiveness ratios (ICERs) are confidential and cannot be presented. The cost-effectiveness estimates for early stage disease are uncertain but below what NICE normally considers an acceptable use of NHS resources. The committee was aware of the uncertainty associated with the effectiveness estimates of phototherapy and dosage used. However, it agreed that the most plausible ICER is unlikely to be above what NICE normally considers an acceptable use of NHS resources. It therefore recommended chlormethine gel as an option for treating adults with early stage (stage 1A, 1B, and 2A) MF‑CTCL."}
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https://www.nice.org.uk/guidance/ta720
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Evidence-based recommendations on chlormethine gel (Ledaga) for treating early-stage mycosis fungoides-type cutaneous T-cell lymphoma in adults.
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4475a34d3b17bab3c34b0b45f0db0b3d5291a10e
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nice
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Abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer
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Abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer
Evidence-based recommendations on abiraterone (Zytiga) for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer in adults.
# Recommendations
Abiraterone with prednisone or prednisolone plus androgen deprivation therapy (ADT) is not recommended, within its marketing authorisation, for treating newly diagnosed high-risk hormone‑sensitive metastatic prostate cancer in adults.
This recommendation is not intended to affect treatment with abiraterone with prednisone or prednisolone plus ADT that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer in the NHS in England includes ADT alone, docetaxel plus ADT and, as of July 2021, enzalutamide plus ADT.
Clinical trial results show that, compared with ADT alone, a combination of abiraterone plus ADT and either prednisone or prednisolone increases the time until the disease progresses and how long people live. Results also show that, compared with docetaxel plus ADT, abiraterone plus ADT increases the time until the disease progresses, but not how long people live. Docetaxel plus ADT cannot be used by or is unsuitable for some people but there is no clinical evidence for abiraterone plus ADT compared with ADT alone for this group.
There is a proposed commercial arrangement that would make abiraterone available to the NHS at a discount. Even accounting for this, the cost-effectiveness estimates of either abiraterone in combination compared with ADT alone or with docetaxel plus ADT for the whole population are higher than what NICE considers cost effective. There are no appropriate cost-effectiveness estimates for when docetaxel cannot be used or is unsuitable. Therefore, abiraterone is not recommended for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer.# Information about abiraterone
# Marketing authorisation
Abiraterone (Zytiga; Janssen) with prednisone or prednisolone has a UK marketing authorisation for treating 'newly diagnosed high-risk metastatic hormone-sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT)'. In LATITUDE, a key trial in this appraisal, high-risk prognosis was defined as having at least 2 of the following 3 risk factors: a Gleason score of 8 or more; 3 or more lesions on bone scan; and measurable visceral metastasis (excluding lymph node disease).
# Dosage in the marketing authorisation
The dosage is available in the summary of product characteristics.
# Price
The cost of abiraterone is £2,735 for a pack of 56 x 500 mg tablets (excluding VAT; BNF online, accessed June 2021). The company has a commercial arrangement that makes abiraterone available to the NHS with a confidential discount when it is used later in the disease pathway for treating hormone-relapsed metastatic prostate cancer before chemotherapy is indicated, or for hormone-relapsed metastatic prostate cancer previously treated with a docetaxel-containing regimen. Had abiraterone been recommended, it would have been available to the NHS with a discount for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer.# Committee discussion
The appraisal committee considered evidence submitted by Janssen and a review of this submission by the evidence review group (ERG). It also considered the decision of the appeal panel. See the committee papers for full details of the evidence.
This appraisal consultation document reflects discussions had during the fifth committee meeting after 4 committee meetings and an appeal. The first public consultation on this topic occurred after the first committee meeting in May 2018. NICE suspended the appraisal to allow price negotiations between the company and NHS England after the second meeting in July 2018. The third meeting was held in January 2020 without an agreement having been reached. Then, after further negotiations in which the company and NHS England did not reach an agreement, NICE issued a final appraisal determination in June 2020. An appeal followed in September 2020. NICE's guidance executive decided, on the basis of the appeal panel's decision, that the appraisal committee should address any upheld appeal points. It also decided to allow some of the appellants (the British Uro-oncology Group (BUG), Prostate Cancer UK and Tackle Prostate Cancer) to submit data because they considered they had not been given the opportunity to do so for previous committee meetings. To address the appeal points, a fourth committee meeting was held in December 2020, after which there was a further public consultation and fifth committee meeting.
# Clinical management
## Androgen deprivation therapy with or without docetaxel are the first-line treatment options for hormone-sensitive metastatic prostate cancer
The clinical experts explained in the first committee meeting in May 2018 that, in clinical practice, people with newly diagnosed hormone-sensitive metastatic prostate cancer have androgen deprivation therapy (ADT) alone or docetaxel plus ADT plus the oral corticosteroid prednisolone (from now on, 'docetaxel in combination'). NICE's guideline on prostate cancer recommends ADT in the form of continuous luteinising hormone-releasing hormone agonists, bilateral orchidectomy (removal of the testicles) or bicalutamide with ADT. The guideline also recommends docetaxel. Docetaxel is now licensed for hormone-sensitive metastatic prostate cancer, and NHS England commissions it for up to 6 cycles at this point in the treatment pathway. Docetaxel is administered intravenously with oral prednisolone 5 mg twice daily for 3 weeks. The clinical experts explained that orchidectomy and bicalutamide are rarely used in the NHS. The committee was aware that NICE's technology appraisal guidance on enzalutamide plus ADT for treating hormone-sensitive metastatic prostate cancer and apalutamide plus ADT for hormone-sensitive metastatic prostate cancer started during this appraisal, and enzalutamide plus ADT was recommended. Because the final guidance for enzalutamide plus ADT was not published by the time of the fifth committee meeting, it did not become a comparator in this appraisal. The committee agreed that ADT includes luteinising hormone-releasing hormone agonists. It concluded that ADT alone and docetaxel in combination were appropriate comparators to abiraterone plus ADT plus 5 mg of the oral corticosteroid prednisone (from now on, 'abiraterone in combination').
## It may be appropriate to consider the comparator for abiraterone in combination separately when docetaxel is contraindicated or unsuitable
The committee recognised its obligation to appraise technologies across their marketing authorisations. This meant that, if abiraterone in combination was not cost effective across its marketing authorisation, the committee could consider a narrower population if there was a case for this. Although the company's original submission was for the full population covered in the marketing authorisation, it noted at the time that there was a group of people for whom docetaxel was clinically unsuitable or who chose not to have docetaxel. The company proposed abiraterone in combination as an alternative treatment to ADT alone for this group, which it termed 'chemotherapy ineligible' in its submission for the third committee meeting. The Cancer Drugs Fund's clinical lead noted in the third meeting that, at that time (January 2020), up to two-thirds of people presenting with hormone-sensitive metastatic prostate cancer in England had ADT alone. The committee noted that this included both people for whom docetaxel is contraindicated or unsuitable (the terminology agreed by the company, experts and committee in the fourth meeting) and people who choose not to have docetaxel. A patient expert explained that there is an unmet need for an alternative treatment option to ADT alone for this group. The committee recognised that most people who choose to have ADT alone rather than docetaxel in combination may wish to avoid the adverse events associated with docetaxel. The committee considered that this unmet need was in part addressed by NICE recommending enzalutamide plus ADT at this point in the pathway, which occurred during the course of this appraisal. The committee agreed that patient choice was important but that, for people who could have docetaxel, the comparators should be docetaxel in combination and ADT alone. If clinically and cost effective, abiraterone would be recommended as an option for the populations who can and cannot have docetaxel (from now, referred to as the 'whole population'). The committee agreed that it would be appropriate to define a group of people for whom docetaxel is unsuitable. It also agreed that the clinical and cost effectiveness of abiraterone in combination in this group should be considered if it was not cost effective for the whole population.
## Identifying who cannot or should not have docetaxel involves assessing a person's risks and may include people who cannot take abiraterone
In its fourth meeting, the committee set out to understand more clearly how experts define people for whom docetaxel is contraindicated or unsuitable. The clinical and patient experts had previously explained that, although there are contraindications for docetaxel, defining the group for whom it is unsuitable is complicated. The committee had been aware that NHS England's clinical commissioning policy statement for docetaxel in combination with ADT indicates that someone may not be fit enough for docetaxel if they have a poor overall performance status (World Health Organization performance 3 to 4), pre-existing peripheral neuropathy, poor bone marrow function or a life-limiting illness. The policy also states that docetaxel should be used with caution in people with a WHO performance status of 2 and that there are few absolute contraindications for docetaxel therapy. The Cancer Drugs Fund's clinical lead explained that many factors besides a person's performance status may affect whether they could have docetaxel. One of these is patient choice after hearing the risks and benefits of each available treatment. In the fourth meeting, the clinical experts explained that, while creating an exhaustive list of criteria for this group is unfeasible, developing a framework would be possible. The clinical lead for the Cancer Drugs Fund explained that a clinician assesses whether docetaxel is suitable for someone based on contraindications, fitness, comorbidities and preference. An oncologist would identify and discuss with a patient the individual risks and benefits associated with any treatment option before starting treatment. People for whom docetaxel is contraindicated or unsuitable would include:
people who have contraindications to docetaxel as listed in the summary of product characteristics for docetaxel and NHS England's clinical commissioning policy statement for docetaxel in combination with ADT
people with poor performance status (WHO or Eastern Cooperative Oncology Group performance status 3 or 4, and possibly status 2 because docetaxel is used with caution in this group), which is a measure of fitness
people with significant comorbidity (for example, cardiovascular, respiratory or liver disease) such that prostate cancer is not likely to be the only life-limiting illness
people with peripheral sensory neuropathy or poor bone marrow function
people with poor cognition or social support leading to a decreased ability to understand treatment options or make a decision.Prescribing clinicians should assess the individual risks and potential benefits of having docetaxel. This should include the advantages and disadvantages of all treatment options, including fewer later treatments for people who would choose to start with abiraterone (see section 3.4). The clinical experts explained that some people who would not be fit enough for treatment with docetaxel would also not be fit enough for abiraterone, and would be offered ADT alone. It concluded that identifying people in whom docetaxel was contraindicated or unsuitable would be based on a clinical framework considering individual patient risk, and may include people who cannot take abiraterone.
## The first treatment for hormone-sensitive prostate cancer affects the type and number of later treatments for hormone-refractory disease
The clinical experts explained that people who have docetaxel as first-line treatment in the hormone-sensitive setting can have docetaxel again for up to an additional 10 cycles in the hormone-relapsed setting. This is because the benefit of docetaxel is not exhausted when used for only 6 cycles. The Cancer Drugs Fund's clinical lead explained that abiraterone and enzalutamide are commissioned by NHS England only once in the treatment pathway. This is because there is no evidence of substantial clinical benefit for enzalutamide after abiraterone or for abiraterone after enzalutamide. The committee understood that people who have abiraterone in combination for hormone-sensitive prostate cancer have fewer options for active follow-on treatments (when the disease becomes hormone refractory) than people who start with ADT alone, or docetaxel in combination. This is because people who started with abiraterone cannot have abiraterone or enzalutamide later in the treatment pathway. The committee noted that the sequence of follow-on treatments when disease becomes hormone refractory may vary from person to person, but that ADT would be continued alongside subsequent therapies. It considered that possible follow-on treatments include:
after ADT alone:
abiraterone or enzalutamide (before or after docetaxel)
docetaxel (unless docetaxel is contraindicated or unsuitable)
-ther active treatments such as cabazitaxel or radium 223
after docetaxel in combination:
abiraterone or enzalutamide (before or after docetaxel)
docetaxel again
-ther active treatments such as cabazitaxel or radium 223
after abiraterone in combination:
docetaxel (unless docetaxel is contraindicated or unsuitable)
-ther active treatments such as cabazitaxel or radium 223.The committee concluded that the first-choice treatment for hormone-sensitive metastatic prostate cancer affects the follow-on treatments a person may have. It also concluded that having abiraterone in combination at this position in the pathway limits the options for follow-on treatments for people who develop hormone-relapsed disease compared with people who have had ADT alone or docetaxel in combination.
# Clinical evidence
## LATITUDE and STAMPEDE are both relevant for assessing the clinical effectiveness of abiraterone in combination in the whole population
Two randomised controlled trials have investigated the clinical effectiveness of abiraterone in combination in hormone-sensitive metastatic disease:
LATITUDE was a multinational double-blind trial including 1,199 people with newly diagnosed high‑risk hormone-sensitive metastatic prostate cancer. High-risk was defined as at least 2 of a Gleason score of 8 or more (that is, cancer which is aggressive or likely to spread); 3 or more lesions on a bone scan; or visceral metastasis (excluding lymph nodes). People were randomised to either abiraterone plus ADT plus a corticosteroid (5 mg prednisone once daily) or ADT alone. The co-primary endpoint of the trial was progression‑free and overall survival.
STAMPEDE was a UK multi-arm non-blinded adaptive trial that included some people with newly diagnosed hormone-sensitive metastatic, node-positive or high-risk localised disease (with at least 2 of: a tumour stage of 3 or 4; a Gleason score of 8 to 10, and prostate-specific antigen levels of 40 ng/ml or more); or prostate cancer previously treated with radical surgery or radiotherapy and now relapsing with high-risk features. Randomised trial arms included, but were not limited to, abiraterone plus ADT plus a corticosteroid (5 mg prednisolone once daily), ADT alone, and docetaxel plus ADT plus a corticosteroid (10 mg prednisolone once daily). The primary endpoint was overall survival. Data were available for 502 people with metastatic prostate cancer in the ADT alone arm, 500 in the abiraterone-in-combination arm and 115 in the docetaxel in combination arm. A comparison between abiraterone in combination and ADT alone was prespecified in the trial protocol. A comparison between abiraterone and docetaxel was done post hoc with 115 people in the docetaxel in combination arm and 227 people in the abiraterone-in-combination arm.The company considered that LATITUDE evaluated the clinical effectiveness of abiraterone in combination in the population in the marketing authorisation. STAMPEDE included people with locally advanced disease and metastatic disease and provided analyses for metastatic prostate cancer for both relevant comparators: ADT alone and docetaxel in combination. During the course of the appraisal, the STAMPEDE investigators published 2 analyses aligned to the licensed population (that is, the subgroup of people with high-risk metastatic disease). These were for abiraterone in combination compared with ADT alone (Hoyle et al. 2018) and docetaxel in combination compared with ADT alone (Clarke et al. 2019). The committee concluded that both LATITUDE and STAMPEDE were relevant for assessing the clinical effectiveness for abiraterone in combination in the whole population for whom it is licensed.
## To compare abiraterone in combination with docetaxel in combination, estimates from STAMPEDE are preferred
To compare abiraterone in combination with docetaxel in combination, the company was concerned that results from the subgroup of people with metastatic disease in STAMPEDE did not reflect the population included in the licence for abiraterone for the proposed indication (see section 3.5). The company further stated that STAMPEDE was not statistically powered to detect a difference in survival in this post-hoc analysis. The company instead developed a network meta-analysis which, as well as including the direct data from STAMPEDE, included several other trials. The company argued that additional trials contributed information to the estimated treatment effect of abiraterone compared with docetaxel. The trials included in the network were:
abiraterone in combination compared with docetaxel in combination: data from the STAMPEDE broad metastatic subgroup
abiraterone in combination compared with ADT alone: data from LATITUDE (licensed population) and STAMPEDE (subgroup matching the licensed population)
docetaxel in combination compared with ADT alone: data from STAMPEDE (subgroup matching the licensed population), CHAARTED and GETUG‑AFU 15 (subgroups with 'high-volume' disease, which the company considered similar to the licensed population).The committee noted that the company had not requested data from STAMPEDE directly comparing abiraterone in combination with docetaxel in combination for the subgroup matching the licensed population. It considered that the trials in the network may have differed in ways that could have influenced the effect estimate. The committee acknowledged that both direct and indirect evidence contributes to the total body of evidence. However, given the difference in results between the direct and indirect comparisons (see section 3.8), it concluded that the results from the direct comparison, being randomised, were less likely to be biased.
## Abiraterone in combination extends survival compared with ADT alone in the whole population
Abiraterone in combination improved both progression-free and overall survival compared with ADT alone in LATITUDE and in people with high-risk metastatic disease in STAMPEDE. The size of the relative improvement for abiraterone plus ADT compared with ADT alone was similar in the 2 trials. In LATITUDE, median progression-free survival was 14.8 months with ADT alone and 33.0 months with abiraterone in combination (hazard ratio 0.47, 95% confidence interval 0.39 to 0.55). Based on the planned final analysis of overall survival, the median overall survival with ADT alone was 36.5 months compared with 53.3 months with abiraterone in combination (HR 0.66, 95% CI 0.56 to 0.78). In STAMPEDE, at a median follow up of 3.3 years, the HR for progression-free survival in the high-risk metastatic subgroup was 0.46 (95% CI 0.36 to 0.59), and for overall survival was 0.54 (95% CI 0.41 to 0.70). Data from STAMPEDE shared after the appeal showed that the HR for overall survival was maintained after 8 years of follow up (HR 0.54, 95% CI 0.43 to 0.69). The committee noted that the survival benefit reported in LATITUDE was larger than that seen in clinical trials using abiraterone in hormone-relapsed disease, in which median overall survival was extended by 4.4 months compared with ADT alone. However, it acknowledged that its remit was to appraise abiraterone in the proposed indication and not to identify the best order and sequence of treatments. The committee concluded that abiraterone in combination improved both progression-free and overall survival compared with ADT alone. However, it noted that there was uncertainty about the magnitude of the long-term survival gain with abiraterone in combination. This was because of potential differences in the proportion of people who had life-extending treatments after disease progression on ADT in LATITUDE and STAMPEDE compared with clinical practice (see section 3.9).
## Compared with docetaxel in combination, abiraterone in combination may improve progression-free survival, but not overall survival
In people with metastatic disease in STAMPEDE, abiraterone in combination improved progression-free survival compared with docetaxel in combination (HR 0.69, 95% CI 0.50 to 0.95). However, for overall survival, the HR favoured docetaxel (HR 1.13, 95% CI 0.77 to 1.66). In the company's updated base case, rather than use the results reflecting a direct comparison from STAMPEDE, it used the results of the indirect network meta-analysis that included data from LATITUDE, CHAARTED, GETUG‑AFU 15 and STAMPEDE. This showed similar results to the direct comparison for progression-free survival. However, the point estimate for overall survival favoured abiraterone, but the credible interval included 1, that is, the possibility of no difference in benefit of 1 treatment over the other. The company considered these values to be academic in confidence so they cannot be reported here. Considering the direct and indirect comparisons, the committee concluded that abiraterone in combination improves progression-free survival, but not overall survival compared with docetaxel in combination.
## Neither STAMPEDE nor LATITUDE likely capture all the overall survival benefit of follow-on treatments used in current NHS clinical practice
The committee recognised that life-extending treatments offered when the disease is no longer hormone sensitive (that is, is hormone relapsed) affects life-expectancy. Follow-on treatments in the unblinded UK STAMPEDE trial were expected to reflect what people would have in NHS clinical practice, for example, not getting abiraterone twice. This was because the choice of next treatment depended on knowing the first treatment. In STAMPEDE, people were aware of their treatment but, in the blinded LATITUDE trial, people were not. The committee noted that the trials differed from UK clinical practice in 2 ways:
In LATITUDE, after abiraterone, 10% of the intention-to-treat (ITT) population had enzalutamide, and 5% had abiraterone again. In STAMPEDE 3% of the ITT population had enzalutamide after abiraterone, and 1% had abiraterone again.
After ADT alone, fewer people in both STAMPEDE and in LATITUDE had follow-on treatment for hormone-relapsed disease with abiraterone or enzalutamide than would occur in NHS clinical practice. Of people who had treatments for hormone-relapsed disease, 40% had enzalutamide or abiraterone in LATITUDE, and 55% had enzalutamide or abiraterone in STAMPEDE. This was lower than the 80% modelled by the company, which was based on an estimate of UK market shares for these treatments (see section 3.18).The committee concluded that differences between the subsequent treatments used in STAMPEDE and current UK market shares are likely to be related to abiraterone and enzalutamide becoming increasingly available over time. It recognised that the trials may have overestimated the relative clinical effectiveness of abiraterone if fewer people in the ADT arms of the trials had benefitted from follow-on treatments for hormone-relapsed prostate cancer than do in NHS clinical practice. The committee concluded that the estimates of survival from STAMPEDE were likely more relevant to clinical practice in the NHS than those from LATITUDE because they better reflected the options available on the NHS after a patient needed a next treatment.
## No data are available on the effectiveness of abiraterone compared with ADT in people for whom docetaxel is contraindicated or unsuitable
No evidence was presented for abiraterone's relative effectiveness compared with ADT alone, specifically for the group for whom docetaxel is contraindicated or unsuitable. LATITUDE and STAMPEDE, the key clinical trials of abiraterone in this indication (see section 3.5), only included people with adequate haematological function, and an ECOG or WHO performance status of 0, 1 or 2 (meaning they were reasonably fit). Also, they could not have any condition that would interfere with them taking part in the trial. As part of the initial protocol, all people recruited to STAMPEDE had to be able to have docetaxel because it was 1 of the arms in the trial. A clinical expert explained that, in 2013, that arm closed but the trial continued to recruit to the ADT alone and abiraterone-in-combination arms (among others). This meant people recruited to the trial from this point could have included people for whom docetaxel was contraindicated or unsuitable. They noted that James et al. (2017) presented an analysis showing that the HR for overall survival for abiraterone in combination compared with ADT was 0.69 (95% CI 0.53 to 0.90) between November 2011 and January 2013. This was when the docetaxel arm of the trial was open. After the docetaxel arm closed, the HR for data collected between April 2013 and January 2014 was 0.59 (95% CI 0.44 to 0.78). The ERG highlighted, and the committee agreed, that this did not provide the evidence specifically for the group for whom docetaxel was contraindicated or unsuitable. This was because the 2013 to 2014 data would also have included people who could have docetaxel. The committee heard during its fourth meeting that STAMPEDE enrolled people who could take abiraterone but could not have docetaxel. However, in response to the consultation after the committee's fourth meeting, the company and consultees commented that data specific to this subgroup could not be separated from the metastatic, high-risk cohort in STAMPEDE. This was because the trial did not collect data on all the baseline characteristics specified in the suggested clinical framework describing people who cannot or should not have docetaxel (see section 3.3). The committee was aware that many of these characteristics were similar to the STAMPEDE exclusion criteria. It noted that stakeholders had explored several further data sources for people who are 'chemotherapy ineligible' but identified none that would resolve the uncertainty about clinical and cost effectiveness in this population. The company agreed that it was reasonable for the committee to request data specific to people who cannot or should not have docetaxel. However, the company did not consider it ethical to conduct a new clinical trial specifically in this group because trials have already shown that abiraterone is superior to ADT alone in the whole population. Acknowledging the uncertainties in the existing data, the company preferred to use the treatment effect from the whole population to represent the group for whom docetaxel is contraindicated or unsuitable. The committee concluded that assessing data specific to the relevant population was preferred, but acknowledged that this evidence was not available. It therefore considered the treatment effect from the LATITUDE whole population for people who cannot or should not have docetaxel in its decision making, while acknowledging this uncertainty.
## Abiraterone in combination may be less effective in people who are unlikely to be able to have docetaxel, but data are limited and uncertain
No data were presented specifically for the group of people who cannot have docetaxel (see section 3.10). So, the committee discussed the uncertainties associated with applying the treatment effect of abiraterone in combination for the whole trial population to people who cannot or should not have docetaxel. It did this by looking at the treatment effect in people whose baseline characteristics meant they were unlikely to be able to have docetaxel. It was aware that older people (see section 3.23) and people with poorer levels of performance status would be less likely to have docetaxel. It noted the available evidence from LATITUDE and STAMPEDE on subgroups based on age and performance status. For the comparison of abiraterone in combination with ADT alone from STAMPEDE, the committee noted effect modification by age. For overall survival, abiraterone was not as effective in people 70 years and over (HR 0.94, 95% CI 0.69 to 1.29) compared with people under 70 years (HR 0.51, 95% CI 0.40 to 0.65; test for interaction p value 0.003) (James et al. 2017). The company argued that these results were not representative of the population covered by the licence for the proposed indication. This was because they included people with non-metastatic prostate cancer, who are generally younger and have earlier stage disease. The committee noted a similar pattern in LATITUDE, in which the HR for overall survival for abiraterone in combination compared with ADT alone was: 0.65 (95% CI 0.50 to 0.84) for people under 65 years; 0.68 (95% CI 0.55 to 0.83) for people 65 years and over and 0.86 (95% CI 0·62 to 1·21) for people 75 years and over (Fizazi et al. 2019). In response to the second consultation, the company stated that the test for interaction based on age was non-significant, suggesting that it was possible that age had no effect on treatment response. However, it also acknowledged in the fifth committee meeting that the test may be underpowered to detect a difference. The committee also noted a HR of 0.64 (95% CI 0.50 to 0.75) in people with an ECOG status of 0 or 1, and a HR of 1.42 (95% CI 0.65 to 3.08) for those with an ECOG status of 2 in LATITUDE (Fizazi et al. 2019). It recognised that age alone would not determine whether a person could have docetaxel, but that age was associated with decreased docetaxel use based on data provided by BUG. It also heard that people with a poor performance status may not get abiraterone. The committee agreed that abiraterone appears less effective among people with characteristics shared by people who cannot or should not have docetaxel based on subgroup data. However, it noted that subgroup data should be interpreted with caution when based on data from a small group of people (40 out of 1,159 people in LATITUDE had a performance status of 2). The committee recalled that the subgroups did not specifically reflect the population for whom docetaxel is contraindicated or unsuitable. Overall, the committee concluded it was not possible to determine the size of the effectiveness for people for whom docetaxel is contraindicated or unsuitable. It therefore chose to look at its preferred effect measures from existing data (the treatment effect seen in the whole LATITUDE population; see section 3.10), acknowledging the uncertainty.
## The baseline risks from which to estimate the absolute effectiveness of abiraterone in people who cannot have docetaxel are not presented
Both the relative benefits of treatment with abiraterone compared with ADT alone, and the baseline risks of progression and dying, may differ between populations who can and cannot have docetaxel. The committee recognised that many of the risk factors for not having docetaxel (for example, age and poor performance status) are also risk factors for dying. It concluded that any modelling should take this into account (see section 3.15).
## Overall survival estimates from LATITUDE include follow-on treatments not used in people who cannot or should not have docetaxel
The company considered that the results of LATITUDE could be generalised to people who cannot or should not have docetaxel in its modelling (see section 3.15). The clinical experts explained that, with some exceptions, people with hormone-sensitive disease for whom docetaxel is contraindicated or unsuitable would not have docetaxel after their cancer progressed to being hormone relapsed. People in LATITUDE and STAMPEDE could go on to have docetaxel after abiraterone in combination or ADT alone. This did not reflect the treatment pathway for people who cannot have docetaxel, and yet was reflected in the trial results. The evidence of clinical effectiveness from LATITUDE does not reflect the treatment pathway for people for whom docetaxel is contraindicated or unsuitable. The committee therefore again agreed that it had not been presented with data on the effectiveness of abiraterone in combination compared with ADT in people for whom docetaxel is contraindicated or unsuitable. It concluded that estimates of overall survival from LATITUDE included the effect of taking docetaxel when indicated for hormone-relapsed metastatic disease, which would not apply to people who cannot or should not have docetaxel.
# Company's economic model
## A partitioned survival model is appropriate
The company provided 2 models. In its original submission, it provided a multistate Markov model. The committee deemed that this did not provide plausible estimates of post-progression or overall survival and did not generate valid estimates of cost effectiveness. In its submission for the third committee meeting, the company provided a partitioned survival model. Both models were split into 2 phases:
A hormone-sensitive phase, in which the company used LATITUDE to model probabilities of progressing and dying while on abiraterone in combination or ADT alone: For abiraterone in combination compared with docetaxel in combination, the company applied HRs from its revised network meta-analysis (including STAMPEDE) to data from LATITUDE.
A hormone-relapsed phase: In the Markov model, the company based the time spent in the hormone-relapsed phase on the survival curves from NICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before docetaxel is indicated. However, this approach did not produce valid estimates of overall survival for docetaxel. For example, modelled overall survival was much longer with abiraterone in combination than with docetaxel in combination, even when using the hazard ratio for overall survival that suggested a survival benefit for docetaxel (1.13 from the STAMPEDE direct comparison). The partitioned survival model extrapolated progression-free and overall survival from LATITUDE, with the time spent in the hormone-relapsed phase being the difference between these 2 survival curves.The committee concluded in its third and fourth meetings that, because the company's Markov model did not give plausible estimates of post-progression and overall survival, it would consider the company's partitioned survival model.
## There is no modelling reflecting the treatment pathway, costs and benefits for people for whom docetaxel is contraindicated or unsuitable
For the third committee discussion, the company provided estimates of the cost effectiveness of abiraterone in combination compared with ADT alone for a population it referred to as 'chemotherapy ineligible' (see section 3.2). The committee noted that the company based these estimates on data for the whole population. The committee recognised that the clinical data used in the model may not be generalisable to the 'chemotherapy ineligible' group. It also recognised that the modelled treatment pathway did not reflect the treatments people would have for whom docetaxel is contraindicated or unsuitable. Specifically:
It is uncertain whether abiraterone is as effective for people for whom docetaxel is contraindicated or unsuitable as it is for people able to have docetaxel (see section 3.11).
People in the modelled abiraterone-in-combination arm or the ADT arm went on to have docetaxel once their prostate cancer was hormone relapsed (see section 3.13).
People for whom docetaxel is contraindicated or unsuitable compared with people who can have docetaxel may:
have differing rates of adverse effects that would influence health-related quality of life
have a higher baseline risk of dying
have a different risk of dying over time.The committee concluded that the company had not provided it with modelling that reflected the treatment pathway, costs, survival and quality of life for people for whom docetaxel is contraindicated or unsuitable.
## In the full population, Weibull and log-logistic distributions are plausible for extrapolating progression-free and overall survival respectively
The committee agreed with the company that the hazards of progression and death for abiraterone in combination compared with ADT alone from LATITUDE were not proportional. It concluded that it was appropriate to fit curves to each arm separately. During the committee's third meeting, the company presented results for both progression-free and overall survival. It used the log-logistic distribution for each modelled treatment arm (which the company considered plausible but optimistic) and the Weibull distribution (which it considered plausible but pessimistic). The committee considered that the Weibull curves were plausible for progression-free survival. It noted that results from STAMPEDE for abiraterone in combination compared with ADT (submitted by BUG after the appeal for the fourth meeting) represented an 8‑year follow up. These suggested an ongoing benefit with abiraterone in combination compared with ADT alone (HR 0.54, 95% CI 0.43 to 0.69). The results supported using the log-logistic distribution to extrapolate overall survival from LATITUDE. At the third meeting, the ERG highlighted that a consequence of the model was that the company assumed the treatment effect to be maintained over the long term. However, in clinical practice, it may wane and the ERG provided scenarios to adjust for this at that time. The committee noted that the longer-term data from STAMPEDE could be used to determine the validity of these adjustments. It concluded that the progression-free survival extrapolation using the Weibull distribution was broadly appropriate for the overall population. However, it did not see evidence of extrapolating outcomes in people for whom docetaxel is contraindicated or unsuitable. The committee recognised that these people, being on average older, may have a different pattern of mortality. It further concluded that the predicted overall survival based on extrapolations using the log-logistic distribution was plausible for the overall trial population. The committee would have preferred to see further extrapolations exploring alternative time points for equalising the hazard using 2 plausible curves: 1 for the whole population, and another for people for whom docetaxel is contraindicated or unsuitable.
# Utility values in the model
## The utility estimates should be taken from the same source as the data on effectiveness
The company considered separately the effects on quality of life of adverse effects and of being on treatment. The sources of these data are in table 1.
Treatment
Quality of life relating to treatment
Quality of life relating to adverse events
Androgen deprivation therapy (ADT) alone
Based on EQ‑5D data from LATITUDE
Published utility values for adverse effects and skeletal-related events
Abiraterone plus ADT plus 5 mg of the oral corticosteroid prednisone
Based on EQ‑5D data from LATITUDE: the company modelled a further utility increase for being on abiraterone compared with androgen deprivation therapy alone
Published utility values for adverse effects and skeletal-related events
Docetaxel plus ADT plus the oral corticosteroid prednisolone
Based on a preference study commissioned by the company: the company modelled a further utility decrement for being on docetaxel
Published utility values for adverse effects and skeletal-related events
The company used different approaches to estimate the effect on quality of life of having abiraterone in combination or ADT alone than it did to estimate the effect with docetaxel in combination. It sourced utility values for being on abiraterone in combination from EQ‑5D results from LATITUDE, and for being on docetaxel in combination from a separate preference study of the general public that it had carried out. The NICE methods guide states that EQ‑5D is the preferred measure of health-related quality of life. The committee noted that STAMPEDE collected EQ‑5D data for a UK population randomised to abiraterone in combination, to docetaxel in combination and to ADT alone. In response to the first consultation and in the third committee meeting, the company confirmed that it did not request or have access to these data. The ERG carried out a scenario using the disutility estimate for docetaxel from the economic evaluation of docetaxel in combination in NICE's guideline for prostate cancer. The ERG derived the disutility value from EQ‑5D data collected in STAMPEDE (whole population and metastatic subgroup). The company stated that the ERG's and company's scenarios were consistent, irrespective of the disutility source used. The committee considered that the effectiveness data from the metastatic subgroup from STAMPEDE were generalisable to the higher-risk population under appraisal (see section 3.5). However, it considered that it was plausible that the level of risk affects quality of life. It concluded that it was preferable to use EQ‑5D data from the subgroup of people from STAMPEDE with high-risk hormone-sensitive metastatic prostate cancer to assess quality of life. It further noted that comparable data were available for abiraterone in combination, docetaxel in combination and ADT alone. The committee then went on to consider evidence submitted by BUG after the appeal. This showed the results of a quality-of-life study from STAMPEDE using data relevant to people with metastatic disease but not limited to high-risk disease. The data used a different measure of quality of life to EQ-5D. Results supported an improved quality of life for abiraterone in combination compared with docetaxel in combination. However, the difference was clinically meaningful according to predefined criteria only for the first 6 months after starting treatment. The committee considered that the findings supported the company's modelling that showed a worse quality of life with docetaxel in combination compared with abiraterone in combination. It also agreed that the ERG's estimate was likely to be broadly appropriate. The committee concluded that, in the absence of STAMPEDE trial data from the company, the company's and ERG's approaches were broadly consistent with each other and acceptable for decision making.
# Costs used in the company's model
## The company's model includes costs of follow-on treatments for metastatic hormone-relapsed disease, but not the full benefits
In response to the committee's second meeting, the company revised the treatment pathways in the hormone-relapsed state to reflect NHS market shares of treatments for hormone-relapsed disease. It based its estimates of market shares on the opinion of 4 clinicians, which the committee concluded may not reflect the actual market shares in UK clinical practice. The company assumed that:
About 80% of people had abiraterone or enzalutamide after ADT alone or docetaxel in combination.
People who had docetaxel in combination could have docetaxel again.
People in each modelled treatment arm could have 3 treatments once their prostate cancer was hormone relapsed. Fewer people in the abiraterone arm had an active treatment as their third treatment for hormone-relapsed prostate cancer than in the comparator arms.The committee noted that there was a mismatch between the modelling of treatments for hormone-relapsed prostate cancer and the proportions of people who had these treatments in LATITUDE and STAMPEDE (see section 3.9). The committee recognised that the company's model therefore accounted for the high costs of some of these treatments, but potentially not all of the life-extending benefits. So, the benefits may not have been fully captured in the trials. The committee concluded that it had not been presented with a validated estimate of treatments offered in the NHS. It further concluded that accounting for the costs, but not the benefits, of life-extending treatment could have biased the cost-effectiveness results. This would mean that the incremental cost-effectiveness ratio (ICER) for abiraterone in combination compared with its comparators may be higher than that estimated by the model.
# Cost-effectiveness results
## The company's base case for the whole population covered by abiraterone's licence does not reflect the preferred assumptions
The committee agreed that its preferred approach to modelling would reflect the company's base case with the following assumptions:
incremental probabilistic, rather than pairwise deterministic, analyses comparing abiraterone in combination with the relevant comparators (that is, ADT alone and docetaxel in combination)
progression-free survival extrapolated using the Weibull distribution and overall survival extrapolated using the log-logistic distribution
the same rates of overall survival for abiraterone in combination and docetaxel in combination (that is, assume an overall survival HR of 1.00).The committee concluded that the following scenarios were useful:
using the HR of 1.13 for overall survival for abiraterone in combination compared with docetaxel in combination from the direct comparison of the metastatic subgroup from STAMPEDE
using the HR for overall survival for abiraterone in combination compared with docetaxel in combination from the company's indirect comparison (the HR is academic in confidence)
assuming equal hazards of progression and overall survival at various time points to account for potential treatment waning.
## The results of the cost-effectiveness analyses should be made transparent
The prices of abiraterone made by Janssen and technologies made by company's other than Janssen are confidential. This meant that estimates of the ICERs could not be presented in the final appraisal determination that followed the committee's third meeting. In this meeting, NICE asked the committee to consider abiraterone at list price for this indication (and abiraterone at a discount for its other indications). This was because the company and NHS had not agreed a discounted price. The final appraisal determination stated that the cost-effectiveness estimates without a commercial arrangement were considerably higher than the range normally considered a cost-effective use of NHS resources. The company appealed, and the appeal panel concluded that this was not transparent. At the time of the fourth committee meeting, the company agreed a confidential discounted price for abiraterone but noted it did not wish NICE to publish a narrow range of ICERs. This was because the cost-effectiveness estimates using list prices had been published previously and the company stated that this would allow back calculation of its discount for abiraterone. The committee addressed this appeal point (see section 3.21) by stating a figure above which the ICER lies. It supported transparency in reporting cost effectiveness, and agreed that this did not fully address the appeal panel's suggestion. However, the company acknowledged in the fifth meeting that it had not agreed to a range of cost-effectiveness estimates being available for publication for the reasons stated above. So, the committee could not provide a more accurate representation of the ICER. The committee concluded that it strongly supported being more transparent in reporting estimates of cost effectiveness when possible without compromising confidential commercial arrangements.
## Abiraterone is not a cost-effective use of NHS resources for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer
The committee noted its duty to appraise technologies across their marketing authorisation. At the confidential discount chosen by the company, the company's base case with the appraisal committee's preferred modelling assumptions was:
Over £100,000 per quality-adjusted life year (QALY) gained when compared with docetaxel in combination
Over £30,000 per QALY gained compared with ADT alone.The committee concluded that, for the whole population, the ICERs were above the range considered a good use of NHS resources. It reflected this decision in the appraisal consultation document that followed its fourth meeting. For the committee's fifth meeting, the company presented no new inputs, assumptions or price in its modelling. The committee then considered whether abiraterone in combination might be a clinically effective and cost-effective treatment option for people for whom docetaxel was contraindicated or unsuitable, and for whom the relevant comparator would therefore be ADT alone. It agreed that the modelled comparison with ADT as presented by the company was not a valid estimate for people for whom docetaxel is contraindicated or unsuitable (see sections 3.10 to 3.13 and section 3.15). Despite this, in the absence of any data specific to this group, the committee considered estimates from the whole LATITUDE population, while acknowledging the uncertainty in its decision-making. It also noted that the ERG had presented scenarios which attempted to model the group in whom docetaxel was contraindicated or unsuitable. It did this by removing chemotherapy as a follow-on treatment, along with any associated survival benefit. The committee noted that in the company's own base case and in all ERG scenarios comparing abiraterone in combination with ADT alone, the ICERs were above £30,000 per QALY gained. It concluded that cost-effectiveness results in the population who cannot or should not have docetaxel were highly uncertain. However, even when considering the company's own modelling for this group compared with ADT alone, the ICERs were above the range considered a good use of NHS resources. The committee also agreed that there was considerable uncertainty around the cost effectiveness of abiraterone in people for whom docetaxel is contraindicated or unsuitable, which should be taken into account in decision making.
## Abiraterone may be associated with benefits unaccounted for in the modelling
The committee recognised that there was an unmet need for another treatment option to ADT in people for whom docetaxel is contraindicated or unsuitable. However, it agreed that this need was lessened by enzalutamide plus ADT having been recommended for this indication. It noted that the benefits of abiraterone being an oral treatment that could be taken at home were not captured in the model. It also acknowledged the increasing need for oral treatments during the COVID‑19 pandemic. The committee concluded that abiraterone may be associated with benefits unaccounted for in the modelling.
# Equality issues
## The recommendations apply to all people with prostate cancer and do not discriminate on the basis of age
The committee noted that, as in previous NICE technology appraisals of technologies for treating prostate cancer, its recommendations should apply to anyone with a prostate. It also noted that, in clinical practice, older people are less likely to have docetaxel than younger people based on NHS data from appellants presented at the fourth committee meeting. The clinical experts explained that, although docetaxel is more likely to be contraindicated or unsuitable for older people, age itself will not determine whether a person could or should have docetaxel in clinical practice. The committee was aware that making recommendations by age to reflect people who cannot or should not have docetaxel could discriminate against younger people for whom docetaxel is contraindicated or unsuitable. It noted the appeal panel's conclusions that: 'the current reasoning around the failure to define this subgroup does not address the fact that the subgroup will tend to comprise older men'. It also noted that the appeal panel: 'wishes to be clear that although equality legislation requires this subgroup to be more fully considered it does not necessarily follow that in this case, after appropriate consideration, special provision will need to be made for them'. The committee concluded that its recommendations should apply to all people with prostate cancer and not discriminate on the basis of age.
## The points upheld in appeal are addressed
The committee noted that 22 points were discussed in the appeal, 16 of which were dismissed by the appeal panel and 6 of which were upheld. The upheld points related to transparency (see section 3.20), equality issues (see section 3.23) and defining a population for whom docetaxel is contraindicated or unsuitable (see section 3.3). The appeal panel stated that the committee should:
consider whether it is possible to define a group of people for whom docetaxel is contraindicated or unsuitable (see section 3.3)
consider whether there is evidence available for the clinical and cost effectiveness of abiraterone in this group (see sections 3.10 to 3.12 and section 3.15)
if it concludes that approaches taken in other settings (notably NICE's technology appraisal guidance on radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases) are unsuitable in this appraisal, give clear reasons for this.Similar to the appraisal for radium‑223 dichloride, section 3.3 in this appraisal defines a group for whom docetaxel is contraindicated or unsuitable. The committee noted that, for the radium‑223 appraisal, clinical trial data were available for people not eligible to have docetaxel, who declined docetaxel, or for whom docetaxel was unavailable. However, no such data were presented in this appraisal for abiraterone in combination (see sections 3.10 to 3.12). The committee concluded that, having defined a framework for identifying people for whom docetaxel is contraindicated or unsuitable (see section 3.3), it had used a consistent approach to radium‑223 in this appraisal. It also noted that radium‑223 is used in a different position in the treatment pathway to abiraterone in combination (see section 3.4). It further concluded that it had addressed all the points upheld in the appeal.
|
{'Recommendations': 'Abiraterone with prednisone or prednisolone plus androgen deprivation therapy (ADT) is not recommended, within its marketing authorisation, for treating newly diagnosed high-risk hormone‑sensitive metastatic prostate cancer in adults.\n\nThis recommendation is not intended to affect treatment with abiraterone with prednisone or prednisolone plus ADT that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer in the NHS in England includes ADT alone, docetaxel plus ADT and, as of July\xa02021, enzalutamide plus ADT.\n\nClinical trial results show that, compared with ADT alone, a combination of abiraterone plus ADT and either prednisone or prednisolone increases the time until the disease progresses and how long people live. Results also show that, compared with docetaxel plus ADT, abiraterone plus ADT increases the time until the disease progresses, but not how long people live. Docetaxel plus ADT cannot be used by or is unsuitable for some people but there is no clinical evidence for abiraterone plus ADT compared with ADT alone for this group.\n\nThere is a proposed commercial arrangement that would make abiraterone available to the NHS at a discount. Even accounting for this, the cost-effectiveness estimates of either abiraterone in combination compared with ADT alone or with docetaxel plus ADT for the whole population are higher than what NICE considers cost effective. There are no appropriate cost-effectiveness estimates for when docetaxel cannot be used or is unsuitable. Therefore, abiraterone is not recommended for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer.', 'Information about abiraterone': "# Marketing authorisation\n\nAbiraterone (Zytiga; Janssen) with prednisone or prednisolone has a UK marketing authorisation for treating 'newly diagnosed high-risk metastatic hormone-sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT)'. In LATITUDE, a key trial in this appraisal, high-risk prognosis was defined as having at least 2\xa0of the following 3\xa0risk factors: a Gleason score of 8\xa0or more; 3\xa0or more lesions on bone scan; and measurable visceral metastasis (excluding lymph node disease).\n\n# Dosage in the marketing authorisation\n\nThe dosage is available in the summary of product characteristics.\n\n# Price\n\nThe cost of abiraterone is £2,735 for a pack of 56\xa0x\xa0500\xa0mg tablets (excluding VAT; BNF online, accessed June\xa02021). The company has a commercial arrangement that makes abiraterone available to the NHS with a confidential discount when it is used later in the disease pathway for treating hormone-relapsed metastatic prostate cancer before chemotherapy is indicated, or for hormone-relapsed metastatic prostate cancer previously treated with a docetaxel-containing regimen. Had abiraterone been recommended, it would have been available to the NHS with a discount for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer.", 'Committee discussion': "The appraisal committee considered evidence submitted by Janssen and a review of this submission by the evidence review group (ERG). It also considered the decision of the appeal panel. See the committee papers for full details of the evidence.\n\nThis appraisal consultation document reflects discussions had during the fifth committee meeting after 4\xa0committee meetings and an appeal. The first public consultation on this topic occurred after the first committee meeting in May\xa02018. NICE suspended the appraisal to allow price negotiations between the company and NHS England after the second meeting in July\xa02018. The third meeting was held in January\xa02020 without an agreement having been reached. Then, after further negotiations in which the company and NHS England did not reach an agreement, NICE issued a final appraisal determination in June\xa02020. An appeal followed in September\xa02020. NICE's guidance executive decided, on the basis of the appeal panel's decision, that the appraisal committee should address any upheld appeal points. It also decided to allow some of the appellants (the British Uro-oncology Group (BUG), Prostate Cancer UK and Tackle Prostate Cancer) to submit data because they considered they had not been given the opportunity to do so for previous committee meetings. To address the appeal points, a fourth committee meeting was held in December\xa02020, after which there was a further public consultation and fifth committee meeting.\n\n# Clinical management\n\n## Androgen deprivation therapy with or without docetaxel are the first-line treatment options for hormone-sensitive metastatic prostate cancer\n\nThe clinical experts explained in the first committee meeting in May\xa02018 that, in clinical practice, people with newly diagnosed hormone-sensitive metastatic prostate cancer have androgen deprivation therapy (ADT) alone or docetaxel plus ADT plus the oral corticosteroid prednisolone (from now on, 'docetaxel in combination'). NICE's guideline on prostate cancer recommends ADT in the form of continuous luteinising hormone-releasing hormone agonists, bilateral orchidectomy (removal of the testicles) or bicalutamide with ADT. The guideline also recommends docetaxel. Docetaxel is now licensed for hormone-sensitive metastatic prostate cancer, and NHS England commissions it for up to 6\xa0cycles at this point in the treatment pathway. Docetaxel is administered intravenously with oral prednisolone 5\xa0mg twice daily for 3\xa0weeks. The clinical experts explained that orchidectomy and bicalutamide are rarely used in the NHS. The committee was aware that NICE's technology appraisal guidance on enzalutamide plus ADT for treating hormone-sensitive metastatic prostate cancer and apalutamide plus ADT for hormone-sensitive metastatic prostate cancer started during this appraisal, and enzalutamide plus ADT was recommended. Because the final guidance for enzalutamide plus ADT was not published by the time of the fifth committee meeting, it did not become a comparator in this appraisal. The committee agreed that ADT includes luteinising hormone-releasing hormone agonists. It concluded that ADT alone and docetaxel in combination were appropriate comparators to abiraterone plus ADT plus 5\xa0mg of the oral corticosteroid prednisone (from now on, 'abiraterone in combination').\n\n## It may be appropriate to consider the comparator for abiraterone in combination separately when docetaxel is contraindicated or unsuitable\n\nThe committee recognised its obligation to appraise technologies across their marketing authorisations. This meant that, if abiraterone in combination was not cost effective across its marketing authorisation, the committee could consider a narrower population if there was a case for this. Although the company's original submission was for the full population covered in the marketing authorisation, it noted at the time that there was a group of people for whom docetaxel was clinically unsuitable or who chose not to have docetaxel. The company proposed abiraterone in combination as an alternative treatment to ADT alone for this group, which it termed 'chemotherapy ineligible' in its submission for the third committee meeting. The Cancer Drugs Fund's clinical lead noted in the third meeting that, at that time (January\xa02020), up to two-thirds of people presenting with hormone-sensitive metastatic prostate cancer in England had ADT alone. The committee noted that this included both people for whom docetaxel is contraindicated or unsuitable (the terminology agreed by the company, experts and committee in the fourth meeting) and people who choose not to have docetaxel. A patient expert explained that there is an unmet need for an alternative treatment option to ADT alone for this group. The committee recognised that most people who choose to have ADT alone rather than docetaxel in combination may wish to avoid the adverse events associated with docetaxel. The committee considered that this unmet need was in part addressed by NICE recommending enzalutamide plus ADT at this point in the pathway, which occurred during the course of this appraisal. The committee agreed that patient choice was important but that, for people who could have docetaxel, the comparators should be docetaxel in combination and ADT alone. If clinically and cost effective, abiraterone would be recommended as an option for the populations who can and cannot have docetaxel (from now, referred to as the 'whole population'). The committee agreed that it would be appropriate to define a group of people for whom docetaxel is unsuitable. It also agreed that the clinical and cost effectiveness of abiraterone in combination in this group should be considered if it was not cost effective for the whole population.\n\n## Identifying who cannot or should not have docetaxel involves assessing a person's risks and may include people who cannot take abiraterone\n\nIn its fourth meeting, the committee set out to understand more clearly how experts define people for whom docetaxel is contraindicated or unsuitable. The clinical and patient experts had previously explained that, although there are contraindications for docetaxel, defining the group for whom it is unsuitable is complicated. The committee had been aware that NHS England's clinical commissioning policy statement for docetaxel in combination with ADT indicates that someone may not be fit enough for docetaxel if they have a poor overall performance status (World Health Organization [WHO] performance 3\xa0to\xa04), pre-existing peripheral neuropathy, poor bone marrow function or a life-limiting illness. The policy also states that docetaxel should be used with caution in people with a WHO performance status of\xa02 and that there are few absolute contraindications for docetaxel therapy. The Cancer Drugs Fund's clinical lead explained that many factors besides a person's performance status may affect whether they could have docetaxel. One of these is patient choice after hearing the risks and benefits of each available treatment. In the fourth meeting, the clinical experts explained that, while creating an exhaustive list of criteria for this group is unfeasible, developing a framework would be possible. The clinical lead for the Cancer Drugs Fund explained that a clinician assesses whether docetaxel is suitable for someone based on contraindications, fitness, comorbidities and preference. An oncologist would identify and discuss with a patient the individual risks and benefits associated with any treatment option before starting treatment. People for whom docetaxel is contraindicated or unsuitable would include:\n\npeople who have contraindications to docetaxel as listed in the summary of product characteristics for docetaxel and NHS England's clinical commissioning policy statement for docetaxel in combination with ADT\n\npeople with poor performance status (WHO or Eastern Cooperative Oncology Group [ECOG] performance status\xa03 or\xa04, and possibly status\xa02 because docetaxel is used with caution in this group), which is a measure of fitness\n\npeople with significant comorbidity (for example, cardiovascular, respiratory or liver disease) such that prostate cancer is not likely to be the only life-limiting illness\n\npeople with peripheral sensory neuropathy or poor bone marrow function\n\npeople with poor cognition or social support leading to a decreased ability to understand treatment options or make a decision.Prescribing clinicians should assess the individual risks and potential benefits of having docetaxel. This should include the advantages and disadvantages of all treatment options, including fewer later treatments for people who would choose to start with abiraterone (see section\xa03.4). The clinical experts explained that some people who would not be fit enough for treatment with docetaxel would also not be fit enough for abiraterone, and would be offered ADT alone. It concluded that identifying people in whom docetaxel was contraindicated or unsuitable would be based on a clinical framework considering individual patient risk, and may include people who cannot take abiraterone.\n\n## The first treatment for hormone-sensitive prostate cancer affects the type and number of later treatments for hormone-refractory disease\n\nThe clinical experts explained that people who have docetaxel as first-line treatment in the hormone-sensitive setting can have docetaxel again for up to an additional 10 cycles in the hormone-relapsed setting. This is because the benefit of docetaxel is not exhausted when used for only 6 cycles. The Cancer Drugs Fund's clinical lead explained that abiraterone and enzalutamide are commissioned by NHS England only once in the treatment pathway. This is because there is no evidence of substantial clinical benefit for enzalutamide after abiraterone or for abiraterone after enzalutamide. The committee understood that people who have abiraterone in combination for hormone-sensitive prostate cancer have fewer options for active follow-on treatments (when the disease becomes hormone refractory) than people who start with ADT alone, or docetaxel in combination. This is because people who started with abiraterone cannot have abiraterone or enzalutamide later in the treatment pathway. The committee noted that the sequence of follow-on treatments when disease becomes hormone refractory may vary from person to person, but that ADT would be continued alongside subsequent therapies. It considered that possible follow-on treatments include:\n\nafter ADT alone:\n\n\n\nabiraterone or enzalutamide (before or after docetaxel)\n\ndocetaxel (unless docetaxel is contraindicated or unsuitable)\n\nother active treatments such as cabazitaxel or radium 223\n\n\n\nafter docetaxel in combination:\n\n\n\nabiraterone or enzalutamide (before or after docetaxel)\n\ndocetaxel again\n\nother active treatments such as cabazitaxel or radium 223\n\n\n\nafter abiraterone in combination:\n\n\n\ndocetaxel (unless docetaxel is contraindicated or unsuitable)\n\nother active treatments such as cabazitaxel or radium 223.The committee concluded that the first-choice treatment for hormone-sensitive metastatic prostate cancer affects the follow-on treatments a person may have. It also concluded that having abiraterone in combination at this position in the pathway limits the options for follow-on treatments for people who develop hormone-relapsed disease compared with people who have had ADT alone or docetaxel in combination.\n\n\n\n# Clinical evidence\n\n## LATITUDE and STAMPEDE are both relevant for assessing the clinical effectiveness of abiraterone in combination in the whole population\n\nTwo randomised controlled trials have investigated the clinical effectiveness of abiraterone in combination in hormone-sensitive metastatic disease:\n\nLATITUDE was a multinational double-blind trial including 1,199\xa0people with newly diagnosed high‑risk hormone-sensitive metastatic prostate cancer. High-risk was defined as at least 2\xa0of a Gleason score of\xa08 or more (that is, cancer which is aggressive or likely to spread); 3\xa0or more lesions on a bone scan; or visceral metastasis (excluding lymph nodes). People were randomised to either abiraterone plus ADT plus a corticosteroid (5\xa0mg prednisone once daily) or ADT alone. The co-primary endpoint of the trial was progression‑free and overall survival.\n\nSTAMPEDE was a UK multi-arm non-blinded adaptive trial that included some people with newly diagnosed hormone-sensitive metastatic, node-positive or high-risk localised disease (with at least\xa02 of: a tumour stage of 3\xa0or\xa04; a Gleason score of 8\xa0to\xa010, and prostate-specific antigen levels of 40\xa0ng/ml or more); or prostate cancer previously treated with radical surgery or radiotherapy and now relapsing with high-risk features. Randomised trial arms included, but were not limited to, abiraterone plus ADT plus a corticosteroid (5\xa0mg prednisolone once daily), ADT alone, and docetaxel plus ADT plus a corticosteroid (10\xa0mg prednisolone once daily). The primary endpoint was overall survival. Data were available for 502\xa0people with metastatic prostate cancer in the ADT alone arm, 500\xa0in the abiraterone-in-combination arm and 115\xa0in the docetaxel in combination arm. A comparison between abiraterone in combination and ADT alone was prespecified in the trial protocol. A comparison between abiraterone and docetaxel was done post hoc with 115\xa0people in the docetaxel in combination arm and 227\xa0people in the abiraterone-in-combination arm.The company considered that LATITUDE evaluated the clinical effectiveness of abiraterone in combination in the population in the marketing authorisation. STAMPEDE included people with locally advanced disease and metastatic disease and provided analyses for metastatic prostate cancer for both relevant comparators: ADT alone and docetaxel in combination. During the course of the appraisal, the STAMPEDE investigators published 2\xa0analyses aligned to the licensed population (that is, the subgroup of people with high-risk metastatic disease). These were for abiraterone in combination compared with ADT alone (Hoyle et al. 2018) and docetaxel in combination compared with ADT alone (Clarke et al. 2019). The committee concluded that both LATITUDE and STAMPEDE were relevant for assessing the clinical effectiveness for abiraterone in combination in the whole population for whom it is licensed.\n\n## To compare abiraterone in combination with docetaxel in combination, estimates from STAMPEDE are preferred\n\nTo compare abiraterone in combination with docetaxel in combination, the company was concerned that results from the subgroup of people with metastatic disease in STAMPEDE did not reflect the population included in the licence for abiraterone for the proposed indication (see section\xa03.5). The company further stated that STAMPEDE was not statistically powered to detect a difference in survival in this post-hoc analysis. The company instead developed a network meta-analysis which, as well as including the direct data from STAMPEDE, included several other trials. The company argued that additional trials contributed information to the estimated treatment effect of abiraterone compared with docetaxel. The trials included in the network were:\n\nabiraterone in combination compared with docetaxel in combination: data from the STAMPEDE broad metastatic subgroup\n\nabiraterone in combination compared with ADT alone: data from LATITUDE (licensed population) and STAMPEDE (subgroup matching the licensed population)\n\ndocetaxel in combination compared with ADT alone: data from STAMPEDE (subgroup matching the licensed population), CHAARTED and GETUG‑AFU\xa015 (subgroups with 'high-volume' disease, which the company considered similar to the licensed population).The committee noted that the company had not requested data from STAMPEDE directly comparing abiraterone in combination with docetaxel in combination for the subgroup matching the licensed population. It considered that the trials in the network may have differed in ways that could have influenced the effect estimate. The committee acknowledged that both direct and indirect evidence contributes to the total body of evidence. However, given the difference in results between the direct and indirect comparisons (see section\xa03.8), it concluded that the results from the direct comparison, being randomised, were less likely to be biased.\n\n## Abiraterone in combination extends survival compared with ADT alone in the whole population\n\nAbiraterone in combination improved both progression-free and overall survival compared with ADT alone in LATITUDE and in people with high-risk metastatic disease in STAMPEDE. The size of the relative improvement for abiraterone plus ADT compared with ADT alone was similar in the 2 trials. In LATITUDE, median progression-free survival was 14.8 months with ADT alone and 33.0 months with abiraterone in combination (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.39 to 0.55). Based on the planned final analysis of overall survival, the median overall survival with ADT alone was 36.5 months compared with 53.3 months with abiraterone in combination (HR 0.66, 95% CI 0.56 to 0.78). In STAMPEDE, at a median follow up of 3.3 years, the HR for progression-free survival in the high-risk metastatic subgroup was 0.46 (95% CI 0.36 to 0.59), and for overall survival was 0.54 (95% CI 0.41 to 0.70). Data from STAMPEDE shared after the appeal showed that the HR for overall survival was maintained after 8 years of follow up (HR 0.54, 95% CI 0.43 to 0.69). The committee noted that the survival benefit reported in LATITUDE was larger than that seen in clinical trials using abiraterone in hormone-relapsed disease, in which median overall survival was extended by 4.4 months compared with ADT alone. However, it acknowledged that its remit was to appraise abiraterone in the proposed indication and not to identify the best order and sequence of treatments. The committee concluded that abiraterone in combination improved both progression-free and overall survival compared with ADT alone. However, it noted that there was uncertainty about the magnitude of the long-term survival gain with abiraterone in combination. This was because of potential differences in the proportion of people who had life-extending treatments after disease progression on ADT in LATITUDE and STAMPEDE compared with clinical practice (see section 3.9).\n\n## Compared with docetaxel in combination, abiraterone in combination may improve progression-free survival, but not overall survival\n\nIn people with metastatic disease in STAMPEDE, abiraterone in combination improved progression-free survival compared with docetaxel in combination (HR\xa00.69, 95%\xa0CI 0.50\xa0to\xa00.95). However, for overall survival, the HR favoured docetaxel (HR\xa01.13, 95%\xa0CI 0.77\xa0to\xa01.66). In the company's updated base case, rather than use the results reflecting a direct comparison from STAMPEDE, it used the results of the indirect network meta-analysis that included data from LATITUDE, CHAARTED, GETUG‑AFU\xa015 and STAMPEDE. This showed similar results to the direct comparison for progression-free survival. However, the point estimate for overall survival favoured abiraterone, but the credible interval included\xa01, that is, the possibility of no difference in benefit of 1\xa0treatment over the other. The company considered these values to be academic in confidence so they cannot be reported here. Considering the direct and indirect comparisons, the committee concluded that abiraterone in combination improves progression-free survival, but not overall survival compared with docetaxel in combination.\n\n## Neither STAMPEDE nor LATITUDE likely capture all the overall survival benefit of follow-on treatments used in current NHS clinical practice\n\nThe committee recognised that life-extending treatments offered when the disease is no longer hormone sensitive (that is, is hormone relapsed) affects life-expectancy. Follow-on treatments in the unblinded UK STAMPEDE trial were expected to reflect what people would have in NHS clinical practice, for example, not getting abiraterone twice. This was because the choice of next treatment depended on knowing the first treatment. In STAMPEDE, people were aware of their treatment but, in the blinded LATITUDE trial, people were not. The committee noted that the trials differed from UK clinical practice in 2\xa0ways:\n\nIn LATITUDE, after abiraterone, 10% of the intention-to-treat (ITT) population had enzalutamide, and 5% had abiraterone again. In STAMPEDE 3% of the ITT population had enzalutamide after abiraterone, and 1% had abiraterone again.\n\nAfter ADT alone, fewer people in both STAMPEDE and in LATITUDE had follow-on treatment for hormone-relapsed disease with abiraterone or enzalutamide than would occur in NHS clinical practice. Of people who had treatments for hormone-relapsed disease, 40% had enzalutamide or abiraterone in LATITUDE, and 55% had enzalutamide or abiraterone in STAMPEDE. This was lower than the 80% modelled by the company, which was based on an estimate of UK market shares for these treatments (see section\xa03.18).The committee concluded that differences between the subsequent treatments used in STAMPEDE and current UK market shares are likely to be related to abiraterone and enzalutamide becoming increasingly available over time. It recognised that the trials may have overestimated the relative clinical effectiveness of abiraterone if fewer people in the ADT arms of the trials had benefitted from follow-on treatments for hormone-relapsed prostate cancer than do in NHS clinical practice. The committee concluded that the estimates of survival from STAMPEDE were likely more relevant to clinical practice in the NHS than those from LATITUDE because they better reflected the options available on the NHS after a patient needed a next treatment.\n\n## No data are available on the effectiveness of abiraterone compared with ADT in people for whom docetaxel is contraindicated or unsuitable\n\nNo evidence was presented for abiraterone's relative effectiveness compared with ADT alone, specifically for the group for whom docetaxel is contraindicated or unsuitable. LATITUDE and STAMPEDE, the key clinical trials of abiraterone in this indication (see section\xa03.5), only included people with adequate haematological function, and an ECOG or WHO performance status of 0,\xa01 or\xa02 (meaning they were reasonably fit). Also, they could not have any condition that would interfere with them taking part in the trial. As part of the initial protocol, all people recruited to STAMPEDE had to be able to have docetaxel because it was 1 of the arms in the trial. A clinical expert explained that, in 2013, that arm closed but the trial continued to recruit to the ADT alone and abiraterone-in-combination arms (among others). This meant people recruited to the trial from this point could have included people for whom docetaxel was contraindicated or unsuitable. They noted that James et al. (2017) presented an analysis showing that the HR for overall survival for abiraterone in combination compared with ADT was 0.69 (95%\xa0CI 0.53\xa0to\xa00.90) between November\xa02011 and January\xa02013. This was when the docetaxel arm of the trial was open. After the docetaxel arm closed, the HR for data collected between April\xa02013 and January\xa02014 was 0.59 (95%\xa0CI 0.44\xa0to\xa00.78). The ERG highlighted, and the committee agreed, that this did not provide the evidence specifically for the group for whom docetaxel was contraindicated or unsuitable. This was because the 2013 to 2014 data would also have included people who could have docetaxel. The committee heard during its fourth meeting that STAMPEDE enrolled people who could take abiraterone but could not have docetaxel. However, in response to the consultation after the committee's fourth meeting, the company and consultees commented that data specific to this subgroup could not be separated from the metastatic, high-risk cohort in STAMPEDE. This was because the trial did not collect data on all the baseline characteristics specified in the suggested clinical framework describing people who cannot or should not have docetaxel (see section\xa03.3). The committee was aware that many of these characteristics were similar to the STAMPEDE exclusion criteria. It noted that stakeholders had explored several further data sources for people who are 'chemotherapy ineligible' but identified none that would resolve the uncertainty about clinical and cost effectiveness in this population. The company agreed that it was reasonable for the committee to request data specific to people who cannot or should not have docetaxel. However, the company did not consider it ethical to conduct a new clinical trial specifically in this group because trials have already shown that abiraterone is superior to ADT alone in the whole population. Acknowledging the uncertainties in the existing data, the company preferred to use the treatment effect from the whole population to represent the group for whom docetaxel is contraindicated or unsuitable. The committee concluded that assessing data specific to the relevant population was preferred, but acknowledged that this evidence was not available. It therefore considered the treatment effect from the LATITUDE whole population for people who cannot or should not have docetaxel in its decision making, while acknowledging this uncertainty.\n\n## Abiraterone in combination may be less effective in people who are unlikely to be able to have docetaxel, but data are limited and uncertain\n\nNo data were presented specifically for the group of people who cannot have docetaxel (see section\xa03.10). So, the committee discussed the uncertainties associated with applying the treatment effect of abiraterone in combination for the whole trial population to people who cannot or should not have docetaxel. It did this by looking at the treatment effect in people whose baseline characteristics meant they were unlikely to be able to have docetaxel. It was aware that older people (see section\xa03.23) and people with poorer levels of performance status would be less likely to have docetaxel. It noted the available evidence from LATITUDE and STAMPEDE on subgroups based on age and performance status. For the comparison of abiraterone in combination with ADT alone from STAMPEDE, the committee noted effect modification by age. For overall survival, abiraterone was not as effective in people 70\xa0years and over (HR\xa00.94, 95%\xa0CI 0.69\xa0to\xa01.29) compared with people under 70\xa0years (HR\xa00.51, 95%\xa0CI 0.40\xa0to\xa00.65; test for interaction p\xa0value 0.003) (James et al. 2017). The company argued that these results were not representative of the population covered by the licence for the proposed indication. This was because they included people with non-metastatic prostate cancer, who are generally younger and have earlier stage disease. The committee noted a similar pattern in LATITUDE, in which the HR for overall survival for abiraterone in combination compared with ADT alone was: 0.65 (95%\xa0CI 0.50\xa0to\xa00.84) for people under 65\xa0years; 0.68 (95%\xa0CI 0.55\xa0to\xa00.83) for people 65\xa0years and over and 0.86 (95%\xa0CI 0·62\xa0to\xa01·21) for people 75\xa0years and over (Fizazi et al. 2019). In response to the second consultation, the company stated that the test for interaction based on age was non-significant, suggesting that it was possible that age had no effect on treatment response. However, it also acknowledged in the fifth committee meeting that the test may be underpowered to detect a difference. The committee also noted a HR of 0.64 (95%\xa0CI 0.50\xa0to\xa00.75) in people with an ECOG status of 0\xa0or\xa01, and a HR of 1.42 (95%\xa0CI 0.65\xa0to\xa03.08) for those with an ECOG status of\xa02 in LATITUDE (Fizazi et al. 2019). It recognised that age alone would not determine whether a person could have docetaxel, but that age was associated with decreased docetaxel use based on data provided by BUG. It also heard that people with a poor performance status may not get abiraterone. The committee agreed that abiraterone appears less effective among people with characteristics shared by people who cannot or should not have docetaxel based on subgroup data. However, it noted that subgroup data should be interpreted with caution when based on data from a small group of people (40\xa0out of 1,159\xa0people in LATITUDE had a performance status of\xa02). The committee recalled that the subgroups did not specifically reflect the population for whom docetaxel is contraindicated or unsuitable. Overall, the committee concluded it was not possible to determine the size of the effectiveness for people for whom docetaxel is contraindicated or unsuitable. It therefore chose to look at its preferred effect measures from existing data (the treatment effect seen in the whole LATITUDE population; see section\xa03.10), acknowledging the uncertainty.\n\n## The baseline risks from which to estimate the absolute effectiveness of abiraterone in people who cannot have docetaxel are not presented\n\nBoth the relative benefits of treatment with abiraterone compared with ADT alone, and the baseline risks of progression and dying, may differ between populations who can and cannot have docetaxel. The committee recognised that many of the risk factors for not having docetaxel (for example, age and poor performance status) are also risk factors for dying. It concluded that any modelling should take this into account (see section\xa03.15).\n\n## Overall survival estimates from LATITUDE include follow-on treatments not used in people who cannot or should not have docetaxel\n\nThe company considered that the results of LATITUDE could be generalised to people who cannot or should not have docetaxel in its modelling (see section\xa03.15). The clinical experts explained that, with some exceptions, people with hormone-sensitive disease for whom docetaxel is contraindicated or unsuitable would not have docetaxel after their cancer progressed to being hormone relapsed. People in LATITUDE and STAMPEDE could go on to have docetaxel after abiraterone in combination or ADT alone. This did not reflect the treatment pathway for people who cannot have docetaxel, and yet was reflected in the trial results. The evidence of clinical effectiveness from LATITUDE does not reflect the treatment pathway for people for whom docetaxel is contraindicated or unsuitable. The committee therefore again agreed that it had not been presented with data on the effectiveness of abiraterone in combination compared with ADT in people for whom docetaxel is contraindicated or unsuitable. It concluded that estimates of overall survival from LATITUDE included the effect of taking docetaxel when indicated for hormone-relapsed metastatic disease, which would not apply to people who cannot or should not have docetaxel.\n\n# Company's economic model\n\n## A partitioned survival model is appropriate\n\nThe company provided 2\xa0models. In its original submission, it provided a multistate Markov model. The committee deemed that this did not provide plausible estimates of post-progression or overall survival and did not generate valid estimates of cost effectiveness. In its submission for the third committee meeting, the company provided a partitioned survival model. Both models were split into 2\xa0phases:\n\nA hormone-sensitive phase, in which the company used LATITUDE to model probabilities of progressing and dying while on abiraterone in combination or ADT alone: For abiraterone in combination compared with docetaxel in combination, the company applied HRs from its revised network meta-analysis (including STAMPEDE) to data from LATITUDE.\n\nA hormone-relapsed phase: In the Markov model, the company based the time spent in the hormone-relapsed phase on the survival curves from NICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before docetaxel is indicated. However, this approach did not produce valid estimates of overall survival for docetaxel. For example, modelled overall survival was much longer with abiraterone in combination than with docetaxel in combination, even when using the hazard ratio for overall survival that suggested a survival benefit for docetaxel (1.13 from the STAMPEDE direct comparison). The partitioned survival model extrapolated progression-free and overall survival from LATITUDE, with the time spent in the hormone-relapsed phase being the difference between these 2\xa0survival curves.The committee concluded in its third and fourth meetings that, because the company's Markov model did not give plausible estimates of post-progression and overall survival, it would consider the company's partitioned survival model.\n\n## There is no modelling reflecting the treatment pathway, costs and benefits for people for whom docetaxel is contraindicated or unsuitable\n\nFor the third committee discussion, the company provided estimates of the cost effectiveness of abiraterone in combination compared with ADT alone for a population it referred to as 'chemotherapy ineligible' (see section\xa03.2). The committee noted that the company based these estimates on data for the whole population. The committee recognised that the clinical data used in the model may not be generalisable to the 'chemotherapy ineligible' group. It also recognised that the modelled treatment pathway did not reflect the treatments people would have for whom docetaxel is contraindicated or unsuitable. Specifically:\n\nIt is uncertain whether abiraterone is as effective for people for whom docetaxel is contraindicated or unsuitable as it is for people able to have docetaxel (see section\xa03.11).\n\nPeople in the modelled abiraterone-in-combination arm or the ADT arm went on to have docetaxel once their prostate cancer was hormone relapsed (see section\xa03.13).\n\nPeople for whom docetaxel is contraindicated or unsuitable compared with people who can have docetaxel may:\n\n\n\nhave differing rates of adverse effects that would influence health-related quality of life\n\nhave a higher baseline risk of dying\n\nhave a different risk of dying over time.The committee concluded that the company had not provided it with modelling that reflected the treatment pathway, costs, survival and quality of life for people for whom docetaxel is contraindicated or unsuitable.\n\n\n\n## In the full population, Weibull and log-logistic distributions are plausible for extrapolating progression-free and overall survival respectively\n\nThe committee agreed with the company that the hazards of progression and death for abiraterone in combination compared with ADT alone from LATITUDE were not proportional. It concluded that it was appropriate to fit curves to each arm separately. During the committee's third meeting, the company presented results for both progression-free and overall survival. It used the log-logistic distribution for each modelled treatment arm (which the company considered plausible but optimistic) and the Weibull distribution (which it considered plausible but pessimistic). The committee considered that the Weibull curves were plausible for progression-free survival. It noted that results from STAMPEDE for abiraterone in combination compared with ADT (submitted by BUG after the appeal for the fourth meeting) represented an 8‑year follow up. These suggested an ongoing benefit with abiraterone in combination compared with ADT alone (HR\xa00.54, 95%\xa0CI 0.43\xa0to\xa00.69). The results supported using the log-logistic distribution to extrapolate overall survival from LATITUDE. At the third meeting, the ERG highlighted that a consequence of the model was that the company assumed the treatment effect to be maintained over the long term. However, in clinical practice, it may wane and the ERG provided scenarios to adjust for this at that time. The committee noted that the longer-term data from STAMPEDE could be used to determine the validity of these adjustments. It concluded that the progression-free survival extrapolation using the Weibull distribution was broadly appropriate for the overall population. However, it did not see evidence of extrapolating outcomes in people for whom docetaxel is contraindicated or unsuitable. The committee recognised that these people, being on average older, may have a different pattern of mortality. It further concluded that the predicted overall survival based on extrapolations using the log-logistic distribution was plausible for the overall trial population. The committee would have preferred to see further extrapolations exploring alternative time points for equalising the hazard using 2\xa0plausible curves: 1\xa0for the whole population, and another for people for whom docetaxel is contraindicated or unsuitable.\n\n# Utility values in the model\n\n## The utility estimates should be taken from the same source as the data on effectiveness\n\nThe company considered separately the effects on quality of life of adverse effects and of being on treatment. The sources of these data are in table\xa01.\n\nTreatment\n\nQuality of life relating to treatment\n\nQuality of life relating to adverse events\n\nAndrogen deprivation therapy (ADT) alone\n\nBased on EQ‑5D data from LATITUDE\n\nPublished utility values for adverse effects and skeletal-related events\n\nAbiraterone plus ADT plus 5\xa0mg of the oral corticosteroid prednisone\n\nBased on EQ‑5D data from LATITUDE: the company modelled a further utility increase for being on abiraterone compared with androgen deprivation therapy alone\n\nPublished utility values for adverse effects and skeletal-related events\n\nDocetaxel plus ADT plus the oral corticosteroid prednisolone\n\nBased on a preference study commissioned by the company: the company modelled a further utility decrement for being on docetaxel\n\nPublished utility values for adverse effects and skeletal-related events\n\nThe company used different approaches to estimate the effect on quality of life of having abiraterone in combination or ADT alone than it did to estimate the effect with docetaxel in combination. It sourced utility values for being on abiraterone in combination from EQ‑5D results from LATITUDE, and for being on docetaxel in combination from a separate preference study of the general public that it had carried out. The NICE methods guide states that EQ‑5D is the preferred measure of health-related quality of life. The committee noted that STAMPEDE collected EQ‑5D data for a UK population randomised to abiraterone in combination, to docetaxel in combination and to ADT alone. In response to the first consultation and in the third committee meeting, the company confirmed that it did not request or have access to these data. The ERG carried out a scenario using the disutility estimate for docetaxel from the economic evaluation of docetaxel in combination in NICE's guideline for prostate cancer. The ERG derived the disutility value from EQ‑5D data collected in STAMPEDE (whole population and metastatic subgroup). The company stated that the ERG's and company's scenarios were consistent, irrespective of the disutility source used. The committee considered that the effectiveness data from the metastatic subgroup from STAMPEDE were generalisable to the higher-risk population under appraisal (see section\xa03.5). However, it considered that it was plausible that the level of risk affects quality of life. It concluded that it was preferable to use EQ‑5D data from the subgroup of people from STAMPEDE with high-risk hormone-sensitive metastatic prostate cancer to assess quality of life. It further noted that comparable data were available for abiraterone in combination, docetaxel in combination and ADT alone. The committee then went on to consider evidence submitted by BUG after the appeal. This showed the results of a quality-of-life study from STAMPEDE using data relevant to people with metastatic disease but not limited to high-risk disease. The data used a different measure of quality of life to EQ-5D. Results supported an improved quality of life for abiraterone in combination compared with docetaxel in combination. However, the difference was clinically meaningful according to predefined criteria only for the first 6\xa0months after starting treatment. The committee considered that the findings supported the company's modelling that showed a worse quality of life with docetaxel in combination compared with abiraterone in combination. It also agreed that the ERG's estimate was likely to be broadly appropriate. The committee concluded that, in the absence of STAMPEDE trial data from the company, the company's and ERG's approaches were broadly consistent with each other and acceptable for decision making.\n\n# Costs used in the company's model\n\n## The company's model includes costs of follow-on treatments for metastatic hormone-relapsed disease, but not the full benefits\n\nIn response to the committee's second meeting, the company revised the treatment pathways in the hormone-relapsed state to reflect NHS market shares of treatments for hormone-relapsed disease. It based its estimates of market shares on the opinion of 4\xa0clinicians, which the committee concluded may not reflect the actual market shares in UK clinical practice. The company assumed that:\n\nAbout 80% of people had abiraterone or enzalutamide after ADT alone or docetaxel in combination.\n\nPeople who had docetaxel in combination could have docetaxel again.\n\nPeople in each modelled treatment arm could have 3\xa0treatments once their prostate cancer was hormone relapsed. Fewer people in the abiraterone arm had an active treatment as their third treatment for hormone-relapsed prostate cancer than in the comparator arms.The committee noted that there was a mismatch between the modelling of treatments for hormone-relapsed prostate cancer and the proportions of people who had these treatments in LATITUDE and STAMPEDE (see section\xa03.9). The committee recognised that the company's model therefore accounted for the high costs of some of these treatments, but potentially not all of the life-extending benefits. So, the benefits may not have been fully captured in the trials. The committee concluded that it had not been presented with a validated estimate of treatments offered in the NHS. It further concluded that accounting for the costs, but not the benefits, of life-extending treatment could have biased the cost-effectiveness results. This would mean that the incremental cost-effectiveness ratio (ICER) for abiraterone in combination compared with its comparators may be higher than that estimated by the model.\n\n# Cost-effectiveness results\n\n## The company's base case for the whole population covered by abiraterone's licence does not reflect the preferred assumptions\n\nThe committee agreed that its preferred approach to modelling would reflect the company's base case with the following assumptions:\n\nincremental probabilistic, rather than pairwise deterministic, analyses comparing abiraterone in combination with the relevant comparators (that is, ADT alone and docetaxel in combination)\n\nprogression-free survival extrapolated using the Weibull distribution and overall survival extrapolated using the log-logistic distribution\n\nthe same rates of overall survival for abiraterone in combination and docetaxel in combination (that is, assume an overall survival HR of\xa01.00).The committee concluded that the following scenarios were useful:\n\nusing the HR of\xa01.13 for overall survival for abiraterone in combination compared with docetaxel in combination from the direct comparison of the metastatic subgroup from STAMPEDE\n\nusing the HR for overall survival for abiraterone in combination compared with docetaxel in combination from the company's indirect comparison (the HR is academic in confidence)\n\nassuming equal hazards of progression and overall survival at various time points to account for potential treatment waning.\n\n## The results of the cost-effectiveness analyses should be made transparent\n\nThe prices of abiraterone made by Janssen and technologies made by company's other than Janssen are confidential. This meant that estimates of the ICERs could not be presented in the final appraisal determination that followed the committee's third meeting. In this meeting, NICE asked the committee to consider abiraterone at list price for this indication (and abiraterone at a discount for its other indications). This was because the company and NHS had not agreed a discounted price. The final appraisal determination stated that the cost-effectiveness estimates without a commercial arrangement were considerably higher than the range normally considered a cost-effective use of NHS resources. The company appealed, and the appeal panel concluded that this was not transparent. At the time of the fourth committee meeting, the company agreed a confidential discounted price for abiraterone but noted it did not wish NICE to publish a narrow range of ICERs. This was because the cost-effectiveness estimates using list prices had been published previously and the company stated that this would allow back calculation of its discount for abiraterone. The committee addressed this appeal point (see section\xa03.21) by stating a figure above which the ICER lies. It supported transparency in reporting cost effectiveness, and agreed that this did not fully address the appeal panel's suggestion. However, the company acknowledged in the fifth meeting that it had not agreed to a range of cost-effectiveness estimates being available for publication for the reasons stated above. So, the committee could not provide a more accurate representation of the ICER. The committee concluded that it strongly supported being more transparent in reporting estimates of cost effectiveness when possible without compromising confidential commercial arrangements.\n\n## Abiraterone is not a cost-effective use of NHS resources for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer\n\nThe committee noted its duty to appraise technologies across their marketing authorisation. At the confidential discount chosen by the company, the company's base case with the appraisal committee's preferred modelling assumptions was:\n\nOver £100,000 per quality-adjusted life year (QALY) gained when compared with docetaxel in combination\n\nOver £30,000 per QALY gained compared with ADT alone.The committee concluded that, for the whole population, the ICERs were above the range considered a good use of NHS resources. It reflected this decision in the appraisal consultation document that followed its fourth meeting. For the committee's fifth meeting, the company presented no new inputs, assumptions or price in its modelling. The committee then considered whether abiraterone in combination might be a clinically effective and cost-effective treatment option for people for whom docetaxel was contraindicated or unsuitable, and for whom the relevant comparator would therefore be ADT alone. It agreed that the modelled comparison with ADT as presented by the company was not a valid estimate for people for whom docetaxel is contraindicated or unsuitable (see sections\xa03.10 to 3.13 and\xa0section 3.15). Despite this, in the absence of any data specific to this group, the committee considered estimates from the whole LATITUDE population, while acknowledging the uncertainty in its decision-making. It also noted that the ERG had presented scenarios which attempted to model the group in whom docetaxel was contraindicated or unsuitable. It did this by removing chemotherapy as a follow-on treatment, along with any associated survival benefit. The committee noted that in the company's own base case and in all ERG scenarios comparing abiraterone in combination with ADT alone, the ICERs were above £30,000 per QALY gained. It concluded that cost-effectiveness results in the population who cannot or should not have docetaxel were highly uncertain. However, even when considering the company's own modelling for this group compared with ADT alone, the ICERs were above the range considered a good use of NHS resources. The committee also agreed that there was considerable uncertainty around the cost effectiveness of abiraterone in people for whom docetaxel is contraindicated or unsuitable, which should be taken into account in decision making.\n\n## Abiraterone may be associated with benefits unaccounted for in the modelling\n\nThe committee recognised that there was an unmet need for another treatment option to ADT in people for whom docetaxel is contraindicated or unsuitable. However, it agreed that this need was lessened by enzalutamide plus ADT having been recommended for this indication. It noted that the benefits of abiraterone being an oral treatment that could be taken at home were not captured in the model. It also acknowledged the increasing need for oral treatments during the COVID‑19 pandemic. The committee concluded that abiraterone may be associated with benefits unaccounted for in the modelling.\n\n# Equality issues\n\n## The recommendations apply to all people with prostate cancer and do not discriminate on the basis of age\n\nThe committee noted that, as in previous NICE technology appraisals of technologies for treating prostate cancer, its recommendations should apply to anyone with a prostate. It also noted that, in clinical practice, older people are less likely to have docetaxel than younger people based on NHS data from appellants presented at the fourth committee meeting. The clinical experts explained that, although docetaxel is more likely to be contraindicated or unsuitable for older people, age itself will not determine whether a person could or should have docetaxel in clinical practice. The committee was aware that making recommendations by age to reflect people who cannot or should not have docetaxel could discriminate against younger people for whom docetaxel is contraindicated or unsuitable. It noted the appeal panel's conclusions that: 'the current reasoning around the failure to define this subgroup does not address the fact that the subgroup will tend to comprise older men'. It also noted that the appeal panel: 'wishes to be clear that although equality legislation requires this subgroup to be more fully considered it does not necessarily follow that in this case, after appropriate consideration, special provision will need to be made for them'. The committee concluded that its recommendations should apply to all people with prostate cancer and not discriminate on the basis of age.\n\n## The points upheld in appeal are addressed\n\nThe committee noted that 22\xa0points were discussed in the appeal, 16\xa0of which were dismissed by the appeal panel and 6\xa0of which were upheld. The upheld points related to transparency (see section\xa03.20), equality issues (see section\xa03.23) and defining a population for whom docetaxel is contraindicated or unsuitable (see section\xa03.3). The appeal panel stated that the committee should:\n\nconsider whether it is possible to define a group of people for whom docetaxel is contraindicated or unsuitable (see section\xa03.3)\n\nconsider whether there is evidence available for the clinical and cost effectiveness of abiraterone in this group (see sections\xa03.10 to 3.12 and\xa0section 3.15)\n\nif it concludes that approaches taken in other settings (notably NICE's technology appraisal guidance on radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases) are unsuitable in this appraisal, give clear reasons for this.Similar to the appraisal for radium‑223 dichloride, section\xa03.3 in this appraisal defines a group for whom docetaxel is contraindicated or unsuitable. The committee noted that, for the radium‑223 appraisal, clinical trial data were available for people not eligible to have docetaxel, who declined docetaxel, or for whom docetaxel was unavailable. However, no such data were presented in this appraisal for abiraterone in combination (see sections\xa03.10 to 3.12). The committee concluded that, having defined a framework for identifying people for whom docetaxel is contraindicated or unsuitable (see section\xa03.3), it had used a consistent approach to radium‑223 in this appraisal. It also noted that radium‑223 is used in a different position in the treatment pathway to abiraterone in combination (see section\xa03.4). It further concluded that it had addressed all the points upheld in the appeal."}
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https://www.nice.org.uk/guidance/ta721
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Evidence-based recommendations on abiraterone (Zytiga) for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer in adults.
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4f16f0c0f7207d30d4d48c4b149fd7afb92a30de
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nice
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Bronchiolitis in children: diagnosis and management
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Bronchiolitis in children: diagnosis and management
This guideline covers diagnosing and managing bronchiolitis in babies and children. It aims to help healthcare professionals diagnose bronchiolitis and identify if babies and children should be cared for at home or in hospital. It describes treatments and interventions that can be used to help with the symptoms of bronchiolitis.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Assessment and diagnosis
When diagnosing bronchiolitis, take into account that it occurs in babies and children under 2 years of age and most commonly in the first year of life, peaking between 3 and 6 months.
When diagnosing bronchiolitis, take into account that symptoms usually peak between 3 and 5 days, and that cough resolves in 90% of infants within 3 weeks.
Diagnose bronchiolitis if the baby or child has a coryzal prodrome lasting 1 to 3 days, followed by:
persistent cough and
either tachypnoea or chest recession (or both) and
either wheeze or crackles on chest auscultation (or both).
When diagnosing bronchiolitis, take into account that the following symptoms are common in babies and children with this disease:
fever (in around 30% of cases, usually of less than 39°C)
poor feeding (typically after 3 to 5 days of illness).
When diagnosing bronchiolitis, take into account that young infants with this disease (in particular those under 6 weeks of age) may present with apnoea without other clinical signs.
Consider a diagnosis of pneumonia if the baby or child has:
high fever (over 39°C) and/or
persistently focal crackles.See also the NICE guideline on sepsis and risk stratification tool for sepsis in under 5s.
Think about a diagnosis of viral‑induced wheeze or early‑onset asthma rather than bronchiolitis in older infants and young children if they have:
persistent wheeze without crackles or
recurrent episodic wheeze or
a personal or family history of atopy.Take into account that these conditions are unusual in children under 1 year of age.
Measure oxygen saturation in every baby and child presenting with suspected bronchiolitis, including those presenting to primary care if pulse oximetry is available.
Ensure healthcare professionals performing pulse oximetry are appropriately trained in its use specifically in babies and young children. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin.
Suspect impending respiratory failure, and take appropriate action as these babies and children may need intensive care (see recommendations 1.2.1 and 1.4.5), if any of the following are present:
signs of exhaustion, for example listlessness or decreased respiratory effort
recurrent apnoea
failure to maintain adequate oxygen saturation despite oxygen supplementation.
# When to refer
Immediately refer babies and children with bronchiolitis for emergency hospital care (usually by 999 ambulance) if they have any of the following:
apnoea (observed or reported)
baby or child looks seriously unwell to a healthcare professional
severe respiratory distress, for example grunting, marked chest recession, or a respiratory rate of over 70 breaths/minute
central cyanosis.
Consider referring babies and children with bronchiolitis to hospital if they have any of the following:
a respiratory rate of over 60 breaths/minute
difficulty with breastfeeding or inadequate oral fluid intake (50% to 75% of usual volume, taking account of risk factors and using clinical judgement)
clinical dehydration
persistent oxygen saturation of less than 92%, when breathing air. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
When deciding whether to refer a baby or child with bronchiolitis to secondary care, take account of any known risk factors for more severe bronchiolitis such as:
chronic lung disease (including bronchopulmonary dysplasia)
haemodynamically significant congenital heart disease
age in young infants (under 3 months)
premature birth, particularly under 32 weeks
neuromuscular disorders
immunodeficiency.
When deciding whether to refer a baby or child to secondary care, take into account factors that might affect a carer's ability to look after a child with bronchiolitis, for example:
social circumstances
the skill and confidence of the carer in looking after a child with bronchiolitis at home
confidence in being able to spot red flag symptoms (see recommendation 1.6.1)
distance to healthcare in case of deterioration.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on when to refer .
Full details of the evidence and the committee's discussion are in evidence review A: criteria for referral, admission, oxygen supplementation and discharge.
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# When to admit
Measure oxygen saturation using pulse oximetry in every baby and child presenting to secondary care with clinical evidence of bronchiolitis. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin.
When assessing a baby or child in a secondary care setting, admit them to hospital if they have any of the following:
apnoea (observed or reported)
persistent oxygen saturation (when breathing air) of:
less than 90%, for children aged 6 weeks and over
less than 92%, for babies under 6 weeks or children of any age with underlying health conditions
inadequate oral fluid intake (50% to 75% of usual volume, taking account of risk factors and using clinical judgement)
persisting severe respiratory distress, for example grunting, marked chest recession, or a respiratory rate of over 70 breaths/minute.
When deciding whether to admit a baby or child with bronchiolitis, take account of any known risk factors for more severe bronchiolitis, such as:
chronic lung disease (including bronchopulmonary dysplasia)
haemodynamically significant congenital heart disease
age in young infants (under 3 months)
premature birth, particularly under 32 weeks
neuromuscular disorders
immunodeficiency.
When deciding whether to admit a baby or child, take into account factors that might affect a carer's ability to look after a child with bronchiolitis, for example:
social circumstances
the skill and confidence of the carer in looking after a child with bronchiolitis at home
confidence in being able to spot red flag symptoms (see recommendation 1.6.1)
distance to healthcare in case of deterioration.
Clinically assess the hydration status of babies and children with bronchiolitis.
Do not routinely perform blood tests in the assessment of a baby or child with bronchiolitis.
Do not routinely perform a chest X‑ray in babies or children with bronchiolitis, because changes on X‑ray may mimic pneumonia and should not be used to determine the need for antibiotics.
Consider performing a chest X‑ray if intensive care is being proposed for a baby or child.
Provide parents or carers with key safety information (see recommendation 1.6.1) if the baby or child is not admitted.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on when to admit .
Full details of the evidence and the committee's discussion are in evidence review A: criteria for referral, admission, oxygen supplementation and discharge.
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# Management of bronchiolitis
Do not perform chest physiotherapy on babies and children with bronchiolitis who do not have relevant comorbidities (for example spinal muscular atrophy, severe tracheomalacia).
Consider requesting a chest physiotherapy assessment in babies and children who have relevant comorbidities (for example spinal muscular atrophy, severe tracheomalacia) when there may be additional difficulty clearing secretions.
Do not use any of the following to treat bronchiolitis in babies or children:
antibiotics
hypertonic saline
adrenaline (nebulised)
salbutamol
montelukast
ipratropium bromide
systemic or inhaled corticosteroids
a combination of systemic corticosteroids and nebulised adrenaline.
Give oxygen supplementation to babies and children with bronchiolitis if their oxygen saturation is:
persistently less than 90%, for children aged 6 weeks and over
persistently less than 92%, for babies under 6 weeks or children of any age with underlying health conditions. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Consider continuous positive airway pressure (CPAP) in babies and children with bronchiolitis who have impending respiratory failure (see recommendation 1.1.10).
Do not routinely perform upper airway suctioning in babies or children with bronchiolitis.
Consider upper airway suctioning in babies and children who have respiratory distress or feeding difficulties because of upper airway secretions.
Perform upper airway suctioning in babies and children with bronchiolitis presenting with apnoea even if there are no obvious upper airway secretions.
Do not routinely carry out blood gas testing in babies or children with bronchiolitis.
Consider carrying out capillary blood gas testing in babies and children with severe worsening respiratory distress (when supplemental oxygen concentration is greater than 50%) or suspected impending respiratory failure (see recommendation 1.1.10).
Give fluids by nasogastric or orogastric tube in babies and children with bronchiolitis if they cannot take enough fluid by mouth.
Give intravenous isotonic fluids (see the NICE guideline on intravenous fluid therapy in children) to babies and children who:
do not tolerate nasogastric or orogastric fluids or
have impending respiratory failure.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on management of bronchiolitis .
Full details of the evidence and the committee's discussion are in evidence review A: criteria for referral, admission, oxygen supplementation and discharge.
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# When to discharge
When deciding on the timing of discharge for babies and children admitted to hospital, make sure that they:
are clinically stable
are taking adequate oral fluids
have maintained an oxygen saturation in air at the following levels for 4 hours, including a period of sleep:
-ver 90%, for children aged 6 weeks and over
-ver 92%, for babies under 6 weeks or children of any age with underlying health conditions. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
When deciding whether to discharge a baby or child, take into account factors that might affect a carer's ability to look after a baby or child with bronchiolitis, for example:
social circumstances
the skill and confidence of the carer in looking after a baby or child with bronchiolitis at home
confidence in being able to spot red flag symptoms (see recommendation 1.6.1)
distance to healthcare in case of deterioration.
Provide parents or carers with key safety information (see recommendation 1.6.1) when the baby or child is discharged.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on when to discharge .
Full details of the evidence and the committee's discussion are in evidence review A: criteria for referral, admission, oxygen supplementation and discharge.
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# Key safety information for looking after a baby or child at home
Provide key safety information for parents and carers to take away for reference for babies and children who will be looked after at home. This should cover:
how to recognise developing 'red flag' symptoms:
worsening work of breathing (for example grunting, nasal flaring, marked chest recession)
fluid intake is 50% to 75% of normal or no wet nappy for 12 hours
apnoea or cyanosis
exhaustion (for example, not responding normally to social cues, wakes only with prolonged stimulation).
that people should not smoke in the baby or child's home because it increases the risk of more severe symptoms in bronchiolitis
how to get immediate help from an appropriate professional if any red flag symptoms develop
arrangements for follow‑up if necessary. # Research recommendations
The 2015 guideline committee made the following recommendations for research.
# Oxygen saturation measurement in primary care
What is the clinical and cost effectiveness of oxygen saturation (SpO2) measurement in primary care in babies and children with bronchiolitis?
## Why this is important
There are no studies to inform the use of SpO2 measurement in primary care. SpO2 is used routinely in secondary care to help decide on the need for admission to hospital. The clinical and cost effectiveness of SpO2 measurement in primary care is also important. SpO2 is not routinely measured in infants and young children with bronchiolitis in primary care. The value of SpO2 measurement to help identify those who need admission to hospital should be assessed. Possible outcomes might be fewer or more infants being referred to hospital, or admitted.
# Paediatric early warning score (PEWS) as a predictor of deterioration
In babies and children with bronchiolitis can paediatric early warning score (PEWS) predict deterioration?
## Why this is important
In babies and children with bronchiolitis there is clinical uncertainty about the prediction of deterioration. There are a number of clinical scores for bronchiolitis that include objective and subjective measures. No bronchiolitis score is currently in widespread use in clinical practice. Increasingly, PEWS is being employed generically in paediatric practice in the UK. The effectiveness of PEWS in predicting deterioration for infants with bronchiolitis needs to be assessed.
# Combined bronchodilator and corticosteroid therapy for bronchiolitis
What is the efficacy of combined bronchodilator and corticosteroid therapy?
## Why this is important
There are no effective therapies for the treatment of bronchiolitis. One study reported that infants provided with both nebulised adrenaline and systemic steroids had improved clinical outcomes. This was a subgroup analysis, so was not anticipated in the trial design and consequently the analysis was not adequately powered to answer this question. A multicentre randomised controlled trial (RCT) that assesses the clinical and cost effectiveness of combined adrenaline and corticosteroids treatment for bronchiolitis is needed.
# High‑flow humidified oxygen and oxygen
What is the clinical and cost effectiveness of high‑flow humidified oxygen versus standard supplemental oxygen?
## Why this is important
Providing oxygen (typically by nasal cannula) is standard care for bronchiolitis. Newly‑developed medical devices can now deliver high‑flow humidified oxygen that is thought to provide more comfortable and effective delivery of gases while retaining airway humidity. The use of this medical device is becoming widespread without demonstration of additional efficacy. A multicentre RCT comparing high‑flow humidified oxygen and standard supplemental oxygen would be of benefit, as would including weaning strategies for high‑flow humidified oxygen.
# Nasal suction
What is the clinical and cost effectiveness of suction to remove secretions from the upper respiratory tract compared with minimal handling?
## Why this is important
Suction is a commonly used therapy in bronchiolitis. Infants are obligate nasal breathers, so removal of secretions is thought to relieve respiratory distress. However, suction is distressing to infants and parents. Methods vary and there is no evidence on which approach, if any, is most effective. In some trials it appears that minimal handling is more effective than therapies. A multicentre RCT comparing the clinical and cost effectiveness of suction (also covering different suction strategies, for example superficial versus deep) with minimal handling is needed.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# When to refer
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendations
The committee did not consider any of the evidence on oxygen saturation thresholds that they reviewed to be directly relevant to referral, because the studies focused on admission, management, and discharge. However, they needed to review these recommendations to ensure that they were in line with the changes to the recommendations on admission, management and discharge, and to avoid any contradictions.
For most babies and children, the oxygen saturation threshold has been lowered to 90% for admission, management and discharge, but the committee felt that the original threshold of 92% remained appropriate for referral. They agreed with the rationale in the 2015 guideline that this threshold of 92% enabled a safety margin for babies and children whose condition may be deteriorating, because their oxygen saturation level may drop further.
Although an oxygen saturation level of less than 92% indicates that a baby or child needs further clinical assessment, the committee did not feel that this criterion alone was enough to justify immediate transfer to hospital (as specified in the 2015 guideline). Oxygen saturation measurement may be less accurate in primary care than in hospital (for example, because paediatric oximeters are often not available in primary care). As a result, the committee removed the oxygen saturation threshold as a criterion that requires immediate referral to hospital and instead included it as a criterion that requires consideration of referral to hospital. They did not think that this change is likely to mean significant changes in practice, because:
it is unlikely for a baby or child to have an oxygen saturation level of less than 92% but none of the other criteria for immediate referral, so seriously unwell babies and children will still be immediately referred to hospital
the oxygen saturation threshold has been moved to recommendation 1.2.2 and can still be used to justify a referral to hospital, based on the clinical judgement of the healthcare professional.
Because the oxygen saturation thresholds are now lower for discharge from hospital than they are for referral to hospital, the committee discussed whether this could lead to babies and children being inappropriately referred straight back to hospital after discharge. The committee agreed that the changes to the referral recommendations would avoid this, because the recommendations now put less emphasis on using oxygen saturation level alone as the reason for referral. They also noted that many babies and children would have a post-discharge management plan, which could give guidance on when re-referral would and would not be needed.
## How the recommendations might affect practice
The recommendations are unlikely to result in a significant change to the number of referrals to hospital. Oxygen saturation level alone can still be used as a reason for referral, but it is no longer a reason for immediate referral (for example by ambulance).
There may be a small increase in the number of babies and children being immediately referred to hospital if they meet one of the other criteria in recommendation 1.2.1. This is because, in the committee's experience, some babies and children who met the other criteria in recommendation 1.2.1 were not referred if they did not also have an oxygen saturation below 92%.
## Other factors the committee took into account
See the rationale and impact section on when to discharge , for the committee's discussion of the variations in pulse oximeter accuracy based on skin tone.
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# When to admit
Recommendation 1.3.2
## Why the committee made the recommendation
The committee reviewed an observational study and a randomised controlled trial. They did not feel that the evidence from the observational study could be used to change the 2015 recommendations. It was assessed as being very low-quality evidence, based on the study design and a very serious risk of bias. However, the committee believed that the randomised controlled trial could be used to change the 2015 recommendations, because it involved babies and children who were assessed in an emergency department and so was directly relevant to this part of the guideline.
The 2015 recommendation specifies 'persistent' oxygen saturation levels, and the committee felt that this means babies and children would be assessed and monitored for some time in an emergency healthcare setting. This extended assessment and monitoring would allow healthcare professionals to understand the baby or child's overall health and whether it was worsening. In this context, there is very little risk of harm from reducing the oxygen saturation threshold level needed for admission from 92% to 90%. However, the committee acknowledged that some babies and children are at higher risk of severe bronchiolitis (babies under 6 weeks, and children with underlying health conditions). The randomised controlled trial did not include this group, so there was no evidence available for them. Because of this, the committee agreed it would be safer to retain the threshold of 92% for babies and children at higher risk.
Parents and carers of babies and children who are not admitted should receive key safety advice (see recommendation 1.6.1).
Reducing the oxygen saturation threshold for admission also makes these recommendations consistent with the updated management and discharge recommendations.
## How the recommendation might affect practice
Babies and children assessed for bronchiolitis in hospital often meet multiple admission criteria. For these babies and children, there will be no impact from the updated recommendation, because they will still be admitted based on other criteria. There may be fewer admissions for babies and children whose only indication is persistent decreased oxygen saturation level.
There would be a reduction in NHS costs if the change in threshold led to a substantial reduction in the number of babies and children admitted to hospital, but it is unclear how large the change would be in practice.
## Other factors the committee took into account
See the rationale and impact section on when to discharge , for the committee's discussion of the variations in pulse oximeter accuracy based on skin tone.
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# Management of bronchiolitis
Recommendation 1.4.4
## Why the committee made the recommendation
A randomised controlled trial found that using an oxygen saturation threshold of 90% (compared with a threshold of 94%) for deciding whether to provide supplementary oxygen and discharge from hospital significantly reduced the need for supplemental oxygen and the time to discharge. The trial also showed that readmission rates were not higher with a 90% threshold, compared with a 94% threshold.
The intervention, population and setting of the trial were directly relevant to management and discharge from hospital, so the committee believed it was appropriate to change the oxygen saturation thresholds used in the 2015 guideline. In addition, they noted that the 2015 thresholds were based on the 2015 committee's experience alone, because no direct evidence was available at the time. The trial included babies and children with fewer comorbidities who had less risk of poor outcomes compared with babies and children with bronchiolitis typically seen in hospital, who may have a more varied risk profile. Because there was no evidence for babies and children at higher risk (babies under 6 weeks and children of any age with underlying health conditions), the committee agreed it would be safer to retain the threshold of 92% for this group.
## How the recommendation might affect practice
Reducing the oxygen saturation threshold will mean that fewer babies and children are given supplementary oxygen. All other aspects of bronchiolitis management remain unchanged and healthcare professionals should stay aware of the full clinical picture.
There is likely to be a reduction in NHS costs as a result of this recommendation, due to both a reduced duration of oxygen therapy in hospital, and a reduced length of hospital stay.
## Other factors the committee took into account
See the rationale and impact section on when to discharge , for the committee's discussion of the variations in pulse oximeter accuracy based on skin tone.
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# When to discharge
Recommendation 1.5.1
## Why the committee made the recommendation
A randomised controlled trial found that using an oxygen saturation threshold of 90% (compared with a threshold of 94%) for deciding whether to provide supplementary oxygen and discharge from hospital significantly reduced the need for supplemental oxygen and the time to discharge. The trial also showed that readmission rates were not higher with a 90% threshold, compared with a 94% threshold.
The intervention, population and setting of the trial were directly relevant to management and discharge from hospital, so the committee believed it was appropriate to change the oxygen saturation thresholds used in the 2015 guideline. In addition, they noted that the 2015 thresholds were based on the 2015 committee's experience alone, because no direct evidence was available at the time. The trial included babies and children with fewer comorbidities who had less risk of poor outcomes compared with babies and children with bronchiolitis typically seen in hospital, who may have a more varied risk profile. Because there was no evidence for children at higher risk (babies under 6 weeks and children of any age with underlying health conditions), the committee agreed it would be safer to retain the threshold of 92% for this group.
The committee noted that the decision to discharge should not just be based on oxygen saturation. The guideline includes other recommendations on criteria for discharge, and a recommendation on key safety criteria for parents and carers looking after the baby or child at home (recommendation 1.6.1), so the committee did not believe there was a significant risk to reducing the oxygen saturation threshold criteria.
## How the recommendation might affect practice
The reduction in oxygen saturation threshold will allow more babies and children to be discharged sooner, without increasing the risk of worse outcomes. Other criteria for discharge have not changed, so the decision to discharge will not be based on oxygen saturation alone.
## Other factors the committee took into account
There are emerging reports in other areas of clinical care that there may be variation in the accuracy of pulse oximetry depending on a person's skin tone. The 2021 update of the guideline did not look at the evidence in this area, so the committee did not make a recommendation to address the issue or a recommendation for further research.
The NHS Race and Health Observatory published a rapid review of the evidence in this area in March 2021. NICE will monitor for formal guidance from NHS England and NHS Improvement in this area, and update this guideline further as needed.
Return to recommendations# Context
Bronchiolitis is the most common disease of the lower respiratory tract during the first year of life. It usually presents with cough with increased work of breathing, and it often affects a baby's ability to feed. In primary care, the condition may often be confused with a common cold, though the presence of lower respiratory tract signs (wheeze or crackles on auscultation) in a baby in mid‑winter would be consistent with this clinical diagnosis. The symptoms are usually mild and may only last for a few days, but in some cases the disease can cause severe illness.
There are several individual and environmental risk factors that can put babies and children with bronchiolitis at increased risk of severe illness. These include congenital heart disease, neuromuscular disorders, immunodeficiency and chronic lung disease.
The management of bronchiolitis depends on the severity of the illness. In most babies and children bronchiolitis can be managed at home by parents or carers.
Approximately 1 in 3 babies will develop clinical bronchiolitis in the first year of life and 2% to 3% of all babies will need to be admitted to hospital. In 2011/12 in England, there were 30,451 secondary care admissions for the management of bronchiolitis. It is uncommon for bronchiolitis to cause death. In 2009/10 in England, there were 72 recorded deaths of babies and children within 90 days of hospital admission for bronchiolitis.
Bronchiolitis is associated with an increased risk of chronic respiratory conditions, including asthma, but it is not known if it causes these conditions.
The guideline covers babies and children with bronchiolitis but not those with other respiratory conditions, such as recurrent viral induced wheeze or asthma.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessment and diagnosis\n\nWhen diagnosing bronchiolitis, take into account that it occurs in babies and children under 2\xa0years of age and most commonly in the first year of life, peaking between 3 and 6\xa0months. \n\nWhen diagnosing bronchiolitis, take into account that symptoms usually peak between 3 and 5\xa0days, and that cough resolves in 90% of infants within 3\xa0weeks. \n\nDiagnose bronchiolitis if the baby or child has a coryzal prodrome lasting 1 to 3\xa0days, followed by:\n\npersistent cough and\n\neither tachypnoea or chest recession (or both) and\n\neither wheeze or crackles on chest auscultation (or both). \n\nWhen diagnosing bronchiolitis, take into account that the following symptoms are common in babies and children with this disease:\n\nfever (in around 30% of cases, usually of less than 39°C)\n\npoor feeding (typically after 3 to 5\xa0days of illness). \n\nWhen diagnosing bronchiolitis, take into account that young infants with this disease (in particular those under 6\xa0weeks of age) may present with apnoea without other clinical signs. \n\nConsider a diagnosis of pneumonia if the baby or child has:\n\nhigh fever (over 39°C) and/or\n\npersistently focal crackles.See also the NICE guideline on sepsis and risk stratification tool for sepsis in under 5s. \n\nThink about a diagnosis of viral‑induced wheeze or early‑onset asthma rather than bronchiolitis in older infants and young children if they have:\n\npersistent wheeze without crackles or\n\nrecurrent episodic wheeze or\n\na personal or family history of atopy.Take into account that these conditions are unusual in children under 1\xa0year of age. \n\nMeasure oxygen saturation in every baby and child presenting with suspected bronchiolitis, including those presenting to primary care if pulse oximetry is available. \n\nEnsure healthcare professionals performing pulse oximetry are appropriately trained in its use specifically in babies and young children. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin.\n\nSuspect impending respiratory failure, and take appropriate action as these babies and children may need intensive care (see recommendations 1.2.1 and 1.4.5), if any of the following are present:\n\nsigns of exhaustion, for example listlessness or decreased respiratory effort\n\nrecurrent apnoea\n\nfailure to maintain adequate oxygen saturation despite oxygen supplementation. \n\n# When to refer\n\nImmediately refer babies and children with bronchiolitis for emergency hospital care (usually by 999 ambulance) if they have any of the following:\n\napnoea (observed or reported)\n\nbaby or child looks seriously unwell to a healthcare professional\n\nsevere respiratory distress, for example grunting, marked chest recession, or a respiratory rate of over 70\xa0breaths/minute\n\ncentral cyanosis. \n\nConsider referring babies and children with bronchiolitis to hospital if they have any of the following:\n\na respiratory rate of over 60\xa0breaths/minute \n\ndifficulty with breastfeeding or inadequate oral fluid intake (50% to 75% of usual volume, taking account of risk factors [see recommendation 1.3.3] and using clinical judgement) \n\nclinical dehydration \n\npersistent oxygen saturation of less than 92%, when breathing air. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nWhen deciding whether to refer a baby or child with bronchiolitis to secondary care, take account of any known risk factors for more severe bronchiolitis such as:\n\nchronic lung disease (including bronchopulmonary dysplasia)\n\nhaemodynamically significant congenital heart disease\n\nage in young infants (under 3\xa0months)\n\npremature birth, particularly under 32\xa0weeks\n\nneuromuscular disorders\n\nimmunodeficiency. \n\nWhen deciding whether to refer a baby or child to secondary care, take into account factors that might affect a carer's ability to look after a child with bronchiolitis, for example:\n\nsocial circumstances\n\nthe skill and confidence of the carer in looking after a child with bronchiolitis at home\n\nconfidence in being able to spot red flag symptoms (see recommendation 1.6.1)\n\ndistance to healthcare in case of deterioration. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on when to refer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: criteria for referral, admission, oxygen supplementation and discharge.\n\nLoading. Please wait.\n\n# When to admit\n\nMeasure oxygen saturation using pulse oximetry in every baby and child presenting to secondary care with clinical evidence of bronchiolitis. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin.\n\nWhen assessing a baby or child in a secondary care setting, admit them to hospital if they have any of the following:\n\napnoea (observed or reported) \n\npersistent oxygen saturation (when breathing air) of:\n\n\n\nless than 90%, for children aged 6\xa0weeks and over\n\nless than 92%, for babies under 6\xa0weeks or children of any age with underlying health conditions \n\n\n\ninadequate oral fluid intake (50% to 75% of usual volume, taking account of risk factors [see recommendation 1.3.3] and using clinical judgement) \n\npersisting severe respiratory distress, for example grunting, marked chest recession, or a respiratory rate of over 70\xa0breaths/minute. \n\nWhen deciding whether to admit a baby or child with bronchiolitis, take account of any known risk factors for more severe bronchiolitis, such as:\n\nchronic lung disease (including bronchopulmonary dysplasia)\n\nhaemodynamically significant congenital heart disease\n\nage in young infants (under 3\xa0months)\n\npremature birth, particularly under 32\xa0weeks\n\nneuromuscular disorders\n\nimmunodeficiency. \n\nWhen deciding whether to admit a baby or child, take into account factors that might affect a carer's ability to look after a child with bronchiolitis, for example:\n\nsocial circumstances\n\nthe skill and confidence of the carer in looking after a child with bronchiolitis at home\n\nconfidence in being able to spot red flag symptoms (see recommendation 1.6.1)\n\ndistance to healthcare in case of deterioration. \n\nClinically assess the hydration status of babies and children with bronchiolitis. \n\nDo not routinely perform blood tests in the assessment of a baby or child with bronchiolitis. \n\nDo not routinely perform a chest X‑ray in babies or children with bronchiolitis, because changes on X‑ray may mimic pneumonia and should not be used to determine the need for antibiotics. \n\nConsider performing a chest X‑ray if intensive care is being proposed for a baby or child. \n\nProvide parents or carers with key safety information (see recommendation 1.6.1) if the baby or child is not admitted. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on when to admit\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: criteria for referral, admission, oxygen supplementation and discharge.\n\nLoading. Please wait.\n\n# Management of bronchiolitis\n\nDo not perform chest physiotherapy on babies and children with bronchiolitis who do not have relevant comorbidities (for example spinal muscular atrophy, severe tracheomalacia). \n\nConsider requesting a chest physiotherapy assessment in babies and children who have relevant comorbidities (for example spinal muscular atrophy, severe tracheomalacia) when there may be additional difficulty clearing secretions. \n\nDo not use any of the following to treat bronchiolitis in babies or children:\n\nantibiotics\n\nhypertonic saline\n\nadrenaline (nebulised)\n\nsalbutamol\n\nmontelukast\n\nipratropium bromide\n\nsystemic or inhaled corticosteroids\n\na combination of systemic corticosteroids and nebulised adrenaline. \n\nGive oxygen supplementation to babies and children with bronchiolitis if their oxygen saturation is:\n\npersistently less than 90%, for children aged 6\xa0weeks and over\n\npersistently less than 92%, for babies under 6\xa0weeks or children of any age with underlying health conditions. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nConsider continuous positive airway pressure (CPAP) in babies and children with bronchiolitis who have impending respiratory failure (see recommendation 1.1.10). \n\nDo not routinely perform upper airway suctioning in babies or children with bronchiolitis. \n\nConsider upper airway suctioning in babies and children who have respiratory distress or feeding difficulties because of upper airway secretions. \n\nPerform upper airway suctioning in babies and children with bronchiolitis presenting with apnoea even if there are no obvious upper airway secretions. \n\nDo not routinely carry out blood gas testing in babies or children with bronchiolitis. \n\nConsider carrying out capillary blood gas testing in babies and children with severe worsening respiratory distress (when supplemental oxygen concentration is greater than 50%) or suspected impending respiratory failure (see recommendation 1.1.10). \n\nGive fluids by nasogastric or orogastric tube in babies and children with bronchiolitis if they cannot take enough fluid by mouth. \n\nGive intravenous isotonic fluids (see the NICE guideline on intravenous fluid therapy in children) to babies and children who:\n\ndo not tolerate nasogastric or orogastric fluids or\n\nhave impending respiratory failure. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on management of bronchiolitis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: criteria for referral, admission, oxygen supplementation and discharge.\n\nLoading. Please wait.\n\n# When to discharge\n\nWhen deciding on the timing of discharge for babies and children admitted to hospital, make sure that they:\n\nare clinically stable \n\nare taking adequate oral fluids \n\nhave maintained an oxygen saturation in air at the following levels for 4\xa0hours, including a period of sleep:\n\n\n\nover 90%, for children aged 6\xa0weeks and over\n\nover 92%, for babies under 6\xa0weeks or children of any age with underlying health conditions. December 2018: Follow the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\n\n\nWhen deciding whether to discharge a baby or child, take into account factors that might affect a carer's ability to look after a baby or child with bronchiolitis, for example:\n\nsocial circumstances\n\nthe skill and confidence of the carer in looking after a baby or child with bronchiolitis at home\n\nconfidence in being able to spot red flag symptoms (see recommendation 1.6.1)\n\ndistance to healthcare in case of deterioration. \n\nProvide parents or carers with key safety information (see recommendation 1.6.1) when the baby or child is discharged. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on when to discharge\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: criteria for referral, admission, oxygen supplementation and discharge.\n\nLoading. Please wait.\n\n# Key safety information for looking after a baby or child at home\n\nProvide key safety information for parents and carers to take away for reference for babies and children who will be looked after at home. This should cover:\n\nhow to recognise developing 'red flag' symptoms:\n\n\n\nworsening work of breathing (for example grunting, nasal flaring, marked chest recession)\n\nfluid intake is 50% to 75% of normal or no wet nappy for 12\xa0hours\n\napnoea or cyanosis\n\nexhaustion (for example, not responding normally to social cues, wakes only with prolonged stimulation).\n\n\n\nthat people should not smoke in the baby or child's home because it increases the risk of more severe symptoms in bronchiolitis\n\nhow to get immediate help from an appropriate professional if any red flag symptoms develop\n\narrangements for follow‑up if necessary. ", 'Research recommendations': 'The 2015 guideline committee made the following recommendations for research.\n\n# Oxygen saturation measurement in primary care\n\nWhat is the clinical and cost effectiveness of oxygen saturation (SpO2) measurement in primary care in babies and children with bronchiolitis?\n\n## Why this is important\n\nThere are no studies to inform the use of SpO2 measurement in primary care. SpO2 is used routinely in secondary care to help decide on the need for admission to hospital. The clinical and cost effectiveness of SpO2 measurement in primary care is also important. SpO2 is not routinely measured in infants and young children with bronchiolitis in primary care. The value of SpO2 measurement to help identify those who need admission to hospital should be assessed. Possible outcomes might be fewer or more infants being referred to hospital, or admitted.\n\n# Paediatric early warning score (PEWS) as a predictor of deterioration\n\nIn babies and children with bronchiolitis can paediatric early warning score (PEWS) predict deterioration?\n\n## Why this is important\n\nIn babies and children with bronchiolitis there is clinical uncertainty about the prediction of deterioration. There are a number of clinical scores for bronchiolitis that include objective and subjective measures. No bronchiolitis score is currently in widespread use in clinical practice. Increasingly, PEWS is being employed generically in paediatric practice in the UK. The effectiveness of PEWS in predicting deterioration for infants with bronchiolitis needs to be assessed.\n\n# Combined bronchodilator and corticosteroid therapy for bronchiolitis\n\nWhat is the efficacy of combined bronchodilator and corticosteroid therapy?\n\n## Why this is important\n\nThere are no effective therapies for the treatment of bronchiolitis. One study reported that infants provided with both nebulised adrenaline and systemic steroids had improved clinical outcomes. This was a subgroup analysis, so was not anticipated in the trial design and consequently the analysis was not adequately powered to answer this question. A multicentre randomised controlled trial (RCT) that assesses the clinical and cost effectiveness of combined adrenaline and corticosteroids treatment for bronchiolitis is needed.\n\n# High‑flow humidified oxygen and oxygen\n\nWhat is the clinical and cost effectiveness of high‑flow humidified oxygen versus standard supplemental oxygen?\n\n## Why this is important\n\nProviding oxygen (typically by nasal cannula) is standard care for bronchiolitis. Newly‑developed medical devices can now deliver high‑flow humidified oxygen that is thought to provide more comfortable and effective delivery of gases while retaining airway humidity. The use of this medical device is becoming widespread without demonstration of additional efficacy. A multicentre RCT comparing high‑flow humidified oxygen and standard supplemental oxygen would be of benefit, as would including weaning strategies for high‑flow humidified oxygen.\n\n# Nasal suction\n\nWhat is the clinical and cost effectiveness of suction to remove secretions from the upper respiratory tract compared with minimal handling?\n\n## Why this is important\n\nSuction is a commonly used therapy in bronchiolitis. Infants are obligate nasal breathers, so removal of secretions is thought to relieve respiratory distress. However, suction is distressing to infants and parents. Methods vary and there is no evidence on which approach, if any, is most effective. In some trials it appears that minimal handling is more effective than therapies. A multicentre RCT comparing the clinical and cost effectiveness of suction (also covering different suction strategies, for example superficial versus deep) with minimal handling is needed.', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# When to refer\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nThe committee did not consider any of the evidence on oxygen saturation thresholds that they reviewed to be directly relevant to referral, because the studies focused on admission, management, and discharge. However, they needed to review these recommendations to ensure that they were in line with the changes to the recommendations on admission, management and discharge, and to avoid any contradictions.\n\nFor most babies and children, the oxygen saturation threshold has been lowered to 90% for admission, management and discharge, but the committee felt that the original threshold of 92% remained appropriate for referral. They agreed with the rationale in the 2015 guideline that this threshold of 92% enabled a safety margin for babies and children whose condition may be deteriorating, because their oxygen saturation level may drop further.\n\nAlthough an oxygen saturation level of less than 92% indicates that a baby or child needs further clinical assessment, the committee did not feel that this criterion alone was enough to justify immediate transfer to hospital (as specified in the 2015 guideline). Oxygen saturation measurement may be less accurate in primary care than in hospital (for example, because paediatric oximeters are often not available in primary care). As a result, the committee removed the oxygen saturation threshold as a criterion that requires immediate referral to hospital and instead included it as a criterion that requires consideration of referral to hospital. They did not think that this change is likely to mean significant changes in practice, because:\n\nit is unlikely for a baby or child to have an oxygen saturation level of less than 92% but none of the other criteria for immediate referral, so seriously unwell babies and children will still be immediately referred to hospital\n\nthe oxygen saturation threshold has been moved to recommendation 1.2.2 and can still be used to justify a referral to hospital, based on the clinical judgement of the healthcare professional.\n\nBecause the oxygen saturation thresholds are now lower for discharge from hospital than they are for referral to hospital, the committee discussed whether this could lead to babies and children being inappropriately referred straight back to hospital after discharge. The committee agreed that the changes to the referral recommendations would avoid this, because the recommendations now put less emphasis on using oxygen saturation level alone as the reason for referral. They also noted that many babies and children would have a post-discharge management plan, which could give guidance on when re-referral would and would not be needed.\n\n## How the recommendations might affect practice\n\nThe recommendations are unlikely to result in a significant change to the number of referrals to hospital. Oxygen saturation level alone can still be used as a reason for referral, but it is no longer a reason for immediate referral (for example by ambulance).\n\nThere may be a small increase in the number of babies and children being immediately referred to hospital if they meet one of the other criteria in recommendation 1.2.1. This is because, in the committee's experience, some babies and children who met the other criteria in recommendation 1.2.1 were not referred if they did not also have an oxygen saturation below 92%.\n\n## Other factors the committee took into account\n\nSee the rationale and impact section on when to discharge\xa0, for the committee's discussion of the variations in pulse oximeter accuracy based on skin tone.\n\nReturn to recommendations\n\nLoading. Please wait.\n\n# When to admit\n\nRecommendation 1.3.2\n\n## Why the committee made the recommendation\n\nThe committee reviewed an observational study and a randomised controlled trial. They did not feel that the evidence from the observational study could be used to change the 2015 recommendations. It was assessed as being very low-quality evidence, based on the study design and a very serious risk of bias. However, the committee believed that the randomised controlled trial could be used to change the 2015 recommendations, because it involved babies and children who were assessed in an emergency department and so was directly relevant to this part of the guideline.\n\nThe 2015 recommendation specifies 'persistent' oxygen saturation levels, and the committee felt that this means babies and children would be assessed and monitored for some time in an emergency healthcare setting. This extended assessment and monitoring would allow healthcare professionals to understand the baby or child's overall health and whether it was worsening. In this context, there is very little risk of harm from reducing the oxygen saturation threshold level needed for admission from 92% to 90%. However, the committee acknowledged that some babies and children are at higher risk of severe bronchiolitis (babies under 6\xa0weeks, and children with underlying health conditions). The randomised controlled trial did not include this group, so there was no evidence available for them. Because of this, the committee agreed it would be safer to retain the threshold of 92% for babies and children at higher risk.\n\nParents and carers of babies and children who are not admitted should receive key safety advice (see recommendation 1.6.1).\n\nReducing the oxygen saturation threshold for admission also makes these recommendations consistent with the updated management and discharge recommendations.\n\n## How the recommendation might affect practice\n\nBabies and children assessed for bronchiolitis in hospital often meet multiple admission criteria. For these babies and children, there will be no impact from the updated recommendation, because they will still be admitted based on other criteria. There may be fewer admissions for babies and children whose only indication is persistent decreased oxygen saturation level.\n\nThere would be a reduction in NHS costs if the change in threshold led to a substantial reduction in the number of babies and children admitted to hospital, but it is unclear how large the change would be in practice.\n\n## Other factors the committee took into account\n\nSee the rationale and impact section on when to discharge\xa0, for the committee's discussion of the variations in pulse oximeter accuracy based on skin tone.\n\nReturn to recommendations\n\nLoading. Please wait.\n\n# Management of bronchiolitis\n\nRecommendation 1.4.4\n\n## Why the committee made the recommendation\n\nA randomised controlled trial found that using an oxygen saturation threshold of 90% (compared with a threshold of 94%) for deciding whether to provide supplementary oxygen and discharge from hospital significantly reduced the need for supplemental oxygen and the time to discharge. The trial also showed that readmission rates were not higher with a 90% threshold, compared with a 94% threshold.\n\nThe intervention, population and setting of the trial were directly relevant to management and discharge from hospital, so the committee believed it was appropriate to change the oxygen saturation thresholds used in the 2015 guideline. In addition, they noted that the 2015 thresholds were based on the 2015 committee's experience alone, because no direct evidence was available at the time. The trial included babies and children with fewer comorbidities who had less risk of poor outcomes compared with babies and children with bronchiolitis typically seen in hospital, who may have a more varied risk profile. Because there was no evidence for babies and children at higher risk (babies under 6\xa0weeks and children of any age with underlying health conditions), the committee agreed it would be safer to retain the threshold of 92% for this group.\n\n## How the recommendation might affect practice\n\nReducing the oxygen saturation threshold will mean that fewer babies and children are given supplementary oxygen. All other aspects of bronchiolitis management remain unchanged and healthcare professionals should stay aware of the full clinical picture.\n\nThere is likely to be a reduction in NHS costs as a result of this recommendation, due to both a reduced duration of oxygen therapy in hospital, and a reduced length of hospital stay.\n\n## Other factors the committee took into account\n\nSee the rationale and impact section on when to discharge\xa0, for the committee's discussion of the variations in pulse oximeter accuracy based on skin tone.\n\nReturn to recommendations\n\nLoading. Please wait.\n\n# When to discharge\n\nRecommendation 1.5.1\n\n## Why the committee made the recommendation\n\nA randomised controlled trial found that using an oxygen saturation threshold of 90% (compared with a threshold of 94%) for deciding whether to provide supplementary oxygen and discharge from hospital significantly reduced the need for supplemental oxygen and the time to discharge. The trial also showed that readmission rates were not higher with a 90% threshold, compared with a 94% threshold.\n\nThe intervention, population and setting of the trial were directly relevant to management and discharge from hospital, so the committee believed it was appropriate to change the oxygen saturation thresholds used in the 2015 guideline. In addition, they noted that the 2015 thresholds were based on the 2015 committee's experience alone, because no direct evidence was available at the time. The trial included babies and children with fewer comorbidities who had less risk of poor outcomes compared with babies and children with bronchiolitis typically seen in hospital, who may have a more varied risk profile. Because there was no evidence for children at higher risk (babies under 6\xa0weeks and children of any age with underlying health conditions), the committee agreed it would be safer to retain the threshold of 92% for this group.\n\nThe committee noted that the decision to discharge should not just be based on oxygen saturation. The guideline includes other recommendations on criteria for discharge, and a recommendation on key safety criteria for parents and carers looking after the baby or child at home (recommendation 1.6.1), so the committee did not believe there was a significant risk to reducing the oxygen saturation threshold criteria.\n\n## How the recommendation might affect practice\n\nThe reduction in oxygen saturation threshold will allow more babies and children to be discharged sooner, without increasing the risk of worse outcomes. Other criteria for discharge have not changed, so the decision to discharge will not be based on oxygen saturation alone.\n\n## Other factors the committee took into account\n\nThere are emerging reports in other areas of clinical care that there may be variation in the accuracy of pulse oximetry depending on a person's skin tone. The 2021 update of the guideline did not look at the evidence in this area, so the committee did not make a recommendation to address the issue or a recommendation for further research.\n\nThe NHS Race and Health Observatory published a rapid review of the evidence in this area in March 2021. NICE will monitor for formal guidance from NHS England and NHS Improvement in this area, and update this guideline further as needed.\n\nReturn to recommendations", 'Context': "Bronchiolitis is the most common disease of the lower respiratory tract during the first year of life. It usually presents with cough with increased work of breathing, and it often affects a baby's ability to feed. In primary care, the condition may often be confused with a common cold, though the presence of lower respiratory tract signs (wheeze or crackles on auscultation) in a baby in mid‑winter would be consistent with this clinical diagnosis. The symptoms are usually mild and may only last for a few days, but in some cases the disease can cause severe illness.\n\nThere are several individual and environmental risk factors that can put babies and children with bronchiolitis at increased risk of severe illness. These include congenital heart disease, neuromuscular disorders, immunodeficiency and chronic lung disease.\n\nThe management of bronchiolitis depends on the severity of the illness. In most babies and children bronchiolitis can be managed at home by parents or carers.\n\nApproximately 1\xa0in\xa03 babies will develop clinical bronchiolitis in the first year of life and 2% to 3% of all babies will need to be admitted to hospital. In 2011/12 in England, there were 30,451\xa0secondary care admissions for the management of bronchiolitis. It is uncommon for bronchiolitis to cause death. In 2009/10 in England, there were 72\xa0recorded deaths of babies and children within 90\xa0days of hospital admission for bronchiolitis.\n\nBronchiolitis is associated with an increased risk of chronic respiratory conditions, including asthma, but it is not known if it causes these conditions.\n\nThe guideline covers babies and children with bronchiolitis but not those with other respiratory conditions, such as recurrent viral induced wheeze or asthma."}
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https://www.nice.org.uk/guidance/ng9
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This guideline covers diagnosing and managing bronchiolitis in babies and children. It aims to help healthcare professionals diagnose bronchiolitis and identify if babies and children should be cared for at home or in hospital. It describes treatments and interventions that can be used to help with the symptoms of bronchiolitis.
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a90f5703532576f08879a35d6975e8a6fda61003
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nice
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Inducing and maintaining normothermia using temperature modulation devices to improve outcomes after stroke or subarachnoid haemorrhage
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Inducing and maintaining normothermia using temperature modulation devices to improve outcomes after stroke or subarachnoid haemorrhage
Evidence-based recommendations on inducing and maintaining normothermia using temperature modulation devices after stroke or subarachnoid haemorrhage in adults. This involves cooling the body using pads placed on the skin or tubes put into the body.
# Recommendations
Evidence on the safety and efficacy of inducing and maintaining normothermia using temperature modulation devices to improve outcomes after stroke or subarachnoid haemorrhage is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should preferably be randomised controlled trials. It should report details of patient selection (including cause of fever, severity of stroke and neurological injury), method and duration of cooling, time from the neurological injury and onset of fever to starting cooling, complications related to the procedure and the device, neurological outcomes assessed using validated measures, and patient-reported outcomes (including quality of life) in the long term.# The condition, current treatments and procedure
# The condition
Stroke (ischaemic stroke and intracerebral haemorrhage) is an acute neurological event presumed to be vascular in origin and causing cerebral ischaemia, cerebral infarction or cerebral haemorrhage. Subarachnoid haemorrhage (SAH) is a haemorrhage from a cerebral blood vessel, aneurysm or vascular malformation into the subarachnoid space.
Both conditions can interrupt blood flow to the brain, damage brain cells and cause abnormalities of thermoregulation and an abnormally high body temperature (neurogenic fever). The abnormally high temperature may result in secondary neurological injury and is associated with worse outcomes, greater morbidity and mortality.
# Current treatments
Diagnosis and initial management of stroke is described in NICE's guideline on stroke and transient ischaemic attack in over 16s. Current treatments for managing fever after stroke or SAH include identifying and treating a cause, antipyretic medications and standard physical methods of cooling such as fans and cooling blankets to lower body temperature.
# The procedure
In this procedure, a temperature modulation device is used to maintain the patient's core temperature within normal limits (37.0±0.5oC). Either surface techniques (such as heat exchange cooling pads) or internal techniques (such as an endovascular cooling device) may be used. Heat is exchanged between the patient and the device to allow the body temperature to be controlled to a pre-set point determined by the clinician.
This procedure aims to reduce brain injury and improve neurological outcomes after stroke or SAH by maintaining normothermia with precise temperature control.
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{'Recommendations': 'Evidence on the safety and efficacy of inducing and maintaining normothermia using temperature modulation devices to improve outcomes after stroke or subarachnoid haemorrhage is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should preferably be randomised controlled trials. It should report details of patient selection (including cause of fever, severity of stroke and neurological injury), method and duration of cooling, time from the neurological injury and onset of fever to starting cooling, complications related to the procedure and the device, neurological outcomes assessed using validated measures, and patient-reported outcomes (including quality of life) in the long term.', 'The condition, current treatments and procedure': "# The condition\n\nStroke (ischaemic stroke and intracerebral haemorrhage) is an acute neurological event presumed to be vascular in origin and causing cerebral ischaemia, cerebral infarction or cerebral haemorrhage. Subarachnoid haemorrhage (SAH) is a haemorrhage from a cerebral blood vessel, aneurysm or vascular malformation into the subarachnoid space.\n\nBoth conditions can interrupt blood flow to the brain, damage brain cells and cause abnormalities of thermoregulation and an abnormally high body temperature (neurogenic fever). The abnormally high temperature may result in secondary neurological injury and is associated with worse outcomes, greater morbidity and mortality.\n\n# Current treatments\n\nDiagnosis and initial management of stroke is described in NICE's guideline on stroke and transient ischaemic attack in over 16s. Current treatments for managing fever after stroke or SAH include identifying and treating a cause, antipyretic medications and standard physical methods of cooling such as fans and cooling blankets to lower body temperature.\n\n# The procedure\n\nIn this procedure, a temperature modulation device is used to maintain the patient's core temperature within normal limits (37.0±0.5oC). Either surface techniques (such as heat exchange cooling pads) or internal techniques (such as an endovascular cooling device) may be used. Heat is exchanged between the patient and the device to allow the body temperature to be controlled to a pre-set point determined by the clinician.\n\nThis procedure aims to reduce brain injury and improve neurological outcomes after stroke or SAH by maintaining normothermia with precise temperature control."}
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https://www.nice.org.uk/guidance/ipg701
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Evidence-based recommendations on inducing and maintaining normothermia using temperature modulation devices after stroke or subarachnoid haemorrhage in adults. This involves cooling the body using pads placed on the skin or tubes put into the body.
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68a504ddc3476b17f946fa5aab173eed6e6f959e
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nice
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Nivolumab with ipilimumab for previously treated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency
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Nivolumab with ipilimumab for previously treated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency
Evidence-based recommendations on nivolumab with ipilimumab for previously treated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency in adults.
# Recommendations
Nivolumab plus ipilimumab is recommended, within its marketing authorisation, as an option for treating metastatic colorectal cancer with high microsatellite instability (MSI) or mismatch repair (MMR) deficiency after fluoropyrimidine-based combination chemotherapy. It is recommended only if the company provides nivolumab and ipilimumab according to the commercial arrangement.
Why the committee made these recommendations
People with previously treated metastatic colorectal cancer that has high MSI or MMR deficiency are usually offered combination chemotherapy including FOLFOX, FOLFIRI or trifluridine–tipiracil, and best supportive care. This is the same as what is offered for most other types of metastatic colorectal cancer.
Clinical trial evidence suggests that nivolumab plus ipilimumab may extend how long people live. The most relevant trial did not directly compare nivolumab plus ipilimumab with usual treatments, but indirect comparisons suggest that it substantially increases how long it takes for the cancer to get worse and how long people live.
The cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So, nivolumab plus ipilimumab is recommended.# Information about nivolumab with ipilimumab
# Marketing authorisation indication
On 21 May 2021 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the extension of indication for nivolumab with ipilimumab (Opdivo and Yervoy, Bristol–Myers Squibb). The CHMP adopted a new indication as follows: adults with mismatch repair deficient or microsatellite instability-high metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy.
The exact wording of this indication will be available in the summary of product characteristics when nivolumab and ipilimumab receives its marketing authorisation.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of nivolumab is £2,633 per 240 mg per 24‑ml vial (excluding VAT; BNF online, assessed March 2021). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.
The list price of ipilimumab is £15,000 per 200‑mg vial (excluding VAT; BNF online, assessed March 2021). The company has a commercial arrangement. This makes ipilimumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bristol–Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee recognised that there were areas of uncertainty associated with the analyses presented (see ERG report, table 1, page 18), and took these into account in its decision making. It discussed the following issues (issues 1 to 6), which were outstanding after the technical engagement stage.
# The condition
## There is an unmet need for treatments for metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency
Colorectal cancer is a malignant tumour arising from the lining of the large intestine (colon and rectum). Mutations can cause microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency in some metastatic colorectal cancer cells. DNA MMR corrects errors that occur during DNA replication, so problems with DNA MMR can lead to mutations in the microsatellites (repetitive DNA sequences). This causes them to become unstable, resulting in cancerous tumours with high MSI. High MSI or DNA MMR deficiency occurs in around 4% of metastatic colorectal cancer. It is associated with a poorer prognosis and a greater risk of death than metastatic colorectal cancer without microsatellite instability. There are currently no specific treatments routinely commissioned for this type of colorectal cancer, so people are offered the same treatment whether or not their colorectal cancer has high MSI or DNA MMR deficiency. The committee concluded that there is an unmet need for treatments for this condition.
## People with the condition and clinicians would welcome new treatment options
The patient experts explained that a diagnosis of metastatic colorectal cancer with high MSI or DNA MMR deficiency affects the quality of life both physically and psychologically. They highlighted that current treatment options approved for use in the NHS for metastatic bowel cancer are extremely limited. They explained that nivolumab with ipilimumab offers them greater hope, additional treatment choice and extended survival. It also may have less debilitating side effects compared with current treatments that may not work as well for this type of colorectal cancer. In contrast to chemotherapy, the absence of side effects like nausea, stomach pain and fatigue means people have a better quality of life. The committee noted that nivolumab and ipilimumab are immunotherapies and work in a different way to chemotherapy and have a different safety profile. The patient experts noted that people appreciated the faster and less frequent administration of nivolumab with ipilimumab, and having potential fewer adverse effects compared with standard care. A clinical expert explained that, with a more effective treatment, there was potential that a person's cancer would respond well enough to have both longer survival and a better quality of life. The committee concluded that people with the condition and clinicians would welcome new treatment options.
# The treatment pathway
## Current standard care for people who have had previous treatment usually includes another fluoropyrimidine-based chemotherapy
Clinical experts explained that treatment options for previously treated metastatic colorectal cancer depend on previous treatments, fitness level and patient and clinician preference. Clinical experts explained there are currently no specific treatments available for colorectal cancer with high MSI or MMR deficiency, so the treatment pathway is normally the same as for colorectal cancer without these mutations. First-line treatments would normally use fluoropyrimidine-based combination chemotherapies such as folinic acid, fluorouracil (5‑FU) and oxaliplatin (FOLFOX) or folinic acid, 5‑FU and irinotecan (FOLFIRI) or capecitabine and oxaliplatin (CAPOX). The clinical experts also noted that a proportion of people have 'triple therapy' that consists of folinic acid, 5‑FU, irinotecan and oxaliplatin (FOLFOXIRI or FOLFIRINOX), but this has a higher toxicity than other combinations. Clinical experts explained that there are limited second-line treatment options, so the treatment options are very similar and would normally involve trying an alternative combination (for example, FOLFOX if previously treated with FOLFIRI). Trifluridine–tipiracil is used as a third-line treatment and beyond, and once other options are exhausted. Best supportive care is used for people who cannot tolerate active treatment. The NICE scope also included single-agent irinotecan and raltitrexed as comparators, but the company did not include these as comparator treatments. Clinical experts explained that single-agent irinotecan is rarely used because of the toxicities compared with other options and similar efficacy. They also explained that raltitrexed is rarely used in clinical practice for specific indications only, such as for people with a history of heart disease or who develop angina on 5‑FU‑based chemotherapy. The committee concluded that the most appropriate comparators are FOLFOX, FOLFIRI and best supportive care for second-line treatments, and trifluridine–tipiracil and best supportive care for further lines of treatment.
## Testing is routinely funded at diagnosis of metastatic colorectal cancer, and nivolumab with ipilimumab will be used as a second-line treatment
The committee was aware that molecular testing is needed to confirm high MSI or MMR deficiency. NICE diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer recommends testing all people with colorectal cancer, when first diagnosed. The clinical experts explained that nivolumab with ipilimumab would likely be used as a second-line treatment for people with high MSI or MMR deficiency because it has a higher expected benefit and lower treatment burden. The clinical lead for the Cancer Drugs Fund explained that testing for high MSI and MMR deficiency is routinely commissioned for all people newly diagnosed with metastatic colorectal cancer. Therefore, people who are eligible would already be identified at an earlier treatment stage. The committee was satisfied with the place in therapy and that people who are eligible would be identified at diagnosis of metastatic disease.
# Clinical evidence
## The population in CheckMate 142 is generalisable to people seen in NHS clinical practice
The clinical evidence for nivolumab with ipilimumab came from the single-arm phase 2, open-label, CheckMate 142 study. This study included 119 people with metastatic colorectal cancer with high MSI or MMR deficiency, previously treated with combination therapies. The clinical experts considered that people in the trial had a lot of previous treatments, with 40% having 3 or more previous systemic treatments. Some treatments did not reflect the UK treatment pathway, including vascular endothelial growth factor inhibitors and regorafenib. However, the clinical experts considered that these treatments would have minimal effect on treatment outcomes. The clinical experts considered the population included in CheckMate 142 would be generalisable to the people who would have nivolumab with ipilimumab in clinical practice. However, the population in CheckMate 142 may have had more extensive previous treatments than in NHS clinical practice because clinicians would prefer to use nivolumab with ipilimumab as a second-line treatment (see section 3.4). The committee concluded that CheckMate 142 is broadly generalisable to NHS clinical practice and appropriate for decision making.
## The CheckMate 142 outcomes show high response rates and long overall and progression-free survival
The primary outcome in CheckMate 142 was objective response rate, which was a composite end point of complete and partial response measured by RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumours). The objective response rate was 65% after a follow up of 51 months. The clinical experts considered that these response rates for nivolumab with ipilimumab were considerably greater than those they were used to seeing with current treatment. Clinical and patient experts explained that response rates in colorectal cancer are not always accurate because inflammatory tissue or scarring can be seen with conventional imaging techniques. Therefore, the committee noted that response rates may not fully represent clinical benefit and other outcomes should also be considered. Secondary outcomes in the trial were progression-free survival and overall survival. The clinical experts considered that the observed survival results suggested highly promising efficacy of nivolumab with ipilimumab with long progression-free and overall survival, which suggested that the treatment could be curative. Median progression-free and median overall survival are academic-in-confidence and cannot be reported here. The committee concluded that nivolumab with ipilimumab is likely to be a clinically effective treatment for metastatic colorectal cancer.
## The indirect comparison is highly uncertain, but nivolumab with ipilimumab is likely to substantially improve overall survival
CheckMate 142 is a single-arm trial and there is no evidence directly comparing the efficacy of nivolumab plus ipilimumab with other treatments. So, the company presented an indirect treatment comparison using unanchored matching-adjusted indirect comparisons (MAICs) with each relevant comparator. Mean progression-free survival and overall survival results from different studies were estimated by extrapolating from single arms of randomised controlled trials that used each comparator. The MAIC uses individual patient data from trials of 1 treatment to match baseline characteristics with trials of another treatment. After matching, outcomes may be easier to compare because the populations are likely to be more balanced. The company considered that this analysis compensated for some of the differences in study populations and was most appropriate in the absence of head-to-head clinical trial evidence or anchored indirect comparisons. The ERG considered that the adjustment provided in the MAIC analysis may have provided less biased estimates but there was no way of assessing residual bias or evaluate which adjustments reduced bias. Therefore, the ERG preferred a naive comparison because it was transparent in terms of the likely biases that existed within the comparison and to ensure the analysis did not introduce additional bias. The ERG also noted that both the naive comparison and the MAIC gave similar results. The committee understood that for an unanchored MAIC, population adjustment methods should adjust for all effect modifiers and prognostic variables. It considered this was unlikely for each analysis in the MAIC and this would allow for residual bias. The committee considered whether the use of mean survival was appropriate because it is very sensitive to the extrapolation used (see section 3.10), and whether a restricted mean may have been more appropriate to provide the lower bound for the matching adjustment. The committee considered that both the unanchored MAIC and naive comparisons may not reduce the uncertainty or bias in any meaningful way. It concluded that, despite methodological concerns and substantial uncertainty, the size of benefit of nivolumab plus ipilimumab as measured by overall survival and progression-free survival was likely to be greater than current standard care.
# Economic model
## The company's economic model is suitable for decision making
The company used a partitioned survival model to estimate the cost effectiveness of nivolumab plus ipilimumab compared with FOLFOX, FOLFIRI, trifluridine–tipiracil and best supportive care. The model included 3 health states: pre-progression, post-progression, and death. Transitions between each health state were informed by progression-free survival and overall survival from CheckMate 142 and the MAIC comparison (see section 3.7). Each progression health state was also divided into people having treatment and not having treatment, with proportions determined by time on treatment in each trial. The ERG agreed that the company's model captured all relevant health states and partitioned survival models are used widely used in cancer modelling. The committee concluded that the company's model structure was acceptable for decision making.
## Nivolumab with ipilimumab should be stopped as seen in CheckMate 142
In CheckMate 142, nivolumab with ipilimumab could be used until disease progression or stopping treatment because of toxicity or death. The company also introduced a change in study protocol that meant people could stop treatment when clinicians considered maximum clinical benefit had been achieved after a minimum of 2 years. The company originally included a 2‑year stopping rule in its model but removed this at technical engagement. The ERG considers that using the time on treatment seen in CheckMate 142 was appropriate and reflected how nivolumab with ipilimumab will be used in NHS clinical practice. Clinical experts explained that in NHS clinical practice, some people may benefit after 2 years of treatment and treatment would be stopped at the clinician's discretion. The patient experts also agreed that continuing treatment is circumstantial, and some people would benefit from continued treatment. The committee considered that the maximum clinical benefit had not been explicitly defined, but that the trial was likely to reflect clinical practice. The committee also considered a scenario where people did not stop treatment based on maximum clinical benefit and continued treatment until progression, but did not consider this would reflect its expected use. Therefore, it concluded that implementing a formal stopping rule was not necessary and the observed treatment stopping in CheckMate 142 was likely to be appropriate.
# Survival extrapolations
## A log-logistic parametric distribution is appropriate for extrapolating overall survival
For overall survival, progression-free survival and time on treatment, the company used semi-parametric models to extrapolate the outcomes of nivolumab plus ipilimumab across the full time horizon. These extrapolations used 6.44 months of Kaplan−Meier data and different parametric distributions for each outcome. The ERG considered that at the latest data-cut, using Kaplan−Meier data until 6.44 months was appropriate. The company used the log-logistic distribution to extrapolate progression-free survival, which the ERG considered had an excellent visual and statistical fit and appropriately represented the decreasing hazard. The company used the log-normal distribution to extrapolate overall survival. The ERG considered the log-logistic distribution to be more appropriate to extrapolate overall survival because this was also chosen for progression-free survival and both distributions have excellent visual and statistical fit. The committee noted that the choice of either log-normal or log-logistic extrapolation had minimal effect on the cost-effectiveness results. It noted concerns that using the partitioned survival model (see section 3.8) and the chosen extrapolations resulted in a modelled output that suggested people would stay in the post-progression health state for extended periods of time. The clinical experts considered it more likely that people would survive in a progression-free state and that the modelled output would not reflect what would be seen in clinical practice. The committee was aware that the company had incorporated background mortality into survival projections, which it considered appropriate. Also, the semi-parametric modelling approach was used to account for the complex shape of hazard and survival functions. The committee considered that there are limitations associated with combining the Kaplan−Meier data and parametric models in this way. Instead, a more flexible parametric model could have been used. It concluded that the log-logistic extrapolation was appropriate for decision making but that long-term survival extrapolations are highly uncertain.
# Utility values
## It is more appropriate to use post-progression utility values from the CORRECT study than the company approach
The company used progression-based health state utility values in the economic model from NICE'S technology appraisal guidance on cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy (from now, TA242). It considered these utility values most represented the population in CheckMate 142 because TA242 is for people with metastatic colorectal cancer after 1 line of therapy. The ERG noted some concerns with the source of data and considered the post-progression utility value of 0.69 as being too high. The ERG explained that the utility source used in TA242 was derived from health utility index rather than EuroQol 5D (EQ‑5D), so it does not follow the NICE reference case. In addition, it considered there were issues with reporting because people were alive for many months after their final health-related quality-of-life measurement. The ERG proposed using data from the CORRECT study with a utility value of 0.59 for the post-progressed state. These people had more previous treatments but the data were derived from a more recent study and used EQ‑5D. The clinical experts considered that because nivolumab and ipilimumab are expected to be used second line (see section 3.4), the utility values may be higher than those derived at later lines. But they also considered it appropriate to make conservative assumptions about post-progression utility values. The committee noted that the source of the progression-based utility values had minimal effect on the cost-effectiveness results. It concluded that the scenario using the CORRECT utility values was more appropriate but could be conservative.
## It is not appropriate to use treatment-specific utility values for nivolumab with ipilimumab
The company measured health-related quality of life using EQ-5D-3L in the single arm of CheckMate 142 and mapped this to UK preference scores to derive treatment-specific utility values for nivolumab with ipilimumab. The utility values derived for treatment with nivolumab were higher than in the general population and so, for face validity, the company capped utility values to that of the general population. The company explained that the novel mechanism of action for nivolumab with ipilimumab drives several key benefits, including improved toxicity and survival, that improve quality of life. The ERG considered that it would expect people having second-line treatment for metastatic colorectal cancer to have a lower quality of life than the general population. Without utility values from a randomised controlled trial with an appropriate comparator arm, the ERG did not consider there was enough justification to use utility values according to treatment status. Therefore, it considered using utility values according to progression status only from 1 source to be appropriate and used the CORRECT study in their base case. Removing treatment-specific utility values resulted in minimal effect on cost-effectiveness results. The committee concluded that it is more appropriate to use conservative utility values according to progression status from the CORRECT study.
# Subsequent treatments
## The costs of subsequent treatments in CheckMate 142 do not reflect NHS clinical practice
For simplicity, the company considered that the cost of treatments after any current line would be the same for all treatment arms and applied this as a one-off cost in the economic model. The ERG considered that the composition and duration of subsequent treatments are likely to differ according to treatment arm and requested further scenarios to explore these differences. To address the ERG's concerns, the company provided 3 scenarios:
A scenario based on clinical expert opinion that patients having nivolumab with ipilimumab would try further combination chemotherapy after progression.
A scenario as above but including encorafenib and cetuximab for about one-third of patients that also have BRAF mutations to align with NICE technology appraisal guidance on encorafenib plus cetuximab for previously treated BRAF V600E mutation-positive metastatic colorectal cancer.
A scenario based on the subsequent treatment data collected in CheckMate 142.The ERG highlighted that both scenarios based on clinical expert opinion used a median of 3 to 4 cycles of FOLFOX. But clinical experts noted that up to 12 cycles could be given if people are very fit and therefore increased the number of cycles to account for this. The ERG also considered that scenarios based on subsequent treatment data from CheckMate 142 were less appropriate because they included treatments that are not available in NHS clinical practice and the subsequent treatment data from CheckMate 142 are very immature. The ERG considered that analysis based on clinical expert opinion, including encorafenib with cetuximab for BRAF mutated, is one step closer to reflecting the subsequent treatments that will be used in clinical practice. The committee preferences were more aligned with the ERG but noted that that all scenarios had minimal effect on the cost-effectiveness results.
# Cost-effectiveness estimates
## Nivolumab with ipilimumab is cost effective compared with all comparators
The company's cost-effectiveness estimate included a patient access scheme discount, the results of which cannot be presented because of confidentiality. The company's base case gave an incremental cost-effectiveness ratio (ICER) range below £20,000 per quality-adjusted life year (QALY) gained for nivolumab plus ipilimumab compared with all other comparators. Some of the comparators and subsequent treatments also had confidential patient access schemes that were included in the ERG analysis. The ERG assumptions included:
A naive comparison in the MAIC (see section 3.7).
Overall survival extrapolation using the log-logistic distribution for extrapolation (see section 3.10).
Progression-based utility values from the CORRECT study (see sections 3.11 and 3.12).
Subsequent treatment costs using clinical expert opinion and assuming some people have encorafenib and cetuximab (see section 3.13).All ERG base-case analyses ICERs were also below £20,000 per QALY gained. The committee considered these results to be robust despite major uncertainties about comparative effectiveness (see section 3.7). It concluded that nivolumab with ipilimumab is a cost-effective use of NHS resources compared with all other comparators.
## Nivolumab and ipilimumab is likely to meet the end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Clinical experts explained that life expectancy after progressing in absence of nivolumab with ipilimumab was likely to be less than 24 months in most cases. They also explained that the preliminary overall survival results from CheckMate 142 were promising, with the likely extension to life of at least 3 months. The ERG agreed that, based on the latest data-cut, there is an improvement in overall survival of at least 3 months. The committee agreed that nivolumab with ipilimumab was likely to give an extension to life of at least 3 months. It concluded that nivolumab with ipilimumab meets the end of life criteria.
# Other factors
## There are no equality issues relevant to the recommendations
No equality or social value judgement issues were identified.
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{'Recommendations': 'Nivolumab plus ipilimumab is recommended, within its marketing authorisation, as an option for treating metastatic colorectal cancer with high microsatellite instability (MSI) or mismatch repair (MMR) deficiency after fluoropyrimidine-based combination chemotherapy. It is recommended only if the company provides nivolumab and ipilimumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nPeople with previously treated metastatic colorectal cancer that has high MSI or MMR deficiency are usually offered combination chemotherapy including FOLFOX, FOLFIRI or trifluridine–tipiracil, and best supportive care. This is the same as what is offered for most other types of metastatic colorectal cancer.\n\nClinical trial evidence suggests that nivolumab plus ipilimumab may extend how long people live. The most relevant trial did not directly compare nivolumab plus ipilimumab with usual treatments, but indirect comparisons suggest that it substantially increases how long it takes for the cancer to get worse and how long people live.\n\nThe cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So, nivolumab plus ipilimumab is recommended.', 'Information about nivolumab with ipilimumab': "# Marketing authorisation indication\n\nOn 21\xa0May\xa02021 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the extension of indication for nivolumab with ipilimumab (Opdivo and Yervoy, Bristol–Myers Squibb). The CHMP adopted a new indication as follows: adults with mismatch repair deficient or microsatellite instability-high metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy.\n\nThe exact wording of this indication will be available in the summary of product characteristics when nivolumab and ipilimumab receives its marketing authorisation.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of nivolumab is £2,633 per 240\xa0mg per 24‑ml vial (excluding VAT; BNF online, assessed March\xa02021). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\nThe list price of ipilimumab is £15,000 per 200‑mg vial (excluding VAT; BNF online, assessed March\xa02021). The company has a commercial arrangement. This makes ipilimumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol–Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee recognised that there were areas of uncertainty associated with the analyses presented (see ERG report, table\xa01, page\xa018), and took these into account in its decision making. It discussed the following issues (issues\xa01 to\xa06), which were outstanding after the technical engagement stage.\n\n# The condition\n\n## There is an unmet need for treatments for metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency\n\nColorectal cancer is a malignant tumour arising from the lining of the large intestine (colon and rectum). Mutations can cause microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency in some metastatic colorectal cancer cells. DNA MMR corrects errors that occur during DNA replication, so problems with DNA MMR can lead to mutations in the microsatellites (repetitive DNA sequences). This causes them to become unstable, resulting in cancerous tumours with high MSI. High MSI or DNA MMR deficiency occurs in around 4% of metastatic colorectal cancer. It is associated with a poorer prognosis and a greater risk of death than metastatic colorectal cancer without microsatellite instability. There are currently no specific treatments routinely commissioned for this type of colorectal cancer, so people are offered the same treatment whether or not their colorectal cancer has high MSI or DNA MMR deficiency. The committee concluded that there is an unmet need for treatments for this condition.\n\n## People with the condition and clinicians would welcome new treatment options\n\nThe patient experts explained that a diagnosis of metastatic colorectal cancer with high MSI or DNA MMR deficiency affects the quality of life both physically and psychologically. They highlighted that current treatment options approved for use in the NHS for metastatic bowel cancer are extremely limited. They explained that nivolumab with ipilimumab offers them greater hope, additional treatment choice and extended survival. It also may have less debilitating side effects compared with current treatments that may not work as well for this type of colorectal cancer. In contrast to chemotherapy, the absence of side effects like nausea, stomach pain and fatigue means people have a better quality of life. The committee noted that nivolumab and ipilimumab are immunotherapies and work in a different way to chemotherapy and have a different safety profile. The patient experts noted that people appreciated the faster and less frequent administration of nivolumab with ipilimumab, and having potential fewer adverse effects compared with standard care. A clinical expert explained that, with a more effective treatment, there was potential that a person's cancer would respond well enough to have both longer survival and a better quality of life. The committee concluded that people with the condition and clinicians would welcome new treatment options.\n\n# The treatment pathway\n\n## Current standard care for people who have had previous treatment usually includes another fluoropyrimidine-based chemotherapy\n\nClinical experts explained that treatment options for previously treated metastatic colorectal cancer depend on previous treatments, fitness level and patient and clinician preference. Clinical experts explained there are currently no specific treatments available for colorectal cancer with high MSI or MMR deficiency, so the treatment pathway is normally the same as for colorectal cancer without these mutations. First-line treatments would normally use fluoropyrimidine-based combination chemotherapies such as folinic acid, fluorouracil (5‑FU) and oxaliplatin (FOLFOX) or folinic acid, 5‑FU and irinotecan (FOLFIRI) or capecitabine and oxaliplatin (CAPOX). The clinical experts also noted that a proportion of people have 'triple therapy' that consists of folinic acid, 5‑FU, irinotecan and oxaliplatin (FOLFOXIRI or FOLFIRINOX), but this has a higher toxicity than other combinations. Clinical experts explained that there are limited second-line treatment options, so the treatment options are very similar and would normally involve trying an alternative combination (for example, FOLFOX if previously treated with FOLFIRI). Trifluridine–tipiracil is used as a third-line treatment and beyond, and once other options are exhausted. Best supportive care is used for people who cannot tolerate active treatment. The NICE scope also included single-agent irinotecan and raltitrexed as comparators, but the company did not include these as comparator treatments. Clinical experts explained that single-agent irinotecan is rarely used because of the toxicities compared with other options and similar efficacy. They also explained that raltitrexed is rarely used in clinical practice for specific indications only, such as for people with a history of heart disease or who develop angina on 5‑FU‑based chemotherapy. The committee concluded that the most appropriate comparators are FOLFOX, FOLFIRI and best supportive care for second-line treatments, and trifluridine–tipiracil and best supportive care for further lines of treatment.\n\n## Testing is routinely funded at diagnosis of metastatic colorectal cancer, and nivolumab with ipilimumab will be used as a second-line treatment\n\nThe committee was aware that molecular testing is needed to confirm high MSI or MMR deficiency. NICE diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer recommends testing all people with colorectal cancer, when first diagnosed. The clinical experts explained that nivolumab with ipilimumab would likely be used as a second-line treatment for people with high MSI or MMR deficiency because it has a higher expected benefit and lower treatment burden. The clinical lead for the Cancer Drugs Fund explained that testing for high MSI and MMR deficiency is routinely commissioned for all people newly diagnosed with metastatic colorectal cancer. Therefore, people who are eligible would already be identified at an earlier treatment stage. The committee was satisfied with the place in therapy and that people who are eligible would be identified at diagnosis of metastatic disease.\n\n# Clinical evidence\n\n## The population in CheckMate 142 is generalisable to people seen in NHS clinical practice\n\nThe clinical evidence for nivolumab with ipilimumab came from the single-arm phase\xa02, open-label, CheckMate\xa0142 study. This study included 119\xa0people with metastatic colorectal cancer with high MSI or MMR deficiency, previously treated with combination therapies. The clinical experts considered that people in the trial had a lot of previous treatments, with 40% having 3 or more previous systemic treatments. Some treatments did not reflect the UK treatment pathway, including vascular endothelial growth factor inhibitors and regorafenib. However, the clinical experts considered that these treatments would have minimal effect on treatment outcomes. The clinical experts considered the population included in CheckMate\xa0142 would be generalisable to the people who would have nivolumab with ipilimumab in clinical practice. However, the population in CheckMate\xa0142 may have had more extensive previous treatments than in NHS clinical practice because clinicians would prefer to use nivolumab with ipilimumab as a second-line treatment (see section\xa03.4). The committee concluded that CheckMate\xa0142 is broadly generalisable to NHS clinical practice and appropriate for decision making.\n\n## The CheckMate 142 outcomes show high response rates and long overall and progression-free survival\n\nThe primary outcome in CheckMate\xa0142 was objective response rate, which was a composite end point of complete and partial response measured by RECIST\xa01.1 criteria (Response Evaluation Criteria in Solid Tumours). The objective response rate was 65% after a follow up of 51\xa0months. The clinical experts considered that these response rates for nivolumab with ipilimumab were considerably greater than those they were used to seeing with current treatment. Clinical and patient experts explained that response rates in colorectal cancer are not always accurate because inflammatory tissue or scarring can be seen with conventional imaging techniques. Therefore, the committee noted that response rates may not fully represent clinical benefit and other outcomes should also be considered. Secondary outcomes in the trial were progression-free survival and overall survival. The clinical experts considered that the observed survival results suggested highly promising efficacy of nivolumab with ipilimumab with long progression-free and overall survival, which suggested that the treatment could be curative. Median progression-free and median overall survival are academic-in-confidence and cannot be reported here. The committee concluded that nivolumab with ipilimumab is likely to be a clinically effective treatment for metastatic colorectal cancer.\n\n## The indirect comparison is highly uncertain, but nivolumab with ipilimumab is likely to substantially improve overall survival\n\nCheckMate\xa0142 is a single-arm trial and there is no evidence directly comparing the efficacy of nivolumab plus ipilimumab with other treatments. So, the company presented an indirect treatment comparison using unanchored matching-adjusted indirect comparisons (MAICs) with each relevant comparator. Mean progression-free survival and overall survival results from different studies were estimated by extrapolating from single arms of randomised controlled trials that used each comparator. The MAIC uses individual patient data from trials of 1 treatment to match baseline characteristics with trials of another treatment. After matching, outcomes may be easier to compare because the populations are likely to be more balanced. The company considered that this analysis compensated for some of the differences in study populations and was most appropriate in the absence of head-to-head clinical trial evidence or anchored indirect comparisons. The ERG considered that the adjustment provided in the MAIC analysis may have provided less biased estimates but there was no way of assessing residual bias or evaluate which adjustments reduced bias. Therefore, the ERG preferred a naive comparison because it was transparent in terms of the likely biases that existed within the comparison and to ensure the analysis did not introduce additional bias. The ERG also noted that both the naive comparison and the MAIC gave similar results. The committee understood that for an unanchored MAIC, population adjustment methods should adjust for all effect modifiers and prognostic variables. It considered this was unlikely for each analysis in the MAIC and this would allow for residual bias. The committee considered whether the use of mean survival was appropriate because it is very sensitive to the extrapolation used (see section\xa03.10), and whether a restricted mean may have been more appropriate to provide the lower bound for the matching adjustment. The committee considered that both the unanchored MAIC and naive comparisons may not reduce the uncertainty or bias in any meaningful way. It concluded that, despite methodological concerns and substantial uncertainty, the size of benefit of nivolumab plus ipilimumab as measured by overall survival and progression-free survival was likely to be greater than current standard care.\n\n# Economic model\n\n## The company's economic model is suitable for decision making\n\nThe company used a partitioned survival model to estimate the cost effectiveness of nivolumab plus ipilimumab compared with FOLFOX, FOLFIRI, trifluridine–tipiracil and best supportive care. The model included 3 health states: pre-progression, post-progression, and death. Transitions between each health state were informed by progression-free survival and overall survival from CheckMate\xa0142 and the MAIC comparison (see section\xa03.7). Each progression health state was also divided into people having treatment and not having treatment, with proportions determined by time on treatment in each trial. The ERG agreed that the company's model captured all relevant health states and partitioned survival models are used widely used in cancer modelling. The committee concluded that the company's model structure was acceptable for decision making.\n\n## Nivolumab with ipilimumab should be stopped as seen in CheckMate\xa0142\n\nIn CheckMate\xa0142, nivolumab with ipilimumab could be used until disease progression or stopping treatment because of toxicity or death. The company also introduced a change in study protocol that meant people could stop treatment when clinicians considered maximum clinical benefit had been achieved after a minimum of 2\xa0years. The company originally included a 2‑year stopping rule in its model but removed this at technical engagement. The ERG considers that using the time on treatment seen in CheckMate\xa0142 was appropriate and reflected how nivolumab with ipilimumab will be used in NHS clinical practice. Clinical experts explained that in NHS clinical practice, some people may benefit after 2\xa0years of treatment and treatment would be stopped at the clinician's discretion. The patient experts also agreed that continuing treatment is circumstantial, and some people would benefit from continued treatment. The committee considered that the maximum clinical benefit had not been explicitly defined, but that the trial was likely to reflect clinical practice. The committee also considered a scenario where people did not stop treatment based on maximum clinical benefit and continued treatment until progression, but did not consider this would reflect its expected use. Therefore, it concluded that implementing a formal stopping rule was not necessary and the observed treatment stopping in CheckMate\xa0142 was likely to be appropriate.\n\n# Survival extrapolations\n\n## A log-logistic parametric distribution is appropriate for extrapolating overall survival\n\nFor overall survival, progression-free survival and time on treatment, the company used semi-parametric models to extrapolate the outcomes of nivolumab plus ipilimumab across the full time horizon. These extrapolations used 6.44\xa0months of Kaplan−Meier data and different parametric distributions for each outcome. The ERG considered that at the latest data-cut, using Kaplan−Meier data until 6.44\xa0months was appropriate. The company used the log-logistic distribution to extrapolate progression-free survival, which the ERG considered had an excellent visual and statistical fit and appropriately represented the decreasing hazard. The company used the log-normal distribution to extrapolate overall survival. The ERG considered the log-logistic distribution to be more appropriate to extrapolate overall survival because this was also chosen for progression-free survival and both distributions have excellent visual and statistical fit. The committee noted that the choice of either log-normal or log-logistic extrapolation had minimal effect on the cost-effectiveness results. It noted concerns that using the partitioned survival model (see section\xa03.8) and the chosen extrapolations resulted in a modelled output that suggested people would stay in the post-progression health state for extended periods of time. The clinical experts considered it more likely that people would survive in a progression-free state and that the modelled output would not reflect what would be seen in clinical practice. The committee was aware that the company had incorporated background mortality into survival projections, which it considered appropriate. Also, the semi-parametric modelling approach was used to account for the complex shape of hazard and survival functions. The committee considered that there are limitations associated with combining the Kaplan−Meier data and parametric models in this way. Instead, a more flexible parametric model could have been used. It concluded that the log-logistic extrapolation was appropriate for decision making but that long-term survival extrapolations are highly uncertain.\n\n# Utility values\n\n## It is more appropriate to use post-progression utility values from the CORRECT study than the company approach\n\nThe company used progression-based health state utility values in the economic model from NICE'S technology appraisal guidance on cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy (from now, TA242). It considered these utility values most represented the population in CheckMate\xa0142 because TA242 is for people with metastatic colorectal cancer after 1 line of therapy. The ERG noted some concerns with the source of data and considered the post-progression utility value of 0.69 as being too high. The ERG explained that the utility source used in TA242 was derived from health utility index rather than EuroQol\xa05D (EQ‑5D), so it does not follow the NICE reference case. In addition, it considered there were issues with reporting because people were alive for many months after their final health-related quality-of-life measurement. The ERG proposed using data from the CORRECT study with a utility value of 0.59 for the post-progressed state. These people had more previous treatments but the data were derived from a more recent study and used EQ‑5D. The clinical experts considered that because nivolumab and ipilimumab are expected to be used second line (see section\xa03.4), the utility values may be higher than those derived at later lines. But they also considered it appropriate to make conservative assumptions about post-progression utility values. The committee noted that the source of the progression-based utility values had minimal effect on the cost-effectiveness results. It concluded that the scenario using the CORRECT utility values was more appropriate but could be conservative.\n\n## It is not appropriate to use treatment-specific utility values for nivolumab with ipilimumab\n\nThe company measured health-related quality of life using EQ-5D-3L in the single arm of CheckMate\xa0142 and mapped this to UK preference scores to derive treatment-specific utility values for nivolumab with ipilimumab. The utility values derived for treatment with nivolumab were higher than in the general population and so, for face validity, the company capped utility values to that of the general population. The company explained that the novel mechanism of action for nivolumab with ipilimumab drives several key benefits, including improved toxicity and survival, that improve quality of life. The ERG considered that it would expect people having second-line treatment for metastatic colorectal cancer to have a lower quality of life than the general population. Without utility values from a randomised controlled trial with an appropriate comparator arm, the ERG did not consider there was enough justification to use utility values according to treatment status. Therefore, it considered using utility values according to progression status only from 1 source to be appropriate and used the CORRECT study in their base case. Removing treatment-specific utility values resulted in minimal effect on cost-effectiveness results. The committee concluded that it is more appropriate to use conservative utility values according to progression status from the CORRECT study.\n\n# Subsequent treatments\n\n## The costs of subsequent treatments in CheckMate 142 do not reflect NHS clinical practice\n\nFor simplicity, the company considered that the cost of treatments after any current line would be the same for all treatment arms and applied this as a one-off cost in the economic model. The ERG considered that the composition and duration of subsequent treatments are likely to differ according to treatment arm and requested further scenarios to explore these differences. To address the ERG's concerns, the company provided 3\xa0scenarios:\n\nA scenario based on clinical expert opinion that patients having nivolumab with ipilimumab would try further combination chemotherapy after progression.\n\nA scenario as above but including encorafenib and cetuximab for about one-third of patients that also have BRAF mutations to align with NICE technology appraisal guidance on encorafenib plus cetuximab for previously treated BRAF V600E mutation-positive metastatic colorectal cancer.\n\nA scenario based on the subsequent treatment data collected in CheckMate\xa0142.The ERG highlighted that both scenarios based on clinical expert opinion used a median of 3\xa0to 4\xa0cycles of FOLFOX. But clinical experts noted that up to 12\xa0cycles could be given if people are very fit and therefore increased the number of cycles to account for this. The ERG also considered that scenarios based on subsequent treatment data from CheckMate\xa0142 were less appropriate because they included treatments that are not available in NHS clinical practice and the subsequent treatment data from CheckMate\xa0142 are very immature. The ERG considered that analysis based on clinical expert opinion, including encorafenib with cetuximab for BRAF mutated, is one step closer to reflecting the subsequent treatments that will be used in clinical practice. The committee preferences were more aligned with the ERG but noted that that all scenarios had minimal effect on the cost-effectiveness results.\n\n# Cost-effectiveness estimates\n\n## Nivolumab with ipilimumab is cost effective compared with all comparators\n\nThe company's cost-effectiveness estimate included a patient access scheme discount, the results of which cannot be presented because of confidentiality. The company's base case gave an incremental cost-effectiveness ratio (ICER) range below £20,000 per quality-adjusted life year (QALY) gained for nivolumab plus ipilimumab compared with all other comparators. Some of the comparators and subsequent treatments also had confidential patient access schemes that were included in the ERG analysis. The ERG assumptions included:\n\nA naive comparison in the MAIC (see section\xa03.7).\n\nOverall survival extrapolation using the log-logistic distribution for extrapolation (see section\xa03.10).\n\nProgression-based utility values from the CORRECT study (see sections\xa03.11 and\xa03.12).\n\nSubsequent treatment costs using clinical expert opinion and assuming some people have encorafenib and cetuximab (see section\xa03.13).All ERG base-case analyses ICERs were also below £20,000 per QALY gained. The committee considered these results to be robust despite major uncertainties about comparative effectiveness (see section\xa03.7). It concluded that nivolumab with ipilimumab is a cost-effective use of NHS resources compared with all other comparators.\n\n## Nivolumab and ipilimumab is likely to meet the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Clinical experts explained that life expectancy after progressing in absence of nivolumab with ipilimumab was likely to be less than 24\xa0months in most cases. They also explained that the preliminary overall survival results from CheckMate\xa0142 were promising, with the likely extension to life of at least 3\xa0months. The ERG agreed that, based on the latest data-cut, there is an improvement in overall survival of at least 3\xa0months. The committee agreed that nivolumab with ipilimumab was likely to give an extension to life of at least 3\xa0months. It concluded that nivolumab with ipilimumab meets the end of life criteria.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nNo equality or social value judgement issues were identified."}
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https://www.nice.org.uk/guidance/ta716
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Evidence-based recommendations on nivolumab with ipilimumab for previously treated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency in adults.
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4dae4215367e94dc270c96ade67445d3ea759ae2
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nice
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Clostridioides difficile infection: antimicrobial prescribing
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Clostridioides difficile infection: antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for managing Clostridioides difficile infection in adults, young people and children aged 72 hours and over in community and hospital settings. It aims to optimise antibiotic use and reduce antibiotic resistance. The recommendations do not cover diagnosis.
# Recommendations
The recommendations in this guideline update existing Public Health England guidance on treating Clostridioides difficile infection.
# Managing suspected or confirmed Clostridioides difficile infection
## Assessment
For people with suspected or confirmed C. difficile infection, see Public Health England's guidance on diagnosis and reporting.
For people with suspected or confirmed C. difficile infection, assess:
whether it is a first or further episode (relapse or recurrence) of C. difficile infection
the severity of C. difficile infection
individual factors such as age, frailty or comorbidities that may affect the risk of complications or recurrence.
For people with suspected or confirmed C. difficile infection, review existing antibiotic treatment and stop it unless essential. If an antibiotic is still essential, consider changing to one with a lower risk of causing C. difficile infection.
For people with suspected or confirmed C. difficile infection, review the need to continue any treatment with:
proton pump inhibitors
-ther medicines with gastrointestinal activity or adverse effects, such as laxatives
medicines that may cause problems if people are dehydrated, such as non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin‑2 receptor antagonists and diuretics.
For a short explanation of why the committee made these recommendations, see the rationale section on assessment .
For more details, see the evidence review.
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## Treating suspected or confirmed C. difficile infection
For adults, offer an oral antibiotic to treat suspected or confirmed C. difficile infection (see the recommendations on choice of antibiotic). In the community, consider seeking prompt specialist advice from a microbiologist or infectious diseases specialist before starting treatment.
For children and young people under 18 years, offer an oral antibiotic to treat suspected or confirmed C. difficile infection. Treatment should be started by, or after advice from, a microbiologist, paediatric infectious diseases specialist or paediatric gastroenterologist.
For people with suspected or confirmed C. difficile infection who cannot take oral medicines, seek specialist advice from a gastroenterologist or pharmacist about alternative enteral routes for antibiotics, such as a nasogastric tube or rectal catheter.
Manage fluid loss and symptoms associated with suspected or confirmed C. difficile infection as for acute gastroenteritis. Do not offer antimotility medicines such as loperamide.
Do not offer bezlotoxumab to prevent recurrence of C. difficile infection because it is not cost effective.
Consider a faecal microbiota transplant for a recurrent episode of C. difficile infection in adults who have had 2 or more previous episodes (see NICE's interventional procedures guidance on faecal microbiota transplant for recurrent C. difficile infection).
For a short explanation of why the committee made these recommendations, see the rationale section on treating suspected or confirmed C. difficile infection .
For more details, see the summary of the evidence.
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## Advice
Advise people with suspected or confirmed C. difficile infection about:
drinking enough fluids to avoid dehydration
preventing the spread of infection (see recommendation 1.3.1)
seeking medical help if symptoms worsen rapidly or significantly at any time.
For a short explanation of why the committee made this recommendation, see the rationale section on advice .
For more details, see the evidence review.
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## Reassessment
Reassess people with suspected or confirmed C. difficile infection if symptoms or signs do not improve as expected, or worsen rapidly or significantly at any time. Daily review may be needed, for example, if the person is in hospital.
If antibiotics have been started for suspected C. difficile infection, and subsequent stool sample tests do not confirm C. difficile infection, consider stopping these antibiotics (see Public Health England's guidance on diagnosis and reporting for recommendations on stool sample tests).
For a short explanation of why the committee made these recommendations, see the rationale section on reassessment .
For more details, see the evidence review.
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## Referral
Refer people in the community with suspected or confirmed C. difficile infection to hospital if they are severely unwell, or their symptoms or signs worsen rapidly or significantly at any time. Refer urgently if the person has a life-threatening infection.
Consider referring people in the community to hospital if they could be at high risk of complications or recurrence because of individual factors such as age, frailty or comorbidities.
Ensure that people in hospital with suspected or confirmed C. difficile infection have care from a multidisciplinary team that may include a microbiologist, infectious diseases specialist, gastroenterologist, surgeon, pharmacist or dietitian, as needed.
For a short explanation of why the committee made these recommendations, see the rationale section on referral or seeking specialist advice .
For more details, see the evidence review.
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# Choice of antibiotic
When prescribing antibiotics for suspected or confirmed C. difficile infection in adults, follow table 1.
When prescribing antibiotics for suspected or confirmed C. difficile infection in children and young people under 18 years, base the choice of antibiotic on what is recommended for C. difficile infection in adults. Take into account licensed indications for children and young people, and what products are available (see the BNF for Children for dosing information).
Use clinical judgement to determine whether antibiotic treatment for C. difficile is ineffective. It is not usually possible to determine this until day 7 because diarrhoea may take 1 to 2 weeks to resolve.
Treatment
Antibiotic, dosage and course length
First-line antibiotic for a first episode of mild, moderate or severe C. difficile infection
Vancomycin:
mg orally four times a day for 10 days
Second-line antibiotic for a first episode of mild, moderate or severe C. difficile infection if vancomycin is ineffective
Fidaxomicin:
mg orally twice a day for 10 days
Antibiotics for C. difficile infection if first- and second-line antibiotics are ineffective
Seek specialist advice. Specialists may initially offer:
Vancomycin:
Up to 500 mg orally four times a day for 10 days
With or without
Metronidazole:
mg intravenously three times a day for 10 days
Antibiotic for a further episode of C. difficile infection within 12 weeks of symptom resolution (relapse)
Fidaxomicin:
mg orally twice a day for 10 days
Antibiotics for a further episode of C. difficile infection more than 12 weeks after symptom resolution (recurrence)
Vancomycin:
mg orally four times a day for 10 days
Or
Fidaxomicin:
mg orally twice a day for 10 days
Antibiotics for life-threatening C. difficile infection (also see recommendation 1.1.16)
Seek urgent specialist advice, which may include surgery. Antibiotics that specialists may initially offer are:
Vancomycin:
mg orally four times a day for 10 days
With
Metronidazole:
mg intravenously three times a day for 10 days
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding. Also see medicines safety.
See Specialist Pharmacy Service guidance on choosing between oral vancomycin options. If ileus is present, specialists may use vancomycin rectally.
For a short explanation of why the committee made these recommendations, see the rationale section on choice of antibiotic .
For more details, see the summary of the evidence.
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# Preventing C. difficile infection
For how to prevent C. difficile infection through good antimicrobial stewardship, infection control and environmental hygiene measures, see:
Public Health England's guidance on C. difficile infection: how to deal with the problem
NICE's guidance on healthcare-associated infections
and
NICE's guidance on antimicrobial stewardship.
Ensure a diagnosis of C. difficile infection is recorded (particularly when a person transfers from one care setting to another). This is so that it can be taken into account before any future antibiotics are prescribed.
Do not offer antibiotics to prevent C. difficile infection.
Do not advise people taking antibiotics to take prebiotics or probiotics to prevent C. difficile infection.
For a short explanation of why the committee made these recommendations, see the rationale section on preventing C. difficile infection .
For more details, see the summary of the evidence.
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# Terms used in the guideline
## C. difficile infection
This is defined (by Public Health England, 2013) as diarrhoea and:
a positive C. difficile toxin test or
results of a C. difficile toxin test pending and clinical suspicion of C. difficile infection.
## Further episode (relapse or recurrence) of C. difficile infection
A further episode of C. difficile infection could either be a relapse, which is more likely to be with the same C. difficile strain, or a recurrence, which is more likely to be with a different C. difficile strain. There is no agreement on the precise definition of relapse and recurrence, and it is difficult to distinguish between them in clinical practice. In this guideline, it was agreed that a relapse occurs within 12 weeks of previous symptom resolution and recurrence occurs more than 12 weeks after previous symptom resolution.
## Severity of C. difficile infection
This is defined (by Public Health England, 2013) as:
Mild infection: not associated with an increased white cell count (WCC). Typically associated with fewer than 3 episodes of loose stools (defined as loose enough to take the shape of the container used to sample them) per day.
Moderate infection: associated with an increased WCC (but less than 15 × 109 per litre). Typically associated with 3 to 5 loose stools per day.
Severe infection: associated with a WCC greater than 15 × 109 per litre, or an acutely increased serum creatinine concentration (greater than 50% increase above baseline), or a temperature higher than 38.5 degrees Celsius, or evidence of severe colitis (abdominal or radiological signs). The number of stools may be a less reliable indicator of severity.
Life-threatening infection: symptoms and signs include hypotension, partial or complete ileus, toxic megacolon or CT evidence of severe disease.
## Probiotics
Probiotics are live bacteria and yeasts that are promoted as having various health benefits. They are usually added to yoghurts or taken as food supplements. They are often described as 'good', 'friendly' or 'healthy' gut bacteria, and are thought to help restore the natural balance of bacteria in the gastrointestinal tract.
## Prebiotics
Prebiotics are a source of food for the 'healthy' bacteria in the gastrointestinal tract. They are a group of non-digestible food ingredients, such as fructo-oligosaccharides, that are a source of food for these bacteria. Prebiotics are found naturally in many fruits and vegetables, but can also be taken as supplements.# Recommendations for research
The guideline committee has made the following recommendation for research.
# Oral teicoplanin compared with oral vancomycin or oral fidaxomicin for treating Clostridioides difficile infection
What is the clinical effectiveness, cost effectiveness and safety of oral teicoplanin 100 mg to 200 mg twice a day for 7 to 14 days compared with oral vancomycin or oral fidaxomicin for treating C. difficile infection in adults?
For a short explanation of why the committee made the recommendation for research, see the rationale section on choice of antibiotic .
Loading. Please wait.# Rationales
The recommendations in this guideline are based on the evidence identified and the experience of the committee.
# Assessment
## Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.4
The committee agreed that although diagnostics and reporting were out-of-scope for this guideline, a recommendation should be included on where to find such information. They concluded, from experience, that people should see Public Health England's updated guidance on the diagnosis and reporting of Clostridioides difficile.
The committee discussed that, in practice, there has been a change in the definition of the severity of C. difficile from the 4 categories (mild, moderate, severe and life threatening) used by Public Health England to 3 categories (non-severe, severe and life threatening). However, the Public Health England categories still apply because this is current national guidance.
The committee discussed the findings of the economic model, which took into account severity by adjusting for older age, increased risk of recurrence, increased hospitalisation and a higher risk of fulminant colitis (see the economic analysis in the evidence review for full details; there was a lack of useful direct evidence for severity that could be used in the economic model). The economic model found that severity did not cause a substantial change in which antibiotic was the most cost effective. Therefore, the committee agreed that the main reason to assess severity was to identify the appropriate place of care, overall management, and any subsequent improvement or worsening. They also agreed that an assessment of whether the current infection was a first or further episode (relapse or recurrence) of C. difficile infection should be included. This was because recurrence was a driver in the economic model and determines antibiotic choice (see also the rationale on choice of antibiotic).
The committee recognised that C. difficile infection most commonly affects people who are taking or have recently taken antibiotics. They discussed that, even though antibiotics being taken may be associated with the C. difficile infection, the person may still need antibiotics for the original infection. They agreed that, in line with good antimicrobial stewardship, prescribers should review existing antibiotic treatment and:
stop it unless essential, or
if an antibiotic is still essential, consider changing to one with a lower risk of causing C. difficile infection.
The committee agreed that it is good prescribing practice to review the continuing need for existing proton pump inhibitor (PPI) treatment in people with suspected or confirmed C. difficile infection, in line with NICE's guideline on medicines optimisation. They were aware that, although some associations have been made between PPI use and the risk of C. difficile infection or recurrence, there is no definitive evidence of a causal or exacerbator effect. Also, no evidence from systematic reviews or randomised controlled trials was found to support stopping current PPI treatment. The committee agreed that suddenly stopping a PPI during an acute episode of infection may cause additional gastric symptoms. Additionally, some people will need ongoing gastroprotection for a clinical indication. However, they were aware that many people may be taking a PPI without a clear indication, so concluded that the use and need for a PPI should be reviewed.
The committee agreed that, when people present with suspected or confirmed C. difficile infection, it is good prescribing practice to review other medicines with gastrointestinal activity or adverse effects (such as laxatives) being taken. They also agreed that it is good practice to review other medicines being taken that may have detrimental effects if people are acutely ill and dehydrated. These include non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin‑2 receptor antagonists and diuretics.
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# Treating suspected or confirmed C. difficile infection
## Why the committee made the recommendations
Recommendations 1.1.5 to 1.1.10
The committee agreed that an oral antibiotic should be offered for suspected or confirmed C. difficile infection in adults, young people and children.
For adults presenting in the community, the committee agreed that GPs may be unfamiliar with diagnosing and treating C. difficile infection, so may want to seek prompt specialist advice from a microbiologist or infectious diseases specialist before starting treatment. The committee noted that, for people in hospital, once diagnosed, they would be under the care of a multidisciplinary team, which would ensure appropriate review and care.
The committee discussed the lack of evidence on treating C. difficile infection in children and young people. They were aware that, in practice, very few children have C. difficile infection. The committee agreed that a positive test for C. difficile in children 2 years and under is often because of high carriage rates of the bacteria rather than because of actual infection. They considered that this may lead to overprescribing of antibiotics. The committee concluded that treatment for C. difficile infection in children and young people should only be started by a microbiologist, paediatric infectious diseases specialist or paediatric gastroenterologist, or after advice from such a specialist.
The committee discussed the most appropriate route of administration of antibiotics for C. difficile infection. They agreed that the enteral route is best because sufficient concentrations within the intestinal lumen need to be reached. The committee concluded that it is preferable to take antibiotics orally or, if this is not possible, enterally in some other way (such as a nasogastric or enteral feeding tube, or rectally). They advised seeking specialist advice on administration from a specialist gastroenterologist or pharmacist if the oral route is not available.
The committee agreed that, in line with the general management of gastroenteritis (see the NICE clinical knowledge summary on adult gastroenteritis and NICE's guideline on diarrhoea and vomiting caused by gastroenteritis in under 5s), prescribers and other care staff should monitor and manage fluid loss and gastroenteritis symptoms. Antimotility drugs such as loperamide should be avoided because they slow down the action of the gut. This can lead to C. difficile toxins being retained for longer, which may make a person more unwell.
Bezlotoxumab was not recommended as adjunctive therapy to antibiotics to prevent recurrent C. difficile infection. The committee discussed the clinical evidence, which showed that bezlotoxumab was more effective than placebo at preventing recurrence. However, they also reviewed the economic analysis and agreed that adding bezlotoxumab to either vancomycin or fidaxomicin was not a cost-effective option (there is a 0% probability of it being cost effective at £30,000 per quality-adjusted life year gained). The committee agreed that this finding was robust, even in people with a higher risk of recurrence, and were confident in making a recommendation for bezlotoxumab not to be used.
The committee noted that faecal microbiota transplantation (FMT; a procedure done in a small number of specialist centres) was not effective as a first-line treatment for C. difficile infection compared with vancomycin. They were aware that long-term safety data on, and regulations about the use of, FMT are minimal compared with medicines. They were aware of variation in mortality rates associated with FMT use, and that there is almost no evidence for its use in children. NICE's interventional procedures guidance on FMT for recurrent C. difficile infection states that 'current evidence on the efficacy and safety of FMT for recurrent Clostridium difficile infection is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit'. In the economic model, FMT was placed as a third-line treatment (for people with continuing symptoms after first- and second-line antibiotics) that may help prevent serious complications. The committee agreed that FMT may be useful in adults who have had 2 or more previous episodes of C. difficile infection in addition to the current episode to prevent recurrence of C. difficile infection. They were aware of ongoing developments around the screening of faecal microbiota donors to identify multidrug-resistant organisms.
For more details, see the summary of the evidence on treating initial or first recurrent C. difficile infection.
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# Advice
## Why the committee made the recommendation
Recommendation 1.1.11
The committee discussed what advice on self-care people with a C. difficile infection would need and agreed that, from their experience, 3 key areas of advice were needed:
maintaining fluid intake to avoid dehydration (and on the symptoms or signs of dehydration that people should be aware of)
the need to help reduce the spread of C. difficile infection, which is contagious (that is, people should follow the advice in the NICE clinical knowledge summary on adult gastroenteritis and in NICE's guideline on diarrhoea and vomiting caused by gastroenteritis in under 5s)
when to seek medical help.
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# Reassessment
## Why the committee made the recommendations
Recommendations 1.1.12 to 1.1.13
The committee were aware that C. difficile infection should be managed as a diagnosis in its own right. They agreed that the management and progress of suspected or confirmed C. difficile infection should be monitored during treatment. This could include assessing the severity of the infection and symptoms, and the need for hydration. The committee concluded that, from their experience, it would be good practice to reassess people if symptoms or signs of infection do not improve as expected or worsen rapidly or significantly at any time. They agreed that daily review is usual in hospital and that, in the community, people should be given appropriate safety netting advice to ensure that they return for reassessment if needed.
The committee also agreed that clinicians should consider stopping antibiotics for C. difficile infection if they have been started for clinically suspected C. difficile infection before stool sample test results are available and subsequent results do not confirm infection.
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# Referral or seeking specialist advice
## Why the committee made the recommendations
Recommendations 1.1.14 to 1.1.16
The committee agreed that people with suspected or confirmed C. difficile infection in the community should be referred to hospital if they are severely unwell, or their symptoms or signs worsen rapidly or significantly at any time. For life-threatening infection, an urgent referral is needed. The committee recognised that there are some individual factors (such as age, frailty and comorbidities) for which it may also be appropriate to consider referral to hospital. This is because they are associated with a higher risk of complications or recurrence.
The committee agreed that people who develop C. difficile infection while in hospital are unlikely to be having care from a microbiologist or infectious diseases specialist at diagnosis. However, once diagnosed they should be under the care of a multidisciplinary team to ensure appropriate review and care. The team could include, as needed, a microbiologist, infectious diseases specialist, gastroenterologist, surgeon, pharmacist and dietitian. This would depend, for example, on the severity of illness and need for surgery.
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# Choice of antibiotic
Recommendations 1.2.1 to 1.2.3
## Why the committee made the recommendations
The committee discussed the evidence for the effectiveness and cost effectiveness of the different antibiotic options for treating C. difficile infection. They were aware that antibiotic resistance is not a major concern when treating C. difficile infection.
Oral vancomycin was recommended by the committee as the first-line antibiotic for a first episode of C. difficile infection of any severity. Fidaxomicin was recommended as the second-line antibiotic for a first episode of C. difficile infection of any severity when vancomycin is ineffective (treatment failure). The committee noted that, although fidaxomicin was more effective than vancomycin for sustained symptomatic cure in the network meta-analysis, the cost of fidaxomicin is substantially higher. In the base-case analysis, there was only a 2% probability of first-line fidaxomicin being cost effective compared with first-line vancomycin (at £30,000 per QALY gained). They also discussed that vancomycin treatment failure should not be judged too early. Diarrhoea can take 1 to 2 weeks to resolve, and it is not usually possible to determine whether antibiotic treatment for C. difficile is ineffective until day 7.
The committee agreed that, when teicoplanin and second-line metronidazole were excluded from the economic model, the remaining results clearly showed that vancomycin was the most cost-effective first-line antibiotic across a range of scenarios. This was the case when results from people at both higher and lower risks of recurrence were included (in particular, it was more cost effective as a first-line option than either metronidazole or fidaxomicin). They also agreed that fidaxomicin was the appropriate second-line option.
The committee noted that, from experience, some hospital trusts use fidaxomicin for first-line treatment of C. difficile infection in people who are older or frailer as a strategy to reduce recurrence and readmission. The aim is to offset the cost of using fidaxomicin by reducing future costs. The committee were made aware of a real-world evaluation of fidaxomicin in which its use first line had a greater effect on reducing mortality than its use second line after vancomycin. However, they heard that the economic model considered a range of benefits and harms (including deaths), as well as the costs of each strategy. Vancomycin (not fidaxomicin) was still the most cost-effective first-line option, even in people at higher risk of recurrence. The committee concluded that a recommendation to use fidaxomicin first line would incur unreasonably large opportunity costs that are not appropriate in the wider context of overall healthcare resource allocation. There are possible rare exceptions when vancomycin may not be acceptable, such as for an infection that is vancomycin resistant.
The committee noted that, when taken orally, vancomycin is not well absorbed from the gut into the circulation (although absorption may increase if the gut is damaged). So, the likelihood of side effects (such as ototoxicity) is lower with oral than with intravenous administration, although there is still a need to monitor for this in some people (see medicines safety). They also discussed the development of drug-resistant bacteria, in particular, vancomycin-resistant enterococci. However, they agreed with expert testimony that this is not a major concern in clinical practice when vancomycin is used orally for C. difficile infection.
The committee discussed that vancomycin capsules would usually be the preferred formulation for taking vancomycin orally. They were aware that vancomycin powder for solution is also licensed to be taken orally for C. difficile infection, and that it is used in some settings (particularly if people cannot take solid oral medicines). However, they discussed that locally agreed protocols should be in place to reduce the risk of medication errors around reconstitution and administration, and to take account of the practicalities of administration, particularly in community settings. This is discussed further in Specialist Pharmacy Service guidance on choosing between oral vancomycin options.
Fidaxomicin was recommended by the committee for a further episode of C. difficile infection of any severity occurring within 12 weeks of symptom resolution. They defined this as a relapse. For a further episode of C. difficile infection occurring more than 12 weeks after symptom resolution (defined as recurrence), either vancomycin or fidaxomicin was recommended, with choice being an individualised patient decision.
The committee noted there was no clinical evidence comparing vancomycin with fidaxomicin in a population having a further episode of C. difficile infection after initial cure. Their decisions were therefore heavily influenced by the threshold analyses around risks of future recurrence. This was because they agreed that 1 key difference with a further episode of infection is the higher risk of subsequent additional recurrences. The committee noted that the risk of future recurrence needed to be around 30% to 40% for fidaxomicin to be cost effective as a first-line option compared with vancomycin (at £30,000 per QALY gained). While they did not believe that this would be the case for all people with a recurrent infection, they did agree that there would be people with a risk of recurrence that high. They therefore agreed that it was appropriate for both vancomycin and fidaxomicin to be first-line options for further episodes. They concluded that the choice would come down to an individualised patient decision based around severity, the risk of additional recurrences (which increases after each recurrent episode) and the time between recurrences. The committee favoured fidaxomicin for more severe, more recent or multiple recurrent episodes. They thought that vancomycin would be suitable for less severe or first recurrent episodes, or if there had been a long time between episodes.
The committee were aware that there is poor agreement on the definition of relapse or recurrence in C. difficile infection, both nationally and internationally. They discussed different time periods and agreed, based on expert opinion, that 30 days from resolution of symptoms was too short a time period to define recurrence. They thought that further symptoms within this time period after initial symptom resolution were more likely to represent relapse with the same strain of C. difficile infection. The committee heard that, in practice, further symptoms within 12 to 24 months may be considered a recurrence, likely with a different strain of C. difficile infection. However, they were also aware of evidence that suggested recurrence generally relates to a further episode within 20 weeks. Defining relapse or recurrence is outside of the remit of the committee, and evidence on this issue was not searched for. So, the committee agreed that it could not be certain about the time period but thought that 12 weeks was a reasonable cut-off point between relapse and recurrence.
The committee agreed that specialist advice should be sought about the choice of antibiotics for C. difficile infection that has not responded to either first- or second-line antibiotics, or for a life-threatening infection. However, they recognised that, in practice, specialists will often initially recommend high-dose oral vancomycin with or without intravenous metronidazole for this. If ileus is present, specialists may use vancomycin rectally.
Teicoplanin was not recommended by the committee for treating C. difficile infection. It was ranked first in the network meta-analysis results. However, the committee were concerned about the extensive limitations of the 2 small studies of teicoplanin included in the network meta-analysis, both of which were at considerable risk of bias. The committee noted that the point estimate of effect was important. However, the 95% confidence intervals were wide, revealing much uncertainty in the estimate. This meant that there was little difference from, and overlap with, the estimate of effect for vancomycin. The committee were also aware of the limited clinical experience with using teicoplanin in the UK for C. difficile infection. They concluded that further research was needed on teicoplanin for treating C. difficile infection and made a recommendation for research.
The committee had an initial discussion about the findings from the economic model. They noted that, if the results from the studies of teicoplanin were considered robust, it would come out clearly as the most cost-effective first-line treatment. However, they were not convinced by either the sample size or quality of the studies on teicoplanin. They agreed there was not enough clinical evidence to recommend it, so focused on the economic model results excluding teicoplanin.
Metronidazole was not recommended by the committee for treating C. difficile infection. The committee agreed that not using metronidazole first line for mild and moderate C. difficile infection represented a change in practice for some clinicians. However, they were confident in the evidence that metronidazole was neither clinically nor cost effective compared with vancomycin. In the network meta-analysis results, metronidazole was ranked lowest out of all the antibiotics available in the UK (below teicoplanin, fidaxomicin, vancomycin, rifaximin and fusidic acid). In the economic modelling, when the costs of rehospitalisation were included in the analysis, metronidazole was a less cost-effective first-line treatment than vancomycin, which was dominant in most scenarios (meaning using vancomycin was both less costly and more effective than using metronidazole). From the evidence, metronidazole had lower initial cure rates and higher recurrence rates than vancomycin. The committee heard that metronidazole is comparatively inexpensive compared with other antibiotic treatments. However, they discussed that, from experience, many hospital trusts have already moved away from using metronidazole, prompted by lower efficacy compared with other antibiotics and potential side effects. The committee also heard expert testimony that cure or improvement may take longer with metronidazole compared with other antibiotic treatments. A longer period before treatment becomes effective is concerning. This is because it may lead to increased transmission of the infection, particularly in hospital or residential care settings. Neither of these issues were addressed in the economic model.
When considering the economic model, the committee agreed that it was appropriate to exclude strategies in which metronidazole was used as a second-line intervention. They noted that a limitation of the analysis was that interventions were assumed to be equally effective as second-line options compared with first-line options. This was because there were no data to test this assumption. They agreed that, when C. difficile is not clinically cured using first-line vancomycin or fidaxomicin it is likely to represent infection that is harder to treat. So, it would also be less likely to respond to metronidazole, meaning it would not be effective as a second-line agent.
The committee recognised that intravenous metronidazole may be a treatment option in the rare event that C. difficile infection fails to respond to either vancomycin or fidaxomicin, or in people with a life-threatening infection. The committee noted that, from experience, intravenous metronidazole (as an adjunct to vancomycin by the enteral route) is used in practice for some people in these circumstances.
The committee noted the evidence showing no statistically significant difference in clinical effectiveness with low-dose (125 mg four times a day) compared with high-dose (500 mg four times a day) vancomycin. The committee concluded that the standard licensed dose of oral vancomycin 125 mg four times a day for 10 days was sufficient to treat a first episode of mild, moderate or severe C. difficile infection, or a further episode of infection more than 12 weeks after symptom resolution (recurrence). The committee were also aware that specialists may use higher licensed doses of oral vancomycin (up to 500 mg four times a day) for C. difficile infection not responding to first- or second-line antibiotics or for life-threatening infection.
Oral vancomycin can be taken as capsules or the powder for solution can be reconstituted and taken orally as a drink or by nasogastric tube (a licensed use). The committee discussed that capsules would be the preferred formulation, particularly in community settings, for ease of use and to avoid any safety concerns around reconstitution and administration.
A tapered or pulsed regimen of vancomycin was not recommended because, in the evidence review, its use was limited to studies in which there was co-administration of FMT. The committee were aware that there are ongoing trials which might provide evidence for wider use of pulsed or tapered vancomycin.
The committee noted the evidence suggesting that fidaxomicin 400 mg daily was more clinically effective than 100 mg or 200 mg daily. They concluded that the standard licensed dose of oral fidaxomicin 200 mg twice a day for 10 days was sufficient to treat C. difficile infection.
The committee considered the comparison of the standard and extended-pulsed regimens of fidaxomicin in the economic model. The unlicensed extended-pulsed regimen of fidaxomicin is 200 mg twice a day on days 1 to 5, then 200 mg once a day on alternate days from days 7 to 25. The committee noted that the point estimates were in favour of extended-pulsed fidaxomicin. However, there was considerable uncertainty in this conclusion (with a 36% chance of standard fidaxomicin being more cost effective than extended-pulsed fidaxomicin at £30,000 per QALY gained). Also, the absolute magnitude of the differences was small. The committee agreed that there was insufficient evidence of benefits from the extended-pulsed regimen to justify recommending an unlicensed treatment regimen over a licensed one.
The committee agreed that treatment for C. difficile infection in children and young people should only be started by, or after advice from, a specialist. And that antibiotic choice can be based on recommendations for adults, taking into account the varying licensed indications for children and the availability of suitable products.
Vancomycin capsules are licensed to treat C. difficile infection only in people aged 12 years and over (see the vancomycin capsules summary of product characteristics). Vancomycin powder for solution taken orally is licensed to treat C. difficile infection in all age groups (see the vancomycin powder for solution summary of product characteristics).
Fidaxomicin tablets are licensed to treat C. difficile infection in children with a body weight of at least 12.5 kg (see the fidaxomicin summary of product characteristics). Fidaxomicin granules for oral suspension are licensed to treat C. difficile infection from birth (and are likely to become available in the UK). However, there is a caution for use in babies less than 6 months and in babies with body weight less than 4 kg (see the Medicines and Healthcare products Regulatory Agency information on fidaxomicin granules).
For more detail see the summary of the evidence on antibiotic dose.
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# Preventing C. difficile infection
## Why the committee made the recommendations
Recommendations 1.3.1 to 1.3.4
The committee agreed that, although preventing C. difficile infection through good antimicrobial stewardship, infection control and environmental hygiene were out-of-scope for this guideline, a recommendation should be included on where to find such information. They concluded, from experience, that people should see Public Health England's guidance on C. difficile infection: how to deal with the problem, and NICE's guidance on healthcare-associated infections and antimicrobial stewardship.
The committee also discussed the importance of ensuring that a diagnosis of C. difficile infection is recorded in a person's medical records. This is particularly important when transferring from one care setting to another, so that it can be taken into account before prescribing any future antibiotics, to help minimise the risk of recurrent episodes.
The committee noted the lack of evidence of clinical or cost effectiveness to prevent C. difficile infection with antibiotics. They recognised that there was some evidence for rifaximin preventing further recurrences from a single study in people who already had recurrent infection. However, the intensive way in which antibiotics were used in the study has raised concerns about the possible emergence of rifamycin resistance, which has been reported in C. difficile infection cases, and prolonged flora disturbance.
The committee also recognised the limited evidence of benefit for:
fidaxomicin in preventing C. difficile infection in people having a haematopoietic stem cell transplant who had fluoroquinolone prophylaxis
vancomycin in preventing C. difficile infection in people who are in hospital.
The economic model only included treatment options, including adjunctive treatment with bezlotoxumab (which is used to prevent recurrent infection) and FMT to determine sequencing of treatments. It did not include comparisons for preventing a first episode of C. difficile infection with antibiotics, prebiotics or probiotics. The committee concluded that, because of the lack of evidence and concerns about antimicrobial resistance, antibiotics should not be offered for preventing C. difficile infection.
The committee noted the lack of convincing evidence of effect for prebiotics (oligofructose), which showed little difference in preventing C. difficile-associated outcomes in the included studies. They concluded that prebiotics conferred no benefit and that people taking antibiotics should not be advised to take prebiotics to prevent C. difficile infection.
The committee agreed that there is some evidence of a small effect with probiotics in preventing C. difficile infection. However, there were many limitations in the evidence, including:
a high number needed to treat
aggregation of the results of different types of probiotics in meta-analyses
the lack of effectiveness when using confirmed cases only (in everyone, but particularly in children).
The committee also noted concerns from expert testimony about the high prevalence of C. difficile infection in the placebo arms of some studies, which does not reflect clinical practice in the UK. The single study done in a UK setting found no evidence of effect for probiotics in people aged over 65 years. They further noted that NHS England's guidance on conditions for which over the counter items should not routinely be prescribed in primary care states that probiotics should not routinely be prescribed.
The committee concluded that, because of concerns about the evidence base (including cost effectiveness), people taking antibiotics should not be advised to take probiotics to prevent C. difficile infection.
Return to the recommendations# Context
Clostridioides difficile is a bacterium that can infect the bowel and cause diarrhoea. Certain groups, such as older people, are at higher risk of C. difficile infection. The infection most commonly affects people who are taking, or have recently taken, antibiotics, and it can be transmitted very easily. It can be mild, moderate, severe or life threatening, and is treated with antibiotics.# Summary of the evidence
This is a summary of the evidence, for full details (including the economic analysis) see the evidence review.
The evidence for treating Clostridioides difficile infection in adults specifically included antibiotic efficacy, choice, dose and dose frequency, faecal microbiota transplantation (FMT), bezlotoxumab and prebiotics. The evidence for treating C. difficile infection in children included antibiotic choice and probiotics.
For C. difficile infection in adults, young people or children, no evidence from systematic reviews or randomised controlled trials (RCTs) was identified for antibiotic prescribing strategies, course length or route of administration. There was also no evidence found for probiotics for C. difficile infection in adults, nor for antibiotic efficacy, dose or dose frequency, FMT, bezlotoxumab or prebiotics for infection in children.
There was evidence found for prophylactic antibiotics (in adults having a stem cell transplant or in hospital), prebiotics and probiotics to prevent C. difficile infection in adults. There was evidence for probiotics to prevent C. difficile infection in children.
Interventions included in the search were antimicrobial interventions, non-antimicrobial interventions (bezlotoxumab and intravenous immunoglobulin), and non-pharmacological interventions (probiotics, prebiotics, FMT, and stopping current antibiotics or proton pump inhibitors). No evidence from systematic reviews or RCTs was found for intravenous immunoglobulin or stopping current antibiotics or proton pump inhibitors. In addition, the following interventions were outside the scope of this guideline because there is no UK licensed product available: ridinilazole, cadazolid, surotomycin, nitazoxanide, tolevamer, LFF517, bacitracin and tolevamer.
# Treating initial or first recurrent C. difficile infection in adults
## Antibiotics
A statistically significant improvement was seen in symptomatic and bacteriological cure with vancomycin 125 mg four times daily for 5 days compared with placebo in adults with first-episode pseudomembranous colitis (some associated with evidence of C. difficile infection; Nelson et al. 2017).
In 1 network meta-analysis, different antibiotic treatments were compared for treating the initial or first recurrent episode of C. difficile infection. Vancomycin was used as the reference treatment (Beinortas et al. 2018), and the treatments were ranked using P scores. Of the antibiotics available in the UK, sustained symptomatic cure was most effective with teicoplanin (P score=0.9386), followed by fidaxomicin (P score=0.7922), vancomycin (P score=0.4850), rifaximin (P score=0.4296), fusidic acid (P score=0.3794) and metronidazole (P score=0.2411). P scores are calculated as the average p value for superiority for that intervention compared with all the other interventions in the network meta-analysis. They take account of the magnitude of the difference and the level of uncertainty. Higher P scores (on a 0 to 1 scale) represent treatments in which there is more confidence that they are better than the other alternatives in the network meta-analysis.
A sensitivity analysis was done in which the effect was explored of removing studies with fewer than 50 people per arm, studies that were published before 2000, and unblinded studies. When non-blinded studies or studies with fewer than 50 people per arm were removed, fidaxomicin was the highest ranked treatment available in the UK. When studies published before the year 2000 were removed, teicoplanin was the highest ranked treatment available in the UK, followed by fidaxomicin.
Subgroup analysis was done for severe C. difficile infection, non-severe C. difficile infection, initial C. difficile infection, non-initial C. difficile infection, people aged 65 years and over and people aged under 65 years. For all subgroups, fidaxomicin was the highest ranked treatment available in the UK, and metronidazole was the least effective (being ranked either the fifth, sixth or seventh most effective option in the different subgroups).
There were no statistically significant differences in clinical effectiveness (recurrence of C. difficile infection, clinical resolution of C. difficile infection, relapse of C. difficile infection at 5 weeks and adverse events) for oral vancomycin compared with fidaxomicin (Hvas et al. 2019).
There was no statistically significant difference in clinical effectiveness (symptomatic cure) with low-dose (125 mg four times a day) compared with high-dose (500 mg four times a day) vancomycin, both taken for 5 to 15 days (Nelson et al. 2017).
There was a statistically significant improvement in clinical effectiveness (symptomatic cure) with fidaxomicin 400 mg daily compared with fidaxomicin 100 mg or 200 mg daily, all taken for 10 days.
There was no statistically significant difference in clinical effectiveness (symptomatic cure) with 100 mg of teicoplanin twice daily compared with 50 mg of teicoplanin four times daily (Nelson et al. 2017).
## FMT for treating initial C. difficile infection
There were no statistically significant differences in clinical effectiveness (resolution of C. difficile infection, treatment failure, all-cause and C. difficile infection attributable mortality or length of stay) of:
the first dose of FMT compared with vancomycin
the second dose of FMT compared with vancomycin (Camacho-Ortiz et al. 2017).
## FMT for treating recurrent C. difficile infection
There were statistically significant increases in clinical effectiveness (resolution of symptoms, resolution of diarrhoea, relapse of diarrhoea) with:
a 4- to 10‑day course of vancomycin followed by FMT compared with 10 days of vancomycin at 1- and 8‑week follow up (Hvas et al. 2019)
a 4- to 10‑day course of vancomycin followed by FMT compared with 10 days of fidaxomicin at 8‑week follow up (Hvas et al. 2019)
a 4- to 5‑day course of vancomycin plus bowel lavage followed by FMT compared with either 14 days of vancomycin (with or without bowel lavage) at 10‑week follow up, and at 5‑week follow up for relapse (van Nood et al. 2013)
a 3‑day course of vancomycin followed by FMT compared with a standard then a pulsed course of vancomycin at 10‑week follow up (Cammarota et al. 2015).
There were no statistically significant differences in all-cause or C. difficile infection-related mortality for a short course of vancomycin plus bowel lavage followed by FMT compared with 14 days of vancomycin or 14 days of vancomycin plus bowel lavage (van Nood et al. 2013).
There were no statistically significant differences in adverse events for:
a short course of oral vancomycin followed by FMT compared with either 10 days of vancomycin or fidaxomicin (Hvas et al. 2019)
a short course of vancomycin followed by FMT compared with vancomycin, either with or without bowel lavage (van Nood et al. 2013).
There was a statistically significant lower mean number of days of diarrhoea compared with a course of vancomycin followed by FMT compared with tapered vancomycin (Hota et al. 2017). However, a short course of vancomycin followed by FMT or bowel lavage plus FMT statistically significantly increased treatment-related diarrhoea, bloating or cramping (Cammarota et al. 2015; van Nood et al. 2013).
Serious adverse events were reported in 2 RCTs. In 1 RCT, a sepsis-like response occurred (possibly related to FMT) but resolved without admission or treatment (Hvas et al. 2019). In the other RCT, 3 serious adverse events were noted but none were thought to be treatment related (Hota et al. 2017).
# Preventing recurrence in people with C. difficile infection in adults
## Antibiotics
In adults who had an initial or first recurrent episode of C. difficile infection treated with vancomycin or metronidazole, immediate rifaximin for 20 days was statistically significantly more effective than placebo at reducing recurrence of both C. difficile infection-confirmed diarrhoea and self-reported diarrhoea. However, when the outcomes of recurrent C. difficile infection-confirmed diarrhoea and recurrent self-reported diarrhoea were analysed separately, there was no statistically significant difference between rifaximin and placebo in either group (Garey et al. 2011).
In adults who had an initial, first recurrent, or second or later recurrent episode of C. difficile infection treated with vancomycin or metronidazole, there was no statistically significant difference between immediate rifaximin for 28 days and placebo for recurrent C. difficile infection at 12 weeks or 6 months, or for rehospitalisation for C. difficile infection within 6 months. When subgroup analysis was done for standard care antibiotic treatment with metronidazole or vancomycin, there was no statistically significant difference between rifaximin and placebo for C. difficile infection recurrence. There was also no statistically significant difference in effect between rifaximin and placebo on C. difficile infection recurrence when post‑hoc analyses were done for C. difficile infection history (Major et al. 2019).
A Kaplan–Meier analysis showed that rifaximin led to a statistically significant increased time to both recurrent C. difficile infection-confirmed diarrhoea and recurrent self-reported diarrhoea compared with placebo (Garey et al. 2011). However, when the time to C. difficile infection-confirmed diarrhoea and time to self-reported diarrhoea were analysed separately, there was no statistically significant difference between rifaximin and placebo.
There were no statistically significant differences between rifaximin and placebo for mortality, serious and non-serious adverse events (Major et al. 2019).
## Monoclonal antibodies
In adults with an initial or recurrent episode of C. difficile infection treated with standard care antibiotic treatment (that is, metronidazole, vancomycin or fidaxomicin), bezlotoxumab was statistically significantly more effective than placebo for recurrent C. difficile infection, 12 weeks of sustained cure and recurrence of diarrhoea (regardless of whether it was associated with a positive toxin test; Wilcox et al. 2017). A Kaplan–Meier analysis suggested that bezlotoxumab increased time to recurrence of C. difficile infection compared with placebo, but it was unclear if the differences were statistically significant.
Various subgroup analyses for C. difficile infection risk factors and stratification variables were done. Bezlotoxumab was statistically significantly more effective than placebo for recurrence of C. difficile infection for the stratification variables of inpatients and outpatients, and whether people had vancomycin or metronidazole as their standard care antibiotic treatment. However, there was no statistically significant difference between bezlotoxumab and placebo for the outcome of recurrence of C. difficile infection for the stratification variable of people having fidaxomicin as their standard care antibiotic treatment.
There were no statistically significant differences between bezlotoxumab and placebo for the outcomes of initial clinical cure at 2 days and mortality.
There was no statistically significant difference between bezlotoxumab and placebo for infusion-specific adverse events or adverse events leading to treatment being stopped at 24‑hour follow up. There was also no statistically significant difference between bezlotoxumab and placebo for drug-related adverse events, other adverse events (most commonly abdominal pain, diarrhoea, nausea, vomiting, fatigue, pyrexia, serious C. difficile, urinary tract infection or headache), serious adverse events or for drug-related serious adverse events, occurring during the 4 weeks after the bezlotoxumab infusion.
## FMT for preventing C. difficile infection recurrence
In NICE analyses, there were no statistically significant differences in the clinical effectiveness (recurrence) of the following doses of FMT taken after antibiotic treatment for a current episode of C. difficile infection in adults with multiple recurrent infections:
a single dose of FMT compared with placebo
doses of FMT compared with placebo
doses of FMT compared with a single dose of FMT
-r 2 doses of FMT (pooled) compared with placebo (Dubberke et al. 2018).
There was no statistically significant difference in adverse events. However, 3 severe adverse events were reported and thought to be related to FMT in the '2 doses of FMT' group. There were 6 deaths (3 in the '2 doses of FMT' group and 3 in the '1 dose of FMT' group) in the FMT arms of the trial and none in the placebo group.
## Prebiotics for relapse of diarrhoea
There was a statistically significant decrease in relapse of diarrhoea with metronidazole or vancomycin plus the prebiotic oligofructose compared with metronidazole or vancomycin plus placebo for diarrhoea associated with C. difficile infection in adults aged over 65 years (Lewis et al. 2005a). No statistically significant difference was noted for C. difficile culture positivity at 30- or 60‑day follow up.
# Treating initial or recurrent C. difficile infection in children and young people
## Antibiotics choice
There was no statistically significant difference in clinical effectiveness (C. difficile infection cure rate or recurrent C. difficile infection) with oral metronidazole compared with oral rifaximin for a first episode of C. difficile infection in children with inflammatory bowel disease (Gawronska et al. 2017).
There was no statistically significant difference in confirmed clinical response or resolution of diarrhoea with oral fidaxomicin compared with oral vancomycin for confirmed C. difficile infection in children and young people aged under 18 years (Wolf et al. 2020).
In the total study population and subgroup of children aged under 2 years, there was no statistically significant difference between oral fidaxomicin and oral vancomycin for the outcome of global cure. However, in other subgroups (those aged 2 years and over and those with a positive toxin test aged 2 years and over), fidaxomicin was statically significantly more effective than vancomycin for global cure.
Oral fidaxomicin statistically significantly reduced C. difficile infection recurrence compared with oral vancomycin in children and young people aged under 18 years. When results were stratified by age, fidaxomicin was statistically significantly more effective than vancomycin in children aged 2 years and over and in children with a positive toxin test aged 2 years and over, but the effect was no longer statistically significant in those aged under 2 years.
There was no statistically significant difference for treatment-emergent adverse events (including serious events, drug-related events, those leading to death or withdrawal from treatment).
## Probiotics for persistent diarrhoea
There was a statistically significant reduction in the mean number of days of diarrhoea with oral rehydration solution plus the probiotic Lactobacillus rhamnosus GG compared with oral rehydration solution alone in children with a positive C. difficile stool culture (Basu et al. 2007). However, there was no statistically significant difference in the mean number of days of vomiting.
# Preventing C. difficile infection in adults without infection
## Antibiotics
In people without C. difficile infection having a haematopoietic stem cell transplant and fluoroquinolone prophylaxis during neutropenia, there was no statistically significant difference between fidaxomicin and placebo for reducing prophylaxis failure at 30, 60 or 70 days (Mullane et al. 2019). There was also no statistically significant difference between fidaxomicin and placebo for any adverse events reported in the study.
Fidaxomicin was statistically significantly more effective than placebo at reducing confirmed diarrhoea associated with C. difficile infection at 30, 60 and 70 days. A Kaplan–Meier analysis showed a statistically significantly increased time to recurrence of C. difficile infection with fidaxomicin compared with placebo.
In people without C. difficile infection who were hospitalised for up to 30 days before their current hospitalisation, there was no statistically significant difference between oral vancomycin and placebo for:
healthcare facility-onset (symptomatic infection more than 72 hours after hospital admission) C. difficile infection, or
community-onset healthcare facility-associated (symptomatic infection up to 3 months after hospital discharge) C. difficile infection after hospital discharge (Johnson et al. 2020).
## Prebiotics
In inpatients aged over 65 years without C. difficile infection who were prescribed a broad-spectrum antibiotic, the prebiotic oligofructose did not have a statistically significantly different effect to placebo at end of follow up for all-cause mortality or for incidence of diarrhoea, significant diarrhoea (3 loose stools or more in a 24‑hour period), non-significant diarrhoea (1 or 2 loose stools in a 24‑hour period), C. difficile-associated diarrhoea or C. difficile-associated significant diarrhoea (Lewis et al. 2005b).
In the oligofructose group, the median (interquartile range) length of hospital stay was 17 days (13 to 22) compared with 15 days (11 to 18) in the placebo group.
## Probiotics
The evidence for probiotics in the prevention of C. difficile infection in adults comes from 1 systematic review (Goldenberg et al. 2017). The population in the included studies was people aged over 18 years having antibiotic treatment for any reason.
Probiotics statistically significantly reduced the incidence of C. difficile infection compared with any comparator (follow-up time point not reported) in studies in inpatients, but not in studies in outpatients or patients in mixed settings.
Probiotics were not statistically significantly different compared with any comparator for the outcome of incidence of C. difficile infection determined by detection of C. difficile in stools, either overall or in any setting (inpatients, outpatients, or mixed settings; follow-up time points not reported).
Probiotics statistically significantly reduced the number of adverse events compared with any comparator (follow-up time point not reported). Details of the adverse events were not reported.
# Preventing C. difficile infection in children and young people without infection
## Probiotics
The evidence for probiotics in preventing C. difficile infection in children and young people comes from 1 systematic review (Goldenberg et al. 2017) and 1 RCT (Kolodziej and Szajewska 2019). The population in the included studies was children and young people aged under 18 years who were having antibiotic treatment for any reason.
Probiotics statistically significantly reduced the incidence of C. difficile infection compared with any comparator (follow-up time point not reported) in the inpatient and mixed settings studies.
Probiotics were not statistically significantly different compared with any comparator in inpatient studies for the outcome of incidence of C. difficile infection determined by detection of C. difficile in stool (follow-up time point not reported).
Probiotics were not statistically significantly different compared with any comparator for adverse events.# Other considerations
# Medicines safety
## Vancomycin
Vancomycin is a glycopeptide that is taken orally to treat Clostridioides difficile infection. With oral use, the company advises monitoring serum vancomycin concentration in people with inflammatory intestinal disorders in which absorption may be enhanced. It also advises that serial auditory function tests may help to minimise the risk of ototoxicity in people with an underlying hearing loss, or who are having concomitant therapy with other ototoxic drugs. In renal impairment or in people having concomitant treatment with an aminoglycoside or other nephrotoxic drug, the manufacturer advises serial monitoring of renal function. The manufacturer advises that vancomycin should be used in pregnancy only if the potential benefit outweighs the risk. Prolonged use of vancomycin may result in the overgrowth of non-susceptible organisms. Acquired resistance to glycopeptides is most common in enterococci, in which multiresistant strains have been seen (see BNF information on vancomycin and vancomycin summary of product characteristics).
## Fidaxomicin
Fidaxomicin is a macrocyclic antibacterial that is poorly absorbed from the gastrointestinal tract, so is not used to treat systemic infections. It is taken orally to treat C. difficile infection. Common side effects when taken orally for C. difficile infection include constipation, nausea and vomiting. The manufacturer advises that it is preferable to avoid using fidaxomicin in pregnancy as a precaution (see BNF information on fidaxomicin and fidaxomicin summary of product characteristics).
## Faecal microbiota transplant
In NICE's interventional procedures guidance on faecal microbiota transplant for recurrent C. difficile infection, it states that 'The US Food and Drug Administration has advised that stool donors for faecal microbiota transplantation should be screened with questions that specifically address risk factors for colonisation with multidrug-resistant organisms (MDROs), and individuals at higher risk of colonisation with MDROs should be excluded as donors. In addition, donor stool should be specifically tested for MDROs and not used if positive'. While short-term safety and adverse events with a faecal microbiota transplant were reported in the included studies for this guidance, the committee identified that longer-term safety of the procedure is not yet known.
# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see NICE's guideline on medicines adherence).
# Resource implications
See the economic analysis in the evidence review for detailed costs, including estimated costs of a faecal microbiota transplant. Vancomycin capsules and powder for solution are available as generic formulations. Fidaxomicin tablets are a proprietary product.
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{'Recommendations': "The recommendations in this guideline update existing Public Health England guidance on treating Clostridioides difficile infection.\n\n# Managing suspected or confirmed Clostridioides difficile infection\n\n## Assessment\n\nFor people with suspected or confirmed C. difficile infection, see Public Health England's guidance on diagnosis and reporting.\n\nFor people with suspected or confirmed C.\xa0difficile infection, assess:\n\nwhether it is a first or further episode (relapse or recurrence) of C.\xa0difficile infection\n\nthe severity of C.\xa0difficile infection\n\nindividual factors such as age, frailty or comorbidities that may affect the risk of complications or recurrence.\n\nFor people with suspected or confirmed C.\xa0difficile infection, review existing antibiotic treatment and stop it unless essential. If an antibiotic is still essential, consider changing to one with a lower risk of causing C.\xa0difficile infection.\n\nFor people with suspected or confirmed C.\xa0difficile infection, review the need to continue any treatment with:\n\nproton pump inhibitors\n\nother medicines with gastrointestinal activity or adverse effects, such as laxatives\n\nmedicines that may cause problems if people are dehydrated, such as non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin‑2 receptor antagonists and diuretics.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on assessment\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Treating suspected or confirmed C.\xa0difficile infection\n\nFor adults, offer an oral antibiotic to treat suspected or confirmed C.\xa0difficile infection (see the recommendations on choice of antibiotic). In the community, consider seeking prompt specialist advice from a microbiologist or infectious diseases specialist before starting treatment.\n\nFor children and young people under 18\xa0years, offer an oral antibiotic to treat suspected or confirmed C.\xa0difficile infection. Treatment should be started by, or after advice from, a microbiologist, paediatric infectious diseases specialist or paediatric gastroenterologist.\n\nFor people with suspected or confirmed C.\xa0difficile infection who cannot take oral medicines, seek specialist advice from a gastroenterologist or pharmacist about alternative enteral routes for antibiotics, such as a nasogastric tube or rectal catheter.\n\nManage fluid loss and symptoms associated with suspected or confirmed C.\xa0difficile infection as for acute gastroenteritis. Do not offer antimotility medicines such as loperamide.\n\nDo not offer bezlotoxumab to prevent recurrence of C.\xa0difficile infection because it is not cost effective.\n\nConsider a faecal microbiota transplant for a recurrent episode of C.\xa0difficile infection in adults who have had 2\xa0or more previous episodes (see NICE's interventional procedures guidance on faecal microbiota transplant for recurrent C.\xa0difficile infection).\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on treating suspected or confirmed C.\xa0difficile infection\xa0.\n\nFor more details, see the summary of the evidence.\n\nLoading. Please wait.\n\n## Advice\n\nAdvise people with suspected or confirmed C.\xa0difficile infection about:\n\ndrinking enough fluids to avoid dehydration\n\npreventing the spread of infection (see recommendation 1.3.1)\n\nseeking medical help if symptoms worsen rapidly or significantly at any time.\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on advice\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Reassessment\n\nReassess people with suspected or confirmed C.\xa0difficile infection if symptoms or signs do not improve as expected, or worsen rapidly or significantly at any time. Daily review may be needed, for example, if the person is in hospital.\n\nIf antibiotics have been started for suspected C.\xa0difficile infection, and subsequent stool sample tests do not confirm C.\xa0difficile infection, consider stopping these antibiotics (see Public Health England's guidance on diagnosis and reporting for recommendations on stool sample tests).\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on reassessment\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Referral\n\nRefer people in the community with suspected or confirmed C.\xa0difficile infection to hospital if they are severely unwell, or their symptoms or signs worsen rapidly or significantly at any time. Refer urgently if the person has a life-threatening infection.\n\nConsider referring people in the community to hospital if they could be at high risk of complications or recurrence because of individual factors such as age, frailty or comorbidities.\n\nEnsure that people in hospital with suspected or confirmed C.\xa0difficile infection have care from a multidisciplinary team that may include a microbiologist, infectious diseases specialist, gastroenterologist, surgeon, pharmacist or dietitian, as needed.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on referral or seeking specialist advice\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n# Choice of antibiotic\n\nWhen prescribing antibiotics for suspected or confirmed C.\xa0difficile infection in adults, follow table\xa01.\n\nWhen prescribing antibiotics for suspected or confirmed C.\xa0difficile infection in children and young people under 18\xa0years, base the choice of antibiotic on what is recommended for C.\xa0difficile infection in adults. Take into account licensed indications for children and young people, and what products are available (see the BNF for Children for dosing information).\n\nUse clinical judgement to determine whether antibiotic treatment for C.\xa0difficile is ineffective. It is not usually possible to determine this until day\xa07 because diarrhoea may take 1\xa0to 2\xa0weeks to resolve.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-line antibiotic for a first episode of mild, moderate or severe C.\xa0difficile infection\n\nVancomycin:\n\nmg orally four times a day for 10\xa0days\n\nSecond-line antibiotic for a first episode of mild, moderate or severe C.\xa0difficile infection if vancomycin is ineffective\n\nFidaxomicin:\n\nmg orally twice a day for 10\xa0days\n\nAntibiotics for C.\xa0difficile infection if first- and second-line antibiotics are ineffective\n\nSeek specialist advice. Specialists may initially offer:\n\nVancomycin:\n\nUp to 500\xa0mg orally four times a day for 10\xa0days\n\nWith or without\n\nMetronidazole:\n\nmg intravenously three times a day for 10\xa0days\n\nAntibiotic for a further episode of C.\xa0difficile infection within 12\xa0weeks of symptom resolution (relapse)\n\nFidaxomicin:\n\nmg orally twice a day for 10\xa0days\n\nAntibiotics for a further episode of C.\xa0difficile infection more than 12\xa0weeks after symptom resolution (recurrence)\n\nVancomycin:\n\nmg orally four times a day for 10\xa0days\n\n\n\nOr\n\n\n\nFidaxomicin:\n\nmg orally twice a day for 10\xa0days\n\nAntibiotics for life-threatening C.\xa0difficile infection (also see recommendation 1.1.16)\n\nSeek urgent specialist advice, which may include surgery. Antibiotics that specialists may initially offer are:\n\nVancomycin:\n\nmg orally four times a day for 10\xa0days\n\nWith\n\nMetronidazole:\n\nmg intravenously three times a day for 10\xa0days\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding. Also see medicines safety.\n\nSee Specialist Pharmacy Service guidance on choosing between oral vancomycin options. If ileus is present, specialists may use vancomycin rectally.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on choice of antibiotic\xa0.\n\nFor more details, see the summary of the evidence.\n\nLoading. Please wait.\n\n# Preventing C. difficile infection\n\nFor how to prevent C.\xa0difficile infection through good antimicrobial stewardship, infection control and environmental hygiene measures, see:\n\nPublic Health England's guidance on C.\xa0difficile infection: how to deal with the problem\n\nNICE's guidance on healthcare-associated infections\n and\n\nNICE's guidance on antimicrobial stewardship.\n\nEnsure a diagnosis of C.\xa0difficile infection is recorded (particularly when a person transfers from one care setting to another). This is so that it can be taken into account before any future antibiotics are prescribed.\n\nDo not offer antibiotics to prevent C.\xa0difficile infection.\n\nDo not advise people taking antibiotics to take prebiotics or probiotics to prevent C.\xa0difficile infection.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on preventing C.\xa0difficile infection\xa0.\n\nFor more details, see the summary of the evidence.\n\nLoading. Please wait.\n\n# Terms used in the guideline\n\n## C.\xa0difficile infection\n\nThis is defined (by Public Health England, 2013) as diarrhoea and:\n\na positive C.\xa0difficile toxin test or\n\nresults of a C.\xa0difficile toxin test pending and clinical suspicion of C.\xa0difficile infection.\n\n## Further episode (relapse or recurrence) of C.\xa0difficile infection\n\nA further episode of C.\xa0difficile infection could either be a relapse, which is more likely to be with the same C.\xa0difficile strain, or a recurrence, which is more likely to be with a different C.\xa0difficile strain. There is no agreement on the precise definition of relapse and recurrence, and it is difficult to distinguish between them in clinical practice. In this guideline, it was agreed that a relapse occurs within 12\xa0weeks of previous symptom resolution and recurrence occurs more than 12\xa0weeks after previous symptom resolution.\n\n## Severity of C.\xa0difficile infection\n\nThis is defined (by Public Health England, 2013) as:\n\nMild infection: not associated with an increased white cell count (WCC). Typically associated with fewer than 3\xa0episodes of loose stools (defined as loose enough to take the shape of the container used to sample them) per day.\n\nModerate infection: associated with an increased WCC (but less than 15\xa0×\xa0109 per litre). Typically associated with 3\xa0to 5\xa0loose stools per day.\n\nSevere infection: associated with a WCC greater than 15\xa0×\xa0109 per litre, or an acutely increased serum creatinine concentration (greater than 50% increase above baseline), or a temperature higher than 38.5 degrees Celsius, or evidence of severe colitis (abdominal or radiological signs). The number of stools may be a less reliable indicator of severity.\n\nLife-threatening infection: symptoms and signs include hypotension, partial or complete ileus, toxic megacolon or CT evidence of severe disease.\n\n## Probiotics\n\nProbiotics are live bacteria and yeasts that are promoted as having various health benefits. They are usually added to yoghurts or taken as food supplements. They are often described as 'good', 'friendly' or 'healthy' gut bacteria, and are thought to help restore the natural balance of bacteria in the gastrointestinal tract.\n\n## Prebiotics\n\nPrebiotics are a source of food for the 'healthy' bacteria in the gastrointestinal tract. They are a group of non-digestible food ingredients, such as fructo-oligosaccharides, that are a source of food for these bacteria. Prebiotics are found naturally in many fruits and vegetables, but can also be taken as supplements.", 'Recommendations for research': 'The guideline committee has made the following recommendation for research.\n\n# Oral teicoplanin compared with oral vancomycin or oral fidaxomicin for treating Clostridioides\xa0difficile infection\n\nWhat is the clinical effectiveness, cost effectiveness and safety of oral teicoplanin 100\xa0mg to 200\xa0mg twice a day for 7\xa0to 14\xa0days compared with oral vancomycin or oral fidaxomicin for treating C.\xa0difficile infection in adults?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on choice of antibiotic\xa0.\n\nLoading. Please wait.', 'Rationales': "The recommendations in this guideline are based on the evidence identified and the experience of the committee.\n\n# Assessment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.1 to 1.1.4\n\nThe committee agreed that although diagnostics and reporting were out-of-scope for this guideline, a recommendation should be included on where to find such information. They concluded, from experience, that people should see Public Health England's updated guidance on the diagnosis and reporting of Clostridioides difficile.\n\nThe committee discussed that, in practice, there has been a change in the definition of the severity of C.\xa0difficile from the 4\xa0categories (mild, moderate, severe and life threatening) used by Public Health England to 3\xa0categories (non-severe, severe and life threatening). However, the Public Health England categories still apply because this is current national guidance.\n\nThe committee discussed the findings of the economic model, which took into account severity by adjusting for older age, increased risk of recurrence, increased hospitalisation and a higher risk of fulminant colitis (see the economic analysis in the evidence review for full details; there was a lack of useful direct evidence for severity that could be used in the economic model). The economic model found that severity did not cause a substantial change in which antibiotic was the most cost effective. Therefore, the committee agreed that the main reason to assess severity was to identify the appropriate place of care, overall management, and any subsequent improvement or worsening. They also agreed that an assessment of whether the current infection was a first or further episode (relapse or recurrence) of C.\xa0difficile infection should be included. This was because recurrence was a driver in the economic model and determines antibiotic choice (see also the rationale on choice of antibiotic).\n\nThe committee recognised that C.\xa0difficile infection most commonly affects people who are taking or have recently taken antibiotics. They discussed that, even though antibiotics being taken may be associated with the C.\xa0difficile infection, the person may still need antibiotics for the original infection. They agreed that, in line with good antimicrobial stewardship, prescribers should review existing antibiotic treatment and:\n\nstop it unless essential, or\n\nif an antibiotic is still essential, consider changing to one with a lower risk of causing C.\xa0difficile infection.\n\nThe committee agreed that it is good prescribing practice to review the continuing need for existing proton pump inhibitor (PPI) treatment in people with suspected or confirmed C.\xa0difficile infection, in line with NICE's guideline on medicines optimisation. They were aware that, although some associations have been made between PPI use and the risk of C.\xa0difficile infection or recurrence, there is no definitive evidence of a causal or exacerbator effect. Also, no evidence from systematic reviews or randomised controlled trials was found to support stopping current PPI treatment. The committee agreed that suddenly stopping a PPI during an acute episode of infection may cause additional gastric symptoms. Additionally, some people will need ongoing gastroprotection for a clinical indication. However, they were aware that many people may be taking a PPI without a clear indication, so concluded that the use and need for a PPI should be reviewed.\n\nThe committee agreed that, when people present with suspected or confirmed C.\xa0difficile infection, it is good prescribing practice to review other medicines with gastrointestinal activity or adverse effects (such as laxatives) being taken. They also agreed that it is good practice to review other medicines being taken that may have detrimental effects if people are acutely ill and dehydrated. These include non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin‑2 receptor antagonists and diuretics.\n\nReturn to the recommendations\n\n# Treating suspected or confirmed C.\xa0difficile infection\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.5 to 1.1.10\n\nThe committee agreed that an oral antibiotic should be offered for suspected or confirmed C.\xa0difficile infection in adults, young people and children.\n\nFor adults presenting in the community, the committee agreed that GPs may be unfamiliar with diagnosing and treating C.\xa0difficile infection, so may want to seek prompt specialist advice from a microbiologist or infectious diseases specialist before starting treatment. The committee noted that, for people in hospital, once diagnosed, they would be under the care of a multidisciplinary team, which would ensure appropriate review and care.\n\nThe committee discussed the lack of evidence on treating C.\xa0difficile infection in children and young people. They were aware that, in practice, very few children have C.\xa0difficile infection. The committee agreed that a positive test for C.\xa0difficile in children 2\xa0years and under is often because of high carriage rates of the bacteria rather than because of actual infection. They considered that this may lead to overprescribing of antibiotics. The committee concluded that treatment for C.\xa0difficile infection in children and young people should only be started by a microbiologist, paediatric infectious diseases specialist or paediatric gastroenterologist, or after advice from such a specialist.\n\nThe committee discussed the most appropriate route of administration of antibiotics for C.\xa0difficile infection. They agreed that the enteral route is best because sufficient concentrations within the intestinal lumen need to be reached. The committee concluded that it is preferable to take antibiotics orally or, if this is not possible, enterally in some other way (such as a nasogastric or enteral feeding tube, or rectally). They advised seeking specialist advice on administration from a specialist gastroenterologist or pharmacist if the oral route is not available.\n\nThe committee agreed that, in line with the general management of gastroenteritis (see the NICE clinical knowledge summary on adult gastroenteritis and NICE's guideline on diarrhoea and vomiting caused by gastroenteritis in under\xa05s), prescribers and other care staff should monitor and manage fluid loss and gastroenteritis symptoms. Antimotility drugs such as loperamide should be avoided because they slow down the action of the gut. This can lead to C.\xa0difficile toxins being retained for longer, which may make a person more unwell.\n\nBezlotoxumab was not recommended as adjunctive therapy to antibiotics to prevent recurrent C.\xa0difficile infection. The committee discussed the clinical evidence, which showed that bezlotoxumab was more effective than placebo at preventing recurrence. However, they also reviewed the economic analysis and agreed that adding bezlotoxumab to either vancomycin or fidaxomicin was not a cost-effective option (there is a 0% probability of it being cost effective at £30,000 per quality-adjusted life year [QALY] gained). The committee agreed that this finding was robust, even in people with a higher risk of recurrence, and were confident in making a recommendation for bezlotoxumab not to be used.\n\nThe committee noted that faecal microbiota transplantation (FMT; a procedure done in a small number of specialist centres) was not effective as a first-line treatment for C.\xa0difficile infection compared with vancomycin. They were aware that long-term safety data on, and regulations about the use of, FMT are minimal compared with medicines. They were aware of variation in mortality rates associated with FMT use, and that there is almost no evidence for its use in children. NICE's interventional procedures guidance on FMT for recurrent C.\xa0difficile infection states that 'current evidence on the efficacy and safety of FMT for recurrent Clostridium difficile infection is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit'. In the economic model, FMT was placed as a third-line treatment (for people with continuing symptoms after first- and second-line antibiotics) that may help prevent serious complications. The committee agreed that FMT may be useful in adults who have had 2\xa0or more previous episodes of C.\xa0difficile infection in addition to the current episode to prevent recurrence of C.\xa0difficile infection. They were aware of ongoing developments around the screening of faecal microbiota donors to identify multidrug-resistant organisms.\n\nFor more details, see the summary of the evidence on treating initial or first recurrent C.\xa0difficile infection.\n\nReturn to the recommendations\n\n# Advice\n\n## Why the committee made the recommendation\n\nRecommendation 1.1.11\n\nThe committee discussed what advice on self-care people with a C.\xa0difficile infection would need and agreed that, from their experience, 3\xa0key areas of advice were needed:\n\nmaintaining fluid intake to avoid dehydration (and on the symptoms or signs of dehydration that people should be aware of)\n\nthe need to help reduce the spread of C.\xa0difficile infection, which is contagious (that is, people should follow the advice in the NICE clinical knowledge summary on adult gastroenteritis and in NICE's guideline on diarrhoea and vomiting caused by gastroenteritis in under\xa05s)\n\nwhen to seek medical help.\n\nReturn to the recommendation\n\n# Reassessment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.12 to 1.1.13\n\nThe committee were aware that C.\xa0difficile infection should be managed as a diagnosis in its own right. They agreed that the management and progress of suspected or confirmed C.\xa0difficile infection should be monitored during treatment. This could include assessing the severity of the infection and symptoms, and the need for hydration. The committee concluded that, from their experience, it would be good practice to reassess people if symptoms or signs of infection do not improve as expected or worsen rapidly or significantly at any time. They agreed that daily review is usual in hospital and that, in the community, people should be given appropriate safety netting advice to ensure that they return for reassessment if needed.\n\nThe committee also agreed that clinicians should consider stopping antibiotics for C.\xa0difficile infection if they have been started for clinically suspected C.\xa0difficile infection before stool sample test results are available and subsequent results do not confirm infection.\n\nReturn to the recommendations\n\n# Referral or seeking specialist advice\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.14 to 1.1.16\n\nThe committee agreed that people with suspected or confirmed C.\xa0difficile infection in the community should be referred to hospital if they are severely unwell, or their symptoms or signs worsen rapidly or significantly at any time. For life-threatening infection, an urgent referral is needed. The committee recognised that there are some individual factors (such as age, frailty and comorbidities) for which it may also be appropriate to consider referral to hospital. This is because they are associated with a higher risk of complications or recurrence.\n\nThe committee agreed that people who develop C.\xa0difficile infection while in hospital are unlikely to be having care from a microbiologist or infectious diseases specialist at diagnosis. However, once diagnosed they should be under the care of a multidisciplinary team to ensure appropriate review and care. The team could include, as needed, a microbiologist, infectious diseases specialist, gastroenterologist, surgeon, pharmacist and dietitian. This would depend, for example, on the severity of illness and need for surgery.\n\nReturn to the recommendations\n\n# Choice of antibiotic\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nThe committee discussed the evidence for the effectiveness and cost effectiveness of the different antibiotic options for treating C.\xa0difficile infection. They were aware that antibiotic resistance is not a major concern when treating C.\xa0difficile infection.\n\nOral vancomycin was recommended by the committee as the first-line antibiotic for a first episode of C.\xa0difficile infection of any severity. Fidaxomicin was recommended as the second-line antibiotic for a first episode of C.\xa0difficile infection of any severity when vancomycin is ineffective (treatment failure). The committee noted that, although fidaxomicin was more effective than vancomycin for sustained symptomatic cure in the network meta-analysis, the cost of fidaxomicin is substantially higher. In the base-case analysis, there was only a 2% probability of first-line fidaxomicin being cost effective compared with first-line vancomycin (at £30,000 per QALY gained). They also discussed that vancomycin treatment failure should not be judged too early. Diarrhoea can take 1\xa0to 2\xa0weeks to resolve, and it is not usually possible to determine whether antibiotic treatment for C.\xa0difficile is ineffective until day\xa07.\n\nThe committee agreed that, when teicoplanin and second-line metronidazole were excluded from the economic model, the remaining results clearly showed that vancomycin was the most cost-effective first-line antibiotic across a range of scenarios. This was the case when results from people at both higher and lower risks of recurrence were included (in particular, it was more cost effective as a first-line option than either metronidazole or fidaxomicin). They also agreed that fidaxomicin was the appropriate second-line option.\n\nThe committee noted that, from experience, some hospital trusts use fidaxomicin for first-line treatment of C.\xa0difficile infection in people who are older or frailer as a strategy to reduce recurrence and readmission. The aim is to offset the cost of using fidaxomicin by reducing future costs. The committee were made aware of a real-world evaluation of fidaxomicin in which its use first line had a greater effect on reducing mortality than its use second line after vancomycin. However, they heard that the economic model considered a range of benefits and harms (including deaths), as well as the costs of each strategy. Vancomycin (not fidaxomicin) was still the most cost-effective first-line option, even in people at higher risk of recurrence. The committee concluded that a recommendation to use fidaxomicin first line would incur unreasonably large opportunity costs that are not appropriate in the wider context of overall healthcare resource allocation. There are possible rare exceptions when vancomycin may not be acceptable, such as for an infection that is vancomycin resistant.\n\nThe committee noted that, when taken orally, vancomycin is not well absorbed from the gut into the circulation (although absorption may increase if the gut is damaged). So, the likelihood of side effects (such as ototoxicity) is lower with oral than with intravenous administration, although there is still a need to monitor for this in some people (see medicines safety). They also discussed the development of drug-resistant bacteria, in particular, vancomycin-resistant enterococci. However, they agreed with expert testimony that this is not a major concern in clinical practice when vancomycin is used orally for C.\xa0difficile infection.\n\nThe committee discussed that vancomycin capsules would usually be the preferred formulation for taking vancomycin orally. They were aware that vancomycin powder for solution is also licensed to be taken orally for C.\xa0difficile infection, and that it is used in some settings (particularly if people cannot take solid oral medicines). However, they discussed that locally agreed protocols should be in place to reduce the risk of medication errors around reconstitution and administration, and to take account of the practicalities of administration, particularly in community settings. This is discussed further in Specialist Pharmacy Service guidance on choosing between oral vancomycin options.\n\nFidaxomicin was recommended by the committee for a further episode of C.\xa0difficile infection of any severity occurring within 12\xa0weeks of symptom resolution. They defined this as a relapse. For a further episode of C.\xa0difficile infection occurring more than 12\xa0weeks after symptom resolution (defined as recurrence), either vancomycin or fidaxomicin was recommended, with choice being an individualised patient decision.\n\nThe committee noted there was no clinical evidence comparing vancomycin with fidaxomicin in a population having a further episode of C.\xa0difficile infection after initial cure. Their decisions were therefore heavily influenced by the threshold analyses around risks of future recurrence. This was because they agreed that 1\xa0key difference with a further episode of infection is the higher risk of subsequent additional recurrences. The committee noted that the risk of future recurrence needed to be around 30% to 40% for fidaxomicin to be cost effective as a first-line option compared with vancomycin (at £30,000 per QALY gained). While they did not believe that this would be the case for all people with a recurrent infection, they did agree that there would be people with a risk of recurrence that high. They therefore agreed that it was appropriate for both vancomycin and fidaxomicin to be first-line options for further episodes. They concluded that the choice would come down to an individualised patient decision based around severity, the risk of additional recurrences (which increases after each recurrent episode) and the time between recurrences. The committee favoured fidaxomicin for more severe, more recent or multiple recurrent episodes. They thought that vancomycin would be suitable for less severe or first recurrent episodes, or if there had been a long time between episodes.\n\nThe committee were aware that there is poor agreement on the definition of relapse or recurrence in C.\xa0difficile infection, both nationally and internationally. They discussed different time periods and agreed, based on expert opinion, that 30\xa0days from resolution of symptoms was too short a time period to define recurrence. They thought that further symptoms within this time period after initial symptom resolution were more likely to represent relapse with the same strain of C.\xa0difficile infection. The committee heard that, in practice, further symptoms within 12\xa0to 24\xa0months may be considered a recurrence, likely with a different strain of C.\xa0difficile infection. However, they were also aware of evidence that suggested recurrence generally relates to a further episode within 20\xa0weeks. Defining relapse or recurrence is outside of the remit of the committee, and evidence on this issue was not searched for. So, the committee agreed that it could not be certain about the time period but thought that 12\xa0weeks was a reasonable cut-off point between relapse and recurrence.\n\nThe committee agreed that specialist advice should be sought about the choice of antibiotics for C.\xa0difficile infection that has not responded to either first- or second-line antibiotics, or for a life-threatening infection. However, they recognised that, in practice, specialists will often initially recommend high-dose oral vancomycin with or without intravenous metronidazole for this. If ileus is present, specialists may use vancomycin rectally.\n\nTeicoplanin was not recommended by the committee for treating C.\xa0difficile infection. It was ranked first in the network meta-analysis results. However, the committee were concerned about the extensive limitations of the 2\xa0small studies of teicoplanin included in the network meta-analysis, both of which were at considerable risk of bias. The committee noted that the point estimate of effect was important. However, the 95% confidence intervals were wide, revealing much uncertainty in the estimate. This meant that there was little difference from, and overlap with, the estimate of effect for vancomycin. The committee were also aware of the limited clinical experience with using teicoplanin in the UK for C.\xa0difficile infection. They concluded that further research was needed on teicoplanin for treating C.\xa0difficile infection and made a recommendation for research.\n\nThe committee had an initial discussion about the findings from the economic model. They noted that, if the results from the studies of teicoplanin were considered robust, it would come out clearly as the most cost-effective first-line treatment. However, they were not convinced by either the sample size or quality of the studies on teicoplanin. They agreed there was not enough clinical evidence to recommend it, so focused on the economic model results excluding teicoplanin.\n\nMetronidazole was not recommended by the committee for treating C.\xa0difficile infection. The committee agreed that not using metronidazole first line for mild and moderate C.\xa0difficile infection represented a change in practice for some clinicians. However, they were confident in the evidence that metronidazole was neither clinically nor cost effective compared with vancomycin. In the network meta-analysis results, metronidazole was ranked lowest out of all the antibiotics available in the UK (below teicoplanin, fidaxomicin, vancomycin, rifaximin and fusidic acid). In the economic modelling, when the costs of rehospitalisation were included in the analysis, metronidazole was a less cost-effective first-line treatment than vancomycin, which was dominant in most scenarios (meaning using vancomycin was both less costly and more effective than using metronidazole). From the evidence, metronidazole had lower initial cure rates and higher recurrence rates than vancomycin. The committee heard that metronidazole is comparatively inexpensive compared with other antibiotic treatments. However, they discussed that, from experience, many hospital trusts have already moved away from using metronidazole, prompted by lower efficacy compared with other antibiotics and potential side effects. The committee also heard expert testimony that cure or improvement may take longer with metronidazole compared with other antibiotic treatments. A longer period before treatment becomes effective is concerning. This is because it may lead to increased transmission of the infection, particularly in hospital or residential care settings. Neither of these issues were addressed in the economic model.\n\nWhen considering the economic model, the committee agreed that it was appropriate to exclude strategies in which metronidazole was used as a second-line intervention. They noted that a limitation of the analysis was that interventions were assumed to be equally effective as second-line options compared with first-line options. This was because there were no data to test this assumption. They agreed that, when C.\xa0difficile is not clinically cured using first-line vancomycin or fidaxomicin it is likely to represent infection that is harder to treat. So, it would also be less likely to respond to metronidazole, meaning it would not be effective as a second-line agent.\n\nThe committee recognised that intravenous metronidazole may be a treatment option in the rare event that C.\xa0difficile infection fails to respond to either vancomycin or fidaxomicin, or in people with a life-threatening infection. The committee noted that, from experience, intravenous metronidazole (as an adjunct to vancomycin by the enteral route) is used in practice for some people in these circumstances.\n\nThe committee noted the evidence showing no statistically significant difference in clinical effectiveness with low-dose (125\xa0mg four times a day) compared with high-dose (500\xa0mg four times a day) vancomycin. The committee concluded that the standard licensed dose of oral vancomycin 125\xa0mg four times a day for 10\xa0days was sufficient to treat a first episode of mild, moderate or severe C.\xa0difficile infection, or a further episode of infection more than 12\xa0weeks after symptom resolution (recurrence). The committee were also aware that specialists may use higher licensed doses of oral vancomycin (up to 500\xa0mg four times a day) for C.\xa0difficile infection not responding to first- or second-line antibiotics or for life-threatening infection.\n\nOral vancomycin can be taken as capsules or the powder for solution can be reconstituted and taken orally as a drink or by nasogastric tube (a licensed use). The committee discussed that capsules would be the preferred formulation, particularly in community settings, for ease of use and to avoid any safety concerns around reconstitution and administration.\n\nA tapered or pulsed regimen of vancomycin was not recommended because, in the evidence review, its use was limited to studies in which there was co-administration of FMT. The committee were aware that there are ongoing trials which might provide evidence for wider use of pulsed or tapered vancomycin.\n\nThe committee noted the evidence suggesting that fidaxomicin 400\xa0mg daily was more clinically effective than 100\xa0mg or 200\xa0mg daily. They concluded that the standard licensed dose of oral fidaxomicin 200\xa0mg twice a day for 10\xa0days was sufficient to treat C.\xa0difficile infection.\n\nThe committee considered the comparison of the standard and extended-pulsed regimens of fidaxomicin in the economic model. The unlicensed extended-pulsed regimen of fidaxomicin is 200\xa0mg twice a day on days\xa01 to\xa05, then 200\xa0mg once a day on alternate days from days\xa07 to\xa025. The committee noted that the point estimates were in favour of extended-pulsed fidaxomicin. However, there was considerable uncertainty in this conclusion (with a 36% chance of standard fidaxomicin being more cost effective than extended-pulsed fidaxomicin at £30,000 per QALY gained). Also, the absolute magnitude of the differences was small. The committee agreed that there was insufficient evidence of benefits from the extended-pulsed regimen to justify recommending an unlicensed treatment regimen over a licensed one.\n\nThe committee agreed that treatment for C.\xa0difficile infection in children and young people should only be started by, or after advice from, a specialist. And that antibiotic choice can be based on recommendations for adults, taking into account the varying licensed indications for children and the availability of suitable products.\n\nVancomycin capsules are licensed to treat C.\xa0difficile infection only in people aged 12\xa0years and over (see the vancomycin capsules summary of product characteristics). Vancomycin powder for solution taken orally is licensed to treat C.\xa0difficile infection in all age groups (see the vancomycin powder for solution summary of product characteristics).\n\nFidaxomicin tablets are licensed to treat C.\xa0difficile infection in children with a body weight of at least 12.5\xa0kg (see the fidaxomicin summary of product characteristics). Fidaxomicin granules for oral suspension are licensed to treat C.\xa0difficile infection from birth (and are likely to become available in the UK). However, there is a caution for use in babies less than 6\xa0months and in babies with body weight less than 4\xa0kg (see the Medicines and Healthcare products Regulatory Agency information on fidaxomicin granules).\n\nFor more detail see the summary of the evidence on antibiotic dose.\n\nReturn to the recommendations\n\n# Preventing C.\xa0difficile infection\n\n## Why the committee made the recommendations\n\nRecommendations 1.3.1 to 1.3.4\n\nThe committee agreed that, although preventing C.\xa0difficile infection through good antimicrobial stewardship, infection control and environmental hygiene were out-of-scope for this guideline, a recommendation should be included on where to find such information. They concluded, from experience, that people should see Public Health England's guidance on C.\xa0difficile infection: how to deal with the problem, and NICE's guidance on healthcare-associated infections and antimicrobial stewardship.\n\nThe committee also discussed the importance of ensuring that a diagnosis of C.\xa0difficile infection is recorded in a person's medical records. This is particularly important when transferring from one care setting to another, so that it can be taken into account before prescribing any future antibiotics, to help minimise the risk of recurrent episodes.\n\nThe committee noted the lack of evidence of clinical or cost effectiveness to prevent C.\xa0difficile infection with antibiotics. They recognised that there was some evidence for rifaximin preventing further recurrences from a single study in people who already had recurrent infection. However, the intensive way in which antibiotics were used in the study has raised concerns about the possible emergence of rifamycin resistance, which has been reported in C.\xa0difficile infection cases, and prolonged flora disturbance.\n\nThe committee also recognised the limited evidence of benefit for:\n\nfidaxomicin in preventing C.\xa0difficile infection in people having a haematopoietic stem cell transplant who had fluoroquinolone prophylaxis\n\nvancomycin in preventing C.\xa0difficile infection in people who are in hospital.\n\nThe economic model only included treatment options, including adjunctive treatment with bezlotoxumab (which is used to prevent recurrent infection) and FMT to determine sequencing of treatments. It did not include comparisons for preventing a first episode of C.\xa0difficile infection with antibiotics, prebiotics or probiotics. The committee concluded that, because of the lack of evidence and concerns about antimicrobial resistance, antibiotics should not be offered for preventing C.\xa0difficile infection.\n\nThe committee noted the lack of convincing evidence of effect for prebiotics (oligofructose), which showed little difference in preventing C.\xa0difficile-associated outcomes in the included studies. They concluded that prebiotics conferred no benefit and that people taking antibiotics should not be advised to take prebiotics to prevent C.\xa0difficile infection.\n\nThe committee agreed that there is some evidence of a small effect with probiotics in preventing C.\xa0difficile infection. However, there were many limitations in the evidence, including:\n\na high number needed to treat\n\naggregation of the results of different types of probiotics in meta-analyses\n\nthe lack of effectiveness when using confirmed cases only (in everyone, but particularly in children).\n\nThe committee also noted concerns from expert testimony about the high prevalence of C.\xa0difficile infection in the placebo arms of some studies, which does not reflect clinical practice in the UK. The single study done in a UK setting found no evidence of effect for probiotics in people aged over 65\xa0years. They further noted that NHS England's guidance on conditions for which over the counter items should not routinely be prescribed in primary care states that probiotics should not routinely be prescribed.\n\nThe committee concluded that, because of concerns about the evidence base (including cost effectiveness), people taking antibiotics should not be advised to take probiotics to prevent C.\xa0difficile infection.\n\nReturn to the recommendations", 'Context': 'Clostridioides difficile is a bacterium that can infect the bowel and cause diarrhoea. Certain groups, such as older people, are at higher risk of C.\xa0difficile infection. The infection most commonly affects people who are taking, or have recently taken, antibiotics, and it can be transmitted very easily. It can be mild, moderate, severe or life threatening, and is treated with antibiotics.', 'Summary of the evidence': "This is a summary of the evidence, for full details (including the economic analysis) see the evidence review.\n\nThe evidence for treating Clostridioides difficile infection in adults specifically included antibiotic efficacy, choice, dose and dose frequency, faecal microbiota transplantation (FMT), bezlotoxumab and prebiotics. The evidence for treating C.\xa0difficile infection in children included antibiotic choice and probiotics.\n\nFor C.\xa0difficile infection in adults, young people or children, no evidence from systematic reviews or randomised controlled trials (RCTs) was identified for antibiotic prescribing strategies, course length or route of administration. There was also no evidence found for probiotics for C.\xa0difficile infection in adults, nor for antibiotic efficacy, dose or dose frequency, FMT, bezlotoxumab or prebiotics for infection in children.\n\nThere was evidence found for prophylactic antibiotics (in adults having a stem cell transplant or in hospital), prebiotics and probiotics to prevent C.\xa0difficile infection in adults. There was evidence for probiotics to prevent C.\xa0difficile infection in children.\n\nInterventions included in the search were antimicrobial interventions, non-antimicrobial interventions (bezlotoxumab and intravenous immunoglobulin), and non-pharmacological interventions (probiotics, prebiotics, FMT, and stopping current antibiotics or proton pump inhibitors). No evidence from systematic reviews or RCTs was found for intravenous immunoglobulin or stopping current antibiotics or proton pump inhibitors. In addition, the following interventions were outside the scope of this guideline because there is no UK licensed product available: ridinilazole, cadazolid, surotomycin, nitazoxanide, tolevamer, LFF517, bacitracin and tolevamer.\n\n# Treating initial or first recurrent C.\xa0difficile infection in adults\n\n## Antibiotics\n\nA statistically significant improvement was seen in symptomatic and bacteriological cure with vancomycin 125\xa0mg four times daily for 5\xa0days compared with placebo in adults with first-episode pseudomembranous colitis (some associated with evidence of C.\xa0difficile infection; Nelson et al. 2017).\n\nIn 1\xa0network meta-analysis, different antibiotic treatments were compared for treating the initial or first recurrent episode of C.\xa0difficile infection. Vancomycin was used as the reference treatment (Beinortas et al. 2018), and the treatments were ranked using P scores. Of the antibiotics available in the UK, sustained symptomatic cure was most effective with teicoplanin (P\xa0score=0.9386), followed by fidaxomicin (P\xa0score=0.7922), vancomycin (P\xa0score=0.4850), rifaximin (P\xa0score=0.4296), fusidic acid (P\xa0score=0.3794) and metronidazole (P\xa0score=0.2411). P scores are calculated as the average p value for superiority for that intervention compared with all the other interventions in the network meta-analysis. They take account of the magnitude of the difference and the level of uncertainty. Higher P scores (on a 0\xa0to\xa01 scale) represent treatments in which there is more confidence that they are better than the other alternatives in the network meta-analysis.\n\nA sensitivity analysis was done in which the effect was explored of removing studies with fewer than 50\xa0people per arm, studies that were published before 2000, and unblinded studies. When non-blinded studies or studies with fewer than 50\xa0people per arm were removed, fidaxomicin was the highest ranked treatment available in the UK. When studies published before the year 2000 were removed, teicoplanin was the highest ranked treatment available in the UK, followed by fidaxomicin.\n\nSubgroup analysis was done for severe C.\xa0difficile infection, non-severe C.\xa0difficile infection, initial C.\xa0difficile infection, non-initial C.\xa0difficile infection, people aged 65\xa0years and over and people aged under 65\xa0years. For all subgroups, fidaxomicin was the highest ranked treatment available in the UK, and metronidazole was the least effective (being ranked either the fifth, sixth or seventh most effective option in the different subgroups).\n\nThere were no statistically significant differences in clinical effectiveness (recurrence of C.\xa0difficile infection, clinical resolution of C.\xa0difficile infection, relapse of C.\xa0difficile infection at 5\xa0weeks and adverse events) for oral vancomycin compared with fidaxomicin (Hvas et al. 2019).\n\nThere was no statistically significant difference in clinical effectiveness (symptomatic cure) with low-dose (125\xa0mg four times a day) compared with high-dose (500\xa0mg four times a day) vancomycin, both taken for 5\xa0to 15\xa0days (Nelson et al. 2017).\n\nThere was a statistically significant improvement in clinical effectiveness (symptomatic cure) with fidaxomicin 400\xa0mg daily compared with fidaxomicin 100\xa0mg or 200\xa0mg daily, all taken for 10\xa0days.\n\nThere was no statistically significant difference in clinical effectiveness (symptomatic cure) with 100\xa0mg of teicoplanin twice daily compared with 50\xa0mg of teicoplanin four times daily (Nelson et al. 2017).\n\n## FMT for treating initial C.\xa0difficile infection\n\nThere were no statistically significant differences in clinical effectiveness (resolution of C.\xa0difficile infection, treatment failure, all-cause and C.\xa0difficile infection attributable mortality or length of stay) of:\n\nthe first dose of FMT compared with vancomycin\n\nthe second dose of FMT compared with vancomycin (Camacho-Ortiz et al. 2017).\n\n## FMT for treating recurrent C.\xa0difficile infection\n\nThere were statistically significant increases in clinical effectiveness (resolution of symptoms, resolution of diarrhoea, relapse of diarrhoea) with:\n\na 4- to 10‑day course of vancomycin followed by FMT compared with 10\xa0days of vancomycin at 1- and 8‑week follow up (Hvas et al. 2019)\n\na 4- to 10‑day course of vancomycin followed by FMT compared with 10\xa0days of fidaxomicin at 8‑week follow up (Hvas et al. 2019)\n\na 4- to 5‑day course of vancomycin plus bowel lavage followed by FMT compared with either 14\xa0days of vancomycin (with or without bowel lavage) at 10‑week follow up, and at 5‑week follow up for relapse (van Nood et al. 2013)\n\na 3‑day course of vancomycin followed by FMT compared with a standard then a pulsed course of vancomycin at 10‑week follow up (Cammarota et al. 2015).\n\nThere were no statistically significant differences in all-cause or C.\xa0difficile infection-related mortality for a short course of vancomycin plus bowel lavage followed by FMT compared with 14\xa0days of vancomycin or 14\xa0days of vancomycin plus bowel lavage (van Nood et al. 2013).\n\nThere were no statistically significant differences in adverse events for:\n\na short course of oral vancomycin followed by FMT compared with either 10\xa0days of vancomycin or fidaxomicin (Hvas et al. 2019)\n\na short course of vancomycin followed by FMT compared with vancomycin, either with or without bowel lavage (van Nood et al. 2013).\n\nThere was a statistically significant lower mean number of days of diarrhoea compared with a course of vancomycin followed by FMT compared with tapered vancomycin (Hota et al. 2017). However, a short course of vancomycin followed by FMT or bowel lavage plus FMT statistically significantly increased treatment-related diarrhoea, bloating or cramping (Cammarota et al. 2015; van Nood et al. 2013).\n\nSerious adverse events were reported in 2\xa0RCTs. In 1\xa0RCT, a sepsis-like response occurred (possibly related to FMT) but resolved without admission or treatment (Hvas et al. 2019). In the other RCT, 3\xa0serious adverse events were noted but none were thought to be treatment related (Hota et al. 2017).\n\n# Preventing recurrence in people with C.\xa0difficile infection in adults\n\n## Antibiotics\n\nIn adults who had an initial or first recurrent episode of C.\xa0difficile infection treated with vancomycin or metronidazole, immediate rifaximin for 20\xa0days was statistically significantly more effective than placebo at reducing recurrence of both C.\xa0difficile infection-confirmed diarrhoea and self-reported diarrhoea. However, when the outcomes of recurrent C.\xa0difficile infection-confirmed diarrhoea and recurrent self-reported diarrhoea were analysed separately, there was no statistically significant difference between rifaximin and placebo in either group (Garey et al. 2011).\n\nIn adults who had an initial, first recurrent, or second or later recurrent episode of C.\xa0difficile infection treated with vancomycin or metronidazole, there was no statistically significant difference between immediate rifaximin for 28\xa0days and placebo for recurrent C.\xa0difficile infection at 12\xa0weeks or 6\xa0months, or for rehospitalisation for C.\xa0difficile infection within 6\xa0months. When subgroup analysis was done for standard care antibiotic treatment with metronidazole or vancomycin, there was no statistically significant difference between rifaximin and placebo for C.\xa0difficile infection recurrence. There was also no statistically significant difference in effect between rifaximin and placebo on C.\xa0difficile infection recurrence when post‑hoc analyses were done for C.\xa0difficile infection history (Major et al. 2019).\n\nA Kaplan–Meier analysis showed that rifaximin led to a statistically significant increased time to both recurrent C.\xa0difficile infection-confirmed diarrhoea and recurrent self-reported diarrhoea compared with placebo (Garey et al. 2011). However, when the time to C.\xa0difficile infection-confirmed diarrhoea and time to self-reported diarrhoea were analysed separately, there was no statistically significant difference between rifaximin and placebo.\n\nThere were no statistically significant differences between rifaximin and placebo for mortality, serious and non-serious adverse events (Major et al. 2019).\n\n## Monoclonal antibodies\n\nIn adults with an initial or recurrent episode of C.\xa0difficile infection treated with standard care antibiotic treatment (that is, metronidazole, vancomycin or fidaxomicin), bezlotoxumab was statistically significantly more effective than placebo for recurrent C.\xa0difficile infection, 12\xa0weeks of sustained cure and recurrence of diarrhoea (regardless of whether it was associated with a positive toxin test; Wilcox et al. 2017). A Kaplan–Meier analysis suggested that bezlotoxumab increased time to recurrence of C.\xa0difficile infection compared with placebo, but it was unclear if the differences were statistically significant.\n\nVarious subgroup analyses for C.\xa0difficile infection risk factors and stratification variables were done. Bezlotoxumab was statistically significantly more effective than placebo for recurrence of C.\xa0difficile infection for the stratification variables of inpatients and outpatients, and whether people had vancomycin or metronidazole as their standard care antibiotic treatment. However, there was no statistically significant difference between bezlotoxumab and placebo for the outcome of recurrence of C.\xa0difficile infection for the stratification variable of people having fidaxomicin as their standard care antibiotic treatment.\n\nThere were no statistically significant differences between bezlotoxumab and placebo for the outcomes of initial clinical cure at 2\xa0days and mortality.\n\nThere was no statistically significant difference between bezlotoxumab and placebo for infusion-specific adverse events or adverse events leading to treatment being stopped at 24‑hour follow up. There was also no statistically significant difference between bezlotoxumab and placebo for drug-related adverse events, other adverse events (most commonly abdominal pain, diarrhoea, nausea, vomiting, fatigue, pyrexia, serious C.\xa0difficile, urinary tract infection or headache), serious adverse events or for drug-related serious adverse events, occurring during the 4\xa0weeks after the bezlotoxumab infusion.\n\n## FMT for preventing C.\xa0difficile infection recurrence\n\nIn NICE analyses, there were no statistically significant differences in the clinical effectiveness (recurrence) of the following doses of FMT taken after antibiotic treatment for a current episode of C.\xa0difficile infection in adults with multiple recurrent infections:\n\na single dose of FMT compared with placebo\n\ndoses of FMT compared with placebo\n\ndoses of FMT compared with a single dose of FMT\n\nor 2\xa0doses of FMT (pooled) compared with placebo (Dubberke et al. 2018).\n\nThere was no statistically significant difference in adverse events. However, 3\xa0severe adverse events were reported and thought to be related to FMT in the '2\xa0doses of FMT' group. There were 6\xa0deaths (3\xa0in the '2\xa0doses of FMT' group and 3\xa0in the '1\xa0dose of FMT' group) in the FMT arms of the trial and none in the placebo group.\n\n## Prebiotics for relapse of diarrhoea\n\nThere was a statistically significant decrease in relapse of diarrhoea with metronidazole or vancomycin plus the prebiotic oligofructose compared with metronidazole or vancomycin plus placebo for diarrhoea associated with C.\xa0difficile infection in adults aged over 65\xa0years (Lewis et al. 2005a). No statistically significant difference was noted for C.\xa0difficile culture positivity at 30- or 60‑day follow up.\n\n# Treating initial or recurrent C.\xa0difficile infection in children and young people\n\n## Antibiotics choice\n\nThere was no statistically significant difference in clinical effectiveness (C.\xa0difficile infection cure rate or recurrent C.\xa0difficile infection) with oral metronidazole compared with oral rifaximin for a first episode of C.\xa0difficile infection in children with inflammatory bowel disease (Gawronska et al. 2017).\n\nThere was no statistically significant difference in confirmed clinical response or resolution of diarrhoea with oral fidaxomicin compared with oral vancomycin for confirmed C.\xa0difficile infection in children and young people aged under 18\xa0years (Wolf et al. 2020).\n\nIn the total study population and subgroup of children aged under 2\xa0years, there was no statistically significant difference between oral fidaxomicin and oral vancomycin for the outcome of global cure. However, in other subgroups (those aged 2\xa0years and over and those with a positive toxin test aged 2\xa0years and over), fidaxomicin was statically significantly more effective than vancomycin for global cure.\n\nOral fidaxomicin statistically significantly reduced C.\xa0difficile infection recurrence compared with oral vancomycin in children and young people aged under 18\xa0years. When results were stratified by age, fidaxomicin was statistically significantly more effective than vancomycin in children aged 2\xa0years and over and in children with a positive toxin test aged 2\xa0years and over, but the effect was no longer statistically significant in those aged under 2\xa0years.\n\nThere was no statistically significant difference for treatment-emergent adverse events (including serious events, drug-related events, those leading to death or withdrawal from treatment).\n\n## Probiotics for persistent diarrhoea\n\nThere was a statistically significant reduction in the mean number of days of diarrhoea with oral rehydration solution plus the probiotic Lactobacillus rhamnosus\xa0GG compared with oral rehydration solution alone in children with a positive C.\xa0difficile stool culture (Basu et al. 2007). However, there was no statistically significant difference in the mean number of days of vomiting.\n\n# Preventing C.\xa0difficile infection in adults without infection\n\n## Antibiotics\n\nIn people without C.\xa0difficile infection having a haematopoietic stem cell transplant and fluoroquinolone prophylaxis during neutropenia, there was no statistically significant difference between fidaxomicin and placebo for reducing prophylaxis failure at 30,\xa060\xa0or 70\xa0days (Mullane et al. 2019). There was also no statistically significant difference between fidaxomicin and placebo for any adverse events reported in the study.\n\nFidaxomicin was statistically significantly more effective than placebo at reducing confirmed diarrhoea associated with C.\xa0difficile infection at 30, 60\xa0and 70\xa0days. A Kaplan–Meier analysis showed a statistically significantly increased time to recurrence of C.\xa0difficile infection with fidaxomicin compared with placebo.\n\nIn people without C.\xa0difficile infection who were hospitalised for up to 30\xa0days before their current hospitalisation, there was no statistically significant difference between oral vancomycin and placebo for:\n\nhealthcare facility-onset (symptomatic infection more than 72\xa0hours after hospital admission) C.\xa0difficile infection, or\n\ncommunity-onset healthcare facility-associated (symptomatic infection up to 3\xa0months after hospital discharge) C.\xa0difficile infection after hospital discharge (Johnson et al. 2020).\n\n## Prebiotics\n\nIn inpatients aged over 65\xa0years without C.\xa0difficile infection who were prescribed a broad-spectrum antibiotic, the prebiotic oligofructose did not have a statistically significantly different effect to placebo at end of follow up for all-cause mortality or for incidence of diarrhoea, significant diarrhoea (3\xa0loose stools or more in a 24‑hour period), non-significant diarrhoea (1\xa0or 2\xa0loose stools in a 24‑hour period), C.\xa0difficile-associated diarrhoea or C.\xa0difficile-associated significant diarrhoea (Lewis et al. 2005b).\n\nIn the oligofructose group, the median (interquartile range) length of hospital stay was 17\xa0days (13\xa0to\xa022) compared with 15\xa0days (11\xa0to\xa018) in the placebo group.\n\n## Probiotics\n\nThe evidence for probiotics in the prevention of C.\xa0difficile infection in adults comes from 1\xa0systematic review (Goldenberg et al. 2017). The population in the included studies was people aged over 18\xa0years having antibiotic treatment for any reason.\n\nProbiotics statistically significantly reduced the incidence of C.\xa0difficile infection compared with any comparator (follow-up time point not reported) in studies in inpatients, but not in studies in outpatients or patients in mixed settings.\n\nProbiotics were not statistically significantly different compared with any comparator for the outcome of incidence of C.\xa0difficile infection determined by detection of C.\xa0difficile in stools, either overall or in any setting (inpatients, outpatients, or mixed settings; follow-up time points not reported).\n\nProbiotics statistically significantly reduced the number of adverse events compared with any comparator (follow-up time point not reported). Details of the adverse events were not reported.\n\n# Preventing C.\xa0difficile infection in children and young people without infection\n\n## Probiotics\n\nThe evidence for probiotics in preventing C.\xa0difficile infection in children and young people comes from 1\xa0systematic review (Goldenberg et al. 2017) and 1\xa0RCT (Kolodziej and Szajewska 2019). The population in the included studies was children and young people aged under 18 years who were having antibiotic treatment for any reason.\n\nProbiotics statistically significantly reduced the incidence of C.\xa0difficile infection compared with any comparator (follow-up time point not reported) in the inpatient and mixed settings studies.\n\nProbiotics were not statistically significantly different compared with any comparator in inpatient studies for the outcome of incidence of C.\xa0difficile infection determined by detection of C.\xa0difficile in stool (follow-up time point not reported).\n\nProbiotics were not statistically significantly different compared with any comparator for adverse events.", 'Other considerations': "# Medicines safety\n\n## Vancomycin\n\nVancomycin is a glycopeptide that is taken orally to treat Clostridioides\xa0difficile infection. With oral use, the company advises monitoring serum vancomycin concentration in people with inflammatory intestinal disorders in which absorption may be enhanced. It also advises that serial auditory function tests may help to minimise the risk of ototoxicity in people with an underlying hearing loss, or who are having concomitant therapy with other ototoxic drugs. In renal impairment or in people having concomitant treatment with an aminoglycoside or other nephrotoxic drug, the manufacturer advises serial monitoring of renal function. The manufacturer advises that vancomycin should be used in pregnancy only if the potential benefit outweighs the risk. Prolonged use of vancomycin may result in the overgrowth of non-susceptible organisms. Acquired resistance to glycopeptides is most common in enterococci, in which multiresistant strains have been seen (see BNF information on vancomycin and vancomycin summary of product characteristics).\n\n## Fidaxomicin\n\nFidaxomicin is a macrocyclic antibacterial that is poorly absorbed from the gastrointestinal tract, so is not used to treat systemic infections. It is taken orally to treat C.\xa0difficile infection. Common side effects when taken orally for C.\xa0difficile infection include constipation, nausea and vomiting. The manufacturer advises that it is preferable to avoid using fidaxomicin in pregnancy as a precaution (see BNF information on fidaxomicin and fidaxomicin summary of product characteristics).\n\n## Faecal microbiota transplant\n\nIn NICE's interventional procedures guidance on faecal microbiota transplant for recurrent C.\xa0difficile infection, it states that 'The US Food and Drug Administration has advised that stool donors for faecal microbiota transplantation should be screened with questions that specifically address risk factors for colonisation with multidrug-resistant organisms (MDROs), and individuals at higher risk of colonisation with MDROs should be excluded as donors. In addition, donor stool should be specifically tested for MDROs and not used if positive'. While short-term safety and adverse events with a faecal microbiota transplant were reported in the included studies for this guidance, the committee identified that longer-term safety of the procedure is not yet known.\n\n# Medicines adherence\n\nMedicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see NICE's guideline on medicines adherence).\n\n# Resource implications\n\nSee the economic analysis in the evidence review for detailed costs, including estimated costs of a faecal microbiota transplant. Vancomycin capsules and powder for solution are available as generic formulations. Fidaxomicin tablets are a proprietary product."}
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https://www.nice.org.uk/guidance/ng199
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This guideline sets out an antimicrobial prescribing strategy for managing Clostridioides difficile infection in adults, young people and children aged 72 hours and over in community and hospital settings. It aims to optimise antibiotic use and reduce antibiotic resistance. The recommendations do not cover diagnosis.
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6bfb37d13a499ba47f64cb059babe73eac3c2294
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nice
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ENDURALIFE powered CRT-D devices for treating heart failure
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ENDURALIFE powered CRT-D devices for treating heart failure
Evidence-based recommendations on ENDURALIFE-powered CRT-D devices for treating heart failure.
# Recommendations
The case for adopting ENDURALIFE‑powered cardiac resynchronisation therapy-defibrillator (CRT‑D) devices for treating heart failure is supported by the published evidence. Extended battery life is of clinical and patient benefit and associated with fewer replacement procedures.
ENDURALIFE‑powered CRT‑Ds should be considered as an option in people offered CRT‑D devices in line with NICE technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure.
Cost modelling was based on published data using predecessor devices, and showed that the price and lifespan of the CRT‑D have the greatest effect on overall treatment costs. Assuming an average selling price of £15,322, across different devices, using ENDURALIFE-powered CRT-Ds may save between £2,614 and £6,941 per patient using NHS tariff costs and between £2,313 and £6,140 per patient using NHS reference costs over 15 years through a reduction in the need for replacement procedures . This could save the NHS in England around £6 million in the first 5 years.# The technology
# Description of the technology
The ENDURALIFE battery technology (Boston Scientific) is designed to extend the battery life of Boston Scientific cardiac resynchronisation therapy-defibrillator (CRT‑D) devices. CRT‑Ds are a treatment option for heart failure and life-threatening ventricular arrhythmias. ENDURALIFE battery technology uses a lithium manganese dioxide (Li/MnO2) battery chemistry, which is claimed to be less susceptible to the variations in voltage and resistance associated with early battery depletion. CRT‑Ds with ENDURALIFE battery technology are also claimed to use less current than other CRT‑Ds.
ENDURALIFE battery technology was first incorporated into the COGNIS CRT‑D device in February 2008. The ENDURALIFE brand was launched in 2015, but the technology has been in all Boston Scientific CRT‑Ds since 2008; the CE marks for the RESONATE, MOMENTUM, CHARISMA, VIGILANT, AUTOGEN, DYNAGEN, INOGEN, ORIGEN, INCEPTA, ENERGEN, PUNCTUA and COGNIS CRT‑Ds all include the ENDURALIFE battery technology. ENDURALIFE‑powered CRT‑Ds are CE-marked as class III medical devices.
According to the company's submission, the cost model uses an average industry-wide cost of £12,404 for a complete CRT‑D system. This cost was derived from the average selling prices used in the economic modelling for NICE technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure. The cost was inflated using the 2015 Bank of England inflation rate of 0.9%.
The claimed benefits of ENDURALIFE‑powered CRT‑Ds in the case for adoption presented by the company are:
Longer battery life for devices could help improve patient experience by increasing the time between replacements (meaning fewer overall replacement surgeries).
Fewer CRT‑D replacements could be particularly beneficial for patients with heart failure who are already very unwell and may have difficulty lying down for a long time.
Fewer replacements will also reduce the risk of complications, which is higher in replacement procedures than in primary implants. The increased risk of complications and infections can have a measurable impact on morbidity and mortality.
Fewer early replacements will lead to savings for the healthcare system, such as a reduction in hospital admissions, bed days and procurement costs. Fewer replacement procedures also means a reduction in associated costs such as post-operative complications and infections. Preliminary estimates suggest it could represent £33 million over 6 years.
Reduced replacement rates will allow more new patients to have implants within the same resource constraints, thus supporting the implementation of NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure and helping to meet the recommended levels of CRT‑D implants in the UK.
# Current management
NICE has published a guideline on the diagnosis and management of chronic heart failure in adults. NICE technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure recommends CRT‑Ds as an adjunctive treatment option for heart failure in people on optimal medical therapy who have left ventricular dysfunction with a left ventricular ejection fraction of 35% or less.
Implantation of an ENDURALIFE‑powered device uses standard CRT‑D insertion techniques. Expert advisers have stated that people with a CRT‑D are typically followed-up by a physiologist in a technical device clinic and either a routine cardiology or specialist heart failure clinic. Patients with a CRT‑D usually attend a technical device clinic every 3 months, unless remote telemonitoring is used. It is recommended that patients should have one face-to-face technical device review annually. Patients will also need to be seen by a cardiologist; these clinics are dictated by clinical need/patient stability but are usually 6-monthly. When possible, the aim is to coincide the technical and cardiology clinics once a year. At each attendance, the patient's clinical status is noted and the device interrogated. Tests include the pacing function, the defibrillation leads (including lead impedance), the time spent pacing and the incidence of arrhythmias. The rate of battery depletion, and therefore the anticipated lifespan of the device, is also noted.
Remote device monitoring systems, which may reduce the need for technical device attendances, are available for all CRT‑Ds, including those with ENDURALIFE battery technology.# Clinical evidence
# Summary of clinical evidence
The key clinical outcomes for ENDURALIFE‑powered cardiac resynchronisation therapy-defibrillator (CRT‑D) devices in the decision problem were:
device survival
battery survival (or time to battery depletion)
CRT‑D component failure
number of invasive procedures including CRT‑D replacements
incidence of complications after replacement procedures for battery depletion or CRT‑D component failure (as per definitions in the REPLACE registry)
inpatient admissions and bed days (related to interventions)
death
patient satisfaction
quality of life
device-related adverse events.
The company did 2 searches for published literature on studies of device lifespan, the incidence of complications associated with device replacement, and outcomes relating to patient quality of life or satisfaction associated with device replacement. Its submission included: 6 case series studies of CRT‑D lifespan reported in 7 sources; 5 product performance reviews (see section 3.9); and 20 studies (17 observational studies and 3 systematic reviews) that highlight the complications associated with implantable cardioverter defibrillators or CRT‑D replacement, as well as patient preference for device size or lifespan. The external assessment centre (EAC) excluded 14 of the 17 observational studies because data from these studies were also used in the submitted systematic reviews. It judged that 1 further study on complications (Kirkfeldt et al. 2014), identified by clinical experts, was relevant. In total, the EAC assessed 6 observational studies on ENDURALIFE‑powered CRT‑D battery life (Alam et al. 2016, Ellis et al. 2016, Landolina et al. 2015, Von Gunten et al. 2015, Lau et al. 2015 and Williams and Stevenson 2014), 5 product performance reviews (Boston Scientific, Biotronik, Medtronic, Sorin and St Jude Medical) and 6 studies on adverse events arising from cardiac device replacement (Lewis et al. 2016, Polyzos et al. 2015, Zeitler et al. 2015, Nichols et al. 2016, Lovelock et al. 2014 and Kirkfeldt et al. 2014).
## Battery life
Alam et al. (2016) and Alam et al. (2014) are retrospective observational studies, both reporting on the same cohort, evaluating the time from device implantation to battery depletion. The most recent publication included 621 patients, of which 122 had ENDURALIFE‑powered CRT‑Ds, 51 had a non‑ENDURALIFE-powered Boston Scientific device and 448 had a device from another company (Medtronic n=391, St Jude Medical n=57). The devices were implanted between January 2008 and December 2010, with a maximum possible follow-up of 8 years and mean follow-up was 3.4 years. Rates of CRT‑D replacement because of battery depletion were 16% (Boston Scientific) compared with 51% to 53% for devices from other companies. When comparing time to battery depletion, Boston Scientific devices lasted longer than either Medtronic (hazard ratio 0.15, 95% confidence interval 0.10 to 0.22, p<0.001) or St Jude Medical devices (HR 0.28, 95% CI 0.16 to 0.48, p<0.001). The hazard ratios for battery depletion (adjusted for unbalanced electrical pacing parameters) were:
Boston Scientific compared with Medtronic: 0.11 (95% CI 0.07 to 0.16, p<0.001)
Boston Scientific compared with St Jude Medical: 0.25 (95% CI 0.13 to 0.47, p<0.001).Of the 67 patients still alive 6 years after implantation, battery survival rates were 77% (Boston Scientific), 44% (St Jude Medical) and 10% (Medtronic).
Ellis et al. (2016) is a retrospective observational study designed to assess how the battery capacity of a CRT‑D affects the time until the elective replacement indicator (ERI) is reached. A total of 1,302 CRT‑Ds (Boston Scientific n=322 (97.0% ENDURALIFE‑powered CRT‑Ds), Medtronic n=794 and St Jude Medical n=186) were implanted between August 2008 and December 2010. Over a mean follow-up of 3 years, the proportions of devices reaching ERI were: 0.3% (Boston Scientific, battery capacity=2.0 Ah), 13.5% (Medtronic, 1.0 Ah) and 3.8% (St Jude Medical, 1.4 Ah). The odds ratio (OR) for reaching ERI with a Medtronic device (1.0 Ah) compared with a St Jude Medical (1.4 Ah) or Boston Scientific (2.0 Ah) device was 9.73 (p1,000 versus 500 Ohms) 0.38, 95% CI 0.20 to 0.71, p=0.0025.
Landolina et al. (2015) is a retrospective observational study examining the rate of replacement for battery depletion and to identify reasons for early depletion. A total of 1,726 CRT‑Ds (Boston Scientific n=608 , Biotronik n=49, Sorin n=99, St Jude Medical n=172 and Medtronic n=798) were implanted from January 2008 to March 2010. The CRT‑Ds were commercially released between 2003 and 2010 and had different battery types; 708 were early-generation (released before 2007) and 1,018 were recent-generation families (since 2007). The median follow-up was 3.6 years. Among the recent-generation CRT‑Ds (excluding those from Sorin and Biotronik, because there were fewer than 100 of these implants included in the study), rates of devices still working after 5 years were 88% (Boston Scientific), 75% (St Jude Medical) and 52% (Medtronic). Table 1 shows multivariate analysis factors associated with CRT‑D replacement because of battery depletion.
Factors associated with battery depletion
Hazard ratio
% confidence interval
P value
Boston Scientific vs Medtronic
Recent-generation device
Battery chemistry:
Li/MnO2 vs Li/SVO
Li/CFx-SVO vs Li/SVO
High left ventricle lead output (pulse amplitude >2.5 V, duration >0.5 ms)
Unipolar left ventricular lead
Von Gunten et al. (2015) report findings from a retrospective observational study looking at device lifespan. Only 26.3% (n=1,284) of devices included in the study were CRT‑Ds, but the results are presented separately for this subgroup. ENDURALIFE‑powered CRT‑Ds comprised 39% of Boston Scientific devices. Median follow-up was 4.4 years. For devices implanted after 2006, the proportions of devices still working after 6 years were 97.6% (Boston Scientific), 26.5% (St Jude Medical), 46.3% (Medtronic) and 44.9% (Biotronik).
Lau et al. (2015) is a published abstract based on a conference poster presentation reporting the findings from a UK hospital. The study compared battery life after 6 years of use in Boston Scientific ENDURALIFE‑powered CRT‑Ds, and Medtronic and St Jude Medical CRT‑Ds. At 6-year follow-up, none of the Boston Scientific devices needed replacement because of battery depletion. St Jude Medical CRT‑Ds first began to reach ERI after 2.8 years, and Medtronic CRT‑Ds after 2.5 years. Pairwise comparisons showed a significant difference between Boston Scientific and St Jude Medical (p=0.0018) and between Boston Scientific and Medtronic (p<0.0001).
Williams and Stevenson (2014) is a published abstract from a conference poster presentation reporting battery life of CRT‑Ds. The primary end point was device replacement after reaching ERI. A total of 91 CRT‑Ds were implanted from July 2008 to July 2010 (final device follow-up: October 2013): Boston Scientific n=53 (company's submission states that 51 were ENDURALIFE‑powered), St Jude Medical n=10 and Medtronic n=28. At 4-year follow-up, the ERI rates were 1.9% (Boston Scientific), 10.0% (St Jude Medical) and 50.0% (Medtronic). Multivariate analysis showed that CRT‑Ds reaching ERI had higher right ventricle lead output, left ventricle lead output and right ventricle pulse width (no values reported).
## PPRs reporting on device malfunction and survival probability
Product performance reviews (PPRs) are based on devices that have been replaced and returned to the manufacturer, as well as additional information provided to the manufacturer from various sources about out-of-service devices that have not been returned. They aim to report device malfunctions in a standard format. PPRs report survival probability in 2 ways (based on real, observed data): survival free from both malfunction and normal battery depletion, and survival free of malfunction alone leading to device removal (cases of normal battery depletion are excluded from the analysis). In both cases the definition of 'normal battery depletion' is a function of the manufacturer's predicted device lifespan (based on bench testing, which differs by manufacturer and may not accurately reflect clinical performance). The company presented PPRs from 5 manufacturers of CRT‑Ds in its submission. The EAC accepted that the PPRs showed that normal battery depletion, rather than CRT‑D malfunction, is the main reason for CRT‑D replacement. However, it judged that data in the PPRs could not be used to reliably compare the lifespan of ENDURALIFE‑powered devices with that of other devices.
## Adverse events associated with CRT‑D replacement
Lewis et al. (2016) is a systematic review assessing the risks and benefits of replacing implantable cardioverter defibrillators, which included 17 studies (n≥167,000 patients). The median rate for major complications was 4.05% (range: 0.55% to 7.37%), of which the most frequent was infection needing antibiotic therapy and/or device removal (median rate 1.70% ). Other reported major complications included haematoma needing evacuation (median 0.57%; range: 0 to 1.55%), stroke (median 0.45%, range 0.01% to 0.82%) and reoperation for any other reason (such as pocket erosion or device repositioning because of pain; median 1.56%; range: 0.07% to 3.24%). The median rate for minor complications was 3.5% (range: 0.36% to 7.37%), with the most frequent being pocket haematoma (median 0.93%; range: 0.35% to 3.49%). Other reported minor outcomes include: incisional infection (median 0.9%; range: 0.01% to 1.77%) and discomfort or pain at the site (median 0.44%; range: 0.39% to 0.45%).
Polyzos et al. (2015) conducted a systematic review and meta-analysis on risk factors associated with cardiac implantable electronic device infection, including 60 studies with a total of 233,184 patients. The average reported device infection rates were 1.6 for prospective studies (n=21 studies), 1.0% for case-control studies (n=9 studies) and 1.2% for retrospective cohort studies (n=30 studies). The pooled OR for the risk of infection associated with generator change (20 studies; 33,322 patients) was 1.74 (95% CI 1.22 to 2.49). Device replacement or revision was associated with a pooled OR of 1.98 (95% CI 1.46 to 2.70) for infection. The authors concluded that a 'decision to replace a device should be made on a risk/benefit approach weighting the risk for death because of device failure, the rate of device failure, and the risk for procedure-related death'.
Zeitler et al. (2015) present a systematic review and meta-analysis of the complications associated with the replacement of cardiac implantable electronic device generators, following US Food & Drug Administration (FDA) recall. The review included 7 studies (1,435 patients) with a primary end point of major complications and mortality; other end points included reoperation and pocket revision. Device replacement following FDA recall was associated with a combined major complication rate of 2.60% (95% CI 0.9% to 4.8%). Five of the 7 included studies reported mortality, which showed an overall mortality of 0.4% (95% CI 0.1% to 1.1%). The rate of reoperation/pocket revision (5 studies) was 2.7% (95% CI 0.8% to 5.1%). The authors conclude that generator replacement in response to an FDA recall has a similar rate of major complications as elective generator replacement. The authors also conclude that patient and device characteristics, patient preference and remaining battery life should all be considered when replacing devices, elective or otherwise.
Nichols et al. (2016) investigated the incidence of lead damage following cardiac implantable electronic device replacement procedures and its economic impact. The study included 45,252 patients: 22,557 (50%) pacemaker generator replacements, 20,632 (46%) implantable cardioverter defibrillator replacements, and 2,063 (5%) CRT‑D device replacements. Lead damage was observed in 406 patients (0.90%) at a median of 107 days following device replacement. Lead damage incidence was 1.94% for patients with CRT‑Ds. In a Cox proportional hazards model, controlling for patient demographic and clinical characteristics, CRT‑D replacement showed >2.5 times (HR 2.58, 95% CI 1.73 to 3.83) the risk of lead damage compared with pacemaker replacement. Of the 406 patients with lead damage, 368 (91%) were inpatients with a median length of stay for lead damage of 3 days; this did not significantly differ based on device type. The mean cost of lead damage management across all device types in the first year was $25,797. Average lead damage hospitalisation costs were significantly different across device types: $19,959 for pacemaker replacement; $24,885 for implantable cardioverter defibrillator replacement; and $46,229 for CRT‑D replacement (p=0.048). The authors conclude that the higher rates of lead damage observed in implantable cardioverter defibrillator and CRT‑D replacement are likely to be attributable to the greater number of and complexity of leads in these procedures.
Lovelock et al. (2014) investigated the risk of lead alerts after replacing implantable cardioverter defibrillators. This study utilised patients enrolled on the ALTITUDE project, an initiative to prospectively analyse data obtained from implanted Boston Scientific devices through its LATITUDE home monitoring system. A total of 60,219 patients were eligible for inclusion in the study, of which 7,458 patients (12.4%) had implantable cardioverter defibrillator replacement. A time-dependent Cox proportional hazards model (adjusted for age, gender and device type) was used to evaluate potential associations between lead failure and device replacement. Lead performance in the 7,458 patients having device replacement was compared with leads of similar age (68 months) in patients who did not have device replacement. Patients who had device replacement showed a 5-times higher lead alert rate (HR 5.20, 95% CI 3.45 to 7.84) compared with those who did not; this was significantly different even when covariates were adjusted for (p<0.001). Younger age and single-lead implantable cardioverter defibrillators were also associated with an increase in lead alerts: HR 1.02, 95% CI 0.98 to 0.99, p<0.001; HR 2.49, 95% CI 1.96 to 3.17, p<0.001 respectively. However, both age and system type were associated with lead alerts to a lesser degree than device replacement. The authors suggest that surveillance is needed after device replacement in addition to technique development and lead modifications to minimise the risk of lead damage during surgery. In another study, Lovelock et al. (2012) reported that the rate of failure in Medtronic Fidelis leads was 20.8% following device replacement and 2.5% in lead age-matched controls (p<0.001).
Kirkfeldt et al. (2014) was a retrospective multicentre (14 hospitals) cohort study in Denmark which analysed complications occurring within 6 months of cardiac electronic devices implanted between May 2010 and April 2011. The analysis included 5,918 patients: 74% (n=4,355) had new implants, 19% (n=1,136) had device replacements and 7% (n=427) had system upgrades or lead revisions. The complication rate was 5.9% following a device replacement. Infection rates for new implants and generator replacements were 0.6% and 1.5% respectively. When complications were categorised, 3.5% of patients experienced a major complication within 6 months of a device replacement.
## EAC's critique of the clinical evidence
The EAC felt that although the studies of battery life were done under similar conditions to normal clinical practice, they were retrospective and it was not possible to determine the rationale for choice of CRT‑D. It concluded that the published studies demonstrate that ENDURALIFE‑powered CRT‑Ds implanted between 2008 and 2010 lasted longer than other CRT‑Ds implanted during the same period. However, some of the CRT‑Ds in these studies, particularly the comparator devices, are no longer marketed.
The EAC accepted the company's submission of evidence on the rate of complications following CRT‑D replacements. The EAC acknowledged that the PPRs submitted by the company demonstrated that most CRT‑Ds are replaced because of normal battery depletion, and not device malfunctions.
## Committee considerations
The committee concluded that ENDURALIFE‑powered CRT‑Ds have a greater battery capacity and longer battery life compared with other CRT‑Ds available at the time of the published studies. It noted that, because of the follow-up time needed to study battery life, the retrospective, observational studies presented included CRT‑Ds no longer marketed. Clinical experts advised the committee that the company's claims relating to battery life and the ENDURALIFE battery technology have been borne out in their own subsequent clinical experience, as well as in the published literature.
The committee heard that other technologies claim to offer similar advantages to ENDURALIFE‑powered CRT‑Ds, but these have not been reviewed in this assessment.
The committee was advised by clinical experts that in terms of determining the lifespans of different CRT‑Ds, published, peer-reviewed clinical studies are a more reliable source of information than unpublished, extrapolated and predicted lifespan data. The committee considered that the updating and publication of further clinical outcome studies in patients with CRT‑Ds from all manufacturers would be helpful. In this regard, the committee was made aware of the existence of a large volume of data possessed by the National Institute for Cardiovascular Outcomes Research (NICOR) relating to CRT‑Ds implanted in the NHS since 2008 (when ENDURALIFE‑powered CRT‑Ds entered the market). These data include lifespan outcomes for almost all CRT‑Ds implanted in the UK since 2008. The committee was advised that further analyses of these data may provide valuable insights into how long different CRT‑Ds last in real-world clinical practice. The committee encouraged the publication of these lifespan outcomes.
The committee heard from clinical experts that battery depletion depends on a number of factors including the needs of the patient, lead technology, battery design and the algorithms used in the CRT‑D. However, it was advised that a central factor in determining device lifespan is the ampere hours a battery can carry. The experts stated that accepting recent developments in battery technology by all CRT‑D manufacturers, ENDURALIFE‑powered batteries still have one of the largest ampere hours ratings.
The experts acknowledged that advances in CRT‑D technology continue to be made by all manufacturers, particularly in minimising battery drain. However, the experts advised that these developments applied to all manufactured devices including ENDURALIFE‑powered CRT‑D devices.
The committee was advised that replacement procedures are associated with a risk of serious complications and that complications are more common in replacement than primary implants. Infection can have major consequences in terms of patient morbidity and resource use, including the need for hospital admission that may last days or weeks. The committee heard from a patient expert that replacement procedures have a detrimental impact on quality of life. The clinical experts also advised that patients see replacement procedures as a significant life event.
The committee heard from the clinical experts that predicting a patient's individual life expectancy after device implantation is difficult. Nonetheless, experts advised that given the prognostic benefit of CRT‑D implantation in patients with heart failure, the choice of a CRT‑D with a greater lifespan is logical.
The committee was advised that CRT‑Ds differ in size and shape between manufacturers and that Boston Scientific devices are slightly thinner than others. Experts stated that the shape of the CRT‑D is sometimes more important than the size, and that the choice of device needs to be personalised to the patient's individual needs. This usually involves shared decision-making between the patient and the clinician.# NHS considerations
# System impact
The company claimed that fewer avoidable replacement procedures will lead to a reduction in hospital admissions, bed days and procurement costs. Fewer replacement procedures could result in more efficient use of resources, because it would allow more primary (that is, non‑replacement) implants within the same resource constraints. The company also claimed that using ENDURALIFE‑powered cardiac resynchronisation therapy-defibrillator (CRT‑D) devices could lead to cost savings through a reduction in associated costs such as post-operative complications and infections resulting from replacement procedures.
## Committee considerations
The committee was advised by clinical experts that although replacements are done for a variety of reasons, including lead failures, 80% to 90% of CRT‑D replacements are because of battery depletion.
The committee heard from experts that the cost of replacing a CRT‑D is between £10,000 and £15,000, not including the cost of additional leads.
The committee was advised that remote monitoring affects battery drain across all manufacturers' devices to a variable degree.
The committee heard from experts that, despite increased battery life being an important patient benefit, it is standard practice for a single centre to use CRT‑Ds from more than 1 manufacturer. The rationale is to spread the risk of undue pressure on clinical services in the face of possible future device-related technical failure necessitating recall and replacement. In view of this important consideration, professional advice was that it was unwise for a department to rely entirely on the use of a CRT‑D from a single manufacturer.# Cost considerations
# Cost evidence
The company identified 7 studies that incorporated a cost-effectiveness analysis. It did not rely on these economic studies for its model, but the structure of the de novo model is similar to that described in Gadler et al. (2016). The external assessment centre (EAC) judged the company's search strategy and inclusion/exclusion criteria reasonable, but noted that it could be improved with access to more databases and a more thorough strategy. The EAC considered that the population used by the company in its selection of economic evidence – 'patients implanted with cardiac resynchronisation therapy-defibrillators (CRT‑Ds)' – differed from the population specified in the scope. The company's population is broader and the EAC acknowledged that this probably reflects the lack of detail in the published evidence on the specific criteria used to define heart failure and CRT‑D use from the NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure.
The EAC excluded 3 studies included by the company because they were outside the scope. Boriani et al. (2013) report on a model comparing hypothesised CRT‑Ds with 4-year and 7-year lifespans over a 15-year time horizon. The devices were not specifically named technologies and the lifespans were not based on data, but were chosen specifically to investigate how battery life affects costs. Biffi et al. (2011) focused on implantable cardioverter defibrillators and included only 10 patients with CRT‑Ds. It did not include devices from Boston Scientific. The Chung et al. (2015) abstract does not directly compare specific devices although it includes a device survival curve based on manufacturer data, but looks at the costs for different patient groups using devices with different lifespans.
Gadler et al. (2016) describes an economic model with a 6-year time horizon based on the data from Landolina (2015; see section 3.5), Swedish ICD and Pacemaker Registry and Swedish public tendering data. Survival data were taken from Yao et al. (2007). The authors found in the base case that using Boston Scientific devices reduced replacement procedures and saved SEK 19,172 (£1,687 based on XE.com currency conversion on 15 July 2016) per patient over 6 years. The study was funded by Boston Scientific.
Landolina et al. (2016) is an economic analysis based on a subset of the data from Landolina et al. (2015), with a 6-year time horizon and 2 perspectives: a hospital perspective and the Italian healthcare system perspective. Boston Scientific provided funding for the economic analysis. Of 1,726 heart failure patients in Landolina 2015, 1,399 were included in the economic analysis. The analysis compared devices released between 2007 and 2010 with devices released between 2003 and 2007 for 3 manufacturers (Boston Scientific, Medtronic and St Jude Medical) and for all manufacturers together. Weighted average prices of the devices were taken from tender information. The authors found that among recent-generation CRT‑Ds from different manufacturers, the total cost per patient over 6 years ranged from €25,579 to €31,536 (£21,665 to £26,711 based on XE.com currency conversion on 12 July 2016), with a maximum difference in cost of 40% for hospitals and 19% for the Italian healthcare system.
Priest et al. (2015) is a published abstract from a conference poster presentation comparing the costs for industry-standard and longer-lifespan devices from an Australian health system perspective over 15 years, using real-world data for implantable cardioverter defibrillators and CRT‑Ds (using the methods described by Boriani et al. 2013). Patient survival following first implant was taken from published literature. Average battery life was taken from a recent NICE review (not specified, but the figures quoted are found in NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure), and Boston Scientific real-world battery life data from more than 100,000 for implantable cardioverter defibrillators using the LATITUDE NXT remote monitoring system. The study concluded that if all patients switched from industry-standard devices to longer-lifespan batteries, the average cost per patient would fall by 19% and overall number of replacements would fall by 70%. This would result in cumulative cost savings of more than $900 million over 15 years.
The paper by Duxbury et al. (2014) is a published abstract from a conference poster presentation reporting the economic impact of implanting cardiac devices with longer lifespans from a UK perspective. The methodology was similar to that of the Priest et al. study (2015), in that it was based on Boriani et al. (2013). It also used the average lifespans described in the NICE technology appraisal and Boston Scientific real-world battery life data using the LATITUDE NXT remote monitoring system. The authors modelled the potential cumulative costs over 10 years for industry-standard and longer-lifespan devices using real-world battery data for implantable cardioverter defibrillators and CRT‑Ds. The study concluded that using devices with longer battery life could result in cumulative savings of up to £158 million over 10 years.
## EAC's critique of the cost evidence
The EAC identified that the main weakness of the published economic evidence was it relates to devices no longer marketed, because of the rapid turnover of new models of the technology. The study by Gadler et al. (2016) was funded by Boston Scientific, so may be subject to bias. The EAC considered the lifespan data for the LATITUDE NXT system used in Priest et al. (2015) may not be directly comparable with that reported in NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure, because the patient populations may be different. The EAC concluded that because the Priest et al. (2015) and Duxbury et al. (2014) studies are only available as abstracts, the results should be treated with caution.
## Cost model
The company presented a de novo economic model adapted from Gadler et al. (2016) estimating mean cost savings per patient. The model is a decision tree with a 6-year time horizon and an NHS perspective. It compares Boston Scientific ENDURALIFE‑powered CRT‑Ds with Medtronic and St Jude Medical CRT‑Ds. For each device there are branches for procedural complications or no complications, with further branches for death, replacement or no replacement at 1 year and at each subsequent year. Clinical data in the model are taken from the Landolina et al. (2016) study on event-free battery survival and Yao et al. (2007) for cumulative probability of patient survival. The incidence of complications is taken from Tang et al. (2010) and the follow-up arrangements from NHS England 2013/14 NHS standard contract for cardiology: implantable cardioverter defibrillator and cardiac resynchronisation therapy (adult). The model assumes follow-up appointments at 6-month intervals with an additional post-procedure appointment.
The company's scenario analyses included exploring differences in device survival and device cost to identify thresholds at which the model becomes cost neutral. The price was varied by ±20% for each device separately using a one-way sensitivity analysis. The analyses showed that the cost model is highly sensitive to changes in both device survival and device cost. Higher device survival resulted in a marked decrease in relative costs. The one-way sensitivity analysis of device cost showed that ENDURALIFE‑powered CRT‑Ds remained cost saving.
The company's base case showed that ENDURALIFE‑powered CRT‑Ds cost £22,322 per patient over a 6-year period compared with £27,309 and £29,158 per patient for St Jude Medical and Medtronic CRT‑Ds respectively. The company therefore estimated that using ENDURALIFE‑powered CRT‑Ds would save between £4,987 and £6,836 per patient over 6 years. Cost savings come mainly from fewer replacement procedures.
## Additional work by the external assessment centre
The EAC re-ran the company's base case and univariate sensitivity analyses and conducted additional analyses using its preferred estimates. The EAC also did a threshold analysis using the average selling price for ENDURALIFE‑powered CRT‑Ds and allowing the cost of the comparator devices to fall to the point at which each becomes cost neutral. The main changes to the company's model were:
Changes to the list prices of ENDURALIFE‑powered CRT‑Ds and both comparators.
Using warranty data from the comparator manufacturers instead of that from Boston Scientific.
Using NHS reference costs instead of Payment-by-Results tariff costs.
Changes to the sensitivity analysis for complication rates (infection), based on the results of a large Danish cohort study (Kirkfeldt et al. 2014). This changed the infection rate from 2.4% to 0.6% for new implants.
Using patient survival data from the National Institute for Cardiovascular Outcomes Research (NICOR) instead of from Yao et al. (2007).
The results of the EAC analysis suggested that changing the device cost in the model to the lowest and highest list price for each of the 3 manufacturers results in ENDURALIFE‑powered CRT‑Ds becoming more costly than those from Medtronic, but remaining cost saving compared with those from St Jude Medical.
The threshold analysis investigated the effect of introducing a price difference between the devices, and calculated the threshold at which ENDURALIFE‑powered CRT‑Ds become cost incurring compared with the comparators. The results showed that, using the same cost of implanting and replacing the CRT‑D as used in the company's base case, ENDURALIFE‑powered CRT‑Ds become cost incurring when they are £4,858 more expensive to purchase than Medtronic CRT‑Ds and £3,858 more expensive to purchase than St Jude Medical CRT‑Ds, with all other model inputs unchanged.
Using NHS reference costs instead of the Payment-by-Results tariff increased the cost of ENDURALIFE‑powered CRT‑Ds from £22,322 in the company's base case to £30,957. ENDURALIFE‑powered CRT‑Ds remain cost saving compared with the comparators but to a lesser extent than in the company's base case.
Substituting the actual warranty information supplied by the manufacturers into the model showed that ENDURALIFE‑powered CRT‑Ds remained cost saving.
Changing the rate of infection for new implants from 2.4% to 0.6% had little effect on the costs.
Following expert advice, the EAC contacted NICOR, which holds a registry of NHS patients who have had CRT‑Ds implanted, including data on overall survival.
Using patient survival data from NICOR to replace that from Yao et al. (2007), ENDURALIFE‑powered CRT‑Ds remained cost saving when using the company's base-case device cost. At the lowest and highest list prices, ENDURALIFE‑powered CRT‑Ds become more costly than those from Medtronic, but remain cost saving compared with those from St Jude Medical.
The EAC concluded that the main driver of the cost model was device price.
The committee considered that the 6-year time horizon made the cost case uncertain. The EAC was therefore asked to carry out further analyses extrapolating the data available over a patient's lifetime (sections 5.20 to 5.24).
NICOR provided unpublished data in confidence which showed patient survival by age group after primary implantation of a CRT‑D. The EAC extrapolated CRT‑D lifespan to 15 years using a survival profile for comparator devices: this took an average distribution based on Medtronic and St Jude Medical CRT‑D lifespans reported in Landolina et al. (2015), and then applied the average distribution to the ENDURALIFE‑powered CRT‑Ds from the point at which the ENDURALIFE‑powered CRT‑Ds begin to reach the elective replacement indicator (ERI), at 5 years following implantation.
The EAC extrapolated patient survival to 15 years using NICOR data for patients aged 50 to 84 years at primary implantation.
Using the average selling price in the company's base case and the extrapolated data outlined above, the results showed that ENDURALIFE‑powered CRT‑Ds cost £28,234 per patient over 15 years compared with £30,354 and £33,861 per patient for St Jude Medical and Medtronic CRT‑Ds respectively. The EAC therefore estimated that using ENDURALIFE‑powered CRT‑Ds could save between £2,120 and £5,627 per patient over 15 years.
A threshold analysis investigated the effect of allowing a price difference between the devices, and calculated the threshold at which ENDURALIFE‑powered CRT‑Ds become cost incurring compared with the comparators. The results showed that, using the same cost of implanting and replacing the CRT‑D as used in the company's base case, ENDURALIFE‑powered CRT‑Ds become cost incurring when they are £3,304 more expensive to purchase than Medtronic CRT‑Ds and £1,404 more expensive to purchase than St Jude Medical CRT‑Ds.
## EAC's critique of the cost model
The EAC considered that the 6-year time horizon used in the model may overestimate the potential cost saving of a slightly longer-lasting device. It concluded that a time horizon over the patient's lifetime may be more appropriate.
## Committee considerations
The committee was advised that device costs were accurately reflected in the company's base case, which used average selling prices, and that prices are similar between manufacturers. List prices are not a true reflection of what the NHS pays for CRT‑Ds.
The committee concluded that it would be difficult to ascertain actual NHS device costs for ENDURALIFE‑powered and comparator CRT‑Ds. The EAC was asked to carry out a differential cost threshold analysis to overcome some of these uncertainties.
The committee accepted that the EAC's revisions to the company's cost modelling provided the most plausible estimates for the cost consequences of adopting ENDURALIFE‑powered CRT‑Ds.
For the guidance review, the external assessment centre revised the model to reflect 2020 costs (original guidance costs are given in brackets). The main parameter changes were the estimated costs:
ENDURALIFE-powered CRT-Ds £15,322 (£12,404)
procedural complications
£24,686 (£21,774) for infection
£6,975 (£6,152) for a complication requiring reintervention
£20,418 (£18,010) for device pocket issues
de novo procedures £5,931 (NHS tariff costs; EY01B) and £3,342 (NHS reference costs; EY01B) (£6,201; EY10B)
replacement procedures £5,931 (NHS tariff costs; EY01B) and £3,342 (NHS reference costs; EY01B) (£4,700)
follow-up procedures £78 (NHS tariff costs) and £135 (NHS reference costs) (£96; WF01A). Base-case results for the 2020 revised model shows the cost saving associated with ENDURALIFE-powered CRT-Ds was between £2,614 and £6,941 per patient using NHS national tariff costs and between £2,313 and £6,140 per patient using NHS reference costs over 15 years. Further details of the 2020 revised model are in the revised model summary in the review decision .# Conclusions
The committee concluded that there is good evidence to support the clinical benefit of longer battery life and the associated reduction in cardiac resynchronisation therapy-defibrillator (CRT‑D) replacements.
The committee concluded that developments in CRT‑D technology are ongoing and that the evidence available suggests that the advantages of longer battery life have not been surpassed by other types of technical advances.
The committee noted the potential hazards of a clinical service relying solely on a single manufacturer's CRT‑D devices.
The committee encouraged further studies that provide data on the battery life of different CRT‑Ds, including an analysis of currently available UK NHS clinical data.
Based on cost modelling, the committee concluded that using ENDURALIFE‑powered CRT‑Ds in patients with heart failure is likely to save costs by reducing the number of replacement procedures.
|
{'Recommendations': 'The case for adopting ENDURALIFE‑powered cardiac resynchronisation therapy-defibrillator (CRT‑D) devices for treating heart failure is supported by the published evidence. Extended battery life is of clinical and patient benefit and associated with fewer replacement procedures.\n\nENDURALIFE‑powered CRT‑Ds should be considered as an option in people offered CRT‑D devices in line with NICE technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure.\n\nCost modelling was based on published data using predecessor devices, and showed that the price and lifespan of the CRT‑D have the greatest effect on overall treatment costs. Assuming an average selling price of £15,322, across different devices, using ENDURALIFE-powered CRT-Ds may save between £2,614 and £6,941 per patient using NHS tariff costs and between £2,313 and £6,140 per patient using NHS reference costs over 15 years through a reduction in the need for replacement procedures . This could save the NHS in England around £6\xa0million in the first 5\xa0years.', 'The technology': "# Description of the technology\n\nThe ENDURALIFE battery technology (Boston Scientific) is designed to extend the battery life of Boston Scientific cardiac resynchronisation therapy-defibrillator (CRT‑D) devices. CRT‑Ds are a treatment option for heart failure and life-threatening ventricular arrhythmias. ENDURALIFE battery technology uses a lithium manganese dioxide (Li/MnO2) battery chemistry, which is claimed to be less susceptible to the variations in voltage and resistance associated with early battery depletion. CRT‑Ds with ENDURALIFE battery technology are also claimed to use less current than other CRT‑Ds.\n\nENDURALIFE battery technology was first incorporated into the COGNIS CRT‑D device in February\xa02008. The ENDURALIFE brand was launched in 2015, but the technology has been in all Boston Scientific CRT‑Ds since 2008; the CE marks for the RESONATE, MOMENTUM, CHARISMA, VIGILANT, AUTOGEN, DYNAGEN, INOGEN, ORIGEN, INCEPTA, ENERGEN, PUNCTUA and COGNIS CRT‑Ds all include the ENDURALIFE battery technology. ENDURALIFE‑powered CRT‑Ds are CE-marked as class III medical devices.\n\nAccording to the company's submission, the cost model uses an average industry-wide cost of £12,404 for a complete CRT‑D system. This cost was derived from the average selling prices used in the economic modelling for NICE technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure. The cost was inflated using the 2015 Bank of England inflation rate of 0.9%.\n\nThe claimed benefits of ENDURALIFE‑powered CRT‑Ds in the case for adoption presented by the company are:\n\nLonger battery life for devices could help improve patient experience by increasing the time between replacements (meaning fewer overall replacement surgeries).\n\nFewer CRT‑D replacements could be particularly beneficial for patients with heart failure who are already very unwell and may have difficulty lying down for a long time.\n\nFewer replacements will also reduce the risk of complications, which is higher in replacement procedures than in primary implants. The increased risk of complications and infections can have a measurable impact on morbidity and mortality.\n\nFewer early replacements will lead to savings for the healthcare system, such as a reduction in hospital admissions, bed days and procurement costs. Fewer replacement procedures also means a reduction in associated costs such as post-operative complications and infections. Preliminary estimates suggest it could represent £33\xa0million over 6\xa0years.\n\nReduced replacement rates will allow more new patients to have implants within the same resource constraints, thus supporting the implementation of NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure and helping to meet the recommended levels of CRT‑D implants in the UK.\n\n# Current management\n\nNICE has published a guideline on the diagnosis and management of chronic heart failure in adults. NICE technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure recommends CRT‑Ds as an adjunctive treatment option for heart failure in people on optimal medical therapy who have left ventricular dysfunction with a left ventricular ejection fraction of 35% or less.\n\nImplantation of an ENDURALIFE‑powered device uses standard CRT‑D insertion techniques. Expert advisers have stated that people with a CRT‑D are typically followed-up by a physiologist in a technical device clinic and either a routine cardiology or specialist heart failure clinic. Patients with a CRT‑D usually attend a technical device clinic every 3\xa0months, unless remote telemonitoring is used. It is recommended that patients should have one face-to-face technical device review annually. Patients will also need to be seen by a cardiologist; these clinics are dictated by clinical need/patient stability but are usually 6-monthly. When possible, the aim is to coincide the technical and cardiology clinics once a year. At each attendance, the patient's clinical status is noted and the device interrogated. Tests include the pacing function, the defibrillation leads (including lead impedance), the time spent pacing and the incidence of arrhythmias. The rate of battery depletion, and therefore the anticipated lifespan of the device, is also noted.\n\nRemote device monitoring systems, which may reduce the need for technical device attendances, are available for all CRT‑Ds, including those with ENDURALIFE battery technology.", 'Clinical evidence': "# Summary of clinical evidence\n\nThe key clinical outcomes for ENDURALIFE‑powered cardiac resynchronisation therapy-defibrillator (CRT‑D) devices in the decision problem were:\n\ndevice survival\n\nbattery survival (or time to battery depletion)\n\nCRT‑D component failure\n\nnumber of invasive procedures including CRT‑D replacements\n\nincidence of complications after replacement procedures for battery depletion or CRT‑D component failure (as per definitions in the REPLACE registry)\n\ninpatient admissions and bed days (related to interventions)\n\ndeath\n\npatient satisfaction\n\nquality of life\n\ndevice-related adverse events.\n\nThe company did 2\xa0searches for published literature on studies of device lifespan, the incidence of complications associated with device replacement, and outcomes relating to patient quality of life or satisfaction associated with device replacement. Its submission included: 6\xa0case series studies of CRT‑D lifespan reported in 7\xa0sources; 5\xa0product performance reviews (see section 3.9); and 20\xa0studies (17\xa0observational studies and 3\xa0systematic reviews) that highlight the complications associated with implantable cardioverter defibrillators or CRT‑D replacement, as well as patient preference for device size or lifespan. The external assessment centre (EAC) excluded 14 of the 17\xa0observational studies because data from these studies were also used in the submitted systematic reviews. It judged that 1 further study on complications (Kirkfeldt et\xa0al. 2014), identified by clinical experts, was relevant. In total, the EAC assessed 6\xa0observational studies on ENDURALIFE‑powered CRT‑D battery life (Alam et\xa0al. 2016, Ellis et\xa0al. 2016, Landolina et\xa0al. 2015, Von Gunten et\xa0al. 2015, Lau et\xa0al. 2015 and Williams and Stevenson 2014), 5\xa0product performance reviews (Boston Scientific, Biotronik, Medtronic, Sorin and St Jude Medical) and 6\xa0studies on adverse events arising from cardiac device replacement (Lewis et\xa0al. 2016, Polyzos et\xa0al. 2015, Zeitler et\xa0al. 2015, Nichols et\xa0al. 2016, Lovelock et\xa0al. 2014 and Kirkfeldt et\xa0al. 2014).\n\n## Battery life\n\nAlam et\xa0al. (2016) and Alam et\xa0al. (2014) are retrospective observational studies, both reporting on the same cohort, evaluating the time from device implantation to battery depletion. The most recent publication included 621\xa0patients, of which 122 had ENDURALIFE‑powered CRT‑Ds, 51 had a non‑ENDURALIFE-powered Boston Scientific device and 448 had a device from another company (Medtronic n=391, St Jude Medical n=57). The devices were implanted between January\xa02008 and December\xa02010, with a maximum possible follow-up of 8\xa0years and mean follow-up was 3.4\xa0years. Rates of CRT‑D replacement because of battery depletion were 16% (Boston Scientific) compared with 51% to 53% for devices from other companies. When comparing time to battery depletion, Boston Scientific devices lasted longer than either Medtronic (hazard ratio [HR] 0.15, 95% confidence interval [CI] 0.10 to 0.22, p<0.001) or St Jude Medical devices (HR 0.28, 95%\xa0CI\xa00.16 to 0.48, p<0.001). The hazard ratios for battery depletion (adjusted for unbalanced electrical pacing parameters) were:\n\nBoston Scientific compared with Medtronic: 0.11 (95%\xa0CI\xa00.07 to 0.16, p<0.001)\n\nBoston Scientific compared with St Jude Medical: 0.25 (95%\xa0CI\xa00.13 to 0.47, p<0.001).Of the 67\xa0patients still alive 6\xa0years after implantation, battery survival rates were 77% (Boston Scientific), 44% (St Jude Medical) and 10% (Medtronic).\n\nEllis et\xa0al. (2016) is a retrospective observational study designed to assess how the battery capacity of a CRT‑D affects the time until the elective replacement indicator (ERI) is reached. A total of 1,302\xa0CRT‑Ds (Boston Scientific n=322 (97.0% ENDURALIFE‑powered CRT‑Ds), Medtronic n=794 and St Jude Medical n=186) were implanted between August\xa02008 and December\xa02010. Over a mean follow-up of 3\xa0years, the proportions of devices reaching ERI were: 0.3% (Boston Scientific, battery capacity=2.0\xa0Ah), 13.5% (Medtronic, 1.0\xa0Ah) and 3.8% (St Jude Medical, 1.4\xa0Ah). The odds ratio (OR) for reaching ERI with a Medtronic device (1.0\xa0Ah) compared with a St Jude Medical (1.4\xa0Ah) or Boston Scientific (2.0\xa0Ah) device was 9.73 (p<0.0001). Univariate predictors for ERI included 1.0\xa0Ah device and an LV pacing output of over 3\xa0V at 1\xa0ms (OR: 3.74, p<0.001). Mortality rates with each device were 28.0% (Boston Scientific), 16.7% (St Jude Medical) and 21.8% (Medtronic). No CRT‑D failures were observed. High left ventricle lead impedance was protective of reaching ERI: OR (>1,000 versus 500 Ohms) 0.38, 95%\xa0CI\xa00.20 to 0.71, p=0.0025.\n\nLandolina et\xa0al. (2015) is a retrospective observational study examining the rate of replacement for battery depletion and to identify reasons for early depletion. A total of 1,726\xa0CRT‑Ds (Boston Scientific n=608 [291 (47.9%) ENDURALIFE‑powered CRT‑Ds], Biotronik n=49, Sorin n=99, St Jude Medical n=172 and Medtronic n=798) were implanted from January 2008 to March 2010. The CRT‑Ds were commercially released between 2003 and 2010 and had different battery types; 708 were early-generation (released before 2007) and 1,018 were recent-generation families (since 2007). The median follow-up was 3.6\xa0years. Among the recent-generation CRT‑Ds (excluding those from Sorin and Biotronik, because there were fewer than 100 of these implants included in the study), rates of devices still working after 5\xa0years were 88% (Boston Scientific), 75% (St Jude Medical) and 52% (Medtronic). Table 1 shows multivariate analysis factors associated with CRT‑D replacement because of battery depletion.\n\nFactors associated with battery depletion\n\nHazard ratio\n\n% confidence interval\n\nP\xa0value\n\nBoston Scientific vs Medtronic\n\n\n\n–0.89\n\n\n\nRecent-generation device\n\n\n\n–0.72\n\n<0.001\n\nBattery chemistry:\n\nLi/MnO2 vs Li/SVO\n\nLi/CFx-SVO vs Li/SVO\n\n\n\n\n\n\n\n\n\n–0.64\n\n–0.50\n\n\n\n<0.001\n\n<0.001\n\nHigh left ventricle lead output (pulse amplitude >2.5\xa0V, duration >0.5\xa0ms)\n\n\n\n–2.46\n\n<0.001\n\nUnipolar left ventricular lead\n\n\n\n–2.01\n\n<0.001\n\nVon Gunten et\xa0al. (2015) report findings from a retrospective observational study looking at device lifespan. Only 26.3% (n=1,284) of devices included in the study were CRT‑Ds, but the results are presented separately for this subgroup. ENDURALIFE‑powered CRT‑Ds comprised 39% of Boston Scientific devices. Median follow-up was 4.4\xa0years. For devices implanted after 2006, the proportions of devices still working after 6\xa0years were 97.6% (Boston Scientific), 26.5% (St Jude Medical), 46.3% (Medtronic) and 44.9% (Biotronik).\n\nLau et\xa0al. (2015) is a published abstract based on a conference poster presentation reporting the findings from a UK hospital. The study compared battery life after 6\xa0years of use in Boston Scientific ENDURALIFE‑powered CRT‑Ds, and Medtronic and St Jude Medical CRT‑Ds. At 6-year follow-up, none of the Boston Scientific devices needed replacement because of battery depletion. St Jude Medical CRT‑Ds first began to reach ERI after 2.8\xa0years, and Medtronic CRT‑Ds after 2.5\xa0years. Pairwise comparisons showed a significant difference between Boston Scientific and St Jude Medical (p=0.0018) and between Boston Scientific and Medtronic (p<0.0001).\n\nWilliams and Stevenson (2014) is a published abstract from a conference poster presentation reporting battery life of CRT‑Ds. The primary end point was device replacement after reaching ERI. A total of 91 CRT‑Ds were implanted from July 2008 to July 2010 (final device follow-up: October 2013): Boston Scientific n=53 (company's submission states that 51 [96.2%] were ENDURALIFE‑powered), St Jude Medical n=10 and Medtronic n=28. At 4-year follow-up, the ERI rates were 1.9% (Boston Scientific), 10.0% (St Jude Medical) and 50.0% (Medtronic). Multivariate analysis showed that CRT‑Ds reaching ERI had higher right ventricle lead output, left ventricle lead output and right ventricle pulse width (no values reported).\n\n## PPRs reporting on device malfunction and survival probability\n\nProduct performance reviews (PPRs) are based on devices that have been replaced and returned to the manufacturer, as well as additional information provided to the manufacturer from various sources about out-of-service devices that have not been returned. They aim to report device malfunctions in a standard format. PPRs report survival probability in 2\xa0ways (based on real, observed data): survival free from both malfunction and normal battery depletion, and survival free of malfunction alone leading to device removal (cases of normal battery depletion are excluded from the analysis). In both cases the definition of 'normal battery depletion' is a function of the manufacturer's predicted device lifespan (based on bench testing, which differs by manufacturer and may not accurately reflect clinical performance). The company presented PPRs from 5\xa0manufacturers of CRT‑Ds in its submission. The EAC accepted that the PPRs showed that normal battery depletion, rather than CRT‑D malfunction, is the main reason for CRT‑D replacement. However, it judged that data in the PPRs could not be used to reliably compare the lifespan of ENDURALIFE‑powered devices with that of other devices.\n\n## Adverse events associated with CRT‑D replacement\n\nLewis et\xa0al. (2016) is a systematic review assessing the risks and benefits of replacing implantable cardioverter defibrillators, which included 17\xa0studies (n≥167,000 patients). The median rate for major complications was 4.05% (range: 0.55% to 7.37%), of which the most frequent was infection needing antibiotic therapy and/or device removal (median rate 1.70% [range: 0 to 5.23%]). Other reported major complications included haematoma needing evacuation (median 0.57%; range: 0 to 1.55%), stroke (median 0.45%, range 0.01% to 0.82%) and reoperation for any other reason (such as pocket erosion or device repositioning because of pain; median 1.56%; range: 0.07% to 3.24%). The median rate for minor complications was 3.5% (range: 0.36% to 7.37%), with the most frequent being pocket haematoma (median 0.93%; range: 0.35% to 3.49%). Other reported minor outcomes include: incisional infection (median 0.9%; range: 0.01% to 1.77%) and discomfort or pain at the site (median 0.44%; range: 0.39% to 0.45%).\n\nPolyzos et\xa0al. (2015) conducted a systematic review and meta-analysis on risk factors associated with cardiac implantable electronic device infection, including 60\xa0studies with a total of 233,184\xa0patients. The average reported device infection rates were 1.6 for prospective studies (n=21 studies), 1.0% for case-control studies (n=9 studies) and 1.2% for retrospective cohort studies (n=30 studies). The pooled OR for the risk of infection associated with generator change (20\xa0studies; 33,322 patients) was 1.74 (95%\xa0CI\xa01.22 to 2.49). Device replacement or revision was associated with a pooled OR of 1.98 (95%\xa0CI\xa01.46 to 2.70) for infection. The authors concluded that a 'decision to replace a device should be made on a risk/benefit approach weighting the risk for death because of device failure, the rate of device failure, and the risk for procedure-related death'.\n\nZeitler et\xa0al. (2015) present a systematic review and meta-analysis of the complications associated with the replacement of cardiac implantable electronic device generators, following US Food & Drug Administration (FDA) recall. The review included 7\xa0studies (1,435\xa0patients) with a primary end point of major complications and mortality; other end points included reoperation and pocket revision. Device replacement following FDA recall was associated with a combined major complication rate of 2.60% (95%\xa0CI\xa00.9% to 4.8%). Five of the 7 included studies reported mortality, which showed an overall mortality of 0.4% (95%\xa0CI\xa00.1% to 1.1%). The rate of reoperation/pocket revision (5\xa0studies) was 2.7% (95%\xa0CI\xa00.8% to 5.1%). The authors conclude that generator replacement in response to an FDA recall has a similar rate of major complications as elective generator replacement. The authors also conclude that patient and device characteristics, patient preference and remaining battery life should all be considered when replacing devices, elective or otherwise.\n\nNichols et\xa0al. (2016) investigated the incidence of lead damage following cardiac implantable electronic device replacement procedures and its economic impact. The study included 45,252\xa0patients: 22,557 (50%) pacemaker generator replacements, 20,632 (46%) implantable cardioverter defibrillator replacements, and 2,063 (5%) CRT‑D device replacements. Lead damage was observed in 406\xa0patients (0.90%) at a median of 107\xa0days following device replacement. Lead damage incidence was 1.94% for patients with CRT‑Ds. In a Cox proportional hazards model, controlling for patient demographic and clinical characteristics, CRT‑D replacement showed >2.5\xa0times (HR 2.58, 95%\xa0CI\xa01.73 to 3.83) the risk of lead damage compared with pacemaker replacement. Of the 406\xa0patients with lead damage, 368 (91%) were inpatients with a median length of stay for lead damage of 3\xa0days; this did not significantly differ based on device type. The mean cost of lead damage management across all device types in the first year was $25,797. Average lead damage hospitalisation costs were significantly different across device types: $19,959 for pacemaker replacement; $24,885 for implantable cardioverter defibrillator replacement; and $46,229 for CRT‑D replacement (p=0.048). The authors conclude that the higher rates of lead damage observed in implantable cardioverter defibrillator and CRT‑D replacement are likely to be attributable to the greater number of and complexity of leads in these procedures.\n\nLovelock et\xa0al. (2014) investigated the risk of lead alerts after replacing implantable cardioverter defibrillators. This study utilised patients enrolled on the ALTITUDE project, an initiative to prospectively analyse data obtained from implanted Boston Scientific devices through its LATITUDE home monitoring system. A total of 60,219\xa0patients were eligible for inclusion in the study, of which 7,458\xa0patients (12.4%) had implantable cardioverter defibrillator replacement. A time-dependent Cox proportional hazards model (adjusted for age, gender and device type) was used to evaluate potential associations between lead failure and device replacement. Lead performance in the 7,458\xa0patients having device replacement was compared with leads of similar age (68\xa0months) in patients who did not have device replacement. Patients who had device replacement showed a 5-times higher lead alert rate (HR 5.20, 95%\xa0CI\xa03.45 to 7.84) compared with those who did not; this was significantly different even when covariates were adjusted for (p<0.001). Younger age and single-lead implantable cardioverter defibrillators were also associated with an increase in lead alerts: HR 1.02, 95%\xa0CI\xa00.98 to 0.99, p<0.001; HR 2.49, 95%\xa0CI\xa01.96 to 3.17, p<0.001 respectively. However, both age and system type were associated with lead alerts to a lesser degree than device replacement. The authors suggest that surveillance is needed after device replacement in addition to technique development and lead modifications to minimise the risk of lead damage during surgery. In another study, Lovelock et\xa0al. (2012) reported that the rate of failure in Medtronic Fidelis leads was 20.8% following device replacement and 2.5% in lead age-matched controls (p<0.001).\n\nKirkfeldt et\xa0al. (2014) was a retrospective multicentre (14 hospitals) cohort study in Denmark which analysed complications occurring within 6\xa0months of cardiac electronic devices implanted between May\xa02010 and April\xa02011. The analysis included 5,918\xa0patients: 74% (n=4,355) had new implants, 19% (n=1,136) had device replacements and 7% (n=427) had system upgrades or lead revisions. The complication rate was 5.9% following a device replacement. Infection rates for new implants and generator replacements were 0.6% and 1.5% respectively. When complications were categorised, 3.5% of patients experienced a major complication within 6\xa0months of a device replacement.\n\n## EAC's critique of the clinical evidence\n\nThe EAC felt that although the studies of battery life were done under similar conditions to normal clinical practice, they were retrospective and it was not possible to determine the rationale for choice of CRT‑D. It concluded that the published studies demonstrate that ENDURALIFE‑powered CRT‑Ds implanted between 2008 and 2010 lasted longer than other CRT‑Ds implanted during the same period. However, some of the CRT‑Ds in these studies, particularly the comparator devices, are no longer marketed.\n\nThe EAC accepted the company's submission of evidence on the rate of complications following CRT‑D replacements. The EAC acknowledged that the PPRs submitted by the company demonstrated that most CRT‑Ds are replaced because of normal battery depletion, and not device malfunctions.\n\n## Committee considerations\n\nThe committee concluded that ENDURALIFE‑powered CRT‑Ds have a greater battery capacity and longer battery life compared with other CRT‑Ds available at the time of the published studies. It noted that, because of the follow-up time needed to study battery life, the retrospective, observational studies presented included CRT‑Ds no longer marketed. Clinical experts advised the committee that the company's claims relating to battery life and the ENDURALIFE battery technology have been borne out in their own subsequent clinical experience, as well as in the published literature.\n\nThe committee heard that other technologies claim to offer similar advantages to ENDURALIFE‑powered CRT‑Ds, but these have not been reviewed in this assessment.\n\nThe committee was advised by clinical experts that in terms of determining the lifespans of different CRT‑Ds, published, peer-reviewed clinical studies are a more reliable source of information than unpublished, extrapolated and predicted lifespan data. The committee considered that the updating and publication of further clinical outcome studies in patients with CRT‑Ds from all manufacturers would be helpful. In this regard, the committee was made aware of the existence of a large volume of data possessed by the National Institute for Cardiovascular Outcomes Research (NICOR) relating to CRT‑Ds implanted in the NHS since 2008 (when ENDURALIFE‑powered CRT‑Ds entered the market). These data include lifespan outcomes for almost all CRT‑Ds implanted in the UK since 2008. The committee was advised that further analyses of these data may provide valuable insights into how long different CRT‑Ds last in real-world clinical practice. The committee encouraged the publication of these lifespan outcomes.\n\nThe committee heard from clinical experts that battery depletion depends on a number of factors including the needs of the patient, lead technology, battery design and the algorithms used in the CRT‑D. However, it was advised that a central factor in determining device lifespan is the ampere hours a battery can carry. The experts stated that accepting recent developments in battery technology by all CRT‑D manufacturers, ENDURALIFE‑powered batteries still have one of the largest ampere hours ratings.\n\nThe experts acknowledged that advances in CRT‑D technology continue to be made by all manufacturers, particularly in minimising battery drain. However, the experts advised that these developments applied to all manufactured devices including ENDURALIFE‑powered CRT‑D devices.\n\nThe committee was advised that replacement procedures are associated with a risk of serious complications and that complications are more common in replacement than primary implants. Infection can have major consequences in terms of patient morbidity and resource use, including the need for hospital admission that may last days or weeks. The committee heard from a patient expert that replacement procedures have a detrimental impact on quality of life. The clinical experts also advised that patients see replacement procedures as a significant life event.\n\nThe committee heard from the clinical experts that predicting a patient's individual life expectancy after device implantation is difficult. Nonetheless, experts advised that given the prognostic benefit of CRT‑D implantation in patients with heart failure, the choice of a CRT‑D with a greater lifespan is logical.\n\nThe committee was advised that CRT‑Ds differ in size and shape between manufacturers and that Boston Scientific devices are slightly thinner than others. Experts stated that the shape of the CRT‑D is sometimes more important than the size, and that the choice of device needs to be personalised to the patient's individual needs. This usually involves shared decision-making between the patient and the clinician.", 'NHS considerations': "# System impact\n\nThe company claimed that fewer avoidable replacement procedures will lead to a reduction in hospital admissions, bed days and procurement costs. Fewer replacement procedures could result in more efficient use of resources, because it would allow more primary (that is, non‑replacement) implants within the same resource constraints. The company also claimed that using ENDURALIFE‑powered cardiac resynchronisation therapy-defibrillator (CRT‑D) devices could lead to cost savings through a reduction in associated costs such as post-operative complications and infections resulting from replacement procedures.\n\n## Committee considerations\n\nThe committee was advised by clinical experts that although replacements are done for a variety of reasons, including lead failures, 80% to 90% of CRT‑D replacements are because of battery depletion.\n\nThe committee heard from experts that the cost of replacing a CRT‑D is between £10,000 and £15,000, not including the cost of additional leads.\n\nThe committee was advised that remote monitoring affects battery drain across all manufacturers' devices to a variable degree.\n\nThe committee heard from experts that, despite increased battery life being an important patient benefit, it is standard practice for a single centre to use CRT‑Ds from more than 1\xa0manufacturer. The rationale is to spread the risk of undue pressure on clinical services in the face of possible future device-related technical failure necessitating recall and replacement. In view of this important consideration, professional advice was that it was unwise for a department to rely entirely on the use of a CRT‑D from a single manufacturer.", 'Cost considerations': "# Cost evidence\n\nThe company identified 7\xa0studies that incorporated a cost-effectiveness analysis. It did not rely on these economic studies for its model, but the structure of the de novo model is similar to that described in Gadler et\xa0al. (2016). The external assessment centre (EAC) judged the company's search strategy and inclusion/exclusion criteria reasonable, but noted that it could be improved with access to more databases and a more thorough strategy. The EAC considered that the population used by the company in its selection of economic evidence – 'patients implanted with cardiac resynchronisation therapy-defibrillators (CRT‑Ds)' – differed from the population specified in the scope. The company's population is broader and the EAC acknowledged that this probably reflects the lack of detail in the published evidence on the specific criteria used to define heart failure and CRT‑D use from the NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure.\n\nThe EAC excluded 3\xa0studies included by the company because they were outside the scope. Boriani et\xa0al. (2013) report on a model comparing hypothesised CRT‑Ds with 4-year and 7-year lifespans over a 15-year time horizon. The devices were not specifically named technologies and the lifespans were not based on data, but were chosen specifically to investigate how battery life affects costs. Biffi et\xa0al. (2011) focused on implantable cardioverter defibrillators and included only 10\xa0patients with CRT‑Ds. It did not include devices from Boston Scientific. The Chung et\xa0al. (2015) abstract does not directly compare specific devices although it includes a device survival curve based on manufacturer data, but looks at the costs for different patient groups using devices with different lifespans.\n\nGadler et\xa0al. (2016) describes an economic model with a 6-year time horizon based on the data from Landolina (2015; see section 3.5), Swedish ICD and Pacemaker Registry and Swedish public tendering data. Survival data were taken from Yao et\xa0al. (2007). The authors found in the base case that using Boston Scientific devices reduced replacement procedures and saved SEK 19,172 (£1,687 based on XE.com currency conversion on 15 July 2016) per patient over 6\xa0years. The study was funded by Boston Scientific.\n\nLandolina et\xa0al. (2016) is an economic analysis based on a subset of the data from Landolina et\xa0al. (2015), with a 6-year time horizon and 2 perspectives: a hospital perspective and the Italian healthcare system perspective. Boston Scientific provided funding for the economic analysis. Of 1,726\xa0heart failure patients in Landolina 2015, 1,399 were included in the economic analysis. The analysis compared devices released between 2007 and 2010 with devices released between 2003 and 2007 for 3 manufacturers (Boston Scientific, Medtronic and St Jude Medical) and for all manufacturers together. Weighted average prices of the devices were taken from tender information. The authors found that among recent-generation CRT‑Ds from different manufacturers, the total cost per patient over 6\xa0years ranged from €25,579 to €31,536 (£21,665 to £26,711 based on XE.com currency conversion on 12\xa0July\xa02016), with a maximum difference in cost of 40% for hospitals and 19% for the Italian healthcare system.\n\nPriest et\xa0al. (2015) is a published abstract from a conference poster presentation comparing the costs for industry-standard and longer-lifespan devices from an Australian health system perspective over 15\xa0years, using real-world data for implantable cardioverter defibrillators and CRT‑Ds (using the methods described by Boriani et\xa0al. 2013). Patient survival following first implant was taken from published literature. Average battery life was taken from a recent NICE review (not specified, but the figures quoted are found in NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure), and Boston Scientific real-world battery life data from more than 100,000 for implantable cardioverter defibrillators using the LATITUDE NXT remote monitoring system. The study concluded that if all patients switched from industry-standard devices to longer-lifespan batteries, the average cost per patient would fall by 19% and overall number of replacements would fall by 70%. This would result in cumulative cost savings of more than $900\xa0million over 15\xa0years.\n\nThe paper by Duxbury et\xa0al. (2014) is a published abstract from a conference poster presentation reporting the economic impact of implanting cardiac devices with longer lifespans from a UK perspective. The methodology was similar to that of the Priest et\xa0al. study (2015), in that it was based on Boriani et\xa0al. (2013). It also used the average lifespans described in the NICE technology appraisal and Boston Scientific real-world battery life data using the LATITUDE NXT remote monitoring system. The authors modelled the potential cumulative costs over 10\xa0years for industry-standard and longer-lifespan devices using real-world battery data for implantable cardioverter defibrillators and CRT‑Ds. The study concluded that using devices with longer battery life could result in cumulative savings of up to £158\xa0million over 10\xa0years.\n\n## EAC's critique of the cost evidence\n\nThe EAC identified that the main weakness of the published economic evidence was it relates to devices no longer marketed, because of the rapid turnover of new models of the technology. The study by Gadler et\xa0al. (2016) was funded by Boston Scientific, so may be subject to bias. The EAC considered the lifespan data for the LATITUDE NXT system used in Priest et\xa0al. (2015) may not be directly comparable with that reported in NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure, because the patient populations may be different. The EAC concluded that because the Priest et\xa0al. (2015) and Duxbury et\xa0al. (2014) studies are only available as abstracts, the results should be treated with caution.\n\n## Cost model\n\nThe company presented a de novo economic model adapted from Gadler et\xa0al. (2016) estimating mean cost savings per patient. The model is a decision tree with a 6-year time horizon and an NHS perspective. It compares Boston Scientific ENDURALIFE‑powered CRT‑Ds with Medtronic and St Jude Medical CRT‑Ds. For each device there are branches for procedural complications or no complications, with further branches for death, replacement or no replacement at 1 year and at each subsequent year. Clinical data in the model are taken from the Landolina et\xa0al. (2016) study on event-free battery survival and Yao et\xa0al. (2007) for cumulative probability of patient survival. The incidence of complications is taken from Tang et\xa0al. (2010) and the follow-up arrangements from NHS England 2013/14 NHS standard contract for cardiology: implantable cardioverter defibrillator and cardiac resynchronisation therapy (adult). The model assumes follow-up appointments at 6-month intervals with an additional post-procedure appointment.\n\nThe company's scenario analyses included exploring differences in device survival and device cost to identify thresholds at which the model becomes cost neutral. The price was varied by ±20% for each device separately using a one-way sensitivity analysis. The analyses showed that the cost model is highly sensitive to changes in both device survival and device cost. Higher device survival resulted in a marked decrease in relative costs. The one-way sensitivity analysis of device cost showed that ENDURALIFE‑powered CRT‑Ds remained cost saving.\n\nThe company's base case showed that ENDURALIFE‑powered CRT‑Ds cost £22,322 per patient over a 6-year period compared with £27,309 and £29,158 per patient for St Jude Medical and Medtronic CRT‑Ds respectively. The company therefore estimated that using ENDURALIFE‑powered CRT‑Ds would save between £4,987 and £6,836 per patient over 6\xa0years. Cost savings come mainly from fewer replacement procedures.\n\n## Additional work by the external assessment centre\n\nThe EAC re-ran the company's base case and univariate sensitivity analyses and conducted additional analyses using its preferred estimates. The EAC also did a threshold analysis using the average selling price for ENDURALIFE‑powered CRT‑Ds and allowing the cost of the comparator devices to fall to the point at which each becomes cost neutral. The main changes to the company's model were:\n\nChanges to the list prices of ENDURALIFE‑powered CRT‑Ds and both comparators.\n\nUsing warranty data from the comparator manufacturers instead of that from Boston Scientific.\n\nUsing NHS reference costs instead of Payment-by-Results tariff costs.\n\nChanges to the sensitivity analysis for complication rates (infection), based on the results of a large Danish cohort study (Kirkfeldt et\xa0al. 2014). This changed the infection rate from 2.4% to 0.6% for new implants.\n\nUsing patient survival data from the National Institute for Cardiovascular Outcomes Research (NICOR) instead of from Yao et\xa0al. (2007).\n\nThe results of the EAC analysis suggested that changing the device cost in the model to the lowest and highest list price for each of the 3 manufacturers results in ENDURALIFE‑powered CRT‑Ds becoming more costly than those from Medtronic, but remaining cost saving compared with those from St Jude Medical.\n\nThe threshold analysis investigated the effect of introducing a price difference between the devices, and calculated the threshold at which ENDURALIFE‑powered CRT‑Ds become cost incurring compared with the comparators. The results showed that, using the same cost of implanting and replacing the CRT‑D as used in the company's base case, ENDURALIFE‑powered CRT‑Ds become cost incurring when they are £4,858 more expensive to purchase than Medtronic CRT‑Ds and £3,858 more expensive to purchase than St Jude Medical CRT‑Ds, with all other model inputs unchanged.\n\nUsing NHS reference costs instead of the Payment-by-Results tariff increased the cost of ENDURALIFE‑powered CRT‑Ds from £22,322 in the company's base case to £30,957. ENDURALIFE‑powered CRT‑Ds remain cost saving compared with the comparators but to a lesser extent than in the company's base case.\n\nSubstituting the actual warranty information supplied by the manufacturers into the model showed that ENDURALIFE‑powered CRT‑Ds remained cost saving.\n\nChanging the rate of infection for new implants from 2.4% to 0.6% had little effect on the costs.\n\nFollowing expert advice, the EAC contacted NICOR, which holds a registry of NHS patients who have had CRT‑Ds implanted, including data on overall survival.\n\nUsing patient survival data from NICOR to replace that from Yao et\xa0al. (2007), ENDURALIFE‑powered CRT‑Ds remained cost saving when using the company's base-case device cost. At the lowest and highest list prices, ENDURALIFE‑powered CRT‑Ds become more costly than those from Medtronic, but remain cost saving compared with those from St Jude Medical.\n\nThe EAC concluded that the main driver of the cost model was device price.\n\nThe committee considered that the 6-year time horizon made the cost case uncertain. The EAC was therefore asked to carry out further analyses extrapolating the data available over a patient's lifetime (sections 5.20 to 5.24).\n\nNICOR provided unpublished data in confidence which showed patient survival by age group after primary implantation of a CRT‑D. The EAC extrapolated CRT‑D lifespan to 15\xa0years using a survival profile for comparator devices: this took an average distribution based on Medtronic and St Jude Medical CRT‑D lifespans reported in Landolina et\xa0al. (2015), and then applied the average distribution to the ENDURALIFE‑powered CRT‑Ds from the point at which the ENDURALIFE‑powered CRT‑Ds begin to reach the elective replacement indicator (ERI), at 5\xa0years following implantation.\n\nThe EAC extrapolated patient survival to 15\xa0years using NICOR data for patients aged 50 to 84\xa0years at primary implantation.\n\nUsing the average selling price in the company's base case and the extrapolated data outlined above, the results showed that ENDURALIFE‑powered CRT‑Ds cost £28,234 per patient over 15\xa0years compared with £30,354 and £33,861 per patient for St Jude Medical and Medtronic CRT‑Ds respectively. The EAC therefore estimated that using ENDURALIFE‑powered CRT‑Ds could save between £2,120 and £5,627 per patient over 15\xa0years.\n\nA threshold analysis investigated the effect of allowing a price difference between the devices, and calculated the threshold at which ENDURALIFE‑powered CRT‑Ds become cost incurring compared with the comparators. The results showed that, using the same cost of implanting and replacing the CRT‑D as used in the company's base case, ENDURALIFE‑powered CRT‑Ds become cost incurring when they are £3,304 more expensive to purchase than Medtronic CRT‑Ds and £1,404 more expensive to purchase than St Jude Medical CRT‑Ds.\n\n## EAC's critique of the cost model\n\nThe EAC considered that the 6-year time horizon used in the model may overestimate the potential cost saving of a slightly longer-lasting device. It concluded that a time horizon over the patient's lifetime may be more appropriate.\n\n## Committee considerations\n\nThe committee was advised that device costs were accurately reflected in the company's base case, which used average selling prices, and that prices are similar between manufacturers. List prices are not a true reflection of what the NHS pays for CRT‑Ds.\n\nThe committee concluded that it would be difficult to ascertain actual NHS device costs for ENDURALIFE‑powered and comparator CRT‑Ds. The EAC was asked to carry out a differential cost threshold analysis to overcome some of these uncertainties.\n\nThe committee accepted that the EAC's revisions to the company's cost modelling provided the most plausible estimates for the cost consequences of adopting ENDURALIFE‑powered CRT‑Ds.\n\nFor the guidance review, the external assessment centre revised the model to reflect 2020 costs (original guidance costs are given in brackets). The main parameter changes were the estimated costs:\n\nENDURALIFE-powered CRT-Ds £15,322 (£12,404)\n\nprocedural complications\n\n\n\n£24,686 (£21,774) for infection\n\n£6,975 (£6,152) for a complication requiring reintervention\n\n£20,418 (£18,010) for device pocket issues\n\n\n\nde novo procedures £5,931 (NHS tariff costs; EY01B) and £3,342 (NHS reference costs; EY01B) (£6,201; EY10B)\n\nreplacement procedures £5,931 (NHS tariff costs; EY01B) and £3,342 (NHS reference costs; EY01B) (£4,700)\n\nfollow-up procedures £78 (NHS tariff costs) and £135 (NHS reference costs) (£96; WF01A). Base-case results for the 2020 revised model shows the cost saving associated with ENDURALIFE-powered CRT-Ds was between £2,614 and £6,941 per patient using NHS national tariff costs and between £2,313 and £6,140 per patient using NHS reference costs over 15 years. Further details of the 2020 revised model are in the revised model summary in the review decision .", 'Conclusions': "The committee concluded that there is good evidence to support the clinical benefit of longer battery life and the associated reduction in cardiac resynchronisation therapy-defibrillator (CRT‑D) replacements.\n\nThe committee concluded that developments in CRT‑D technology are ongoing and that the evidence available suggests that the advantages of longer battery life have not been surpassed by other types of technical advances.\n\nThe committee noted the potential hazards of a clinical service relying solely on a single manufacturer's CRT‑D devices.\n\nThe committee encouraged further studies that provide data on the battery life of different CRT‑Ds, including an analysis of currently available UK NHS clinical data.\n\nBased on cost modelling, the committee concluded that using ENDURALIFE‑powered CRT‑Ds in patients with heart failure is likely to save costs by reducing the number of replacement procedures."}
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https://www.nice.org.uk/guidance/mtg33
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Evidence-based recommendations on ENDURALIFE-powered CRT-D devices for treating heart failure.
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caa2aa909b9777cede19552bf93e3987eecf51dd
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nice
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Ixekizumab for treating axial spondyloarthritis
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Ixekizumab for treating axial spondyloarthritis
Evidence-based recommendations on ixekizumab (Taltz) for treating axial spondyloarthritis in adults.
# Recommendations
Ixekizumab is recommended as an option for treating active ankylosing spondylitis that is not controlled well enough with conventional therapy, or active non-radiographic axial spondyloarthritis with objective signs of inflammation (shown by elevated C-reactive protein or MRI) that is not controlled well enough with non-steroidal anti-inflammatory drugs (NSAIDs), in adults. It is recommended only if:
tumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough, and
the company provides ixekizumab according to the commercial arrangement.
Assess response to ixekizumab after 16 to 20 weeks of treatment. Continue treatment only if there is clear evidence of response, defined as:
a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and
a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more.
Take into account any communication difficulties, or physical, psychological, sensory or learning disabilities that could affect responses to the BASDAI and spinal pain VAS questionnaires, and make any appropriate adjustments.
These recommendations are not intended to affect treatment with ixekizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
When people cannot have TNF-alpha inhibitors or they have not worked well enough the current treatment option is conventional therapy. This includes NSAIDs and physiotherapy. Secukinumab is also an option for treating radiographic disease but there is not enough data to reliably compare it with ixekizumab.
Evidence from clinical trials shows that ixekizumab is effective compared with placebo. The cost-effectiveness estimates for ixekizumab compared with conventional therapy are within what NICE usually considers cost effective. Therefore, ixekizumab is recommended.# Information about ixekizumab
# Marketing authorisation indication
Ixekizumab (Taltz, Eli Lily) is indicated for 'the treatment of adult patients with active ankylosing spondylitis who have responded inadequately to conventional therapy, and active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) who have responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of ixekizumab is £1,125 for 1 pre-filled syringe containing 80 mg per 1 ml solution (excluding VAT; BNF online, accessed March 2021). The annual cost is £16,875 for 15 injections in year 1 and £14,625 for 13 injections in year 2 (excluding VAT; BNF online, accessed March 2021).
The company has a commercial arrangement. This makes ixekizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Eli Lily, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The company's approach to modelling functional impairment after treatment discontinuation is appropriate (issue 5, see technical report, page 21).
The choice of utility regression equation in the economic model is not relevant to the company's updated version of the model because all treatments result in equivalent quality-adjusted life years (QALYs; issue 6, see technical report, page 21).
The use of a modification factor to convert clinical effectiveness estimates across active ankylosing spondylitis (radiographic disease) populations who have, and have not, had a biologic is not relevant to the company's updated version of the model (issue 7, see technical report, page 21).
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, pages 23 to 31), and took these into account in its decision making. It discussed the following issues (issues 1, 2 and 3), which were outstanding after the technical engagement stage.
# Clinical need and current management
## Axial spondyloarthritis is a debilitating condition
Axial spondyloarthritis is a chronic rheumatic condition characterised by inflammation of the sacroiliac joints and spine, although other joints can be affected. It can lead to functional impairment (difficulties doing day-to-day activities). It can also be associated with conditions affecting the eyes, bowel and skin. Axial spondyloarthritis is an umbrella term. It includes radiographic disease, known as ankylosing spondylitis (AS), in which inflammatory changes in the sacroiliac joints or spine can be seen on X‑ray, and non-radiographic axial spondyloarthritis (nr‑axSpA). Non-radiographic means there is no visible structural damage on X-ray but inflammation is visible on MRI or the person has symptoms. The committee heard from the patient expert that symptoms are often present for a long time (7 to 10 years) before the diagnosis is made, because symptoms can be non-specific and difficult to differentiate from other conditions. Symptoms usually begin in adolescence or early adulthood and include chronic back pain, stiffness, joint and tendon pain, arthritis and swelling of the fingers. A patient group explained in its written submission that many people experience depression, fatigue and poor sleep. This can have a profound effect on quality of life and affect education, work and the establishment of social frameworks and relationships. The committee concluded that axial spondyloarthritis is a painful and debilitating condition that can severely affect quality of life.
## A new treatment option would be valuable for patients
The patient organisation submission included a survey of 303 people with axial spondyloarthritis and their carers, which showed a high unmet clinical need for new treatments. More than half the people surveyed believed that current treatments for axial spondyloarthritis are not sufficient. For some people, no medication has been effective. Others cannot tolerate current treatments, and for some the efficacy of treatment has worn off over time. There were also worries about possible side effects with current treatments and concerns for people with severe disease who do not meet the criteria for current biologic therapy. Ixekizumab works differently to tumour necrosis factor (TNF)-alpha inhibitors. It would be particularly beneficial to people with nr‑axSpA for whom TNF-alpha inhibitors are the only biologics currently available. Ixekizumab would also provide an additional treatment option for people with radiographic disease. The patient expert stated that having a choice of treatments is important to meet individual needs. The committee concluded that the availability of an effective new treatment option would be valuable for people with axial spondyloarthritis.
## Ixekizumab would be used when TNF-alpha inhibitors are not suitable or have not worked well enough
Conventional therapy for axial spondyloarthritis includes non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy. NICE technology appraisal guidance recommends TNF-alpha inhibitors for disease that has not responded adequately to conventional therapy. Ixekizumab and secukinumab are both interleukin (IL)‑17‑a inhibitors. NICE's technology appraisal guidance recommends secukinumab as a treatment option for active ankylosing spondylitis that has responded inadequately to NSAIDs or TNF-alpha inhibitors. Secukinumab is currently being appraised for treating nr‑axSpA. The committee recalled that in previous technology appraisals of TNF-alpha inhibitors and secukinumab, clinical experts stated that the response criteria used in clinical practice for deciding to continue treatment were:
a reduction in the BASDAI score to 50% of the pre-treatment value or by 2 or more units and
a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more.The scope for ixekizumab issued by NICE is for people with axial spondyloarthritis for whom NSAIDs or TNF-alpha inhibitors are inadequately effective, not tolerated or contraindicated. In its response to technical engagement, the company stated that ixekizumab would be used primarily when TNF-alpha inhibitors are not suitable or have not controlled the condition well enough. The clinical experts explained that IL‑17‑a inhibitors are most needed by people with tolerability issues or contraindications to TNF-alpha inhibitors, or with disease that does not respond to TNF-alpha inhibitors (that is, primary non-response) or in whom the response is poor or lost after TNF-alpha inhibitor therapy. IL‑17‑a inhibitors would not be expected to replace TNF-alpha inhibitors as the standard first-line treatment because they are more expensive than the biosimilar TNF-alpha inhibitors and there is less clinical experience with using them. The committee concluded that ixekizumab would be used when TNF-alpha inhibitors are contraindicated or otherwise not suitable, after primary non-response to a TNF-alpha inhibitor or after a poor response or loss of response to TNF-alpha therapy.
## Conventional therapy is the most reliable comparator for ixekizumab
The committee considered the most relevant comparators, given the treatment position for ixekizumab described in section 3.3. For active AS, the comparators in the NICE scope were TNF-alpha inhibitors, secukinumab and conventional therapy without biologics. For nr‑axSpA the comparators in the NICE scope were TNF‑alpha inhibitors and conventional therapy without biologics. The committee concluded that TNF-alpha inhibitors were not relevant comparators because ixekizumab would be used for people in whom TNF‑alpha inhibitors are contraindicated or otherwise not suitable, or after non-response or poor response to TNF-alpha inhibitors (see section 3.3). The committee acknowledged that secukinumab was a comparator in the scope for AS, however it considered that there was insufficient clinical evidence to allow a robust comparison between secukinumab and ixekizumab (see section 3.8). Following consultation on the appraisal consultation document, the committee noted the company's comment that not all people for whom TNF-alpha inhibitors have worked inadequately would stop biologic therapy and return to conventional therapy. Some people may have the newer TNF-alpha inhibitor options such as golimumab or certolizumab pegol, on the rationale that even a sub-optimal response to these therapies may be greater than the expected response to conventional therapy alone. The committee accepted that this may reflect clinical practice in some circumstances. However, it concluded that conventional therapy was the most reliable comparator for ixekizumab because there was direct evidence for this from the COAST trials for both the AS and nr‑axSpA populations (see section 3.5). In contrast, the comparisons between ixekizumab and TNF-alpha inhibitors used results from an indirect comparison that the committee did not consider to be robust (see section 3.6), or an assumption of a class effect for biologic drugs that has not been established (see section 3.8).
## Treatment effects are not reliably generalisable across active ankylosing spondylitis and non-radiographic axial spondyloarthritis
Active AS and nr-axSpA have traditionally been considered as 2 distinct disease entities. The company argued that clinical practice has moved towards classifying axial spondyloarthritis as a continuous disease spectrum with active AS and nr‑axSpA being subtypes of the same condition. The company believed that the response rates to ixekizumab would be generalisable across the AS and nr‑axSpA populations. The clinical experts agreed that axial spondyloarthritis is a disease spectrum containing radiographic and non-radiographic subtypes. However, they explained that factors such as the extent of radiographic damage, inflammatory burden, disease duration and treatment history are likely to differ in AS and nr‑axSpA, which may affect treatment outcomes. The committee accepted that axial spondyloarthritis is a continuous spectrum of disease. However, it concluded that the response rate to ixekizumab could not be reliably generalised across the AS and nr‑axSpA populations because of differences in patient characteristics and disease presentation.
# Clinical evidence
## Ixekizumab is effective compared with placebo
The main clinical trial evidence came from 3 international placebo-controlled randomised controlled trials in people who had an inadequate response or intolerance to NSAIDs. Two of the trials were in AS: COAST‑V included 341 people who had not had a biologic before, and COAST‑W included 316 people who had previously had at least 1 biologic (a TNF-alpha inhibitor). The COAST‑X study included 303 people with nr‑axSpA who had never had a biologic. The clinical experts confirmed that the patients in the COAST trials were representative of people having treatment in the NHS. The ERG considered that patient baseline characteristics were well balanced across the arms within each trial. The primary outcome was the proportion of patients who had an Assessment in Spondyloarthritis International Society (ASAS) 40 response (improvement of at least 40% in at least 2 units in 3 of the 4 main domains of ASAS and no worsening in the remaining domains) at week 16. Secondary endpoints were the proportion of patients whose Bath Ankylosing Spondylitis Disease Activity Index score improved by 50% from baseline (BASDAI 50), and the change in the Bath Ankylosing Spondylitis Functional Index (BASFI) score from baseline. Ixekizumab showed a statistically significant clinical effect compared with placebo for all primary and secondary outcome measures. The company also presented evidence from the COAST‑Y study, an ongoing, multicentre, long-term extension study to evaluate the maintenance of treatment effect with ixekizumab. COAST‑Y includes people who completed COAST‑V, COAST‑W, and COAST‑X and continued having ixekizumab up to 116 weeks after their first dose. The company stated the results of COAST‑Y provide evidence to support the maintenance of treatment effects for ixekizumab on ASAS 40 response, BASDAI 50 response and the BASFI change from baseline. The committee concluded that ixekizumab is an effective treatment compared with placebo.
# The company's network meta-analysis
## Results of the network meta-analysis in the company's original submission are uncertain and not suitable for decision making
In the absence of direct evidence, the original company submission included a network meta-analysis (NMA) that compared the relative efficacy of ixekizumab and the comparators in the scope (see section 3.4). It used placebo as the common comparator. The company did separate NMAs for the AS populations who had and had not had a biologic before, and the nr‑axSpA population that had not had a biologic. This was in line with COAST‑V, COAST‑W and COAST‑X, respectively. The company did 'base-case' NMAs that included studies known to be in the relevant patient population, and 'sensitivity' NMAs that included additional studies with mixed populations or that were unclear about previous biologic treatment. The ERG considered the company's methods to be appropriate. However, it noted that the company's base-case NMAs were too sparsely populated to generate results for all relevant comparator treatments, so the cost-effectiveness results were informed by the sensitivity NMAs. The ERG was concerned about the substantial differences in the absolute effect estimates generated by the base-case and sensitivity NMAs. It considered the sensitivity NMAs to be less reliable than the base-case NMAs because of high levels of heterogeneity, and concluded that 3 of the sensitivity NMAs for the AS population were not robust. The committee agreed with the ERG that the results of the NMAs were not robust and were therefore not suitable for decision making.
## There is insufficient evidence to compare the effectiveness of ixekizumab and secukinumab
Secukinumab was a comparator in the NICE scope for the AS population (see section 3.4). In its original submission, the company indicated that there was insufficient published data available to allow for a full comparison of the effectiveness of ixekizumab and secukinumab. Following technical engagement, the company updated its NMAs to include data from the PREVENT trial, which compared secukinumab with placebo in an nr‑axSpA population. The company argued that results for the nr‑axSpA population are generalisable to the AS population because axial spondyloarthritis is a disease spectrum (see section 3.5). The ERG noted substantial differences between the response rates for ixekizumab in COAST‑V, which included an active AS population, and COAST‑X, which included an nr‑axSpA population. Both populations had not had a biologic. The ERG stated that if these differences were because of underlying disease biology then it would be unreliable to use results from the nr‑axSpA population as a proxy for results in AS. If the differences in the response rates were because of differences in patient characteristics, then results from the nr‑axSpA population could only be used to inform the effectiveness of ixekizumab for patients with AS if appropriate adjustments were made for these patient characteristics. The committee concluded that insufficient evidence was presented to allow for a robust comparison of ixekizumab and secukinumab, given that treatment effectiveness was not considered to be generalisable across AS and nr‑axSpA populations (see section 3.5).
# Assumptions about a class effect
## It is not reasonable to assume a class effect for all biologic treatments
Following technical engagement, the company considered it reasonable to assume that all biologic treatments for axial spondyloarthritis have equivalent efficacy (that is, there is a class effect for all TNF-alpha and IL‑17‑a inhibitors). It commented that the evidence demonstrates that the pathophysiology of axial spondyloarthritis is driven by dysregulation of inflammatory cytokines, in which both TNF-alpha inhibitors and IL‑17‑a inhibitors play key roles. The company also highlighted that the updated NMAs found no statistically significant difference between TNF-alpha inhibitors and IL‑17‑a inhibitors for any of the outcomes assessed. The clinical experts explained that IL‑17‑a inhibitors are expected to have similar effectiveness to TNF‑alpha inhibitors in clinical practice, but this has not been investigated in head-to-head clinical trials. They explained that application of a class effect for all biologics may be an oversimplification because TNF-alpha inhibitors and IL‑17‑a inhibitors have different mechanisms of action. This is a potential advantage of IL‑17‑a inhibitors after non-response or poor response to TNF-alpha inhibitors. The committee concluded that a class effect had not been established for all TNF-alpha inhibitors and IL‑17‑a inhibitors.
# Cost effectiveness
## The results of the model using the network meta-analysis are not reliable for decision making
The company presented a Markov model to estimate the cost effectiveness of ixekizumab compared with TNF-alpha inhibitors, secukinumab (for AS only) and conventional therapy in people for whom NSAIDs or TNF-alpha inhibitors had been inadequately effective, not tolerated, or contraindicated. The committee recalled that conventional therapy was the most reliable comparator (see section 3.4). The committee considered that the structure of the model was appropriate. However, the efficacy inputs in the original version of the model were informed by the results of the NMA, which the committee considered were not robust (see section 3.7). The committee also noted that the company's incremental cost-effectiveness ratios (ICERs) for ixekizumab compared with conventional therapy were above the range NICE normally considers cost effective (that is, £20,000 to £30,000 per QALY gained). The committee concluded that the results of the model using the NMA were not reliable for decision making.
## The company's updated model assuming a class effect for biologic treatments is not appropriate
After technical engagement, the company updated its cost-effectiveness analysis. It applied a class effect across the IL‑17‑a inhibitors and TNF‑alpha inhibitors. It presented 2 analyses. One analysis was for the AS population who previously had a biologic, in which the efficacy inputs for all biologics were assumed to equal the efficacy of ixekizumab in COAST‑W. The other analysis was for the nr‑axSpA population who had not had a biologic, in which the efficacy inputs for all biologics were assumed to equal the efficacy of ixekizumab in COAST‑X. This was intended as a proxy for the use of ixekizumab in a nr‑axSpA population who had had a biologic, in the absence of trial data for this group. The assumption of a class effect meant that there were equivalent QALYs for all biologics. However, the QALYs differed across the analyses for the AS population, who had had a biologic, and the nr‑axSpA populations, who had not. The committee appreciated the need to find alternative ways to model the efficacy of the treatments given the limitations of the NMAs. However, it was not persuaded that a class effect had been demonstrated across all biologics (see section 3.9). The committee was also concerned that the company had not presented an ICER for ixekizumab compared with conventional therapy in its updated analyses. The committee considered this was the key comparator in situations when ixekizumab would be used in clinical practice (see section 3.4). It concluded that the updated version of the model could not be used for decision making.
## The company's analyses comparing ixekizumab with conventional therapy using direct evidence from the COAST trials are appropriate
The appraisal consultation document stated that further analyses are needed to assess the cost effectiveness of ixekizumab. The most reliable comparator for ixekizumab in the populations for whom it would be used is conventional therapy (see section 3.4). The committee had concluded that an analysis comparing ixekizumab with conventional therapy using direct evidence from the COAST trials would be the most robust way of assessing the cost effectiveness of ixekizumab. Following consultation, the company presented updated analyses. These compared ixekizumab with conventional therapy for the AS population who had never had a biologic (using data from COAST‑V), the AS population who had had at least 1 biologic (using COAST‑W data) and the nr‑axSpA population who had never had a biologic (using COAST‑X data). The committee noted the lack of direct evidence on ixekizumab in nr‑axSpA following inadequate or loss of response to TNF-alpha inhibitors. However, it was reassured that the COAST trials covered the treatment pathway, for people who both had and had not had a biologic before, and the full spectrum of axial spondyloarthritis. The committee concluded that the company's revised analyses were suitable for decision making.
## Ixekizumab is cost effective compared with conventional therapy
The ICERs for ixekizumab compared with conventional therapy using direct data from the COAST trials for the AS population were £18,775 per QALY gained for people who had not had a biologic before and £19,012 for those who had. The ICER for the nr‑axSpA population who had never had a biologic was £24,772. The ICERs were within the range NICE normally considers cost effective. Therefore, the committee concluded that ixekizumab could be recommended as an option for treating AS and nr‑axSpA in adults when TNF-alpha inhibitors have not controlled the condition well enough, or these are not suitable.
# Conclusion
## Ixekizumab is a cost-effective treatment for AS and nr-axSpA when TNF-alpha inhibitors are not suitable or have not worked well enough
Ixekizumab would be offered to people who cannot have TNF-alpha inhibitors or when they have not worked well enough. The most reliable comparator in these populations is conventional therapy. Evidence from the COAST trials shows that ixekizumab is effective compared with placebo, which is a proxy for conventional therapy. The company's cost-effectiveness estimates for ixekizumab compared with conventional therapy using direct evidence from the COAST trials were within the range NICE normally considers cost effective. Therefore, ixekizumab is recommended as an option for treating AS and nr‑axSpA in adults when TNF-alpha inhibitors have not controlled the condition well enough, or these are not suitable.
|
{'Recommendations': 'Ixekizumab is recommended as an option for treating active ankylosing spondylitis that is not controlled well enough with conventional therapy, or active non-radiographic axial spondyloarthritis with objective signs of inflammation (shown by elevated C-reactive protein or MRI) that is not controlled well enough with non-steroidal anti-inflammatory drugs (NSAIDs), in adults. It is recommended only if:\n\ntumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough, and\n\nthe company provides ixekizumab according to the commercial arrangement.\n\nAssess response to ixekizumab after 16\xa0to 20\xa0weeks of treatment. Continue treatment only if there is clear evidence of response, defined as:\n\na reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) by 2\xa0cm or more.\n\nTake into account any communication difficulties, or physical, psychological, sensory or learning disabilities that could affect responses to the BASDAI and spinal pain VAS questionnaires, and make any appropriate adjustments.\n\nThese recommendations are not intended to affect treatment with ixekizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nWhen people cannot have TNF-alpha inhibitors or they have not worked well enough the current treatment option is conventional therapy. This includes NSAIDs and physiotherapy. Secukinumab is also an option for treating radiographic disease but there is not enough data to reliably compare it with ixekizumab.\n\nEvidence from clinical trials shows that ixekizumab is effective compared with placebo. The cost-effectiveness estimates for ixekizumab compared with conventional therapy are within what NICE usually considers cost effective. Therefore, ixekizumab is recommended.', 'Information about ixekizumab': "# Marketing authorisation indication\n\nIxekizumab (Taltz, Eli Lily) is indicated for 'the treatment of adult patients with active ankylosing spondylitis [radiographic axial spondyloarthritis] who have responded inadequately to conventional therapy, and active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) who have responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of ixekizumab is £1,125 for 1\xa0pre-filled syringe containing 80\xa0mg per 1\xa0ml solution (excluding VAT; BNF online, accessed March 2021). The annual cost is £16,875 for 15\xa0injections in year\xa01 and £14,625 for 13\xa0injections in year\xa02 (excluding VAT; BNF online, accessed March\xa02021).\n\nThe company has a commercial arrangement. This makes ixekizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Eli Lily, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe company's approach to modelling functional impairment after treatment discontinuation is appropriate (issue\xa05, see technical report, page\xa021).\n\nThe choice of utility regression equation in the economic model is not relevant to the company's updated version of the model because all treatments result in equivalent quality-adjusted life years (QALYs; issue\xa06, see technical report, page\xa021).\n\nThe use of a modification factor to convert clinical effectiveness estimates across active ankylosing spondylitis (radiographic disease) populations who have, and have not, had a biologic is not relevant to the company's updated version of the model (issue\xa07, see technical report, page\xa021).\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, pages 23\xa0to\xa031), and took these into account in its decision making. It discussed the following issues (issues\xa01, 2 and 3), which were outstanding after the technical engagement stage.\n\n# Clinical need and current management\n\n## Axial spondyloarthritis is a debilitating condition\n\nAxial spondyloarthritis is a chronic rheumatic condition characterised by inflammation of the sacroiliac joints and spine, although other joints can be affected. It can lead to functional impairment (difficulties doing day-to-day activities). It can also be associated with conditions affecting the eyes, bowel and skin. Axial spondyloarthritis is an umbrella term. It includes radiographic disease, known as ankylosing spondylitis (AS), in which inflammatory changes in the sacroiliac joints or spine can be seen on X‑ray, and non-radiographic axial spondyloarthritis (nr‑axSpA). Non-radiographic means there is no visible structural damage on X-ray but inflammation is visible on MRI or the person has symptoms. The committee heard from the patient expert that symptoms are often present for a long time (7 to 10\xa0years) before the diagnosis is made, because symptoms can be non-specific and difficult to differentiate from other conditions. Symptoms usually begin in adolescence or early adulthood and include chronic back pain, stiffness, joint and tendon pain, arthritis and swelling of the fingers. A patient group explained in its written submission that many people experience depression, fatigue and poor sleep. This can have a profound effect on quality of life and affect education, work and the establishment of social frameworks and relationships. The committee concluded that axial spondyloarthritis is a painful and debilitating condition that can severely affect quality of life.\n\n## A new treatment option would be valuable for patients\n\nThe patient organisation submission included a survey of 303\xa0people with axial spondyloarthritis and their carers, which showed a high unmet clinical need for new treatments. More than half the people surveyed believed that current treatments for axial spondyloarthritis are not sufficient. For some people, no medication has been effective. Others cannot tolerate current treatments, and for some the efficacy of treatment has worn off over time. There were also worries about possible side effects with current treatments and concerns for people with severe disease who do not meet the criteria for current biologic therapy. Ixekizumab works differently to tumour necrosis factor (TNF)-alpha inhibitors. It would be particularly beneficial to people with nr‑axSpA for whom TNF-alpha inhibitors are the only biologics currently available. Ixekizumab would also provide an additional treatment option for people with radiographic disease. The patient expert stated that having a choice of treatments is important to meet individual needs. The committee concluded that the availability of an effective new treatment option would be valuable for people with axial spondyloarthritis.\n\n## Ixekizumab would be used when TNF-alpha inhibitors are not suitable or have not worked well enough\n\nConventional therapy for axial spondyloarthritis includes non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy. NICE technology appraisal guidance recommends TNF-alpha inhibitors for disease that has not responded adequately to conventional therapy. Ixekizumab and secukinumab are both interleukin (IL)‑17‑a inhibitors. NICE's technology appraisal guidance recommends secukinumab as a treatment option for active ankylosing spondylitis that has responded inadequately to NSAIDs or TNF-alpha inhibitors. Secukinumab is currently being appraised for treating nr‑axSpA. The committee recalled that in previous technology appraisals of TNF-alpha inhibitors and secukinumab, clinical experts stated that the response criteria used in clinical practice for deciding to continue treatment were:\n\na reduction in the BASDAI score to 50% of the pre-treatment value or by 2 or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) by 2\xa0cm or more.The scope for ixekizumab issued by NICE is for people with axial spondyloarthritis for whom NSAIDs or TNF-alpha inhibitors are inadequately effective, not tolerated or contraindicated. In its response to technical engagement, the company stated that ixekizumab would be used primarily when TNF-alpha inhibitors are not suitable or have not controlled the condition well enough. The clinical experts explained that IL‑17‑a inhibitors are most needed by people with tolerability issues or contraindications to TNF-alpha inhibitors, or with disease that does not respond to TNF-alpha inhibitors (that is, primary non-response) or in whom the response is poor or lost after TNF-alpha inhibitor therapy. IL‑17‑a inhibitors would not be expected to replace TNF-alpha inhibitors as the standard first-line treatment because they are more expensive than the biosimilar TNF-alpha inhibitors and there is less clinical experience with using them. The committee concluded that ixekizumab would be used when TNF-alpha inhibitors are contraindicated or otherwise not suitable, after primary non-response to a TNF-alpha inhibitor or after a poor response or loss of response to TNF-alpha therapy.\n\n## Conventional therapy is the most reliable comparator for ixekizumab\n\nThe committee considered the most relevant comparators, given the treatment position for ixekizumab described in section\xa03.3. For active AS, the comparators in the NICE scope were TNF-alpha inhibitors, secukinumab and conventional therapy without biologics. For nr‑axSpA the comparators in the NICE scope were TNF‑alpha inhibitors and conventional therapy without biologics. The committee concluded that TNF-alpha inhibitors were not relevant comparators because ixekizumab would be used for people in whom TNF‑alpha inhibitors are contraindicated or otherwise not suitable, or after non-response or poor response to TNF-alpha inhibitors (see section\xa03.3). The committee acknowledged that secukinumab was a comparator in the scope for AS, however it considered that there was insufficient clinical evidence to allow a robust comparison between secukinumab and ixekizumab (see section\xa03.8). Following consultation on the appraisal consultation document, the committee noted the company's comment that not all people for whom TNF-alpha inhibitors have worked inadequately would stop biologic therapy and return to conventional therapy. Some people may have the newer TNF-alpha inhibitor options such as golimumab or certolizumab pegol, on the rationale that even a sub-optimal response to these therapies may be greater than the expected response to conventional therapy alone. The committee accepted that this may reflect clinical practice in some circumstances. However, it concluded that conventional therapy was the most reliable comparator for ixekizumab because there was direct evidence for this from the COAST trials for both the AS and nr‑axSpA populations (see section\xa03.5). In contrast, the comparisons between ixekizumab and TNF-alpha inhibitors used results from an indirect comparison that the committee did not consider to be robust (see section\xa03.6), or an assumption of a class effect for biologic drugs that has not been established (see section 3.8).\n\n## Treatment effects are not reliably generalisable across active ankylosing spondylitis and non-radiographic axial spondyloarthritis\n\nActive AS and nr-axSpA have traditionally been considered as 2 distinct disease entities. The company argued that clinical practice has moved towards classifying axial spondyloarthritis as a continuous disease spectrum with active AS and nr‑axSpA being subtypes of the same condition. The company believed that the response rates to ixekizumab would be generalisable across the AS and nr‑axSpA populations. The clinical experts agreed that axial spondyloarthritis is a disease spectrum containing radiographic and non-radiographic subtypes. However, they explained that factors such as the extent of radiographic damage, inflammatory burden, disease duration and treatment history are likely to differ in AS and nr‑axSpA, which may affect treatment outcomes. The committee accepted that axial spondyloarthritis is a continuous spectrum of disease. However, it concluded that the response rate to ixekizumab could not be reliably generalised across the AS and nr‑axSpA populations because of differences in patient characteristics and disease presentation.\n\n# Clinical evidence\n\n## Ixekizumab is effective compared with placebo\n\nThe main clinical trial evidence came from 3 international placebo-controlled randomised controlled trials in people who had an inadequate response or intolerance to NSAIDs. Two of the trials were in AS: COAST‑V included 341\xa0people who had not had a biologic before, and COAST‑W included 316\xa0people who had previously had at least 1 biologic (a TNF-alpha inhibitor). The COAST‑X study included 303\xa0people with nr‑axSpA who had never had a biologic. The clinical experts confirmed that the patients in the COAST trials were representative of people having treatment in the NHS. The ERG considered that patient baseline characteristics were well balanced across the arms within each trial. The primary outcome was the proportion of patients who had an Assessment in Spondyloarthritis International Society (ASAS)\xa040 response (improvement of at least 40% in at least 2\xa0units in 3 of the 4 main domains of ASAS and no worsening in the remaining domains) at week\xa016. Secondary endpoints were the proportion of patients whose Bath Ankylosing Spondylitis Disease Activity Index score improved by 50% from baseline (BASDAI\xa050), and the change in the Bath Ankylosing Spondylitis Functional Index (BASFI) score from baseline. Ixekizumab showed a statistically significant clinical effect compared with placebo for all primary and secondary outcome measures. The company also presented evidence from the COAST‑Y study, an ongoing, multicentre, long-term extension study to evaluate the maintenance of treatment effect with ixekizumab. COAST‑Y includes people who completed COAST‑V, COAST‑W, and COAST‑X and continued having ixekizumab up to 116\xa0weeks after their first dose. The company stated the results of COAST‑Y provide evidence to support the maintenance of treatment effects for ixekizumab on ASAS\xa040 response, BASDAI\xa050 response and the BASFI change from baseline. The committee concluded that ixekizumab is an effective treatment compared with placebo.\n\n# The company's network meta-analysis\n\n## Results of the network meta-analysis in the company's original submission are uncertain and not suitable for decision making\n\nIn the absence of direct evidence, the original company submission included a network meta-analysis (NMA) that compared the relative efficacy of ixekizumab and the comparators in the scope (see section\xa03.4). It used placebo as the common comparator. The company did separate NMAs for the AS populations who had and had not had a biologic before, and the nr‑axSpA population that had not had a biologic. This was in line with COAST‑V, COAST‑W and COAST‑X, respectively. The company did 'base-case' NMAs that included studies known to be in the relevant patient population, and 'sensitivity' NMAs that included additional studies with mixed populations or that were unclear about previous biologic treatment. The ERG considered the company's methods to be appropriate. However, it noted that the company's base-case NMAs were too sparsely populated to generate results for all relevant comparator treatments, so the cost-effectiveness results were informed by the sensitivity NMAs. The ERG was concerned about the substantial differences in the absolute effect estimates generated by the base-case and sensitivity NMAs. It considered the sensitivity NMAs to be less reliable than the base-case NMAs because of high levels of heterogeneity, and concluded that 3 of the sensitivity NMAs for the AS population were not robust. The committee agreed with the ERG that the results of the NMAs were not robust and were therefore not suitable for decision making.\n\n## There is insufficient evidence to compare the effectiveness of ixekizumab and secukinumab\n\nSecukinumab was a comparator in the NICE scope for the AS population (see section\xa03.4). In its original submission, the company indicated that there was insufficient published data available to allow for a full comparison of the effectiveness of ixekizumab and secukinumab. Following technical engagement, the company updated its NMAs to include data from the PREVENT trial, which compared secukinumab with placebo in an nr‑axSpA population. The company argued that results for the nr‑axSpA population are generalisable to the AS population because axial spondyloarthritis is a disease spectrum (see section\xa03.5). The ERG noted substantial differences between the response rates for ixekizumab in COAST‑V, which included an active AS population, and COAST‑X, which included an nr‑axSpA population. Both populations had not had a biologic. The ERG stated that if these differences were because of underlying disease biology then it would be unreliable to use results from the nr‑axSpA population as a proxy for results in AS. If the differences in the response rates were because of differences in patient characteristics, then results from the nr‑axSpA population could only be used to inform the effectiveness of ixekizumab for patients with AS if appropriate adjustments were made for these patient characteristics. The committee concluded that insufficient evidence was presented to allow for a robust comparison of ixekizumab and secukinumab, given that treatment effectiveness was not considered to be generalisable across AS and nr‑axSpA populations (see section 3.5).\n\n# Assumptions about a class effect\n\n## It is not reasonable to assume a class effect for all biologic treatments\n\nFollowing technical engagement, the company considered it reasonable to assume that all biologic treatments for axial spondyloarthritis have equivalent efficacy (that is, there is a class effect for all TNF-alpha and IL‑17‑a inhibitors). It commented that the evidence demonstrates that the pathophysiology of axial spondyloarthritis is driven by dysregulation of inflammatory cytokines, in which both TNF-alpha inhibitors and IL‑17‑a inhibitors play key roles. The company also highlighted that the updated NMAs found no statistically significant difference between TNF-alpha inhibitors and IL‑17‑a inhibitors for any of the outcomes assessed. The clinical experts explained that IL‑17‑a inhibitors are expected to have similar effectiveness to TNF‑alpha inhibitors in clinical practice, but this has not been investigated in head-to-head clinical trials. They explained that application of a class effect for all biologics may be an oversimplification because TNF-alpha inhibitors and IL‑17‑a inhibitors have different mechanisms of action. This is a potential advantage of IL‑17‑a inhibitors after non-response or poor response to TNF-alpha inhibitors. The committee concluded that a class effect had not been established for all TNF-alpha inhibitors and IL‑17‑a inhibitors.\n\n# Cost effectiveness\n\n## The results of the model using the network meta-analysis are not reliable for decision making\n\nThe company presented a Markov model to estimate the cost effectiveness of ixekizumab compared with TNF-alpha inhibitors, secukinumab (for AS only) and conventional therapy in people for whom NSAIDs or TNF-alpha inhibitors had been inadequately effective, not tolerated, or contraindicated. The committee recalled that conventional therapy was the most reliable comparator (see section\xa03.4). The committee considered that the structure of the model was appropriate. However, the efficacy inputs in the original version of the model were informed by the results of the NMA, which the committee considered were not robust (see section\xa03.7). The committee also noted that the company's incremental cost-effectiveness ratios (ICERs) for ixekizumab compared with conventional therapy were above the range NICE normally considers cost effective (that is, £20,000 to £30,000 per QALY gained). The committee concluded that the results of the model using the NMA were not reliable for decision making.\n\n## The company's updated model assuming a class effect for biologic treatments is not appropriate\n\nAfter technical engagement, the company updated its cost-effectiveness analysis. It applied a class effect across the IL‑17‑a inhibitors and TNF‑alpha inhibitors. It presented 2 analyses. One analysis was for the AS population who previously had a biologic, in which the efficacy inputs for all biologics were assumed to equal the efficacy of ixekizumab in COAST‑W. The other analysis was for the nr‑axSpA population who had not had a biologic, in which the efficacy inputs for all biologics were assumed to equal the efficacy of ixekizumab in COAST‑X. This was intended as a proxy for the use of ixekizumab in a nr‑axSpA population who had had a biologic, in the absence of trial data for this group. The assumption of a class effect meant that there were equivalent QALYs for all biologics. However, the QALYs differed across the analyses for the AS population, who had had a biologic, and the nr‑axSpA populations, who had not. The committee appreciated the need to find alternative ways to model the efficacy of the treatments given the limitations of the NMAs. However, it was not persuaded that a class effect had been demonstrated across all biologics (see section\xa03.9). The committee was also concerned that the company had not presented an ICER for ixekizumab compared with conventional therapy in its updated analyses. The committee considered this was the key comparator in situations when ixekizumab would be used in clinical practice (see section\xa03.4). It concluded that the updated version of the model could not be used for decision making.\n\n## The company's analyses comparing ixekizumab with conventional therapy using direct evidence from the COAST trials are appropriate\n\nThe appraisal consultation document stated that further analyses are needed to assess the cost effectiveness of ixekizumab. The most reliable comparator for ixekizumab in the populations for whom it would be used is conventional therapy (see section\xa03.4). The committee had concluded that an analysis comparing ixekizumab with conventional therapy using direct evidence from the COAST trials would be the most robust way of assessing the cost effectiveness of ixekizumab. Following consultation, the company presented updated analyses. These compared ixekizumab with conventional therapy for the AS population who had never had a biologic (using data from COAST‑V), the AS population who had had at least 1\xa0biologic (using COAST‑W data) and the nr‑axSpA population who had never had a biologic (using COAST‑X data). The committee noted the lack of direct evidence on ixekizumab in nr‑axSpA following inadequate or loss of response to TNF-alpha inhibitors. However, it was reassured that the COAST trials covered the treatment pathway, for people who both had and had not had a biologic before, and the full spectrum of axial spondyloarthritis. The committee concluded that the company's revised analyses were suitable for decision making.\n\n## Ixekizumab is cost effective compared with conventional therapy\n\nThe ICERs for ixekizumab compared with conventional therapy using direct data from the COAST trials for the AS population were £18,775 per QALY gained for people who had not had a biologic before and £19,012 for those who had. The ICER for the nr‑axSpA population who had never had a biologic was £24,772. The ICERs were within the range NICE normally considers cost effective. Therefore, the committee concluded that ixekizumab could be recommended as an option for treating AS and nr‑axSpA in adults when TNF-alpha inhibitors have not controlled the condition well enough, or these are not suitable.\n\n# Conclusion\n\n## Ixekizumab is a cost-effective treatment for AS and nr-axSpA when TNF-alpha inhibitors are not suitable or have not worked well enough\n\nIxekizumab would be offered to people who cannot have TNF-alpha inhibitors or when they have not worked well enough. The most reliable comparator in these populations is conventional therapy. Evidence from the COAST trials shows that ixekizumab is effective compared with placebo, which is a proxy for conventional therapy. The company's cost-effectiveness estimates for ixekizumab compared with conventional therapy using direct evidence from the COAST trials were within the range NICE normally considers cost effective. Therefore, ixekizumab is recommended as an option for treating AS and nr‑axSpA in adults when TNF-alpha inhibitors have not controlled the condition well enough, or these are not suitable."}
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https://www.nice.org.uk/guidance/ta718
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Evidence-based recommendations on ixekizumab (Taltz) for treating axial spondyloarthritis in adults.
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7a3b50efd7aef6c7340186a059aba9885c88a6e9
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Secukinumab for treating non-radiographic axial spondyloarthritis
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Secukinumab for treating non-radiographic axial spondyloarthritis
Evidence-based recommendations on secukinumab (Cosentyx) for treating non-radiographic axial spondyloarthritis in adults.
# Recommendations
Secukinumab is recommended as an option for treating active non-radiographic axial spondyloarthritis with objective signs of inflammation (shown by elevated C-reactive protein or MRI) that is not controlled well enough with non-steroidal anti-inflammatory drugs (NSAIDs) in adults. It is recommended only if:
tumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough and
the company provides secukinumab according to the commercial arrangement.
Assess response to secukinumab after 16 weeks of treatment. Continue treatment only if there is clear evidence of response, defined as:
a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and
a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more.
Take into account any communication difficulties, or physical, psychological, sensory or learning disabilities that could affect responses to the BASDAI and spinal pain VAS questionnaires, and make any appropriate adjustments.
These recommendations are not intended to affect treatment with secukinumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment for non-radiographic axial spondyloarthritis that is not controlled well enough with NSAIDs is limited to TNF-alpha inhibitors (adalimumab, certolizumab pegol, etanercept and golimumab). There are no treatment options when people cannot have TNF-alpha inhibitors, or if TNF-alpha inhibitors have not worked well enough.
Clinical trial evidence shows that secukinumab is effective compared with placebo. There are no trials directly comparing secukinumab with TNF-alpha inhibitors. But an indirect comparison suggests that secukinumab may be less effective than TNF‑alpha inhibitors. However, this evidence is uncertain.
Different TNF-alpha inhibitors have different costs but similar effectiveness. When more than one TNF-alpha inhibitor is suitable, the cheapest is used, currently adalimumab biosimilar. Because of this, secukinumab is not a cost-effective use of NHS resources when compared with TNF-alpha inhibitors. Secukinumab is only considered to be cost effective for people who cannot have TNF-alpha inhibitors, or when TNF-alpha inhibitors have not worked well enough. Therefore, it is recommended in these situations.# Information about secukinumab
# Marketing authorisation indication
Secukinumab (Cosentyx, Novartis) is 'indicated for the treatment of active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) in adults who have responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs)'.
# Dosage in the marketing authorisation
The dosage schedule is in the summary of product characteristics.
# Price
The list price is £1,218.78 for 2 pre-filled pens or syringes containing 150 mg per 1 ml solution (excluding VAT, BNF online accessed March 2021). Annual cost of treatment for the first year is £9,750.24 and subsequent years is £7,312.68. The company has a commercial arrangement. This makes secukinumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
In the PREVENT trial, the response criteria used to determine continuing treatment beyond 12 weeks are different from the response criteria used in the NHS, but it is appropriate to use data from this trial in the model.
Although PREVENT assessed secukinumab with and without a loading dose, the load-dose regimen is the regimen licensed for use in the UK. Therefore, the results from the load-dose arm of PREVENT are generalisable to how secukinumab would be used in NHS clinical practice.
Trial evidence suggests that there may be differences in efficacy in certain subgroups of the trial population. However, because PREVENT was not powered to detect differences between subgroups based on MRI or C-reactive protein status, it is not possible to conclude that there is genuine heterogeneity in treatment effect. Therefore, the cost-effectiveness results in these subgroups are not relevant for decision making.
There were remaining areas of uncertainty associated with the analyses presented, which were considered further by the committee. The appraisal committee discussed the following issues (issues 1, 2, 6, 7, 8 and 9 from the technical report), which were outstanding after the technical engagement stage.
# Clinical need and current management
## Non-radiographic axial spondyloarthritis causes pain, reduced mobility and affects quality of life
Axial spondyloarthritis is a chronic rheumatic condition characterised by inflammation at the sacroiliac joints and spine, although other joints can be affected. It can be associated with other conditions affecting the eyes, bowel and skin. Axial spondyloarthritis is an umbrella term encompassing both non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis (also known as ankylosing spondylitis). Non-radiographic means that a person has symptoms but the condition cannot be identified on an X-ray. It is a painful and debilitating condition and is considered incurable with current treatments. The clinical experts explained that although the disease burden is variable, progressive spinal pain, immobility and disability experienced by people with non-radiographic axial spondyloarthritis substantially affects their quality of life and mental wellbeing. The clinical experts noted that there can be a delay in diagnosis because of non-specific symptoms, an absence of visible structural damage on X-rays, and normal or ambiguous MRI results. They noted that the condition can be mistaken for other conditions such as fibromyalgia. This delay in diagnosis can result in high functional impairment (difficulties doing day-to-day activities). Almost half of people with non-radiographic axial spondyloarthritis progress to the radiographic version of the disease over a period of 8 to 10 years. People with axial spondyloarthritis report that it profoundly affects their quality of life and day-to-day activities, such as work.
## People would welcome a new treatment option that works differently to TNF-alpha inhibitors
NICE's guideline on spondyloarthritis in over 16s recommends that the first treatment for people with non-radiographic axial spondyloarthritis is physical therapy and first-line pharmacological treatment with non-steroidal anti-inflammatory drugs (NSAIDs). For disease that responds inadequately to NSAIDs, or if these are not tolerated, NICE recommends tumour necrosis factor (TNF)-alpha inhibitors (see NICE's technology appraisal guidance on TNF-alpha inhibitors and golimumab) as options for treating severe non-radiographic axial spondyloarthritis. If the first TNF-alpha inhibitor is not tolerated, or the person's condition has not responded or stops responding, NICE's technology appraisal guidance on TNF-alpha inhibitors recommends treatment with another TNF-alpha inhibitor. The committee recalled that in previous technology appraisals for axial spondyloarthritis, clinical experts stated that the response criteria used in clinical practice for deciding to continue treatment were:
a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and
a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more.The clinical expert explained that secukinumab is an additional treatment option when TNF-alpha inhibitors are not suitable, or when the disease has not responded or stopped responding to TNF-alpha inhibitors. The clinical expert explained that if a person's disease responded to a first TNF-alpha inhibitor, it would likely respond to another TNF-alpha inhibitor. However, they noted that for disease that has had an inadequate response to TNF-alpha inhibitors, it is preferable to try a new treatment option with an alternative mechanism of action. The clinical expert also noted that some people with non-radiographic axial spondyloarthritis also have psoriasis and explained that secukinumab is more effective than TNF-alpha inhibitors for treating psoriasis. The committee concluded that people with non-radiographic axial spondyloarthritis would welcome a new treatment option with a different mechanism of action.
## Secukinumab can be used first line or second line after NSAIDs, but TNF-alpha inhibitors would likely be used first, unless unsuitable
The company noted that the marketing authorisation for secukinumab does not limit its use to a particular line of treatment. The ERG considered it unlikely that secukinumab would be the first-line biologic of choice, given the extensive clinical experience with TNF-alpha inhibitors and the lower price of biosimilar versions now available. It noted that secukinumab was more likely to be used as a second-line treatment after TNF-alpha inhibitors. The clinical experts explained that in line with NICE guidance, when more than 1 treatment is suitable, clinicians generally consider the least expensive treatment (taking into account administration costs and patient access schemes). Currently, the adalimumab biosimilar is usually the first-line biologic used when the disease has not responded to NSAIDs. The second choice is usually etanercept biosimilar when the adalimumab biosimilar is unsuitable or has failed. The committee concluded that secukinumab is licensed as a first-line or second-line treatment option after NSAIDs have not worked well enough. However, clinicians are more likely to choose a TNF-alpha inhibitor as the first biologic treatment unless these are contraindicated or unsuitable.
# Clinical evidence
## Secukinumab increases the proportion of people having an ASAS 40 response compared with placebo when used as first-line treatment
PREVENT is a multicentre double-blind randomised placebo-controlled trial comparing 150 mg secukinumab with a loading dose (an initial higher dose of a drug given at the beginning of a course of treatment; n=185) with placebo (n=186). It included adults with axial spondyloarthritis who fulfilled the Assessment of Spondylarthritis International Society (ASAS) classification criteria for axial spondyloarthritis, with abnormal C-reactive protein or MRI, and no radiographic evidence of changes in the sacroiliac joints. As such, the disease also fulfilled the modified New York criteria for non-radiographic axial spondyloarthritis. The primary outcome measure is the proportion of patients who have not had a TNF-alpha inhibitor before who had an ASAS 40 response (improvement of at least 40% in the ASAS, improvement in at least 2 units in 3 of the 4 main domains of ASAS and no worsening in the remaining domains) at week 16. Secukinumab increased the proportion of people who had an ASAS 40 response compared with placebo (odds ratio 1.72, p<0.0197; 95% confidence intervals are confidential and cannot be reported here). The proportion of patients whose BASDAI score improved by 50% from baseline (BASDAI 50), and the change in Bath Ankylosing Spondylitis Functional Index (BASFI) score from baseline, were collected as secondary endpoints. Secukinumab improved these outcomes compared with placebo. The committee concluded that, compared with placebo, secukinumab increases the proportion of people having an ASAS 40 response, BASDAI 50 response and improved function as assessed by BASFI.
## There are limited clinical-effectiveness data for secukinumab used after a TNF-alpha inhibitor, but it is likely to be effective
Less than 10% of the population in PREVENT had previously had treatment with a TNF-alpha inhibitor before being randomised to the trial. The committee noted that, as a result, there is limited evidence about how effective secukinumab is when used after a TNF-alpha inhibitor has failed. The ERG acknowledged that the relative effect estimates of secukinumab compared with placebo were similar for people who had a TNF-alpha inhibitor before and those who had not. However, it noted that PREVENT was not powered to detect differences between these subgroups. The committee concluded that there are limited data from PREVENT to measure the clinical effectiveness of secukinumab when used after a TNF-alpha inhibitor. It further concluded that secukinumab was likely to be clinically effective compared with placebo in this situation.
## People in PREVENT may have more functional impairment than people in similar trials, or those who would have secukinumab in the NHS
The ERG noted that the mean baseline BASFI score (around 6) in the PREVENT trial population is higher than in other clinical trials in this disease area, and possibly higher than would be expected in clinical practice. This suggested a high functional impairment in the trial population. The company considered that, because BASFI scores are a predictor of response, treatment effect estimates for secukinumab from PREVENT can be considered conservative. This is because people with higher baseline BASFI scores (more functional impairment) may be less likely to have a good response to treatment than people with less functional impairment at baseline. The committee concluded that a higher baseline BASFI score in the trial population may affect the comparison with TNF-alpha inhibitors and the generalisability of trial results to NHS clinical practice.
## No data were presented for people for whom TNF-alpha inhibitors are unsuitable, where the alternative would be conventional care
The committee noted that there will be people for whom TNF-alpha inhibitors are unsuitable for a variety of reasons, either first line or second line. According to the clinical experts, this was the group most likely to be offered secukinumab in clinical practice. The committee considered that for these people the alternative is conventional care (NSAIDs and physical therapies) without treatment with biologics. The committee noted that no data had been presented specifically for this subgroup.
# The company's network meta-analysis
## The company's network meta-analysis cannot exclude the possibility that secukinumab may be less effective than TNF-alpha inhibitors
There were no trials directly comparing secukinumab with TNF-alpha inhibitors. Therefore, the company did a network meta-analysis to estimate the relative effectiveness of secukinumab compared with the relevant TNF-alpha inhibitors (etanercept, adalimumab, golimumab and certolizumab pegol). The company's base‑case analysis was based on the joint modelling approach used in NICE's technology appraisal guidance on TNF-alpha inhibitors. It compared secukinumab with each individual TNF‑alpha inhibitor, and with TNF-alpha inhibitors as a drug class. The committee recalled that NICE's technology appraisal guidance on TNF-alpha inhibitors concluded that, because of the lack of difference in treatment effect, TNF-alpha inhibitors should be considered as a class with broadly similar, if not identical, effects. The committee agreed that it was appropriate to consider the comparison with TNF-alpha inhibitors as a class. Numerical results from the network meta-analyses are confidential and cannot be reported here, but point estimates for secukinumab were lower for some outcomes compared with TNF-alpha inhibitors as a class. The committee noted that credible intervals around these estimates were wide and there were no statistically significant differences. Several sources of heterogeneity across the trials, such as differences in placebo response rates and baseline characteristics, were identified. These may have affected the results of the network meta-analyses, but because of a lack of data it was not possible to test whether the results were biased against secukinumab. The ERG considered that the company's network meta-analysis was appropriate but noted that because there were only a few trials included, it was not possible to check for consistency in the network or estimate heterogeneity between the studies. The company stated that the clinical efficacy of secukinumab is not expected to differ substantially from TNF‑alpha inhibitors, which the clinical expert supported. The committee acknowledged that this was in line with the committee conclusion in NICE's technology appraisal guidance on secukinumab for active ankylosing spondylitis. The committee concluded that the results of the company's network meta-analysis were uncertain and it could not exclude the possibility that secukinumab may be less effective than TNF-alpha inhibitors.
# The company's economic model
## The model structure is appropriate for decision making
The company modelled costs and quality-adjusted life years (QALYs) for secukinumab, TNF-alpha inhibitors (individually and as a class) and conventional care (NSAIDs and physical therapies) using a short-term decision tree followed by a long-term Markov model. The decision tree covered the induction period until response to treatment was assessed at 12 weeks for TNF-alpha inhibitors or at 16 weeks for secukinumab. People with disease response during the induction period continued with the same biologic therapy and entered the 3 state Markov model in the 'biologic treatment' health state. People whose disease did not respond stopped initial treatment and started in the 'conventional care' health state. The model structure and most model parameters (excluding treatment effectiveness parameters) were the same as in NICE's technology appraisal guidance on TNF-alpha inhibitors. The ERG considered the model structure to be appropriate. However, it noted that the primary analysis modelled by the company only included the population in PREVENT who had not had TNF-alpha inhibitors before, so related only to first-line use of secukinumab. The company also presented a secondary analysis, which included the small subgroup of people in PREVENT who had treatment with 1 TNF-alpha inhibitor before. No base-case analysis for the subgroup who cannot have TNF-alpha inhibitors was presented by the company. The response criterion used in the company model was the proportion of people with a BASDAI 50 response. Changes in BASDAI and BASFI after starting treatment were informed by results from the company's network meta-analysis. The committee concluded that the structure of the company's model was appropriate for decision making.
## Adalimumab biosimilar costs best represent the costs for first-line use of TNF-alpha inhibitors as a class
The committee recalled that it considered the TNF-alpha inhibitors as a class because they have broadly similar clinical effectiveness (see section 3.8). However, it noted that TNF-alpha inhibitors have very different costs. The company and ERG used different assumptions to estimate the cost of TNF-alpha inhibitors. The company used confidential market share information to estimate an average cost of TNF-alpha inhibitors. The ERG considered that the company's market share information was not representative of the expected current first-line use of TNF-alpha inhibitors in clinical practice. It explained that the cheapest TNF-alpha inhibitor was the adalimumab biosimilar. This became available in late 2018 and its use in the NHS is expected to keep increasing. The clinical expert agreed that the adalimumab biosimilar is the cheapest and most widely used TNF-alpha inhibitor in the NHS and should be considered the relevant comparator for first-line use of secukinumab. The company agreed that the adalimumab biosimilar is the most widely used TNF-alpha inhibitor in clinical practice for treating non-radiographic axial spondyloarthritis. However, it considered it inappropriate to use the cost of the adalimumab biosimilar to represent the costs for TNF-alpha inhibitors as a class, because some people do not have adalimumab first line. At the appraisal consultation stage a consultee commented that NHS England expected an uptake of less than 100% for the adalimumab biosimilar for first-line and second-line use across all of its indications. The committee noted that NICE's technology appraisal guidance on TNF-alpha inhibitors states that when more than 1 TNF-alpha inhibitor is suitable, the least expensive should be used. It agreed that this guidance is being implemented, and the lower cost of adalimumab biosimilar means that it is now the first choice TNF-alpha inhibitor for treating non-radiographic axial spondyloarthritis. It heard that if another TNF-alpha inhibitor were used (usually after failure of the first TNF-alpha inhibitor), another biosimilar, etanercept, would be second choice. The committee concluded that in clinical practice, people having a TNF-alpha inhibitor for non-radiographic axial spondyloarthritis are most likely to start taking adalimumab biosimilar. The more expensive branded agents would only be used first line if there was a specific reason relating to an individual's circumstances. It further concluded that, given NICE guidance on using the cheapest drug and expert information about the current use of TNF-alpha inhibitors in clinical practice, adalimumab biosimilar costs were representative of the costs of first-line use of TNF-alpha inhibitors as a class.
## The use of common or conditional baselines in the economic model is an area of uncertainty
The company's base-case model assumed that baseline BASDAI and BASFI scores are conditional on response. This meant that people modelled to have a BASDAI 50 response had different baseline BASDAI and BASFI scores than those modelled to not have a response. This was based on observations from clinical trials of secukinumab (PREVENT) and adalimumab (ABILITY-1), which showed that people who had a BASDAI 50 response had lower baseline BASFI and BASDAI scores than people whose disease did not respond. However, the committee recalled the preference in NICE's technology appraisal guidance on TNF-alpha inhibitors for common baselines. This was because there was no evidence showing that people with more severe disease were less likely to have a clinically meaningful benefit with TNF-alpha inhibitors than people with less severe disease. The ERG commented that, when using the measures of disease response used to decide whether to continue treatment in UK clinical practice (see section 3.2), differences in baseline BASDAI score between people with disease response and those without may be less likely. The committee concluded that the use of common or conditional baselines in the economic model was an area of substantial uncertainty.
## Modelling a further line of treatment after secukinumab or a TNF-alpha inhibitor reflects the treatment pathway, but relies on common baselines
The company's base-case model did not consider further treatment with a biologic after first-line treatment with secukinumab or a TNF-alpha inhibitor. After treatment with secukinumab or a TNF-alpha inhibitor, the company initially assumed that people would have conventional care. The committee noted that this did not reflect clinical practice because people may go on to have another biologic treatment. The company did a scenario analysis in which it developed a sequence model. This compared secukinumab followed by a TNF-alpha inhibitor with a TNF-alpha inhibitor followed by a second TNF-alpha inhibitor. The ERG noted that there were errors in how the company had modelled underlying disease activity and that it was inappropriate to use conditional baselines in a sequence model. Therefore, the ERG modelled a sequence of treatments using common baselines. This assumed that if secukinumab is used first line, then adalimumab biosimilar would be the next treatment. This sequence was compared with adalimumab followed by biosimilar etanercept (the second cheapest TNF-alpha inhibitor after adalimumab). The committee concluded that a sequence model better reflects the treatment pathway. However, it noted that this relied on using common baselines, which was not favoured by the company or the ERG and is an area of uncertainty.
## Results for the second-line use of both secukinumab and TNF-alpha inhibitors are uncertain because of limited evidence
The ERG highlighted that TNF-alpha inhibitors are relevant comparators for second-line secukinumab. It acknowledged that there is limited randomised data available to inform cost-effectiveness estimates. The committee noted that the baseline characteristics of people starting second-line treatment in the economic model were based on the subgroup of people who had a TNF-alpha inhibitor before in PREVENT. The ERG considered that estimates from the DANBIO registry, a registry of biologics in Denmark, were more reliable than results from this small subgroup. The company argued that the randomised data available provided more robust evidence than the DANBIO registry, which did not have a control arm. The committee concluded that because of the limited evidence available, results for second-line use of both secukinumab and TNF-alpha inhibitors are uncertain.
# Cost-effectiveness results
## Secukinumab is more costly and less effective than TNF-alpha inhibitors
The committee noted that there is a confidential patient access scheme (PAS) for secukinumab. Some of the TNF-alpha inhibitors are available to the NHS at a confidential discount and the exact incremental costs and QALYs cannot be reported here. The committee noted that:
Secukinumab was less costly and less effective than TNF-alpha inhibitors in the:
company base case, which compared secukinumab with TNF-alpha inhibitors as a class (with modelling errors corrected by the ERG). This analysis used market share estimates of TNF-alpha inhibitors to estimate an average of TNF-alpha inhibitor costs (see section 3.10)
ERG's exploratory base case for secukinumab as a second-line treatment. This analysis used the cost of etanercept biosimilar for the second-line TNF-alpha inhibitor (see section 3.13).
Secukinumab was more costly and less effective in the:
company base case, which compared secukinumab with TNF-alpha inhibitors as a class (without modelling errors corrected by the ERG; see section 3.10)
ERG exploratory base case, which compared secukinumab with TNF-alpha inhibitors as a class and used the costs of adalimumab biosimilar for the TNF-alpha inhibitor costs (see section 3.10)
ERG sequence model with common baselines. This used the costs of adalimumab biosimilar for the first TNF-alpha inhibitor, and used the costs of etanercept biosimilar for the second TNF-alpha inhibitor. Adalimumab biosimilar was assumed to be the next treatment after secukinumab (see section 3.12).The committee concluded that secukinumab had fewer QALYs in all the company and ERG's analyses. The committee noted that in analyses where the cost of biosimilar adalimumab is assumed for all TNF-alpha inhibitors, the costs of secukinumab were also higher than TNF-alpha inhibitors. For the full population covered by the marketing authorisation, the committee did not consider secukinumab to be cost effective compared with TNF-alpha inhibitors for treating non-radiographic axial spondyloarthritis.
## Secukinumab is cost effective for people who would otherwise have conventional care
Compared with conventional care, secukinumab gave incremental cost-effectiveness ratios (ICERs) of:
£5,413 per QALY gained in the company base case (with modelling errors corrected by the ERG)
£8,399 per QALY gained in the ERG exploratory base case
£7,727 per QALY gained using the ERG exploratory base-case assumptions but assuming common baselines
£19,421 per QALY gained in the ERG exploratory base case for second-line treatments.The committee noted that these estimates were for the whole population, not just people for whom TNF-alpha inhibitors were contraindicated or unsuitable. There were no data to determine if these results would be different in the subgroup of people who cannot have TNF-alpha inhibitors or whose condition had not responded to a TNF-alpha inhibitor. However, given the ICERs were lower than £20,000 compared with conventional care in the whole population, it was reasonable to consider secukinumab a cost-effective use of NHS resources for people who would otherwise have conventional care.
# Conclusion
## Secukinumab is likely to be cost effective only if TNF-alpha inhibitors do not work or are not suitable, so it is recommended in these situations
The committee considered the whole population who can have TNF-alpha inhibitors and noted that, considering the PAS price for secukinumab and the discounted NHS Commercial Medicines Unit prices for adalimumab biosimilar and etanercept biosimilar, secukinumab was not cost effective. It recalled that secukinumab gave fewer QALYs than biosimilar TNF-alpha inhibitors. It also noted that the costs for secukinumab were higher than biosimilar TNF-alpha inhibitors, which are used first line when 1 or more inhibitors are suitable, because of their lower cost. The committee considered the population who cannot have TNF-alpha inhibitors (for whom conventional care would be the appropriate comparator) and noted that the ICERs for secukinumab compared with conventional care were less than £20,000 per QALY gained. It was only presented with cost-effectiveness estimates for secukinumab compared with conventional care for people who could have a TNF-alpha inhibitor, but considered that secukinumab was likely to be a cost-effective use of NHS resources for people who cannot have TNF-alpha inhibitors. It would also provide an alternative biologic therapy to address the currently unmet need in this population. The committee concluded that secukinumab was recommended for people with non-radiographic axial spondyloarthritis when TNF-alpha inhibitors are not suitable or do not control the condition well enough.
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{'Recommendations': 'Secukinumab is recommended as an option for treating active non-radiographic axial spondyloarthritis with objective signs of inflammation (shown by elevated C-reactive protein or MRI) that is not controlled well enough with non-steroidal anti-inflammatory drugs (NSAIDs) in adults. It is recommended only if:\n\ntumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough and\n\nthe company provides secukinumab according to the commercial arrangement.\n\nAssess response to secukinumab after 16\xa0weeks of treatment. Continue treatment only if there is clear evidence of response, defined as:\n\na reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) by 2\xa0cm or more.\n\nTake into account any communication difficulties, or physical, psychological, sensory or learning disabilities that could affect responses to the BASDAI and spinal pain VAS questionnaires, and make any appropriate adjustments.\n\nThese recommendations are not intended to affect treatment with secukinumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for non-radiographic axial spondyloarthritis that is not controlled well enough with NSAIDs is limited to TNF-alpha inhibitors (adalimumab, certolizumab pegol, etanercept and golimumab). There are no treatment options when people cannot have TNF-alpha inhibitors, or if TNF-alpha inhibitors have not worked well enough.\n\nClinical trial evidence shows that secukinumab is effective compared with placebo. There are no trials directly comparing secukinumab with TNF-alpha inhibitors. But an indirect comparison suggests that secukinumab may be less effective than TNF‑alpha inhibitors. However, this evidence is uncertain.\n\nDifferent TNF-alpha inhibitors have different costs but similar effectiveness. When more than one TNF-alpha inhibitor is suitable, the cheapest is used, currently adalimumab biosimilar. Because of this, secukinumab is not a cost-effective use of NHS resources when compared with TNF-alpha inhibitors. Secukinumab is only considered to be cost effective for people who cannot have TNF-alpha inhibitors, or when TNF-alpha inhibitors have not worked well enough. Therefore, it is recommended in these situations.', 'Information about secukinumab': "# Marketing authorisation indication\n\nSecukinumab (Cosentyx, Novartis) is 'indicated for the treatment of active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) in adults who have responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is in the summary of product characteristics.\n\n# Price\n\nThe list price is £1,218.78 for 2 pre-filled pens or syringes containing 150\xa0mg per 1\xa0ml solution (excluding VAT, BNF online accessed March 2021). Annual cost of treatment for the first year is £9,750.24 and subsequent years is £7,312.68. The company has a commercial arrangement. This makes secukinumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nIn the PREVENT trial, the response criteria used to determine continuing treatment beyond 12\xa0weeks are different from the response criteria used in the NHS, but it is appropriate to use data from this trial in the model.\n\nAlthough PREVENT assessed secukinumab with and without a loading dose, the load-dose regimen is the regimen licensed for use in the UK. Therefore, the results from the load-dose arm of PREVENT are generalisable to how secukinumab would be used in NHS clinical practice.\n\nTrial evidence suggests that there may be differences in efficacy in certain subgroups of the trial population. However, because PREVENT was not powered to detect differences between subgroups based on MRI or C-reactive protein status, it is not possible to conclude that there is genuine heterogeneity in treatment effect. Therefore, the cost-effectiveness results in these subgroups are not relevant for decision making.\n\nThere were remaining areas of uncertainty associated with the analyses presented, which were considered further by the committee. The appraisal committee discussed the following issues (issues 1, 2, 6, 7, 8 and 9 from the technical report), which were outstanding after the technical engagement stage.\n\n# Clinical need and current management\n\n## Non-radiographic axial spondyloarthritis causes pain, reduced mobility and affects quality of life\n\nAxial spondyloarthritis is a chronic rheumatic condition characterised by inflammation at the sacroiliac joints and spine, although other joints can be affected. It can be associated with other conditions affecting the eyes, bowel and skin. Axial spondyloarthritis is an umbrella term encompassing both non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis (also known as ankylosing spondylitis). Non-radiographic means that a person has symptoms but the condition cannot be identified on an X-ray. It is a painful and debilitating condition and is considered incurable with current treatments. The clinical experts explained that although the disease burden is variable, progressive spinal pain, immobility and disability experienced by people with non-radiographic axial spondyloarthritis substantially affects their quality of life and mental wellbeing. The clinical experts noted that there can be a delay in diagnosis because of non-specific symptoms, an absence of visible structural damage on X-rays, and normal or ambiguous MRI results. They noted that the condition can be mistaken for other conditions such as fibromyalgia. This delay in diagnosis can result in high functional impairment (difficulties doing day-to-day activities). Almost half of people with non-radiographic axial spondyloarthritis progress to the radiographic version of the disease over a period of 8 to 10\xa0years. People with axial spondyloarthritis report that it profoundly affects their quality of life and day-to-day activities, such as work.\n\n## People would welcome a new treatment option that works differently to TNF-alpha inhibitors\n\nNICE's guideline on spondyloarthritis in over 16s recommends that the first treatment for people with non-radiographic axial spondyloarthritis is physical therapy and first-line pharmacological treatment with non-steroidal anti-inflammatory drugs (NSAIDs). For disease that responds inadequately to NSAIDs, or if these are not tolerated, NICE recommends tumour necrosis factor (TNF)-alpha inhibitors (see NICE's technology appraisal guidance on TNF-alpha inhibitors and golimumab) as options for treating severe non-radiographic axial spondyloarthritis. If the first TNF-alpha inhibitor is not tolerated, or the person's condition has not responded or stops responding, NICE's technology appraisal guidance on TNF-alpha inhibitors recommends treatment with another TNF-alpha inhibitor. The committee recalled that in previous technology appraisals for axial spondyloarthritis, clinical experts stated that the response criteria used in clinical practice for deciding to continue treatment were:\n\na reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2\xa0or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) by 2\xa0cm or more.The clinical expert explained that secukinumab is an additional treatment option when TNF-alpha inhibitors are not suitable, or when the disease has not responded or stopped responding to TNF-alpha inhibitors. The clinical expert explained that if a person's disease responded to a first TNF-alpha inhibitor, it would likely respond to another TNF-alpha inhibitor. However, they noted that for disease that has had an inadequate response to TNF-alpha inhibitors, it is preferable to try a new treatment option with an alternative mechanism of action. The clinical expert also noted that some people with non-radiographic axial spondyloarthritis also have psoriasis and explained that secukinumab is more effective than TNF-alpha inhibitors for treating psoriasis. The committee concluded that people with non-radiographic axial spondyloarthritis would welcome a new treatment option with a different mechanism of action.\n\n## Secukinumab can be used first line or second line after NSAIDs, but TNF-alpha inhibitors would likely be used first, unless unsuitable\n\nThe company noted that the marketing authorisation for secukinumab does not limit its use to a particular line of treatment. The ERG considered it unlikely that secukinumab would be the first-line biologic of choice, given the extensive clinical experience with TNF-alpha inhibitors and the lower price of biosimilar versions now available. It noted that secukinumab was more likely to be used as a second-line treatment after TNF-alpha inhibitors. The clinical experts explained that in line with NICE guidance, when more than 1 treatment is suitable, clinicians generally consider the least expensive treatment (taking into account administration costs and patient access schemes). Currently, the adalimumab biosimilar is usually the first-line biologic used when the disease has not responded to NSAIDs. The second choice is usually etanercept biosimilar when the adalimumab biosimilar is unsuitable or has failed. The committee concluded that secukinumab is licensed as a first-line or second-line treatment option after NSAIDs have not worked well enough. However, clinicians are more likely to choose a TNF-alpha inhibitor as the first biologic treatment unless these are contraindicated or unsuitable.\n\n# Clinical evidence\n\n## Secukinumab increases the proportion of people having an ASAS 40 response compared with placebo when used as first-line treatment\n\nPREVENT is a multicentre double-blind randomised placebo-controlled trial comparing 150\xa0mg secukinumab with a loading dose (an initial higher dose of a drug given at the beginning of a course of treatment; n=185) with placebo (n=186). It included adults with axial spondyloarthritis who fulfilled the Assessment of Spondylarthritis International Society (ASAS) classification criteria for axial spondyloarthritis, with abnormal C-reactive protein or MRI, and no radiographic evidence of changes in the sacroiliac joints. As such, the disease also fulfilled the modified New York criteria for non-radiographic axial spondyloarthritis. The primary outcome measure is the proportion of patients who have not had a TNF-alpha inhibitor before who had an ASAS\xa040 response (improvement of at least 40% in the ASAS, improvement in at least 2 units in 3 of the 4 main domains of ASAS and no worsening in the remaining domains) at week\xa016. Secukinumab increased the proportion of people who had an ASAS\xa040 response compared with placebo (odds ratio 1.72, p<0.0197; 95% confidence intervals are confidential and cannot be reported here). The proportion of patients whose BASDAI score improved by 50% from baseline (BASDAI\xa050), and the change in Bath Ankylosing Spondylitis Functional Index (BASFI) score from baseline, were collected as secondary endpoints. Secukinumab improved these outcomes compared with placebo. The committee concluded that, compared with placebo, secukinumab increases the proportion of people having an ASAS 40 response, BASDAI\xa050 response and improved function as assessed by BASFI.\n\n## There are limited clinical-effectiveness data for secukinumab used after a TNF-alpha inhibitor, but it is likely to be effective\n\nLess than 10% of the population in PREVENT had previously had treatment with a TNF-alpha inhibitor before being randomised to the trial. The committee noted that, as a result, there is limited evidence about how effective secukinumab is when used after a TNF-alpha inhibitor has failed. The ERG acknowledged that the relative effect estimates of secukinumab compared with placebo were similar for people who had a TNF-alpha inhibitor before and those who had not. However, it noted that PREVENT was not powered to detect differences between these subgroups. The committee concluded that there are limited data from PREVENT to measure the clinical effectiveness of secukinumab when used after a TNF-alpha inhibitor. It further concluded that secukinumab was likely to be clinically effective compared with placebo in this situation.\n\n## People in PREVENT may have more functional impairment than people in similar trials, or those who would have secukinumab in the NHS\n\nThe ERG noted that the mean baseline BASFI score (around 6) in the PREVENT trial population is higher than in other clinical trials in this disease area, and possibly higher than would be expected in clinical practice. This suggested a high functional impairment in the trial population. The company considered that, because BASFI scores are a predictor of response, treatment effect estimates for secukinumab from PREVENT can be considered conservative. This is because people with higher baseline BASFI scores (more functional impairment) may be less likely to have a good response to treatment than people with less functional impairment at baseline. The committee concluded that a higher baseline BASFI score in the trial population may affect the comparison with TNF-alpha inhibitors and the generalisability of trial results to NHS clinical practice.\n\n## No data were presented for people for whom TNF-alpha inhibitors are unsuitable, where the alternative would be conventional care\n\nThe committee noted that there will be people for whom TNF-alpha inhibitors are unsuitable for a variety of reasons, either first line or second line. According to the clinical experts, this was the group most likely to be offered secukinumab in clinical practice. The committee considered that for these people the alternative is conventional care (NSAIDs and physical therapies) without treatment with biologics. The committee noted that no data had been presented specifically for this subgroup.\n\n# The company's network meta-analysis\n\n## The company's network meta-analysis cannot exclude the possibility that secukinumab may be less effective than TNF-alpha inhibitors\n\nThere were no trials directly comparing secukinumab with TNF-alpha inhibitors. Therefore, the company did a network meta-analysis to estimate the relative effectiveness of secukinumab compared with the relevant TNF-alpha inhibitors (etanercept, adalimumab, golimumab and certolizumab pegol). The company's base‑case analysis was based on the joint modelling approach used in NICE's technology appraisal guidance on TNF-alpha inhibitors. It compared secukinumab with each individual TNF‑alpha inhibitor, and with TNF-alpha inhibitors as a drug class. The committee recalled that NICE's technology appraisal guidance on TNF-alpha inhibitors concluded that, because of the lack of difference in treatment effect, TNF-alpha inhibitors should be considered as a class with broadly similar, if not identical, effects. The committee agreed that it was appropriate to consider the comparison with TNF-alpha inhibitors as a class. Numerical results from the network meta-analyses are confidential and cannot be reported here, but point estimates for secukinumab were lower for some outcomes compared with TNF-alpha inhibitors as a class. The committee noted that credible intervals around these estimates were wide and there were no statistically significant differences. Several sources of heterogeneity across the trials, such as differences in placebo response rates and baseline characteristics, were identified. These may have affected the results of the network meta-analyses, but because of a lack of data it was not possible to test whether the results were biased against secukinumab. The ERG considered that the company's network meta-analysis was appropriate but noted that because there were only a few trials included, it was not possible to check for consistency in the network or estimate heterogeneity between the studies. The company stated that the clinical efficacy of secukinumab is not expected to differ substantially from TNF‑alpha inhibitors, which the clinical expert supported. The committee acknowledged that this was in line with the committee conclusion in NICE's technology appraisal guidance on secukinumab for active ankylosing spondylitis. The committee concluded that the results of the company's network meta-analysis were uncertain and it could not exclude the possibility that secukinumab may be less effective than TNF-alpha inhibitors.\n\n# The company's economic model\n\n## The model structure is appropriate for decision making\n\nThe company modelled costs and quality-adjusted life years (QALYs) for secukinumab, TNF-alpha inhibitors (individually and as a class) and conventional care (NSAIDs and physical therapies) using a short-term decision tree followed by a long-term Markov model. The decision tree covered the induction period until response to treatment was assessed at 12\xa0weeks for TNF-alpha inhibitors or at 16\xa0weeks for secukinumab. People with disease response during the induction period continued with the same biologic therapy and entered the 3 state Markov model in the 'biologic treatment' health state. People whose disease did not respond stopped initial treatment and started in the 'conventional care' health state. The model structure and most model parameters (excluding treatment effectiveness parameters) were the same as in NICE's technology appraisal guidance on TNF-alpha inhibitors. The ERG considered the model structure to be appropriate. However, it noted that the primary analysis modelled by the company only included the population in PREVENT who had not had TNF-alpha inhibitors before, so related only to first-line use of secukinumab. The company also presented a secondary analysis, which included the small subgroup of people in PREVENT who had treatment with 1 TNF-alpha inhibitor before. No base-case analysis for the subgroup who cannot have TNF-alpha inhibitors was presented by the company. The response criterion used in the company model was the proportion of people with a BASDAI\xa050 response. Changes in BASDAI and BASFI after starting treatment were informed by results from the company's network meta-analysis. The committee concluded that the structure of the company's model was appropriate for decision making.\n\n## Adalimumab biosimilar costs best represent the costs for first-line use of TNF-alpha inhibitors as a class\n\nThe committee recalled that it considered the TNF-alpha inhibitors as a class because they have broadly similar clinical effectiveness (see section 3.8). However, it noted that TNF-alpha inhibitors have very different costs. The company and ERG used different assumptions to estimate the cost of TNF-alpha inhibitors. The company used confidential market share information to estimate an average cost of TNF-alpha inhibitors. The ERG considered that the company's market share information was not representative of the expected current first-line use of TNF-alpha inhibitors in clinical practice. It explained that the cheapest TNF-alpha inhibitor was the adalimumab biosimilar. This became available in late 2018 and its use in the NHS is expected to keep increasing. The clinical expert agreed that the adalimumab biosimilar is the cheapest and most widely used TNF-alpha inhibitor in the NHS and should be considered the relevant comparator for first-line use of secukinumab. The company agreed that the adalimumab biosimilar is the most widely used TNF-alpha inhibitor in clinical practice for treating non-radiographic axial spondyloarthritis. However, it considered it inappropriate to use the cost of the adalimumab biosimilar to represent the costs for TNF-alpha inhibitors as a class, because some people do not have adalimumab first line. At the appraisal consultation stage a consultee commented that NHS England expected an uptake of less than 100% for the adalimumab biosimilar for first-line and second-line use across all of its indications. The committee noted that NICE's technology appraisal guidance on TNF-alpha inhibitors states that when more than 1 TNF-alpha inhibitor is suitable, the least expensive should be used. It agreed that this guidance is being implemented, and the lower cost of adalimumab biosimilar means that it is now the first choice TNF-alpha inhibitor for treating non-radiographic axial spondyloarthritis. It heard that if another TNF-alpha inhibitor were used (usually after failure of the first TNF-alpha inhibitor), another biosimilar, etanercept, would be second choice. The committee concluded that in clinical practice, people having a TNF-alpha inhibitor for non-radiographic axial spondyloarthritis are most likely to start taking adalimumab biosimilar. The more expensive branded agents would only be used first line if there was a specific reason relating to an individual's circumstances. It further concluded that, given NICE guidance on using the cheapest drug and expert information about the current use of TNF-alpha inhibitors in clinical practice, adalimumab biosimilar costs were representative of the costs of first-line use of TNF-alpha inhibitors as a class.\n\n## The use of common or conditional baselines in the economic model is an area of uncertainty\n\nThe company's base-case model assumed that baseline BASDAI and BASFI scores are conditional on response. This meant that people modelled to have a BASDAI\xa050 response had different baseline BASDAI and BASFI scores than those modelled to not have a response. This was based on observations from clinical trials of secukinumab (PREVENT) and adalimumab (ABILITY-1), which showed that people who had a BASDAI\xa050 response had lower baseline BASFI and BASDAI scores than people whose disease did not respond. However, the committee recalled the preference in NICE's technology appraisal guidance on TNF-alpha inhibitors for common baselines. This was because there was no evidence showing that people with more severe disease were less likely to have a clinically meaningful benefit with TNF-alpha inhibitors than people with less severe disease. The ERG commented that, when using the measures of disease response used to decide whether to continue treatment in UK clinical practice (see section 3.2), differences in baseline BASDAI score between people with disease response and those without may be less likely. The committee concluded that the use of common or conditional baselines in the economic model was an area of substantial uncertainty.\n\n## Modelling a further line of treatment after secukinumab or a TNF-alpha inhibitor reflects the treatment pathway, but relies on common baselines\n\nThe company's base-case model did not consider further treatment with a biologic after first-line treatment with secukinumab or a TNF-alpha inhibitor. After treatment with secukinumab or a TNF-alpha inhibitor, the company initially assumed that people would have conventional care. The committee noted that this did not reflect clinical practice because people may go on to have another biologic treatment. The company did a scenario analysis in which it developed a sequence model. This compared secukinumab followed by a TNF-alpha inhibitor with a TNF-alpha inhibitor followed by a second TNF-alpha inhibitor. The ERG noted that there were errors in how the company had modelled underlying disease activity and that it was inappropriate to use conditional baselines in a sequence model. Therefore, the ERG modelled a sequence of treatments using common baselines. This assumed that if secukinumab is used first line, then adalimumab biosimilar would be the next treatment. This sequence was compared with adalimumab followed by biosimilar etanercept (the second cheapest TNF-alpha inhibitor after adalimumab). The committee concluded that a sequence model better reflects the treatment pathway. However, it noted that this relied on using common baselines, which was not favoured by the company or the ERG and is an area of uncertainty.\n\n## Results for the second-line use of both secukinumab and TNF-alpha inhibitors are uncertain because of limited evidence\n\nThe ERG highlighted that TNF-alpha inhibitors are relevant comparators for second-line secukinumab. It acknowledged that there is limited randomised data available to inform cost-effectiveness estimates. The committee noted that the baseline characteristics of people starting second-line treatment in the economic model were based on the subgroup of people who had a TNF-alpha inhibitor before in PREVENT. The ERG considered that estimates from the DANBIO registry, a registry of biologics in Denmark, were more reliable than results from this small subgroup. The company argued that the randomised data available provided more robust evidence than the DANBIO registry, which did not have a control arm. The committee concluded that because of the limited evidence available, results for second-line use of both secukinumab and TNF-alpha inhibitors are uncertain.\n\n# Cost-effectiveness results\n\n## Secukinumab is more costly and less effective than TNF-alpha inhibitors\n\nThe committee noted that there is a confidential patient access scheme (PAS) for secukinumab. Some of the TNF-alpha inhibitors are available to the NHS at a confidential discount and the exact incremental costs and QALYs cannot be reported here. The committee noted that:\n\nSecukinumab was less costly and less effective than TNF-alpha inhibitors in the:\n\n\n\ncompany base case, which compared secukinumab with TNF-alpha inhibitors as a class (with modelling errors corrected by the ERG). This analysis used market share estimates of TNF-alpha inhibitors to estimate an average of TNF-alpha inhibitor costs (see section 3.10)\n\nERG's exploratory base case for secukinumab as a second-line treatment. This analysis used the cost of etanercept biosimilar for the second-line TNF-alpha inhibitor (see section 3.13).\n\n\n\nSecukinumab was more costly and less effective in the:\n\n\n\ncompany base case, which compared secukinumab with TNF-alpha inhibitors as a class (without modelling errors corrected by the ERG; see section 3.10)\n\nERG exploratory base case, which compared secukinumab with TNF-alpha inhibitors as a class and used the costs of adalimumab biosimilar for the TNF-alpha inhibitor costs (see section 3.10)\n\nERG sequence model with common baselines. This used the costs of adalimumab biosimilar for the first TNF-alpha inhibitor, and used the costs of etanercept biosimilar for the second TNF-alpha inhibitor. Adalimumab biosimilar was assumed to be the next treatment after secukinumab (see section 3.12).The committee concluded that secukinumab had fewer QALYs in all the company and ERG's analyses. The committee noted that in analyses where the cost of biosimilar adalimumab is assumed for all TNF-alpha inhibitors, the costs of secukinumab were also higher than TNF-alpha inhibitors. For the full population covered by the marketing authorisation, the committee did not consider secukinumab to be cost effective compared with TNF-alpha inhibitors for treating non-radiographic axial spondyloarthritis.\n\n\n\n## Secukinumab is cost effective for people who would otherwise have conventional care\n\nCompared with conventional care, secukinumab gave incremental cost-effectiveness ratios (ICERs) of:\n\n£5,413 per QALY gained in the company base case (with modelling errors corrected by the ERG)\n\n£8,399 per QALY gained in the ERG exploratory base case\n\n£7,727 per QALY gained using the ERG exploratory base-case assumptions but assuming common baselines\n\n£19,421 per QALY gained in the ERG exploratory base case for second-line treatments.The committee noted that these estimates were for the whole population, not just people for whom TNF-alpha inhibitors were contraindicated or unsuitable. There were no data to determine if these results would be different in the subgroup of people who cannot have TNF-alpha inhibitors or whose condition had not responded to a TNF-alpha inhibitor. However, given the ICERs were lower than £20,000 compared with conventional care in the whole population, it was reasonable to consider secukinumab a cost-effective use of NHS resources for people who would otherwise have conventional care.\n\n# Conclusion\n\n## Secukinumab is likely to be cost effective only if TNF-alpha inhibitors do not work or are not suitable, so it is recommended in these situations\n\nThe committee considered the whole population who can have TNF-alpha inhibitors and noted that, considering the PAS price for secukinumab and the discounted NHS Commercial Medicines Unit prices for adalimumab biosimilar and etanercept biosimilar, secukinumab was not cost effective. It recalled that secukinumab gave fewer QALYs than biosimilar TNF-alpha inhibitors. It also noted that the costs for secukinumab were higher than biosimilar TNF-alpha inhibitors, which are used first line when 1\xa0or more inhibitors are suitable, because of their lower cost. The committee considered the population who cannot have TNF-alpha inhibitors (for whom conventional care would be the appropriate comparator) and noted that the ICERs for secukinumab compared with conventional care were less than £20,000 per QALY gained. It was only presented with cost-effectiveness estimates for secukinumab compared with conventional care for people who could have a TNF-alpha inhibitor, but considered that secukinumab was likely to be a cost-effective use of NHS resources for people who cannot have TNF-alpha inhibitors. It would also provide an alternative biologic therapy to address the currently unmet need in this population. The committee concluded that secukinumab was recommended for people with non-radiographic axial spondyloarthritis when TNF-alpha inhibitors are not suitable or do not control the condition well enough."}
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https://www.nice.org.uk/guidance/ta719
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Evidence-based recommendations on secukinumab (Cosentyx) for treating non-radiographic axial spondyloarthritis in adults.
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37f9181648f5fb2787361c9143c133f612931c4b
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nice
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Adalimumab, etanercept, infliximab and abatacept for treating moderate rheumatoid arthritis after conventional DMARDs have failed
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Adalimumab, etanercept, infliximab and abatacept for treating moderate rheumatoid arthritis after conventional DMARDs have failed
Evidence-based recommendations on adalimumab, etanercept, infliximab and abatacept for adults with moderate rheumatoid arthritis who have tried conventional DMARDs but they have not worked.
# Recommendations
Adalimumab, etanercept and infliximab, all with methotrexate, are recommended as options for treating active rheumatoid arthritis in adults, only if:
intensive therapy with 2 or more conventional disease-modifying antirheumatic drugs (DMARDs) has not controlled the disease well enough and
disease is moderate (a disease activity score of 3.2 to 5.1) and
the companies provide adalimumab, etanercept and infliximab at the same or lower prices than those agreed with the Commercial Medicines Unit.
Adalimumab and etanercept can be used as monotherapy when methotrexate is contraindicated or not tolerated, when the criteria in 1.1 are met.
Continue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months after starting therapy. If this initial response is not maintained, stop treatment.
If more than one treatment is suitable, start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary because of differences in how the drugs are used and treatment schedules.
Take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any appropriate adjustments.
Abatacept with methotrexate is not recommended, within its marketing authorisation, for treating moderate active rheumatoid arthritis in adults when 1 or more DMARDs has not controlled the disease well enough.
Why the committee made these recommendations
This appraisal reviews some of the treatments (adalimumab, etanercept, infliximab and abatacept) recommended for severe rheumatoid arthritis in NICE technology appraisal guidance 375 and considers them for moderate rheumatoid arthritis. The clinical evidence suggests that these treatments are likely to be similarly effective in both moderate and severe disease.
The most likely estimates suggest that adalimumab, etanercept and infliximab after 2 or more conventional DMARDs are a cost-effective use of NHS resources. So, they are recommended for treating moderate rheumatoid arthritis. The most likely cost-effectiveness estimates for abatacept are higher than what NICE normally considers cost effective, so it is not recommended for moderate disease.# Information about adalimumab, etanercept, infliximab and abatacept
This technology appraisal includes 4 different biological medicines as either the originator medicine (the medicine first authorised for use) or a biosimilar product (see table 1). A biosimilar medicine is a medicine that is developed to be similar to an existing biological medicine.
Technology
Originator
(company)
Biosimilar (company)
Mechanism of action
Method of administration
Adalimumab
Humira (AbbVie)
Amgevita (Amgen)
Imraldi (Biogen)
Idacio (Fresenius Kabi)
Hyrimoz (Sandoz)
Tumour necrosis factor (TNF)‑alpha inhibitor
Subcutaneous injection
Etanercept
Enbrel (Pfizer)
Benepali (Biogen)
Erelzi (Sandoz)
TNF‑alpha inhibitor
Subcutaneous injection
Infliximab
Flixabi (Biogen)
Remsima (Celltrion Healthcare)
Inflectra (Pfizer)
Zessly (Sandoz)
TNF‑alpha inhibitor
Intravenous injection
Abatacept
Orencia (Bristol-Myers Squibb)
Selective modulator of the T‑lymphocyte activation pathway. Inhibits activation of T lymphocytes
Subcutaneous or intravenous injection
The subcutaneous formulation of Remsima was not considered in this partial review because it was not included in the final scope for NICE technology appraisal guidance 375. The originator product for infliximab (Remicade) was also not considered because the manufacturer of this technology did not participate in this appraisal
# Adalimumab
Adalimumab (Humira, AbbVie; Amgevita, Amgen; Imraldi, Biogen; Idacio, Fresenius Kabi; Hyrimoz, Sandoz), in combination with methotrexate, is indicated 'for the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs including methotrexate has been inadequate'. Adalimumab can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
The dosage schedule is available in the summary of product characteristics.
The list price of originator adalimumab (Humira, AbbVie) is £352.14 per 40 mg pre-filled pen or pre-filled syringe (excluding VAT; BNF online, accessed March 2021). The list price of adalimumab biosimilars per 40 mg pre-filled pen or pre-filled syringe are £316.80 (Amgevita, Amgen); £316.93 (Imraldi, Biogen); £316.93 (Idacio, Fresenius Kabi); £323.09 (Hyrimoz, Sandoz; all prices exclude VAT; BNF online, accessed March 2021).
The companies have each agreed a regional or nationally available price reduction for adalimumab with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.
# Etanercept
Etanercept (Enbrel, Pfizer; Benepali, Biogen; Erelzi, Sandoz) in combination with methotrexate, is indicated 'for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate'. Etanercept can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
The dosage schedule is available in the summary of product characteristics.
The list price of originator etanercept (Enbrel, Pfizer) is £89.38 per 25 mg pre-filled pen or pre-filled syringe (excluding VAT; BNF online, accessed March 2021). The list price of etanercept biosimilars per 25 mg pre-filled pen or pre-filled syringe are £82.00 (Benepali, Biogen); £80.44 (Erelzi, Sandoz; all prices exclude VAT; BNF online, accessed March 2021).
The companies have each agreed a nationally available price reduction for etanercept with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.
# Infliximab
Infliximab (Flixabi, Biogen; Remsima, Celltrion Healthcare; Inflectra, Pfizer; Zessly, Sandoz), in combination with methotrexate, is indicated 'for the reduction of signs and symptoms as well as the improvement in physical function in: adult patients with active disease when the response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate, has been inadequate'.
The dosage schedule is available in the summary of product characteristics.
The list price of infliximab biosimilars per 100 mg vial are £377.00 (Flixabi, Biogen); £377.66 (Remsima, Celltrion Healthcare); £377.66 (Inflectra, Pfizer); £377.66 (Zessly, Sandoz; all prices exclude VAT; BNF online, accessed March 2021).
The companies have each agreed a nationally available price reduction for infliximab with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.
# Abatacept
Abatacept (Orencia, Bristol-Myers Squibb), in combination with methotrexate, is indicated for 'the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who responded inadequately to previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) or a tumour necrosis factor (TNF)-alpha inhibitor'.
The dosage schedule is available in the summary of product characteristics.
The list price of abatacept (Orencia, Bristol-Myers Squibb) is £302.40 per 125 mg pre-filled pen or pre-filled syringe and £302.40 per 250 mg vial (excluding VAT; BNF online, accessed March 2021).
The company has a commercial arrangement. This makes abatacept available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.
This appraisal is a partial review of NICE technology appraisal guidance 375, which recommended adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept as treatment options for people with severe rheumatoid arthritis only, assessed by having a disease activity score (DAS28) more than 5.1. This partial review considers moderate disease, that is, with a DAS28 between 3.2 and 5.1. Although certolizumab pegol, golimumab and tocilizumab were included in the original guidance, the manufacturers of these technologies decided not to participate in this partial review. So, the committee could only consider adalimumab, etanercept, infliximab and abatacept when making recommendations for moderate disease.
A partial review has been done because biosimilar versions of adalimumab and etanercept are now available, and there have been changes in the prices for some of the other technologies. The committee assessed the cost effectiveness of the technologies using the original clinical evidence and economic model developed by the assessment group for NICE technology appraisal 375. The partial review has taken a pragmatic approach, which was consulted on in a review proposal, so the assessment group made only minor updates to the original model (see section 3.4 and section 3.5).
# New treatment options
## People with moderate rheumatoid arthritis would welcome new treatment options
The patient experts explained that people with moderate active rheumatoid arthritis have significant disability and reduced quality of life if their disease is not adequately controlled. This can affect a person's ability to work and do everyday activities. It also increases the need for continual NHS care. The patient experts described how this substantially affects emotional wellbeing, causing stress and anxiety, which can trigger further flare-ups of the disease. Although there are a range of advanced treatment options for severe rheumatoid arthritis, only filgotinib is recommended for treating moderate disease after failure of 2 or more conventional disease-modifying antirheumatic drugs (DMARDs; such as methotrexate, leflunomide, sulfasalazine and hydroxychloroquine; see NICE's technology appraisal guidance on filgotinib). The committee noted that when this partial update started, the appraisal of filgotinib had not concluded. Therefore, filgotinib was not included in the scope as a comparator. The patient experts explained that it is important that there is a wide range of treatment options available for rheumatoid arthritis. This is because the differing nature of the disease means that a treatment may work well for one person but not another. The clinical experts explained that although the medicines appraised are similarly beneficial for treating the articular features of rheumatoid arthritis, they differ in their effectiveness in preventing particular comorbidities. This means that it is important for people with rheumatoid arthritis to have a range of different medicines available, even within the same drug class. The clinical experts explained that earlier access to advanced treatments in moderate disease would reduce disease progression and increase the likelihood of remission. The committee concluded that people with moderate rheumatoid arthritis would welcome a range of advanced treatment options.
# Cycling of TNF-alpha inhibitors
## This appraisal only considers first-line biological treatments in moderate disease
A company representative explained that the moderate treatment sequences modelled by the assessment group did not consider cycling of tumour necrosis factor (TNF)-alpha inhibitors (taking another TNF-alpha inhibitor after a first one). This would happen if a person does not tolerate the first treatment, or if their disease either does not respond or responds inadequately after an initial response. The clinical experts explained that because the technologies are protein-based drugs, there is a risk of developing antidrug antibodies, which reduces the treatment benefit over time. They noted that around 50% of people will stop treatment within 3 years because of loss of efficacy. The clinical experts explained that the cycling of TNF-alpha inhibitors has a place in treating rheumatoid arthritis. They explained that, for this reason, having a variety of therapeutic choices for moderate disease would benefit people. The committee noted that the scope for the appraisal includes only first-line use of biological DMARDs (after a person's disease has responded inadequately to 2 or more conventional DMARDs) as in NICE technology appraisal guidance 375. It agreed that it was appropriate to assume that after the first biological treatment has failed, if the disease progresses to severe, NICE technology appraisal guidance for severe rheumatoid arthritis would be followed.
# Clinical evidence
## The clinical evidence used in NICE technology appraisal 375 is appropriate for this partial review
The clinical evidence used in this review is the same as that assessed in NICE technology appraisal guidance 375. So, the treatment efficacy of the interventions and comparators (adalimumab, etanercept, infliximab, abatacept all with methotrexate, and methotrexate alone) and subsequent treatments (rituximab and tocilizumab both with methotrexate) were informed by the results of the network meta-analysis done by the assessment group in NICE technology appraisal 375. The trials in the network meta-analysis included people with moderate and severe disease, so the efficacy of treatments was assumed to be the same in both populations. The committee considered the uncertainty around the midpoint estimates used when making its recommendations for treatments used in severe disease in NICE technology appraisal 375. The clinical experts explained that there is long-term clinical trial evidence and real-world evidence that strongly supports using biological DMARDs for treating moderate active disease. The committee concluded that the efficacy data accepted in the original guidance was appropriate to assess the cost effectiveness of adalimumab, etanercept, infliximab and abatacept for people with moderate active disease as part of this partial review.
# The assessment group's model
## The cost-effectiveness model used in NICE technology appraisal 375 is appropriate for this partial review
The assessment group developed an individual patient-based discrete event simulation model for its economic evaluation in NICE technology appraisal guidance 375. The scope for this appraisal included only the first-line use of biological DMARDs after an inadequate disease response to 2 or more conventional DMARDs. In the economic model, after the first biological treatment had failed, if disease progresses to severe, NICE technology appraisal guidance for severe rheumatoid arthritis was followed. For all analyses it was assumed that methotrexate was used in combination with the biological DMARD, and that the results for combination therapy could be generalised to biological DMARD monotherapy (if monotherapy use was included in the marketing authorisation). This assumption was also made in NICE technology appraisal 375. The model incorporated a response criterion based on European League Against Rheumatism (EULAR) response at 6 months to reflect UK clinical practice. If there was no EULAR response to a biological DMARD after 6 months then the next treatment in the strategy was used. Further details about the assessment group's original economic model can be found in the final guidance for NICE technology appraisal 375. The committee concluded that the cost-effectiveness model accepted in the original guidance was appropriate to use in this partial review, with some updates (see section 3.5).
## The changes to the assessment group's model are appropriate for decision making and reflect current NICE guidance
The assessment group's analyses included the assumptions preferred by the committee in NICE technology appraisal guidance 375. There were several updates to its original model:
Updating the prices of interventions and subsequent treatments to reflect any changes to the prices of technologies.
Amending the model so people with moderate disease who only have treatment with conventional DMARDs can have biological DMARDs after progression to severe disease (disease activity score more than 5.1). The committee understood that this treatment pathway was not an option in the original model but that it reflected current clinical practice. To include this change in the model, the assessment group estimated the relationship between changes in Health Assessment Questionnaire (HAQ) score, which was the measure used in the modelling, and changes in DAS28 score, which is the measure used to determine severity of disease. The assessment group did a systematic review to identify the best estimate of change in DAS28 score associated with a 0.125 change in HAQ score, which was considered to be 0.48. The assessment group also did sensitivity analyses using a lower estimate (the exact figure is confidential and cannot be reported here) and a higher estimate of 0.70.
After stakeholder consultation, 1 company commented that the moderate treatment sequence used in the assessment group's updated model did not align with current NICE guidance recommendations for treating rheumatoid arthritis, or with the sequences modelled in NICE's technology appraisal guidance on filgotinib. In response, the assessment group further updated the treatment sequences used in the model to reflect current NICE guidance. The model assumed that for the treatment arm, a person with moderate disease would initially have a biological DMARD (either adalimumab, etanercept, infliximab or abatacept) followed by conventional DMARDs. For the comparator arm, the model assumed that a person would have initial treatment with methotrexate followed by other conventional DMARDs. Once disease progressed to severe (DAS28 more than 5.1) they would then move through a series of subsequent treatments.
## The treatment sequences in the updated economic model are appropriate
The trials included in the network meta-analysis showed people's disease responded to methotrexate (a conventional DMARD) when it is used as the first treatment. Therefore, the assessment group included a response to methotrexate when used as a first treatment in the comparator arm of the model (for people with moderate disease who had had 2 conventional DMARDs) but did not include a response to methotrexate after a biological DMARD in the treatment arm of the model. The trials also showed a response with methotrexate following treatment with tocilizumab (in both treatment arms) and this efficacy was also included in the model in the treatment sequence for severe disease. The efficacy of conventional DMARDs when used later in the treatment pathway for moderate disease and at the end of the pathway in severe disease was assumed to be zero for both arms. In response to consultation, one consultee noted that in NICE technology appraisal guidance 375, in moderate disease, it was assumed that after biological treatments people would have methotrexate, which was associated with a response. A similar assumption was also made in NICE's technology appraisal guidance on baricitinib, tofacitinib and sarilumab. The committee noted that none of these appraisals had made positive recommendations for moderate disease. So, it did not consider that this point had been fully accepted by the committee in these appraisals. Also, it noted that it was debatable whether methotrexate would be used at this point in the treatment pathway or what size of response would be expected. However, because no new clinical evidence was being considered in this appraisal, it agreed there was no strong reason to deviate from the assumption put forward in NICE technology appraisal 375 and subsequent appraisals. The committee concluded that the assessment group's model was previously considered acceptable in NICE technology appraisal 375 and that the updates made to reflect current NICE guidance and consultation responses are appropriate for decision making (see table 2).
Treatment arm
Treatment
Comparator
First treatment for moderate disease
Biological DMARD
Methotrexate
Second treatment for moderate disease
Methotrexate
Conventional DMARDs
Third treatment for moderate disease
Conventional DMARDs
First treatment for severe disease
Adalimumab (infliximab if adalimumab is used in moderate disease)
Adalimumab
Second treatment for severe disease
Rituximab
Rituximab
Third treatment for severe disease
Tocilizumab
Tocilizumab
Abbreviations: DMARDs, disease-modifying antirheumatic drugs
# Cost-effectiveness estimates
## The most plausible ICERs for adalimumab, etanercept and infliximab are below £30,000 per QALY gained
NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee agreed that an acceptable ICER would be within the range NICE normally considers a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). Because of the confidential discounts for the treatments and some of the subsequent therapies, the exact ICERs are confidential and cannot be reported here. The assessment group's base-case analyses used the cheapest formulation of each intervention and prices included homecare support (when available). The assessment group's base-case ICERs for adalimumab and infliximab compared with conventional DMARDs were both substantially lower than £20,000 per QALY gained. The assessment group's base-case ICER for etanercept compared with conventional DMARDs was lower than £30,000 per QALY gained. For abatacept (intravenous and subcutaneous formulations) the ICER was substantially higher than £30,000 per QALY gained.
## The assessment group's sensitivity analyses do not change the cost-effectiveness conclusions
The assessment group did several sensitivity analyses including using lower (the exact figure is confidential and cannot be reported here) and higher values (0.70) for change in DAS28 score when HAQ score increases (see section 3.5). These had a small effect on the ICERs. Another sensitivity analysis was done to remove methotrexate after tocilizumab in the treatment sequences following progression to severe disease (in line with NICE's technology appraisal guidance on filgotinib), which also had little effect on the ICERs. The committee understood that there was some uncertainty about the efficacy estimates used in the model, which may have influenced the cost-effectiveness results. However, it agreed that these estimates were considered acceptable by the committee in NICE technology appraisal guidance 375. The committee discussed that there are multiple biosimilars for adalimumab, and the availability of these differs regionally in England, unlike etanercept and infliximab biosimilars, which are nationally available. The committee considered a further sensitivity analysis using the highest price that any region would need to pay for adalimumab. It was reassured that this did not change the cost-effectiveness conclusions for adalimumab.
## Adalimumab, etanercept and infliximab are cost-effective treatment options for moderate disease but abatacept is not recommended
The committee accepted the assessment group's updated base-case analyses. The assessment group's base-case ICERs for adalimumab and infliximab were both below the range NICE considers to be an acceptable use of NHS resources. Therefore, the committee recommended adalimumab and infliximab as first-line biological treatments for moderate active rheumatoid arthritis that has had an inadequate response to intensive therapy with 2 or more conventional DMARDs. Although the assessment group's ICER for etanercept was higher than those for adalimumab and infliximab, it was below £30,000 per QALY gained. In response to consultation, it was highlighted that there are some people for whom etanercept would be a particularly useful treatment option. For example, etanercept has a much lower risk of reactivating latent tuberculosis, which has a higher prevalence in people with a South Asian family background. In addition, compared with some of the other biologicals, etanercept does not need to be stopped as far in advance by people wishing to conceive. The committee recognised that these groups would likely only represent a small number of people with moderate rheumatoid arthritis. The committee noted that the recommendations state that if more than 1 biological is an appropriate treatment option, treatment should start with the least expensive. So it also recommended etanercept as an option. The assessment group's base-case ICER for abatacept was above the range NICE considers to be an acceptable use of NHS resources. The committee therefore did not recommend abatacept as a treatment option for moderate active rheumatoid arthritis.
## Adalimumab monotherapy and etanercept monotherapy are also recommended for people who cannot have methotrexate
The committee agreed that people with moderate rheumatoid arthritis who cannot tolerate methotrexate should not be disadvantaged compared with other people with moderate disease, as far as possible. The committee concluded that, based on the marketing authorisation and the cost-effectiveness estimates, adalimumab and etanercept could be recommended as monotherapy for moderate active disease previously treated with conventional DMARDs.
# Equality considerations
## Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure
A potential equality issue was raised in NICE's technology appraisal guidance on upadacitinib for treating severe rheumatoid arthritis, about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee agreed that this equality issue was also important to consider for this appraisal. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any appropriate adjustments.
## Etanercept may be particularly beneficial for some people with protected characteristics
Some of the people for whom etanercept may be particularly beneficial have protected characteristics. The committee took this into account in its decision making about etanercept (see section 3.9).
## No other equality issues have been identified that can be addressed in this technology appraisal
The patient experts explained that certolizumab pegol, another TNF-alpha inhibitor, is often used to treat rheumatoid arthritis in women who are planning to become pregnant or who are pregnant. They described how not having this as a treatment option for people with moderate disease could potentially discriminate against women of childbearing age. The clinical experts explained that certolizumab pegol does not easily cross the placenta so is usually the preferred treatment choice during pregnancy. However, they explained that other TNF-alpha inhibitors can be used in different stages of pregnancy but that there is a risk of active transport across the placenta, which often means that treatment is stopped. The committee concluded that this issue could not be addressed in this technology appraisal, because the company manufacturing certolizumab pegol decided not to participate in this partial review. So, the committee could not make recommendations on its use for moderate disease.
# Other factors
## Healthcare professionals should choose the most appropriate treatment after discussing the options with the person having treatment
The committee understood that having a range of treatment options is important in treating moderate rheumatoid arthritis. It understood that NICE recommended filgotinib for treating moderate to severe rheumatoid arthritis (see NICE's technology appraisal guidance on filgotinib) and noted NICE's ongoing technology appraisal on upadacitinib for previously treated moderate active rheumatoid arthritis. The committee concluded that healthcare professionals should choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If more than 1 treatment is suitable, they should start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary because of differences in how the drugs are used and treatment schedules.
## The benefits of the technologies were adequately captured in the cost-effectiveness analysis
The patient and clinical experts explained that biological DMARDs are highly effective in reducing disease progression and improving quality of life in people with rheumatoid arthritis. The committee noted that biological DMARDs were considered to be innovative in NICE technology appraisal guidance 375 for people with severe disease. It discussed that while filgotinib is the only advanced treatment option currently available for people with moderate disease, its mechanism of action is different to the biological DMARDs, of which none are currently available for people with moderate disease. The committee agreed that the technologies are important treatment options for these people. It concluded that all the benefits of the technologies were adequately captured in the model.
|
{'Recommendations': 'Adalimumab, etanercept and infliximab, all with methotrexate, are recommended as options for treating active rheumatoid arthritis in adults, only if:\n\nintensive therapy with 2 or more conventional disease-modifying antirheumatic drugs (DMARDs) has not controlled the disease well enough and\n\ndisease is moderate (a disease activity score [DAS28] of 3.2 to 5.1) and\n\nthe companies provide adalimumab, etanercept and infliximab at the same or lower prices than those agreed with the Commercial Medicines Unit.\n\nAdalimumab and etanercept can be used as monotherapy when methotrexate is contraindicated or not tolerated, when the criteria in 1.1 are met.\n\nContinue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6\xa0months after starting therapy. If this initial response is not maintained, stop treatment.\n\nIf more than one treatment is suitable, start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary because of differences in how the drugs are used and treatment schedules.\n\nTake into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any appropriate adjustments.\n\nAbatacept with methotrexate is not recommended, within its marketing authorisation, for treating moderate active rheumatoid arthritis in adults when 1 or more DMARDs has not controlled the disease well enough.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews some of the treatments (adalimumab, etanercept, infliximab and abatacept) recommended for severe rheumatoid arthritis in NICE technology appraisal guidance 375 and considers them for moderate rheumatoid arthritis. The clinical evidence suggests that these treatments are likely to be similarly effective in both moderate and severe disease.\n\nThe most likely estimates suggest that adalimumab, etanercept and infliximab after 2\xa0or more conventional DMARDs are a cost-effective use of NHS resources. So, they are recommended for treating moderate rheumatoid arthritis. The most likely cost-effectiveness estimates for abatacept are higher than what NICE normally considers cost effective, so it is not recommended for moderate disease.', 'Information about adalimumab, etanercept, infliximab and abatacept': "This technology appraisal includes 4 different biological medicines as either the originator medicine (the medicine first authorised for use) or a biosimilar product (see table 1). A biosimilar medicine is a medicine that is developed to be similar to an existing biological medicine.\n\nTechnology\n\nOriginator\n\n(company)\n\nBiosimilar (company)\n\nMechanism of action\n\nMethod of administration\n\nAdalimumab\n\nHumira (AbbVie)\n\nAmgevita (Amgen)\n\nImraldi (Biogen)\n\nIdacio (Fresenius Kabi)\n\nHyrimoz (Sandoz)\n\nTumour necrosis factor (TNF)‑alpha inhibitor\n\nSubcutaneous injection\n\nEtanercept\n\nEnbrel (Pfizer)\n\nBenepali (Biogen)\n\nErelzi (Sandoz)\n\nTNF‑alpha inhibitor\n\nSubcutaneous injection\n\nInfliximab\n\n–\n\nFlixabi (Biogen)\n\nRemsima (Celltrion Healthcare)\n\nInflectra (Pfizer)\n\nZessly (Sandoz)\n\nTNF‑alpha inhibitor\n\nIntravenous injection\n\nAbatacept\n\nOrencia (Bristol-Myers Squibb)\n\n–\n\nSelective modulator of the T‑lymphocyte activation pathway. Inhibits activation of T lymphocytes\n\nSubcutaneous or intravenous injection\n\nThe subcutaneous formulation of Remsima was not considered in this partial review because it was not included in the final scope for NICE technology appraisal guidance 375. The originator product for infliximab (Remicade) was also not considered because the manufacturer of this technology did not participate in this appraisal\n\n# Adalimumab\n\nAdalimumab (Humira, AbbVie; Amgevita, Amgen; Imraldi, Biogen; Idacio, Fresenius Kabi; Hyrimoz, Sandoz), in combination with methotrexate, is indicated 'for the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs including methotrexate has been inadequate'. Adalimumab can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.\n\nThe dosage schedule is available in the summary of product characteristics.\n\nThe list price of originator adalimumab (Humira, AbbVie) is £352.14 per 40\xa0mg pre-filled pen or pre-filled syringe (excluding VAT; BNF online, accessed March 2021). The list price of adalimumab biosimilars per 40\xa0mg pre-filled pen or pre-filled syringe are £316.80 (Amgevita, Amgen); £316.93 (Imraldi, Biogen); £316.93 (Idacio, Fresenius Kabi); £323.09 (Hyrimoz, Sandoz; all prices exclude VAT; BNF online, accessed March 2021).\n\nThe companies have each agreed a regional or nationally available price reduction for adalimumab with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.\n\n# Etanercept\n\nEtanercept (Enbrel, Pfizer; Benepali, Biogen; Erelzi, Sandoz) in combination with methotrexate, is indicated 'for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate'. Etanercept can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.\n\nThe dosage schedule is available in the summary of product characteristics.\n\nThe list price of originator etanercept (Enbrel, Pfizer) is £89.38 per 25\xa0mg pre-filled pen or pre-filled syringe (excluding VAT; BNF online, accessed March 2021). The list price of etanercept biosimilars per 25\xa0mg pre-filled pen or pre-filled syringe are £82.00 (Benepali, Biogen); £80.44 (Erelzi, Sandoz; all prices exclude VAT; BNF online, accessed March 2021).\n\nThe companies have each agreed a nationally available price reduction for etanercept with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.\n\n# Infliximab\n\nInfliximab (Flixabi, Biogen; Remsima, Celltrion Healthcare; Inflectra, Pfizer; Zessly, Sandoz), in combination with methotrexate, is indicated 'for the reduction of signs and symptoms as well as the improvement in physical function in: adult patients with active disease when the response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate, has been inadequate'.\n\nThe dosage schedule is available in the summary of product characteristics.\n\nThe list price of infliximab biosimilars per 100\xa0mg vial are £377.00 (Flixabi, Biogen); £377.66 (Remsima, Celltrion Healthcare); £377.66 (Inflectra, Pfizer); £377.66 (Zessly, Sandoz; all prices exclude VAT; BNF online, accessed March 2021).\n\nThe companies have each agreed a nationally available price reduction for infliximab with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.\n\n# Abatacept\n\nAbatacept (Orencia, Bristol-Myers Squibb), in combination with methotrexate, is indicated for 'the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who responded inadequately to previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) or a tumour necrosis factor (TNF)-alpha inhibitor'.\n\nThe dosage schedule is available in the summary of product characteristics.\n\nThe list price of abatacept (Orencia, Bristol-Myers Squibb) is £302.40 per 125\xa0mg pre-filled pen or pre-filled syringe and £302.40 per 250\xa0mg vial (excluding VAT; BNF online, accessed March 2021).\n\nThe company has a commercial arrangement. This makes abatacept available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\nThis appraisal is a partial review of NICE technology appraisal guidance 375, which recommended adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept as treatment options for people with severe rheumatoid arthritis only, assessed by having a disease activity score (DAS28) more than 5.1. This partial review considers moderate disease, that is, with a DAS28 between 3.2 and 5.1. Although certolizumab pegol, golimumab and tocilizumab were included in the original guidance, the manufacturers of these technologies decided not to participate in this partial review. So, the committee could only consider adalimumab, etanercept, infliximab and abatacept when making recommendations for moderate disease.\n\nA partial review has been done because biosimilar versions of adalimumab and etanercept are now available, and there have been changes in the prices for some of the other technologies. The committee assessed the cost effectiveness of the technologies using the original clinical evidence and economic model developed by the assessment group for NICE technology appraisal 375. The partial review has taken a pragmatic approach, which was consulted on in a review proposal, so the assessment group made only minor updates to the original model (see section 3.4 and section 3.5).\n\n# New treatment options\n\n## People with moderate rheumatoid arthritis would welcome new treatment options\n\nThe patient experts explained that people with moderate active rheumatoid arthritis have significant disability and reduced quality of life if their disease is not adequately controlled. This can affect a person's ability to work and do everyday activities. It also increases the need for continual NHS care. The patient experts described how this substantially affects emotional wellbeing, causing stress and anxiety, which can trigger further flare-ups of the disease. Although there are a range of advanced treatment options for severe rheumatoid arthritis, only filgotinib is recommended for treating moderate disease after failure of 2 or more conventional disease-modifying antirheumatic drugs (DMARDs; such as methotrexate, leflunomide, sulfasalazine and hydroxychloroquine; see NICE's technology appraisal guidance on filgotinib). The committee noted that when this partial update started, the appraisal of filgotinib had not concluded. Therefore, filgotinib was not included in the scope as a comparator. The patient experts explained that it is important that there is a wide range of treatment options available for rheumatoid arthritis. This is because the differing nature of the disease means that a treatment may work well for one person but not another. The clinical experts explained that although the medicines appraised are similarly beneficial for treating the articular features of rheumatoid arthritis, they differ in their effectiveness in preventing particular comorbidities. This means that it is important for people with rheumatoid arthritis to have a range of different medicines available, even within the same drug class. The clinical experts explained that earlier access to advanced treatments in moderate disease would reduce disease progression and increase the likelihood of remission. The committee concluded that people with moderate rheumatoid arthritis would welcome a range of advanced treatment options.\n\n# Cycling of TNF-alpha inhibitors\n\n## This appraisal only considers first-line biological treatments in moderate disease\n\nA company representative explained that the moderate treatment sequences modelled by the assessment group did not consider cycling of tumour necrosis factor (TNF)-alpha inhibitors (taking another TNF-alpha inhibitor after a first one). This would happen if a person does not tolerate the first treatment, or if their disease either does not respond or responds inadequately after an initial response. The clinical experts explained that because the technologies are protein-based drugs, there is a risk of developing antidrug antibodies, which reduces the treatment benefit over time. They noted that around 50% of people will stop treatment within 3\xa0years because of loss of efficacy. The clinical experts explained that the cycling of TNF-alpha inhibitors has a place in treating rheumatoid arthritis. They explained that, for this reason, having a variety of therapeutic choices for moderate disease would benefit people. The committee noted that the scope for the appraisal includes only first-line use of biological DMARDs (after a person's disease has responded inadequately to 2 or more conventional DMARDs) as in NICE technology appraisal guidance 375. It agreed that it was appropriate to assume that after the first biological treatment has failed, if the disease progresses to severe, NICE technology appraisal guidance for severe rheumatoid arthritis would be followed.\n\n# Clinical evidence\n\n## The clinical evidence used in NICE technology appraisal 375 is appropriate for this partial review\n\nThe clinical evidence used in this review is the same as that assessed in NICE technology appraisal guidance 375. So, the treatment efficacy of the interventions and comparators (adalimumab, etanercept, infliximab, abatacept all with methotrexate, and methotrexate alone) and subsequent treatments (rituximab and tocilizumab both with methotrexate) were informed by the results of the network meta-analysis done by the assessment group in NICE technology appraisal 375. The trials in the network meta-analysis included people with moderate and severe disease, so the efficacy of treatments was assumed to be the same in both populations. The committee considered the uncertainty around the midpoint estimates used when making its recommendations for treatments used in severe disease in NICE technology appraisal 375. The clinical experts explained that there is long-term clinical trial evidence and real-world evidence that strongly supports using biological DMARDs for treating moderate active disease. The committee concluded that the efficacy data accepted in the original guidance was appropriate to assess the cost effectiveness of adalimumab, etanercept, infliximab and abatacept for people with moderate active disease as part of this partial review.\n\n# The assessment group's model\n\n## The cost-effectiveness model used in NICE technology appraisal 375 is appropriate for this partial review\n\nThe assessment group developed an individual patient-based discrete event simulation model for its economic evaluation in NICE technology appraisal guidance 375. The scope for this appraisal included only the first-line use of biological DMARDs after an inadequate disease response to 2 or more conventional DMARDs. In the economic model, after the first biological treatment had failed, if disease progresses to severe, NICE technology appraisal guidance for severe rheumatoid arthritis was followed. For all analyses it was assumed that methotrexate was used in combination with the biological DMARD, and that the results for combination therapy could be generalised to biological DMARD monotherapy (if monotherapy use was included in the marketing authorisation). This assumption was also made in NICE technology appraisal 375. The model incorporated a response criterion based on European League Against Rheumatism (EULAR) response at 6\xa0months to reflect UK clinical practice. If there was no EULAR response to a biological DMARD after 6\xa0months then the next treatment in the strategy was used. Further details about the assessment group's original economic model can be found in the final guidance for NICE technology appraisal 375. The committee concluded that the cost-effectiveness model accepted in the original guidance was appropriate to use in this partial review, with some updates (see section 3.5).\n\n## The changes to the assessment group's model are appropriate for decision making and reflect current NICE guidance\n\nThe assessment group's analyses included the assumptions preferred by the committee in NICE technology appraisal guidance 375. There were several updates to its original model:\n\nUpdating the prices of interventions and subsequent treatments to reflect any changes to the prices of technologies.\n\nAmending the model so people with moderate disease who only have treatment with conventional DMARDs can have biological DMARDs after progression to severe disease (disease activity score [DAS28] more than 5.1). The committee understood that this treatment pathway was not an option in the original model but that it reflected current clinical practice. To include this change in the model, the assessment group estimated the relationship between changes in Health Assessment Questionnaire (HAQ) score, which was the measure used in the modelling, and changes in DAS28 score, which is the measure used to determine severity of disease. The assessment group did a systematic review to identify the best estimate of change in DAS28 score associated with a 0.125 change in HAQ score, which was considered to be 0.48. The assessment group also did sensitivity analyses using a lower estimate (the exact figure is confidential and cannot be reported here) and a higher estimate of 0.70.\n\nAfter stakeholder consultation, 1 company commented that the moderate treatment sequence used in the assessment group's updated model did not align with current NICE guidance recommendations for treating rheumatoid arthritis, or with the sequences modelled in NICE's technology appraisal guidance on filgotinib. In response, the assessment group further updated the treatment sequences used in the model to reflect current NICE guidance. The model assumed that for the treatment arm, a person with moderate disease would initially have a biological DMARD (either adalimumab, etanercept, infliximab or abatacept) followed by conventional DMARDs. For the comparator arm, the model assumed that a person would have initial treatment with methotrexate followed by other conventional DMARDs. Once disease progressed to severe (DAS28 more than 5.1) they would then move through a series of subsequent treatments.\n\n## The treatment sequences in the updated economic model are appropriate\n\nThe trials included in the network meta-analysis showed people's disease responded to methotrexate (a conventional DMARD) when it is used as the first treatment. Therefore, the assessment group included a response to methotrexate when used as a first treatment in the comparator arm of the model (for people with moderate disease who had had 2 conventional DMARDs) but did not include a response to methotrexate after a biological DMARD in the treatment arm of the model. The trials also showed a response with methotrexate following treatment with tocilizumab (in both treatment arms) and this efficacy was also included in the model in the treatment sequence for severe disease. The efficacy of conventional DMARDs when used later in the treatment pathway for moderate disease and at the end of the pathway in severe disease was assumed to be zero for both arms. In response to consultation, one consultee noted that in NICE technology appraisal guidance 375, in moderate disease, it was assumed that after biological treatments people would have methotrexate, which was associated with a response. A similar assumption was also made in NICE's technology appraisal guidance on baricitinib, tofacitinib and sarilumab. The committee noted that none of these appraisals had made positive recommendations for moderate disease. So, it did not consider that this point had been fully accepted by the committee in these appraisals. Also, it noted that it was debatable whether methotrexate would be used at this point in the treatment pathway or what size of response would be expected. However, because no new clinical evidence was being considered in this appraisal, it agreed there was no strong reason to deviate from the assumption put forward in NICE technology appraisal 375 and subsequent appraisals. The committee concluded that the assessment group's model was previously considered acceptable in NICE technology appraisal 375 and that the updates made to reflect current NICE guidance and consultation responses are appropriate for decision making (see table 2).\n\nTreatment arm\n\nTreatment\n\nComparator\n\nFirst treatment for moderate disease\n\nBiological DMARD\n\nMethotrexate\n\nSecond treatment for moderate disease\n\nMethotrexate\n\nConventional DMARDs\n\nThird treatment for moderate disease\n\nConventional DMARDs\n\n-\n\nFirst treatment for severe disease\n\nAdalimumab (infliximab if adalimumab is used in moderate disease)\n\n\n\nAdalimumab\n\nSecond treatment for severe disease\n\nRituximab\n\nRituximab\n\nThird treatment for severe disease\n\nTocilizumab\n\nTocilizumab\n\nAbbreviations: DMARDs, disease-modifying antirheumatic drugs\n\n# Cost-effectiveness estimates\n\n## The most plausible ICERs for adalimumab, etanercept and infliximab are below £30,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee agreed that an acceptable ICER would be within the range NICE normally considers a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). Because of the confidential discounts for the treatments and some of the subsequent therapies, the exact ICERs are confidential and cannot be reported here. The assessment group's base-case analyses used the cheapest formulation of each intervention and prices included homecare support (when available). The assessment group's base-case ICERs for adalimumab and infliximab compared with conventional DMARDs were both substantially lower than £20,000 per QALY gained. The assessment group's base-case ICER for etanercept compared with conventional DMARDs was lower than £30,000 per QALY gained. For abatacept (intravenous and subcutaneous formulations) the ICER was substantially higher than £30,000 per QALY gained.\n\n## The assessment group's sensitivity analyses do not change the cost-effectiveness conclusions\n\nThe assessment group did several sensitivity analyses including using lower (the exact figure is confidential and cannot be reported here) and higher values (0.70) for change in DAS28 score when HAQ score increases (see section 3.5). These had a small effect on the ICERs. Another sensitivity analysis was done to remove methotrexate after tocilizumab in the treatment sequences following progression to severe disease (in line with NICE's technology appraisal guidance on filgotinib), which also had little effect on the ICERs. The committee understood that there was some uncertainty about the efficacy estimates used in the model, which may have influenced the cost-effectiveness results. However, it agreed that these estimates were considered acceptable by the committee in NICE technology appraisal guidance 375. The committee discussed that there are multiple biosimilars for adalimumab, and the availability of these differs regionally in England, unlike etanercept and infliximab biosimilars, which are nationally available. The committee considered a further sensitivity analysis using the highest price that any region would need to pay for adalimumab. It was reassured that this did not change the cost-effectiveness conclusions for adalimumab.\n\n## Adalimumab, etanercept and infliximab are cost-effective treatment options for moderate disease but abatacept is not recommended\n\nThe committee accepted the assessment group's updated base-case analyses. The assessment group's base-case ICERs for adalimumab and infliximab were both below the range NICE considers to be an acceptable use of NHS resources. Therefore, the committee recommended adalimumab and infliximab as first-line biological treatments for moderate active rheumatoid arthritis that has had an inadequate response to intensive therapy with 2 or more conventional DMARDs. Although the assessment group's ICER for etanercept was higher than those for adalimumab and infliximab, it was below £30,000 per QALY gained. In response to consultation, it was highlighted that there are some people for whom etanercept would be a particularly useful treatment option. For example, etanercept has a much lower risk of reactivating latent tuberculosis, which has a higher prevalence in people with a South Asian family background. In addition, compared with some of the other biologicals, etanercept does not need to be stopped as far in advance by people wishing to conceive. The committee recognised that these groups would likely only represent a small number of people with moderate rheumatoid arthritis. The committee noted that the recommendations state that if more than 1 biological is an appropriate treatment option, treatment should start with the least expensive. So it also recommended etanercept as an option. The assessment group's base-case ICER for abatacept was above the range NICE considers to be an acceptable use of NHS resources. The committee therefore did not recommend abatacept as a treatment option for moderate active rheumatoid arthritis.\n\n## Adalimumab monotherapy and etanercept monotherapy are also recommended for people who cannot have methotrexate\n\nThe committee agreed that people with moderate rheumatoid arthritis who cannot tolerate methotrexate should not be disadvantaged compared with other people with moderate disease, as far as possible. The committee concluded that, based on the marketing authorisation and the cost-effectiveness estimates, adalimumab and etanercept could be recommended as monotherapy for moderate active disease previously treated with conventional DMARDs.\n\n# Equality considerations\n\n## Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure\n\nA potential equality issue was raised in NICE's technology appraisal guidance on upadacitinib for treating severe rheumatoid arthritis, about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee agreed that this equality issue was also important to consider for this appraisal. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any appropriate adjustments.\n\n## Etanercept may be particularly beneficial for some people with protected characteristics\n\nSome of the people for whom etanercept may be particularly beneficial have protected characteristics. The committee took this into account in its decision making about etanercept (see section 3.9).\n\n## No other equality issues have been identified that can be addressed in this technology appraisal\n\nThe patient experts explained that certolizumab pegol, another TNF-alpha inhibitor, is often used to treat rheumatoid arthritis in women who are planning to become pregnant or who are pregnant. They described how not having this as a treatment option for people with moderate disease could potentially discriminate against women of childbearing age. The clinical experts explained that certolizumab pegol does not easily cross the placenta so is usually the preferred treatment choice during pregnancy. However, they explained that other TNF-alpha inhibitors can be used in different stages of pregnancy but that there is a risk of active transport across the placenta, which often means that treatment is stopped. The committee concluded that this issue could not be addressed in this technology appraisal, because the company manufacturing certolizumab pegol decided not to participate in this partial review. So, the committee could not make recommendations on its use for moderate disease.\n\n# Other factors\n\n## Healthcare professionals should choose the most appropriate treatment after discussing the options with the person having treatment\n\nThe committee understood that having a range of treatment options is important in treating moderate rheumatoid arthritis. It understood that NICE recommended filgotinib for treating moderate to severe rheumatoid arthritis (see NICE's technology appraisal guidance on filgotinib) and noted NICE's ongoing technology appraisal on upadacitinib for previously treated moderate active rheumatoid arthritis. The committee concluded that healthcare professionals should choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If more than 1\xa0treatment is suitable, they should start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary because of differences in how the drugs are used and treatment schedules.\n\n## The benefits of the technologies were adequately captured in the cost-effectiveness analysis\n\nThe patient and clinical experts explained that biological DMARDs are highly effective in reducing disease progression and improving quality of life in people with rheumatoid arthritis. The committee noted that biological DMARDs were considered to be innovative in NICE technology appraisal guidance 375 for people with severe disease. It discussed that while filgotinib is the only advanced treatment option currently available for people with moderate disease, its mechanism of action is different to the biological DMARDs, of which none are currently available for people with moderate disease. The committee agreed that the technologies are important treatment options for these people. It concluded that all the benefits of the technologies were adequately captured in the model."}
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https://www.nice.org.uk/guidance/ta715
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Evidence-based recommendations on adalimumab, etanercept, infliximab and abatacept for adults with moderate rheumatoid arthritis who have tried conventional DMARDs but they have not worked.
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707a68a0541b44d7071d6f364d5c8db04ebec442
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nice
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Enzalutamide for treating hormone-sensitive metastatic prostate cancer
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Enzalutamide for treating hormone-sensitive metastatic prostate cancer
Evidence-based recommendations on enzalutamide (Xtandi) for treating hormone-sensitive metastatic prostate cancer in adults.
# Recommendations
Enzalutamide plus androgen deprivation therapy (ADT) is recommended, within its marketing authorisation, as an option for treating hormone-sensitive metastatic prostate cancer in adults. It is only recommended if the company provides enzalutamide according to the agreed commercial arrangement.
Why the committee made these recommendations
Current treatment for hormone-sensitive metastatic prostate cancer in the NHS is ADT alone, or docetaxel plus prednisolone or prednisone (from now, docetaxel) plus ADT. Enzalutamide plus ADT would offer another option for people with hormone-sensitive metastatic prostate cancer, especially for people who cannot have docetaxel. It is taken by mouth so is more convenient than docetaxel, which is an intravenous treatment.
Trial results suggest that, compared with ADT alone, enzalutamide plus ADT increases the time until the cancer progresses and how long people live. Also, an indirect comparison suggests that, compared with docetaxel plus ADT, enzalutamide plus ADT increases the time until the cancer progresses. But, it is unclear whether there is a difference between the 2 treatments in the length of time people live.
The cost-effectiveness estimates are within the range NICE considers an acceptable use of NHS resources. Therefore, enzalutamide plus ADT is recommended for hormone-sensitive metastatic prostate cancer.# Information about enzalutamide
# Marketing authorisation indication
Enzalutamide (Xtandi, Astellas) is indicated for 'the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of a 112‑capsule pack of 40 mg enzalutamide is £2,734.67 (excluding VAT; BNF online, accessed May 2020). The daily dose of enzalutamide is 160 mg and costs £97.67.
The company has a commercial arrangement. This makes enzalutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Astellas, the company that markets enzalutamide, a review of this submission by the evidence review group (ERG), the technical report prepared by NICE and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage. It agreed that there should be a total utility decrement of 0.093 across the hormone-relapsed health sub-states (issue 7 page 26 of the technical report). It discussed the issues that were outstanding after the technical engagement stage.
# Clinical need and clinical management
## People with hormone-sensitive metastatic prostate cancer would welcome the option of treatment with enzalutamide
The clinical and patient experts noted that people with hormone-sensitive metastatic prostate cancer have limited treatment options. NICE's guideline on prostate cancer recommends androgen deprivation therapy (ADT) alone, and docetaxel with prednisolone or prednisone (from now, docetaxel) plus ADT. The patient experts explained that, when people are first diagnosed with metastatic prostate cancer, they may have no or few symptoms. They also explained that some people perceive that treatment with docetaxel worsens quality of life and choose to have ADT alone, even though the long-term outcomes may be worse than with docetaxel plus ADT. So, because enzalutamide plus ADT is generally better tolerated than docetaxel plus ADT, and is more effective than ADT alone, people would welcome it as an option at this point in the treatment pathway. The committee concluded that some people with hormone-sensitive metastatic prostate cancer would welcome the option of treatment with enzalutamide plus ADT.
## Temporary guidance on enzalutamide for hormone-sensitive metastatic prostate cancer will be superseded by this appraisal's recommendations
NICE's rapid guideline on the delivery of systemic anticancer treatments during the COVID-19 pandemic aims to:
maximise the safety of patients with cancer
make the best use of NHS resources
protect staff from infection
enable services to match the capacity for cancer treatment to patient needs if services become limited because of the COVID‑19 pandemic.The guideline provides a link to the interim treatment change options during the COVID-pandemic, which are endorsed by NHS England. It includes the option of giving enzalutamide plus ADT instead of docetaxel to reduce toxicity and the potential for hospital admission. Treatment regimens will revert to the standard commissioned position after this period unless the guideline is updated. Any interim treatment subject to an ongoing NICE technology appraisal will be superseded by an appraisal guidance.
## ADT alone and docetaxel plus ADT are both relevant comparators
The committee was aware that the NICE scope included as comparators, ADT alone and docetaxel plus ADT. The clinical experts explained that both are offered in the NHS to people with hormone-sensitive metastatic prostate cancer. The committee was also aware of the ongoing NICE technology appraisals on abiraterone plus ADT for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer and apalutamide for treating prostate cancer. The committee concluded that neither abiraterone plus prednisone (from now, abiraterone) and ADT nor apalutamide plus ADT were comparators because they are not routinely commissioned at this point in the treatment pathway. The Cancer Drugs Fund's clinical lead noted that around two-thirds of people presenting with hormone-sensitive metastatic prostate cancer in England have ADT alone. Of these people, some are not fit enough for docetaxel, and some choose not to have it because of its adverse events (see section 3.1). NHS England's docetaxel commissioning policy states that someone may not be fit enough for docetaxel if they have:
a poor overall performance status (World Health Organization performance 3 to 4)
pre-existing peripheral neuropathy
poor bone marrow function or
a life-limiting illness.The policy also states that docetaxel should be used with caution in people with a WHO performance status of 2, and that there are few absolute contraindications for docetaxel therapy. The committee concluded that ADT alone and docetaxel plus ADT were relevant comparators for people who could have docetaxel plus ADT, and that ADT alone was the relevant comparator for people who could not have docetaxel. The committee recognised the importance of patient choice when all treatment options are clinically and cost effective.
## The first treatment for hormone-sensitive metastatic prostate cancer affects the number of life-extending treatments people have later
Under NHS policy, people who have docetaxel plus ADT for hormone-sensitive prostate cancer for up to 6 cycles can have docetaxel again (for up to 10 cycles) for hormone-relapsed prostate cancer. This is because the benefit of docetaxel is not exhausted. Other treatment options for hormone-relapsed metastatic prostate cancer include both enzalutamide and abiraterone when chemotherapy is not yet clinically indicated, or after a docetaxel-based regimen. In summary, enzalutamide has a licence for 4 positions in the treatment pathway (including 1 for non-metastatic prostate cancer). However, the Cancer Drugs Fund clinical lead explained that NHS England commissions each of enzalutamide and abiraterone only once in the treatment pathway. This is because there is no evidence of clinical benefit for using one after the other. It means that people who have enzalutamide plus ADT for hormone-sensitive metastatic prostate cancer cannot have enzalutamide or abiraterone later in the treatment pathway. It also means that people who have docetaxel plus ADT first for hormone-sensitive metastatic prostate cancer have more treatment options than people who have enzalutamide plus ADT first. This is because they can have either enzalutamide or abiraterone, and can also have docetaxel again. The sequence of follow-on treatments when the cancer is hormone-relapsed may vary from person to person. Possible treatments include:
After ADT alone, or docetaxel plus ADT:
enzalutamide or abiraterone (before or after docetaxel)
docetaxel
-ther active treatments such as cabazitaxel or radium 223.
After enzalutamide plus ADT:
docetaxel
-ther active treatments such as cabazitaxel or radium 223.The committee concluded that the treatment choice for hormone-sensitive metastatic prostate cancer affects the treatments a person can have when the cancer is hormone-relapsed. It also concluded that having enzalutamide plus ADT at this point in the pathway limits the number of life-extending treatment options compared with having ADT alone or docetaxel plus ADT.
# Clinical evidence
## ARCHES and ENZAMET are both relevant trials for assessing the clinical effectiveness of enzalutamide plus ADT
Two randomised controlled trials, ARCHES and ENZAMET, have investigated the clinical effectiveness of enzalutamide plus ADT for treating hormone-sensitive metastatic prostate cancer:
ARCHES was a double-blind trial including 1,150 people with hormone-sensitive metastatic prostate cancer. It compared enzalutamide plus ADT (n=574) with ADT alone (n=576). The primary endpoint was progression-free survival. Overall survival and health-related quality of life were secondary endpoints.
ENZAMET was an investigator-led open-label trial including 1,125 people with hormone-sensitive metastatic prostate cancer. It compared enzalutamide plus ADT (n=563) with conventional non-steroidal anti-androgens (NSAAs) plus ADT (n=562). The primary endpoint was overall survival. Progression-free survival and health-related quality of life were secondary endpoints. People could have concomitant docetaxel, which is not included in the marketing authorisation for enzalutamide. Therefore, the company submission included data only from the 622 people who did not have concomitant docetaxel (309 in the enzalutamide plus ADT arm and 313 in the comparator arm).The company had access to patient-level data for both trials. The trials differed by proportion of people with high-volume disease (see section 3.6), comparator (the control treatment; see section 3.7), concomitant use of docetaxel and definition of progression-free survival (see section 3.8). The committee discussed these in turn. It concluded that both trials were relevant for assessing the clinical effectiveness of enzalutamide plus ADT for hormone-sensitive metastatic prostate cancer.
## Patient characteristics in ARCHES and ENZAMET are broadly generalisable to NHS clinical practice
The baseline characteristics of the people in ARCHES and ENZAMET were similar. However, more people in ARCHES had Gleason scores equal to or greater than 8, or high-volume disease. The proportion of people with high-volume disease in ARCHES was similar to that in STAMPEDE, an entirely UK-based trial assessing the best way to treat newly diagnosed advanced prostate cancer. The clinical experts agreed that people with high-volume disease have poorer prognoses than people with low-volume disease. However, they disagreed on whether disease volume modifies the relative effectiveness of treatment. One clinical expert noted that, in STAMPEDE, volume of disease did not alter treatment effectiveness. The committee noted that the evidence for enzalutamide plus ADT was based on a relatively fit population. It specifically excluded people with an Eastern Cooperative Oncology Group performance status of 2 or above, significant cardiovascular or renal disease, and other conditions. So, it may not be representative of some of the people who cannot have docetaxel. The committee appreciated that these issues could have added uncertainty to the results of the economic modelling. It concluded that the trials were broadly generalisable to NHS practice.
## ENZAMET employs a comparator not used in the NHS, but the results of ARCHES and ENZAMET are appropriate for decision making
ARCHES compared enzalutamide plus ADT with ADT alone while ENZAMET compared it with conventional NSAAs plus ADT. The committee highlighted that using NSAAs does not reflect UK clinical practice and the company acknowledged this. However, the company did not think that it would affect the generalisability of the results to NHS clinical practice. The clinical experts confirmed that conventional NSAAs are not used in the NHS in this setting. They explained that evidence suggested the combination may be more effective than ADT alone, but that adverse events are increased when adding NSAAs to ADT. The committee concluded that the results of both trials were appropriate for decision making.
## The definition of progression-free survival in ENZAMET more closely reflects NHS clinical practice than that in ARCHES
The 2 trials measured progression-free survival differently. In ENZAMET, it was defined based on clinical progression by radiographic imaging, symptoms attributable to cancer progression or starting another treatment for prostate cancer. This was broader than in ARCHES, in which progression-free survival was defined based on radiographic disease progression by an independent blinded and central review. The company chose only to model progression-free survival from ARCHES (see section 3.13). The clinical experts explained that there is more than a single way in clinical practice to assess progression-free survival, and that different centres might use different definitions. They confirmed that other measures might include serum prostate specific antigen. The committee concluded that it was appropriate to consider progression-free survival from both trials, and that the definition from ENZAMET better reflected NHS practice.
## Enzalutamide plus ADT extends progression-free survival compared with ADT alone or NSAAs plus ADT; overall-survival data are immature
The company presented data from planned final analyses for progression-free survival from ARCHES and ENZAMET. However, the trials are ongoing for the endpoint of overall survival. In ARCHES, enzalutamide plus ADT improved progression-free survival compared with ADT alone. The time to median progression-free survival was not reached for enzalutamide plus ADT and, for ADT alone, was 19 months. The hazard ratio was 0.39 (95% confidence interval 0.30 to 0.50). In ARCHES, cancer progressed in 16% of people in the treatment group and in 35% in the control group. In ENZAMET, enzalutamide plus ADT improved progression-free survival compared with conventional NSAAs plus ADT (hazard ratio 0.34, 95% CI 0.26 to 0.44). The number of events was not available for ENZAMET. The median follow up was 14.4 months in ARCHES and 37.0 months in ENZAMET. At the same time as doing final analyses for progression-free survival, the investigators did interim data analyses for overall survival. In ARCHES, 84 deaths had occurred at the time of the interim analysis out of the 342 deaths specified in the statistical analysis plan for the final analysis. In ENZAMET, 245 deaths had occurred at the time of the interim analysis out of the specified 470 deaths. At the time of the interim analysis, most people were still alive in both trials, and median overall survival could not be estimated in any treatment arm. Interim analyses from both trials suggested that enzalutamide plus ADT improved overall survival (ARCHES: HR 0.81, 95% CI 0.53 to 1.25; ENZAMET: HR 0.53, 95% CI 0.37 to 0.74). The confidence interval for the estimate from ENZAMET included the possibility of no effect. The company presented an analysis for overall survival based on unadjusted pooling of patient-level data from both trials. The committee did not support unadjusted pooling of results (see section 3.11). The ERG did not use the unadjusted pooled data to estimate overall survival. Instead, it modelled overall survival using hazard ratios from the company's network meta-analysis applied to the ADT-alone overall-survival curve. The committee concluded that enzalutamide plus ADT delayed time to progression compared with ADT alone, but that the data for overall survival were immature. This meant that the size of the overall benefit of enzalutamide plus ADT compared with ADT alone was uncertain.
## Enzalutamide plus ADT extends progression-free survival compared with docetaxel plus ADT, but evidence on overall survival is uncertain
There are no trials that directly compare enzalutamide plus ADT with docetaxel plus ADT. The company did a network meta-analysis that included ARCHES and ENZAMET, 3 trials of docetaxel plus ADT compared with ADT alone (STAMPEDE1, CHAARTED and GETUG) and 6 trials of conventional NSAAs plus ADT compared with ADT alone (DAPROC, EORTC 30853, INTERGROUP STUDY 0036, SWOG‑8894, Janknegt 1993 and Zalcberg 1996). The results suggested longer progression-free survival for enzalutamide plus ADT compared with docetaxel plus ADT. For overall survival, the point estimate suggested a benefit for enzalutamide plus ADT but included the possibility of no effect. None of the results can be reported here because the company considers them confidential. The committee concluded that enzalutamide plus ADT extended progression-free survival when compared with docetaxel plus ADT, but evidence on overall survival was uncertain.
## A network meta-analysis is better than unadjusted pooling to estimate effect on survival of enzalutamide plus ADT compared with ADT alone
The committee discussed the implications of pooling data from the 2 trials, ARCHES and ENZAMET, with different treatments for the control arm. It was aware that the company's network meta-analysis (see section 3.10) included 6 trials of conventional NSAAs plus ADT compared with ADT alone. The results of the network meta-analysis also showed a benefit of NSAAs plus ADT compared with ADT alone, which included the possibility of no effect. To avoid using the pooled overall-survival data, the ERG estimated overall survival using hazard ratios from the company's network meta-analysis applied to the ADT-alone overall-survival curve. The committee concluded that, when comparing enzalutamide plus ADT to ADT alone, the network meta-analysis should inform the treatment effect for overall survival. It was aware that the data from ARCHES for ADT alone and ENZAMET for conventional NSAAs plus ADT would still need to be pooled to provide a reference curve for applying treatment effect hazard ratios.
# Cost effectiveness
## The company's partitioned survival model is appropriate for decision making
The company presented a partitioned survival model that included 3 main health states: hormone-sensitive disease, hormone-relapsed disease and death. The hormone-sensitive health state included on- and off-treatment sub-states. The hormone-relapsed health state included 3 sub‑states for follow-on treatments. The committee concluded that the model structure was appropriate for decision making.
## A scenario analysis using data from ENZAMET to model progression-free survival would be informative
Both ARCHES and ENZAMET provided data on progression-free survival, but ENZAMET had a longer duration. According to the company, progression-free survival in ARCHES closely resembled that of ENZAMET. Therefore, it used patient-level data from ARCHES to model progression-free survival for enzalutamide plus ADT and ADT alone. It considered that it could not combine data from ENZAMET and ARCHES for progression-free survival because of the different ways in which this outcome was measured. The committee recalled that the definition of progression-free survival in ENZAMET more closely reflected that used in NHS clinical practice (see section 3.8). However, the hazard ratios from both trials were similar (ARCHES: HR 0.39 and ENZAMET: HR 0.34; see section 3.9). As such, the committee considered that using 1 trial instead of another was unlikely to have had a large effect on the cost-effectiveness results. It concluded that it was reasonable to use data from ARCHES if using data from only a single trial to model progression-free survival.
## The company's methods for estimating progression-free survival is not appropriate
To extrapolate progression-free survival beyond the trial duration and over the lifetime horizon defined in the model, the company used data only from ARCHES (see section 3.13). It fitted a log-normal distribution to both arms of the trial. The committee noted that median follow up in ARCHES was only 14.4 months, and that cancer had not progressed in most people at the final analysis for progression-free survival. This increased the uncertainties associated with estimating average progression-free survival by treatment arm. The immaturity of the data also meant that most distributions fitted well to the observed trial data. The company based its choice of distribution, the log-normal distribution, on input from clinical experts. It externally validated its choice using data from long-term survival on ADT from STAMPEDE and GETUG. The ERG commented that, when extrapolating progression-free survival using the log-normal distribution, the 5- and 10‑year estimates for progression-free survival for ADT seemed implausibly low. The clinical experts considered that around 20% of people who take enzalutamide plus ADT remain progression free at 5 years, which drops to 10% at 10 years. Both values are lower than those suggested in the company's model. The ERG suggested that:
for ADT alone:
the exponential distribution produced estimates for progression-free survival that were more in line with those seen in the UK (based on data from STAMPEDE with a 4‑year median follow up)
for enzalutamide plus ADT:
the log-logistic distribution predicted progression-free survival more in line with the clinical experts' opinion in the shorter term
applying the hazard ratio from the network meta-analysis for enzalutamide plus ADT to the extrapolated ADT curve produced estimates more in line with clinical expert expectations for later years.The committee concluded that, for ADT alone, it preferred using an exponential distribution to extrapolate the data from ARCHES. For enzalutamide plus ADT, it considered that using the hazard ratios from the network meta-analysis produced more plausible estimates than separately fitting a curve to the immature enzalutamide plus ADT data. However, the committee was concerned that this approach implied that the treatment effect would be expected to continue indefinitely, which may not be credible.
## The ERG's estimates of survival for people taking enzalutamide plus ADT are more plausible than the company's estimates
To model overall survival for ADT alone and enzalutamide plus ADT, the company pooled data from ARCHES and ENZAMET (see section 3.9). It extrapolated beyond the trial duration and over the lifetime horizon defined in the model by fitting a Weibull distribution to both arms. The company based its choice of a Weibull distribution on input from clinical experts, and by externally validating its choice using data from STAMPEDE, CHAARTED and GETUG. The ERG considered that the predictions for how long people survive who take ADT alone were reasonably consistent with long-term data from STAMPEDE. However, it was concerned that 10- and 20‑year figures reflecting the proportion of people still alive after taking enzalutamide plus ADT were implausibly high with the Weibull distribution. The clinical experts estimated that overall survival with enzalutamide plus ADT would be around 10% to 20% at 10 years, and 0% to 5% at 20 years. The company's modelling suggested that a greater proportion of people would be alive at 20 years than estimated by the clinical experts. The committee noted that, because of the immaturity of the data, most distributions provided similar predictions. Only the Gompertz distribution predicted lower survival for enzalutamide plus ADT than the company's choice. The ERG explained that the Gompertz distribution may have underpredicted survival on enzalutamide plus ADT at later years. The ERG preferred using the hazard ratio from the network meta-analysis applied to the ADT alone curve because it gave better predictions than other curves for enzalutamide plus ADT survival after around 10 years. The committee agreed with the ERG. It concluded that using hazard ratios for enzalutamide plus ADT compared with ADT alone from the network meta-analysis (see section 3.11) estimated the relative treatment effect for enzalutamide plus ADT compared with ADT alone better than the company's approach. This was because it accounted for the different comparators in ARCHES and ENZAMET better than the company's approach of unadjusted pooling. However, the committee was again concerned that this approach implied that the treatment effect would be expected to continue indefinitely.
## It is important to consider the survival advantage scenarios associated with enzalutamide plus ADT compared with docetaxel plus ADT
To model overall survival with docetaxel plus ADT, the company applied hazard ratios from the network meta-analysis for docetaxel plus ADT compared with ADT alone to the ADT curve. This predicted a survival benefit for docetaxel plus ADT compared with ADT alone, reflecting trial evidence. The company's model also predicted a survival benefit with enzalutamide plus ADT compared with docetaxel plus ADT. The point estimate from the network meta-analysis favoured enzalutamide plus ADT, but the credible interval included 1, the possibility of no effect. The committee noted that people who take enzalutamide plus ADT have fewer life-extending treatment options later (see section 3.4). Therefore, it considered that there might be no survival benefit with enzalutamide plus ADT compared with docetaxel plus ADT. To explore this uncertainty, the ERG provided scenario analyses modelling no survival benefit for enzalutamide plus ADT compared with docetaxel plus ADT. The committee concluded that, given the uncertainty around the overall-survival estimate, it was appropriate to consider these analyses.
## Life-extending treatments during hormone-relapsed prostate cancer in ARCHES differ from those used in NHS clinical practice
The committee acknowledged that people with hormone-sensitive metastatic prostate cancer:
have enzalutamide plus ADT, docetaxel plus ADT or ADT alone until disease progression
at progression, have other treatment options
can have enzalutamide or abiraterone only once
have fewer options for life-extending follow-on treatments if they have enzalutamide early in the treatment pathway than people who first have ADT alone or docetaxel plus ADT (see section 3.4).ARCHES was a double-blind trial, and people could have enzalutamide or abiraterone as follow-on treatments in both treatment arms. At the time of the interim analysis, 54% of people who had follow-on treatments in ARCHES had enzalutamide again or abiraterone after enzalutamide. Also, fewer people in the ADT arm went on to have follow-on treatment with enzalutamide or abiraterone in ARCHES (46%) than was modelled by the company (70%). The company did not provide details of treatments during hormone-relapsed prostate cancer in ENZAMET. The committee agreed that the company's modelling of the costs of follow-on treatments reflected NHS costs, but was concerned that the company had not adjusted the effectiveness data to match. In the model, a greater proportion of people having ADT alone incurred costs from having enzalutamide or abiraterone after progression than in ARCHES. However, the company did not account for the benefits of treatment. The committee acknowledged the immaturity of the data from ARCHES, and that the proportion of people on different treatments could change over time. It concluded that it would have preferred the company to adjust for both the costs and effects of treatments for hormone-relapsed metastatic prostate cancer to match NHS practice.
## It is uncertain whether the benefits of active treatments persist
The company's model predicted that the benefit for overall survival with enzalutamide plus ADT compared with ADT alone or docetaxel plus ADT lasted for the model's 30‑year time horizon. This was the case whether extrapolated survival curves were used to estimate enzalutamide's treatment effect compared with ADT or the hazard ratio from the network meta-analysis. Data from STAMPEDE showed that there was an initial survival benefit at 5 years with docetaxel plus ADT compared with ADT alone (49% compared with 37%). However, the ERG highlighted that there was no difference in actual overall survival after 8.5 years (23% compared with 22%). This may have been because people on ADT alone go on to have other life-extending treatments and so 'catch-up' (see section 3.4 and section 3.17). One clinical expert explained that the effect of early systemic treatment lasts for a long time, so catching up might be unlikely. He noted that there were longer follow-up data for abiraterone plus ADT than for enzalutamide plus ADT, and that he thought that both have a similar mechanism of action. These data for abiraterone showed that more people remained alive on abiraterone plus ADT than on docetaxel plus ADT or on ADT alone beyond 5 years. The ERG presented scenario analyses in which the hazards of survival for enzalutamide plus ADT and the comparators were the same after 8.5 years. The committee concluded that, in the absence of long-term data for enzalutamide plus ADT, the ERG's scenarios in which the hazard ratios were equalised between treatment options after 8.5 years were useful for assessing the uncertainty.
## Few people will stop treatment with enzalutamide plus ADT before disease progression
In the company's model, people could be on or off treatment before disease progression. The ERG was concerned that people who were off treatment before disease progression would maintain the same quality of life as people on treatment, but at no additional cost. In ARCHES, around 12% of people stopped treatment before disease progression. According to the company, only about half of them stopped because of adverse events, while others withdrew consent. The clinical experts explained that, in clinical practice, few people would stop having enzalutamide plus ADT before disease progression because it is generally well tolerated. The committee considered that withdrawing consent is specific to trials and would not be reflected in clinical practice. The ERG noted that, in the company's model, there was a substantial gap between the curves for progression-free survival and time to stopping treatment. The ERG proposed extrapolating the time to stopping treatment using the log-logistic rather than exponential distribution. It considered that this aligned more closely with the progression-free survival curve. The ERG further noted that, if enzalutamide plus ADT progression-free survival was estimated by applying hazard ratios from the network meta-analysis, the time to stopping treatment could not be modelled separately from progression-free survival. The committee concluded that the time to stopping treatment should have closely resembled progression-free survival. The committee agreed with the ERG using hazard ratios to estimate progression-free survival. So, it also concluded that, in this case, progression-free survival should be used to model treatment discontinuation.
# Cost-effectiveness estimate
## There is a preferred approach to the economic modelling
The committee's first meeting occurred before the European Medicines Agency (EMA) granted a marketing authorisation. At this point, the committee agreed that its preferred approach to modelling would:
extrapolate progression-free survival for ADT alone from ARCHES using the exponential distribution (see section 3.14)
extrapolate overall survival for ADT alone from pooled data using the Weibull distribution (see section 3.15)
model survival with enzalutamide plus ADT using the hazard ratios from the network meta-analysis applied to the ADT progression-free and overall-survival curves (see section 3.14 and section 3.15)
model survival with docetaxel plus ADT using the hazard ratios from the network meta-analysis applied to the ADT progression-free and overall-survival curves (see section 3.16)
adjust the cost-effectiveness estimates for the costs and benefits of treatments used for hormone-resistant metastatic prostate cancer (see section 3.17).The committee also agreed that it would like to see a scenario in which the hazards of survival are the same at 8.5 years for all comparators (see section 3.18).
## The company has updated its commercial offer, which takes into account the preferred approach if possible
After the committee's first meeting, the appraisal was paused. After the EMA granted a positive opinion, the company updated its commercial offer and acknowledged the committee's preferred assumptions. The committee, in a second closed meeting, considered the ERG's base case, which reflected its preferred assumptions, plus a scenario in which the hazards of survival were the same at 8.5 years for all comparators. The committee was aware that, because of the model the company chose, it adjusted only for costs, and not for the effects of subsequent treatments for hormone-relapsed metastatic prostate cancer to match NHS practice, (see section 3.18).
## Enzalutamide plus ADT for hormone-sensitive metastatic prostate cancer is a cost-effective use of NHS resources
Because of confidential discounts for therapies taken during the hormone-relapsed metastatic stage, none of the cost-effectiveness results can be reported here. The ERG presented analyses reflecting the committee's preferred assumptions and scenarios (see section 3.20). In these analyses, the incremental cost-effectiveness ratios were within the range that NICE usually considers an acceptable use of NHS resources (£20,000 to £30,000 per quality-adjusted life year gained). The committee was aware that it had not seen data for people who could take enzalutamide plus ADT, but who could not have docetaxel plus ADT (see section 3.6) and for whom ADT alone is the only NHS treatment option. However, the committee took into account the uncertainties in these people around the relative effectiveness, baseline risk of dying and health-related quality of life. It then concluded that estimates of cost effectiveness were sufficiently low to account for this uncertainty for people who could not have docetaxel plus ADT. The committee therefore concluded that it could recommend enzalutamide plus ADT for routine commissioning.
# Equality issues
## The recommendations apply to all people with prostate cancer
The committee noted that, as in previous appraisals for technologies for treating prostate cancer, its recommendations should apply to trans women as well as to men. No other equality issues were raised during the scoping process or in the submissions for this appraisal.
# Innovation
## The modelling captures all the benefits
The company considered enzalutamide to be innovative because it is an oral treatment and needs less monitoring than docetaxel plus ADT. It discussed whether enzalutamide reflects a 'step change' in treatment and whether the model captured the benefits of treatment. The committee recognised that many individuals who have not had enzalutamide plus ADT for hormone-sensitive metastatic prostate cancer have the option of getting it at 2 different points later in the treatment pathway for hormone-relapsed metastatic prostate cancer. It concluded that enzalutamide plus ADT, despite its associated advantages, is not a step change in the treatment of hormone-sensitive metastatic prostate cancer, but that the model captured the relevant benefits.
# Other factors
## End of life criteria are not met
The company did not make a case for enzalutamide plus ADT meeting NICE's end of life criteria. NICE's advice about life-extending treatments for people with a short life expectancy did not apply.
# Conclusion
## Enzalutamide plus ADT is recommended for hormone-sensitive metastatic prostate cancer
Early trial results suggested that enzalutamide plus ADT increases progression-free and overall survival compared with ADT alone. Also, the results of an indirect comparison suggested that, compared with docetaxel plus ADT, enzalutamide plus ADT increases progression-free survival but its comparative effect on overall survival is unclear. The cost-effectiveness estimates are below what NICE considers an acceptable use of NHS resources. Therefore, the committee concluded that enzalutamide plus ADT is recommended for hormone-sensitive metastatic prostate cancer.
|
{'Recommendations': 'Enzalutamide plus androgen deprivation therapy (ADT) is recommended, within its marketing authorisation, as an option for treating hormone-sensitive metastatic prostate cancer in adults. It is only recommended if the company provides enzalutamide according to the agreed commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for hormone-sensitive metastatic prostate cancer in the NHS is ADT alone, or docetaxel plus prednisolone or prednisone (from now, docetaxel) plus ADT. Enzalutamide plus ADT would offer another option for people with hormone-sensitive metastatic prostate cancer, especially for people who cannot have docetaxel. It is taken by mouth so is more convenient than docetaxel, which is an intravenous treatment.\n\nTrial results suggest that, compared with ADT alone, enzalutamide plus ADT increases the time until the cancer progresses and how long people live. Also, an indirect comparison suggests that, compared with docetaxel plus ADT, enzalutamide plus ADT increases the time until the cancer progresses. But, it is unclear whether there is a difference between the 2\xa0treatments in the length of time people live.\n\nThe cost-effectiveness estimates are within the range NICE considers an acceptable use of NHS resources. Therefore, enzalutamide plus ADT is recommended for hormone-sensitive metastatic prostate cancer.', 'Information about enzalutamide': "# Marketing authorisation indication\n\nEnzalutamide (Xtandi, Astellas) is indicated for 'the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of a 112‑capsule pack of 40\xa0mg enzalutamide is £2,734.67 (excluding VAT; BNF online, accessed May\xa02020). The daily dose of enzalutamide is 160\xa0mg and costs £97.67.\n\nThe company has a commercial arrangement. This makes enzalutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Astellas, the company that markets enzalutamide, a review of this submission by the evidence review group (ERG), the technical report prepared by NICE and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage. It agreed that there should be a total utility decrement of 0.093 across the hormone-relapsed health sub-states (issue\xa07 page\xa026 of the technical report). It discussed the issues that were outstanding after the technical engagement stage.\n\n# Clinical need and clinical management\n\n## People with hormone-sensitive metastatic prostate cancer would welcome the option of treatment with enzalutamide\n\nThe clinical and patient experts noted that people with hormone-sensitive metastatic prostate cancer have limited treatment options. NICE's guideline on prostate cancer recommends androgen deprivation therapy (ADT) alone, and docetaxel with prednisolone or prednisone (from now, docetaxel) plus ADT. The patient experts explained that, when people are first diagnosed with metastatic prostate cancer, they may have no or few symptoms. They also explained that some people perceive that treatment with docetaxel worsens quality of life and choose to have ADT alone, even though the long-term outcomes may be worse than with docetaxel plus ADT. So, because enzalutamide plus ADT is generally better tolerated than docetaxel plus ADT, and is more effective than ADT alone, people would welcome it as an option at this point in the treatment pathway. The committee concluded that some people with hormone-sensitive metastatic prostate cancer would welcome the option of treatment with enzalutamide plus ADT.\n\n## Temporary guidance on enzalutamide for hormone-sensitive metastatic prostate cancer will be superseded by this appraisal's recommendations\n\nNICE's rapid guideline on the delivery of systemic anticancer treatments during the COVID-19 pandemic aims to:\n\nmaximise the safety of patients with cancer\n\nmake the best use of NHS resources\n\nprotect staff from infection\n\nenable services to match the capacity for cancer treatment to patient needs if services become limited because of the COVID‑19 pandemic.The guideline provides a link to the interim treatment change options during the COVID-pandemic, which are endorsed by NHS England. It includes the option of giving enzalutamide plus ADT instead of docetaxel to reduce toxicity and the potential for hospital admission. Treatment regimens will revert to the standard commissioned position after this period unless the guideline is updated. Any interim treatment subject to an ongoing NICE technology appraisal will be superseded by an appraisal guidance.\n\n## ADT alone and docetaxel plus ADT are both relevant comparators\n\nThe committee was aware that the NICE scope included as comparators, ADT alone and docetaxel plus ADT. The clinical experts explained that both are offered in the NHS to people with hormone-sensitive metastatic prostate cancer. The committee was also aware of the ongoing NICE technology appraisals on abiraterone plus ADT for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer and apalutamide for treating prostate cancer. The committee concluded that neither abiraterone plus prednisone (from now, abiraterone) and ADT nor apalutamide plus ADT were comparators because they are not routinely commissioned at this point in the treatment pathway. The Cancer Drugs Fund's clinical lead noted that around two-thirds of people presenting with hormone-sensitive metastatic prostate cancer in England have ADT alone. Of these people, some are not fit enough for docetaxel, and some choose not to have it because of its adverse events (see section\xa03.1). NHS England's docetaxel commissioning policy states that someone may not be fit enough for docetaxel if they have:\n\na poor overall performance status (World Health Organization [WHO] performance 3\xa0to\xa04)\n\npre-existing peripheral neuropathy\n\npoor bone marrow function or\n\na life-limiting illness.The policy also states that docetaxel should be used with caution in people with a WHO performance status of 2, and that there are few absolute contraindications for docetaxel therapy. The committee concluded that ADT alone and docetaxel plus ADT were relevant comparators for people who could have docetaxel plus ADT, and that ADT alone was the relevant comparator for people who could not have docetaxel. The committee recognised the importance of patient choice when all treatment options are clinically and cost effective.\n\n## The first treatment for hormone-sensitive metastatic prostate cancer affects the number of life-extending treatments people have later\n\nUnder NHS policy, people who have docetaxel plus ADT for hormone-sensitive prostate cancer for up to 6 cycles can have docetaxel again (for up to 10 cycles) for hormone-relapsed prostate cancer. This is because the benefit of docetaxel is not exhausted. Other treatment options for hormone-relapsed metastatic prostate cancer include both enzalutamide and abiraterone when chemotherapy is not yet clinically indicated, or after a docetaxel-based regimen. In summary, enzalutamide has a licence for 4 positions in the treatment pathway (including 1 for non-metastatic prostate cancer). However, the Cancer Drugs Fund clinical lead explained that NHS England commissions each of enzalutamide and abiraterone only once in the treatment pathway. This is because there is no evidence of clinical benefit for using one after the other. It means that people who have enzalutamide plus ADT for hormone-sensitive metastatic prostate cancer cannot have enzalutamide or abiraterone later in the treatment pathway. It also means that people who have docetaxel plus ADT first for hormone-sensitive metastatic prostate cancer have more treatment options than people who have enzalutamide plus ADT first. This is because they can have either enzalutamide or abiraterone, and can also have docetaxel again. The sequence of follow-on treatments when the cancer is hormone-relapsed may vary from person to person. Possible treatments include:\n\nAfter ADT alone, or docetaxel plus ADT:\n\n\n\nenzalutamide or abiraterone (before or after docetaxel)\n\ndocetaxel\n\nother active treatments such as cabazitaxel or radium 223.\n\n\n\nAfter enzalutamide plus ADT:\n\n\n\ndocetaxel\n\nother active treatments such as cabazitaxel or radium 223.The committee concluded that the treatment choice for hormone-sensitive metastatic prostate cancer affects the treatments a person can have when the cancer is hormone-relapsed. It also concluded that having enzalutamide plus ADT at this point in the pathway limits the number of life-extending treatment options compared with having ADT alone or docetaxel plus ADT.\n\n\n\n# Clinical evidence\n\n## ARCHES and ENZAMET are both relevant trials for assessing the clinical effectiveness of enzalutamide plus ADT\n\nTwo randomised controlled trials, ARCHES and ENZAMET, have investigated the clinical effectiveness of enzalutamide plus ADT for treating hormone-sensitive metastatic prostate cancer:\n\nARCHES was a double-blind trial including 1,150\xa0people with hormone-sensitive metastatic prostate cancer. It compared enzalutamide plus ADT (n=574) with ADT alone (n=576). The primary endpoint was progression-free survival. Overall survival and health-related quality of life were secondary endpoints.\n\nENZAMET was an investigator-led open-label trial including 1,125\xa0people with hormone-sensitive metastatic prostate cancer. It compared enzalutamide plus ADT (n=563) with conventional non-steroidal anti-androgens (NSAAs) plus ADT (n=562). The primary endpoint was overall survival. Progression-free survival and health-related quality of life were secondary endpoints. People could have concomitant docetaxel, which is not included in the marketing authorisation for enzalutamide. Therefore, the company submission included data only from the 622\xa0people who did not have concomitant docetaxel (309\xa0in the enzalutamide plus ADT arm and 313\xa0in the comparator arm).The company had access to patient-level data for both trials. The trials differed by proportion of people with high-volume disease (see section\xa03.6), comparator (the control treatment; see section\xa03.7), concomitant use of docetaxel and definition of progression-free survival (see section\xa03.8). The committee discussed these in turn. It concluded that both trials were relevant for assessing the clinical effectiveness of enzalutamide plus ADT for hormone-sensitive metastatic prostate cancer.\n\n## Patient characteristics in ARCHES and ENZAMET are broadly generalisable to NHS clinical practice\n\nThe baseline characteristics of the people in ARCHES and ENZAMET were similar. However, more people in ARCHES had Gleason scores equal to or greater than\xa08, or high-volume disease. The proportion of people with high-volume disease in ARCHES was similar to that in STAMPEDE, an entirely UK-based trial assessing the best way to treat newly diagnosed advanced prostate cancer. The clinical experts agreed that people with high-volume disease have poorer prognoses than people with low-volume disease. However, they disagreed on whether disease volume modifies the relative effectiveness of treatment. One clinical expert noted that, in STAMPEDE, volume of disease did not alter treatment effectiveness. The committee noted that the evidence for enzalutamide plus ADT was based on a relatively fit population. It specifically excluded people with an Eastern Cooperative Oncology Group performance status of 2\xa0or above, significant cardiovascular or renal disease, and other conditions. So, it may not be representative of some of the people who cannot have docetaxel. The committee appreciated that these issues could have added uncertainty to the results of the economic modelling. It concluded that the trials were broadly generalisable to NHS practice.\n\n## ENZAMET employs a comparator not used in the NHS, but the results of ARCHES and ENZAMET are appropriate for decision making\n\nARCHES compared enzalutamide plus ADT with ADT alone while ENZAMET compared it with conventional NSAAs plus ADT. The committee highlighted that using NSAAs does not reflect UK clinical practice and the company acknowledged this. However, the company did not think that it would affect the generalisability of the results to NHS clinical practice. The clinical experts confirmed that conventional NSAAs are not used in the NHS in this setting. They explained that evidence suggested the combination may be more effective than ADT alone, but that adverse events are increased when adding NSAAs to ADT. The committee concluded that the results of both trials were appropriate for decision making.\n\n## The definition of progression-free survival in ENZAMET more closely reflects NHS clinical practice than that in ARCHES\n\nThe 2\xa0trials measured progression-free survival differently. In ENZAMET, it was defined based on clinical progression by radiographic imaging, symptoms attributable to cancer progression or starting another treatment for prostate cancer. This was broader than in ARCHES, in which progression-free survival was defined based on radiographic disease progression by an independent blinded and central review. The company chose only to model progression-free survival from ARCHES (see section\xa03.13). The clinical experts explained that there is more than a single way in clinical practice to assess progression-free survival, and that different centres might use different definitions. They confirmed that other measures might include serum prostate specific antigen. The committee concluded that it was appropriate to consider progression-free survival from both trials, and that the definition from ENZAMET better reflected NHS practice.\n\n## Enzalutamide plus ADT extends progression-free survival compared with ADT alone or NSAAs plus ADT; overall-survival data are immature\n\nThe company presented data from planned final analyses for progression-free survival from ARCHES and ENZAMET. However, the trials are ongoing for the endpoint of overall survival. In ARCHES, enzalutamide plus ADT improved progression-free survival compared with ADT alone. The time to median progression-free survival was not reached for enzalutamide plus ADT and, for ADT alone, was 19\xa0months. The hazard ratio was 0.39 (95% confidence interval [CI] 0.30\xa0to\xa00.50). In ARCHES, cancer progressed in 16% of people in the treatment group and in 35% in the control group. In ENZAMET, enzalutamide plus ADT improved progression-free survival compared with conventional NSAAs plus ADT (hazard ratio [HR]\xa00.34, 95%\xa0CI 0.26\xa0to\xa00.44). The number of events was not available for ENZAMET. The median follow up was 14.4\xa0months in ARCHES and 37.0\xa0months in ENZAMET. At the same time as doing final analyses for progression-free survival, the investigators did interim data analyses for overall survival. In ARCHES, 84\xa0deaths had occurred at the time of the interim analysis out of the 342\xa0deaths specified in the statistical analysis plan for the final analysis. In ENZAMET, 245\xa0deaths had occurred at the time of the interim analysis out of the specified 470\xa0deaths. At the time of the interim analysis, most people were still alive in both trials, and median overall survival could not be estimated in any treatment arm. Interim analyses from both trials suggested that enzalutamide plus ADT improved overall survival (ARCHES: HR\xa00.81, 95%\xa0CI 0.53\xa0to\xa01.25; ENZAMET: HR\xa00.53, 95%\xa0CI 0.37\xa0to\xa00.74). The confidence interval for the estimate from ENZAMET included the possibility of no effect. The company presented an analysis for overall survival based on unadjusted pooling of patient-level data from both trials. The committee did not support unadjusted pooling of results (see section\xa03.11). The ERG did not use the unadjusted pooled data to estimate overall survival. Instead, it modelled overall survival using hazard ratios from the company's network meta-analysis applied to the ADT-alone overall-survival curve. The committee concluded that enzalutamide plus ADT delayed time to progression compared with ADT alone, but that the data for overall survival were immature. This meant that the size of the overall benefit of enzalutamide plus ADT compared with ADT alone was uncertain.\n\n## Enzalutamide plus ADT extends progression-free survival compared with docetaxel plus ADT, but evidence on overall survival is uncertain\n\nThere are no trials that directly compare enzalutamide plus ADT with docetaxel plus ADT. The company did a network meta-analysis that included ARCHES and ENZAMET, 3\xa0trials of docetaxel plus ADT compared with ADT alone (STAMPEDE1, CHAARTED and GETUG) and 6\xa0trials of conventional NSAAs plus ADT compared with ADT alone (DAPROC, EORTC\xa030853, INTERGROUP STUDY\xa00036, SWOG‑8894, Janknegt 1993 and Zalcberg 1996). The results suggested longer progression-free survival for enzalutamide plus ADT compared with docetaxel plus ADT. For overall survival, the point estimate suggested a benefit for enzalutamide plus ADT but included the possibility of no effect. None of the results can be reported here because the company considers them confidential. The committee concluded that enzalutamide plus ADT extended progression-free survival when compared with docetaxel plus ADT, but evidence on overall survival was uncertain.\n\n## A network meta-analysis is better than unadjusted pooling to estimate effect on survival of enzalutamide plus ADT compared with ADT alone\n\nThe committee discussed the implications of pooling data from the 2\xa0trials, ARCHES and ENZAMET, with different treatments for the control arm. It was aware that the company's network meta-analysis (see section\xa03.10) included 6\xa0trials of conventional NSAAs plus ADT compared with ADT alone. The results of the network meta-analysis also showed a benefit of NSAAs plus ADT compared with ADT alone, which included the possibility of no effect. To avoid using the pooled overall-survival data, the ERG estimated overall survival using hazard ratios from the company's network meta-analysis applied to the ADT-alone overall-survival curve. The committee concluded that, when comparing enzalutamide plus ADT to ADT alone, the network meta-analysis should inform the treatment effect for overall survival. It was aware that the data from ARCHES for ADT alone and ENZAMET for conventional NSAAs plus ADT would still need to be pooled to provide a reference curve for applying treatment effect hazard ratios.\n\n# Cost effectiveness\n\n## The company's partitioned survival model is appropriate for decision making\n\nThe company presented a partitioned survival model that included 3\xa0main health states: hormone-sensitive disease, hormone-relapsed disease and death. The hormone-sensitive health state included on- and off-treatment sub-states. The hormone-relapsed health state included 3\xa0sub‑states for follow-on treatments. The committee concluded that the model structure was appropriate for decision making.\n\n## A scenario analysis using data from ENZAMET to model progression-free survival would be informative\n\nBoth ARCHES and ENZAMET provided data on progression-free survival, but ENZAMET had a longer duration. According to the company, progression-free survival in ARCHES closely resembled that of ENZAMET. Therefore, it used patient-level data from ARCHES to model progression-free survival for enzalutamide plus ADT and ADT alone. It considered that it could not combine data from ENZAMET and ARCHES for progression-free survival because of the different ways in which this outcome was measured. The committee recalled that the definition of progression-free survival in ENZAMET more closely reflected that used in NHS clinical practice (see section\xa03.8). However, the hazard ratios from both trials were similar (ARCHES: HR\xa00.39 and ENZAMET: HR\xa00.34; see section\xa03.9). As such, the committee considered that using 1\xa0trial instead of another was unlikely to have had a large effect on the cost-effectiveness results. It concluded that it was reasonable to use data from ARCHES if using data from only a single trial to model progression-free survival.\n\n## The company's methods for estimating progression-free survival is not appropriate\n\nTo extrapolate progression-free survival beyond the trial duration and over the lifetime horizon defined in the model, the company used data only from ARCHES (see section\xa03.13). It fitted a log-normal distribution to both arms of the trial. The committee noted that median follow up in ARCHES was only 14.4\xa0months, and that cancer had not progressed in most people at the final analysis for progression-free survival. This increased the uncertainties associated with estimating average progression-free survival by treatment arm. The immaturity of the data also meant that most distributions fitted well to the observed trial data. The company based its choice of distribution, the log-normal distribution, on input from clinical experts. It externally validated its choice using data from long-term survival on ADT from STAMPEDE and GETUG. The ERG commented that, when extrapolating progression-free survival using the log-normal distribution, the 5- and 10‑year estimates for progression-free survival for ADT seemed implausibly low. The clinical experts considered that around 20% of people who take enzalutamide plus ADT remain progression free at 5\xa0years, which drops to 10% at 10\xa0years. Both values are lower than those suggested in the company's model. The ERG suggested that:\n\nfor ADT alone:\n\n\n\nthe exponential distribution produced estimates for progression-free survival that were more in line with those seen in the UK (based on data from STAMPEDE with a 4‑year median follow up)\n\n\n\nfor enzalutamide plus ADT:\n\n\n\nthe log-logistic distribution predicted progression-free survival more in line with the clinical experts' opinion in the shorter term\n\napplying the hazard ratio from the network meta-analysis for enzalutamide plus ADT to the extrapolated ADT curve produced estimates more in line with clinical expert expectations for later years.The committee concluded that, for ADT alone, it preferred using an exponential distribution to extrapolate the data from ARCHES. For enzalutamide plus ADT, it considered that using the hazard ratios from the network meta-analysis produced more plausible estimates than separately fitting a curve to the immature enzalutamide plus ADT data. However, the committee was concerned that this approach implied that the treatment effect would be expected to continue indefinitely, which may not be credible.\n\n\n\n## The ERG's estimates of survival for people taking enzalutamide plus ADT are more plausible than the company's estimates\n\nTo model overall survival for ADT alone and enzalutamide plus ADT, the company pooled data from ARCHES and ENZAMET (see section\xa03.9). It extrapolated beyond the trial duration and over the lifetime horizon defined in the model by fitting a Weibull distribution to both arms. The company based its choice of a Weibull distribution on input from clinical experts, and by externally validating its choice using data from STAMPEDE, CHAARTED and GETUG. The ERG considered that the predictions for how long people survive who take ADT alone were reasonably consistent with long-term data from STAMPEDE. However, it was concerned that 10- and 20‑year figures reflecting the proportion of people still alive after taking enzalutamide plus ADT were implausibly high with the Weibull distribution. The clinical experts estimated that overall survival with enzalutamide plus ADT would be around 10% to 20% at 10\xa0years, and 0% to 5% at 20\xa0years. The company's modelling suggested that a greater proportion of people would be alive at 20\xa0years than estimated by the clinical experts. The committee noted that, because of the immaturity of the data, most distributions provided similar predictions. Only the Gompertz distribution predicted lower survival for enzalutamide plus ADT than the company's choice. The ERG explained that the Gompertz distribution may have underpredicted survival on enzalutamide plus ADT at later years. The ERG preferred using the hazard ratio from the network meta-analysis applied to the ADT alone curve because it gave better predictions than other curves for enzalutamide plus ADT survival after around 10\xa0years. The committee agreed with the ERG. It concluded that using hazard ratios for enzalutamide plus ADT compared with ADT alone from the network meta-analysis (see section\xa03.11) estimated the relative treatment effect for enzalutamide plus ADT compared with ADT alone better than the company's approach. This was because it accounted for the different comparators in ARCHES and ENZAMET better than the company's approach of unadjusted pooling. However, the committee was again concerned that this approach implied that the treatment effect would be expected to continue indefinitely.\n\n## It is important to consider the survival advantage scenarios associated with enzalutamide plus ADT compared with docetaxel plus ADT\n\nTo model overall survival with docetaxel plus ADT, the company applied hazard ratios from the network meta-analysis for docetaxel plus ADT compared with ADT alone to the ADT curve. This predicted a survival benefit for docetaxel plus ADT compared with ADT alone, reflecting trial evidence. The company's model also predicted a survival benefit with enzalutamide plus ADT compared with docetaxel plus ADT. The point estimate from the network meta-analysis favoured enzalutamide plus ADT, but the credible interval included\xa01, the possibility of no effect. The committee noted that people who take enzalutamide plus ADT have fewer life-extending treatment options later (see section\xa03.4). Therefore, it considered that there might be no survival benefit with enzalutamide plus ADT compared with docetaxel plus ADT. To explore this uncertainty, the ERG provided scenario analyses modelling no survival benefit for enzalutamide plus ADT compared with docetaxel plus ADT. The committee concluded that, given the uncertainty around the overall-survival estimate, it was appropriate to consider these analyses.\n\n## Life-extending treatments during hormone-relapsed prostate cancer in ARCHES differ from those used in NHS clinical practice\n\nThe committee acknowledged that people with hormone-sensitive metastatic prostate cancer:\n\nhave enzalutamide plus ADT, docetaxel plus ADT or ADT alone until disease progression\n\nat progression, have other treatment options\n\ncan have enzalutamide or abiraterone only once\n\nhave fewer options for life-extending follow-on treatments if they have enzalutamide early in the treatment pathway than people who first have ADT alone or docetaxel plus ADT (see section\xa03.4).ARCHES was a double-blind trial, and people could have enzalutamide or abiraterone as follow-on treatments in both treatment arms. At the time of the interim analysis, 54% of people who had follow-on treatments in ARCHES had enzalutamide again or abiraterone after enzalutamide. Also, fewer people in the ADT arm went on to have follow-on treatment with enzalutamide or abiraterone in ARCHES (46%) than was modelled by the company (70%). The company did not provide details of treatments during hormone-relapsed prostate cancer in ENZAMET. The committee agreed that the company's modelling of the costs of follow-on treatments reflected NHS costs, but was concerned that the company had not adjusted the effectiveness data to match. In the model, a greater proportion of people having ADT alone incurred costs from having enzalutamide or abiraterone after progression than in ARCHES. However, the company did not account for the benefits of treatment. The committee acknowledged the immaturity of the data from ARCHES, and that the proportion of people on different treatments could change over time. It concluded that it would have preferred the company to adjust for both the costs and effects of treatments for hormone-relapsed metastatic prostate cancer to match NHS practice.\n\n## It is uncertain whether the benefits of active treatments persist\n\nThe company's model predicted that the benefit for overall survival with enzalutamide plus ADT compared with ADT alone or docetaxel plus ADT lasted for the model's 30‑year time horizon. This was the case whether extrapolated survival curves were used to estimate enzalutamide's treatment effect compared with ADT or the hazard ratio from the network meta-analysis. Data from STAMPEDE showed that there was an initial survival benefit at 5\xa0years with docetaxel plus ADT compared with ADT alone (49% compared with 37%). However, the ERG highlighted that there was no difference in actual overall survival after 8.5\xa0years (23% compared with 22%). This may have been because people on ADT alone go on to have other life-extending treatments and so 'catch-up' (see section\xa03.4 and\xa0section 3.17). One clinical expert explained that the effect of early systemic treatment lasts for a long time, so catching up might be unlikely. He noted that there were longer follow-up data for abiraterone plus ADT than for enzalutamide plus ADT, and that he thought that both have a similar mechanism of action. These data for abiraterone showed that more people remained alive on abiraterone plus ADT than on docetaxel plus ADT or on ADT alone beyond 5\xa0years. The ERG presented scenario analyses in which the hazards of survival for enzalutamide plus ADT and the comparators were the same after 8.5\xa0years. The committee concluded that, in the absence of long-term data for enzalutamide plus ADT, the ERG's scenarios in which the hazard ratios were equalised between treatment options after 8.5\xa0years were useful for assessing the uncertainty.\n\n## Few people will stop treatment with enzalutamide plus ADT before disease progression\n\nIn the company's model, people could be on or off treatment before disease progression. The ERG was concerned that people who were off treatment before disease progression would maintain the same quality of life as people on treatment, but at no additional cost. In ARCHES, around 12% of people stopped treatment before disease progression. According to the company, only about half of them stopped because of adverse events, while others withdrew consent. The clinical experts explained that, in clinical practice, few people would stop having enzalutamide plus ADT before disease progression because it is generally well tolerated. The committee considered that withdrawing consent is specific to trials and would not be reflected in clinical practice. The ERG noted that, in the company's model, there was a substantial gap between the curves for progression-free survival and time to stopping treatment. The ERG proposed extrapolating the time to stopping treatment using the log-logistic rather than exponential distribution. It considered that this aligned more closely with the progression-free survival curve. The ERG further noted that, if enzalutamide plus ADT progression-free survival was estimated by applying hazard ratios from the network meta-analysis, the time to stopping treatment could not be modelled separately from progression-free survival. The committee concluded that the time to stopping treatment should have closely resembled progression-free survival. The committee agreed with the ERG using hazard ratios to estimate progression-free survival. So, it also concluded that, in this case, progression-free survival should be used to model treatment discontinuation.\n\n# Cost-effectiveness estimate\n\n## There is a preferred approach to the economic modelling\n\nThe committee's first meeting occurred before the European Medicines Agency (EMA) granted a marketing authorisation. At this point, the committee agreed that its preferred approach to modelling would:\n\nextrapolate progression-free survival for ADT alone from ARCHES using the exponential distribution (see section\xa03.14)\n\nextrapolate overall survival for ADT alone from pooled data using the Weibull distribution (see section\xa03.15)\n\nmodel survival with enzalutamide plus ADT using the hazard ratios from the network meta-analysis applied to the ADT progression-free and overall-survival curves (see section\xa03.14 and\xa0section 3.15)\n\nmodel survival with docetaxel plus ADT using the hazard ratios from the network meta-analysis applied to the ADT progression-free and overall-survival curves (see section\xa03.16)\n\nadjust the cost-effectiveness estimates for the costs and benefits of treatments used for hormone-resistant metastatic prostate cancer (see section\xa03.17).The committee also agreed that it would like to see a scenario in which the hazards of survival are the same at 8.5\xa0years for all comparators (see section\xa03.18).\n\n## The company has updated its commercial offer, which takes into account the preferred approach if possible\n\nAfter the committee's first meeting, the appraisal was paused. After the EMA granted a positive opinion, the company updated its commercial offer and acknowledged the committee's preferred assumptions. The committee, in a second closed meeting, considered the ERG's base case, which reflected its preferred assumptions, plus a scenario in which the hazards of survival were the same at 8.5\xa0years for all comparators. The committee was aware that, because of the model the company chose, it adjusted only for costs, and not for the effects of subsequent treatments for hormone-relapsed metastatic prostate cancer to match NHS practice, (see section\xa03.18).\n\n## Enzalutamide plus ADT for hormone-sensitive metastatic prostate cancer is a cost-effective use of NHS resources\n\nBecause of confidential discounts for therapies taken during the hormone-relapsed metastatic stage, none of the cost-effectiveness results can be reported here. The ERG presented analyses reflecting the committee's preferred assumptions and scenarios (see section\xa03.20). In these analyses, the incremental cost-effectiveness ratios were within the range that NICE usually considers an acceptable use of NHS resources (£20,000 to £30,000 per quality-adjusted life year gained). The committee was aware that it had not seen data for people who could take enzalutamide plus ADT, but who could not have docetaxel plus ADT (see section\xa03.6) and for whom ADT alone is the only NHS treatment option. However, the committee took into account the uncertainties in these people around the relative effectiveness, baseline risk of dying and health-related quality of life. It then concluded that estimates of cost effectiveness were sufficiently low to account for this uncertainty for people who could not have docetaxel plus ADT. The committee therefore concluded that it could recommend enzalutamide plus ADT for routine commissioning.\n\n# Equality issues\n\n## The recommendations apply to all people with prostate cancer\n\nThe committee noted that, as in previous appraisals for technologies for treating prostate cancer, its recommendations should apply to trans women as well as to men. No other equality issues were raised during the scoping process or in the submissions for this appraisal.\n\n# Innovation\n\n## The modelling captures all the benefits\n\nThe company considered enzalutamide to be innovative because it is an oral treatment and needs less monitoring than docetaxel plus ADT. It discussed whether enzalutamide reflects a 'step change' in treatment and whether the model captured the benefits of treatment. The committee recognised that many individuals who have not had enzalutamide plus ADT for hormone-sensitive metastatic prostate cancer have the option of getting it at 2\xa0different points later in the treatment pathway for hormone-relapsed metastatic prostate cancer. It concluded that enzalutamide plus ADT, despite its associated advantages, is not a step change in the treatment of hormone-sensitive metastatic prostate cancer, but that the model captured the relevant benefits.\n\n# Other factors\n\n## End of life criteria are not met\n\nThe company did not make a case for enzalutamide plus ADT meeting NICE's end of life criteria. NICE's advice about life-extending treatments for people with a short life expectancy did not apply.\n\n# Conclusion\n\n## Enzalutamide plus ADT is recommended for hormone-sensitive metastatic prostate cancer\n\nEarly trial results suggested that enzalutamide plus ADT increases progression-free and overall survival compared with ADT alone. Also, the results of an indirect comparison suggested that, compared with docetaxel plus ADT, enzalutamide plus ADT increases progression-free survival but its comparative effect on overall survival is unclear. The cost-effectiveness estimates are below what NICE considers an acceptable use of NHS resources. Therefore, the committee concluded that enzalutamide plus ADT is recommended for hormone-sensitive metastatic prostate cancer."}
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https://www.nice.org.uk/guidance/ta712
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Evidence-based recommendations on enzalutamide (Xtandi) for treating hormone-sensitive metastatic prostate cancer in adults.
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6f100411bf6a9c1d8b9897b25a54eeed34749034
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nice
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Nivolumab for advanced non-squamous non-small-cell lung cancer after chemotherapy
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Nivolumab for advanced non-squamous non-small-cell lung cancer after chemotherapy
Evidence-based recommendations on nivolumab (Opdivo) for advanced non-squamous non-small-cell lung cancer in adults after chemotherapy.
# Recommendations
Nivolumab is recommended as an option for treating locally advanced or metastatic non-squamous non-small-cell lung cancer (NSCLC) in adults after chemotherapy, only if:
their tumours are PD-L1 positive, and
it is stopped at 2 years of uninterrupted treatment, or earlier if their disease progresses, and
they have not had a PD-1 or PD-L1 inhibitor before.It is recommended only if the company provides nivolumab according to the commercial arrangement.
Why the committee made these recommendations
The treatment pathway for locally advanced or metastatic non-squamous NSCLC starts with a PD-1 or PD-L1 inhibitor or chemotherapy. Nivolumab would be used after chemotherapy.
Evidence collected in the Cancer Drugs Fund is for people with PD‑L1-positive disease having up to 2 years of nivolumab treatment in the NHS. The key clinical trial shows that people with PD‑L1-positive tumours who have nivolumab live longer than those who have docetaxel, which is the most appropriate comparator. There is uncertainty about how long people should have nivolumab for, but evidence shows that there is continued benefit when treatment is stopped at 2 years.
Nivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates for nivolumab compared with docetaxel are likely to be within what NICE considers an acceptable use of NHS resources. Therefore, it is now recommended in the NHS for people with PD‑L1-positive tumours who have not had a PD‑1 or PD‑L1 inhibitor before, when it is stopped at 2 years.# Information about nivolumab
# Marketing authorisation indication
Nivolumab (Opdivo, Bristol–Myers Squibb) has a marketing authorisation for 'the treatment of locally advanced or metastatic non-small-cell lung cancer after prior chemotherapy in adults'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of nivolumab is £2,633 per 240 mg per 24 ml vial (excluding VAT; BNF online, accessed March 2020). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bristol–Myers Squibb and a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
This review looks at data collected after time in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal can be found in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the CheckMate 057 study. In addition, data were collected on nivolumab for people with PD‑L1-positive disease in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.
The committee recognised that there were remaining areas of uncertainty in the analyses presented (see technical report, table 3, page 23) and took these into account in its decision making. The committee discussed the following issues, which were outstanding after the technical engagement stage:
the appropriate comparator
parametric models to predict overall survival and progression-free survival
utility values
the 2-year stopping rule for nivolumab and the continued duration of treatment benefit if nivolumab is stopped at 2 years.
# Clinical need
## People with previously treated advanced NSCLC with PD-L1-positive tumours value nivolumab as a treatment
Non-squamous non-small-cell lung cancer (NSCLC) is often diagnosed late in life and causes debilitating and distressing symptoms. The clinical expert submission explained that overall survival for lung cancer in the UK is poor, but the introduction of immunotherapies such as nivolumab means people can live longer. The committee was aware that patients and professionals want treatments that are effective, minimally disruptive, and improve quality of life. It noted that some patients had experienced anxiety and distress because of the 2-year stopping rule used in the original guidance. This was because they did not want to stop benefitting from treatment. The clinical expert submission suggested that in clinical practice nivolumab would be used when people had not had a previous PD-1 or PD-L1 inhibitor. The committee concluded that people with locally advanced or metastatic non-squamous NSCLC with PD-L1-positive tumours would value nivolumab as a treatment option.
## Docetaxel alone is the most appropriate comparator
In the original appraisal, docetaxel monotherapy, nintedanib plus docetaxel for people with adenocarcinoma and best supportive care were considered relevant comparators. The committee was aware that since its publication, pembrolizumab and atezolizumab have been recommended for previously treated locally advanced or metastatic NSCLC (see NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic NSCLC after chemotherapy and pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy). There have also been changes to treatment options for untreated disease (see NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC and pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous NSCLC). The Cancer Drugs Fund clinical lead from NHS England confirmed that the treatment pathway had changed and because immunotherapies were now available for untreated disease, nivolumab was not used as often for previously treated disease. In line with NICE's methods guide for technology appraisals, the original scope was not changed for this Cancer Drugs Fund review. This meant that pembrolizumab and atezolizumab could not be considered comparators because they were recommended after the original guidance was published. The company only submitted cost-effectiveness analyses comparing nivolumab with docetaxel alone because it stated that neither best supportive care nor nintedanib and docetaxel are commonly used in clinical practice. Clinical advice to the ERG also suggested that nintedanib plus docetaxel is not commonly used to treat non-squamous NSCLC, and at technical engagement, a professional organisation advised that less than 5% of people have this combination. Furthermore, the Cancer Drugs Fund clinical lead explained that nintedanib plus docetaxel is not commonly used because it is associated with a wide range of side effects. The committee was concerned that the company had not presented cost-effectiveness estimates comparing nivolumab with nintedanib plus docetaxel, which was considered a relevant comparator in the original appraisal. However, it understood that this was because changes to the treatment pathway after publication of the original appraisal mean it is now very unlikely to be used in clinical practice in the NHS in England. The committee agreed that best supportive care was also very unlikely to be used after chemotherapy. It concluded that docetaxel alone was the most appropriate comparator for this Cancer Drugs Fund review.
# Clinical effectiveness
## Nivolumab is clinically effective compared with docetaxel alone for people with PD-L1-positive non-squamous NSCLC after chemotherapy
As well as new data from the CheckMate 057 and CheckMate 003 studies, there were new SACT data available for this review. This was collected from 43 people who had nivolumab in the Cancer Drugs Fund between September 2017 and December 2018. CheckMate 057 is an open-label trial that included 582 adults with non-squamous NSCLC, whose disease had progressed after previous platinum-based chemotherapy and who had not previously had a PD-1 or PD-L1 inhibitor. Patients were randomised to have either nivolumab (3 mg per kg, the recommended dose in the summary of product characteristics at the time) or docetaxel. There were 122 patients with PD-L1-positive disease (PD-L1 on at least 1% of tumour cells) in the nivolumab arm and 123 patients with PD-L1-positive disease in the docetaxel arm. For the PD-L1-positive subgroup, the hazard ratio using 5‑year data from CheckMate 057 showed nivolumab was associated with a statistically significant improvement in overall survival compared with docetaxel (the exact data are confidential and cannot be reported here). The committee understood that 1‑year overall survival reported in the SACT data (43%, 95% confidence interval: 28% to 58%) was considerably lower than that in the nivolumab arm of the trial (for which the exact data are confidential and cannot be reported here). However, the SACT data were limited by their small sample size and short follow up. The committee agreed that data from the CheckMate 057 trial were the most robust and were suitable for assessing the clinical effectiveness of nivolumab. It concluded that nivolumab was clinically effective compared with docetaxel alone for people with PD‑L1-positive non-squamous NSCLC after chemotherapy.
# Dose of nivolumab
## The new dosage for nivolumab was not used in CheckMate 057 but is unlikely to have a large effect on the clinical and cost-effectiveness results
At the time of the original appraisal the recommended dose of nivolumab in its summary of product characteristics was 3 mg per kg every 2 weeks. This has since changed to 240 mg every 2 weeks. The company assumed that the new dose has the same clinical effectiveness as the previously recommended dose. The committee understood that there were no clinical-effectiveness data using the new dosage. The Cancer Drugs Fund clinical lead advised that the dose change for nivolumab was not considered important because it had been accepted by the regulatory body and was already being used in clinical practice in the NHS. The committee concluded that although it had not seen clinical-effectiveness evidence for the new dosage, it was unlikely to have a large effect on the clinical and cost effectiveness of nivolumab.
# Economic model
## The company's economic model is suitable for decision making
The company's updated model used the same approach as the original appraisal. The model had 3 health states: progression-free disease, progressed disease and death. Health-state occupancy over time was informed by survival curves from CheckMate 057, but the committee only considered data for the relevant subgroup (PD-L1 of at least 1%). The company modelled nivolumab using clinical-effectiveness data for the 3 mg per kg dose but applied the costs of 240 mg every 2 weeks, and the committee considered this approach appropriate. It concluded that the company's model was suitable for decision making.
# Modelling overall survival and progression-free survival
## The company's spline 1-knot model for progression-free survival is appropriate
The company fitted several models to the updated 5‑year progression-free survival data from CheckMate 057 for both treatment arms. It preferred the spline 1‑knot normal curve for its base-case analysis. The ERG considered the company's model to be a good fit to the observed Kaplan−Meier data. The committee concluded that the company's spline 1‑knot normal model was appropriate.
## The company's log-normal model for overall survival and scenario analysis using a spline 3-knot model for nivolumab are both plausible
The company also fitted several models to the updated 5‑year overall survival data from CheckMate 057 for both treatment arms. It preferred the log-normal curve for its base-case analysis. The company explained that the log-normal curve was selected based on statistical fit to the trial data, but it did not provide a good visual fit to the middle or tail of the observed data for the nivolumab arm. The company reasoned that this could underestimate long-term survival and so provided a scenario analysis using a spline 3‑knot hazard curve to model survival for the nivolumab arm. The ERG suggested that the spline 3‑knot hazard model gave a better visual fit to the data, but because the CheckMate 057 data were mature the choice between alternative plausible distributions was unlikely to have a large effect on the cost-effectiveness results. The committee considered the company's models for overall survival. It accepted that for nivolumab, the spline 3‑knot hazard curve gave a slightly better visual fit to the observed Kaplan−Meier data than the log-normal curve, but noted that both curve fits were similar. Using the spline 3‑knot hazard curve to model overall survival for nivolumab improved its cost-effectiveness results. The committee concluded that the company's base-case log-normal model for overall survival, and scenario analysis using a spline 3‑knot hazard model for nivolumab, were both clinically plausible.
# Stopping rule and continued treatment effect
## It is likely that nivolumab's survival benefit continues after it is stopped
The company asserted that people who had nivolumab would continue to accumulate further survival benefit after nivolumab was stopped. In response to technical engagement, 1 professional organisation considered it clinically plausible that nivolumab could 'reset' the immune system and that its benefit could last for years after it was stopped. The company advised that data from CheckMate 003 showed that, out of 16 people who survived for 5 years and had no therapy after stopping nivolumab, 12 (75%) still did not have progressed disease. CheckMate 003 is a single-arm study of 129 patients with squamous or non-squamous NSCLC, of whom 19 had non-squamous NSCLC and had 3 mg per kg of nivolumab. It included people who had between 1 and 5 previous therapies and disease progression after at least 1 platinum or taxane-based chemotherapy, and who stopped nivolumab after 1.8 years. The company also explained that only a small proportion of people were still on treatment with nivolumab after 5 years in CheckMate 057 in the PD‑L1-positive subgroup (the exact data are confidential and cannot be reported here). However, an overall survival benefit was seen compared with docetaxel (see section 3.3). The Cancer Drugs Fund clinical lead agreed that the long-term data from CheckMate 003 and CheckMate 057 suggested a continued survival benefit after treatment was stopped. Data from CheckMate 003 were limited because:
it included a mixed population and only 19 people had non-squamous NSCLC and had the recommended 3 mg per kg dose of nivolumab
after 4 years, the number of patients that remained in the trial was too small to detect the risk of an event
the results were not specific to people with PD-L1-positive disease.The committee recognised the limitations of CheckMate 003, but accepted that it was biologically plausible that nivolumab's survival benefit continued after treatment was stopped. It concluded that nivolumab is likely to provide a continued survival benefit after it is stopped.
## The 2-year stopping rule for nivolumab is appropriate
The company preferred to include a 2‑year stopping rule for nivolumab. The ERG explained that there was no robust evidence to show the optimal duration of treatment. The company did not submit any data from CheckMate 153, an ongoing study investigating the effect of a maximum of 1‑year treatment with nivolumab. The committee understood that the summary of product characteristics approved nivolumab to be used as long as clinical benefit was observed or until treatment was no longer tolerated, and that no stopping rule was used in CheckMate 057. It agreed that there was uncertainty about how long people should have nivolumab for, based on the updated CheckMate 057 and 003 data. The Cancer Drugs Fund clinical lead explained that a 2‑year stopping rule for immunotherapies such as nivolumab was commonly used in clinical practice in the NHS. Some patients experienced anxiety and distress because of having treatment stopped at 2 years (see section 3.1). At the committee meeting, the company suggested that this was not the experience of all patients and some might welcome a break from treatment. The committee was aware that removing the 2‑year stopping rule had a large effect on the cost-effectiveness results. It concluded that a 2‑year stopping rule for nivolumab was appropriate because it is likely there is a continued survival benefit. Also, there was no new evidence to show that continuing treatment for longer gave additional benefit.
## When nivolumab is stopped at 2 years, it is acceptable to assume an additional survival benefit for at least 3 more years
In its base-case analysis, the company preferred to assume that if nivolumab is stopped at 2 years, it will provide a lasting, lifetime survival benefit. The ERG reiterated that the duration of any continued treatment effect is unknown. The company agreed that this is uncertain. It provided 2‑way sensitivity analyses increasing the duration of additional benefit and the proportion of patients who experience it. Evidence from CheckMate 003 showed a continued survival benefit after stopping nivolumab, so the committee considered it clinically plausible that benefit could last for years after it was stopped (see section 3.8 and section 3.9). However, it was not convinced that the company's preferred lifetime survival benefit was plausible. Also, it had not seen evidence to favour any of the company's 2‑way sensitivity analyses. The committee was aware that in the original guidance a 3‑year continued benefit after stopping nivolumab was accepted. It recognised that 5‑year data were now available from CheckMate 057, but there was no new robust evidence on the overall duration of the continued benefit. So, the assumption accepted in the original guidance had not changed. The committee concluded that the exact duration of treatment benefit was unclear, but it was likely to be at least 3 years after treatment had stopped.
# Health-related quality of life
## A post-progression utility value of 0.569 is appropriate
The company's base-case analysis used a post-progression utility value of 0.688, based on the updated 5‑year EQ‑5D data from CheckMate 057. However, the committee understood that a decline in the EQ‑5D completion rate meant that post-progression values may be influenced by selection bias. This is because it is likely that responses were increasingly provided by relatively healthy patients in the trial. In the original guidance, the committee's preferred post-progression utility value (0.569) was based on the midpoint between 0.480 (based on van den Hout, 2006, a Dutch study of people having palliative radiotherapy for NSCLC) and 0.657 (based on 3‑year EQ‑5D data from CheckMate 057 with a disutility for end-of-life care applied). The committee was aware that the post-progression values used in technology appraisals for NSCLC were based on time to end of life, with values declining from 0.68 to 0.32 in NICE's technology appraisal guidance for pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy, and from 0.68 to 0.35 in NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic NSCLC after chemotherapy. The company advised that NHS practice has moved on since the van den Hout study, giving better quality of life. The committee considered that the updated utility values from CheckMate 057 would still be influenced by the same selection bias as in the original data. It also agreed that while NHS practice has moved on since 2006, the midpoint value of 0.569 is higher than the van den Hout study's 0.480. Also, the relevant patients still have advanced or metastatic NSCLC at the end of life. The committee agreed that it had not heard any robust evidence to change the assumption accepted in the original guidance. Therefore, it concluded that it was appropriate to use the 0.569 utility value for progressed disease from the original appraisal.
# End of life
## Nivolumab meets the end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that life expectancy for people with PD-L1-positive NSCLC was less than 24 months and that nivolumab extended life by at least 3 months. The committee did not hear any robust evidence to change this conclusion. Therefore, it concluded that nivolumab met the end of life criteria and could be considered a life-extending treatment at the end of life.
# Cost effectiveness
## The most plausible ICER is within what NICE considers an acceptable use of NHS resources
The company's preferred incremental cost-effectiveness ratio (ICER) compared with docetaxel alone for people with PD‑L-positive non-squamous NSCLC was £33,191 per quality-adjusted life year (QALY) gained. No cost-effectiveness results were reported that compared nivolumab with nintedanib plus docetaxel. The comparison of nivolumab and docetaxel included a 2‑year stopping rule for nivolumab, but did not include the committee's other preferred assumptions of:
a spline 3‑knot hazard as a plausible alternative curve to model overall survival (see section 3.7)
a continued survival benefit of 3 years after nivolumab is stopped at 2 years (see section 3.10)
a post-progression utility value of 0.569 (see section 3.11).Using its preferred assumptions, the committee noted that the most plausible ICER was between £44,169 (spline 3‑knot hazard curve) and £44,547 (log-normal curve) per QALY gained. It concluded that this was within the range that NICE considers a cost-effective use of NHS resources.
# Other factors
No equality or social value judgement issues were identified.
# Conclusion
## Nivolumab is recommended for routine commissioning for people with PD-L1-positive advanced non-squamous NSCLC after chemotherapy
New evidence was considered from CheckMate 057, CheckMate 003, Cancer Drugs Fund SACT data and the committee's preferred assumptions. All estimates of cost effectiveness for nivolumab compared with docetaxel alone were below what is considered to be a cost-effective use of NHS resources when the end-of-life criteria were applied. Nivolumab is therefore recommended for use in the NHS as an option for treating locally advanced or metastatic non-squamous NSCLC after chemotherapy in adults, only if:
their tumours are PD-L1 positive, and
it is stopped at 2 years of uninterrupted treatment, or earlier if disease progresses, and
they have not had a PD-1 or PD-L1 inhibitor before.
|
{'Recommendations': "Nivolumab is recommended as an option for treating locally advanced or metastatic non-squamous non-small-cell lung cancer (NSCLC) in adults after chemotherapy, only if:\n\ntheir tumours are PD-L1 positive, and\n\nit is stopped at 2\xa0years of uninterrupted treatment, or earlier if their disease progresses, and\n\nthey have not had a PD-1 or PD-L1 inhibitor before.It is recommended only if the company provides nivolumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThe treatment pathway for locally advanced or metastatic non-squamous NSCLC starts with a PD-1 or PD-L1 inhibitor or chemotherapy. Nivolumab would be used after chemotherapy.\n\nEvidence collected in the Cancer Drugs Fund is for people with PD‑L1-positive disease having up to 2\xa0years of nivolumab treatment in the NHS. The key clinical trial shows that people with PD‑L1-positive tumours who have nivolumab live longer than those who have docetaxel, which is the most appropriate comparator. There is uncertainty about how long people should have nivolumab for, but evidence shows that there is continued benefit when treatment is stopped at 2\xa0years.\n\nNivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates for nivolumab compared with docetaxel are likely to be within what NICE considers an acceptable use of NHS resources. Therefore, it is now recommended in the NHS for people with PD‑L1-positive tumours who have not had a PD‑1 or PD‑L1 inhibitor before, when it is stopped at 2\xa0years.", 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol–Myers Squibb) has a marketing authorisation for 'the treatment of locally advanced or metastatic non-small-cell lung cancer after prior chemotherapy in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of nivolumab is £2,633 per 240\xa0mg per 24\xa0ml vial (excluding VAT; BNF online, accessed March\xa02020). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol–Myers Squibb and a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected after time in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal can be found in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the CheckMate\xa0057 study. In addition, data were collected on nivolumab for people with PD‑L1-positive disease in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\nThe committee recognised that there were remaining areas of uncertainty in the analyses presented (see technical report, table\xa03, page\xa023) and took these into account in its decision making. The committee discussed the following issues, which were outstanding after the technical engagement stage:\n\nthe appropriate comparator\n\nparametric models to predict overall survival and progression-free survival\n\nutility values\n\nthe 2-year stopping rule for nivolumab and the continued duration of treatment benefit if nivolumab is stopped at 2\xa0years.\n\n# Clinical need\n\n## People with previously treated advanced NSCLC with PD-L1-positive tumours value nivolumab as a treatment\n\nNon-squamous non-small-cell lung cancer (NSCLC) is often diagnosed late in life and causes debilitating and distressing symptoms. The clinical expert submission explained that overall survival for lung cancer in the UK is poor, but the introduction of immunotherapies such as nivolumab means people can live longer. The committee was aware that patients and professionals want treatments that are effective, minimally disruptive, and improve quality of life. It noted that some patients had experienced anxiety and distress because of the 2-year stopping rule used in the original guidance. This was because they did not want to stop benefitting from treatment. The clinical expert submission suggested that in clinical practice nivolumab would be used when people had not had a previous PD-1 or PD-L1 inhibitor. The committee concluded that people with locally advanced or metastatic non-squamous NSCLC with PD-L1-positive tumours would value nivolumab as a treatment option.\n\n## Docetaxel alone is the most appropriate comparator\n\nIn the original appraisal, docetaxel monotherapy, nintedanib plus docetaxel for people with adenocarcinoma and best supportive care were considered relevant comparators. The committee was aware that since its publication, pembrolizumab and atezolizumab have been recommended for previously treated locally advanced or metastatic NSCLC (see NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic NSCLC after chemotherapy and pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy). There have also been changes to treatment options for untreated disease (see NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC and pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous NSCLC). The Cancer Drugs Fund clinical lead from NHS England confirmed that the treatment pathway had changed and because immunotherapies were now available for untreated disease, nivolumab was not used as often for previously treated disease. In line with NICE's methods guide for technology appraisals, the original scope was not changed for this Cancer Drugs Fund review. This meant that pembrolizumab and atezolizumab could not be considered comparators because they were recommended after the original guidance was published. The company only submitted cost-effectiveness analyses comparing nivolumab with docetaxel alone because it stated that neither best supportive care nor nintedanib and docetaxel are commonly used in clinical practice. Clinical advice to the ERG also suggested that nintedanib plus docetaxel is not commonly used to treat non-squamous NSCLC, and at technical engagement, a professional organisation advised that less than 5% of people have this combination. Furthermore, the Cancer Drugs Fund clinical lead explained that nintedanib plus docetaxel is not commonly used because it is associated with a wide range of side effects. The committee was concerned that the company had not presented cost-effectiveness estimates comparing nivolumab with nintedanib plus docetaxel, which was considered a relevant comparator in the original appraisal. However, it understood that this was because changes to the treatment pathway after publication of the original appraisal mean it is now very unlikely to be used in clinical practice in the NHS in England. The committee agreed that best supportive care was also very unlikely to be used after chemotherapy. It concluded that docetaxel alone was the most appropriate comparator for this Cancer Drugs Fund review.\n\n# Clinical effectiveness\n\n## Nivolumab is clinically effective compared with docetaxel alone for people with PD-L1-positive non-squamous NSCLC after chemotherapy\n\nAs well as new data from the CheckMate\xa0057 and CheckMate\xa0003 studies, there were new SACT data available for this review. This was collected from 43\xa0people who had nivolumab in the Cancer Drugs Fund between September\xa02017 and December\xa02018. CheckMate\xa0057 is an open-label trial that included 582\xa0adults with non-squamous NSCLC, whose disease had progressed after previous platinum-based chemotherapy and who had not previously had a PD-1 or PD-L1 inhibitor. Patients were randomised to have either nivolumab (3\xa0mg per kg, the recommended dose in the summary of product characteristics at the time) or docetaxel. There were 122\xa0patients with PD-L1-positive disease (PD-L1 on at least 1% of tumour cells) in the nivolumab arm and 123\xa0patients with PD-L1-positive disease in the docetaxel arm. For the PD-L1-positive subgroup, the hazard ratio using 5‑year data from CheckMate\xa0057 showed nivolumab was associated with a statistically significant improvement in overall survival compared with docetaxel (the exact data are confidential and cannot be reported here). The committee understood that 1‑year overall survival reported in the SACT data (43%, 95% confidence interval: 28% to 58%) was considerably lower than that in the nivolumab arm of the trial (for which the exact data are confidential and cannot be reported here). However, the SACT data were limited by their small sample size and short follow up. The committee agreed that data from the CheckMate\xa0057 trial were the most robust and were suitable for assessing the clinical effectiveness of nivolumab. It concluded that nivolumab was clinically effective compared with docetaxel alone for people with PD‑L1-positive non-squamous NSCLC after chemotherapy.\n\n# Dose of nivolumab\n\n## The new dosage for nivolumab was not used in CheckMate 057 but is unlikely to have a large effect on the clinical and cost-effectiveness results\n\nAt the time of the original appraisal the recommended dose of nivolumab in its summary of product characteristics was 3\xa0mg per kg every 2\xa0weeks. This has since changed to 240\xa0mg every 2\xa0weeks. The company assumed that the new dose has the same clinical effectiveness as the previously recommended dose. The committee understood that there were no clinical-effectiveness data using the new dosage. The Cancer Drugs Fund clinical lead advised that the dose change for nivolumab was not considered important because it had been accepted by the regulatory body and was already being used in clinical practice in the NHS. The committee concluded that although it had not seen clinical-effectiveness evidence for the new dosage, it was unlikely to have a large effect on the clinical and cost effectiveness of nivolumab.\n\n# Economic model\n\n## The company's economic model is suitable for decision making\n\nThe company's updated model used the same approach as the original appraisal. The model had 3\xa0health states: progression-free disease, progressed disease and death. Health-state occupancy over time was informed by survival curves from CheckMate\xa0057, but the committee only considered data for the relevant subgroup (PD-L1 of at least 1%). The company modelled nivolumab using clinical-effectiveness data for the 3\xa0mg per kg dose but applied the costs of 240\xa0mg every 2\xa0weeks, and the committee considered this approach appropriate. It concluded that the company's model was suitable for decision making.\n\n# Modelling overall survival and progression-free survival\n\n## The company's spline 1-knot model for progression-free survival is appropriate\n\nThe company fitted several models to the updated 5‑year progression-free survival data from CheckMate\xa0057 for both treatment arms. It preferred the spline 1‑knot normal curve for its base-case analysis. The ERG considered the company's model to be a good fit to the observed Kaplan−Meier data. The committee concluded that the company's spline 1‑knot normal model was appropriate.\n\n## The company's log-normal model for overall survival and scenario analysis using a spline 3-knot model for nivolumab are both plausible\n\nThe company also fitted several models to the updated 5‑year overall survival data from CheckMate\xa0057 for both treatment arms. It preferred the log-normal curve for its base-case analysis. The company explained that the log-normal curve was selected based on statistical fit to the trial data, but it did not provide a good visual fit to the middle or tail of the observed data for the nivolumab arm. The company reasoned that this could underestimate long-term survival and so provided a scenario analysis using a spline 3‑knot hazard curve to model survival for the nivolumab arm. The ERG suggested that the spline 3‑knot hazard model gave a better visual fit to the data, but because the CheckMate\xa0057 data were mature the choice between alternative plausible distributions was unlikely to have a large effect on the cost-effectiveness results. The committee considered the company's models for overall survival. It accepted that for nivolumab, the spline 3‑knot hazard curve gave a slightly better visual fit to the observed Kaplan−Meier data than the log-normal curve, but noted that both curve fits were similar. Using the spline 3‑knot hazard curve to model overall survival for nivolumab improved its cost-effectiveness results. The committee concluded that the company's base-case log-normal model for overall survival, and scenario analysis using a spline 3‑knot hazard model for nivolumab, were both clinically plausible.\n\n# Stopping rule and continued treatment effect\n\n## It is likely that nivolumab's survival benefit continues after it is stopped\n\nThe company asserted that people who had nivolumab would continue to accumulate further survival benefit after nivolumab was stopped. In response to technical engagement, 1\xa0professional organisation considered it clinically plausible that nivolumab could 'reset' the immune system and that its benefit could last for years after it was stopped. The company advised that data from CheckMate\xa0003 showed that, out of 16\xa0people who survived for 5\xa0years and had no therapy after stopping nivolumab, 12 (75%) still did not have progressed disease. CheckMate\xa0003 is a single-arm study of 129\xa0patients with squamous or non-squamous NSCLC, of whom 19 had non-squamous NSCLC and had 3\xa0mg per kg of nivolumab. It included people who had between 1\xa0and 5\xa0previous therapies and disease progression after at least 1\xa0platinum or taxane-based chemotherapy, and who stopped nivolumab after 1.8\xa0years. The company also explained that only a small proportion of people were still on treatment with nivolumab after 5\xa0years in CheckMate\xa0057 in the PD‑L1-positive subgroup (the exact data are confidential and cannot be reported here). However, an overall survival benefit was seen compared with docetaxel (see section\xa03.3). The Cancer Drugs Fund clinical lead agreed that the long-term data from CheckMate\xa0003 and CheckMate\xa0057 suggested a continued survival benefit after treatment was stopped. Data from CheckMate\xa0003 were limited because:\n\nit included a mixed population and only 19\xa0people had non-squamous NSCLC and had the recommended 3\xa0mg per kg dose of nivolumab\n\nafter 4\xa0years, the number of patients that remained in the trial was too small to detect the risk of an event\n\nthe results were not specific to people with PD-L1-positive disease.The committee recognised the limitations of CheckMate\xa0003, but accepted that it was biologically plausible that nivolumab's survival benefit continued after treatment was stopped. It concluded that nivolumab is likely to provide a continued survival benefit after it is stopped.\n\n## The 2-year stopping rule for nivolumab is appropriate\n\nThe company preferred to include a 2‑year stopping rule for nivolumab. The ERG explained that there was no robust evidence to show the optimal duration of treatment. The company did not submit any data from CheckMate\xa0153, an ongoing study investigating the effect of a maximum of 1‑year treatment with nivolumab. The committee understood that the summary of product characteristics approved nivolumab to be used as long as clinical benefit was observed or until treatment was no longer tolerated, and that no stopping rule was used in CheckMate\xa0057. It agreed that there was uncertainty about how long people should have nivolumab for, based on the updated CheckMate\xa0057 and 003\xa0data. The Cancer Drugs Fund clinical lead explained that a 2‑year stopping rule for immunotherapies such as nivolumab was commonly used in clinical practice in the NHS. Some patients experienced anxiety and distress because of having treatment stopped at 2\xa0years (see section\xa03.1). At the committee meeting, the company suggested that this was not the experience of all patients and some might welcome a break from treatment. The committee was aware that removing the 2‑year stopping rule had a large effect on the cost-effectiveness results. It concluded that a 2‑year stopping rule for nivolumab was appropriate because it is likely there is a continued survival benefit. Also, there was no new evidence to show that continuing treatment for longer gave additional benefit.\n\n## When nivolumab is stopped at 2 years, it is acceptable to assume an additional survival benefit for at least 3 more years\n\nIn its base-case analysis, the company preferred to assume that if nivolumab is stopped at 2\xa0years, it will provide a lasting, lifetime survival benefit. The ERG reiterated that the duration of any continued treatment effect is unknown. The company agreed that this is uncertain. It provided 2‑way sensitivity analyses increasing the duration of additional benefit and the proportion of patients who experience it. Evidence from CheckMate\xa0003 showed a continued survival benefit after stopping nivolumab, so the committee considered it clinically plausible that benefit could last for years after it was stopped (see section\xa03.8 and\xa0section 3.9). However, it was not convinced that the company's preferred lifetime survival benefit was plausible. Also, it had not seen evidence to favour any of the company's 2‑way sensitivity analyses. The committee was aware that in the original guidance a 3‑year continued benefit after stopping nivolumab was accepted. It recognised that 5‑year data were now available from CheckMate\xa0057, but there was no new robust evidence on the overall duration of the continued benefit. So, the assumption accepted in the original guidance had not changed. The committee concluded that the exact duration of treatment benefit was unclear, but it was likely to be at least 3\xa0years after treatment had stopped.\n\n# Health-related quality of life\n\n## A post-progression utility value of 0.569 is appropriate\n\nThe company's base-case analysis used a post-progression utility value of 0.688, based on the updated 5‑year EQ‑5D data from CheckMate\xa0057. However, the committee understood that a decline in the EQ‑5D completion rate meant that post-progression values may be influenced by selection bias. This is because it is likely that responses were increasingly provided by relatively healthy patients in the trial. In the original guidance, the committee's preferred post-progression utility value (0.569) was based on the midpoint between 0.480 (based on van den Hout, 2006, a Dutch study of people having palliative radiotherapy for NSCLC) and 0.657 (based on 3‑year EQ‑5D data from CheckMate\xa0057 with a disutility for end-of-life care applied). The committee was aware that the post-progression values used in technology appraisals for NSCLC were based on time to end of life, with values declining from 0.68\xa0to\xa00.32 in NICE's technology appraisal guidance for pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy, and from 0.68\xa0to\xa00.35 in NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic NSCLC after chemotherapy. The company advised that NHS practice has moved on since the van den Hout study, giving better quality of life. The committee considered that the updated utility values from CheckMate\xa0057 would still be influenced by the same selection bias as in the original data. It also agreed that while NHS practice has moved on since 2006, the midpoint value of 0.569 is higher than the van den Hout study's 0.480. Also, the relevant patients still have advanced or metastatic NSCLC at the end of life. The committee agreed that it had not heard any robust evidence to change the assumption accepted in the original guidance. Therefore, it concluded that it was appropriate to use the 0.569\xa0utility value for progressed disease from the original appraisal.\n\n# End of life\n\n## Nivolumab meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that life expectancy for people with PD-L1-positive NSCLC was less than 24\xa0months and that nivolumab extended life by at least 3\xa0months. The committee did not hear any robust evidence to change this conclusion. Therefore, it concluded that nivolumab met the end of life criteria and could be considered a life-extending treatment at the end of life.\n\n# Cost effectiveness\n\n## The most plausible ICER is within what NICE considers an acceptable use of NHS resources\n\nThe company's preferred incremental cost-effectiveness ratio (ICER) compared with docetaxel alone for people with PD‑L-positive non-squamous NSCLC was £33,191 per quality-adjusted life year (QALY) gained. No cost-effectiveness results were reported that compared nivolumab with nintedanib plus docetaxel. The comparison of nivolumab and docetaxel included a 2‑year stopping rule for nivolumab, but did not include the committee's other preferred assumptions of:\n\na spline 3‑knot hazard as a plausible alternative curve to model overall survival (see section\xa03.7)\n\na continued survival benefit of 3\xa0years after nivolumab is stopped at 2\xa0years (see section\xa03.10)\n\na post-progression utility value of\xa00.569 (see section\xa03.11).Using its preferred assumptions, the committee noted that the most plausible ICER was between £44,169 (spline 3‑knot hazard curve) and £44,547 (log-normal curve) per QALY gained. It concluded that this was within the range that NICE considers a cost-effective use of NHS resources.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Nivolumab is recommended for routine commissioning for people with PD-L1-positive advanced non-squamous NSCLC after chemotherapy\n\nNew evidence was considered from CheckMate\xa0057, CheckMate\xa0003, Cancer Drugs Fund SACT data and the committee's preferred assumptions. All estimates of cost effectiveness for nivolumab compared with docetaxel alone were below what is considered to be a cost-effective use of NHS resources when the end-of-life criteria were applied. Nivolumab is therefore recommended for use in the NHS as an option for treating locally advanced or metastatic non-squamous NSCLC after chemotherapy in adults, only if:\n\ntheir tumours are PD-L1 positive, and\n\nit is stopped at 2\xa0years of uninterrupted treatment, or earlier if disease progresses, and\n\nthey have not had a PD-1 or PD-L1 inhibitor before."}
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https://www.nice.org.uk/guidance/ta713
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Evidence-based recommendations on nivolumab (Opdivo) for advanced non-squamous non-small-cell lung cancer in adults after chemotherapy.
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Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation
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Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation
Evidence-based recommendations on dabigatran etexilate (Pradaxa) for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation.
# Recommendations
Dabigatran etexilate is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more of the following risk factors:
previous stroke, transient ischaemic attack or systemic embolism
left ventricular ejection fraction below 40%
symptomatic heart failure of New York Heart Association (NYHA) class 2 or above
age 75 years or older
age 65 years or older with one of the following: diabetes mellitus, coronary artery disease or hypertension.
Decide whether to start treatment with dabigatran etexilate after an informed discussion with the person about its risks and benefits compared with warfarin, apixaban, edoxaban and rivaroxaban. For people taking warfarin, consider the potential risks and benefits of switching to dabigatran etexilate taking into account their level of international normalised ratio (INR) control.# The technology
Dabigatran etexilate (Pradaxa, Boehringer Ingelheim; hereafter referred to as dabigatran) is an orally administered anticoagulant that inhibits the thrombin enzyme. Dabigatran has a UK marketing authorisation for the 'prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors:
previous stroke, transient ischaemic attack, or systemic embolism
left ventricular ejection fraction below 40%
symptomatic heart failure of New York Heart Association (NYHA) class 2 or above
age 75 years or over
age 65 years or over with one of the following: diabetes mellitus, coronary artery disease, or hypertension'.
The summary of product characteristics states that the recommended daily dose of dabigatran is 300 mg taken as one 150 mg capsule twice daily. Therapy is continued long term. For patients aged 75 to 80 years, a dose of 220 mg taken as one 110 mg capsule twice daily can be considered at the discretion of the physician for individual patients whose thromboembolic risk is low and bleeding risk is high. Patients aged 80 years or older should be treated with a daily dose of 220 mg taken as one 110 mg capsule twice daily because of the increased risk of bleeding in this population.
Dabigatran is contraindicated in people with severe renal impairment, active clinically significant bleeding, organic lesions at risk of bleeding, impairment of haemostasis, and hepatic impairment or liver disease expected to have an impact on survival. Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole or tacrolimus is also contraindicated. The most common adverse events in people receiving dabigatran are anaemia, abdominal pain, diarrhoea, dyspepsia, gastrointestinal haemorrhage, genitourinary haemorrhage (patients may notice blood in their urine), nausea and nose bleeds. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Dabigatran is available as 110 mg and 150 mg capsules and comes in packs of 60 capsules. The manufacturer has stated that the cost to the NHS of a pack of 60 capsules of either dabigatran 110 mg or 150 mg will be £75.60 (excluding VAT). The cost per day per patient based on the recommended dosage will be £2.52 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee considered evidence submitted by the manufacturer of dabigatran and a review of this submission by the Evidence Review Group (ERG).
The manufacturer's submission included three trials that directly compared dabigatran with dose-adjusted warfarin: RE-LY, PETRO and 1160.49. The PETRO and 1160.49 trials were both dose-finding studies with safety data collection as the primary objective. The main evidence for clinical effectiveness presented in the manufacturer's submission was based on the RE-LY randomised controlled trial.
RE-LY was a non-inferiority trial in which two blinded doses of dabigatran (110 mg twice daily and 150 mg twice daily) were compared with open-label warfarin (with a target international normalised ratio of 2.0 to 3.0) for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation and at least one additional risk factor for stroke. The RE-LY trial included people with documented atrial fibrillation and at least one of the following additional risk factors: history of stroke, transient ischaemic attack, or systemic embolism; left ventricular ejection fraction of less than 40%; symptomatic heart failure; age 75 years or older; age 65 years or older with diabetes mellitus, documented coronary artery disease or hypertension. People were excluded from the RE-LY trial if they had a severe, disabling stroke in the previous 6 months or any stroke within the previous 14 days, conditions associated with increased risk of bleeding, or a contraindication to warfarin treatment.
The RE-LY study took place in 44 countries including the UK and a total of 18,113 people were randomised across the three treatment arms in a 1:1:1 ratio. People recruited into the study were randomised within 14 days of the screening visit and were randomly allocated to dabigatran 110 mg twice daily (n=6015), dabigatran 150 mg twice daily (n=6076) or warfarin (n=6022). Minimum follow-up was 1 year, and median follow-up was 23.7 months. The mean age of people in the study was 71.5 years and 63.6% were male. Risk of stroke at baseline was classified according to CHADS2 score, which is used to estimate the risk of stroke in people with atrial fibrillation to determine whether they need anticoagulation treatment. The score was calculated by giving one point each for the presence of congestive heart failure, hypertension or diabetes mellitus, and age 75 years or older. Two points were given if people had already had an ischaemic stroke or transient ischaemic attack.
The primary outcome in the study was incidence of all types of stroke (including haemorrhagic stroke) or systemic embolism. To show non-inferiority in the RE-LY trial, the upper limits of the confidence interval (CI) of the hazard ratio (HR) for dabigatran versus warfarin had to be less than the margin specified. Two margins were used in the manufacturer's submission, 1.46 and 1.38, of which 1.38 was specified as the preferred margin of non-inferiority by the US Food and Drug Administration (FDA).
The reduction in relative risk of stroke or systemic embolism compared with warfarin was 10% for dabigatran 110 mg and 35% for dabigatran 150 mg. Dabigatran 150 mg twice daily was associated with a lower incidence of stroke or systemic embolism compared with warfarin and this was statistically significant (HR=0.65, 95% CI 0.52 to 0.81). A statistically significant beneficial effect of dabigatran 150 mg twice daily was also demonstrated in terms of a reduced incidence of ischaemic stroke (HR=0.75, 95% CI 0.58 to 0.97) and vascular mortality (HR=0.85, 95% CI 0.72 to 0.99). A reduction in all-cause mortality was also observed and, although it did not reach statistical significance, it showed dabigatran 150 mg twice daily to be non-inferior to warfarin (HR=0.88, 95% CI 0.77 to 1.00). There were no statistically significant differences between dabigatran 110 mg twice daily and warfarin in the incidence of stroke or systemic embolism, ischaemic stroke or vascular mortality. Both doses of dabigatran were associated with an increased risk of acute myocardial infarction compared with warfarin but this was not statistically significant (HR=1.29, 95% CI 0.96 to 1.75 ; HR=1.27, 95% CI 0.94 to 1.71 ).
The manufacturer's submission included post hoc subgroup analyses of people older and younger than 80 years of age. In both age groups, there were no statistically significant differences between either dose of dabigatran and warfarin in the incidence of ischaemic stroke, systemic embolism and myocardial infarction. However, the manufacturer did report a statistically significant reduction in the incidence of transient ischaemic attack (HR=0.45, 95% CI 0.23 to 0.89) in people older than 80 years receiving dabigatran 110 mg twice daily, compared with warfarin.
The manufacturer's submission reported results from pre-planned subgroup analyses of people naive to vitamin K antagonists such as warfarin (defined as treatment for 2 months or less in a person's lifetime) and people who have previously used vitamin K antagonists (defined as treatment for more than 2 months during a person's lifetime). In both groups, dabigatran 150 mg twice daily was associated with a statistically significant reduction in the incidence of stroke or systemic embolism compared with warfarin (HR=0.63, 95% CI 0.46 to 0.87 and HR=0.63, 95% CI 0.49 to 0.89 ). No statistically significant differences were reported for the lower, 110 mg twice daily, dose of dabigatran compared with warfarin.
For adverse events, the manufacturer reported a statistically significant reduction in the incidence of haemorrhagic stroke for both doses of dabigatran compared with warfarin (HR=0.31, 95% CI 0.17 to 0.56 and HR=0.26, 95% CI 0.14 to 0.49 ). Both doses of dabigatran were also associated with statistically significantly fewer life-threatening bleeds compared with warfarin (HR=0.67, 95% CI 0.54 to 0.82 and HR=0.80, 95% CI 0.66 to 0.98 ). Both doses of dabigatran were associated with fewer cases of intracranial haemorrhage (including haemorrhagic stroke) than warfarin (HR=0.30, 95% CI 0.19 to 0.45 ; HR=0.41, 95% CI 0.28 to 0.61 ). Treatment with dabigatran 110 mg was also associated with a statistically significant reduction in major bleeding compared with warfarin. In contrast, both doses of dabigatran were associated with a significantly higher rate of gastrointestinal bleeding compared with warfarin (HR=1.35, 95% CI 1.19 to 1.53 and HR=1.52, 95% CI 1.35 to 1.72 ). Dabigatran 150 mg twice daily was associated with a significantly higher incidence of major gastrointestinal bleeding (HR=1.47, 95% CI 1.17 to 1.85) and life-threatening gastrointestinal bleeding (HR=1.62, 95% CI 1.17 to 2.26). The manufacturer reported that more people in the dabigatran groups discontinued the study drug (22.0% in the dabigatran 110 mg twice daily group and 22.8% in the dabigatran 150 mg twice daily group), compared with those on warfarin (17.9%). More people in the dabigatran groups also discontinued study medication because of outcome events; however discontinuations caused by major bleeds were similar for all treatments.
The manufacturer reported a statistically significant reduction in the incidence of haemorrhagic stroke in the post hoc subgroup analyses of people younger than 80 years compared with warfarin for both doses of dabigatran (HR=0.33, 95% CI 0.16 to 0.65 ; HR=0.21, 95% CI 0.09 to 0.47 ) and in people older than 80 years receiving dabigatran 110 mg twice daily (HR=0.26, 95% CI 0.07 to 0.91). However, the reduction in incidence of haemorrhagic stroke in people older than 80 years for dabigatran 150 mg twice daily compared with warfarin was not statistically significant (HR=0.93, 95% CI 0.81 to 1.07).
Health-related quality of life data were collected in a sub-study of the RE-LY trial (1440 of the 18,113 people enrolled in the RE-LY study completed the EQ-5D questionnaire as part of the quality of life sub-study). The manufacturer reported that the sub-study was reasonably representative of the overall RE-LY population with patients having similar demographic and disease characteristics. The manufacturer stated that analysing the EQ-5D data for specific events of interest was not possible and the quality of life sub-study was unable to provide utility values for event-driven health states to use in the economic model. However, background utility values could be derived from the quality of life sub-study for people being treated with warfarin and dabigatran, the details of which are academic-in-confidence and are not reported here.
The manufacturer performed a mixed-treatment comparison of dabigatran, aspirin monotherapy and aspirin plus clopidogrel. The treatments considered by the manufacturer to be relevant in this analysis were dabigatran 150 mg twice daily, dabigatran 110 mg twice daily, dose-adjusted warfarin, aspirin, aspirin plus clopidogrel, and placebo. An additional sequential regimen of dabigatran was used in the mixed-treatment comparison. This was intended to reflect the use of dabigatran according to the licensed regimen which is 150 mg twice daily in people up to the age of 80 years, and then 110 mg twice daily in those aged 80 years and older. Results from the RE-LY trial and the mixed-treatment comparison were very similar for both dabigatran doses compared with dose-adjusted warfarin.
The manufacturer's economic evaluation was based on a cost–utility analysis designed to compare the costs and outcomes of dabigatran with treatments used in the UK (warfarin, aspirin and aspirin plus clopidogrel). The manufacturer developed a Markov model that used three levels of disability (independent, moderate and severe) and death to define health states. A hypothetical cohort entered the model at risk of specified clinical events and was on one of the treatments under comparison. They moved between health states when a clinical event occurred and their disability status changed. The clinical events considered were ischaemic stroke, intracranial haemorrhage, haemorrhagic stroke, extracranial haemorrhage, systemic embolism, transient ischaemic attack and acute myocardial infarction. All clinical outcomes were associated with acute costs and disutility. Further longer-term costs and disutility beyond the acute stage were associated with ischaemic stroke, haemorrhagic stroke and intracranial haemorrhage. The model permitted one clinical event per 3-month cycle over a lifetime horizon. The model also allowed for a switch to second-line treatment or a discontinuation of treatment.
The manufacturer presented two economic models: a single-dose model and a sequential regimen model. In the single-dose model, the cohort with atrial fibrillation received either 110 mg twice daily or 150 mg twice daily throughout their treatment. In the sequential regimen model, the cohort was divided by age and modelled separately. The model for people younger than 80 years assumed that treatment began with dabigatran 150 mg twice daily, and switched to dabigatran 110 mg twice daily when the age of 80 years was reached. The model for people aged 80 years or older at baseline assumed a dose of dabigatran 110 mg twice daily throughout. Therefore, the sequential regimen model resulted in two sets of outputs: a sequential regimen model for people starting treatment younger than 80 years (incorporating a life-time horizon including the switch to 110 mg twice daily at 80 years) and a sequential regimen model for those starting treatment at 80 years or older.
The event risk for all treatment strategies was applied to the baseline risk of events in people treated with warfarin in the RE-LY trial. Therefore, treatment effects were converted into relative risks and applied to the warfarin arm of the RE-LY trial. The relative risks for the various clinical events while on treatment with dabigatran 110 mg twice daily and 150 mg twice daily were obtained from the RE-LY trial. In the sequential regimen model, the relative risks were derived from the post hoc subgroup analyses of people older and younger than 80 years of age. The relative risks for aspirin, aspirin plus clopidogrel and placebo were obtained from the mixed-treatment comparison.
The manufacturer's economic evaluation focused on health-related quality of life associated with disability and disutility caused by the various clinical events. The baseline utility value for people with atrial fibrillation in the base-case analyses was taken from the RE‑LY quality of life sub-study. Utility values associated with clinical events and disability status were derived from published sources.
The manufacturer's model considered resource costs associated with anti-thrombotic treatment, acute event costs, and long-term follow‑up costs resulting from disability. These costs were derived from the national payment by results tariff, systematic reviews and a manufacturer-sponsored study based on the Oxford Vascular study (OXVASC) cohort. The cost of dabigatran was £2.52 (excluding VAT) per day for either the 110 mg twice daily or 150 mg twice daily doses. Treatment with warfarin, aspirin and aspirin plus clopidogrel was assumed to cost £0.04, £0.09, and £0.26 per day, respectively. Treatment with dabigatran was not considered to need any monitoring, but the cost of INR monitoring for warfarin was estimated to be £414.90 per annum. The model assumed an NHS perspective and costs and benefits were discounted at 3.5% per annum.
The manufacturer reported pairwise cost-effectiveness results for dabigatran compared with warfarin. The incremental cost-effectiveness ratios (ICERs) for the dabigatran sequential regimen in which people started treatment when younger than 80 years and continued for the rest of their lives, and the sequential regimen in which people started treatment when older than 80 years were £7314 and £7873 per QALY gained respectively, compared with warfarin. The ICERs for dabigatran 150 mg and 110 mg twice daily compared with warfarin were £6264 and £18,691 per QALY gained respectively.
The manufacturer performed structural, univariate and probabilistic sensitivity analyses to reflect uncertainty in the model inputs and assumptions. The structural sensitivity analysis explored the cost effectiveness of dabigatran by varying INR cost (±25%), time horizon (2, 10 and 15 years), and discount rate (0 to 6%). The cost effectiveness of dabigatran was highly sensitive to the time horizon specified. A 2-year time horizon resulted in ICERs of £75,891 and £23,403 per QALY gained, respectively, for the dabigatran sequential regimen in people starting treatment when younger than 80 years and the dabigatran sequential regimen in people starting treatment when older than 80 years, compared with warfarin. For dabigatran 150 mg and 110 mg twice daily, the ICERs were £75,601 and £108,736 per QALY gained, respectively.
In the univariate sensitivity analysis, the cost effectiveness of the dabigatran sequential regimen in people starting treatment when younger than 80 years was most sensitive to risk of ischaemic stroke. Setting the relative risk for ischaemic stroke to the 95% upper confidence limits increased the base-case ICER compared with warfarin from £7314 to £17,100 per QALY gained. The cost effectiveness of the dabigatran sequential regimen in people starting treatment when older than 80 years was most sensitive to risk of ischaemic stroke and high baseline CHADS2 scores. Setting the relative risks for ischaemic stroke to the 95% upper confidence limits increased the base-case ICER for the dabigatran sequential regimen in people older than 80 years compared with warfarin from £7873 to £46,509 per QALY gained. The ICER for the dabigatran sequential regimen in people starting treatment when older than 80 years compared with warfarin increased from the base-case estimate of £7873 to £21,129 per QALY gained for a group with a CHADS2 score of 5. The ICER for dabigatran 150 mg twice daily compared with warfarin was robust to the parameters and ranges tested by the manufacturer, and the highest ICER was £10,234 per QALY gained. The cost effectiveness of dabigatran 110 mg twice daily in relation to warfarin was highly sensitive to high baseline CHADS2 scores, risk of ischaemic stroke and risk of intracranial haemorrhage.
In the probabilistic sensitivity analysis, the ICERs for the dabigatran sequential regimens in people starting treatment when younger than 80 years and in people starting treatment when older than 80 years compared with warfarin were £7811 and £11,912 per QALY gained respectively. The probabilistic ICERs for dabigatran 150 mg and 110 mg twice daily compared with warfarin were £7940 and £15,867 per QALY gained respectively.
The ERG noted that the manufacturer's submission included two generally well-conducted systematic reviews: the first was of dabigatran trials in the relevant indication, and the second was of all potentially relevant pharmacological interventions for the prevention of stroke in people with atrial fibrillation. The ERG commented that the RE‑LY trial was of good quality and that the manufacturer appropriately concentrated on the results from this trial. The ERG highlighted the limitations of non-inferiority trials, such as establishing the non-inferiority margin and the population on which to base analyses. Overall, the ERG felt that adequate measures were taken by the manufacturer to reduce the impact of potential bias associated with non-inferiority trials.
The ERG commented that the results of the RE-LY trial showed both doses of dabigatran to be non-inferior to dose-adjusted warfarin in the prevention of stroke or systemic embolism. The ERG noted that a submission from the manufacturer to the FDA indicated that dabigatran 150 mg twice daily reduced the risk of stroke or systemic embolism compared with warfarin in people with good INR control (HR=0.68, 95% CI 0.50 to 0.92 for time in therapeutic INR range 65% or above; HR=0.70, 95% CI 0.51 to 0.96 for time in therapeutic INR range 68% or above). The ERG also highlighted that an analysis in the submission produced for the FDA showed a greater benefit of dabigatran in people with poor INR control than in those whose INR was well controlled (the threshold being the centre-level median of 67%). The FDA report concluded that, although the results showed efficacy of dabigatran in people who had INR control above the centre-level median, the results did not show superiority over warfarin. The submission further subdivided people by INR control (less than 58.5%, 58.5% or above, less than 66.8%, 66.8% or above, and less than 74.2%). This demonstrated that the greatest benefit of dabigatran was in the lowest quartile of INR control and that, in people with good INR control with warfarin, little or no additional benefit in terms of effectiveness would be gained with dabigatran.
A key uncertainty highlighted by the ERG was the generalisability of the results to people with atrial fibrillation in the NHS. The ERG commented that the definition of moderate or high risk of stroke or systemic embolism in the manufacturer's submission differed slightly to the definition in 'The management of atrial fibrillation' (NICE clinical guideline 36). The ERG commented that the population in the manufacturer's submission seemed to be at higher risk of stroke because the definition of moderate risk included those aged 75 years and over with no additional risk factors, whereas NICE clinical guideline 36 defines moderate risk as people aged 65 years and over with no additional risk factors. The ERG commented that including the potentially large subgroup of people over 65 years with atrial fibrillation but with no other risk factors for stroke would have been useful, and would reflect NICE clinical guideline 36 more closely and reduce the overall risk level of the population. The clinical specialists advising the ERG noted that the threshold for treatment with warfarin seems to be decreasing, therefore decreasing the risk of stroke in the eligible atrial fibrillation population, making the population in the RE-LY trial less representative of clinical practice over time.
The ERG commented that the general approach taken by the manufacturer to estimate lifetime cost effectiveness was appropriate and met the requirements of the NICE reference case. The ERG noted that the model included most of the relevant clinical events in atrial fibrillation; however, pulmonary embolism was not included in the model. The ERG commented that excluding pulmonary embolism is potentially an optimistic approach in favour of dabigatran because dabigatran is associated with higher rates of pulmonary embolism than warfarin.
The ERG noted that, although the manufacturer's submission considered the atrial fibrillation population to be heterogeneous, reflected by the distribution of CHADS2 scores, the manufacturer assumed that all people would be treated the same. The ERG commented that this may be an over-simplification of the decision problem and does not allow the potential impact of clinical heterogeneity on cost effectiveness to be considered.
The ERG highlighted that acute myocardial infarction and systemic embolism were assumed by the manufacturer to be associated with acute costs and disutility, but not with any ongoing or long-term consequences. The ERG considered this assumption to be over-simplistic and that the effect of including long-term consequences of acute myocardial infarction and systemic embolism on the cost effectiveness of dabigatran is uncertain. The ERG commented that dabigatran was associated with higher discontinuation rates than warfarin in the first 2 years of the trial, which could suggest that people tend to tolerate warfarin better than dabigatran.
The two main weaknesses of the manufacturer's model were considered by the ERG to be related to the sequence of treatments and the cost of anticoagulation monitoring. The ERG commented that the full set of relevant sequences of treatment was not fully investigated by the manufacturer. For example, the ERG considered that starting treatment with dabigatran and subsequently switching to warfarin would be a reasonable treatment sequence, but the manufacturer's model assumed that a person could not switch to warfarin if dabigatran was the first treatment. In addition, the ERG stated that the cost of anticoagulation monitoring was a key driver of the model in terms of resources and costs, and that it was likely that the average cost of monitoring had been overestimated in the model, biasing the results in favour of dabigatran. The ERG also highlighted that its clinical advisers were concerned about the high variability of monitoring costs in practice. This heterogeneity was not considered in the manufacturer's submission. The ERG commented that uncertainty around the monitoring costs was also inadequately modelled in the manufacturer's submission.
The ERG carried out exploratory cost-effectiveness analyses by subgroups according to INR control with warfarin. The ICER for dabigatran 150 mg twice daily compared with warfarin in people with perfect INR control (that is, in target INR range 100% of the time for the entire duration of treatment) was £60,895 per QALY gained. Dabigatran 110 mg twice daily was dominated by warfarin because it was associated with greater costs but lower health benefits. The group of people with poor INR control was also evaluated by the ERG. The ICER for dabigatran 150 mg twice daily compared with warfarin for people with an INR below 2 was £740 per QALY gained. For people with an INR above 3, warfarin was dominated by dabigatran 150 mg twice daily. The ERG did not include pairwise cost-effectiveness results for dabigatran in the sequential regimen compared with warfarin. The ERG concluded that INR control is a key parameter in the economic evaluation.
The ERG used three approaches to calculate the variable costs of INR monitoring, which it considered had been overestimated in the manufacturer's model. The alternative costs used by the ERG were £279.36, £241.54 and £115.14, instead of £414.90 as assumed by the manufacturer. Adjusting the model to test each individual cost assumption increased the ICER for dabigatran 150 mg twice daily compared with warfarin to £10,528, £11,720 and £15,701 per QALY gained respectively.
The ERG considered that the disutility of dabigatran captured by the RE-LY quality of life sub-study had not been fully reflected in the manufacturer's cost-effectiveness analysis. The disutility associated with dabigatran treatment was tested by the ERG but it did not change the overall conclusions about the cost effectiveness of this intervention.
The ERG commented that treatment with dabigatran was associated with an increased incidence of dyspepsia compared with warfarin treatment, but that the model assumed that the cost of dyspepsia was only accrued in the first cycle. The ERG considered that a more conservative approach would be to assume that costs of dyspepsia continue throughout treatment. This caused the ICER for dabigatran 150 mg twice daily compared with warfarin to increase slightly from £6262 per QALY to £6659 per QALY gained.
The ERG highlighted that disability and mortality risk after stroke is considered to be treatment dependent in the manufacturer's model. Therefore the ERG explored the model assuming that disability caused by stroke is independent of treatment. The ICER for dabigatran 150 mg twice daily compared with warfarin increased from £6262 to £8393 per QALY gained.
The ERG presented analyses using an alternative set of assumptions to those provided by the manufacturer. The ERG's alternative base case assumed:
A patient cohort representing people with atrial fibrillation in the UK, using the data reported by Gallagher et al. (2008).
The variable (per patient) costs of anticoagulant monitoring are £115.14.
People have dyspepsia throughout dabigatran treatment, not just in the first 3 months of treatment.
Disability and mortality risks after stroke are treatment independent.
Disutility associated with dabigatran during the first 12 months of treatment as used in the RE-LY quality of life sub-study (the details are academic-in-confidence).
By introducing these assumptions, the ICER for dabigatran 150 mg twice daily compared with warfarin increased from £6264 to £24,173 per QALY gained in the ERG's alternative base-case analysis.
# Manufacturer's additional analyses
Additional analyses were provided by the manufacturer in response to NICE's request for further clarification on the cost effectiveness of dabigatran presented in the appraisal consultation document. The manufacturer submitted a revised cost-effectiveness analysis of the sequential regimen model comparing dabigatran with warfarin using relative risks from the whole RE-LY trial population rather than from the post hoc subgroup analysis, as requested by the Committee. Given the uncertainty about costs of warfarin prescription and monitoring because of wide variations in local practice, it also conducted sensitivity analyses that varied the annual cost of INR monitoring (£115.14, £241.54, £279.36 and £414.90) and explored the ERG's preferred assumptions (see section 3.33).
The manufacturer highlighted that its new base-case analysis included INR costs of £241.54. The manufacturer selected this cost based on the conclusions of the first Appraisal Committee meeting, which stated that the real cost of INR monitoring was likely to lie between the ERG's lower estimate of £115.14 and the manufacturer's upper estimate of £414.90. Assuming an INR monitoring cost of £241.54, the manufacturer's revised base-case ICERs were £14,518 per QALY gained for the dabigatran sequential regimen in people starting treatment when younger than 80 years and £18,269 per QALY gained for the sequential regimen in people starting treatment at 80 years and older, compared with warfarin.
In response to the Committee's request to include a patient cohort that better reflected people with atrial fibrillation in the UK, the manufacturer highlighted that data from Gallagher et al. (2008) were not easily adapted to the model and that many of the patients included in the Gallagher analysis would not be covered by the marketing authorisation for dabigatran. To address the Committee's request the manufacturer performed an analysis of the General Practice Research Database to derive data required for the model. Applying these data increased the ICERs to £17,373 and £19,680 per QALY gained for the dabigatran sequential regimen in people starting treatment when younger than 80 years and at 80 years and older respectively, compared with warfarin. The manufacturer stated that applying the ERG's preferred assumptions relating to dyspepsia management costs, disability and mortality risks, and disutility associated with dabigatran (see section 3.33) individually had minimal effect on the base-case ICER. Combining an INR monitoring cost of £241.54 with the ERG's preferred assumptions resulted in ICERs of £17,660 and £18,392 per QALY gained for the sequential regimen in people starting treatment when younger than 80 years and people starting treatment at 80 years and older respectively, compared with warfarin.
The manufacturer also responded to the Committee's request in the appraisal consultation document for further comment and consideration of the cost effectiveness of dabigatran in the subgroup of people whose condition is already well controlled on warfarin. The manufacturer highlighted that the INR control analyses submitted to the FDA (see section 3.22) were stratified by time in therapeutic range only in the warfarin arm and should therefore be interpreted with caution. The manufacturer stated that analyses presented in a study by Wallentin et al. (2010), which was stratified on treatment centre time in therapeutic range (a method that maintains randomisation within a centre), would be more relevant if such an analysis were to be carried out. The manufacturer highlighted that the ERG's initial analysis of good INR control (see section 3.28) assumed a time in therapeutic range of 100%, which is unlikely to be achieved in clinical practice for most patients. The manufacturer further explained that for both the full sequential regimen in people starting treatment younger than 80 years and the over 80 cohort, INR would need to be within target range an average of approximately 83% to 85% of the time for the ICERs to be above £30,000 per QALY gained compared with warfarin.
The ERG provided a critique and exploratory analysis of the manufacturer's additional analyses. The ERG compared inputs in the revised model with inputs used for the original single-dose and sequential regimen model. It commented that the values for ischaemic stroke disability and mortality rates by treatment used in the revised sequential regimen model were the same as those used in the initial sequential regimen model rather than those from the single-dose model. The ERG commented that correcting for this had the effect of reducing the manufacturer's ICERs slightly. The ERG agreed with the manufacturer that the data presented by Gallagher et al. (2008) are not easily adapted to the model. It commented that the General Practice Research Database data presented by the manufacturer have advantages over the Gallagher study in that they are more recent and therefore more reflective of the current UK atrial fibrillation population, and they refer solely to the people with atrial fibrillation for whom dabigatran is licensed. The ERG compared the results of the incremental analyses presented by the manufacturer with the results obtained by the ERG after including the correct values for ischaemic stroke disability and mortality rates by treatment and including all of the assumptions requested by the Committee. The ERG commented that its results were broadly in line with those presented by the manufacturer. The ERG's estimate of the ICER for the sequential regimen in people starting treatment when younger than 80 years, including the relative risks from the whole RE-LY trial population, an INR cost of £241.54 and all of the assumptions requested by the Committee, was £18,863 per QALY gained compared with the manufacturer's estimate of £17,660 per QALY gained.
The ERG acknowledged the manufacturer's view that 100% time in therapeutic range is difficult to achieve in clinical practice. The ERG identified a UK-based study by Jones et al. (2005) that reported that the average time in therapeutic range was 67.9%. The ERG commented that the Jones et al. (2005) study indicated that the people with the best INR control (upper quartile) were within therapeutic range an average of 83.7% of the time, so the ERG performed further exploratory sensitivity analyses testing this value. For the subgroup of patients whose INR is within range 83.7% of the time, the ICER for dabigatran compared with warfarin was £46,989 per QALY gained assuming INR monitoring costs of £241.54 per annum. If the INR costs were increased to £414.90 per annum, the ICER decreased to £31,386 per QALY gained compared with warfarin. The ERG commented that it is unclear how INR monitoring costs vary by time in therapeutic range. The ERG also performed a threshold analysis to estimate the level of time in therapeutic range needed to raise the ICER above £30,000 per QALY gained compared with warfarin, assuming an INR monitoring cost of £241.54 per annum and including all of the ERG's preferred assumptions. The ERG commented that the INR would need to be within the target range an average of 75–76% of the time or more for the ICER to be above £30,000 per QALY gained compared with warfarin.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dabigatran, having considered evidence on the nature of atrial fibrillation and the value placed on the benefits of dabigatran by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee heard from the clinical specialists and patient experts that the current standard treatment for the prevention of stroke and systemic embolism in people with atrial fibrillation is warfarin, and that because of its lower efficacy, aspirin is used only in people for whom warfarin is unsuitable. The Committee also heard that warfarin, although an effective treatment, is associated with a number of problems. The main concerns for people with atrial fibrillation were fear of having a stroke and anxiety about the difficulty of keeping the INR within the satisfactory therapeutic range. The Committee heard from the patient experts that stroke is a major concern for people with atrial fibrillation and that stroke severity is usually greater in this group than in people who have strokes from other causes. The patient experts also highlighted that many people taking warfarin are outside their target therapeutic INR range at any one time and that warfarin, unlike dabigatran, is associated with a number of inconveniences that make adherence difficult. These include numerous food and drug interactions that can have an impact on people's work, social and family life, and regular monitoring and dose adjustments that can cause disruption and inconvenience. The Committee accepted the limitations of warfarin therapy, and the considerable effect that it may have on the lives of the people who take it, and recognised the potential benefits of dabigatran for people with atrial fibrillation.
The Committee considered the clinical-effectiveness data from the RE-LY trial comparing dabigatran with warfarin. It noted that this formed most of the clinical-effectiveness evidence in the manufacturer's submission and was the largest published trial in people with atrial fibrillation. The Committee considered that the RE-LY trial was of good quality but noted that a key uncertainty highlighted by the ERG was the generalisability of the results to people diagnosed with atrial fibrillation in the NHS. The Committee noted that the definition of moderate to high risk of stroke in the RE-LY trial was different from the definition used in NICE clinical guideline 36 and did not include people aged 65 years and over with no additional risk factors for stroke, resulting in a higher risk profile in the trial than in the general population eligible for anticoagulation prophylaxis. However, the Committee was persuaded by the clinical specialists that the RE-LY trial included a broad range of people that reflected those seen in UK clinical practice and that the results were applicable to a wide range of people with atrial fibrillation. The Committee concluded that the population included in the trial was appropriate and broadly relevant to UK clinical practice.
The Committee considered the results of the RE-LY trial. It noted that dabigatran 150 mg twice daily was associated with a statistically significantly lower incidence of stroke or systemic embolism, ischaemic stroke and vascular mortality compared with warfarin, but that there were no statistically significant differences in these outcomes between dabigatran 110 mg twice daily and warfarin. It also noted that both doses of dabigatran were associated with an increased risk of acute myocardial infarction compared with warfarin but that this was not statistically significant. The Committee heard from the clinical specialists that this reflected a small absolute difference in the incidence of acute myocardial infarction between the treatment groups, but it was unclear whether this was because of a protective effect of warfarin or a negative effect of dabigatran treatment, and that the effects did not appear to translate into an increased vascular mortality risk. The Committee concluded that dabigatran 150 mg twice daily was more clinically effective than warfarin in reducing the risk of stroke or systemic embolism, ischaemic stroke and vascular mortality and that this represented an important development for people with atrial fibrillation. It also concluded that the lower 110 mg dabigatran twice-daily dose had shown non-inferiority to warfarin.
The Committee considered the results of the manufacturer's subgroup analyses. It was aware, however, that the manufacturer's analyses by age had been defined post hoc and it therefore considered that the results should be interpreted with caution. The Committee also considered the results of the manufacturer's pre-planned analyses of people naive to vitamin K antagonists and people who have previously used vitamin K antagonists. It noted that dabigatran 150 mg twice daily was associated with a statistically significant reduction in the incidence of stroke or systemic embolism compared with warfarin in both vitamin K antagonist-naive and vitamin K antagonist-experienced subgroups, but dabigatran 110 mg twice daily did not show a statistically significant reduction in either group. The Committee concluded that dabigatran 150 mg twice daily showed increased efficacy compared with warfarin in people with atrial fibrillation irrespective of their previous exposure to vitamin K antagonists.
The Committee discussed the effectiveness of dabigatran compared with warfarin according to INR control. It noted the evidence presented by the ERG that people with good INR control with warfarin may not gain additional clinical benefit by taking dabigatran. However, the clinical specialists emphasised the importance of the significantly lower rates of intracranial haemorrhage and haemorrhagic stroke associated with both doses of dabigatran compared with warfarin in the RE-LY trial, and that this effect is maintained in people with good INR control. The Committee heard that haemorrhagic stroke and intracranial haemorrhage have devastating and life-threatening consequences and concluded that the lower rates associated with dabigatran represent an important advance in the treatment of atrial fibrillation alongside reduction in ischaemic stroke. It concluded that this applied to all patients with atrial fibrillation, including those with good INR control, and that there were also benefits of taking a treatment that didn't need INR monitoring or dietary restriction.
The Committee considered the additional adverse events reported in the RE-LY trial. It noted that both doses of dabigatran were associated with statistically significant reductions in the incidence of life-threatening bleeds compared with warfarin. However, it also noted that the incidence of gastrointestinal bleeding, in contrast to cerebral haemorrhage, was statistically significantly higher for both doses of dabigatran, and the comment from the manufacturer that this may be the result of a local effect of the orally administered drug on the gastrointestinal mucosa. Dabigatran 150 mg twice daily was associated with a statistically significantly higher incidence of major and life-threatening gastrointestinal bleeding. The Committee noted that even small changes in total gastrointestinal bleeding rates might have a substantial impact on the provision of services and that major gastrointestinal bleeding is associated with a significant mortality risk. The Committee concluded that treatment with dabigatran resulted in more gastrointestinal bleeding than warfarin, but also recognised the particular importance of the effects of dabigatran on reducing the risk of haemorrhagic stroke and intracranial haemorrhage for people with atrial fibrillation when compared with warfarin.
The Committee was aware that health-related quality of life data were collected in a sub-study of the RE-LY trial. It noted that baseline utility values for people with atrial fibrillation were derived from the sub-study. The Committee agreed that because the sub-study was reasonably representative of the overall RE-LY population, this approach was appropriate.
The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. The Committee considered the utility values used in the model and noted that it was unclear how the utility values relating to the effect of stroke were derived. However, the Committee agreed with the ERG that the general approach taken by the manufacturer to estimate the lifetime cost effectiveness of dabigatran was appropriate.
The Committee noted that the manufacturer presented a single-dose model, and a sequential regimen model in which people younger than 80 years began treatment with dabigatran 150 mg twice daily, and at the age of 80 years were switched to dabigatran 110 mg twice daily. As the summary of product characteristics for dabigatran excludes people older than 80 years from treatment with dabigatran 150 mg twice daily because of additional risks in this group, the Committee concluded that the sequence of dabigatran 150 mg twice daily followed by dabigatran 110 mg twice daily once people reach 80 years would be the only regimen appropriate for the assessment of the cost effectiveness of dabigatran relative to warfarin in the whole eligible UK population.
The Committee heard from the ERG that the relative risks used to inform the manufacturer's original sequential regimen model were derived from people in the younger than 80 years and older than 80 years subgroups of the RE-LY trial that were defined post hoc. It also heard that using relative risks from the whole RE-LY trial population would be more appropriate to determine reliable effectiveness estimates for the dabigatran sequence. Therefore the Committee asked the manufacturer to submit a re-analysis of the data for discussion at the second Appraisal Committee meeting using the relative risks from the whole RE-LY trial population.
At the first Appraisal Committee meeting, the Committee noted that the ERG had highlighted a number of uncertainties relating to assumptions used in the manufacturer's economic model. First, the Committee noted the ERG's view that an analysis based on an older patient cohort with a lower risk of stroke using data reported by Gallagher et al. (2008) would be more representative of people with atrial fibrillation in the UK than the cohort from the RE-LY trial used by the manufacturer. The Committee accepted that there was uncertainty around which cohort most realistically reflected the population of people with atrial fibrillation in the UK.
Second, the Committee noted that the ERG questioned whether disability and mortality were independent of the treatment received. The Committee heard from the clinical specialists that the manufacturer's assumption that a stroke would be less severe after treatment with dabigatran than warfarin was plausible and that there is evidence that both the incidence and the severity of stroke may vary according to the treatment received. The Committee also noted the ERG's views about disutility of dabigatran and the inclusion of dyspepsia management costs throughout treatment (see sections 3.30 and 3.31). The Committee agreed that including all of these assumptions would be a more conservative approach.
Third, the Committee noted the ERG's view that the cost of INR monitoring had been overestimated in the manufacturer's model. The Committee heard from the clinical specialists that the introduction of dabigatran would not result in complete closure of anticoagulation services with release of all the funding, and the manufacturer's estimate (£414.90) was likely to be too high. It also heard that INR monitoring costs varied in different settings and could not be quantified precisely. The Committee agreed that exploring the effect of assuming the alternative INR monitoring costs put forward by the ERG (£115.14, £241.54, £279.36), in addition to the cost assumed in the manufacturer's submission, would enable it to make a more accurate judgement about the cost effectiveness of dabigatran.
Finally, the Committee noted the ERG's comments that the cost effectiveness of dabigatran compared with warfarin varied substantially according to level of INR control in those already being treated with warfarin. In the appraisal consultation document, the manufacturer of dabigatran was therefore asked to provide further analyses addressing the uncertainties outlined in sections 4.11 to 4.15.
The Committee discussed the manufacturer's revised analyses and the critique and the exploratory analyses performed by the ERG. The Committee noted that the manufacturer's revised analysis included the relative risks from the whole RE-LY trial population rather than from the post hoc subgroup analysis and had explored the effect of varying the cost of INR monitoring as requested. It also noted that the manufacturer's revised analysis incorporated an INR monitoring cost of £241.54 in its base case as opposed to £414.90 in the original submission. The Committee was aware that comments received during the consultation largely agreed that INR monitoring costs are likely to be higher than the ERG's lower estimate of £115.14 and possibly higher than £414.90 in some cases. The Committee accepted the manufacturer's approach, acknowledging that although INR costs may vary widely, this assumption was reasonable.
The Committee discussed the manufacturer's approach to including the ERG's other preferred assumptions in the revised analysis (see section 3.33). The Committee noted that the Gallagher et al. (2008) data on atrial fibrillation had not been incorporated. However, the Committee accepted the manufacturer's rationale and the supporting views of the ERG for using General Practice Research Database data instead (see section 3.39). The Committee noted that, in its revised analyses, the manufacturer had incorporated the ERG's preferred assumptions about dyspepsia management costs throughout treatment, disability and mortality risks being treatment independent, and disutility associated with dabigatran. It further noted that combining all of these assumptions together with an INR monitoring cost of £241.54 resulted in an ICER for dabigatran of £17,700 per QALY gained for the full sequential regimen in people starting treatment when younger than 80 years and £18,400 per QALY gained in people starting treatment at 80 years and older, compared with warfarin. Finally, the Committee noted that the ERG's analysis, which included all of the requested assumptions, an INR monitoring cost of £241.54, and the corrected values for ischaemic stroke and disability rates (see section 3.39) resulted in an ICER of £18,900 per QALY gained for the sequential regimen in people starting treatment younger than 80 years, compared with warfarin. The Committee concluded that this was broadly in line with the manufacturer's estimate and that the ICERs presented by the manufacturer were robust to the changes requested. The Committee therefore accepted the manufacturer's approach and concluded that the most plausible ICERs for the whole population eligible for dabigatran were within the range normally considered a cost-effective use of NHS resources, being less than £20,000 per QALY gained.
The Committee discussed comments from consultees that suggested it may be appropriate to recommend dabigatran for use only in people with atrial fibrillation whose INR is not well controlled on warfarin. The Committee was satisfied that the technology was a cost-effective treatment for the whole patient group. It noted that robust evidence of differential clinical effectiveness and cost effectiveness, with clear justification of the threshold level chosen, would be needed to select out a subgroup, based on INR control, for whom dabigatran would not be recommended.
The Committee was aware of the need for guidance to apply equally to those already on warfarin and to those newly diagnosed with atrial fibrillation. The Committee noted that, for people newly diagnosed but not already taking an anticoagulant, any stratification of the population according to INR control would mean that all patients would have to try warfarin for at least a few months to assess whether the INR was well controlled and to estimate the time in therapeutic range. The Committee heard from clinical specialists that many of the significant complications of warfarin therapy are experienced in the first months of treatment before the dose is established and stabilised. The Committee accepted therefore that a large number of people having a trial of warfarin at initial diagnosis could be expected to switch to dabigatran. It also accepted that it was not reasonable to expect all patients to try warfarin first, with the associated risks, for the purpose of selecting out a subgroup for whom dabigatran was less cost effective.
The Committee was also aware of the estimates of the time that the INR in people already taking warfarin would need to be in the target range for the ICERs for dabigatran compared with warfarin to be above £30,000 per QALY gained. Assuming an INR monitoring cost of £241.54 per annum, the manufacturer and ERG estimated an average of 83% to 85% and 75% to 76% of the time respectively. The Committee noted that this would apply to only a proportion of the whole population. The Committee was aware that the average time spent in therapeutic range for the UK centres in the RE-LY trial was 72%, and in the UK-based study by Jones et al. (2005) there was an average time in therapeutic range of 67.9%. It noted the ERG's analysis that explored the effects of time in therapeutic range on the cost effectiveness of dabigatran compared with warfarin. This calculated the ICER for the people with the best-controlled INR (that is, within range 83.7% of the time) at £47,000 per QALY gained. However, this figure incorporated INR monitoring costs of £241.54 (per annum) and the ICER reduced considerably if higher INR monitoring costs of £414.90 per annum were used. The Committee concluded that evidence for stratifying by INR control was insufficient to exclude the minority of people with very good control from the recommendation of dabigatran as a potential treatment option, and that the ICER for the whole population should be the basis of the recommendation.
The Committee was mindful of the higher gastrointestinal bleeding rates associated with dabigatran and of the relatively short-term safety data compared with the established standard of care, warfarin. It was also mindful that for those with very well-controlled INR on warfarin, the clinical benefits are likely to be less than for those with poorly controlled INR. The Committee therefore concluded that the decision about whether to start treatment with dabigatran in people with atrial fibrillation should be made after an informed discussion between the responsible clinician and the person about the safety risks and benefits of dabigatran compared with warfarin. It also concluded that, for people currently receiving warfarin, the potential risks and benefits of switching to dabigatran should be considered in light of their level of INR control.
The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.
# Summary of Appraisal Committee's key conclusions
TA249
Appraisal title: Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation
Section
Key conclusion
Dabigatran etexilate is recommended as an option for the prevention of stroke and systemic embolism in people with nonvalvular atrial fibrillation within its licensed indication.
The decision about whether to start treatment with dabigatran etexilate should be made after an informed discussion between the clinician and the person about the risks and benefits of dabigatran compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to dabigatran should be considered in light of their level of international normalised ratio (INR) control.
The Committee concluded that dabigatran 150 mg twice daily was more clinically effective than warfarin in reducing the risk of stroke or systemic embolism, ischaemic stroke and vascular mortality whereas dabigatran 110 mg twice daily was non-inferior to warfarin. It concluded that dabigatran represented an important development for people with atrial fibrillation.
The Committee concluded that the most plausible ICERs for the whole population eligible for dabigatran were within the range normally considered a cost-effective use of NHS resources, being less than £20,000 per QALY gained.
The Committee concluded that evidence for stratifying by INR control was insufficient to exclude the minority of people with very good control from the recommendation of dabigatran as a potential treatment option, and that the ICER for the whole population should be the basis of the recommendation.
Current practice
Clinical need of patients, including the availability of alternative treatments
The clinical specialists commented that current standard treatment for the prevention of stroke and systemic embolism in people with atrial fibrillation is warfarin, and that because of its lower efficacy, aspirin is used only in people for whom warfarin is unsuitable. The main concerns for people with atrial fibrillation were fear of having a stroke and anxiety about the difficulty of keeping the INR within the satisfactory therapeutic range.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The patient experts stated that warfarin, unlike dabigatran, is associated with a number of inconveniences that make adherence difficult. These include numerous food and drug interactions that can have an impact on people's work, social and family life, and regular monitoring and dose adjustments that can cause disruption and inconvenience. The Committee accepted the limitations of warfarin therapy, and the considerable effect that it may have on the lives of the people who take it, and recognised the potential benefits of dabigatran for people with atrial fibrillation.
The Committee was not made aware of health-related benefits that were not captured in the QALY.
What is the position of the treatment in the pathway of care for the condition?
Dabigatran is used as an alternative to warfarin and is an anticoagulant treatment for the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors:
previous stroke, transient ischaemic attack, or systemic embolism
left ventricular ejection fraction below 40%
symptomatic heart failure of New York Heart Association (NYHA) class 2 or above
age 75 years or over
age 65 years or over with one of the following: diabetes mellitus, coronary artery disease, or hypertension.
Adverse effects
The Committee noted that both doses of dabigatran were associated with statistically significant reductions in the incidence of life-threatening bleeds compared with warfarin.
The Committee concluded that treatment with dabigatran resulted in more gastrointestinal bleeding than warfarin, which may be the result of a local effect of the orally administered drug on the gastrointestinal mucosa, but also recognised the particular importance of the effects of dabigatran on reducing the risk of haemorrhagic stroke and intracranial haemorrhage for people with atrial fibrillation when compared with warfarin.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The RE-LY trial formed most of the clinical-effectiveness evidence in the manufacturer's submission and was the largest published trial in people with atrial fibrillation. The Committee considered that the RE-LY trial was of good quality.
Relevance to general clinical practice in the NHS
The Committee concluded that the population included in the RE-LY trial was appropriate and broadly relevant to UK clinical practice.
Uncertainties generated by the evidence
The Committee was aware that the manufacturer's analyses by age had been defined post hoc and it therefore considered that the results should be interpreted with caution.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
Evidence was presented by the ERG indicating that people with good INR control with warfarin may not gain additional clinical benefit by taking dabigatran.
The Committee was aware that the manufacturer's analyses by age had been defined post hoc and it therefore considered that the results should be interpreted with caution. The Committee also considered the results of the manufacturer's pre-planned analyses of people naive to vitamin K antagonists and people who have previously used vitamin K antagonists. The Committee concluded that dabigatran 150 mg twice daily showed increased efficacy compared with warfarin in people with atrial fibrillation irrespective of their previous exposure to vitamin K antagonists.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Dabigatran 150 mg twice daily was associated with a statistically significantly lower incidence of stroke or systemic embolism, ischaemic stroke and vascular mortality compared with warfarin, but there were no statistically significant differences between dabigatran 110 mg twice daily and warfarin. The Committee concluded that dabigatran 150 mg twice daily was more clinically effective than warfarin in reducing the risk of stroke or systemic embolism, ischaemic stroke and vascular mortality and that this represented an important development for people with atrial fibrillation. It also concluded that the lower 110 mg dabigatran twice-daily dose had shown non-inferiority to warfarin.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee agreed with the ERG that the general approach taken by the manufacturer to estimate the lifetime cost effectiveness of dabigatran was appropriate.
The Committee noted that the manufacturer presented a single-dose model and a sequential regimen model in which people younger than 80 years began treatment with dabigatran 150 mg twice daily, and at the age of 80 years were switched to dabigatran 110 mg twice daily. As the summary of product characteristics for dabigatran excludes people older than 80 years from treatment with dabigatran 150 mg twice daily because of additional risks in this group, the Committee concluded that the sequence of dabigatran 150 mg twice daily followed by dabigatran 110 mg twice daily once people reach 80 years would be the only regimen appropriate for the assessment of the cost effectiveness of dabigatran relative to warfarin in the whole eligible UK population
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee was aware that there was uncertainty around INR monitoring costs, which cohort most realistically reflected the population of people with atrial fibrillation in the UK, and whether disability and mortality were independent of the treatment received.
to 4.14
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that baseline utility values for people with atrial fibrillation were derived from the sub-study of the RE-LY trial.
The Committee noted that it was unclear how the utility values relating to the effect of stroke were derived.
No health-related benefits were identified that were not included in the economic model.
Are there specific groups of people for whom the technology is particularly cost effective?
Dabigatran is recommended as an option for all people with nonvalvular atrial fibrillation within its licensed indication.
What are the key drivers of cost effectiveness?
The Committee noted the ERG's comments that the cost effectiveness of dabigatran compared with warfarin varied substantially according to level of INR control in those already being treated with warfarin.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee noted that the ERG's analysis, which included all of the requested assumptions, an INR monitoring cost of £241.54, and the correct values for ischaemic stroke and disability rates (see section 3.39) increased the manufacturer's base-case ICER to £18,900 per QALY gained for the sequential regimen in people starting younger than 80 years, compared with warfarin.
The Committee concluded that the most plausible ICERs for the whole population eligible for dabigatran were within the range normally considered a cost-effective use of NHS resources, being less than £20,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
End-of-life considerations were not discussed.
Equalities considerations and social value judgements
The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.
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{'Recommendations': 'Dabigatran etexilate is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more of the following risk factors:\n\nprevious stroke, transient ischaemic attack or systemic embolism\n\nleft ventricular ejection fraction below\xa040%\n\nsymptomatic heart failure of New York Heart Association (NYHA) class\xa02 or above\n\nage\xa075\xa0years or older\n\nage 65\xa0years or older with one of the following: diabetes mellitus, coronary artery disease or hypertension.\n\nDecide whether to start treatment with dabigatran etexilate after an informed discussion with the person about its risks and benefits compared with warfarin, apixaban, edoxaban and rivaroxaban. For people taking warfarin, consider the potential risks and benefits of switching to dabigatran etexilate taking into account their level of international normalised ratio (INR) control.', 'The technology ': "Dabigatran etexilate (Pradaxa, Boehringer Ingelheim; hereafter referred to as dabigatran) is an orally administered anticoagulant that inhibits the thrombin enzyme. Dabigatran has a UK marketing authorisation for the 'prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors:\n\nprevious stroke, transient ischaemic attack, or systemic embolism\n\nleft ventricular ejection fraction below\xa040%\n\nsymptomatic heart failure of New York Heart Association (NYHA) class\xa02 or above\n\nage\xa075\xa0years or over\n\nage 65\xa0years or over with one of the following: diabetes mellitus, coronary artery disease, or hypertension'.\n\nThe summary of product characteristics states that the recommended daily dose of dabigatran is 300\xa0mg taken as one 150\xa0mg capsule twice daily. Therapy is continued long term. For patients aged\xa075 to 80\xa0years, a dose of 220\xa0mg taken as one 110\xa0mg capsule twice daily can be considered at the discretion of the physician for individual patients whose thromboembolic risk is low and bleeding risk is high. Patients aged 80\xa0years or older should be treated with a daily dose of 220\xa0mg taken as one 110\xa0mg capsule twice daily because of the increased risk of bleeding in this population.\n\nDabigatran is contraindicated in people with severe renal impairment, active clinically significant bleeding, organic lesions at risk of bleeding, impairment of haemostasis, and hepatic impairment or liver disease expected to have an impact on survival. Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole or tacrolimus is also contraindicated. The most common adverse events in people receiving dabigatran are anaemia, abdominal pain, diarrhoea, dyspepsia, gastrointestinal haemorrhage, genitourinary haemorrhage (patients may notice blood in their urine), nausea and nose bleeds. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nDabigatran is available as 110\xa0mg and 150\xa0mg capsules and comes in packs of 60\xa0capsules. The manufacturer has stated that the cost to the NHS of a pack of 60\xa0capsules of either dabigatran 110\xa0mg or 150\xa0mg will be £75.60 (excluding VAT). The cost per day per patient based on the recommended dosage will be £2.52 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee considered evidence submitted by the manufacturer of dabigatran and a review of this submission by the Evidence Review Group (ERG).\n\nThe manufacturer's submission included three trials that directly compared dabigatran with dose-adjusted warfarin: RE-LY, PETRO and 1160.49. The PETRO and 1160.49 trials were both dose-finding studies with safety data collection as the primary objective. The main evidence for clinical effectiveness presented in the manufacturer's submission was based on the RE-LY randomised controlled trial.\n\nRE-LY was a non-inferiority trial in which two blinded doses of dabigatran (110\xa0mg twice daily and 150\xa0mg twice daily) were compared with open-label warfarin (with a target international normalised ratio [INR] of 2.0\xa0to\xa03.0) for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation and at least one additional risk factor for stroke. The RE-LY trial included people with documented atrial fibrillation and at least one of the following additional risk factors: history of stroke, transient ischaemic attack, or systemic embolism; left ventricular ejection fraction of less than 40%; symptomatic heart failure; age 75\xa0years or older; age 65\xa0years or older with diabetes mellitus, documented coronary artery disease or hypertension. People were excluded from the RE-LY trial if they had a severe, disabling stroke in the previous 6\xa0months or any stroke within the previous 14\xa0days, conditions associated with increased risk of bleeding, or a contraindication to warfarin treatment.\n\nThe RE-LY study took place in 44 countries including the UK and a total of 18,113\xa0people were randomised across the three treatment arms in a 1:1:1 ratio. People recruited into the study were randomised within 14\xa0days of the screening visit and were randomly allocated to dabigatran 110\xa0mg twice daily (n=6015), dabigatran 150\xa0mg twice daily (n=6076) or warfarin (n=6022). Minimum follow-up was 1\xa0year, and median follow-up was 23.7\xa0months. The mean age of people in the study was 71.5\xa0years and 63.6% were male. Risk of stroke at baseline was classified according to CHADS2 score, which is used to estimate the risk of stroke in people with atrial fibrillation to determine whether they need anticoagulation treatment. The score was calculated by giving one point each for the presence of congestive heart failure, hypertension or diabetes mellitus, and age 75\xa0years or older. Two points were given if people had already had an ischaemic stroke or transient ischaemic attack.\n\nThe primary outcome in the study was incidence of all types of stroke (including haemorrhagic stroke) or systemic embolism. To show non-inferiority in the RE-LY trial, the upper limits of the confidence interval (CI) of the hazard ratio (HR) for dabigatran versus warfarin had to be less than the margin specified. Two margins were used in the manufacturer's submission, 1.46 and 1.38, of which 1.38 was specified as the preferred margin of non-inferiority by the US Food and Drug Administration (FDA).\n\nThe reduction in relative risk of stroke or systemic embolism compared with warfarin was 10% for dabigatran 110\xa0mg and 35% for dabigatran 150\xa0mg. Dabigatran 150\xa0mg twice daily was associated with a lower incidence of stroke or systemic embolism compared with warfarin and this was statistically significant (HR=0.65, 95% CI 0.52 to 0.81). A statistically significant beneficial effect of dabigatran 150\xa0mg twice daily was also demonstrated in terms of a reduced incidence of ischaemic stroke (HR=0.75, 95% CI 0.58 to 0.97) and vascular mortality (HR=0.85, 95% CI 0.72 to 0.99). A reduction in all-cause mortality was also observed and, although it did not reach statistical significance, it showed dabigatran 150\xa0mg twice daily to be non-inferior to warfarin (HR=0.88, 95% CI 0.77 to 1.00). There were no statistically significant differences between dabigatran 110\xa0mg twice daily and warfarin in the incidence of stroke or systemic embolism, ischaemic stroke or vascular mortality. Both doses of dabigatran were associated with an increased risk of acute myocardial infarction compared with warfarin but this was not statistically significant (HR=1.29, 95% CI 0.96 to 1.75 [110\xa0mg twice daily]; HR=1.27, 95% CI 0.94 to 1.71 [150\xa0mg twice daily]).\n\nThe manufacturer's submission included post hoc subgroup analyses of people older and younger than 80\xa0years of age. In both age groups, there were no statistically significant differences between either dose of dabigatran and warfarin in the incidence of ischaemic stroke, systemic embolism and myocardial infarction. However, the manufacturer did report a statistically significant reduction in the incidence of transient ischaemic attack (HR=0.45, 95% CI 0.23 to 0.89) in people older than 80\xa0years receiving dabigatran 110\xa0mg twice daily, compared with warfarin.\n\nThe manufacturer's submission reported results from pre-planned subgroup analyses of people naive to vitamin K antagonists such as warfarin (defined as treatment for 2\xa0months or less in a person's lifetime) and people who have previously used vitamin K antagonists (defined as treatment for more than 2\xa0months during a person's lifetime). In both groups, dabigatran 150\xa0mg twice daily was associated with a statistically significant reduction in the incidence of stroke or systemic embolism compared with warfarin (HR=0.63, 95% CI 0.46 to 0.87 [vitamin K antagonist-naive group] and HR=0.63, 95% CI 0.49 to 0.89 [vitamin K antagonist-experienced group]). No statistically significant differences were reported for the lower, 110\xa0mg twice daily, dose of dabigatran compared with warfarin.\n\nFor adverse events, the manufacturer reported a statistically significant reduction in the incidence of haemorrhagic stroke for both doses of dabigatran compared with warfarin (HR=0.31, 95%\xa0CI\xa00.17\xa0to\xa00.56 [dabigatran 110\xa0mg twice daily] and HR=0.26, 95%\xa0CI\xa00.14 to 0.49 [dabigatran 150\xa0mg twice daily]). Both doses of dabigatran were also associated with statistically significantly fewer life-threatening bleeds compared with warfarin (HR=0.67, 95% CI 0.54 to 0.82 [dabigatran 110\xa0mg twice daily] and HR=0.80, 95% CI 0.66 to 0.98 [dabigatran 150\xa0mg twice daily]). Both doses of dabigatran were associated with fewer cases of intracranial haemorrhage (including haemorrhagic stroke) than warfarin (HR=0.30, 95% CI 0.19 to 0.45 [dabigatran 110\xa0mg twice daily]; HR=0.41, 95% CI 0.28 to 0.61 [dabigatran 150\xa0mg twice daily]). Treatment with dabigatran 110\xa0mg was also associated with a statistically significant reduction in major bleeding compared with warfarin. In contrast, both doses of dabigatran were associated with a significantly higher rate of gastrointestinal bleeding compared with warfarin (HR=1.35, 95% CI 1.19 to 1.53 [dabigatran 110\xa0mg twice daily] and HR=1.52, 95% CI 1.35 to 1.72 [dabigatran 150\xa0mg twice daily]). Dabigatran 150\xa0mg twice daily was associated with a significantly higher incidence of major gastrointestinal bleeding (HR=1.47, 95% CI 1.17 to 1.85) and life-threatening gastrointestinal bleeding (HR=1.62, 95% CI 1.17 to 2.26). The manufacturer reported that more people in the dabigatran groups discontinued the study drug (22.0% in the dabigatran 110\xa0mg twice daily group and 22.8% in the dabigatran 150\xa0mg twice daily group), compared with those on warfarin (17.9%). More people in the dabigatran groups also discontinued study medication because of outcome events; however discontinuations caused by major bleeds were similar for all treatments.\n\nThe manufacturer reported a statistically significant reduction in the incidence of haemorrhagic stroke in the post hoc subgroup analyses of people younger than 80\xa0years compared with warfarin for both doses of dabigatran (HR=0.33, 95% CI 0.16 to 0.65 [dabigatran 110\xa0mg twice daily]; HR=0.21, 95% CI 0.09 to 0.47 [dabigatran 150\xa0mg twice daily]) and in people older than 80\xa0years receiving dabigatran 110\xa0mg twice daily (HR=0.26, 95%\xa0CI\xa00.07\xa0to\xa00.91). However, the reduction in incidence of haemorrhagic stroke in people older than 80 years for dabigatran 150\xa0mg twice daily compared with warfarin was not statistically significant (HR=0.93, 95% CI 0.81 to 1.07).\n\nHealth-related quality of life data were collected in a sub-study of the RE-LY trial (1440 of the 18,113\xa0people enrolled in the RE-LY study completed the EQ-5D questionnaire as part of the quality of life sub-study). The manufacturer reported that the sub-study was reasonably representative of the overall RE-LY population with patients having similar demographic and disease characteristics. The manufacturer stated that analysing the EQ-5D data for specific events of interest was not possible and the quality of life sub-study was unable to provide utility values for event-driven health states to use in the economic model. However, background utility values could be derived from the quality of life sub-study for people being treated with warfarin and dabigatran, the details of which are academic-in-confidence and are not reported here.\n\nThe manufacturer performed a mixed-treatment comparison of dabigatran, aspirin monotherapy and aspirin plus clopidogrel. The treatments considered by the manufacturer to be relevant in this analysis were dabigatran 150\xa0mg twice daily, dabigatran 110\xa0mg twice daily, dose-adjusted warfarin, aspirin, aspirin plus clopidogrel, and placebo. An additional sequential regimen of dabigatran was used in the mixed-treatment comparison. This was intended to reflect the use of dabigatran according to the licensed regimen which is 150\xa0mg twice daily in people up to the age of 80\xa0years, and then 110\xa0mg twice daily in those aged 80\xa0years and older. Results from the RE-LY trial and the mixed-treatment comparison were very similar for both dabigatran doses compared with dose-adjusted warfarin.\n\nThe manufacturer's economic evaluation was based on a cost–utility analysis designed to compare the costs and outcomes of dabigatran with treatments used in the UK (warfarin, aspirin and aspirin plus clopidogrel). The manufacturer developed a Markov model that used three levels of disability (independent, moderate and severe) and death to define health states. A hypothetical cohort entered the model at risk of specified clinical events and was on one of the treatments under comparison. They moved between health states when a clinical event occurred and their disability status changed. The clinical events considered were ischaemic stroke, intracranial haemorrhage, haemorrhagic stroke, extracranial haemorrhage, systemic embolism, transient ischaemic attack and acute myocardial infarction. All clinical outcomes were associated with acute costs and disutility. Further longer-term costs and disutility beyond the acute stage were associated with ischaemic stroke, haemorrhagic stroke and intracranial haemorrhage. The model permitted one clinical event per 3-month cycle over a lifetime horizon. The model also allowed for a switch to second-line treatment or a discontinuation of treatment.\n\nThe manufacturer presented two economic models: a single-dose model and a sequential regimen model. In the single-dose model, the cohort with atrial fibrillation received either 110\xa0mg twice daily or 150\xa0mg twice daily throughout their treatment. In the sequential regimen model, the cohort was divided by age and modelled separately. The model for people younger than 80\xa0years assumed that treatment began with dabigatran 150\xa0mg twice daily, and switched to dabigatran 110\xa0mg twice daily when the age of 80\xa0years was reached. The model for people aged 80\xa0years or older at baseline assumed a dose of dabigatran 110\xa0mg twice daily throughout. Therefore, the sequential regimen model resulted in two sets of outputs: a sequential regimen model for people starting treatment younger than 80\xa0years (incorporating a life-time horizon including the switch to 110\xa0mg twice daily at 80\xa0years) and a sequential regimen model for those starting treatment at 80\xa0years or older.\n\nThe event risk for all treatment strategies was applied to the baseline risk of events in people treated with warfarin in the RE-LY trial. Therefore, treatment effects were converted into relative risks and applied to the warfarin arm of the RE-LY trial. The relative risks for the various clinical events while on treatment with dabigatran 110\xa0mg twice daily and 150\xa0mg twice daily were obtained from the RE-LY trial. In the sequential regimen model, the relative risks were derived from the post hoc subgroup analyses of people older and younger than 80\xa0years of age. The relative risks for aspirin, aspirin plus clopidogrel and placebo were obtained from the mixed-treatment comparison.\n\nThe manufacturer's economic evaluation focused on health-related quality of life associated with disability and disutility caused by the various clinical events. The baseline utility value for people with atrial fibrillation in the base-case analyses was taken from the RE‑LY quality of life sub-study. Utility values associated with clinical events and disability status were derived from published sources.\n\nThe manufacturer's model considered resource costs associated with anti-thrombotic treatment, acute event costs, and long-term follow‑up costs resulting from disability. These costs were derived from the national payment by results tariff, systematic reviews and a manufacturer-sponsored study based on the Oxford Vascular study (OXVASC) cohort. The cost of dabigatran was £2.52 (excluding VAT) per day for either the 110\xa0mg twice daily or 150\xa0mg twice daily doses. Treatment with warfarin, aspirin and aspirin plus clopidogrel was assumed to cost £0.04, £0.09, and £0.26 per day, respectively. Treatment with dabigatran was not considered to need any monitoring, but the cost of INR monitoring for warfarin was estimated to be £414.90 per annum. The model assumed an NHS perspective and costs and benefits were discounted at 3.5% per annum.\n\nThe manufacturer reported pairwise cost-effectiveness results for dabigatran compared with warfarin. The incremental cost-effectiveness ratios (ICERs) for the dabigatran sequential regimen in which people started treatment when younger than 80\xa0years and continued for the rest of their lives, and the sequential regimen in which people started treatment when older than 80\xa0years were £7314 and £7873 per QALY gained respectively, compared with warfarin. The ICERs for dabigatran 150\xa0mg and 110\xa0mg twice daily compared with warfarin were £6264 and £18,691 per QALY gained respectively.\n\nThe manufacturer performed structural, univariate and probabilistic sensitivity analyses to reflect uncertainty in the model inputs and assumptions. The structural sensitivity analysis explored the cost effectiveness of dabigatran by varying INR cost (±25%), time horizon (2, 10 and 15\xa0years), and discount rate (0 to 6%). The cost effectiveness of dabigatran was highly sensitive to the time horizon specified. A 2-year time horizon resulted in ICERs of £75,891 and £23,403 per QALY gained, respectively, for the dabigatran sequential regimen in people starting treatment when younger than 80\xa0years and the dabigatran sequential regimen in people starting treatment when older than 80\xa0years, compared with warfarin. For dabigatran 150\xa0mg and 110\xa0mg twice daily, the ICERs were £75,601 and £108,736 per QALY gained, respectively.\n\nIn the univariate sensitivity analysis, the cost effectiveness of the dabigatran sequential regimen in people starting treatment when younger than 80\xa0years was most sensitive to risk of ischaemic stroke. Setting the relative risk for ischaemic stroke to the 95% upper confidence limits increased the base-case ICER compared with warfarin from £7314 to £17,100 per QALY gained. The cost effectiveness of the dabigatran sequential regimen in people starting treatment when older than 80\xa0years was most sensitive to risk of ischaemic stroke and high baseline CHADS2 scores. Setting the relative risks for ischaemic stroke to the 95% upper confidence limits increased the base-case ICER for the dabigatran sequential regimen in people older than 80\xa0years compared with warfarin from £7873 to £46,509 per QALY gained. The ICER for the dabigatran sequential regimen in people starting treatment when older than 80\xa0years compared with warfarin increased from the base-case estimate of £7873 to £21,129 per QALY gained for a group with a CHADS2 score of 5. The ICER for dabigatran 150\xa0mg twice daily compared with warfarin was robust to the parameters and ranges tested by the manufacturer, and the highest ICER was £10,234 per QALY gained. The cost effectiveness of dabigatran 110\xa0mg twice daily in relation to warfarin was highly sensitive to high baseline CHADS2 scores, risk of ischaemic stroke and risk of intracranial haemorrhage.\n\nIn the probabilistic sensitivity analysis, the ICERs for the dabigatran sequential regimens in people starting treatment when younger than 80\xa0years and in people starting treatment when older than 80\xa0years compared with warfarin were £7811 and £11,912 per QALY gained respectively. The probabilistic ICERs for dabigatran 150\xa0mg and 110\xa0mg twice daily compared with warfarin were £7940 and £15,867 per QALY gained respectively.\n\nThe ERG noted that the manufacturer's submission included two generally well-conducted systematic reviews: the first was of dabigatran trials in the relevant indication, and the second was of all potentially relevant pharmacological interventions for the prevention of stroke in people with atrial fibrillation. The ERG commented that the RE‑LY trial was of good quality and that the manufacturer appropriately concentrated on the results from this trial. The ERG highlighted the limitations of non-inferiority trials, such as establishing the non-inferiority margin and the population on which to base analyses. Overall, the ERG felt that adequate measures were taken by the manufacturer to reduce the impact of potential bias associated with non-inferiority trials.\n\nThe ERG commented that the results of the RE-LY trial showed both doses of dabigatran to be non-inferior to dose-adjusted warfarin in the prevention of stroke or systemic embolism. The ERG noted that a submission from the manufacturer to the FDA indicated that dabigatran 150\xa0mg twice daily reduced the risk of stroke or systemic embolism compared with warfarin in people with good INR control (HR=0.68, 95% CI 0.50 to 0.92 for time in therapeutic INR range 65% or above; HR=0.70, 95% CI 0.51 to 0.96 for time in therapeutic INR range 68% or above). The ERG also highlighted that an analysis in the submission produced for the FDA showed a greater benefit of dabigatran in people with poor INR control than in those whose INR was well controlled (the threshold being the centre-level median of 67%). The FDA report concluded that, although the results showed efficacy of dabigatran in people who had INR control above the centre-level median, the results did not show superiority over warfarin. The submission further subdivided people by INR control (less than 58.5%, 58.5% or above, less than 66.8%, 66.8% or above, and less than 74.2%). This demonstrated that the greatest benefit of dabigatran was in the lowest quartile of INR control and that, in people with good INR control with warfarin, little or no additional benefit in terms of effectiveness would be gained with dabigatran.\n\nA key uncertainty highlighted by the ERG was the generalisability of the results to people with atrial fibrillation in the NHS. The ERG commented that the definition of moderate or high risk of stroke or systemic embolism in the manufacturer's submission differed slightly to the definition in 'The management of atrial fibrillation' (NICE clinical guideline\xa036). The ERG commented that the population in the manufacturer's submission seemed to be at higher risk of stroke because the definition of moderate risk included those aged 75\xa0years and over with no additional risk factors, whereas NICE clinical guideline 36 defines moderate risk as people aged 65\xa0years and over with no additional risk factors. The ERG commented that including the potentially large subgroup of people over 65\xa0years with atrial fibrillation but with no other risk factors for stroke would have been useful, and would reflect NICE clinical guideline\xa036 more closely and reduce the overall risk level of the population. The clinical specialists advising the ERG noted that the threshold for treatment with warfarin seems to be decreasing, therefore decreasing the risk of stroke in the eligible atrial fibrillation population, making the population in the RE-LY trial less representative of clinical practice over time.\n\nThe ERG commented that the general approach taken by the manufacturer to estimate lifetime cost effectiveness was appropriate and met the requirements of the NICE reference case. The ERG noted that the model included most of the relevant clinical events in atrial fibrillation; however, pulmonary embolism was not included in the model. The ERG commented that excluding pulmonary embolism is potentially an optimistic approach in favour of dabigatran because dabigatran is associated with higher rates of pulmonary embolism than warfarin.\n\nThe ERG noted that, although the manufacturer's submission considered the atrial fibrillation population to be heterogeneous, reflected by the distribution of CHADS2 scores, the manufacturer assumed that all people would be treated the same. The ERG commented that this may be an over-simplification of the decision problem and does not allow the potential impact of clinical heterogeneity on cost effectiveness to be considered.\n\nThe ERG highlighted that acute myocardial infarction and systemic embolism were assumed by the manufacturer to be associated with acute costs and disutility, but not with any ongoing or long-term consequences. The ERG considered this assumption to be over-simplistic and that the effect of including long-term consequences of acute myocardial infarction and systemic embolism on the cost effectiveness of dabigatran is uncertain. The ERG commented that dabigatran was associated with higher discontinuation rates than warfarin in the first 2\xa0years of the trial, which could suggest that people tend to tolerate warfarin better than dabigatran.\n\nThe two main weaknesses of the manufacturer's model were considered by the ERG to be related to the sequence of treatments and the cost of anticoagulation monitoring. The ERG commented that the full set of relevant sequences of treatment was not fully investigated by the manufacturer. For example, the ERG considered that starting treatment with dabigatran and subsequently switching to warfarin would be a reasonable treatment sequence, but the manufacturer's model assumed that a person could not switch to warfarin if dabigatran was the first treatment. In addition, the ERG stated that the cost of anticoagulation monitoring was a key driver of the model in terms of resources and costs, and that it was likely that the average cost of monitoring had been overestimated in the model, biasing the results in favour of dabigatran. The ERG also highlighted that its clinical advisers were concerned about the high variability of monitoring costs in practice. This heterogeneity was not considered in the manufacturer's submission. The ERG commented that uncertainty around the monitoring costs was also inadequately modelled in the manufacturer's submission.\n\nThe ERG carried out exploratory cost-effectiveness analyses by subgroups according to INR control with warfarin. The ICER for dabigatran 150\xa0mg twice daily compared with warfarin in people with perfect INR control (that is, in target INR range 100% of the time for the entire duration of treatment) was £60,895 per QALY gained. Dabigatran 110\xa0mg twice daily was dominated by warfarin because it was associated with greater costs but lower health benefits. The group of people with poor INR control was also evaluated by the ERG. The ICER for dabigatran 150\xa0mg twice daily compared with warfarin for people with an INR below 2 was £740 per QALY gained. For people with an INR above 3, warfarin was dominated by dabigatran 150\xa0mg twice daily. The ERG did not include pairwise cost-effectiveness results for dabigatran in the sequential regimen compared with warfarin. The ERG concluded that INR control is a key parameter in the economic evaluation.\n\nThe ERG used three approaches to calculate the variable costs of INR monitoring, which it considered had been overestimated in the manufacturer's model. The alternative costs used by the ERG were £279.36, £241.54 and £115.14, instead of £414.90 as assumed by the manufacturer. Adjusting the model to test each individual cost assumption increased the ICER for dabigatran 150\xa0mg twice daily compared with warfarin to £10,528, £11,720 and £15,701 per QALY gained respectively.\n\nThe ERG considered that the disutility of dabigatran captured by the RE-LY quality of life sub-study had not been fully reflected in the manufacturer's cost-effectiveness analysis. The disutility associated with dabigatran treatment was tested by the ERG but it did not change the overall conclusions about the cost effectiveness of this intervention.\n\nThe ERG commented that treatment with dabigatran was associated with an increased incidence of dyspepsia compared with warfarin treatment, but that the model assumed that the cost of dyspepsia was only accrued in the first cycle. The ERG considered that a more conservative approach would be to assume that costs of dyspepsia continue throughout treatment. This caused the ICER for dabigatran 150\xa0mg twice daily compared with warfarin to increase slightly from £6262 per QALY to £6659 per QALY gained.\n\nThe ERG highlighted that disability and mortality risk after stroke is considered to be treatment dependent in the manufacturer's model. Therefore the ERG explored the model assuming that disability caused by stroke is independent of treatment. The ICER for dabigatran 150\xa0mg twice daily compared with warfarin increased from £6262 to £8393 per QALY gained.\n\nThe ERG presented analyses using an alternative set of assumptions to those provided by the manufacturer. The ERG's alternative base case assumed:\n\nA patient cohort representing people with atrial fibrillation in the UK, using the data reported by Gallagher et al. (2008).\n\nThe variable (per patient) costs of anticoagulant monitoring are £115.14.\n\nPeople have dyspepsia throughout dabigatran treatment, not just in the first 3 months of treatment.\n\nDisability and mortality risks after stroke are treatment independent.\n\nDisutility associated with dabigatran during the first 12\xa0months of treatment as used in the RE-LY quality of life sub-study (the details are academic-in-confidence).\n\nBy introducing these assumptions, the ICER for dabigatran 150\xa0mg twice daily compared with warfarin increased from £6264 to £24,173 per QALY gained in the ERG's alternative base-case analysis.\n\n# Manufacturer's additional analyses\n\nAdditional analyses were provided by the manufacturer in response to NICE's request for further clarification on the cost effectiveness of dabigatran presented in the appraisal consultation document. The manufacturer submitted a revised cost-effectiveness analysis of the sequential regimen model comparing dabigatran with warfarin using relative risks from the whole RE-LY trial population rather than from the post hoc subgroup analysis, as requested by the Committee. Given the uncertainty about costs of warfarin prescription and monitoring because of wide variations in local practice, it also conducted sensitivity analyses that varied the annual cost of INR monitoring (£115.14, £241.54, £279.36 and £414.90) and explored the ERG's preferred assumptions (see section 3.33).\n\nThe manufacturer highlighted that its new base-case analysis included INR costs of £241.54. The manufacturer selected this cost based on the conclusions of the first Appraisal Committee meeting, which stated that the real cost of INR monitoring was likely to lie between the ERG's lower estimate of £115.14 and the manufacturer's upper estimate of £414.90. Assuming an INR monitoring cost of £241.54, the manufacturer's revised base-case ICERs were £14,518 per QALY gained for the dabigatran sequential regimen in people starting treatment when younger than 80\xa0years and £18,269 per QALY gained for the sequential regimen in people starting treatment at 80 years and older, compared with warfarin.\n\nIn response to the Committee's request to include a patient cohort that better reflected people with atrial fibrillation in the UK, the manufacturer highlighted that data from Gallagher et al. (2008) were not easily adapted to the model and that many of the patients included in the Gallagher analysis would not be covered by the marketing authorisation for dabigatran. To address the Committee's request the manufacturer performed an analysis of the General Practice Research Database to derive data required for the model. Applying these data increased the ICERs to £17,373 and £19,680 per QALY gained for the dabigatran sequential regimen in people starting treatment when younger than 80\xa0years and at 80\xa0years and older respectively, compared with warfarin. The manufacturer stated that applying the ERG's preferred assumptions relating to dyspepsia management costs, disability and mortality risks, and disutility associated with dabigatran (see section 3.33) individually had minimal effect on the base-case ICER. Combining an INR monitoring cost of £241.54 with the ERG's preferred assumptions resulted in ICERs of £17,660 and £18,392 per QALY gained for the sequential regimen in people starting treatment when younger than 80\xa0years and people starting treatment at 80 years and older respectively, compared with warfarin.\n\nThe manufacturer also responded to the Committee's request in the appraisal consultation document for further comment and consideration of the cost effectiveness of dabigatran in the subgroup of people whose condition is already well controlled on warfarin. The manufacturer highlighted that the INR control analyses submitted to the FDA (see section 3.22) were stratified by time in therapeutic range only in the warfarin arm and should therefore be interpreted with caution. The manufacturer stated that analyses presented in a study by Wallentin et al. (2010), which was stratified on treatment centre time in therapeutic range (a method that maintains randomisation within a centre), would be more relevant if such an analysis were to be carried out. The manufacturer highlighted that the ERG's initial analysis of good INR control (see section 3.28) assumed a time in therapeutic range of 100%, which is unlikely to be achieved in clinical practice for most patients. The manufacturer further explained that for both the full sequential regimen in people starting treatment younger than 80\xa0years and the over 80 cohort, INR would need to be within target range an average of approximately 83% to 85% of the time for the ICERs to be above £30,000 per QALY gained compared with warfarin.\n\nThe ERG provided a critique and exploratory analysis of the manufacturer's additional analyses. The ERG compared inputs in the revised model with inputs used for the original single-dose and sequential regimen model. It commented that the values for ischaemic stroke disability and mortality rates by treatment used in the revised sequential regimen model were the same as those used in the initial sequential regimen model rather than those from the single-dose model. The ERG commented that correcting for this had the effect of reducing the manufacturer's ICERs slightly. The ERG agreed with the manufacturer that the data presented by Gallagher et al. (2008) are not easily adapted to the model. It commented that the General Practice Research Database data presented by the manufacturer have advantages over the Gallagher study in that they are more recent and therefore more reflective of the current UK atrial fibrillation population, and they refer solely to the people with atrial fibrillation for whom dabigatran is licensed. The ERG compared the results of the incremental analyses presented by the manufacturer with the results obtained by the ERG after including the correct values for ischaemic stroke disability and mortality rates by treatment and including all of the assumptions requested by the Committee. The ERG commented that its results were broadly in line with those presented by the manufacturer. The ERG's estimate of the ICER for the sequential regimen in people starting treatment when younger than 80\xa0years, including the relative risks from the whole RE-LY trial population, an INR cost of £241.54 and all of the assumptions requested by the Committee, was £18,863 per QALY gained compared with the manufacturer's estimate of £17,660 per QALY gained.\n\nThe ERG acknowledged the manufacturer's view that 100% time in therapeutic range is difficult to achieve in clinical practice. The ERG identified a UK-based study by Jones et al. (2005) that reported that the average time in therapeutic range was 67.9%. The ERG commented that the Jones et al. (2005) study indicated that the people with the best INR control (upper quartile) were within therapeutic range an average of 83.7% of the time, so the ERG performed further exploratory sensitivity analyses testing this value. For the subgroup of patients whose INR is within range 83.7% of the time, the ICER for dabigatran compared with warfarin was £46,989 per QALY gained assuming INR monitoring costs of £241.54 per annum. If the INR costs were increased to £414.90 per annum, the ICER decreased to £31,386 per QALY gained compared with warfarin. The ERG commented that it is unclear how INR monitoring costs vary by time in therapeutic range. The ERG also performed a threshold analysis to estimate the level of time in therapeutic range needed to raise the ICER above £30,000 per QALY gained compared with warfarin, assuming an INR monitoring cost of £241.54 per annum and including all of the ERG's preferred assumptions. The ERG commented that the INR would need to be within the target range an average of 75–76% of the time or more for the ICER to be above £30,000 per QALY gained compared with warfarin.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dabigatran, having considered evidence on the nature of atrial fibrillation and the value placed on the benefits of dabigatran by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from the clinical specialists and patient experts that the current standard treatment for the prevention of stroke and systemic embolism in people with atrial fibrillation is warfarin, and that because of its lower efficacy, aspirin is used only in people for whom warfarin is unsuitable. The Committee also heard that warfarin, although an effective treatment, is associated with a number of problems. The main concerns for people with atrial fibrillation were fear of having a stroke and anxiety about the difficulty of keeping the INR within the satisfactory therapeutic range. The Committee heard from the patient experts that stroke is a major concern for people with atrial fibrillation and that stroke severity is usually greater in this group than in people who have strokes from other causes. The patient experts also highlighted that many people taking warfarin are outside their target therapeutic INR range at any one time and that warfarin, unlike dabigatran, is associated with a number of inconveniences that make adherence difficult. These include numerous food and drug interactions that can have an impact on people's work, social and family life, and regular monitoring and dose adjustments that can cause disruption and inconvenience. The Committee accepted the limitations of warfarin therapy, and the considerable effect that it may have on the lives of the people who take it, and recognised the potential benefits of dabigatran for people with atrial fibrillation.\n\nThe Committee considered the clinical-effectiveness data from the RE-LY trial comparing dabigatran with warfarin. It noted that this formed most of the clinical-effectiveness evidence in the manufacturer's submission and was the largest published trial in people with atrial fibrillation. The Committee considered that the RE-LY trial was of good quality but noted that a key uncertainty highlighted by the ERG was the generalisability of the results to people diagnosed with atrial fibrillation in the NHS. The Committee noted that the definition of moderate to high risk of stroke in the RE-LY trial was different from the definition used in NICE clinical guideline 36 and did not include people aged 65\xa0years and over with no additional risk factors for stroke, resulting in a higher risk profile in the trial than in the general population eligible for anticoagulation prophylaxis. However, the Committee was persuaded by the clinical specialists that the RE-LY trial included a broad range of people that reflected those seen in UK clinical practice and that the results were applicable to a wide range of people with atrial fibrillation. The Committee concluded that the population included in the trial was appropriate and broadly relevant to UK clinical practice.\n\nThe Committee considered the results of the RE-LY trial. It noted that dabigatran 150\xa0mg twice daily was associated with a statistically significantly lower incidence of stroke or systemic embolism, ischaemic stroke and vascular mortality compared with warfarin, but that there were no statistically significant differences in these outcomes between dabigatran 110\xa0mg twice daily and warfarin. It also noted that both doses of dabigatran were associated with an increased risk of acute myocardial infarction compared with warfarin but that this was not statistically significant. The Committee heard from the clinical specialists that this reflected a small absolute difference in the incidence of acute myocardial infarction between the treatment groups, but it was unclear whether this was because of a protective effect of warfarin or a negative effect of dabigatran treatment, and that the effects did not appear to translate into an increased vascular mortality risk. The Committee concluded that dabigatran 150\xa0mg twice daily was more clinically effective than warfarin in reducing the risk of stroke or systemic embolism, ischaemic stroke and vascular mortality and that this represented an important development for people with atrial fibrillation. It also concluded that the lower 110\xa0mg dabigatran twice-daily dose had shown non-inferiority to warfarin.\n\nThe Committee considered the results of the manufacturer's subgroup analyses. It was aware, however, that the manufacturer's analyses by age had been defined post hoc and it therefore considered that the results should be interpreted with caution. The Committee also considered the results of the manufacturer's pre-planned analyses of people naive to vitamin K antagonists and people who have previously used vitamin K antagonists. It noted that dabigatran 150\xa0mg twice daily was associated with a statistically significant reduction in the incidence of stroke or systemic embolism compared with warfarin in both vitamin K antagonist-naive and vitamin K antagonist-experienced subgroups, but dabigatran 110\xa0mg twice daily did not show a statistically significant reduction in either group. The Committee concluded that dabigatran 150\xa0mg twice daily showed increased efficacy compared with warfarin in people with atrial fibrillation irrespective of their previous exposure to vitamin K antagonists.\n\nThe Committee discussed the effectiveness of dabigatran compared with warfarin according to INR control. It noted the evidence presented by the ERG that people with good INR control with warfarin may not gain additional clinical benefit by taking dabigatran. However, the clinical specialists emphasised the importance of the significantly lower rates of intracranial haemorrhage and haemorrhagic stroke associated with both doses of dabigatran compared with warfarin in the RE-LY trial, and that this effect is maintained in people with good INR control. The Committee heard that haemorrhagic stroke and intracranial haemorrhage have devastating and life-threatening consequences and concluded that the lower rates associated with dabigatran represent an important advance in the treatment of atrial fibrillation alongside reduction in ischaemic stroke. It concluded that this applied to all patients with atrial fibrillation, including those with good INR control, and that there were also benefits of taking a treatment that didn't need INR monitoring or dietary restriction.\n\nThe Committee considered the additional adverse events reported in the RE-LY trial. It noted that both doses of dabigatran were associated with statistically significant reductions in the incidence of life-threatening bleeds compared with warfarin. However, it also noted that the incidence of gastrointestinal bleeding, in contrast to cerebral haemorrhage, was statistically significantly higher for both doses of dabigatran, and the comment from the manufacturer that this may be the result of a local effect of the orally administered drug on the gastrointestinal mucosa. Dabigatran 150\xa0mg twice daily was associated with a statistically significantly higher incidence of major and life-threatening gastrointestinal bleeding. The Committee noted that even small changes in total gastrointestinal bleeding rates might have a substantial impact on the provision of services and that major gastrointestinal bleeding is associated with a significant mortality risk. The Committee concluded that treatment with dabigatran resulted in more gastrointestinal bleeding than warfarin, but also recognised the particular importance of the effects of dabigatran on reducing the risk of haemorrhagic stroke and intracranial haemorrhage for people with atrial fibrillation when compared with warfarin.\n\nThe Committee was aware that health-related quality of life data were collected in a sub-study of the RE-LY trial. It noted that baseline utility values for people with atrial fibrillation were derived from the sub-study. The Committee agreed that because the sub-study was reasonably representative of the overall RE-LY population, this approach was appropriate.\n\nThe Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. The Committee considered the utility values used in the model and noted that it was unclear how the utility values relating to the effect of stroke were derived. However, the Committee agreed with the ERG that the general approach taken by the manufacturer to estimate the lifetime cost effectiveness of dabigatran was appropriate.\n\nThe Committee noted that the manufacturer presented a single-dose model, and a sequential regimen model in which people younger than 80\xa0years began treatment with dabigatran 150\xa0mg twice daily, and at the age of 80\xa0years were switched to dabigatran 110\xa0mg twice daily. As the summary of product characteristics for dabigatran excludes people older than 80\xa0years from treatment with dabigatran 150\xa0mg twice daily because of additional risks in this group, the Committee concluded that the sequence of dabigatran 150\xa0mg twice daily followed by dabigatran 110\xa0mg twice daily once people reach 80\xa0years would be the only regimen appropriate for the assessment of the cost effectiveness of dabigatran relative to warfarin in the whole eligible UK population.\n\nThe Committee heard from the ERG that the relative risks used to inform the manufacturer's original sequential regimen model were derived from people in the younger than 80\xa0years and older than 80\xa0years subgroups of the RE-LY trial that were defined post hoc. It also heard that using relative risks from the whole RE-LY trial population would be more appropriate to determine reliable effectiveness estimates for the dabigatran sequence. Therefore the Committee asked the manufacturer to submit a re-analysis of the data for discussion at the second Appraisal Committee meeting using the relative risks from the whole RE-LY trial population.\n\nAt the first Appraisal Committee meeting, the Committee noted that the ERG had highlighted a number of uncertainties relating to assumptions used in the manufacturer's economic model. First, the Committee noted the ERG's view that an analysis based on an older patient cohort with a lower risk of stroke using data reported by Gallagher et al. (2008) would be more representative of people with atrial fibrillation in the UK than the cohort from the RE-LY trial used by the manufacturer. The Committee accepted that there was uncertainty around which cohort most realistically reflected the population of people with atrial fibrillation in the UK.\n\nSecond, the Committee noted that the ERG questioned whether disability and mortality were independent of the treatment received. The Committee heard from the clinical specialists that the manufacturer's assumption that a stroke would be less severe after treatment with dabigatran than warfarin was plausible and that there is evidence that both the incidence and the severity of stroke may vary according to the treatment received. The Committee also noted the ERG's views about disutility of dabigatran and the inclusion of dyspepsia management costs throughout treatment (see sections 3.30 and 3.31). The Committee agreed that including all of these assumptions would be a more conservative approach.\n\nThird, the Committee noted the ERG's view that the cost of INR monitoring had been overestimated in the manufacturer's model. The Committee heard from the clinical specialists that the introduction of dabigatran would not result in complete closure of anticoagulation services with release of all the funding, and the manufacturer's estimate (£414.90) was likely to be too high. It also heard that INR monitoring costs varied in different settings and could not be quantified precisely. The Committee agreed that exploring the effect of assuming the alternative INR monitoring costs put forward by the ERG (£115.14, £241.54, £279.36), in addition to the cost assumed in the manufacturer's submission, would enable it to make a more accurate judgement about the cost effectiveness of dabigatran.\n\nFinally, the Committee noted the ERG's comments that the cost effectiveness of dabigatran compared with warfarin varied substantially according to level of INR control in those already being treated with warfarin. In the appraisal consultation document, the manufacturer of dabigatran was therefore asked to provide further analyses addressing the uncertainties outlined in sections\xa04.11 to 4.15.\n\nThe Committee discussed the manufacturer's revised analyses and the critique and the exploratory analyses performed by the ERG. The Committee noted that the manufacturer's revised analysis included the relative risks from the whole RE-LY trial population rather than from the post hoc subgroup analysis and had explored the effect of varying the cost of INR monitoring as requested. It also noted that the manufacturer's revised analysis incorporated an INR monitoring cost of £241.54 in its base case as opposed to £414.90 in the original submission. The Committee was aware that comments received during the consultation largely agreed that INR monitoring costs are likely to be higher than the ERG's lower estimate of £115.14 and possibly higher than £414.90 in some cases. The Committee accepted the manufacturer's approach, acknowledging that although INR costs may vary widely, this assumption was reasonable.\n\nThe Committee discussed the manufacturer's approach to including the ERG's other preferred assumptions in the revised analysis (see section 3.33). The Committee noted that the Gallagher et al. (2008) data on atrial fibrillation had not been incorporated. However, the Committee accepted the manufacturer's rationale and the supporting views of the ERG for using General Practice Research Database data instead (see section 3.39). The Committee noted that, in its revised analyses, the manufacturer had incorporated the ERG's preferred assumptions about dyspepsia management costs throughout treatment, disability and mortality risks being treatment independent, and disutility associated with dabigatran. It further noted that combining all of these assumptions together with an INR monitoring cost of £241.54 resulted in an ICER for dabigatran of £17,700 per QALY gained for the full sequential regimen in people starting treatment when younger than 80\xa0years and £18,400 per QALY gained in people starting treatment at 80 years and older, compared with warfarin. Finally, the Committee noted that the ERG's analysis, which included all of the requested assumptions, an INR monitoring cost of £241.54, and the corrected values for ischaemic stroke and disability rates (see section 3.39) resulted in an ICER of £18,900 per QALY gained for the sequential regimen in people starting treatment younger than 80\xa0years, compared with warfarin. The Committee concluded that this was broadly in line with the manufacturer's estimate and that the ICERs presented by the manufacturer were robust to the changes requested. The Committee therefore accepted the manufacturer's approach and concluded that the most plausible ICERs for the whole population eligible for dabigatran were within the range normally considered a cost-effective use of NHS resources, being less than £20,000 per QALY gained.\n\nThe Committee discussed comments from consultees that suggested it may be appropriate to recommend dabigatran for use only in people with atrial fibrillation whose INR is not well controlled on warfarin. The Committee was satisfied that the technology was a cost-effective treatment for the whole patient group. It noted that robust evidence of differential clinical effectiveness and cost effectiveness, with clear justification of the threshold level chosen, would be needed to select out a subgroup, based on INR control, for whom dabigatran would not be recommended.\n\nThe Committee was aware of the need for guidance to apply equally to those already on warfarin and to those newly diagnosed with atrial fibrillation. The Committee noted that, for people newly diagnosed but not already taking an anticoagulant, any stratification of the population according to INR control would mean that all patients would have to try warfarin for at least a few months to assess whether the INR was well controlled and to estimate the time in therapeutic range. The Committee heard from clinical specialists that many of the significant complications of warfarin therapy are experienced in the first months of treatment before the dose is established and stabilised. The Committee accepted therefore that a large number of people having a trial of warfarin at initial diagnosis could be expected to switch to dabigatran. It also accepted that it was not reasonable to expect all patients to try warfarin first, with the associated risks, for the purpose of selecting out a subgroup for whom dabigatran was less cost effective.\n\nThe Committee was also aware of the estimates of the time that the INR in people already taking warfarin would need to be in the target range for the ICERs for dabigatran compared with warfarin to be above £30,000 per QALY gained. Assuming an INR monitoring cost of £241.54 per annum, the manufacturer and ERG estimated an average of 83% to 85% and 75% to 76% of the time respectively. The Committee noted that this would apply to only a proportion of the whole population. The Committee was aware that the average time spent in therapeutic range for the UK centres in the RE-LY trial was 72%, and in the UK-based study by Jones et al. (2005) there was an average time in therapeutic range of 67.9%. It noted the ERG's analysis that explored the effects of time in therapeutic range on the cost effectiveness of dabigatran compared with warfarin. This calculated the ICER for the people with the best-controlled INR (that is, within range 83.7% of the time) at £47,000 per QALY gained. However, this figure incorporated INR monitoring costs of £241.54 (per annum) and the ICER reduced considerably if higher INR monitoring costs of £414.90 per annum were used. The Committee concluded that evidence for stratifying by INR control was insufficient to exclude the minority of people with very good control from the recommendation of dabigatran as a potential treatment option, and that the ICER for the whole population should be the basis of the recommendation.\n\nThe Committee was mindful of the higher gastrointestinal bleeding rates associated with dabigatran and of the relatively short-term safety data compared with the established standard of care, warfarin. It was also mindful that for those with very well-controlled INR on warfarin, the clinical benefits are likely to be less than for those with poorly controlled INR. The Committee therefore concluded that the decision about whether to start treatment with dabigatran in people with atrial fibrillation should be made after an informed discussion between the responsible clinician and the person about the safety risks and benefits of dabigatran compared with warfarin. It also concluded that, for people currently receiving warfarin, the potential risks and benefits of switching to dabigatran should be considered in light of their level of INR control.\n\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA249\n\nAppraisal title: Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation\n\nSection\n\nKey conclusion\n\nDabigatran etexilate is recommended as an option for the prevention of stroke and systemic embolism in people with nonvalvular atrial fibrillation within its licensed indication.\n\n\n\nThe decision about whether to start treatment with dabigatran etexilate should be made after an informed discussion between the clinician and the person about the risks and benefits of dabigatran compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to dabigatran should be considered in light of their level of international normalised ratio (INR) control.\n\n\n\nThe Committee concluded that dabigatran 150 mg twice daily was more clinically effective than warfarin in reducing the risk of stroke or systemic embolism, ischaemic stroke and vascular mortality whereas dabigatran 110 mg twice daily was non-inferior to warfarin. It concluded that dabigatran represented an important development for people with atrial fibrillation.\n\n\n\nThe Committee concluded that the most plausible ICERs for the whole population eligible for dabigatran were within the range normally considered a cost-effective use of NHS resources, being less than £20,000 per QALY gained.\n\n\n\nThe Committee concluded that evidence for stratifying by INR control was insufficient to exclude the minority of people with very good control from the recommendation of dabigatran as a potential treatment option, and that the ICER for the whole population should be the basis of the recommendation.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe clinical specialists commented that current standard treatment for the prevention of stroke and systemic embolism in people with atrial fibrillation is warfarin, and that because of its lower efficacy, aspirin is used only in people for whom warfarin is unsuitable. The main concerns for people with atrial fibrillation were fear of having a stroke and anxiety about the difficulty of keeping the INR within the satisfactory therapeutic range.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe patient experts stated that warfarin, unlike dabigatran, is associated with a number of inconveniences that make adherence difficult. These include numerous food and drug interactions that can have an impact on people's work, social and family life, and regular monitoring and dose adjustments that can cause disruption and inconvenience. The Committee accepted the limitations of warfarin therapy, and the considerable effect that it may have on the lives of the people who take it, and recognised the potential benefits of dabigatran for people with atrial fibrillation.\n\nThe Committee was not made aware of health-related benefits that were not captured in the QALY.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nDabigatran is used as an alternative to warfarin and is an anticoagulant treatment for the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors:\n\nprevious stroke, transient ischaemic attack, or systemic embolism\n\nleft ventricular ejection fraction below\xa040%\n\nsymptomatic heart failure of New York Heart Association (NYHA) class\xa02 or above\n\nage 75\xa0years or over\n\nage 65\xa0years or over with one of the following: diabetes mellitus, coronary artery disease, or hypertension.\n\n\n\nAdverse effects\n\nThe Committee noted that both doses of dabigatran were associated with statistically significant reductions in the incidence of life-threatening bleeds compared with warfarin.\n\nThe Committee concluded that treatment with dabigatran resulted in more gastrointestinal bleeding than warfarin, which may be the result of a local effect of the orally administered drug on the gastrointestinal mucosa, but also recognised the particular importance of the effects of dabigatran on reducing the risk of haemorrhagic stroke and intracranial haemorrhage for people with atrial fibrillation when compared with warfarin.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe RE-LY trial formed most of the clinical-effectiveness evidence in the manufacturer's submission and was the largest published trial in people with atrial fibrillation. The Committee considered that the RE-LY trial was of good quality.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee concluded that the population included in the RE-LY trial was appropriate and broadly relevant to UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee was aware that the manufacturer's analyses by age had been defined post hoc and it therefore considered that the results should be interpreted with caution.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nEvidence was presented by the ERG indicating that people with good INR control with warfarin may not gain additional clinical benefit by taking dabigatran.\n\n\n\n\n\nThe Committee was aware that the manufacturer's analyses by age had been defined post hoc and it therefore considered that the results should be interpreted with caution. The Committee also considered the results of the manufacturer's pre-planned analyses of people naive to vitamin K antagonists and people who have previously used vitamin K antagonists. The Committee concluded that dabigatran 150\xa0mg twice daily showed increased efficacy compared with warfarin in people with atrial fibrillation irrespective of their previous exposure to vitamin K antagonists.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nDabigatran 150\xa0mg twice daily was associated with a statistically significantly lower incidence of stroke or systemic embolism, ischaemic stroke and vascular mortality compared with warfarin, but there were no statistically significant differences between dabigatran 110\xa0mg twice daily and warfarin. The Committee concluded that dabigatran 150\xa0mg twice daily was more clinically effective than warfarin in reducing the risk of stroke or systemic embolism, ischaemic stroke and vascular mortality and that this represented an important development for people with atrial fibrillation. It also concluded that the lower 110\xa0mg dabigatran twice-daily dose had shown non-inferiority to warfarin.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee agreed with the ERG that the general approach taken by the manufacturer to estimate the lifetime cost effectiveness of dabigatran was appropriate.\n\n\n\n\n\nThe Committee noted that the manufacturer presented a single-dose model and a sequential regimen model in which people younger than 80\xa0years began treatment with dabigatran 150\xa0mg twice daily, and at the age of 80\xa0years were switched to dabigatran 110\xa0mg twice daily. As the summary of product characteristics for dabigatran excludes people older than 80\xa0years from treatment with dabigatran 150 mg twice daily because of additional risks in this group, the Committee concluded that the sequence of dabigatran 150\xa0mg twice daily followed by dabigatran 110\xa0mg twice daily once people reach 80\xa0years would be the only regimen appropriate for the assessment of the cost effectiveness of dabigatran relative to warfarin in the whole eligible UK population\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee was aware that there was uncertainty around INR monitoring costs, which cohort most realistically reflected the population of people with atrial fibrillation in the UK, and whether disability and mortality were independent of the treatment received.\n\nto 4.14\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that baseline utility values for people with atrial fibrillation were derived from the sub-study of the RE-LY trial.\n\n\n\n\n\nThe Committee noted that it was unclear how the utility values relating to the effect of stroke were derived.\n\nNo health-related benefits were identified that were not included in the economic model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nDabigatran is recommended as an option for all people with nonvalvular atrial fibrillation within its licensed indication.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted the ERG's comments that the cost effectiveness of dabigatran compared with warfarin varied substantially according to level of INR control in those already being treated with warfarin.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that the ERG's analysis, which included all of the requested assumptions, an INR monitoring cost of £241.54, and the correct values for ischaemic stroke and disability rates (see section 3.39) increased the manufacturer's base-case ICER to £18,900 per QALY gained for the sequential regimen in people starting younger than 80 years, compared with warfarin.\n\nThe Committee concluded that the most plausible ICERs for the whole population eligible for dabigatran were within the range normally considered a cost-effective use of NHS resources, being less than £20,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nEnd-of-life considerations were not discussed.\n\n–\n\nEqualities considerations and social value judgements\n\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.\n\n"}
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Evidence-based recommendations on dabigatran etexilate (Pradaxa) for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation.
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nice
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Apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation
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Apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation
Evidence-based recommendations on apixaban (Eliquis) for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation.
# Recommendations
Apixaban is recommended as an option for preventing stroke and systemic embolism within its marketing authorisation, that is, in people with non-valvular atrial fibrillation with 1 or more risk factors such as:
prior stroke or transient ischaemic attack
age 75 years or older
hypertension
diabetes mellitus
symptomatic heart failure.
Decide whether to start treatment with apixaban after an informed discussion with the person about its risks and benefits compared with warfarin, dabigatran etexilate, edoxaban and rivaroxaban. For people taking warfarin, consider the potential risks and benefits of switching to apixaban taking into account their level of international normalised ratio (INR) control.# The technology
Apixaban (Eliquis, Bristol-Myers Squibb and Pfizer) is a potent, oral, direct and highly selective active site inhibitor of factor Xa. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Apixaban 5 mg twice daily and 2.5 mg twice daily has a European marketing authorisation for the 'prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation, with 1 or more risk factors, such as prior stroke or transient ischaemic attack, age 75 years or older, hypertension, diabetes mellitus, or symptomatic heart failure (New York Heart Association class 2 or higher)'.
The summary of product characteristics lists the following adverse reactions for apixaban: epistaxis (nosebleed), contusion (bruising), haematuria (blood in urine), haematoma, eye haemorrhage, and gastrointestinal haemorrhage. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The manufacturer has stated that the cost per day for both doses (2.5 mg and 5 mg twice daily) of apixaban (excluding VAT) is £2.20, and the annual cost is £803. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee considered evidence submitted by the manufacturer of apixaban and a review of this submission by the Evidence Review Group (ERG).
The main clinical effectiveness evidence for apixaban came from 2 international, multicentre, double-blind, double-dummy, placebo-controlled, randomised controlled trials, which had investigated apixaban. ARISTOTLE (n=18,201) compared apixaban (5 mg twice daily; 2.5 mg twice daily in selected patients) with warfarin (in patients with an international normalised ratio target range of 2.0 to 3.0). AVERROES (n=5598) compared apixaban (5 mg twice daily; 2.5 mg twice daily in selected patients) with aspirin (81 mg to 324 mg once daily) in people 50 years or older with atrial fibrillation and at least 1 additional risk factor for stroke for whom treatment with warfarin had failed, or for whom warfarin was unsuitable or who were unwilling to take warfarin.
The primary objective of ARISTOTLE was to determine if apixaban was non-inferior to warfarin for the combined end point of stroke and systemic embolism. Stroke included both ischaemic stroke, caused by embolism from the heart, and haemorrhagic stroke, which can be a complication of anticoagulant treatment (although it may also occur spontaneously or as a result of secondary haemorrhage into an ischaemic stroke). ARISTOTLE included adults with atrial fibrillation or atrial flutter not resulting from a reversible cause and at least 1 additional risk factor for stroke (assessed by CHADS2 criteria). It enrolled patients from 39 countries; 40% of participants were from Europe and this included patients from 41 sites in the UK. The average age was 69 years and 65% of the population were male. The mean time in therapeutic range for patients in the warfarin arm was 62.2%, and the median time in therapeutic range was 66%. Approximately 4% of the study population received 2.5 mg apixaban (those who had 2 or more of the following criteria: 80 years or older, a body weight of 60 kg or less, or a serum creatinine level of 1.5 mg/100 ml or more). The mean CHADS2 score at baseline was 2.1 and approximately 65% of patients had a CHADS2 score of 2 or more.
In the intention-to-treat population, apixaban met non-inferiority criteria using a non-inferiority margin of 1.38, over a median follow-up of 1.8 years. Apixaban was associated with a significantly lower rate of stroke and systemic embolism than warfarin (hazard ratio 0.79, 95% confidence interval 0.66 to 0.95, p=0.01). The rate of fatal or disabling stroke was significantly lower in the apixaban group than the warfarin group (HR 0.71, 95% CI 0.54 to 0.94). When the outcomes included in the composite primary outcome (ischaemic or uncertain type, haemorrhagic stroke and systemic embolism) were analysed separately, apixaban was associated with a significant reduction in haemorrhagic stroke compared with warfarin (HR 0.51, 95% CI 0.35 to 0.75), but the decrease for apixaban compared with warfarin in ischaemic or uncertain type stroke or systemic embolism was not statistically significant (ischaemic or uncertain type stroke HR 0.92, 95% CI 0.74 to 1.13, p=0.42; systemic embolism HR 0.87, 95% CI 0.44 to 1.75, p=0.70). The rates of myocardial infarction, and pulmonary embolism or deep vein thrombosis, were lower with apixaban than warfarin, but were not statistically significant (HR 0.88, 95% CI 0.66 to 1.17, p=0.37, and HR 0.78, 95% CI 0.29 to 2.10, p=0.63 respectively). Apixaban was associated with fewer all-cause deaths than warfarin, which was of borderline statistical significance (3.52% and 3.94% respectively ).
The manufacturer presented results for the primary efficacy outcomes for 21 pre-specified subgroups in ARISTOTLE including subgroups broken down by baseline risk of stroke or systemic embolism (grouped by CHADS2 scores ≤1, 2 and ≥3). ARISTOTLE was not statistically powered to demonstrate superiority in subgroup analyses. The hazard ratios for apixaban relative to warfarin for stroke and systemic embolism in the 3 stroke risk subgroups were consistently less than 1, but the confidence intervals of the CHADS2 ≤1 and 2 groups crossed 1, meaning that that the difference between apixaban and warfarin was not statistically significant for these groups. The hazard ratios for stroke and systemic embolism in the groups of patients who received 5 mg and 2.5 mg apixaban were also both below 1 (the hazard ratios for CHADS2 score subgroups and for the groups of patients who received 5 mg and 2.5 mg apixaban are commercial-in-confidence). The manufacturer also presented data for subgroups based on INR (international normalised ratio) control using quartiles of centre time in therapeutic range (less than 58.0%, 58.0% to 65.7%, 65.7% to 72.2% and more than 72.2%). A centre's time in therapeutic range was calculated as the median of individual time in therapeutic ranges among the centre's patients on warfarin. The manufacturer reported that the benefits of apixaban over warfarin in preventing stroke or systemic embolism were consistent (HR 72.2% ).
The adverse events and safety analyses were reported for the on-treatment population in ARISTOTLE (all patients who received at least 1 dose of study medication). Apixaban was superior to warfarin for the primary safety outcome of time from first dose of study drug to first occurrence of confirmed International Society on Thrombosis and Haemostasis (ISTH) major bleeding (HR 0.69, 95% CI 0.60 to 0.80; p<0.001). Apixaban resulted in significantly fewer bleeding events than warfarin for all of the major bleed types (intracranial major bleeding HR 0.42, 95% CI 0.30 to 0.58; other location major bleeding HR 0.79, 95% CI 0.68 to 0.93) and clinically relevant non-major bleeding events reported by the manufacturer apart from major gastrointestinal bleeding, for which the difference between apixaban and warfarin was not statistically significant (HR 0.89, 95% CI 0.70 to 1.15, p=0.37). There were similar proportions of patients who experienced adverse events with apixaban (81.5%) and warfarin (83.1%) and a lower proportion of patients who experienced bleeding adverse events with apixaban (25.2%) compared with warfarin (32.7%). Serious adverse events occurred in 35.0% of patients treated with apixaban and 36.5% of patients treated with warfarin. Fewer patients stopped the study drug in the apixaban group than the warfarin group (25.3% compared with 27.5% respectively, p=0.001); 7.6% of patients in the apixaban arm and 8.4% of patients in the warfarin arm stopped treatment because of an adverse event. The safety of apixaban was maintained across patients at different levels of stroke risk, regardless of warfarin control (time in therapeutic range) and in patients who needed dose reduction.
The primary objective of AVERROES was to determine if apixaban was superior to aspirin for preventing the composite outcome of stroke or systemic embolism in adults with at least 1 risk factor for stroke in whom vitamin K antagonists were unsuitable. In the intention-to-treat population apixaban reduced the rate of stroke and systemic embolism compared with aspirin over a mean follow-up of 1.1 years (HR 0.45, 95% CI 0.32 to 0.62, p<0.001). The rates of disabling or fatal stroke were also lower in patients who received apixaban compared with patients who received aspirin (HR 0.43, 95% CI 0.28 to 0.65). When considered as a separate outcome apixaban reduced the rates of ischaemic stroke compared with aspirin (HR 0.37, 95% CI 0.25 to 0.55) but did not statistically significantly reduce the rates of haemorrhagic stroke (HR 0.67, 95% CI 0.24 to 1.88, p=0.45). Apixaban was associated with a higher rate of all bleeding than aspirin (HR 1.30, 95% CI 1.10 to 1.53) and of major or clinically relevant non-major bleeding (HR 1.38, 95% CI 1.07 to 1.78). Although apixaban was associated with higher rates of major bleeding than aspirin, this was not statistically significant (HR 1.54, 95% CI 0.96 to 2.45, p=0.07).
No head-to-head data were available for apixaban compared with dabigatran etexilate (hereafter referred to as dabigatran) or rivaroxaban. The manufacturer used a Bayesian Markov chain Monte Carlo stimulation in WinBUGS to conduct 2 network meta-analyses using a fixed-effect model. The first meta-analysis included patients for whom vitamin K antagonist treatment was suitable and it compared apixaban, warfarin, dabigatran and rivaroxaban. The second meta-analysis was intended to assess a population of patients for whom vitamin K antagonists were unsuitable, comparing apixaban, dabigatran, rivaroxaban and aspirin.
The first meta-analysis included ARISTOTLE, RE-LY and ROCKET-AF trials. RE-LY compared dabigatran (150 mg and 110 mg twice daily) with warfarin. ROCKET-AF compared rivaroxaban (20 mg once daily) with warfarin. There were differences between the trials of apixaban, dabigatran and rivaroxaban: ARISTOTLE and ROCKET-AF were double-blind, double-dummy trials, whereas RE-LY was an open-label trial; the population in ROCKET-AF had a higher stroke or systemic embolism risk at baseline (baseline CHADS2 of 3.6 , 2.1 , 2.1 ) and the mean percentage time in therapeutic range was lower in ROCKET-AF (55%) than in ARISTOTLE (62%) and RE-LY (64%). Where possible, the manufacturer used intention-to-treat data from each trial. However, the manufacturer highlighted that there was an absence of published intention-to-treat outcome data for some secondary outcomes from ROCKET-AF including fatal stroke, disabling stroke and non-disabling stroke. Therefore, data from the on-treatment population were also used. The second meta-analysis included ARISTOTLE, RE-LY, ROCKET-AF and AVERROES.
The manufacturer did not present any statistical analysis of heterogeneity but commented that potential sources of clinical heterogeneity between the trials were the differences in baseline stroke risk scores, study blinding, and whether the intention-to-treat or on-treatment populations had been used to assess efficacy and safety outcomes. Additionally, the manufacturer highlighted a statistically significant difference in myocardial infarction at baseline between treatment groups in ROCKET-AF.
The base-case results of the first meta-analysis indicated that there were no statistically significant differences between apixaban and rivaroxaban or dabigatran in the incidence of stroke, systemic embolism and all-cause mortality. The results did however suggest that apixaban was associated with a significantly lower incidence of myocardial infarction compared with dabigatran (150 mg or 110 mg twice daily). Apixaban was associated with a significantly lower incidence of all bleeding outcomes compared with rivaroxaban (intracranial haemorrhage, major bleeding, gastrointestinal bleeding, other major bleeding, clinically relevant non-major bleeding, any bleeding). Apixaban had a significantly lower incidence of all bleeding events except intracranial haemorrhage and clinically relevant non-major bleeding (which was not measured in RE-LY) than dabigatran 150 mg. Apixaban had a significantly lower incidence of any bleeding than dabigatran 110 mg. In addition, apixaban was associated with significantly fewer discontinuations compared with dabigatran 150 mg, dabigatran 110 mg and rivaroxaban. All of the hazard ratios from the first network meta-analysis are academic-in-confidence. The manufacturer reported that the results for apixaban compared with warfarin generated by the first meta-analysis were consistent with the pair-wise comparisons between warfarin and apixaban in ARISTOTLE (see sections 3.3 and 3.5).
The manufacturer conducted 2 sensitivity analyses of its first network meta-analysis. The first used data from a later publication of RE-LY (Connolly et al. 2010) rather than the RE-LY 2009 data. The results for the first sensitivity analysis were generally consistent with the base case, however the reduction in myocardial infarction with apixaban compared with both doses of dabigatran was no longer statistically significantly different. The second sensitivity analysis used the safety on-treatment dataset from ROCKET-AF rather than the intention-to-treat data from this trial, which was also generally consistent with the base case. The hazard ratios from the sensitivity analysis of the manufacturer's first network meta-analysis are academic-in-confidence.
The manufacturer commented that there were no data for rivaroxaban or dabigatran in the population for whom warfarin was unsuitable, so data from ROCKET-AF (which assessed rivaroxaban compared with warfarin) and RE-LY (which assessed dabigatran compared with warfarin) were included, alongside ARISTOTLE and AVERROES. This meant that the second meta-analysis represented a mix of patients for whom warfarin was suitable and unsuitable ('warfarin-suitable' and '-unsuitable' populations).
The manufacturer also used data from ARISTOTLE, RE-LY and ROCKET-AF to estimate the distribution of stroke severity and bleed type associated with apixaban, warfarin, rivaroxaban and dabigatran. Mild, moderate, severe and fatal stroke were classified by modified Rankin scores, with scores of 0 to 2 classed as a mild stroke, scores of 3 to 4 classed as a moderate stroke, a score of 5 classed as a severe stroke and a score of 6 classed as a fatal stroke. Data corresponding to these modified Rankin scores were available for apixaban and warfarin from ARISTOTLE, but ROCKET-AF and RE-LY grouped stroke severity scores differently. The manufacturer therefore estimated the proportion of patients that would be expected to have scores of 3 to 4 or 5 in the group of patients reported as having a stroke with a modified Rankin score of 3 to 5 with rivaroxaban or dabigatran in ROCKET-AF and RE-LY. The manufacturer based this estimate on the relative proportions of patients treated with apixaban who had these scores in ARISTOTLE. The distribution of stroke severity across treatments in the population for whom a VKA antagonist was suitable is academic-in-confidence.
The manufacturer constructed a Markov model to evaluate the long- and medium-term consequences of apixaban for preventing stroke and systemic embolism in people with atrial fibrillation. The model considered warfarin-suitable and -unsuitable populations separately. The baseline characteristics of both populations were considered to be equivalent to the characteristics of a cohort of patients with a diagnosis of atrial fibrillation from a UK GP-based survey (Gallagher et al. 2011). Data from both network meta-analyses were used to inform the clinical effectiveness of treatments in the warfarin-suitable and -unsuitable populations respectively and to derive the transition probabilities used in the model. The risk of stroke was adjusted for baseline CHADS2 score distribution. The risks of stroke, intracranial haemorrhage, myocardial infarction, other major bleeds and clinically relevant non-major bleeds were adjusted for age. The model had a lifetime time horizon. The intervention and comparators were implemented in the model according to their marketing authorisations. For dabigatran 150 mg it was assumed that patients would switch to the 110 mg dose when they reached 80 years in line with the marketing authorisation. The average dosage of warfarin in the warfarin-suitable population was assumed to be 4.5 mg once daily. The evaluation was undertaken from the perspective of the NHS and Personal Social Services in England and Wales, and costs and benefits were discounted at 3.5% per year after the first year.
The model had 18 health states, including death. Both event-related mortality and other-cause mortality were incorporated in the model. Hypothetical patients transitioned between health states in cycles of 6 weeks with only 1 clinical event permitted per cycle. Patients entered the model in the non-valvular atrial fibrillation ('NVAF') health state, and stayed in this state until they died or experienced 1 of the following permanent events: ischaemic stroke (mild, moderate, severe or fatal); haemorrhagic stroke (mild, moderate, severe or fatal); systemic embolism or myocardial infarction; or 1 of the following temporary events: other intracranial haemorrhage (that is not a haemorrhagic stroke); other major bleeds (gastrointestinal bleeds or other bleeds besides intracranial haemorrhage and gastrointestinal-related bleeds); clinically relevant non-major bleeds; or other cardiovascular hospitalisations (that is, cardiovascular hospitalisations unrelated to stroke or myocardial infarction). The model allowed a maximum of 2 lines of therapy. After a switch to second-line therapy, patients transitioned into the 'NVAF without original anticoagulant' health state and were at risk of the same events as patients in the 'NVAF' health state (with the exception of the switch to second-line therapy).
The manufacturer classified the events as permanent or temporary. Patients who experienced a permanent event accrued both acute and long-term maintenance costs and were not assumed to recover to their previous level of health. After a permanent event, patients in the model were not exposed to the risks of all events: patients who had systemic embolism or myocardial infarction stayed in those health states until they died; patients who had a non-fatal stroke could remain in that health state, have 1 recurrent stroke or die. Recurrent strokes were assumed to be of the same type as the initial event (ischaemic or haemorrhagic) but could be of different severity. The resource use and disutility associated with the second stroke was assumed to be equal to that of the most severe stroke experienced. After a temporary event, all patients were assumed to recover to their previous health status.
A switch from first-line to second-line therapy was permitted after discontinuation because of a clinical event (intracranial haemorrhage or other major bleed) or after discontinuation because of other causes. Patients could switch to aspirin or have no treatment. In the base case, anyone who discontinued treatment was assumed to receive aspirin as second-line treatment. Only a switch from first-line anticoagulation therapy to second-line therapy with aspirin altered patients' risk of subsequent clinical events. Patients who experienced certain permanent events also switched treatment: patients who had a myocardial infarction or haemorrhagic stroke were assumed to stop treatment, and patients receiving aspirin as second-line therapy switched to warfarin if they had an ischaemic stroke or systemic embolism. However, all other patients who had ischaemic stroke or systemic embolism were assumed to remain on their original treatment in the base case. The risk of subsequent events for patients after a permanent event was assumed to be independent of treatment received, so switching did not affect their risk profile.
The manufacturer conducted a systematic review of health-state utility value studies relevant to the health states considered in the model, focusing on studies that reported EQ-5D values. Values from 21 studies that presented EQ-5D data in a population with atrial fibrillation and 3 studies that reported EQ-5D values for a variety of chronic conditions after controlling for comorbidities were included. As there were some health states for which a utility value had not been identified, studies of a population with atrial fibrillation that reported utilities elicited by methods other than the EQ-5D were screened, and data from a further 8 studies were included. One further study was identified from the reference list from the submissions for:
NICE's technology appraisal guidance 249 on dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation and
NICE's technology appraisal guidance 256 on rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation.
The manufacturer used unit costs taken from NHS reference costs 2010/11 where possible. If available, Healthcare Resource Group codes specified in the costing report for atrial fibrillation from NICE's clinical guideline 36 on the management of atrial fibrillation were used. The average daily drug acquisition costs were £2.20 for apixaban, £2.20 for dabigatran (either dose), £2.10 for rivaroxaban and £0.12 for warfarin (4.5 mg average daily dose). The manufacturer's model included intervention costs such as an annual INR monitoring cost of £248, which was an inflated estimate of the ERG's calculation in technology appraisal guidance 249, and a £3 renal monitoring cost for 19.4% of patients treated with dabigatran. The manufacturer used NHS reference costs for acute costs per episode for the temporary health states. The acute and long-term costs for systemic embolism and stroke were taken from a UK population-based assessment. Dyspepsia was the only adverse event that was not explicitly modelled as a health state, and a yearly cost of £27.60 was applied to all patients who had dyspepsia.
The manufacturer presented a deterministic base case for the warfarin-suitable and -unsuitable populations. In the population for whom warfarin was suitable, the ICER for apixaban compared with warfarin was £11,008 per QALY gained. This represented a gain of 0.164 QALYs for an incremental cost of £1795. Dabigatran 110 mg twice daily was strictly dominated (was more costly and less effective) than the dabigatran blend (dabigatran used as per its marketing authorisation, that is, people who are younger than 80 years receive a 150 mg twice daily dose and people 80 years or older receive a 110 mg twice daily dose). Apixaban extendedly dominated rivaroxaban and the dabigatran blend (resulted in a lower ICER compared with warfarin despite having higher total QALYs and total costs than rivaroxaban and the dabigatran blend).
Although aspirin was not included as a comparator in the scope, the manufacturer compared apixaban with aspirin in a population for whom warfarin was unsuitable. In this population apixaban was associated with an ICER of £2903 per QALY gained compared with aspirin.
The manufacturer assessed the univariate sensitivity of the model to 117 parameters using deterministic sensitivity analyses. In the warfarin-suitable population, parameters that had the most influential effect on the ICER for apixaban compared with warfarin were disutility associated with warfarin use, the hazard ratios for intracranial haemorrhage, ischaemic stroke or other-cause mortality during the trial, the cost of INR monitoring visit and the discount rate applied to QALYs. For apixaban compared with rivaroxaban or dabigatran, the most influential parameters were the hazard ratios associated with stroke, intracranial haemorrhage and other-cause mortality during the trial for these comparators compared with apixaban, the absolute stroke risk for apixaban, and the second-line stroke risk for aspirin. All of the ICERs calculated in the manufacturer's deterministic sensitivity analysis for apixaban compared with the comparator drugs were below £20,000 per QALY gained. In addition, the manufacturer carried out 19 scenario analyses. The majority of the scenario analyses decreased the base-case ICER (for apixaban compared with comparator). The probabilistic sensitivity analysis indicated that the probability that apixaban was cost effective at £20,000 and £30,000 per QALY gained was 80% and 87% respectively. For the dabigatran blend, rivaroxaban and warfarin the probabilities of being cost effective at £20,000 were 10%, 9% and 1% respectively. At £30,000 these were 5%, 7% and 0% respectively.
The ERG considered that, of the 2 trials of apixaban, only ARISTOTLE met the inclusion criteria for this technology appraisal, although it did acknowledge that aspirin is sometimes used in clinical practice in the UK. With respect to the network meta-analyses, the ERG did not consider the second analysis to be appropriate to determine the relative effectiveness of aspirin, apixaban, rivaroxaban and dabigatran in a population for whom vitamin K antagonists were unsuitable because the majority of trials in the second network meta-analysis included patients for whom warfarin was suitable. The ERG therefore focused its critique on the ARISTOTLE trial and the first network meta-analysis which compared the safety and efficacy of apixaban with warfarin, rivaroxaban and dabigatran.
The ERG considered that the inclusion and exclusion criteria, follow-up and statistical analysis of ARISTOTLE were acceptable and that the baseline characteristics of the randomised populations were well balanced between trial arms. The ERG commented that, based on advice given by clinicians on the time in therapeutic range expected in a UK population, the mean time in therapeutic range in ARISTOTLE (62.2%) was acceptable. It also considered the INR monitoring in ARISTOTLE to be consistent with that which would occur routinely in the UK. The ERG additionally considered that the distribution of CHADS2 scores in ARISTOTLE was comparable to the UK population. However, the ERG highlighted that no data on transient ischaemic attack or health-related quality of life were collected in ARISTOTLE or AVERROES, and that the effectiveness of apixaban in reducing transient ischaemic attacks and improving health-related quality of life was therefore unclear.
The ERG noted that the results of the manufacturer's base case were generated deterministically rather than probabilistically. Therefore the ERG used the manufacturer's probabilistic sensitivity analysis to estimate the manufacturer's probabilistic base case. The ICER for apixaban compared with warfarin in the probabilistic base case was £16,852 per QALY gained. The ERG considered that the manufacturer had presented a robust and predominantly conservative (direction of bias more likely to be against rather than towards apixaban) economic evaluation of apixaban compared with warfarin, dabigatran 110 mg, dabigatran blend and rivaroxaban in the warfarin suitable population. However, the ERG commented on the plausibility of some of the assumptions and inputs used in the manufacturer's model. The ERG considered whether certain outcomes would be expected to be dependent on the treatment a person received. It noted that severity of stroke event and bleed type was assumed to be dependent on the treatment received. The ERG considered that this may not be clinically appropriate and that there may be limitations to the data that informed these assumptions. The ERG also noted that the within-trial rate of other-cause mortality was different for patients treated with warfarin than apixaban, dabigatran or rivaroxaban. Although patients treated with warfarin may be at a higher risk of event-specific death, the ERG did not expect that they would be at a different risk of other-cause mortality.
The ERG noted that patients who had a stroke (haemorrhagic or ischaemic), systemic embolism or myocardial infarction were assumed to be at risk of fewer types of subsequent clinical events than patients in other health states. The ERG accepted the risk limitation applied to patients who experienced a stroke but that patients with systemic embolism or myocardial infarction would remain at risk of further events (in particular ischaemic stroke). The ERG considered that some people who stop therapy with apixaban, dabigatran or rivaroxaban may be eligible for treatment with warfarin or a different oral anticoagulant rather than aspirin which was the second-line treatment in the manufacturer's model. The ERG additionally commented that the risk profile of people on second-line therapy was not adjusted for characteristics such as age or CHADS2 score in the manufacturer's model, but it accepted that adjusting for characteristics in second-line treatment may be beyond the reasonable scope of a Markov model.
The ERG commented that utilities were not age adjusted in the manufacturer's model, meaning that a person's quality of life would be affected by events experienced but not by increasing age. The ERG considered that the assumption of equivalent disutility between the apixaban, rivaroxaban and dabigatran may not be robust but that any resultant bias was likely to be against apixaban.
The ERG noted that the acute cost of systemic embolism in the manufacturer's model (£4077.98) was approximately double the acute costs used in the submissions for NICE technology appraisal guidance 249 (dabigatran £2772 ) and NICE technology appraisal guidance 256 (rivaroxaban £1658). These submissions had used NHS reference costs.
For its revised base case the ERG changed some of the assumptions used in the manufacturer's model. The ERG assumed that other-cause mortality, stroke severity and bleed type were independent of the type of anticoagulant treatment received. The ERG adjusted utility for increasing age by -0.00029 per year. The ERG assumed that people who had myocardial infarction or systemic embolism were at risk of recurrent stroke, and used the same acute costs for systemic embolism as in NICE technology appraisal guidance 256, as this was the most conservative cost used in the submissions for NICE technology appraisal guidance 256 and 249. The ERG also assumed the time horizon was 26 years.
The ERG noted that after these amendments, dabigatran 110 mg continued to be strictly dominated by the dabigatran blend and rivaroxaban and the dabigatran blend remained extendedly dominated by apixaban. The ICER for apixaban compared with warfarin for each individual amendment was relatively consistent with the manufacturer's base-case ICER. The ERG noted that assuming stroke severity was independent of treatment increased the ICER of apixaban compared with warfarin to £12,277 per QALY gained, whereas assuming bleed type was independent of treatment decreased this ICER to £9771 per QALY gained. When all of the amendments were combined to form the ERG's revised base case, this resulted in an ICER for apixaban compared with warfarin of £12,757 per QALY gained. This represented an incremental cost of £1823 compared with warfarin for an additional 0.14 QALY.
The ERG carried out 3 further exploratory analyses that were not included in its revised base case. These were:
Age adjustment of event risks for people on second-line therapy, using the same risk adjustment factors as for people receiving first-line therapy. Dabigatran blend and rivaroxaban continued to be extendedly dominated by apixaban. The ICER for apixaban compared with warfarin fell slightly from the manufacturer's base case of £11,008 to £10,779 per QALY gained.
Removal of treatment-related disutility. Dabigatran blend and rivaroxaban continued to be extendedly dominated by apixaban but the ICER for apixaban compared with warfarin increased from £11,008 to £14,530 per QALY gained.
Changes to the treatment sequence to allow second-line treatment with warfarin, apixaban, rivaroxaban or dabigatran. The results of these analyses were highly variable, with ICERs for apixaban varying between £287 per QALY gained (compared with warfarin when dabigatran 110 mg was the second-line treatment) and £60,366 per QALY gained (compared with dabigatran blend when rivaroxaban was the second-line treatment). However, the ERG commented that the results of this analysis should be interpreted with caution because the main driver of the ICERs was discontinuation rates associated with first-line therapy and, consequently, treatments with higher discontinuation rates such as dabigatran appeared more effective than in the manufacturer's base case.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of apixaban, having considered evidence on the nature of non-valvular atrial fibrillation and the value placed on the benefits of apixaban by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee heard from clinical specialists and patient experts that the current standard treatment for people with non-valvular atrial fibrillation who need anticoagulation is warfarin or the newer oral anticoagulants rivaroxaban or dabigatran. The clinical specialists explained that the majority of people receiving an anticoagulant currently receive warfarin. In addition, some people who meet criteria for anticoagulation are currently receiving the antiplatelet agent aspirin inappropriately because of clinical reluctance to prescribe warfarin. The Committee heard that warfarin is an effective treatment but that it is associated with a number of problems. The patient experts explained that repeated INR monitoring tests with warfarin can cause pain and scarring and limit a person's choice of leisure or other activities and that warfarin can have a greater impact on a person's quality of life than atrial fibrillation itself. They also highlighted that warfarin has multiple interactions with food, alcohol and drugs that can cause further inconvenience that make adherence to treatment difficult. Overall, the patient experts considered that making the day-to-day choices about lifestyle needed in order to take and monitor warfarin appropriately has a substantial impact on a person's quality of life. The Committee accepted the limitations of warfarin therapy and the considerable effect it may have on the people who take it, and recognised the potential benefits of apixaban for people with atrial fibrillation.
The Committee considered the clinical-effectiveness data from the ARISTOTLE trial comparing apixaban with warfarin. It considered that the ARISTOTLE trial was of good quality and it discussed whether the results were generalisable to people diagnosed with atrial fibrillation in the NHS. The Committee noted that the mean time in therapeutic range for those in the warfarin arm was 62.2% (the median was 66%) and asked the clinical specialists whether this was representative of what would be achieved in clinical practice in the UK. The clinical specialists explained that there is variation in time in therapeutic range achieved between centres. One clinical specialist quoted a benchmarking study using a computerised dose adjustment system in which a mean time in therapeutic range of over 70% was achieved. Another clinical specialist stated that the time in therapeutic range observed in ARISTOTLE reflected what is generally seen in the UK, not what is observed in centres achieving the best time in therapeutic range, and that centres should aim for a time in therapeutic range for each individual of 70% and above. One clinical specialist also highlighted that in their experience people treated for atrial fibrillation tended to be older and more likely to be on non-steroidal anti-inflammatory drugs (NSAIDS), which can impact on bleeding complications, than the ARISTOTLE population. The Committee noted the potential differences between the trial population and people treated for atrial fibrillation in the UK but concluded that the characteristics of the people who participated in ARISTOTLE were broadly generalisable to the UK population.
The Committee considered the results of the ARISTOTLE trial. It noted that apixaban was more effective than warfarin in reducing the primary efficacy outcome of all stroke (ischaemic and haemorrhagic), and systemic embolism. The Committee noted that the primary efficacy outcome was a composite of the effectiveness outcomes (ischaemic stroke and systemic embolism) and a bleeding outcome (haemorrhagic stroke). The Committee heard from the clinical specialists that there is debate about the primary outcomes to use in trials of anticoagulants for atrial fibrillation, but that it is common to use composite outcomes, such as the primary efficacy outcome in ARISTOTLE. The Committee considered the individual components of the composite outcome. It heard from the clinical specialists that once an embolus leaves the heart it is a matter of chance whether it flows to the brain, resulting in ischaemic stroke, or to the rest of the body, causing systemic embolism. The proportion of each was therefore not a treatment effect. The Committee also heard from the clinical specialists that a particular benefit conferred by the new anticoagulants compared with warfarin was the reduction in haemorrhagic strokes. This was also shown in the ARISTOTLE trial, in which there was a statistically significant reduction in haemorrhagic stroke with apixaban compared with warfarin, whereas for the other individual components of the composite end points (ischaemic stroke and systemic embolism) there was no statistically significant difference. The Committee concluded that apixaban was more clinically effective than warfarin for the primary efficacy outcome of reducing stroke and systemic embolism.
The Committee considered the results of the manufacturer's subgroup analyses from ARISTOTLE. It noted that the subgroup analysis by CHADS2 score comprised 3 groups: people with a CHADS2 score of 1 or less, people with a CHADS2 score of 2 and people with a CHADS2 score of 3 or over. The Committee was aware that the ERG had concerns that because people with CHADS2 scores of 3 to 6 had been grouped together, it was not possible to comment on potential variation in treatment effect for these subgroups. The Committee concluded that there was no biologically plausible reason to indicate that the relative treatment effect would be dependent on baseline risk and that the mean CHADS2 score of 2.1 in the trial was a reasonable reflection of the UK population currently on anticoagulant therapy.
The Committee noted that the manufacturer presented data for subgroups based on INR control using quartiles of centre time in therapeutic range. It further noted that there was a numerically lower rate of stroke or systemic embolism with apixaban compared with warfarin in all analyses broken down by centre time in therapeutic range, but that ARISTOTLE was not statistically powered to demonstrate superiority across subgroups. The Committee concluded that the evidence from subgroups based on centre time in therapeutic range was not sufficiently robust to use to formulate guidance based on an individual's time in therapeutic range.
The Committee considered the adverse events reported in ARISTOTLE. The Committee noted that for the primary safety outcome of major bleeding (using the International Society on Thrombosis and Haemostasis definition), treatment with apixaban resulted in fewer bleeding events than warfarin, including a reduced rate of intracranial bleeding. The Committee recognised that this has a high mortality rate and a large impact on a person's quality of life, and is the most feared bleeding outcome for people taking any type of anticoagulant. The Committee noted however that there were no statistically significant differences in the rates of gastrointestinal bleeding between apixaban and warfarin. The Committee concluded that apixaban resulted in fewer bleeds than warfarin and it recognised the particular importance of the effects of apixaban in reducing the risk of intracranial bleeding for people with atrial fibrillation when compared with warfarin.
The Committee noted that all anticoagulants are associated with a risk of bleeding and discussed the management of atrial fibrillation in people who experience a bleed while taking warfarin or apixaban. The Committee heard from the clinical specialists that people taking warfarin who experience a bleed may be given vitamin K to reverse the effects of warfarin. However, there are no standard treatments to reverse the effects of apixaban (or the other newer oral anticoagulants rivaroxaban and dabigatran) and that this is an area of ongoing research. Current clinical opinion is that the newer oral anticoagulants have moderate half-lives and that people who have bleeds while taking these drugs should stop treatment. The Committee also heard from the patient experts and the clinical specialists that reversing the effect of warfarin with vitamin K may take several hours, but that there are other approaches, such as using a prothrombin concentrate, that are fast-acting. The Committee concluded that there is a standard approach to reverse significant bleeding for a person taking warfarin, but that there is uncertainty about the most effective way to stop active bleeding when a person is taking apixaban.
The Committee noted that the manufacturer had included evidence on the efficacy of apixaban compared with aspirin for people for whom vitamin K antagonist treatment was unsuitable, but that this was not part of the scope issued by NICE. The Committee understood that the manufacturer's rationale for including aspirin as an additional comparator reflected the recommendation in NICE clinical guideline 36 that people who need anticoagulation but for whom warfarin is unsuitable should be offered aspirin. The Committee was also aware that aspirin had not been included as a comparator in the apixaban scope because, since the publication of NICE clinical guideline 36, dabigatran and rivaroxaban had been recommended for use by NICE and these were now alternative treatments to warfarin. The Committee heard from the clinical specialists that aspirin is a less effective treatment than the anticoagulants but is still being prescribed for some people with atrial fibrillation despite publication of NICE technology appraisal guidance 249 and 256. The Committee further heard that although AVERROES was a useful trial, the population for whom warfarin was unsuitable was very mixed, including people for whom warfarin was clinically unsuitable and those who were unwilling to take it. The Committee noted that the ERG did not consider that AVERROES met the inclusion criteria for this appraisal and had focused its critique on ARISTOTLE. The Committee agreed that the comparators defined in the final scope were appropriate and that the key trial for this appraisal was ARISTOTLE. However, it noted with interest that the evidence presented in AVERROES showed that apixaban was associated with a reduced rate of stroke or systemic embolism compared with aspirin and an increased rate of bleeding events overall, but not an increased rate of major bleeds.
The Committee discussed the indirect clinical-effectiveness evidence for apixaban compared with dabigatran (both the 110 mg twice daily dose and 150 mg twice daily dose) and rivaroxaban. The Committee noted that the manufacturer presented 2 network meta-analyses for vitamin K antagonist-suitable and -unsuitable populations (which included aspirin) respectively. The Committee noted that the ERG considered the second meta-analysis to be flawed as there were no specific data available for rivaroxaban or dabigatran for a warfarin-unsuitable population and the network meta-analysis included a mixed population including people for whom warfarin was suitable and unsuitable. The Committee considered that only the first network meta-analysis, relating to the warfarin-suitable population, was appropriate to the decision problem. The Committee noted that the population in the study comparing rivaroxaban with warfarin (ROCKET-AF) had a higher mean baseline CHADS2 score than the population in the study comparing dabigatran with warfarin (RE-LY) or ARISTOTLE. The Committee additionally noted that the mean time in therapeutic range in the warfarin arm was lower in ROCKET-AF than in RE-LY or ARISTOTLE. The Committee considered that the differences in baseline characteristics between the study populations meant that there was uncertainty surrounding the results of the network meta-analysis. The Committee noted that the network meta-analysis did not detect any difference between apixaban, rivaroxaban and dabigatran in the rate of stroke or systemic embolism; showed a lower rate of all bleeding outcomes with apixaban compared with rivaroxaban and of all bleeding outcomes except intracranial haemorrhage and clinically relevant non-major bleeding (which was not measured in RE-LY) compared with dabigatran 150 mg; a lower rate of 'any bleeding' compared with dabigatran 110 mg; and a lower rate of myocardial infarction with apixaban compared with dabigatran (both doses). The Committee noted that the network meta-analysis had shown broadly similar outcomes and some differences between apixaban, rivaroxaban and dabigatran, but because of differences in the trial populations the results of the network meta-analysis should be viewed with caution. It also noted that some of the criteria in the network meta-analysis were in fact not a direct treatment effect, such as the proportion of ischaemic stroke compared with systemic embolism, and evidence was lacking that the severity of an ischaemic or haemorrhagic stroke was treatment specific for the new agents. The Committee concluded that the network meta-analysis results should be interpreted in the light of these uncertainties and were not sufficiently robust to reliably differentiate between apixaban, rivaroxaban and dabigatran.
The Committee considered the manufacturer's economic model and the exploratory analyses performed by the ERG. It agreed with the ERG that the general modelling approach was reasonable and consistent with other analyses of atrial fibrillation treatments. The Committee noted the discussion on the proportion of ischaemic stroke compared with systemic embolism being unrelated to the treatment (see 4.4). It also questioned whether the severity of an ischaemic or haemorrhagic stroke was treatment specific (see 3.13). In a previous appraisal the Committee had heard from experts that it was plausible and that there is evidence that strokes on warfarin were likely to be more severe than on dabigatran, but the clinical specialists for the appraisal of apixaban did not put forward any evidence that this had been substantiated and were of the opinion that at least for the newer agents, there was no biologically plausible reason or evidence that the severity of strokes would differ between apixaban, rivaroxaban and dabigatran. The Committee concluded that although the general modelling approach was appropriate, weaknesses included the assumption that whether a person experienced an ischaemic stroke or systemic embolism was treatment related, and that there is currently insufficient evidence to support the assumption in the model that the severity of an ischaemic or haemorrhagic stroke was dependent on the specific anticoagulant agent they had received.
The Committee considered the utility values used in the model. The Committee noted that ARISTOTLE had not assessed health-related quality of life and that the utility values used in the manufacturer's model were identified through a systematic review. The Committee questioned whether the manufacturer's assumption of a permanent utility decrement following a myocardial infarction was appropriate. However, it accepted the views of the clinical specialists that disutility following a myocardial infarction would not be expected to change substantially after 6 months. The Committee concluded that the utilities used in the model were appropriate.
The Committee considered the costs used in the model. It noted that the estimates for stroke and systemic embolism were based on a cohort study of a population living in the Oxford area of the UK and that the costs for ischaemic stroke were lower than those for haemorrhagic stroke. The Committee questioned whether the study had been able to estimate haemorrhagic stroke costs accurately given the lower incidence of this event than ischaemic stroke in the population, and whether the higher haemorrhagic stroke costs assumed in the model could have driven the cost-effectiveness results. The Committee heard from the ERG that the haemorrhagic stroke costs were consistent with those used in NICE technology appraisal guidance 249 and 256 and that, as a small proportion of people had a haemorrhagic stroke in the model, other factors such as discontinuation rates drove the cost-effectiveness results to a greater extent than the cost of haemorrhagic stroke. The Committee also noted that an INR monitoring cost of £248 was assumed by the manufacturer, and that this was consistent with the monitoring costs used in NICE technology appraisal guidance 249 (and was updated for inflation). The Committee concluded that the costs used in the model were appropriate.
The Committee considered the results of the economic model. It noted that the manufacturer's base-case deterministic and probabilistic ICERs for apixaban compared with warfarin were £11,000 and £16,900 per QALY gained respectively, and that the ERG's revised deterministic base case, (see 3.30) resulted in an ICER of £12,800 per QALY gained. The Committee noted that only one of the sensitivity analyses performed by the ERG (in which alternative second-line treatments rather than aspirin were considered, see 3.31) influenced the results substantially. The Committee accepted the ERG's comment that this analysis should be interpreted with caution because the main driver of the ICER was discontinuation rates on first-line treatment. The Committee noted that the ERG's sensitivity analysis assuming stroke severity was independent of treatment had a modest effect on the ICER compared with warfarin (the ICER increased to £12,300 per QALY gained when stroke severity was assumed to be the same for all of the anticoagulants). The Committee concluded that apixaban had been shown to be cost effective compared with warfarin, the most plausible ICER being less than £20,000 per QALY gained, and could be recommended as an option for preventing stroke and systemic embolism for people with non-valvular atrial fibrillation who have 1 or more risk factors for stroke.
The Committee noted that in the manufacturer's model dabigatran and rivaroxaban had higher ICERs compared with warfarin than the ICER for apixaban compared with warfarin. In addition, in the incremental analysis dabigatran 110 mg twice daily was dominated by the dabigatran blend and the dabigatran blend and rivaroxaban were extendedly dominated by apixaban. However, the Committee was concerned that there was considerable uncertainty about the relative treatment effects and cost effectiveness of apixaban, rivaroxaban and dabigatran arising from differences in the baseline characteristics of the people included in the trials and the relative treatment effects attributed to the individual anticoagulants that informed the network meta-analysis. The Committee concluded that there was insufficient evidence to distinguish between the cost effectiveness of apixaban, dabigatran and rivaroxaban at this time.
Finally, the Committee concluded that the decision about whether to start treatment with apixaban should be made after an informed discussion between the clinician and the person about the risks and benefits of apixaban compared with warfarin, dabigatran and rivaroxaban. For people who are taking warfarin, the potential risks and benefits of switching to apixaban should be considered in light of their level of INR control.
# Summary of Appraisal Committee's key conclusions
TA275
Appraisal title: Apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation
Section
Key conclusion
Apixaban is recommended as an option for preventing stroke and systemic embolism within its marketing authorisation.
The decision about whether to start treatment with apixaban should be made after an informed discussion between the clinician and the person about the risks and benefits of apixaban compared with warfarin, dabigatran etexilate or rivaroxaban. For people who are taking warfarin, the potential risks and benefits of switching to apixaban should be considered in light of their level of international normalised ratio (INR) control.
The Committee concluded that apixaban was more clinically effective than warfarin for the primary efficacy outcome of reducing stroke and systemic embolism.
The Committee concluded that apixaban resulted in fewer bleeds than warfarin and it recognised the particular importance of the effects of apixaban in reducing the risk of intracranial bleeding for people with atrial fibrillation when compared with warfarin.
The Committee concluded that apixaban had been shown to be cost effective compared with warfarin, the most plausible ICER being less than £20,000 per QALY gained, and could be recommended as an option for preventing stroke and systemic embolism for people with non-valvular atrial fibrillation who have 1 or more risk factors for stroke.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from clinical specialists and patient experts that the current standard treatment for people with non-valvular atrial fibrillation who need anticoagulation is warfarin or the newer oral anticoagulants rivaroxaban or dabigatran. The clinical specialists explained that the majority of people receiving an anticoagulant currently receive warfarin. The clinical specialists said that some people who meet criteria for anticoagulation are currently receiving the antiplatelet agent aspirin inappropriately because of clinical reluctance to prescribe warfarin.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee accepted the limitations of warfarin therapy (for example, the inconvenience, pain and scarring associated with INR monitoring, and the multiple interactions with food, alcohol and drugs) and the considerable effect it may have on the people who take it, and recognised the potential benefits of apixaban for people with atrial fibrillation.
What is the position of the treatment in the pathway of care for the condition?
Apixaban is used as an alternative to warfarin, rivaroxaban and dabigatran and is an anticoagulant treatment for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation with 1 or more risk factors for stroke.
Adverse reactions
The Committee concluded that apixaban resulted in fewer bleeds than warfarin and it recognised the particular importance of the effects of apixaban in reducing the risk of intracranial bleeding for people with atrial fibrillation when compared with warfarin.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered the clinical-effectiveness data from the ARISTOTLE trial comparing apixaban with warfarin.
The Committee noted that the manufacturer had included evidence on the efficacy of apixaban compared with aspirin for people for whom vitamin K antagonist treatment was unsuitable, which was not part of the scope issued by NICE. The Committee agreed that the comparators defined in the final scope (warfarin, rivaroxaban and dabigatran etexilate) were appropriate and that the key trial for this appraisal was ARISTOTLE.
Relevance to general clinical practice in the NHS
The Committee concluded that the characteristics of the people who participated in ARISTOTLE were broadly generalisable to the UK population.
Uncertainties generated by the evidence
The Committee concluded that the network meta-analysis results should be interpreted with caution (for example, because of the differences in baseline characteristics between the study populations) and were not sufficiently robust to reliably differentiate between apixaban, rivaroxaban and dabigatran.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee concluded that the evidence from subgroups based on centre time in therapeutic range was not sufficiently robust to use to formulate guidance based on an individual's time in therapeutic range.
The Committee concluded that there was no biologically plausible reason to indicate that the relative treatment effect would be dependent on baseline risk.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that apixaban was more clinically effective than warfarin for the primary efficacy outcome of reducing stroke and systemic embolism.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee agreed with the ERG that the general modelling approach was reasonable and consistent with other analyses of atrial fibrillation treatments.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee concluded that although the general modelling approach was appropriate, weaknesses included the assumption that whether a person experienced a ischaemic stroke or systemic embolism was treatment related, and there is currently insufficient evidence to support the assumption in the model that the severity of an ischaemic or haemorrhagic stroke was dependent on the specific anticoagulant agent they had received.
The Committee was concerned that there was considerable uncertainty surrounding the relative treatment effects and cost-effectiveness of apixaban, rivaroxaban and dabigatran arising from differences in the baseline characteristics of the people included in the trials and the relative treatment effects attributed to the individual anticoagulants that informed the network meta-analysis. The Committee concluded that there was insufficient evidence to distinguish between the cost effectiveness of apixaban, dabigatran and rivaroxaban at this time.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that ARISTOTLE had not assessed health-related quality of life and that the utility values used in the manufacturer's model were identified through a systematic review. The Committee questioned whether the manufacturer's assumption of a permanent utility decrement following a myocardial infarction was appropriate. However, it accepted the views of the clinical specialists that disutility following a myocardial infarction would not be expected to change substantially after 6 months. The Committee concluded that the utilities used in the model were appropriate.
No health-related benefits were identified that were not included in the economic model.
Are there specific groups of people for whom the technology is particularly cost effective?
Apixaban is recommended as an option for all people with non-valvular atrial fibrillation within its marketing authorisation. No specific groups of people for whom the technology is particularly cost effective were identified.
What are the key drivers of cost effectiveness?
The Committee noted that only one of the sensitivity analyses performed by the ERG (in which alternative second-line treatments rather than aspirin were considered, see 3.31) influenced the results substantially. The Committee accepted the ERG's comment that this analysis should be interpreted with caution because the main driver of the ICER was discontinuation rates on first-line treatment.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee concluded that apixaban had been shown to be cost-effective compared with warfarin, the most plausible ICER being less than £20,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
No equalities issues were identified.
–# Recommendations for further research
During this appraisal it was noted that there is a need for additional research on the management of bleeds that occur while people are receiving apixaban, rivaroxaban or dabigatran etexilate, as there are no antidotes or established treatments to stop active bleeding for these agents.
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{'Recommendations': 'Apixaban is recommended as an option for preventing stroke and systemic embolism within its marketing authorisation, that is, in people with non-valvular atrial fibrillation with 1\xa0or more risk factors such as:\n\nprior stroke or transient ischaemic attack\n\nage 75\xa0years or older\n\nhypertension\n\ndiabetes mellitus\n\nsymptomatic heart failure.\n\nDecide whether to start treatment with apixaban after an informed discussion with the person about its risks and benefits compared with warfarin, dabigatran etexilate, edoxaban and rivaroxaban. For people taking warfarin, consider the potential risks and benefits of switching to apixaban taking into account their level of international normalised ratio (INR) control.', 'The technology ': "Apixaban (Eliquis, Bristol-Myers Squibb and Pfizer) is a potent, oral, direct and highly selective active site inhibitor of factor Xa. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Apixaban 5\xa0mg twice daily and 2.5\xa0mg twice daily has a European marketing authorisation for the 'prevention of stroke and systemic embolism in adult\xa0patients with non-valvular atrial fibrillation, with 1\xa0or more risk factors, such as prior stroke or transient ischaemic attack, age 75\xa0years or older, hypertension, diabetes mellitus, or symptomatic heart failure (New York Heart Association [NYHA] class 2\xa0or higher)'.\n\nThe summary of product characteristics lists the following adverse reactions for apixaban: epistaxis (nosebleed), contusion (bruising), haematuria (blood in urine), haematoma, eye haemorrhage, and gastrointestinal haemorrhage. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe manufacturer has stated that the cost per day for both doses (2.5\xa0mg and 5\xa0mg twice daily) of apixaban (excluding VAT) is £2.20, and the annual cost is £803. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee considered evidence submitted by the manufacturer of apixaban and a review of this submission by the Evidence Review Group (ERG).\n\nThe main clinical effectiveness evidence for apixaban came from 2\xa0international, multicentre, double-blind, double-dummy, placebo-controlled, randomised controlled trials, which had investigated apixaban. ARISTOTLE (n=18,201) compared apixaban (5\xa0mg twice daily; 2.5\xa0mg twice daily in selected patients) with warfarin (in patients with an international normalised ratio [INR] target range of 2.0\xa0to\xa03.0). AVERROES (n=5598) compared apixaban (5\xa0mg twice daily; 2.5\xa0mg twice daily in selected patients) with aspirin (81\xa0mg to 324\xa0mg once daily) in people 50\xa0years or older with atrial fibrillation and at least 1\xa0additional risk factor for stroke for whom treatment with warfarin had failed, or for whom warfarin was unsuitable or who were unwilling to take warfarin.\n\nThe primary objective of ARISTOTLE was to determine if apixaban was non-inferior to warfarin for the combined end point of stroke and systemic embolism. Stroke included both ischaemic stroke, caused by embolism from the heart, and haemorrhagic stroke, which can be a complication of anticoagulant treatment (although it may also occur spontaneously or as a result of secondary haemorrhage into an ischaemic stroke). ARISTOTLE included adults with atrial fibrillation or atrial flutter not resulting from a reversible cause and at least 1\xa0additional risk factor for stroke (assessed by CHADS2 criteria). It enrolled patients from 39\xa0countries; 40% of participants were from Europe and this included patients from 41\xa0sites in the UK. The average age was 69\xa0years and 65% of the population were male. The mean time in therapeutic range for patients in the warfarin arm was 62.2%, and the median time in therapeutic range was 66%. Approximately 4% of the study population received 2.5\xa0mg apixaban (those who had 2\xa0or more of the following criteria: 80\xa0years or older, a body weight of 60\xa0kg or less, or a serum creatinine level of 1.5\xa0mg/100\xa0ml [133\xa0micromole/l] or more). The mean CHADS2 score at baseline was 2.1\xa0and approximately 65% of patients had a CHADS2\xa0score of 2\xa0or more.\n\nIn the intention-to-treat population, apixaban met non-inferiority criteria using a non-inferiority margin of 1.38, over a median follow-up of 1.8\xa0years. Apixaban was associated with a significantly lower rate of stroke and systemic embolism than warfarin (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66\xa0to 0.95, p=0.01). The rate of fatal or disabling stroke was significantly lower in the apixaban group than the warfarin group (HR\xa00.71, 95% CI 0.54\xa0to 0.94). When the outcomes included in the composite primary outcome (ischaemic or uncertain type, haemorrhagic stroke and systemic embolism) were analysed separately, apixaban was associated with a significant reduction in haemorrhagic stroke compared with warfarin (HR\xa00.51, 95% CI 0.35\xa0to 0.75), but the decrease for apixaban compared with warfarin in ischaemic or uncertain type stroke or systemic embolism was not statistically significant (ischaemic or uncertain type stroke HR 0.92, 95% CI 0.74\xa0to 1.13, p=0.42; systemic embolism HR 0.87, 95% CI 0.44\xa0to 1.75, p=0.70). The rates of myocardial infarction, and pulmonary embolism or deep vein thrombosis, were lower with apixaban than warfarin, but were not statistically significant (HR\xa00.88, 95% CI 0.66\xa0to 1.17, p=0.37, and HR\xa00.78, 95% CI 0.29\xa0to 2.10, p=0.63\xa0respectively). Apixaban was associated with fewer all-cause deaths than warfarin, which was of borderline statistical significance (3.52% and 3.94% respectively [HR\xa00.89, 95% CI 0.80\xa0to 0.99, p=0.047]).\n\nThe manufacturer presented results for the primary efficacy outcomes for 21\xa0pre-specified subgroups in ARISTOTLE including subgroups broken down by baseline risk of stroke or systemic embolism (grouped by CHADS2\xa0scores ≤1, 2\xa0and ≥3). ARISTOTLE was not statistically powered to demonstrate superiority in subgroup analyses. The hazard ratios for apixaban relative to warfarin for stroke and systemic embolism in the 3\xa0stroke risk subgroups were consistently less than 1, but the confidence intervals of the CHADS2\xa0≤1\xa0and 2\xa0groups crossed 1, meaning that that the difference between apixaban and warfarin was not statistically significant for these groups. The hazard ratios for stroke and systemic embolism in the groups of patients who received 5\xa0mg and 2.5\xa0mg apixaban were also both below 1\xa0(the hazard ratios for CHADS2\xa0score subgroups and for the groups of patients who received 5\xa0mg and 2.5\xa0mg apixaban are commercial-in-confidence). The manufacturer also presented data for subgroups based on INR (international normalised ratio) control using quartiles of centre time in therapeutic range (less than 58.0%, 58.0% to 65.7%, 65.7% to 72.2% and more than 72.2%). A centre's time in therapeutic range was calculated as the median of individual time in therapeutic ranges among the centre's patients on warfarin. The manufacturer reported that the benefits of apixaban over warfarin in preventing stroke or systemic embolism were consistent (HR\xa0<1) regardless of INR control (centre time in therapeutic range\xa0<58.0% [HR\xa00.77, 95% CI 0.56\xa0to 1.06], centre time in therapeutic range\xa058.0% to 65.7% [HR\xa00.80, 95% CI 0.56\xa0to 1.15], centre time in therapeutic range\xa065.7% to 72.2% [HR\xa00.79, 95% CI 0.54\xa0to 1.13], centre time in therapeutic range\xa0>72.2% [HR\xa00.81, 95% CI 0.52\xa0to 1.26]).\n\nThe adverse events and safety analyses were reported for the on-treatment population in ARISTOTLE (all patients who received at least 1\xa0dose of study medication). Apixaban was superior to warfarin for the primary safety outcome of time from first dose of study drug to first occurrence of confirmed International Society on Thrombosis and Haemostasis (ISTH) major bleeding (HR\xa00.69, 95% CI 0.60\xa0to 0.80; p<0.001). Apixaban resulted in significantly fewer bleeding events than warfarin for all of the major bleed types (intracranial major bleeding HR\xa00.42, 95% CI 0.30\xa0to 0.58; other location major bleeding HR\xa00.79, 95% CI 0.68\xa0to 0.93) and clinically relevant non-major bleeding events reported by the manufacturer apart from major gastrointestinal bleeding, for which the difference between apixaban and warfarin was not statistically significant (HR\xa00.89, 95% CI 0.70\xa0to 1.15, p=0.37). There were similar proportions of patients who experienced adverse events with apixaban (81.5%) and warfarin (83.1%) and a lower proportion of patients who experienced bleeding adverse events with apixaban (25.2%) compared with warfarin (32.7%). Serious adverse events occurred in 35.0% of patients treated with apixaban and 36.5% of patients treated with warfarin. Fewer patients stopped the study drug in the apixaban group than the warfarin group (25.3% compared with 27.5% respectively, p=0.001); 7.6% of patients in the apixaban arm and 8.4% of patients in the warfarin arm stopped treatment because of an adverse event. The safety of apixaban was maintained across patients at different levels of stroke risk, regardless of warfarin control (time in therapeutic range) and in patients who needed dose reduction.\n\nThe primary objective of AVERROES was to determine if apixaban was superior to aspirin for preventing the composite outcome of stroke or systemic embolism in adults with at least 1\xa0risk factor for stroke in whom vitamin K antagonists were unsuitable. In the intention-to-treat population apixaban reduced the rate of stroke and systemic embolism compared with aspirin over a mean follow-up of 1.1\xa0years (HR\xa00.45, 95% CI 0.32\xa0to 0.62, p<0.001). The rates of disabling or fatal stroke were also lower in patients who received apixaban compared with patients who received aspirin (HR\xa00.43, 95% CI 0.28\xa0to 0.65). When considered as a separate outcome apixaban reduced the rates of ischaemic stroke compared with aspirin (HR\xa00.37, 95% CI 0.25\xa0to 0.55) but did not statistically significantly reduce the rates of haemorrhagic stroke (HR\xa00.67, 95% CI 0.24\xa0to 1.88, p=0.45). Apixaban was associated with a higher rate of all bleeding than aspirin (HR\xa01.30, 95% CI 1.10\xa0to 1.53) and of major or clinically relevant non-major bleeding (HR\xa01.38, 95% CI 1.07\xa0to 1.78). Although apixaban was associated with higher rates of major bleeding than aspirin, this was not statistically significant (HR\xa01.54, 95% CI 0.96\xa0to 2.45, p=0.07).\n\nNo head-to-head data were available for apixaban compared with dabigatran etexilate (hereafter referred to as dabigatran) or rivaroxaban. The manufacturer used a Bayesian Markov chain Monte Carlo stimulation in WinBUGS to conduct 2\xa0network meta-analyses using a fixed-effect model. The first meta-analysis included patients for whom vitamin K antagonist treatment was suitable and it compared apixaban, warfarin, dabigatran and rivaroxaban. The second meta-analysis was intended to assess a population of patients for whom vitamin K antagonists were unsuitable, comparing apixaban, dabigatran, rivaroxaban and aspirin.\n\nThe first meta-analysis included ARISTOTLE, RE-LY and ROCKET-AF trials. RE-LY compared dabigatran (150\xa0mg and 110\xa0mg twice daily) with warfarin. ROCKET-AF compared rivaroxaban (20\xa0mg once daily) with warfarin. There were differences between the trials of apixaban, dabigatran and rivaroxaban: ARISTOTLE and ROCKET-AF were double-blind, double-dummy trials, whereas RE-LY was an open-label trial; the population in ROCKET-AF had a higher stroke or systemic embolism risk at baseline (baseline CHADS2\xa0of 3.6\xa0[ROCKET-AF], 2.1\xa0[ARISTOTLE], 2.1\xa0[RE-LY]) and the mean percentage time in therapeutic range was lower in ROCKET-AF (55%) than in ARISTOTLE (62%) and RE-LY (64%). Where possible, the manufacturer used intention-to-treat data from each trial. However, the manufacturer highlighted that there was an absence of published intention-to-treat outcome data for some secondary outcomes from ROCKET-AF including fatal stroke, disabling stroke and non-disabling stroke. Therefore, data from the on-treatment population were also used. The second meta-analysis included ARISTOTLE, RE-LY, ROCKET-AF and AVERROES.\n\nThe manufacturer did not present any statistical analysis of heterogeneity but commented that potential sources of clinical heterogeneity between the trials were the differences in baseline stroke risk scores, study blinding, and whether the intention-to-treat or on-treatment populations had been used to assess efficacy and safety outcomes. Additionally, the manufacturer highlighted a statistically significant difference in myocardial infarction at baseline between treatment groups in ROCKET-AF.\n\nThe base-case results of the first meta-analysis indicated that there were no statistically significant differences between apixaban and rivaroxaban or dabigatran in the incidence of stroke, systemic embolism and all-cause mortality. The results did however suggest that apixaban was associated with a significantly lower incidence of myocardial infarction compared with dabigatran (150\xa0mg or 110\xa0mg twice daily). Apixaban was associated with a significantly lower incidence of all bleeding outcomes compared with rivaroxaban (intracranial haemorrhage, major bleeding, gastrointestinal bleeding, other major bleeding, clinically relevant non-major bleeding, any bleeding). Apixaban had a significantly lower incidence of all bleeding events except intracranial haemorrhage and clinically relevant non-major bleeding (which was not measured in RE-LY) than dabigatran 150\xa0mg. Apixaban had a significantly lower incidence of any bleeding than dabigatran 110\xa0mg. In addition, apixaban was associated with significantly fewer discontinuations compared with dabigatran 150\xa0mg, dabigatran 110\xa0mg and rivaroxaban. All of the hazard ratios from the first network meta-analysis are academic-in-confidence. The manufacturer reported that the results for apixaban compared with warfarin generated by the first meta-analysis were consistent with the pair-wise comparisons between warfarin and apixaban in ARISTOTLE (see sections 3.3\xa0and 3.5).\n\nThe manufacturer conducted 2\xa0sensitivity analyses of its first network meta-analysis. The first used data from a later publication of RE-LY (Connolly et al. 2010) rather than the RE-LY 2009\xa0data. The results for the first sensitivity analysis were generally consistent with the base case, however the reduction in myocardial infarction with apixaban compared with both doses of dabigatran was no longer statistically significantly different. The second sensitivity analysis used the safety on-treatment dataset from ROCKET-AF rather than the intention-to-treat data from this trial, which was also generally consistent with the base case. The hazard ratios from the sensitivity analysis of the manufacturer's first network meta-analysis are academic-in-confidence.\n\nThe manufacturer commented that there were no data for rivaroxaban or dabigatran in the population for whom warfarin was unsuitable, so data from ROCKET-AF (which assessed rivaroxaban compared with warfarin) and RE-LY (which assessed dabigatran compared with warfarin) were included, alongside ARISTOTLE and AVERROES. This meant that the second meta-analysis represented a mix of patients for whom warfarin was suitable and unsuitable ('warfarin-suitable' and '-unsuitable' populations).\n\nThe manufacturer also used data from ARISTOTLE, RE-LY and ROCKET-AF to estimate the distribution of stroke severity and bleed type associated with apixaban, warfarin, rivaroxaban and dabigatran. Mild, moderate, severe and fatal stroke were classified by modified Rankin scores, with scores of 0\xa0to 2\xa0classed as a mild stroke, scores of 3\xa0to 4\xa0classed as a moderate stroke, a score of 5\xa0classed as a severe stroke and a score of 6\xa0classed as a fatal stroke. Data corresponding to these modified Rankin scores were available for apixaban and warfarin from ARISTOTLE, but ROCKET-AF and RE-LY grouped stroke severity scores differently. The manufacturer therefore estimated the proportion of patients that would be expected to have scores of 3\xa0to\xa04 or 5\xa0in the group of patients reported as having a stroke with a modified Rankin score of 3\xa0to 5\xa0with rivaroxaban or dabigatran in ROCKET-AF and RE-LY. The manufacturer based this estimate on the relative proportions of patients treated with apixaban who had these scores in ARISTOTLE. The distribution of stroke severity across treatments in the population for whom a VKA antagonist was suitable is academic-in-confidence.\n\nThe manufacturer constructed a Markov model to evaluate the long- and medium-term consequences of apixaban for preventing stroke and systemic embolism in people with atrial fibrillation. The model considered warfarin-suitable and -unsuitable populations separately. The baseline characteristics of both populations were considered to be equivalent to the characteristics of a cohort of\xa0patients with a diagnosis of atrial fibrillation from a UK GP-based survey (Gallagher et al. 2011). Data from both network meta-analyses were used to inform the clinical effectiveness of treatments in the warfarin-suitable and -unsuitable populations respectively and to derive the transition probabilities used in the model. The risk of stroke was adjusted for baseline CHADS2\xa0score distribution. The risks of stroke, intracranial haemorrhage, myocardial infarction, other major bleeds and clinically relevant non-major bleeds were adjusted for age. The model had a lifetime time horizon. The intervention and comparators were implemented in the model according to their marketing authorisations. For dabigatran 150\xa0mg it was assumed that patients would switch to the 110\xa0mg dose when they reached 80\xa0years in line with the marketing authorisation. The average dosage of warfarin in the warfarin-suitable population was assumed to be 4.5\xa0mg once daily. The evaluation was undertaken from the perspective of the NHS and Personal Social Services in England and Wales, and costs and benefits were discounted at 3.5% per year after the first year.\n\nThe model had 18\xa0health states, including death. Both event-related mortality and other-cause mortality were incorporated in the model. Hypothetical patients transitioned between health states in cycles of 6\xa0weeks with only 1\xa0clinical event permitted per cycle. Patients entered the model in the non-valvular atrial fibrillation ('NVAF') health state, and stayed in this state until they died or experienced 1\xa0of the following permanent events: ischaemic stroke (mild, moderate, severe or fatal); haemorrhagic stroke (mild, moderate, severe or fatal); systemic embolism or myocardial infarction; or 1\xa0of the following temporary events: other intracranial haemorrhage (that is not a haemorrhagic stroke); other major bleeds (gastrointestinal bleeds or other bleeds besides intracranial haemorrhage and gastrointestinal-related bleeds); clinically relevant non-major bleeds; or other cardiovascular hospitalisations (that is, cardiovascular hospitalisations unrelated to stroke or myocardial infarction). The model allowed a maximum of 2\xa0lines of therapy. After a switch to second-line therapy,\xa0patients transitioned into the 'NVAF without original anticoagulant' health state and were at risk of the same events as\xa0patients in the 'NVAF' health state (with the exception of the switch to second-line therapy).\n\nThe manufacturer classified the events as permanent or temporary.\xa0Patients who experienced a permanent event accrued both acute and long-term maintenance costs and were not assumed to recover to their previous level of health. After a permanent event, patients in the model were not exposed to the risks of all events: patients who had systemic embolism or myocardial infarction stayed in those health states until they died; patients who had a non-fatal stroke could remain in that health state, have 1\xa0recurrent stroke or die. Recurrent strokes were assumed to be of the same type as the initial event (ischaemic or haemorrhagic) but could be of different severity. The resource use and disutility associated with the second stroke was assumed to be equal to that of the most severe stroke experienced. After a temporary event, all\xa0patients were assumed to recover to their previous health status.\n\nA switch from first-line to second-line therapy was permitted after discontinuation because of a clinical event (intracranial haemorrhage or other major bleed) or after discontinuation because of other causes. Patients could switch to aspirin or have no treatment. In the base case, anyone who discontinued treatment was assumed to receive aspirin as second-line treatment. Only a switch from first-line anticoagulation therapy to second-line therapy with aspirin altered patients' risk of subsequent clinical events. Patients who experienced certain permanent events also switched treatment: patients who had a myocardial infarction or haemorrhagic stroke were assumed to stop treatment, and patients receiving aspirin as second-line therapy switched to warfarin if they had an ischaemic stroke or systemic embolism. However, all other patients who had ischaemic stroke or systemic embolism were assumed to remain on their original treatment in the base case. The risk of subsequent events for\xa0patients after a permanent event was assumed to be independent of treatment received, so switching did not affect their risk profile.\n\nThe manufacturer conducted a systematic review of health-state utility value studies relevant to the health states considered in the model, focusing on studies that reported EQ-5D values. Values from 21\xa0studies that presented EQ-5D data in a population with atrial fibrillation and 3\xa0studies that reported EQ-5D values for a variety of chronic conditions after controlling for comorbidities were included. As there were some health states for which a utility value had not been identified, studies of a population with atrial fibrillation that reported utilities elicited by methods other than the EQ-5D were screened, and data from a further 8\xa0studies were included. One further study was identified from the reference list from the submissions for:\n\nNICE's technology appraisal guidance 249 on dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation and\n\nNICE's technology appraisal guidance 256 on rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation.\n\nThe manufacturer used unit costs taken from NHS reference costs 2010/11\xa0where possible. If available, Healthcare Resource Group codes specified in the costing report for atrial fibrillation from NICE's clinical guideline 36\xa0on the management of atrial fibrillation were used. The average daily drug acquisition costs were £2.20\xa0for apixaban, £2.20\xa0for dabigatran (either dose), £2.10\xa0for rivaroxaban and £0.12\xa0for warfarin (4.5\xa0mg average daily dose). The manufacturer's model included intervention costs such as an annual INR monitoring cost of £248, which was an inflated estimate of the ERG's calculation in technology appraisal guidance 249, and a £3\xa0renal monitoring cost for 19.4% of patients treated with dabigatran. The manufacturer used NHS reference costs for acute costs per episode for the temporary health states. The acute and long-term costs for systemic embolism and stroke were taken from a UK population-based assessment. Dyspepsia was the only adverse event that was not explicitly modelled as a health state, and a yearly cost of £27.60\xa0was applied to all patients who had dyspepsia.\n\nThe manufacturer presented a deterministic base case for the warfarin-suitable and -unsuitable populations. In the population for whom warfarin was suitable, the ICER for apixaban compared with warfarin was £11,008\xa0per QALY gained. This represented a gain of 0.164\xa0QALYs for an incremental cost of £1795. Dabigatran 110\xa0mg twice daily was strictly dominated (was more costly and less effective) than the dabigatran blend (dabigatran used as per its marketing authorisation, that is, people who are younger than 80\xa0years receive a 150\xa0mg twice daily dose and people 80\xa0years or older receive a 110\xa0mg twice daily dose). Apixaban extendedly dominated rivaroxaban and the dabigatran blend (resulted in a lower ICER compared with warfarin despite having higher total QALYs and total costs than rivaroxaban and the dabigatran blend).\n\nAlthough aspirin was not included as a comparator in the scope, the manufacturer compared apixaban with aspirin in a population for whom warfarin was unsuitable. In this population apixaban was associated with an ICER of £2903\xa0per QALY gained compared with aspirin.\n\nThe manufacturer assessed the univariate sensitivity of the model to 117\xa0parameters using deterministic sensitivity analyses. In the warfarin-suitable population, parameters that had the most influential effect on the ICER for apixaban compared with warfarin were disutility associated with warfarin use, the hazard ratios for intracranial haemorrhage, ischaemic stroke or other-cause mortality during the trial, the cost of INR monitoring visit and the discount rate applied to QALYs. For apixaban compared with rivaroxaban or dabigatran, the most influential parameters were the hazard ratios associated with stroke, intracranial haemorrhage and other-cause mortality during the trial for these comparators compared with apixaban, the absolute stroke risk for apixaban, and the second-line stroke risk for aspirin. All of the ICERs calculated in the manufacturer's deterministic sensitivity analysis for apixaban compared with the comparator drugs were below £20,000\xa0per QALY gained. In addition, the manufacturer carried out 19\xa0scenario analyses. The majority of the scenario analyses decreased the base-case ICER (for apixaban compared with comparator). The probabilistic sensitivity analysis indicated that the probability that apixaban was cost effective at £20,000\xa0and £30,000\xa0per QALY gained was 80% and 87% respectively. For the dabigatran blend, rivaroxaban and warfarin the probabilities of being cost effective at £20,000\xa0were 10%, 9% and 1% respectively. At £30,000\xa0these were 5%, 7% and 0% respectively.\n\nThe ERG considered that, of the 2\xa0trials of apixaban, only ARISTOTLE met the inclusion criteria for this technology appraisal, although it did acknowledge that aspirin is sometimes used in clinical practice in the UK. With respect to the network meta-analyses, the ERG did not consider the second analysis to be appropriate to determine the relative effectiveness of aspirin, apixaban, rivaroxaban and dabigatran in a population for whom vitamin K antagonists were unsuitable because the majority of trials in the second network meta-analysis included patients for whom warfarin was suitable. The ERG therefore focused its critique on the ARISTOTLE trial and the first network meta-analysis which compared the safety and efficacy of apixaban with warfarin, rivaroxaban and dabigatran.\n\nThe ERG considered that the inclusion and exclusion criteria, follow-up and statistical analysis of ARISTOTLE were acceptable and that the baseline characteristics of the randomised populations were well balanced between trial arms. The ERG commented that, based on advice given by clinicians on the time in therapeutic range expected in a UK population, the mean time in therapeutic range in ARISTOTLE (62.2%) was acceptable. It also considered the INR monitoring in ARISTOTLE to be consistent with that which would occur routinely in the UK. The ERG additionally considered that the distribution of CHADS2\xa0scores in ARISTOTLE was comparable to the UK population. However, the ERG highlighted that no data on transient ischaemic attack or health-related quality of life were collected in ARISTOTLE or AVERROES, and that the effectiveness of apixaban in reducing transient ischaemic attacks and improving health-related quality of life was therefore unclear.\n\nThe ERG noted that the results of the manufacturer's base case were generated deterministically rather than probabilistically. Therefore the ERG used the manufacturer's probabilistic sensitivity analysis to estimate the manufacturer's probabilistic base case. The ICER for apixaban compared with warfarin in the probabilistic base case was £16,852\xa0per QALY gained. The ERG considered that the manufacturer had presented a robust and predominantly conservative (direction of bias more likely to be against rather than towards apixaban) economic evaluation of apixaban compared with warfarin, dabigatran 110\xa0mg, dabigatran blend and rivaroxaban in the warfarin suitable population. However, the ERG commented on the plausibility of some of the assumptions and inputs used in the manufacturer's model. The ERG considered whether certain outcomes would be expected to be dependent on the treatment a person received. It noted that severity of stroke event and bleed type was assumed to be dependent on the treatment received. The ERG considered that this may not be clinically appropriate and that there may be limitations to the data that informed these assumptions. The ERG also noted that the within-trial rate of other-cause mortality was different for\xa0patients treated with warfarin than apixaban, dabigatran or rivaroxaban. Although\xa0patients treated with warfarin may be at a higher risk of event-specific death, the ERG did not expect that they would be at a different risk of other-cause mortality.\n\nThe ERG noted that patients who had a stroke (haemorrhagic or ischaemic), systemic embolism or myocardial infarction were assumed to be at risk of fewer types of subsequent clinical events than patients in other health states. The ERG accepted the risk limitation applied to patients who experienced a stroke but that patients with systemic embolism or myocardial infarction would remain at risk of further events (in particular ischaemic stroke). The ERG considered that some people who stop therapy with apixaban, dabigatran or rivaroxaban may be eligible for treatment with warfarin or a different oral anticoagulant rather than aspirin which was the second-line treatment in the manufacturer's model. The ERG additionally commented that the risk profile of people on second-line therapy was not adjusted for characteristics such as age or CHADS2\xa0score in the manufacturer's model, but it accepted that adjusting for characteristics in second-line treatment may be beyond the reasonable scope of a Markov model.\n\nThe ERG commented that utilities were not age adjusted in the manufacturer's model, meaning that a person's quality of life would be affected by events experienced but not by increasing age. The ERG considered that the assumption of equivalent disutility between the apixaban, rivaroxaban and dabigatran may not be robust but that any resultant bias was likely to be against apixaban.\n\nThe ERG noted that the acute cost of systemic embolism in the manufacturer's model (£4077.98) was approximately double the acute costs used in the submissions for NICE technology appraisal guidance 249\xa0(dabigatran £2772\xa0[fatal and non-fatal acute costs]) and NICE technology appraisal guidance 256\xa0(rivaroxaban £1658). These submissions had used NHS reference costs.\n\nFor its revised base case the ERG changed some of the assumptions used in the manufacturer's model. The ERG assumed that other-cause mortality, stroke severity and bleed type were independent of the type of anticoagulant treatment received. The ERG adjusted utility for increasing age by -0.00029\xa0per year. The ERG assumed that people who had myocardial infarction or systemic embolism were at risk of recurrent stroke, and used the same acute costs for systemic embolism as in NICE technology appraisal guidance 256, as this was the most conservative cost used in the submissions for NICE technology appraisal guidance 256\xa0and 249. The ERG also assumed the time horizon was 26\xa0years.\n\nThe ERG noted that after these amendments, dabigatran 110\xa0mg continued to be strictly dominated by the dabigatran blend and rivaroxaban and the dabigatran blend remained extendedly dominated by apixaban. The ICER for apixaban compared with warfarin for each individual amendment was relatively consistent with the manufacturer's base-case ICER. The ERG noted that assuming stroke severity was independent of treatment increased the ICER of apixaban compared with warfarin to £12,277\xa0per QALY gained, whereas assuming bleed type was independent of treatment decreased this ICER to £9771\xa0per QALY gained. When all of the amendments were combined to form the ERG's revised base case, this resulted in an ICER for apixaban compared with warfarin of £12,757\xa0per QALY gained. This represented an incremental cost of £1823\xa0compared with warfarin for an additional 0.14\xa0QALY.\n\nThe ERG carried out 3\xa0further exploratory analyses that were not included in its revised base case. These were:\n\nAge adjustment of event risks for people on second-line therapy, using the same risk adjustment factors as for people receiving first-line therapy. Dabigatran blend and rivaroxaban continued to be extendedly dominated by apixaban. The ICER for apixaban compared with warfarin fell slightly from the manufacturer's base case of £11,008\xa0to £10,779\xa0per QALY gained.\n\nRemoval of treatment-related disutility. Dabigatran blend and rivaroxaban continued to be extendedly dominated by apixaban but the ICER for apixaban compared with warfarin increased from £11,008\xa0to £14,530\xa0per QALY gained.\n\nChanges to the treatment sequence to allow second-line treatment with warfarin, apixaban, rivaroxaban or dabigatran. The results of these analyses were highly variable, with ICERs for apixaban varying between £287\xa0per QALY gained (compared with warfarin when dabigatran 110\xa0mg was the second-line treatment) and £60,366\xa0per QALY gained (compared with dabigatran blend when rivaroxaban was the second-line treatment). However, the ERG commented that the results of this analysis should be interpreted with caution because the main driver of the ICERs was discontinuation rates associated with first-line therapy and, consequently, treatments with higher discontinuation rates such as dabigatran appeared more effective than in the manufacturer's base case.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of apixaban, having considered evidence on the nature of non-valvular atrial fibrillation and the value placed on the benefits of apixaban by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from clinical specialists and patient experts that the current standard treatment for people with non-valvular atrial fibrillation who need anticoagulation is warfarin or the newer oral anticoagulants rivaroxaban or dabigatran. The clinical specialists explained that the majority of people receiving an anticoagulant currently receive warfarin. In addition, some people who meet criteria for anticoagulation are currently receiving the antiplatelet agent aspirin inappropriately because of clinical reluctance to prescribe warfarin. The Committee heard that warfarin is an effective treatment but that it is associated with a number of problems. The patient experts explained that repeated INR monitoring tests with warfarin can cause pain and scarring and limit a person's choice of leisure or other activities and that warfarin can have a greater impact on a person's quality of life than atrial fibrillation itself. They also highlighted that warfarin has multiple interactions with food, alcohol and drugs that can cause further inconvenience that make adherence to treatment difficult. Overall, the patient experts considered that making the day-to-day choices about lifestyle needed in order to take and monitor warfarin appropriately has a substantial impact on a person's quality of life. The Committee accepted the limitations of warfarin therapy and the considerable effect it may have on the people who take it, and recognised the potential benefits of apixaban for people with atrial fibrillation.\n\nThe Committee considered the clinical-effectiveness data from the ARISTOTLE trial comparing apixaban with warfarin. It considered that the ARISTOTLE trial was of good quality and it discussed whether the results were generalisable to people diagnosed with atrial fibrillation in the NHS. The Committee noted that the mean time in therapeutic range for those in the warfarin arm was 62.2% (the median was 66%) and asked the clinical specialists whether this was representative of what would be achieved in clinical practice in the UK. The clinical specialists explained that there is variation in time in therapeutic range achieved between centres. One clinical specialist quoted a benchmarking study using a computerised dose adjustment system in which a mean time in therapeutic range of over 70% was achieved. Another clinical specialist stated that the time in therapeutic range observed in ARISTOTLE reflected what is generally seen in the UK, not what is observed in centres achieving the best time in therapeutic range, and that centres should aim for a time in therapeutic range for each individual of 70% and above. One clinical specialist also highlighted that in their experience people treated for atrial fibrillation tended to be older and more likely to be on non-steroidal anti-inflammatory drugs (NSAIDS), which can impact on bleeding complications, than the ARISTOTLE population. The Committee noted the potential differences between the trial population and people treated for atrial fibrillation in the UK but concluded that the characteristics of the people who participated in ARISTOTLE were broadly generalisable to the UK population.\n\nThe Committee considered the results of the ARISTOTLE trial. It noted that apixaban was more effective than warfarin in reducing the primary efficacy outcome of all stroke (ischaemic and haemorrhagic), and systemic embolism. The Committee noted that the primary efficacy outcome was a composite of the effectiveness outcomes (ischaemic stroke and systemic embolism) and a bleeding outcome (haemorrhagic stroke). The Committee heard from the clinical specialists that there is debate about the primary outcomes to use in trials of anticoagulants for atrial fibrillation, but that it is common to use composite outcomes, such as the primary efficacy outcome in ARISTOTLE. The Committee considered the individual components of the composite outcome. It heard from the clinical specialists that once an embolus leaves the heart it is a matter of chance whether it flows to the brain, resulting in ischaemic stroke, or to the rest of the body, causing systemic embolism. The proportion of each was therefore not a treatment effect. The Committee also heard from the clinical specialists that a particular benefit conferred by the new anticoagulants compared with warfarin was the reduction in haemorrhagic strokes. This was also shown in the ARISTOTLE trial, in which there was a statistically significant reduction in haemorrhagic stroke with apixaban compared with warfarin, whereas for the other individual components of the composite end points (ischaemic stroke and systemic embolism) there was no statistically significant difference. The Committee concluded that apixaban was more clinically effective than warfarin for the primary efficacy outcome of reducing stroke and systemic embolism.\n\nThe Committee considered the results of the manufacturer's subgroup analyses from ARISTOTLE. It noted that the subgroup analysis by CHADS2\xa0score comprised 3\xa0groups: people with a CHADS2\xa0score of 1\xa0or less, people with a CHADS2\xa0score of 2\xa0and people with a CHADS2\xa0score of 3\xa0or over. The Committee was aware that the ERG had concerns that because people with CHADS2\xa0scores of 3\xa0to\xa06 had been grouped together, it was not possible to comment on potential variation in treatment effect for these subgroups. The Committee concluded that there was no biologically plausible reason to indicate that the relative treatment effect would be dependent on baseline risk and that the mean CHADS2\xa0score of 2.1\xa0in the trial was a reasonable reflection of the UK population currently on anticoagulant therapy.\n\nThe Committee noted that the manufacturer presented data for subgroups based on INR control using quartiles of centre time in therapeutic range. It further noted that there was a numerically lower rate of stroke or systemic embolism with apixaban compared with warfarin in all analyses broken down by centre time in therapeutic range, but that ARISTOTLE was not statistically powered to demonstrate superiority across subgroups. The Committee concluded that the evidence from subgroups based on centre time in therapeutic range was not sufficiently robust to use to formulate guidance based on an individual's time in therapeutic range.\n\nThe Committee considered the adverse events reported in ARISTOTLE. The Committee noted that for the primary safety outcome of major bleeding (using the International Society on Thrombosis and Haemostasis definition), treatment with apixaban resulted in fewer bleeding events than warfarin, including a reduced rate of intracranial bleeding. The Committee recognised that this has a high mortality rate and a large impact on a person's quality of life, and is the most feared bleeding outcome for people taking any type of anticoagulant. The Committee noted however that there were no statistically significant differences in the rates of gastrointestinal bleeding between apixaban and warfarin. The Committee concluded that apixaban resulted in fewer bleeds than warfarin and it recognised the particular importance of the effects of apixaban in reducing the risk of intracranial bleeding for people with atrial fibrillation when compared with warfarin.\n\nThe Committee noted that all anticoagulants are associated with a risk of bleeding and discussed the management of atrial fibrillation in people who experience a bleed while taking warfarin or apixaban. The Committee heard from the clinical specialists that people taking warfarin who experience a bleed may be given vitamin K to reverse the effects of warfarin. However, there are no standard treatments to reverse the effects of apixaban (or the other newer oral anticoagulants rivaroxaban and dabigatran) and that this is an area of ongoing research. Current clinical opinion is that the newer oral anticoagulants have moderate half-lives and that people who have bleeds while taking these drugs should stop treatment. The Committee also heard from the patient experts and the clinical specialists that reversing the effect of warfarin with vitamin K may take several hours, but that there are other approaches, such as using a prothrombin concentrate, that are fast-acting. The Committee concluded that there is a standard approach to reverse significant bleeding for a person taking warfarin, but that there is uncertainty about the most effective way to stop active bleeding when a person is taking apixaban.\n\nThe Committee noted that the manufacturer had included evidence on the efficacy of apixaban compared with aspirin for people for whom vitamin K antagonist treatment was unsuitable, but that this was not part of the scope issued by NICE. The Committee understood that the manufacturer's rationale for including aspirin as an additional comparator reflected the recommendation in NICE clinical guideline 36 that people who need anticoagulation but for whom warfarin is unsuitable should be offered aspirin. The Committee was also aware that aspirin had not been included as a comparator in the apixaban scope because, since the publication of NICE clinical guideline 36, dabigatran and rivaroxaban had been recommended for use by NICE and these were now alternative treatments to warfarin. The Committee heard from the clinical specialists that aspirin is a less effective treatment than the anticoagulants but is still being prescribed for some people with atrial fibrillation despite publication of NICE technology appraisal guidance 249\xa0and 256. The Committee further heard that although AVERROES was a useful trial, the population for whom warfarin was unsuitable was very mixed, including people for whom warfarin was clinically unsuitable and those who were unwilling to take it. The Committee noted that the ERG did not consider that AVERROES met the inclusion criteria for this appraisal and had focused its critique on ARISTOTLE. The Committee agreed that the comparators defined in the final scope were appropriate and that the key trial for this appraisal was ARISTOTLE. However, it noted with interest that the evidence presented in AVERROES showed that apixaban was associated with a reduced rate of stroke or systemic embolism compared with aspirin and an increased rate of bleeding events overall, but not an increased rate of major bleeds.\n\nThe Committee discussed the indirect clinical-effectiveness evidence for apixaban compared with dabigatran (both the 110\xa0mg twice daily dose and 150\xa0mg twice daily dose) and rivaroxaban. The Committee noted that the manufacturer presented 2\xa0network meta-analyses for vitamin K antagonist-suitable and -unsuitable populations (which included aspirin) respectively. The Committee noted that the ERG considered the second meta-analysis to be flawed as there were no specific data available for rivaroxaban or dabigatran for a warfarin-unsuitable population and the network meta-analysis included a mixed population including people for whom warfarin was suitable and unsuitable. The Committee considered that only the first network meta-analysis, relating to the warfarin-suitable population, was appropriate to the decision problem. The Committee noted that the population in the study comparing rivaroxaban with warfarin (ROCKET-AF) had a higher mean baseline CHADS2\xa0score than the population in the study comparing dabigatran with warfarin (RE-LY) or ARISTOTLE. The Committee additionally noted that the mean time in therapeutic range in the warfarin arm was lower in ROCKET-AF than in RE-LY or ARISTOTLE. The Committee considered that the differences in baseline characteristics between the study populations meant that there was uncertainty surrounding the results of the network meta-analysis. The Committee noted that the network meta-analysis did not detect any difference between apixaban, rivaroxaban and dabigatran in the rate of stroke or systemic embolism; showed a lower rate of all bleeding outcomes with apixaban compared with rivaroxaban and of all bleeding outcomes except intracranial haemorrhage and clinically relevant non-major bleeding (which was not measured in RE-LY) compared with dabigatran 150\xa0mg; a lower rate of 'any bleeding' compared with dabigatran 110\xa0mg; and a lower rate of myocardial infarction with apixaban compared with dabigatran (both doses). The Committee noted that the network meta-analysis had shown broadly similar outcomes and some differences between apixaban, rivaroxaban and dabigatran, but because of differences in the trial populations the results of the network meta-analysis should be viewed with caution. It also noted that some of the criteria in the network meta-analysis were in fact not a direct treatment effect, such as the proportion of ischaemic stroke compared with systemic embolism, and evidence was lacking that the severity of an ischaemic or haemorrhagic stroke was treatment specific for the new agents. The Committee concluded that the network meta-analysis results should be interpreted in the light of these uncertainties and were not sufficiently robust to reliably differentiate between apixaban, rivaroxaban and dabigatran.\n\nThe Committee considered the manufacturer's economic model and the exploratory analyses performed by the ERG. It agreed with the ERG that the general modelling approach was reasonable and consistent with other analyses of atrial fibrillation treatments. The Committee noted the discussion on the proportion of ischaemic stroke compared with systemic embolism being unrelated to the treatment (see 4.4). It also questioned whether the severity of an ischaemic or haemorrhagic stroke was treatment specific (see 3.13). In a previous appraisal the Committee had heard from experts that it was plausible and that there is evidence that strokes on warfarin were likely to be more severe than on dabigatran, but the clinical specialists for the appraisal of apixaban did not put forward any evidence that this had been substantiated and were of the opinion that at least for the newer agents, there was no biologically plausible reason or evidence that the severity of strokes would differ between apixaban, rivaroxaban and dabigatran. The Committee concluded that although the general modelling approach was appropriate, weaknesses included the assumption that whether a person experienced an ischaemic stroke or systemic embolism was treatment related, and that there is currently insufficient evidence to support the assumption in the model that the severity of an ischaemic or haemorrhagic stroke was dependent on the specific anticoagulant agent they had received.\n\nThe Committee considered the utility values used in the model. The Committee noted that ARISTOTLE had not assessed health-related quality of life and that the utility values used in the manufacturer's model were identified through a systematic review. The Committee questioned whether the manufacturer's assumption of a permanent utility decrement following a myocardial infarction was appropriate. However, it accepted the views of the clinical specialists that disutility following a myocardial infarction would not be expected to change substantially after 6\xa0months. The Committee concluded that the utilities used in the model were appropriate.\n\nThe Committee considered the costs used in the model. It noted that the estimates for stroke and systemic embolism were based on a cohort study of a population living in the Oxford area of the UK and that the costs for ischaemic stroke were lower than those for haemorrhagic stroke. The Committee questioned whether the study had been able to estimate haemorrhagic stroke costs accurately given the lower incidence of this event than ischaemic stroke in the population, and whether the higher haemorrhagic stroke costs assumed in the model could have driven the cost-effectiveness results. The Committee heard from the ERG that the haemorrhagic stroke costs were consistent with those used in NICE technology appraisal guidance 249\xa0and 256\xa0and that, as a small proportion of people had a haemorrhagic stroke in the model, other factors such as discontinuation rates drove the cost-effectiveness results to a greater extent than the cost of haemorrhagic stroke. The Committee also noted that an INR monitoring cost of £248\xa0was assumed by the manufacturer, and that this was consistent with the monitoring costs used in NICE technology appraisal guidance 249\xa0(and was updated for inflation). The Committee concluded that the costs used in the model were appropriate.\n\nThe Committee considered the results of the economic model. It noted that the manufacturer's base-case deterministic and probabilistic ICERs for apixaban compared with warfarin were £11,000\xa0and £16,900\xa0per QALY gained respectively, and that the ERG's revised deterministic base case, (see 3.30) resulted in an ICER of £12,800\xa0per QALY gained. The Committee noted that only one of the sensitivity analyses performed by the ERG (in which alternative second-line treatments rather than aspirin were considered, see 3.31) influenced the results substantially. The Committee accepted the ERG's comment that this analysis should be interpreted with caution because the main driver of the ICER was discontinuation rates on first-line treatment. The Committee noted that the ERG's sensitivity analysis assuming stroke severity was independent of treatment had a modest effect on the ICER compared with warfarin (the ICER increased to £12,300\xa0per QALY gained when stroke severity was assumed to be the same for all of the anticoagulants). The Committee concluded that apixaban had been shown to be cost effective compared with warfarin, the most plausible ICER being less than £20,000\xa0per QALY gained, and could be recommended as an option for preventing stroke and systemic embolism for people with non-valvular atrial fibrillation who have 1\xa0or more risk factors for stroke.\n\nThe Committee noted that in the manufacturer's model dabigatran and rivaroxaban had higher ICERs compared with warfarin than the ICER for apixaban compared with warfarin. In addition, in the incremental analysis dabigatran 110\xa0mg twice daily was dominated by the dabigatran blend and the dabigatran blend and rivaroxaban were extendedly dominated by apixaban. However, the Committee was concerned that there was considerable uncertainty about the relative treatment effects and cost effectiveness of apixaban, rivaroxaban and dabigatran arising from differences in the baseline characteristics of the people included in the trials and the relative treatment effects attributed to the individual anticoagulants that informed the network meta-analysis. The Committee concluded that there was insufficient evidence to distinguish between the cost effectiveness of apixaban, dabigatran and rivaroxaban at this time.\n\nFinally, the Committee concluded that the decision about whether to start treatment with apixaban should be made after an informed discussion between the clinician and the person about the risks and benefits of apixaban compared with warfarin, dabigatran and rivaroxaban. For people who are taking warfarin, the potential risks and benefits of switching to apixaban should be considered in light of their level of INR control.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA275\n\nAppraisal title: Apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation\n\nSection\n\nKey conclusion\n\nApixaban is recommended as an option for preventing stroke and systemic embolism within its marketing authorisation.\n\n\n\nThe decision about whether to start treatment with apixaban should be made after an informed discussion between the clinician and the person about the risks and benefits of apixaban compared with warfarin, dabigatran etexilate or rivaroxaban. For people who are taking warfarin, the potential risks and benefits of switching to apixaban should be considered in light of their level of international normalised ratio (INR) control.\n\n\n\nThe Committee concluded that apixaban was more clinically effective than warfarin for the primary efficacy outcome of reducing stroke and systemic embolism.\n\n\n\nThe Committee concluded that apixaban resulted in fewer bleeds than warfarin and it recognised the particular importance of the effects of apixaban in reducing the risk of intracranial bleeding for people with atrial fibrillation when compared with warfarin.\n\n\n\nThe Committee concluded that apixaban had been shown to be cost effective compared with warfarin, the most plausible ICER being less than £20,000\xa0per QALY gained, and could be recommended as an option for preventing stroke and systemic embolism for people with non-valvular atrial fibrillation who have 1\xa0or more risk factors for stroke.\n\n\n\nCurrent practice\n\nClinical need of\xa0patients, including the availability of alternative treatments\n\nThe Committee heard from clinical specialists and patient experts that the current standard treatment for people with non-valvular atrial fibrillation who need anticoagulation is warfarin or the newer oral anticoagulants rivaroxaban or dabigatran. The clinical specialists explained that the majority of people receiving an anticoagulant currently receive warfarin. The clinical specialists said that some people who meet criteria for anticoagulation are currently receiving the antiplatelet agent aspirin inappropriately because of clinical reluctance to prescribe warfarin.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee accepted the limitations of warfarin therapy (for example, the inconvenience, pain and scarring associated with INR monitoring, and the multiple interactions with food, alcohol and drugs) and the considerable effect it may have on the people who take it, and recognised the potential benefits of apixaban for people with atrial fibrillation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nApixaban is used as an alternative to warfarin, rivaroxaban and dabigatran and is an anticoagulant treatment for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation with 1\xa0or more risk factors for stroke.\n\n\n\nAdverse reactions\n\nThe Committee concluded that apixaban resulted in fewer bleeds than warfarin and it recognised the particular importance of the effects of apixaban in reducing the risk of intracranial bleeding for people with atrial fibrillation when compared with warfarin.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered the clinical-effectiveness data from the ARISTOTLE trial comparing apixaban with warfarin.\n\n\n\nThe Committee noted that the manufacturer had included evidence on the efficacy of apixaban compared with aspirin for people for whom vitamin K antagonist treatment was unsuitable, which was not part of the scope issued by NICE. The Committee agreed that the comparators defined in the final scope (warfarin, rivaroxaban and dabigatran etexilate) were appropriate and that the key trial for this appraisal was ARISTOTLE.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee concluded that the characteristics of the people who participated in ARISTOTLE were broadly generalisable to the UK population.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that the network meta-analysis results should be interpreted with caution (for example, because of the differences in baseline characteristics between the study populations) and were not sufficiently robust to reliably differentiate between apixaban, rivaroxaban and dabigatran.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee concluded that the evidence from subgroups based on centre time in therapeutic range was not sufficiently robust to use to formulate guidance based on an individual's time in therapeutic range.\n\n\n\nThe Committee concluded that there was no biologically plausible reason to indicate that the relative treatment effect would be dependent on baseline risk.\n\n\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that apixaban was more clinically effective than warfarin for the primary efficacy outcome of reducing stroke and systemic embolism.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee agreed with the ERG that the general modelling approach was reasonable and consistent with other analyses of atrial fibrillation treatments.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee concluded that although the general modelling approach was appropriate, weaknesses included the assumption that whether a person experienced a ischaemic stroke or systemic embolism was treatment related, and there is currently insufficient evidence to support the assumption in the model that the severity of an ischaemic or haemorrhagic stroke was dependent on the specific anticoagulant agent they had received.\n\n\n\n\n\nThe Committee was concerned that there was considerable uncertainty surrounding the relative treatment effects and cost-effectiveness of apixaban, rivaroxaban and dabigatran arising from differences in the baseline characteristics of the people included in the trials and the relative treatment effects attributed to the individual anticoagulants that informed the network meta-analysis. The Committee concluded that there was insufficient evidence to distinguish between the cost effectiveness of apixaban, dabigatran and rivaroxaban at this time.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that ARISTOTLE had not assessed health-related quality of life and that the utility values used in the manufacturer's model were identified through a systematic review. The Committee questioned whether the manufacturer's assumption of a permanent utility decrement following a myocardial infarction was appropriate. However, it accepted the views of the clinical specialists that disutility following a myocardial infarction would not be expected to change substantially after 6\xa0months. The Committee concluded that the utilities used in the model were appropriate.\n\nNo health-related benefits were identified that were not included in the economic model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nApixaban is recommended as an option for all people with non-valvular atrial fibrillation within its marketing authorisation. No specific groups of people for whom the technology is particularly cost effective were identified.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted that only one of the sensitivity analyses performed by the ERG (in which alternative second-line treatments rather than aspirin were considered, see 3.31) influenced the results substantially. The Committee accepted the ERG's comment that this analysis should be interpreted with caution because the main driver of the ICER was discontinuation rates on first-line treatment.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that apixaban had been shown to be cost-effective compared with warfarin, the most plausible ICER being less than £20,000\xa0per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNo equalities issues were identified.\n\n–", 'Recommendations for further research ': 'During this appraisal it was noted that there is a need for additional research on the management of bleeds that occur while people are receiving apixaban, rivaroxaban or dabigatran etexilate, as there are no antidotes or established treatments to stop active bleeding for these agents.'}
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Evidence-based recommendations on apixaban (Eliquis) for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation.
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Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation
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Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation
Evidence-based recommendations on rivaroxaban (Xarelto) for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation.
# Recommendations
Rivaroxaban is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with non-valvular atrial fibrillation with one or more risk factors such as:
congestive heart failure
hypertension
age 75 years or older
diabetes mellitus
prior stroke or transient ischaemic attack.
Decide whether to start treatment with rivaroxaban after an informed discussion with the person about its risks and benefits compared with warfarin, apixaban, dabigatran etexilate and edoxaban. For people taking warfarin, consider the potential risks and benefits of switching to rivaroxaban taking into account their level of international normalised ratio (INR) control.# The technology
Rivaroxaban (Xarelto, Bayer HealthCare) is an anticoagulant that directly inhibits activated factor X (factor Xa). Factor Xa is a key component in the formation of blood clots. Rivaroxaban has a UK marketing authorisation for the 'prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors such as: congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, prior stroke or transient ischaemic attack'.
According to the summary of product characteristics, approximately 14% of people treated with rivaroxaban in clinical studies experienced adverse reactions. Bleeding occurred in approximately 3.3% of patients and anaemia in approximately 1% of patients. Other common adverse reactions were nausea and an increase in transaminases. The summary of product characteristics states that the risk of bleeding may be increased in certain patient groups, for example those with uncontrolled severe arterial hypertension and/or those taking other treatments that affect haemostasis. For full details of adverse reactions and contraindications see the summary of product characteristics.
The price of rivaroxaban is £58.80 for a pack of 28 15-mg tablets and £58.80 for a pack of 28 20‑mg tablets (MIMS March 2012). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG).
The main clinical effectiveness evidence came from one multicentre, double-blind randomised controlled trial. The ROCKET-AF trial ('Rivaroxaban once daily oral direct factor Xa inhibitor compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation') compared rivaroxaban with dose-adjusted warfarin. The manufacturer also compared rivaroxaban with aspirin and dabigatran etexilate (110 mg or 150 mg twice a day) using a network meta-analysis in people for whom anticoagulation therapy was considered suitable. The ROCKET-AF trial was designed as double-blind, double dummy trial comparing rivaroxaban (20 mg or 15 mg once a day) with warfarin (target INR of 2.0 to 3.0) for the prevention of stroke and thromboembolic events in people with non-valvular atrial fibrillation at risk of future thromboembolic events. People were randomly allocated to one of the two treatment groups with equal probability (1:1 allocation ratio). The study took place in 45 countries, including the UK, and a total of 14,264 people were enrolled across the two treatment arms (rivaroxaban n = 7131, warfarin n = 7133). Treatment continued until approximately 405 adjudicated primary efficacy end point events had occurred in the per-protocol population on treatment. As a result, the time on treatment varied from patient to patient depending on when they enrolled in the trial. The median duration of treatment was 590 days.
The primary efficacy end point in ROCKET-AF was a composite of stroke (ischaemic and haemorrhagic stroke) and non-central nervous system systemic embolism. The primary safety end point was defined as a composite of major bleeding and clinically relevant non-major bleeding. To show non-inferiority in preventing stroke and non-central nervous system embolism, the upper boundary of the confidence interval of the hazard ratio (HR) for rivaroxaban compared with warfarin had to be less than 1.46. Once non-inferiority was demonstrated for the primary outcome, further analyses investigated superiority of rivaroxaban over warfarin.
More than 50% of people in the trial received treatment for at least 18 months. The median age of study participants was 73 years and 60.3% were men. The majority of the trial population (62.4%) had previously received warfarin therapy and 36.5% had previously received aspirin. Risk of stroke at baseline was classified according to CHADS2 score, which is used to predict the risk of stroke in people with atrial fibrillation. The trial entry criteria included a history of stroke, transient ischaemic attack or systemic embolism, or a CHADS2 score of 2 or more. The mean CHADS2 score was 3.48 for the rivaroxaban group and 3.46 for the warfarin group; 99.98% of the trial population had a baseline CHADS2 score of 2 or more and 86.95% a baseline CHADS2 score of 3 or more. Three participants (0.02% of the trial population) had a baseline CHADS2 score of 1. In the warfarin group the mean time in therapeutic range for the INR range of 2.0 to 3.0 was 55% (58% median). Some variability was observed in time in therapeutic range by region: north America had the highest overall INR control, followed by western Europe, Latin America, Asia Pacific, and eastern Europe.
Three analyses were defined in the manufacturer's submission for the efficacy analysis: the intention-to-treat set (all patients randomised), the safety-on-treatment set (all intention-to-treat patients who had taken at least one dose of the study drug and were followed for events) and the per-protocol set (all intention-to-treat patients excluding those who had major pre-defined protocol deviations). The primary non-inferiority analysis of the ROCKET-AF trial was conducted on the per-protocol and the safety-on-treatment population data sets. The superiority analyses were conducted on the safety-on-treatment population data sets. In addition to these analyses, sensitivity analyses were performed to assess non-inferiority and superiority in the intention-to-treat population. The primary safety analysis was conducted on the safety-on-treatment population data.
Pre-planned subgroup analyses were conducted. These were by region, prior use of vitamin K antagonists (such as warfarin), and history of stroke, transient ischaemic attack, and non-central nervous system systemic embolism. Other subgroups included prior chronic aspirin use, sex, age, family origin, renal function, body mass index, weight, CHADS2 score, congestive heart failure, hypertension, diabetes, type of atrial fibrillation, proton pump inhibitor use at baseline, and prior myocardial infarction. Results were summarised by subgroup based on data from the safety-on-treatment and intention-to-treat populations.
The non-inferiority of rivaroxaban compared with warfarin was demonstrated for the primary outcome (composite of stroke and non-central nervous system systemic embolism) in both the per-protocol and safety-on-treatment populations. The results for the per-protocol population were HR 0.79 (95% confidence interval 0.66 to 0.96) and HR 0.79 (95% CI 0.65 to 0.95) for the safety-on treatment population. Superiority of rivaroxaban over warfarin was also demonstrated in the safety-on-treatment population, but was not demonstrated for this outcome in the sensitivity analysis using the intention-to-treat population data set (HR 0.88, 95% CI 0.75 to 1.03).
For the primary safety end point of major or non-major clinically relevant bleeding, the results from the safety-on-treatment population data for ROCKET-AF suggest a comparable safety profile for rivaroxaban and warfarin, with no statistically significant difference between the two treatments (HR 1.03, 95% CI 0.96 to 1.11). Bleeding sites for the primary safety end point differed between treatment groups. Rivaroxaban was more often associated with bleeding at sites throughout the gastrointestinal tract (3.15% compared with 2.16%, p < 0.001) but intracranial haemorrhage rates were significantly lower with rivaroxaban than with warfarin (0.5% compared with 0.7%, p = 0.02). Following a request from the ERG the manufacturer provided subgroup analyses for the safety-on-treatment and intention-to-treat populations in people who had previously used vitamin K antagonists, people who had not previously used vitamin K antagonists, people with a time in therapeutic range below 60%, and those with a time in therapeutic range above 60%. In the safety-on-treatment population, superiority of rivaroxaban compared with warfarin was demonstrated for the primary outcome (composite of stroke and non-central nervous system systemic embolism) in people who had not previously used vitamin K antagonists (HR 0.72, 95% CI 0.53 to 0.97) but not in people who had previously used vitamin K antagonists (HR 0.84, 95% CI 0.66 to 1.08).
The manufacturer undertook a Bayesian network meta-analysis comparison of rivaroxaban with warfarin, aspirin, no treatment and dabigatran etexilate. The clinical evidence for the rivaroxaban with warfarin comparison was taken from the ROCKET-AF trial. Evidence for the other comparators was obtained from studies found by a systematic literature search. The manufacturer identified 18 studies for inclusion in the network meta-analysis:
-ne comparing rivaroxaban with warfarin
seven comparing aspirin with placebo or control
eight comparing warfarin with aspirin
-ne comparing a vitamin K antagonist with clopidogrel plus aspirin
-ne comparing dabigatran etexilate with warfarin (the RE-LY study). The manufacturer reported network meta-analysis results for the outcomes using the ROCKET-AF safety-on-treatment population data set. At the request of the ERG, the manufacturer also provided the results for the outcomes using the ROCKET-AF intention-to-treat population dataset. The efficacy estimates from this network meta-analysis using the ROCKET-AF safety-on-treatment population data set were used in the manufacturer's cost-effectiveness analyses.
The ERG undertook an exploratory network meta-analysis comparing rivaroxaban with dabigatran etexilate, aspirin, placebo, and adjusted standard dose warfarin. It included data from eight of the 18 studies from the manufacturer's network meta-analysis:
-ne comparing dabigatran etexilate with warfarin
-ne comparing rivaroxaban with warfarin
three comparing aspirin with warfarin
three comparing warfarin with placebo. The ERG judged that including only these eight trials would reduce the amount of heterogeneity in the network. Only dosing strategies that the ERG considered to be comparable were included (that is, rivaroxaban 20 mg per day, dabigatran etexilate 150 mg twice a day, aspirin 300 mg per day, and adjusted dose warfarin aiming at a target INR range between 2 and 3). Dabigatran etexilate at a dose of 110 mg twice daily was not included in the analysis because the economic model could not accommodate a dosing regimen in which the dose is reduced from 150 mg twice daily to 110 mg twice daily when the patient reaches the age of 80 years. A fixed-effect model was used because of the high degree of homogeneity between the included trials. The efficacy estimates from this network meta-analysis were used in the ERG's cost-effectiveness analyses.
The manufacturer developed a Markov model that compares rivaroxaban (20 mg once a day) with warfarin (adjusted dose warfarin at 4.5 mg once a day, target INR 2.5, range 2.0 to 3.0), aspirin (150 mg once a day), dabigatran etexilate (110 mg to 150 mg twice a day) and no treatment. The population in the model is the same as the ROCKET-AF safety-on-treatment population. The model has a lifetime time horizon and a UK NHS perspective.
The model included the following health states:
anticoagulant initiation
stable atrial fibrillation (on or off therapy)
minor stroke (on or off therapy)
major stroke (on or off therapy)
post minor stroke (on therapy)
post major stroke (on therapy)
minor bleed (on or off therapy)
major bleed (on or off therapy)
intracranial bleed (on or off therapy)
post intracranial bleed (on or off therapy)
systemic embolism (on or off therapy)
myocardial infarction (on or off therapy)
post myocardial infarction (on or off therapy)
death.The ROCKET-AF trial results for the safety-on-treatment population were used to inform the efficacy estimates for rivaroxaban compared with warfarin, rivaroxaban compared with warfarin in people whose atrial fibrillation is poorly controlled on warfarin, and the vitamin K antagonist-naive model populations. The characteristics of the population for the analyses of rivaroxaban compared with aspirin, dabigatran etexilate and no treatment were based on the patient characteristics of a UK GP practice-based survey (Gallagher et al. 2008). Efficacy estimates for rivaroxaban compared with dabigatran etexilate and aspirin were obtained from the manufacturer's network meta-analysis.
The manufacturer classified all model events as either transient or permanent depending on associated long-term costs and consequences:
Systemic embolism, minor extracranial bleeds and major extracranial bleeds were assumed to have no lasting clinical or economic consequences and as such were considered transient events in the model.
Minor stroke, major stroke, intracranial bleeding and myocardial infarction were considered by the manufacturer to be permanent events, in the sense that they have lasting clinical and economic consequences. Consequently, the manufacturer developed post-event health states to account for the different risks, costs and utilities associated with surviving a permanent event.
The manufacturer highlighted that increasing age was an important risk factor for ischaemic stroke and systemic embolism, and adjusted the baseline risk of these events to account for patients aging as they move through the model. Risks were calculated using the Framingham risk equations. In the model, a weighted average relative risk (weighted by the proportion of patients in each risk group at initiation) is calculated for each age group and applied to the baseline risk as patients enter that age group. The risks of extracranial bleeding, intracranial bleeding and myocardial infarction were assumed to be independent of time and, therefore, were not adjusted for.
The baseline risk of each event was adjusted according to the treatment regimen the patient was receiving. Patients may stop their primary therapy and switch to a pre-specified secondary therapy at any time, although the risk adjustment applied for the remainder of that cycle is that of the primary therapy. The probabilities of treatment discontinuation for warfarin and rivaroxaban were based on data from the ROCKET-AF trial. The manufacturer assumed that treatment-discontinuation rates for aspirin, dabigatran etexilate and placebo were equivalent to that for rivaroxaban, given the similarity of administration between these interventions.
The health-state utility values and treatment-related utility values in atrial fibrillation were obtained from published sources identified by a systematic literature search. The ROCKET-AF trial did not include a generic measure of health-related quality of life (such as the EQ-5D) that could be used to estimate utilities in the model. The estimates of resources and costs were obtained from NHS reference costs for 2009/10 and systematic literature searching. The manufacturer's model categorised monitoring costs into the following distinct phases: initiation, maintenance, and re-initiation. The manufacturer's model calculated the quarterly cost of initiation, maintenance and re-initiation by taking a weighted average of each cost; the costs of the individual phases were weighted by the proportion of people treated in primary and secondary care, as indicated by the manufacturer's survey. The resulting annual cost estimates for warfarin monitoring were £663 (£448 in primary care and £215 in secondary care) for the first year and £525 (£359 in primary care and £166 in secondary care) for subsequent years.
The manufacturer's base-case analysis of rivaroxaban compared with warfarin used only statistically significant data from the ROCKET-AF safety-on-treatment population. The analysis produced an incremental cost of £740 and a QALY gain of 0.039 resulting in an incremental cost-effectiveness ratio (ICER) of £18,883 per quality-adjusted life year (QALY) gained. The manufacturer also presented the results of four subgroup analyses:
For rivaroxaban compared with warfarin in people whose INR is poorly controlled on warfarin, rivaroxaban dominated (was more effective and cost less) warfarin.
For rivaroxaban compared with warfarin in people who had not previously received warfarin, the ICER was £15,494 per QALY gained.
For rivaroxaban compared with aspirin, the ICER was £2083 per QALY gained.
For rivaroxaban compared with dabigatran etexilate, rivaroxaban dominated dabigatran etexilate. The manufacturer carried out univariate sensitivity analysis on the base case, scenario analyses and subgroup analyses. The main drivers of the model results were consistent across analyses, with the cost of warfarin monitoring in primary care having a major impact on all ROCKET-AF-based analyses. The probabilistic sensitivity analyses indicated that, using the base case, rivaroxaban had a 75% probability of being cost effective at a maximum acceptable ICER of £20,000 per QALY gained and an 88% probability at £30,000 per QALY gained. The manufacturer's scenario analysis of rivaroxaban compared with warfarin used all point estimates from the ROCKET-AF safety-on-treatment population regardless of their statistical significance (that is, both statistically significant and non-statistically significant point estimates were used). The resulting ICER was £8732 per QALY gained.
In the ERG's view, a Markov model was an appropriate choice for modelling the chronic condition of atrial fibrillation. The ERG noted that the manufacturer chose a cycle length of 3 months and that only one event per 3-month cycle was possible because of the nature of the model. The manufacturer acknowledged that, in reality, people may experience more than one event in 3 months, but clinical opinion was that the probability of this would be low. The ERG agreed that assuming one event per model cycle was necessary and reasonable. However, the ERG noted that the manufacturer's model also suspends the risk of further events in the subsequent model cycle. The ERG considered that this additional suspension of risk was likely to bias the analysis against the more effective treatment because the overall event rate would be lower, and the potential to demonstrate clinical and economic benefits would also be lower.
The ERG identified the following limitations to the model's structural assumptions and parameter sources:
not separating out the number of hospital visits needed by people who were within and outside recommended INR control
not adjusting risk of bleeding by age; not adjusting utility by age
the source of myocardial infarction risk for people treated with aspirin
-ut of date source of post-myocardial infarction mortality risk
double counting of re-initiation costs of warfarin monitoring
suspending the risk of further events for the subsequent model cycle after an event
excluding transient ischaemic attack as a potential event.
The ERG presented an exploratory analysis in which, if possible, adjustments were made to account for the limitations identified (see section 3.18). The analysis for rivaroxaban compared with warfarin produced an incremental cost of £1134 and a QALY gain of 0.034, resulting in an ICER of £33,758 per QALY gained. Similarly, for warfarin-naive people, after incorporating the ERG's model adjustments, the ICER for rivaroxaban compared with warfarin increased from £15,494 to £29,894 per QALY gained. However, rivaroxaban remained dominant in people whose INR was poorly controlled on warfarin after the ERG's model adjustments were incorporated. The structure of the manufacturer's model meant it wasn't possible to remove risk suspension or add transient ischaemic attack as a potential event. Consequently, the ERG was unable to fully quantify the impact of these limitations on the ICERs. However, the ERG considered that suspending risk and excluding transient ischaemic attack as an event would favour rivaroxaban (that is, the removal of these limitations would decrease the ICER for rivaroxaban compared with warfarin), because warfarin is generally less effective than rivaroxaban (based on the safety-on-treatment population of ROCKET-AF).
In the ERG's view the manufacturer's base-case model is driven by the cost of anticoagulation monitoring rather than the differential effectiveness of rivaroxaban and warfarin. The ROCKET-AF trial showed that, for most outcomes, there was no statistically significant difference between rivaroxaban and warfarin. The ERG highlighted that when the cost of anticoagulation monitoring was separated out by INR range the ICER substantially increased from £18,883 per QALY gained to £27,281 per QALY gained. In addition, the ERG's scenario analysis using the alternative anticoagulation monitoring costs of £242 per person (discussed by the Committee in the ongoing appraisal of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation) increased the ICER to £62,568 per QALY gained.
The ERG was concerned that the trials included in the network meta-analysis presented by the manufacturer to compare rivaroxaban with aspirin and dabigatran etexilate were heterogeneous. The high levels of heterogeneity were not shown when the ERG conducted its own network meta-analysis restricting the network to the comparators specified in the final scope. When the ERG applied the treatment effects estimated by its network meta-analysis to the manufacturer's model, and a full incremental analysis of rivaroxaban, dabigatran etexilate, warfarin and aspirin was conducted, an ICER of £34,680 per QALY gained was obtained for dabigatran etexilate compared with rivaroxaban, whereas rivaroxaban had dominated dabigatran etexilate in the manufacturer's analysis. The ERG applied further adjustments to account for the following limitations:
the absence of a post-systemic embolism health state
not adjusting bleeding risk by age
not adjusting utility by age
-ut of date source of post-myocardial infarction mortality risk
assuming equivalent discontinuation rates. This reduced the ICER to £12,701 per QALY gained for dabigatran etexilate compared with rivaroxaban. Exploratory analysis assuming an equivalent ability of rivaroxaban and dabigatran etexilate to prevent myocardial infarction further decreased the ICER to £3578 per QALY gained for dabigatran etexilate compared with rivaroxaban.
The ERG noted the presence of potential biases in the model, with limitations of risk suspension and the absence of transient ischaemic attack and dyspepsia as adverse reactions. Removing risk suspension is likely to favour dabigatran etexilate whereas including transient ischaemic attack and dyspepsia is likely to reduce the ICER for rivaroxaban compared with dabigatran etexilate. Furthermore, the ERG noted that there is a large amount of uncertainty in the model and that the model is highly sensitive to even small changes to the discontinuation rates. Therefore, the ERG concluded that the results of the probabilistic sensitivity analysis should be taken into account when considering its alternative ICER for dabigatran etexilate compared with rivaroxaban. The probabilistic sensitivity analysis indicated that dabigatran etexilate was dominant in 45% of the 1000 runs and dominated in 35% of runs.
# Manufacturer's additional analyses
The manufacturer provided additional analyses in response to the Appraisal Committee's request for further clarification on the cost effectiveness of rivaroxaban presented in the appraisal consultation document. The manufacturer provided a revised cost-effectiveness analysis incorporating the following amendments requested by the Appraisal Committee:
data from the General Practice Research Database to provide event rates according to baseline level of stroke risk and the distribution of patients with different CHADS2 scores from the study of Gallagher et al. (2008)
all the efficacy point estimates from the safety-on-treatment population of the ROCKET-AF trial
revised event rate in the warfarin arm to reflect the time in therapeutic range achieved in trial centres in western Europe (60.62%)
fixed annual warfarin INR monitoring cost of £242 per person in the sensitivity analysis only.
In addition to the amendments requested by the Appraisal Committee, the manufacturer also amended the model to include the following:
Revised annual warfarin INR monitoring cost of £580. The manufacturer used the same unit costs as the original model; however, the number of visits needed for the re-initiation was reduced from seven to five per 3-month cycle. The costs associated with warfarin monitoring in primary care in the updated model were £175.50 for initiation of warfarin (calculated as a weighted average of patients who had, and had not received previous warfarin), £135 for maintenance on warfarin and £135 for re-initiation of warfarin.
Case fatality rates of 90 days instead of the 30-day rates in the original model.
Updated 'real world' discontinuation rates. For warfarin these came from the General Practice Research Database. For rivaroxaban they were calculated by applying relative risks from the General Practice Research Database to discontinuation rates from the ROCKET-AF trial.
Treatment-related disutility applied to warfarin of 0.05. This was obtained from a study evaluating how patients with atrial fibrillation (attending GP- and hospital-led clinics) value different health outcomes. The disutility figures for warfarin were weighted by the UK distribution of primary and secondary care anticoagulation management.
Updated results for rivaroxaban compared with aspirin based on an additional indirect comparison. This comparison used only trials comparing rivaroxaban with warfarin and warfarin with aspirin, to reduce the network heterogeneity.
The manufacturer presented the following cost-effectiveness results when all the amendments in sections 3.23 and 3.24 were applied, with an annual warfarin INR monitoring cost of £580 (that is, excluding the Appraisal Committee's request to incorporate a fixed annual warfarin INR monitoring cost of £242 per person):
for rivaroxaban versus warfarin in the licensed population (the population with one or more risk factors for stroke), an incremental cost of £705, an incremental QALY of 0.2459 resulting in an ICER of £2869 per QALY gained
for rivaroxaban versus warfarin in the population whose INR is poorly controlled on warfarin, rivaroxaban dominated warfarin
for rivaroxaban versus warfarin in the population for whom warfarin is considered unsuitable, the ICER was £9170 per QALY gained.
The manufacturer presented the following cost-effectiveness results when all the amendments detailed in sections 3.23 and 3.24 were applied, with an annual warfarin INR monitoring cost of £242 per person (that is, including all of the Appraisal Committee's requests):
for rivaroxaban versus warfarin in the licensed population (the population with one or more risk factors for stroke), an incremental cost of £2220, a QALY gain of 0.2459 resulting in an ICER of £9031 per QALY gained
for rivaroxaban versus warfarin in the population whose INR is poorly controlled on warfarin, the ICER was £4350 per QALY gained.
The ERG provided a critique and exploratory analysis of the manufacturer's additional analyses. The ERG agreed that the manufacturer had adequately provided a model cohort representative of people with atrial fibrillation in the UK, and that the analysis was based on all efficacy point estimates from the ROCKET-AF trial. The ERG also agreed that it was reasonable to use a discontinuation rate of five and a 90-day case fatality rate in the model. However the ERG noted that the Committee's request to evaluate the effect of low time in therapeutic range was addressed as an amendment to the base case rather than the subgroup analysis requested. The ERG noted that varying the risk of stroke and systemic embolism according to level of INR control resulted in an increase in the ICER of £3742 per QALY gained.
In the ERG's view, the manufacturer's inclusion of a disutility for warfarin in the model was not appropriate. The ERG noted that the manufacturer had not provided any justification for the assumption that no disutility is associated with rivaroxaban, aspirin or dabigatran etexilate. The ERG pointed out that there is evidence of disutility associated with other oral anticoagulants such as dabigatran etexilate and therefore it is unreasonable to assume there is no disutility associated with rivaroxaban. The ERG found that removing the disutility for warfarin has a substantial impact on the ICER, increasing it from £2869 to £10,764 per QALY gained.
The ERG re-ran the manufacturer's updated cost-effectiveness analysis. The ERG noted that in both the original and updated models the manufacturer had categorised systemic embolism as a temporary event. The ERG judged that in order to adequately approximate a post-systemic embolism health state (which would account for the increased risk of stroke following a systemic embolism) it was appropriate to amend the model so that after a systemic embolism patients move into the post-minor stroke health state. The ERG also noted that the manufacturer's updated model continues to use the out of date source of post-myocardial infarction mortality risk. The ERG judged that it was more appropriate to use an updated mortality risk post myocardial infarction that took account of current use of statins. The ERG's analysis included a fixed annual warfarin INR monitoring cost of £242 per person as requested by the Appraisal Committee (see section 3.23) but did not include any disutility associated with warfarin or any other treatment (see section 3.24). The ERG's revised analysis for rivaroxaban compared with warfarin produced an incremental cost of £1815, an incremental QALY of 0.061 and an ICER of £29,537 per QALY gained.
See the manufacturer's submission and the ERG report for full details of all the evidence.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of stroke and systemic embolism and the value placed on the benefits of rivaroxaban by people with atrial fibrillation, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee was aware that the main concerns for people with atrial fibrillation were fear of having a stroke and anxiety about the difficulty of keeping the INR within the therapeutic range. The Committee heard from the clinical specialists, patient experts and from comments received during consultation that the current standard treatment for preventing stroke and systemic embolism in people with atrial fibrillation is warfarin, and that because aspirin is less effective it is used only in people for whom warfarin is unsuitable. The Committee also heard that warfarin, although an effective treatment, it is associated with a number of problems. The Committee was aware from the patient expert and from comments received during consultation that taking warfarin adversely affects quality of life. This is because people taking warfarin often worry about their level of INR control and they might find regular GP and hospital visits disruptive and inconvenient. The Committee heard from the clinical specialists that a substantial proportion of people taking warfarin have poorly controlled INR and are often not within the target therapeutic range at any one time. In particular, older people with atrial fibrillation are more likely to have poorly controlled INR because of comorbidities. The clinical specialists also explained that the need for regular monitoring and dose adjustments, occasionally involving complicated regimens such as different doses on alternate days, can cause difficulties with adherence to treatment. The Committee recognised the potential benefits of alternatives such as rivaroxaban for people with atrial fibrillation, including the positive effect on quality of life of removing the restrictions and difficulties associated with taking warfarin.
The Committee considered the clinical-effectiveness data from the ROCKET-AF trial comparing rivaroxaban with warfarin. It noted that this study was the basis of the clinical-effectiveness evidence in the manufacturer's submission. The Committee noted that the efficacy analysis in the manufacturer's submission had been undertaken on three different populations in the ROCKET-AF trial, the intention-to-treat set (all randomised patients), the safety-on-treatment set (all intention-to-treat patients who had taken at least one dose of study drug and were followed for events) and the per-protocol set (all intention-to-treat patients excluding those who have major pre-defined protocol deviations). The Committee noted that the manufacturer had presented data from the safety-on-treatment population for its primary analyses. The Committee heard from the clinical specialists that using a trial intention-to-treat population was considered to be the gold standard for estimating clinical effectiveness in a superiority trial, but the primary objective of ROCKET-AF was to establish non-inferiority of rivaroxaban compared with warfarin so the primary analysis was different. The Committee noted the comments received during consultation that suggested that it would be more appropriate to consider the intention-to-treat population rather than the safety-on-treatment population. The Committee reconsidered which of the two study populations was the most appropriate. The Committee noted that the intention-to-treat population included people who had either had no treatment or switched treatment during the trial, and agreed that the estimates derived from the safety-on-treatment population of the ROCKET-AF trial provided an adequate basis for evaluating clinical effectiveness.
The Committee noted that a key uncertainty highlighted by the ERG was the generalisability of the results of ROCKET-AF to people diagnosed with atrial fibrillation in the NHS. The Committee noted that the mean time in therapeutic range for the INR range of 2.0–3.0 for warfarin was 55% for the safety-on-treatment population in the ROCKET-AF trial. The clinical specialists confirmed this could be considered to be around the lower end of the level of control that would be expected in UK clinical practice, but there is considerable variation between different centres and also between different settings, depending on the patient group. The Committee noted that the ROCKET-AF trial had been undertaken in a number of countries, which did not all achieve similar levels of time in therapeutic range. The majority (66.5%) of the participants were recruited from centres in eastern Europe, Latin America and Asia, and in these centres the proportion of time in therapeutic range was lower than in the centres in North America and western Europe. The Committee was concerned that the effectiveness of warfarin could be underestimated if the proportion of time in therapeutic range was low, and that the UK context might be better reflected by results from centres where the time in therapeutic range in the warfarin arm more closely matched the usual levels in the UK. The Committee concluded that the trial results were broadly applicable to a UK setting, but for those already taking warfarin the current level of INR control should be taken into account in any decision to switch to rivaroxaban.
The Committee also noted that patients in the ROCKET-AF trial had a mean CHADS2 score of 3.47, and that an inclusion criterion of the trial was a baseline CHADS2 score of 2 or more. The scope specified that the appraisal population would be people with a medium to high risk of stroke. The clinical specialists confirmed that people with a CHADS2 score of 3 or more would be at high risk of stroke and that this population was typical of people seen in secondary care. However, this did not necessarily represent people with atrial fibrillation treated in primary care, who tended to have a lower risk of stroke. The Committee heard that people with atrial fibrillation treated with warfarin in primary care often have a CHADS2 score of less than 2 and that it is estimated that between 20 and 75% of people with atrial fibrillation and a CHADS2 score of less than 2 are prescribed warfarin in the UK. Only 0.02% of the trial population had a CHADS2 score less than 2. The clinical specialists agreed that it was likely that although people with a CHADS2 score of 2 or more would benefit similarly to those in the ROCKET-AF trial, this cannot be assumed for people with a CHADS2 score of less than 2. The Committee noted the comments received during consultation that suggested that consultees and commentators had differing opinions on the generalisability of the results of ROCKET-AF to UK clinical practice. The Committee was made aware by the manufacturer that a systematic review of the literature had suggested that there does not appear to be an interaction between treatment effect and baseline CHADS2 risk. The Committee heard from the manufacturer that rivaroxaban would be indicated for atrial fibrillation in people with one or more risk factors for stroke, which equates to a CHADS2 score of 1 or more. The Committee noted that the European Medicines Agency had stated in the 'European public assessment report' for rivaroxaban that efficacy results were essentially consistent in important subgroups, such as different CHADS2 scores (CHADS2 scores 2 to 6).The Committee accepted that, given the broad spectrum of risk covered by the licensed indication for rivaroxaban, there was no plausible reason to expect that the results of ROCKET-AF would not translate to people with a lower CHADS2 score. However the Committee was mindful of the very small number of patients recruited to the ROCKET-AF trial with a baseline CHADS2 score of less than 2, but concluded that the results of the ROCKET-AF trial were generalisable to UK clinical practice.
The Committee discussed the safety data from the ROCKET-AF trial. It noted that analysis of the primary safety end point of all major and non-major clinically significant bleeding events showed no significant differences between rivaroxaban and warfarin. There was a significant reduction in the rate of fatal bleeds and intracranial haemorrhage with rivaroxaban compared with warfarin, but a higher rate of gastrointestinal bleeds. The Committee heard from the patient experts that intracranial bleeds were considered to be a more serious complication than gastrointestinal bleeds in clinical practice, because they were more difficult to treat and often result in permanent disability. The Committee noted that the possible uncertainty in these results related to the relatively low proportion of time in therapeutic range of 55% in the warfarin arm of the trial, but concluded that the primary safety end point showed no statistically significant difference between rivaroxaban and warfarin.
The Committee then discussed the indirect clinical-effectiveness evidence for rivaroxaban compared with dabigatran etexilate and aspirin. The Committee noted that the population in the study comparing dabigatran etexilate with warfarin (RE-LY) had a lower risk of stroke (mean CHADS2 score 2.1) than the population in the ROCKET-AF trial (mean CHADS2 score of 3.47). The Committee noted that the manufacturer's interpretation of its network meta-analysis was that there was no significant difference between rivaroxaban and dabigatran etexilate for any outcome. The Committee noted the ERG's concerns about the validity of the manufacturer's network meta-analysis because of the clinical heterogeneity of the included trials, and the different levels of time in therapeutic range in the warfarin arms of the rivaroxaban and dabigatran etexilate trials. The Committee also noted that both the manufacturer's and ERG's network meta-analyses contained wide confidence intervals, and therefore the resulting efficacy point estimates were subject to considerable uncertainty. The Committee noted the comments received during consultation suggesting that the Committee should reconsider the value of the network meta-analysis. The Committee also noted the additional indirect comparison submitted by the manufacturer during consultation comparing rivaroxaban with aspirin. The Committee reconsidered the data from the manufacturer's and ERG's network meta-analyses and considered the manufacturer's additional indirect comparison comparing rivaroxaban with aspirin. The Committee concluded that it would not consider further the clinical effectiveness of rivaroxaban compared with aspirin or dabigatran etexilate.
The Committee considered the manufacturer's updated base-case analysis for rivaroxaban compared with warfarin for the licensed population. The Committee noted the ERG's comments on the manufacturer's updated cost-effectiveness analyses and the ERG's revised base-case analysis. The Committee noted that the manufacturer presented an ICER of £2870 per QALY gained (see section 3.25) and the ERG presented an ICER of £29,500 per QALY gained (see section 3.29). The Committee was made aware by both the manufacturer and the ERG that the difference in the ICERs resulted from two main factors. One was the manufacturer's inclusion in its updated analysis of a disutility value associated with warfarin treatment. The second was the different costs included by the manufacturer and ERG for warfarin monitoring (£580 and £242 respectively).
The Committee discussed the disutility values used in the manufacturer's updated economic analyses. It noted that the manufacturer had used a small study of 57 patients to justify including a disutility associated with warfarin. The Committee acknowledged that comments received during consultation implied that warfarin was associated with disadvantages. However the Committee was mindful that the manufacturer had assumed that there was no disutility associated with rivaroxaban and had not provided any rationale for its exclusion. The Committee noted the comments from the ERG and consultees and commentators suggesting that there could be some disutility associated with newer anticoagulation therapy, including concerns about non-reversibility in the case of bleeding. However, the Committee noted that no specific evidence relating to disutility associated with anticoagulation therapy other than warfarin had been submitted by any consultees and commentators or by the ERG. The Committee therefore agreed that although it was appropriate to consider that there might be a disutility associated with warfarin treatment, it was not appropriate to assume that there was no disutility associated with rivaroxaban and other anticoagulant treatments. The Committee concluded that the disutility value used in the economic model for warfarin may have resulted in a bias in the manufacturer's economic analysis in favour of rivaroxaban.
The Committee discussed the costs associated with warfarin INR monitoring. The Committee noted that the manufacturer' model assumed an average annual anticoagulant monitoring cost of £580 per person in the year that treatment is first initiated and £535 once the person is stabilised on warfarin. The clinical specialists agreed that the annual cost of anticoagulant monitoring for each person treated with warfarin was likely to be lower than the manufacturer's estimate in clinical practice, but a precise estimate could not be given because costs varied considerably between people (for example, they are higher in those with poor INR control) and between centres. The Committee was aware of the uncertainty, but in the interests of consistency had requested that the manufacturer use £242 in its economic model, in line with what it had accepted for the ongoing appraisal of dabigatran etexilate for the same indication. However, the Committee noted the comments received during consultation, which suggested that significant numbers of people have difficulties managing their INR control and could therefore visit a clinic for monitoring up to once a week, making 30 visits a year not implausible. The Committee also noted the manufacturer's comments highlighting its concerns about the plausibility of a cost of £242 per person. The Committee therefore agreed that £242 per person was likely to be a conservative estimate of annual anticoagulant monitoring for warfarin if fixed costs were fully included, and that there was uncertainty about the cost of warfarin INR monitoring in clinical practice.
The Committee considered what the most plausible ICER would be for rivaroxaban compared with warfarin. It noted the ICERs of £2870 per QALY gained presented by the manufacturer (which included disutility associated with warfarin, and warfarin monitoring costs of £580) and £29,500 per QALY gained (which excluded disutility associated with warfarin, and used warfarin monitoring costs of £242) presented by the ERG. The Committee agreed that because there could be some degree of utility decrement associated with treatment, and the estimate of annual anticoagulation monitoring costs of £242 was likely to be conservative, the ICER for rivaroxaban compared with warfarin would be no more than £29,500 per QALY gained and would lie somewhere between £2870 and £29,500 per QALY gained. The Committee therefore concluded that the most plausible ICER for the whole population eligible for rivaroxaban was within the range that could be considered a cost-effective use of NHS resources.
The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.
# Summary of Appraisal Committee's key conclusions
TA256
Appraisal
title:
Rivaroxaban
for
the
prevention
of
stroke
and
systemic
embolism
in
people
with
atrial
fibrillation
Section
Key
conclusion
Rivaroxaban is recommended as an option within its licensed indication for the prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation.
The Committee recognised that decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin, and noting the limited direct trial evidence for people with a low risk of stroke (CHADS2 score of less than 2). For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in light of their level of international normalised ratio (INR) control.
Current
practice
Clinical need of patients, including the availability of alternative treatments
The current standard treatment for the prevention of stroke and systemic embolism in people with atrial fibrillation is warfarin. Because aspirin is less effective, it is used only in people for whom warfarin is unsuitable.
Warfarin is associated with a number of problems such as fear of having a stroke and anxiety about keeping the INR within the therapeutic range. In addition, people taking warfarin often worry about their level of INR control and they might find regular GP and hospital visits disruptive and inconvenient.
A substantial proportion of people taking warfarin have poorly controlled INR and are often not within the target therapeutic range at any one time.
The
technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee recognised the potential benefits of alternatives such as rivaroxaban for people with atrial fibrillation, including the positive effect on quality of life of removing the restrictions and difficulties associated with taking warfarin.
What is the position of the treatment in the pathway of care for the condition?
Rivaroxaban would be used to prevent stroke and systemic embolism in people with atrial fibrillation and one or more risk factor for stroke.
Adverse reactions
The Committee noted the possible uncertainty in the results from the ROCKET-AF trial related to the relatively low proportion of time in therapeutic range of 55% in the warfarin arm of the trial, but concluded that the primary safety end point showed no statistically significant difference between rivaroxaban and warfarin.
Evidence
for
clinical
effectiveness
Availability, nature and quality of evidence
The main clinical-effectiveness evidence came from one multicentre, double-blind randomised controlled trial. The ROCKET-AF trial compared rivaroxaban with dose-adjusted warfarin. The manufacturer also compared rivaroxaban with aspirin and dabigatran etexilate (110 mg or 150 mg twice a day) using a network meta-analysis in people for whom anticoagulation therapy was considered suitable.
The Committee also noted the additional indirect comparison submitted by the manufacturer during consultation comparing rivaroxaban with aspirin.
Relevance to general clinical practice in the NHS
The Committee concluded that the results of the ROCKET-AF trial were generalisable to UK clinical practice. However the Committee also agreed that when treatment with rivaroxaban is being considered, clinicians and patients should be aware that there is limited direct evidence available from the ROCKET-AF trial on the efficacy of rivaroxaban in people with a baseline CHADS2 score of less than 2.
Uncertainties generated by the evidence
The Committee noted that there were differing opinions among consultees and commentators on the generalisability of the ROCKET-AF trial to UK clinical practice.
The Committee agreed that the clinical-effectiveness estimates for rivaroxaban compared with dabigatran etexilate obtained from the network meta-analyses were unreliable
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee heard from the manufacturer that rivaroxaban would be indicated for atrial fibrillation in people with one or more risk factors for stroke, which equates to a CHADS2 score of 1 or more. The Committee noted that the European Medicines Agency had stated in the 'European public assessment report' for rivaroxaban that efficacy results were essentially consistent in important subgroups, such as different CHADS2 scores (CHADS2 scores 2 to 6).The Committee accepted that, given the broad spectrum of risk covered by the licensed indication for rivaroxaban, there was no plausible reason to expect that the results of ROCKET-AF would not translate to people with a lower CHADS2 score.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee was aware that primary objective of the ROCKET-AF was to establish non-inferiority of rivaroxaban versus warfarin.
Evidence
for
cost
effectiveness
Availability and nature of evidence
The manufacturer developed a Markov model that compares rivaroxaban (20 mg once a day) with warfarin (adjusted dose warfarin at 4.5 mg once a day, target INR 2.5, range 2.0 to 3.0), aspirin (150 mg once a day), dabigatran etexilate (110 mg to 150 mg twice a day) and no treatment.
The Committee considered the manufacturer's updated base-case analysis for rivaroxaban compared with warfarin for the licensed population and the ERG's comments on the manufacturer's updated cost-effectiveness analyses and the ERG's revised base-case analysis.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that both the manufacturer and ERG identified the costs associated with warfarin INR monitoring as a major factor affecting the cost-effectiveness estimate in the model.
The Committee noted that the manufacturer had assumed an average annual anticoagulant monitoring cost of £580 per person when treatment is first initiated and £535 once stabilised on warfarin. The Committee had in the interests of consistency requested that the manufacturer use £242 in its economic model, in line with what it had accepted for an ongoing appraisal of dabigatran etexilate for the same indication. The Committee agreed that the estimate of annual anticoagulant monitoring cost of £242 per person for warfarin was likely to be conservative if fixed costs were fully included, and that there was uncertainty about the cost of warfarin INR monitoring in clinical practice.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted the comments from the ERG and consultees and commentators suggesting that there could be some disutility associated with newer anticoagulation therapy, including concerns about non-reversibility in the case of bleeding. However, the Committee noted that no specific evidence relating to disutility associated with anticoagulation therapy other than warfarin had been submitted by any consultees and commentators or by the ERG. The Committee therefore agreed that although it was appropriate to consider that there might be a disutility associated with warfarin treatment, it was not appropriate to assume that there was no disutility associated with rivaroxaban and other anticoagulant treatments.
Are there specific groups of people for whom the technology is particularly cost effective?
None were identified.
What are the key drivers of cost effectiveness?
In the ERG's view the manufacturer's base-case model is driven by the cost of anticoagulation monitoring rather than the differential effectiveness of rivaroxaban and warfarin.
The Committee noted that the manufacturer's model assumed an average annual anticoagulant monitoring cost of £580 per person in the year that treatment is first initiated and £535 once the person is stabilised on warfarin. The clinical specialists agreed that the annual cost of anticoagulant monitoring for each person treated with warfarin was likely to be lower than the manufacturer's estimate in clinical practice.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee considered the most plausible ICER for rivaroxaban compared with warfarin. It noted the ICERs of £2870 per QALY gained presented by the manufacturer (which included disutility associated with warfarin, and warfarin monitoring costs of £580) and £29,500 per QALY gained (which excluded disutility associated with warfarin, and used warfarin monitoring costs of £242) presented by the ERG.
The Committee agreed that because there could be some degree of utility decrement associated with treatment, and the estimate of annual anticoagulation monitoring costs of £242 was likely to be conservative, the ICER for rivaroxaban compared with warfarin would be no more than £29,500 per QALY gained and would lie somewhere between £2870 and £29,500 per QALY gained.
Additional
factors
taken
into
account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
No equalities issues were identified.
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{'Recommendations': 'Rivaroxaban is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with non-valvular atrial fibrillation with one or more risk factors such as:\n\ncongestive heart failure\n\nhypertension\n\nage 75\xa0years or older\n\ndiabetes mellitus\n\nprior stroke or transient ischaemic attack.\n\nDecide whether to start treatment with rivaroxaban after an informed discussion with the person about its risks and benefits compared with warfarin, apixaban, dabigatran etexilate and edoxaban. For people taking warfarin, consider the potential risks and benefits of switching to rivaroxaban taking into account their level of international normalised ratio (INR) control.', 'The technology ': "Rivaroxaban (Xarelto, Bayer HealthCare) is an anticoagulant that directly inhibits activated factor X (factor Xa). Factor Xa is a key component in the formation of blood clots. Rivaroxaban has a UK marketing authorisation for the 'prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors such as: congestive heart failure, hypertension, age 75\xa0years or older, diabetes mellitus, prior stroke or transient ischaemic attack'.\n\nAccording to the summary of product characteristics, approximately 14% of people treated with rivaroxaban in clinical studies experienced adverse reactions. Bleeding occurred in approximately 3.3% of patients and anaemia in approximately 1% of patients. Other common adverse reactions were nausea and an increase in transaminases. The summary of product characteristics states that the risk of bleeding may be increased in certain patient groups, for example those with uncontrolled severe arterial hypertension and/or those taking other treatments that affect haemostasis. For full details of adverse reactions and contraindications see the summary of product characteristics.\n\nThe price of rivaroxaban is £58.80 for a pack of 28 15-mg tablets and £58.80 for a pack of 28 20‑mg tablets (MIMS March 2012). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission ": "The Appraisal Committee considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG).\n\nThe main clinical effectiveness evidence came from one multicentre, double-blind randomised controlled trial. The ROCKET-AF trial ('Rivaroxaban once daily oral direct factor Xa inhibitor compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation') compared rivaroxaban with dose-adjusted warfarin. The manufacturer also compared rivaroxaban with aspirin and dabigatran etexilate (110\xa0mg or 150\xa0mg twice a\xa0day) using a network meta-analysis in people for whom anticoagulation therapy was considered suitable. The ROCKET-AF trial was designed as double-blind, double dummy trial comparing rivaroxaban (20\xa0mg or 15\xa0mg once a\xa0day) with warfarin (target INR of 2.0 to 3.0) for the prevention of stroke and thromboembolic events in people with non-valvular atrial fibrillation at risk of future thromboembolic events. People were randomly allocated to one of the two treatment groups with equal probability (1:1 allocation ratio). The study took place in 45 countries, including the UK, and a total of 14,264 people were enrolled across the two treatment arms (rivaroxaban n\xa0=\xa07131, warfarin n\xa0=\xa07133). Treatment continued until approximately 405 adjudicated primary efficacy end point events had occurred in the per-protocol population on treatment. As a result, the time on treatment varied from patient to patient depending on when they enrolled in the trial. The median duration of treatment was 590\xa0days.\n\nThe primary efficacy end point in ROCKET-AF was a composite of stroke (ischaemic and haemorrhagic stroke) and non-central nervous system systemic embolism. The primary safety end point was defined as a composite of major bleeding and clinically relevant non-major bleeding. To show non-inferiority in preventing stroke and non-central nervous system embolism, the upper boundary of the confidence interval of the hazard ratio (HR) for rivaroxaban compared with warfarin had to be less than 1.46. Once non-inferiority was demonstrated for the primary outcome, further analyses investigated superiority of rivaroxaban over warfarin.\n\nMore than 50% of people in the trial received treatment for at least 18\xa0months. The median age of study participants was 73\xa0years and 60.3% were men. The majority of the trial population (62.4%) had previously received warfarin therapy and 36.5% had previously received aspirin. Risk of stroke at baseline was classified according to CHADS2 score, which is used to predict the risk of stroke in people with atrial fibrillation. The trial entry criteria included a history of stroke, transient ischaemic attack or systemic embolism, or a CHADS2 score of 2 or more. The mean CHADS2 score was 3.48 for the rivaroxaban group and 3.46 for the warfarin group; 99.98% of the trial population had a baseline CHADS2 score of 2 or more and 86.95% a baseline CHADS2 score of 3 or more. Three participants (0.02% of the trial population) had a baseline CHADS2 score of 1. In the warfarin group the mean time in therapeutic range for the INR range of 2.0 to 3.0 was 55% (58% median). Some variability was observed in time in therapeutic range by region: north America had the highest overall INR control, followed by western Europe, Latin America, Asia Pacific, and eastern Europe.\n\nThree analyses were defined in the manufacturer's submission for the efficacy analysis: the intention-to-treat set (all patients randomised), the safety-on-treatment set (all intention-to-treat patients who had taken at least one dose of the study drug and were followed for events) and the per-protocol set (all intention-to-treat patients excluding those who had major pre-defined protocol deviations). The primary non-inferiority analysis of the ROCKET-AF trial was conducted on the per-protocol and the safety-on-treatment population data sets. The superiority analyses were conducted on the safety-on-treatment population data sets. In addition to these analyses, sensitivity analyses were performed to assess non-inferiority and superiority in the intention-to-treat population. The primary safety analysis was conducted on the safety-on-treatment population data.\n\nPre-planned subgroup analyses were conducted. These were by region, prior use of vitamin K antagonists (such as warfarin), and history of stroke, transient ischaemic attack, and non-central nervous system systemic embolism. Other subgroups included prior chronic aspirin use, sex, age, family origin, renal function, body mass index, weight, CHADS2 score, congestive heart failure, hypertension, diabetes, type of atrial fibrillation, proton pump inhibitor use at baseline, and prior myocardial infarction. Results were summarised by subgroup based on data from the safety-on-treatment and intention-to-treat populations.\n\nThe non-inferiority of rivaroxaban compared with warfarin was demonstrated for the primary outcome (composite of stroke and non-central nervous system systemic embolism) in both the per-protocol and safety-on-treatment populations. The results for the per-protocol population were HR\xa00.79 (95% confidence interval [CI] 0.66 to 0.96) and HR 0.79 (95%\xa0CI 0.65 to 0.95) for the safety-on treatment population. Superiority of rivaroxaban over warfarin was also demonstrated in the safety-on-treatment population, but was not demonstrated for this outcome in the sensitivity analysis using the intention-to-treat population data set (HR\xa00.88, 95%\xa0CI 0.75 to 1.03).\n\nFor the primary safety end point of major or non-major clinically relevant bleeding, the results from the safety-on-treatment population data for ROCKET-AF suggest a comparable safety profile for rivaroxaban and warfarin, with no statistically significant difference between the two treatments (HR\xa01.03, 95%\xa0CI 0.96 to 1.11). Bleeding sites for the primary safety end point differed between treatment groups. Rivaroxaban was more often associated with bleeding at sites throughout the gastrointestinal tract (3.15% compared with 2.16%, p\xa0<\xa00.001) but intracranial haemorrhage rates were significantly lower with rivaroxaban than with warfarin (0.5% compared with 0.7%, p\xa0=\xa00.02). Following a request from the ERG the manufacturer provided subgroup analyses for the safety-on-treatment and intention-to-treat populations in people who had previously used vitamin K antagonists, people who had not previously used vitamin K antagonists, people with a time in therapeutic range below 60%, and those with a time in therapeutic range above 60%. In the safety-on-treatment population, superiority of rivaroxaban compared with warfarin was demonstrated for the primary outcome (composite of stroke and non-central nervous system systemic embolism) in people who had not previously used vitamin K antagonists (HR\xa00.72, 95%\xa0CI 0.53 to 0.97) but not in people who had previously used vitamin K antagonists (HR 0.84, 95%\xa0CI 0.66 to 1.08).\n\nThe manufacturer undertook a Bayesian network meta-analysis comparison of rivaroxaban with warfarin, aspirin, no treatment and dabigatran etexilate. The clinical evidence for the rivaroxaban with warfarin comparison was taken from the ROCKET-AF trial. Evidence for the other comparators was obtained from studies found by a systematic literature search. The manufacturer identified 18\xa0studies for inclusion in the network meta-analysis:\n\none comparing rivaroxaban with warfarin\n\nseven comparing aspirin with placebo or control\n\neight comparing warfarin with aspirin\n\none comparing a vitamin K antagonist with clopidogrel plus aspirin\n\none comparing dabigatran etexilate with warfarin (the RE-LY study). The manufacturer reported network meta-analysis results for the outcomes using the ROCKET-AF safety-on-treatment population data set. At the request of the ERG, the manufacturer also provided the results for the outcomes using the ROCKET-AF intention-to-treat population dataset. The efficacy estimates from this network meta-analysis using the ROCKET-AF safety-on-treatment population data set were used in the manufacturer's cost-effectiveness analyses.\n\nThe ERG undertook an exploratory network meta-analysis comparing rivaroxaban with dabigatran etexilate, aspirin, placebo, and adjusted standard dose warfarin. It included data from eight of the 18 studies from the manufacturer's network meta-analysis:\n\none comparing dabigatran etexilate with warfarin\n\none comparing rivaroxaban with warfarin\n\nthree comparing aspirin with warfarin\n\nthree comparing warfarin with placebo. The ERG judged that including only these eight trials would reduce the amount of heterogeneity in the network. Only dosing strategies that the ERG considered to be comparable were included (that is, rivaroxaban 20\xa0mg per\xa0day, dabigatran etexilate 150\xa0mg twice a\xa0day, aspirin 300\xa0mg per\xa0day, and adjusted dose warfarin aiming at a target INR range between 2 and 3). Dabigatran etexilate at a dose of 110\xa0mg twice daily was not included in the analysis because the economic model could not accommodate a dosing regimen in which the dose is reduced from 150\xa0mg twice daily to 110\xa0mg twice daily when the patient reaches the age of 80\xa0years. A fixed-effect model was used because of the high degree of homogeneity between the included trials. The efficacy estimates from this network meta-analysis were used in the ERG's cost-effectiveness analyses.\n\nThe manufacturer developed a Markov model that compares rivaroxaban (20\xa0mg once a\xa0day) with warfarin (adjusted dose warfarin at 4.5\xa0mg once a\xa0day, target INR 2.5, range 2.0 to 3.0), aspirin (150\xa0mg once a\xa0day), dabigatran etexilate (110\xa0mg to 150\xa0mg twice a\xa0day) and no treatment. The population in the model is the same as the ROCKET-AF safety-on-treatment population. The model has a lifetime time horizon and a UK NHS perspective.\n\nThe model included the following health states:\n\nanticoagulant initiation\n\nstable atrial fibrillation (on or off therapy)\n\nminor stroke (on or off therapy)\n\nmajor stroke (on or off therapy)\n\npost minor stroke (on therapy)\n\npost major stroke (on therapy)\n\nminor bleed (on or off therapy)\n\nmajor bleed (on or off therapy)\n\nintracranial bleed (on or off therapy)\n\npost intracranial bleed (on or off therapy)\n\nsystemic embolism (on or off therapy)\n\nmyocardial infarction (on or off therapy)\n\npost myocardial infarction (on or off therapy)\n\ndeath.The ROCKET-AF trial results for the safety-on-treatment population were used to inform the efficacy estimates for rivaroxaban compared with warfarin, rivaroxaban compared with warfarin in people whose atrial fibrillation is poorly controlled on warfarin, and the vitamin K antagonist-naive model populations. The characteristics of the population for the analyses of rivaroxaban compared with aspirin, dabigatran etexilate and no treatment were based on the patient characteristics of a UK GP practice-based survey (Gallagher et al. 2008). Efficacy estimates for rivaroxaban compared with dabigatran etexilate and aspirin were obtained from the manufacturer's network meta-analysis.\n\nThe manufacturer classified all model events as either transient or permanent depending on associated long-term costs and consequences:\n\nSystemic embolism, minor extracranial bleeds and major extracranial bleeds were assumed to have no lasting clinical or economic consequences and as such were considered transient events in the model.\n\nMinor stroke, major stroke, intracranial bleeding and myocardial infarction were considered by the manufacturer to be permanent events, in the sense that they have lasting clinical and economic consequences. Consequently, the manufacturer developed post-event health states to account for the different risks, costs and utilities associated with surviving a permanent event.\n\nThe manufacturer highlighted that increasing age was an important risk factor for ischaemic stroke and systemic embolism, and adjusted the baseline risk of these events to account for patients aging as they move through the model. Risks were calculated using the Framingham risk equations. In the model, a weighted average relative risk (weighted by the proportion of patients in each risk group at initiation) is calculated for each age group and applied to the baseline risk as patients enter that age group. The risks of extracranial bleeding, intracranial bleeding and myocardial infarction were assumed to be independent of time and, therefore, were not adjusted for.\n\nThe baseline risk of each event was adjusted according to the treatment regimen the patient was receiving. Patients may stop their primary therapy and switch to a pre-specified\xa0secondary therapy at any time, although the risk adjustment applied for the remainder of that cycle is that of the primary therapy. The probabilities of treatment discontinuation for warfarin and rivaroxaban were based on data from the ROCKET-AF trial. The manufacturer assumed that treatment-discontinuation rates for aspirin, dabigatran etexilate and placebo were equivalent to that for rivaroxaban, given the similarity of administration between these interventions.\n\nThe health-state utility values and treatment-related utility values in atrial fibrillation were obtained from published sources identified by a systematic literature search. The ROCKET-AF trial did not include a generic measure of health-related quality of life (such as the EQ-5D) that could be used to estimate utilities in the model. The estimates of resources and costs were obtained from NHS reference costs for 2009/10 and systematic literature searching. The manufacturer's model categorised monitoring costs into the following distinct phases: initiation, maintenance, and re-initiation. The manufacturer's model calculated the quarterly cost of initiation, maintenance and re-initiation by taking a weighted average of each cost; the costs of the individual phases were weighted by the proportion of people treated in primary and\xa0secondary care, as indicated by the manufacturer's survey. The resulting annual cost estimates for warfarin monitoring were £663 (£448 in primary care and £215 in\xa0secondary care) for the first\xa0year and £525 (£359 in primary care and £166 in\xa0secondary care) for subsequent\xa0years.\n\nThe manufacturer's base-case analysis of rivaroxaban compared with warfarin used only statistically significant data from the ROCKET-AF safety-on-treatment population. The analysis produced an incremental cost of £740 and a QALY gain of 0.039 resulting in an incremental cost-effectiveness ratio (ICER) of £18,883 per quality-adjusted life\xa0year (QALY) gained. The manufacturer also presented the results of four subgroup analyses:\n\nFor rivaroxaban compared with warfarin in people whose INR is poorly controlled on warfarin, rivaroxaban dominated (was more effective and cost less) warfarin.\n\nFor rivaroxaban compared with warfarin in people who had not previously received warfarin, the ICER was £15,494 per QALY gained.\n\nFor rivaroxaban compared with aspirin, the ICER was £2083 per QALY gained.\n\nFor rivaroxaban compared with dabigatran etexilate, rivaroxaban dominated dabigatran etexilate. The manufacturer carried out univariate sensitivity analysis on the base case, scenario analyses and subgroup analyses. The main drivers of the model results were consistent across analyses, with the cost of warfarin monitoring in primary care having a major impact on all ROCKET-AF-based analyses. The probabilistic sensitivity analyses indicated that, using the base case, rivaroxaban had a 75% probability of being cost effective at a maximum acceptable ICER of £20,000 per QALY gained and an 88% probability at £30,000 per QALY gained. The manufacturer's scenario analysis of rivaroxaban compared with warfarin used all point estimates from the ROCKET-AF safety-on-treatment population regardless of their statistical significance (that is, both statistically significant and non-statistically significant point estimates were used). The resulting ICER was £8732 per QALY gained.\n\nIn the ERG's view, a Markov model was an appropriate choice for modelling the chronic condition of atrial fibrillation. The ERG noted that the manufacturer chose a cycle length of 3\xa0months and that only one event per 3-month cycle was possible because of the nature of the model. The manufacturer acknowledged that, in reality, people may experience more than one event in 3\xa0months, but clinical opinion was that the probability of this would be low. The ERG agreed that assuming one event per model cycle was necessary and reasonable. However, the ERG noted that the manufacturer's model also suspends the risk of further events in the subsequent model cycle. The ERG considered that this additional suspension of risk was likely to bias the analysis against the more effective treatment because the overall event rate would be lower, and the potential to demonstrate clinical and economic benefits would also be lower.\n\nThe ERG identified the following limitations to the model's structural assumptions and parameter sources:\n\nnot separating out the number of hospital visits needed by people who were within and outside recommended INR control\n\nnot adjusting risk of bleeding by age; not adjusting utility by age\n\nthe source of myocardial infarction risk for people treated with aspirin\n\nout of date source of post-myocardial infarction mortality risk\n\ndouble counting of re-initiation costs of warfarin monitoring\n\nsuspending the risk of further events for the subsequent model cycle after an event\n\nexcluding transient ischaemic attack as a potential event.\n\nThe ERG presented an exploratory analysis in which, if possible, adjustments were made to account for the limitations identified (see section 3.18). The analysis for rivaroxaban compared with warfarin produced an incremental cost of £1134 and a QALY gain of 0.034, resulting in an ICER of £33,758 per QALY gained. Similarly, for warfarin-naive people, after incorporating the ERG's model adjustments, the ICER for rivaroxaban compared with warfarin increased from £15,494 to £29,894 per QALY gained. However, rivaroxaban remained dominant in people whose INR was poorly controlled on warfarin after the ERG's model adjustments were incorporated. The structure of the manufacturer's model meant it wasn't possible to remove risk suspension or add transient ischaemic attack as a potential event. Consequently, the ERG was unable to fully quantify the impact of these limitations on the ICERs. However, the ERG considered that suspending risk and excluding transient ischaemic attack as an event would favour rivaroxaban (that is, the removal of these limitations would decrease the ICER for rivaroxaban compared with warfarin), because warfarin is generally less effective than rivaroxaban (based on the safety-on-treatment population of ROCKET-AF).\n\nIn the ERG's view the manufacturer's base-case model is driven by the cost of anticoagulation monitoring rather than the differential effectiveness of rivaroxaban and warfarin. The ROCKET-AF trial showed that, for most outcomes, there was no statistically significant difference between rivaroxaban and warfarin. The ERG highlighted that when the cost of anticoagulation monitoring was separated out by INR range the ICER substantially increased from £18,883 per QALY gained to £27,281 per QALY gained. In addition, the ERG's scenario analysis using the alternative anticoagulation monitoring costs of £242 per person (discussed by the Committee in the ongoing appraisal of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation) increased the ICER to £62,568 per QALY gained.\n\nThe ERG was concerned that the trials included in the network meta-analysis presented by the manufacturer to compare rivaroxaban with aspirin and dabigatran etexilate were heterogeneous. The high levels of heterogeneity were not shown when the ERG conducted its own network meta-analysis restricting the network to the comparators specified in the final scope. When the ERG applied the treatment effects estimated by its network meta-analysis to the manufacturer's model, and a full incremental analysis of rivaroxaban, dabigatran etexilate, warfarin and aspirin was conducted, an ICER of £34,680 per QALY gained was obtained for dabigatran etexilate compared with rivaroxaban, whereas rivaroxaban had dominated dabigatran etexilate in the manufacturer's analysis. The ERG applied further adjustments to account for the following limitations:\n\nthe absence of a post-systemic embolism health state\n\nnot adjusting bleeding risk by age\n\nnot adjusting utility by age\n\nout of date source of post-myocardial infarction mortality risk\n\nassuming equivalent discontinuation rates. This reduced the ICER to £12,701 per QALY gained for dabigatran etexilate compared with rivaroxaban. Exploratory analysis assuming an equivalent ability of rivaroxaban and dabigatran etexilate to prevent myocardial infarction further decreased the ICER to £3578 per QALY gained for dabigatran etexilate compared with rivaroxaban.\n\nThe ERG noted the presence of potential biases in the model, with limitations of risk suspension and the absence of transient ischaemic attack and dyspepsia as adverse reactions. Removing risk suspension is likely to favour dabigatran etexilate whereas including transient ischaemic attack and dyspepsia is likely to reduce the ICER for rivaroxaban compared with dabigatran etexilate. Furthermore, the ERG noted that there is a large amount of uncertainty in the model and that the model is highly sensitive to even small changes to the discontinuation rates. Therefore, the ERG concluded that the results of the probabilistic sensitivity analysis should be taken into account when considering its alternative ICER for dabigatran etexilate compared with rivaroxaban. The probabilistic sensitivity analysis indicated that dabigatran etexilate was dominant in 45% of the 1000 runs and dominated in 35% of runs.\n\n# Manufacturer's additional analyses\n\nThe manufacturer provided additional analyses in response to the Appraisal Committee's request for further clarification on the cost effectiveness of rivaroxaban presented in the appraisal consultation document. The manufacturer provided a revised cost-effectiveness analysis incorporating the following amendments requested by the Appraisal Committee:\n\ndata from the General Practice Research Database to provide event rates according to baseline level of stroke risk and the distribution of patients with different CHADS2 scores from the study of Gallagher et al. (2008)\n\nall the efficacy point estimates from the safety-on-treatment population of the ROCKET-AF trial\n\nrevised event rate in the warfarin arm to reflect the time in therapeutic range achieved in trial centres in western Europe (60.62%)\n\nfixed annual warfarin INR monitoring cost of £242 per person in the sensitivity analysis only.\n\nIn addition to the amendments requested by the Appraisal Committee, the manufacturer also amended the model to include the following:\n\nRevised annual warfarin INR monitoring cost of £580. The manufacturer used the same unit costs as the original model; however, the number of visits needed for the re-initiation was reduced from seven to five per 3-month cycle. The costs associated with warfarin monitoring in primary care in the updated model were £175.50 for initiation of warfarin (calculated as a weighted average of patients who had, and had not received previous warfarin), £135 for maintenance on warfarin and £135 for re-initiation of warfarin.\n\nCase fatality rates of 90\xa0days instead of the 30-day rates in the original model.\n\nUpdated 'real world' discontinuation rates. For warfarin these came from the General Practice Research Database. For rivaroxaban they were calculated by applying relative risks from the General Practice Research Database to discontinuation rates from the ROCKET-AF trial.\n\nTreatment-related disutility applied to warfarin of 0.05. This was obtained from a study evaluating how patients with atrial fibrillation (attending GP- and hospital-led clinics) value different health outcomes. The disutility figures for warfarin were weighted by the UK distribution of primary and\xa0secondary care anticoagulation management.\n\nUpdated results for rivaroxaban compared with aspirin based on an additional indirect comparison. This comparison used only trials comparing rivaroxaban with warfarin and warfarin with aspirin, to reduce the network heterogeneity.\n\nThe manufacturer presented the following cost-effectiveness results when all the amendments in sections 3.23 and 3.24 were applied, with an annual warfarin INR monitoring cost of £580 (that is, excluding the Appraisal Committee's request to incorporate a fixed annual warfarin INR monitoring cost of £242 per person):\n\nfor rivaroxaban versus warfarin in the licensed population (the population with one or more risk factors for stroke), an incremental cost of £705, an incremental QALY of 0.2459 resulting in an ICER of £2869 per QALY gained\n\nfor rivaroxaban versus warfarin in the population whose INR is poorly controlled on warfarin, rivaroxaban dominated warfarin\n\nfor rivaroxaban versus warfarin in the population for whom warfarin is considered unsuitable, the ICER was £9170 per QALY gained.\n\nThe manufacturer presented the following cost-effectiveness results when all the amendments detailed in sections 3.23 and 3.24 were applied, with an annual warfarin INR monitoring cost of £242 per person (that is, including all of the Appraisal Committee's requests):\n\nfor rivaroxaban versus warfarin in the licensed population (the population with one or more risk factors for stroke), an incremental cost of £2220, a QALY gain of 0.2459 resulting in an ICER of £9031 per QALY gained\n\nfor rivaroxaban versus warfarin in the population whose INR is poorly controlled on warfarin, the ICER was £4350 per QALY gained.\n\nThe ERG provided a critique and exploratory analysis of the manufacturer's additional analyses. The ERG agreed that the manufacturer had adequately provided a model cohort representative of people with atrial fibrillation in the UK, and that the analysis was based on all efficacy point estimates from the ROCKET-AF trial. The ERG also agreed that it was reasonable to use a discontinuation rate of five and a 90-day case fatality rate in the model. However the ERG noted that the Committee's request to evaluate the effect of low time in therapeutic range was addressed as an amendment to the base case rather than the subgroup analysis requested. The ERG noted that varying the risk of stroke and systemic embolism according to level of INR control resulted in an increase in the ICER of £3742 per QALY gained.\n\nIn the ERG's view, the manufacturer's inclusion of a disutility for warfarin in the model was not appropriate. The ERG noted that the manufacturer had not provided any justification for the assumption that no disutility is associated with rivaroxaban, aspirin or dabigatran etexilate. The ERG pointed out that there is evidence of disutility associated with other oral anticoagulants such as dabigatran etexilate and therefore it is unreasonable to assume there is no disutility associated with rivaroxaban. The ERG found that removing the disutility for warfarin has a substantial impact on the ICER, increasing it from £2869 to £10,764 per QALY gained.\n\nThe ERG re-ran the manufacturer's updated cost-effectiveness analysis. The ERG noted that in both the original and updated models the manufacturer had categorised systemic embolism as a temporary event. The ERG judged that in order to adequately approximate a post-systemic embolism health state (which would account for the increased risk of stroke following a systemic embolism) it was appropriate to amend the model so that after a systemic embolism patients move into the post-minor stroke health state. The ERG also noted that the manufacturer's updated model continues to use the out of date source of post-myocardial infarction mortality risk. The ERG judged that it was more appropriate to use an updated mortality risk post myocardial infarction that took account of current use of statins. The ERG's analysis included a fixed annual warfarin INR monitoring cost of £242 per person as requested by the Appraisal Committee (see section 3.23) but did not include any disutility associated with warfarin or any other treatment (see section 3.24). The ERG's revised analysis for rivaroxaban compared with warfarin produced an incremental cost of £1815, an incremental QALY of 0.061 and an ICER of £29,537 per QALY gained.\n\nSee the manufacturer's submission and the ERG report for full details of all the evidence.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of stroke and systemic embolism and the value placed on the benefits of rivaroxaban by people with atrial fibrillation, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee was aware that the main concerns for people with atrial fibrillation were fear of having a stroke and anxiety about the difficulty of keeping the INR within the therapeutic range. The Committee heard from the clinical specialists, patient experts and from comments received during consultation that the current standard treatment for preventing stroke and systemic embolism in people with atrial fibrillation is warfarin, and that because aspirin is less effective it is used only in people for whom warfarin is unsuitable. The Committee also heard that warfarin, although an effective treatment, it is associated with a number of problems. The Committee was aware from the patient expert and from comments received during consultation that taking warfarin adversely affects quality of life. This is because people taking warfarin often worry about their level of INR control and they might find regular GP and hospital visits disruptive and inconvenient. The Committee heard from the clinical specialists that a substantial proportion of people taking warfarin have poorly controlled INR and are often not within the target therapeutic range at any one time. In particular, older people with atrial fibrillation are more likely to have poorly controlled INR because of comorbidities. The clinical specialists also explained that the need for regular monitoring and dose adjustments, occasionally involving complicated regimens such as different doses on alternate\xa0days, can cause difficulties with adherence to treatment. The Committee recognised the potential benefits of alternatives such as rivaroxaban for people with atrial fibrillation, including the positive effect on quality of life of removing the restrictions and difficulties associated with taking warfarin.\n\nThe Committee considered the clinical-effectiveness data from the ROCKET-AF trial comparing rivaroxaban with warfarin. It noted that this study was the basis of the clinical-effectiveness evidence in the manufacturer's submission. The Committee noted that the efficacy analysis in the manufacturer's submission had been undertaken on three different populations in the ROCKET-AF trial, the intention-to-treat set (all randomised patients), the safety-on-treatment set (all intention-to-treat patients who had taken at least one dose of study drug and were followed for events) and the per-protocol set (all intention-to-treat patients excluding those who have major pre-defined protocol deviations). The Committee noted that the manufacturer had presented data from the safety-on-treatment population for its primary analyses. The Committee heard from the clinical specialists that using a trial intention-to-treat population was considered to be the gold standard for estimating clinical effectiveness in a superiority trial, but the primary objective of ROCKET-AF was to establish non-inferiority of rivaroxaban compared with warfarin so the primary analysis was different. The Committee noted the comments received during consultation that suggested that it would be more appropriate to consider the intention-to-treat population rather than the safety-on-treatment population. The Committee reconsidered which of the two study populations was the most appropriate. The Committee noted that the intention-to-treat population included people who had either had no treatment or switched treatment during the trial, and agreed that the estimates derived from the safety-on-treatment population of the ROCKET-AF trial provided an adequate basis for evaluating clinical effectiveness.\n\nThe Committee noted that a key uncertainty highlighted by the ERG was the generalisability of the results of ROCKET-AF to people diagnosed with atrial fibrillation in the NHS. The Committee noted that the mean time in therapeutic range for the INR range of 2.0–3.0 for warfarin was 55% for the safety-on-treatment population in the ROCKET-AF trial. The clinical specialists confirmed this could be considered to be around the lower end of the level of control that would be expected in UK clinical practice, but there is considerable variation between different centres and also between different settings, depending on the patient group. The Committee noted that the ROCKET-AF trial had been undertaken in a number of countries, which did not all achieve similar levels of time in therapeutic range. The majority (66.5%) of the participants were recruited from centres in eastern Europe, Latin America and Asia, and in these centres the proportion of time in therapeutic range was lower than in the centres in North America and western Europe. The Committee was concerned that the effectiveness of warfarin could be underestimated if the proportion of time in therapeutic range was low, and that the UK context might be better reflected by results from centres where the time in therapeutic range in the warfarin arm more closely matched the usual levels in the UK. The Committee concluded that the trial results were broadly applicable to a UK setting, but for those already taking warfarin the current level of INR control should be taken into account in any decision to switch to rivaroxaban.\n\nThe Committee also noted that patients in the ROCKET-AF trial had a mean CHADS2 score of 3.47, and that an inclusion criterion of the trial was a baseline CHADS2 score of 2 or more. The scope specified that the appraisal population would be people with a medium to high risk of stroke. The clinical specialists confirmed that people with a CHADS2 score of 3 or more would be at high risk of stroke and that this population was typical of people seen in\xa0secondary care. However, this did not necessarily represent people with atrial fibrillation treated in primary care, who tended to have a lower risk of stroke. The Committee heard that people with atrial fibrillation treated with warfarin in primary care often have a CHADS2 score of less than 2 and that it is estimated that between 20 and 75% of people with atrial fibrillation and a CHADS2 score of less than 2 are prescribed warfarin in the UK. Only 0.02% of the trial population had a CHADS2 score less than 2. The clinical specialists agreed that it was likely that although people with a CHADS2 score of 2 or more would benefit similarly to those in the ROCKET-AF trial, this cannot be assumed for people with a CHADS2 score of less than 2. The Committee noted the comments received during consultation that suggested that consultees and commentators had differing opinions on the generalisability of the results of ROCKET-AF to UK clinical practice. The Committee was made aware by the manufacturer that a systematic review of the literature had suggested that there does not appear to be an interaction between treatment effect and baseline CHADS2 risk. The Committee heard from the manufacturer that rivaroxaban would be indicated for atrial fibrillation in people with one or more risk factors for stroke, which equates to a CHADS2 score of 1 or more. The Committee noted that the European Medicines Agency had stated in the 'European public assessment report' for rivaroxaban that efficacy results were essentially consistent in important subgroups, such as different CHADS2 scores (CHADS2 scores 2 to 6).The Committee accepted that, given the broad spectrum of risk covered by the licensed indication for rivaroxaban, there was no plausible reason to expect that the results of ROCKET-AF would not translate to people with a lower CHADS2 score. However the Committee was mindful of the very small number of patients recruited to the ROCKET-AF trial with a baseline CHADS2 score of less than 2, but concluded that the results of the ROCKET-AF trial were generalisable to UK clinical practice.\n\nThe Committee discussed the safety data from the ROCKET-AF trial. It noted that analysis of the primary safety end point of all major and non-major clinically significant bleeding events showed no significant differences between rivaroxaban and warfarin. There was a significant reduction in the rate of fatal bleeds and intracranial haemorrhage with rivaroxaban compared with warfarin, but a higher rate of gastrointestinal bleeds. The Committee heard from the patient experts that intracranial bleeds were considered to be a more serious complication than gastrointestinal bleeds in clinical practice, because they were more difficult to treat and often result in permanent disability. The Committee noted that the possible uncertainty in these results related to the relatively low proportion of time in therapeutic range of 55% in the warfarin arm of the trial, but concluded that the primary safety end point showed no statistically significant difference between rivaroxaban and warfarin.\n\nThe Committee then discussed the indirect clinical-effectiveness evidence for rivaroxaban compared with dabigatran etexilate and aspirin. The Committee noted that the population in the study comparing dabigatran etexilate with warfarin (RE-LY) had a lower risk of stroke (mean CHADS2 score 2.1) than the population in the ROCKET-AF trial (mean CHADS2 score of 3.47). The Committee noted that the manufacturer's interpretation of its network meta-analysis was that there was no significant difference between rivaroxaban and dabigatran etexilate for any outcome. The Committee noted the ERG's concerns about the validity of the manufacturer's network meta-analysis because of the clinical heterogeneity of the included trials, and the different levels of time in therapeutic range in the warfarin arms of the rivaroxaban and dabigatran etexilate trials. The Committee also noted that both the manufacturer's and ERG's network meta-analyses contained wide confidence intervals, and therefore the resulting efficacy point estimates were subject to considerable uncertainty. The Committee noted the comments received during consultation suggesting that the Committee should reconsider the value of the network meta-analysis. The Committee also noted the additional indirect comparison submitted by the manufacturer during consultation comparing rivaroxaban with aspirin. The Committee reconsidered the data from the manufacturer's and ERG's network meta-analyses and considered the manufacturer's additional indirect comparison comparing rivaroxaban with aspirin. The Committee concluded that it would not consider further the clinical effectiveness of rivaroxaban compared with aspirin or dabigatran etexilate.\n\nThe Committee considered the manufacturer's updated base-case analysis for rivaroxaban compared with warfarin for the licensed population. The Committee noted the ERG's comments on the manufacturer's updated cost-effectiveness analyses and the ERG's revised base-case analysis. The Committee noted that the manufacturer presented an ICER of £2870 per QALY gained (see section 3.25) and the ERG presented an ICER of £29,500 per QALY gained (see section 3.29). The Committee was made aware by both the manufacturer and the ERG that the difference in the ICERs resulted from two main factors. One was the manufacturer's inclusion in its updated analysis of a disutility value associated with warfarin treatment. The\xa0second was the different costs included by the manufacturer and ERG for warfarin monitoring (£580 and £242 respectively).\n\nThe Committee discussed the disutility values used in the manufacturer's updated economic analyses. It noted that the manufacturer had used a small study of 57 patients to justify including a disutility associated with warfarin. The Committee acknowledged that comments received during consultation implied that warfarin was associated with disadvantages. However the Committee was mindful that the manufacturer had assumed that there was no disutility associated with rivaroxaban and had not provided any rationale for its exclusion. The Committee noted the comments from the ERG and consultees and commentators suggesting that there could be some disutility associated with newer anticoagulation therapy, including concerns about non-reversibility in the case of bleeding. However, the Committee noted that no specific evidence relating to disutility associated with anticoagulation therapy other than warfarin had been submitted by any consultees and commentators or by the ERG. The Committee therefore agreed that although it was appropriate to consider that there might be a disutility associated with warfarin treatment, it was not appropriate to assume that there was no disutility associated with rivaroxaban and other anticoagulant treatments. The Committee concluded that the disutility value used in the economic model for warfarin may have resulted in a bias in the manufacturer's economic analysis in favour of rivaroxaban.\n\nThe Committee discussed the costs associated with warfarin INR monitoring. The Committee noted that the manufacturer' model assumed an average annual anticoagulant monitoring cost of £580 per person in the\xa0year that treatment is first initiated and £535 once the person is stabilised on warfarin. The clinical specialists agreed that the annual cost of anticoagulant monitoring for each person treated with warfarin was likely to be lower than the manufacturer's estimate in clinical practice, but a precise estimate could not be given because costs varied considerably between people (for example, they are higher in those with poor INR control) and between centres. The Committee was aware of the uncertainty, but in the interests of consistency had requested that the manufacturer use £242 in its economic model, in line with what it had accepted for the ongoing appraisal of dabigatran etexilate for the same indication. However, the Committee noted the comments received during consultation, which suggested that significant numbers of people have difficulties managing their INR control and could therefore visit a clinic for monitoring up to once a\xa0week, making 30 visits a\xa0year not implausible. The Committee also noted the manufacturer's comments highlighting its concerns about the plausibility of a cost of £242 per person. The Committee therefore agreed that £242 per person was likely to be a conservative estimate of annual anticoagulant monitoring for warfarin if fixed costs were fully included, and that there was uncertainty about the cost of warfarin INR monitoring in clinical practice.\n\nThe Committee considered what the most plausible ICER would be for rivaroxaban compared with warfarin. It noted the ICERs of £2870 per QALY gained presented by the manufacturer (which included disutility associated with warfarin, and warfarin monitoring costs of £580) and £29,500 per QALY gained (which excluded disutility associated with warfarin, and used warfarin monitoring costs of £242) presented by the ERG. The Committee agreed that because there could be some degree of utility decrement associated with treatment, and the estimate of annual anticoagulation monitoring costs of £242 was likely to be conservative, the ICER for rivaroxaban compared with warfarin would be no more than £29,500 per QALY gained and would lie somewhere between £2870 and £29,500 per QALY gained. The Committee therefore concluded that the most plausible ICER for the whole population eligible for rivaroxaban was within the range that could be considered a cost-effective use of NHS resources.\n\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA256\n\nAppraisal\n title:\n Rivaroxaban\n for\n the\n prevention\n of\n stroke\n and\n systemic\n embolism\n in\n people\n with\n atrial\n fibrillation\n\nSection\n\nKey\n conclusion\n\nRivaroxaban is recommended as an option within its licensed indication for the prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation.\n\n\n\nThe Committee recognised that decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin, and noting the limited direct trial evidence for people with a low risk of stroke (CHADS2 score of less than 2). For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in light of their level of international normalised ratio (INR) control.\n\n\n\nCurrent\n practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe current standard treatment for the prevention of stroke and systemic embolism in people with atrial fibrillation is warfarin. Because aspirin is less effective, it is used only in people for whom warfarin is unsuitable.\n\nWarfarin is associated with a number of problems such as fear of having a stroke and anxiety about keeping the INR within the therapeutic range. In addition, people taking warfarin often worry about their level of INR control and they might find regular GP and hospital visits disruptive and inconvenient.\n\nA substantial proportion of people taking warfarin have poorly controlled INR and are often not within the target therapeutic range at any one time.\n\n\n\nThe\n technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee recognised the potential benefits of alternatives such as rivaroxaban for people with atrial fibrillation, including the positive effect on quality of life of removing the restrictions and difficulties associated with taking warfarin.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nRivaroxaban would be used to prevent stroke and systemic embolism in people with atrial fibrillation and one or more risk factor for stroke.\n\n\n\nAdverse reactions\n\nThe Committee noted the possible uncertainty in the results from the ROCKET-AF trial related to the relatively low proportion of time in therapeutic range of 55% in the warfarin arm of the trial, but concluded that the primary safety end point showed no statistically significant difference between rivaroxaban and warfarin.\n\n\n\nEvidence\n for\n clinical\n effectiveness\n\nAvailability, nature and quality of evidence\n\nThe main clinical-effectiveness evidence came from one multicentre, double-blind randomised controlled trial. The ROCKET-AF trial compared rivaroxaban with dose-adjusted warfarin. The manufacturer also compared rivaroxaban with aspirin and dabigatran etexilate (110\xa0mg or 150\xa0mg twice a\xa0day) using a network meta-analysis in people for whom anticoagulation therapy was considered suitable.\n\n\n\nThe Committee also noted the additional indirect comparison submitted by the manufacturer during consultation comparing rivaroxaban with aspirin.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee concluded that the results of the ROCKET-AF trial were generalisable to UK clinical practice. However the Committee also agreed that when treatment with rivaroxaban is being considered, clinicians and patients should be aware that there is limited direct evidence available from the ROCKET-AF trial on the efficacy of rivaroxaban in people with a baseline CHADS2 score of less than 2.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted that there were differing opinions among consultees and commentators on the generalisability of the ROCKET-AF trial to UK clinical practice.\n\n\n\nThe Committee agreed that the clinical-effectiveness estimates for rivaroxaban compared with dabigatran etexilate obtained from the network meta-analyses were unreliable\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee heard from the manufacturer that rivaroxaban would be indicated for atrial fibrillation in people with one or more risk factors for stroke, which equates to a CHADS2 score of 1 or more. The Committee noted that the European Medicines Agency had stated in the 'European public assessment report' for rivaroxaban that efficacy results were essentially consistent in important subgroups, such as different CHADS2 scores (CHADS2 scores 2 to 6).The Committee accepted that, given the broad spectrum of risk covered by the licensed indication for rivaroxaban, there was no plausible reason to expect that the results of ROCKET-AF would not translate to people with a lower CHADS2 score.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee was aware that primary objective of the ROCKET-AF was to establish non-inferiority of rivaroxaban versus warfarin.\n\n\n\nEvidence\n for\n cost\n effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer developed a Markov model that compares rivaroxaban (20\xa0mg once a\xa0day) with warfarin (adjusted dose warfarin at 4.5\xa0mg once a\xa0day, target INR 2.5, range 2.0 to 3.0), aspirin (150\xa0mg once a\xa0day), dabigatran etexilate (110\xa0mg to 150\xa0mg twice a\xa0day) and no treatment.\n\n\n\nThe Committee considered the manufacturer's updated base-case analysis for rivaroxaban compared with warfarin for the licensed population and the ERG's comments on the manufacturer's updated cost-effectiveness analyses and the ERG's revised base-case analysis.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that both the manufacturer and ERG identified the costs associated with warfarin INR monitoring as a major factor affecting the cost-effectiveness estimate in the model.\n\n\n\nThe Committee noted that the manufacturer had assumed an average annual anticoagulant monitoring cost of £580 per person when treatment is first initiated and £535 once stabilised on warfarin. The Committee had in the interests of consistency requested that the manufacturer use £242 in its economic model, in line with what it had accepted for an ongoing appraisal of dabigatran etexilate for the same indication. The Committee agreed that the estimate of annual anticoagulant monitoring cost of £242 per person for warfarin was likely to be conservative if fixed costs were fully included, and that there was uncertainty about the cost of warfarin INR monitoring in clinical practice.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted the comments from the ERG and consultees and commentators suggesting that there could be some disutility associated with newer anticoagulation therapy, including concerns about non-reversibility in the case of bleeding. However, the Committee noted that no specific evidence relating to disutility associated with anticoagulation therapy other than warfarin had been submitted by any consultees and commentators or by the ERG. The Committee therefore agreed that although it was appropriate to consider that there might be a disutility associated with warfarin treatment, it was not appropriate to assume that there was no disutility associated with rivaroxaban and other anticoagulant treatments.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone were identified.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nIn the ERG's view the manufacturer's base-case model is driven by the cost of anticoagulation monitoring rather than the differential effectiveness of rivaroxaban and warfarin.\n\n\n\nThe Committee noted that the manufacturer's model assumed an average annual anticoagulant monitoring cost of £580 per person in the\xa0year that treatment is first initiated and £535 once the person is stabilised on warfarin. The clinical specialists agreed that the annual cost of anticoagulant monitoring for each person treated with warfarin was likely to be lower than the manufacturer's estimate in clinical practice.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee considered the most plausible ICER for rivaroxaban compared with warfarin. It noted the ICERs of £2870 per QALY gained presented by the manufacturer (which included disutility associated with warfarin, and warfarin monitoring costs of £580) and £29,500 per QALY gained (which excluded disutility associated with warfarin, and used warfarin monitoring costs of £242) presented by the ERG.\n\n\n\nThe Committee agreed that because there could be some degree of utility decrement associated with treatment, and the estimate of annual anticoagulation monitoring costs of £242 was likely to be conservative, the ICER for rivaroxaban compared with warfarin would be no more than £29,500 per QALY gained and would lie somewhere between £2870 and £29,500 per QALY gained.\n\n\n\nAdditional\n factors\n taken\n into\n account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNo equalities issues were identified.\n\n"}
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Evidence-based recommendations on rivaroxaban (Xarelto) for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation.
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nice
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Edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation
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Edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation
Evidence-based recommendations on edoxaban (Lixiana) for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation.
# Recommendations
Edoxaban is recommended, within its marketing authorisation, as an option for preventing stroke and systemic embolism in adults with non‑valvular atrial fibrillation with one or more risk factors, including:
congestive heart failure
hypertension
diabetes
prior stroke or transient ischaemic attack
age 75 years or older.
Decide whether to start treatment with edoxaban after an informed discussion with the person about its risks and benefits compared with warfarin, apixaban, dabigatran etexilate and rivaroxaban. For people taking warfarin, consider the potential risks and benefits of switching to edoxaban taking into account their level of international normalised ratio (INR) control.# The technology
Edoxaban (Lixiana, Daiichi Sankyo) is an anticoagulant that directly inhibits factor X (factor Xa), which is a key component in the formation of blood clots. It is administered orally. Edoxaban has a marketing authorisation for the 'prevention of stroke and systemic embolism in adult patients with non‑valvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, prior stroke or transient ischaemic attack (TIA).' The summary of product characteristics states that the recommended dose is 60 mg once daily. The recommended dose is 30 mg once daily in people with one or more of the following clinical factors: moderate or severe renal impairment (creatinine clearance 15 to 50 ml/min); body weight of 60 kg or less; concomitant use of the P‑glycoprotein inhibitors ciclosporin, dronedarone, erythromycin or ketoconazole.
The summary of product characteristics includes the following adverse reactions for edoxaban: bleeding, anaemia, nausea, rash, hepatobiliary disorders (increased blood bilirubin and gamma‑glutamyl transferase) and abnormal liver function test. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Edoxaban costs £58.80 for a 28‑tablet pack (60 mg or 30 mg) and the daily cost of treatment is £2.10 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.# The company's submission
The Appraisal Committee considered evidence submitted by Daiichi Sankyo and a review of this submission by the Evidence Review Group (ERG).
# Clinical effectiveness
## Overview of clinical trials
The primary source of evidence was ENGAGE AF‑TIMI 48, a randomised, international (46 countries, including 31 centres in the UK) double‑blind, double‑dummy, parallel‑group, non‑inferiority trial comparing edoxaban with warfarin. It included a total of 21,105 people with non‑valvular atrial fibrillation and a moderate‑to‑high risk of stroke, defined as a CHADS2 score of 2 or more (CHADS2 is a scoring system that measures risk factors associated with congestive heart failure, hypertension, age, diabetes and stroke). People were randomly assigned to treatment with low‑dose edoxaban (30 mg, n=7034), high‑dose edoxaban (60 mg, n=7035) or warfarin (n=7036). People randomised to edoxaban who were at increased risk of bleeding because of higher drug exposure (those weighing 60 kg or less, with creatinine clearance 30 to 50 ml/min, or having concomitant treatment with potent permeability glycoprotein inhibitors) had the dose reduced, either at randomisation or during the study, to 15 mg in the low‑dose group and to 30 mg in the high‑dose group. The clinical trial results presented below focus on the higher dose treatment arm because this is the recommended dose in the marketing authorisation. This is referred to throughout as the 60 mg/30 mg treatment arm because it included people who were given 30 mg because of clinical factors. The dose in the warfarin group was adjusted to maintain an international normalised ratio of 2.0 to 3.0, and people in the trial were 'well controlled' on warfarin (median time spent in the therapeutic range was 68.4%).
Patient characteristics were similar between the treatment groups including age, sex, ethnicity, risk factors, CHADS2 score and renal function. The mean CHADS2 score was 2.8 and approximately 53% of patients had a CHADS2 score of 3 or more, indicating that the patient population was at a moderate‑to‑high risk of stroke. The median age of people in the study was 72 years and 62% were male.
The primary efficacy outcome was time to the first stroke (ischaemic or haemorrhagic) or systemic embolic event. People in the trial continued treatment and were followed up until approximately 672 primary efficacy endpoint events had been collected, which provided 87% power for confirming non‑inferiority for each edoxaban regimen. A non‑inferiority test using the modified intent‑to‑treat (mITT) population for the on‑treatment period was pre‑specified in the statistical analysis plan. To satisfy non‑inferiority, the upper boundary of the one‑sided 97.5% confidence interval for the hazard ratio of the primary efficacy endpoint comparing edoxaban with warfarin could not exceed 1.38, which was an estimate that preserved at least 50% of the benefit of warfarin over placebo. If edoxaban was shown to be statistically significantly non‑inferior to warfarin, a superiority test would be performed using the intent‑to‑treat (ITT) population and the overall study period.
## Clinical trial results
For the primary efficacy outcome (prevention of stroke or systemic embolic event) in the mITT analysis set (on‑treatment and overall study period), edoxaban 60 mg/30 mg met the criteria for non‑inferiority compared with warfarin. Stroke or a systemic embolic event occurred in 182 people in the edoxaban 60 mg/30 mg arm of the trial (1.18% per year) compared with 232 people in the warfarin arm (1.50% per year, hazard ratio 0.79, 97.5% confidence interval 0.63 to 0.99, p<0.001 for non‑inferiority). In the pre‑specified superiority analysis performed in the ITT analysis set (overall study period), the rate of stroke or systemic embolic event was 1.57% per year in the edoxaban 60 mg/30 mg arm compared with 1.80% in the warfarin arm (HR compared with warfarin 0.87; 97.5% CI 0.73 to 1.04, p=0.08 for superiority). Results for the mITT overall study period were consistent with those in the ITT overall study period.
The company presented results for the analyses of the components of the primary endpoint (stroke and systemic embolism) and the subcomponents of stroke (ischaemic, haemorrhagic, fatal and disabling) for the mITT analysis set (on‑treatment period, and overall study period) and the ITT analysis overall study period. For the mITT overall study period, edoxaban was shown to be superior to warfarin for haemorrhagic stroke (p=0.001). The results were similar for the mITT population, the on‑treatment period analysis and the ITT population analysis.
The company presented analyses for the primary efficacy results using the mITT analysis set (overall study period) for subgroups according to risk of stroke (defined by CHADS2 score) and renal function (creatinine clearance). The subgroup analysis for risk of stroke demonstrated that, compared with warfarin, the hazard ratio for the edoxaban 60 mg/30 mg dose was stable and non‑inferior across CHADS2 scores of 2 to 6. The subgroup analysis for renal function across 3 categories of creatinine clearance (normal renal function 80 ml/min or more; mild renal impairment more than 50 to less than 80 ml/min; and moderate renal impairment 30 to 50 ml/min), suggested that renal function had a significant impact on the efficacy of edoxaban in comparison to warfarin (p=0.0042). This result was shown to be consistent across analysis sets. The hazard ratios for the primary efficacy endpoint were 0.68 (95% CI 0.54 to 0.85) and 0.86 (95% CI 0.63 to 1.17) for the subgroups of people with mild or moderate renal impairment, respectively. In contrast, the relative risk of stroke or systemic embolic event was higher with edoxaban than with warfarin in the subgroup of people with normal renal function (HR 1.31, 95% CI 0.96 to 1.79). The company noted that this analysis should be treated with caution because a variety of factors (including an unusually low event rate in the warfarin group, and potential imbalances between treatment groups because of randomisation not being performed within subgroups) could have contributed to the observed hazard ratio for stroke or systemic embolic event compared with warfarin in the subgroup of people with normal renal function.
The company also did an analysis comparing centre‑level TTR above and below 60%. The p value for interaction was 0.0361 which indicated that in centres with a TTR above 60% edoxaban had a similar effect compared with warfarin to that observed in the total study population, but there was a significant reduction in risk of stroke and systemic embolism in the subgroup with a centre‑level TTR of less than 60%. When the TTR data were examined by quartiles, however, the p value for interaction was 0.50.
## Health‑related quality of life
Health‑related quality of life data were collected in ENGAGE AF‑TIMI 48 using the self‑administered EQ‑5D questionnaire at baseline and then every 3 months, until the end of the study. Approximately 60% of patients (11,995 patients) provided quality‑of‑life data; 164 (1.4%) patients were from the UK.
## ERG comments on the clinical effectiveness data
The ERG noted that the statistically significant result for non‑inferiority in ENGAGE AF‑TIMI 48 was driven largely by a reduction in haemorrhagic stroke events in patients treated with edoxaban, but there was no statistically significant difference between edoxaban and warfarin for any other listed component or subcomponent.
The ERG commented that the estimate of treatment effect (hazard ratio) for the primary outcome may not be reliable because the assumption of proportional hazards between treatment with edoxaban or warfarin for haemorrhagic stroke (one of the components of the primary outcome) appeared to be violated. The hazard trend in the warfarin group changed sharply at 6 months, in comparison with a smooth hazard trend over time in the edoxaban group.
The ERG noted that the results of the analysis for centre‑level TTR suggested that the efficacy of edoxaban in comparison to warfarin is significantly greater in the subgroup of centres achieving TTR of less than 60%, but this was not consistent across all analysis sets. There was no significant difference in the results from centres with a TTR of less than or greater than 60% when the analysis was conducted using the mITT population and the on‑treatment observation period. The ERG therefore suggested that the finding that centre‑level TTR may affect the efficacy of edoxaban in comparison to warfarin may be spurious.
The ERG stated that the health‑related quality of life data provided during the clarification process were difficult to interpret because of the low response rate and incomplete analysis. The ERG therefore suggested that it was difficult to draw any firm conclusions about any differences in patients' experiences that are attributable to the choice of treatment.
## Adverse effects of treatment
The company presented the results of the safety analyses, which included all people who had at least 1 dose of study drug for the on‑treatment period in ENGAGE AF‑TIMI 48. In the principal safety analysis for the edoxaban 60 mg/30 mg arm compared with warfarin, the company stated that edoxaban had a significantly reduced rate of major bleeding (HR 0.80, 95% CI 0.71 to 0.91; p<0.001) and of several secondary bleeding endpoints including intracranial, fatal, clinically relevant non‑major and life‑threatening bleeds (p≤0.01 for all comparisons). However, the company highlighted that major gastrointestinal bleeding occurred slightly more frequently in the edoxaban 60 mg/30 mg arm than in the warfarin arm (annualised rate of 1.51% compared with 1.23%, respectively; HR 1.23 ; p=0.03).
The company stated that the 5 most frequent treatment‑emergent adverse events in the edoxaban or warfarin groups were urinary tract infections, nasopharyngitis, bronchitis, dizziness and peripheral oedema. The company presented subgroup analyses for the primary safety outcome by centre‑level TTR and by risk of stroke (as defined by CHADS2), which were consistent with the overall population.
## Network meta‑analysis
The company did not find any head‑to‑head studies that compared edoxaban with rivaroxaban, dabigatran etexilate or apixaban so it did a network meta‑analysis to estimate the relative efficacy and safety of edoxaban for treating atrial fibrillation, that included 4 trials: ENGAGE AF‑TIMI 48, and 3 trials of other newer oral anticoagulants (apixaban 5 mg twice‑daily ; dabigatran etexilate 150 mg twice‑daily or 110 mg twice‑daily ; and rivaroxaban 20 mg once‑daily ). All 4 RCTs had a warfarin treatment arm. Because of significant differences in the patient characteristics and trial design between the 4 trials (for example, ARISTOTLE and RE‑LY included people with a CHADS2 score of 1 or more, whereas the CHADS2 score was 2 or more in both ENGAGE AF‑TIMI 48 and ROCKET‑AF) only data from patients with a CHADS2 score of 2 or more from RE‑LY and ARISTOTLE were used in the network meta‑analyses.
The results of the meta‑analysis demonstrated that for the composite endpoint of stroke and systemic embolism, efficacy was similar for high‑dose edoxaban compared to other newer oral anticoagulants, but edoxaban significantly reduced major bleeding risk by 24%, 28%, and 17% compared to rivaroxaban, dabigatran etexilate 150 mg and dabigatran etexilate 110 mg, respectively. Major bleeding rates were similar between high‑dose edoxaban and apixaban.
## Evidence Review Group's comments on the network meta‑analysis
The ERG considered that the key characteristics of the trials (study population, design, outcome measures; and effect modifiers such as age, disease severity, and duration of follow‑up) included in the network meta‑analyses were sufficiently similar to justify combining the results. The company's approach used annualised event rates and the ERG considered that this approach minimised any potential bias resulting from differences in trial duration, which ranged from 1.8 years in ARISTOTLE (apixaban) to 2.8 years in ENGAGE AF‑TIMI 48 (edoxaban).
The ERG noted that in addition to the violation of the proportional hazards assumption for some end points within ENGAGE AF‑TIMI 48, it was also violated within trials of the other 3 newer oral anticoagulants, and in the warfarin groups of the 4 trials included in the evidence network. The ERG highlighted that this meant the hazard ratios from the network meta‑analysis were not reliable and should not be used to inform the company's economic model.
# Cost effectiveness
The company developed a Markov cohort model to compare edoxaban with warfarin, apixaban, rivaroxaban and dabigatran etexilate for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation with 1 or more risk factors, such as congestive heart failure, hypertension, age 75 years or more, diabetes, previous stroke or transient ischaemic attack, and a CHADS2 score of at least 2 (the baseline characteristics of ENGAGE AF‑TIMI 48). The model consisted of 18 health states (patients entering the model with 'stable AF'), with 1‑month cycles and a 30‑year (remaining lifetime) time horizon from a starting age of 71 years. The company conducted the analysis from the perspective of the NHS and personal social services, and discounted costs and health effects at an annual rate of 3.5%. A half‑cycle correction was applied to both costs and QALYs (with the exception of drug costs). The model design was based on previous economic analyses that were submitted to NICE (for example, apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation).
The health states in the company's model were defined by the clinical events considered to have a permanent impact on patients and were assumed to have an initial, as well a long‑term, impact on costs, quality of life and mortality. The health states captured the main thrombotic events and adverse events of treatment including haemorrhagic and ischaemic stroke (separated into mild, moderate and severe), systemic embolism and myocardial infarction. Health states were further subdivided into an initial health state (in which costs and quality of life associated with the acute event and the case fatality rate were applied in the month after the initial event), and a long‑term health state in which ongoing event costs, quality of life and mortality were applied in each monthly cycle. Events that were considered to have no long‑term impact in the model were other intracranial haemorrhage, non‑intracranial haemorrhage major bleeds, clinically relevant non‑major bleeds, and transient ischaemic attack. In the model, these events incurred costs and a disutility for the length of the event.
The monthly probability of each clinical outcome for edoxaban was estimated from annual event rates from ENGAGE AF‑TIMI 48. The transition probabilities for the comparators were obtained by applying the hazard ratio from the network meta‑analysis for the intervention to the baseline probability. When there were no available data for a clinical outcome, it was assumed that the hazard ratio was equivalent to the hazard ratio estimated in the 'all patients' analysis. If there were no available data in the 'all patients' analysis, the hazard ratio was assumed to be 1.
In the model, people could permanently stop or switch treatment after an ischaemic stroke or a haemorrhagic stroke. After stopping treatment and switching to a new therapy, the transition probability (of health state and event) did not change to reflect the new therapy. The company assumed that people could not stop or switch treatment for any other reason because there would be no difference between treatment groups.
The adverse events considered in the company's model were non‑intracranial haemorrhage major bleed, clinically relevant non‑major bleeds, other intracranial haemorrhage, and transient ischaemic attack (assumed to be transient on clinical advice).
## ERG comments
The ERG considered that the assumption of proportionality that underpinned the network meta‑analysis had been shown to be violated both within and between trials (see also sections 3.10 and 3.18). The ERG highlighted that this meant the hazard ratios used to inform the company's economic model were therefore unreliable.
The ERG highlighted that the model predicted that, of a cohort of 1000 people with non‑valvular atrial fibrillation having warfarin, there will be 157 stroke events. Using the company's approach to applying the risk of acute‑stroke mortality, approximately 15 (9.6%) of these would be fatal, which is substantially less than the 16.8% reported in the study by Janes. The ERG assessed the impact of applying the acute mortality rates reported by Janes to all patients experiencing a stroke (ischaemic stroke and haemorrhagic stroke analysed separately) (see sections 3.40 and 3.41). The ERG noted that mortality data from ENGAGE AF‑TIMI 48 were not used in the model and no rationale for this was given by the company. The ERG considered it more appropriate to use mortality data from ENGAGE AF‑TIMI 48. Therefore, in its exploratory analyses, the ERG extracted acute mortality data for ischaemic stroke and haemorrhagic stroke from the clinical study report (CSR50, page 132) and pooled it across the warfarin and edoxaban groups of the trial (see sections 3.40 and 3.41).
The ERG highlighted that the model overestimated overall survival for both treatment groups compared with ENGAGE AF‑TIMI 48, and that this potentially underestimated the relative effectiveness of edoxaban compared to warfarin.
## Utility values
The baseline quality of life for the health state of stable atrial fibrillation in the company's model (0.78) was taken from a study of patients with atrial fibrillation having warfarin in the UK (Khan, 2004). In the sensitivity analyses, health‑related quality of life data from ENGAGE AF‑TIMI 48 were used (0.836). Health‑related quality of life declined over time based on an adjustment for cohort aging (-0.00029 per year) to reflect the impact of age and thrombotic events on a patient's quality of life. Utility estimates for mild, moderate and severe stroke were derived from a published study by Gage (1996). The company assumed that patients who have a stroke, myocardial infarction or systemic embolic event experience a permanent decrement to their health‑related quality of life.
## ERG comments
The ERG noted that the base case utility value for the stable atrial fibrillation health state had been derived from a UK study by Khan which had a modest sample size of 125 patients, with a low response rate, and was designed to assess the effectiveness of an anticoagulation education programme and self‑monitoring of patients with atrial fibrillation taking warfarin. The ERG did not consider this to be representative of a general atrial fibrillation population and it preferred the use of EQ‑5D data collected in ENGAGE AF‑TIMI 48.
The ERG highlighted that the age‑related utility decrement in the model (-0.00029 per annum) based on self‑reported health status of a US population and valued using the UK tariff may not be generalisable to a UK population. The ERG preferred to use EQ‑5D data from the Health Survey for England in its analysis, because this was a more representative population for the UK. This produced an estimated annual utility decrement of -0.00646.
## Resource use
The company used the British National Formulary 68 (July 2014) to obtain drug costs in the model. All costs for the health states of ischaemic stroke, haemorrhagic stroke and systemic embolic events were based on the Oxford Vascular study (OXVASC, 2013), a large study of healthcare costs after stroke in patients with atrial fibrillation. Costs associated with myocardial infarction were based on NHS reference costs. Post‑myocardial infarction costs were based on the Electronic Drug Tariff and the British National Formulary 68 (July 2014).
The monitoring costs for warfarin patients were adapted from the unit cost of anticoagulation monitoring used in the NHS Costing Template for dabigatran etexilate, which was also used in the apixaban technology appraisal. These costs were inflated to 2013 costs using the Personal Social Services Research Unit Hospital and Community Services Health Index (HCHS). The model assumed that 34% of patients will be seen in a secondary care setting (at a cost of £323.10) with the remaining 66% seen in primary care (£235.11) giving a weighted average annual cost of £265.03.
## ERG comments on resource use
The ERG noted that although the cost of warfarin used in the company's model (£0.11 per day) was estimated using the list prices reported in the British National Formulary, it is widely available to the NHS at discounted prices. The ERG did an exploratory analysis using the warfarin cost estimated from figures reported in the Department of Health's eMit database (£0.0375).
## Company's base‑case results and sensitivity analysis
In the company's deterministic base case analysis (based on people with CHADS2 ≥2), edoxaban, dabigatran etexilate 110 mg, apixaban and rivaroxaban were strictly dominated (less effective and more costly) by dabigatran etexilate 150 mg, which had an incremental cost‑effectiveness ratio (ICER) of £7645 per additional QALY gained compared to warfarin (table 1).
Technology
Total costs
Total QALYs*
Inc costs
Inc QALYs
ICER vs warfarin (QALYs)
ICER per QALY gained (£)
Warfarin
Dabigatran etexilate 150 mg
Apixaban
Strictly dominated
Edoxaban
Strictly dominated
Dabigatran etexilate 110 mg
Strictly dominated
Rivaroxaban
Strictly dominated
Abbreviations: ICER, incremental cost‑effectiveness ratio; Inc, incremental; QALYs, quality-adjusted life years.
The company presented cost‑effectiveness acceptability curves for the incremental analysis, which showed that the probability of edoxaban being cost effective was 2.9% at a maximum acceptable ICER of £20,000 per QALY gained, and 3.4% at a threshold of £30,000 per QALY gained. Warfarin had the highest probability (36.8%) of being the most cost‑effective option at a threshold of £20,000 per QALY gained. At a maximum acceptable ICER of £30,000 per QALY gained, apixaban had the highest probability of being the most cost‑effective option (32.6%). In the pairwise comparison of edoxaban compared with warfarin, the probability of edoxaban being cost effective was 47.1% at a maximum acceptable ICER of £20,000 per QALY gained and 57.1% at a maximum acceptable ICER of £30,000 per QALY gained.
The company did 14 pairwise deterministic sensitivity analyses. It highlighted that the variables that had the most impact on the deterministic base case results were patients' starting age (lower limit 52.1 years, upper limit 89.1 years), cost of treatment, monitoring costs for patients treated with edoxaban (baseline £0, upper limit £26.50), and the utility values of stable atrial fibrillation, post‑event myocardial infarction and haemorrhagic stroke.
The company presented results of subgroup analyses for people with a CHADS2 score of 3 or more, or with a centre‑level TTR of 60% or more. In people with a CHADS2 score of 3 or more edoxaban, dabigatran etexilate 110 mg, and rivaroxaban were strictly dominated (less effective and more costly) by apixaban and dabigatran etexilate 150 mg. For the subgroup of people with a centre‑level TTR of 60% or more, edoxaban, dabigatran etexilate 110 mg, apixaban and rivaroxaban were strictly dominated by dabigatran etexilate 150 mg, which had an ICER of £11,738 per additional QALY gained compared to warfarin.
## ERG's comments on the company's cost‑effectiveness model results
Results from the company's base case probabilistic analysis were not explicitly included in the submission. However, they were calculated by the ERG using the company's model (table 2). Edoxaban, dabigatran etexilate 110 mg and rivaroxaban were strictly dominated by dabigatran etexilate 150 mg and apixaban extendedly dominated dabigatran etexilate 150 mg (more effective and less costly) with an ICER of £13,036 per QALY gained compared to warfarin.
Costs
QALYs
Incremental Cost
Incremental QALY
ICER
Warfarin
Rivaroxaban
Dominated
Dabigatran etexilate 110 mg
Dominated
Edoxaban
Dominated
Dabigatran etexilate 150 mg
Extendedly dominated
Apixaban
Abbreviations: ICER, incremental cost‑effectiveness ratio; Inc, incremental; QALYs, quality-adjusted life years.
The ERG highlighted that in the company's probabilistic and deterministic analyses edoxaban was dominated (less effective and more costly than at least one alternative treatment). However, in the deterministic analysis dabigatran etexilate 150 mg dominated (was less costly and more effective than) the other, newer, oral anticoagulants, whereas in the probabilistic analysis apixaban dominated dabigatran etexilate 150 mg. The ERG considered that this was because of the very small differences in QALYs between dabigatran etexilate 150 mg and apixaban in all analyses. In addition, the ERG noted that the results of the probabilistic analysis were not completely stable (repeated runs of the same analyses gave slightly different results).
The ERG considered that because the subgroup analyses for patients with a CHADS2 of 3 or more and for centre‑level TTR of 60% or more were based on very limited data, the extent to which these results were truly representative of effects in these subgroups is unclear.
## ERG's exploratory analyses
The ERG noted that the economic model appeared to be robust to the sensitivity analyses carried out by the company. The ERG carried out 17 individual exploratory scenarios, which used its preferred alternative parameter values or formulae. The ERG also combined multiple parameters to give their preferred base case, which included:
corrected implementation of age‑related utility adjustment
ERG‑sourced utility values for systemic embolism
alternative utility values for myocardial infarction, transient ischaemic attack and ERG‑sourced utility values for acute and post‑stroke health states
assumption regarding the method used to switch patient medication from dabigatran 150 mg to 110 mg at age 80
assumption regarding treatment discontinuation after haemorrhagic stroke
acute stroke fatality rate applied to all stroke events (16.8% for ischaemic and 31.6% for haemorrhagic stroke)
trial data on acute stroke case fatality rates used for all ischaemic and haemorrhagic strokes
age‑adjusted utility decrement per year amended to -0.00646 instead of -0.00029
the daily cost of warfarin amended
the ENGAGE trial HR applied for haemorrhagic stroke.
None of the ERG's amendments to the company's model changed the results of the full incremental analyses; edoxaban was more expensive and less effective than at least one of the alternative treatments. When all of the ERG's preferred values were used in the model the pairwise deterministic ICER for the comparison of edoxaban with warfarin was £16,008 per QALY gained, and the probabilistic ICER was £22,079 per QALY gained. When additional alternative amendments were included to reconcile the model survival outputs with the trial data, and to reflect the changing age and sex distribution over time, this changed the deterministic pairwise ICER to between approximately £15,176 and £15,807, and the probabilistic ICER to between £21,728 and £23,634 per QALY gained.
See the committee papers for full details of the evidence.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of edoxaban, having considered evidence on the nature of non‑valvular atrial fibrillation and the value placed on the benefits of edoxaban by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The Committee heard from clinical and patient experts that the current standard treatment for non‑valvular atrial fibrillation is warfarin, although there is increasing use of newer agents. The Committee was aware that non‑valvular atrial fibrillation is well‑managed with warfarin for many people, but is associated with a number of problems including the need for regular monitoring and dose adjustment, and it has multiple food and drug interactions. The Committee heard from the patient and clinical experts that the number of people being prescribed anticoagulation treatment for atrial fibrillation is increasing following publication of the NICE guideline on managing atrial fibrillation. This does not recommend aspirin for the treatment of non‑valvular atrial fibrillation, which has led to a higher uptake of both warfarin and the newer oral anticoagulants. The Committee concluded that both warfarin and the newer oral anticoagulants are relevant comparators for edoxaban. The Committee accepted the limitations of warfarin therapy and the considerable impact it may have on people who take it, and recognised the potential benefits of edoxaban for people with non‑valvular atrial fibrillation.
# Clinical effectiveness
The Committee considered the clinical‑effectiveness data from ENGAGE AF‑TIMI 48, that compared edoxaban with warfarin. It considered that this trial was of good quality and discussed whether the results were generalisable to people with atrial fibrillation in the UK. The Committee noted that ENGAGE AF‑TIMI 48, like other trials of newer anticoagulants, used CHADS2 to assess the risk of stroke rather than CHADS2‑VASc, which is now used in clinical practice, as recommended in the NICE guideline on managing atrial fibrillation. The Committee understood from the clinical expert that the CHADS2‑VASc scoring system was developed to better define those who would benefit from anticoagulation because a number people with a CHADS2 score of 1 would still benefit. It also heard that although these people were not included in ENGAGE AF‑TIMI 48, a lower baseline risk of stroke would not be expected to reduce the relative efficacy of the treatment. In clinical practice, edoxaban is expected to be offered in the same place in the treatment pathway as other anticoagulants (that is, to women with a CHADS2‑VASc score of 2 and above, and to men with a score of 1 or above), while taking bleeding risk into account. The Committee concluded that the trial was well designed and generalisable to clinical practice.
The Committee considered the results of ENGAGE AF‑TIMI 48. It noted that the primary efficacy outcome was a composite of stroke (both ischaemic and haemorrhagic) and systemic embolism. However, ischaemic stroke and systemic embolism could be considered direct treatment effects, whereas haemorrhagic stroke was a bleeding outcome and therefore an adverse event. The Committee noted that for the composite primary outcome, edoxaban was non‑inferior to, but not superior to, well‑controlled warfarin (which was defined in the trial as a median time in therapeutic range of 68.4%). The Committee noted that when the individual components of the primary outcome were considered separately, there was only a statistically significant reduction in haemorrhagic stroke with edoxaban compared with warfarin. The Committee concluded that edoxaban was as clinically effective as warfarin for the primary efficacy outcome of reducing stroke (ischaemic and haemorrhagic) and systemic embolism, and had nearly half the rate of haemorrhagic stroke events compared to warfarin.
The Committee considered the results of the company's subgroup analyses, which used data from ENGAGE AF‑TIMI 48. It noted that the company presented data for subgroups based on international normalised ratio (INR) control, that compared the efficacy of edoxaban and warfarin in relation to the median TTR for the study centre. One of the analyses showed that the relative benefits of edoxaban compared with warfarin were greater in centres where the centre‑level TTR was less than 60%. The Committee noted comments from the company and the Evidence Review Group (ERG) that this was not consistent across all analysis sets. The Committee concluded that there was insufficient evidence to consider different treatment effects according to centre‑level TTR.
The Committee noted that the company's subgroup analyses for risk of stroke (as defined by CHADS2 score) showed that the hazard ratio for edoxaban compared with warfarin was stable and non‑inferior across CHADS2 scores of 2 to 6. The Committee concluded that there was no biologically plausible reason to indicate that the relative treatment effect would be dependent on the baseline risk of stroke.
The Committee discussed the subgroup analysis based on renal function, which used 3 categories of creatinine clearance (normal renal function, and mild or moderate impairment). It noted that the results of this analysis suggested a trend towards decreasing efficacy of edoxaban with increasing creatinine clearance (see section 3.6). The Committee heard from a clinical expert that this was likely to be because with better renal function edoxaban is removed by the kidneys more quickly, leading to a reduction in treatment effect. It also heard that this may apply to all newer oral anticoagulants, but data need to be re‑evaluated to confirm this. It heard from the clinical experts that the proportion of people with good renal function (measured by creatinine clearance) who would be eligible for treatment with edoxaban was in the region of 5% to 10%, and that these are often younger people. The Committee noted the company's rationale that the results of this sub‑group analysis should be interpreted with caution (see section 3.6). It also noted the summary of product characteristics which states that, in people with non‑valvular atrial fibrillation and high creatinine clearance, edoxaban should only be used after careful evaluation of a person's thromboembolic and bleeding risk. The Committee concluded that if edoxaban is used in accordance with the summary of product characteristics, there is no reason to make differential recommendations based on creatinine clearance.
The Committee considered the adverse events reported in ENGAGE AF‑TIMI 48. It noted that for the primary safety outcome of major bleeding, edoxaban resulted in statistically significantly fewer bleeds than warfarin. Edoxaban also had statistically significantly fewer other bleeding events including fatal, intracranial and clinically relevant non‑major bleeds. The Committee recognised the particular importance of the reduction in intracranial bleeding compared with warfarin. It also noted the statistically significantly higher numbers of gastrointestinal bleeds in people treated with edoxaban compared with warfarin. The Committee was aware that this is not unique to edoxaban, and that clinicians are now more experienced in using the newer oral anticoagulants and in managing the adverse events. It also heard from the clinical experts that administration of 4‑factor prothrombin complex concentrate has been shown to reverse the effects of edoxaban. The Committee concluded that the risk–benefit profile of edoxaban was acceptable.
The Committee discussed the data for edoxaban compared with rivaroxaban, apixaban, dabigatran etexilate (110 mg twice daily and 150 mg twice daily) and rivaroxaban, that were used in the company's network meta‑analysis. The Committee noted that the trials included in the network meta‑analysis were not directly comparable; for example, they had different baseline risks of stroke (with different CHADS2 inclusion criteria and mean CHADS2 scores) and differences in time in the therapeutic range in the warfarin groups. The Committee also noted the ERG's concerns about the violation of the proportional hazards assumption in data from ENGAGE AF‑TIMI 48, from the trials of the other 3 newer oral anticoagulants, and in the warfarin groups of the 4 trials included in the network meta‑analysis. It understood from the ERG that this meant that the hazard ratios produced by the network meta‑analysis were not sufficiently robust to compare the relative clinical effectiveness of the newer oral anticoagulants. The Committee considered the results of the network meta‑analysis in the light of the methodological issues and noted that all the newer oral anticoagulants appeared to have comparable efficacy for the composite primary and bleeding outcomes. The Committee concluded that the network meta‑analysis results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban and dabigatran etexilate in clinical practice.
# Cost effectiveness
The Committee considered the company's economic model. It noted that the economic analysis was largely based on the model used in NICE's technology appraisal guidance on apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation, which captured the main efficacy and adverse events of treatment. The Committee agreed that the model structure, perspective and time horizon were appropriate, although it questioned the relevance of the inclusion of myocardial infarction. It concluded that the analysis was consistent with the NICE reference case.
The Committee considered the clinical‑effectiveness estimates used in the company's model. It noted that the comparison of edoxaban with warfarin used direct evidence from ENGAGE AF‑TIMI 48 to inform the company's economic model. The Committee was aware of the ERG's concern that the assumption of proportional hazards for edoxaban and warfarin for haemorrhagic stroke (one of the components of the primary outcome) appeared to be violated in ENGAGE AF‑TIMI 48. However, the Committee considered that the general modelling approach and the pairwise comparison with warfarin were appropriate. The Committee noted that for the comparison of edoxaban with the other newer oral anticoagulants, hazard ratios obtained from the network meta‑analysis were used in the economic model and that these estimates were considered unreliable by the ERG (see section 4.8). The Committee concluded that data from ENGAGE AF‑TIMI 48 were appropriate for calculating the cost effectiveness of edoxaban compared with warfarin, but the estimates of the cost effectiveness of edoxaban compared with dabigatran etexilate, apixaban and rivaroxaban were based on data that were associated with a high degree of uncertainty.
The Committee heard from the ERG that there were differences in the utility values used in the economic model, compared with other NICE technology appraisals for atrial fibrillation (apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation; rivaroxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation; dabigatran for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation). It noted that even though EQ‑5D data were collected at baseline in ENGAGE AF‑TIMI 48 , the baseline utility value for stable atrial fibrillation used in the model was from another small UK study. The Committee noted that the ERG had identified a number of inconsistencies and had raised concerns about some of the sources of data used in the company model. However, the Committee noted that when the ERG's suggested revisions (alternative utility estimates for systemic embolism, myocardial infarction, and transient ischaemic attack) were applied, together with an amended age‑adjusted utility decrement per year of -0.00646 instead of -0.00029 (see sections 3.40 and 3.41), they had only a minor impact on the incremental cost‑effectiveness ratio (ICER). The Committee concluded that the utility values used in the model, although open to debate, were not key drivers of the cost effectiveness.
The Committee considered the costs used in the company's model. It noted that costs for ischaemic stroke, haemorrhagic stroke, and systemic embolism were based on the Oxford Vascular Study (a cohort study of a UK population) and the costs were similar to those used in other NICE technology appraisals for atrial fibrillation (apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation; rivaroxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation; dabigatran for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation). The Committee also noted that an INR monitoring cost of £265 was used by the company, and that this fell within a range previously accepted in NICE technology appraisals. The Committee concluded that the costs used in the model were appropriate.
The Committee considered the cost effectiveness of edoxaban compared with warfarin. It noted that the company's base‑case deterministic and probabilistic ICERs for edoxaban compared with warfarin were £12,900 and £16,900 per QALY gained respectively. The Committee noted that the ERG considered the economic model to be robust to all of the company's sensitivity analyses, and to most of those done by the ERG. The Committee further considered the ERG's exploratory analyses. It noted that the change which had the largest single impact on the ICER was applying the hazard ratio from ENGAGE AF‑TIMI 48 for haemorrhagic stroke (which increased the ICER to £17,100 per QALY gained). The Committee noted that the inclusion of all the ERG's preferred values in the model (see sections 3.40 and 3.41) resulted in a deterministic ICER of £16,000 per QALY gained and a probabilistic ICER of £22,100 per QALY gained. The Committee concluded that taking all of the analyses into account, edoxaban was cost effective compared with warfarin and could be recommended as an alternative to warfarin for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation who have 1 or more risk factors for stroke.
The Committee noted that the cost effectiveness of edoxaban compared with other newer oral anticoagulants was calculated using hazard ratios from the network meta‑analysis, which the Committee considered to lack robustness (see section 4.8). In the full incremental analysis edoxaban, dabigatran etexilate 110 mg, apixaban and rivaroxaban were strictly dominated by dabigatran etexilate 150 mg, which had an ICER of £7645 per additional QALY gained compared to warfarin. However, there were very small differences in QALYs and costs between the newer oral anticoagulants. The Committee concluded that there was insufficient evidence to distinguish between the clinical and cost effectiveness of edoxaban and the newer oral anticoagulants recommended in previous appraisals (apixaban, dabigatran etexilate and rivaroxaban). Therefore, edoxaban could be recommended as a cost‑effective treatment for non‑valvular atrial fibrillation in people who have 1 or more risk factors for stroke.
The Committee concluded that the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran etexilate and rivaroxaban. For people considering switching from warfarin to edoxaban, the potential risks and benefits of edoxaban should be considered in the light of their level of international normalised ratio (INR) control.
The Committee was aware of NICE's position statement with regard to the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism, when appraising edoxaban. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal of everolimus. It therefore concluded that the PPRS payment mechanism was irrelevant for the consideration of the cost effectiveness of edoxaban.
# Summary of Appraisal Committee's key conclusions
TA355
Appraisal title: Edoxaban for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation
Section
Key conclusion
Edoxaban is recommended, within its marketing authorisation, as an option for preventing stroke and systemic embolism in adults with non‑valvular atrial fibrillation with one or more risk factors, including:
congestive heart failure
hypertension
diabetes
prior stroke or transient ischaemic attack
age 75 years or older.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee was aware that that non‑valvular atrial fibrillation is well‑managed with warfarin for many people but it is associated with a number of problems including the need for regular monitoring and dose adjustment, and it has multiple food and drug interactions. The NICE guideline on managing atrial fibrillation no longer recommends aspirin for the treatment of non‑valvular atrial fibrillation, which has led to a higher uptake of both warfarin and newer oral anticoagulants.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?
The Committee accepted the limitations of warfarin therapy and the considerable impact it may have on the people who take it, and recognised the potential benefits of edoxaban for people with atrial fibrillation.
What is the position of the treatment in the pathway of care for the condition?
Edoxaban is used as an alternative to warfarin, apixaban, rivaroxaban and dabigatran etexilate and is an anticoagulant treatment for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation with 1 or more risk factors for stroke.
Adverse reactions
The Committee concluded that the risk‑benefit profile of edoxaban was acceptable because it resulted in statistically significantly fewer bleeds than warfarin, and a statistically significant reduction in several secondary bleeding endpoints including fatal, intracranial and clinically relevant non‑major bleeds. The Committee recognised the particular importance of the reduction in intracranial bleeding compared with warfarin.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered the clinical effectiveness data from the ENGAGE AF‑TIMI 48 trial that compared edoxaban with warfarin. It considered that the trial was of good quality.
Relevance to general clinical practice in the NHS
Although ENGAGE AF‑TIMI 48 used CHADS2 to assess risk of stroke rather than CHADS2‑VASc (which is now used in clinical practice, as recommended in the NICE guideline on managing atrial fibrillation), the Committee concluded that the trial was well designed and generalisable to clinical practice.
Uncertainties generated by the evidence
The Committee considered the results of the network meta‑analysis in the light of the methodological issues and noted that all the newer oral anticoagulants appeared to have comparable efficacy for the composite primary and bleeding outcomes. The Committee concluded that the network meta‑analysis results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban and dabigatran etexilate in clinical practice.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee concluded that there was insufficient evidence to consider different treatment effects according to centre‑level time in therapeutic range (TTR).
The Committee concluded that there was no biologically plausible reason to indicate that the relative treatment effect would be dependent on baseline risk of stroke.
The Committee concluded that if edoxaban is used in accordance with the summary of product characteristics, there is no reason to make differential recommendations based on creatinine clearance.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that edoxaban was as clinically effective as warfarin for the primary efficacy outcome of reducing stroke (ischaemic and haemorrhagic) and systemic embolism, and had nearly half the rate of haemorrhagic stroke events compared to warfarin.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee agreed that the model structure, perspective and time horizon were appropriate, although it questioned the relevance of the inclusion of myocardial infarction. It concluded that the analysis was consistent with the NICE reference case.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that for the comparison of edoxaban with the other newer oral anticoagulants, hazard ratios obtained from the network meta‑analysis were used in the economic model and that these estimates were considered unreliable by the Evidence Review Group (ERG) (see section 4.8). The Committee concluded that data from ENGAGE AF‑TIMI 48 were appropriate for calculating the cost effectiveness of edoxaban compared with warfarin, but that estimates of the cost effectiveness of edoxaban compared with dabigatran etexilate, apixaban and rivaroxaban were based on data that were associated with a high degree of uncertainty.
Incorporation of health‑related quality‑of‑life benefits and utility values
Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee heard from the ERG that there were differences in the utility values used in the economic model compared with other technology appraisals for atrial fibrillation. The Committee concluded that the utility values used in the model, although open to debate, were not key drivers of the cost effectiveness.
No health‑related benefits were identified that were not included in the economic model.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee concluded that there was insufficient evidence to consider different treatment effects according to centre‑level TTR.
The Committee concluded that if edoxaban is used in accordance with the summary of product characteristics, there is no reason to make differential recommendations based on creatinine clearance.
What are the key drivers of cost effectiveness?
The Committee noted the ERG's exploratory analyses, in which the change that had the largest single impact on the incremental cost‑effectiveness ratio (ICER) for edoxaban compared with warfarin was applying the hazard ratio from ENGAGE AF‑TIMI 48 for haemorrhagic stroke (which increased the ICER to £17,100 per QALY gained).
The Committee concluded that there was insufficient evidence to distinguish between the clinical and cost effectiveness of edoxaban and the newer oral anticoagulants recommended in previous appraisals (apixaban, dabigatran etexilate and rivaroxaban). Therefore, edoxaban could be recommended as a cost‑effective treatment for non‑valvular atrial fibrillation in people who have 1 or more risk factors for stroke.
Most likely cost‑effectiveness estimate (given as an ICER)
The Committee noted that the inclusion of all the ERG's preferred values in the model resulted in a deterministic ICER of £16,000 per QALY gained and a probabilistic ICER of £22,100 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The Committee concluded that the PPRS payment mechanism was irrelevant for the consideration of the cost effectiveness of edoxaban.
End‑of‑life considerations
Not applicable.
Equalities considerations and social value judgements
No equalities issues were identified.
|
{'Recommendations': 'Edoxaban is recommended, within its marketing authorisation, as an option for preventing stroke and systemic embolism in adults with non‑valvular atrial fibrillation with one or more risk factors, including:\n\ncongestive heart failure\n\nhypertension\n\ndiabetes\n\nprior stroke or transient ischaemic attack\n\nage 75\xa0years or older.\n\nDecide whether to start treatment with edoxaban after an informed discussion with the person about its risks and benefits compared with warfarin, apixaban, dabigatran etexilate and rivaroxaban. For people taking warfarin, consider the potential risks and benefits of switching to edoxaban taking into account their level of international normalised ratio (INR) control.', 'The technology': "Edoxaban (Lixiana, Daiichi Sankyo) is an anticoagulant that directly inhibits factor X (factor Xa), which is a key component in the formation of blood clots. It is administered orally. Edoxaban has a marketing authorisation for the 'prevention of stroke and systemic embolism in adult patients with non‑valvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age 75\xa0years or older, diabetes mellitus, prior stroke or transient ischaemic attack (TIA).' The summary of product characteristics states that the recommended dose is 60\xa0mg once daily. The recommended dose is 30\xa0mg once daily in people with one or more of the following clinical factors: moderate or severe renal impairment (creatinine clearance 15 to 50\xa0ml/min); body weight of 60\xa0kg or less; concomitant use of the P‑glycoprotein inhibitors ciclosporin, dronedarone, erythromycin or ketoconazole.\n\nThe summary of product characteristics includes the following adverse reactions for edoxaban: bleeding, anaemia, nausea, rash, hepatobiliary disorders (increased blood bilirubin and gamma‑glutamyl transferase) and abnormal liver function test. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nEdoxaban costs £58.80 for a 28‑tablet pack (60\xa0mg or 30\xa0mg) and the daily cost of treatment is £2.10 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.", "The company's submission": "The Appraisal Committee considered evidence submitted by Daiichi Sankyo and a review of this submission by the Evidence Review Group (ERG).\n\n# Clinical effectiveness\n\n## Overview of clinical trials\n\nThe primary source of evidence was ENGAGE AF‑TIMI\xa048, a randomised, international (46\xa0countries, including 31\xa0centres in the UK) double‑blind, double‑dummy, parallel‑group, non‑inferiority trial comparing edoxaban with warfarin. It included a total of 21,105\xa0people with non‑valvular atrial fibrillation and a moderate‑to‑high risk of stroke, defined as a CHADS2 score of 2 or more (CHADS2 is a scoring system that measures risk factors associated with congestive heart failure, hypertension, age, diabetes and stroke). People were randomly assigned to treatment with low‑dose edoxaban (30\xa0mg, n=7034), high‑dose edoxaban (60\xa0mg, n=7035) or warfarin (n=7036). People randomised to edoxaban who were at increased risk of bleeding because of higher drug exposure (those weighing 60\xa0kg or less, with creatinine clearance 30 to 50\xa0ml/min, or having concomitant treatment with potent permeability glycoprotein inhibitors) had the dose reduced, either at randomisation or during the study, to 15\xa0mg in the low‑dose group and to 30\xa0mg in the high‑dose group. The clinical trial results presented below focus on the higher dose treatment arm because this is the recommended dose in the marketing authorisation. This is referred to throughout as the 60\xa0mg/30\xa0mg treatment arm because it included people who were given 30\xa0mg because of clinical factors. The dose in the warfarin group was adjusted to maintain an international normalised ratio [INR] of 2.0 to 3.0, and people in the trial were 'well controlled' on warfarin (median time spent in the therapeutic range [TTR] was 68.4%).\n\nPatient characteristics were similar between the treatment groups including age, sex, ethnicity, risk factors, CHADS2 score and renal function. The mean CHADS2 score was 2.8 and approximately 53% of patients had a CHADS2 score of 3 or more, indicating that the patient population was at a moderate‑to‑high risk of stroke. The median age of people in the study was 72\xa0years and 62% were male.\n\nThe primary efficacy outcome was time to the first stroke (ischaemic or haemorrhagic) or systemic embolic event. People in the trial continued treatment and were followed up until approximately 672\xa0primary efficacy endpoint events had been collected, which provided 87% power for confirming non‑inferiority for each edoxaban regimen. A non‑inferiority test using the modified intent‑to‑treat (mITT) population for the on‑treatment period was pre‑specified in the statistical analysis plan. To satisfy non‑inferiority, the upper boundary of the one‑sided 97.5% confidence interval for the hazard ratio of the primary efficacy endpoint comparing edoxaban with warfarin could not exceed 1.38, which was an estimate that preserved at least 50% of the benefit of warfarin over placebo. If edoxaban was shown to be statistically significantly non‑inferior to warfarin, a superiority test would be performed using the intent‑to‑treat (ITT) population and the overall study period.\n\n## Clinical trial results\n\nFor the primary efficacy outcome (prevention of stroke or systemic embolic event) in the mITT analysis set (on‑treatment and overall study period), edoxaban 60\xa0mg/30\xa0mg met the criteria for non‑inferiority compared with warfarin. Stroke or a systemic embolic event occurred in 182\xa0people in the edoxaban 60\xa0mg/30\xa0mg arm of the trial (1.18% per year) compared with 232\xa0people in the warfarin arm (1.50% per year, hazard ratio [HR] 0.79, 97.5% confidence interval [CI] 0.63 to 0.99, p<0.001 for non‑inferiority). In the pre‑specified superiority analysis performed in the ITT analysis set (overall study period), the rate of stroke or systemic embolic event was 1.57% per year in the edoxaban 60\xa0mg/30\xa0mg arm compared with 1.80% in the warfarin arm (HR compared with warfarin 0.87; 97.5% CI 0.73 to 1.04, p=0.08 for superiority). Results for the mITT overall study period were consistent with those in the ITT overall study period.\n\nThe company presented results for the analyses of the components of the primary endpoint (stroke and systemic embolism) and the subcomponents of stroke (ischaemic, haemorrhagic, fatal and disabling) for the mITT analysis set (on‑treatment period, and overall study period) and the ITT analysis overall study period. For the mITT overall study period, edoxaban was shown to be superior to warfarin for haemorrhagic stroke (p=0.001). The results were similar for the mITT population, the on‑treatment period analysis and the ITT population analysis.\n\nThe company presented analyses for the primary efficacy results using the mITT analysis set (overall study period) for subgroups according to risk of stroke (defined by CHADS2 score) and renal function (creatinine clearance). The subgroup analysis for risk of stroke demonstrated that, compared with warfarin, the hazard ratio for the edoxaban 60\xa0mg/30\xa0mg dose was stable and non‑inferior across CHADS2 scores of 2 to 6. The subgroup analysis for renal function across 3\xa0categories of creatinine clearance (normal renal function 80\xa0ml/min or more; mild renal impairment more than 50 to less than 80\xa0ml/min; and moderate renal impairment 30 to 50\xa0ml/min), suggested that renal function had a significant impact on the efficacy of edoxaban in comparison to warfarin (p=0.0042). This result was shown to be consistent across analysis sets. The hazard ratios for the primary efficacy endpoint were 0.68 (95% CI 0.54 to 0.85) and 0.86 (95% CI 0.63 to 1.17) for the subgroups of people with mild or moderate renal impairment, respectively. In contrast, the relative risk of stroke or systemic embolic event was higher with edoxaban than with warfarin in the subgroup of people with normal renal function (HR 1.31, 95% CI 0.96 to 1.79). The company noted that this analysis should be treated with caution because a variety of factors (including an unusually low event rate in the warfarin group, and potential imbalances between treatment groups because of randomisation not being performed within subgroups) could have contributed to the observed hazard ratio for stroke or systemic embolic event compared with warfarin in the subgroup of people with normal renal function.\n\nThe company also did an analysis comparing centre‑level TTR above and below 60%. The p\xa0value for interaction was 0.0361 which indicated that in centres with a TTR above 60% edoxaban had a similar effect compared with warfarin to that observed in the total study population, but there was a significant reduction in risk of stroke and systemic embolism in the subgroup with a centre‑level TTR of less than 60%. When the TTR data were examined by quartiles, however, the p\xa0value for interaction was 0.50.\n\n## Health‑related quality of life\n\nHealth‑related quality of life data were collected in ENGAGE AF‑TIMI\xa048 using the self‑administered EQ‑5D questionnaire at baseline and then every 3\xa0months, until the end of the study. Approximately 60% of patients (11,995\xa0patients) provided quality‑of‑life data; 164\xa0(1.4%) patients were from the UK.\n\n## ERG comments on the clinical effectiveness data\n\nThe ERG noted that the statistically significant result for non‑inferiority in ENGAGE AF‑TIMI\xa048 was driven largely by a reduction in haemorrhagic stroke events in patients treated with edoxaban, but there was no statistically significant difference between edoxaban and warfarin for any other listed component or subcomponent.\n\nThe ERG commented that the estimate of treatment effect (hazard ratio) for the primary outcome may not be reliable because the assumption of proportional hazards between treatment with edoxaban or warfarin for haemorrhagic stroke (one of the components of the primary outcome) appeared to be violated. The hazard trend in the warfarin group changed sharply at 6\xa0months, in comparison with a smooth hazard trend over time in the edoxaban group.\n\nThe ERG noted that the results of the analysis for centre‑level TTR suggested that the efficacy of edoxaban in comparison to warfarin is significantly greater in the subgroup of centres achieving TTR of less than 60%, but this was not consistent across all analysis sets. There was no significant difference in the results from centres with a TTR of less than or greater than 60% when the analysis was conducted using the mITT population and the on‑treatment observation period. The ERG therefore suggested that the finding that centre‑level TTR may affect the efficacy of edoxaban in comparison to warfarin may be spurious.\n\nThe ERG stated that the health‑related quality of life data provided during the clarification process were difficult to interpret because of the low response rate and incomplete analysis. The ERG therefore suggested that it was difficult to draw any firm conclusions about any differences in patients' experiences that are attributable to the choice of treatment.\n\n## Adverse effects of treatment\n\nThe company presented the results of the safety analyses, which included all people who had at least 1\xa0dose of study drug for the on‑treatment period in ENGAGE AF‑TIMI\xa048. In the principal safety analysis for the edoxaban 60\xa0mg/30\xa0mg arm compared with warfarin, the company stated that edoxaban had a significantly reduced rate of major bleeding (HR 0.80, 95% CI 0.71 to 0.91; p<0.001) and of several secondary bleeding endpoints including intracranial, fatal, clinically relevant non‑major and life‑threatening bleeds (p≤0.01 for all comparisons). However, the company highlighted that major gastrointestinal bleeding occurred slightly more frequently in the edoxaban 60\xa0mg/30\xa0mg arm than in the warfarin arm (annualised rate of 1.51% compared with 1.23%, respectively; HR 1.23 [1.02 to 1.50]; p=0.03).\n\nThe company stated that the 5\xa0most frequent treatment‑emergent adverse events in the edoxaban or warfarin groups were urinary tract infections, nasopharyngitis, bronchitis, dizziness and peripheral oedema. The company presented subgroup analyses for the primary safety outcome by centre‑level TTR and by risk of stroke (as defined by CHADS2), which were consistent with the overall population.\n\n## Network meta‑analysis\n\nThe company did not find any head‑to‑head studies that compared edoxaban with rivaroxaban, dabigatran etexilate or apixaban so it did a network meta‑analysis to estimate the relative efficacy and safety of edoxaban for treating atrial fibrillation, that included 4\xa0trials: ENGAGE AF‑TIMI\xa048, and 3\xa0trials of other newer oral anticoagulants (apixaban 5\xa0mg twice‑daily [ARISTOTLE]; dabigatran etexilate 150\xa0mg twice‑daily or 110\xa0mg twice‑daily [RE‑LY]; and rivaroxaban 20\xa0mg once‑daily [ROCKET‑AF]). All 4\xa0RCTs had a warfarin treatment arm. Because of significant differences in the patient characteristics and trial design between the 4\xa0trials (for example, ARISTOTLE and RE‑LY included people with a CHADS2 score of 1\xa0or more, whereas the CHADS2 score was 2\xa0or more in both ENGAGE AF‑TIMI\xa048 and ROCKET‑AF) only data from patients with a CHADS2 score of 2\xa0or more from RE‑LY and ARISTOTLE were used in the network meta‑analyses.\n\nThe results of the meta‑analysis demonstrated that for the composite endpoint of stroke and systemic embolism, efficacy was similar for high‑dose edoxaban compared to other newer oral anticoagulants, but edoxaban significantly reduced major bleeding risk by 24%, 28%, and 17% compared to rivaroxaban, dabigatran etexilate 150\xa0mg and dabigatran etexilate 110\xa0mg, respectively. Major bleeding rates were similar between high‑dose edoxaban and apixaban.\n\n## Evidence Review Group's comments on the network meta‑analysis\n\nThe ERG considered that the key characteristics of the trials (study population, design, outcome measures; and effect modifiers such as age, disease severity, and duration of follow‑up) included in the network meta‑analyses were sufficiently similar to justify combining the results. The company's approach used annualised event rates and the ERG considered that this approach minimised any potential bias resulting from differences in trial duration, which ranged from 1.8\xa0years in ARISTOTLE (apixaban) to 2.8\xa0years in ENGAGE AF‑TIMI\xa048 (edoxaban).\n\nThe ERG noted that in addition to the violation of the proportional hazards assumption for some end points within ENGAGE AF‑TIMI\xa048, it was also violated within trials of the other 3\xa0newer oral anticoagulants, and in the warfarin groups of the 4\xa0trials included in the evidence network. The ERG highlighted that this meant the hazard ratios from the network meta‑analysis were not reliable and should not be used to inform the company's economic model.\n\n# Cost effectiveness\n\nThe company developed a Markov cohort model to compare edoxaban with warfarin, apixaban, rivaroxaban and dabigatran etexilate for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation with 1\xa0or more risk factors, such as congestive heart failure, hypertension, age 75\xa0years or more, diabetes, previous stroke or transient ischaemic attack, and a CHADS2 score of at least 2 (the baseline characteristics of ENGAGE AF‑TIMI\xa048). The model consisted of 18\xa0health states (patients entering the model with 'stable AF'), with 1‑month cycles and a 30‑year (remaining lifetime) time horizon from a starting age of 71\xa0years. The company conducted the analysis from the perspective of the NHS and personal social services, and discounted costs and health effects at an annual rate of 3.5%. A half‑cycle correction was applied to both costs and QALYs (with the exception of drug costs). The model design was based on previous economic analyses that were submitted to NICE (for example, apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation).\n\nThe health states in the company's model were defined by the clinical events considered to have a permanent impact on patients and were assumed to have an initial, as well a long‑term, impact on costs, quality of life and mortality. The health states captured the main thrombotic events and adverse events of treatment including haemorrhagic and ischaemic stroke (separated into mild, moderate and severe), systemic embolism and myocardial infarction. Health states were further subdivided into an initial health state (in which costs and quality of life associated with the acute event and the case fatality rate were applied in the month after the initial event), and a long‑term health state in which ongoing event costs, quality of life and mortality were applied in each monthly cycle. Events that were considered to have no long‑term impact in the model were other intracranial haemorrhage, non‑intracranial haemorrhage major bleeds, clinically relevant non‑major bleeds, and transient ischaemic attack. In the model, these events incurred costs and a disutility for the length of the event.\n\nThe monthly probability of each clinical outcome for edoxaban was estimated from annual event rates from ENGAGE AF‑TIMI\xa048. The transition probabilities for the comparators were obtained by applying the hazard ratio from the network meta‑analysis for the intervention to the baseline probability. When there were no available data for a clinical outcome, it was assumed that the hazard ratio was equivalent to the hazard ratio estimated in the 'all patients' analysis. If there were no available data in the 'all patients' analysis, the hazard ratio was assumed to be 1.\n\nIn the model, people could permanently stop or switch treatment after an ischaemic stroke or a haemorrhagic stroke. After stopping treatment and switching to a new therapy, the transition probability (of health state and event) did not change to reflect the new therapy. The company assumed that people could not stop or switch treatment for any other reason because there would be no difference between treatment groups.\n\nThe adverse events considered in the company's model were non‑intracranial haemorrhage major bleed, clinically relevant non‑major bleeds, other intracranial haemorrhage, and transient ischaemic attack (assumed to be transient on clinical advice).\n\n## ERG comments\n\nThe ERG considered that the assumption of proportionality that underpinned the network meta‑analysis had been shown to be violated both within and between trials (see also sections 3.10 and 3.18). The ERG highlighted that this meant the hazard ratios used to inform the company's economic model were therefore unreliable.\n\nThe ERG highlighted that the model predicted that, of a cohort of 1000\xa0people with non‑valvular atrial fibrillation having warfarin, there will be 157\xa0stroke events. Using the company's approach to applying the risk of acute‑stroke mortality, approximately 15 (9.6%) of these would be fatal, which is substantially less than the 16.8% reported in the study by Janes. The ERG assessed the impact of applying the acute mortality rates reported by Janes to all patients experiencing a stroke (ischaemic stroke and haemorrhagic stroke analysed separately) (see sections 3.40 and 3.41). The ERG noted that mortality data from ENGAGE AF‑TIMI\xa048 were not used in the model and no rationale for this was given by the company. The ERG considered it more appropriate to use mortality data from ENGAGE AF‑TIMI 48. Therefore, in its exploratory analyses, the ERG extracted acute mortality data for ischaemic stroke and haemorrhagic stroke from the clinical study report (CSR50, page 132) and pooled it across the warfarin and edoxaban groups of the trial (see sections 3.40 and 3.41).\n\nThe ERG highlighted that the model overestimated overall survival for both treatment groups compared with ENGAGE AF‑TIMI\xa048, and that this potentially underestimated the relative effectiveness of edoxaban compared to warfarin.\n\n## Utility values\n\nThe baseline quality of life for the health state of stable atrial fibrillation in the company's model (0.78) was taken from a study of patients with atrial fibrillation having warfarin in the UK (Khan, 2004). In the sensitivity analyses, health‑related quality of life data from ENGAGE AF‑TIMI\xa048 were used (0.836). Health‑related quality of life declined over time based on an adjustment for cohort aging (-0.00029 per year) to reflect the impact of age and thrombotic events on a patient's quality of life. Utility estimates for mild, moderate and severe stroke were derived from a published study by Gage (1996). The company assumed that patients who have a stroke, myocardial infarction or systemic embolic event experience a permanent decrement to their health‑related quality of life.\n\n## ERG comments\n\nThe ERG noted that the base case utility value for the stable atrial fibrillation health state had been derived from a UK study by Khan which had a modest sample size of 125\xa0patients, with a low response rate, and was designed to assess the effectiveness of an anticoagulation education programme and self‑monitoring of patients with atrial fibrillation taking warfarin. The ERG did not consider this to be representative of a general atrial fibrillation population and it preferred the use of EQ‑5D data collected in ENGAGE AF‑TIMI\xa048.\n\nThe ERG highlighted that the age‑related utility decrement in the model (-0.00029 per annum) based on self‑reported health status of a US population and valued using the UK tariff may not be generalisable to a UK population. The ERG preferred to use EQ‑5D data from the Health Survey for England in its analysis, because this was a more representative population for the UK. This produced an estimated annual utility decrement of -0.00646.\n\n## Resource use\n\nThe company used the British National Formulary 68 (July 2014) to obtain drug costs in the model. All costs for the health states of ischaemic stroke, haemorrhagic stroke and systemic embolic events were based on the Oxford Vascular study (OXVASC, 2013), a large study of healthcare costs after stroke in patients with atrial fibrillation. Costs associated with myocardial infarction were based on NHS reference costs. Post‑myocardial infarction costs were based on the Electronic Drug Tariff and the British National Formulary 68 (July 2014).\n\nThe monitoring costs for warfarin patients were adapted from the unit cost of anticoagulation monitoring used in the NHS Costing Template for dabigatran etexilate, which was also used in the apixaban technology appraisal. These costs were inflated to 2013 costs using the Personal Social Services Research Unit Hospital and Community Services Health Index (HCHS). The model assumed that 34% of patients will be seen in a secondary care setting (at a cost of £323.10) with the remaining 66% seen in primary care (£235.11) giving a weighted average annual cost of £265.03.\n\n## ERG comments on resource use\n\nThe ERG noted that although the cost of warfarin used in the company's model (£0.11 per day) was estimated using the list prices reported in the British National Formulary, it is widely available to the NHS at discounted prices. The ERG did an exploratory analysis using the warfarin cost estimated from figures reported in the Department of Health's eMit database (£0.0375).\n\n## Company's base‑case results and sensitivity analysis\n\nIn the company's deterministic base case analysis (based on people with CHADS2 ≥2), edoxaban, dabigatran etexilate 110\xa0mg, apixaban and rivaroxaban were strictly dominated (less effective and more costly) by dabigatran etexilate 150\xa0mg, which had an incremental cost‑effectiveness ratio (ICER) of £7645 per additional QALY gained compared to warfarin (table 1).\n\nTechnology\n\nTotal costs\n\nTotal QALYs*\n\nInc costs\n\nInc QALYs\n\nICER vs warfarin (QALYs)\n\nICER per QALY gained (£)\n\nWarfarin\n\n£13,413\n\n\n\n–\n\n–\n\n–\n\n–\n\nDabigatran etexilate 150\xa0mg\n\n£15,563\n\n\n\n£2150\n\n\n\n£7645\n\n£7645\n\nApixaban\n\n£15,940\n\n\n\n£377\n\n-0.01\n\n£9383\n\nStrictly dominated\n\nEdoxaban\n\n£15,957\n\n\n\n£17\n\n-0.07\n\n£12,881\n\nStrictly dominated\n\nDabigatran etexilate 110\xa0mg\n\n£16,074\n\n\n\n£117\n\n\n\n£13,565\n\nStrictly dominated\n\nRivaroxaban\n\n£16,744\n\n\n\n£670\n\n-0.08\n\n£28,180\n\nStrictly dominated\n\nAbbreviations: ICER, incremental cost‑effectiveness ratio; Inc, incremental; QALYs, quality-adjusted life years.\n\nThe company presented cost‑effectiveness acceptability curves for the incremental analysis, which showed that the probability of edoxaban being cost effective was 2.9% at a maximum acceptable ICER of £20,000 per QALY gained, and 3.4% at a threshold of £30,000 per QALY gained. Warfarin had the highest probability (36.8%) of being the most cost‑effective option at a threshold of £20,000 per QALY gained. At a maximum acceptable ICER of £30,000 per QALY gained, apixaban had the highest probability of being the most cost‑effective option (32.6%). In the pairwise comparison of edoxaban compared with warfarin, the probability of edoxaban being cost effective was 47.1% at a maximum acceptable ICER of £20,000 per QALY gained and 57.1% at a maximum acceptable ICER of £30,000 per QALY gained.\n\nThe company did 14\xa0pairwise deterministic sensitivity analyses. It highlighted that the variables that had the most impact on the deterministic base case results were patients' starting age (lower limit 52.1\xa0years, upper limit 89.1\xa0years), cost of treatment, monitoring costs for patients treated with edoxaban (baseline £0, upper limit £26.50), and the utility values of stable atrial fibrillation, post‑event myocardial infarction and haemorrhagic stroke.\n\nThe company presented results of subgroup analyses for people with a CHADS2 score of 3\xa0or more, or with a centre‑level TTR of 60% or more. In people with a CHADS2 score of 3\xa0or more edoxaban, dabigatran etexilate 110\xa0mg, and rivaroxaban were strictly dominated (less effective and more costly) by apixaban and dabigatran etexilate 150\xa0mg. For the subgroup of people with a centre‑level TTR of 60% or more, edoxaban, dabigatran etexilate 110\xa0mg, apixaban and rivaroxaban were strictly dominated by dabigatran etexilate 150\xa0mg, which had an ICER of £11,738 per additional QALY gained compared to warfarin.\n\n## ERG's comments on the company's cost‑effectiveness model results\n\nResults from the company's base case probabilistic analysis were not explicitly included in the submission. However, they were calculated by the ERG using the company's model (table\xa02). Edoxaban, dabigatran etexilate 110\xa0mg and rivaroxaban were strictly dominated by dabigatran etexilate 150\xa0mg and apixaban extendedly dominated dabigatran etexilate 150\xa0mg (more effective and less costly) with an ICER of £13,036 per QALY gained compared to warfarin.\n\n\n\nCosts\n\nQALYs\n\nIncremental Cost\n\nIncremental QALY\n\nICER\n\nWarfarin\n\n£12,868\n\n\n\n–\n\n–\n\n–\n\nRivaroxaban\n\n£16,313\n\n\n\n–\n\n–\n\nDominated\n\nDabigatran etexilate 110\xa0mg\n\n£15,732\n\n\n\n–\n\n–\n\nDominated\n\nEdoxaban\n\n£15,451\n\n\n\n–\n\n–\n\nDominated\n\nDabigatran etexilate 150\xa0mg\n\n£15,293\n\n\n\n£2425\n\n\n\nExtendedly dominated\n\nApixaban\n\n£15,531\n\n\n\n£2662\n\n\n\n£13,036\n\nAbbreviations: ICER, incremental cost‑effectiveness ratio; Inc, incremental; QALYs, quality-adjusted life years.\n\nThe ERG highlighted that in the company's probabilistic and deterministic analyses edoxaban was dominated (less effective and more costly than at least one alternative treatment). However, in the deterministic analysis dabigatran etexilate 150\xa0mg dominated (was less costly and more effective than) the other, newer, oral anticoagulants, whereas in the probabilistic analysis apixaban dominated dabigatran etexilate 150\xa0mg. The ERG considered that this was because of the very small differences in QALYs between dabigatran etexilate 150\xa0mg and apixaban in all analyses. In addition, the ERG noted that the results of the probabilistic analysis were not completely stable (repeated runs of the same analyses gave slightly different results).\n\nThe ERG considered that because the subgroup analyses for patients with a CHADS2 of 3\xa0or more and for centre‑level TTR of 60% or more were based on very limited data, the extent to which these results were truly representative of effects in these subgroups is unclear.\n\n## ERG's exploratory analyses\n\nThe ERG noted that the economic model appeared to be robust to the sensitivity analyses carried out by the company. The ERG carried out 17\xa0individual exploratory scenarios, which used its preferred alternative parameter values or formulae. The ERG also combined multiple parameters to give their preferred base case, which included:\n\ncorrected implementation of age‑related utility adjustment\n\nERG‑sourced utility values for systemic embolism\n\nalternative utility values for myocardial infarction, transient ischaemic attack and ERG‑sourced utility values for acute and post‑stroke health states\n\nassumption regarding the method used to switch patient medication from dabigatran 150\xa0mg to 110\xa0mg at age 80\n\nassumption regarding treatment discontinuation after haemorrhagic stroke\n\nacute stroke fatality rate applied to all stroke events (16.8% for ischaemic and 31.6% for haemorrhagic stroke)\n\ntrial data on acute stroke case fatality rates used for all ischaemic and haemorrhagic strokes\n\nage‑adjusted utility decrement per year amended to -0.00646 instead of -0.00029\n\nthe daily cost of warfarin amended\n\nthe ENGAGE trial HR applied for haemorrhagic stroke.\n\nNone of the ERG's amendments to the company's model changed the results of the full incremental analyses; edoxaban was more expensive and less effective than at least one of the alternative treatments. When all of the ERG's preferred values were used in the model the pairwise deterministic ICER for the comparison of edoxaban with warfarin was £16,008 per QALY gained, and the probabilistic ICER was £22,079 per QALY gained. When additional alternative amendments were included to reconcile the model survival outputs with the trial data, and to reflect the changing age and sex distribution over time, this changed the deterministic pairwise ICER to between approximately £15,176 and £15,807, and the probabilistic ICER to between £21,728 and £23,634 per QALY gained.\n\nSee the committee papers for full details of the evidence.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of edoxaban, having considered evidence on the nature of non‑valvular atrial fibrillation and the value placed on the benefits of edoxaban by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe Committee heard from clinical and patient experts that the current standard treatment for non‑valvular atrial fibrillation is warfarin, although there is increasing use of newer agents. The Committee was aware that non‑valvular atrial fibrillation is well‑managed with warfarin for many people, but is associated with a number of problems including the need for regular monitoring and dose adjustment, and it has multiple food and drug interactions. The Committee heard from the patient and clinical experts that the number of people being prescribed anticoagulation treatment for atrial fibrillation is increasing following publication of the NICE guideline on managing atrial fibrillation. This does not recommend aspirin for the treatment of non‑valvular atrial fibrillation, which has led to a higher uptake of both warfarin and the newer oral anticoagulants. The Committee concluded that both warfarin and the newer oral anticoagulants are relevant comparators for edoxaban. The Committee accepted the limitations of warfarin therapy and the considerable impact it may have on people who take it, and recognised the potential benefits of edoxaban for people with non‑valvular atrial fibrillation.\n\n# Clinical effectiveness\n\nThe Committee considered the clinical‑effectiveness data from ENGAGE AF‑TIMI\xa048, that compared edoxaban with warfarin. It considered that this trial was of good quality and discussed whether the results were generalisable to people with atrial fibrillation in the UK. The Committee noted that ENGAGE AF‑TIMI\xa048, like other trials of newer anticoagulants, used CHADS2 to assess the risk of stroke rather than CHADS2‑VASc, which is now used in clinical practice, as recommended in the NICE guideline on managing atrial fibrillation. The Committee understood from the clinical expert that the CHADS2‑VASc scoring system was developed to better define those who would benefit from anticoagulation because a number people with a CHADS2 score of\xa01 would still benefit. It also heard that although these people were not included in ENGAGE AF‑TIMI\xa048, a lower baseline risk of stroke would not be expected to reduce the relative efficacy of the treatment. In clinical practice, edoxaban is expected to be offered in the same place in the treatment pathway as other anticoagulants (that is, to women with a CHADS2‑VASc score of 2 and above, and to men with a score of 1 or above), while taking bleeding risk into account. The Committee concluded that the trial was well designed and generalisable to clinical practice.\n\nThe Committee considered the results of ENGAGE AF‑TIMI\xa048. It noted that the primary efficacy outcome was a composite of stroke (both ischaemic and haemorrhagic) and systemic embolism. However, ischaemic stroke and systemic embolism could be considered direct treatment effects, whereas haemorrhagic stroke was a bleeding outcome and therefore an adverse event. The Committee noted that for the composite primary outcome, edoxaban was non‑inferior to, but not superior to, well‑controlled warfarin (which was defined in the trial as a median time in therapeutic range [TTR] of 68.4%). The Committee noted that when the individual components of the primary outcome were considered separately, there was only a statistically significant reduction in haemorrhagic stroke with edoxaban compared with warfarin. The Committee concluded that edoxaban was as clinically effective as warfarin for the primary efficacy outcome of reducing stroke (ischaemic and haemorrhagic) and systemic embolism, and had nearly half the rate of haemorrhagic stroke events compared to warfarin.\n\nThe Committee considered the results of the company's subgroup analyses, which used data from ENGAGE AF‑TIMI\xa048. It noted that the company presented data for subgroups based on international normalised ratio (INR) control, that compared the efficacy of edoxaban and warfarin in relation to the median TTR for the study centre. One of the analyses showed that the relative benefits of edoxaban compared with warfarin were greater in centres where the centre‑level TTR was less than 60%. The Committee noted comments from the company and the Evidence Review Group (ERG) that this was not consistent across all analysis sets. The Committee concluded that there was insufficient evidence to consider different treatment effects according to centre‑level TTR.\n\nThe Committee noted that the company's subgroup analyses for risk of stroke (as defined by CHADS2 score) showed that the hazard ratio for edoxaban compared with warfarin was stable and non‑inferior across CHADS2 scores of 2 to 6. The Committee concluded that there was no biologically plausible reason to indicate that the relative treatment effect would be dependent on the baseline risk of stroke.\n\nThe Committee discussed the subgroup analysis based on renal function, which used 3\xa0categories of creatinine clearance (normal renal function, and mild or moderate impairment). It noted that the results of this analysis suggested a trend towards decreasing efficacy of edoxaban with increasing creatinine clearance (see section\xa03.6). The Committee heard from a clinical expert that this was likely to be because with better renal function edoxaban is removed by the kidneys more quickly, leading to a reduction in treatment effect. It also heard that this may apply to all newer oral anticoagulants, but data need to be re‑evaluated to confirm this. It heard from the clinical experts that the proportion of people with good renal function (measured by creatinine clearance) who would be eligible for treatment with edoxaban was in the region of 5% to 10%, and that these are often younger people. The Committee noted the company's rationale that the results of this sub‑group analysis should be interpreted with caution (see section 3.6). It also noted the summary of product characteristics which states that, in people with non‑valvular atrial fibrillation and high creatinine clearance, edoxaban should only be used after careful evaluation of a person's thromboembolic and bleeding risk. The Committee concluded that if edoxaban is used in accordance with the summary of product characteristics, there is no reason to make differential recommendations based on creatinine clearance.\n\nThe Committee considered the adverse events reported in ENGAGE AF‑TIMI\xa048. It noted that for the primary safety outcome of major bleeding, edoxaban resulted in statistically significantly fewer bleeds than warfarin. Edoxaban also had statistically significantly fewer other bleeding events including fatal, intracranial and clinically relevant non‑major bleeds. The Committee recognised the particular importance of the reduction in intracranial bleeding compared with warfarin. It also noted the statistically significantly higher numbers of gastrointestinal bleeds in people treated with edoxaban compared with warfarin. The Committee was aware that this is not unique to edoxaban, and that clinicians are now more experienced in using the newer oral anticoagulants and in managing the adverse events. It also heard from the clinical experts that administration of 4‑factor prothrombin complex concentrate has been shown to reverse the effects of edoxaban. The Committee concluded that the risk–benefit profile of edoxaban was acceptable.\n\nThe Committee discussed the data for edoxaban compared with rivaroxaban, apixaban, dabigatran etexilate (110\xa0mg twice daily and 150\xa0mg twice daily) and rivaroxaban, that were used in the company's network meta‑analysis. The Committee noted that the trials included in the network meta‑analysis were not directly comparable; for example, they had different baseline risks of stroke (with different CHADS2 inclusion criteria and mean CHADS2 scores) and differences in time in the therapeutic range in the warfarin groups. The Committee also noted the ERG's concerns about the violation of the proportional hazards assumption in data from ENGAGE AF‑TIMI\xa048, from the trials of the other 3\xa0newer oral anticoagulants, and in the warfarin groups of the 4\xa0trials included in the network meta‑analysis. It understood from the ERG that this meant that the hazard ratios produced by the network meta‑analysis were not sufficiently robust to compare the relative clinical effectiveness of the newer oral anticoagulants. The Committee considered the results of the network meta‑analysis in the light of the methodological issues and noted that all the newer oral anticoagulants appeared to have comparable efficacy for the composite primary and bleeding outcomes. The Committee concluded that the network meta‑analysis results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban and dabigatran etexilate in clinical practice.\n\n# Cost effectiveness\n\nThe Committee considered the company's economic model. It noted that the economic analysis was largely based on the model used in NICE's technology appraisal guidance on apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation, which captured the main efficacy and adverse events of treatment. The Committee agreed that the model structure, perspective and time horizon were appropriate, although it questioned the relevance of the inclusion of myocardial infarction. It concluded that the analysis was consistent with the NICE reference case.\n\nThe Committee considered the clinical‑effectiveness estimates used in the company's model. It noted that the comparison of edoxaban with warfarin used direct evidence from ENGAGE AF‑TIMI\xa048 to inform the company's economic model. The Committee was aware of the ERG's concern that the assumption of proportional hazards for edoxaban and warfarin for haemorrhagic stroke (one of the components of the primary outcome) appeared to be violated in ENGAGE AF‑TIMI 48. However, the Committee considered that the general modelling approach and the pairwise comparison with warfarin were appropriate. The Committee noted that for the comparison of edoxaban with the other newer oral anticoagulants, hazard ratios obtained from the network meta‑analysis were used in the economic model and that these estimates were considered unreliable by the ERG (see section\xa04.8). The Committee concluded that data from ENGAGE AF‑TIMI\xa048 were appropriate for calculating the cost effectiveness of edoxaban compared with warfarin, but the estimates of the cost effectiveness of edoxaban compared with dabigatran etexilate, apixaban and rivaroxaban were based on data that were associated with a high degree of uncertainty.\n\nThe Committee heard from the ERG that there were differences in the utility values used in the economic model, compared with other NICE technology appraisals for atrial fibrillation (apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation; rivaroxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation; dabigatran for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation). It noted that even though EQ‑5D data were collected at baseline in ENGAGE AF‑TIMI\xa048 , the baseline utility value for stable atrial fibrillation used in the model was from another small UK study. The Committee noted that the ERG had identified a number of inconsistencies and had raised concerns about some of the sources of data used in the company model. However, the Committee noted that when the ERG's suggested revisions (alternative utility estimates for systemic embolism, myocardial infarction, and transient ischaemic attack) were applied, together with an amended age‑adjusted utility decrement per year of -0.00646 instead of -0.00029 (see sections 3.40 and 3.41), they had only a minor impact on the incremental cost‑effectiveness ratio (ICER). The Committee concluded that the utility values used in the model, although open to debate, were not key drivers of the cost effectiveness.\n\nThe Committee considered the costs used in the company's model. It noted that costs for ischaemic stroke, haemorrhagic stroke, and systemic embolism were based on the Oxford Vascular Study (a cohort study of a UK population) and the costs were similar to those used in other NICE technology appraisals for atrial fibrillation (apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation; rivaroxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation; dabigatran for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation). The Committee also noted that an INR monitoring cost of £265 was used by the company, and that this fell within a range previously accepted in NICE technology appraisals. The Committee concluded that the costs used in the model were appropriate.\n\nThe Committee considered the cost effectiveness of edoxaban compared with warfarin. It noted that the company's base‑case deterministic and probabilistic ICERs for edoxaban compared with warfarin were £12,900 and £16,900 per QALY gained respectively. The Committee noted that the ERG considered the economic model to be robust to all of the company's sensitivity analyses, and to most of those done by the ERG. The Committee further considered the ERG's exploratory analyses. It noted that the change which had the largest single impact on the ICER was applying the hazard ratio from ENGAGE AF‑TIMI\xa048 for haemorrhagic stroke (which increased the ICER to £17,100 per QALY gained). The Committee noted that the inclusion of all the ERG's preferred values in the model (see sections 3.40 and 3.41) resulted in a deterministic ICER of £16,000 per QALY gained and a probabilistic ICER of £22,100 per QALY gained. The Committee concluded that taking all of the analyses into account, edoxaban was cost effective compared with warfarin and could be recommended as an alternative to warfarin for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation who have 1\xa0or more risk factors for stroke.\n\nThe Committee noted that the cost effectiveness of edoxaban compared with other newer oral anticoagulants was calculated using hazard ratios from the network meta‑analysis, which the Committee considered to lack robustness (see section\xa04.8). In the full incremental analysis edoxaban, dabigatran etexilate 110\xa0mg, apixaban and rivaroxaban were strictly dominated by dabigatran etexilate 150\xa0mg, which had an ICER of £7645 per additional QALY gained compared to warfarin. However, there were very small differences in QALYs and costs between the newer oral anticoagulants. The Committee concluded that there was insufficient evidence to distinguish between the clinical and cost effectiveness of edoxaban and the newer oral anticoagulants recommended in previous appraisals (apixaban, dabigatran etexilate and rivaroxaban). Therefore, edoxaban could be recommended as a cost‑effective treatment for non‑valvular atrial fibrillation in people who have 1\xa0or more risk factors for stroke.\n\nThe Committee concluded that the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran etexilate and rivaroxaban. For people considering switching from warfarin to edoxaban, the potential risks and benefits of edoxaban should be considered in the light of their level of international normalised ratio (INR) control.\n\nThe Committee was aware of NICE's position statement with regard to the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism, when appraising edoxaban. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal of everolimus. It therefore concluded that the PPRS payment mechanism was irrelevant for the consideration of the cost effectiveness of edoxaban.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA355\n\nAppraisal title: Edoxaban for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation\n\nSection\n\nKey conclusion\n\nEdoxaban is recommended, within its marketing authorisation, as an option for preventing stroke and systemic embolism in adults with non‑valvular atrial fibrillation with one or more risk factors, including:\n\ncongestive heart failure\n\nhypertension\n\ndiabetes\n\nprior stroke or transient ischaemic attack\n\nage 75 years or older.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee was aware that that non‑valvular atrial fibrillation is well‑managed with warfarin for many people but it is associated with a number of problems including the need for regular monitoring and dose adjustment, and it has multiple food and drug interactions. The NICE guideline on managing atrial fibrillation no longer recommends aspirin for the treatment of non‑valvular atrial fibrillation, which has led to a higher uptake of both warfarin and newer oral anticoagulants.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee accepted the limitations of warfarin therapy and the considerable impact it may have on the people who take it, and recognised the potential benefits of edoxaban for people with atrial fibrillation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nEdoxaban is used as an alternative to warfarin, apixaban, rivaroxaban and dabigatran etexilate and is an anticoagulant treatment for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation with 1 or more risk factors for stroke.\n\n\n\nAdverse reactions\n\nThe Committee concluded that the risk‑benefit profile of edoxaban was acceptable because it resulted in statistically significantly fewer bleeds than warfarin, and a statistically significant reduction in several secondary bleeding endpoints including fatal, intracranial and clinically relevant non‑major bleeds. The Committee recognised the particular importance of the reduction in intracranial bleeding compared with warfarin.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered the clinical effectiveness data from the ENGAGE AF‑TIMI\xa048 trial that compared edoxaban with warfarin. It considered that the trial was of good quality.\n\n\n\nRelevance to general clinical practice in the NHS\n\nAlthough ENGAGE AF‑TIMI\xa048 used CHADS2 to assess risk of stroke rather than CHADS2‑VASc (which is now used in clinical practice, as recommended in the NICE guideline on managing atrial fibrillation), the Committee concluded that the trial was well designed and generalisable to clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee considered the results of the network meta‑analysis in the light of the methodological issues and noted that all the newer oral anticoagulants appeared to have comparable efficacy for the composite primary and bleeding outcomes. The Committee concluded that the network meta‑analysis results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban and dabigatran etexilate in clinical practice.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee concluded that there was insufficient evidence to consider different treatment effects according to centre‑level time in therapeutic range (TTR).\n\n\n\nThe Committee concluded that there was no biologically plausible reason to indicate that the relative treatment effect would be dependent on baseline risk of stroke.\n\n\n\nThe Committee concluded that if edoxaban is used in accordance with the summary of product characteristics, there is no reason to make differential recommendations based on creatinine clearance.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that edoxaban was as clinically effective as warfarin for the primary efficacy outcome of reducing stroke (ischaemic and haemorrhagic) and systemic embolism, and had nearly half the rate of haemorrhagic stroke events compared to warfarin.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee agreed that the model structure, perspective and time horizon were appropriate, although it questioned the relevance of the inclusion of myocardial infarction. It concluded that the analysis was consistent with the NICE reference case.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that for the comparison of edoxaban with the other newer oral anticoagulants, hazard ratios obtained from the network meta‑analysis were used in the economic model and that these estimates were considered unreliable by the Evidence Review Group (ERG) (see section\xa04.8). The Committee concluded that data from ENGAGE AF‑TIMI\xa048 were appropriate for calculating the cost effectiveness of edoxaban compared with warfarin, but that estimates of the cost effectiveness of edoxaban compared with dabigatran etexilate, apixaban and rivaroxaban were based on data that were associated with a high degree of uncertainty.\n\n\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee heard from the ERG that there were differences in the utility values used in the economic model compared with other technology appraisals for atrial fibrillation. The Committee concluded that the utility values used in the model, although open to debate, were not key drivers of the cost effectiveness.\n\nNo health‑related benefits were identified that were not included in the economic model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that there was insufficient evidence to consider different treatment effects according to centre‑level TTR.\n\n\n\nThe Committee concluded that if edoxaban is used in accordance with the summary of product characteristics, there is no reason to make differential recommendations based on creatinine clearance.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted the ERG's exploratory analyses, in which the change that had the largest single impact on the incremental cost‑effectiveness ratio (ICER) for edoxaban compared with warfarin was applying the hazard ratio from ENGAGE AF‑TIMI\xa048 for haemorrhagic stroke (which increased the ICER to £17,100 per QALY gained).\n\n\n\nThe Committee concluded that there was insufficient evidence to distinguish between the clinical and cost effectiveness of edoxaban and the newer oral anticoagulants recommended in previous appraisals (apixaban, dabigatran etexilate and rivaroxaban). Therefore, edoxaban could be recommended as a cost‑effective treatment for non‑valvular atrial fibrillation in people who have 1\xa0or more risk factors for stroke.\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee noted that the inclusion of all the ERG's preferred values in the model resulted in a deterministic ICER of £16,000 per QALY gained and a probabilistic ICER of £22,100 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe Committee concluded that the PPRS payment mechanism was irrelevant for the consideration of the cost effectiveness of edoxaban.\n\n\n\nEnd‑of‑life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNo equalities issues were identified.\n\n–"}
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https://www.nice.org.uk/guidance/ta355
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Evidence-based recommendations on edoxaban (Lixiana) for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation.
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d92734d2bc7949ee84976e98631879a71ec68aa9
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Atrial fibrillation: diagnosis and management
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Atrial fibrillation: diagnosis and management
This guideline covers diagnosing and managing atrial fibrillation in adults. It includes guidance on providing the best care and treatment for people with atrial fibrillation, including assessing and managing risks of stroke and bleeding.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Detection and diagnosis
Perform manual pulse palpation to assess for the presence of an irregular pulse if there is a suspicion of atrial fibrillation. This includes people presenting with any of the following:
breathlessness
palpitations
syncope or dizziness
chest discomfort
stroke or transient ischaemic attack.
Perform a 12‑lead electrocardiogram (ECG) to make a diagnosis of atrial fibrillation if an irregular pulse is detected in people with suspected atrial fibrillation with or without symptoms.
In people with suspected paroxysmal atrial fibrillation undetected by 12‑lead ECG recording:
use a 24‑hour ambulatory ECG monitor if asymptomatic episodes are suspected or symptomatic episodes are less than 24 hours apart
use an ambulatory ECG monitor, event recorder or other ECG technology for a period appropriate to detect atrial fibrillation if symptomatic episodes are more than 24 hours apart.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on detection and diagnosis .
Full details of the evidence and the committee's discussion are in evidence review A: effectiveness of tests for detection and evidence review B: accuracy of tests for detection.
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# Assessment of stroke and bleeding risks
## Stroke risk
Use the CHA2DS2-VASc stroke risk score to assess stroke risk in people with any of the following:
symptomatic or asymptomatic paroxysmal, persistent or permanent atrial fibrillation
atrial flutter
a continuing risk of arrhythmia recurrence after cardioversion back to sinus rhythm or catheter ablation. See the section on review of people with atrial fibrillation for advice on reassessment of stroke risk.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on stroke risk .
Full details of the evidence and the committee's discussion are in evidence review C and D: tools to predict stroke in people with atrial fibrillation.
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## Bleeding risk
Assess the risk of bleeding when:
considering starting anticoagulation in people with atrial fibrillation and
reviewing people already taking anticoagulation. Use the ORBIT bleeding risk score because evidence shows that it has a higher accuracy in predicting absolute bleeding risk than other bleeding risk tools. Accurate knowledge of bleeding risk supports shared decision making and has practical benefits, for example, increasing patient confidence and willingness to accept treatment when risk is low and prompting discussion of risk reduction when risk is high. Although ORBIT is the best tool for this purpose, other bleeding risk tools may need to be used until it is embedded in clinical pathways and electronic systems.
Offer monitoring and support to modify risk factors for bleeding, including:
uncontrolled hypertension (see NICE's guideline on hypertension in adults)
poor control of international normalised ratio (INR) in patients on vitamin K antagonists
concurrent medication, including antiplatelets, selective serotonin reuptake inhibitors (SSRIs) and non‑steroidal anti‑inflammatory drugs (NSAIDs)
harmful alcohol consumption (see NICE's guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence)
reversible causes of anaemia.
## Discussing the results of the risk assessment
Discuss the results of the assessments of stroke and bleeding risk with the person taking into account their specific characteristics, for example comorbidities, and their individual preferences. For further guidance, see the section on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on bleeding risk .
Full details of the evidence and the committee's discussion are in evidence review E and F: risk stratification tools for predicting bleeding in people with atrial fibrillation.
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# Assessment of cardiac function
Perform transthoracic echocardiography (TTE) in people with atrial fibrillation:
for whom a baseline echocardiogram is important for long‑term management
for whom a rhythm‑control strategy that includes cardioversion (electrical or pharmacological) is being considered
in whom there is a high risk or a suspicion of underlying structural or functional heart disease (such as heart failure or heart murmur) that influences their subsequent management (for example, choice of antiarrhythmic drug)
in whom refinement of clinical risk stratification for antithrombotic therapy is needed (see section 1.2 on assessment of stroke and bleeding risks and section 1.6 on stroke prevention).
Do not routinely perform TTE solely for the purpose of further stroke risk stratification in people with atrial fibrillation for whom the need to start anticoagulation therapy has already been agreed on appropriate clinical criteria (see section 1.2 on assessment of stroke and bleeding risks and section 1.6 on stroke prevention).
Perform transoesophageal echocardiography (TOE) in people with atrial fibrillation:
when TTE demonstrates an abnormality (such as valvular heart disease) that warrants further specific assessment
in whom TTE is technically difficult and/or of questionable quality and when there is a need to exclude cardiac abnormalities
for whom TOE‑guided cardioversion is being considered.
# Personalised package of care and information
Offer people with atrial fibrillation a personalised package of care. Ensure that the package of care is documented and delivered, and that it covers:
stroke awareness and measures to prevent stroke
rate control
assessment of symptoms for rhythm control
who to contact for advice if needed
psychological support if needed
up‑to‑date and comprehensive education and information on:
cause, effects and possible complications of atrial fibrillation
management of rate and rhythm control
anticoagulation
practical advice on anticoagulation in line with the recommendations on information and support for people having anticoagulation treatment in NICE's guideline on venous thromboembolic diseases
support networks (for example, cardiovascular charities).
Follow the recommendations in NICE's guideline on shared decision making.
## Medicines adherences and optimisation
To support adherence and ensure safe and effective medicines use in people with atrial fibrillation, follow the recommendations in NICE's guidelines on medicines adherence and medicines optimisation.
# Referral for specialised management
Refer people promptly at any stage if treatment fails to control the symptoms of atrial fibrillation and more specialised management is needed. This should be within 4 weeks after the failed treatment or after recurrence of atrial fibrillation after cardioversion.
# Stroke prevention
## Anticoagulation
When discussing the benefits and risks of anticoagulation use clinical risk profiles and personal preferences to guide treatment choices. Discuss with the person that:
for most people the benefit of anticoagulation outweighs the bleeding risk
for people with an increased risk of bleeding, the benefit of anticoagulation may not always outweigh the bleeding risk, and careful monitoring of bleeding risk is important.
When deciding between anticoagulation treatment options:
Discuss the risks and benefits of different drugs with the person and follow the
Follow the recommendations on patient involvement in decisions about medicines in NICE's guideline on medicines adherence and patient decision aids in NICE's guideline on medicines optimisation.
Take into account any contraindications for each drug and follow the guidance in the British National Formulary and the MHRA advice on direct-acting oral anticoagulants, in particular for advice on dosages in people with renal impairment, reversal agents and monitoring.
Offer anticoagulation with a direct‑acting oral anticoagulant to people with atrial fibrillation and a CHA2DS2‑VASc score of 2 or above, taking into account the risk of bleeding. Apixaban, dabigatran, edoxaban and rivaroxaban are all recommended as options, when used in line with the criteria specified in the relevant NICE technology appraisal guidance (see the NICE technology appraisal guidance on our topic page on embolism and thrombosis).
Consider anticoagulation with a direct‑acting oral anticoagulant for men with atrial fibrillation and a CHA2DS2‑VASc score of 1, taking into account the risk of bleeding. Apixaban, dabigatran, edoxaban and rivaroxaban are all recommended as options, when used in line with the criteria specified in the relevant NICE technology appraisal guidance (see the NICE technology appraisal guidance on our topic page on embolism and thrombosis).
If direct‑acting oral anticoagulants are contraindicated, not tolerated or not suitable in people with atrial fibrillation, offer a vitamin K antagonist. See the section on self-monitoring and self-management of vitamin K antagonists. .
For adults with atrial fibrillation who are already taking a vitamin K antagonist and are stable, continue with their current medication and discuss the option of switching treatment at their next routine appointment, taking into account the person's time in therapeutic range.
Do not offer stroke prevention therapy with anticoagulation to people aged under 65 years with atrial fibrillation and no risk factors other than their sex (that is, very low risk of stroke equating to a CHA2DS2‑VASc score of 0 for men or 1 for women).
Do not withhold anticoagulation solely because of a person's age or their risk of falls.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on stroke prevention .
Full details of the evidence and the committee's discussion are in evidence review G1: anticoagulant therapy for stroke prevention in people with atrial fibrillation and evidence review G2: anticoagulant therapy health economics analysis.
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## Assessing anticoagulation control with vitamin K antagonists
Calculate the person's time in therapeutic range (TTR) at each visit. When calculating TTR:
use a validated method of measurement such as the Rosendaal method for computer‑assisted dosing or proportion of tests in range for manual dosing
exclude measurements taken during the first 6 weeks of treatment
calculate TTR over a maintenance period of at least 6 months.
Reassess anticoagulation for a person whose anticoagulation is poorly controlled shown by any of the following:
INR values higher than 5 or 1 INR value higher than 8 within the past 6 months
INR values less than 1.5 within the past 6 months
TTR less than 65%.
When reassessing anticoagulation, take into account and if possible address the following factors that may contribute to poor anticoagulation control:
cognitive function
adherence to prescribed therapy
illness
interacting drug therapy
lifestyle factors including diet and alcohol consumption.
If poor anticoagulation control cannot be improved, evaluate the risks and benefits of alternative stroke prevention strategies and discuss these with the person.
NICE has developed diagnostics guidance on atrial fibrillation and heart valve disease: self-monitoring coagulation status using point-of-care coagulometers (the CoaguChek XS system).
## Antiplatelets
For guidance on antiplatelet therapy for people who have had a myocardial infarction and are having anticoagulation, see antiplatelet therapy for people with an ongoing separate indication for anticoagulation in NICE's guideline on acute coronary syndromes.
Do not offer aspirin monotherapy solely for stroke prevention to people with atrial fibrillation.
## Review of people with atrial fibrillation
For people who are not taking an anticoagulant, review stroke risk when they reach age 65 or if they develop any of the following at any age:
diabetes
heart failure
peripheral arterial disease
coronary heart disease
stroke, transient ischaemic attack or systemic thromboembolism.
For people who are not taking an anticoagulant because of bleeding risk or other factors, review stroke and bleeding risks annually, and ensure that all reviews and decisions are documented.
For people who are taking an anticoagulant, review the need for anticoagulation and the quality of anticoagulation (taking into account MHRA advice on direct-acting oral anticoagulants about bleeding risk and the need to monitor renal function in patients with renal impairment) at least annually, or more frequently if clinically relevant events occur affecting anticoagulation or bleeding risk.
## Left atrial appendage occlusion
Consider left atrial appendage occlusion (LAAO) if anticoagulation is contraindicated or not tolerated and discuss the benefits and risks of LAAO with the person. For more information see NICE's interventional procedure guidance on percutaneous occlusion of the left atrial appendage in non-valvular atrial fibrillation for the prevention of thromboembolism.
Do not offer LAAO as an alternative to anticoagulation unless anticoagulation is contraindicated or not tolerated.
# Rate and rhythm control
This section covers rate and rhythm control in non‑acute settings. See section 1.8 for rate and rhythm control for people presenting acutely (either new onset or destabilisation of existing atrial fibrillation).
## Rate control
Offer rate control as the first‑line treatment strategy for atrial fibrillation except in people:
whose atrial fibrillation has a reversible cause
who have heart failure thought to be primarily caused by atrial fibrillation
with new‑onset atrial fibrillation
with atrial flutter whose condition is considered suitable for an ablation strategy to restore sinus rhythm
for whom a rhythm‑control strategy would be more suitable based on clinical judgement.
Offer either a standard beta‑blocker (that is, a beta‑blocker other than sotalol) or a rate‑limiting calcium‑channel blocker (diltiazem or verapamil) as initial rate‑control monotherapy to people with atrial fibrillation unless the person has the features described in recommendation 1.7.4. Base the choice of drug on the person's symptoms, heart rate, comorbidities and preferences. In April 2021, this was an off‑label use of diltiazem. See NICE's information on prescribing medicines.
For people with atrial fibrillation and concomitant heart failure, follow the recommendations on the use of beta-blockers and avoiding calcium-channel blockers in NICE's guideline on chronic heart failure.
Consider digoxin monotherapy for initial rate control for people with non‑paroxysmal atrial fibrillation if:
the person does no or very little physical exercise or
-ther rate‑limiting drug options are ruled out because of comorbidities or the person's preferences.
If monotherapy does not control the person's symptoms, and if continuing symptoms are thought to be caused by poor ventricular rate control, consider combination therapy with any 2 of the following:
a beta‑blocker
diltiazem
digoxin. In April 2021, this was an off‑label use of diltiazem. See NICE's information on prescribing medicines.
Do not offer amiodarone for long-term rate control.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on rate control .
Full details of the evidence and the committee's discussion are in evidence review I: non-ablative rate control therapies.
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## Rhythm control
Consider pharmacological and/or electrical rhythm control for people with atrial fibrillation whose symptoms continue after heart rate has been controlled or for whom a rate‑control strategy has not been successful.
Assess the need for drug treatment for long‑term rhythm control, taking into account the person's preferences, associated comorbidities, risks of treatment and likelihood of recurrence of atrial fibrillation.
Do not offer class 1c antiarrhythmic drugs such as flecainide or propafenone to people with known ischaemic or structural heart disease.
If drug treatment for long‑term rhythm control is needed, consider a standard beta‑blocker (that is, a beta‑blocker other than sotalol) as first‑line treatment unless there are contraindications.
If beta‑blockers are contraindicated or unsuccessful, assess the suitability of alternative drugs for rhythm control, taking comorbidities into account.
Follow the advice on dronedarone as a second‑line treatment option for long‑term rhythm control after successful cardioversion in NICE's technology appraisal guidance on dronedarone for the treatment of non-permanent atrial fibrillation.
Consider amiodarone for people with left ventricular impairment or heart failure.
In people with infrequent paroxysms and few symptoms, or if symptoms are induced by known precipitants (such as alcohol, caffeine), a 'no drug treatment' strategy or a 'pill-in-the-pocket' strategy (in which antiarrhythmic drugs are taken only when an episode starts) should be considered and discussed with the person.
In people with paroxysmal atrial fibrillation, a 'pill‑in‑the‑pocket' strategy should be considered for those who:
have no history of left ventricular dysfunction, or valvular or ischaemic heart disease and
have a history of infrequent symptomatic episodes of paroxysmal atrial fibrillation and
have a systolic blood pressure greater than 100 mmHg and a resting heart rate above 70 bpm and
are able to understand how to, and when to, take the medication.
For people having cardioversion for atrial fibrillation that has persisted for longer than 48 hours, offer electrical (rather than pharmacological) cardioversion.
Consider amiodarone therapy starting 4 weeks before and continuing for up to 12 months after electrical cardioversion to maintain sinus rhythm, and discuss the benefits and risks of amiodarone with the person.
For people with atrial fibrillation of greater than 48 hours' duration, in whom elective cardioversion is indicated:
both transoesophageal echocardiography (TOE)‑guided cardioversion and conventional cardioversion should be considered equally effective
a TOE‑guided cardioversion strategy should be considered:
if experienced staff and appropriate facilities are available and
if a minimal period of precardioversion anticoagulation is indicated due to the person's choice or bleeding risks.
## Left atrial ablation
If drug treatment is unsuccessful, unsuitable or not tolerated in people with symptomatic paroxysmal or persistent atrial fibrillation:
consider radiofrequency point‑by‑point ablation or
if radiofrequency point‑by‑point ablation is assessed as being unsuitable, consider cryoballoon ablation or laser balloon ablation.
When considering left atrial ablation, discuss the risks and benefits and take into account the person's preferences. In particular, explain that the procedure is not always effective and that the resolution of symptoms may not be long‑lasting.
Consider left atrial surgical ablation at the same time as other cardiothoracic surgery for people with symptomatic atrial fibrillation.
For NICE interventional procedures guidance on left atrial ablation for atrial fibrillation, see the NICE interventional procedures guidance on our topic page on heart rhythm conditions.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on left atrial ablation .
Full details of the evidence and the committee's discussion are in evidence review J1: ablation, evidence review J2: ablation network meta-analysis and evidence review J3: ablation cost-effectiveness analysis.
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Consider antiarrhythmic drug treatment for 3 months after left atrial ablation to prevent recurrence of atrial fibrillation, taking into account the person's preferences, and the risks and potential benefits.
Reassess the need for antiarrhythmic drug treatment at 3 months after left atrial ablation.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing recurrence after ablation .
Full details of the evidence and the committee's discussion are in evidence review K: antiarrhythmic drugs after ablation.
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## Pace and ablate strategy
Consider pacing and atrioventricular node ablation for people with permanent atrial fibrillation with symptoms or left ventricular dysfunction thought to be caused by high ventricular rates.
When considering pacing and atrioventricular node ablation, reassess symptoms and the consequent need for ablation after pacing has been carried out and drug treatment further optimised.
Consider left atrial catheter ablation before pacing and atrioventricular node ablation for people with paroxysmal atrial fibrillation or heart failure caused by non‑permanent (paroxysmal or persistent) atrial fibrillation.
# Management for people presenting acutely with atrial fibrillation
## Rate and rhythm control for people presenting acutely
Carry out emergency electrical cardioversion, without delaying to achieve anticoagulation, in people with life‑threatening haemodynamic instability caused by new‑onset atrial fibrillation.
In people with atrial fibrillation presenting acutely without life-threatening haemodynamic instability:
-ffer either rate or rhythm control if the onset of the arrhythmia is less than 48 hours
-ffer rate control if onset is more than 48 hours or is uncertain.
In people with atrial fibrillation presenting acutely with suspected concomitant acute decompensated heart failure, seek senior specialist input on the use of beta‑blockers and do not use calcium‑channel blockers.
Consider either pharmacological or electrical cardioversion depending on clinical circumstances and resources in people with new‑onset atrial fibrillation who will be treated with a rhythm‑control strategy.
If pharmacological cardioversion has been agreed on clinical and resource grounds for new‑onset atrial fibrillation, offer:
a choice of flecainide or amiodarone to people with no evidence of structural or ischaemic heart disease or
amiodarone to people with evidence of structural heart disease.
In people with atrial fibrillation in whom the duration of the arrhythmia is greater than 48 hours or uncertain and considered for long‑term rhythm control, delay cardioversion until they have been maintained on therapeutic anticoagulation for a minimum of 3 weeks. During this period offer rate control as appropriate.
Do not offer magnesium or a calcium‑channel blocker for pharmacological cardioversion.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on rate and rhythm control for people presenting acutely .
Full details of the evidence and the committee's discussion are in evidence review I: non-ablative rate control therapies.
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## Anticoagulation for people presenting acutely with atrial fibrillation
In people with new‑onset atrial fibrillation who are receiving no, or subtherapeutic, anticoagulation therapy:
in the absence of contraindications, offer heparin at initial presentation
continue heparin until a full assessment has been made and appropriate antithrombotic therapy has been started, based on risk stratification (see section 1.2 on assessment of stroke and bleeding risks and section 1.6 on stroke prevention).
In people with a confirmed diagnosis of atrial fibrillation of recent onset (less than 48 hours since onset), offer oral anticoagulation if:
stable sinus rhythm is not successfully restored within the same 48‑hour period after onset of atrial fibrillation or
there are factors indicating a high risk of atrial fibrillation recurrence, including history of failed cardioversion, structural heart disease, prolonged atrial fibrillation (more than 12 months), or previous recurrences or
it is recommended in section 1.2 on assessment of stroke and bleeding risks and section 1.6 on stroke prevention.
In people with new‑onset atrial fibrillation, if there is uncertainty over the precise time since onset, offer oral anticoagulation as for persistent atrial fibrillation (see section 1.2 on assessment of stroke and bleeding risks and section 1.6 stroke prevention).
# Initial management of stroke and atrial fibrillation
For guidance on the initial management of stroke and atrial fibrillation see recommendation 1.4.17 in NICE's guideline on stroke and transient ischaemic attack in over 16s.
# Preventing and managing postoperative atrial fibrillation
## Preventing postoperative atrial fibrillation
In people having cardiothoracic surgery:
reduce the risk of postoperative atrial fibrillation by offering 1 of the following:
amiodarone
a standard beta‑blocker (that is, a beta-blocker other than sotalol)
a rate‑limiting calcium‑channel blocker (diltiazem or verapamil)
do not offer digoxin. In April 2021, this was an off‑label use of diltiazem. See NICE's information on prescribing medicines.
In people having cardiothoracic surgery who are already on beta‑blocker therapy, continue this treatment unless contraindications develop (such as postoperative bradycardia or hypotension).
Do not start statins in people having cardiothoracic surgery solely to prevent postoperative atrial fibrillation.
In people having cardiothoracic surgery who are already on statins, continue this treatment. For further advice on statins for the prevention of cardiovascular disease, see NICE's guideline on cardiovascular disease: risk assessment and reduction.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on preventing postoperative atrial fibrillation .
Full details of the evidence and the committee's discussion are in evidence review M: statins for preventing atrial fibrillation after cardiothoracic surgery.
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## Managing postoperative atrial fibrillation
Consider either a rhythm‑control or rate‑control strategy for the initial treatment of new‑onset postoperative atrial fibrillation after cardiothoracic surgery.
If a rhythm‑control strategy is chosen, reassess the need for antiarrhythmic drug treatment at a suitable time point (usually at around 6 weeks).
Manage postoperative atrial fibrillation after non‑cardiothoracic surgery in the same way as for new-onset atrial fibrillation with any other cause.
In the prophylaxis and management of postoperative atrial fibrillation, use appropriate antithrombotic therapy and correct identifiable causes (such as electrolyte imbalance or hypoxia).
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on managing atrial fibrillation after cardiothoracic surgery .
Full details of the evidence and the committee's discussion are in evidence review L: treatment strategies for atrial fibrillation after cardiothoracic surgery.
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# Stopping anticoagulation
In people with a diagnosis of atrial fibrillation, do not stop anticoagulation solely because atrial fibrillation is no longer detectable.
Base decisions to stop anticoagulation on a reassessment of stroke and bleeding risk using CHA2DS2‑VASc and ORBIT and a discussion of the person's preferences.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on stopping anticoagulation .
Full details of the evidence and the committee's discussion are in evidence review H: discontinuing anticoagulation in people whose atrial fibrillation has resolved.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
## People with atrial fibrillation presenting acutely
People presenting with atrial fibrillation of definite recent onset or with destabilisation of existing atrial fibrillation. This does not include people with atrial fibrillation that has been discovered incidentally, for example through pulse palpitation before routine blood pressure measurement.
## Pill-in-the-pocket strategy
The person self‑manages paroxysmal atrial fibrillation by taking antiarrhythmic drugs only when an episode of atrial fibrillation starts.
## Paroxysmal atrial fibrillation
Episodes of atrial fibrillation that stop within 7 days, usually within 48 hours, without any treatment.# Recommendations for research
As part of the 2021 update, the guideline committee made 4 new research recommendations (marked ). Research recommendations retained from the 2014 guideline are labelled .
# Key recommendations for research
## Tests to diagnose persistent atrial fibrillation
What is the diagnostic accuracy of key index tests (such as the KardiaMobile heart monitor (AliveCor), MyDiagnostik, Microlife BP monitors, iPhone plethysmography and pulse palpation) compared with the gold standard of 12‑lead ECG in people with risk factors for or symptoms of atrial fibrillation?
For a short explanation of why the committee made the recommendation for research, see the rationale on detection and diagnosis .
Full details of the evidence and the committee's discussion are in evidence review B: accuracy of tests for detection.
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## Tests to diagnose paroxysmal atrial fibrillation
What is the diagnostic accuracy of key index tests compared with the gold standard of prolonged ambulatory monitoring in people suspected of having paroxysmal atrial fibrillation?
For a short explanation of why the committee made the recommendation for research, see the rationale on detection and diagnosis .
Full details of the evidence and the committee's discussion are in evidence review B: accuracy of tests for detection.
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## Stopping anticoagulation after ablation
What is the clinical and cost effectiveness of stopping anticoagulation in people whose atrial fibrillation has resolved after ablation?
For a short explanation of why the committee made the recommendation for research, see the rationale on stopping anticoagulation .
Full details of the evidence and the committee's discussion are in evidence review H: discontinuing anticoagulation in people whose atrial fibrillation has resolved.
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## Stopping anticoagulation after resolution of postoperative atrial fibrillation
What is the clinical and cost effectiveness of stopping anticoagulation in people whose postoperative atrial fibrillation after cardiac surgery has resolved?
For a short explanation of why the committee made the recommendation for research, see the rationale on stopping anticoagulation .
Full details of the evidence and the committee's discussion are in evidence review H: discontinuing anticoagulation in people whose atrial fibrillation has resolved.
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## Cognitive behavioural therapy for people with atrial fibrillation
What is the clinical and cost effectiveness of cognitive behavioural therapy compared with usual care for people with newly diagnosed atrial fibrillation?
## Rate-control drug treatment for people aged 75 and over with atrial fibrillation
What is the comparative effectiveness of the 3 main drug classes used for rate control (beta‑blockers, calcium‑channel blockers and digoxin) in people aged 75 and over with atrial fibrillation in controlling symptoms, improving quality of life and reducing morbidity and mortality?
## Stroke risk assessment
Can routine data from UK primary care databases clarify stroke risk in people with atrial fibrillation according to baseline risk factors and treatment? # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Detection and diagnosis
Recommendations 1.1.2 and 1.1.3
## Why the committee made the recommendations
The evidence did not support changing the recommended diagnostic tests to either replace 12‑lead ECG as the test to confirm persistent atrial fibrillation or replace pulse palpation as the initial step for persistent atrial fibrillation in a 2‑step strategy. The committee clarified that 12‑lead ECG should be used as the test to confirm atrial fibrillation, to prevent the use of less accurate ECG devices, such as mobile and lead‑I ECG devices. The committee agreed that, although the evidence showed that accuracy varied, there was some evidence that new devices were accurate and showed promise. It was noted that NICE has produced diagnostics guidance on lead-I ECG devices for detecting symptomatic atrial fibrillation using single time point testing in primary care. The committee made a research recommendation on tests to diagnose persistent atrial fibrillation to encourage further high‑quality research in this area to guide future practice.
The committee agreed that the evidence on tests to detect paroxysmal atrial fibrillation was not clear enough to warrant a change in practice from the 2014 recommendation. However, the evidence did show that longer durations of detection increased accuracy. The committee made a research recommendation on tests to diagnose paroxysmal atrial fibrillation.
## How the recommendations might affect practice
The recommendations reflect current good practice and are unlikely to have an impact on practice.
Return to recommendations
# Stroke risk
Recommendation 1.2.1
## Why the committee made the recommendations
The committee decided to prioritise identifying people above or below a certain risk threshold (discrimination) in its interpretation of the evidence rather than estimating a person's risk of stroke in absolute terms.
The evidence suggested that a score of 2 or more is the ideal threshold for the CHA2DS2‑VASC in terms of indicating the need for anticoagulation. (Men with a CHA2DS2‑VASc score of 1 were regarded as being at intermediate risk, and a group in whom anticoagulation should also be considered.) The evidence showed that this threshold of 2 or more offered a good combination of high sensitivity (0.92) and adequate specificity (0.23).
The high sensitivity means that the tool would correctly identify almost everyone who would later have a stroke if they did not receive anticoagulants. Importantly, this will allow them to be prescribed anticoagulants to reduce their risk of stroke.
The adequate specificity means that 23% of the people who would not later have a stroke (even when not taking anticoagulants) would be correctly identified as not needing anticoagulation. This would prevent these people from having adverse events from anticoagulants. It also means that 77% of people who would not later have a stroke (without anticoagulation) would be wrongly identified as needing anticoagulation. However, this was thought to be acceptable given the perceived lesser harms from unnecessarily giving anticoagulants compared with not giving anticoagulants to people who need them, together with the inevitable trade‑off between sensitivity and specificity.
The ATRIA stroke risk score was shown to have better overall accuracy, but although it had better specificity than CHA2DS2‑VASc (fewer false-positive results) it had lower sensitivity, meaning that more people at risk would be missed (more false‑negative results) compared with the CHA2DS2‑VASc score. As already suggested, sensitivity was agreed by the committee to be more important than specificity because the risks of unnecessary anticoagulation are outweighed by the risks of not treating people who need anticoagulation. In addition, the ATRIA risk score may result in a time delay in calculating the results.
The committee also discussed that the evidence for the QStroke risk calculator suggested that it might be a useful tool. However, the evidence was limited, and they agreed that further research was needed.
## How the recommendation might affect practice
The recommendation does not constitute a change in practice, and so there would not be a resource impact on the NHS.
Return to recommendations
# Bleeding risk
Recommendations 1.2.2 to 1.2.4
## Why the committee made the recommendations
The committee agreed that anticoagulation should usually be considered in people at risk of stroke even if bleeding risk is high, and so a bleeding risk tool should not be used to provide a cut off for determining who should have anticoagulation. Instead, the tool should be used to provide accurate knowledge of absolute bleeding risk, which can support discussions between the person and their healthcare professional about bleeding risk modification and appropriate levels of vigilance. They therefore agreed that accurately estimating absolute risk (calibration) is more important than identifying a risk threshold for anticoagulation (discrimination) when choosing between different bleeding risk tools.
The committee focused on calibration data for the tools with the most evidence: ORBIT, HAS-BLED and ATRIA. The calibration evidence clearly suggested that ORBIT was more accurate than HAS‑BLED and ATRIA at predicting absolute risk of major bleeding, both for people using vitamin K antagonists and those using direct‑acting oral anticoagulants. Importantly, ORBIT was better calibrated at all levels of major bleeding risk, including higher levels. ORBIT was also better at predicting absolute risk of intracranial haemorrhage.
The discrimination data showed little difference between tools in predicting major bleeding, with some outcome measures showing no difference and others showing a slight benefit for either ORBIT or HAS‑BLED. Evidence showed that ORBIT had a significantly higher specificity and a slighter lower sensitivity than the other tools, but the committee agreed that the lower sensitivity would not be a drawback when used to inform discussions of risk.
The committee agreed that the evidence overall, and particularly the calibration data demonstrating higher accuracy of absolute risk, strongly supported ORBIT as the tool of choice.
The committee agreed that NICE's previous advice on monitoring and addressing modifiable risk factors was still relevant and added reversible causes of anaemia because it is a component of the ORBIT tool.
## How the recommendations might affect practice
Use of the ORBIT score is a change in practice, which will take time to implement. The committee considered that the more accurate prediction of the absolute risk of bleeding is a real advantage in supporting patients and clinicians in shared decision making, which should lead to better clinical outcomes. The committee considered carefully a number of practical issues set out in this section. Overall, the committee concluded that this change is one that is worth making.
One potential concern discussed by the committee is that ORBIT does not include all of the modifiable risk factors included in HAS‑BLED so does not serve as a reminder of these to clinicians. However, the committee considered that fully investigating modifiable risk factors is established clinical practice, regardless of the tool used.
Another potential challenge is that ORBIT is not the recommended bleeding risk tool for other conditions (such as venous thromboembolism). Therefore, an initial transition period may be needed for training and education in both primary and secondary care while healthcare professionals become familiar with the tool. This will have a resource impact, although it will be time limited. The committee also noted that use of the ORBIT tool, and access to online versions, is straightforward.
Finally, the committee also discussed that, unlike HAS‑BLED, ORBIT is not embedded in GP systems, which may cause some initial practical difficulties. However, because this will involve changes to centralised software, it is thought that it will be straightforward to implement and ORBIT will quickly be included in GP systems. Neither tool is included in hospital systems although both are widely available on smartphone apps.
Return to recommendations
# Stroke prevention
Recommendations 1.6.1 to 1.6.8
## Why the committee made the recommendations
Evidence from an analysis of several studies showed that direct‑acting oral anticoagulants are more effective than warfarin for a number of outcomes. An economic model also showed that they offered a better balance of benefits to costs than warfarin. There were no studies directly comparing the direct‑acting anticoagulants head‑to‑head but indirect comparisons based on the clinical evidence showed that the different direct‑acting oral anticoagulants offered different benefits depending on the outcome considered. When all these outcomes were combined in the cost‑effectiveness analysis, apixaban was the most clinically effective and cost‑effective anticoagulant based on UK drug tariff prices at the time. However, the committee had concerns over the lack of head‑to‑head comparisons, differences in the study populations and uncertainties in the economic model.
Based on the evidence and their experience, the committee decided not to recommend one direct‑acting oral anticoagulant over the others, but instead to emphasise that treatment should be tailored to the person's clinical needs and preferences. Each anticoagulant has different risks and benefits that should be considered and fully discussed with the person as part of informed shared decision making. The committee highlighted that the choice might be affected by factors such as renal impairment and swallowing difficulties, and that healthcare professionals should refer to the BNF for advice on contraindications and cautions. They also stressed the importance of adherence and factors that might affect this, such as dosing frequency, when making the decision. If direct‑acting oral anticoagulants are not suitable, for example in people with antiphospholipid syndrome, the committee agreed that a vitamin K antagonist should be offered.
For people already established and stable on a vitamin K antagonist, the committee agreed that the benefits of changing to a direct‑acting anticoagulant need to be discussed. Therefore, the risks and benefits of changing medication, the person's time in therapeutic range and the person's preferences should be explored at their next routine appointment.
The committee agreed that the existing thresholds for the CHA2DS2‑VASc score threshold for anticoagulation are in line with current practice.
Although bleeding risk scores may occasionally be used as a reason not to offer anticoagulation, the committee agreed that they should typically be used as a prompt to identify and manage modifiable risk factors for bleeding rather than as a reason for not offering anticoagulation in people at increased risk. The committee discussed that when anticoagulation is not given because of bleeding risk, people should have regular review and reconsideration for treatment.
The committee were concerned that anticoagulation is sometimes not recommended for people at risk of falls and for older people, even though age is factored into the bleeding risk score and falls are rarely a cause of major haemorrhage. Age was therefore added to the previous recommendation on people at risk of falls to ensure that anticoagulation is offered in this population when needed. The benefits and harms should be discussed with the person.
## How the recommendations might affect practice
The recommendations are likely to lead to a change in current practice, with a reduction in warfarin use. The committee noted that this has been a prescribing trend over recent years and it may lead to a contraction in warfarin clinic services. The unit cost of direct‑acting anticoagulants is greater than that for warfarin, so there is likely to be a resource impact from increased use of direct‑acting anticoagulants.
Return to recommendations
# Rate control
Recommendations 1.7.2 to 1.7.6
## Why the committee made the recommendations
The committee made some updates to the 2014 recommendations, based on their experience and knowledge.
The use of beta‑blockers or rate‑limiting calcium‑channel blockers for initial rate‑control treatment was retained by the committee because this is current practice and there was insufficient evidence to suggest an alternative option. The committee agreed that the choice of treatment should still be made based on the symptoms, heart rate, comorbidities and preferences of those being treated.
The committee agreed that the recommendations should refer to NICE's guideline on chronic heart failure for advice on using beta‑blockers and avoiding rate‑limiting calcium‑channel blockers such as diltiazem and verapamil in people who have atrial fibrillation with heart failure.
The committee agreed that digoxin monotherapy for non-paroxysmal atrial fibrillation should continue to be considered for people who are sedentary. Based on their experience, the committee agreed that it may also be considered as a treatment option when other rate‑limiting drugs are not suitable, so they expanded the recommendation in the previous guideline to also cover these circumstances. The committee were aware that some clinicians feel that digoxin monotherapy is often better than alternatives for improving symptoms; however, the lack of evidence currently available meant that the recommendation for digoxin was not expanded to cover further groups of people.
In the absence of new evidence, the committee also agreed with the existing recommendation for combination therapy options if initial monotherapy fails, which is consistent with the committee's experience and current practice.
There was a lack of evidence on long‑term rate control, and the committee were aware of numerous serious side effects associated with the long‑term use of amiodarone (including thyroid, lung and nerve damage), many of which are irreversible. The committee noted that although the most common side effects were less severe, the occurrence of severe side effects was unpredictable and long‑term rate control with amiodarone should be avoided. Amiodarone should only be used as an interim therapy, for example while waiting for cardioversion, and would not usually be taken for longer than 12 months.
## How the recommendations might affect practice
The recommendations reflect current practice. Digoxin monotherapy may now be an option in non‑paroxysmal atrial fibrillation if comorbidities or patient preferences limit other rate‑control drug choices. However, the committee agreed that this already happens in practice.
Return to recommendations
# Left atrial ablation
Recommendations 1.7.19 to 1.7.20
## Why the committee made the recommendations
Ablation may be a treatment option if antiarrhythmic drug treatment has not been successful or is not tolerated. The committee reviewed new clinical and health economic evidence for the different types of ablation for people with paroxysmal atrial fibrillation and agreed that the catheter ablation techniques were the most clinically effective ablation options. Thoracoscopy and the hybrid techniques led to lower recurrence, but they also led to more serious adverse effects. There were no clear differences in efficacy between the 4 catheter ablation techniques: radiofrequency point‑by‑point, radiofrequency multi‑electrode, laser and cryoballoon ablation.
A new economic model was developed for the guideline using the clinical evidence from people with paroxysmal atrial fibrillation. It showed that radiofrequency point‑by‑point ablation was more cost effective over a lifetime than antiarrhythmic drug treatment and other ablation strategies in people for whom 1 or more antiarrhythmic drug has failed. Cryoballoon, radiofrequency multi-electrode and laser ablation were the second, third and fourth most cost‑effective options respectively.
The committee acknowledged that the NHS reference cost used for the catheter ablation procedures may not fully capture differences in resource use between the different techniques. However, despite further analysis to adjust costs and account for this, radiofrequency point‑by‑point ablation remained the most cost‑effective option, and other catheter ablation techniques are therefore unlikely to provide a cost‑effective use of NHS resources. Based on the economic model results the committee agreed that radiofrequency point‑by‑point ablation should be considered in people with symptomatic paroxysmal atrial fibrillation if drug treatment is unsuccessful, unsuitable or not tolerated.
The committee noted that cryoballoon and laser ablation may be more suitable for some patients because they can sometimes be carried out without general anaesthesia, and cryoballoon ablation may be quicker to perform, with same‑day discharge more likely. There is also an increased risk of fluid overload from saline irrigated radiofrequency ablation. They decided that either cryoballoon or laser ablation could be considered if radiofrequency point‑by‑point ablation is not suitable; for example, if a short procedure time is a priority or for people with a recent history of decompensated heart failure who are at increased risk of fluid overload. Radiofrequency multi-electrode was not included as an alternative due to its lower efficacy relative to cryoballoon and laser ablation and concerns about a higher risk of stroke.
There was limited evidence for ablation in people with persistent atrial fibrillation. Despite this, the committee decided that the evidence, combined with their experience and knowledge (also noting the Packer et al. CABANA randomized clinical trial, 2019, which contained a mixed population of people with persistent and paroxysmal atrial fibrillation) was sufficient to support ablation as an option to be considered for those with persistent symptoms that are not alleviated by, or who cannot have, antiarrhythmic drugs. The committee agreed that ablation can be effective in people with persistent atrial fibrillation, and that this population might have as much to gain from ablation as people with paroxysmal symptoms. The committee agreed that the cost‑effectiveness analyses of different types of ablation in paroxysmal atrial fibrillation could also be applied to this population.
The committee emphasised the importance of discussing the risks and benefits of catheter ablation with the person, in particular the risk of adverse events. The discussion should also include that, in the experience of the committee, the effects of ablation may not be long term.
## How the recommendations might affect practice
The committee noted that the recommendations are likely to reinforce current practice. Ablation is carried out in a relatively restricted population (approximately 1% to 2% of all people with atrial fibrillation currently have ablation) and is usually reserved for people in whom antiarrhythmic drugs have failed. The recommendation is likely to lead to a change in the types of ablation offered, with more people receiving radiofrequency point‑by‑point ablation and fewer having other catheter ablation techniques.
Return to recommendations
# Preventing recurrence after ablation
Recommendations 1.7.22 and 1.7.23
## Why the committee made the recommendations
Most of the evidence on preventing recurrence after ablation was for amiodarone. The evidence suggested that amiodarone may reduce recurrence of atrial fibrillation after ablation. However, there was evidence of an increased risk of hospitalisation and the committee noted the known side effects of amiodarone, which, although rare, can be severe and life‑threatening.
There was a lack of evidence for other antiarrhythmic drugs and there were no comparisons between different antiarrhythmic drugs. Therefore, the committee agreed that there was too much uncertainty to recommend one specific antiarrhythmic drug over others.
In addition, the studies often made no distinction between people who had been on antiarrhythmic drugs up to ablation and those who had not. There is variation in current practice on whether people who were not previously taking antiarrhythmic drugs should start them after ablation to reduce recurrence. However, the evidence did not support making separate recommendations to clarify this.
The committee decided that antiarrhythmic drug treatment should be considered after ablation, but only after discussion with the person, taking into account their preferences for treatment and the potential individual risks and benefits. In particular, the committee noted that people should fully understand the potential adverse events associated with these drugs. While there is some variation, the committee agreed that good current practice is for patients taking antiarrhythmic drugs up to ablation to continue them for 3 months after ablation and reassess the need for drug treatment after this time.
## How the recommendations might affect practice
There is some variation in current practice. Practice is likely to change in some centres both in prescribing and in the need for a more formal reassessment of treatment at 3 months. The impact on use of antiarrhythmic drugs is difficult to predict, but there may be an increase from current levels. Increased resources may be needed for reassessment, but it is anticipated that this could be performed at routine follow‑up appointments with a cardiologist.
Return to recommendations
# Rate and rhythm control for people presenting acutely
Recommendation 1.8.3
## Why the committee made the recommendation
The committee agreed that the evidence was too limited in quality and quantity to be able to specify a preferred rate‑control drug for acute atrial fibrillation. Although there was some evidence that amiodarone was better than digoxin for rate control, the committee had concerns about the quality of the evidence and the short timeframe used in 1 study, which it agreed could disadvantage digoxin. In addition, there was limited evidence available for morbidity and adverse events for this comparison and no evidence identified for other drug classes.
The committee highlighted that the existing recommendations gave no guidance on acute atrial fibrillation with acute decompensated heart failure. Using their expertise and experience the committee agreed that advice on the use of beta-blockers and rate-limiting calcium‑channel blockers should be included because they can lead to further deterioration in people with pulmonary oedema caused by heart failure.
## How the recommendation might affect practice
The recommendations do not constitute a change in practice, and so are unlikely to have a resource impact.
Return to recommendations
# Preventing postoperative atrial fibrillation
Recommendations 1.10.3 and 1.10.4
## Why the committee made the recommendations
The committee noted that the most recent studies reviewed showed no benefit from statins in reducing atrial fibrillation after cardiothoracic surgery. This contrasted with analysis of the evidence overall, which showed a small but definite benefit from statins. The committee agreed that the evidence of no effect in the newer studies was important, because these studies were larger and of higher quality than the older studies included in the analysis.
Although the newer studies suggested that statins did not affect the short‑term risk of stroke, they did suggest a greater risk of mortality in the peri‑operative period compared with placebo treatment or usual care. The committee agreed that although the additional risk of death was probably small, it was important, especially alongside the lack of convincing evidence of benefit.
For these reasons, the committee decided that statins should not be given to prevent atrial fibrillation after cardiothoracic surgery. However, the committee wanted to highlight that statins have an important role in preventing cardiovascular events other than atrial fibrillation and that people already taking statins for other reasons should continue to do so.
## How the recommendations might affect practice
The committee agreed that the recommendation would not constitute a change in practice, and that there would not be a resource impact on the NHS.
Return to recommendations
# Managing atrial fibrillation after cardiothoracic surgery
Recommendations 1.10.5 and 1.10.6
## Why the committee made the recommendations
The evidence on managing postoperative atrial fibrillation after cardiothoracic surgery in people without pre‑existing atrial fibrillation was limited – many of the studies reviewed were old and included small numbers of participants. There were few studies comparing drug classes, and the committee agreed that they could not recommend a particular class of drugs based on such limited evidence.
One larger study comparing mixed rate control and rhythm control with a potassium‑channel blocker (amiodarone) with or without rate control suggested little difference between the 2 groups. Based on this evidence and their experience, the committee decided that rhythm control could be considered but that the evidence no longer supported the stronger recommendation included in the 2014 guideline. The committee noted that postoperative atrial fibrillation often resolves naturally, meaning that rate control rather than rhythm control may be a suitable option for some people. Reducing the emphasis on rhythm‑control strategies will allow rate‑control strategies to be considered if appropriate for the person.
The committee were also aware of the risk of adverse events if amiodarone, a rhythm control drug, is taken long‑term. They highlighted that if a rhythm‑control strategy is chosen, the need for rhythm control drugs should be reassessed at approximately 6 weeks, in line with current practice, and they should not be continued automatically for long periods of time. The committee agreed that 6 weeks is an appropriate time point to assess the person's recovery, including for example prosthetic valve function, and to check if sinus rhythm has been restored.
The committee did not make a separate recommendation for people with pre‑existing atrial fibrillation because of a lack of evidence. The committee noted that most people undergoing mitral valve surgery with pre‑existing atrial fibrillation would undergo left atrial surgery to treat atrial fibrillation at the same time.
## How the recommendations might affect practice
Rhythm control for the treatment of new‑onset atrial fibrillation after cardiothoracic surgery is current practice and amiodarone is most commonly used. This can still be considered, but there may be a reduction in the use of rhythm control in this population and an increase in the use of rate‑control drugs instead.
Return to recommendations
# Stopping anticoagulation
Recommendations 1.11.1 and 1.11.2
## Why the committee made the recommendations
There was limited evidence on whether to continue anticoagulation or to stop it and switch to aspirin after successful treatment of atrial fibrillation by catheter ablation. The committee agreed that the evidence was insufficient and that there was too much uncertainty in the results to make a recommendation based on the evidence. The committee therefore developed research recommendations on stopping anticoagulation after ablation and stopping anticoagulation after resolution of postoperative atrial fibrillation to encourage further research.
The committee was concerned about the potential withdrawal of anticoagulation in people who had not had ablation or cardiac surgery for atrial fibrillation, but in whom sinus rhythm is now present and atrial fibrillation is no longer detectable. In particular, the committee noted that paroxysmal atrial fibrillation is not always detectable. Based on their experience, the committee made a consensus‑based recommendation to ensure that decisions about stopping anticoagulation in this population are based on formal risk assessment of stroke and bleeding risks and patient preference.
## How the recommendations might affect practice
The committee felt that the recommendation would not constitute a change in practice, and that there would not be a resource impact on the NHS.
Return to recommendations# Context
Atrial fibrillation is the most common heart rhythm disorder (affecting approximately 2% of the adult population), and estimates suggest its prevalence is increasing. Atrial fibrillation causes palpitations and breathlessness in many people but it may be silent and undetected. If left untreated it is a significant risk factor for stroke and other morbidities: it is estimated that it is responsible for approximately 20% of all strokes and is associated with increased mortality. Men are more commonly affected than women and the prevalence increases with age and in underlying heart disease, diabetes, obesity and hypertension.
Atrial fibrillation is typically detected as an irregular pulse or an irregular rhythm on an electrocardiogram (ECG). This may be an incidental finding or may arise while investigating symptoms suggestive of the disease. Because atrial fibrillation can be intermittent, detection and diagnosis may be challenging.
The aim of treatment is to prevent complications, particularly stroke, and alleviate symptoms. Drug treatments include anticoagulants to reduce the risk of stroke and antiarrhythmics to restore or maintain the normal heart rhythm or to slow the heart rate in people who remain in atrial fibrillation. Non‑pharmacological management includes electrical cardioversion, which may be used to 'shock' the heart back to its normal rhythm, and catheter or surgical ablation to create lesions to stop the triggers that cause atrial fibrillation. These procedures can markedly reduce the symptom burden when drug therapy is ineffective or not tolerated.
This update focuses on areas of new evidence and changing practice since the 2014 NICE guideline. These include methods of identifying atrial fibrillation; assessing stroke and bleeding risk; antithrombotic agents; ablation strategies; preventing recurrence; and preventing and managing postoperative atrial fibrillation. This guideline update includes recommendations on these specific issues.
The recommendations apply to adults (18 years or older) with atrial fibrillation, including paroxysmal (recurrent), persistent and permanent atrial fibrillation, and atrial flutter. They do not apply to people with congenital heart disease precipitating atrial fibrillation.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Detection and diagnosis\n\nPerform manual pulse palpation to assess for the presence of an irregular pulse if there is a suspicion of atrial fibrillation. This includes people presenting with any of the following:\n\nbreathlessness\n\npalpitations\n\nsyncope or dizziness\n\nchest discomfort\n\nstroke or transient ischaemic attack. \n\nPerform a 12‑lead electrocardiogram (ECG) to make a diagnosis of atrial fibrillation if an irregular pulse is detected in people with suspected atrial fibrillation with or without symptoms. \n\nIn people with suspected paroxysmal atrial fibrillation undetected by 12‑lead ECG recording:\n\nuse a 24‑hour ambulatory ECG monitor if asymptomatic episodes are suspected or symptomatic episodes are less than 24\xa0hours apart\n\nuse an ambulatory ECG monitor, event recorder or other ECG technology for a period appropriate to detect atrial fibrillation if symptomatic episodes are more than 24\xa0hours apart. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on detection and diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: effectiveness of tests for detection and evidence review B: accuracy of tests for detection.\n\nLoading. Please wait.\n\n# Assessment of stroke and bleeding risks\n\n## Stroke risk\n\nUse the CHA2DS2-VASc stroke risk score to assess stroke risk in people with any of the following:\n\nsymptomatic or asymptomatic paroxysmal, persistent or permanent atrial fibrillation\n\natrial flutter\n\na continuing risk of arrhythmia recurrence after cardioversion back to sinus rhythm or catheter ablation. See the section on review of people with atrial fibrillation for advice on reassessment of stroke risk.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on stroke risk\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C and D: tools to predict stroke in people with atrial fibrillation.\n\nLoading. Please wait.\n\n## Bleeding risk\n\nAssess the risk of bleeding when:\n\nconsidering starting anticoagulation in people with atrial fibrillation and\n\nreviewing people already taking anticoagulation. Use the ORBIT bleeding risk score because evidence shows that it has a higher accuracy in predicting absolute bleeding risk than other bleeding risk tools. Accurate knowledge of bleeding risk supports shared decision making and has practical benefits, for example, increasing patient confidence and willingness to accept treatment when risk is low and prompting discussion of risk reduction when risk is high. Although ORBIT is the best tool for this purpose, other bleeding risk tools may need to be used until it is embedded in clinical pathways and electronic systems. \n\nOffer monitoring and support to modify risk factors for bleeding, including:\n\nuncontrolled hypertension (see NICE's guideline on hypertension in adults)\n\npoor control of international normalised ratio (INR) in patients on vitamin K antagonists\n\nconcurrent medication, including antiplatelets, selective serotonin reuptake inhibitors (SSRIs) and non‑steroidal anti‑inflammatory drugs (NSAIDs)\n\nharmful alcohol consumption (see NICE's guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence)\n\nreversible causes of anaemia. \n\n## Discussing the results of the risk assessment\n\nDiscuss the results of the assessments of stroke and bleeding risk with the person taking into account their specific characteristics, for example comorbidities, and their individual preferences. For further guidance, see the section on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on bleeding risk\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E and F: risk stratification tools for predicting bleeding in people with atrial fibrillation.\n\nLoading. Please wait.\n\n# Assessment of cardiac function\n\nPerform transthoracic echocardiography (TTE) in people with atrial fibrillation:\n\nfor whom a baseline echocardiogram is important for long‑term management\n\nfor whom a rhythm‑control strategy that includes cardioversion (electrical or pharmacological) is being considered\n\nin whom there is a high risk or a suspicion of underlying structural or functional heart disease (such as heart failure or heart murmur) that influences their subsequent management (for example, choice of antiarrhythmic drug)\n\nin whom refinement of clinical risk stratification for antithrombotic therapy is needed (see section 1.2 on assessment of stroke and bleeding risks and section 1.6 on stroke prevention). [2006, amended 2014]\n\nDo not routinely perform TTE solely for the purpose of further stroke risk stratification in people with atrial fibrillation for whom the need to start anticoagulation therapy has already been agreed on appropriate clinical criteria (see section 1.2 on assessment of stroke and bleeding risks and section 1.6 on stroke prevention). [2006, amended 2014]\n\nPerform transoesophageal echocardiography (TOE) in people with atrial fibrillation:\n\nwhen TTE demonstrates an abnormality (such as valvular heart disease) that warrants further specific assessment\n\nin whom TTE is technically difficult and/or of questionable quality and when there is a need to exclude cardiac abnormalities\n\nfor whom TOE‑guided cardioversion is being considered. \n\n# Personalised package of care and information\n\nOffer people with atrial fibrillation a personalised package of care. Ensure that the package of care is documented and delivered, and that it covers:\n\nstroke awareness and measures to prevent stroke\n\nrate control\n\nassessment of symptoms for rhythm control\n\nwho to contact for advice if needed\n\npsychological support if needed\n\nup‑to‑date and comprehensive education and information on:\n\n\n\ncause, effects and possible complications of atrial fibrillation\n\nmanagement of rate and rhythm control\n\nanticoagulation\n\npractical advice on anticoagulation in line with the recommendations on information and support for people having anticoagulation treatment in NICE's guideline on venous thromboembolic diseases\n\nsupport networks (for example, cardiovascular charities). \n\n\n\nFollow the recommendations in NICE's guideline on shared decision making. \n\n## Medicines adherences and optimisation\n\nTo support adherence and ensure safe and effective medicines use in people with atrial fibrillation, follow the recommendations in NICE's guidelines on medicines adherence and medicines optimisation. \n\n# Referral for specialised management\n\nRefer people promptly at any stage if treatment fails to control the symptoms of atrial fibrillation and more specialised management is needed. This should be within 4\xa0weeks after the failed treatment or after recurrence of atrial fibrillation after cardioversion. \n\n# Stroke prevention\n\n## Anticoagulation\n\nWhen discussing the benefits and risks of anticoagulation use clinical risk profiles and personal preferences to guide treatment choices. Discuss with the person that:\n\nfor most people the benefit of anticoagulation outweighs the bleeding risk\n\nfor people with an increased risk of bleeding, the benefit of anticoagulation may not always outweigh the bleeding risk, and careful monitoring of bleeding risk is important. \n\nWhen deciding between anticoagulation treatment options:\n\nDiscuss the risks and benefits of different drugs with the person and follow the\n\nFollow the recommendations on patient involvement in decisions about medicines in NICE's guideline on medicines adherence and patient decision aids in NICE's guideline on medicines optimisation.\n\nTake into account any contraindications for each drug and follow the guidance in the British National Formulary and the MHRA advice on direct-acting oral anticoagulants, in particular for advice on dosages in people with renal impairment, reversal agents and monitoring. \n\nOffer anticoagulation with a direct‑acting oral anticoagulant to people with atrial fibrillation and a CHA2DS2‑VASc score of 2 or above, taking into account the risk of bleeding. Apixaban, dabigatran, edoxaban and rivaroxaban are all recommended as options, when used in line with the criteria specified in the relevant NICE technology appraisal guidance (see the NICE technology appraisal guidance on our topic page on embolism and thrombosis). \n\nConsider anticoagulation with a direct‑acting oral anticoagulant for men with atrial fibrillation and a CHA2DS2‑VASc score of 1, taking into account the risk of bleeding. Apixaban, dabigatran, edoxaban and rivaroxaban are all recommended as options, when used in line with the criteria specified in the relevant NICE technology appraisal guidance (see the NICE technology appraisal guidance on our topic page on embolism and thrombosis). \n\nIf direct‑acting oral anticoagulants are contraindicated, not tolerated or not suitable in people with atrial fibrillation, offer a vitamin\xa0K antagonist. See the section on self-monitoring and self-management of vitamin K antagonists. .\n\nFor adults with atrial fibrillation who are already taking a vitamin\xa0K antagonist and are stable, continue with their current medication and discuss the option of switching treatment at their next routine appointment, taking into account the person's time in therapeutic range. \n\nDo not offer stroke prevention therapy with anticoagulation to people aged under 65\xa0years with atrial fibrillation and no risk factors other than their sex (that is, very low risk of stroke equating to a CHA2DS2‑VASc score of 0 for men or 1 for women). \n\nDo not withhold anticoagulation solely because of a person's age or their risk of falls. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on stroke prevention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G1: anticoagulant therapy for stroke prevention in people with atrial fibrillation and evidence review G2: anticoagulant therapy health economics analysis.\n\nLoading. Please wait.\n\n## Assessing anticoagulation control with vitamin K antagonists\n\nCalculate the person's time in therapeutic range (TTR) at each visit. When calculating TTR:\n\nuse a validated method of measurement such as the Rosendaal method for computer‑assisted dosing or proportion of tests in range for manual dosing\n\nexclude measurements taken during the first 6\xa0weeks of treatment\n\ncalculate TTR over a maintenance period of at least 6\xa0months. \n\nReassess anticoagulation for a person whose anticoagulation is poorly controlled shown by any of the following:\n\nINR values higher than 5 or 1\xa0INR value higher than 8 within the past 6\xa0months\n\nINR values less than 1.5 within the past 6\xa0months\n\nTTR less than 65%. \n\nWhen reassessing anticoagulation, take into account and if possible address the following factors that may contribute to poor anticoagulation control:\n\ncognitive function\n\nadherence to prescribed therapy\n\nillness\n\ninteracting drug therapy\n\nlifestyle factors including diet and alcohol consumption. \n\nIf poor anticoagulation control cannot be improved, evaluate the risks and benefits of alternative stroke prevention strategies and discuss these with the person. \n\nNICE has developed diagnostics guidance on atrial fibrillation and heart valve disease: self-monitoring coagulation status using point-of-care coagulometers (the CoaguChek XS system).\n\n## Antiplatelets\n\nFor guidance on antiplatelet therapy for people who have had a myocardial infarction and are having anticoagulation, see antiplatelet therapy for people with an ongoing separate indication for anticoagulation in NICE's guideline on acute coronary syndromes.\n\nDo not offer aspirin monotherapy solely for stroke prevention to people with atrial fibrillation. \n\n## Review of people with atrial fibrillation\n\nFor people who are not taking an anticoagulant, review stroke risk when they reach age\xa065 or if they develop any of the following at any age:\n\ndiabetes\n\nheart failure\n\nperipheral arterial disease\n\ncoronary heart disease\n\nstroke, transient ischaemic attack or systemic thromboembolism. \n\nFor people who are not taking an anticoagulant because of bleeding risk or other factors, review stroke and bleeding risks annually, and ensure that all reviews and decisions are documented. \n\nFor people who are taking an anticoagulant, review the need for anticoagulation and the quality of anticoagulation (taking into account MHRA advice on direct-acting oral anticoagulants about bleeding risk and the need to monitor renal function in patients with renal impairment) at least annually, or more frequently if clinically relevant events occur affecting anticoagulation or bleeding risk. \n\n## Left atrial appendage occlusion\n\nConsider left atrial appendage occlusion (LAAO) if anticoagulation is contraindicated or not tolerated and discuss the benefits and risks of LAAO with the person. For more information see NICE's interventional procedure guidance on percutaneous occlusion of the left atrial appendage in non-valvular atrial fibrillation for the prevention of thromboembolism. \n\nDo not offer LAAO as an alternative to anticoagulation unless anticoagulation is contraindicated or not tolerated. \n\n# Rate and rhythm control\n\nThis section covers rate and rhythm control in non‑acute settings. See section 1.8 for rate and rhythm control for people presenting acutely (either new onset or destabilisation of existing atrial fibrillation).\n\n## Rate control\n\nOffer rate control as the first‑line treatment strategy for atrial fibrillation except in people:\n\nwhose atrial fibrillation has a reversible cause\n\nwho have heart failure thought to be primarily caused by atrial fibrillation\n\nwith new‑onset atrial fibrillation\n\nwith atrial flutter whose condition is considered suitable for an ablation strategy to restore sinus rhythm\n\nfor whom a rhythm‑control strategy would be more suitable based on clinical judgement. \n\nOffer either a standard beta‑blocker (that is, a beta‑blocker other than sotalol) or a rate‑limiting calcium‑channel blocker (diltiazem or verapamil) as initial rate‑control monotherapy to people with atrial fibrillation unless the person has the features described in recommendation 1.7.4. Base the choice of drug on the person's symptoms, heart rate, comorbidities and preferences. In April 2021, this was an off‑label use of diltiazem. See NICE's information on prescribing medicines.\n\nFor people with atrial fibrillation and concomitant heart failure, follow the recommendations on the use of beta-blockers and avoiding calcium-channel blockers in NICE's guideline on chronic heart failure. \n\nConsider digoxin monotherapy for initial rate control for people with non‑paroxysmal atrial fibrillation if:\n\nthe person does no or very little physical exercise or\n\nother rate‑limiting drug options are ruled out because of comorbidities or the person's preferences. \n\nIf monotherapy does not control the person's symptoms, and if continuing symptoms are thought to be caused by poor ventricular rate control, consider combination therapy with any 2 of the following:\n\na beta‑blocker\n\ndiltiazem\n\ndigoxin. In April 2021, this was an off‑label use of diltiazem. See NICE's information on prescribing medicines.\n\nDo not offer amiodarone for long-term rate control. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on rate control\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: non-ablative rate control therapies.\n\nLoading. Please wait.\n\n## Rhythm control\n\nConsider pharmacological and/or electrical rhythm control for people with atrial fibrillation whose symptoms continue after heart rate has been controlled or for whom a rate‑control strategy has not been successful. \n\nAssess the need for drug treatment for long‑term rhythm control, taking into account the person's preferences, associated comorbidities, risks of treatment and likelihood of recurrence of atrial fibrillation. \n\nDo not offer class\xa01c antiarrhythmic drugs such as flecainide or propafenone to people with known ischaemic or structural heart disease. \n\nIf drug treatment for long‑term rhythm control is needed, consider a standard beta‑blocker (that is, a beta‑blocker other than sotalol) as first‑line treatment unless there are contraindications. \n\nIf beta‑blockers are contraindicated or unsuccessful, assess the suitability of alternative drugs for rhythm control, taking comorbidities into account. \n\nFollow the advice on dronedarone as a second‑line treatment option for long‑term rhythm control after successful cardioversion in NICE's technology appraisal guidance on dronedarone for the treatment of non-permanent atrial fibrillation. \n\nConsider amiodarone for people with left ventricular impairment or heart failure. \n\nIn people with infrequent paroxysms and few symptoms, or if symptoms are induced by known precipitants (such as alcohol, caffeine), a 'no drug treatment' strategy or a 'pill-in-the-pocket' strategy (in which antiarrhythmic drugs are taken only when an episode starts) should be considered and discussed with the person. \n\nIn people with paroxysmal atrial fibrillation, a 'pill‑in‑the‑pocket' strategy should be considered for those who:\n\nhave no history of left ventricular dysfunction, or valvular or ischaemic heart disease and\n\nhave a history of infrequent symptomatic episodes of paroxysmal atrial fibrillation and\n\nhave a systolic blood pressure greater than 100\xa0mmHg and a resting heart rate above 70\xa0bpm and\n\nare able to understand how to, and when to, take the medication. \n\nFor people having cardioversion for atrial fibrillation that has persisted for longer than 48\xa0hours, offer electrical (rather than pharmacological) cardioversion. \n\nConsider amiodarone therapy starting 4\xa0weeks before and continuing for up to 12\xa0months after electrical cardioversion to maintain sinus rhythm, and discuss the benefits and risks of amiodarone with the person. \n\nFor people with atrial fibrillation of greater than 48\xa0hours' duration, in whom elective cardioversion is indicated:\n\nboth transoesophageal echocardiography (TOE)‑guided cardioversion and conventional cardioversion should be considered equally effective\n\na TOE‑guided cardioversion strategy should be considered:\n\n\n\nif experienced staff and appropriate facilities are available and\n\nif a minimal period of precardioversion anticoagulation is indicated due to the person's choice or bleeding risks. \n\n\n\n## Left atrial ablation\n\nIf drug treatment is unsuccessful, unsuitable or not tolerated in people with symptomatic paroxysmal or persistent atrial fibrillation:\n\nconsider radiofrequency point‑by‑point ablation or\n\nif radiofrequency point‑by‑point ablation is assessed as being unsuitable, consider cryoballoon ablation or laser balloon ablation. \n\nWhen considering left atrial ablation, discuss the risks and benefits and take into account the person's preferences. In particular, explain that the procedure is not always effective and that the resolution of symptoms may not be long‑lasting. \n\nConsider left atrial surgical ablation at the same time as other cardiothoracic surgery for people with symptomatic atrial fibrillation. \n\nFor NICE interventional procedures guidance on left atrial ablation for atrial fibrillation, see the NICE interventional procedures guidance on our topic page on heart rhythm conditions.\n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on left atrial ablation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J1: ablation, evidence review J2: ablation network meta-analysis and evidence review J3: ablation cost-effectiveness analysis.\n\nLoading. Please wait.\n\nConsider antiarrhythmic drug treatment for 3\xa0months after left atrial ablation to prevent recurrence of atrial fibrillation, taking into account the person's preferences, and the risks and potential benefits. \n\nReassess the need for antiarrhythmic drug treatment at 3\xa0months after left atrial ablation. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing recurrence after ablation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: antiarrhythmic drugs after ablation.\n\nLoading. Please wait.\n\n## Pace and ablate strategy\n\nConsider pacing and atrioventricular node ablation for people with permanent atrial fibrillation with symptoms or left ventricular dysfunction thought to be caused by high ventricular rates. \n\nWhen considering pacing and atrioventricular node ablation, reassess symptoms and the consequent need for ablation after pacing has been carried out and drug treatment further optimised. \n\nConsider left atrial catheter ablation before pacing and atrioventricular node ablation for people with paroxysmal atrial fibrillation or heart failure caused by non‑permanent (paroxysmal or persistent) atrial fibrillation. \n\n# Management for people presenting acutely with atrial fibrillation\n\n## Rate and rhythm control for people presenting acutely\n\nCarry out emergency electrical cardioversion, without delaying to achieve anticoagulation, in people with life‑threatening haemodynamic instability caused by new‑onset atrial fibrillation. \n\nIn people with atrial fibrillation presenting acutely without life-threatening haemodynamic instability:\n\noffer either rate or rhythm control if the onset of the arrhythmia is less than 48\xa0hours\n\noffer rate control if onset is more than 48\xa0hours or is uncertain. \n\nIn people with atrial fibrillation presenting acutely with suspected concomitant acute decompensated heart failure, seek senior specialist input on the use of beta‑blockers and do not use calcium‑channel blockers. \n\nConsider either pharmacological or electrical cardioversion depending on clinical circumstances and resources in people with new‑onset atrial fibrillation who will be treated with a rhythm‑control strategy. \n\nIf pharmacological cardioversion has been agreed on clinical and resource grounds for new‑onset atrial fibrillation, offer:\n\na choice of flecainide or amiodarone to people with no evidence of structural or ischaemic heart disease or\n\namiodarone to people with evidence of structural heart disease. \n\nIn people with atrial fibrillation in whom the duration of the arrhythmia is greater than 48\xa0hours or uncertain and considered for long‑term rhythm control, delay cardioversion until they have been maintained on therapeutic anticoagulation for a minimum of 3\xa0weeks. During this period offer rate control as appropriate. [2006, amended 2014]\n\nDo not offer magnesium or a calcium‑channel blocker for pharmacological cardioversion. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on rate and rhythm control for people presenting acutely\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: non-ablative rate control therapies.\n\nLoading. Please wait.\n\n## Anticoagulation for people presenting acutely with atrial fibrillation\n\nIn people with new‑onset atrial fibrillation who are receiving no, or subtherapeutic, anticoagulation therapy:\n\nin the absence of contraindications, offer heparin at initial presentation\n\ncontinue heparin until a full assessment has been made and appropriate antithrombotic therapy has been started, based on risk stratification (see section 1.2 on assessment of stroke and bleeding risks and section 1.6 on stroke prevention). [2006, amended 2014]\n\nIn people with a confirmed diagnosis of atrial fibrillation of recent onset (less than 48\xa0hours since onset), offer oral anticoagulation if:\n\nstable sinus rhythm is not successfully restored within the same 48‑hour period after onset of atrial fibrillation or\n\nthere are factors indicating a high risk of atrial fibrillation recurrence, including history of failed cardioversion, structural heart disease, prolonged atrial fibrillation (more than 12\xa0months), or previous recurrences or\n\nit is recommended in section 1.2 on assessment of stroke and bleeding risks and section 1.6 on stroke prevention. [2006, amended 2014]\n\nIn people with new‑onset atrial fibrillation, if there is uncertainty over the precise time since onset, offer oral anticoagulation as for persistent atrial fibrillation (see section 1.2 on assessment of stroke and bleeding risks and section 1.6 stroke prevention). [2006, amended 2014]\n\n# Initial management of stroke and atrial fibrillation\n\nFor guidance on the initial management of stroke and atrial fibrillation see recommendation 1.4.17 in NICE's guideline on stroke and transient ischaemic attack in over 16s. \n\n# Preventing and managing postoperative atrial fibrillation\n\n## Preventing postoperative atrial fibrillation\n\nIn people having cardiothoracic surgery:\n\nreduce the risk of postoperative atrial fibrillation by offering 1\xa0of the following:\n\n\n\namiodarone\n\na standard beta‑blocker (that is, a beta-blocker other than sotalol)\n\na rate‑limiting calcium‑channel blocker (diltiazem or verapamil)\n\n\n\ndo not offer digoxin. [2006, amended 2014]In April 2021, this was an off‑label use of diltiazem. See NICE's information on prescribing medicines.\n\nIn people having cardiothoracic surgery who are already on beta‑blocker therapy, continue this treatment unless contraindications develop (such as postoperative bradycardia or hypotension). [2006, amended 2014]\n\nDo not start statins in people having cardiothoracic surgery solely to prevent postoperative atrial fibrillation. \n\nIn people having cardiothoracic surgery who are already on statins, continue this treatment. For further advice on statins for the prevention of cardiovascular disease, see NICE's guideline on cardiovascular disease: risk assessment and reduction. \n\nFor a short explanation of why the committee made the 2021\xa0recommendations and how they might affect practice, see the rationale and impact section on preventing postoperative atrial fibrillation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: statins for preventing atrial fibrillation after cardiothoracic surgery.\n\nLoading. Please wait.\n\n## Managing postoperative atrial fibrillation\n\nConsider either a rhythm‑control or rate‑control strategy for the initial treatment of new‑onset postoperative atrial fibrillation after cardiothoracic surgery. \n\nIf a rhythm‑control strategy is chosen, reassess the need for antiarrhythmic drug treatment at a suitable time point (usually at around 6\xa0weeks). \n\nManage postoperative atrial fibrillation after non‑cardiothoracic surgery in the same way as for new-onset atrial fibrillation with any other cause. [2006, amended 2014]\n\nIn the prophylaxis and management of postoperative atrial fibrillation, use appropriate antithrombotic therapy and correct identifiable causes (such as electrolyte imbalance or hypoxia). [2006, amended 2014]\n\nFor a short explanation of why the committee made the 2021\xa0recommendations and how they might affect practice, see the rationale and impact section on managing atrial fibrillation after cardiothoracic surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: treatment strategies for atrial fibrillation after cardiothoracic surgery.\n\nLoading. Please wait.\n\n# Stopping anticoagulation\n\nIn people with a diagnosis of atrial fibrillation, do not stop anticoagulation solely because atrial fibrillation is no longer detectable. \n\nBase decisions to stop anticoagulation on a reassessment of stroke and bleeding risk using CHA2DS2‑VASc and ORBIT and a discussion of the person's preferences. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on stopping anticoagulation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: discontinuing anticoagulation in people whose atrial fibrillation has resolved.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## People with atrial fibrillation presenting acutely\n\nPeople presenting with atrial fibrillation of definite recent onset or with destabilisation of existing atrial fibrillation. This does not include people with atrial fibrillation that has been discovered incidentally, for example through pulse palpitation before routine blood pressure measurement.\n\n## Pill-in-the-pocket strategy\n\nThe person self‑manages paroxysmal atrial fibrillation by taking antiarrhythmic drugs only when an episode of atrial fibrillation starts.\n\n## Paroxysmal atrial fibrillation\n\nEpisodes of atrial fibrillation that stop within 7\xa0days, usually within 48\xa0hours, without any treatment.", 'Recommendations for research': "As part of the 2021\xa0update, the guideline committee made 4\xa0new research recommendations (marked ). Research recommendations retained from the 2014\xa0guideline are labelled .\n\n# Key recommendations for research\n\n## Tests to diagnose persistent atrial fibrillation\n\nWhat is the diagnostic accuracy of key index tests (such as the KardiaMobile heart monitor (AliveCor), MyDiagnostik, Microlife BP monitors, iPhone plethysmography and pulse palpation) compared with the gold standard of 12‑lead ECG in people with risk factors for or symptoms of atrial fibrillation? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on detection and diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: accuracy of tests for detection.\n\nLoading. Please wait.\n\n## Tests to diagnose paroxysmal atrial fibrillation\n\nWhat is the diagnostic accuracy of key index tests compared with the gold standard of prolonged ambulatory monitoring in people suspected of having paroxysmal atrial fibrillation? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on detection and diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: accuracy of tests for detection.\n\nLoading. Please wait.\n\n## Stopping anticoagulation after ablation\n\nWhat is the clinical and cost effectiveness of stopping anticoagulation in people whose atrial fibrillation has resolved after ablation? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on stopping anticoagulation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: discontinuing anticoagulation in people whose atrial fibrillation has resolved.\n\nLoading. Please wait.\n\n## Stopping anticoagulation after resolution of postoperative atrial fibrillation\n\nWhat is the clinical and cost effectiveness of stopping anticoagulation in people whose postoperative atrial fibrillation after cardiac surgery has resolved? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on stopping anticoagulation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: discontinuing anticoagulation in people whose atrial fibrillation has resolved.\n\nLoading. Please wait.\n\n## Cognitive behavioural therapy for people with atrial fibrillation\n\nWhat is the clinical and cost effectiveness of cognitive behavioural therapy compared with usual care for people with newly diagnosed atrial fibrillation? \n\n## Rate-control drug treatment for people aged 75\xa0and over with atrial fibrillation\n\nWhat is the comparative effectiveness of the 3\xa0main drug classes used for rate control (beta‑blockers, calcium‑channel blockers and digoxin) in people aged 75\xa0and over with atrial fibrillation in controlling symptoms, improving quality of life and reducing morbidity and mortality? \n\n## Stroke risk assessment\n\nCan routine data from UK primary care databases clarify stroke risk in people with atrial fibrillation according to baseline risk factors and treatment? ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Detection and diagnosis\n\nRecommendations 1.1.2 and 1.1.3\n\n## Why the committee made the recommendations\n\nThe evidence did not support changing the recommended diagnostic tests to either replace 12‑lead ECG as the test to confirm persistent atrial fibrillation or replace pulse palpation as the initial step for persistent atrial fibrillation in a 2‑step strategy. The committee clarified that 12‑lead ECG should be used as the test to confirm atrial fibrillation, to prevent the use of less accurate ECG devices, such as mobile and lead‑I ECG devices. The committee agreed that, although the evidence showed that accuracy varied, there was some evidence that new devices were accurate and showed promise. It was noted that NICE has produced diagnostics guidance on lead-I ECG devices for detecting symptomatic atrial fibrillation using single time point testing in primary care. The committee made a research recommendation on tests to diagnose persistent atrial fibrillation to encourage further high‑quality research in this area to guide future practice.\n\nThe committee agreed that the evidence on tests to detect paroxysmal atrial fibrillation was not clear enough to warrant a change in practice from the 2014\xa0recommendation. However, the evidence did show that longer durations of detection increased accuracy. The committee made a research recommendation on tests to diagnose paroxysmal atrial fibrillation.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current good practice and are unlikely to have an impact on practice.\n\nReturn to recommendations\n\n# Stroke risk\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendations\n\nThe committee decided to prioritise identifying people above or below a certain risk threshold (discrimination) in its interpretation of the evidence rather than estimating a person's risk of stroke in absolute terms.\n\nThe evidence suggested that a score of 2\xa0or more is the ideal threshold for the CHA2DS2‑VASC in terms of indicating the need for anticoagulation. (Men with a CHA2DS2‑VASc score of\xa01 were regarded as being at intermediate risk, and a group in whom anticoagulation should also be considered.) The evidence showed that this threshold of 2\xa0or more offered a good combination of high sensitivity (0.92) and adequate specificity (0.23).\n\nThe high sensitivity means that the tool would correctly identify almost everyone who would later have a stroke if they did not receive anticoagulants. Importantly, this will allow them to be prescribed anticoagulants to reduce their risk of stroke.\n\nThe adequate specificity means that 23% of the people who would not later have a stroke (even when not taking anticoagulants) would be correctly identified as not needing anticoagulation. This would prevent these people from having adverse events from anticoagulants. It also means that 77% of people who would not later have a stroke (without anticoagulation) would be wrongly identified as needing anticoagulation. However, this was thought to be acceptable given the perceived lesser harms from unnecessarily giving anticoagulants compared with not giving anticoagulants to people who need them, together with the inevitable trade‑off between sensitivity and specificity.\n\nThe ATRIA stroke risk score was shown to have better overall accuracy, but although it had better specificity than CHA2DS2‑VASc (fewer false-positive results) it had lower sensitivity, meaning that more people at risk would be missed (more false‑negative results) compared with the CHA2DS2‑VASc score. As already suggested, sensitivity was agreed by the committee to be more important than specificity because the risks of unnecessary anticoagulation are outweighed by the risks of not treating people who need anticoagulation. In addition, the ATRIA risk score may result in a time delay in calculating the results.\n\nThe committee also discussed that the evidence for the QStroke risk calculator suggested that it might be a useful tool. However, the evidence was limited, and they agreed that further research was needed.\n\n## How the recommendation might affect practice\n\nThe recommendation does not constitute a change in practice, and so there would not be a resource impact on the NHS.\n\nReturn to recommendations\n\n# Bleeding risk\n\nRecommendations 1.2.2 to 1.2.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that anticoagulation should usually be considered in people at risk of stroke even if bleeding risk is high, and so a bleeding risk tool should not be used to provide a cut off for determining who should have anticoagulation. Instead, the tool should be used to provide accurate knowledge of absolute bleeding risk, which can support discussions between the person and their healthcare professional about bleeding risk modification and appropriate levels of vigilance. They therefore agreed that accurately estimating absolute risk (calibration) is more important than identifying a risk threshold for anticoagulation (discrimination) when choosing between different bleeding risk tools.\n\nThe committee focused on calibration data for the tools with the most evidence: ORBIT, HAS-BLED and ATRIA. The calibration evidence clearly suggested that ORBIT was more accurate than HAS‑BLED and ATRIA at predicting absolute risk of major bleeding, both for people using vitamin K antagonists and those using direct‑acting oral anticoagulants. Importantly, ORBIT was better calibrated at all levels of major bleeding risk, including higher levels. ORBIT was also better at predicting absolute risk of intracranial haemorrhage.\n\nThe discrimination data showed little difference between tools in predicting major bleeding, with some outcome measures showing no difference and others showing a slight benefit for either ORBIT or HAS‑BLED. Evidence showed that ORBIT had a significantly higher specificity and a slighter lower sensitivity than the other tools, but the committee agreed that the lower sensitivity would not be a drawback when used to inform discussions of risk.\n\nThe committee agreed that the evidence overall, and particularly the calibration data demonstrating higher accuracy of absolute risk, strongly supported ORBIT as the tool of choice.\n\nThe committee agreed that NICE's previous advice on monitoring and addressing modifiable risk factors was still relevant and added reversible causes of anaemia because it is a component of the ORBIT tool.\n\n## How the recommendations might affect practice\n\nUse of the ORBIT score is a change in practice, which will take time to implement. The committee considered that the more accurate prediction of the absolute risk of bleeding is a real advantage in supporting patients and clinicians in shared decision making, which should lead to better clinical outcomes. The committee considered carefully a number of practical issues set out in this section. Overall, the committee concluded that this change is one that is worth making.\n\nOne potential concern discussed by the committee is that ORBIT does not include all of the modifiable risk factors included in HAS‑BLED so does not serve as a reminder of these to clinicians. However, the committee considered that fully investigating modifiable risk factors is established clinical practice, regardless of the tool used.\n\nAnother potential challenge is that ORBIT is not the recommended bleeding risk tool for other conditions (such as venous thromboembolism). Therefore, an initial transition period may be needed for training and education in both primary and secondary care while healthcare professionals become familiar with the tool. This will have a resource impact, although it will be time limited. The committee also noted that use of the ORBIT tool, and access to online versions, is straightforward.\n\nFinally, the committee also discussed that, unlike HAS‑BLED, ORBIT is not embedded in GP systems, which may cause some initial practical difficulties. However, because this will involve changes to centralised software, it is thought that it will be straightforward to implement and ORBIT will quickly be included in GP systems. Neither tool is included in hospital systems although both are widely available on smartphone apps.\n\nReturn to recommendations\n\n# Stroke prevention\n\nRecommendations 1.6.1 to 1.6.8\n\n## Why the committee made the recommendations\n\nEvidence from an analysis of several studies showed that direct‑acting oral anticoagulants are more effective than warfarin for a number of outcomes. An economic model also showed that they offered a better balance of benefits to costs than warfarin. There were no studies directly comparing the direct‑acting anticoagulants head‑to‑head but indirect comparisons based on the clinical evidence showed that the different direct‑acting oral anticoagulants offered different benefits depending on the outcome considered. When all these outcomes were combined in the cost‑effectiveness analysis, apixaban was the most clinically effective and cost‑effective anticoagulant based on UK drug tariff prices at the time. However, the committee had concerns over the lack of head‑to‑head comparisons, differences in the study populations and uncertainties in the economic model.\n\nBased on the evidence and their experience, the committee decided not to recommend one direct‑acting oral anticoagulant over the others, but instead to emphasise that treatment should be tailored to the person's clinical needs and preferences. Each anticoagulant has different risks and benefits that should be considered and fully discussed with the person as part of informed shared decision making. The committee highlighted that the choice might be affected by factors such as renal impairment and swallowing difficulties, and that healthcare professionals should refer to the BNF for advice on contraindications and cautions. They also stressed the importance of adherence and factors that might affect this, such as dosing frequency, when making the decision. If direct‑acting oral anticoagulants are not suitable, for example in people with antiphospholipid syndrome, the committee agreed that a vitamin K antagonist should be offered.\n\nFor people already established and stable on a vitamin\xa0K antagonist, the committee agreed that the benefits of changing to a direct‑acting anticoagulant need to be discussed. Therefore, the risks and benefits of changing medication, the person's time in therapeutic range and the person's preferences should be explored at their next routine appointment.\n\nThe committee agreed that the existing thresholds for the CHA2DS2‑VASc score threshold for anticoagulation are in line with current practice.\n\nAlthough bleeding risk scores may occasionally be used as a reason not to offer anticoagulation, the committee agreed that they should typically be used as a prompt to identify and manage modifiable risk factors for bleeding rather than as a reason for not offering anticoagulation in people at increased risk. The committee discussed that when anticoagulation is not given because of bleeding risk, people should have regular review and reconsideration for treatment.\n\nThe committee were concerned that anticoagulation is sometimes not recommended for people at risk of falls and for older people, even though age is factored into the bleeding risk score and falls are rarely a cause of major haemorrhage. Age was therefore added to the previous recommendation on people at risk of falls to ensure that anticoagulation is offered in this population when needed. The benefits and harms should be discussed with the person.\n\n## How the recommendations might affect practice\n\nThe recommendations are likely to lead to a change in current practice, with a reduction in warfarin use. The committee noted that this has been a prescribing trend over recent years and it may lead to a contraction in warfarin clinic services. The unit cost of direct‑acting anticoagulants is greater than that for warfarin, so there is likely to be a resource impact from increased use of direct‑acting anticoagulants.\n\nReturn to recommendations\n\n# Rate control\n\nRecommendations 1.7.2 to 1.7.6\n\n## Why the committee made the recommendations\n\nThe committee made some updates to the 2014\xa0recommendations, based on their experience and knowledge.\n\nThe use of beta‑blockers or rate‑limiting calcium‑channel blockers for initial rate‑control treatment was retained by the committee because this is current practice and there was insufficient evidence to suggest an alternative option. The committee agreed that the choice of treatment should still be made based on the symptoms, heart rate, comorbidities and preferences of those being treated.\n\nThe committee agreed that the recommendations should refer to NICE's guideline on chronic heart failure for advice on using beta‑blockers and avoiding rate‑limiting calcium‑channel blockers such as diltiazem and verapamil in people who have atrial fibrillation with heart failure.\n\nThe committee agreed that digoxin monotherapy for non-paroxysmal atrial fibrillation should continue to be considered for people who are sedentary. Based on their experience, the committee agreed that it may also be considered as a treatment option when other rate‑limiting drugs are not suitable, so they expanded the recommendation in the previous guideline to also cover these circumstances. The committee were aware that some clinicians feel that digoxin monotherapy is often better than alternatives for improving symptoms; however, the lack of evidence currently available meant that the recommendation for digoxin was not expanded to cover further groups of people.\n\nIn the absence of new evidence, the committee also agreed with the existing recommendation for combination therapy options if initial monotherapy fails, which is consistent with the committee's experience and current practice.\n\nThere was a lack of evidence on long‑term rate control, and the committee were aware of numerous serious side effects associated with the long‑term use of amiodarone (including thyroid, lung and nerve damage), many of which are irreversible. The committee noted that although the most common side effects were less severe, the occurrence of severe side effects was unpredictable and long‑term rate control with amiodarone should be avoided. Amiodarone should only be used as an interim therapy, for example while waiting for cardioversion, and would not usually be taken for longer than 12\xa0months.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice. Digoxin monotherapy may now be an option in non‑paroxysmal atrial fibrillation if comorbidities or patient preferences limit other rate‑control drug choices. However, the committee agreed that this already happens in practice.\n\nReturn to recommendations\n\n# Left atrial ablation\n\nRecommendations 1.7.19 to 1.7.20\n\n## Why the committee made the recommendations\n\nAblation may be a treatment option if antiarrhythmic drug treatment has not been successful or is not tolerated. The committee reviewed new clinical and health economic evidence for the different types of ablation for people with paroxysmal atrial fibrillation and agreed that the catheter ablation techniques were the most clinically effective ablation options. Thoracoscopy and the hybrid techniques led to lower recurrence, but they also led to more serious adverse effects. There were no clear differences in efficacy between the 4\xa0catheter ablation techniques: radiofrequency point‑by‑point, radiofrequency multi‑electrode, laser and cryoballoon ablation.\n\nA new economic model was developed for the guideline using the clinical evidence from people with paroxysmal atrial fibrillation. It showed that radiofrequency point‑by‑point ablation was more cost effective over a lifetime than antiarrhythmic drug treatment and other ablation strategies in people for whom 1\xa0or more antiarrhythmic drug has failed. Cryoballoon, radiofrequency multi-electrode and laser ablation were the second, third and fourth most cost‑effective options respectively.\n\nThe committee acknowledged that the NHS reference cost used for the catheter ablation procedures may not fully capture differences in resource use between the different techniques. However, despite further analysis to adjust costs and account for this, radiofrequency point‑by‑point ablation remained the most cost‑effective option, and other catheter ablation techniques are therefore unlikely to provide a cost‑effective use of NHS resources. Based on the economic model results the committee agreed that radiofrequency point‑by‑point ablation should be considered in people with symptomatic paroxysmal atrial fibrillation if drug treatment is unsuccessful, unsuitable or not tolerated.\n\nThe committee noted that cryoballoon and laser ablation may be more suitable for some patients because they can sometimes be carried out without general anaesthesia, and cryoballoon ablation may be quicker to perform, with same‑day discharge more likely. There is also an increased risk of fluid overload from saline irrigated radiofrequency ablation. They decided that either cryoballoon or laser ablation could be considered if radiofrequency point‑by‑point ablation is not suitable; for example, if a short procedure time is a priority or for people with a recent history of decompensated heart failure who are at increased risk of fluid overload. Radiofrequency multi-electrode was not included as an alternative due to its lower efficacy relative to cryoballoon and laser ablation and concerns about a higher risk of stroke.\n\nThere was limited evidence for ablation in people with persistent atrial fibrillation. Despite this, the committee decided that the evidence, combined with their experience and knowledge (also noting the Packer et al. CABANA randomized clinical trial, 2019, which contained a mixed population of people with persistent and paroxysmal atrial fibrillation) was sufficient to support ablation as an option to be considered for those with persistent symptoms that are not alleviated by, or who cannot have, antiarrhythmic drugs. The committee agreed that ablation can be effective in people with persistent atrial fibrillation, and that this population might have as much to gain from ablation as people with paroxysmal symptoms. The committee agreed that the cost‑effectiveness analyses of different types of ablation in paroxysmal atrial fibrillation could also be applied to this population.\n\nThe committee emphasised the importance of discussing the risks and benefits of catheter ablation with the person, in particular the risk of adverse events. The discussion should also include that, in the experience of the committee, the effects of ablation may not be long term.\n\n## How the recommendations might affect practice\n\nThe committee noted that the recommendations are likely to reinforce current practice. Ablation is carried out in a relatively restricted population (approximately 1%\xa0to 2% of all people with atrial fibrillation currently have ablation) and is usually reserved for people in whom antiarrhythmic drugs have failed. The recommendation is likely to lead to a change in the types of ablation offered, with more people receiving radiofrequency point‑by‑point ablation and fewer having other catheter ablation techniques.\n\nReturn to recommendations\n\n# Preventing recurrence after ablation\n\nRecommendations 1.7.22 and 1.7.23\n\n## Why the committee made the recommendations\n\nMost of the evidence on preventing recurrence after ablation was for amiodarone. The evidence suggested that amiodarone may reduce recurrence of atrial fibrillation after ablation. However, there was evidence of an increased risk of hospitalisation and the committee noted the known side effects of amiodarone, which, although rare, can be severe and life‑threatening.\n\nThere was a lack of evidence for other antiarrhythmic drugs and there were no comparisons between different antiarrhythmic drugs. Therefore, the committee agreed that there was too much uncertainty to recommend one specific antiarrhythmic drug over others.\n\nIn addition, the studies often made no distinction between people who had been on antiarrhythmic drugs up to ablation and those who had not. There is variation in current practice on whether people who were not previously taking antiarrhythmic drugs should start them after ablation to reduce recurrence. However, the evidence did not support making separate recommendations to clarify this.\n\nThe committee decided that antiarrhythmic drug treatment should be considered after ablation, but only after discussion with the person, taking into account their preferences for treatment and the potential individual risks and benefits. In particular, the committee noted that people should fully understand the potential adverse events associated with these drugs. While there is some variation, the committee agreed that good current practice is for patients taking antiarrhythmic drugs up to ablation to continue them for 3\xa0months after ablation and reassess the need for drug treatment after this time.\n\n## How the recommendations might affect practice\n\nThere is some variation in current practice. Practice is likely to change in some centres both in prescribing and in the need for a more formal reassessment of treatment at 3\xa0months. The impact on use of antiarrhythmic drugs is difficult to predict, but there may be an increase from current levels. Increased resources may be needed for reassessment, but it is anticipated that this could be performed at routine follow‑up appointments with a cardiologist.\n\nReturn to recommendations\n\n# Rate and rhythm control for people presenting acutely\n\nRecommendation 1.8.3\n\n## Why the committee made the recommendation\n\nThe committee agreed that the evidence was too limited in quality and quantity to be able to specify a preferred rate‑control drug for acute atrial fibrillation. Although there was some evidence that amiodarone was better than digoxin for rate control, the committee had concerns about the quality of the evidence and the short timeframe used in 1 study, which it agreed could disadvantage digoxin. In addition, there was limited evidence available for morbidity and adverse events for this comparison and no evidence identified for other drug classes.\n\nThe committee highlighted that the existing recommendations gave no guidance on acute atrial fibrillation with acute decompensated heart failure. Using their expertise and experience the committee agreed that advice on the use of beta-blockers and rate-limiting calcium‑channel blockers should be included because they can lead to further deterioration in people with pulmonary oedema caused by heart failure.\n\n## How the recommendation might affect practice\n\nThe recommendations do not constitute a change in practice, and so are unlikely to have a resource impact.\n\nReturn to recommendations\n\n# Preventing postoperative atrial fibrillation\n\nRecommendations 1.10.3 and 1.10.4\n\n## Why the committee made the recommendations\n\nThe committee noted that the most recent studies reviewed showed no benefit from statins in reducing atrial fibrillation after cardiothoracic surgery. This contrasted with analysis of the evidence overall, which showed a small but definite benefit from statins. The committee agreed that the evidence of no effect in the newer studies was important, because these studies were larger and of higher quality than the older studies included in the analysis.\n\nAlthough the newer studies suggested that statins did not affect the short‑term risk of stroke, they did suggest a greater risk of mortality in the peri‑operative period compared with placebo treatment or usual care. The committee agreed that although the additional risk of death was probably small, it was important, especially alongside the lack of convincing evidence of benefit.\n\nFor these reasons, the committee decided that statins should not be given to prevent atrial fibrillation after cardiothoracic surgery. However, the committee wanted to highlight that statins have an important role in preventing cardiovascular events other than atrial fibrillation and that people already taking statins for other reasons should continue to do so.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendation would not constitute a change in practice, and that there would not be a resource impact on the NHS.\n\nReturn to recommendations\n\n# Managing atrial fibrillation after cardiothoracic surgery\n\nRecommendations 1.10.5 and 1.10.6\n\n## Why the committee made the recommendations\n\nThe evidence on managing postoperative atrial fibrillation after cardiothoracic surgery in people without pre‑existing atrial fibrillation was limited – many of the studies reviewed were old and included small numbers of participants. There were few studies comparing drug classes, and the committee agreed that they could not recommend a particular class of drugs based on such limited evidence.\n\nOne larger study comparing mixed rate control and rhythm control with a potassium‑channel blocker (amiodarone) with or without rate control suggested little difference between the 2\xa0groups. Based on this evidence and their experience, the committee decided that rhythm control could be considered but that the evidence no longer supported the stronger recommendation included in the 2014\xa0guideline. The committee noted that postoperative atrial fibrillation often resolves naturally, meaning that rate control rather than rhythm control may be a suitable option for some people. Reducing the emphasis on rhythm‑control strategies will allow rate‑control strategies to be considered if appropriate for the person.\n\nThe committee were also aware of the risk of adverse events if amiodarone, a rhythm control drug, is taken long‑term. They highlighted that if a rhythm‑control strategy is chosen, the need for rhythm control drugs should be reassessed at approximately 6 weeks, in line with current practice, and they should not be continued automatically for long periods of time. The committee agreed that 6\xa0weeks is an appropriate time point to assess the person's recovery, including for example prosthetic valve function, and to check if sinus rhythm has been restored.\n\nThe committee did not make a separate recommendation for people with pre‑existing atrial fibrillation because of a lack of evidence. The committee noted that most people undergoing mitral valve surgery with pre‑existing atrial fibrillation would undergo left atrial surgery to treat atrial fibrillation at the same time.\n\n## How the recommendations might affect practice\n\nRhythm control for the treatment of new‑onset atrial fibrillation after cardiothoracic surgery is current practice and amiodarone is most commonly used. This can still be considered, but there may be a reduction in the use of rhythm control in this population and an increase in the use of rate‑control drugs instead.\n\nReturn to recommendations\n\n# Stopping anticoagulation\n\nRecommendations 1.11.1 and 1.11.2\n\n## Why the committee made the recommendations\n\nThere was limited evidence on whether to continue anticoagulation or to stop it and switch to aspirin after successful treatment of atrial fibrillation by catheter ablation. The committee agreed that the evidence was insufficient and that there was too much uncertainty in the results to make a recommendation based on the evidence. The committee therefore developed research recommendations on stopping anticoagulation after ablation and stopping anticoagulation after resolution of postoperative atrial fibrillation to encourage further research.\n\nThe committee was concerned about the potential withdrawal of anticoagulation in people who had not had ablation or cardiac surgery for atrial fibrillation, but in whom sinus rhythm is now present and atrial fibrillation is no longer detectable. In particular, the committee noted that paroxysmal atrial fibrillation is not always detectable. Based on their experience, the committee made a consensus‑based recommendation to ensure that decisions about stopping anticoagulation in this population are based on formal risk assessment of stroke and bleeding risks and patient preference.\n\n## How the recommendations might affect practice\n\nThe committee felt that the recommendation would not constitute a change in practice, and that there would not be a resource impact on the NHS.\n\nReturn to recommendations", 'Context': "Atrial fibrillation is the most common heart rhythm disorder (affecting approximately 2% of the adult population), and estimates suggest its prevalence is increasing. Atrial fibrillation causes palpitations and breathlessness in many people but it may be silent and undetected. If left untreated it is a significant risk factor for stroke and other morbidities: it is estimated that it is responsible for approximately 20% of all strokes and is associated with increased mortality. Men are more commonly affected than women and the prevalence increases with age and in underlying heart disease, diabetes, obesity and hypertension.\n\nAtrial fibrillation is typically detected as an irregular pulse or an irregular rhythm on an electrocardiogram (ECG). This may be an incidental finding or may arise while investigating symptoms suggestive of the disease. Because atrial fibrillation can be intermittent, detection and diagnosis may be challenging.\n\nThe aim of treatment is to prevent complications, particularly stroke, and alleviate symptoms. Drug treatments include anticoagulants to reduce the risk of stroke and antiarrhythmics to restore or maintain the normal heart rhythm or to slow the heart rate in people who remain in atrial fibrillation. Non‑pharmacological management includes electrical cardioversion, which may be used to 'shock' the heart back to its normal rhythm, and catheter or surgical ablation to create lesions to stop the triggers that cause atrial fibrillation. These procedures can markedly reduce the symptom burden when drug therapy is ineffective or not tolerated.\n\nThis update focuses on areas of new evidence and changing practice since the 2014\xa0NICE guideline. These include methods of identifying atrial fibrillation; assessing stroke and bleeding risk; antithrombotic agents; ablation strategies; preventing recurrence; and preventing and managing postoperative atrial fibrillation. This guideline update includes recommendations on these specific issues.\n\nThe recommendations apply to adults (18\xa0years or older) with atrial fibrillation, including paroxysmal (recurrent), persistent and permanent atrial fibrillation, and atrial flutter. They do not apply to people with congenital heart disease precipitating atrial fibrillation."}
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https://www.nice.org.uk/guidance/ng196
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This guideline covers diagnosing and managing atrial fibrillation in adults. It includes guidance on providing the best care and treatment for people with atrial fibrillation, including assessing and managing risks of stroke and bleeding.
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daa7fa62ad46b5eb8a6512036e2605440c3ba79f
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nice
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Plus Sutures for preventing surgical site infection
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Plus Sutures for preventing surgical site infection
Evidence-based recommendations on Plus Sutures for preventing surgical site infection.
# Recommendations
Evidence supports the case for adopting Plus Sutures as part of a bundle of care for preventing surgical site infection in the NHS for people who need wound closure after a surgical procedure when absorbable sutures are an appropriate option.
Cost modelling shows that Plus Sutures is cost saving compared with non-triclosan absorbable sutures by an average of £13.62 per patient. These savings are from reduced surgical site infections. Cost savings will vary by surgery type and baseline risk of surgical site infection. For more information on the cost impact to the NHS please see the NICE resource impact summary report.
Why the committee made these recommendations
Plus Sutures is a range of synthetic, absorbable sutures with triclosan (Irgacare MP), a purified medical grade antimicrobial.
Clinical evidence shows that using Plus Sutures instead of standard absorbable sutures reduces the chance of a surgical site infection.
Even though Plus Sutures is more expensive than standard sutures, cost analyses show that it still leads to cost savings because of the reduction in surgical site infections.# The technology
# Technology
Plus Sutures (Ethicon, Johnson & Johnson Medical) is a range of synthetic, absorbable sutures that are either impregnated with or coated with triclosan (Irgacare MP), a purified medical grade antimicrobial, depending on the suture type. Absorbable sutures are absorbed by tissue over a period of time and do not need removing. The 3 sutures considered in this evaluation are indicated for general soft tissue approximation and ligation. Each has different physical properties and absorption rates, which affects which tissue types it is best suited to:
Coated VICRYL Plus Antibacterial (polyglactin 910) Suture is a multifilament suture (multiple braided threads). VICRYL Plus retains 75% of its original tensile strength at 2 weeks after implantation; 40% to 50% at 3 weeks and 25% at 4 weeks. Complete absorption happens between 57 days and 70 days.
MONOCRYL Plus Antibacterial (poliglecaprone 25) Suture is a monofilament suture (solid and smooth thread). MONOCRYL Plus retains 50% to 60% of its original tensile strength at 1 week and 20% to 30% at 2 weeks. Complete absorption happens between 91 days and 119 days. This suture is also available in a barbed design for knotless suturing (STRATAFIX Plus) but this version of the technology was not included in the evaluation.
PDS Plus Antibacterial (polydioxanone) Suture is a monofilament suture (solid and smooth thread). PDS Plus Antibacterial retains 60% to 80% of its original tensile strength at 2 weeks, 40% to 70% at 4 weeks, and 35% to 60% at 6 weeks. Complete absorption happens between 182 days and 238 days. This suture is also available in a barbed design for knotless suturing (STRATAFIX Plus) but this version of the technology was not included in the evaluation.PDS Plus and MONOCRYL Plus contain no more than 2,360 micrograms/metre triclosan. VICRYL Plus has a coating of copolymer and calcium stearate as well as up to 472 micrograms/metre triclosan. The absorption rates and handling properties are the same as non-triclosan sutures.
# Innovative aspects
Plus Sutures is innovative because sutures are coated or impregnated with triclosan (Irgacare MP). Triclosan is a broad-spectrum antibacterial agent. It helps reduce biofilm formation and bacterial colonisation, preventing the growth of most common organisms associated with surgical site infection for at least 7 days. Plus Sutures is already used in the NHS.
# Intended use
Plus Sutures would replace using non-triclosan absorbable sutures for wound closure in people that have had a surgical procedure, when absorbable sutures are an appropriate option. Plus Sutures should be used as part of a locally agreed bundle of care to reduce surgical site infections. Clinical experts reported that the handling properties of Plus Sutures were identical to non-triclosan sutures. Adopting Plus Sutures would not alter the current care pathway or need any additional training. The technology is already used extensively within the NHS.
# Costs
The cost of Plus Sutures is around £4.25 per suture, based on average prices of the 3 suture types.For more details, see the Johnson & Johnson webpage on Plus Sutures.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The clinical evidence comprises 31 randomised controlled trials
The evidence assessed by the EAC included 31 randomised controlled trials including over 14,000 people. For full details of the clinical evidence, see section 3 of the assessment report in the supporting documentation on the NICE website.
## The evidence for reducing surgical site infection incidence is of good quality
The evidence base for Plus Sutures is extensive, of relatively high quality and is generalisable to the UK NHS. The EAC used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology for appraising the quality of evidence for each outcome and said that the quality of evidence for surgical site infection incidence was high. This was considered the most important outcome and was reported by nearly all the included studies, with most of them using the same definition. None of the other outcomes listed in the scope had sufficiently robust empirical evidence to show Plus Sutures was statistically superior to standard sutures. However, some other outcomes can be inferred or extrapolated from the established reduction in incidence of surgical site infection, such as a shorter hospital stay, and lower readmission rates and healthcare costs. The EAC concluded that Plus Sutures use is associated with a causative reduction in the incidence of surgical site infection.
## Device-related adverse events reported in the evidence suggest using Plus Sutures is safe
To assess device-related adverse events, the EAC reviewed the randomised controlled trial data included in the assessment and also did a dedicated literature review to assess the nature of adverse events after using Plus Sutures. Studies that reported adverse events included 18 of the randomised controlled trials that were included in the assessment and an additional 17 randomised and non-randomised studies. Triclosan allergy was noted in a published case report that referenced a retrospective analysis of 113,162 patients who had been patch tested with triclosan 2% petroleum. A positive reaction was seen in only 363 patients (0.32%) but 54% of positive reactions were considered clinically relevant. The EAC concluded that there is no discernible safety signal from using Plus Sutures. The EAC noted that this conclusion was supported by information from the company (on the very low amounts of triclosan used in the sutures and on the rapid metabolism of triclosan) and by the clinical experts, who had not seen any cases of triclosan reactions. For full details of the adverse events, see section 6 of the assessment report in the supporting documentation on the NICE website.
## Results of company meta-analyses show that Plus Sutures is associated with a 30% reduction in the risk of surgical site infection
The company did 6 de novo meta-analyses to establish the overall pooled effect size associated with Plus Sutures on the incidence of surgical site infections. The primary outcome was the relative risk of developing a surgical site infection between Plus Sutures and control groups. The 6 separate meta-analyses were done using:
all studies that provided enough data (base case, 28 studies)
a subset of studies in adults (25 studies)
a subset of studies in children (2 studies)
a subset of studies in patients with clean wounds (15 studies)
a subset of studies in patients with non-clean wounds (12 studies)
all studies of Plus Sutures including STRATAFIX Plus that provided enough data, as a sensitivity analysis (31 studies).The results of the meta-analyses showed that Plus Sutures is associated with a nearly 30% reduction in the risk of surgical site infection in the base case and all results were considered statistically significant (with a 95% confidence interval of 0.59 to 0.85). The EAC noted that the company meta-analyses are of a high quality and at a low risk of bias. The methodology and results are transparent and clearly reported.
## The EAC did additional meta-analyses
The EAC validated the company's meta-analyses by replicating the analysis, and did 3 additional analyses. The EAC noted that because of heterogeneity the studies were not similar enough for fixed effects analysis, and the analysis should primarily be reported using a random effects model. However, this variation had minimal effects on the results. The additional analyses included stratifying the evidence by study quality, sample size and location. The results of the additional analyses indicated that Plus Sutures reduced the risk of surgical site infection, but the size of the effect appeared to be related to study quality and sample size. When only high-quality studies were included in the analysis the difference was not statistically significant. However, the EAC advised that this should be interpreted with caution because the smaller sample sizes and varied event rates will affect the precision and impact of the analysis.
## The company submitted additional analyses suggesting sustainability benefits
Based on the Sustainable Care Pathways Guidance, the company provided an analysis of the environmental impact of surgical site infections to NHS England. Environmental impact is presented in the guidance document in terms of 3 main environmental metrics: greenhouse gas emissions, fresh water use and waste generation. The report indicates that by preventing surgical site infections, using Plus Sutures results in potential environmental benefits to the NHS in England.
# Cost evidence
## The company identified 8 economic studies
The company identified 8 studies that were relevant to the economic submission. The EAC concluded that the literature search was satisfactory and agreed that the 8 studies were relevant to the evaluation. The company said that all of the studies reporting on introduction of Plus Sutures resulted in cost savings but that none of the parameters in the company's de novo model were informed by the economic literature. For full details of the cost evidence, see section 9.1.2 of the assessment report in the supporting documentation on the NICE website.
## The company's model structure and time horizon are appropriate
The company submitted a simple decision tree which models a population of adults and children who need wound closure after a surgical procedure. The model assesses the cost of wound closure plus the cost of treatment for people who develop a surgical site infection. An additional branch of the decision tree modelled the mortality of people with a surgical site infection and was used by the company to calculate a cost per death avoided using cost-effectiveness methodology. The EAC considered the model structure to be appropriate, except for the mortality branch of the decision tree which complicates the model for the purposes of a cost-consequence modelling approach. The time horizon modelled was 1 year. The EAC noted that this aligns with published economic evaluations of Plus Sutures.
## The EAC accepted all assumptions in the company model
The company model made the following assumptions:
Risk of surgical site infection relates only to those detected and treated during the initial inpatient episode or on readmission.
The average surgical site infection episode cost does not include the cost of treating surgical site infections in the community.
The risk of infection with Plus Sutures is calculated by applying the relative risk of surgical site infection associated with using Plus Sutures reported in the meta-analyses to a baseline risk of surgical site infection. The baseline risk of surgical site infection is based on UK data.
Adverse events were not included in the model.The EAC concluded that the model assumptions were appropriate, conservative and supported by the evidence.
## The EAC made some minor changes to the costs of the technology
The company provided an estimate of the cost of Plus Sutures based on a weighted average of sales, including knotless, barbed sutures, and STRATAFIX Plus. The EAC reported that the company's estimation of the cost was not sufficiently transparent or reproducible, and included STRATAFIX Plus, which the EAC did not include in their analysis. The EAC amended the cost of the technology by calculating a mean cost of £3.63 to £4.94 depending on Plus Suture type.
## The EAC's changes to the model have a minimal effect on results
Because there were so few changes to the model parameters the EAC and the company's results were similar. In the EAC's base-case analysis Plus Sutures was found to be cost saving by a mean of £13.62 per person compared with the company's £13.88 per person.
## The company's extensive sensitivity analyses suggest that using Plus Sutures is cost saving
The company reported results of a 1‑way deterministic sensitivity analysis that showed that the model was most sensitive to changes in the incidence of surgical site infection. However, the model was still cost saving even when the lowest plausible surgical site infection incidence was used (0.5%). Two‑way deterministic sensitivity analyses were used to explore the combined effect of surgical site infection incidence and relative risk, and surgical site infection incidence and cost of surgical site infection. The results were cost saving in all cases. This was further supported by threshold analyses that reported the following break-even points (deemed by the company and the EAC to be unlikely or implausible):
a cost of surgical site infection of less than £1,410
incidence of surgical site infection of less than 0.24%
a relative risk of 0.93
at least 21 sutures.The results of the probabilistic sensitivity analysis, reported for the base case only, showed that Plus Sutures was cost saving in 99.8% of iterations (out of 1,000 iterations). The summary result was that Plus Sutures was associated with cost savings of £13.96 (95% credible intervals £4.97 to £22.22) per person.
## Plus Sutures remains cost saving in the EAC's additional sensitivity analyses
The EAC did additional sensitivity analyses that explored the uncertainty in the cost savings associated with each subgroup (adults, children, clean wounds and non-clean wounds) and the effect of different relative risk values reported in the EAC's meta-analyses of the clinical evidence (study quality, sample size and location). Plus Sutures was cost saving in all subgroups investigated. The most uncertainty was in the clean wound subgroup (£9.30; 95% credible intervals -£2.24 to £19.26; 94.6% probability of cost saving). The meta-analysis showed that the size of the effect of using Plus Sutures (lowering the risk of surgical site infection) diminished when only studies of a high quality, or large sample size, were included in the analysis (see section 3.5). The sensitivity analyses showed that using Plus Sutures remains cost saving when the relative risk from the higher quality studies and studies with larger samples sizes was adopted, but there was more uncertainty in the results.# Committee discussion
# Clinical-effectiveness overview
## The evidence shows that Plus Sutures is effective in reducing the incidence of surgical site infection
The evidence base for Plus Sutures is large, of relatively high quality and is likely to be generalisable to the NHS. Some of the individual studies did not show a significant reduction in surgical site infection incidence for Plus Sutures. However, when all results were combined in the meta-analyses, the effect was significant. Additional analyses done by the external assessment centre (EAC) showed that the size of effect was smaller when studies were stratified by quality or sample size. But it was not possible to determine if this was because of the effect measured in the studies or because of the small number of studies included in the analyses. The committee concluded that, although the effect size may vary depending on population and type of procedure, the evidence showed that Plus Sutures is likely to lead to overall reductions in surgical site infections.
# Side effects and adverse events
## Using Plus Sutures is safe and allergies to triclosan are very rare
No significant device-related adverse events were identified from the published evidence. The clinical experts noted that triclosan is safe and is used in many consumer products, at much higher concentrations and amounts than in Plus Sutures. None of the clinical experts had encountered anyone who had an allergic reaction to triclosan in Plus Sutures. The committee concluded that using Plus Sutures is safe and that adverse or allergic reactions to triclosan are likely to be very rare. The committee discussed antimicrobial stewardship considerations and concluded that neither the product nor concentration of triclosan raised concerns about resistance.
# Equality considerations
## Surgeons consider a number of factors when choosing the appropriate suture
The committee discussed equality considerations for the use of Plus Sutures in the general population. The instructions for use highlight that 'absorbable sutures, including Plus Sutures may not be appropriate for older people, those who are malnourished, debilitated or have conditions that may prevent wound healing'. The clinical experts explained that a number of factors must be taken into consideration by the surgeon choosing the suture, including comorbidities, surgery type, tissue type and condition. The committee concluded that these were factors that surgeons would consider within the patient assessment for appropriate management plans. It did not consider there to be any equality issues as a result of its recommendations.
# Relevance to the NHS
## Plus Sutures should be used as part of a bundle of care to reduce surgical site infections
The clinical experts noted that, in their experience, Plus Sutures was most effective at reducing infections in deep and superficial tissue layers, rather than deep organ space tissues. However, the experts stated that while using Plus Sutures has been shown to reduce surgical site infection risk, to maximise their effect, they should be used alongside an appropriate care bundle for surgical site infection prevention, including antibiotic use, appropriate hair removal, glycaemic control and normothermia. The clinical experts reported their experience that introducing Plus Sutures to the surgical site infection prevention care bundle had resulted in fewer surgical site infections. The committee concluded that Plus Sutures should be used as part of a bundle of care to reduce surgical site infections.
# NHS considerations overview
## GPs with minor surgery clinics may also benefit from using Plus Sutures
The evidence on Plus Sutures was from hospitals. However, the committee noted that some GP clinics provide minor surgery services and use broadly the same care bundles for infection prevention as used in hospitals. The committee stated that the evidence collected in secondary care is likely to be largely generalisable to primary care settings. The committee concluded that Plus Sutures could be considered in GP minor surgery clinics.
# Training
## No additional training is needed to use Plus Sutures
The clinical experts advised that no further training is needed to use Plus Sutures compared with non-triclosan sutures. The addition of triclosan does not change the absorption profile when identifying the appropriate suture or change the handling of the suture itself. Clinical experts reported that the handling properties of Plus Sutures were identical to non-triclosan sutures and no modification of existing procedures is needed. The committee concluded that adopting Plus Sutures would not need a change to services.
# Cost-modelling overview
## The EAC's changes to the cost model are appropriate
The committee noted that the EAC made minor changes to the cost model, which were appropriate and accepted. The committee concluded that the comprehensive subgroup and sensitivity analyses supported cost savings in all subgroups.
# Main cost drivers
## Reduction in surgical site infection incidence is the main cost driver in the model
The committee discussed the estimated cost of surgical site infections and accepted the use of a UK study, which reported the cost savings associated with surgical site infections in hospitals (Jenks et al. 2014). Reduction in surgical site infection was the main driver for the cost savings. The committee concluded that the cost savings were likely to be realised in practice and were supported by the evidence and experience of the clinical experts.
# Scenario analyses
## Plus Sutures is cost saving in all likely scenarios
The committee discussed the comprehensive scenario analyses completed by the company and EAC, which showed Plus Sutures reduced the risk of surgical site infections in most scenarios. It accepted that results from the subgroups in which statistical significance was reduced should be interpreted with caution because the smaller sample sizes affect the analysis. The committee concluded that Plus Sutures is likely to save costs in most scenarios and that the scenarios at which costs break even are clinically unlikely.
# Cost savings
## The true cost of treating surgical site infections in the community is likely to be underestimated
The committee discussed the potential for further cost savings in the community as a result of fewer hospital-acquired surgical site infections and therefore less need for follow-up care, which was not captured in the economic model. The committee agreed with the company and the EAC that the cost savings in the cost modelling are likely to be conservative.
## Plus Sutures is likely to be cost saving across all groups
The committee was satisfied that the cost-modelling evidence indicates that Plus Sutures is cost saving compared with non-triclosan absorbable sutures by an average of £13.62 per patient. The committee concluded that the sensitivity analyses showed that Plus Sutures remained cost saving across all subgroups.
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{'Recommendations': 'Evidence supports the case for adopting Plus Sutures as part of a bundle of care for preventing surgical site infection in the NHS for people who need wound closure after a surgical procedure when absorbable sutures are an appropriate option.\n\nCost modelling shows that Plus Sutures is cost saving compared with non-triclosan absorbable sutures by an average of £13.62 per patient. These savings are from reduced surgical site infections. Cost savings will vary by surgery type and baseline risk of surgical site infection. For more information on the cost impact to the NHS please see the NICE resource impact summary report.\n\nWhy the committee made these recommendations\n\nPlus Sutures is a range of synthetic, absorbable sutures with triclosan (Irgacare MP), a purified medical grade antimicrobial.\n\nClinical evidence shows that using Plus Sutures instead of standard absorbable sutures reduces the chance of a surgical site infection.\n\nEven though Plus Sutures is more expensive than standard sutures, cost analyses show that it still leads to cost savings because of the reduction in surgical site infections.', 'The technology': '# Technology\n\nPlus Sutures (Ethicon, Johnson & Johnson Medical) is a range of synthetic, absorbable sutures that are either impregnated with or coated with triclosan (Irgacare MP), a purified medical grade antimicrobial, depending on the suture type. Absorbable sutures are absorbed by tissue over a period of time and do not need removing. The 3 sutures considered in this evaluation are indicated for general soft tissue approximation and ligation. Each has different physical properties and absorption rates, which affects which tissue types it is best suited to:\n\nCoated VICRYL Plus Antibacterial (polyglactin 910) Suture is a multifilament suture (multiple braided threads). VICRYL Plus retains 75% of its original tensile strength at 2\xa0weeks after implantation; 40% to 50% at 3\xa0weeks and 25% at 4\xa0weeks. Complete absorption happens between 57\xa0days and 70\xa0days.\n\nMONOCRYL Plus Antibacterial (poliglecaprone 25) Suture is a monofilament suture (solid and smooth thread). MONOCRYL Plus retains 50% to 60% of its original tensile strength at 1\xa0week and 20% to 30% at 2\xa0weeks. Complete absorption happens between 91\xa0days and 119\xa0days. This suture is also available in a barbed design for knotless suturing (STRATAFIX\xa0Plus) but this version of the technology was not included in the evaluation.\n\nPDS Plus Antibacterial (polydioxanone) Suture is a monofilament suture (solid and smooth thread). PDS Plus Antibacterial retains 60% to 80% of its original tensile strength at 2\xa0weeks, 40% to 70% at 4\xa0weeks, and 35% to 60% at 6\xa0weeks. Complete absorption happens between 182\xa0days and 238\xa0days. This suture is also available in a barbed design for knotless suturing (STRATAFIX\xa0Plus) but this version of the technology was not included in the evaluation.PDS Plus and MONOCRYL Plus contain no more than 2,360\xa0micrograms/metre triclosan. VICRYL Plus has a coating of copolymer and calcium stearate as well as up to 472\xa0micrograms/metre triclosan. The absorption rates and handling properties are the same as non-triclosan sutures.\n\n# Innovative aspects\n\nPlus Sutures is innovative because sutures are coated or impregnated with triclosan (Irgacare MP). Triclosan is a broad-spectrum antibacterial agent. It helps reduce biofilm formation and bacterial colonisation, preventing the growth of most common organisms associated with surgical site infection for at least 7\xa0days. Plus Sutures is already used in the NHS.\n\n# Intended use\n\nPlus Sutures would replace using non-triclosan absorbable sutures for wound closure in people that have had a surgical procedure, when absorbable sutures are an appropriate option. Plus Sutures should be used as part of a locally agreed bundle of care to reduce surgical site infections. Clinical experts reported that the handling properties of Plus Sutures were identical to non-triclosan sutures. Adopting Plus Sutures would not alter the current care pathway or need any additional training. The technology is already used extensively within the NHS.\n\n# Costs\n\nThe cost of Plus Sutures is around £4.25 per suture, based on average prices of the 3\xa0suture types.For more details, see the Johnson & Johnson webpage on Plus Sutures.', 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The clinical evidence comprises 31\xa0randomised controlled trials\n\nThe evidence assessed by the EAC included 31\xa0randomised controlled trials including over 14,000\xa0people. For full details of the clinical evidence, see section\xa03 of the assessment report in the supporting documentation on the NICE website.\n\n## The evidence for reducing surgical site infection incidence is of good quality\n\nThe evidence base for Plus Sutures is extensive, of relatively high quality and is generalisable to the UK NHS. The EAC used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology for appraising the quality of evidence for each outcome and said that the quality of evidence for surgical site infection incidence was high. This was considered the most important outcome and was reported by nearly all the included studies, with most of them using the same definition. None of the other outcomes listed in the scope had sufficiently robust empirical evidence to show Plus Sutures was statistically superior to standard sutures. However, some other outcomes can be inferred or extrapolated from the established reduction in incidence of surgical site infection, such as a shorter hospital stay, and lower readmission rates and healthcare costs. The EAC concluded that Plus Sutures use is associated with a causative reduction in the incidence of surgical site infection.\n\n## Device-related adverse events reported in the evidence suggest using Plus Sutures is safe\n\nTo assess device-related adverse events, the EAC reviewed the randomised controlled trial data included in the assessment and also did a dedicated literature review to assess the nature of adverse events after using Plus Sutures. Studies that reported adverse events included 18 of the randomised controlled trials that were included in the assessment and an additional 17 randomised and non-randomised studies. Triclosan allergy was noted in a published case report that referenced a retrospective analysis of 113,162\xa0patients who had been patch tested with triclosan 2% petroleum. A positive reaction was seen in only 363\xa0patients (0.32%) but 54% of positive reactions were considered clinically relevant. The EAC concluded that there is no discernible safety signal from using Plus Sutures. The EAC noted that this conclusion was supported by information from the company (on the very low amounts of triclosan used in the sutures and on the rapid metabolism of triclosan) and by the clinical experts, who had not seen any cases of triclosan reactions. For full details of the adverse events, see section\xa06 of the assessment report in the supporting documentation on the NICE website.\n\n## Results of company meta-analyses show that Plus Sutures is associated with a 30% reduction in the risk of surgical site infection\n\nThe company did 6 de novo meta-analyses to establish the overall pooled effect size associated with Plus Sutures on the incidence of surgical site infections. The primary outcome was the relative risk of developing a surgical site infection between Plus Sutures and control groups. The 6\xa0separate meta-analyses were done using:\n\nall studies that provided enough data (base case, 28\xa0studies)\n\na subset of studies in adults (25\xa0studies)\n\na subset of studies in children (2\xa0studies)\n\na subset of studies in patients with clean wounds (15\xa0studies)\n\na subset of studies in patients with non-clean wounds (12\xa0studies)\n\nall studies of Plus Sutures including STRATAFIX\xa0Plus that provided enough data, as a sensitivity analysis (31\xa0studies).The results of the meta-analyses showed that Plus Sutures is associated with a nearly 30% reduction in the risk of surgical site infection in the base case and all results were considered statistically significant (with a 95% confidence interval of 0.59 to 0.85). The EAC noted that the company meta-analyses are of a high quality and at a low risk of bias. The methodology and results are transparent and clearly reported.\n\n## The EAC did additional meta-analyses\n\nThe EAC validated the company's meta-analyses by replicating the analysis, and did 3\xa0additional analyses. The EAC noted that because of heterogeneity the studies were not similar enough for fixed effects analysis, and the analysis should primarily be reported using a random effects model. However, this variation had minimal effects on the results. The additional analyses included stratifying the evidence by study quality, sample size and location. The results of the additional analyses indicated that Plus Sutures reduced the risk of surgical site infection, but the size of the effect appeared to be related to study quality and sample size. When only high-quality studies were included in the analysis the difference was not statistically significant. However, the EAC advised that this should be interpreted with caution because the smaller sample sizes and varied event rates will affect the precision and impact of the analysis.\n\n## The company submitted additional analyses suggesting sustainability benefits\n\nBased on the Sustainable Care Pathways Guidance, the company provided an analysis of the environmental impact of surgical site infections to NHS England. Environmental impact is presented in the guidance document in terms of 3\xa0main environmental metrics: greenhouse gas emissions, fresh water use and waste generation. The report indicates that by preventing surgical site infections, using Plus Sutures results in potential environmental benefits to the NHS in England.\n\n# Cost evidence\n\n## The company identified 8\xa0economic studies\n\nThe company identified 8\xa0studies that were relevant to the economic submission. The EAC concluded that the literature search was satisfactory and agreed that the 8\xa0studies were relevant to the evaluation. The company said that all of the studies reporting on introduction of Plus Sutures resulted in cost savings but that none of the parameters in the company's de novo model were informed by the economic literature. For full details of the cost evidence, see section\xa09.1.2 of the assessment report in the supporting documentation on the NICE website.\n\n## The company's model structure and time horizon are appropriate\n\nThe company submitted a simple decision tree which models a population of adults and children who need wound closure after a surgical procedure. The model assesses the cost of wound closure plus the cost of treatment for people who develop a surgical site infection. An additional branch of the decision tree modelled the mortality of people with a surgical site infection and was used by the company to calculate a cost per death avoided using cost-effectiveness methodology. The EAC considered the model structure to be appropriate, except for the mortality branch of the decision tree which complicates the model for the purposes of a cost-consequence modelling approach. The time horizon modelled was 1\xa0year. The EAC noted that this aligns with published economic evaluations of Plus Sutures.\n\n## The EAC accepted all assumptions in the company model\n\nThe company model made the following assumptions:\n\nRisk of surgical site infection relates only to those detected and treated during the initial inpatient episode or on readmission.\n\nThe average surgical site infection episode cost does not include the cost of treating surgical site infections in the community.\n\nThe risk of infection with Plus Sutures is calculated by applying the relative risk of surgical site infection associated with using Plus Sutures reported in the meta-analyses to a baseline risk of surgical site infection. The baseline risk of surgical site infection is based on UK data.\n\nAdverse events were not included in the model.The EAC concluded that the model assumptions were appropriate, conservative and supported by the evidence.\n\n## The EAC made some minor changes to the costs of the technology\n\nThe company provided an estimate of the cost of Plus Sutures based on a weighted average of sales, including knotless, barbed sutures, and STRATAFIX\xa0Plus. The EAC reported that the company's estimation of the cost was not sufficiently transparent or reproducible, and included STRATAFIX\xa0Plus, which the EAC did not include in their analysis. The EAC amended the cost of the technology by calculating a mean cost of £3.63 to £4.94 depending on Plus Suture type.\n\n## The EAC's changes to the model have a minimal effect on results\n\nBecause there were so few changes to the model parameters the EAC and the company's results were similar. In the EAC's base-case analysis Plus Sutures was found to be cost saving by a mean of £13.62 per person compared with the company's £13.88 per person.\n\n## The company's extensive sensitivity analyses suggest that using Plus Sutures is cost saving\n\nThe company reported results of a 1‑way deterministic sensitivity analysis that showed that the model was most sensitive to changes in the incidence of surgical site infection. However, the model was still cost saving even when the lowest plausible surgical site infection incidence was used (0.5%). Two‑way deterministic sensitivity analyses were used to explore the combined effect of surgical site infection incidence and relative risk, and surgical site infection incidence and cost of surgical site infection. The results were cost saving in all cases. This was further supported by threshold analyses that reported the following break-even points (deemed by the company and the EAC to be unlikely or implausible):\n\na cost of surgical site infection of less than £1,410\n\nincidence of surgical site infection of less than 0.24%\n\na relative risk of 0.93\n\nat least 21\xa0sutures.The results of the probabilistic sensitivity analysis, reported for the base case only, showed that Plus Sutures was cost saving in 99.8% of iterations (out of 1,000 iterations). The summary result was that Plus Sutures was associated with cost savings of £13.96 (95% credible intervals £4.97 to £22.22) per person.\n\n## Plus Sutures remains cost saving in the EAC's additional sensitivity analyses\n\nThe EAC did additional sensitivity analyses that explored the uncertainty in the cost savings associated with each subgroup (adults, children, clean wounds and non-clean wounds) and the effect of different relative risk values reported in the EAC's meta-analyses of the clinical evidence (study quality, sample size and location). Plus Sutures was cost saving in all subgroups investigated. The most uncertainty was in the clean wound subgroup (£9.30; 95% credible intervals -£2.24 to £19.26; 94.6% probability of cost saving). The meta-analysis showed that the size of the effect of using Plus Sutures (lowering the risk of surgical site infection) diminished when only studies of a high quality, or large sample size, were included in the analysis (see section 3.5). The sensitivity analyses showed that using Plus Sutures remains cost saving when the relative risk from the higher quality studies and studies with larger samples sizes was adopted, but there was more uncertainty in the results.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## The evidence shows that Plus Sutures is effective in reducing the incidence of surgical site infection\n\nThe evidence base for Plus Sutures is large, of relatively high quality and is likely to be generalisable to the NHS. Some of the individual studies did not show a significant reduction in surgical site infection incidence for Plus Sutures. However, when all results were combined in the meta-analyses, the effect was significant. Additional analyses done by the external assessment centre (EAC) showed that the size of effect was smaller when studies were stratified by quality or sample size. But it was not possible to determine if this was because of the effect measured in the studies or because of the small number of studies included in the analyses. The committee concluded that, although the effect size may vary depending on population and type of procedure, the evidence showed that Plus Sutures is likely to lead to overall reductions in surgical site infections.\n\n# Side effects and adverse events\n\n## Using Plus Sutures is safe and allergies to triclosan are very rare\n\nNo significant device-related adverse events were identified from the published evidence. The clinical experts noted that triclosan is safe and is used in many consumer products, at much higher concentrations and amounts than in Plus Sutures. None of the clinical experts had encountered anyone who had an allergic reaction to triclosan in Plus Sutures. The committee concluded that using Plus Sutures is safe and that adverse or allergic reactions to triclosan are likely to be very rare. The committee discussed antimicrobial stewardship considerations and concluded that neither the product nor concentration of triclosan raised concerns about resistance.\n\n# Equality considerations\n\n## Surgeons consider a number of factors when choosing the appropriate suture\n\nThe committee discussed equality considerations for the use of Plus Sutures in the general population. The instructions for use highlight that 'absorbable sutures, including Plus Sutures may not be appropriate for older people, those who are malnourished, debilitated or have conditions that may prevent wound healing'. The clinical experts explained that a number of factors must be taken into consideration by the surgeon choosing the suture, including comorbidities, surgery type, tissue type and condition. The committee concluded that these were factors that surgeons would consider within the patient assessment for appropriate management plans. It did not consider there to be any equality issues as a result of its recommendations.\n\n# Relevance to the NHS\n\n## Plus Sutures should be used as part of a bundle of care to reduce surgical site infections\n\nThe clinical experts noted that, in their experience, Plus Sutures was most effective at reducing infections in deep and superficial tissue layers, rather than deep organ space tissues. However, the experts stated that while using Plus Sutures has been shown to reduce surgical site infection risk, to maximise their effect, they should be used alongside an appropriate care bundle for surgical site infection prevention, including antibiotic use, appropriate hair removal, glycaemic control and normothermia. The clinical experts reported their experience that introducing Plus Sutures to the surgical site infection prevention care bundle had resulted in fewer surgical site infections. The committee concluded that Plus Sutures should be used as part of a bundle of care to reduce surgical site infections.\n\n# NHS considerations overview\n\n## GPs with minor surgery clinics may also benefit from using Plus Sutures\n\nThe evidence on Plus Sutures was from hospitals. However, the committee noted that some GP clinics provide minor surgery services and use broadly the same care bundles for infection prevention as used in hospitals. The committee stated that the evidence collected in secondary care is likely to be largely generalisable to primary care settings. The committee concluded that Plus Sutures could be considered in GP minor surgery clinics.\n\n# Training\n\n## No additional training is needed to use Plus Sutures\n\nThe clinical experts advised that no further training is needed to use Plus Sutures compared with non-triclosan sutures. The addition of triclosan does not change the absorption profile when identifying the appropriate suture or change the handling of the suture itself. Clinical experts reported that the handling properties of Plus Sutures were identical to non-triclosan sutures and no modification of existing procedures is needed. The committee concluded that adopting Plus Sutures would not need a change to services.\n\n# Cost-modelling overview\n\n## The EAC's changes to the cost model are appropriate\n\nThe committee noted that the EAC made minor changes to the cost model, which were appropriate and accepted. The committee concluded that the comprehensive subgroup and sensitivity analyses supported cost savings in all subgroups.\n\n# Main cost drivers\n\n## Reduction in surgical site infection incidence is the main cost driver in the model\n\nThe committee discussed the estimated cost of surgical site infections and accepted the use of a UK study, which reported the cost savings associated with surgical site infections in hospitals (Jenks et al. 2014). Reduction in surgical site infection was the main driver for the cost savings. The committee concluded that the cost savings were likely to be realised in practice and were supported by the evidence and experience of the clinical experts.\n\n# Scenario analyses\n\n## Plus Sutures is cost saving in all likely scenarios\n\nThe committee discussed the comprehensive scenario analyses completed by the company and EAC, which showed Plus Sutures reduced the risk of surgical site infections in most scenarios. It accepted that results from the subgroups in which statistical significance was reduced should be interpreted with caution because the smaller sample sizes affect the analysis. The committee concluded that Plus Sutures is likely to save costs in most scenarios and that the scenarios at which costs break even are clinically unlikely.\n\n# Cost savings\n\n## The true cost of treating surgical site infections in the community is likely to be underestimated\n\nThe committee discussed the potential for further cost savings in the community as a result of fewer hospital-acquired surgical site infections and therefore less need for follow-up care, which was not captured in the economic model. The committee agreed with the company and the EAC that the cost savings in the cost modelling are likely to be conservative.\n\n## Plus Sutures is likely to be cost saving across all groups\n\nThe committee was satisfied that the cost-modelling evidence indicates that Plus Sutures is cost saving compared with non-triclosan absorbable sutures by an average of £13.62 per patient. The committee concluded that the sensitivity analyses showed that Plus Sutures remained cost saving across all subgroups."}
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https://www.nice.org.uk/guidance/mtg59
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Evidence-based recommendations on Plus Sutures for preventing surgical site infection.
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65c8b00b066a01cbfb0787c23a545734d4b349df
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nice
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Budesonide orodispersible tablet for inducing remission of eosinophilic oesophagitis
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Budesonide orodispersible tablet for inducing remission of eosinophilic oesophagitis
Evidence-based recommendations on budesonide as an orodispersible tablet for inducing remission of eosinophilic oesophagitis in adults.
# Recommendations
Budesonide as an orodispersible tablet (ODT) is recommended as an option for inducing remission of eosinophilic oesophagitis in adults.
This recommendation is not intended to affect treatment with budesonide ODT that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Although budesonide ODT has a marketing authorisation for both inducing and maintaining remission in eosinophilic oesophagitis, at the time this appraisal started it was only licensed for induction. So, the company's evidence is for inducing remission only (with treatment of up to 12 weeks) and the committee is unable to make recommendations for maintenance treatment.
There is currently no standard care for inducing remission in eosinophilic oesophagitis. Fluticasone is one treatment option, but it is an asthma treatment that is not easy to use for eosinophilic oesophagitis. Dietary changes are also an option, for example the 6‑food elimination diet, which involves cutting out the known allergens milk, eggs, nuts, wheat, soy and seafood from your diet. These treatments can be difficult to access and adhere to. And people often have no treatment at all, so there is an unmet need for this condition.
Clinical trial evidence shows that budesonide ODT improves the signs and symptoms of eosinophilic oesophagitis compared with placebo. There is no direct evidence for budesonide ODT compared with fluticasone or the 6‑food elimination diet and the results of an indirect comparison with these treatments are very uncertain.
The cost-effectiveness estimates vary and are also very uncertain. However, the most likely estimates are within what NICE considers a cost-effective use of NHS resources. Therefore, it is recommended for inducing remission in eosinophilic oesophagitis in adults.# Information about budesonide orodispersible tablet
# Marketing authorisation indication
Budesonide orodispersible tablet (Jorveza, Dr Falk Pharma UK) is indicated for the treatment of eosinophilic esophagitis in adults.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £323 per pack of 90 one‑mg tablets (excluding VAT; BNF online, accessed April 2021). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee considered evidence submitted by Dr Falk Pharma UK, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Clinical pathway
## Patients need an effective treatment for eosinophilic oesophagitis
Eosinophilic oesophagitis is a rare, chronic, immune-mediated disease. The body over-produces white blood cells (eosinophils) in the oesophagus, leading to inflammation. Symptoms can be unpleasant and socially embarrassing, and have a significant impact on quality of life. People with eosinophilic oesophagitis can have difficulty swallowing and eating. This can sometimes lead to food becoming stuck in the oesophagus to the point that people cannot even swallow water. People with eosinophilic oesophagitis can also have chest pains, heartburn, upper abdominal pain and food regurgitation. The patient and clinical experts said that one of the biggest challenges of this condition is the lack of a treatment pathway. Treatment includes off-label proton pump inhibitors (such as omeprazole or lansoprazole) and corticosteroids (off-label fluticasone and unlicensed budesonide). People can also try elimination diets such as the 6‑food elimination diet (SFED), which involves eliminating the known allergens milk, eggs, nuts, wheat, soy and seafood. Access to treatment varies and the patient and clinical experts explained that even if people can get treatment, it is not always effective. Although proton pump inhibitors can be used for reflux, they are not effective for eosinophilic oesophagitis in most people. Off-label corticosteroids are effective when used properly. But dosing and delivery of off-label corticosteroids is difficult and imprecise because it involves swallowing formulations originally designed for inhalation, which is counterintuitive and poorly understood by patients and clinicians. Dietary interventions are hugely challenging and professional support is often difficult to access. Specialist diets can be expensive so they are not affordable for many people with this disease. The committee concluded there was an unmet need for a licensed, effective treatment for eosinophilic oesophagitis.
## Off-label fluticasone, SFED and no treatment are appropriate comparators for budesonide ODT
The company expected budesonide orodispersible tablet (ODT) to be used as first-line treatment for eosinophilic oesophagitis, replacing off-label fluticasone and SFED. An unlicensed viscous formulation of budesonide has been used, but the company did not include this as a comparator because most people are treated with off-label fluticasone. A comparison with no treatment was added after technical engagement because fluticasone is used off-label and SFED is not suitable for everyone. The company did not include proton pump inhibitors as a comparator because it expected budesonide ODT to be used after this treatment (see section 3.3). The ERG agreed with the company's choice of comparators. The clinical and patient experts explained that proton pump inhibitors are generally not effective for this population, and off-label corticosteroids and SFED are not suitable for everyone. People can also wait a long time to get treatment. This means that many people with active eosinophilic oesophagitis are not treated and only get care in an emergency like a bolus food impaction (when the oesophagus is obstructed by swallowed food). The committee concluded that off-label fluticasone, SFED and no treatment are appropriate comparators for budesonide ODT.
# Population
## Adults with active eosinophilic oesophagitis are the relevant population
The company's key trial (see section 3.5) recruited people whose condition did not respond to treatment with proton pump inhibitors. This was a more limited population than that of the scope, in which the population was adults with active eosinophilic oesophagitis. Although the licence does not include this restriction, the company considered that people are prescribed proton pump inhibitors before they are diagnosed with eosinophilic oesophagitis, and some may continue on them alongside budesonide ODT. The ERG agreed with the company's approach and also limited the population to people who have already had proton pump inhibitors. The clinical experts explained that, although in practice nearly everyone has proton pump inhibitors before their diagnosis, proton pump inhibitors are not a first-line treatment for eosinophilic oesophagitis. They agreed that limiting the population to people who had tried proton pump inhibitors was not appropriate and could delay treatment. The committee agreed that treatment access was a substantial issue for this population. It noted that, because most people in the NHS are likely to have had proton pump inhibitors before diagnosis, the clinical trial results are likely to be generalisable to NHS practice. The committee concluded that the whole population defined in the scope – adults with active eosinophilic oesophagitis – is the relevant population for this appraisal.
# Intervention
## Budesonide ODT for inducing remission is the relevant intervention for this appraisal
The company's submission included evidence only on induction treatment with budesonide ODT and none for maintaining remission. This is because, at the time of the submission, the marketing authorisation was for induction treatment only and no evidence for maintenance treatment was available. The usual duration of induction treatment with budesonide ODT is 6 weeks. If the condition has not appropriately responded after 6 weeks then treatment can be extended for up to 12 weeks. The marketing authorisation was extended in June 2020 to include maintenance treatment (see section 2). The company decided to continue with the appraisal of induction therapy only, rather than start a new appraisal, because it did not want to delay patient access. The company submission included analyses for people having multiple inductions with budesonide ODT for people who relapse after the first induction. The ERG focused on a single induction, but noted that this approach may not apply to clinical practice because budesonide ODT is likely to be used for both induction and maintenance therapy. The clinical and patient experts confirmed that they would like to use budesonide ODT for both. The clinical experts said that although they would consider a second induction after a relapse, they would generally consider moving to maintenance treatment only if there were multiple relapses. The committee agreed that, because evidence for maintenance treatment had not been submitted, it could not be considered in this appraisal. The committee concluded that budesonide ODT for inducing remission is the relevant intervention for this appraisal.
# Clinical evidence
## Budesonide ODT improves remission rates compared with placebo
The key evidence was from BUL‑1/EEA, a double-blind, multicentre, placebo-controlled study. It compared induction treatment with budesonide ODT with placebo in 88 people with active eosinophilic oesophagitis whose condition was refractory to proton pump inhibitors. Induction treatment with budesonide ODT was given for 6 weeks and if the condition did not go into remission it was extended for another 6 weeks. The mean age in the trial was 37 years. The primary outcome was clinico-histological remission. This combined:
endoscopy-measured histological remission, defined as a peak eosinophil count of under 16 eos/mm2 hpf (eosinophils per millimetre squared high-power field), and
symptom resolution, defined as a severity of 2 points or less on 0 to 10 dysphagia (difficulty swallowing) and odynophagia (pain during swallowing) scales.Clinico-histological remission was seen in 57.6% of patients (34 out of 59) who had budesonide ODT, and none of the 29 patients on placebo (p<0.0001). Similarly, histological remission was seen in 93.2% of patients (55 out of 59) who had budesonide ODT, and none of the patients on placebo (p<0.0001). Evidence from a 2‑week trial of induction with budesonide ODT (BUU‑2/EEA) and from 6 weeks of open-label treatment with budesonide ODT (BUL‑2/EER) also supports its efficacy. The committee concluded that induction treatment with budesonide ODT increases the rate of histologic and clinico-histologic remission compared with placebo.
# Indirect treatment comparison
## The studies included are small, have different designs and have no UK patients
No trial compared budesonide ODT with off-label use of corticosteroids formulated for inhalation or dietary treatment. The company did an indirect comparison using data for histological remission from 5 trials: the budesonide trials BUL‑1/EEA and BUU‑2/EEA (see section 3.5), and Alexander et al. (2012), Philpott et al. (2016) and Dellon et al. (2017). Alexander et al. compared fluticasone with placebo in 42 patients with eosinophilic oesophagitis in the US. Philpott et al. (2016) compared SFED (alongside proton pump inhibitors) with budesonide (viscous formulation) in an observational Australian study of 56 people with eosinophilic oesophagitis whose condition was refractory to proton pump inhibitors. Dellon et al. compared off-label budesonide with placebo in 100 patients with eosinophilic oesophagitis in the US. None of the studies included UK patients. All the studies were small, had different designs and recruited people with different baseline characteristics.
## The results of both the company's and the ERG's indirect comparisons are very uncertain
For its indirect treatment comparisons, the company used a Bayesian random effects network meta-analysis without a continuity correction for zero events in the placebo arm. The high number of zero events was one of the drivers of the very wide credible intervals in the company's model. The company provided a Bayesian model with a continuity correction during clarification, but the ERG found that this version of the model did not work properly when different inputs were used. Instead, the ERG used a frequentist random effects model, which automatically adds a continuity correction for the zero events. Despite this correction, both analyses still had very wide credible intervals (company) and confidence intervals (ERG), indicating substantial uncertainty in the results. The company's analyses suggested a response rate per 12‑week cycle of 68% for fluticasone and 18% for SFED. The ERG's analyses suggested a response rate per cycle of 73% for fluticasone and 44% for SFED. Both analyses suggested a response rate per cycle of 95% for budesonide ODT and 4% for no treatment. The clinical experts considered the ERG's SFED estimates to be more plausible. The patient expert noted the particularly challenging nature of SFED, which can be expensive and require professional support (see section 3.1). For fluticasone, the clinical and patient experts considered the company's estimates to be more plausible because of the difficulty in administering it and adherence to treatment among patients (see section 3.1). The committee noted that the impact of effect-modifying variables in the analyses was unknown and concluded that both the company's and ERG's results were very uncertain.
# Model structure
## The model structure is appropriate
The company used a Markov model with 3 health states: active eosinophilic oesophagitis, remission with maintenance, and remission without maintenance, plus a death state. After technical engagement, the company modelled multiple inductions with budesonide ODT for people with eosinophilic oesophagitis whose disease relapses after the initial induction. Maintenance for budesonide ODT was not modelled, but it was included for comparators. The ERG used the version of the company's model from before technical engagement because it allowed a longer time horizon. Both models had the same structure, but not all inputs could be set in the same way, so the 2 models could not provide the same results. The ERG modelled a single induction with budesonide ODT. Maintenance for budesonide ODT was not modelled. The clinical experts agreed that the 3 health states were appropriate for this disease area. They repeated that an ideal model of clinical practice would include budesonide ODT as both induction and maintenance treatment (see section 3.4), and said that they hoped for a future appraisal of budesonide ODT as maintenance treatment. The committee concluded that the model structure was appropriate.
## The company's and the ERG's approach to modelling are both suitable for decision making
The company's multiple inductions model explored a 1‑year and 2‑year time horizon and included maintenance treatment for comparators. It assumed that the rate of response to budesonide remains the same for all inductions (rates of response to fluticasone were also assumed to be the same for all inductions). However, the ERG noted that the company had not presented any evidence on the response rates for subsequent inductions in relation to the initial induction. The ERG's single induction model used a 5‑year time horizon for a scenario modelling maintenance treatment for comparators and a 3‑year horizon for a scenario without maintenance treatment for comparators. Both the company and ERG agreed that a longer time horizon would be needed for a model that includes maintenance treatment with budesonide ODT. The clinical experts said that although eosinophilic oesophagitis is a chronic condition, a shorter time horizon is acceptable to model induction. The clinical experts explained that they would consider re-induction but noted that the treatment protocol with budesonide ODT was yet to be established. The committee agreed that the way the induction treatment would be used was uncertain and concluded that it would consider both the company's and the ERG's approach to modelling.
# Remission rates
## The company's and the ERG's assumptions about remission are both suitable for decision making
Remission rates were based on the results of the indirect treatment comparison. The committee had already concluded that the company's and the ERG's results were very uncertain (see section 3.7). Only data for histological remission were analysed by the company. Remission states in the model therefore included people in histological remission regardless of whether their clinical symptoms were resolved. The clinical experts explained that some people who have histological remission will still have clinical symptoms. In the key trial, the primary outcome was clinico-histological remission, which combined resolution of inflammation (endoscopy-measured histological remission) and clinical symptoms (dysphagia and odynophagia reported by patients). The rates of clinico-histological remission were lower than the rates of histological remission (see section 3.5). The company also assumed that people who are in remission at 1 year will remain in remission. The ERG assumed that people who remain in remission at 1 year will continue to relapse. The clinical experts agreed that there may be a proportion of people who would remain in a long remission after a successful treatment but they were unable to confirm whether the company's assumption was appropriate or not. The committee concluded that the assumption about long-term remission was uncertain and concluded that it would consider both the company's and the ERG's approach in its decision making.
# Relapse rates
## The company's and the ERG's approach to relapse rates are both suitable for decision making
Relapse rates were not collected in the company's trials. The company assumed the following rates per 12‑week cycle:
%, based on the rates in the placebo group of BUL‑2/EER, for the first 4 cycles used for no treatment and all active treatments (budesonide ODT, fluticasone and SFED)
% for fluticasone when used for maintenance
% for SFED at 1 year because of non-adherence (based on Lucendo et al. 2013).The ERG used the following rates per 12‑week cycle:
% for no treatment and all active treatments, based on Dellon et al. (2019)
% for fluticasone and SFED when used for maintenance, based on a review of maintenance studies.The clinical experts agreed that that all the proposed rates were uncertain. But they considered the relapse rates for no treatment from BUL‑2/EER to be more appropriate because it was a higher quality study than Dellon et al. (2019). The committee concluded that both approaches to relapse rates were uncertain and that it would consider both the company's and the ERG's approach in its decision making.
# Utilities
## The company's and the ERG's approach to utilities are both suitable for decision making
The company and the ERG both used age-adjusted UK population norms to calculate a utility of 0.93 for EQ‑5D for remission of eosinophilic oesophagitis. For active eosinophilic oesophagitis, the company applied a disutility of 0.15 for gastro-oesophageal reflux disease (which the company considered to be a proxy for eosinophilic oesophagitis) from Kartman et al. (2004; n=1,011). The ERG used a disutility of 0.07 for eosinophilic oesophagitis based on Hewett et al. (2017; n=44). The utilities for active disease were 0.78 using the company's and 0.86 using the ERG's approach. The company noted that the Hewett et al. study included patients with active eosinophilic oesophagitis and patients in remission. The ERG agreed that this introduced additional uncertainty, but it explained that another study, by Larsson et al. (2015) in 47 people with eosinophilic oesophagitis, reported similar results. The clinical and patient experts said that, although there were some similarities between gastro-oesophageal reflux disease and eosinophilic oesophagitis (they both include breakthrough symptoms and treatment breaks), there were differences. For example, a major issue with gastro-oesophageal reflux disease is sleep disturbance, whereas with eosinophilic oesophagitis it is food disturbance. However, they would not expect utilities for active eosinophilic oesophagitis to be higher than utilities for gastro-oesophageal reflux disease. Overall, the clinical experts agreed that gastro-oesophageal reflux utilities could be used as a proxy for eosinophilic oesophagitis. They also noted that some patients in the remission state may still have clinical symptoms, so using the UK population norms may be an overestimate. The committee agreed that the utilities were uncertain, but it noted that proxy utilities are usually considered only when disease-specific utilities are not available. The committee concluded that it would consider both the company's and the ERG's approach in its decision making.
# Costs
## The induction dose for off-label fluticasone is 2 mg per day and wastage for budesonide ODT should be included
The company used a 2 mg per day induction dose for fluticasone based on Butz et al. (2017). For budesonide ODT it did not include wastage because it assumed multiple inductions in its base case. The ERG used a 1.5 mg per day induction dose for fluticasone based on Lucendo et al. (2020). For budesonide ODT it included wastage because 84 one‑mg tablets would be needed for 6 weeks of induction treatment, and a pack contains 90 tablets. Another pack of 90 tablets would be used if induction was extended to 12 weeks. The clinical and patient experts agreed that wastage for budesonide should be included. They considered the company's estimate of the fluticasone dosage to be more plausible. The committee concluded that the more likely induction dose for off-label fluticasone was 2 mg per day and that wastage for budesonide ODT should be included in the model.
## The committee prefers the company's approach to follow-up and monitoring costs
The company assumed 1 gastroenterologist visit and 0.5 of an endoscopy visit per 12‑week cycle for budesonide ODT and fluticasone. For no treatment it assumed half of the follow-up and monitoring costs of budesonide ODT and fluticasone. For SFED it assumed 1 gastroenterologist visit, 1.3 endoscopy visits and 1.8 dietitian visits per cycle. The ERG considered the company's assumption to be appropriate, but assumed no follow-up and monitoring costs for no treatment. The clinical and patient experts agreed that assuming no cost for patients on no treatment was not realistic because they would still need NHS services such as endoscopies and admissions to A&E for food bolus obstruction. They therefore preferred the company's approach. The committee concluded that it was likely that people having no treatment would still need some healthcare services, and they therefore preferred the company's approach.
## The company's and the ERG's assumptions about endoscopic interventions are both suitable for decision making
The company assumed the following endoscopic dilation rates per 12‑week cycle:
% for active disease with no treatment (based on Shoepfer et al. 2010)
% for disease in remission with no treatment (half of the active disease rate)
% for active disease with treatment (half of the active disease rate with no treatment)
% for disease in remission with treatment (half of the active disease rate).The ERG used a similar approach, but assumed different rates:
% for active disease with no treatment (based on clinical advice)
% for disease in remission with no treatment (half of the active disease rate)
% for active disease with treatment (based on Runge et al. 2016)
% for disease in remission with treatment (half of the active disease rate).The clinical experts agreed that the most plausible rates were somewhere between the company's and ERG's estimates. The committee agreed with the experts and concluded that it would consider both the company's and ERG's approach in its decision making.
# Cost-effectiveness estimate
## The cost-effectiveness estimates are uncertain and sensitive to even very small changes in the model's inputs
In the company's analyses of multiple inductions, budesonide ODT was the most expensive treatment and provided the most quality-adjusted life years (QALYs). The fully incremental ICER (incremental cost-effectiveness ratio) for budesonide ODT was £1,958 per QALY gained when compared with no treatment in the 2‑year horizon model, and £4,780 per QALY gained when compared with fluticasone in the 1‑year horizon model. The company did not provide any probabilistic results exploring the inherent uncertainty. The analyses were sensitive to changes in assumptions and when all the ERG's assumptions were applied, some pairwise ICERs were higher than £30,000 per QALY gained. In the ERG's analysis of a single induction with maintenance treatment for comparators (5‑year horizon), budesonide ODT was the second cheapest treatment after no treatment, but it did not provide the most QALYs (fluticasone was the most expensive treatment with the most QALYs). The fully incremental ICER for fluticasone was £14,012 per QALY gained when compared with budesonide ODT. However, in the ERG's analysis of a single induction without maintenance treatment for comparators (3‑year horizon), budesonide ODT was the most expensive treatment with the most QALYs. The fully incremental ICER for budesonide ODT was £27,078 per QALY gained when compared with fluticasone. The committee noted the differences in the total cost of budesonide ODT based on the modelling approach and agreed that this, together with the very small QALY gains, means that the results are sensitive to even very small changes in the model's inputs.
## The most likely estimate is within the range NICE considers a cost-effective use of NHS resources
The committee made the following conclusions about the key model inputs.
Remission rates (section 3.10): both the company's and the ERG's approaches were uncertain, and both were considered for decision making.
Relapse rates (section 3.11): both the company's and the ERG's approaches were uncertain, and both were considered for decision making.
Utilities (section 3.12): both the company's and the ERG's approaches were uncertain, and both were considered for decision making.
Treatment cost (section 3.13): the induction dose for off-label fluticasone should be 2 mg per day and wastage for budesonide ODT should be included.
Follow-up and monitoring costs (section 3.14): both the company's and the ERG's approaches were uncertain, but the company's approach was preferred.
Endoscopic dilation (section 3.15): both the company's and the ERG's approaches were uncertain, and both were considered for decision making.The committee noted the high level of uncertainty in the model inputs. However, because of the challenges with using off-label corticosteroids and dietary interventions outside clinical trials, the committee agreed that the comparative effectiveness of budesonide ODT was likely to have been underestimated. Therefore, the cost-effectiveness estimates were likely to be biased against it. The committee also agreed that budesonide ODT is a licensed treatment option for people with eosinophilic oesophagitis who had few other treatment options. Taking all this into account, the committee concluded that the most likely ICER would be within the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained).
# Conclusion
## Budesonide ODT is recommended for routine use
The committee concluded that the most plausible estimates were within the range NICE considers a cost-effective use of NHS resources. Therefore, it recommended budesonide ODT for inducing remission in adults with eosinophilic oesophagitis.
|
{'Recommendations': "Budesonide as an orodispersible tablet (ODT) is recommended as an option for inducing remission of eosinophilic oesophagitis in adults.\n\nThis recommendation is not intended to affect treatment with budesonide ODT that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nAlthough budesonide ODT has a marketing authorisation for both inducing and maintaining remission in eosinophilic oesophagitis, at the time this appraisal started it was only licensed for induction. So, the company's evidence is for inducing remission only (with treatment of up to 12\xa0weeks) and the committee is unable to make recommendations for maintenance treatment.\n\nThere is currently no standard care for inducing remission in eosinophilic oesophagitis. Fluticasone is one treatment option, but it is an asthma treatment that is not easy to use for eosinophilic oesophagitis. Dietary changes are also an option, for example the 6‑food elimination diet, which involves cutting out the known allergens milk, eggs, nuts, wheat, soy and seafood from your diet. These treatments can be difficult to access and adhere to. And people often have no treatment at all, so there is an unmet need for this condition.\n\nClinical trial evidence shows that budesonide ODT improves the signs and symptoms of eosinophilic oesophagitis compared with placebo. There is no direct evidence for budesonide ODT compared with fluticasone or the 6‑food elimination diet and the results of an indirect comparison with these treatments are very uncertain.\n\nThe cost-effectiveness estimates vary and are also very uncertain. However, the most likely estimates are within what NICE considers a cost-effective use of NHS resources. Therefore, it is recommended for inducing remission in eosinophilic oesophagitis in adults.", 'Information about budesonide orodispersible tablet': '# Marketing authorisation indication\n\nBudesonide orodispersible tablet (Jorveza, Dr Falk Pharma UK) is indicated for the treatment of eosinophilic esophagitis in adults.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £323 per pack of 90 one‑mg tablets (excluding VAT; BNF online, accessed April 2021). Costs may vary in different settings because of negotiated procurement discounts.', 'Committee discussion': "The appraisal committee considered evidence submitted by Dr Falk Pharma UK, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical pathway\n\n## Patients need an effective treatment for eosinophilic oesophagitis\n\nEosinophilic oesophagitis is a rare, chronic, immune-mediated disease. The body over-produces white blood cells (eosinophils) in the oesophagus, leading to inflammation. Symptoms can be unpleasant and socially embarrassing, and have a significant impact on quality of life. People with eosinophilic oesophagitis can have difficulty swallowing and eating. This can sometimes lead to food becoming stuck in the oesophagus to the point that people cannot even swallow water. People with eosinophilic oesophagitis can also have chest pains, heartburn, upper abdominal pain and food regurgitation. The patient and clinical experts said that one of the biggest challenges of this condition is the lack of a treatment pathway. Treatment includes off-label proton pump inhibitors (such as omeprazole or lansoprazole) and corticosteroids (off-label fluticasone and unlicensed budesonide). People can also try elimination diets such as the 6‑food elimination diet (SFED), which involves eliminating the known allergens milk, eggs, nuts, wheat, soy and seafood. Access to treatment varies and the patient and clinical experts explained that even if people can get treatment, it is not always effective. Although proton pump inhibitors can be used for reflux, they are not effective for eosinophilic oesophagitis in most people. Off-label corticosteroids are effective when used properly. But dosing and delivery of off-label corticosteroids is difficult and imprecise because it involves swallowing formulations originally designed for inhalation, which is counterintuitive and poorly understood by patients and clinicians. Dietary interventions are hugely challenging and professional support is often difficult to access. Specialist diets can be expensive so they are not affordable for many people with this disease. The committee concluded there was an unmet need for a licensed, effective treatment for eosinophilic oesophagitis.\n\n## Off-label fluticasone, SFED and no treatment are appropriate comparators for budesonide ODT\n\nThe company expected budesonide orodispersible tablet (ODT) to be used as first-line treatment for eosinophilic oesophagitis, replacing off-label fluticasone and SFED. An unlicensed viscous formulation of budesonide has been used, but the company did not include this as a comparator because most people are treated with off-label fluticasone. A comparison with no treatment was added after technical engagement because fluticasone is used off-label and SFED is not suitable for everyone. The company did not include proton pump inhibitors as a comparator because it expected budesonide ODT to be used after this treatment (see section 3.3). The ERG agreed with the company's choice of comparators. The clinical and patient experts explained that proton pump inhibitors are generally not effective for this population, and off-label corticosteroids and SFED are not suitable for everyone. People can also wait a long time to get treatment. This means that many people with active eosinophilic oesophagitis are not treated and only get care in an emergency like a bolus food impaction (when the oesophagus is obstructed by swallowed food). The committee concluded that off-label fluticasone, SFED and no treatment are appropriate comparators for budesonide ODT.\n\n# Population\n\n## Adults with active eosinophilic oesophagitis are the relevant population\n\nThe company's key trial (see section 3.5) recruited people whose condition did not respond to treatment with proton pump inhibitors. This was a more limited population than that of the scope, in which the population was adults with active eosinophilic oesophagitis. Although the licence does not include this restriction, the company considered that people are prescribed proton pump inhibitors before they are diagnosed with eosinophilic oesophagitis, and some may continue on them alongside budesonide ODT. The ERG agreed with the company's approach and also limited the population to people who have already had proton pump inhibitors. The clinical experts explained that, although in practice nearly everyone has proton pump inhibitors before their diagnosis, proton pump inhibitors are not a first-line treatment for eosinophilic oesophagitis. They agreed that limiting the population to people who had tried proton pump inhibitors was not appropriate and could delay treatment. The committee agreed that treatment access was a substantial issue for this population. It noted that, because most people in the NHS are likely to have had proton pump inhibitors before diagnosis, the clinical trial results are likely to be generalisable to NHS practice. The committee concluded that the whole population defined in the scope – adults with active eosinophilic oesophagitis – is the relevant population for this appraisal.\n\n# Intervention\n\n## Budesonide ODT for inducing remission is the relevant intervention for this appraisal\n\nThe company's submission included evidence only on induction treatment with budesonide ODT and none for maintaining remission. This is because, at the time of the submission, the marketing authorisation was for induction treatment only and no evidence for maintenance treatment was available. The usual duration of induction treatment with budesonide ODT is 6\xa0weeks. If the condition has not appropriately responded after 6\xa0weeks then treatment can be extended for up to 12\xa0weeks. The marketing authorisation was extended in June 2020 to include maintenance treatment (see section 2). The company decided to continue with the appraisal of induction therapy only, rather than start a new appraisal, because it did not want to delay patient access. The company submission included analyses for people having multiple inductions with budesonide ODT for people who relapse after the first induction. The ERG focused on a single induction, but noted that this approach may not apply to clinical practice because budesonide ODT is likely to be used for both induction and maintenance therapy. The clinical and patient experts confirmed that they would like to use budesonide ODT for both. The clinical experts said that although they would consider a second induction after a relapse, they would generally consider moving to maintenance treatment only if there were multiple relapses. The committee agreed that, because evidence for maintenance treatment had not been submitted, it could not be considered in this appraisal. The committee concluded that budesonide ODT for inducing remission is the relevant intervention for this appraisal.\n\n# Clinical evidence\n\n## Budesonide ODT improves remission rates compared with placebo\n\nThe key evidence was from BUL‑1/EEA, a double-blind, multicentre, placebo-controlled study. It compared induction treatment with budesonide ODT with placebo in 88\xa0people with active eosinophilic oesophagitis whose condition was refractory to proton pump inhibitors. Induction treatment with budesonide ODT was given for 6\xa0weeks and if the condition did not go into remission it was extended for another 6\xa0weeks. The mean age in the trial was 37\xa0years. The primary outcome was clinico-histological remission. This combined:\n\nendoscopy-measured histological remission, defined as a peak eosinophil count of under 16\xa0eos/mm2\xa0hpf (eosinophils per millimetre squared high-power field), and\n\nsymptom resolution, defined as a severity of 2\xa0points or less on 0 to 10 dysphagia (difficulty swallowing) and odynophagia (pain during swallowing) scales.Clinico-histological remission was seen in 57.6% of patients (34 out of 59) who had budesonide ODT, and none of the 29\xa0patients on placebo (p<0.0001). Similarly, histological remission was seen in 93.2% of patients (55 out of 59) who had budesonide ODT, and none of the patients on placebo (p<0.0001). Evidence from a 2‑week trial of induction with budesonide ODT (BUU‑2/EEA) and from 6\xa0weeks of open-label treatment with budesonide ODT (BUL‑2/EER) also supports its efficacy. The committee concluded that induction treatment with budesonide ODT increases the rate of histologic and clinico-histologic remission compared with placebo.\n\n# Indirect treatment comparison\n\n## The studies included are small, have different designs and have no UK patients\n\nNo trial compared budesonide ODT with off-label use of corticosteroids formulated for inhalation or dietary treatment. The company did an indirect comparison using data for histological remission from 5\xa0trials: the budesonide trials BUL‑1/EEA and BUU‑2/EEA (see section 3.5), and Alexander et al. (2012), Philpott et al. (2016) and Dellon et al. (2017). Alexander et al. compared fluticasone with placebo in 42\xa0patients with eosinophilic oesophagitis in the US. Philpott et al. (2016) compared SFED (alongside proton pump inhibitors) with budesonide (viscous formulation) in an observational Australian study of 56\xa0people with eosinophilic oesophagitis whose condition was refractory to proton pump inhibitors. Dellon et al. compared off-label budesonide with placebo in 100\xa0patients with eosinophilic oesophagitis in the US. None of the studies included UK patients. All the studies were small, had different designs and recruited people with different baseline characteristics.\n\n## The results of both the company's and the ERG's indirect comparisons are very uncertain\n\nFor its indirect treatment comparisons, the company used a Bayesian random effects network meta-analysis without a continuity correction for zero events in the placebo arm. The high number of zero events was one of the drivers of the very wide credible intervals in the company's model. The company provided a Bayesian model with a continuity correction during clarification, but the ERG found that this version of the model did not work properly when different inputs were used. Instead, the ERG used a frequentist random effects model, which automatically adds a continuity correction for the zero events. Despite this correction, both analyses still had very wide credible intervals (company) and confidence intervals (ERG), indicating substantial uncertainty in the results. The company's analyses suggested a response rate per 12‑week cycle of 68% for fluticasone and 18% for SFED. The ERG's analyses suggested a response rate per cycle of 73% for fluticasone and 44% for SFED. Both analyses suggested a response rate per cycle of 95% for budesonide ODT and 4% for no treatment. The clinical experts considered the ERG's SFED estimates to be more plausible. The patient expert noted the particularly challenging nature of SFED, which can be expensive and require professional support (see section 3.1). For fluticasone, the clinical and patient experts considered the company's estimates to be more plausible because of the difficulty in administering it and adherence to treatment among patients (see section\xa03.1). The committee noted that the impact of effect-modifying variables in the analyses was unknown and concluded that both the company's and ERG's results were very uncertain.\n\n# Model structure\n\n## The model structure is appropriate\n\nThe company used a Markov model with 3\xa0health\xa0states: active eosinophilic oesophagitis, remission with maintenance, and remission without maintenance, plus a death state. After technical engagement, the company modelled multiple inductions with budesonide ODT for people with eosinophilic oesophagitis whose disease relapses after the initial induction. Maintenance for budesonide ODT was not modelled, but it was included for comparators. The ERG used the version of the company's model from before technical engagement because it allowed a longer time horizon. Both models had the same structure, but not all inputs could be set in the same way, so the 2 models could not provide the same results. The ERG modelled a single induction with budesonide ODT. Maintenance for budesonide ODT was not modelled. The clinical experts agreed that the 3\xa0health\xa0states were appropriate for this disease area. They repeated that an ideal model of clinical practice would include budesonide ODT as both induction and maintenance treatment (see section 3.4), and said that they hoped for a future appraisal of budesonide ODT as maintenance treatment. The committee concluded that the model structure was appropriate.\n\n## The company's and the ERG's approach to modelling are both suitable for decision making\n\nThe company's multiple inductions model explored a 1‑year and 2‑year time horizon and included maintenance treatment for comparators. It assumed that the rate of response to budesonide remains the same for all inductions (rates of response to fluticasone were also assumed to be the same for all inductions). However, the ERG noted that the company had not presented any evidence on the response rates for subsequent inductions in relation to the initial induction. The ERG's single induction model used a 5‑year time horizon for a scenario modelling maintenance treatment for comparators and a 3‑year horizon for a scenario without maintenance treatment for comparators. Both the company and ERG agreed that a longer time horizon would be needed for a model that includes maintenance treatment with budesonide ODT. The clinical experts said that although eosinophilic oesophagitis is a chronic condition, a shorter time horizon is acceptable to model induction. The clinical experts explained that they would consider re-induction but noted that the treatment protocol with budesonide ODT was yet to be established. The committee agreed that the way the induction treatment would be used was uncertain and concluded that it would consider both the company's and the ERG's approach to modelling.\n\n# Remission rates\n\n## The company's and the ERG's assumptions about remission are both suitable for decision making\n\nRemission rates were based on the results of the indirect treatment comparison. The committee had already concluded that the company's and the ERG's results were very uncertain (see section 3.7). Only data for histological remission were analysed by the company. Remission states in the model therefore included people in histological remission regardless of whether their clinical symptoms were resolved. The clinical experts explained that some people who have histological remission will still have clinical symptoms. In the key trial, the primary outcome was clinico-histological remission, which combined resolution of inflammation (endoscopy-measured histological remission) and clinical symptoms (dysphagia and odynophagia reported by patients). The rates of clinico-histological remission were lower than the rates of histological remission (see section 3.5). The company also assumed that people who are in remission at 1\xa0year will remain in remission. The ERG assumed that people who remain in remission at 1\xa0year will continue to relapse. The clinical experts agreed that there may be a proportion of people who would remain in a long remission after a successful treatment but they were unable to confirm whether the company's assumption was appropriate or not. The committee concluded that the assumption about long-term remission was uncertain and concluded that it would consider both the company's and the ERG's approach in its decision making.\n\n# Relapse rates\n\n## The company's and the ERG's approach to relapse rates are both suitable for decision making\n\nRelapse rates were not collected in the company's trials. The company assumed the following rates per 12‑week cycle:\n\n%, based on the rates in the placebo group of BUL‑2/EER, for the first 4\xa0cycles used for no treatment and all active treatments (budesonide ODT, fluticasone and SFED)\n\n% for fluticasone when used for maintenance\n\n% for SFED at 1\xa0year because of non-adherence (based on Lucendo et al. 2013).The ERG used the following rates per 12‑week cycle:\n\n% for no treatment and all active treatments, based on Dellon et al. (2019)\n\n% for fluticasone and SFED when used for maintenance, based on a review of maintenance studies.The clinical experts agreed that that all the proposed rates were uncertain. But they considered the relapse rates for no treatment from BUL‑2/EER to be more appropriate because it was a higher quality study than Dellon et al. (2019). The committee concluded that both approaches to relapse rates were uncertain and that it would consider both the company's and the ERG's approach in its decision making.\n\n# Utilities\n\n## The company's and the ERG's approach to utilities are both suitable for decision making\n\nThe company and the ERG both used age-adjusted UK population norms to calculate a utility of 0.93 for EQ‑5D for remission of eosinophilic oesophagitis. For active eosinophilic oesophagitis, the company applied a disutility of 0.15 for gastro-oesophageal reflux disease (which the company considered to be a proxy for eosinophilic oesophagitis) from Kartman et al. (2004; n=1,011). The ERG used a disutility of 0.07 for eosinophilic oesophagitis based on Hewett et al. (2017; n=44). The utilities for active disease were 0.78 using the company's and 0.86 using the ERG's approach. The company noted that the Hewett et al. study included patients with active eosinophilic oesophagitis and patients in remission. The ERG agreed that this introduced additional uncertainty, but it explained that another study, by Larsson et al. (2015) in 47\xa0people with eosinophilic oesophagitis, reported similar results. The clinical and patient experts said that, although there were some similarities between gastro-oesophageal reflux disease and eosinophilic oesophagitis (they both include breakthrough symptoms and treatment breaks), there were differences. For example, a major issue with gastro-oesophageal reflux disease is sleep disturbance, whereas with eosinophilic oesophagitis it is food disturbance. However, they would not expect utilities for active eosinophilic oesophagitis to be higher than utilities for gastro-oesophageal reflux disease. Overall, the clinical experts agreed that gastro-oesophageal reflux utilities could be used as a proxy for eosinophilic oesophagitis. They also noted that some patients in the remission state may still have clinical symptoms, so using the UK population norms may be an overestimate. The committee agreed that the utilities were uncertain, but it noted that proxy utilities are usually considered only when disease-specific utilities are not available. The committee concluded that it would consider both the company's and the ERG's approach in its decision making.\n\n# Costs\n\n## The induction dose for off-label fluticasone is 2\xa0mg per day and wastage for budesonide ODT should be included\n\nThe company used a 2\xa0mg per day induction dose for fluticasone based on Butz et al. (2017). For budesonide ODT it did not include wastage because it assumed multiple inductions in its base case. The ERG used a 1.5\xa0mg per day induction dose for fluticasone based on Lucendo et al. (2020). For budesonide ODT it included wastage because 84 one‑mg tablets would be needed for 6\xa0weeks of induction treatment, and a pack contains 90\xa0tablets. Another pack of 90\xa0tablets would be used if induction was extended to 12\xa0weeks. The clinical and patient experts agreed that wastage for budesonide should be included. They considered the company's estimate of the fluticasone dosage to be more plausible. The committee concluded that the more likely induction dose for off-label fluticasone was 2\xa0mg per day and that wastage for budesonide ODT should be included in the model.\n\n## The committee prefers the company's approach to follow-up and monitoring costs\n\nThe company assumed 1 gastroenterologist visit and 0.5 of an endoscopy visit per 12‑week cycle for budesonide ODT and fluticasone. For no treatment it assumed half of the follow-up and monitoring costs of budesonide ODT and fluticasone. For SFED it assumed 1 gastroenterologist visit, 1.3 endoscopy visits and 1.8 dietitian visits per cycle. The ERG considered the company's assumption to be appropriate, but assumed no follow-up and monitoring costs for no treatment. The clinical and patient experts agreed that assuming no cost for patients on no treatment was not realistic because they would still need NHS services such as endoscopies and admissions to A&E for food bolus obstruction. They therefore preferred the company's approach. The committee concluded that it was likely that people having no treatment would still need some healthcare services, and they therefore preferred the company's approach.\n\n## The company's and the ERG's assumptions about endoscopic interventions are both suitable for decision making\n\nThe company assumed the following endoscopic dilation rates per 12‑week cycle:\n\n% for active disease with no treatment (based on Shoepfer et al. 2010)\n\n% for disease in remission with no treatment (half of the active disease rate)\n\n% for active disease with treatment (half of the active disease rate with no treatment)\n\n% for disease in remission with treatment (half of the active disease rate).The ERG used a similar approach, but assumed different rates:\n\n% for active disease with no treatment (based on clinical advice)\n\n% for disease in remission with no treatment (half of the active disease rate)\n\n% for active disease with treatment (based on Runge et al. 2016)\n\n% for disease in remission with treatment (half of the active disease rate).The clinical experts agreed that the most plausible rates were somewhere between the company's and ERG's estimates. The committee agreed with the experts and concluded that it would consider both the company's and ERG's approach in its decision making.\n\n# Cost-effectiveness estimate\n\n## The cost-effectiveness estimates are uncertain and sensitive to even very small changes in the model's inputs\n\nIn the company's analyses of multiple inductions, budesonide ODT was the most expensive treatment and provided the most quality-adjusted life years (QALYs). The fully incremental ICER (incremental cost-effectiveness ratio) for budesonide ODT was £1,958 per QALY gained when compared with no treatment in the 2‑year horizon model, and £4,780 per QALY gained when compared with fluticasone in the 1‑year horizon model. The company did not provide any probabilistic results exploring the inherent uncertainty. The analyses were sensitive to changes in assumptions and when all the ERG's assumptions were applied, some pairwise ICERs were higher than £30,000 per QALY gained. In the ERG's analysis of a single induction with maintenance treatment for comparators (5‑year horizon), budesonide ODT was the second cheapest treatment after no treatment, but it did not provide the most QALYs (fluticasone was the most expensive treatment with the most QALYs). The fully incremental ICER for fluticasone was £14,012 per QALY gained when compared with budesonide ODT. However, in the ERG's analysis of a single induction without maintenance treatment for comparators (3‑year horizon), budesonide ODT was the most expensive treatment with the most QALYs. The fully incremental ICER for budesonide ODT was £27,078 per QALY gained when compared with fluticasone. The committee noted the differences in the total cost of budesonide ODT based on the modelling approach and agreed that this, together with the very small QALY gains, means that the results are sensitive to even very small changes in the model's inputs.\n\n## The most likely estimate is within the range NICE considers a cost-effective use of NHS resources\n\nThe committee made the following conclusions about the key model inputs.\n\nRemission rates (section 3.10): both the company's and the ERG's approaches were uncertain, and both were considered for decision making.\n\nRelapse rates (section 3.11): both the company's and the ERG's approaches were uncertain, and both were considered for decision making.\n\nUtilities (section 3.12): both the company's and the ERG's approaches were uncertain, and both were considered for decision making.\n\nTreatment cost (section 3.13): the induction dose for off-label fluticasone should be 2\xa0mg per day and wastage for budesonide ODT should be included.\n\nFollow-up and monitoring costs (section 3.14): both the company's and the ERG's approaches were uncertain, but the company's approach was preferred.\n\nEndoscopic dilation (section 3.15): both the company's and the ERG's approaches were uncertain, and both were considered for decision making.The committee noted the high level of uncertainty in the model inputs. However, because of the challenges with using off-label corticosteroids and dietary interventions outside clinical trials, the committee agreed that the comparative effectiveness of budesonide ODT was likely to have been underestimated. Therefore, the cost-effectiveness estimates were likely to be biased against it. The committee also agreed that budesonide ODT is a licensed treatment option for people with eosinophilic oesophagitis who had few other treatment options. Taking all this into account, the committee concluded that the most likely ICER would be within the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained).\n\n# Conclusion\n\n## Budesonide ODT is recommended for routine use\n\nThe committee concluded that the most plausible estimates were within the range NICE considers a cost-effective use of NHS resources. Therefore, it recommended budesonide ODT for inducing remission in adults with eosinophilic oesophagitis."}
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https://www.nice.org.uk/guidance/ta708
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Evidence-based recommendations on budesonide as an orodispersible tablet for inducing remission of eosinophilic oesophagitis in adults.
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07c27d42d7dc5bc5364b3da2ebd113157d8d7b56
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nice
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Pembrolizumab for untreated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency
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Pembrolizumab for untreated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency
Evidence-based recommendations on pembrolizumab (Keytruda) for treating metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency in adults.
# Recommendations
Pembrolizumab is recommended as an option for untreated metastatic colorectal cancer with high microsatellite instability (MSI) or mismatch repair (MMR) deficiency in adults, only if:
pembrolizumab is stopped after 2 years and no documented disease progression, and
the company provides pembrolizumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with pembrolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with untreated metastatic colorectal cancer that has high MSI or MMR deficiency are usually offered combination chemotherapy including FOLFOX, FOLFIRI or CAPOX. For RAS wild-type cancer, cetuximab or panitumumab is added to FOLFOX or FOLFIRI.
Clinical trial evidence shows that pembrolizumab increases the time until the condition gets worse compared with current treatments. Pembrolizumab may also be more effective at extending life, but the evidence is limited and in the trial people had subsequent treatments that are not available in the NHS. So, it is uncertain how much benefit it offers over a person's lifetime.
There is no evidence from clinical trials that use pembrolizumab for more than 2 years of treatment so the benefit beyond this duration is uncertain.
The cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So, pembrolizumab is recommended.# Information about pembrolizumab
# Marketing authorisation indication
Pembrolizumab (Keytruda; Merck Sharp and Dohme) has a marketing authorisation as monotherapy 'for the first-line treatment of metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer in adults'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of pembrolizumab is £2,630 per 100-mg vial (excluding VAT; BNF online, accessed March 2021). The cost of a single administration is £5,260. This represents 3 weeks of treatment.
The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck Sharp and Dohme, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
Subsequent treatment costs in the model should not include cetuximab because it is not recommended after first-line treatment in the NHS.
Time-on-treatment for panitumumab with FOLFOX in the model should equal time-on-treatment for standard care in KEYNOTE‑177.
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see ERG report, table 1, page 18), and took these into account in its decision making. It discussed issues 1 to 5, which were outstanding after the technical engagement stage.
# The condition
## There is an unmet need for treatments for high microsatellite instability or mismatch repair deficiency metastatic colorectal cancer
Colorectal cancer is a malignant tumour arising from the lining of the large intestine (colon and rectum). Mutations can cause microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency in some metastatic colorectal cancer cells. DNA MMR corrects errors that occur during DNA replication, so problems with DNA MMR can lead to mutations in the microsatellites (repetitive DNA sequences). This causes them to become unstable, resulting in cancerous tumours with high MSI. High MSI or DNA MMR deficiency occurs in around 4% of metastatic colorectal cancer. It is associated with a poorer prognosis and a greater risk of death than metastatic colorectal cancer without MSI. There are currently no specific treatments for this type of colorectal cancer, so people are offered the same treatment whether or not their colorectal cancer has high MSI or DNA MMR deficiency. The committee concluded that there is an unmet need for treatments for this condition.
## People with the condition and clinicians would welcome new treatment options
The patient experts explained that a diagnosis of metastatic colorectal cancer with high MSI or DNA MMR deficiency affects quality of life both physically and psychologically. They highlighted that current treatments were highly toxic, which could lead to hospital admissions during treatment and permanent adverse effects like nerve damage. They explained that having progressed on several different treatments, their cancers had responded well to pembrolizumab, which was life changing. The committee noted that pembrolizumab, a checkpoint inhibitor, worked in a different way to chemotherapy. It heard that people appreciated the faster and less frequent administration of pembrolizumab, and preferable adverse effects compared with standard care. A clinical expert explained that, with a more effective treatment, there was potential that a patient's condition would respond well enough for them to have surgery with curative intent. The committee concluded that people with the condition and clinicians would welcome new treatment options.
# The treatment pathway
## Current standard care for metastatic colorectal cancer depends on fitness, RAS mutation, clinician judgement and the patient's informed preferences
Clinical experts explained that there are several first-line treatment options for metastatic colorectal cancer. Individualised treatment pathways are common and consider potential impacts of first-line treatment on available subsequent therapies because of the limited number of options for this cancer. Clinical experts explained that, because of the high toxicity of many standard care treatments, a patient's clinical status and performance status (their ability to complete daily tasks and ordinary activities), along with any comorbidities, would impact clinicians' judgement on the most suitable treatments. For example, people who are less frail would be offered more intense combinations according to the clinical evidence. A patient expert highlighted that people might also decline some chemotherapy regimens to avoid toxic side effects. The committee noted that first‑line treatment options are limited by whether a mutation in the RAS gene is present. The committee concluded that current standard care for metastatic colorectal cancer with high MSI or DNA MMR deficiency depends on fitness, RAS mutation status, clinician judgement and the person's informed preferences.
## Most people have combination chemotherapy at first line
Clinical experts explained that most people with untreated colorectal cancer have combination chemotherapy, usually with: folinic acid; fluorouracil (5 FU) and oxaliplatin (known as FOLFOX); 5 FU, folinic acid and irinotecan (known as FOLFIRI); or capecitabine and oxaliplatin (known as CAPOX). Clinical experts discussed the effectiveness of these regimens, noting that they are used interchangeably in clinical practice and are considered equivalent. The committee heard that, to increase the chance of good clinical outcomes, a small proportion of people with RAS‑mutant disease would have FOLFOXIRI (folinic acid, 5 FU, oxaliplatin and irinotecan). But, because of the higher toxicity of the combination, this would only be offered to fitter people. The committee concluded that FOLFOX, FOLFIRI, FOLFOXIRI and CAPOX were relevant comparators at first line.
## People with RAS wild-type colorectal cancer would have cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI
Clinical experts explained that people with cancers with no mutation in the RAS gene (referred to as RAS wild-type) would be offered an epidermal growth factor receptor (EGFR) inhibitor in addition to chemotherapy with FOLFOX or FOLFIRI. This is in line with NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer. The committee heard that cetuximab is used only in tumours that also express the EGFR protein, and noted that this is not a requirement for panitumumab. Clinical experts explained that, if recommended, pembrolizumab would be the preferred option for people with colorectal cancer regardless of RAS status, because of the poor outcomes for people with high MSI or DNA MMR‑deficient disease. The clinical experts acknowledged this meant EGFR inhibitors would not be used for this population because their recommendation is limited to first‑line treatment. The committee concluded that, in current clinical practice, people with RAS wild-type tumours would have cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI.
## Capecitabine is used less commonly than other treatments, but is a relevant comparator for some people
Although listed in the NICE scope as a comparator, the company did not include capecitabine, raltitrexed or tegafur with uracil in its submission. NICE's technology appraisal guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer recommends capecitabine monotherapy as an option for untreated metastatic colorectal cancer. Clinical experts explained that capecitabine is used only in people with a poor performance status (Eastern Cooperative Oncology Group score of 2 or more), who are likely to be frail and so cannot tolerate the toxicities of combination chemotherapy. Clinicians noted that they would be unlikely to use a monotherapy to treat high MSI or DNA MMR‑deficient colorectal cancer because of the poor outcomes of monotherapy and poor prognosis in this population. However, capecitabine monotherapy would be appropriate if the person had a very low performance status. One clinical expert estimated that capecitabine would be used in less than 10% of people with high MSI or DNA MMR‑deficient tumours. However, the committee considered that, although likely to be small in clinical practice, the population who would have capecitabine would also be able to have pembrolizumab. It was aware that the summary of product characteristics for pembrolizumab allows treatment of people with an ECOG status of 2 and above 'after careful consideration of the potential increased risk' and 'with appropriate clinical management'. The committee concluded that capecitabine may be used less commonly than other treatment options but is a relevant comparator for a small group of people and may be less effective than combination therapies.
## Tegafur with uracil and raltitrexed are not relevant comparators for pembrolizumab
The company excluded tegafur with uracil and raltitrexed as comparators in its submission, despite having been included in the NICE scope. Clinical experts confirmed that tegafur with uracil was not available in the NHS in England and did not consider it relevant as a comparator. The committee also heard that although raltitrexed is used in clinical practice, it is reserved for specific indications, such as people with a history of heart disease or who develop angina on 5 FU‑based chemotherapy. However, because it has a marketing authorisation for first-line use only, pembrolizumab would not be used in people who develop side effects on chemotherapy. The committee agreed that the population who would receive raltitrexed in clinical practice and could also receive pembrolizumab is negligible. It concluded that tegafur with uracil and raltitrexed are not relevant comparators for pembrolizumab in untreated metastatic colorectal cancer with high MSI or DNA MMR deficiency.
# Testing
## Although routinely funded, not all people newly diagnosed with colorectal cancer are tested for high MSI or DNA MMR deficiency in the NHS
NICE's diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer recommends testing all people with colorectal cancer to identify DNA MMR‑deficient tumours. This can be done either by immunohistochemistry testing for MMR proteins or polymerase chain reaction for determining MSI. Clinical experts noted variation in local uptake for high MSI or DNA MMR deficiency testing across the NHS, which was supported by testimonials from the patient experts. However, the clinical lead for the Cancer Drugs Fund confirmed that this testing is routinely commissioned by NHS England. It was explained that uptake is currently low in some places, but it is increasing. They clarified that testing should be offered to all newly diagnosed people before starting treatment. The committee noted that nivolumab and pembrolizumab are already available as interim treatment options during the COVID-19 pandemic for untreated colorectal cancer with high MSI or DNA MMR deficiency. So, the committee was aware that treatment decisions in the NHS are already being made based on the results of these tests. The committee agreed that it is correct to exclude the costs of testing for high MSI or DNA MMR deficiency from the company's model, because the tests are already routinely done by the NHS. It concluded that the costs associated with pembrolizumab need not include the costs for testing for high MSI or DNA MMR deficiency. It further concluded that if pembrolizumab is used routinely, then the NHS would need to improve testing uptake in some places.
# Clinical evidence
## Clinical evidence for pembrolizumab comes from the KEYNOTE‑177 trial, but the control treatments used in the trial do not reflect NHS practice
KEYNOTE‑177 is a multinational, open-label, randomised, phase 3 trial, comparing pembrolizumab with standard care. It included only people with inoperable untreated metastatic colorectal cancer with high MSI or DNA MMR deficiency. The primary outcomes were progression-free survival and overall survival. Standard care was defined by the company as investigator's choice of:
FOLFOX
FOLFIRI
cetuximab with FOLFOX or FOLFIRI
bevacizumab with FOLFOX or FOLFIRI.The company pooled data from all standard care regimens in its comparison with pembrolizumab. This means that there are no data directly comparing pembrolizumab with each separate regimen in the standard care control arm. Clinical experts explained that the control arm of KEYNOTE‑177 did not accurately reflect clinical practice in the NHS. This was because the trial excluded first-line treatment options for metastatic colorectal cancer in the NHS, including CAPOX and FOLFOXIRI, and for RAS wild-type tumours, panitumumab with FOLFOX or FOLFIRI. Moreover, the KEYNOTE‑177 trial included bevacizumab in the control arm, but NICE does not recommend bevacizumab at first line in this population (see NICE's technology appraisal guidance on bevacizumab and cetuximab for the treatment of metastatic colorectal cancer and bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer). The committee concluded that the comparators used in the trial are not entirely reflective of NHS practice.
## Bevacizumab likely offers a benefit to patients, so the trial may underestimate the relative effect of pembrolizumab compared with standard care
Around 70% of people randomised to standard care in KEYNOTE‑177 had bevacizumab‑containing regimens. The clinical lead from the Cancer Drugs Fund explained that bevacizumab is likely to benefit people with colorectal cancer with high MSI or DNA MMR deficiency. However, there are limited data available for this population, so the extent of any benefit is unknown. The ERG explained that, if bevacizumab were more effective than other available treatments, the results from the KEYNOTE‑177 may underestimate the relative effectiveness of pembrolizumab in the trial compared with in the NHS. A clinical expert agreed that bevacizumab is effective and noted that, unlike cetuximab and panitumumab, its use was not limited by RAS status. The committee noted that the KEYNOTE‑177 trial included some people from outside the UK and that not all of those included in the trial had the RAS status of their tumours determined before treatment. A clinical expert involved in the trial explained all UK participants had a documented RAS status and this determined their treatment options. However, he noted that some participants outside the UK with undetected RAS wild-type tumours may not have had cetuximab or panitumumab with FOLFOX or FOLFIRI as they would have in the NHS. Instead, they had bevacizumab or combination chemotherapy. The committee appreciated that this might overestimate the effectiveness of pembrolizumab relative to standard care in the trial compared with in the NHS. The committee recalled that standard care in KEYNOTE‑177 was not representative of treatment options in the NHS as bevacizumab is not available in England. The company conducted an exploratory analysis for primary outcomes of progression-free survival and overall survival that excluded people who had bevacizumab combination treatments in the standard care arm. The ERG and clinical experts noted that the proportion of the population included in the company's scenario was small (32% of the trial population) and therefore excluded some data, and also broke the trial's randomisation. So, the committee did not consider the scenario further. The committee appreciated that the standard care arm included multiple treatments. So, pooling these treatments across a population meant a blended comparator was being used to determine the efficacy results of pembrolizumab. The committee was aware that the components of the blended comparator have different degrees of benefit, and that using a blended comparator approach averages the clinical effectiveness of the included treatments. The committee agreed that including a blended comparator in the estimates of clinical effectiveness makes the results more uncertain. It concluded that bevacizumab likely offers a small benefit to patients, so the trial may underestimate the relative effect of pembrolizumab compared with standard care. But, it might also overestimate the relative effect because some people in the control arm may not have had the best treatment for their condition. The committee concluded that there is some uncertainty in the results.
## Pembrolizumab extends progression-free survival
The primary outcomes in the KEYNOTE‑177 trial were progression-free survival and overall survival. Intention-to-treat analyses showed that pembrolizumab increased progression-free survival by 40% compared with standard care (hazard ratio 0.60, 95% confidence interval 0.45 to 0.80). Results for overall survival also favoured pembrolizumab; 37% of people taking pembrolizumab died compared with 45% of people taking standard care (hazard ratio 0.77, 95% CI 0.54 to 1.09). However, the committee noted the low number of deaths and that the median follow up was 28 months at the data cut-off point, so the overall survival data were immature. In addition, the KEYNOTE‑177 trial allowed people who progressed on standard care to crossover to take pembrolizumab. The committee noted that 36% of people taking standard care crossed over to pembrolizumab and a further 23% had an alternative checkpoint inhibitor after progression. Therefore, the overall survival results were likely to underestimate the relative treatment effect of pembrolizumab compared with standard care. The committee concluded that, based on the KEYNOTE‑177 results, pembrolizumab likely extends progression-free survival compared with standard care but that the extent of any benefit on overall survival is uncertain.
## Pembrolizumab may be less effective in people with RAS-mutant disease, but results are uncertain
Company analyses of progression-free survival in subgroups from the KEYNOTE‑177 trial suggested a different effect for pembrolizumab for people with RAS-mutant disease compared with RAS wild-type. Results for people with colorectal cancer with high MSI or DNA MMR deficiency who had RAS-mutant disease showed no effect for pembrolizumab (hazard ratio 1.19, 95% CI 0.68 to 2.07). The clinical experts highlighted that there was no biological explanation for a poor response in the RAS-mutant subgroup. The company explained that the number of people with RAS-mutant disease in the subgroup analysis was small and that the confidence intervals included the possibility of a benefit. Also, the subgroup was not prespecified in the KEYNOTE‑177 trial. The committee was aware of analyses done by the regulator, the European Medicines Agency. This included Kaplan–Meier data by subgroup that appeared to show a difference in effectiveness based on RAS status. However, the committee appreciated that the licence included people with RAS-mutant tumours. Clinical experts explained that subgroup analyses of other checkpoint inhibitors had not suggested a different effect by RAS status, although the data were not for first‑line treatments. The ERG noted that 27% of the population did not have a RAS status confirmed in KEYNOTE‑177 and that these people had been excluded from the subgroup analyses. The committee recalled that treatment decisions in the NHS are determined by RAS status so treatments in KEYNOTE‑177 did not reflect standard care in the NHS. The committee concluded that there were limited data available for people with RAS-mutant disease and the subgroup analyses were not prespecified and included small sample sizes. Therefore, the effectiveness of pembrolizumab in people with RAS‑mutant disease is uncertain.
## Subsequent treatments in KEYNOTE‑177 do not reflect NHS clinical practice but may extend life
The committee recalled that over half the people in KEYNOTE‑177 randomised to the standard care arm had checkpoint inhibitors after progression. The committee also noted 24% of those in the standard care arm who had subsequent treatment with pembrolizumab did so before disease progression. The committee was aware that checkpoint inhibitors are not available at second line and beyond in the NHS and may extend life compared with current clinical practice. The clinical experts also explained that the KEYNOTE‑177 trial included cetuximab as a subsequent therapy, which is not recommended after first line in the NHS. A further consideration was raised that people in the pembrolizumab arm who stopped treatment before 2 years could have a further 17 cycles after progression. Clinical experts explained that the number of people who were retreated was less than 3%. The committee concluded that subsequent treatments in the KEYNOTE‑177 trial did not reflect those in the NHS, but may extend life, which may underestimate the relative effectiveness of pembrolizumab. The committee agreed that the modelling of cost effectiveness should reflect this.
## Pembrolizumab is likely better tolerated than standard care, but the company has not included some rare serious adverse events in the economic modelling
In KEYNOTE‑177, a greater proportion of people had a serious adverse event in the standard care arm compared with the pembrolizumab arm (52% and 41%, respectively). The committee heard from patient experts that the side effects of chemotherapy had significantly impacted their quality of life, causing fatigue, sickness and diarrhoea for 1 week after every cycle. In contrast, they had experienced minimal side effects during treatment with pembrolizumab. Although a patient expert developed immune-based complications including rheumatoid arthritis and ulcerative colitis, he preferred these to the adverse effects of standard care. The committee noted that the proportion of people who had at least 1 adverse event of any severity when taking pembrolizumab in the KEYNOTE‑177 trial was high (97% for pembrolizumab compared with 99% for standard care). It heard that the company had included in its model only adverse events that were graded severe and occurred in over 5% of people. The clinical lead for the Cancer Drugs Fund raised concerns that immunotherapies can cause serious adverse events in a small number of people, and that, using the company's approach, these would not have been captured in the economic modelling. The committee concluded that pembrolizumab has an acceptable adverse event profile, but that the company omitted some rare serious adverse events from its economic modelling.
# Indirect treatment comparison
## FOLFOX, FOLFIRI and CAPOX are equally effective
There are no head-to-head trials that compare pembrolizumab with relevant comparators: CAPOX and panitumumab with FOLFOX or FOLFIRI. Therefore, the company compared them indirectly using a network meta-analysis. The committee recalled that the KEYNOTE‑177 standard care arm pooled all treatments, so there were no data in the high MSI or DNA MMR‑deficient population specific to each comparator, including FOLFOX or FOLFIRI. It also noted that the company's network meta-analysis assumed that FOLFOX and FOLFIRI were clinically equivalent. The committee noted that NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer assumed that FOLFOX and FOLFIRI were broadly equivalent. In their base cases, both the ERG and company also assumed that the effectiveness of CAPOX was equivalent to FOLFOX and FOLFIRI. This was because results from the literature reported similar median progression-free survival and overall survival for CAPOX compared with FOLFOX and FOLFIRI. Clinical experts explained that FOLFOX, FOLFIRI and CAPOX treatments are interchangeable and, although each have different advantages and disadvantages, they can be considered equivalent. The committee agreed with the company assumption that the standard care arm of KEYNOTE‑177 could be used for the clinical efficacy of CAPOX. It concluded that FOLFOX, FOLFIRI and CAPOX were equally effective.
## Cetuximab and panitumumab are equally effective
The committee recalled that people with RAS wild-type colorectal cancer would have cetuximab or panitumumab in combination with chemotherapy. The committee was aware that previous appraisals in this area had explored the efficacy of cetuximab and panitumumab. The results of a network meta‑analysis from NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer suggested that there was no significant difference between cetuximab with FOLFOX and panitumumab with FOLFOX and the clinical lead for the Cancer Drugs Fund believed that they should be considered equivalent. The committee concluded that cetuximab and panitumumab are equally effective.
## A network meta-analysis is needed to estimate the relative effectiveness of cetuximab or panitumumab compared with pembrolizumab
The committee recalled the standard care arm in the KEYNOTE‑177 trial included cetuximab, but not panitumumab. It noted that only 12% of participants had cetuximab with FOLFOX or FOLFIRI, and recalled that the trial did not determine RAS status for all participants so treatment may not reflect practice in the NHS. It concluded that an alternative source of evidence would be needed to estimate the relative effectiveness of pembrolizumab compared with cetuximab or panitumumab.
## The company's network meta-analysis is appropriate to assess the treatment effect of pembrolizumab compared with panitumumab or cetuximab with FOLFOX or FOLFIRI
The company used a network meta-analysis to compare progression-free survival and overall survival for pembrolizumab compared with panitumumab with FOLFOX. In its submission, the company stated that, because the hazard plots for pembrolizumab and standard care from KEYNOTE‑177 crossed, proportional hazards could not be assumed. Therefore, a network meta‑analysis with constant hazard ratios was not appropriate. Instead, the company fit parametric curves to data from both arms of KEYNOTE‑177 to estimate time-varying treatment effects. This generated estimates of the probabilities of progression-free and overall survival at 6, 9, 12, 18 and 24 months from randomisation. The company used pooled data from the KEYNOTE‑177 control arm as the common comparator in its network meta-analysis. To compare panitumumab with FOLFOX against standard care, it used the PRIME study. PRIME is an open-label phase 3 trial that enrolled people with metastatic colorectal cancer. The company used the treatment effect from the RAS wild-type subgroup in PRIME to represent the population who would have panitumumab combinations in NHS clinical practice. The committee noted that the comparison with standard care used the whole population from KEYNOTE‑177, not the RAS wild-type subgroup, so the results are uncertain. Also, no data were available from PRIME that were specific to the high MSI or DNA MMR‑deficient population. Because panitumumab with FOLFOX is only used in people with RAS wild-type colorectal cancer in the NHS, the committee would have preferred to see the RAS wild-type subgroup from KEYNOTE‑177 standard care used in the comparison. However, the committee acknowledged that the results of the subgroup analyses suggested that pembrolizumab improves progression-free and overall survival compared with panitumumab plus FOLFOX. The committee recalled that panitumumab and cetuximab combinations were broadly equivalent. It concluded that the company's network meta‑analysis was appropriate and pembrolizumab was clinically effective compared with panitumumab or cetuximab with FOLFOX or FOLFIRI.
# Cost effectiveness
## The company's model is appropriate for decision making
The company's original submission included 2 models. They were a 3‑state partitioned survival model (progression-free, progressed disease and death) and a 5‑state semi-Markov model that included additional post-surgery health states (progression-free and progressed disease). At clarification, the company updated the semi-Markov model to remove the post-surgery states on the ERG's request. This was because under 10% of people had surgery in KEYNOTE‑177 and the company had assumed that having surgery did not affect overall and progression-free survival. The company calculated the probability of being in a health state using the progression-free survival, time to progression or post‑progression survival from KEYNOTE‑177, and applied treatment effects from the network meta‑analysis to standard care results for panitumumab with FOLFOX. The model cycle length was 1 week, and the time horizon was 40 years. The ERG highlighted that the partitioned survival model included the overall survival data from KEYNOTE‑177. The committee acknowledged that both models submitted by the company appeared broadly consistent but recalled its concern that the overall survival data were likely to be biased. For this reason, it agreed that the company's semi-Markov model was most appropriate for decision making.
# Survival extrapolations
## A piece-wise approach is appropriate for modelling progression-free survival and time to progression
Analysis suggested that the hazard rates from KEYNOTE‑177 were not constant over time. For this reason, the company used a 2‑piece model to extrapolate progression-free survival and time to progression. The 2‑piece model used Kaplan–Meier data until week 20, then parametric distributions to extrapolate beyond the trial follow up. This was based on clinical advice and visual inspection. In addition, because the assumption of proportional hazards did not hold for the KEYNOTE‑177 trial, the company fitted independent curves to the data. Both the ERG and company's final base cases used the Weibull curve to extrapolate progression-free survival and time to progression after 20 weeks, to account for the increasing hazard in the standard care arm. Clinical experts expected 5% to 10% of people having standard care and 30% to 50% of people having pembrolizumab to be progression-free at 5 years. These estimates aligned with the company's preferred extrapolations. The committee noted that the company's choice of the Weibull curve was conservative because it predicted that fewer people would be progression-free over the modelled time horizon compared with most other distributions. The company explored different distributions and cut-off points from which to transition from observed to modelled data, but the committee noted that these scenarios had limited impact on the cost‑effectiveness results. It concluded that a 2‑piece model using the Weibull distribution after 20 weeks is appropriate to extrapolate progression-free survival and time to progression.
## The company's use of equal post-progression survival for all comparators is likely conservative, but unlikely to reflect clinical practice
The company used the post-progression survival extrapolated from KEYNOTE‑177 data to calculate the probability of moving from progressed disease to death in the model. Because of the high proportion of people in the standard care arm who had subsequent treatment with checkpoint inhibitors, the company assumed that post‑progression survival for all comparators equalled that for pembrolizumab. The ERG explained that this approach was conservative because not all people who had standard care went on to have checkpoint inhibitors, but were modelled to have the post‑progression survival benefits of pembrolizumab. Clinical experts were concerned that the company's assumption did not reflect outcomes they expected to see in clinical practice, because people who had pembrolizumab would likely have different outcomes after progression than people who had standard care. This was because people whose condition responded to pembrolizumab could have a prolonged response, which was unlikely with standard care, and was associated with improved overall survival and reduced need for subsequent therapies over a person's lifetime. The committee considered that this disease pathway may be better represented by the pembrolizumab progression-free survival curves, which gradually converge with overall survival curves, reflecting that disease progression is not expected to occur in some long-term survivors. The committee recalled its earlier conclusion that overall survival from KEYNOTE‑177 was likely biased because over 50% of the standard care arm had had a subsequent checkpoint inhibitor after progression. It noted that the company had presented analyses that attempted to adjust for treatment switching. However, the company's assumption of equal post-progression survival for all treatments meant it was unnecessary to use these analyses in the economic modelling. It concluded that the company's use of equal post-progression survival for all comparators is likely to be a conservative assumption that avoids using biased overall survival data, but may not reflect what is seen in clinical practice.
# Health related quality of life
## The company's utilities are appropriate for decision making with exceptions
In its base case, the company used utility values derived from the EQ‑5D‑3L health questionnaires collected in the KEYNOTE‑177 clinical trial. The company used utilities based on whether disease had yet to progress or had already progressed in its base-case model. It estimated utility values for pembrolizumab and standard care in the progression-free health state separately and used the utility value from standard care for all comparators. Clinical experts agreed that it was plausible that people taking pembrolizumab would have a higher quality of life than people taking chemotherapy, because pembrolizumab was given as a shorter infusion and needed fewer hospital visits and had fewer adverse events. However, the company also included a disutility for adverse events in the progression-free health state. It calculated the disutility from the difference between the utility for the progression-free health state values for people with and without severe adverse events, which it then adjusted for the duration of adverse events. The ERG disagreed with including a disutility for adverse events, stating that adverse events were double counted. This was because the company's progression-free utility values did not distinguish between people who did and did not have a severe adverse event in KEYNOTE‑177. The committee did not necessarily agree with the ERG and noted that adverse events may have been included in the treatment-specific utility values only if they occurred at the time of completing the questionnaire. The committee also recalled that the company did not include rare serious adverse events in its model. Yet, it noted that modelling a disutility for adverse events had limited impact on the cost-effectiveness results. The committee concluded that the company's use of treatment-specific utilities is appropriate for decision making and including a disutility for adverse events makes, as modelled, little difference to the cost-effectiveness results.
# Resource use in the model
## Pembrolizumab would be given every 6 weeks in the NHS, but this may underestimate costs and resource use
The committee understood that the marketing authorisation for pembrolizumab included a 200 mg once every 3 weeks and 400 mg once every 6 weeks regimen. The Cancer Drugs Fund clinical lead confirmed that the 2 dosing regimens would be expected to be equally effective. Clinical experts explained that, in general, clinicians would prefer to give pembrolizumab every 6 weeks, for patient convenience and to limit NHS resource use. Also, they would only need monitoring for liver dysfunction every 6 weeks. However, the committee also heard that clinicians would initially give pembrolizumab every 3 weeks until they confirmed how well a person tolerated it and how the condition responded to treatment (expected to be around 3 to 6 months from starting treatment). The committee noted that the company and ERG's base cases modelled pembrolizumab as being given every 6 weeks; therefore the costs of administration and resource use for pembrolizumab would be higher in clinical practice. The committee concluded that after an initial period of 3‑weekly administration, pembrolizumab would be given every 6 weeks, and that the model may underestimate costs and resource use.
## It is appropriate to apply a 2-year stopping rule for pembrolizumab
In the economic model, the company assumed that clinicians would stop treatment with pembrolizumab after 2 years (equating to 35 3‑weekly cycles of 200 mg), whether or not a person's condition had progressed. This was in line with the KEYNOTE‑177 protocol. However, the ERG noted that the summary of product characteristics for pembrolizumab specified that pembrolizumab could be used until disease progression or unacceptable toxicity. Clinical experts confirmed that in clinical practice, they would stop treatment with pembrolizumab after a maximum of 35 3-weekly cycles of 200 mg in people who had not progressed. This was to align with the clinical trial evidence and because of the belief that limited benefit would be gained from treatment beyond 2 years. The clinical lead for the Cancer Drugs Fund confirmed that, if a stopping rule were implemented, pembrolizumab would not be funded beyond 2 years. However, because people in KEYNOTE‑177 had 200 mg of pembrolizumab every 3 weeks, people in the NHS may not receive the full 35 cycles given in the trial within 2 years, because of 6-weekly administration using the higher dosage (400 mg; see section 3.23). It also heard from patient experts that they had both chosen to stop treatment early, despite continued response and the possibility of up to 1 year's further treatment being available. For people in the KEYNOTE‑177 trial who stopped their treatment early because they achieved a complete response, they could have 17 more 3-weekly cycles of pembrolizumab (200 mg) upon progression. However, the company confirmed that retreatment was not included in the licence for pembrolizumab. The committee concluded that it was appropriate to apply a 2-year stopping rule for pembrolizumab (given 3‑ or 6‑weekly).
# Costs in the economic model
## Costs of standard care in the NHS lie between the company's and ERG's estimates
The committee recalled that around 70% of people in the KEYNOTE‑177 standard care arm had a combination that contained bevacizumab, which is not available in NHS clinical practice (see section 3.10). To account for this, the company replaced the costs of bevacizumab with the costs for cetuximab combinations and assumed they were equal. The ERG was concerned that, unlike bevacizumab, cetuximab is available in the NHS only for people with RAS wild-type disease. One clinical expert estimated that less than half of people with untreated metastatic colorectal cancer with high MSI or DNA MMR deficiency would be expected to have RAS wild-type disease and therefore have cetuximab in clinical practice. Hence, the ERG believed that the company overestimated the costs for standard care. The ERG's base case assumed that half the costs for standard care in the NHS came from the NHS price for FOLFOX and the other half came from the cost for FOLFIRI. The committee noted that this approach underestimated the true costs in the NHS, as the ERG did not include any costs for cetuximab in its base case. Also, the ERG did not adjust the clinical effectiveness of standard care to account for the worse overall survival with FOLFOX and FOLFIRI compared with bevacizumab or cetuximab. The committee noted that the ERG's assumption was conservative, but that it would have liked to have seen a scenario that included cetuximab in the costs for standard care. The committee also recalled that neither the company nor ERG had included capecitabine or FOLFOXIRI as relevant comparators in the model. However, it noted that the clinical effectiveness results compared with standard care included a blended comparator. It recalled its conclusions about the efficacy of blended comparators and noted that similar assumptions applied to the costs. The committee recalled the clinical experts' description of standard care included a small proportion who would have capecitabine monotherapy, which would have lower costs than FOLFOX or FOLFIRI, and a small proportion who would have FOLFOXIRI, which would have higher costs. The committee concluded that the costs of standard care in the NHS are likely between the company and ERG's estimates but that neither reflect the true costs in the NHS. It agreed that it would consider both the ERGs and the company's scenarios in its decision making.
# Cost-effectiveness estimates
## Pembrolizumab is cost effective against all comparators
Because of confidential commercial arrangements for pembrolizumab and comparators, none of the cost-effectiveness results are reported here. The committee agreed that its preferred assumptions to compare pembrolizumab with comparators included:
the full KEYNOTE‑177 population for treatment effect
a 2-year stopping rule
treatment effect from KEYNOTE‑177 standard care for CAPOX, FOLFIRI and FOLFOX
treatment effect from the company's network meta-analysis for both panitumumab and cetuximab combination therapy
different utility values for pembrolizumab compared with current treatments, and a disutility adjustment in the progression-free health state
administration and consultant visits every 6 weeks.The committee considered the incremental cost-effectiveness ratio (ICER) for both the ERG and company's base cases for pembrolizumab compared with FOLFOX, FOLFIRI, FOLFOXIRI, CAPOX and capecitabine, which differed only in the approach to costing standard care. The ERG's base case, which used standard care costs from FOLFOX and FOLFIRI, increased the ICER compared with the company's assumption that replaced costs of bevacizumab with costs of cetuximab for 70% of the population. It recalled that the cost of standard care in the NHS was likely between the ERG and company's base cases but noted that all estimates of cost effectiveness for this comparison were less than £20,000 per quality adjusted life year (QALY) gained. For the comparison with panitumumab, the company and ERG base cases used identical assumptions and ICERs were less than £20,000 per QALY gained. The committee recalled that pembrolizumab would initially be given every 3 weeks in the NHS and noted that the company and ERG base cases assumed 6-weekly administration. So, the ICER for pembrolizumab in the NHS would be higher against all comparators but would remain below £20,000 per QALY gained. It concluded that pembrolizumab is a cost-effective use of resources in the NHS against all comparators.
# Other factors
## Pembrolizumab is a step change for people with metastatic colorectal cancer with high MSI or DNA MMR deficiency, and the model captures all benefits
The company, clinical experts and patient experts stated pembrolizumab represents a step change in treatment for people with metastatic colorectal cancer with high MSI or DNA MMR deficiency and that there is high unmet need for this population. The committee recalled that there are currently no targeted treatments specific to colorectal cancer with high MSI or DNA MMR deficiency and that these people have worse outcomes than for microsatellite stable disease. The company and clinical experts explained that treatment with pembrolizumab was less toxic, given less frequently and had a shorter administration then comparators. The committee noted that the treatment is not a chemotherapy and has the potential to be curative in some people, which would transform their quality of life. It concluded that pembrolizumab is a step change for people with metastatic colorectal cancer with high MSI or DNA MMR deficiency, and all benefits are captured in the cost-effectiveness estimates.
## The recommendation takes potential equality issues into account
The committee noted an equality concern around testing for high MSI or DNA MMR‑deficient disease. Although routinely funded by NHS England (see section 3.8), local uptake and turnaround times for high MSI or DNA MMR deficiency testing are inconsistent throughout the NHS. Clinical experts raised concerns that some people would not be tested as standard, so would not be able to access pembrolizumab if recommended. The committee considered that all people should have testing for high MSI or DNA MMR deficiency when first diagnosed, in line with NICE's diagnostic guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer. It was reassured by the clinical lead for the Cancer Drugs Fund that, should pembrolizumab be recommended and high MSI or DNA MMR deficiency testing inform treatment decisions, it would become routine and timely throughout the NHS. Clinical experts also noted that the current guidance states that clinicians should not wait for results before starting treatment. This could mean people who needed treatment immediately were starting initially on combination chemotherapy and therefore were no longer eligible for pembrolizumab at first line. The committee considered this but had heard from the clinical lead of the Cancer Drugs Fund that testing should be timely. It was aware that it can only make recommendations within the marketing authorisation and any recommendation to switch treatment from chemotherapy to pembrolizumab was therefore outside of the committee's remit. The committee concluded that it had considered all equalities issues and its recommendation did not need changes.
# Conclusion
## Pembrolizumab is recommended for routine commissioning
The committee agreed that the most plausible ICERs for pembrolizumab compared with all relevant comparators were within what NICE normally considers to be an acceptable use of NHS resources. It therefore concluded that it could recommend pembrolizumab for routine commissioning as an option for untreated metastatic colorectal cancer with high MSI or MMR deficiency.
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{'Recommendations': "Pembrolizumab is recommended as an option for untreated metastatic colorectal cancer with high microsatellite instability (MSI) or mismatch repair (MMR) deficiency in adults, only if:\n\npembrolizumab is stopped after 2\xa0years and no documented disease progression, and\n\nthe company provides pembrolizumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with pembrolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with untreated metastatic colorectal cancer that has high MSI or MMR deficiency are usually offered combination chemotherapy including FOLFOX, FOLFIRI or CAPOX. For RAS wild-type cancer, cetuximab or panitumumab is added to FOLFOX or FOLFIRI.\n\nClinical trial evidence shows that pembrolizumab increases the time until the condition gets worse compared with current treatments. Pembrolizumab may also be more effective at extending life, but the evidence is limited and in the trial people had subsequent treatments that are not available in the NHS. So, it is uncertain how much benefit it offers over a person's lifetime.\n\nThere is no evidence from clinical trials that use pembrolizumab for more than 2\xa0years of treatment so the benefit beyond this duration is uncertain.\n\nThe cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So, pembrolizumab is recommended.", 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda; Merck Sharp and Dohme) has a marketing authorisation as monotherapy 'for the first-line treatment of metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of pembrolizumab is £2,630 per 100-mg vial (excluding VAT; BNF online, accessed March\xa02021). The cost of a single administration is £5,260. This represents 3\xa0weeks of treatment.\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck Sharp and Dohme, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nSubsequent treatment costs in the model should not include cetuximab because it is not recommended after first-line treatment in the NHS.\n\nTime-on-treatment for panitumumab with FOLFOX in the model should equal time-on-treatment for standard care in KEYNOTE‑177.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see ERG report, table 1, page 18), and took these into account in its decision making. It discussed issues 1 to 5, which were outstanding after the technical engagement stage.\n\n# The condition\n\n## There is an unmet need for treatments for high microsatellite instability or mismatch repair deficiency metastatic colorectal cancer\n\nColorectal cancer is a malignant tumour arising from the lining of the large intestine (colon and rectum). Mutations can cause microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency in some metastatic colorectal cancer cells. DNA MMR corrects errors that occur during DNA replication, so problems with DNA MMR can lead to mutations in the microsatellites (repetitive DNA sequences). This causes them to become unstable, resulting in cancerous tumours with high MSI. High MSI or DNA\xa0MMR deficiency occurs in around 4% of metastatic colorectal cancer. It is associated with a poorer prognosis and a greater risk of death than metastatic colorectal cancer without MSI. There are currently no specific treatments for this type of colorectal cancer, so people are offered the same treatment whether or not their colorectal cancer has high MSI or DNA MMR deficiency. The committee concluded that there is an unmet need for treatments for this condition.\n\n## People with the condition and clinicians would welcome new treatment options\n\nThe patient experts explained that a diagnosis of metastatic colorectal cancer with high MSI or DNA MMR deficiency affects quality of life both physically and psychologically. They highlighted that current treatments were highly toxic, which could lead to hospital admissions during treatment and permanent adverse effects like nerve damage. They explained that having progressed on several different treatments, their cancers had responded well to pembrolizumab, which was life changing. The committee noted that pembrolizumab, a checkpoint inhibitor, worked in a different way to chemotherapy. It heard that people appreciated the faster and less frequent administration of pembrolizumab, and preferable adverse effects compared with standard care. A clinical expert explained that, with a more effective treatment, there was potential that a patient's condition would respond well enough for them to have surgery with curative intent. The committee concluded that people with the condition and clinicians would welcome new treatment options.\n\n# The treatment pathway\n\n## Current standard care for metastatic colorectal cancer depends on fitness, RAS mutation, clinician judgement and the patient's informed preferences\n\nClinical experts explained that there are several first-line treatment options for metastatic colorectal cancer. Individualised treatment pathways are common and consider potential impacts of first-line treatment on available subsequent therapies because of the limited number of options for this cancer. Clinical experts explained that, because of the high toxicity of many standard care treatments, a patient's clinical status and performance status (their ability to complete daily tasks and ordinary activities), along with any comorbidities, would impact clinicians' judgement on the most suitable treatments. For example, people who are less frail would be offered more intense combinations according to the clinical evidence. A patient expert highlighted that people might also decline some chemotherapy regimens to avoid toxic side effects. The committee noted that first‑line treatment options are limited by whether a mutation in the RAS gene is present. The committee concluded that current standard care for metastatic colorectal cancer with high MSI or DNA MMR deficiency depends on fitness, RAS mutation status, clinician judgement and the person's informed preferences.\n\n## Most people have combination chemotherapy at first line\n\nClinical experts explained that most people with untreated colorectal cancer have combination chemotherapy, usually with: folinic acid; fluorouracil (5\xa0FU) and oxaliplatin (known as FOLFOX); 5\xa0FU, folinic acid and irinotecan (known as FOLFIRI); or capecitabine and oxaliplatin (known as CAPOX). Clinical experts discussed the effectiveness of these regimens, noting that they are used interchangeably in clinical practice and are considered equivalent. The committee heard that, to increase the chance of good clinical outcomes, a small proportion of people with RAS‑mutant disease would have FOLFOXIRI (folinic acid, 5\xa0FU, oxaliplatin and irinotecan). But, because of the higher toxicity of the combination, this would only be offered to fitter people. The committee concluded that FOLFOX, FOLFIRI, FOLFOXIRI and CAPOX were relevant comparators at first line.\n\n## People with RAS wild-type colorectal cancer would have cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI\n\nClinical experts explained that people with cancers with no mutation in the RAS gene (referred to as RAS wild-type) would be offered an epidermal growth factor receptor (EGFR) inhibitor in addition to chemotherapy with FOLFOX or FOLFIRI. This is in line with NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer. The committee heard that cetuximab is used only in tumours that also express the EGFR protein, and noted that this is not a requirement for panitumumab. Clinical experts explained that, if recommended, pembrolizumab would be the preferred option for people with colorectal cancer regardless of RAS status, because of the poor outcomes for people with high MSI or DNA\xa0MMR‑deficient disease. The clinical experts acknowledged this meant EGFR inhibitors would not be used for this population because their recommendation is limited to first‑line treatment. The committee concluded that, in current clinical practice, people with RAS wild-type tumours would have cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI.\n\n## Capecitabine is used less commonly than other treatments, but is a relevant comparator for some people\n\nAlthough listed in the NICE scope as a comparator, the company did not include capecitabine, raltitrexed or tegafur with uracil in its submission. NICE's technology appraisal guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer recommends capecitabine monotherapy as an option for untreated metastatic colorectal cancer. Clinical experts explained that capecitabine is used only in people with a poor performance status (Eastern Cooperative Oncology Group [ECOG] score of 2 or more), who are likely to be frail and so cannot tolerate the toxicities of combination chemotherapy. Clinicians noted that they would be unlikely to use a monotherapy to treat high MSI or DNA\xa0MMR‑deficient colorectal cancer because of the poor outcomes of monotherapy and poor prognosis in this population. However, capecitabine monotherapy would be appropriate if the person had a very low performance status. One clinical expert estimated that capecitabine would be used in less than 10% of people with high MSI or DNA\xa0MMR‑deficient tumours. However, the committee considered that, although likely to be small in clinical practice, the population who would have capecitabine would also be able to have pembrolizumab. It was aware that the summary of product characteristics for pembrolizumab allows treatment of people with an ECOG status of 2 and above 'after careful consideration of the potential increased risk' and 'with appropriate clinical management'. The committee concluded that capecitabine may be used less commonly than other treatment options but is a relevant comparator for a small group of people and may be less effective than combination therapies.\n\n## Tegafur with uracil and raltitrexed are not relevant comparators for pembrolizumab\n\nThe company excluded tegafur with uracil and raltitrexed as comparators in its submission, despite having been included in the NICE scope. Clinical experts confirmed that tegafur with uracil was not available in the NHS in England and did not consider it relevant as a comparator. The committee also heard that although raltitrexed is used in clinical practice, it is reserved for specific indications, such as people with a history of heart disease or who develop angina on 5\xa0FU‑based chemotherapy. However, because it has a marketing authorisation for first-line use only, pembrolizumab would not be used in people who develop side effects on chemotherapy. The committee agreed that the population who would receive raltitrexed in clinical practice and could also receive pembrolizumab is negligible. It concluded that tegafur with uracil and raltitrexed are not relevant comparators for pembrolizumab in untreated metastatic colorectal cancer with high MSI or DNA MMR deficiency.\n\n# Testing\n\n## Although routinely funded, not all people newly diagnosed with colorectal cancer are tested for high MSI or DNA MMR deficiency in the NHS\n\nNICE's diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer recommends testing all people with colorectal cancer to identify DNA\xa0MMR‑deficient tumours. This can be done either by immunohistochemistry testing for MMR proteins or polymerase chain reaction for determining MSI. Clinical experts noted variation in local uptake for high MSI or DNA MMR deficiency testing across the NHS, which was supported by testimonials from the patient experts. However, the clinical lead for the Cancer Drugs Fund confirmed that this testing is routinely commissioned by NHS England. It was explained that uptake is currently low in some places, but it is increasing. They clarified that testing should be offered to all newly diagnosed people before starting treatment. The committee noted that nivolumab and pembrolizumab are already available as interim treatment options during the COVID-19 pandemic for untreated colorectal cancer with high MSI or DNA MMR deficiency. So, the committee was aware that treatment decisions in the NHS are already being made based on the results of these tests. The committee agreed that it is correct to exclude the costs of testing for high MSI or DNA MMR deficiency from the company's model, because the tests are already routinely done by the NHS. It concluded that the costs associated with pembrolizumab need not include the costs for testing for high MSI or DNA MMR deficiency. It further concluded that if pembrolizumab is used routinely, then the NHS would need to improve testing uptake in some places.\n\n# Clinical evidence\n\n## Clinical evidence for pembrolizumab comes from the KEYNOTE‑177 trial, but the control treatments used in the trial do not reflect NHS practice\n\nKEYNOTE‑177 is a multinational, open-label, randomised, phase\xa03 trial, comparing pembrolizumab with standard care. It included only people with inoperable untreated metastatic colorectal cancer with high MSI or DNA MMR deficiency. The primary outcomes were progression-free survival and overall survival. Standard care was defined by the company as investigator's choice of:\n\nFOLFOX\n\nFOLFIRI\n\ncetuximab with FOLFOX or FOLFIRI\n\nbevacizumab with FOLFOX or FOLFIRI.The company pooled data from all standard care regimens in its comparison with pembrolizumab. This means that there are no data directly comparing pembrolizumab with each separate regimen in the standard care control arm. Clinical experts explained that the control arm of KEYNOTE‑177 did not accurately reflect clinical practice in the NHS. This was because the trial excluded first-line treatment options for metastatic colorectal cancer in the NHS, including CAPOX and FOLFOXIRI, and for RAS wild-type tumours, panitumumab with FOLFOX or FOLFIRI. Moreover, the KEYNOTE‑177 trial included bevacizumab in the control arm, but NICE does not recommend bevacizumab at first line in this population (see NICE's technology appraisal guidance on bevacizumab and cetuximab for the treatment of metastatic colorectal cancer and bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer). The committee concluded that the comparators used in the trial are not entirely reflective of NHS practice.\n\n## Bevacizumab likely offers a benefit to patients, so the trial may underestimate the relative effect of pembrolizumab compared with standard care\n\nAround 70% of people randomised to standard care in KEYNOTE‑177 had bevacizumab‑containing regimens. The clinical lead from the Cancer Drugs Fund explained that bevacizumab is likely to benefit people with colorectal cancer with high MSI or DNA\xa0MMR deficiency. However, there are limited data available for this population, so the extent of any benefit is unknown. The ERG explained that, if bevacizumab were more effective than other available treatments, the results from the KEYNOTE‑177 may underestimate the relative effectiveness of pembrolizumab in the trial compared with in the NHS. A clinical expert agreed that bevacizumab is effective and noted that, unlike cetuximab and panitumumab, its use was not limited by RAS status. The committee noted that the KEYNOTE‑177 trial included some people from outside the UK and that not all of those included in the trial had the RAS status of their tumours determined before treatment. A clinical expert involved in the trial explained all UK participants had a documented RAS status and this determined their treatment options. However, he noted that some participants outside the UK with undetected RAS wild-type tumours may not have had cetuximab or panitumumab with FOLFOX or FOLFIRI as they would have in the NHS. Instead, they had bevacizumab or combination chemotherapy. The committee appreciated that this might overestimate the effectiveness of pembrolizumab relative to standard care in the trial compared with in the NHS. The committee recalled that standard care in KEYNOTE‑177 was not representative of treatment options in the NHS as bevacizumab is not available in England. The company conducted an exploratory analysis for primary outcomes of progression-free survival and overall survival that excluded people who had bevacizumab combination treatments in the standard care arm. The ERG and clinical experts noted that the proportion of the population included in the company's scenario was small (32% of the trial population) and therefore excluded some data, and also broke the trial's randomisation. So, the committee did not consider the scenario further. The committee appreciated that the standard care arm included multiple treatments. So, pooling these treatments across a population meant a blended comparator was being used to determine the efficacy results of pembrolizumab. The committee was aware that the components of the blended comparator have different degrees of benefit, and that using a blended comparator approach averages the clinical effectiveness of the included treatments. The committee agreed that including a blended comparator in the estimates of clinical effectiveness makes the results more uncertain. It concluded that bevacizumab likely offers a small benefit to patients, so the trial may underestimate the relative effect of pembrolizumab compared with standard care. But, it might also overestimate the relative effect because some people in the control arm may not have had the best treatment for their condition. The committee concluded that there is some uncertainty in the results.\n\n## Pembrolizumab extends progression-free survival\n\nThe primary outcomes in the KEYNOTE‑177 trial were progression-free survival and overall survival. Intention-to-treat analyses showed that pembrolizumab increased progression-free survival by 40% compared with standard care (hazard ratio 0.60, 95% confidence interval [CI] 0.45 to 0.80). Results for overall survival also favoured pembrolizumab; 37% of people taking pembrolizumab died compared with 45% of people taking standard care (hazard ratio 0.77, 95%\xa0CI 0.54 to 1.09). However, the committee noted the low number of deaths and that the median follow up was 28\xa0months at the data cut-off point, so the overall survival data were immature. In addition, the KEYNOTE‑177 trial allowed people who progressed on standard care to crossover to take pembrolizumab. The committee noted that 36% of people taking standard care crossed over to pembrolizumab and a further 23% had an alternative checkpoint inhibitor after progression. Therefore, the overall survival results were likely to underestimate the relative treatment effect of pembrolizumab compared with standard care. The committee concluded that, based on the KEYNOTE‑177 results, pembrolizumab likely extends progression-free survival compared with standard care but that the extent of any benefit on overall survival is uncertain.\n\n## Pembrolizumab may be less effective in people with RAS-mutant disease, but results are uncertain\n\nCompany analyses of progression-free survival in subgroups from the KEYNOTE‑177 trial suggested a different effect for pembrolizumab for people with RAS-mutant disease compared with RAS wild-type. Results for people with colorectal cancer with high MSI or DNA MMR deficiency who had RAS-mutant disease showed no effect for pembrolizumab (hazard ratio 1.19, 95%\xa0CI 0.68 to 2.07). The clinical experts highlighted that there was no biological explanation for a poor response in the RAS-mutant subgroup. The company explained that the number of people with RAS-mutant disease in the subgroup analysis was small and that the confidence intervals included the possibility of a benefit. Also, the subgroup was not prespecified in the KEYNOTE‑177 trial. The committee was aware of analyses done by the regulator, the European Medicines Agency. This included Kaplan–Meier data by subgroup that appeared to show a difference in effectiveness based on RAS status. However, the committee appreciated that the licence included people with RAS-mutant tumours. Clinical experts explained that subgroup analyses of other checkpoint inhibitors had not suggested a different effect by RAS status, although the data were not for first‑line treatments. The ERG noted that 27% of the population did not have a RAS status confirmed in KEYNOTE‑177 and that these people had been excluded from the subgroup analyses. The committee recalled that treatment decisions in the NHS are determined by RAS status so treatments in KEYNOTE‑177 did not reflect standard care in the NHS. The committee concluded that there were limited data available for people with RAS-mutant disease and the subgroup analyses were not prespecified and included small sample sizes. Therefore, the effectiveness of pembrolizumab in people with RAS‑mutant disease is uncertain.\n\n## Subsequent treatments in KEYNOTE‑177 do not reflect NHS clinical practice but may extend life\n\nThe committee recalled that over half the people in KEYNOTE‑177 randomised to the standard care arm had checkpoint inhibitors after progression. The committee also noted 24% of those in the standard care arm who had subsequent treatment with pembrolizumab did so before disease progression. The committee was aware that checkpoint inhibitors are not available at second line and beyond in the NHS and may extend life compared with current clinical practice. The clinical experts also explained that the KEYNOTE‑177 trial included cetuximab as a subsequent therapy, which is not recommended after first line in the NHS. A further consideration was raised that people in the pembrolizumab arm who stopped treatment before 2\xa0years could have a further 17\xa0cycles after progression. Clinical experts explained that the number of people who were retreated was less than 3%. The committee concluded that subsequent treatments in the KEYNOTE‑177 trial did not reflect those in the NHS, but may extend life, which may underestimate the relative effectiveness of pembrolizumab. The committee agreed that the modelling of cost effectiveness should reflect this.\n\n## Pembrolizumab is likely better tolerated than standard care, but the company has not included some rare serious adverse events in the economic modelling\n\nIn KEYNOTE‑177, a greater proportion of people had a serious adverse event in the standard care arm compared with the pembrolizumab arm (52% and 41%, respectively). The committee heard from patient experts that the side effects of chemotherapy had significantly impacted their quality of life, causing fatigue, sickness and diarrhoea for 1\xa0week after every cycle. In contrast, they had experienced minimal side effects during treatment with pembrolizumab. Although a\xa0patient expert developed immune-based complications including rheumatoid arthritis and ulcerative colitis, he preferred these to the adverse effects of standard care. The committee noted that the proportion of people who had at least 1\xa0adverse event of any severity when taking pembrolizumab in the KEYNOTE‑177 trial was high (97% for pembrolizumab compared with 99% for standard care). It heard that the company had included in its model only adverse events that were graded severe and occurred in over 5% of people. The clinical lead for the Cancer Drugs Fund raised concerns that immunotherapies can cause serious adverse events in a small number of people, and that, using the company's approach, these would not have been captured in the economic modelling. The committee concluded that pembrolizumab has an acceptable adverse event profile, but that the company omitted some rare serious adverse events from its economic modelling.\n\n# Indirect treatment comparison\n\n## FOLFOX, FOLFIRI and CAPOX are equally effective\n\nThere are no head-to-head trials that compare pembrolizumab with relevant comparators: CAPOX and panitumumab with FOLFOX or FOLFIRI. Therefore, the company compared them indirectly using a network meta-analysis. The committee recalled that the KEYNOTE‑177 standard care arm pooled all treatments, so there were no data in the high MSI or DNA\xa0MMR‑deficient population specific to each comparator, including FOLFOX or FOLFIRI. It also noted that the company's network meta-analysis assumed that FOLFOX and FOLFIRI were clinically equivalent. The committee noted that NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer assumed that FOLFOX and FOLFIRI were broadly equivalent. In their base cases, both the ERG and company also assumed that the effectiveness of CAPOX was equivalent to FOLFOX and FOLFIRI. This was because results from the literature reported similar median progression-free survival and overall survival for CAPOX compared with FOLFOX and FOLFIRI. Clinical experts explained that FOLFOX, FOLFIRI and CAPOX treatments are interchangeable and, although each have different advantages and disadvantages, they can be considered equivalent. The committee agreed with the company assumption that the standard care arm of KEYNOTE‑177 could be used for the clinical efficacy of CAPOX. It concluded that FOLFOX, FOLFIRI and CAPOX were equally effective.\n\n## Cetuximab and panitumumab are equally effective\n\nThe committee recalled that people with RAS wild-type colorectal cancer would have cetuximab or panitumumab in combination with chemotherapy. The committee was aware that previous appraisals in this area had explored the efficacy of cetuximab and panitumumab. The results of a network meta‑analysis from NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer suggested that there was no significant difference between cetuximab with FOLFOX and panitumumab with FOLFOX and the clinical lead for the Cancer Drugs Fund believed that they should be considered equivalent. The committee concluded that cetuximab and panitumumab are equally effective.\n\n## A network meta-analysis is needed to estimate the relative effectiveness of cetuximab or panitumumab compared with pembrolizumab\n\nThe committee recalled the standard care arm in the KEYNOTE‑177 trial included cetuximab, but not panitumumab. It noted that only 12% of participants had cetuximab with FOLFOX or FOLFIRI, and recalled that the trial did not determine RAS status for all participants so treatment may not reflect practice in the NHS. It concluded that an alternative source of evidence would be needed to estimate the relative effectiveness of pembrolizumab compared with cetuximab or panitumumab.\n\n## The company's network meta-analysis is appropriate to assess the treatment effect of pembrolizumab compared with panitumumab or cetuximab with FOLFOX or FOLFIRI\n\nThe company used a network meta-analysis to compare progression-free survival and overall survival for pembrolizumab compared with panitumumab with FOLFOX. In its submission, the company stated that, because the hazard plots for pembrolizumab and standard care from KEYNOTE‑177 crossed, proportional hazards could not be assumed. Therefore, a network meta‑analysis with constant hazard ratios was not appropriate. Instead, the company fit parametric curves to data from both arms of KEYNOTE‑177 to estimate time-varying treatment effects. This generated estimates of the probabilities of progression-free and overall survival at 6, 9, 12, 18 and 24\xa0months from randomisation. The company used pooled data from the KEYNOTE‑177 control arm as the common comparator in its network meta-analysis. To compare panitumumab with FOLFOX against standard care, it used the PRIME study. PRIME is an open-label phase\xa03 trial that enrolled people with metastatic colorectal cancer. The company used the treatment effect from the RAS wild-type subgroup in PRIME to represent the population who would have panitumumab combinations in NHS clinical practice. The committee noted that the comparison with standard care used the whole population from KEYNOTE‑177, not the RAS wild-type subgroup, so the results are uncertain. Also, no data were available from PRIME that were specific to the high MSI or DNA\xa0MMR‑deficient population. Because panitumumab with FOLFOX is only used in people with RAS wild-type colorectal cancer in the NHS, the committee would have preferred to see the RAS wild-type subgroup from KEYNOTE‑177 standard care used in the comparison. However, the committee acknowledged that the results of the subgroup analyses suggested that pembrolizumab improves progression-free and overall survival compared with panitumumab plus FOLFOX. The committee recalled that panitumumab and cetuximab combinations were broadly equivalent. It concluded that the company's network meta‑analysis was appropriate and pembrolizumab was clinically effective compared with panitumumab or cetuximab with FOLFOX or FOLFIRI.\n\n# Cost effectiveness\n\n## The company's model is appropriate for decision making\n\nThe company's original submission included 2\xa0models. They were a 3‑state partitioned survival model (progression-free, progressed disease and death) and a 5‑state semi-Markov model that included additional post-surgery health states (progression-free and progressed disease). At clarification, the company updated the semi-Markov model to remove the post-surgery states on the ERG's request. This was because under 10% of people had surgery in KEYNOTE‑177 and the company had assumed that having surgery did not affect overall and progression-free survival. The company calculated the probability of being in a health state using the progression-free survival, time to progression or post‑progression survival from KEYNOTE‑177, and applied treatment effects from the network meta‑analysis to standard care results for panitumumab with FOLFOX. The model cycle length was 1\xa0week, and the time horizon was 40\xa0years. The ERG highlighted that the partitioned survival model included the overall survival data from KEYNOTE‑177. The committee acknowledged that both models submitted by the company appeared broadly consistent but recalled its concern that the overall survival data were likely to be biased. For this reason, it agreed that the company's semi-Markov model was most appropriate for decision making.\n\n# Survival extrapolations\n\n## A piece-wise approach is appropriate for modelling progression-free survival and time to progression\n\nAnalysis suggested that the hazard rates from KEYNOTE‑177 were not constant over time. For this reason, the company used a 2‑piece model to extrapolate progression-free survival and time to progression. The 2‑piece model used Kaplan–Meier data until week 20, then parametric distributions to extrapolate beyond the trial follow up. This was based on clinical advice and visual inspection. In addition, because the assumption of proportional hazards did not hold for the KEYNOTE‑177 trial, the company fitted independent curves to the data. Both the ERG and company's final base cases used the Weibull curve to extrapolate progression-free survival and time to progression after 20\xa0weeks, to account for the increasing hazard in the standard care arm. Clinical experts expected 5% to 10% of people having standard care and 30% to 50% of people having pembrolizumab to be progression-free at 5\xa0years. These estimates aligned with the company's preferred extrapolations. The committee noted that the company's choice of the Weibull curve was conservative because it predicted that fewer people would be progression-free over the modelled time horizon compared with most other distributions. The company explored different distributions and cut-off points from which to transition from observed to modelled data, but the committee noted that these scenarios had limited impact on the cost‑effectiveness results. It concluded that a 2‑piece model using the Weibull distribution after 20\xa0weeks is appropriate to extrapolate progression-free survival and time to progression.\n\n## The company's use of equal post-progression survival for all comparators is likely conservative, but unlikely to reflect clinical practice\n\nThe company used the post-progression survival extrapolated from KEYNOTE‑177 data to calculate the probability of moving from progressed disease to death in the model. Because of the high proportion of people in the standard care arm who had subsequent treatment with checkpoint inhibitors, the company assumed that post‑progression survival for all comparators equalled that for pembrolizumab. The ERG explained that this approach was conservative because not all people who had standard care went on to have checkpoint inhibitors, but were modelled to have the post‑progression survival benefits of pembrolizumab. Clinical experts were concerned that the company's assumption did not reflect outcomes they expected to see in clinical practice, because people who had pembrolizumab would likely have different outcomes after progression than people who had standard care. This was because people whose condition responded to pembrolizumab could have a prolonged response, which was unlikely with standard care, and was associated with improved overall survival and reduced need for subsequent therapies over a person's lifetime. The committee considered that this disease pathway may be better represented by the pembrolizumab progression-free survival curves, which gradually converge with overall survival curves, reflecting that disease progression is not expected to occur in some long-term survivors. The committee recalled its earlier conclusion that overall survival from KEYNOTE‑177 was likely biased because over 50% of the standard care arm had had a subsequent checkpoint inhibitor after progression. It noted that the company had presented analyses that attempted to adjust for treatment switching. However, the company's assumption of equal post-progression survival for all treatments meant it was unnecessary to use these analyses in the economic modelling. It concluded that the company's use of equal post-progression survival for all comparators is likely to be a conservative assumption that avoids using biased overall survival data, but may not reflect what is seen in clinical practice.\n\n# Health related quality of life\n\n## The company's utilities are appropriate for decision making with exceptions\n\nIn its base case, the company used utility values derived from the EQ‑5D‑3L health questionnaires collected in the KEYNOTE‑177 clinical trial. The company used utilities based on whether disease had yet to progress or had already progressed in its base-case model. It estimated utility values for pembrolizumab and standard care in the progression-free health state separately and used the utility value from standard care for all comparators. Clinical experts agreed that it was plausible that people taking pembrolizumab would have a higher quality of life than people taking chemotherapy, because pembrolizumab was given as a shorter infusion and needed fewer hospital visits and had fewer adverse events. However, the company also included a disutility for adverse events in the progression-free health state. It calculated the disutility from the difference between the utility for the progression-free health state values for people with and without severe adverse events, which it then adjusted for the duration of adverse events. The ERG disagreed with including a disutility for adverse events, stating that adverse events were double counted. This was because the company's progression-free utility values did not distinguish between people who did and did not have a severe adverse event in KEYNOTE‑177. The committee did not necessarily agree with the ERG and noted that adverse events may have been included in the treatment-specific utility values only if they occurred at the time of completing the questionnaire. The committee also recalled that the company did not include rare serious adverse events in its model. Yet, it noted that modelling a disutility for adverse events had limited impact on the cost-effectiveness results. The committee concluded that the company's use of treatment-specific utilities is appropriate for decision making and including a disutility for adverse events makes, as modelled, little difference to the cost-effectiveness results.\n\n# Resource use in the model\n\n## Pembrolizumab would be given every 6\xa0weeks in the NHS, but this may underestimate costs and resource use\n\nThe committee understood that the marketing authorisation for pembrolizumab included a 200\xa0mg once every 3\xa0weeks and 400\xa0mg once every 6\xa0weeks regimen. The Cancer Drugs Fund clinical lead confirmed that the 2\xa0dosing regimens would be expected to be equally effective. Clinical experts explained that, in general, clinicians would prefer to give pembrolizumab every 6\xa0weeks, for patient convenience and to limit NHS resource use. Also, they would only need monitoring for liver dysfunction every 6\xa0weeks. However, the committee also heard that clinicians would initially give pembrolizumab every 3\xa0weeks until they confirmed how well a person tolerated it and how the condition responded to treatment (expected to be around 3\xa0to 6\xa0months from starting treatment). The committee noted that the company and ERG's base cases modelled pembrolizumab as being given every 6\xa0weeks; therefore the costs of administration and resource use for pembrolizumab would be higher in clinical practice. The committee concluded that after an initial period of 3‑weekly administration, pembrolizumab would be given every 6\xa0weeks, and that the model may underestimate costs and resource use.\n\n## It is appropriate to apply a 2-year stopping rule for pembrolizumab\n\nIn the economic model, the company assumed that clinicians would stop treatment with pembrolizumab after 2\xa0years (equating to 35 3‑weekly cycles of 200\xa0mg), whether or not a person's condition had progressed. This was in line with the KEYNOTE‑177 protocol. However, the ERG noted that the summary of product characteristics for pembrolizumab specified that pembrolizumab could be used until disease progression or unacceptable toxicity. Clinical experts confirmed that in clinical practice, they would stop treatment with pembrolizumab after a maximum of 35\xa03-weekly cycles of 200\xa0mg in people who had not progressed. This was to align with the clinical trial evidence and because of the belief that limited benefit would be gained from treatment beyond 2\xa0years. The clinical lead for the Cancer Drugs Fund confirmed that, if a stopping rule were implemented, pembrolizumab would not be funded beyond 2\xa0years. However, because people in KEYNOTE‑177 had 200\xa0mg of pembrolizumab every 3\xa0weeks, people in the NHS may not receive the full 35\xa0cycles given in the trial within 2\xa0years, because of 6-weekly administration using the higher dosage (400\xa0mg; see section\xa03.23). It also heard from patient experts that they had both chosen to stop treatment early, despite continued response and the possibility of up to 1\xa0year's further treatment being available. For people in the KEYNOTE‑177 trial who stopped their treatment early because they achieved a complete response, they could have 17\xa0more 3-weekly cycles of pembrolizumab (200\xa0mg) upon progression. However, the company confirmed that retreatment was not included in the licence for pembrolizumab. The committee concluded that it was appropriate to apply a 2-year stopping rule for pembrolizumab (given 3‑ or 6‑weekly).\n\n# Costs in the economic model\n\n## Costs of standard care in the NHS lie between the company's and ERG's estimates\n\nThe committee recalled that around 70% of people in the KEYNOTE‑177 standard care arm had a combination that contained bevacizumab, which is not available in NHS clinical practice (see section\xa03.10). To account for this, the company replaced the costs of bevacizumab with the costs for cetuximab combinations and assumed they were equal. The ERG was concerned that, unlike bevacizumab, cetuximab is available in the NHS only for people with RAS wild-type disease. One clinical expert estimated that less than half of people with untreated metastatic colorectal cancer with high MSI or DNA MMR deficiency would be expected to have RAS wild-type disease and therefore have cetuximab in clinical practice. Hence, the ERG believed that the company overestimated the costs for standard care. The ERG's base case assumed that half the costs for standard care in the NHS came from the NHS price for FOLFOX and the other half came from the cost for FOLFIRI. The committee noted that this approach underestimated the true costs in the NHS, as the ERG did not include any costs for cetuximab in its base case. Also, the ERG did not adjust the clinical effectiveness of standard care to account for the worse overall survival with FOLFOX and FOLFIRI compared with bevacizumab or cetuximab. The committee noted that the ERG's assumption was conservative, but that it would have liked to have seen a scenario that included cetuximab in the costs for standard care. The committee also recalled that neither the company nor ERG had included capecitabine or FOLFOXIRI as relevant comparators in the model. However, it noted that the clinical effectiveness results compared with standard care included a blended comparator. It recalled its conclusions about the efficacy of blended comparators and noted that similar assumptions applied to the costs. The committee recalled the clinical experts' description of standard care included a small proportion who would have capecitabine monotherapy, which would have lower costs than FOLFOX or FOLFIRI, and a small proportion who would have FOLFOXIRI, which would have higher costs. The committee concluded that the costs of standard care in the NHS are likely between the company and ERG's estimates but that neither reflect the true costs in the NHS. It agreed that it would consider both the ERGs and the company's scenarios in its decision making.\n\n# Cost-effectiveness estimates\n\n## Pembrolizumab is cost effective against all comparators\n\nBecause of confidential commercial arrangements for pembrolizumab and comparators, none of the cost-effectiveness results are reported here. The committee agreed that its preferred assumptions to compare pembrolizumab with comparators included:\n\nthe full KEYNOTE‑177 population for treatment effect\n\na 2-year stopping rule\n\ntreatment effect from KEYNOTE‑177\xa0standard care for CAPOX, FOLFIRI and FOLFOX\n\ntreatment effect from the company's network meta-analysis for both panitumumab and cetuximab combination therapy\n\ndifferent utility values for pembrolizumab compared with current treatments, and a disutility adjustment in the progression-free health state\n\nadministration and consultant visits every 6\xa0weeks.The committee considered the incremental cost-effectiveness ratio (ICER) for both the ERG and company's base cases for pembrolizumab compared with FOLFOX, FOLFIRI, FOLFOXIRI, CAPOX and capecitabine, which differed only in the approach to costing standard care. The ERG's base case, which used standard care costs from FOLFOX and FOLFIRI, increased the ICER compared with the company's assumption that replaced costs of bevacizumab with costs of cetuximab for 70% of the population. It recalled that the cost of standard care in the NHS was likely between the ERG and company's base cases but noted that all estimates of cost effectiveness for this comparison were less than £20,000 per quality adjusted life year (QALY) gained. For the comparison with panitumumab, the company and ERG base cases used identical assumptions and ICERs were less than £20,000 per QALY gained. The committee recalled that pembrolizumab would initially be given every 3\xa0weeks in the NHS and noted that the company and ERG base cases assumed 6-weekly administration. So, the ICER for pembrolizumab in the NHS would be higher against all comparators but would remain below £20,000 per QALY gained. It concluded that pembrolizumab is a cost-effective use of resources in the NHS against all comparators.\n\n# Other factors\n\n## Pembrolizumab is a step change for people with metastatic colorectal cancer with high MSI or DNA MMR deficiency, and the model captures all benefits\n\nThe company, clinical experts and patient experts stated pembrolizumab represents a step change in treatment for people with metastatic colorectal cancer with high MSI or DNA MMR deficiency and that there is high unmet need for this population. The committee recalled that there are currently no targeted treatments specific to colorectal cancer with high MSI or DNA MMR deficiency and that these people have worse outcomes than for microsatellite stable disease. The company and clinical experts explained that treatment with pembrolizumab was less toxic, given less frequently and had a shorter administration then comparators. The committee noted that the treatment is not a chemotherapy and has the potential to be curative in some people, which would transform their quality of life. It concluded that pembrolizumab is a step change for people with metastatic colorectal cancer with high MSI or DNA MMR deficiency, and all benefits are captured in the cost-effectiveness estimates.\n\n## The recommendation takes potential equality issues into account\n\nThe committee noted an equality concern around testing for high MSI or DNA\xa0MMR‑deficient disease. Although routinely funded by NHS England (see section\xa03.8), local uptake and turnaround times for high MSI or DNA MMR deficiency testing are inconsistent throughout the NHS. Clinical experts raised concerns that some people would not be tested as standard, so would not be able to access pembrolizumab if recommended. The committee considered that all people should have testing for high MSI or DNA MMR deficiency when first diagnosed, in line with NICE's diagnostic guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer. It was reassured by the clinical lead for the Cancer Drugs Fund that, should pembrolizumab be recommended and high MSI or DNA MMR deficiency testing inform treatment decisions, it would become routine and timely throughout the NHS. Clinical experts also noted that the current guidance states that clinicians should not wait for results before starting treatment. This could mean people who needed treatment immediately were starting initially on combination chemotherapy and therefore were no longer eligible for pembrolizumab at first line. The committee considered this but had heard from the clinical lead of the Cancer Drugs Fund that testing should be timely. It was aware that it can only make recommendations within the marketing authorisation and any recommendation to switch treatment from chemotherapy to pembrolizumab was therefore outside of the committee's remit. The committee concluded that it had considered all equalities issues and its recommendation did not need changes.\n\n# Conclusion\n\n## Pembrolizumab is recommended for routine commissioning\n\nThe committee agreed that the most plausible ICERs for pembrolizumab compared with all relevant comparators were within what NICE normally considers to be an acceptable use of NHS resources. It therefore concluded that it could recommend pembrolizumab for routine commissioning as an option for untreated metastatic colorectal cancer with high MSI or MMR deficiency."}
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https://www.nice.org.uk/guidance/ta709
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Evidence-based recommendations on pembrolizumab (Keytruda) for treating metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency in adults.
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72151b5351fd79ae019bbe315b9ab0dca67041ea
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nice
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Ravulizumab for treating atypical haemolytic uraemic syndrome
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Ravulizumab for treating atypical haemolytic uraemic syndrome
Evidence-based recommendations on ravulizumab (Ultomiris) for treating atypical haemolytic uraemic syndrome in people weighing 10 kg or more.
# Recommendations
Ravulizumab is recommended, within its marketing authorisation, as an option for treating atypical haemolytic uraemic syndrome (aHUS) in people weighing 10 kg or more:
who have not had a complement inhibitor before or
whose disease has responded to at least 3 months of eculizumab treatment.It is recommended only if the company provides ravulizumab according to the commercial arrangement (see section 2).
Why the committee made these recommendations
Current treatment for aHUS is eculizumab infusions every 2 weeks. People would have ravulizumab infusions every 8 weeks.
Clinical trial evidence suggests that ravulizumab is effective for treating aHUS. But ravulizumab has not been compared directly with eculizumab. The results of indirect comparisons are uncertain, but it is likely that ravulizumab and eculizumab are equally effective because they work in a similar way. Because people have ravulizumab less often than eculizumab it improves quality of life.
Ravulizumab costs less than eculizumab and the cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So, ravulizumab is recommended.# Information about ravulizumab
# Marketing authorisation indication
Ravulizumab (Ultomiris, Alexion Pharmaceuticals) is indicated for 'the treatment of patients with a body weight of 10 kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naive or have received eculizumab for at least 3 months and have evidence of response to eculizumab'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £4,533 for 300 mg per 3 ml concentrate for solution for infusion vial; £16,621 for 1,100 mg per 11 ml concentrate for solution for infusion vial (excluding VAT; company submission).
The company has a commercial arrangement (simple discount patient access scheme). This makes ravulizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Alexion Pharmaceuticals, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 2 issues were resolved during the technical engagement stage, and agreed that:
treatment with ravulizumab may be stopped if adequate renal response is observed (issue 6, see ERG report table 1)
the potential future launch of biosimilars of the comparator drug eculizumab (Soliris, Alexion Pharmaceuticals) is not relevant to this appraisal of ravulizumab.
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see ERG report pages 10 to 20) and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage.
# New treatment option
## People with atypical haemolytic uraemic syndrome would welcome a new treatment option
Atypical haemolytic uraemic syndrome (aHUS) is a rare disease that causes blood clots in small blood vessels, which can lead to organ damage. People can have significant kidney impairment, thrombosis, heart failure and brain injury. The patient and clinical experts explained that there is a need for new treatment options for people with aHUS. Current treatment is eculizumab, which people have by intravenous infusion every other week. The patient experts explained that the fortnightly infusions make it difficult for people to work, socialise and join in with family life. People also face the personal, logistical and financial challenges of travelling to have their infusions. People would have ravulizumab by intravenous infusion every 8 weeks, reducing these challenges greatly compared with eculizumab. The patient experts explained that if ravulizumab were recommended by NICE, people would most likely prefer ravulizumab over eculizumab because of the lower treatment frequency. They noted that longer gaps between treatment reduces the treatment burden, so people who have ravulizumab are likely to have better quality of life than those who have eculizumab. They also noted that they can return to work and arrange holidays. The committee concluded that people would most likely prefer ravulizumab over eculizumab because of the lower treatment frequency and associated positive effect on quality of life.
# Treatment pathway
## Eculizumab is standard first-line therapy for people with aHUS
In NHS practice, people with aHUS are diagnosed and have treatment through the National aHUS Service, which operates as part of the National Renal Complement Therapeutics Centre. The clinical experts explained that aHUS is diagnosed only after other conditions are ruled out by further tests. Treatment with eculizumab, which NICE's highly specialised technologies guidance on eculizumab recommends for treating aHUS, often starts before these tests are complete. Eculizumab has a short half-life, which is beneficial at the start of treatment because it can be stopped more quickly if an alternative diagnosis is reached. The committee agreed that eculizumab is the standard first-line treatment for people with aHUS.
## Ravulizumab is considered for untreated disease or for people whose disease has responded to at least 3 months of eculizumab treatment
Ravulizumab has a marketing authorisation for 'the treatment of patients with a body weight of 10 kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naive or have received eculizumab for at least 3 months and have evidence of response to eculizumab'. In line with ravulizumab's marketing authorisation, the company has positioned it as:
a first-line treatment for people who have not had a complement inhibitor before or
a second-line or maintenance treatment for people who have had eculizumab for at least 3 months and there has been a disease response.The ERG noted that most people would only have ravulizumab as a second-line or maintenance treatment, based on advice from their own clinical experts. This is because of the shorter half-life of eculizumab (see section 3.2). The clinical experts at the committee agreed that most people with suspected aHUS would be offered eculizumab as a first-line treatment, so ravulizumab would be offered as a second-line treatment once the disease had responded to eculizumab. However, the clinical experts also commented that there are some people who could have ravulizumab first line: if there is sufficient evidence that aHUS is the correct diagnosis even ahead of final test results, for example, if there is a family history of aHUS. The committee accepted that ravulizumab could be a treatment option for people who had not had a complement inhibitor before, or for people who had eculizumab for at least 3 months with evidence of a disease response.
# Clinical effectiveness
## Ravulizumab is clinically effective but there is a lack of comparative data
The company presented evidence for ravulizumab from 2 open-label single-arm studies:
ALXN1210-aHUS-311, which included 56 adults in 14 countries who had not had eculizumab before
ALXN1210-aHUS-312, which included 2 groups of young people and children in 8 countries, split into 2 cohorts:
cohort 1, which included 18 patients who had not had treatment with eculizumab before
cohort 2, which included 10 patients with clinically stable disease after at least 90 days' treatment with eculizumab.Both studies consisted of a screening period of up to 7 days, a 26-week initial evaluation period and an extension period of up to 4.5 years. The primary outcome measure for both trials was complete thrombotic microangiopathy (TMA) response. Secondary outcomes included chronic kidney disease (CKD) stage classified as improved, stable (no change), or worsened compared with baseline. 30 adults (54%, 95% confidence interval: 39.6 to 67.5) achieved complete TMA response. 14 children or young people (78%, 95% confidence interval: 52.4 to 93.6) achieved complete TMA response (cohort 1 only). The CKD stage improved in 32 out of 47 adults (68%), and 15 out of 17 children or young people from cohort 1 (88%). CKD stage worsened in 2 out of 47 adults (4%) and in no children or young people in cohort 1. The committee noted that there was no clinical evidence directly comparing ravulizumab with eculizumab because both trials were single‑arm studies. It concluded that ravulizumab was clinically effective but agreed that the lack of comparative data made assessing comparative effectiveness (and any consequent cost‑effectiveness analyses) very challenging.
## Trial results are generalisable to NHS practice
The ERG had concerns about the generalisability of the trial results to NHS practice. This was because most patients in the trials had not had eculizumab before ravulizumab. In NHS practice, it is expected that eculizumab will be offered to people suspected of having aHUS until their diagnosis is confirmed. The ERG was also concerned that the trial population did not resemble the UK population of people with aHUS. This was because rates of genetic mutations and autoantibodies characteristic of aHUS were relatively low in the trial population, compared with the rates expected from the scientific literature and clinical practice. The committee noted that clinical practice varies around the world, and the ERG said it was possible some of the patients in Asia did not have aHUS as per UK diagnostic criteria. The clinical experts agreed that it was possible some patients in the trial did not have aHUS, or that the disease had progressed beyond the usual point of diagnosis in UK practice. They further agreed with the ERG that the low prevalence of genetic mutations and autoantibodies found in people in the trial compared with the known rates of these traits in aHUS suggested some people in the trial did not have the disease. However, the clinical experts explained that the evidence from the clinical trials was sufficiently generalisable to clinical practice. They also confirmed that, in most situations, people would be offered ravulizumab after having treatment with eculizumab, so the issues raised would not be expected in clinical practice. The committee agreed that there was uncertainty in the trial results because of their design, enrolment, and use of genetic testing. But overall, it concluded that the results were generalisable to people seen in NHS practice.
# Indirect treatment comparisons
## The efficacy of ravulizumab compared with eculizumab is based on an uncertain indirect comparison
There was no trial directly comparing ravulizumab with eculizumab. So the company did indirect treatment comparisons to show the similar effectiveness of the 2 treatments. Data for ravulizumab came from the trials ALXN1210-aHUS-311 and ALXN1210-aHUS-312 (see section 3.4). Data for eculizumab came from 3 other open-label, single-arm trials, aHUS-C08-002, aHUS-C10-003, and aHUS-C10-004. Patients were split into 3 groups: adults who had not had a kidney transplant, adults who had a kidney transplant, and children and young people. The data were weighted according to prognostic criteria measured before treatment, such as dialysis status, estimated glomerular filtration rate and blood pressure to reduce differences between the trial populations. The company compared outcomes across the 3 groups for both treatments. It concluded that there were no statistically significant differences between the 2 treatments; the data did not favour either drug over the other (the results of the comparison are academic in confidence so cannot be reported here). The ERG disagreed with the company's view and had identified trends in the data that favoured eculizumab over ravulizumab in clinically important outcomes, for example, the number of patients needing dialysis at the end of the trial. To provide more information, the company also discussed data in paroxysmal nocturnal haemoglobinuria (PNH) which directly compared eculizumab with ravulizumab over longer periods of time, and further concluded that the 2 drugs were similarly effective. The ERG did not rely on this dataset as PNH and aHUS are different conditions. The clinical experts said there was unlikely to be much difference between the effectiveness of the 2 drugs, and similar effectiveness was plausible. They also said the small trial size made it difficult to establish statistically significant differences in the effectiveness of the 2 treatments. The committee agreed that the data were uncertain, but accepted it was biologically plausible that ravulizumab and eculizumab may be similarly effective, because of their similar mechanisms of action.
# Adverse events
## Adverse events are likely to be similar for ravulizumab and eculizumab
The committee noted that deaths had occurred in ravulizumab trial ALXN1210-aHUS-311. There were 3 deaths in the main trial population, 2 from septic shock and 1 from cerebral haemorrhage. One further patient died having previously withdrawn from treatment. The deaths were interpreted by both the company and clinical experts as being a sign that these patients were not representative of people with aHUS seen in UK clinical settings. The committee recalled that some patients in the trials may not have had aHUS, or that the disease had progressed beyond the usual point of diagnosis in UK practice (see section 3.5). The clinical experts stated that they would expect similar adverse event rates for ravulizumab and eculizumab. The committee concluded adverse events are likely to be similar for ravulizumab and eculizumab.
# Economic model
## The company's economic model is suitable for decision making
The company presented a state transition model with 4 CKD states, 2 states for people needing transplant, and 1 mortality-related state. The model also allowed for some people to stop treatment, and a proportion of those people to relapse and restart treatment. Adults and children and young people were modelled separately, and the results combined. The model was based on the one used in NICE's highly specialised technologies guidance on eculizumab for treating aHUS. The committee concluded that the company's model was suitable for decision making.
# Utility values
## The utility values in the economic model are appropriate
The company assumed equal clinical effectiveness and quality of life for ravulizumab and eculizumab in their economic model. It also assumed that children, young people and adults with aHUS would all have an equal quality of life. The company did a discrete choice experiment and determined that a quality-of-life utility gain of 0.013 could be added for ravulizumab, because of the reduced frequency of infusions. The committee recalled that this would have a positive effect on quality of life for people with aHUS (see section 3.1). The committee concluded that the quality-of-life utility gain was not a major driver of ravulizumab's cost effectiveness, so accepted the company's utility values in the cost-effectiveness scenario analyses.
# Assumptions in the economic model
## The company's assumption that ravulizumab and eculizumab are equally effective is associated with uncertainty
In the company's economic model, the long-term efficacy and safety of ravulizumab was assumed to be equivalent to eculizumab. The ERG highlighted that although this is clinically plausible there is insufficient evidence to support this assumption. The committee agreed and noted this assumption is associated with uncertainty (see section 3.6 and section 3.7). The committee noted that both the company and ERG assumed equal efficacy for ravulizumab and eculizumab in their respective base cases. However, it considered that both had also provided scenario analyses in which different efficacy was assumed based on the results of the indirect treatment comparisons. The committee concluded that although there are biologically plausible reasons why ravulizumab and eculizumab may be similar, there is no direct evidence of this, therefore it would consider assumptions of equal and different efficacy in its decision making.
## There is uncertainty about the long-term safety and efficacy of ravulizumab
The ERG considered that there was insufficient follow-up data about the long-term safety and efficacy of ravulizumab. It highlighted that, in the company model, long-term efficacy and safety of ravulizumab are assumed to be equivalent to eculizumab (see section 3.6). The ERG considered that although this is clinically plausible, there is no evidence to support this assumption. The ERG was concerned that it was not possible to examine the long-term safety and efficacy of ravulizumab for aHUS. This was because the clinical trial data presented were for initial evaluation periods of 26 weeks in both trials. Trial extension periods were up to 4.5 years, but the data were not available at the time of this appraisal. The committee noted that no long-term data were presented to show that ravulizumab would be safe and effective beyond the duration of the trial. The company accepted this was a limitation of the data and presented long-term data to show ravulizumab remained safe and effective in people with PNH. The ERG did not accept these data were relevant to aHUS. The clinical experts stated they would expect ravulizumab to be effective long term because of the similarities with eculizumab in terms of structure and mechanism of action. The committee agreed the long-term safety and efficacy of ravulizumab remained uncertain, but it was plausible that it would show similar performance to eculizumab. The committee also agreed that it would take the uncertainty into account in its decision making.
## A time-dependent relapse rate is appropriate for people who stop treatment
In the company's original base-case model, people who stopped treatment relapsed at a constant rate over time. The ERG argued that this was not accurate, and that rates of relapse vary over time, being highest shortly after treatment withdrawal. The company accepted this and modified the economic model in response to technical engagement to make use of a time-dependent relapse rate obtained from the UK registry of data on people with aHUS. The committee considered that some uncertainty remained because this data source was not the ERG's preferred choice. The ERG suggested obtaining the relapse rate from the global registry of people with aHUS. The ERG stated that using the much larger global dataset also provided more information over time and did not produce results favouring ravulizumab. The ERG stated that only using the UK data increased uncertainty and appeared to favour ravulizumab. The clinical experts said that the relapse rate for people having ravulizumab would be the same as that for eculizumab and did not comment on how the rates change over time. The committee concluded that the company had used an appropriate method and that a time-dependent relapse rate was an appropriate assumption. However, some uncertainty would remain because of the choice of data source.
## Some people may stop and restart treatment multiple times
The ERG suggested people with aHUS may have multiple treatments in an 'on demand' approach, meaning they may stop treatment then restart if the disease relapses. The ERG noted that results from the ongoing Stopping Eculizumab Treatment Safely (SETS) study may suggest that such an approach could be an appropriate treatment strategy, and that no data had been provided by the company to support this approach. The company stated that this approach does not represent current NHS practice, and that SETS would not examine the scenario in which people stop multiple times. The clinical experts commented that the decision to stop and restart treatment could be made multiple times, but that this would be down to the individual situation of the person with aHUS and the observed results of them stopping treatment. The clinical experts said this approach may work for some people but not for others. The clinical experts also stated that there were no data to support this approach, and that people may not want to stop and restart treatment multiple times. The committee agreed that this was a possible treatment strategy for some individuals, but that it is not current NHS practice for most people. Therefore, the committee concluded that it would take this possible treatment strategy into account in its decision making.
## It is reasonable to assume that that treatment will stop because of an adequate renal response
The ERG said that current guidelines suggest treatment for aHUS should be lifelong. But several arguments in the literature propose that people may choose to stop treatment when renal response has reached an adequate level. The ERG expected that this would be supported by the SETS study. The company accepted this argument at technical engagement and updated its economic model to reflect this approach. Stakeholders said that this would be supported by SETS, and that people would want to stop in this case. The clinical experts agreed that although SETS was designed to study eculizumab, its results would apply to ravulizumab in practice. The committee concluded that people may stop treatment with ravulizumab if they achieve an adequate renal response.
# Costs in the economic model
## The costs used in the economic model are appropriate
The costs used in the company's economic model included drug acquisition, infusion, transplant and maintenance, dialysis, vaccine, stopping, relapse, and costs associated with the different CKD stages. The ERG commented that the costs used by the company were appropriate. It also stated that in its own analyses, the drug acquisition cost was high compared with all other costs, and that all other costs had a very small effect on the overall analysis. So, the key driver of cost effectiveness was the difference in acquisition costs for ravulizumab and eculizumab. The committee concluded that the costs used by the company in its economic model were appropriate.
## Eculizumab biosimilars may need to be considered in future reviews of ravulizumab
The ERG highlighted that the patent for eculizumab is set to expire in the next 3 years, so biosimilar eculizumab treatments are likely to enter the market. The committee recalled that the difference in the acquisition costs of ravulizumab and eculizumab were the key drivers of the cost-effectiveness estimates, rather than any difference in the effectiveness of the 2 treatments. So, if biosimilar eculizumab treatments became available with a lower acquisition cost than the currently available eculizumab treatment, this may affect the cost effectiveness of both eculizumab and ravulizumab. However, the committee noted that eculizumab biosimilars are not part of the current pathway of care. The committee agreed that they should not be considered in this appraisal. The committee asked for availability of biosimilars to be factored into future reviews of ravulizumab and its cost effectiveness.
# Cost-effectiveness estimates
## Ravulizumab is a cost-effective use of NHS resources for aHUS
The committee agreed that its preferred approach to modelling would:
allow for treatment stopping because of adequate renal response (see section 3.14)
use a time-dependent relapse rate for people who stop treatment, based on the global registry dataset (see section 3.12)
allow for 'on demand' treatment with the ability to stop multiple times (see section 3.13)
include scenarios in which ravulizumab and eculizumab are assumed to be equally effective, and scenarios in which the efficacy of ravulizumab and eculizumab are assumed to be different, because of the uncertainty associated with the results of the indirect comparison (see section 3.6 and section 3.10).Using the committee's preferred assumptions and including the revised confidential discount for ravulizumab, ravulizumab was as effective and cost less than eculizumab in both the company's base case and the ERG's preferred base case, when equivalent efficacy was assumed. The exact savings and incremental cost-effectiveness ratio (ICERs) are commercial in confidence and cannot be reported here. When different efficacy was assumed, the cost-effectiveness estimate for ravulizumab was in the south-west quadrant of the cost-effectiveness plane in both the company's and ERG's scenario analyses, meaning it is less effective but costs less than eculizumab. The committee considered that, when an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment is. The committee noted that the south-west quadrant ICERs were high enough to consider ravulizumab a cost-effective use of NHS resources. The committee concluded that ravulizumab can be considered cost effective for treating aHUS.
# Other considerations
## There are no equality issues relevant to the recommendations
Pregnancy was one of the exclusion criteria for the clinical trials. The summary of product characteristics states that ravulizumab may be offered to pregnant women after an assessment of risks and benefits. The committee acknowledged this and concluded that there were no relevant equality issues.
# Conclusion
## Ravulizumab is recommended
In the committee's preferred analyses, ravulizumab was considered a cost-effective use of NHS resources compared with eculizumab. Therefore, ravulizumab is recommended as a treatment option for people with aHUS who have not had a complement inhibitor before, or whose disease has responded to at least 3 months of eculizumab treatment.
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{'Recommendations': 'Ravulizumab is recommended, within its marketing authorisation, as an option for treating atypical haemolytic uraemic syndrome (aHUS) in people weighing 10\xa0kg or more:\n\nwho have not had a complement inhibitor before or\n\nwhose disease has responded to at least 3\xa0months of eculizumab treatment.It is recommended only if the company provides ravulizumab according to the commercial arrangement (see section\xa02).\n\nWhy the committee made these recommendations\n\nCurrent treatment for aHUS is eculizumab infusions every 2\xa0weeks. People would have ravulizumab infusions every 8\xa0weeks.\n\nClinical trial evidence suggests that ravulizumab is effective for treating aHUS. But ravulizumab has not been compared directly with eculizumab. The results of indirect comparisons are uncertain, but it is likely that ravulizumab and eculizumab are equally effective because they work in a similar way. Because people have ravulizumab less often than eculizumab it improves quality of life.\n\nRavulizumab costs less than eculizumab and the cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So, ravulizumab is recommended.', 'Information about ravulizumab': "# Marketing authorisation indication\n\nRavulizumab (Ultomiris, Alexion Pharmaceuticals) is indicated for 'the treatment of patients with a body weight of 10\xa0kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naive or have received eculizumab for at least 3\xa0months and have evidence of response to eculizumab'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £4,533 for 300\xa0mg per 3\xa0ml concentrate for solution for infusion vial; £16,621 for 1,100\xa0mg per 11\xa0ml concentrate for solution for infusion vial (excluding VAT; company submission).\n\nThe company has a commercial arrangement (simple discount patient access scheme). This makes ravulizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Alexion Pharmaceuticals, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 2 issues were resolved during the technical engagement stage, and agreed that:\n\ntreatment with ravulizumab may be stopped if adequate renal response is observed (issue\xa06, see ERG report table 1)\n\nthe potential future launch of biosimilars of the comparator drug eculizumab (Soliris, Alexion Pharmaceuticals) is not relevant to this appraisal of ravulizumab.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see ERG report pages 10\xa0to\xa020) and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage.\n\n# New treatment option\n\n## People with atypical haemolytic uraemic syndrome would welcome a new treatment option\n\nAtypical haemolytic uraemic syndrome (aHUS) is a rare disease that causes blood clots in small blood vessels, which can lead to organ damage. People can have significant kidney impairment, thrombosis, heart failure and brain injury. The patient and clinical experts explained that there is a need for new treatment options for people with aHUS. Current treatment is eculizumab, which people have by intravenous infusion every other week. The patient experts explained that the fortnightly infusions make it difficult for people to work, socialise and join in with family life. People also face the personal, logistical and financial challenges of travelling to have their infusions. People would have ravulizumab by intravenous infusion every 8\xa0weeks, reducing these challenges greatly compared with eculizumab. The patient experts explained that if ravulizumab were recommended by NICE, people would most likely prefer ravulizumab over eculizumab because of the lower treatment frequency. They noted that longer gaps between treatment reduces the treatment burden, so people who have ravulizumab are likely to have better quality of life than those who have eculizumab. They also noted that they can return to work and arrange holidays. The committee concluded that people would most likely prefer ravulizumab over eculizumab because of the lower treatment frequency and associated positive effect on quality of life.\n\n# Treatment pathway\n\n## Eculizumab is standard first-line therapy for people with aHUS\n\nIn NHS practice, people with aHUS are diagnosed and have treatment through the National aHUS Service, which operates as part of the National Renal Complement Therapeutics Centre. The clinical experts explained that aHUS is diagnosed only after other conditions are ruled out by further tests. Treatment with eculizumab, which NICE's highly specialised technologies guidance on eculizumab recommends for treating aHUS, often starts before these tests are complete. Eculizumab has a short half-life, which is beneficial at the start of treatment because it can be stopped more quickly if an alternative diagnosis is reached. The committee agreed that eculizumab is the standard first-line treatment for people with aHUS.\n\n## Ravulizumab is considered for untreated disease or for people whose disease has responded to at least 3\xa0months of eculizumab treatment\n\nRavulizumab has a marketing authorisation for 'the treatment of patients with a body weight of 10\xa0kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naive or have received eculizumab for at least 3\xa0months and have evidence of response to eculizumab'. In line with ravulizumab's marketing authorisation, the company has positioned it as:\n\na first-line treatment for people who have not had a complement inhibitor before or\n\na second-line or maintenance treatment for people who have had eculizumab for at least 3\xa0months and there has been a disease response.The ERG noted that most people would only have ravulizumab as a second-line or maintenance treatment, based on advice from their own clinical experts. This is because of the shorter half-life of eculizumab (see section\xa03.2). The clinical experts at the committee agreed that most people with suspected aHUS would be offered eculizumab as a first-line treatment, so ravulizumab would be offered as a second-line treatment once the disease had responded to eculizumab. However, the clinical experts also commented that there are some people who could have ravulizumab first line: if there is sufficient evidence that aHUS is the correct diagnosis even ahead of final test results, for example, if there is a family history of aHUS. The committee accepted that ravulizumab could be a treatment option for people who had not had a complement inhibitor before, or for people who had eculizumab for at least 3\xa0months with evidence of a disease response.\n\n# Clinical effectiveness\n\n## Ravulizumab is clinically effective but there is a lack of comparative data\n\nThe company presented evidence for ravulizumab from 2\xa0open-label single-arm studies:\n\nALXN1210-aHUS-311, which included 56\xa0adults in 14\xa0countries who had not had eculizumab before\n\nALXN1210-aHUS-312, which included 2\xa0groups of young people and children in 8\xa0countries, split into 2\xa0cohorts:\n\n\n\ncohort\xa01, which included 18\xa0patients who had not had treatment with eculizumab before\n\ncohort\xa02, which included 10\xa0patients with clinically stable disease after at least 90\xa0days' treatment with eculizumab.Both studies consisted of a screening period of up to 7\xa0days, a 26-week initial evaluation period and an extension period of up to 4.5\xa0years. The primary outcome measure for both trials was complete thrombotic microangiopathy (TMA) response. Secondary outcomes included chronic kidney disease (CKD) stage classified as improved, stable (no change), or worsened compared with baseline. 30\xa0adults (54%, 95% confidence interval: 39.6\xa0to\xa067.5) achieved complete TMA response. 14\xa0children or young people (78%, 95% confidence interval: 52.4\xa0to\xa093.6) achieved complete TMA response (cohort\xa01 only). The CKD stage improved in 32\xa0out of 47\xa0adults (68%), and 15\xa0out of 17\xa0children or young people from cohort\xa01 (88%). CKD stage worsened in 2 out of 47\xa0adults (4%) and in no children or young people in cohort\xa01. The committee noted that there was no clinical evidence directly comparing ravulizumab with eculizumab because both trials were single‑arm studies. It concluded that ravulizumab was clinically effective but agreed that the lack of comparative data made assessing comparative effectiveness (and any consequent cost‑effectiveness analyses) very challenging.\n\n\n\n## Trial results are generalisable to NHS practice\n\nThe ERG had concerns about the generalisability of the trial results to NHS practice. This was because most patients in the trials had not had eculizumab before ravulizumab. In NHS practice, it is expected that eculizumab will be offered to people suspected of having aHUS until their diagnosis is confirmed. The ERG was also concerned that the trial population did not resemble the UK population of people with aHUS. This was because rates of genetic mutations and autoantibodies characteristic of aHUS were relatively low in the trial population, compared with the rates expected from the scientific literature and clinical practice. The committee noted that clinical practice varies around the world, and the ERG said it was possible some of the patients in Asia did not have aHUS as per UK diagnostic criteria. The clinical experts agreed that it was possible some patients in the trial did not have aHUS, or that the disease had progressed beyond the usual point of diagnosis in UK practice. They further agreed with the ERG that the low prevalence of genetic mutations and autoantibodies found in people in the trial compared with the known rates of these traits in aHUS suggested some people in the trial did not have the disease. However, the clinical experts explained that the evidence from the clinical trials was sufficiently generalisable to clinical practice. They also confirmed that, in most situations, people would be offered ravulizumab after having treatment with eculizumab, so the issues raised would not be expected in clinical practice. The committee agreed that there was uncertainty in the trial results because of their design, enrolment, and use of genetic testing. But overall, it concluded that the results were generalisable to people seen in NHS practice.\n\n# Indirect treatment comparisons\n\n## The efficacy of ravulizumab compared with eculizumab is based on an uncertain indirect comparison\n\nThere was no trial directly comparing ravulizumab with eculizumab. So the company did indirect treatment comparisons to show the similar effectiveness of the 2\xa0treatments. Data for ravulizumab came from the trials ALXN1210-aHUS-311 and ALXN1210-aHUS-312 (see section\xa03.4). Data for eculizumab came from 3\xa0other open-label, single-arm trials, aHUS-C08-002, aHUS-C10-003, and aHUS-C10-004. Patients were split into 3\xa0groups: adults who had not had a kidney transplant, adults who had a kidney transplant, and children and young people. The data were weighted according to prognostic criteria measured before treatment, such as dialysis status, estimated glomerular filtration rate and blood pressure to reduce differences between the trial populations. The company compared outcomes across the 3\xa0groups for both treatments. It concluded that there were no statistically significant differences between the 2\xa0treatments; the data did not favour either drug over the other (the results of the comparison are academic in confidence so cannot be reported here). The ERG disagreed with the company's view and had identified trends in the data that favoured eculizumab over ravulizumab in clinically important outcomes, for example, the number of patients needing dialysis at the end of the trial. To provide more information, the company also discussed data in paroxysmal nocturnal haemoglobinuria (PNH) which directly compared eculizumab with ravulizumab over longer periods of time, and further concluded that the 2\xa0drugs were similarly effective. The ERG did not rely on this dataset as PNH and aHUS are different conditions. The clinical experts said there was unlikely to be much difference between the effectiveness of the 2\xa0drugs, and similar effectiveness was plausible. They also said the small trial size made it difficult to establish statistically significant differences in the effectiveness of the 2\xa0treatments. The committee agreed that the data were uncertain, but accepted it was biologically plausible that ravulizumab and eculizumab may be similarly effective, because of their similar mechanisms of action.\n\n# Adverse events\n\n## Adverse events are likely to be similar for ravulizumab and eculizumab\n\nThe committee noted that deaths had occurred in ravulizumab trial ALXN1210-aHUS-311. There were 3\xa0deaths in the main trial population, 2\xa0from septic shock and 1\xa0from cerebral haemorrhage. One further patient died having previously withdrawn from treatment. The deaths were interpreted by both the company and clinical experts as being a sign that these patients were not representative of people with aHUS seen in UK clinical settings. The committee recalled that some patients in the trials may not have had aHUS, or that the disease had progressed beyond the usual point of diagnosis in UK practice (see section\xa03.5). The clinical experts stated that they would expect similar adverse event rates for ravulizumab and eculizumab. The committee concluded adverse events are likely to be similar for ravulizumab and eculizumab.\n\n# Economic model\n\n## The company's economic model is suitable for decision making\n\nThe company presented a state transition model with 4\xa0CKD states, 2\xa0states for people needing transplant, and 1\xa0mortality-related state. The model also allowed for some people to stop treatment, and a proportion of those people to relapse and restart treatment. Adults and children and young people were modelled separately, and the results combined. The model was based on the one used in NICE's highly specialised technologies guidance on eculizumab for treating aHUS. The committee concluded that the company's model was suitable for decision making.\n\n# Utility values\n\n## The utility values in the economic model are appropriate\n\nThe company assumed equal clinical effectiveness and quality of life for ravulizumab and eculizumab in their economic model. It also assumed that children, young people and adults with aHUS would all have an equal quality of life. The company did a discrete choice experiment and determined that a quality-of-life utility gain of\xa00.013 could be added for ravulizumab, because of the reduced frequency of infusions. The committee recalled that this would have a positive effect on quality of life for people with aHUS (see section\xa03.1). The committee concluded that the quality-of-life utility gain was not a major driver of ravulizumab's cost effectiveness, so accepted the company's utility values in the cost-effectiveness scenario analyses.\n\n# Assumptions in the economic model\n\n## The company's assumption that ravulizumab and eculizumab are equally effective is associated with uncertainty\n\nIn the company's economic model, the long-term efficacy and safety of ravulizumab was assumed to be equivalent to eculizumab. The ERG highlighted that although this is clinically plausible there is insufficient evidence to support this assumption. The committee agreed and noted this assumption is associated with uncertainty (see section\xa03.6 and section\xa03.7). The committee noted that both the company and ERG assumed equal efficacy for ravulizumab and eculizumab in their respective base cases. However, it considered that both had also provided scenario analyses in which different efficacy was assumed based on the results of the indirect treatment comparisons. The committee concluded that although there are biologically plausible reasons why ravulizumab and eculizumab may be similar, there is no direct evidence of this, therefore it would consider assumptions of equal and different efficacy in its decision making.\n\n## There is uncertainty about the long-term safety and efficacy of ravulizumab\n\nThe ERG considered that there was insufficient follow-up data about the long-term safety and efficacy of ravulizumab. It highlighted that, in the company model, long-term efficacy and safety of ravulizumab are assumed to be equivalent to eculizumab (see section\xa03.6). The ERG considered that although this is clinically plausible, there is no evidence to support this assumption. The ERG was concerned that it was not possible to examine the long-term safety and efficacy of ravulizumab for aHUS. This was because the clinical trial data presented were for initial evaluation periods of 26\xa0weeks in both trials. Trial extension periods were up to 4.5\xa0years, but the data were not available at the time of this appraisal. The committee noted that no long-term data were presented to show that ravulizumab would be safe and effective beyond the duration of the trial. The company accepted this was a limitation of the data and presented long-term data to show ravulizumab remained safe and effective in people with PNH. The ERG did not accept these data were relevant to aHUS. The clinical experts stated they would expect ravulizumab to be effective long term because of the similarities with eculizumab in terms of structure and mechanism of action. The committee agreed the long-term safety and efficacy of ravulizumab remained uncertain, but it was plausible that it would show similar performance to eculizumab. The committee also agreed that it would take the uncertainty into account in its decision making.\n\n## A time-dependent relapse rate is appropriate for people who stop treatment\n\nIn the company's original base-case model, people who stopped treatment relapsed at a constant rate over time. The ERG argued that this was not accurate, and that rates of relapse vary over time, being highest shortly after treatment withdrawal. The company accepted this and modified the economic model in response to technical engagement to make use of a time-dependent relapse rate obtained from the UK registry of data on people with aHUS. The committee considered that some uncertainty remained because this data source was not the ERG's preferred choice. The ERG suggested obtaining the relapse rate from the global registry of people with aHUS. The ERG stated that using the much larger global dataset also provided more information over time and did not produce results favouring ravulizumab. The ERG stated that only using the UK data increased uncertainty and appeared to favour ravulizumab. The clinical experts said that the relapse rate for people having ravulizumab would be the same as that for eculizumab and did not comment on how the rates change over time. The committee concluded that the company had used an appropriate method and that a time-dependent relapse rate was an appropriate assumption. However, some uncertainty would remain because of the choice of data source.\n\n## Some people may stop and restart treatment multiple times\n\nThe ERG suggested people with aHUS may have multiple treatments in an 'on demand' approach, meaning they may stop treatment then restart if the disease relapses. The ERG noted that results from the ongoing Stopping Eculizumab Treatment Safely (SETS) study may suggest that such an approach could be an appropriate treatment strategy, and that no data had been provided by the company to support this approach. The company stated that this approach does not represent current NHS practice, and that SETS would not examine the scenario in which people stop multiple times. The clinical experts commented that the decision to stop and restart treatment could be made multiple times, but that this would be down to the individual situation of the person with aHUS and the observed results of them stopping treatment. The clinical experts said this approach may work for some people but not for others. The clinical experts also stated that there were no data to support this approach, and that people may not want to stop and restart treatment multiple times. The committee agreed that this was a possible treatment strategy for some individuals, but that it is not current NHS practice for most people. Therefore, the committee concluded that it would take this possible treatment strategy into account in its decision making.\n\n## It is reasonable to assume that that treatment will stop because of an adequate renal response\n\nThe ERG said that current guidelines suggest treatment for aHUS should be lifelong. But several arguments in the literature propose that people may choose to stop treatment when renal response has reached an adequate level. The ERG expected that this would be supported by the SETS study. The company accepted this argument at technical engagement and updated its economic model to reflect this approach. Stakeholders said that this would be supported by SETS, and that people would want to stop in this case. The clinical experts agreed that although SETS was designed to study eculizumab, its results would apply to ravulizumab in practice. The committee concluded that people may stop treatment with ravulizumab if they achieve an adequate renal response.\n\n# Costs in the economic model\n\n## The costs used in the economic model are appropriate\n\nThe costs used in the company's economic model included drug acquisition, infusion, transplant and maintenance, dialysis, vaccine, stopping, relapse, and costs associated with the different CKD stages. The ERG commented that the costs used by the company were appropriate. It also stated that in its own analyses, the drug acquisition cost was high compared with all other costs, and that all other costs had a very small effect on the overall analysis. So, the key driver of cost effectiveness was the difference in acquisition costs for ravulizumab and eculizumab. The committee concluded that the costs used by the company in its economic model were appropriate.\n\n## Eculizumab biosimilars may need to be considered in future reviews of ravulizumab\n\nThe ERG highlighted that the patent for eculizumab is set to expire in the next 3\xa0years, so biosimilar eculizumab treatments are likely to enter the market. The committee recalled that the difference in the acquisition costs of ravulizumab and eculizumab were the key drivers of the cost-effectiveness estimates, rather than any difference in the effectiveness of the 2\xa0treatments. So, if biosimilar eculizumab treatments became available with a lower acquisition cost than the currently available eculizumab treatment, this may affect the cost effectiveness of both eculizumab and ravulizumab. However, the committee noted that eculizumab biosimilars are not part of the current pathway of care. The committee agreed that they should not be considered in this appraisal. The committee asked for availability of biosimilars to be factored into future reviews of ravulizumab and its cost effectiveness.\n\n# Cost-effectiveness estimates\n\n## Ravulizumab is a cost-effective use of NHS resources for aHUS\n\nThe committee agreed that its preferred approach to modelling would:\n\nallow for treatment stopping because of adequate renal response (see section\xa03.14)\n\nuse a time-dependent relapse rate for people who stop treatment, based on the global registry dataset (see section\xa03.12)\n\nallow for 'on demand' treatment with the ability to stop multiple times (see section\xa03.13)\n\ninclude scenarios in which ravulizumab and eculizumab are assumed to be equally effective, and scenarios in which the efficacy of ravulizumab and eculizumab are assumed to be different, because of the uncertainty associated with the results of the indirect comparison (see section\xa03.6 and section\xa03.10).Using the committee's preferred assumptions and including the revised confidential discount for ravulizumab, ravulizumab was as effective and cost less than eculizumab in both the company's base case and the ERG's preferred base case, when equivalent efficacy was assumed. The exact savings and incremental cost-effectiveness ratio (ICERs) are commercial in confidence and cannot be reported here. When different efficacy was assumed, the cost-effectiveness estimate for ravulizumab was in the south-west quadrant of the cost-effectiveness plane in both the company's and ERG's scenario analyses, meaning it is less effective but costs less than eculizumab. The committee considered that, when an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment is. The committee noted that the south-west quadrant ICERs were high enough to consider ravulizumab a cost-effective use of NHS resources. The committee concluded that ravulizumab can be considered cost effective for treating aHUS.\n\n# Other considerations\n\n## There are no equality issues relevant to the recommendations\n\nPregnancy was one of the exclusion criteria for the clinical trials. The summary of product characteristics states that ravulizumab may be offered to pregnant women after an assessment of risks and benefits. The committee acknowledged this and concluded that there were no relevant equality issues.\n\n# Conclusion\n\n## Ravulizumab is recommended\n\nIn the committee's preferred analyses, ravulizumab was considered a cost-effective use of NHS resources compared with eculizumab. Therefore, ravulizumab is recommended as a treatment option for people with aHUS who have not had a complement inhibitor before, or whose disease has responded to at least 3 months of eculizumab treatment."}
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https://www.nice.org.uk/guidance/ta710
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Evidence-based recommendations on ravulizumab (Ultomiris) for treating atypical haemolytic uraemic syndrome in people weighing 10 kg or more.
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c7b15a5017bdea6b9f6d4e2b3584a3bb7f1ec26e
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nice
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Laser lithotripsy for difficult-to-treat bile duct stones
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Laser lithotripsy for difficult-to-treat bile duct stones
Evidence-based recommendations on laser lithotripsy for difficult-to-treat bile duct stones in adults. This involves breaking up the stones using laser light.
# Recommendations
Evidence on the efficacy of laser lithotripsy for difficult-to-treat bile duct stones is adequate. However, evidence on its long-term safety is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do laser lithotripsy for difficult-to-treat bile duct stones should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
The procedure should only be done in specialised centres with experience of managing difficult-to-treat bile duct stones, and by clinicians with specific training in bile duct stone visualisation and the safe use of laser therapy.
Patient selection should be done by a multidisciplinary team including a hepatobiliary surgeon and clinicians with expertise in endoscopic retrograde cholangiopancreatography.
Further research should report long-term safety, including biliary stricture.# The condition, current treatments and procedure
# The condition
Bile duct stones, which form from cholesterol or bile pigments, can block the bile ducts. Difficult-to-treat bile duct stones are defined by their diameter (above 15 mm), number, unusual shape (such as barrel-shaped), location (intrahepatic or cystic duct), stone impaction, narrowing of the bile duct distal to the stone, or the anatomy of the common bile duct (sigmoid-shaped, short distal length or acute distal angulation of less than 135 degrees).
# Current treatments
Diagnosis and management of bile duct stones is described in the section on managing common bile duct stones in NICE's guideline on gallstone disease. Treatments for bile duct stones include bile duct clearance and laparoscopic cholecystectomy. Conventional stone extraction involves endoscopic retrograde cholangiopancreatography and a sphincterotomy, then extracting the stones from the ducts using balloon and basket catheters. For difficult-to-treat bile duct stones, treatment options include temporary stenting to allow biliary drainage if the stones cannot be removed or stone fragmentation (lithotripsy).
# The procedure
Laser lithotripsy aims to fragment bile duct stones that cannot be treated using conventional endoscopic stone removal techniques.
This procedure is usually done using general anaesthesia and direct visualisation of the stones using an endoscope inserted into the biliary tract. A laser fibre is introduced gently through the endoscope. Once the tip of the fibre is in direct contact with the stone, a laser is focused on its surface to create a plasma bubble. This oscillates and induces cavitation with compressive waves to fragment the stone. The procedure is usually done with the endoscope passed orally and through the stomach into the duodenum. However, a percutaneous approach is also possible.
When the stone fragmentation is complete, the fragments are removed by conventional methods (such as a basket or balloon catheter). The endoscope is then removed. Any small sand-like pieces may be retained and will be gradually passed through the body. The procedure usually takes 30 to 60 minutes.
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{'Recommendations': "Evidence on the efficacy of laser lithotripsy for difficult-to-treat bile duct stones is adequate. However, evidence on its long-term safety is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do laser lithotripsy for difficult-to-treat bile duct stones should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThe procedure should only be done in specialised centres with experience of managing difficult-to-treat bile duct stones, and by clinicians with specific training in bile duct stone visualisation and the safe use of laser therapy.\n\nPatient selection should be done by a multidisciplinary team including a hepatobiliary surgeon and clinicians with expertise in endoscopic retrograde cholangiopancreatography.\n\nFurther research should report long-term safety, including biliary stricture.", 'The condition, current treatments and procedure': "# The condition\n\nBile duct stones, which form from cholesterol or bile pigments, can block the bile ducts. Difficult-to-treat bile duct stones are defined by their diameter (above 15\xa0mm), number, unusual shape (such as barrel-shaped), location (intrahepatic or cystic duct), stone impaction, narrowing of the bile duct distal to the stone, or the anatomy of the common bile duct (sigmoid-shaped, short distal length or acute distal angulation of less than 135\xa0degrees).\n\n# Current treatments\n\nDiagnosis and management of bile duct stones is described in the section on managing common bile duct stones in NICE's guideline on gallstone disease. Treatments for bile duct stones include bile duct clearance and laparoscopic cholecystectomy. Conventional stone extraction involves endoscopic retrograde cholangiopancreatography and a sphincterotomy, then extracting the stones from the ducts using balloon and basket catheters. For difficult-to-treat bile duct stones, treatment options include temporary stenting to allow biliary drainage if the stones cannot be removed or stone fragmentation (lithotripsy).\n\n# The procedure\n\nLaser lithotripsy aims to fragment bile duct stones that cannot be treated using conventional endoscopic stone removal techniques.\n\nThis procedure is usually done using general anaesthesia and direct visualisation of the stones using an endoscope inserted into the biliary tract. A laser fibre is introduced gently through the endoscope. Once the tip of the fibre is in direct contact with the stone, a laser is focused on its surface to create a plasma bubble. This oscillates and induces cavitation with compressive waves to fragment the stone. The procedure is usually done with the endoscope passed orally and through the stomach into the duodenum. However, a percutaneous approach is also possible.\n\nWhen the stone fragmentation is complete, the fragments are removed by conventional methods (such as a basket or balloon catheter). The endoscope is then removed. Any small sand-like pieces may be retained and will be gradually passed through the body. The procedure usually takes 30\xa0to 60\xa0minutes."}
|
https://www.nice.org.uk/guidance/ipg699
|
Evidence-based recommendations on laser lithotripsy for difficult-to-treat bile duct stones in adults. This involves breaking up the stones using laser light.
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2ce7d986bb7d09f1574eddf1f4fc744d85fcc033
|
nice
|
Percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve
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Percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve
Evidence-based recommendations on percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve. This involves putting a small tube (catheter) into a blood vessel, usually through the skin (percutaneous) at the top of the leg. A wire is guided through the catheter to the heart valve (aortic or mitral) and a closure device is then passed through the catheter to block the area that is leaking. The aim is to stop the leak.
# Recommendations
Evidence on the safety of percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve shows that this procedure can cause potentially serious but well-recognised complications. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Review local clinical outcomes and enter details about all patients having percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve into the British Cardiovascular Intervention Society database managed by the National Institute for Cardiovascular Outcomes Research. Contact bartshealth.nicor-generalenquiries@nhs.net for details.
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
Patient selection should be done by a multidisciplinary team experienced in managing the condition including interventional cardiologists with specific training in the procedure, cardiac surgeons, specialists in cardiovascular imaging and cardiac anaesthetists.
This is a technically challenging procedure and it should only be done in specialised centres by a multidisciplinary team including clinicians with training and experience in this procedure. Clinicians should only do their initial procedures with an experienced mentor.
Further research should report details of patient selection, device selection, procedural outcomes, long-term outcomes including quality of life, the need for repeat interventions or surgery, and complication rates.# The condition, current treatments and procedure
# The condition
Paravalvular leak is a complication after surgical or transcatheter replacement of a mitral or aortic valve. Most leaks are not significant, but some leaks may lead to heart failure or haemolytic anaemia.
# Current treatments
Current treatments include a second surgical procedure to replace the malfunctioning valve or a valve-in-valve transcatheter aortic valve insertion.
# The procedure
The procedure is done using a combination of local anaesthetic and sedation, or general anaesthesia. The exact technique varies according to the type of leak being repaired.
For mitral valves, an antegrade transseptal approach is most commonly used. In this approach, transseptal left atrial catheterisation is done under imaging guidance using standard techniques. A guidewire may be used to cross the leak. A delivery sheath is then passed from the venous access and 1 or more closure devices are deployed to close the leak. Transoesophageal echocardiography is used to confirm adequate reduction of peri‑mitral regurgitation and fluoroscopy is used to confirm normal mechanical prosthetic leaflet motion before closure device release.
For aortic valves, a retrograde approach is usually used. Transthoracic echocardiography may be enough to image the leak, but for posterior leaks, transoesophageal echocardiography or intracardiac echocardiography may be needed. The leak is usually crossed using a guidewire over a catheter. After crossing, the guidewire is exchanged for a stiffer wire and a delivery sheath is advanced to deploy the closure device.
More than 1 device may be needed to adequately close the leak.
|
{'Recommendations': "Evidence on the safety of percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve shows that this procedure can cause potentially serious but well-recognised complications. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nReview local clinical outcomes and enter details about all patients having percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve into the British Cardiovascular Intervention Society database managed by the National Institute for Cardiovascular Outcomes Research. Contact bartshealth.nicor-generalenquiries@nhs.net for details.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.Healthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team experienced in managing the condition including interventional cardiologists with specific training in the procedure, cardiac surgeons, specialists in cardiovascular imaging and cardiac anaesthetists.\n\nThis is a technically challenging procedure and it should only be done in specialised centres by a multidisciplinary team including clinicians with training and experience in this procedure. Clinicians should only do their initial procedures with an experienced mentor.\n\nFurther research should report details of patient selection, device selection, procedural outcomes, long-term outcomes including quality of life, the need for repeat interventions or surgery, and complication rates.", 'The condition, current treatments and procedure': '# The condition\n\nParavalvular leak is a complication after surgical or transcatheter replacement of a mitral or aortic valve. Most leaks are not significant, but some leaks may lead to heart failure or haemolytic anaemia.\n\n# Current treatments\n\nCurrent treatments include a second surgical procedure to replace the malfunctioning valve or a valve-in-valve transcatheter aortic valve insertion.\n\n# The procedure\n\nThe procedure is done using a combination of local anaesthetic and sedation, or general anaesthesia. The exact technique varies according to the type of leak being repaired.\n\nFor mitral valves, an antegrade transseptal approach is most commonly used. In this approach, transseptal left atrial catheterisation is done under imaging guidance using standard techniques. A guidewire may be used to cross the leak. A delivery sheath is then passed from the venous access and 1 or more closure devices are deployed to close the leak. Transoesophageal echocardiography is used to confirm adequate reduction of peri‑mitral regurgitation and fluoroscopy is used to confirm normal mechanical prosthetic leaflet motion before closure device release.\n\nFor aortic valves, a retrograde approach is usually used. Transthoracic echocardiography may be enough to image the leak, but for posterior leaks, transoesophageal echocardiography or intracardiac echocardiography may be needed. The leak is usually crossed using a guidewire over a catheter. After crossing, the guidewire is exchanged for a stiffer wire and a delivery sheath is advanced to deploy the closure device.\n\nMore than 1\xa0device may be needed to adequately close the leak.'}
|
https://www.nice.org.uk/guidance/ipg700
|
Evidence-based recommendations on percutaneous insertion of a closure device to repair a paravalvular leak around a replaced mitral or aortic valve. This involves putting a small tube (catheter) into a blood vessel, usually through the skin (percutaneous) at the top of the leg. A wire is guided through the catheter to the heart valve (aortic or mitral) and a closure device is then passed through the catheter to block the area that is leaking. The aim is to stop the leak.
|
38e565a9f442c96260e0efd9c5252cad581fb9f3
|
nice
|
Patient experience in adult NHS services: improving the experience of care for people using adult NHS services
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Patient experience in adult NHS services: improving the experience of care for people using adult NHS services
This guideline covers the components of a good patient experience. It aims to make sure that all adults using NHS services have the best possible experience of care.
# Introduction
Over the past few years, several documents and initiatives have highlighted the importance of the patient's experience and the need to focus on improving these experiences where possible.
Lord Darzi's report High quality care for all (2008) highlighted the importance of the entire patient experience within the NHS, ensuring people are treated with compassion, dignity and respect within a clean, safe and well-managed environment.
The development of the NHS Constitution (2009 to 2010) was one of several recommendations from Lord Darzi's report. The Constitution describes the purpose, principles and values of the NHS and illustrates what staff, patients and the public can expect from the service. Since the Health Act came into force in January 2010, service providers and commissioners of NHS care have had a legal obligation to take the Constitution into account in all their decisions and actions.
The Equality Act 2010 replaces all previous anti-discrimination legislation, and includes a public sector equality duty requiring public bodies to have due regard to the need to eliminate discrimination and to advance equality of opportunity and foster good relations between people who share certain protected characteristics and those who do not. The protected characteristics are age, disability, gender reassignment, pregnancy and maternity, race, religion or belief, sex and sexual orientation. The Act provides an important legal framework which should improve the experience of all patients using NHS services.
Despite these policy initiatives, there is evidence to suggest that further work is needed to deliver the best possible experience for users of NHS services. The Government signalled in its 2010 White Paper (Equity and excellence: liberating the NHS, Department of Health and Social Care) that more emphasis needs to be placed on improving patients' experience of NHS care.
This guidance is a direct referral from the Department of Health. It focuses on generic patient experiences and is relevant for all people who use adult NHS services in England and Wales. The aim of the guidance is to provide the NHS with clear guidance on the components of a good patient experience. This guidance provides the evidence and the direction for creating sustainable change that will result in an 'NHS cultural shift' towards a truly patient-centred service.
A NICE quality standard on patient experience in adult NHS services has been developed alongside this guidance. NICE quality standards are a set of specific, concise statements and associated measures. They set out aspirational, but achievable, markers of high-quality, cost-effective care. Quality standards are derived from the best available evidence and address three dimensions of quality: clinical effectiveness, patient safety and patient experience.
NICE clinical guidelines are usually shaped around both clinical and economic evidence, and include recommendations concerned with ensuring a good patient experience, with the recognition that such advice should sit alongside evidence of clinical and cost effectiveness. The recommendations in the current guidance have been informed by research evidence, recommendations in previously published NICE clinical guidelines, national survey data and consensus processes that have identified the key elements that are important to patients and how these can be improved to ensure a good experience of care. The guidance draws on multiple evidence and data sources in developing the recommendations.
The recommendations in this guidance are directed primarily at clinical staff, but patient experience is also significantly affected by contacts with non-clinical staff such as receptionists, clerical staff and domestic staff. Services need to ensure that non-clinical staff are adequately trained and supported to engage with patients in ways that enhance the patient experience.
Taken together, the recommendations in this guidance capture the essence of a good patient experience. Their implementation will help to ensure that healthcare services are acceptable and appropriate, and that all people using the NHS have the best possible experience of care.
NICE has also published a guideline on babies, children and young people's experience of healthcare.# Guidance
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Knowing the patient as an individual
Patients value healthcare professionals acknowledging their individuality and the unique way in which each person experiences a condition and its impact on their life. Patients' values, beliefs and circumstances all influence their expectations of, their needs for and their use of services. It is important to recognise that individual patients are living with their condition (or conditions), so the ways in which their family and broader life affect their health and care need to be taken into account.
Develop an understanding of the patient as an individual, including how the condition (or conditions) affects the person, and how the person's circumstances and experiences affect their condition (or conditions) and treatment. See also NICE's guideline on multimorbidity.
Ensure that factors such as physical or learning disabilities, sight, speech or hearing problems and difficulties with reading, understanding or speaking English are addressed so that the patient is able to participate as fully as possible in consultations and care.
Ask the patient about and take into account any factors, such as their domestic, social and work situation and their previous experience of healthcare, that may:
impact on their health condition (or conditions) and/or
affect their ability or willingness to engage with healthcare services and/or
affect their ability to manage their own care and make decisions about self-management and lifestyle choices.
Listen to and address any health beliefs, concerns and preferences that the patient has, and be aware that these affect how and whether they engage with treatment. Respect their views and offer support if needed to help them engage effectively with healthcare services and participate in self-management as appropriate.
Avoid making assumptions about the patient based on their appearance or other personal characteristics.
Take into account the requirements of the Equality Act 2010 and make sure services are equally accessible to, and supportive of, all people using adult NHS services.
If appropriate, discuss with the patient their need for psychological, social, spiritual and/or financial support. Offer support and information to the patient and/or direct them to sources of support and information. Review their circumstances and need for support regularly.
# Essential requirements of care
Patients have needs other than the treatment of their specific health conditions. There should be recognition of the potential need for psychological and emotional support, as well as of the importance of meeting fundamental needs such as nutrition and pain management. Attention to these fundamental needs applies particularly to inpatient settings, but they should also be addressed in other settings where healthcare is provided.
## Respect for the patient
All staff involved in providing NHS services (including chaplains, domestic staff, porters, receptionists and volunteers) should:
treat patients with respect, kindness, dignity, compassion, understanding, courtesy and honesty
respect the patient's right to confidentiality
not discuss the patient in their presence without involving them in the discussion.
Introduce students and anyone not directly involved in the delivery of care before consultations or meetings begin, and let the patient decide if they want them to stay.
## Patient concerns
Be prepared to raise and discuss sensitive issues (such as sexual activity, continence or end-of-life care), as these are unlikely to be raised by some patients.
Listen to and discuss any fears or concerns the patient has in a non-judgemental and sensitive manner.
If anxiety disorder or depression is suspected, follow the appropriate stepped-care model recommended in:
the NICE guideline on generalised anxiety disorder and panic disorder in adults or
the NICE guideline on depression in adults or
the NICE guideline on depression in adults with a chronic physical health problem.
## Nutrition, pain management and personal needs
All healthcare professionals directly involved in patient care should receive education and training, relevant to their post, on the importance of:
providing adequate and appropriate nutrition
assessing and managing pain.
Ensure that the patient's nutrition and hydration are adequate at all times, if the patient is unable to manage this themselves, by:
providing regular food and fluid of adequate quantity and quality in an environment conducive to eating
placing food and drink where the patient can reach them easily
encouraging and helping the patient to eat and drink if needed
providing appropriate support, such as modified eating and/or drinking aids.
If a patient is unable to manage their own pain relief:
do not assume that pain relief is adequate
ask them regularly about pain
assess pain using a pain scale if necessary (for example, on a scale of 1 to 10)
provide pain relief and adjust as needed.
Ensure that the patient's personal needs (for example, relating to continence, personal hygiene and comfort) are regularly reviewed and addressed. Regularly ask patients who are unable to manage their personal needs what help they need. Address their needs at the time of asking and ensure maximum privacy.
## Patient independence
Give patients using adult NHS services the support they need to maintain their independence as far as possible.
When patients in hospital are taking medicines for long-term conditions, assess and discuss with them whether they are able and would prefer to manage these medicines themselves.
## Consent and capacity
Obtain and document informed consent from the patient, in accordance with:
in England, Department of Health and Social Care policy and guidance
in Wales, advice from the Welsh Government.
Assess the patient's capacity to make each decision using the principles in the Mental Capacity Act (2005).
# Tailoring healthcare services for each patient
Patients wish to be seen as an individual within the healthcare system. This requires healthcare professionals to recognise the individual, and for services to be tailored to respond to the needs, preferences and values of the patient. Advice on treatments and care, including risks and benefits, should be individualised as much as possible.
## An individualised approach to services
Adopt an individualised approach to healthcare services that is tailored to the patient's needs and circumstances, taking into account their ability to access services, personal preferences and coexisting conditions. Review the patient's needs and circumstances regularly.
Inform the patient about healthcare services and social services (for example, smoking cessation services) that are available locally and nationally. Encourage and support them to access services according to their individual needs and preferences.
Give the patient information about relevant treatment options and services that they are entitled to, even if these are not provided locally.
## Patient views and preferences
Hold discussions in a way that encourages the patient to express their personal needs and preferences for care, treatment, management and self-management. Allow adequate time so that discussions do not feel rushed.
Review with the patient at intervals agreed with them:
their knowledge, understanding and concerns about their condition (or conditions) and treatments
their view of their need for treatment.
Accept that the patient may have different views from healthcare professionals about the balance of risks, benefits and consequences of treatments.
Accept that the patient has the right to decide not to have a treatment, even if you do not agree with their decision, as long as they have the capacity to make an informed decision (see recommendation 1.2.13) and have been given and understand the information needed to do this.
Respect and support the patient in their choice of treatment, or if they decide to decline treatment.
Ensure that the patient knows that they can ask for a second opinion from a different healthcare professional, and if necessary how they would go about this.
## Involvement of family members and carers
Clarify with the patient at the first point of contact whether and how they would like their partner, family members and/or carers to be involved in key decisions about the management of their condition (or conditions). Review this regularly. If the patient agrees, share information with their partner, family members and/or carers.
If the patient cannot indicate their agreement to share information, ensure that family members and/or carers are kept involved and appropriately informed, but be mindful of any potentially sensitive issues and the duty of confidentiality.
## Feedback and complaints
Encourage the patient to give feedback about their care. Respond to any feedback given.
If necessary, provide patients with information about complaints procedures and help them to access these.
# Continuity of care and relationships
Continuity and consistency of care and establishing trusting, empathetic and reliable relationships with competent and insightful healthcare professionals is key to patients receiving effective, appropriate care. Relevant information should be shared between professionals and across healthcare boundaries to support high-quality care.
Assess each patient's requirement for continuity of care and how that requirement will be met. This may involve the patient seeing the same healthcare professional throughout a single episode of care, or ensuring continuity within a healthcare team.
For patients who use a number of different services (for example, services in both primary and secondary care, or attending different clinics in a hospital), ensure effective coordination and prioritisation of care to minimise the impact on the patient.
Ensure clear and timely exchange of patient information:
between healthcare professionals (particularly at the point of any transitions in care)
between healthcare and social care professionals in line with the Health and Social Care (Safety and Quality) Act 2015.
All healthcare professionals directly involved in a patient's care should introduce themselves to the patient.
Inform the patient about:
who is responsible for their clinical care and treatment
the roles and responsibilities of the different members of the healthcare team
the communication about their care that takes place between members of the healthcare team.
Give the patient (and their family members and/or carers if appropriate) information about what to do and who to contact in different situations, such as 'out of hours' or in an emergency.
# Enabling patients to actively participate in their care
Many patients wish to be active participants in their own healthcare, and to be involved in creating and managing their health strategy and use of services. Self-care and self-management are particularly important for people with long-term conditions.
## Communication
Ensure that the environment is conducive to discussion and that the patient's privacy is respected, particularly when discussing sensitive, personal issues.
Maximise patient participation in communication by, for example:
maintaining eye contact with the patient (if culturally appropriate)
positioning yourself at the same level as the patient
ensuring that the patient is appropriately covered (if applicable).
Ask the patient how they wish to be addressed and ensure that their choice is respected and used.
Establish the most effective way of communicating with each patient and explore ways to improve communication. Examples include using pictures, symbols, large print, Braille, different languages, sign language or communications aids, or involving an interpreter, a patient advocate or family members.
Ensure that the accent, use of idiom and dialect of both the patient and the healthcare professionals are taken into account when considering communication needs.
Avoid using jargon. Use words the patient will understand, define unfamiliar words and confirm understanding by asking questions.
Use open-ended questions to encourage discussion.
Summarise information at the end of a consultation and check that the patient has understood the most important information.
Offer the patient copies of letters between healthcare professionals. These should be in a form that is accessible to the patient and if possible use language that they will understand. Answer any questions the patient may have about these.
All staff involved in providing NHS services should have demonstrated competency in relevant communication skills.
## Information
Give the patient information, and the support they need to make use of the information, in order to promote their active participation in care and self-management.
Give the patient both oral and written information.
Give the patient information in an accessible format, at the first and subsequent visits. Possible formats include using written information, pictures, symbols, large print, Braille and different languages.
Explore the patient's preferences about the level and type of information they want. Based on this, give the patient (and their family members and/or carers if appropriate) clear, consistent, evidence-based, tailored information throughout all stages of their care. This should include, but not be limited to, information on:
their condition (or conditions) and any treatment options
where they will be seen
who will undertake their care
expected waiting times for consultations, investigations and treatments.
Ensure that mechanisms are in place to:
provide information about appointments to patients who require information in non‑standard formats
alert services of any need for interpreters and non-standard formats to be available when patients move between services.
Ask the patient whether they want to be accompanied at consultations by a family member, friend or advocate, and whether they would like to take notes and/or an audio recording of the consultation.
Give the patient (and/or their family members and carers) information to enable them to use any medicines and equipment correctly. Ensure that the patient and their family members and carers feel adequately informed, prepared and supported to use medicines and equipment and to carry out self-care and self-management.
Advise the patient where they might find reliable high-quality information and support after consultations, from sources such as national and local support groups, networks and information services.
Give the patient regular, accurate information about the duration of any delays during episodes of care.
## Shared decision making
Recommendations 1.5.20 to 1.5.27 have been replaced by NICE's guideline on shared decision making.
Deleted.
Deleted.
Deleted.
Deleted.
Deleted.
Deleted.
Deleted.
Deleted.
## Education programmes
Ensure that patient-education programmes:
are evidence-based
have specific aims and learning objectives
meet the needs of the patient (taking into account cultural, linguistic, cognitive and literacy considerations)
promote the patient's ability to manage their own health if appropriate.
Give the patient the opportunity to take part in evidence-based educational activities, including self-management programmes, that are available and meet the criteria listed in recommendation 1.5.28.
|
{'Introduction': "Over the past few years, several documents and initiatives have highlighted the importance of the patient's experience and the need to focus on improving these experiences where possible.\n\nLord Darzi's report High quality care for all (2008) highlighted the importance of the entire patient experience within the NHS, ensuring people are treated with compassion, dignity and respect within a clean, safe and well-managed environment.\n\nThe development of the NHS Constitution (2009 to 2010) was one of several recommendations from Lord Darzi's report. The Constitution describes the purpose, principles and values of the NHS and illustrates what staff, patients and the public can expect from the service. Since the Health Act came into force in January 2010, service providers and commissioners of NHS care have had a legal obligation to take the Constitution into account in all their decisions and actions.\n\nThe Equality Act 2010 replaces all previous anti-discrimination legislation, and includes a public sector equality duty requiring public bodies to have due regard to the need to eliminate discrimination and to advance equality of opportunity and foster good relations between people who share certain protected characteristics and those who do not. The protected characteristics are age, disability, gender reassignment, pregnancy and maternity, race, religion or belief, sex and sexual orientation. The Act provides an important legal framework which should improve the experience of all patients using NHS services.\n\nDespite these policy initiatives, there is evidence to suggest that further work is needed to deliver the best possible experience for users of NHS services. The Government signalled in its 2010 White Paper (Equity and excellence: liberating the NHS, Department of Health and Social Care) that more emphasis needs to be placed on improving patients' experience of NHS care.\n\nThis guidance is a direct referral from the Department of Health. It focuses on generic patient experiences and is relevant for all people who use adult NHS services in England and Wales. The aim of the guidance is to provide the NHS with clear guidance on the components of a good patient experience. This guidance provides the evidence and the direction for creating sustainable change that will result in an 'NHS cultural shift' towards a truly patient-centred service.\n\nA NICE quality standard on patient experience in adult NHS services has been developed alongside this guidance. NICE quality standards are a set of specific, concise statements and associated measures. They set out aspirational, but achievable, markers of high-quality, cost-effective care. Quality standards are derived from the best available evidence and address three dimensions of quality: clinical effectiveness, patient safety and patient experience.\n\nNICE clinical guidelines are usually shaped around both clinical and economic evidence, and include recommendations concerned with ensuring a good patient experience, with the recognition that such advice should sit alongside evidence of clinical and cost effectiveness. The recommendations in the current guidance have been informed by research evidence, recommendations in previously published NICE clinical guidelines, national survey data and consensus processes that have identified the key elements that are important to patients and how these can be improved to ensure a good experience of care. The guidance draws on multiple evidence and data sources in developing the recommendations.\n\nThe recommendations in this guidance are directed primarily at clinical staff, but patient experience is also significantly affected by contacts with non-clinical staff such as receptionists, clerical staff and domestic staff. Services need to ensure that non-clinical staff are adequately trained and supported to engage with patients in ways that enhance the patient experience.\n\nTaken together, the recommendations in this guidance capture the essence of a good patient experience. Their implementation will help to ensure that healthcare services are acceptable and appropriate, and that all people using the NHS have the best possible experience of care.\n\nNICE has also published a guideline on babies, children and young people's experience of healthcare.", 'Guidance': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Knowing the patient as an individual\n\nPatients value healthcare professionals acknowledging their individuality and the unique way in which each person experiences a condition and its impact on their life. Patients' values, beliefs and circumstances all influence their expectations of, their needs for and their use of services. It is important to recognise that individual patients are living with their condition (or conditions), so the ways in which their family and broader life affect their health and care need to be taken into account.\n\nDevelop an understanding of the patient as an individual, including how the condition (or conditions) affects the person, and how the person's circumstances and experiences affect their condition (or conditions) and treatment. See also NICE's guideline on multimorbidity.\n\nEnsure that factors such as physical or learning disabilities, sight, speech or hearing problems and difficulties with reading, understanding or speaking English are addressed so that the patient is able to participate as fully as possible in consultations and care.\n\nAsk the patient about and take into account any factors, such as their domestic, social and work situation and their previous experience of healthcare, that may:\n\nimpact on their health condition (or conditions) and/or\n\naffect their ability or willingness to engage with healthcare services and/or\n\naffect their ability to manage their own care and make decisions about self-management and lifestyle choices.\n\nListen to and address any health beliefs, concerns and preferences that the patient has, and be aware that these affect how and whether they engage with treatment. Respect their views and offer support if needed to help them engage effectively with healthcare services and participate in self-management as appropriate.\n\nAvoid making assumptions about the patient based on their appearance or other personal characteristics.\n\nTake into account the requirements of the Equality Act 2010 and make sure services are equally accessible to, and supportive of, all people using adult NHS services.\n\nIf appropriate, discuss with the patient their need for psychological, social, spiritual and/or financial support. Offer support and information to the patient and/or direct them to sources of support and information. Review their circumstances and need for support regularly.\n\n# Essential requirements of care\n\nPatients have needs other than the treatment of their specific health conditions. There should be recognition of the potential need for psychological and emotional support, as well as of the importance of meeting fundamental needs such as nutrition and pain management. Attention to these fundamental needs applies particularly to inpatient settings, but they should also be addressed in other settings where healthcare is provided.\n\n## Respect for the patient\n\nAll staff involved in providing NHS services (including chaplains, domestic staff, porters, receptionists and volunteers) should:\n\ntreat patients with respect, kindness, dignity, compassion, understanding, courtesy and honesty\n\nrespect the patient's right to confidentiality\n\nnot discuss the patient in their presence without involving them in the discussion.\n\nIntroduce students and anyone not directly involved in the delivery of care before consultations or meetings begin, and let the patient decide if they want them to stay.\n\n## Patient concerns\n\nBe prepared to raise and discuss sensitive issues (such as sexual activity, continence or end-of-life care), as these are unlikely to be raised by some patients.\n\nListen to and discuss any fears or concerns the patient has in a non-judgemental and sensitive manner.\n\nIf anxiety disorder or depression is suspected, follow the appropriate stepped-care model recommended in:\n\nthe NICE guideline on generalised anxiety disorder and panic disorder in adults or\n\nthe NICE guideline on depression in adults or\n\nthe NICE guideline on depression in adults with a chronic physical health problem.\n\n## Nutrition, pain management and personal needs\n\nAll healthcare professionals directly involved in patient care should receive education and training, relevant to their post, on the importance of:\n\nproviding adequate and appropriate nutrition\n\nassessing and managing pain.\n\nEnsure that the patient's nutrition and hydration are adequate at all times, if the patient is unable to manage this themselves, by:\n\nproviding regular food and fluid of adequate quantity and quality in an environment conducive to eating\n\nplacing food and drink where the patient can reach them easily\n\nencouraging and helping the patient to eat and drink if needed\n\nproviding appropriate support, such as modified eating and/or drinking aids.\n\nIf a patient is unable to manage their own pain relief:\n\ndo not assume that pain relief is adequate\n\nask them regularly about pain\n\nassess pain using a pain scale if necessary (for example, on a scale of 1 to 10)\n\nprovide pain relief and adjust as needed.\n\nEnsure that the patient's personal needs (for example, relating to continence, personal hygiene and comfort) are regularly reviewed and addressed. Regularly ask patients who are unable to manage their personal needs what help they need. Address their needs at the time of asking and ensure maximum privacy.\n\n## Patient independence\n\nGive patients using adult NHS services the support they need to maintain their independence as far as possible.\n\nWhen patients in hospital are taking medicines for long-term conditions, assess and discuss with them whether they are able and would prefer to manage these medicines themselves.\n\n## Consent and capacity\n\nObtain and document informed consent from the patient, in accordance with:\n\nin England, Department of Health and Social Care policy and guidance\n\nin Wales, advice from the Welsh Government.\n\nAssess the patient's capacity to make each decision using the principles in the Mental Capacity Act (2005).\n\n# Tailoring healthcare services for each patient\n\nPatients wish to be seen as an individual within the healthcare system. This requires healthcare professionals to recognise the individual, and for services to be tailored to respond to the needs, preferences and values of the patient. Advice on treatments and care, including risks and benefits, should be individualised as much as possible.\n\n## An individualised approach to services\n\nAdopt an individualised approach to healthcare services that is tailored to the patient's needs and circumstances, taking into account their ability to access services, personal preferences and coexisting conditions. Review the patient's needs and circumstances regularly.\n\nInform the patient about healthcare services and social services (for example, smoking cessation services) that are available locally and nationally. Encourage and support them to access services according to their individual needs and preferences.\n\nGive the patient information about relevant treatment options and services that they are entitled to, even if these are not provided locally.\n\n## Patient views and preferences\n\nHold discussions in a way that encourages the patient to express their personal needs and preferences for care, treatment, management and self-management. Allow adequate time so that discussions do not feel rushed.\n\nReview with the patient at intervals agreed with them:\n\ntheir knowledge, understanding and concerns about their condition (or conditions) and treatments\n\ntheir view of their need for treatment.\n\nAccept that the patient may have different views from healthcare professionals about the balance of risks, benefits and consequences of treatments.\n\nAccept that the patient has the right to decide not to have a treatment, even if you do not agree with their decision, as long as they have the capacity to make an informed decision (see recommendation 1.2.13) and have been given and understand the information needed to do this.\n\nRespect and support the patient in their choice of treatment, or if they decide to decline treatment.\n\nEnsure that the patient knows that they can ask for a second opinion from a different healthcare professional, and if necessary how they would go about this.\n\n## Involvement of family members and carers\n\nClarify with the patient at the first point of contact whether and how they would like their partner, family members and/or carers to be involved in key decisions about the management of their condition (or conditions). Review this regularly. If the patient agrees, share information with their partner, family members and/or carers.\n\nIf the patient cannot indicate their agreement to share information, ensure that family members and/or carers are kept involved and appropriately informed, but be mindful of any potentially sensitive issues and the duty of confidentiality.\n\n## Feedback and complaints\n\nEncourage the patient to give feedback about their care. Respond to any feedback given.\n\nIf necessary, provide patients with information about complaints procedures and help them to access these.\n\n# Continuity of care and relationships\n\nContinuity and consistency of care and establishing trusting, empathetic and reliable relationships with competent and insightful healthcare professionals is key to patients receiving effective, appropriate care. Relevant information should be shared between professionals and across healthcare boundaries to support high-quality care.\n\nAssess each patient's requirement for continuity of care and how that requirement will be met. This may involve the patient seeing the same healthcare professional throughout a single episode of care, or ensuring continuity within a healthcare team.\n\nFor patients who use a number of different services (for example, services in both primary and secondary care, or attending different clinics in a hospital), ensure effective coordination and prioritisation of care to minimise the impact on the patient.\n\nEnsure clear and timely exchange of patient information:\n\nbetween healthcare professionals (particularly at the point of any transitions in care)\n\nbetween healthcare and social care professionals in line with the Health and Social Care (Safety and Quality) Act 2015.\n\nAll healthcare professionals directly involved in a patient's care should introduce themselves to the patient.\n\nInform the patient about:\n\nwho is responsible for their clinical care and treatment\n\nthe roles and responsibilities of the different members of the healthcare team\n\nthe communication about their care that takes place between members of the healthcare team.\n\nGive the patient (and their family members and/or carers if appropriate) information about what to do and who to contact in different situations, such as 'out of hours' or in an emergency.\n\n# Enabling patients to actively participate in their care\n\nMany patients wish to be active participants in their own healthcare, and to be involved in creating and managing their health strategy and use of services. Self-care and self-management are particularly important for people with long-term conditions.\n\n## Communication\n\nEnsure that the environment is conducive to discussion and that the patient's privacy is respected, particularly when discussing sensitive, personal issues.\n\nMaximise patient participation in communication by, for example:\n\nmaintaining eye contact with the patient (if culturally appropriate)\n\npositioning yourself at the same level as the patient\n\nensuring that the patient is appropriately covered (if applicable).\n\nAsk the patient how they wish to be addressed and ensure that their choice is respected and used.\n\nEstablish the most effective way of communicating with each patient and explore ways to improve communication. Examples include using pictures, symbols, large print, Braille, different languages, sign language or communications aids, or involving an interpreter, a patient advocate or family members.\n\nEnsure that the accent, use of idiom and dialect of both the patient and the healthcare professionals are taken into account when considering communication needs.\n\nAvoid using jargon. Use words the patient will understand, define unfamiliar words and confirm understanding by asking questions.\n\nUse open-ended questions to encourage discussion.\n\nSummarise information at the end of a consultation and check that the patient has understood the most important information.\n\nOffer the patient copies of letters between healthcare professionals. These should be in a form that is accessible to the patient and if possible use language that they will understand. Answer any questions the patient may have about these.\n\nAll staff involved in providing NHS services should have demonstrated competency in relevant communication skills.\n\n## Information\n\nGive the patient information, and the support they need to make use of the information, in order to promote their active participation in care and self-management.\n\nGive the patient both oral and written information.\n\nGive the patient information in an accessible format, at the first and subsequent visits. Possible formats include using written information, pictures, symbols, large print, Braille and different languages.\n\nExplore the patient's preferences about the level and type of information they want. Based on this, give the patient (and their family members and/or carers if appropriate) clear, consistent, evidence-based, tailored information throughout all stages of their care. This should include, but not be limited to, information on:\n\ntheir condition (or conditions) and any treatment options\n\nwhere they will be seen\n\nwho will undertake their care\n\nexpected waiting times for consultations, investigations and treatments.\n\nEnsure that mechanisms are in place to:\n\nprovide information about appointments to patients who require information in non‑standard formats\n\nalert services of any need for interpreters and non-standard formats to be available when patients move between services.\n\nAsk the patient whether they want to be accompanied at consultations by a family member, friend or advocate, and whether they would like to take notes and/or an audio recording of the consultation.\n\nGive the patient (and/or their family members and carers) information to enable them to use any medicines and equipment correctly. Ensure that the patient and their family members and carers feel adequately informed, prepared and supported to use medicines and equipment and to carry out self-care and self-management.\n\nAdvise the patient where they might find reliable high-quality information and support after consultations, from sources such as national and local support groups, networks and information services.\n\nGive the patient regular, accurate information about the duration of any delays during episodes of care.\n\n## Shared decision making\n\nRecommendations 1.5.20 to 1.5.27 have been replaced by NICE's guideline on shared decision making.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\n## Education programmes\n\nEnsure that patient-education programmes:\n\nare evidence-based\n\nhave specific aims and learning objectives\n\nmeet the needs of the patient (taking into account cultural, linguistic, cognitive and literacy considerations)\n\npromote the patient's ability to manage their own health if appropriate.\n\nGive the patient the opportunity to take part in evidence-based educational activities, including self-management programmes, that are available and meet the criteria listed in recommendation 1.5.28."}
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https://www.nice.org.uk/guidance/cg138
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This guideline covers the components of a good patient experience. It aims to make sure that all adults using NHS services have the best possible experience of care.
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cc1beb1af70861675d1409196d23254b067634ca
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nice
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Shared decision making
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Shared decision making
This guideline covers how to make shared decision making part of everyday care in all healthcare settings. It promotes ways for healthcare professionals and people using services to work together to make decisions about treatment and care. It includes recommendations on training, communicating risks, benefits and consequences, using decision aids, and how to embed shared decision making in organisational culture and practices.
# Recommendations
Shared decision making is a collaborative process that involves a person and their healthcare professional working together to reach a joint decision about care. It could be care the person needs straightaway or care in the future, for example, through advance care planning. See the full definition of shared decision making.
For more information on what shared decision making means for people receiving care and treatment, see making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Embedding shared decision making at an organisational level
NICE has produced a guideline on babies, children and young people's experience of healthcare.
## High-level leadership
Make a senior leader accountable and responsible for the leadership and embedding of shared decision making across every organisation or system regardless of its size. This should be a board member or, if the organisation does not have a board, a leader at the highest level of the organisation.
Consider appointing a patient director (from a healthcare service user background) to work with the senior leader and be responsible for:
raising the profile of the service user voice in planning, implementing and monitoring shared decision making, especially from those in under-served populations
supporting the embedding of shared decision making at the highest level of the organisation.
Appoint one or more senior healthcare professionals to work with the senior leader and patient director as organisation-wide 'champions' responsible for shared decision making.
Identify one or more organisation-wide 'service user champions' to work with the senior leader, patient director and professional champions for shared decision making. They should be recruited from people who use services.
## Planning and implementing shared decision making
Develop an organisation-wide improvement plan to put shared decision making into practice, based on recommendations 1.1.6 to 1.1.10.
In developing the improvement plan, identify:
existing good practice in departments or teams where shared decision making is already being practised routinely, and use their experience
departments or teams where shared decision making can be put into practice most easily next; continue this process across the whole organisation
key staff and service users to train as shared decision-making trainers, and suitable providers to deliver the training (see recommendation 1.1.13).
Review how information systems might support shared decision making, for example, by:
providing ready access to patient decision aids or information about risks, benefits and consequences during discussions with a healthcare professional
showing the person's past decisions and preferences, values and other information from previous discussions, for example, through a patient-held record (see recommendation 1.2.17).
Set out in the improvement plan how people who use services will be involved in supporting its implementation.
Plan internal or external monitoring and evaluation (including service user and staff feedback activities) and how to present the results to staff at individual, team and management level.
Establish a support network within the organisation for shared decision-making trainers (including service users who are trainers) and healthcare professionals. Consider joining up the support network with others in the wider system and across the region.
## Sharing information
Ensure that expertise and information can be shared effectively both within and between organisations so that healthcare professionals provide people with consistent information. See recommendation 1.1.7 and section 1.4 of the NICE guideline on patient experience in adult NHS services.
## Supporting healthcare professionals' skills and competencies
Organisations should ensure that knowledge, skills and confidence to support shared decision making are included in the induction, training and continuing professional development of all healthcare staff. This should include access to clinical supervision.
Ensure that training and development for healthcare professionals in shared decision making includes the following:
encouraging people to talk about what is important to them
understanding the principles that support shared decision making based on an evidence-based model (for example, the three-talk model)
communicating with people in a way they can understand, using clear language, avoiding jargon and explaining technical terms
sharing and discussing the information people need to make informed decisions, and making sure they understand the choices available to them (including the choice of doing nothing or not changing the current plan)
communicating with and involving family members, friends, carers, advocates or other people who the person chooses to include
using patient decision aids.
Provide access to 'train-the-trainer' style workshops (where healthcare professionals, and potentially service users, are taught to train other healthcare professionals) for key shared decision-making champions in the departments where shared decision making is being rolled out.
Ensure that training is practical (for example, using role play), rather than solely theoretical, so that healthcare professionals can put into practice the skills needed for shared decision making.
## Promoting shared decision making to people who use services
Organisations should actively promote shared decision making to people who use their services, for example, offering people training, and using posters or other media (such as appointment letters or websites) to prompt people to ask questions such as:
What are my options?
What are the possible benefits and risks of those options?
How can we make a decision together that is right for me?
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on embedding shared decision making at an organisational level .
Full details of the evidence and the committee's discussion are in:
evidence review A: effectiveness of approaches and activities to increase engagement in shared decision making and the barriers and facilitators to engagement
evidence review E: effective approaches and activities to normalise shared decision making in the healthcare system.
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# Putting shared decision making into practice
Support shared decision making by offering interventions at different stages, including before, during and after discussions, so that people are fully involved throughout their care.
Tailor the methods used to support shared decision making to the care setting and context in which the decision is being made, including whether the discussion is happening in person or remotely by video or phone.
Ask the person if they want to involve family members, friends, carers or advocates (being aware of safeguarding). If so, include them as a way to help the person:
actively engage in the discussion
explain what matters to them
make decisions about their care
remember information they have been given during the discussion.
When providing information and resources:
-nly use reliable, high-quality sources such as NICE-accredited information, links to the NHS website, information from appropriate patient organisations, or relevant NICE guidelines and quality-assured patient decision aids
take into account accessibility and the requirement to meet the NHS Accessible Information Standard.
## Before a discussion
Before a discussion, offer the person access to resources in their preferred format (for example, a booklet, flyer or app) to help them prepare for discussing options and making shared decisions. It should encourage them to think about:
what matters to them
what they hope will happen as a result of the discussion
what questions they would like to ask (see recommendation 1.1.16).
Offer to arrange additional support for people who might find it difficult to share in decision making, especially if they do not have, or do not want, support from a family member, friend or carer. Support could come from a nurse, social worker, interpreter or volunteer (for example, an advocate) who can:
help them to understand the resources provided
encourage the person to take an active part in decision making
reassure them that shared decision making will be supported by the healthcare professional they see.
## During a discussion
Agree an 'agenda' at the start of each discussion to prioritise together what to discuss. Say how long the discussion will last.
Ensure the person understands they can take part as fully as they want in making choices about their treatment or care.
When discussing decisions about tests, treatments and interventions, do so in a way that encourages people to think about what matters to them, and to express their needs and preferences.
When discussing tests, treatments or other healthcare services:
explain the healthcare aims of each option and discuss how they align with the person's aims, priorities and wider goals
-penly discuss the risks, benefits and consequences of each option, making sure the person knows this includes choosing no treatment, or no change to what they are currently doing
clarify what the person hopes to gain from a treatment or intervention and discuss any misconceptions
set aside enough time to answer questions, and ask the person if they would like a further opportunity to discuss options.
Support the person when they are considering options by:
delivering information in manageable chunks (chunk and check)
checking they understand the information (for example, using the teach back technique)
discussing what matters to them in light of the information provided and checking that their choice is consistent with this.
Give people (and their family members, friends or carers, as appropriate) the time they need to make decisions about tests, treatments and interventions.
Accept and acknowledge that people may vary in their views about the balance of risks, benefits and consequences of treatments, and that they may differ from those of their healthcare professionals.
Make a joint decision or plan about treatment or care, and agree together when this will be reviewed.
At the end of a discussion, state clearly what decisions have been made to make sure there is a shared understanding between the person and their healthcare professional about what has been agreed, what happens next, what the timescales are, and when it will be reviewed.
Explain to the person that they can review their decision earlier than the agreed review date if they want to, and can change their mind about a decision they have made at any time.
When making a record of the discussion (for example, in a person's clinical notes or care plan), record any decisions made along with details of what the person said was important to them in making those decisions. Offer to share this with the person, for example, in a post-clinic letter.
## After or between discussions
Offer people resources in their preferred format to help them understand what was discussed and agreed. This could be a printout summarising their diagnosis, the options and decisions or plans made, and links to high-quality online resources. Ideally, give people this material to take away, or provide it very soon after the discussion.
Ensure that information provided after discussions includes details of who to contact with any further questions.
When writing clinical letters after a discussion, write them to the patient rather than to their healthcare professional, in line with Academy of Medical Royal Colleges' guidance on writing outpatient clinic letters to patients. Send a copy of the letter to the patient (unless they say they do not want a copy) and to the relevant healthcare professional.
Offer additional support to people who are likely to need extra help to engage in shared decision making. This could include encouraging them to record the discussion, explaining in writing the decisions that have been made, or arranging follow up by a clinical member of staff or a suitable alternative.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on putting shared decision making into practice .
Full details of the evidence and the committee's discussion are in evidence review B: interventions to support effective shared decision making.
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# Patient decision aids
## Healthcare professionals
Use patient decision aids as one part of an overall 'toolkit' to support shared decision making alongside the other skills and interventions outlined in section 1.2 and section 1.4 of this guideline. If a relevant decision aid is not available, continue to use the shared decision-making principles outlined in this guideline.
Only use a patient decision aid if it is:
quality assured and reflects evidence-based best practice
relevant to that discussion and the decision that needs to be made
relevant to that clinical setting.
Before using a particular decision aid, healthcare professionals should make sure they are familiar with it, including how it will help people to understand which option is best for them.
## Organisations
Also see recommendations 1.6.10 to 1.6.12 in NICE's guideline on medicines optimisation on making patient decision aids available for consultations about medicines.
Think about ways to give staff in the organisation or system access to quality-assured patient decision aids (assessed against NICE's standards framework for shared decision making support tools, including patient decision aids, or the International Patient Decision Aid Standards). This could be by maintaining a database of decision aids that are regularly reviewed and updated, or signposting staff to decision aids produced by national bodies such as NICE.
Organisations should ensure their facilities and systems support staff to provide patient decision aids in multiple ways to suit people's needs, for example, printed or online and available in different languages and formats.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on patient decision aids .
Full details of the evidence and the committee's discussion are in evidence review C: decision aids for people facing health treatment or screening decisions.
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# Communicating risks, benefits and consequences
Discuss risks, benefits and consequences in the context of each person's life and what matters to them. Be aware that risk communication can often be supported by using good-quality patient decision aids or graphical presentations such as pictographs (see recommendations 1.3.1 to 1.3.3).
Personalise information on risks, benefits and consequences as much as possible. Make it clear to people how the information you are providing applies to them personally and how much uncertainty is associated with it. For more on dealing with uncertainty, see the General Medical Council's guidance on decision making and consent.
Organisations should ensure that staff presenting information about risks, benefits and consequences to people have a good understanding of that information and how to apply and explain it clearly (see recommendations 1.1.12 and 1.1.13).
If information on risks, benefits and consequences specific to the person is not available, continue to use the shared decision making principles outlined in this guideline.
## Discussing numerical information
Think about using a mixture of numbers and pictures, for example, numerical rates along with pictograms or icon arrays, to allow people to see both positive and negative framing (see recommendation 1.4.11) at the same time.
Use numerical data to describe risks if available. Be aware that different people interpret terms such as 'risk', 'rare', 'unusual' and 'common' in different ways.
Use absolute risk rather than relative risk. For example, the risk of an event increases from 1 in 1,000 to 2 in 1,000, rather than the risk of the event doubles.
Use natural frequencies (for example, 10 in 100) rather than percentages (10%).
Be consistent when using data. For example, use the same denominator when comparing risk: 7 in 100 for one risk and 20 in 100 for another, rather than 1 in 14 and 1 in 5.
Present a risk over a defined period of time (months or years) if relevant. For example, if 100 people have treatment for 1 year, 10 will experience a given side effect.
Use both positive and negative framing. For example, treatment will be successful for 97 out of 100 people and it will be unsuccessful for 3 out of 100 people.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communicating risks, benefits and consequences .
Full details of the evidence and the committee's discussion are in evidence review D: risk communication.
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# Terms used in this guideline
## Chunk and check
A technique to break down information into smaller, more manageable chunks rather than providing it all at once. In between each 'chunk', methods such as teach back are used to check for understanding before moving on.
## Discussion
In this guideline, a discussion is any interaction (in person or remote) between a healthcare professional and a person using services in which a healthcare decision might be made.
## Organisation or system
For the purpose of this guideline, this could refer to any organisation or network of organisations, for example, a general practice, a single hospital or clinic, a network or cluster of clinics, practices or services, or an integrated system or partnership between services, for example, a local dental network.
## Patient decision aids
Patient decision aids are tools designed to help people take part in decision making about healthcare options. They provide information on the options and help people to think about, clarify and communicate the value of each option to them personally.
Patient decision aids do not advise people to choose 1 option over another, nor are they meant to replace healthcare professional consultation. Instead, they support people to make informed, values-based decisions with their healthcare professional.
(Adapted from the International Patient Decision Aid Standards Collaboration website.)
## Shared decision making
Shared decision making is a collaborative process that involves a person and their healthcare professional working together to reach a joint decision about care. It could be care the person needs straightaway or care in the future, for example, through advance care planning. It involves choosing tests and treatments based both on evidence and on the person's individual preferences, beliefs and values. It means making sure the person understands the risks, benefits and possible consequences of different options through discussion and information sharing. This joint process empowers people to make decisions about the care that is right for them at that time (with the options of choosing to have no treatment or not changing what they are currently doing always included).
## Teach back
The teach back method is a useful way to confirm that the information provided is being understood by getting people to 'teach back' what has been discussed and what instruction has been given. This is more than saying 'do you understand?' and is a check of how well things have been explained and understood.
## Three-talk model
The three-talk model is a practical model of how to do shared decision making that is based on following choice, option and decision talk stages during the consultation. The model has 3 steps:
introducing choice
describing options, often by integrating the use of patient decision support
helping people explore their preferences and make decisions.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Differing intervention effects in different groups
How do the same shared decision-making interventions differ in effectiveness between different groups of people and different care settings?
For a short explanation of why the committee made the recommendation for research, see the rationale section on putting shared decision making into practice .
Full details of the evidence and the committee's discussion are in evidence review B: interventions to support effective shared decision making.
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# Measuring shared decision making
What are the best ways to measure the effectiveness of shared decision making in different contexts (in different settings and involving different people)?
For a short explanation of why the committee made the recommendation for research, see the rationale section on putting shared decision making into practice .
Full details of the evidence and the committee's discussion are in evidence review B: interventions to support effective shared decision making.
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# Sustaining shared decision making
What interventions are most effective at transferring shared decision-making skills between people and departments, and in sustaining the implementation of shared decision making in an organisation and in clinical teams?
For a short explanation of why the committee made the recommendation for research, see the rationale section on embedding shared decision making at an organisational level .
Full details of the evidence and the committee's discussion are in:
evidence review A: effectiveness of approaches and activities to increase engagement in shared decision making and the barriers and facilitators to engagement
evidence review E: effective approaches and activities to normalise shared decision making in the healthcare system.
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# Acceptability of shared decision making
What influences the acceptability of shared decision making in populations that predominantly believe in the authority of the healthcare professional?
For a short explanation of why the committee made the recommendation for research, see the rationale section on putting shared decision making into practice .
Full details of the evidence and the committee's discussion are in evidence review B: interventions to support effective shared decision making.
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# Shared decision making in remote discussions
How do shared decision-making skills and techniques need to be modified for remote discussions?
For a short explanation of why the committee made the recommendation for research, see the rationale section on putting shared decision making into practice .
Full details of the evidence and the committee's discussion are in evidence review B: interventions to support effective shared decision making.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Embedding shared decision making at an organisational level
Recommendations 1.1.1 to 1.1.16
## Why the committee made the recommendations
Although a reasonable number of quantitative studies were identified, their usefulness was limited because it was often unclear whether or not interventions were effective, so the committee could not recommend specific interventions. There was qualitative evidence and evidence from experts on the ways shared decision making had been implemented internationally. Using this evidence and their own expertise, the committee recommended ways organisations could embed shared decision making into everyday practice.
The importance of strong leadership was a particularly prominent theme in the expert evidence and this was supported by the committee's views. In their experience, having a commitment from senior managers and leaders to shared decision making is essential because they can make sure resources are prioritised to support it and help to instil a culture of involving people who use services across the whole organisation. This could also be supported by choosing staff to be champions within the organisation and appointing patient leaders. These people would provide a strong voice to advocate for this approach and could act as 'influencers', passing on their knowledge and training in shared decision making to their colleagues.
The committee also agreed that appointing a person who uses services to a patient director post enabled service-users' voices to be heard at the highest levels of the organisation. Although the committee agreed this was a good idea, they were also aware that appointing a director-level post in an organisation was a large financial investment that might not be possible, especially in smaller organisations. For this reason, they agreed only to recommend this as an option to consider.
The committee discussed the importance of an organisation-wide plan for implementing shared decision making and made recommendations based on expert evidence from organisations that had successfully achieved this. These included using digital technology to support shared decision making (for example, through patient-held records) and putting in place 'train-the-trainer' style training. The committee agreed this was the most useful way to approach shared decision making training because it brought the necessary expertise in-house. Based on expert evidence and their own expertise, the committee recommended establishing support networks for these trained healthcare professionals and service users. This can improve how the implementation of shared decision making is monitored and communicated across organisations and areas.
The committee also used the expert evidence and their own expertise to recommend how to involve people who use services in implementing shared decision making and monitoring and evaluating its use in practice.
The committee was aware of national resources that might support developing a plan to implement shared decision making, such as the NHS England and NHS Improvement shared decision making summary guide and implementation checklist. In the short term, the roll-out of shared decision making might create further inequalities in services where it had not yet been implemented, but the committee agreed this was temporary and unavoidable.
Although shared decision making is most often carried out between people and their healthcare professionals, other practitioners (for example, healthcare assistants and some administrative and management staff) may also need to have shared decision-making skills, training and support. The committee noted resources and e‑learning that might support this, such as the health literacy e-learning resource produced by Health Education England and NHS Scotland.
Because of the lack of published evidence about rolling out shared decision making across organisations, and about sustaining shared decision making in organisations, the committee made a recommendation for research on sustaining shared decision making.
## How the recommendations might affect services
The committee hopes these recommendations will help increase the use of shared decision making in organisations by overcoming common barriers. Implementing the recommendations could have a modest impact on resources (for example, training or monitoring), but some changes, for example, appointing a patient director, could have a much larger impact.
Return to recommendations
# Putting shared decision making into practice
Recommendations 1.2.1 to 1.2.21
## Why the committee made the recommendations
In the committee's view, shared decision making should be treated as an ongoing process rather than a one‑off event. Using excellent communication and shared decision-making skills alongside a combination of other interventions that support shared decision making is likely to be most effective because no single intervention can be a one-size-fits-all solution, and the evidence supported this. The best available evidence was for multicomponent rather than individual interventions.
The committee also wanted to highlight that shared decision-making interventions may need to be adapted to specific settings and populations. The same intervention would need to be tailored differently to be used in a GP appointment, an outpatient clinic and inpatient hospital admission. In the committee's view, this also applies to remote discussions (for example, by phone or video). The committee agreed that the same skills and principles would be relevant even though the exact methods would be context dependent.
The committee noted the importance of the 'digital divide', with some people being unable to access or less familiar with things like online discussions. The committee did not see strong evidence about this and agreed it was an important area for research because of the increase in remote discussions in response to COVID‑19. As a result, they made a recommendation for research on shared decision making in remote discussions to explore this further.
Providing information is important, but the committee wanted to emphasise that it needs to be of good quality, for example, NICE-accredited. The committee was aware that other quality standards exist, like the PIF TICK quality mark for patient organisations. There are also useful resources, such as 'ask 3 questions' and other tools to help people prepare, on the NHS England website.
There was some evidence supporting offering interventions before discussions. Even though the studies that looked specifically at pre-discussion interventions did not show an increase in shared decision making itself, there was some evidence that these kinds of interventions increased people's knowledge and their satisfaction with their discussions. The committee agreed that, although knowledge alone is not enough for shared decision making to take place, it is a necessary part of it.
Supporting evidence also came from studies looking at other types of interventions that were offered before discussions: support from another person ('third party support') and eliciting people's preferences and values.
The committee recognised the benefits of arranging third party support for people who might need additional support to engage in shared decision making. This could include, for example, people who have a condition or disability that makes it more difficult for them to participate. The committee agreed that everybody should be encouraged to bring a family member, friend or carer to discussions if they choose to.
The committee acknowledged that intervention before a discussion was not always practical, for example, if the person needed care unexpectedly or urgently, so these recommendations would be best suited to non-urgent discussions.
The committee updated recommendations on shared decision making in NICE's guideline on patient experience in adult NHS services using the evidence and their expertise, and brought them into this guideline.
The studies looking at what was effective in shared decision making showed the strongest support for eliciting people's expectations, values, priorities and goals as part of interventions based on key stages of shared decision making from the three-talk model. These include 'choice talk' (also called 'team talk') that introduces the fact that there are options, and that the right option will depend on what matters to each person, and 'option talk', when they discuss alternatives addressing the risks, benefits and consequences of each option. These then lead onto 'decision talk', which makes sure a decision is made that is right for each person. The committee agreed it was useful to think about these key stages of shared decision making, but acknowledged that other models of shared decision making were in common use.
Evidence suggested using the three-talk model as a way to structure the shared decision-making process and the committee agreed that the interventions that showed an effect were all consistent with 1 or more of the stages of the three-talk model. In their view, the three-talk model was simple to use and that made it useful in all healthcare settings. The committee agreed, however, that any evidence-based model for shared decision making is useful so they were not prescriptive in the recommendations.
Agenda setting, explicitly stating decisions, the option of no treatment (that is, not choosing any of the treatments offered), and agreeing when to review a decision were not captured in the effectiveness evidence, but the committee considered them to be key aspects of shared decision making.
The committee noted that some people may not want to be involved in shared decision making. They also noted that not all decisions can be shared. People have a right to refuse any treatment, and similarly, healthcare professionals are not obliged to provide any treatment that in their clinical opinion is medically futile (this may need a second opinion or discussion with a senior colleague). Healthcare professionals cannot provide access to treatments that are not available.
The committee talked about documenting discussions. They agreed that recording which options have been discussed and what is important to the person is the best evidence that a meaningful shared decision making dialogue has taken place.
The committee highlighted that interventions to support shared decision making should carry on after discussions with a healthcare professional because they should be part of a continuing process. They agreed on some methods to support people who might need additional help, such as suggesting that they record the discussion on their phone or other electronic device to help them remember what was said and think about their options.
The committee made recommendations for research to fill the most notable gaps in the evidence. They agreed that research was needed into how the same shared decision-making interventions differ in effectiveness between different populations and different care settings so they made a recommendation for research on differing intervention effects in different groups. The committee also noted from the evidence that it was unclear what the best measures of shared decision making are and how acceptable different interventions are to people who receive them, so they also made recommendations for research about measuring shared decision making and the acceptability of shared decision making.
## How the recommendations might affect services
The recommendations will help to increase the use of shared decision making in day-to-day clinical practice by suggesting effective methods to support it. Some of the options in the recommendations may need additional resources, for example, using a healthcare worker to provide third party support, but others can be integrated into current practice, for example, encouraging a person to record their discussion. There is also a potential that in some healthcare settings, appointments or consultations may need to be longer and this could represent a substantial resource impact, but might lead to fewer subsequent appointments and will ensure that the right decisions are made with people.
Return to recommendations
# Patient decision aids
Recommendations 1.3.1 to 1.3.5
## Why the committee made the recommendations
There was strong evidence to support using patient decision aids before, during and between discussions. However, the committee wanted to make it clear that decision aids alone do not deliver shared decision making but should be seen as 1 component of a wider approach. There would never be a patient decision aid available to support every discussion, and healthcare professionals still need to have the skills described in this guideline to engage people in making shared decisions irrespective of whether decision aids are available.
The committee agreed that for patient decision aids to be most useful, staff should have access to quality‑assured patient decision aids either via a maintained database or signposting to those produced by national bodies. They also highlighted that even though the evidence favoured using patient decision aids, it is crucial to provide them to people in formats they can use and understand otherwise they would not be useful. In the committee's view, organisations should think about ways to make sure that a database of quality‑assured decision aids is available to their staff in many different formats and that systems support using them in different ways. In the committee's experience, accessing decision aids in suitable formats is not always possible – for example, facilities to print out decision aids are not always available in consulting rooms across organisations, and some decision aids cannot be printed because of their format, for example, if they have a block colour background that requires a lot of ink.
## How the recommendations might affect practice
The committee agreed that there were many good-quality patient decision aids that healthcare professionals could use and that more were being developed all the time. Many of them are freely available. Maintaining a database of decision aids could have a moderate resource impact, but the committee noted that these could be set up in collaboration with other organisations to maximise 'economies of scale'. The committee also noted that there might be some resource impact of printing more material for people.
Return to recommendations
# Communicating risks, benefits and consequences
Recommendations 1.4.1 to 1.4.11
## Why the committee made the recommendations
The committee updated recommendations on communicating risks and benefits from NICE's guideline on patient experience in adult NHS services and brought them into this guideline.
The committee agreed that people's interpretation of risks, benefits and consequences is fundamentally embedded in their values and priorities, which explains why people do not weigh risks, benefits and consequences in the same way as others, or indeed in the same way as professionals.
The committee agreed that a person can only make an informed decision if they are given enough information to do so, and if the risks, benefits and consequences presented to them relate directly to their circumstances and what is important to them. Information about risks and benefits will be weighed differently in different situations and depending on a person's prognosis and the decisions they have to make. They discussed the evidence about presenting absolute risks compared with relative risks and noted that absolute risks are much clearer, especially when accompanied by visual summaries. They agreed that presenting relative risks alone was misleading and that relative risk should only be introduced as a supplement to absolute risks.
The committee wanted risks and benefits to be personalised using high-quality numerical data when these are available. Ideally, healthcare professionals would be able to provide personalised risk calculations. However, the committee acknowledged that personalised risk information is often not available. This means healthcare professionals often need to use generalised information about risks, benefits and consequences (usually available in good-quality decision aids) and explain to the person how it relates to them (for example, above average, average or below average levels of risk). Explaining how much uncertainty surrounds these estimates will help people interpret that information and what it means for them. The committee highlighted guidance from the General Medical Council (GMC) for more information – although GMC guidance is written for doctors, they agreed it provided an example of good practice for all professionals.
## How the recommendations might affect practice
These recommendations will help healthcare professionals explore risk, benefits and consequences of healthcare decisions with people. The committee noted that because the recommendations in NICE's guideline on patient experience in adult NHS services have been in place since 2012, there should be no resource impact.
Return to recommendations# Context
Shared decision making is a collaborative process that involves a person and their healthcare professional working together to reach a joint decision about care. It could be care the person needs straightaway or care in the future, for example, through advance care planning. It involves choosing tests and treatments based both on evidence and on the person's individual preferences, beliefs and values. It means making sure the person understands the risks, benefits and possible consequences of different options through discussion and information sharing. This joint process empowers people to make decisions about the care that is right for them at that time (with the options of choosing to have no treatment or not changing what they are currently doing always included). In line with NHS England's personalised care and support planning guidance: guidance for local maternity systems, in maternity services this may be referred to as 'informed decision making'.
Shared decision making is enshrined as a principle in the NHS Constitution, with principle 4 stating that, 'Patients, with their families and carers, where appropriate, will be involved in and consulted on all decisions about their care and treatment'.
Some people prefer not to take an active role in making decisions with their healthcare professionals, but they should always be given the opportunity to choose to what degree they want to engage in decision making and the extent to which decisions that are made on their behalf are discussed and communicated with them, including the reasons for selecting a particular treatment. Involving people in decisions about their care may result in:
greater satisfaction with the decisions made
greater understanding about the risks and benefits of the available options
better communication between people and their healthcare professional, including people feeling that they have 'been heard'
improved trust between people and their healthcare professional
better concordance with an agreed treatment plan
people reporting a better experience of care, including more satisfaction with the outcome.
After the Montgomery v Lanarkshire case (2015), a new legal standard was set to protect people's rights to make informed decisions when giving or withholding consent to treatment. Healthcare professionals should discuss the risks and benefits of each course of action that are meaningful to the particular person. Consent 'must be obtained before treatment interfering with bodily integrity is undertaken', and it should only be gained when a person has shared a decision informed by what is known about the risks, benefits and consequences of all reasonable NHS treatment options. As set out in the NHS Constitution for England, people have the right to be involved in planning and making decisions about their health and care, and to be given information and support to enable this.
The General Medical Council's guidance on decision making and consent (published in 2020) says that healthcare professionals should discuss 'risks of harm and potential benefits that the patient would consider significant for any reason. These will be revealed during your discussion with the patient about what matters to them'. It also states that they should discuss 'any risk of serious harm, however unlikely it is to occur'.
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{'Recommendations': "Shared decision making is a collaborative process that involves a person and their healthcare professional working together to reach a joint decision about care. It could be care the person needs straightaway or care in the future, for example, through advance care planning. See the full definition of shared decision making.\n\nFor more information on what shared decision making means for people receiving care and treatment, see making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Embedding shared decision making at an organisational level\n\nNICE has produced a guideline on babies, children and young people's experience of healthcare.\n\n## High-level leadership\n\nMake a senior leader accountable and responsible for the leadership and embedding of shared decision making across every organisation or system regardless of its size. This should be a board member or, if the organisation does not have a board, a leader at the highest level of the organisation.\n\nConsider appointing a patient director (from a healthcare service user background) to work with the senior leader and be responsible for:\n\nraising the profile of the service user voice in planning, implementing and monitoring shared decision making, especially from those in under-served populations\n\nsupporting the embedding of shared decision making at the highest level of the organisation.\n\nAppoint one or more senior healthcare professionals to work with the senior leader and patient director as organisation-wide 'champions' responsible for shared decision making.\n\nIdentify one or more organisation-wide 'service user champions' to work with the senior leader, patient director and professional champions for shared decision making. They should be recruited from people who use services.\n\n## Planning and implementing shared decision making\n\nDevelop an organisation-wide improvement plan to put shared decision making into practice, based on recommendations 1.1.6 to 1.1.10.\n\nIn developing the improvement plan, identify:\n\nexisting good practice in departments or teams where shared decision making is already being practised routinely, and use their experience\n\ndepartments or teams where shared decision making can be put into practice most easily next; continue this process across the whole organisation\n\nkey staff and service users to train as shared decision-making trainers, and suitable providers to deliver the training (see recommendation 1.1.13).\n\nReview how information systems might support shared decision making, for example, by:\n\nproviding ready access to patient decision aids or information about risks, benefits and consequences during discussions with a healthcare professional\n\nshowing the person's past decisions and preferences, values and other information from previous discussions, for example, through a patient-held record (see recommendation 1.2.17).\n\nSet out in the improvement plan how people who use services will be involved in supporting its implementation.\n\nPlan internal or external monitoring and evaluation (including service user and staff feedback activities) and how to present the results to staff at individual, team and management level.\n\nEstablish a support network within the organisation for shared decision-making trainers (including service users who are trainers) and healthcare professionals. Consider joining up the support network with others in the wider system and across the region.\n\n## Sharing information\n\nEnsure that expertise and information can be shared effectively both within and between organisations so that healthcare professionals provide people with consistent information. See recommendation 1.1.7 and section 1.4 of the NICE guideline on patient experience in adult NHS services.\n\n## Supporting healthcare professionals' skills and competencies\n\nOrganisations should ensure that knowledge, skills and confidence to support shared decision making are included in the induction, training and continuing professional development of all healthcare staff. This should include access to clinical supervision.\n\nEnsure that training and development for healthcare professionals in shared decision making includes the following:\n\nencouraging people to talk about what is important to them\n\nunderstanding the principles that support shared decision making based on an evidence-based model (for example, the three-talk model)\n\ncommunicating with people in a way they can understand, using clear language, avoiding jargon and explaining technical terms\n\nsharing and discussing the information people need to make informed decisions, and making sure they understand the choices available to them (including the choice of doing nothing or not changing the current plan)\n\ncommunicating with and involving family members, friends, carers, advocates or other people who the person chooses to include\n\nusing patient decision aids.\n\nProvide access to 'train-the-trainer' style workshops (where healthcare professionals, and potentially service users, are taught to train other healthcare professionals) for key shared decision-making champions in the departments where shared decision making is being rolled out.\n\nEnsure that training is practical (for example, using role play), rather than solely theoretical, so that healthcare professionals can put into practice the skills needed for shared decision making.\n\n## Promoting shared decision making to people who use services\n\nOrganisations should actively promote shared decision making to people who use their services, for example, offering people training, and using posters or other media (such as appointment letters or websites) to prompt people to ask questions such as:\n\nWhat are my options?\n\nWhat are the possible benefits and risks of those options?\n\nHow can we make a decision together that is right for me?\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on embedding shared decision making at an organisational level\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: effectiveness of approaches and activities to increase engagement in shared decision making and the barriers and facilitators to engagement\n\nevidence review\xa0E: effective approaches and activities to normalise shared decision making in the healthcare system.\n\nLoading. Please wait.\n\n# Putting shared decision making into practice\n\nSupport shared decision making by offering interventions at different stages, including before, during and after discussions, so that people are fully involved throughout their care.\n\nTailor the methods used to support shared decision making to the care setting and context in which the decision is being made, including whether the discussion is happening in person or remotely by video or phone.\n\nAsk the person if they want to involve family members, friends, carers or advocates (being aware of safeguarding). If so, include them as a way to help the person:\n\nactively engage in the discussion\n\nexplain what matters to them\n\nmake decisions about their care\n\nremember information they have been given during the discussion.\n\nWhen providing information and resources:\n\nonly use reliable, high-quality sources such as NICE-accredited information, links to the NHS website, information from appropriate patient organisations, or relevant NICE guidelines and quality-assured patient decision aids\n\ntake into account accessibility and the requirement to meet the NHS Accessible Information Standard.\n\n## Before a discussion\n\nBefore a discussion, offer the person access to resources in their preferred format (for example, a booklet, flyer or app) to help them prepare for discussing options and making shared decisions. It should encourage them to think about:\n\nwhat matters to them\n\nwhat they hope will happen as a result of the discussion\n\nwhat questions they would like to ask (see recommendation\xa01.1.16).\n\nOffer to arrange additional support for people who might find it difficult to share in decision making, especially if they do not have, or do not want, support from a family member, friend or carer. Support could come from a nurse, social worker, interpreter or volunteer (for example, an advocate) who can:\n\nhelp them to understand the resources provided\n\nencourage the person to take an active part in decision making\n\nreassure them that shared decision making will be supported by the healthcare professional they see.\n\n## During a discussion\n\nAgree an 'agenda' at the start of each discussion to prioritise together what to discuss. Say how long the discussion will last.\n\nEnsure the person understands they can take part as fully as they want in making choices about their treatment or care.\n\nWhen discussing decisions about tests, treatments and interventions, do so in a way that encourages people to think about what matters to them, and to express their needs and preferences.\n\nWhen discussing tests, treatments or other healthcare services:\n\nexplain the healthcare aims of each option and discuss how they align with the person's aims, priorities and wider goals\n\nopenly discuss the risks, benefits and consequences of each option, making sure the person knows this includes choosing no treatment, or no change to what they are currently doing\n\nclarify what the person hopes to gain from a treatment or intervention and discuss any misconceptions\n\nset aside enough time to answer questions, and ask the person if they would like a further opportunity to discuss options.\n\nSupport the person when they are considering options by:\n\ndelivering information in manageable chunks (chunk and check)\n\nchecking they understand the information (for example, using the teach back technique)\n\ndiscussing what matters to them in light of the information provided and checking that their choice is consistent with this.\n\nGive people (and their family members, friends or carers, as appropriate) the time they need to make decisions about tests, treatments and interventions.\n\nAccept and acknowledge that people may vary in their views about the balance of risks, benefits and consequences of treatments, and that they may differ from those of their healthcare professionals.\n\nMake a joint decision or plan about treatment or care, and agree together when this will be reviewed.\n\nAt the end of a discussion, state clearly what decisions have been made to make sure there is a shared understanding between the person and their healthcare professional about what has been agreed, what happens next, what the timescales are, and when it will be reviewed.\n\nExplain to the person that they can review their decision earlier than the agreed review date if they want to, and can change their mind about a decision they have made at any time.\n\nWhen making a record of the discussion (for example, in a person's clinical notes or care plan), record any decisions made along with details of what the person said was important to them in making those decisions. Offer to share this with the person, for example, in a post-clinic letter.\n\n## After or between discussions\n\nOffer people resources in their preferred format to help them understand what was discussed and agreed. This could be a printout summarising their diagnosis, the options and decisions or plans made, and links to high-quality online resources. Ideally, give people this material to take away, or provide it very soon after the discussion.\n\nEnsure that information provided after discussions includes details of who to contact with any further questions.\n\nWhen writing clinical letters after a discussion, write them to the patient rather than to their healthcare professional, in line with Academy of Medical Royal Colleges' guidance on writing outpatient clinic letters to patients. Send a copy of the letter to the patient (unless they say they do not want a copy) and to the relevant healthcare professional.\n\nOffer additional support to people who are likely to need extra help to engage in shared decision making. This could include encouraging them to record the discussion, explaining in writing the decisions that have been made, or arranging follow up by a clinical member of staff or a suitable alternative.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on putting shared decision making into practice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: interventions to support effective shared decision making.\n\nLoading. Please wait.\n\n# Patient decision aids\n\n## Healthcare professionals\n\nUse patient decision aids as one part of an overall 'toolkit' to support shared decision making alongside the other skills and interventions outlined in section\xa01.2 and section\xa01.4 of this guideline. If a relevant decision aid is not available, continue to use the shared decision-making principles outlined in this guideline.\n\nOnly use a patient decision aid if it is:\n\nquality assured and reflects evidence-based best practice\n\nrelevant to that discussion and the decision that needs to be made\n\nrelevant to that clinical setting.\n\nBefore using a particular decision aid, healthcare professionals should make sure they are familiar with it, including how it will help people to understand which option is best for them.\n\n## Organisations\n\nAlso see recommendations 1.6.10 to 1.6.12 in NICE's guideline on medicines optimisation on making patient decision aids available for consultations about medicines.\n\nThink about ways to give staff in the organisation or system access to quality-assured patient decision aids (assessed against NICE's standards framework for shared decision making support tools, including patient decision aids, or the International Patient Decision Aid Standards). This could be by maintaining a database of decision aids that are regularly reviewed and updated, or signposting staff to decision aids produced by national bodies such as NICE.\n\nOrganisations should ensure their facilities and systems support staff to provide patient decision aids in multiple ways to suit people's needs, for example, printed or online and available in different languages and formats.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on patient decision aids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: decision aids for people facing health treatment or screening decisions.\n\nLoading. Please wait.\n\n# Communicating risks, benefits and consequences\n\nDiscuss risks, benefits and consequences in the context of each person's life and what matters to them. Be aware that risk communication can often be supported by using good-quality patient decision aids or graphical presentations such as pictographs (see recommendations 1.3.1 to 1.3.3).\n\nPersonalise information on risks, benefits and consequences as much as possible. Make it clear to people how the information you are providing applies to them personally and how much uncertainty is associated with it. For more on dealing with uncertainty, see the General Medical Council's guidance on decision making and consent.\n\nOrganisations should ensure that staff presenting information about risks, benefits and consequences to people have a good understanding of that information and how to apply and explain it clearly (see recommendations 1.1.12 and 1.1.13).\n\nIf information on risks, benefits and consequences specific to the person is not available, continue to use the shared decision making principles outlined in this guideline.\n\n## Discussing numerical information\n\nThink about using a mixture of numbers and pictures, for example, numerical rates along with pictograms or icon arrays, to allow people to see both positive and negative framing (see recommendation 1.4.11) at the same time.\n\nUse numerical data to describe risks if available. Be aware that different people interpret terms such as 'risk', 'rare', 'unusual' and 'common' in different ways.\n\nUse absolute risk rather than relative risk. For example, the risk of an event increases from 1 in 1,000 to 2 in 1,000, rather than the risk of the event doubles.\n\nUse natural frequencies (for example, 10 in 100) rather than percentages (10%).\n\nBe consistent when using data. For example, use the same denominator when comparing risk: 7 in 100 for one risk and 20 in 100 for another, rather than 1 in 14 and 1 in 5.\n\nPresent a risk over a defined period of time (months or years) if relevant. For example, if 100\xa0people have treatment for 1\xa0year, 10 will experience a given side effect.\n\nUse both positive and negative framing. For example, treatment will be successful for 97 out of 100\xa0people and it will be unsuccessful for 3 out of 100\xa0people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communicating risks, benefits and consequences\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: risk communication.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Chunk and check\n\nA technique to break down information into smaller, more manageable chunks rather than providing it all at once. In between each 'chunk', methods such as teach back are used to check for understanding before moving on.\n\n## Discussion\n\nIn this guideline, a discussion is any interaction (in person or remote) between a healthcare professional and a person using services in which a healthcare decision might be made.\n\n## Organisation or system\n\nFor the purpose of this guideline, this could refer to any organisation or network of organisations, for example, a general practice, a single hospital or clinic, a network or cluster of clinics, practices or services, or an integrated system or partnership between services, for example, a local dental network.\n\n## Patient decision aids\n\nPatient decision aids are tools designed to help people take part in decision making about healthcare options. They provide information on the options and help people to think about, clarify and communicate the value of each option to them personally.\n\nPatient decision aids do not advise people to choose 1\xa0option over another, nor are they meant to replace healthcare professional consultation. Instead, they support people to make informed, values-based decisions with their healthcare professional.\n\n(Adapted from the International Patient Decision Aid Standards Collaboration website.)\n\n## Shared decision making\n\nShared decision making is a collaborative process that involves a person and their healthcare professional working together to reach a joint decision about care. It could be care the person needs straightaway or care in the future, for example, through advance care planning. It involves choosing tests and treatments based both on evidence and on the person's individual preferences, beliefs and values. It means making sure the person understands the risks, benefits and possible consequences of different options through discussion and information sharing. This joint process empowers people to make decisions about the care that is right for them at that time (with the options of choosing to have no treatment or not changing what they are currently doing always included).\n\n## Teach back\n\nThe teach back method is a useful way to confirm that the information provided is being understood by getting people to 'teach back' what has been discussed and what instruction has been given. This is more than saying 'do you understand?' and is a check of how well things have been explained and understood.\n\n## Three-talk model\n\nThe three-talk model is a practical model of how to do shared decision making that is based on following choice, option and decision talk stages during the consultation. The model has 3\xa0steps:\n\nintroducing choice\n\ndescribing options, often by integrating the use of patient decision support\n\nhelping people explore their preferences and make decisions.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Differing intervention effects in different groups\n\nHow do the same shared decision-making interventions differ in effectiveness between different groups of people and different care settings?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on putting shared decision making into practice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: interventions to support effective shared decision making.\n\nLoading. Please wait.\n\n# Measuring shared decision making\n\nWhat are the best ways to measure the effectiveness of shared decision making in different contexts (in different settings and involving different people)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on putting shared decision making into practice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: interventions to support effective shared decision making.\n\nLoading. Please wait.\n\n# Sustaining shared decision making\n\nWhat interventions are most effective at transferring shared decision-making skills between people and departments, and in sustaining the implementation of shared decision making in an organisation and in clinical teams?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on embedding shared decision making at an organisational level\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: effectiveness of approaches and activities to increase engagement in shared decision making and the barriers and facilitators to engagement\n\nevidence review\xa0E: effective approaches and activities to normalise shared decision making in the healthcare system.\n\nLoading. Please wait.\n\n# Acceptability of shared decision making\n\nWhat influences the acceptability of shared decision making in populations that predominantly believe in the authority of the healthcare professional?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on putting shared decision making into practice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: interventions to support effective shared decision making.\n\nLoading. Please wait.\n\n# Shared decision making in remote discussions\n\nHow do shared decision-making skills and techniques need to be modified for remote discussions?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on putting shared decision making into practice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: interventions to support effective shared decision making.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Embedding shared decision making at an organisational level\n\nRecommendations 1.1.1 to 1.1.16\n\n## Why the committee made the recommendations\n\nAlthough a reasonable number of quantitative studies were identified, their usefulness was limited because it was often unclear whether or not interventions were effective, so the committee could not recommend specific interventions. There was qualitative evidence and evidence from experts on the ways shared decision making had been implemented internationally. Using this evidence and their own expertise, the committee recommended ways organisations could embed shared decision making into everyday practice.\n\nThe importance of strong leadership was a particularly prominent theme in the expert evidence and this was supported by the committee's views. In their experience, having a commitment from senior managers and leaders to shared decision making is essential because they can make sure resources are prioritised to support it and help to instil a culture of involving people who use services across the whole organisation. This could also be supported by choosing staff to be champions within the organisation and appointing patient leaders. These people would provide a strong voice to advocate for this approach and could act as 'influencers', passing on their knowledge and training in shared decision making to their colleagues.\n\nThe committee also agreed that appointing a person who uses services to a patient director post enabled service-users' voices to be heard at the highest levels of the organisation. Although the committee agreed this was a good idea, they were also aware that appointing a director-level post in an organisation was a large financial investment that might not be possible, especially in smaller organisations. For this reason, they agreed only to recommend this as an option to consider.\n\nThe committee discussed the importance of an organisation-wide plan for implementing shared decision making and made recommendations based on expert evidence from organisations that had successfully achieved this. These included using digital technology to support shared decision making (for example, through patient-held records) and putting in place 'train-the-trainer' style training. The committee agreed this was the most useful way to approach shared decision making training because it brought the necessary expertise in-house. Based on expert evidence and their own expertise, the committee recommended establishing support networks for these trained healthcare professionals and service users. This can improve how the implementation of shared decision making is monitored and communicated across organisations and areas.\n\nThe committee also used the expert evidence and their own expertise to recommend how to involve people who use services in implementing shared decision making and monitoring and evaluating its use in practice.\n\nThe committee was aware of national resources that might support developing a plan to implement shared decision making, such as the NHS England and NHS Improvement shared decision making summary guide and implementation checklist. In the short term, the roll-out of shared decision making might create further inequalities in services where it had not yet been implemented, but the committee agreed this was temporary and unavoidable.\n\nAlthough shared decision making is most often carried out between people and their healthcare professionals, other practitioners (for example, healthcare assistants and some administrative and management staff) may also need to have shared decision-making skills, training and support. The committee noted resources and e‑learning that might support this, such as the health literacy e-learning resource produced by Health Education England and NHS Scotland.\n\nBecause of the lack of published evidence about rolling out shared decision making across organisations, and about sustaining shared decision making in organisations, the committee made a recommendation for research on sustaining shared decision making.\n\n## How the recommendations might affect services\n\nThe committee hopes these recommendations will help increase the use of shared decision making in organisations by overcoming common barriers. Implementing the recommendations could have a modest impact on resources (for example, training or monitoring), but some changes, for example, appointing a patient director, could have a much larger impact.\n\nReturn to recommendations\n\n# Putting shared decision making into practice\n\nRecommendations 1.2.1 to 1.2.21\n\n## Why the committee made the recommendations\n\nIn the committee's view, shared decision making should be treated as an ongoing process rather than a one‑off event. Using excellent communication and shared decision-making skills alongside a combination of other interventions that support shared decision making is likely to be most effective because no single intervention can be a one-size-fits-all solution, and the evidence supported this. The best available evidence was for multicomponent rather than individual interventions.\n\nThe committee also wanted to highlight that shared decision-making interventions may need to be adapted to specific settings and populations. The same intervention would need to be tailored differently to be used in a GP appointment, an outpatient clinic and inpatient hospital admission. In the committee's view, this also applies to remote discussions (for example, by phone or video). The committee agreed that the same skills and principles would be relevant even though the exact methods would be context dependent.\n\nThe committee noted the importance of the 'digital divide', with some people being unable to access or less familiar with things like online discussions. The committee did not see strong evidence about this and agreed it was an important area for research because of the increase in remote discussions in response to COVID‑19. As a result, they made a recommendation for research on shared decision making in remote discussions to explore this further.\n\nProviding information is important, but the committee wanted to emphasise that it needs to be of good quality, for example, NICE-accredited. The committee was aware that other quality standards exist, like the PIF TICK quality mark for patient organisations. There are also useful resources, such as 'ask 3\xa0questions' and other tools to help people prepare, on the NHS England website.\n\nThere was some evidence supporting offering interventions before discussions. Even though the studies that looked specifically at pre-discussion interventions did not show an increase in shared decision making itself, there was some evidence that these kinds of interventions increased people's knowledge and their satisfaction with their discussions. The committee agreed that, although knowledge alone is not enough for shared decision making to take place, it is a necessary part of it.\n\nSupporting evidence also came from studies looking at other types of interventions that were offered before discussions: support from another person ('third party support') and eliciting people's preferences and values.\n\nThe committee recognised the benefits of arranging third party support for people who might need additional support to engage in shared decision making. This could include, for example, people who have a condition or disability that makes it more difficult for them to participate. The committee agreed that everybody should be encouraged to bring a family member, friend or carer to discussions if they choose to.\n\nThe committee acknowledged that intervention before a discussion was not always practical, for example, if the person needed care unexpectedly or urgently, so these recommendations would be best suited to non-urgent discussions.\n\nThe committee updated recommendations on shared decision making in NICE's guideline on patient experience in adult NHS services using the evidence and their expertise, and brought them into this guideline.\n\nThe studies looking at what was effective in shared decision making showed the strongest support for eliciting people's expectations, values, priorities and goals as part of interventions based on key stages of shared decision making from the three-talk model. These include 'choice talk' (also called 'team talk') that introduces the fact that there are options, and that the right option will depend on what matters to each person, and 'option talk', when they discuss alternatives addressing the risks, benefits and consequences of each option. These then lead onto 'decision talk', which makes sure a decision is made that is right for each person. The committee agreed it was useful to think about these key stages of shared decision making, but acknowledged that other models of shared decision making were in common use.\n\nEvidence suggested using the three-talk model as a way to structure the shared decision-making process and the committee agreed that the interventions that showed an effect were all consistent with 1\xa0or more of the stages of the three-talk model. In their view, the three-talk model was simple to use and that made it useful in all healthcare settings. The committee agreed, however, that any evidence-based model for shared decision making is useful so they were not prescriptive in the recommendations.\n\nAgenda setting, explicitly stating decisions, the option of no treatment (that is, not choosing any of the treatments offered), and agreeing when to review a decision were not captured in the effectiveness evidence, but the committee considered them to be key aspects of shared decision making.\n\nThe committee noted that some people may not want to be involved in shared decision making. They also noted that not all decisions can be shared. People have a right to refuse any treatment, and similarly, healthcare professionals are not obliged to provide any treatment that in their clinical opinion is medically futile (this may need a second opinion or discussion with a senior colleague). Healthcare professionals cannot provide access to treatments that are not available.\n\nThe committee talked about documenting discussions. They agreed that recording which options have been discussed and what is important to the person is the best evidence that a meaningful shared decision making dialogue has taken place.\n\nThe committee highlighted that interventions to support shared decision making should carry on after discussions with a healthcare professional because they should be part of a continuing process. They agreed on some methods to support people who might need additional help, such as suggesting that they record the discussion on their phone or other electronic device to help them remember what was said and think about their options.\n\nThe committee made recommendations for research to fill the most notable gaps in the evidence. They agreed that research was needed into how the same shared decision-making interventions differ in effectiveness between different populations and different care settings so they made a recommendation for research on differing intervention effects in different groups. The committee also noted from the evidence that it was unclear what the best measures of shared decision making are and how acceptable different interventions are to people who receive them, so they also made recommendations for research about measuring shared decision making and the acceptability of shared decision making.\n\n## How the recommendations might affect services\n\nThe recommendations will help to increase the use of shared decision making in day-to-day clinical practice by suggesting effective methods to support it. Some of the options in the recommendations may need additional resources, for example, using a healthcare worker to provide third party support, but others can be integrated into current practice, for example, encouraging a person to record their discussion. There is also a potential that in some healthcare settings, appointments or consultations may need to be longer and this could represent a substantial resource impact, but might lead to fewer subsequent appointments and will ensure that the right decisions are made with people.\n\nReturn to recommendations\n\n# Patient decision aids\n\nRecommendations 1.3.1 to 1.3.5\n\n## Why the committee made the recommendations\n\nThere was strong evidence to support using patient decision aids before, during and between discussions. However, the committee wanted to make it clear that decision aids alone do not deliver shared decision making but should be seen as 1\xa0component of a wider approach. There would never be a patient decision aid available to support every discussion, and healthcare professionals still need to have the skills described in this guideline to engage people in making shared decisions irrespective of whether decision aids are available.\n\nThe committee agreed that for patient decision aids to be most useful, staff should have access to quality‑assured patient decision aids either via a maintained database or signposting to those produced by national bodies. They also highlighted that even though the evidence favoured using patient decision aids, it is crucial to provide them to people in formats they can use and understand otherwise they would not be useful. In the committee's view, organisations should think about ways to make sure that a database of quality‑assured decision aids is available to their staff in many different formats and that systems support using them in different ways. In the committee's experience, accessing decision aids in suitable formats is not always possible – for example, facilities to print out decision aids are not always available in consulting rooms across organisations, and some decision aids cannot be printed because of their format, for example, if they have a block colour background that requires a lot of ink.\n\n## How the recommendations might affect practice\n\nThe committee agreed that there were many good-quality patient decision aids that healthcare professionals could use and that more were being developed all the time. Many of them are freely available. Maintaining a database of decision aids could have a moderate resource impact, but the committee noted that these could be set up in collaboration with other organisations to maximise 'economies of scale'. The committee also noted that there might be some resource impact of printing more material for people.\n\nReturn to recommendations\n\n# Communicating risks, benefits and consequences\n\nRecommendations 1.4.1 to 1.4.11\n\n## Why the committee made the recommendations\n\nThe committee updated recommendations on communicating risks and benefits from NICE's guideline on patient experience in adult NHS services and brought them into this guideline.\n\nThe committee agreed that people's interpretation of risks, benefits and consequences is fundamentally embedded in their values and priorities, which explains why people do not weigh risks, benefits and consequences in the same way as others, or indeed in the same way as professionals.\n\nThe committee agreed that a person can only make an informed decision if they are given enough information to do so, and if the risks, benefits and consequences presented to them relate directly to their circumstances and what is important to them. Information about risks and benefits will be weighed differently in different situations and depending on a person's prognosis and the decisions they have to make. They discussed the evidence about presenting absolute risks compared with relative risks and noted that absolute risks are much clearer, especially when accompanied by visual summaries. They agreed that presenting relative risks alone was misleading and that relative risk should only be introduced as a supplement to absolute risks.\n\nThe committee wanted risks and benefits to be personalised using high-quality numerical data when these are available. Ideally, healthcare professionals would be able to provide personalised risk calculations. However, the committee acknowledged that personalised risk information is often not available. This means healthcare professionals often need to use generalised information about risks, benefits and consequences (usually available in good-quality decision aids) and explain to the person how it relates to them (for example, above average, average or below average levels of risk). Explaining how much uncertainty surrounds these estimates will help people interpret that information and what it means for them. The committee highlighted guidance from the General Medical Council (GMC) for more information – although GMC guidance is written for doctors, they agreed it provided an example of good practice for all professionals.\n\n## How the recommendations might affect practice\n\nThese recommendations will help healthcare professionals explore risk, benefits and consequences of healthcare decisions with people. The committee noted that because the recommendations in NICE's guideline on patient experience in adult NHS services have been in place since 2012, there should be no resource impact.\n\nReturn to recommendations", 'Context': "Shared decision making is a collaborative process that involves a person and their healthcare professional working together to reach a joint decision about care. It could be care the person needs straightaway or care in the future, for example, through advance care planning. It involves choosing tests and treatments based both on evidence and on the person's individual preferences, beliefs and values. It means making sure the person understands the risks, benefits and possible consequences of different options through discussion and information sharing. This joint process empowers people to make decisions about the care that is right for them at that time (with the options of choosing to have no treatment or not changing what they are currently doing always included). In line with NHS England's personalised care and support planning guidance: guidance for local maternity systems, in maternity services this may be referred to as 'informed decision making'.\n\nShared decision making is enshrined as a principle in the NHS Constitution, with principle 4 stating that, 'Patients, with their families and carers, where appropriate, will be involved in and consulted on all decisions about their care and treatment'.\n\nSome people prefer not to take an active role in making decisions with their healthcare professionals, but they should always be given the opportunity to choose to what degree they want to engage in decision making and the extent to which decisions that are made on their behalf are discussed and communicated with them, including the reasons for selecting a particular treatment. Involving people in decisions about their care may result in:\n\ngreater satisfaction with the decisions made\n\ngreater understanding about the risks and benefits of the available options\n\nbetter communication between people and their healthcare professional, including people feeling that they have 'been heard'\n\nimproved trust between people and their healthcare professional\n\nbetter concordance with an agreed treatment plan\n\npeople reporting a better experience of care, including more satisfaction with the outcome.\n\nAfter the Montgomery v Lanarkshire case (2015), a new legal standard was set to protect people's rights to make informed decisions when giving or withholding consent to treatment. Healthcare professionals should discuss the risks and benefits of each course of action that are meaningful to the particular person. Consent 'must be obtained before treatment interfering with bodily integrity is undertaken', and it should only be gained when a person has shared a decision informed by what is known about the risks, benefits and consequences of all reasonable NHS treatment options. As set out in the NHS Constitution for England, people have the right to be involved in planning and making decisions about their health and care, and to be given information and support to enable this.\n\nThe General Medical Council's guidance on decision making and consent (published in 2020) says that healthcare professionals should discuss 'risks of harm and potential benefits that the patient would consider significant for any reason. These will be revealed during your discussion with the patient about what matters to them'. It also states that they should discuss 'any risk of serious harm, however unlikely it is to occur'."}
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https://www.nice.org.uk/guidance/ng197
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This guideline covers how to make shared decision making part of everyday care in all healthcare settings. It promotes ways for healthcare professionals and people using services to work together to make decisions about treatment and care. It includes recommendations on training, communicating risks, benefits and consequences, using decision aids, and how to embed shared decision making in organisational culture and practices.
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aa2a780bf15527a3e441fccf66fedeea8b259dc1
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nice
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Nivolumab for previously treated unresectable advanced or recurrent oesophageal cancer
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Nivolumab for previously treated unresectable advanced or recurrent oesophageal cancer
Evidence-based recommendations on Nivolumab (Opdivo) for previously treated unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma in adults.
# Recommendations
Nivolumab is recommended, within its marketing authorisation, for treating unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma in adults after fluoropyrimidine and platinum-based therapy. It is recommended only if the company provides nivolumab according to the commercial arrangement.
Why the committee made these recommendations
Unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma is usually first treated with fluoropyrimidine and platinum-based therapy. Then if the cancer progresses, it is treated with a taxane (docetaxel or paclitaxel).
Clinical trial evidence suggests nivolumab does not increase how long people live without their cancer getting worse compared with taxanes. The trial shows that people are more likely to die in the first 3 months of treatment with nivolumab, even though people with a life expectancy of less than 3 months were not included in the trial. After that, evidence suggests people live for at least 3 months longer if they have nivolumab compared with taxane treatment.
Nivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost‑effectiveness estimates are uncertain, but are likely to be within what NICE normally considers an acceptable use of NHS resources. So, nivolumab is recommended.# Information about nivolumab
# Marketing authorisation indication
Nivolumab (Opdivo, Bristol–Myers Squibb) as monotherapy is indicated 'for the treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma after prior fluoropyrimidine and platinum-based combination chemotherapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
Nivolumab is available in 3 different sizes as a concentrate for solution for infusion vials. The cost varies according to vial size: £439 (40 mg per 4 ml), £1,097 (100 mg per 10 ml) and £2,633 (240 mg per 24 ml) (excluding VAT; BNF online, accessed October 2020). The cost for 1 dose of treatment is £2,633 (240 mg per 24 ml).
The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bristol–Myers Squibb, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 3 issues were resolved during the technical engagement stage, and agreed that:
The model time horizon (issue 7, see technical report page 8) used by the company in the economic model of 40 years was sufficient to capture data for everyone having nivolumab or taxanes.
Nivolumab is likely to improve overall survival by at least 3 months (issue 13, see technical report page 14), meeting the second criterion for end of life treatment.
The approach used to calculate the cost of monitoring response to treatment (issue 12, see technical report page 13) was appropriate.
# Clinical need
## People would welcome a new treatment option
The clinical experts explained that people with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma, whose disease has progressed after fluoropyrimidine and platinum-based combination therapy, have a poor prognosis and no curative treatment options. It disproportionately affects people from lower socioeconomic backgrounds, and smoking and alcohol consumption are risk factors. The taxanes paclitaxel and docetaxel are standard treatment for most people and weekly or 3‑weekly hospital visits are needed for infusions. People often feel unwell and may experience debilitating fatigue and loss of appetite. Many people find the weekly or 3‑weekly treatment regimens difficult to tolerate because of the associated adverse events. Frequent blood tests are needed to monitor neutropenia. The NHS England clinical lead noted that taxanes have limited efficacy and people are often not well enough to have third-line treatment if taxanes do not control the disease. People who are unable to tolerate taxane chemotherapy have best supportive care, which has no effect on disease progression. Older people are less likely to tolerate chemotherapy, and about 40% of people diagnosed with squamous oesophageal cancer are over 75. The committee recognised the unmet need for a treatment with lower toxicity than chemotherapy, that provides long-term benefit and improves quality of life. The clinical expert explained that if people are not well enough to tolerate taxane therapy, they are unlikely to be well enough to tolerate nivolumab. Although immunotherapy is generally better tolerated than chemotherapy, it still carries risks, notably immune-related side effects. The committee concluded that patients and clinicians would welcome an effective treatment that is better tolerated, particularly if it offers an option of further third-line treatment after disease progression.
# Trial design
## The ATTRACTION‑3 study is appropriate for estimating clinical effectiveness
The company's clinical evidence came from ATTRACTION‑3. This included people with unresectable oesophageal squamous cell carcinoma whose disease was refractory or who were intolerant to combination therapy with fluoropyrimidine and platinum-based drugs, and who had a life expectancy of at least 3 months. People were randomly assigned to have either nivolumab or taxane chemotherapy. Disease was monitored every 6 weeks and assessed using RECIST 1.1 criteria. People could continue treatment after first disease progression in both treatment groups, based on the investigators' judgement. The clinical expert explained that immunotherapies are associated with pseudo-progression, which is a distinct radiological pattern of apparent progression from baseline that is not confirmed with subsequent assessment. For this reason, if there is evidence of progression but the person feels well, they usually continue having nivolumab for another cycle and then radiological progression is assessed at the next monitoring appointment. The committee concluded that ATTRACTION‑3 was an appropriate source of clinical data and could be used for estimating clinical effectiveness.
# Clinical evidence
## The results from ATTRACTION-3 are generalisable to people in the NHS
ATTRACTION‑3 was done in the US, Europe and Asia. Of the people included in the study, 96% had an Asian family background, and two-thirds of these people had a Japanese family background. Oesophageal squamous cell cancer is more prevalent in Asia than in Western countries. The clinical expert commented that although the trials were mainly done in Asia, there is no difference in the underlying biology of oesophageal squamous cell cancer compared with people in the UK. Also, treatment is similar because of consensus in the management of advanced oesophageal cancer. The company accepted that the population in the clinical trial was generally younger and fitter (with an Eastern Cooperative Oncology Group performance status of 0 to 1) than the population seen in NHS practice. The committee agreed with the clinical expert and concluded that the clinical trial was broadly generalisable to people with advanced oesophageal squamous cell cancer in the UK.
## Nivolumab improves overall survival but disease progresses faster in the first 3 months of treatment
Nivolumab is associated with a difference in median overall survival of 2.4 months compared with the combined taxane therapy arm (median overall survival 10.91 months for nivolumab, 8.51 months in the taxane arm). However, median progression-free survival was slightly lower for nivolumab (1.68 months compared with 3.35 months), as was the overall response rate (19.3% compared with 21.5%). The 36‑month follow‑up data from ATTRACTION‑3 confirmed the overall survival benefit seen at 24 months. More people had disease progression with nivolumab than with taxanes, and most of the overall survival benefit from nivolumab was after progression. The committee questioned why the benefit was predominantly seen after progression rather than before, which is what would be expected if nivolumab had the potential to be curative. It discussed whether this could be because of people having nivolumab after disease progression and it slowing progression; a carry-over effect after stopping nivolumab into the progression phase; or because people remained well enough for follow-on therapies at progression. The committee concluded that it was unclear why the survival benefit mainly happened after disease progression.
## People are at more risk of dying having nivolumab in the first 3 months
Results up to 36 months for overall survival were provided by the company and analysed by the ERG. At 2 months and 4 months, people having nivolumab had worse overall survival than people having taxanes. However, from 6 months onwards overall survival was higher for nivolumab compared with taxanes (the data cannot be reported here because the company submitted it as academic in confidence). The clinical expert explained that this pattern in overall survival is commonly found with immunotherapies. This is because of the delay in benefit as the immune system is activated, while chemotherapy immediately acts on the cancer cells. The higher death rate in the first 3 months seen with nivolumab was particularly concerning because people in ATTRACTION‑3 were expected to survive at least 3 months. The NHS England clinical lead suggested that people generally have worse performance scores in the NHS than in the trial. In clinical practice, it is possible to distinguish between people who are and are not likely to tolerate nivolumab therapy. Based on the available data, the committee concluded that nivolumab improves overall survival despite a greater death rate in the first 3 months.
# Adverse events
## Nivolumab is better tolerated than taxanes, but immunotherapies can cause significant side effects
Fewer patients experienced drug-related adverse events in the nivolumab group compared with taxanes in the clinical trial (the data cannot be reported here because the company submitted it as academic in confidence). The clinical experts agreed that nivolumab is better tolerated than taxanes, and that taxane therapy can be associated with long-term adverse events, such as neuropathy of the hands and feet. The NHS England clinical lead noted that nivolumab is also associated with rare but potentially life-threatening gastrointestinal, renal, endocrine and hepatic adverse events. The clinical expert commented that there are standard guidelines for managing immunotoxicity associated with treatments like nivolumab, which are well managed in clinical practice. The committee concluded that nivolumab is better tolerated than taxanes, but immunotherapies can cause significant immune-related side effects.
# Comparator
## Taxane chemotherapy is the relevant comparator
The clinical trial compared nivolumab with a combined taxane arm (paclitaxel and docetaxel). The clinical experts and the NHS England clinical lead agreed that there is a class effect for taxanes, both in efficacy and side-effect profile. Best supportive care was not considered to be a relevant comparator, because people who are not well enough to tolerate taxane therapy are unlikely to benefit from nivolumab. The committee concluded that the relevant comparator for nivolumab therapy is taxane chemotherapy.
# Cost effectiveness
## There is uncertainty over the method of extrapolating overall survival
The company used a semi-parametric approach to model overall survival to capture the changing risk of death over time with nivolumab treatment. Kaplan−Meier curves from the trial were used in both groups up to 5.75 months, based on the ERG's preferred cut-point for 24‑month data. After this, the company used a log-logistic distribution in the nivolumab arm and a Weibull distribution in the taxane arm. The ERG critique was based on visual inspection of the extrapolation. This was because it had not had the opportunity to critique each extrapolation to determine the most appropriate method for each arm or calculate how the selected extrapolations affected the cost effectiveness of nivolumab. The ERG noted that the nivolumab extrapolation seemed to fit the trial data well. But, it advised that the taxane extrapolation was not a good fit to the Kaplan−Meier data and underestimated long-term overall survival of patients having taxane therapy. The committee noted that the ERG may have preferred alternative extrapolations from different cut-points than those proposed by the company if it had been able to fully critique the extrapolations of trial data. The committee concluded that there is substantial uncertainty over the most appropriate method of extrapolating overall survival in the nivolumab and taxane arm.
## No adjustment was made to efficacy or additional costs of third-line therapy
In the clinical trial, patients were able to continue initial treatment (see section 3.2) and have subsequent treatment (surgery, radiotherapy or pharmacotherapy) after disease progression. The proportion of people having subsequent therapy after progression was similar in both the nivolumab and taxane groups. However, more people in the nivolumab arm continued having their initial treatment, compared with the taxane arm. The clinical expert explained that nivolumab may be continued after disease progression until the next scheduled scan confirms that the disease has progressed, but treatment would be stopped when progression was confirmed. However, because it is better tolerated than taxanes, more people would be able to have further active treatment after nivolumab than after taxanes. The company did an exploratory analysis of overall survival, which censored people having subsequent therapy. The results showed that having subsequent therapy does not have a big effect on the overall survival of nivolumab compared with taxanes. The committee recognised that the opportunity for active third-line treatment is an important consideration for patients. It concluded that nivolumab would be more likely to be continued in the short term after progression than taxanes, as seen in the trial. It is not possible to tell whether any differences between the third-line treatments in ATTRACTION‑3 and in the NHS would affect the relative effectiveness of nivolumab in the NHS compared with the trial.
# Utility values
## Post-progression utility should be the same in the nivolumab and taxane arms
The company estimated the utilities before and after progression using a statistical model fit to EQ‑5D data from the clinical trial, with missing values imputed under the assumption that they were missing at random. Baseline utility was worse in the taxane arm compared with the nivolumab arm, but this difference was not adjusted for. Nivolumab had a higher utility before progression than taxanes because of its more favourable safety profile (the data cannot be reported here because the company submitted it as academic in confidence). The company model also assumed a higher utility after progression for nivolumab compared with taxanes because of the continued benefit of nivolumab. The ERG considered it plausible that the pre-progression utility would be higher for nivolumab than taxanes because of the improved adverse event profile. But, it questioned the size of the difference because differences in baseline utility had not been adjusted for. It provided an estimate based on values from an alternative statistical model fit by the company that did not include imputation of missing values. For post-progression utility, the ERG did not consider there to be enough justification for a post-progression utility benefit with nivolumab compared with taxanes. Instead, it used a pooled estimate of utility in the nivolumab and taxane arms, giving equal utility values for both treatments. The company also provided a scenario analysis that varied pre-progression utility values according to the company and ERG preferences, and post-progression utility values based on pooled and non-pooled estimates. The committee considered it plausible that the utility before progression for nivolumab was higher than for taxanes, based on differences in tolerability and adverse events. In the post-progression phase, the NHS England clinical lead advised that a constant utility after progression was not plausible. This is because, in reality, utility will fluctuate over time and can be influenced by the choice of follow-on treatments. The choice of utility values had a significant effect on the incremental cost‑effectiveness ratio (ICER). The committee concluded that a differential utility before progression was reasonable, but the size of difference was likely to have been overestimated by the company. The post-progression utility in the short term after nivolumab treatment could be higher than after taxanes because of less spill over of toxic effects. It was unlikely to be better for the whole time that the disease was progressing from when treatment stopped up to the time of the patient's death. The most realistic scenario was for post-progression utility to be the same for nivolumab and taxane therapy.
# Costs
## The company's model underestimates the cost of hospitalisation
The company estimated the cost of each episode of hospitalisation at £534.07 based on an average of 1 bed day per person. The ERG did not consider this method appropriate, instead using the cost of full length of hospitalisation without adjusting for the length of stay. This increased the cost of hospitalisation to £3,379.73. The committee noted that this remains an uncertainty that has a substantial effect on the ICER, and that the company had not given adequate justification for the estimate of hospital costs based on the duration of stay of 1 bed day. The NHS clinical lead commented that patients could be admitted for short periods for procedures such as oesophageal stenting. However, people who had to be admitted because of toxicity from either taxanes or nivolumab would be too ill to be discharged after 1 day. The committee concluded that there remained uncertainty about the average cost of hospitalisation related to the length of hospital stay. However, the most realistic estimate of hospitalisation costs was likely to be between the company and the ERG's preferred cost calculation.
## Taking into account the updated commercial access arrangement, nivolumab is likely to be cost effective
There were uncertainties remaining in the model, particularly related to the extrapolation of overall survival and time on treatment, which the ERG was unable to critique. The committee considered the ERG administration costs and utilities before and after progression to be the most appropriate (see section 3.10). There was still substantial uncertainty about the hospitalisation costs for nivolumab compared with taxanes (see section 3.11). At its second meeting after consultation, the committee noted that the company base-case ICER was £48,205 per quality‑adjusted life year (QALY) gained. The ERG provided analyses of the effect of its preferred assumptions for utility, administration and hospitalisation costs on the company's base-case ICER. These resulted in ICERs that exceeded what NICE considers a cost-effective use of NHS resources even for technologies given special consideration as life-extending treatments for people with a short life expectancy. After the second committee meeting the company updated its commercial arrangement and submitted an updated analysis using the assumptions preferred by the ERG for utilities and administration costs. It also gave a range of hospitalisation costs including both the ERG- and company-preferred estimates. The resulting range of ICERs cannot be reported here because the commercial arrangement is confidential. The committee noted that the commercial arrangement reduced the ICERs so that, other than when the ERG‑preferred hospitalisation costs were used, the ICERs were in the range that could be considered a cost-effective use of NHS resources. The committee was aware that there was remaining uncertainty about the most appropriate extrapolation of overall survival and time on treatment, which could also affect the ICER. It concluded that incorporating the commercial arrangement meant that most of the ICERs were in the range that could be considered cost effective, even though some uncertainties remained.
# End of life
## Nivolumab meets the end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered whether nivolumab meets the end of life criteria for people with unresectable, advanced or recurrent oesophageal cancer who have had fluoropyrimidine and platinum-based therapy. The company and ERG both agreed based on their analyses that life expectancy in this population is less than 24 months. The committee concluded that nivolumab was indicated for people with a short life expectancy. The observed median overall survival benefit with nivolumab of 2.58 months was extrapolated. This gave an expected overall mean survival benefit of 7.8 months in the company's base-case model and 4.0 months in the ERG model. The committee considered that the extension-to-life criterion was met based on the trial data.
# Conclusion
## Nivolumab is recommended
Data from the clinical trial show that nivolumab improves survival benefit compared with taxanes in the long term, but not in the short term. Incorporating the company's updated commercial arrangement brings the ICER into the range that could be considered cost effective. This does not account for the effect on the ICER of other potentially plausible extrapolations of overall survival and time on treatment. However, nivolumab meets the criteria for end of life. Therefore, the committee concluded that a degree of uncertainty in the clinical and cost-effectiveness data was acceptable, given that no additional weighting to the QALY gain was needed to bring the most plausible ICERs into the acceptable range. The committee concluded that the cost-effectiveness estimates were unlikely to exceed the acceptable maximum for treatments that meet the end of life criteria. Therefore, nivolumab is recommended.
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{'Recommendations': "Nivolumab is recommended, within its marketing authorisation, for treating unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma in adults after fluoropyrimidine and platinum-based therapy. It is recommended only if the company provides nivolumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nUnresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma is usually first treated with fluoropyrimidine and platinum-based therapy. Then if the cancer progresses, it is treated with a taxane (docetaxel or paclitaxel).\n\nClinical trial evidence suggests nivolumab does not increase how long people live without their cancer getting worse compared with taxanes. The trial shows that people are more likely to die in the first 3\xa0months of treatment with nivolumab, even though people with a life expectancy of less than 3\xa0months were not included in the trial. After that, evidence suggests people live for at least 3\xa0months longer if they have nivolumab compared with taxane treatment.\n\nNivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost‑effectiveness estimates are uncertain, but are likely to be within what NICE normally considers an acceptable use of NHS resources. So, nivolumab is recommended.", 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol–Myers\xa0Squibb) as monotherapy is indicated 'for the treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma after prior fluoropyrimidine and platinum-based combination chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nNivolumab is available in 3\xa0different sizes as a concentrate for solution for infusion vials. The cost varies according to vial size: £439 (40\xa0mg per 4\xa0ml), £1,097 (100\xa0mg per 10\xa0ml) and £2,633 (240\xa0mg per 24\xa0ml) (excluding VAT; BNF online, accessed October 2020). The cost for 1\xa0dose of treatment is £2,633 (240\xa0mg per 24\xa0ml).\n\nThe company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol–Myers\xa0Squibb, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 3\xa0issues were resolved during the technical engagement stage, and agreed that:\n\nThe model time horizon (issue\xa07, see technical report page\xa08) used by the company in the economic model of 40\xa0years was sufficient to capture data for everyone having nivolumab or taxanes.\n\nNivolumab is likely to improve overall survival by at least 3\xa0months (issue\xa013, see technical report page\xa014), meeting the second criterion for end of life treatment.\n\nThe approach used to calculate the cost of monitoring response to treatment (issue\xa012, see technical report page\xa013) was appropriate.\n\n# Clinical need\n\n## People would welcome a new treatment option\n\nThe clinical experts explained that people with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma, whose disease has progressed after fluoropyrimidine and platinum-based combination therapy, have a poor prognosis and no curative treatment options. It disproportionately affects people from lower socioeconomic backgrounds, and smoking and alcohol consumption are risk factors. The taxanes paclitaxel and docetaxel are standard treatment for most people and weekly or 3‑weekly hospital visits are needed for infusions. People often feel unwell and may experience debilitating fatigue and loss of appetite. Many people find the weekly or 3‑weekly treatment regimens difficult to tolerate because of the associated adverse events. Frequent blood tests are needed to monitor neutropenia. The NHS England clinical lead noted that taxanes have limited efficacy and people are often not well enough to have third-line treatment if taxanes do not control the disease. People who are unable to tolerate taxane chemotherapy have best supportive care, which has no effect on disease progression. Older people are less likely to tolerate chemotherapy, and about 40% of people diagnosed with squamous oesophageal cancer are over\xa075. The committee recognised the unmet need for a treatment with lower toxicity than chemotherapy, that provides long-term benefit and improves quality of life. The clinical expert explained that if people are not well enough to tolerate taxane therapy, they are unlikely to be well enough to tolerate nivolumab. Although immunotherapy is generally better tolerated than chemotherapy, it still carries risks, notably immune-related side effects. The committee concluded that patients and clinicians would welcome an effective treatment that is better tolerated, particularly if it offers an option of further third-line treatment after disease progression.\n\n# Trial design\n\n## The ATTRACTION‑3 study is appropriate for estimating clinical effectiveness\n\nThe company's clinical evidence came from ATTRACTION‑3. This included people with unresectable oesophageal squamous cell carcinoma whose disease was refractory or who were intolerant to combination therapy with fluoropyrimidine and platinum-based drugs, and who had a life expectancy of at least 3\xa0months. People were randomly assigned to have either nivolumab or taxane chemotherapy. Disease was monitored every 6\xa0weeks and assessed using RECIST\xa01.1 criteria. People could continue treatment after first disease progression in both treatment groups, based on the investigators' judgement. The clinical expert explained that immunotherapies are associated with pseudo-progression, which is a distinct radiological pattern of apparent progression from baseline that is not confirmed with subsequent assessment. For this reason, if there is evidence of progression but the person feels well, they usually continue having nivolumab for another cycle and then radiological progression is assessed at the next monitoring appointment. The committee concluded that ATTRACTION‑3 was an appropriate source of clinical data and could be used for estimating clinical effectiveness.\n\n# Clinical evidence\n\n## The results from ATTRACTION-3 are generalisable to people in the NHS\n\nATTRACTION‑3 was done in the US, Europe and Asia. Of the people included in the study, 96% had an Asian family background, and two-thirds of these people had a Japanese family background. Oesophageal squamous cell cancer is more prevalent in Asia than in Western countries. The clinical expert commented that although the trials were mainly done in Asia, there is no difference in the underlying biology of oesophageal squamous cell cancer compared with people in the UK. Also, treatment is similar because of consensus in the management of advanced oesophageal cancer. The company accepted that the population in the clinical trial was generally younger and fitter (with an Eastern Cooperative Oncology Group [ECOG] performance status of 0\xa0to\xa01) than the population seen in NHS practice. The committee agreed with the clinical expert and concluded that the clinical trial was broadly generalisable to people with advanced oesophageal squamous cell cancer in the UK.\n\n## Nivolumab improves overall survival but disease progresses faster in the first 3\xa0months of treatment\n\nNivolumab is associated with a difference in median overall survival of 2.4\xa0months compared with the combined taxane therapy arm (median overall survival 10.91\xa0months for nivolumab, 8.51\xa0months in the taxane arm). However, median progression-free survival was slightly lower for nivolumab (1.68\xa0months compared with 3.35\xa0months), as was the overall response rate (19.3% compared with 21.5%). The 36‑month follow‑up data from ATTRACTION‑3 confirmed the overall survival benefit seen at 24\xa0months. More people had disease progression with nivolumab than with taxanes, and most of the overall survival benefit from nivolumab was after progression. The committee questioned why the benefit was predominantly seen after progression rather than before, which is what would be expected if nivolumab had the potential to be curative. It discussed whether this could be because of people having nivolumab after disease progression and it slowing progression; a carry-over effect after stopping nivolumab into the progression phase; or because people remained well enough for follow-on therapies at progression. The committee concluded that it was unclear why the survival benefit mainly happened after disease progression.\n\n## People are at more risk of dying having nivolumab in the first 3\xa0months\n\nResults up to 36\xa0months for overall survival were provided by the company and analysed by the ERG. At 2\xa0months and 4\xa0months, people having nivolumab had worse overall survival than people having taxanes. However, from 6\xa0months onwards overall survival was higher for nivolumab compared with taxanes (the data cannot be reported here because the company submitted it as academic in confidence). The clinical expert explained that this pattern in overall survival is commonly found with immunotherapies. This is because of the delay in benefit as the immune system is activated, while chemotherapy immediately acts on the cancer cells. The higher death rate in the first 3\xa0months seen with nivolumab was particularly concerning because people in ATTRACTION‑3 were expected to survive at least 3\xa0months. The NHS England clinical lead suggested that people generally have worse performance scores in the NHS than in the trial. In clinical practice, it is possible to distinguish between people who are and are not likely to tolerate nivolumab therapy. Based on the available data, the committee concluded that nivolumab improves overall survival despite a greater death rate in the first 3\xa0months.\n\n# Adverse events\n\n## Nivolumab is better tolerated than taxanes, but immunotherapies can cause significant side effects\n\nFewer patients experienced drug-related adverse events in the nivolumab group compared with taxanes in the clinical trial (the data cannot be reported here because the company submitted it as academic in confidence). The clinical experts agreed that nivolumab is better tolerated than taxanes, and that taxane therapy can be associated with long-term adverse events, such as neuropathy of the hands and feet. The NHS England clinical lead noted that nivolumab is also associated with rare but potentially life-threatening gastrointestinal, renal, endocrine and hepatic adverse events. The clinical expert commented that there are standard guidelines for managing immunotoxicity associated with treatments like nivolumab, which are well managed in clinical practice. The committee concluded that nivolumab is better tolerated than taxanes, but immunotherapies can cause significant immune-related side effects.\n\n# Comparator\n\n## Taxane chemotherapy is the relevant comparator\n\nThe clinical trial compared nivolumab with a combined taxane arm (paclitaxel and docetaxel). The clinical experts and the NHS England clinical lead agreed that there is a class effect for taxanes, both in efficacy and side-effect profile. Best supportive care was not considered to be a relevant comparator, because people who are not well enough to tolerate taxane therapy are unlikely to benefit from nivolumab. The committee concluded that the relevant comparator for nivolumab therapy is taxane chemotherapy.\n\n# Cost effectiveness\n\n## There is uncertainty over the method of extrapolating overall survival\n\nThe company used a semi-parametric approach to model overall survival to capture the changing risk of death over time with nivolumab treatment. Kaplan−Meier curves from the trial were used in both groups up to 5.75\xa0months, based on the ERG's preferred cut-point for 24‑month data. After this, the company used a log-logistic distribution in the nivolumab arm and a Weibull distribution in the taxane arm. The ERG critique was based on visual inspection of the extrapolation. This was because it had not had the opportunity to critique each extrapolation to determine the most appropriate method for each arm or calculate how the selected extrapolations affected the cost effectiveness of nivolumab. The ERG noted that the nivolumab extrapolation seemed to fit the trial data well. But, it advised that the taxane extrapolation was not a good fit to the Kaplan−Meier data and underestimated long-term overall survival of patients having taxane therapy. The committee noted that the ERG may have preferred alternative extrapolations from different cut-points than those proposed by the company if it had been able to fully critique the extrapolations of trial data. The committee concluded that there is substantial uncertainty over the most appropriate method of extrapolating overall survival in the nivolumab and taxane arm.\n\n## No adjustment was made to efficacy or additional costs of third-line therapy\n\nIn the clinical trial, patients were able to continue initial treatment (see section\xa03.2) and have subsequent treatment (surgery, radiotherapy or pharmacotherapy) after disease progression. The proportion of people having subsequent therapy after progression was similar in both the nivolumab and taxane groups. However, more people in the nivolumab arm continued having their initial treatment, compared with the taxane arm. The clinical expert explained that nivolumab may be continued after disease progression until the next scheduled scan confirms that the disease has progressed, but treatment would be stopped when progression was confirmed. However, because it is better tolerated than taxanes, more people would be able to have further active treatment after nivolumab than after taxanes. The company did an exploratory analysis of overall survival, which censored people having subsequent therapy. The results showed that having subsequent therapy does not have a big effect on the overall survival of nivolumab compared with taxanes. The committee recognised that the opportunity for active third-line treatment is an important consideration for patients. It concluded that nivolumab would be more likely to be continued in the short term after progression than taxanes, as seen in the trial. It is not possible to tell whether any differences between the third-line treatments in ATTRACTION‑3 and in the NHS would affect the relative effectiveness of nivolumab in the NHS compared with the trial.\n\n# Utility values\n\n## Post-progression utility should be the same in the nivolumab and taxane arms\n\nThe company estimated the utilities before and after progression using a statistical model fit to EQ‑5D data from the clinical trial, with missing values imputed under the assumption that they were missing at random. Baseline utility was worse in the taxane arm compared with the nivolumab arm, but this difference was not adjusted for. Nivolumab had a higher utility before progression than taxanes because of its more favourable safety profile (the data cannot be reported here because the company submitted it as academic in confidence). The company model also assumed a higher utility after progression for nivolumab compared with taxanes because of the continued benefit of nivolumab. The ERG considered it plausible that the pre-progression utility would be higher for nivolumab than taxanes because of the improved adverse event profile. But, it questioned the size of the difference because differences in baseline utility had not been adjusted for. It provided an estimate based on values from an alternative statistical model fit by the company that did not include imputation of missing values. For post-progression utility, the ERG did not consider there to be enough justification for a post-progression utility benefit with nivolumab compared with taxanes. Instead, it used a pooled estimate of utility in the nivolumab and taxane arms, giving equal utility values for both treatments. The company also provided a scenario analysis that varied pre-progression utility values according to the company and ERG preferences, and post-progression utility values based on pooled and non-pooled estimates. The committee considered it plausible that the utility before progression for nivolumab was higher than for taxanes, based on differences in tolerability and adverse events. In the post-progression phase, the NHS England clinical lead advised that a constant utility after progression was not plausible. This is because, in reality, utility will fluctuate over time and can be influenced by the choice of follow-on treatments. The choice of utility values had a significant effect on the incremental cost‑effectiveness ratio (ICER). The committee concluded that a differential utility before progression was reasonable, but the size of difference was likely to have been overestimated by the company. The post-progression utility in the short term after nivolumab treatment could be higher than after taxanes because of less spill over of toxic effects. It was unlikely to be better for the whole time that the disease was progressing from when treatment stopped up to the time of the patient's death. The most realistic scenario was for post-progression utility to be the same for nivolumab and taxane therapy.\n\n# Costs\n\n## The company's model underestimates the cost of hospitalisation\n\nThe company estimated the cost of each episode of hospitalisation at £534.07 based on an average of 1\xa0bed day per person. The ERG did not consider this method appropriate, instead using the cost of full length of hospitalisation without adjusting for the length of stay. This increased the cost of hospitalisation to £3,379.73. The committee noted that this remains an uncertainty that has a substantial effect on the ICER, and that the company had not given adequate justification for the estimate of hospital costs based on the duration of stay of 1\xa0bed day. The NHS clinical lead commented that patients could be admitted for short periods for procedures such as oesophageal stenting. However, people who had to be admitted because of toxicity from either taxanes or nivolumab would be too ill to be discharged after 1\xa0day. The committee concluded that there remained uncertainty about the average cost of hospitalisation related to the length of hospital stay. However, the most realistic estimate of hospitalisation costs was likely to be between the company and the ERG's preferred cost calculation.\n\n## Taking into account the updated commercial access arrangement, nivolumab is likely to be cost effective\n\nThere were uncertainties remaining in the model, particularly related to the extrapolation of overall survival and time on treatment, which the ERG was unable to critique. The committee considered the ERG administration costs and utilities before and after progression to be the most appropriate (see section\xa03.10). There was still substantial uncertainty about the hospitalisation costs for nivolumab compared with taxanes (see section\xa03.11). At its second meeting after consultation, the committee noted that the company base-case ICER was £48,205 per quality‑adjusted life year (QALY) gained. The ERG provided analyses of the effect of its preferred assumptions for utility, administration and hospitalisation costs on the company's base-case ICER. These resulted in ICERs that exceeded what NICE considers a cost-effective use of NHS resources even for technologies given special consideration as life-extending treatments for people with a short life expectancy. After the second committee meeting the company updated its commercial arrangement and submitted an updated analysis using the assumptions preferred by the ERG for utilities and administration costs. It also gave a range of hospitalisation costs including both the ERG- and company-preferred estimates. The resulting range of ICERs cannot be reported here because the commercial arrangement is confidential. The committee noted that the commercial arrangement reduced the ICERs so that, other than when the ERG‑preferred hospitalisation costs were used, the ICERs were in the range that could be considered a cost-effective use of NHS resources. The committee was aware that there was remaining uncertainty about the most appropriate extrapolation of overall survival and time on treatment, which could also affect the ICER. It concluded that incorporating the commercial arrangement meant that most of the ICERs were in the range that could be considered cost effective, even though some uncertainties remained.\n\n# End of life\n\n## Nivolumab meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered whether nivolumab meets the end of life criteria for people with unresectable, advanced or recurrent oesophageal cancer who have had fluoropyrimidine and platinum-based therapy. The company and ERG both agreed based on their analyses that life expectancy in this population is less than 24\xa0months. The committee concluded that nivolumab was indicated for people with a short life expectancy. The observed median overall survival benefit with nivolumab of 2.58\xa0months was extrapolated. This gave an expected overall mean survival benefit of 7.8\xa0months in the company's base-case model and 4.0\xa0months in the ERG model. The committee considered that the extension-to-life criterion was met based on the trial data.\n\n# Conclusion\n\n## Nivolumab is recommended\n\nData from the clinical trial show that nivolumab improves survival benefit compared with taxanes in the long term, but not in the short term. Incorporating the company's updated commercial arrangement brings the ICER into the range that could be considered cost effective. This does not account for the effect on the ICER of other potentially plausible extrapolations of overall survival and time on treatment. However, nivolumab meets the criteria for end of life. Therefore, the committee concluded that a degree of uncertainty in the clinical and cost-effectiveness data was acceptable, given that no additional weighting to the QALY gain was needed to bring the most plausible ICERs into the acceptable range. The committee concluded that the cost-effectiveness estimates were unlikely to exceed the acceptable maximum for treatments that meet the end of life criteria. Therefore, nivolumab is recommended."}
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https://www.nice.org.uk/guidance/ta707
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Evidence-based recommendations on Nivolumab (Opdivo) for previously treated unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma in adults.
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0f4a370e9977a199a189c03898b2d50c6171795e
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nice
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Autism spectrum disorder in adults: diagnosis and management
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Autism spectrum disorder in adults: diagnosis and management
This guideline covers diagnosing and managing suspected or confirmed autism spectrum disorder (autism, Asperger’s syndrome and atypical autism) in people aged 18 and over. It aims to improve access and engagement with interventions and services, and the experience of care, for people with autism.
# Introduction
Autism is a lifelong neurodevelopmental condition, the core features of which are persistent difficulties in social interaction and communication and the presence of stereotypic (rigid and repetitive) behaviours, resistance to change or restricted interests. The way that autism is expressed in individual people differs at different stages of life, in response to interventions, and with the presence of coexisting conditions such as learning disabilities (also called 'intellectual disabilities'). Autistic people also commonly experience difficulty with cognitive and behavioural flexibility, altered sensory sensitivity, sensory processing difficulties and emotional regulation difficulties. The features of autism may range from mild to severe and may fluctuate over time or in response to changes in circumstances.
A significant proportion of autistic adults across the whole autistic spectrum experience social and economic exclusion. Their condition is often overlooked by healthcare, education and social care professionals, which creates barriers to accessing the support and services they need to live independently. In addition, autistic people are more likely to have coexisting mental and physical disorders, and other developmental disorders. Some may have contact with the criminal justice system, as either victims of crime or offenders, and it is important that their needs are recognised.
There is wide variation in rates of identification and referral for diagnostic assessment, waiting times for diagnosis, models of multi-professional working, assessment criteria and diagnostic practice for adults with features of autism. These factors contribute to delays in reaching a diagnosis and subsequent access to appropriate services.
When the diagnostic assessment process works well, professionals, the autistic person and their family, partner or carer(s) communicate right from the start and the autistic person is involved in the decisions relating to their care. This lays the foundation for a long-term understanding between the autistic person, their family, partner or carer(s) and the professionals supporting their needs. However, many adults have difficulties accessing a diagnostic assessment. Even if they manage to obtain a diagnosis they may receive no follow-up support because of the absence of appropriate services or an agreed care pathway.
In this guideline 'autism' refers to 'autism spectrum disorders' encompassing autism, Asperger's syndrome and atypical autism (or pervasive developmental disorder not otherwise specified). The Guideline Development Group recognises, however, that different individuals and groups prefer a variety of terms for autism including autistic spectrum condition, autistic spectrum difference and neurodiversity (in recent Department of Health, National Audit Office and Public Accounts Committee documents, 'autism' is used to cover all of these terms).
This guideline covers the care provided by primary, community, secondary, tertiary and other health and social care professionals who have direct contact with, and make decisions concerning the care of, autistic adults.
A number of recommendations in this guideline have been adapted from recommendations in other NICE clinical guidelines. Where this occurred, the Guideline Development Group was careful to preserve the meaning and intent of the original recommendations. Changes to wording or structure were made in order to fit the recommendations into this guideline.
The guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) to inform decisions made with individual patients. In this guideline, recommendations are marked with a note if drugs do not have a UK marketing authorisation for the indication in question at the time of publication. Prescribers should check each drug's SPC for current licensed indications.# Recommendations
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# General principles of care
## Principles for working with autistic adults and their families, partners and carers
All staff working with autistic adults should:
work in partnership with autistic adults and, where appropriate, with their families, partners and carers
-ffer support and care respectfully
take time to build a trusting, supportive, empathic and non-judgemental relationship as an essential part of care.
All staff working with autistic adults should have an understanding of the:
nature, development and course of autism
impact on personal, social, educational and occupational functioning
impact of the social and physical environment.
All health and social care professionals providing care and support for autistic adults should have a broad understanding of the:
nature, development and course of autism
impact on personal, social, educational and occupational functioning
impact of and interaction with the social and physical environment
impact on and interaction with other coexisting mental and physical disorders and their management
potential discrepancy between intellectual functioning as measured by IQ and adaptive functioning as reflected, for example, by difficulties in planning and performing activities of daily living including education or employment.
All health and social care professionals providing care and support for autistic adults should:
aim to foster the person's autonomy, promote active participation in decisions about care and support self-management
maintain continuity of individual relationships wherever possible
ensure that comprehensive information about the nature of, and interventions and services for, their difficulties is available in an appropriate language or format (including various visual, verbal and aural, easy read, and different colour and font formats)
consider whether the person may benefit from access to a trained advocate.
All health and social care professionals providing care and support for autistic adults and their families, partners and carers should:
ensure that they are easily identifiable (for example, by producing or wearing appropriate identification) and approachable
clearly communicate their role and function
address the person using the name and title they prefer
clearly explain any clinical language and check that the autistic person understands what is being said
take into account communication needs, including those arising from a learning disability, sight or hearing problems or language difficulties, and provide communication aids or independent interpreters (someone who does not have a personal relationship with the autistic person) if required.
All health and social care professionals providing care and support for autistic adults and their families, partners and carers should ensure that they are:
familiar with recognised local and national sources (organisations and websites) of information and/or support for autistic people
able to discuss and advise on how to access and engage with these resources.
Encourage autistic adults to participate in self-help or support groups or access one-to-one support, and provide support so that they can attend meetings and engage in the activities.
In all settings, take into account the physical environment in which autistic adults are assessed, supported and cared for, including any factors that may trigger behaviour that challenges. If necessary make adjustments or adaptations to the:
amount of personal space given (at least an arm's length)
setting using visual supports (for example, use labels with words or symbols to provide visual cues about expected behaviour)
colour of walls and furnishings (avoid patterns and use low-arousal colours such as cream)
lighting (reduce fluorescent lighting, use blackout curtains or advise use of dark glasses or increase natural light)
noise levels (reduce external sounds or advise use of earplugs or ear defenders). Where it is not possible to adjust or adapt the environment, consider varying the duration or nature of any assessment or intervention (including taking regular breaks) to limit the negative impact of the environment.
All health and social care professionals providing care and support for autistic adults should:
be aware of under-reporting and under-recognition of physical disorders in autistic people
be vigilant for unusual likes and dislikes about food and/or lack of physical activity
-ffer advice about the beneficial effects of a healthy diet and exercise, taking into account any hyper- and/or hypo-sensory sensitivities; if necessary, support referral to a GP or dietician.
All staff working with autistic adults should be sensitive to issues of sexuality, including asexuality and the need to develop personal and sexual relationships. In particular, be aware that problems in social interaction and communication may lead to the autistic person misunderstanding another person's behaviour or to their possible exploitation by others.
Ensure that autistic adults who have caring responsibilities receive support to access the full range of mental and physical health and social care services, including:
specific information, advice and support to parents about their parenting role, including parent training if needed, by professionals experienced in the care of autistic adults and children
social support, such as childcare, to enable them to attend appointments, groups and therapy sessions, and to access education and employment.
## Structures for the organisation and delivery of care and interventions
In order to effectively provide care and support for autistic adults, the local autism multi-agency strategy group should include representation from managers, commissioners and clinicians from adult services, including mental health, learning disability, primary healthcare, social care, housing, educational and employment services, the criminal justice system and the third sector. There should be meaningful representation from autistic people and their families, partners and carers.
In each area a specialist community-based multidisciplinary team for autistic adults (the specialist autism team) should be established. The membership should include:
psychologists with training and experience in working with autistic adults
nurses
-ccupational therapists
psychiatrists
social workers
speech and language therapists
support staff (for example, staff supporting access to housing, educational and employment services, financial advice, and personal and community safety skills).
The specialist autism team should have a key role in the delivery and coordination of:
specialist diagnostic and assessment services
specialist care and interventions
advice and training to other health and social care professionals on the diagnosis, assessment, care and interventions for autistic adults (as not all may be in the care of a specialist team)
support in accessing, and maintaining contact with, housing, educational and employment services
support to families, partners and carers where appropriate
care and interventions for autistic adults living in specialist residential accommodation
training, support and consultation for staff who care for autistic adults in residential and community settings.
## Involving families, partners and carers
Discuss with autistic adults if and how they want their families, partners or carers to be involved in their care. During discussions, take into account any implications of the Mental Capacity Act (2005) and any communication needs the person may have (see recommendation 1.1.5).
If the autistic person wants their family, partner or carer(s) to be involved, encourage this involvement and:
negotiate between the autistic person and their family, partner or carer(s) about confidentiality and sharing of information on an ongoing basis
explain how families, partners and carers can help support the autistic person and help with care plans
make sure that no services are withdrawn because of involvement of the family, partner or carer(s), unless this has been clearly agreed with both the autistic person and their family, partner or carer(s).
Give all families, partners and carer(s) (whether or not the person wants them to be involved in their care) verbal and written information about:
autism and its management
local support groups and services specifically for families, partners and carers
their right to a carer's assessment of their own physical and mental health needs, and how to access this (see the NICE guideline on supporting adult carers).
If an autistic person does not want their family, partners or carer(s) to be involved in their care:
give the family, partner or carer(s) verbal and written information about who they can contact if they are concerned about the person's care
bear in mind that autistic people may be ambivalent or negative towards their family or partner. This may be for many different reasons, including a coexisting mental disorder or prior experience of violence or abuse.
# Identification and assessment
## Principles for the effective assessment of autism
Staff who have responsibility for the identification or assessment of autistic adults should adapt these procedures, if necessary, to ensure their effective delivery, including modifications to the setting in which assessment is delivered (see recommendation 1.1.8) and the duration and pacing of the assessment.
## Identification and initial assessment of possible autism
Consider assessment for possible autism when a person has:
-ne or more of the following:
persistent difficulties in social interaction
persistent difficulties in social communication
stereotypic (rigid and repetitive) behaviours, resistance to change or restricted interests, and
-ne or more of the following:
problems in obtaining or sustaining employment or education
difficulties in initiating or sustaining social relationships
previous or current contact with mental health or learning disability services
a history of a neurodevelopmental condition (including learning disabilities and attention deficit hyperactivity disorder) or mental disorder.
For adults with possible autism who do not have a moderate or severe learning disability, consider using the Autism-Spectrum Quotient – 10 items (AQ-10). (If a person has reading difficulties, read out the AQ-10.) If a person scores 6 or above on the AQ-10, or autism is suspected based on clinical judgement (taking into account any past history provided by an informant), offer a comprehensive assessment for autism.
For adults with possible autism who have a moderate or severe learning disability, consider a brief assessment to ascertain whether the following behaviours are present (if necessary using information from a family member, partner or carer):
difficulties in reciprocal social interaction including:
limited interaction with others (for example, being aloof, indifferent or unusual)
interaction to fulfil needs only
interaction that is naive or one-sided
lack of responsiveness to others
little or no change in behaviour in response to different social situations
limited social demonstration of empathy
rigid routines and resistance to change
marked repetitive activities (for example, rocking and hand or finger flapping), especially when under stress or expressing emotion. If two or more of the above categories of behaviour are present, offer a comprehensive assessment for autism.
## Comprehensive (diagnostic, needs and risks) assessment of suspected autism
A comprehensive assessment should:
be undertaken by professionals who are trained and competent
be team-based and draw on a range of professions and skills
where possible involve a family member, partner, carer or other informant or use documentary evidence (such as school reports) of current and past behaviour and early development.
At the beginning of a comprehensive assessment, discuss with the person the purpose of the assessment and how the outcome of the assessment will be fed back to them. Feedback should be individualised, and consider involving a family member, partner, carer or advocate, where appropriate, to support the person and help explain the feedback.
During a comprehensive assessment, enquire about and assess the following:
core autism features (difficulties in social interaction and communication and the presence of stereotypic behaviour, resistance to change or restricted interests) that have been present in childhood and continuing into adulthood
early developmental history, where possible
behavioural problems
functioning at home, in education or in employment
past and current physical and mental disorders
-ther neurodevelopmental conditions
hyper- and/or hypo-sensory sensitivities and attention to detail. Carry out direct observation of core autism features especially in social situations.
To aid more complex diagnosis and assessment for adults, consider using a formal assessment tool, such as:
the following tools for people who do not have a learning disability:
the Adult Asperger Assessment (AAA; includes the Autism-Spectrum Quotient and the Empathy Quotient )
the Autism Diagnostic Interview – Revised (ADI-R)
the Autism Diagnostic Observation Schedule – Generic (ADOS-G)
the Asperger Syndrome (and high-functioning autism) Diagnostic Interview (ASDI)
the Ritvo Autism Asperger Diagnostic Scale – Revised (RAADS-R)
the following tools in particular for people with a learning disability:
the ADOS-G
the ADI-R.
To organise and structure the process of a more complex assessment, consider using a formal assessment tool, such as the Diagnostic Interview for Social and Communication Disorders (DISCO), the ADOS-G or the ADI-R.
During a comprehensive assessment, take into account and assess for possible differential diagnoses and coexisting disorders or conditions, such as:
-ther neurodevelopmental conditions (use formal assessment tools for learning disabilities)
mental disorders (for example, schizophrenia, depression or other mood disorders, and anxiety disorders, in particular, social anxiety disorder and obsessive–compulsive disorder)
neurological disorders (for example, epilepsy)
physical disorders
communication difficulties (for example, speech and language problems, and selective mutism)
hyper- and/or hypo-sensory sensitivities.
Do not use biological tests, genetic tests or neuroimaging for diagnostic purposes routinely as part of a comprehensive assessment.
During a comprehensive assessment, assess the following risks:
self-harm (in particular in people with depression or a moderate or severe learning disability)
rapid escalation of problems
harm to others
self-neglect
breakdown of family or residential support
exploitation or abuse by others. Develop a risk management plan if needed.
Develop a care plan based on the comprehensive assessment, incorporating the risk management plan and including any particular needs (such as adaptations to the social or physical environment), and also taking into account the needs of the family, partner or carer(s).
Provide a 'health passport' (for example, a laminated card) for autistic adults, which includes information for all staff about the person's care and support needs. Advise the person to carry the health passport at all times.
As part of a comprehensive assessment consider developing a 24-hour crisis management plan, where necessary in conjunction with specialist mental health services, which should detail:
the likely trigger(s) for a crisis
the nature and speed of the reaction to any trigger(s), including details about the way in which autism may impact on a person's behaviour leading up to and during a crisis
the role of the specialist team and other services (including outreach and out-of-hours services) in responding to a crisis
advice to primary care professionals and other services on their responsibilities and appropriate management in a crisis
advice for families, partners and carers about their role in a crisis
the nature of any changes or adaptations to the social or physical environment (see recommendation 1.1.8) needed to manage a crisis.
Consider obtaining a second opinion (including referral to another specialist autism team if necessary), if there is uncertainty about the diagnosis or if any of the following apply after diagnostic assessment:
disagreement about the diagnosis within the autism team
disagreement with the person, their family, partner, carer(s) or advocate about the diagnosis
a lack of local expertise in the skills and competencies needed to reach diagnosis in autistic adults
the person has a complex coexisting condition, such as a severe learning disability, a severe behavioural, visual, hearing or motor problem, or a severe mental disorder.
On an individual basis, and using information from the comprehensive assessment and physical examination, and clinical judgement, consider further investigations, including:
genetic tests, as recommended by the regional genetics centre, if there are specific dysmorphic features, congenital anomalies and/or evidence of a learning disability
electroencephalography if there is suspicion of epilepsy
hearing or sight tests, if there is suspicion of hearing or visual impairment
-ther medical tests depending on individual signs and symptoms (for example, sudden onset of behaviour that challenges, change in usual patterns of behaviour, sudden change in weight, or suspicion that the person might be in pain and is unable to communicate this).
Offer all adults who have received a diagnosis of autism (irrespective of whether they need or have refused further care and support) a follow-up appointment to discuss the implications of the diagnosis, any concerns they have about the diagnosis, and any future care and support they may require.
## Assessment of behaviour that challenges
Assessment of behaviour that challenges should be integrated into a comprehensive assessment for autistic adults.
When assessing behaviour that challenges carry out a functional analysis (see recommendation 1.5.3) including identifying and evaluating any factors that may trigger or maintain the behaviour, such as:
physical disorders
the social environment (including relationships with family members, partners, carers and friends)
the physical environment, including sensory factors
coexisting mental disorders (including depression, anxiety disorders and psychosis)
communication problems
changes to routines or personal circumstances.
# Identifying the correct interventions and monitoring their use
When discussing and deciding on interventions with autistic adults, consider:
their experience of, and response to, previous interventions
the nature and severity of their autism
the extent of any associated functional impairment arising from the autism, a learning disability or a mental or physical disorder
the presence of any social or personal factors that may have a role in the development or maintenance of any identified problem(s)
the presence, nature, severity and duration of any coexisting disorders
the identification of predisposing and possible precipitating factors that could lead to crises if not addressed.
When discussing and deciding on care and interventions with autistic adults, take into account the:
increased propensity for elevated anxiety about decision-making in autistic people
greater risk of altered sensitivity and unpredictable responses to medication
environment, for example whether it is suitably adapted for autistic people, in particular those with hyper- and/or hypo-sensory sensitivities (see recommendation 1.1.8)
presence and nature of hyper- and/or hypo-sensory sensitivities and how these might impact on the delivery of the intervention
importance of predictability, clarity, structure and routine for autistic people
nature of support needed to access interventions.
When discussing and deciding on interventions with autistic adults, provide information about:
the nature, content and duration of any proposed intervention
the acceptability and tolerability of any proposed intervention
possible interactions with any current interventions and possible side effects
the implications for the continuing provision of any current interventions.
When deciding on options for pharmacological interventions for behaviour that challenges or coexisting mental disorders in autistic adults:
be aware of the potential for greater sensitivity to side effects and idiosyncratic responses in autistic people and
consider starting with a low dose.
For any intervention used in autistic adults, there should be a regular review of:
the benefits of the intervention, where feasible using a formal rating of the target behaviour(s)
any adverse events
specific monitoring requirements of pharmacological interventions as highlighted by the summary of product characteristics
adherence to the intervention.
# Interventions for autism
## Psychosocial interventions for the core features of autism
For autistic adults without a learning disability or with a mild to moderate learning disability, who have identified problems with social interaction, consider:
a group-based social learning programme focused on improving social interaction
an individually delivered social learning programme for people who find group-based activities difficult.
Social learning programmes to improve social interaction should typically include:
modelling
peer feedback (for group-based programmes) or individual feedback (for individually delivered programmes)
discussion and decision-making
explicit rules
suggested strategies for dealing with socially difficult situations.
Do not provide facilitated communication for autistic adults.
## Psychosocial interventions focused on life skills
For autistic adults of all ranges of intellectual ability, who need help with activities of daily living, consider a structured and predictable training programme based on behavioural principles.
For autistic adults without a learning disability or with a mild to moderate learning disability, who are socially isolated or have restricted social contact, consider:
a group-based structured leisure activity programme
an individually delivered structured leisure activity programme for people who find group-based activities difficult.
A structured leisure activity programme should typically include:
a focus on the interests and abilities of the participant(s)
regular meetings for a valued leisure activity
for group-based programmes, a facilitator with a broad understanding of autism to help integrate the participants
the provision of structure and support.
For autistic adults without a learning disability or with a mild to moderate learning disability, who have problems with anger and aggression, offer an anger management intervention, adjusted to the needs of autistic adults.
Anger management interventions should typically include:
functional analysis of anger and anger-provoking situations
coping-skills training and behaviour rehearsal
relaxation training
development of problem-solving skills.
For autistic adults without a learning disability or with a mild learning disability, who are at risk of victimisation, consider anti-victimisation interventions based on teaching decision-making and problem-solving skills.
Anti-victimisation interventions should typically include:
identifying and, where possible, modifying and developing decision-making skills in situations associated with abuse
developing personal safety skills.
For autistic adults without a learning disability or with a mild learning disability, who are having difficulty obtaining or maintaining employment, consider an individual supported employment programme.
An individual supported employment programme should typically include:
help with writing CVs and job applications and preparing for interviews
training for the identified work role and work-related behaviours
carefully matching the autistic person with the job
advice to employers about making reasonable adjustments to the workplace
continuing support for the person after they start work
support for the employer before and after the person starts work, including autism awareness training.
## Biomedical (pharmacological, physical and dietary) interventions and the core features of autism
Do not use anticonvulsants for the management of core features of autism in adults.
Do not use chelation for the management of core features of autism in adults.
Do not use the following interventions for the management of core features of autism in adults:
exclusion diets (such as gluten- or casein-free and ketogenic diets)
vitamins, minerals and dietary supplements (such as vitamin B6 or iron supplementation).
Do not use drugs specifically designed to improve cognitive functioning (for example, cholinesterase inhibitors) for the management of core features of autism or routinely for associated cognitive or behavioural problems in adults.
Do not use oxytocin for the management of core features of autism in adults.
Do not use secretin for the management of core features of autism in adults.
Do not use testosterone regulation for the management of core features of autism in adults.
Do not use hyperbaric oxygen therapy for the management of core features of autism in adults.
Do not use antipsychotic medication for the management of core features of autism in adults.
Do not use antidepressant medication for the routine management of core features of autism in adults.
# Interventions for behaviour that challenges
Before initiating other interventions for behaviour that challenges, address any identified factors that may trigger or maintain the behaviour (see recommendation 1.2.20) by offering:
the appropriate care for physical disorders (for example, gastrointestinal problems or chronic pain)
treatment for any coexisting mental disorders, including psychological and pharmacological interventions (for example, anxiolytic, antidepressant or antipsychotic medication), informed by existing NICE guidance
interventions aimed at changing the physical or social environment (for example, who the person lives with) when problems are identified, such as:
advice to the family, partner or carer(s)
changes or accommodations to the physical environment (see recommendation 1.1.8).
First offer a psychosocial intervention for the behaviour that challenges if no coexisting mental or physical disorder, or problem related to the physical or social environment, has been identified as triggering or maintaining behaviour that challenges.
When deciding on the nature and content of a psychosocial intervention to address behaviour that challenges, use a functional analysis. The functional analysis should facilitate the targeting of interventions that address the function(s) of problem behaviour(s) by:
providing information, from a range of environments, on:
factors that appear to trigger the behaviour
the consequences of the behaviour (that is, the reinforcement received as a result of their behaviour)
identifying trends in behaviour occurrence, factors that may be evoking that behaviour, and the needs that the person is attempting to meet by performing the behaviour.
In addition to the functional analysis, base the choice of intervention(s) on:
the nature and severity of the behaviour
the person's physical needs and capabilities
the physical and social environment
the capacity of staff and families, partners or carers to provide support
the preferences of the autistic person and, where appropriate, their family, partner or carer(s)
past history of care and support.
## Psychosocial interventions for behaviour that challenges
Psychosocial interventions for behaviour that challenges should be based on behavioural principles and informed by a functional analysis of behaviour (see recommendation 1.5.3).
Psychosocial interventions for behaviour that challenges should include:
clearly identified target behaviour(s)
a focus on outcomes that are linked to quality of life
assessment and modification of environmental factors that may contribute to initiating or maintaining the behaviour
a clearly defined intervention strategy
a clear schedule of reinforcement, and capacity to offer reinforcement promptly and contingently on demonstration of the desired behaviour
a specified timescale to meet intervention goals (to promote modification of intervention strategies that do not lead to change within a specified time)
a systematic measure of the target behaviour(s) taken before and after the intervention to ascertain whether the agreed outcomes are being met.
## Combined interventions for behaviour that challenges
Consider antipsychotic medication in conjunction with a psychosocial intervention for behaviour that challenges when there has been no or limited response to psychosocial or other interventions (such as environmental adaptations). Antipsychotic medication should be prescribed by a specialist and quality of life outcomes monitored carefully. Review the effects of the medication after 3–4 weeks and discontinue it if there is no indication of a clinically important response at 6 weeks.In June 2012 this was an off-label use of antipsychotic medication. See NICE's information on prescribing medicines.
## Pharmacological interventions for behaviour that challenges
Consider antipsychotic medication alone for behaviour that challenges when psychosocial or other interventions could not be delivered because of the severity of the behaviour that challenges. Antipsychotic medication should be prescribed by a specialist and quality of life outcomes monitored carefully. Review the effects of the medication after 3–4 weeks and discontinue it if there is no indication of a clinically important response at 6 weeks.In June 2012 this was an off-label use of antipsychotic medication. See NICE's information on prescribing medicines.
Do not routinely use anticonvulsants for the management of behaviour that challenges in autistic adults.
# Interventions for coexisting mental disorders
Staff delivering interventions for coexisting mental disorders to autistic adults should:
have an understanding of the core features of autism and their possible impact on the treatment of coexisting mental disorders
consider seeking advice from a specialist autism team regarding delivering and adapting these interventions for autistic people.
## Psychosocial interventions for coexisting mental disorders
For autistic adults and coexisting mental disorders, offer psychosocial interventions informed by existing NICE guidance for the specific disorder.
Adaptations to the method of delivery of cognitive and behavioural interventions for autistic adults and coexisting common mental disorders should include:
a more concrete and structured approach with a greater use of written and visual information (which may include worksheets, thought bubbles, images and 'tool boxes')
placing greater emphasis on changing behaviour, rather than cognitions, and using the behaviour as the starting point for intervention
making rules explicit and explaining their context
using plain English and avoiding excessive use of metaphor, ambiguity and hypothetical situations
involving a family member, partner, carer or professional (if the autistic person agrees) to support the implementation of an intervention
maintaining the person's attention by offering regular breaks and incorporating their special interests into therapy if possible (such as using computers to present information).
## Pharmacological interventions for coexisting mental disorders
For autistic adults and coexisting mental disorders, offer pharmacological interventions informed by existing NICE guidance for the specific disorder.
# Assessment and interventions for families, partners and carers
Offer families, partners and carers of autistic adults an assessment of their own needs (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families, partners and carers).
When the needs of families, partners and carers have been identified, provide information about, and facilitate contact with, a range of support groups including those specifically designed to address the needs of families, partners and carers of autistic people. See the NICE guideline on supporting adult carers.
Offer information, advice, training and support to families, partners and carers if they:
need help with the personal, social or emotional care of the family member, partner or friend or
are involved in supporting the delivery of an intervention for their family member, partner or friend (in collaboration with professionals).
# Organisation and delivery of care
## Developing local care pathways
Local care pathways should be developed to promote implementation of key principles of good care. Pathways should be:
negotiable, workable and understandable for autistic adults, their families, partners and carers, and professionals
accessible and acceptable to all people in need of the services served by the pathway
responsive to the needs of autistic adults and their families, partners and carers
integrated so that there are no barriers to movement between different levels of the pathway
-utcome focused (including measures of quality, service user experience and harm).
Autism strategy groups should be responsible for developing, managing and evaluating local care pathways. The group should appoint a lead professional responsible for the local autism care pathway. The aims of the strategy group should include:
developing clear policy and protocols for the operation of the pathway
ensuring the provision of multi-agency training about features of autism, and training and support on the operation of the pathway
making sure the relevant professionals (health, social care, housing, educational and employment services and the third sector) are aware of the local autism pathway and how to access services
supporting the integrated delivery of services across all care settings
supporting the smooth transition to adult services for young people going through the pathway
auditing and reviewing the performance of the pathway.
The autism strategy group should develop local care pathways that promote access to services for all autistic adults, including:
people with coexisting physical and mental disorders (including substance misuse)
women
people with learning disabilities
-lder people
people from black and minority ethnic groups
transgender people
homeless people
people from the traveller community
people in the criminal justice system
autistic parents.
When providing information about local care pathways to autistic adults and their families, partners and carers, all professionals should:
take into account the person's knowledge and understanding of autism and its care and management
ensure that such information is appropriate to the communities using the pathway.
The autism strategy group should design local care pathways that promote a range of evidence-based interventions at each step in the pathway and support autistic adults in their choice of interventions.
The autism strategy group should design local care pathways that respond promptly and effectively to the changing needs of all populations served by the pathways. Pathways should have in place:
clear and agreed goals for the services offered to autistic adults
robust and effective means for measuring and evaluating the outcomes associated with the agreed goals
clear and agreed mechanisms for responding promptly to identified changes to people's needs.
The autism strategy group should design local care pathways that provide an integrated programme of care across all care settings. Pathways should:
minimise the need for transition between different services or providers
allow services to be built around the pathway and not the pathway around the services
establish clear links (including access and entry points) to other care pathways (including those for physical healthcare needs)
have designated staff who are responsible for the coordination of people's engagement with the pathway.
## Improving access to care
There should be a single point of referral (including self-referral) to specialist services for autistic adults.
Support access to services and increase the uptake of interventions by:
delivering assessment and interventions in a physical environment that is appropriate for people with hyper- and/or hypo-sensory sensitivities (see recommendation 1.1.8)
changing the professional responsible for the person's care if a supportive and caring relationship cannot be established.
Support access to services and increase the uptake of interventions by:
ensuring systems (for example, care coordination or case management) are in place to provide for the overall coordination and continuity of care for autistic adults
designating a professional to oversee the whole period of care (usually a member of the primary healthcare team for those not in the care of a specialist autism team or mental health or learning disability service).
## Residential care
If residential care is needed for autistic adults it should usually be provided in small, local community-based units (of no more than six people and with well-supported single person accommodation). The environment should be structured to support and maintain a collaborative approach between the autistic person and their family, partner or carer(s) for the development and maintenance of interpersonal and community living skills.
Residential care environments should include activities that are:
structured and purposeful
designed to promote integration with the local community and use of local amenities
clearly timetabled with daily, weekly and sequential programmes that promote choice and autonomy.
Residential care environments should have:
designated areas for different activities that provide visual cues about expected behaviour
adaptations to the physical environment for people with hyper- and/or hypo-sensory sensitivities (see recommendation 1.1.8)
inside and outside spaces where the autistic person can be alone (for example, if they are over-stimulated).
Residential care staff should:
understand the principles and attitudes underpinning the effective delivery of residential care for autistic adults
work in collaboration with health and community care staff from a range of specialist services to support the delivery of a comprehensive care plan
be trained in assessing and supporting the needs of autistic adults
be consistent and predictable, but with some flexibility to allow change and choice
be committed to involving families, partners and carers.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
## Augmentative communication
An alternative way of helping people with communication difficulties by using assistive technology such as computers or other devices, such as a speech output device.
## Behavioural principles
Ideas, such as reinforcement and function of behaviour, that underlie behavioural therapies and underpin many interventions teaching adaptive skills for community living for autistic people, including those with behaviour that challenges.
## Behaviour that challenges
A term used to describe behaviour that is a result of the interaction between individual and environmental factors, and includes stereotypic behaviour (such as rocking or hand flapping), anger, aggression, self-injury, and disruptive or destructive behaviour. Such behaviour is seen as challenging when it affects the person's or other people's quality of life and or jeopardises their safety.
## Care pathway
A system designed to improve the overall quality of healthcare by standardising the care process and promoting organised efficient service user care based on best evidence to optimise service user outcomes.
## Chelation
A procedure that involves using one or more substances (chelating agents) to remove materials that are toxic, including heavy metals such as mercury, from the body.
## Easy read
An accessible format for written communication designed for people with a learning disability. It uses simple jargon-free language, short sentences and illustrations.
## Facilitated communication
A therapeutic intervention whereby a facilitator supports the hand or arm of an autistic person while using a keyboard or other devices with the aim of helping the person to develop pointing skills and to communicate.
## Functional analysis
A method for understanding the causes and consequences of behaviour and its relationship to particular stimuli, and the function of the behaviour. The function of a particular behaviour can be analysed by typically identifying (1) the precursor or trigger of the behaviour, (2) the behaviour itself, and (3) the consequence of the behaviour.
## Hyper- and hypo-sensory sensitivities
Being over-sensitive (hyper-sensitive) or under-sensitive (hypo-sensitive) to sound, light, colour, smell or taste, which can cause anxiety or even pain in an autistic person.
## Informant
A family member, partner, carer or other third party known to the autistic person who is able to provide information about the person's features and behaviour so that professionals can have a fuller picture of the person's developmental history. Some assessment tools for autism require information from informants.
## Learning disability
Lower intellectual ability (usually defined as an IQ of less than 70) that leads to problems in learning, developing new skills, communication and carrying out daily activities. Learning disability severities are defined by the following IQ scores: mild=50–69, moderate=35–49 and severe=20–34. A person with a mild to moderate learning disability may only need support in certain areas. However, a person with a moderate to severe learning disability may have no speech or limited communication, a significantly reduced ability to learn new skills and require support with daily activities such as dressing and eating. Learning disabilities are different from 'learning difficulties', like dyslexia, which do not affect intellect. Learning disability is sometimes also called 'intellectual disability'.
## Modelling
A technique used in behavioural therapy that utilises video and other media. The service user observes target behaviour on the video or computer screen, and repeats it.
## Reinforcement
A technique used in behavioural therapy to teach 'rules' of social engagement through providing prompts for behaviour. Reinforcement may be by the autistic person or those working with or caring for them.# Recommendations for research
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline.
# Facilitated self-help for anxiety and depression in autistic adults
What is the clinical and cost effectiveness of facilitated self-help for the treatment of mild anxiety and depressive disorders in autistic adults?
## Why this is important
Anxiety and depressive disorders commonly coexist in autistic people and are associated with poorer health outcomes and quality of life. This may occur because of the direct impact of the anxiety or depression but also because of a negative interaction with the core features of autism. There is limited access and poor uptake of facilitated self-help by autistic people, largely due to limited availability but also because current systems for the delivery of such interventions are not adapted for use by autistic people. In adults without autism, facilitated self-help is an effective intervention for mild to moderate depression and anxiety. The development of novel methods for the delivery of facilitated self-help could make effective interventions available to a wider group of people.
The suggested programme of research would need to: (a) develop current methods for the delivery of self-help measures to take into account the impact of autism and possibly include developments in the nature of the materials, the methods for their delivery and the nature, duration and extent of their facilitation; (b) test the feasibility of the novel methods in a series of pilot studies; and (c) formally evaluate the outcomes (including symptoms, satisfaction and quality of life) in a large-scale randomised trial.
# The structure and organisation of specialist teams
What structure and organisation of specialist autism teams are associated with improvements in care for autistic people?
## Why this is important
The Department of Health's autism strategy (2010) proposes the introduction of a range of specialist services for autistic people; these will usually be built around specialist autism teams. However, there is little evidence to guide the establishment and development of these teams. There is uncertainty about the precise nature of the population to be served (all autistic people or only those who have an IQ of 70 or above), the composition of the team, the extent of the team's role (for example, diagnosis and assessment only, a primarily advisory role or a substantial care coordination role), the interventions provided by the team, and the team's role and relationship with regard to non-statutory care providers. Therefore it is likely that in the near future a number of different models will be developed, which are likely to have varying degrees of success in meeting the needs of autistic people. Given the significant expansion of services, this presents an opportunity for a large-scale observational study, which should provide important information on the characteristics of teams associated with positive outcomes for autistic people in terms of access to services and effective coordination of care.
# Augmentative communication devices for autistic adults
What is the clinical and cost effectiveness of augmentative communication devices for autistic adults?
## Why this is important
Many autistic people experience significant communication problems (for example, the absence of any spoken language or significant deficits in interpersonal skills), which have a profound effect on their ability to lead a full and rewarding life. It is probable that these problems are related to the core features of autism and are likely to persist for most people given the life-long course of autism and the lack of effective interventions for these core features. A number of communication devices have been developed for autism but few, if any, have been subjected to a proper evaluation in adults. Despite this lack of formal evaluation, individual services have made considerable investments in augmentative communication devices. Research that provides high-quality evidence on the acceptability and the clinical and cost effectiveness of augmentative communication devices could bring about significant improvements in the lives of autistic adults.
The suggested programme of research would need to identify current devices for which there is: (a) some evidence of benefit (for example, case series and small-scale pilot studies); (b) some evidence that it meets a key communication need for autistic people (based on reviews of people's need in this area); and (c) indication that the device is feasible for routine use. The identified device(s) should then be formally evaluated in a large-scale randomised trial.
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{'Introduction': "Autism is a lifelong neurodevelopmental condition, the core features of which are persistent difficulties in social interaction and communication and the presence of stereotypic (rigid and repetitive) behaviours, resistance to change or restricted interests. The way that autism is expressed in individual people differs at different stages of life, in response to interventions, and with the presence of coexisting conditions such as learning disabilities (also called 'intellectual disabilities'). Autistic people also commonly experience difficulty with cognitive and behavioural flexibility, altered sensory sensitivity, sensory processing difficulties and emotional regulation difficulties. The features of autism may range from mild to severe and may fluctuate over time or in response to changes in circumstances.\n\nA significant proportion of autistic adults across the whole autistic spectrum experience social and economic exclusion. Their condition is often overlooked by healthcare, education and social care professionals, which creates barriers to accessing the support and services they need to live independently. In addition, autistic people are more likely to have coexisting mental and physical disorders, and other developmental disorders. Some may have contact with the criminal justice system, as either victims of crime or offenders, and it is important that their needs are recognised.\n\nThere is wide variation in rates of identification and referral for diagnostic assessment, waiting times for diagnosis, models of multi-professional working, assessment criteria and diagnostic practice for adults with features of autism. These factors contribute to delays in reaching a diagnosis and subsequent access to appropriate services.\n\nWhen the diagnostic assessment process works well, professionals, the autistic person and their family, partner or carer(s) communicate right from the start and the autistic person is involved in the decisions relating to their care. This lays the foundation for a long-term understanding between the autistic person, their family, partner or carer(s) and the professionals supporting their needs. However, many adults have difficulties accessing a diagnostic assessment. Even if they manage to obtain a diagnosis they may receive no follow-up support because of the absence of appropriate services or an agreed care pathway.\n\nIn this guideline 'autism' refers to 'autism spectrum disorders' encompassing autism, Asperger's syndrome and atypical autism (or pervasive developmental disorder not otherwise specified). The Guideline Development Group recognises, however, that different individuals and groups prefer a variety of terms for autism including autistic spectrum condition, autistic spectrum difference and neurodiversity (in recent Department of Health, National Audit Office and Public Accounts Committee documents, 'autism' is used to cover all of these terms).\n\nThis guideline covers the care provided by primary, community, secondary, tertiary and other health and social care professionals who have direct contact with, and make decisions concerning the care of, autistic adults.\n\nA number of recommendations in this guideline have been adapted from recommendations in other NICE clinical guidelines. Where this occurred, the Guideline Development Group was careful to preserve the meaning and intent of the original recommendations. Changes to wording or structure were made in order to fit the recommendations into this guideline.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) to inform decisions made with individual patients. In this guideline, recommendations are marked with a note if drugs do not have a UK marketing authorisation for the indication in question at the time of publication. Prescribers should check each drug's SPC for current licensed indications.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# General principles of care\n\n## Principles for working with autistic adults and their families, partners and carers\n\nAll staff working with autistic adults should:\n\nwork in partnership with autistic adults and, where appropriate, with their families, partners and carers\n\noffer support and care respectfully\n\ntake time to build a trusting, supportive, empathic and non-judgemental relationship as an essential part of care.\n\nAll staff working with autistic adults should have an understanding of the:\n\nnature, development and course of autism\n\nimpact on personal, social, educational and occupational functioning\n\nimpact of the social and physical environment.\n\nAll health and social care professionals providing care and support for autistic adults should have a broad understanding of the:\n\nnature, development and course of autism\n\nimpact on personal, social, educational and occupational functioning\n\nimpact of and interaction with the social and physical environment\n\nimpact on and interaction with other coexisting mental and physical disorders and their management\n\npotential discrepancy between intellectual functioning as measured by IQ and adaptive functioning as reflected, for example, by difficulties in planning and performing activities of daily living including education or employment.\n\nAll health and social care professionals providing care and support for autistic adults should:\n\naim to foster the person's autonomy, promote active participation in decisions about care and support self-management\n\nmaintain continuity of individual relationships wherever possible\n\nensure that comprehensive information about the nature of, and interventions and services for, their difficulties is available in an appropriate language or format (including various visual, verbal and aural, easy read, and different colour and font formats)\n\nconsider whether the person may benefit from access to a trained advocate.\n\nAll health and social care professionals providing care and support for autistic adults and their families, partners and carers should:\n\nensure that they are easily identifiable (for example, by producing or wearing appropriate identification) and approachable\n\nclearly communicate their role and function\n\naddress the person using the name and title they prefer\n\nclearly explain any clinical language and check that the autistic person understands what is being said\n\ntake into account communication needs, including those arising from a learning disability, sight or hearing problems or language difficulties, and provide communication aids or independent interpreters (someone who does not have a personal relationship with the autistic person) if required.\n\nAll health and social care professionals providing care and support for autistic adults and their families, partners and carers should ensure that they are:\n\nfamiliar with recognised local and national sources (organisations and websites) of information and/or support for autistic people\n\nable to discuss and advise on how to access and engage with these resources.\n\nEncourage autistic adults to participate in self-help or support groups or access one-to-one support, and provide support so that they can attend meetings and engage in the activities.\n\nIn all settings, take into account the physical environment in which autistic adults are assessed, supported and cared for, including any factors that may trigger behaviour that challenges. If necessary make adjustments or adaptations to the:\n\namount of personal space given (at least an arm's length)\n\nsetting using visual supports (for example, use labels with words or symbols to provide visual cues about expected behaviour)\n\ncolour of walls and furnishings (avoid patterns and use low-arousal colours such as cream)\n\nlighting (reduce fluorescent lighting, use blackout curtains or advise use of dark glasses or increase natural light)\n\nnoise levels (reduce external sounds or advise use of earplugs or ear defenders). Where it is not possible to adjust or adapt the environment, consider varying the duration or nature of any assessment or intervention (including taking regular breaks) to limit the negative impact of the environment.\n\nAll health and social care professionals providing care and support for autistic adults should:\n\nbe aware of under-reporting and under-recognition of physical disorders in autistic people\n\nbe vigilant for unusual likes and dislikes about food and/or lack of physical activity\n\noffer advice about the beneficial effects of a healthy diet and exercise, taking into account any hyper- and/or hypo-sensory sensitivities; if necessary, support referral to a GP or dietician.\n\nAll staff working with autistic adults should be sensitive to issues of sexuality, including asexuality and the need to develop personal and sexual relationships. In particular, be aware that problems in social interaction and communication may lead to the autistic person misunderstanding another person's behaviour or to their possible exploitation by others.\n\nEnsure that autistic adults who have caring responsibilities receive support to access the full range of mental and physical health and social care services, including:\n\nspecific information, advice and support to parents about their parenting role, including parent training if needed, by professionals experienced in the care of autistic adults and children\n\nsocial support, such as childcare, to enable them to attend appointments, groups and therapy sessions, and to access education and employment.\n\n## Structures for the organisation and delivery of care and interventions\n\nIn order to effectively provide care and support for autistic adults, the local autism multi-agency strategy group should include representation from managers, commissioners and clinicians from adult services, including mental health, learning disability, primary healthcare, social care, housing, educational and employment services, the criminal justice system and the third sector. There should be meaningful representation from autistic people and their families, partners and carers.\n\nIn each area a specialist community-based multidisciplinary team for autistic adults (the specialist autism team) should be established. The membership should include:\n\npsychologists with training and experience in working with autistic adults\n\nnurses\n\noccupational therapists\n\npsychiatrists\n\nsocial workers\n\nspeech and language therapists\n\nsupport staff (for example, staff supporting access to housing, educational and employment services, financial advice, and personal and community safety skills).\n\nThe specialist autism team should have a key role in the delivery and coordination of:\n\nspecialist diagnostic and assessment services\n\nspecialist care and interventions\n\nadvice and training to other health and social care professionals on the diagnosis, assessment, care and interventions for autistic adults (as not all may be in the care of a specialist team)\n\nsupport in accessing, and maintaining contact with, housing, educational and employment services\n\nsupport to families, partners and carers where appropriate\n\ncare and interventions for autistic adults living in specialist residential accommodation\n\ntraining, support and consultation for staff who care for autistic adults in residential and community settings.\n\n## Involving families, partners and carers\n\nDiscuss with autistic adults if and how they want their families, partners or carers to be involved in their care. During discussions, take into account any implications of the Mental Capacity Act (2005) and any communication needs the person may have (see recommendation 1.1.5).\n\nIf the autistic person wants their family, partner or carer(s) to be involved, encourage this involvement and:\n\nnegotiate between the autistic person and their family, partner or carer(s) about confidentiality and sharing of information on an ongoing basis\n\nexplain how families, partners and carers can help support the autistic person and help with care plans\n\nmake sure that no services are withdrawn because of involvement of the family, partner or carer(s), unless this has been clearly agreed with both the autistic person and their family, partner or carer(s).\n\nGive all families, partners and carer(s) (whether or not the person wants them to be involved in their care) verbal and written information about:\n\nautism and its management\n\nlocal support groups and services specifically for families, partners and carers\n\ntheir right to a carer's assessment of their own physical and mental health needs, and how to access this (see the NICE guideline on supporting adult carers).\n\nIf an autistic person does not want their family, partners or carer(s) to be involved in their care:\n\ngive the family, partner or carer(s) verbal and written information about who they can contact if they are concerned about the person's care\n\nbear in mind that autistic people may be ambivalent or negative towards their family or partner. This may be for many different reasons, including a coexisting mental disorder or prior experience of violence or abuse.\n\n# Identification and assessment\n\n## Principles for the effective assessment of autism\n\nStaff who have responsibility for the identification or assessment of autistic adults should adapt these procedures, if necessary, to ensure their effective delivery, including modifications to the setting in which assessment is delivered (see recommendation 1.1.8) and the duration and pacing of the assessment.\n\n## Identification and initial assessment of possible autism\n\nConsider assessment for possible autism when a person has:\n\none or more of the following:\n\n\n\npersistent difficulties in social interaction\n\npersistent difficulties in social communication\n\nstereotypic (rigid and repetitive) behaviours, resistance to change or restricted interests, and\n\n\n\none or more of the following:\n\n\n\nproblems in obtaining or sustaining employment or education\n\ndifficulties in initiating or sustaining social relationships\n\nprevious or current contact with mental health or learning disability services\n\na history of a neurodevelopmental condition (including learning disabilities and attention deficit hyperactivity disorder) or mental disorder.\n\n\n\nFor adults with possible autism who do not have a moderate or severe learning disability, consider using the Autism-Spectrum Quotient – 10 items (AQ-10). (If a person has reading difficulties, read out the AQ-10.) If a person scores 6 or above on the AQ-10, or autism is suspected based on clinical judgement (taking into account any past history provided by an informant), offer a comprehensive assessment for autism. [amended 2021]\n\nFor adults with possible autism who have a moderate or severe learning disability, consider a brief assessment to ascertain whether the following behaviours are present (if necessary using information from a family member, partner or carer):\n\ndifficulties in reciprocal social interaction including:\n\n\n\nlimited interaction with others (for example, being aloof, indifferent or unusual)\n\ninteraction to fulfil needs only\n\ninteraction that is naive or one-sided\n\n\n\nlack of responsiveness to others\n\nlittle or no change in behaviour in response to different social situations\n\nlimited social demonstration of empathy\n\nrigid routines and resistance to change\n\nmarked repetitive activities (for example, rocking and hand or finger flapping), especially when under stress or expressing emotion. If two or more of the above categories of behaviour are present, offer a comprehensive assessment for autism.\n\n## Comprehensive (diagnostic, needs and risks) assessment of suspected autism\n\nA comprehensive assessment should:\n\nbe undertaken by professionals who are trained and competent\n\nbe team-based and draw on a range of professions and skills\n\nwhere possible involve a family member, partner, carer or other informant or use documentary evidence (such as school reports) of current and past behaviour and early development.\n\nAt the beginning of a comprehensive assessment, discuss with the person the purpose of the assessment and how the outcome of the assessment will be fed back to them. Feedback should be individualised, and consider involving a family member, partner, carer or advocate, where appropriate, to support the person and help explain the feedback.\n\nDuring a comprehensive assessment, enquire about and assess the following:\n\ncore autism features (difficulties in social interaction and communication and the presence of stereotypic behaviour, resistance to change or restricted interests) that have been present in childhood and continuing into adulthood\n\nearly developmental history, where possible\n\nbehavioural problems\n\nfunctioning at home, in education or in employment\n\npast and current physical and mental disorders\n\nother neurodevelopmental conditions\n\nhyper- and/or hypo-sensory sensitivities and attention to detail. Carry out direct observation of core autism features especially in social situations.\n\nTo aid more complex diagnosis and assessment for adults, consider using a formal assessment tool, such as:\n\nthe following tools for people who do not have a learning disability:\n\n\n\nthe Adult Asperger Assessment (AAA; includes the Autism-Spectrum Quotient [AQ] and the Empathy Quotient [EQ])\n\nthe Autism Diagnostic Interview – Revised (ADI-R)\n\nthe Autism Diagnostic Observation Schedule – Generic (ADOS-G)\n\nthe Asperger Syndrome (and high-functioning autism) Diagnostic Interview (ASDI)\n\nthe Ritvo Autism Asperger Diagnostic Scale – Revised (RAADS-R)\n\n\n\nthe following tools in particular for people with a learning disability:\n\n\n\nthe ADOS-G\n\nthe ADI-R.\n\n\n\nTo organise and structure the process of a more complex assessment, consider using a formal assessment tool, such as the Diagnostic Interview for Social and Communication Disorders (DISCO), the ADOS-G or the ADI-R.\n\nDuring a comprehensive assessment, take into account and assess for possible differential diagnoses and coexisting disorders or conditions, such as:\n\nother neurodevelopmental conditions (use formal assessment tools for learning disabilities)\n\nmental disorders (for example, schizophrenia, depression or other mood disorders, and anxiety disorders, in particular, social anxiety disorder and obsessive–compulsive disorder)\n\nneurological disorders (for example, epilepsy)\n\nphysical disorders\n\ncommunication difficulties (for example, speech and language problems, and selective mutism)\n\nhyper- and/or hypo-sensory sensitivities.\n\nDo not use biological tests, genetic tests or neuroimaging for diagnostic purposes routinely as part of a comprehensive assessment.\n\nDuring a comprehensive assessment, assess the following risks:\n\nself-harm (in particular in people with depression or a moderate or severe learning disability)\n\nrapid escalation of problems\n\nharm to others\n\nself-neglect\n\nbreakdown of family or residential support\n\nexploitation or abuse by others. Develop a risk management plan if needed.\n\nDevelop a care plan based on the comprehensive assessment, incorporating the risk management plan and including any particular needs (such as adaptations to the social or physical environment), and also taking into account the needs of the family, partner or carer(s).\n\nProvide a 'health passport' (for example, a laminated card) for autistic adults, which includes information for all staff about the person's care and support needs. Advise the person to carry the health passport at all times.\n\nAs part of a comprehensive assessment consider developing a 24-hour crisis management plan, where necessary in conjunction with specialist mental health services, which should detail:\n\nthe likely trigger(s) for a crisis\n\nthe nature and speed of the reaction to any trigger(s), including details about the way in which autism may impact on a person's behaviour leading up to and during a crisis\n\nthe role of the specialist team and other services (including outreach and out-of-hours services) in responding to a crisis\n\nadvice to primary care professionals and other services on their responsibilities and appropriate management in a crisis\n\nadvice for families, partners and carers about their role in a crisis\n\nthe nature of any changes or adaptations to the social or physical environment (see recommendation 1.1.8) needed to manage a crisis.\n\nConsider obtaining a second opinion (including referral to another specialist autism team if necessary), if there is uncertainty about the diagnosis or if any of the following apply after diagnostic assessment:\n\ndisagreement about the diagnosis within the autism team\n\ndisagreement with the person, their family, partner, carer(s) or advocate about the diagnosis\n\na lack of local expertise in the skills and competencies needed to reach diagnosis in autistic adults\n\nthe person has a complex coexisting condition, such as a severe learning disability, a severe behavioural, visual, hearing or motor problem, or a severe mental disorder.\n\nOn an individual basis, and using information from the comprehensive assessment and physical examination, and clinical judgement, consider further investigations, including:\n\ngenetic tests, as recommended by the regional genetics centre, if there are specific dysmorphic features, congenital anomalies and/or evidence of a learning disability\n\nelectroencephalography if there is suspicion of epilepsy\n\nhearing or sight tests, if there is suspicion of hearing or visual impairment\n\nother medical tests depending on individual signs and symptoms (for example, sudden onset of behaviour that challenges, change in usual patterns of behaviour, sudden change in weight, or suspicion that the person might be in pain and is unable to communicate this).\n\nOffer all adults who have received a diagnosis of autism (irrespective of whether they need or have refused further care and support) a follow-up appointment to discuss the implications of the diagnosis, any concerns they have about the diagnosis, and any future care and support they may require.\n\n## Assessment of behaviour that challenges\n\nAssessment of behaviour that challenges should be integrated into a comprehensive assessment for autistic adults.\n\nWhen assessing behaviour that challenges carry out a functional analysis (see recommendation 1.5.3) including identifying and evaluating any factors that may trigger or maintain the behaviour, such as:\n\nphysical disorders\n\nthe social environment (including relationships with family members, partners, carers and friends)\n\nthe physical environment, including sensory factors\n\ncoexisting mental disorders (including depression, anxiety disorders and psychosis)\n\ncommunication problems\n\nchanges to routines or personal circumstances.\n\n# Identifying the correct interventions and monitoring their use\n\nWhen discussing and deciding on interventions with autistic adults, consider:\n\ntheir experience of, and response to, previous interventions\n\nthe nature and severity of their autism\n\nthe extent of any associated functional impairment arising from the autism, a learning disability or a mental or physical disorder\n\nthe presence of any social or personal factors that may have a role in the development or maintenance of any identified problem(s)\n\nthe presence, nature, severity and duration of any coexisting disorders\n\nthe identification of predisposing and possible precipitating factors that could lead to crises if not addressed.\n\nWhen discussing and deciding on care and interventions with autistic adults, take into account the:\n\nincreased propensity for elevated anxiety about decision-making in autistic people\n\ngreater risk of altered sensitivity and unpredictable responses to medication\n\nenvironment, for example whether it is suitably adapted for autistic people, in particular those with hyper- and/or hypo-sensory sensitivities (see recommendation 1.1.8)\n\npresence and nature of hyper- and/or hypo-sensory sensitivities and how these might impact on the delivery of the intervention\n\nimportance of predictability, clarity, structure and routine for autistic people\n\nnature of support needed to access interventions.\n\nWhen discussing and deciding on interventions with autistic adults, provide information about:\n\nthe nature, content and duration of any proposed intervention\n\nthe acceptability and tolerability of any proposed intervention\n\npossible interactions with any current interventions and possible side effects\n\nthe implications for the continuing provision of any current interventions.\n\nWhen deciding on options for pharmacological interventions for behaviour that challenges or coexisting mental disorders in autistic adults:\n\nbe aware of the potential for greater sensitivity to side effects and idiosyncratic responses in autistic people and\n\nconsider starting with a low dose.\n\nFor any intervention used in autistic adults, there should be a regular review of:\n\nthe benefits of the intervention, where feasible using a formal rating of the target behaviour(s)\n\nany adverse events\n\nspecific monitoring requirements of pharmacological interventions as highlighted by the summary of product characteristics\n\nadherence to the intervention.\n\n# Interventions for autism\n\n## Psychosocial interventions for the core features of autism\n\nFor autistic adults without a learning disability or with a mild to moderate learning disability, who have identified problems with social interaction, consider:\n\na group-based social learning programme focused on improving social interaction\n\nan individually delivered social learning programme for people who find group-based activities difficult.\n\nSocial learning programmes to improve social interaction should typically include:\n\nmodelling\n\npeer feedback (for group-based programmes) or individual feedback (for individually delivered programmes)\n\ndiscussion and decision-making\n\nexplicit rules\n\nsuggested strategies for dealing with socially difficult situations.\n\nDo not provide facilitated communication for autistic adults.\n\n## Psychosocial interventions focused on life skills\n\nFor autistic adults of all ranges of intellectual ability, who need help with activities of daily living, consider a structured and predictable training programme based on behavioural principles.\n\nFor autistic adults without a learning disability or with a mild to moderate learning disability, who are socially isolated or have restricted social contact, consider:\n\na group-based structured leisure activity programme\n\nan individually delivered structured leisure activity programme for people who find group-based activities difficult.\n\nA structured leisure activity programme should typically include:\n\na focus on the interests and abilities of the participant(s)\n\nregular meetings for a valued leisure activity\n\nfor group-based programmes, a facilitator with a broad understanding of autism to help integrate the participants\n\nthe provision of structure and support.\n\nFor autistic adults without a learning disability or with a mild to moderate learning disability, who have problems with anger and aggression, offer an anger management intervention, adjusted to the needs of autistic adults.\n\nAnger management interventions should typically include:\n\nfunctional analysis of anger and anger-provoking situations\n\ncoping-skills training and behaviour rehearsal\n\nrelaxation training\n\ndevelopment of problem-solving skills.\n\nFor autistic adults without a learning disability or with a mild learning disability, who are at risk of victimisation, consider anti-victimisation interventions based on teaching decision-making and problem-solving skills.\n\nAnti-victimisation interventions should typically include:\n\nidentifying and, where possible, modifying and developing decision-making skills in situations associated with abuse\n\ndeveloping personal safety skills.\n\nFor autistic adults without a learning disability or with a mild learning disability, who are having difficulty obtaining or maintaining employment, consider an individual supported employment programme.\n\nAn individual supported employment programme should typically include:\n\nhelp with writing CVs and job applications and preparing for interviews\n\ntraining for the identified work role and work-related behaviours\n\ncarefully matching the autistic person with the job\n\nadvice to employers about making reasonable adjustments to the workplace\n\ncontinuing support for the person after they start work\n\nsupport for the employer before and after the person starts work, including autism awareness training.\n\n## Biomedical (pharmacological, physical and dietary) interventions and the core features of autism\n\nDo not use anticonvulsants for the management of core features of autism in adults.\n\nDo not use chelation for the management of core features of autism in adults.\n\nDo not use the following interventions for the management of core features of autism in adults:\n\nexclusion diets (such as gluten- or casein-free and ketogenic diets)\n\nvitamins, minerals and dietary supplements (such as vitamin B6 or iron supplementation).\n\nDo not use drugs specifically designed to improve cognitive functioning (for example, cholinesterase inhibitors) for the management of core features of autism or routinely for associated cognitive or behavioural problems in adults.\n\nDo not use oxytocin for the management of core features of autism in adults.\n\nDo not use secretin for the management of core features of autism in adults.\n\nDo not use testosterone regulation for the management of core features of autism in adults.\n\nDo not use hyperbaric oxygen therapy for the management of core features of autism in adults.\n\nDo not use antipsychotic medication for the management of core features of autism in adults.\n\nDo not use antidepressant medication for the routine management of core features of autism in adults.\n\n# Interventions for behaviour that challenges\n\nBefore initiating other interventions for behaviour that challenges, address any identified factors that may trigger or maintain the behaviour (see recommendation 1.2.20) by offering:\n\nthe appropriate care for physical disorders (for example, gastrointestinal problems or chronic pain)\n\ntreatment for any coexisting mental disorders, including psychological and pharmacological interventions (for example, anxiolytic, antidepressant or antipsychotic medication), informed by existing NICE guidance\n\ninterventions aimed at changing the physical or social environment (for example, who the person lives with) when problems are identified, such as:\n\n\n\nadvice to the family, partner or carer(s)\n\nchanges or accommodations to the physical environment (see recommendation 1.1.8).\n\n\n\nFirst offer a psychosocial intervention for the behaviour that challenges if no coexisting mental or physical disorder, or problem related to the physical or social environment, has been identified as triggering or maintaining behaviour that challenges.\n\nWhen deciding on the nature and content of a psychosocial intervention to address behaviour that challenges, use a functional analysis. The functional analysis should facilitate the targeting of interventions that address the function(s) of problem behaviour(s) by:\n\nproviding information, from a range of environments, on:\n\n\n\nfactors that appear to trigger the behaviour\n\nthe consequences of the behaviour (that is, the reinforcement received as a result of their behaviour)\n\n\n\nidentifying trends in behaviour occurrence, factors that may be evoking that behaviour, and the needs that the person is attempting to meet by performing the behaviour.\n\nIn addition to the functional analysis, base the choice of intervention(s) on:\n\nthe nature and severity of the behaviour\n\nthe person's physical needs and capabilities\n\nthe physical and social environment\n\nthe capacity of staff and families, partners or carers to provide support\n\nthe preferences of the autistic person and, where appropriate, their family, partner or carer(s)\n\npast history of care and support.\n\n## Psychosocial interventions for behaviour that challenges\n\nPsychosocial interventions for behaviour that challenges should be based on behavioural principles and informed by a functional analysis of behaviour (see recommendation 1.5.3).\n\nPsychosocial interventions for behaviour that challenges should include:\n\nclearly identified target behaviour(s)\n\na focus on outcomes that are linked to quality of life\n\nassessment and modification of environmental factors that may contribute to initiating or maintaining the behaviour\n\na clearly defined intervention strategy\n\na clear schedule of reinforcement, and capacity to offer reinforcement promptly and contingently on demonstration of the desired behaviour\n\na specified timescale to meet intervention goals (to promote modification of intervention strategies that do not lead to change within a specified time)\n\na systematic measure of the target behaviour(s) taken before and after the intervention to ascertain whether the agreed outcomes are being met.\n\n## Combined interventions for behaviour that challenges\n\nConsider antipsychotic medication in conjunction with a psychosocial intervention for behaviour that challenges when there has been no or limited response to psychosocial or other interventions (such as environmental adaptations). Antipsychotic medication should be prescribed by a specialist and quality of life outcomes monitored carefully. Review the effects of the medication after 3–4\xa0weeks and discontinue it if there is no indication of a clinically important response at 6\xa0weeks.In June 2012 this was an off-label use of antipsychotic medication. See NICE's information on prescribing medicines.\n\n## Pharmacological interventions for behaviour that challenges\n\nConsider antipsychotic medication alone for behaviour that challenges when psychosocial or other interventions could not be delivered because of the severity of the behaviour that challenges. Antipsychotic medication should be prescribed by a specialist and quality of life outcomes monitored carefully. Review the effects of the medication after 3–4\xa0weeks and discontinue it if there is no indication of a clinically important response at 6\xa0weeks.In June 2012 this was an off-label use of antipsychotic medication. See NICE's information on prescribing medicines.\n\nDo not routinely use anticonvulsants for the management of behaviour that challenges in autistic adults.\n\n# Interventions for coexisting mental disorders\n\nStaff delivering interventions for coexisting mental disorders to autistic adults should:\n\nhave an understanding of the core features of autism and their possible impact on the treatment of coexisting mental disorders\n\nconsider seeking advice from a specialist autism team regarding delivering and adapting these interventions for autistic people.\n\n## Psychosocial interventions for coexisting mental disorders\n\nFor autistic adults and coexisting mental disorders, offer psychosocial interventions informed by existing NICE guidance for the specific disorder.\n\nAdaptations to the method of delivery of cognitive and behavioural interventions for autistic adults and coexisting common mental disorders should include:\n\na more concrete and structured approach with a greater use of written and visual information (which may include worksheets, thought bubbles, images and 'tool boxes')\n\nplacing greater emphasis on changing behaviour, rather than cognitions, and using the behaviour as the starting point for intervention\n\nmaking rules explicit and explaining their context\n\nusing plain English and avoiding excessive use of metaphor, ambiguity and hypothetical situations\n\ninvolving a family member, partner, carer or professional (if the autistic person agrees) to support the implementation of an intervention\n\nmaintaining the person's attention by offering regular breaks and incorporating their special interests into therapy if possible (such as using computers to present information).\n\n## Pharmacological interventions for coexisting mental disorders\n\nFor autistic adults and coexisting mental disorders, offer pharmacological interventions informed by existing NICE guidance for the specific disorder.\n\n# Assessment and interventions for families, partners and carers\n\nOffer families, partners and carers of autistic adults an assessment of their own needs (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families, partners and carers).\n\nWhen the needs of families, partners and carers have been identified, provide information about, and facilitate contact with, a range of support groups including those specifically designed to address the needs of families, partners and carers of autistic people. See the NICE guideline on supporting adult carers.\n\nOffer information, advice, training and support to families, partners and carers if they:\n\nneed help with the personal, social or emotional care of the family member, partner or friend or\n\nare involved in supporting the delivery of an intervention for their family member, partner or friend (in collaboration with professionals).\n\n# Organisation and delivery of care\n\n## Developing local care pathways\n\nLocal care pathways should be developed to promote implementation of key principles of good care. Pathways should be:\n\nnegotiable, workable and understandable for autistic adults, their families, partners and carers, and professionals\n\naccessible and acceptable to all people in need of the services served by the pathway\n\nresponsive to the needs of autistic adults and their families, partners and carers\n\nintegrated so that there are no barriers to movement between different levels of the pathway\n\noutcome focused (including measures of quality, service user experience and harm).\n\nAutism strategy groups should be responsible for developing, managing and evaluating local care pathways. The group should appoint a lead professional responsible for the local autism care pathway. The aims of the strategy group should include:\n\ndeveloping clear policy and protocols for the operation of the pathway\n\nensuring the provision of multi-agency training about features of autism, and training and support on the operation of the pathway\n\nmaking sure the relevant professionals (health, social care, housing, educational and employment services and the third sector) are aware of the local autism pathway and how to access services\n\nsupporting the integrated delivery of services across all care settings\n\nsupporting the smooth transition to adult services for young people going through the pathway\n\nauditing and reviewing the performance of the pathway.\n\nThe autism strategy group should develop local care pathways that promote access to services for all autistic adults, including:\n\npeople with coexisting physical and mental disorders (including substance misuse)\n\nwomen\n\npeople with learning disabilities\n\nolder people\n\npeople from black and minority ethnic groups\n\ntransgender people\n\nhomeless people\n\npeople from the traveller community\n\npeople in the criminal justice system\n\nautistic parents.\n\nWhen providing information about local care pathways to autistic adults and their families, partners and carers, all professionals should:\n\ntake into account the person's knowledge and understanding of autism and its care and management\n\nensure that such information is appropriate to the communities using the pathway.\n\nThe autism strategy group should design local care pathways that promote a range of evidence-based interventions at each step in the pathway and support autistic adults in their choice of interventions.\n\nThe autism strategy group should design local care pathways that respond promptly and effectively to the changing needs of all populations served by the pathways. Pathways should have in place:\n\nclear and agreed goals for the services offered to autistic adults\n\nrobust and effective means for measuring and evaluating the outcomes associated with the agreed goals\n\nclear and agreed mechanisms for responding promptly to identified changes to people's needs.\n\nThe autism strategy group should design local care pathways that provide an integrated programme of care across all care settings. Pathways should:\n\nminimise the need for transition between different services or providers\n\nallow services to be built around the pathway and not the pathway around the services\n\nestablish clear links (including access and entry points) to other care pathways (including those for physical healthcare needs)\n\nhave designated staff who are responsible for the coordination of people's engagement with the pathway.\n\n## Improving access to care\n\nThere should be a single point of referral (including self-referral) to specialist services for autistic adults.\n\nSupport access to services and increase the uptake of interventions by:\n\ndelivering assessment and interventions in a physical environment that is appropriate for people with hyper- and/or hypo-sensory sensitivities (see recommendation 1.1.8)\n\nchanging the professional responsible for the person's care if a supportive and caring relationship cannot be established.\n\nSupport access to services and increase the uptake of interventions by:\n\nensuring systems (for example, care coordination or case management) are in place to provide for the overall coordination and continuity of care for autistic adults\n\ndesignating a professional to oversee the whole period of care (usually a member of the primary healthcare team for those not in the care of a specialist autism team or mental health or learning disability service).\n\n## Residential care\n\nIf residential care is needed for autistic adults it should usually be provided in small, local community-based units (of no more than six people and with well-supported single person accommodation). The environment should be structured to support and maintain a collaborative approach between the autistic person and their family, partner or carer(s) for the development and maintenance of interpersonal and community living skills.\n\nResidential care environments should include activities that are:\n\nstructured and purposeful\n\ndesigned to promote integration with the local community and use of local amenities\n\nclearly timetabled with daily, weekly and sequential programmes that promote choice and autonomy.\n\nResidential care environments should have:\n\ndesignated areas for different activities that provide visual cues about expected behaviour\n\nadaptations to the physical environment for people with hyper- and/or hypo-sensory sensitivities (see recommendation 1.1.8)\n\ninside and outside spaces where the autistic person can be alone (for example, if they are over-stimulated).\n\nResidential care staff should:\n\nunderstand the principles and attitudes underpinning the effective delivery of residential care for autistic adults\n\nwork in collaboration with health and community care staff from a range of specialist services to support the delivery of a comprehensive care plan\n\nbe trained in assessing and supporting the needs of autistic adults\n\nbe consistent and predictable, but with some flexibility to allow change and choice\n\nbe committed to involving families, partners and carers.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Augmentative communication\n\nAn alternative way of helping people with communication difficulties by using assistive technology such as computers or other devices, such as a speech output device.\n\n## Behavioural principles\n\nIdeas, such as reinforcement and function of behaviour, that underlie behavioural therapies and underpin many interventions teaching adaptive skills for community living for autistic people, including those with behaviour that challenges.\n\n## Behaviour that challenges\n\nA term used to describe behaviour that is a result of the interaction between individual and environmental factors, and includes stereotypic behaviour (such as rocking or hand flapping), anger, aggression, self-injury, and disruptive or destructive behaviour. Such behaviour is seen as challenging when it affects the person's or other people's quality of life and or jeopardises their safety.\n\n## Care pathway\n\nA system designed to improve the overall quality of healthcare by standardising the care process and promoting organised efficient service user care based on best evidence to optimise service user outcomes.\n\n## Chelation\n\nA procedure that involves using one or more substances (chelating agents) to remove materials that are toxic, including heavy metals such as mercury, from the body.\n\n## Easy read\n\nAn accessible format for written communication designed for people with a learning disability. It uses simple jargon-free language, short sentences and illustrations.\n\n## Facilitated communication\n\nA therapeutic intervention whereby a facilitator supports the hand or arm of an autistic person while using a keyboard or other devices with the aim of helping the person to develop pointing skills and to communicate.\n\n## Functional analysis\n\nA method for understanding the causes and consequences of behaviour and its relationship to particular stimuli, and the function of the behaviour. The function of a particular behaviour can be analysed by typically identifying (1) the precursor or trigger of the behaviour, (2) the behaviour itself, and (3) the consequence of the behaviour.\n\n## Hyper- and hypo-sensory sensitivities\n\nBeing over-sensitive (hyper-sensitive) or under-sensitive (hypo-sensitive) to sound, light, colour, smell or taste, which can cause anxiety or even pain in an autistic person.\n\n## Informant\n\nA family member, partner, carer or other third party known to the autistic person who is able to provide information about the person's features and behaviour so that professionals can have a fuller picture of the person's developmental history. Some assessment tools for autism require information from informants.\n\n## Learning disability\n\nLower intellectual ability (usually defined as an IQ of less than 70) that leads to problems in learning, developing new skills, communication and carrying out daily activities. Learning disability severities are defined by the following IQ scores: mild=50–69, moderate=35–49 and severe=20–34. A person with a mild to moderate learning disability may only need support in certain areas. However, a person with a moderate to severe learning disability may have no speech or limited communication, a significantly reduced ability to learn new skills and require support with daily activities such as dressing and eating. Learning disabilities are different from 'learning difficulties', like dyslexia, which do not affect intellect. Learning disability is sometimes also called 'intellectual disability'.\n\n## Modelling\n\nA technique used in behavioural therapy that utilises video and other media. The service user observes target behaviour on the video or computer screen, and repeats it.\n\n## Reinforcement\n\nA technique used in behavioural therapy to teach 'rules' of social engagement through providing prompts for behaviour. Reinforcement may be by the autistic person or those working with or caring for them.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline.\n\n# Facilitated self-help for anxiety and depression in autistic adults\n\nWhat is the clinical and cost effectiveness of facilitated self-help for the treatment of mild anxiety and depressive disorders in autistic adults?\n\n## Why this is important\n\nAnxiety and depressive disorders commonly coexist in autistic people and are associated with poorer health outcomes and quality of life. This may occur because of the direct impact of the anxiety or depression but also because of a negative interaction with the core features of autism. There is limited access and poor uptake of facilitated self-help by autistic people, largely due to limited availability but also because current systems for the delivery of such interventions are not adapted for use by autistic people. In adults without autism, facilitated self-help is an effective intervention for mild to moderate depression and anxiety. The development of novel methods for the delivery of facilitated self-help could make effective interventions available to a wider group of people.\n\nThe suggested programme of research would need to: (a) develop current methods for the delivery of self-help measures to take into account the impact of autism and possibly include developments in the nature of the materials, the methods for their delivery and the nature, duration and extent of their facilitation; (b) test the feasibility of the novel methods in a series of pilot studies; and (c) formally evaluate the outcomes (including symptoms, satisfaction and quality of life) in a large-scale randomised trial.\n\n# The structure and organisation of specialist teams\n\nWhat structure and organisation of specialist autism teams are associated with improvements in care for autistic people?\n\n## Why this is important\n\nThe Department of Health's autism strategy (2010) proposes the introduction of a range of specialist services for autistic people; these will usually be built around specialist autism teams. However, there is little evidence to guide the establishment and development of these teams. There is uncertainty about the precise nature of the population to be served (all autistic people or only those who have an IQ of 70 or above), the composition of the team, the extent of the team's role (for example, diagnosis and assessment only, a primarily advisory role or a substantial care coordination role), the interventions provided by the team, and the team's role and relationship with regard to non-statutory care providers. Therefore it is likely that in the near future a number of different models will be developed, which are likely to have varying degrees of success in meeting the needs of autistic people. Given the significant expansion of services, this presents an opportunity for a large-scale observational study, which should provide important information on the characteristics of teams associated with positive outcomes for autistic people in terms of access to services and effective coordination of care.\n\n# Augmentative communication devices for autistic adults\n\nWhat is the clinical and cost effectiveness of augmentative communication devices for autistic adults?\n\n## Why this is important\n\nMany autistic people experience significant communication problems (for example, the absence of any spoken language or significant deficits in interpersonal skills), which have a profound effect on their ability to lead a full and rewarding life. It is probable that these problems are related to the core features of autism and are likely to persist for most people given the life-long course of autism and the lack of effective interventions for these core features. A number of communication devices have been developed for autism but few, if any, have been subjected to a proper evaluation in adults. Despite this lack of formal evaluation, individual services have made considerable investments in augmentative communication devices. Research that provides high-quality evidence on the acceptability and the clinical and cost effectiveness of augmentative communication devices could bring about significant improvements in the lives of autistic adults.\n\nThe suggested programme of research would need to identify current devices for which there is: (a) some evidence of benefit (for example, case series and small-scale pilot studies); (b) some evidence that it meets a key communication need for autistic people (based on reviews of people's need in this area); and (c) indication that the device is feasible for routine use. The identified device(s) should then be formally evaluated in a large-scale randomised trial."}
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https://www.nice.org.uk/guidance/cg142
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This guideline covers diagnosing and managing suspected or confirmed autism spectrum disorder (autism, Asperger’s syndrome and atypical autism) in people aged 18 and over. It aims to improve access and engagement with interventions and services, and the experience of care, for people with autism.
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494b3036897bb7f31b02a68a8c2f9aee08d6c32c
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nice
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Autism spectrum disorder in under 19s: support and management
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Autism spectrum disorder in under 19s: support and management
This guideline covers children and young people with autism spectrum disorder (across the full range of intellectual ability) from birth until their 19th birthday. It covers the different ways that health and social care professionals can provide support, treatment and help for children and young people with autism, and their families and carers, from the early years through to their transition into young adult life.
# Introduction
This guidance has been developed by the National Institute for Health and Care Excellence (NICE) in collaboration with the Social Care Institute for Excellence (SCIE).
The term autism describes qualitative differences and impairments in reciprocal social interaction and social communication, combined with restricted interests and rigid and repetitive behaviours, often with a lifelong impact. In addition to these features, autistic children and young people frequently experience a range of cognitive, learning, language, medical, emotional and behavioural problems, including: a need for routine; difficulty in understanding other people, including their intentions, feelings and perspectives; sleeping and eating disturbances; and mental health problems such as anxiety, depression, problems with attention, self-injurious behaviour and other challenging, sometimes aggressive behaviour. These features may substantially impact on the quality of life of the individual, and their family or carer, and lead to social vulnerability.
The clinical picture of autism is variable because of differences in the severity of autism itself, the presence of coexisting conditions and levels of cognitive ability, from profound intellectual disability in some people to average or above average intelligence quotient (IQ) in others.
Autism spectrum disorders are diagnosed in children, young people and adults if these behaviours meet the criteria defined in the International Statistical Classification of Diseases and Related Health Problems (ICD‑10) and the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM‑IV) and have a significant impact on function. Both these diagnostic classification systems use the term 'pervasive developmental disorder', which encompasses autism, Asperger's syndrome and atypical autism (or 'pervasive developmental disorder not otherwise specified'). For a diagnosis of autism to be made, there must be impairments present and an impact on the person's adaptive function. Both classification systems are undergoing revision and have announced that the term 'autism spectrum disorder' will be used in future editions. For this guideline we will use the term 'autism' to include all autism spectrum disorders.
Although autism was once thought to be an uncommon developmental disorder, recent studies have reported prevalence rates of at least 1% in children and young people. Autism is diagnosed more frequently in boys.
The core autism behaviours are typically present in early childhood, although some features may not manifest until a change of situation, for example, the start of nursery or school or, less commonly, the transition to secondary school. Regression or stasis of language and social behaviour is reported for at least a third of autistic children. This usually, but not exclusively, occurs between the ages of 1 and 2 years, and the reasons for regression and stasis are unknown.
The way in which autism is expressed will differ across different ages and therefore for any individual may change over time as they mature, in response to environmental demands, in response to interventions, and in the context of coexisting conditions.
Around 70% of autistic people also meet diagnostic criteria for at least one other (often unrecognised) psychiatric disorder that further impairs psychosocial functioning, for example, attention deficit hyperactivity disorder (ADHD) or anxiety disorders. Intellectual disability (IQ below 70) coexists in approximately 50% of autistic children and young people.
There are many claims of a 'cure' for autism, all of which are without foundation. However, there are interventions that can help some of the core features of autism, some of the behaviours and problems commonly associated with autism, and support families and carers. There is also evidence for treatment strategies to reduce behaviour that challenges. This guideline will summarise the different ways that health and social care professionals can provide support, treatment and help for autistic children and young people, and their families and carers, from the early years through to their transition into young adult life.
This guideline covers autistic children and young people (across the full range of intellectual ability) from birth until their 19th birthday, and their parents and carers. It should be used alongside the NICE guidelines on autism: recognition, referral and diagnosis of children and young people on the autism spectrum and autism: recognition, referral, diagnosis and management of adults on the autism spectrum.
Good communication between healthcare professionals and autistic children and young people and their families and carers is essential. It should be supported by evidence-based written information tailored to the person's needs. Support and care, and the information people are given about it, should be culturally appropriate. It should also be accessible to people with additional needs such as physical, sensory or learning disabilities, and to people who do not speak or read English.
No antipsychotic medication has a UK marketing authorisation specifically for autistic children. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good advice on practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), this is noted in the recommendations.# Recommendations
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
This guidance is part of a series of NICE guidelines on autism. It should be read alongside the NICE guidelines on recognition, referral and diagnosis of children and young people on the autism spectrum and recognition, referral, diagnosis and management of adults on the autism spectrum.
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# General principles of care
## Access to health and social care services
Ensure that all autistic children and young people have full access to health and social care services, including mental health services, regardless of their intellectual ability or any coexisting diagnosis.
## Organisation and delivery of services
The overall configuration and development of local services (including health, mental health, learning disability, education and social care services) for autistic children and young people, should be coordinated by a local autism multi-agency strategy group (for autistic people of all ages) in line with the NICE guidelines on autism in children and young people (covering identification and diagnosis) and autism in adults.
The assessment, management and coordination of care for autistic children and young people should be provided through local specialist community-based multidisciplinary teams ('local autism teams') which should include professionals from health, mental health, learning disability, education and social care services in line with the NICE guidelines on autism in children and young people (covering identification and diagnosis) and autism in adults.
Local autism teams should ensure that every child or young person diagnosed with autism has a case manager or key worker to manage and coordinate treatment, care, support and transition to adult care in line with the NICE guideline on autism in children and young people (covering identification and diagnosis).
Local autism teams should provide (or organise) the interventions and care recommended in this guideline for autistic children and young people who have particular needs, including:
looked-after children and young people
those from immigrant groups
those with regression in skills
those with coexisting conditions such as:
severe visual and hearing impairments
-ther medical problems including epilepsy or sleep and elimination problems
motor disorders including cerebral palsy
intellectual disability
severe communication impairment, including lack of spoken language, or complex language disorders
mental health problems.
Local autism teams should have a key role in the delivery and coordination of:
specialist care and interventions for autistic children and young people, including those living in specialist residential accommodation
advice, training and support for other health and social care professionals and staff (including in residential and community settings) who may be involved in the care of autistic children and young people
advice and interventions to promote functional adaptive skills including communication and daily living skills
assessing and managing behaviour that challenges
assessing and managing coexisting conditions
reassessing needs throughout childhood and adolescence, taking particular account of transition to adult services
supporting access to leisure and enjoyable activities
supporting access to and maintaining contact with educational, housing and employment services
providing support for families (including siblings) and carers, including offering short breaks and other respite care
producing local protocols for:
information sharing, communication and collaborative working among healthcare, education and social care services, including arrangements for transition to adult services
shared care arrangements with primary care providers and ensuring that clear lines of communication between primary and secondary care are maintained.
Refer autistic children and young people to a regional or national autism service if there is a lack of:
local skills and competencies needed to provide interventions and care for a child or young person with a complex coexisting condition, such as a severe sensory or motor impairment or mental health problem, or
response to the therapeutic interventions provided by the local autism team.
## Knowledge and competence of health and social care professionals
Health and social care professionals working with autistic children and young people in any setting should receive training in autism awareness and skills in managing autism, which should include:
the nature and course of autism
the nature and course of behaviour that challenges in autistic children and young people
recognition of common coexisting conditions, including:
mental health problems such as anxiety and depression
physical health problems such as epilepsy
sleep problems
-ther neurodevelopmental conditions such as attention deficit hyperactivity disorder (ADHD)
the importance of key transition points, such as changing schools or health or social care services
the child or young person's experience of autism and its impact on them
the impact of autism on the family (including siblings) or carers
the impact of the social and physical environment on the child or young person
how to assess risk (including self-harm, harm to others, self-neglect, breakdown of family or residential support, exploitation or abuse by others) and develop a risk management plan
the changing needs that arise with puberty (including the child or young person's understanding of intimate relationships and related problems that may occur, for example, misunderstanding the behaviour of others)
how to provide individualised care and support and ensure a consistent approach is used across all settings
skills for communicating with an autistic child or young person.
## Making adjustments to the social and physical environment and processes of care
Take into account the physical environment in which autistic children and young people are supported and cared for. Minimise any negative impact by:
providing visual supports, for example, words, pictures or symbols that are meaningful for the child or young person
making reasonable adjustments or adaptations to the amount of personal space given
considering individual sensory sensitivities to lighting, noise levels and the colour of walls and furnishings.
Make adjustments or adaptations to the processes of health or social care, for example, arranging appointments at the beginning or end of the day to minimise waiting time, or providing single rooms for children and young people who may need a general anaesthetic in hospital (for example, for dental treatment).
## Information and involvement in decision-making
Provide autistic children and young people, and their families and carers, with information about autism and its management and the support available on an ongoing basis, suitable for the child or young person's needs and developmental level. This may include:
contact details for local and national organisations that can provide:
support and an opportunity to meet other people, including families or carers, with experience of autism
information on courses about autism
advice on welfare benefits, rights and entitlements
information about educational and social support and leisure activities
information about services and treatments available
information to help prepare for the future, for example, transition to adult services.
Make arrangements to support autistic children and young people and their family and carers during times of increased need, including major life changes such as puberty, starting or changing schools, or the birth of a sibling.
Explore with autistic children and young people, and their families and carers, whether they want to be involved in shared decision-making and continue to explore these issues at regular intervals. If children and young people express interest, offer a collaborative approach to treatment and care that takes their preferences into account.
# Families and carers
Offer all families (including siblings) and carers verbal and written information about their right to:
short breaks and other respite care
a formal carer's assessment of their own physical and mental health needs, and how to access these.
Offer families (including siblings) and carers an assessment of their own needs, including whether they have:
personal, social and emotional support
practical support in their caring role, including short breaks and emergency plans
a plan for future care for the child or young person, including transition to adult services.
When the needs of families and carers have been identified, discuss help available locally and, taking into account their preferences, offer information, advice, training and support, especially if they:
need help with the personal, social or emotional care of the child or young person, including age-related needs such as self-care, relationships or sexuality
are involved in the delivery of an intervention for the child or young person in collaboration with health and social care professionals.
# Specific interventions for the core features of autism
## Psychosocial interventions
Consider a specific social-communication intervention for the core features of autism in children and young people that includes play-based strategies with parents, carers and teachers to increase joint attention, engagement and reciprocal communication in the child or young person. Strategies should:
be adjusted to the child or young person's developmental level
aim to increase the parents', carers', teachers' or peers' understanding of, and sensitivity and responsiveness to, the child or young person's patterns of communication and interaction
include techniques of therapist modelling and video-interaction feedback
include techniques to expand the child or young person's communication, interactive play and social routines.The intervention should be delivered by a trained professional. For pre‑school children consider parent, carer or teacher mediation. For school‑aged children consider peer mediation.
## Pharmacological and dietary interventions
Do not use the following interventions for the management of core features of autism in children and young people:
antipsychotics
antidepressants
anticonvulsants
exclusion diets (such as gluten- or casein-free diets).
# Interventions for behaviour that challenges
## Anticipating and preventing behaviour that challenges
Assess factors that may increase the risk of behaviour that challenges in routine assessment and care planning in autistic children and young people, including:
impairments in communication that may result in difficulty understanding situations or in expressing needs and wishes
coexisting physical disorders, such as pain or gastrointestinal disorders
coexisting mental health problems such as anxiety or depression and other neurodevelopmental conditions such as ADHD
the physical environment, such as lighting and noise levels
the social environment, including home, school and leisure activities
changes to routines or personal circumstances
developmental change, including puberty
exploitation or abuse by others
inadvertent reinforcement of behaviour that challenges
the absence of predictability and structure.
Develop a care plan with the child or young person and their families or carers that outlines the steps needed to address the factors that may provoke behaviour that challenges, including:
treatment, for example, for coexisting physical, mental health and behavioural problems
support, for example, for families or carers
necessary adjustments, for example, by increasing structure and minimising unpredictability.
## Assessment and initial intervention for behaviour that challenges
If a child or young person's behaviour becomes challenging, reassess factors identified in the care plan and assess for any new factors that could provoke the behaviour.
Offer the following to address factors that may trigger or maintain behaviour that challenges:
treatment for physical disorders, or coexisting mental health and behavioural problems
interventions aimed at changing the environment, such as:
providing advice to families and carers
making adjustments or adaptations to the physical surroundings (see recommendation 1.1.9).
If behaviour remains challenging despite attempts to address the underlying possible causes, consult senior colleagues and undertake a multidisciplinary review.
At the multidisciplinary review, take into account the following when choosing an intervention for behaviour that challenges:
the nature, severity and impact of the behaviour
the child or young person's physical and communication needs and capabilities
the environment
the support and training that families, carers or staff may need to implement the intervention effectively
the preferences of the child or young person and the family or carers
the child or young person's experience of, and response to, previous interventions.
## Psychosocial interventions for behaviour that challenges
If no coexisting mental health or behavioural problem, physical disorder or environmental problem has been identified as triggering or maintaining the behaviour that challenges, offer the child or young person a psychosocial intervention (informed by a functional assessment of behaviour) as a first-line treatment.
The functional assessment should identify:
factors that appear to trigger the behaviour
patterns of behaviour
the needs that the child or young person is attempting to meet by performing the behaviour
the consequences of the behaviour (that is, the reinforcement received as a result of the behaviour).
Psychosocial interventions for behaviour that challenges should include:
clearly identified target behaviour
a focus on outcomes that are linked to quality of life
assessment and modification of environmental factors that may contribute to initiating or maintaining the behaviour
a clearly defined intervention strategy that takes into account the developmental level and coexisting problems of the child or young person
a specified timescale to meet intervention goals (to promote modification of intervention strategies that do not lead to change within a specified time)
a systematic measure of the target behaviour taken before and after the intervention to ascertain whether the agreed outcomes are being met
consistent application in all areas of the child or young person's environment (for example, at home and at school)
agreement among parents, carers and professionals in all settings about how to implement the intervention.
## Pharmacological interventions for behaviour that challenges
Consider antipsychotic medication for managing behaviour that challenges in autistic children and young people when psychosocial or other interventions are insufficient or could not be delivered because of the severity of the behaviour. Antipsychotic medication should be initially prescribed and monitored by a paediatrician or psychiatrist who should:
identify the target behaviour
decide on an appropriate measure to monitor effectiveness, including frequency and severity of the behaviour and a measure of global impact
review the effectiveness and any side effects of the medication after 3–4 weeks
stop treatment if there is no indication of a clinically important response at 6 weeks. In August 2013, this was an off-label use of antipsychotic medication. See NICE's information on prescribing medicines.
If antipsychotic medication is prescribed:
start with a low dose
use the minimum effective dose needed
regularly review the benefits of the antipsychotic medication and any adverse events.
When choosing antipsychotic medication, take into account side effects, acquisition costs, the child or young person's preference (or that of their parent or carer where appropriate) and response to previous treatment with an antipsychotic.
When prescribing is transferred to primary or community care, the specialist should give clear guidance to the practitioner who will be responsible for continued prescribing about:
the selection of target behaviours
monitoring of beneficial and side effects
the potential for minimally effective dosing
the proposed duration of treatment
plans for stopping treatment.
# Interventions for life skills
Offer autistic children and young people support in developing coping strategies and accessing community services, including developing skills to access public transport, employment and leisure facilities.
# Interventions for autism that should not be used
Do not use neurofeedback to manage speech and language problems in autistic children and young people.
Do not use auditory integration training to manage speech and language problems in autistic children and young people.
Do not use omega‑3 fatty acids to manage sleep problems in autistic children and young people.
Do not use the following interventions to manage autism in any context in children and young people:
secretin
chelation
hyperbaric oxygen therapy.
# Interventions for coexisting problems
Offer psychosocial and pharmacological interventions for the management of coexisting mental health or medical problems in autistic children and young people in line with the:
NICE guideline on attention deficit hyperactivity disorder
NICE guideline on antisocial behaviour and conduct disorders in children and young people
NICE guideline on challenging behaviour and learning disabilities
NICE guideline on constipation in children and young people
NICE guideline on depression in children and young people
NICE guideline on epilepsies
NICE guideline on obsessive-compulsive disorder and body dysmorphic disorder
NICE guideline on post-traumatic stress disorder.
Consider the following for autistic children and young people with anxiety who have the verbal and cognitive ability to engage in a cognitive behavioural therapy (CBT) intervention:
group CBT adjusted to the needs of autistic children and young people
individual CBT for children and young people who find group-based activities difficult.
Consider adapting the method of delivery of CBT for autistic children and young people with anxiety to include:
emotion recognition training
greater use of written and visual information and structured worksheets
a more cognitively concrete and structured approach
simplified cognitive activities, for example, multiple-choice worksheets
involving a parent or carer to support the implementation of the intervention, for example, involving them in therapy sessions
maintaining attention by offering regular breaks
incorporating the child or young person's special interests into therapy if possible.
## Interventions for sleep problems
If an autistic child or young person develops a sleep problem offer an assessment that identifies:
what the sleep problem is (for example, delay in falling asleep, frequent waking, unusual behaviours, breathing problems or sleepiness during the day)
day and night sleep patterns, and any change to those patterns
whether bedtime is regular
what the sleep environment is like, for example:
the level of background noise
use of a blackout blind
a television or computer in the bedroom
whether the child shares the room with someone
presence of comorbidities especially those that feature hyperactivity or other behavioural problems
levels of activity and exercise during the day
possible physical illness or discomfort (for example, reflux, ear or toothache, constipation or eczema)
effects of any medication
any other individual factors thought to enhance or disturb sleep, such as emotional relationships or problems at school
the impact of sleep and behavioural problems on parents or carers and other family members.
If the autistic child or young person snores loudly, chokes or appears to stop breathing while sleeping, refer to a specialist to check for obstructive sleep apnoea.
Develop a sleep plan (this will often be a specific sleep behavioural intervention) with the parents or carers to help address the identified sleep problems and to establish a regular night-time sleep pattern. Ask the parents or carers to record the child or young person's sleep and wakefulness throughout the day and night over a 2‑week period. Use this information to modify the sleep plan if necessary and review the plan regularly until a regular sleep pattern is established.
Do not use a pharmacological intervention to aid sleep unless:
sleep problems persist despite following the sleep plan
sleep problems are having a negative impact on the child or young person and their family or carers.If a pharmacological intervention is needed to aid sleep, consider melatonin and:
-nly use it following consultation with a specialist paediatrician or psychiatrist with expertise in the management of autism or paediatric sleep medicine
use it in conjunction with non-pharmacological interventions
regularly review to evaluate the ongoing need for a pharmacological intervention and to ensure that the benefits continue to outweigh the side effects and risks.
If the sleep problems continue to impact on the child or young person or their parents or carers, consider:
referral to a paediatric sleep specialist and
short breaks and other respite care for one night or more. Short breaks may need to be repeated regularly to ensure that parents or carers are adequately supported. Agree the frequency of breaks with them and record this in the care plan.
## Interventions for feeding problems, including restricted diets
Be aware that feeding problems, including restricted diets can result in nutritional deficiencies that may have serious consequences.
Assess for any feeding, growth or nutritional problems, including restricted diets. Monitor and refer if needed.
As part of a full nutritional assessment and monitoring, blood tests to check for nutritional deficiencies may be required.
# Transition to adult services
Local autism teams should ensure that autistic young people who are receiving treatment and care from child and adolescent mental health services (CAMHS) or child health services are reassessed at around 14 years to establish the need for continuing treatment into adulthood.
If continuing treatment is necessary, make arrangements for a smooth transition to adult services and give information to the young person about the treatment and services they may need.
The timing of transition may vary locally and individually but should usually be completed by the time the young person is 18 years. Variations should be agreed by both child and adult services.
As part of the preparation for the transition to adult services, health and social care professionals should carry out a comprehensive assessment of the autistic young person.
The assessment should make best use of existing documentation about personal, educational, occupational, social and communication functioning, and should include assessment of any coexisting conditions, especially depression, anxiety, ADHD, obsessive-compulsive disorder (OCD) and global delay or intellectual disability in line with the NICE guideline on autism in adults.
For young people aged 16 or older whose needs are complex or severe, use the care programme approach (CPA) in England, or care and treatment plans in Wales, as an aid to transfer between services.
Involve the young person in the planning and, where appropriate, their parents or carers.
Provide information about adult services to the young person, and their parents or carers, including their right to a social care assessment at age 18.
During transition to adult services, consider a formal meeting involving health and social care and other relevant professionals from child and adult services.# Recommendations for research
# A key worker approach for autistic children and young people and their families
What is the value of a key worker approach (defined by protocol and delivered in addition to usual care) for autistic children and young people in terms of parental satisfaction, functioning and stress and child psychopathology?
## Why this is important
Autism is well characterised as a chronic disorder with lifelong disability in some individuals, yet the current health management structure is usually organised around single episodes of care. The theory and practice of management of chronic illness, as well as widely expressed service-user opinion, indicate that a chronic care model for the organisation of autism services could be appropriate and cost effective.
A key worker approach for autistic children and young people and their families should be formally evaluated in a randomised controlled trial (RCT) reporting short- and medium-term outcomes (including cost-effectiveness) with a follow‑up of at least 6 months and again at 12 months. The outcomes (parental satisfaction, functioning and stress and child psychopathology) should be assessed by structured clinical interviews, parent- and self-reports using validated questionnaires and objective measures of behaviour. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators (in particular the child or young person's age) should be investigated.
# Managing behaviour that challenges in autistic children and young people
Is a group-based parent training intervention for parents or carers of autistic children and young people clinically and cost effective in reducing early and emerging behaviour that challenges in the short- and medium-term compared with treatment as usual?
## Why this is important
Behaviour that challenges is common in autistic children and young people but many are referred only when the behaviour has become severely impairing, they pose a threat to themselves or others, or everyday life has broken down. By this time, behavioural interventions may be difficult or impossible and antipsychotic medication is used despite it being symptomatic in its benefits, having long-term adverse effects and behavioural problems typically recurring after use.
A group-based parent training intervention (such as educating parents to identify triggers and patterns of reinforcement) should be evaluated using an RCT. Primary outcomes should be short- and medium-term reduction in behaviour that challenges. Secondary outcomes should include parental and sibling stress, quality of life and the child or young person's adaptive function. The medium-term use of medication should also be assessed. Cost effectiveness should encompass a wide range of services, such as additional educational support and social services, and health service use by families.
# Treating comorbid anxiety in autistic children and young people
What is the comparative clinical and cost effectiveness of pharmacological and psychosocial interventions for anxiety disorders in autistic children and young people?
## Why this is important
Early trials of CBT for anxiety in autistic children and young people have been promising but have methodological shortcomings. Furthermore, the common pharmacological approaches have not been evaluated in this population.
A parallel-arm RCT should compare pharmacological and psychosocial interventions with placebo in autistic children and young people and an anxiety disorder. Pharmacological treatment should be with a selective serotonin reuptake inhibitor (SSRI) and dosing should follow research in typically developing children but with the option of evaluating outcomes at lower doses. The SSRI should be blinded with an identical placebo and an 'attention' or other psychosocial control group. The psychosocial intervention should be manualised and based on cognitive behavioural approaches shown to be effective in previous trials. The sample should cover the full age and intellectual range of children and young people and the size powered to deliver precise effect size estimates for both active arms.
Primary outcome measures should be reduction in anxiety symptoms by parent report. Secondary outcomes may include self- and teacher-report, blinded measures such as heart rate and skin conductance, patient satisfaction, changes in adaptive function, quality of life and disruptive behaviour. Adverse effects should be evaluated and an economic evaluation included.
# Teacher-, parent- and peer-mediated psychosocial interventions in pre‑school autistic children
Are comprehensive early interventions that combine multiple elements and are delivered by parents and teachers (for example, the Learning Experiences – an Alternative Program for Preschoolers and their Parents model) effective in managing the core features of autism and coexisting difficulties (such as adaptive behaviour and developmental skills) in pre‑school children?
## Why this is important
Many autistic children are diagnosed in the pre‑school period when service provision is advice and support to parents and professionals in nursery or early years educational settings. There is evidence from one moderate-sized trial that adequately supervised comprehensive programmes can help with the core features of autism and coexisting difficulties. However, the quality of the trial was low.
The research programme should be in 4 stages:
. Develop a manualised programme suitable to UK public service settings (health services, early years education, and so on).
. Test its feasibility and acceptability in pilot trials with blinded assessment of outcome.
. Formally evaluate the outcomes on core features of autism and coexisting difficulties in a large-scale trial, including health economic analysis.
. Conduct a series of smaller trials to determine the elements, length and intensity required to ensure effectiveness of the programme, as well as longer-term outcomes.
|
{'Introduction ': "This guidance has been developed by the National Institute for Health and Care Excellence (NICE) in collaboration with the Social Care Institute for Excellence (SCIE).\n\nThe term autism describes qualitative differences and impairments in reciprocal social interaction and social communication, combined with restricted interests and rigid and repetitive behaviours, often with a lifelong impact. In addition to these features, autistic children and young people frequently experience a range of cognitive, learning, language, medical, emotional and behavioural problems, including: a need for routine; difficulty in understanding other people, including their intentions, feelings and perspectives; sleeping and eating disturbances; and mental health problems such as anxiety, depression, problems with attention, self-injurious behaviour and other challenging, sometimes aggressive behaviour. These features may substantially impact on the quality of life of the individual, and their family or carer, and lead to social vulnerability.\n\nThe clinical picture of autism is variable because of differences in the severity of autism itself, the presence of coexisting conditions and levels of cognitive ability, from profound intellectual disability in some people to average or above average intelligence quotient (IQ) in others.\n\nAutism spectrum disorders are diagnosed in children, young people and adults if these behaviours meet the criteria defined in the International Statistical Classification of Diseases and Related Health Problems (ICD‑10) and the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM‑IV) and have a significant impact on function. Both these diagnostic classification systems use the term 'pervasive developmental disorder', which encompasses autism, Asperger's syndrome and atypical autism (or 'pervasive developmental disorder not otherwise specified'). For a diagnosis of autism to be made, there must be impairments present and an impact on the person's adaptive function. Both classification systems are undergoing revision and have announced that the term 'autism spectrum disorder' will be used in future editions. For this guideline we will use the term 'autism' to include all autism spectrum disorders.\n\nAlthough autism was once thought to be an uncommon developmental disorder, recent studies have reported prevalence rates of at least 1% in children and young people. Autism is diagnosed more frequently in boys.\n\nThe core autism behaviours are typically present in early childhood, although some features may not manifest until a change of situation, for example, the start of nursery or school or, less commonly, the transition to secondary school. Regression or stasis of language and social behaviour is reported for at least a third of autistic children. This usually, but not exclusively, occurs between the ages of 1\xa0and 2\xa0years, and the reasons for regression and stasis are unknown.\n\nThe way in which autism is expressed will differ across different ages and therefore for any individual may change over time as they mature, in response to environmental demands, in response to interventions, and in the context of coexisting conditions.\n\nAround 70% of autistic people also meet diagnostic criteria for at least one other (often unrecognised) psychiatric disorder that further impairs psychosocial functioning, for example, attention deficit hyperactivity disorder (ADHD) or anxiety disorders. Intellectual disability (IQ\xa0below\xa070) coexists in approximately 50% of autistic children and young people.\n\nThere are many claims of a 'cure' for autism, all of which are without foundation. However, there are interventions that can help some of the core features of autism, some of the behaviours and problems commonly associated with autism, and support families and carers. There is also evidence for treatment strategies to reduce behaviour that challenges. This guideline will summarise the different ways that health and social care professionals can provide support, treatment and help for autistic children and young people, and their families and carers, from the early years through to their transition into young adult life.\n\nThis guideline covers autistic children and young people (across the full range of intellectual ability) from birth until their 19th birthday, and their parents and carers. It should be used alongside the NICE guidelines on autism: recognition, referral and diagnosis of children and young people on the autism spectrum and autism: recognition, referral, diagnosis and management of adults on the autism spectrum.\n\nGood communication between healthcare professionals and autistic children and young people and their families and carers is essential. It should be supported by evidence-based written information tailored to the person's needs. Support and care, and the information people are given about it, should be culturally appropriate. It should also be accessible to people with additional needs such as physical, sensory or learning disabilities, and to people who do not speak or read English.\n\nNo antipsychotic medication has a UK marketing authorisation specifically for autistic children. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good advice on practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), this is noted in the recommendations.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nThis guidance is part of a series of NICE guidelines on autism. It should be read alongside the NICE guidelines on recognition, referral and diagnosis of children and young people on the autism spectrum and recognition, referral, diagnosis and management of adults on the autism spectrum.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# General principles of care\n\n## Access to health and social care services\n\nEnsure that all autistic children and young people have full access to health and social care services, including mental health services, regardless of their intellectual ability or any coexisting diagnosis.\n\n## Organisation and delivery of services\n\nThe overall configuration and development of local services (including health, mental health, learning disability, education and social care services) for autistic children and young people, should be coordinated by a local autism multi-agency strategy group (for autistic people of all ages) in line with the NICE guidelines on autism in children and young people (covering identification and diagnosis) and autism in adults.\n\nThe assessment, management and coordination of care for autistic children and young people should be provided through local specialist community-based multidisciplinary teams ('local autism teams') which should include professionals from health, mental health, learning disability, education and social care services in line with the NICE guidelines on autism in children and young people (covering identification and diagnosis) and autism in adults.\n\nLocal autism teams should ensure that every child or young person diagnosed with autism has a case manager or key worker to manage and coordinate treatment, care, support and transition to adult care in line with the NICE guideline on autism in children and young people (covering identification and diagnosis).\n\nLocal autism teams should provide (or organise) the interventions and care recommended in this guideline for autistic children and young people who have particular needs, including:\n\nlooked-after children and young people\n\nthose from immigrant groups\n\nthose with regression in skills\n\nthose with coexisting conditions such as:\n\n\n\nsevere visual and hearing impairments\n\nother medical problems including epilepsy or sleep and elimination problems\n\nmotor disorders including cerebral palsy\n\nintellectual disability\n\nsevere communication impairment, including lack of spoken language, or complex language disorders\n\nmental health problems.\n\n\n\nLocal autism teams should have a key role in the delivery and coordination of:\n\nspecialist care and interventions for autistic children and young people, including those living in specialist residential accommodation\n\nadvice, training and support for other health and social care professionals and staff (including in residential and community settings) who may be involved in the care of autistic children and young people\n\nadvice and interventions to promote functional adaptive skills including communication and daily living skills\n\nassessing and managing behaviour that challenges\n\nassessing and managing coexisting conditions\n\nreassessing needs throughout childhood and adolescence, taking particular account of transition to adult services\n\nsupporting access to leisure and enjoyable activities\n\nsupporting access to and maintaining contact with educational, housing and employment services\n\nproviding support for families (including siblings) and carers, including offering short breaks and other respite care\n\nproducing local protocols for:\n\n\n\ninformation sharing, communication and collaborative working among healthcare, education and social care services, including arrangements for transition to adult services\n\nshared care arrangements with primary care providers and ensuring that clear lines of communication between primary and secondary care are maintained.\n\n\n\nRefer autistic children and young people to a regional or national autism service if there is a lack of:\n\nlocal skills and competencies needed to provide interventions and care for a child or young person with a complex coexisting condition, such as a severe sensory or motor impairment or mental health problem, or\n\nresponse to the therapeutic interventions provided by the local autism team.\n\n## Knowledge and competence of health and social care professionals\n\nHealth and social care professionals working with autistic children and young people in any setting should receive training in autism awareness and skills in managing autism, which should include:\n\nthe nature and course of autism\n\nthe nature and course of behaviour that challenges in autistic children and young people\n\nrecognition of common coexisting conditions, including:\n\n\n\nmental health problems such as anxiety and depression\n\nphysical health problems such as epilepsy\n\nsleep problems\n\nother neurodevelopmental conditions such as attention deficit hyperactivity disorder (ADHD)\n\n\n\nthe importance of key transition points, such as changing schools or health or social care services\n\nthe child or young person's experience of autism and its impact on them\n\nthe impact of autism on the family (including siblings) or carers\n\nthe impact of the social and physical environment on the child or young person\n\nhow to assess risk (including self-harm, harm to others, self-neglect, breakdown of family or residential support, exploitation or abuse by others) and develop a risk management plan\n\nthe changing needs that arise with puberty (including the child or young person's understanding of intimate relationships and related problems that may occur, for example, misunderstanding the behaviour of others)\n\nhow to provide individualised care and support and ensure a consistent approach is used across all settings\n\nskills for communicating with an autistic child or young person.\n\n## Making adjustments to the social and physical environment and processes of care\n\nTake into account the physical environment in which autistic children and young people are supported and cared for. Minimise any negative impact by:\n\nproviding visual supports, for example, words, pictures or symbols that are meaningful for the child or young person\n\nmaking reasonable adjustments or adaptations to the amount of personal space given\n\nconsidering individual sensory sensitivities to lighting, noise levels and the colour of walls and furnishings.\n\nMake adjustments or adaptations to the processes of health or social care, for example, arranging appointments at the beginning or end of the day to minimise waiting time, or providing single rooms for children and young people who may need a general anaesthetic in hospital (for example, for dental treatment).\n\n## Information and involvement in decision-making\n\nProvide autistic children and young people, and their families and carers, with information about autism and its management and the support available on an ongoing basis, suitable for the child or young person's needs and developmental level. This may include:\n\ncontact details for local and national organisations that can provide:\n\n\n\nsupport and an opportunity to meet other people, including families or carers, with experience of autism\n\ninformation on courses about autism\n\nadvice on welfare benefits, rights and entitlements\n\ninformation about educational and social support and leisure activities\n\n\n\ninformation about services and treatments available\n\ninformation to help prepare for the future, for example, transition to adult services.\n\nMake arrangements to support autistic children and young people and their family and carers during times of increased need, including major life changes such as puberty, starting or changing schools, or the birth of a sibling.\n\nExplore with autistic children and young people, and their families and carers, whether they want to be involved in shared decision-making and continue to explore these issues at regular intervals. If children and young people express interest, offer a collaborative approach to treatment and care that takes their preferences into account.\n\n# Families and carers\n\nOffer all families (including siblings) and carers verbal and written information about their right to:\n\nshort breaks and other respite care\n\na formal carer's assessment of their own physical and mental health needs, and how to access these.\n\nOffer families (including siblings) and carers an assessment of their own needs, including whether they have:\n\npersonal, social and emotional support\n\npractical support in their caring role, including short breaks and emergency plans\n\na plan for future care for the child or young person, including transition to adult services.\n\nWhen the needs of families and carers have been identified, discuss help available locally and, taking into account their preferences, offer information, advice, training and support, especially if they:\n\nneed help with the personal, social or emotional care of the child or young person, including age-related needs such as self-care, relationships or sexuality\n\nare involved in the delivery of an intervention for the child or young person in collaboration with health and social care professionals.\n\n# Specific interventions for the core features of autism\n\n## Psychosocial interventions\n\nConsider a specific social-communication intervention for the core features of autism in children and young people that includes play-based strategies with parents, carers and teachers to increase joint attention, engagement and reciprocal communication in the child or young person. Strategies should:\n\nbe adjusted to the child or young person's developmental level\n\naim to increase the parents', carers', teachers' or peers' understanding of, and sensitivity and responsiveness to, the child or young person's patterns of communication and interaction\n\ninclude techniques of therapist modelling and video-interaction feedback\n\ninclude techniques to expand the child or young person's communication, interactive play and social routines.The intervention should be delivered by a trained professional. For pre‑school children consider parent, carer or teacher mediation. For school‑aged children consider peer mediation.\n\n## Pharmacological and dietary interventions\n\nDo not use the following interventions for the management of core features of autism in children and young people:\n\nantipsychotics\n\nantidepressants\n\nanticonvulsants\n\nexclusion diets (such as gluten- or casein-free diets).\n\n# Interventions for behaviour that challenges\n\n## Anticipating and preventing behaviour that challenges\n\nAssess factors that may increase the risk of behaviour that challenges in routine assessment and care planning in autistic children and young people, including:\n\nimpairments in communication that may result in difficulty understanding situations or in expressing needs and wishes\n\ncoexisting physical disorders, such as pain or gastrointestinal disorders\n\ncoexisting mental health problems such as anxiety or depression and other neurodevelopmental conditions such as ADHD\n\nthe physical environment, such as lighting and noise levels\n\nthe social environment, including home, school and leisure activities\n\nchanges to routines or personal circumstances\n\ndevelopmental change, including puberty\n\nexploitation or abuse by others\n\ninadvertent reinforcement of behaviour that challenges\n\nthe absence of predictability and structure.\n\nDevelop a care plan with the child or young person and their families or carers that outlines the steps needed to address the factors that may provoke behaviour that challenges, including:\n\ntreatment, for example, for coexisting physical, mental health and behavioural problems\n\nsupport, for example, for families or carers\n\nnecessary adjustments, for example, by increasing structure and minimising unpredictability.\n\n## Assessment and initial intervention for behaviour that challenges\n\nIf a child or young person's behaviour becomes challenging, reassess factors identified in the care plan and assess for any new factors that could provoke the behaviour.\n\nOffer the following to address factors that may trigger or maintain behaviour that challenges:\n\ntreatment for physical disorders, or coexisting mental health and behavioural problems\n\ninterventions aimed at changing the environment, such as:\n\n\n\nproviding advice to families and carers\n\nmaking adjustments or adaptations to the physical surroundings (see recommendation 1.1.9).\n\n\n\nIf behaviour remains challenging despite attempts to address the underlying possible causes, consult senior colleagues and undertake a multidisciplinary review.\n\nAt the multidisciplinary review, take into account the following when choosing an intervention for behaviour that challenges:\n\nthe nature, severity and impact of the behaviour\n\nthe child or young person's physical and communication needs and capabilities\n\nthe environment\n\nthe support and training that families, carers or staff may need to implement the intervention effectively\n\nthe preferences of the child or young person and the family or carers\n\nthe child or young person's experience of, and response to, previous interventions.\n\n## Psychosocial interventions for behaviour that challenges\n\nIf no coexisting mental health or behavioural problem, physical disorder or environmental problem has been identified as triggering or maintaining the behaviour that challenges, offer the child or young person a psychosocial intervention (informed by a functional assessment of behaviour) as a first-line treatment.\n\nThe functional assessment should identify:\n\nfactors that appear to trigger the behaviour\n\npatterns of behaviour\n\nthe needs that the child or young person is attempting to meet by performing the behaviour\n\nthe consequences of the behaviour (that is, the reinforcement received as a result of the behaviour).\n\nPsychosocial interventions for behaviour that challenges should include:\n\nclearly identified target behaviour\n\na focus on outcomes that are linked to quality of life\n\nassessment and modification of environmental factors that may contribute to initiating or maintaining the behaviour\n\na clearly defined intervention strategy that takes into account the developmental level and coexisting problems of the child or young person\n\na specified timescale to meet intervention goals (to promote modification of intervention strategies that do not lead to change within a specified time)\n\na systematic measure of the target behaviour taken before and after the intervention to ascertain whether the agreed outcomes are being met\n\nconsistent application in all areas of the child or young person's environment (for example, at home and at school)\n\nagreement among parents, carers and professionals in all settings about how to implement the intervention.\n\n## Pharmacological interventions for behaviour that challenges\n\nConsider antipsychotic medication for managing behaviour that challenges in autistic children and young people when psychosocial or other interventions are insufficient or could not be delivered because of the severity of the behaviour. Antipsychotic medication should be initially prescribed and monitored by a paediatrician or psychiatrist who should:\n\nidentify the target behaviour\n\ndecide on an appropriate measure to monitor effectiveness, including frequency and severity of the behaviour and a measure of global impact\n\nreview the effectiveness and any side effects of the medication after 3–4\xa0weeks\n\nstop treatment if there is no indication of a clinically important response at 6\xa0weeks. In August 2013, this was an off-label use of antipsychotic medication. See NICE's information on prescribing medicines.\n\nIf antipsychotic medication is prescribed:\n\nstart with a low dose\n\nuse the minimum effective dose needed\n\nregularly review the benefits of the antipsychotic medication and any adverse events.\n\nWhen choosing antipsychotic medication, take into account side effects, acquisition costs, the child or young person's preference (or that of their parent or carer where appropriate) and response to previous treatment with an antipsychotic.\n\nWhen prescribing is transferred to primary or community care, the specialist should give clear guidance to the practitioner who will be responsible for continued prescribing about:\n\nthe selection of target behaviours\n\nmonitoring of beneficial and side effects\n\nthe potential for minimally effective dosing\n\nthe proposed duration of treatment\n\nplans for stopping treatment.\n\n# Interventions for life skills\n\nOffer autistic children and young people support in developing coping strategies and accessing community services,\xa0including developing\xa0skills to access public transport, employment\xa0and leisure facilities.\n\n# Interventions for autism that should not be used\n\nDo not use neurofeedback to manage speech and language problems in autistic children and young people.\n\nDo not use auditory integration training to manage speech and language problems in autistic children and young people.\n\nDo not use omega‑3 fatty acids to manage sleep problems in autistic children and young people.\n\nDo not use the following interventions to manage autism in any context in children and young people:\n\nsecretin\n\nchelation\n\nhyperbaric oxygen therapy.\n\n# Interventions for coexisting problems\n\nOffer psychosocial and pharmacological interventions for the management of coexisting mental health or medical problems in autistic children and young people in line with the:\n\nNICE guideline on attention deficit hyperactivity disorder\n\nNICE guideline on antisocial behaviour and conduct disorders in children and young people\n\nNICE guideline on challenging behaviour and learning disabilities\n\nNICE guideline on constipation in children and young people\n\nNICE guideline on depression in children and young people\n\nNICE guideline on epilepsies\n\nNICE guideline on obsessive-compulsive disorder and body dysmorphic disorder\n\nNICE guideline on post-traumatic stress disorder.\n\nConsider the following for autistic children and young people with anxiety who have the verbal and cognitive ability to engage in a cognitive behavioural therapy (CBT) intervention:\n\ngroup CBT adjusted to the needs of autistic children and young people\n\nindividual CBT for children and young people who find group-based activities difficult.\n\nConsider adapting the method of delivery of CBT for autistic children and young people with anxiety to include:\n\nemotion recognition training\n\ngreater use of written and visual information and structured worksheets\n\na more cognitively concrete and structured approach\n\nsimplified cognitive activities, for example, multiple-choice worksheets\n\ninvolving a parent or carer to support the implementation of the intervention, for example, involving them in therapy sessions\n\nmaintaining attention by offering regular breaks\n\nincorporating the child or young person's special interests into therapy if possible.\n\n## Interventions for sleep problems\n\nIf an autistic child or young person develops a sleep problem offer an assessment that identifies:\n\nwhat the sleep problem is (for example, delay in falling asleep, frequent waking, unusual behaviours, breathing problems or sleepiness during the day)\n\nday and night sleep patterns, and any change to those patterns\n\nwhether bedtime is regular\n\nwhat the sleep environment is like, for example:\n\n\n\nthe level of background noise\n\nuse of a blackout blind\n\na television or computer in the bedroom\n\nwhether the child shares the room with someone\n\n\n\npresence of comorbidities especially those that feature hyperactivity or other behavioural problems\n\nlevels of activity and exercise during the day\n\npossible physical illness or discomfort (for example, reflux, ear or toothache, constipation or eczema)\n\neffects of any medication\n\nany other individual factors thought to enhance or disturb sleep, such as emotional relationships or problems at school\n\nthe impact of sleep and behavioural problems on parents or carers and other family members.\n\nIf the autistic child or young person snores loudly, chokes or appears to stop breathing while sleeping, refer to a specialist to check for obstructive sleep apnoea.\n\nDevelop a sleep plan (this will often be a specific sleep behavioural intervention) with the parents or carers to help address the identified sleep problems and to establish a regular night-time sleep pattern. Ask the parents or carers to record the child or young person's sleep and wakefulness throughout the day and night over a 2‑week period. Use this information to modify the sleep plan if necessary and review the plan regularly until a regular sleep pattern is established.\n\nDo not use a pharmacological intervention to aid sleep unless:\n\nsleep problems persist despite following the sleep plan\n\nsleep problems are having a negative impact on the child or young person and their family or carers.If a pharmacological intervention is needed to aid sleep, consider melatonin and:\n\nonly use it following consultation with a specialist paediatrician or psychiatrist with expertise in the management of autism or paediatric sleep medicine\n\nuse it in conjunction with non-pharmacological interventions\n\nregularly review to evaluate the ongoing need for a pharmacological intervention and to ensure that the benefits continue to outweigh the side effects and risks. [amended 2021]\n\nIf the sleep problems continue to impact on the child or young person or their parents or carers, consider:\n\nreferral to a paediatric sleep specialist and\n\nshort breaks and other respite care for one night or more. Short breaks may need to be repeated regularly to ensure that parents or carers are adequately supported. Agree the frequency of breaks with them and record this in the care plan.\n\n## Interventions for feeding problems, including restricted diets\n\nBe aware that feeding problems, including restricted diets can result in nutritional deficiencies that may have serious consequences. \n\nAssess for any feeding, growth or nutritional problems, including restricted diets. Monitor and refer if needed. \n\nAs part of a full nutritional assessment and monitoring, blood tests to check for nutritional deficiencies may be required. \n\n# Transition to adult services\n\nLocal autism teams should ensure that autistic young people who are receiving treatment and care from child and adolescent mental health services (CAMHS) or child health services are reassessed at around 14\xa0years to establish the need for continuing treatment into adulthood.\n\nIf continuing treatment is necessary, make arrangements for a smooth transition to adult services and give information to the young person about the treatment and services they may need.\n\nThe timing of transition may vary locally and individually but should usually be completed by the time the young person is 18\xa0years. Variations should be agreed by both child and adult services.\n\nAs part of the preparation for the transition to adult services, health and social care professionals should carry out a comprehensive assessment of the autistic young person.\n\nThe assessment should make best use of existing documentation about personal, educational, occupational, social and communication functioning, and should include assessment of any coexisting conditions, especially depression, anxiety, ADHD, obsessive-compulsive disorder (OCD) and global delay or intellectual disability in line with the NICE guideline on autism in adults.\n\nFor young people aged 16 or older whose needs are complex or severe, use the care programme approach (CPA) in England, or care and treatment plans in Wales, as an aid to transfer between services.\n\nInvolve the young person in the planning and, where appropriate, their parents or carers.\n\nProvide information about adult services to the young person, and their parents or carers, including their right to a social care assessment at age\xa018.\n\nDuring transition to adult services, consider a formal meeting involving health and social care and other relevant professionals from child and adult services.", 'Recommendations for research': "# A key worker approach for autistic children and young people and their families\n\nWhat is the value of a key worker approach (defined by protocol and delivered in addition to usual care) for autistic children and young people in terms of parental satisfaction, functioning and stress and child psychopathology?\n\n## Why this is important\n\nAutism is well characterised as a chronic disorder with lifelong disability in some individuals, yet the current health management structure is usually organised around single episodes of care. The theory and practice of management of chronic illness, as well as widely expressed service-user opinion, indicate that a chronic care model for the organisation of autism services could be appropriate and cost effective.\n\nA key worker approach for autistic children and young people and their families should be formally evaluated in a randomised controlled trial (RCT) reporting short- and medium-term outcomes (including cost-effectiveness) with a follow‑up of at least 6\xa0months and again at 12\xa0months. The outcomes (parental satisfaction, functioning and stress and child psychopathology) should be assessed by structured clinical interviews, parent- and self-reports using validated questionnaires and objective measures of behaviour. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators (in particular the child or young person's age) should be investigated.\n\n# Managing behaviour that challenges in autistic children and young people\n\nIs a group-based parent training intervention for parents or carers of autistic children and young people clinically and cost effective in reducing early and emerging behaviour that challenges in the short- and medium-term compared with treatment as usual?\n\n## Why this is important\n\nBehaviour that challenges is common in autistic children and young people but many are referred only when the behaviour has become severely impairing, they pose a threat to themselves or others, or everyday life has broken down. By this time, behavioural interventions may be difficult or impossible and antipsychotic medication is used despite it being symptomatic in its benefits, having long-term adverse effects and behavioural problems typically recurring after use.\n\nA group-based parent training intervention (such as educating parents to identify triggers and patterns of reinforcement) should be evaluated using an RCT. Primary outcomes should be short- and medium-term reduction in behaviour that challenges. Secondary outcomes should include parental and sibling stress, quality of life and the child or young person's adaptive function. The medium-term use of medication should also be assessed. Cost effectiveness should encompass a wide range of services, such as additional educational support and social services, and health service use by families.\n\n# Treating comorbid anxiety in autistic children and young people\n\nWhat is the comparative clinical and cost effectiveness of pharmacological and psychosocial interventions for anxiety disorders in autistic children and young people?\n\n## Why this is important\n\nEarly trials of CBT for anxiety in autistic children and young people have been promising but have methodological shortcomings. Furthermore, the common pharmacological approaches have not been evaluated in this population.\n\nA parallel-arm RCT should compare pharmacological and psychosocial interventions with placebo in autistic children and young people and an anxiety disorder. Pharmacological treatment should be with a selective serotonin reuptake inhibitor (SSRI) and dosing should follow research in typically developing children but with the option of evaluating outcomes at lower doses. The SSRI should be blinded with an identical placebo and an 'attention' or other psychosocial control group. The psychosocial intervention should be manualised and based on cognitive behavioural approaches shown to be effective in previous trials. The sample should cover the full age and intellectual range of children and young people and the size powered to deliver precise effect size estimates for both active arms.\n\nPrimary outcome measures should be reduction in anxiety symptoms by parent report. Secondary outcomes may include self- and teacher-report, blinded measures such as heart rate and skin conductance, patient satisfaction, changes in adaptive function, quality of life and disruptive behaviour. Adverse effects should be evaluated and an economic evaluation included.\n\n# Teacher-, parent- and peer-mediated psychosocial interventions in pre‑school autistic children\n\nAre comprehensive early interventions that combine multiple elements and are delivered by parents and teachers (for example, the Learning Experiences – an Alternative Program for Preschoolers and their Parents [LEAP] model) effective in managing the core features of autism and coexisting difficulties (such as adaptive behaviour and developmental skills) in pre‑school children?\n\n## Why this is important\n\nMany autistic children are diagnosed in the pre‑school period when service provision is advice and support to parents and professionals in nursery or early years educational settings. There is evidence from one moderate-sized trial that adequately supervised comprehensive programmes can help with the core features of autism and coexisting difficulties. However, the quality of the trial was low.\n\nThe research programme should be in 4\xa0stages:\n\n. Develop a manualised programme suitable to UK public service settings (health services, early years education, and so on).\n\n. Test its feasibility and acceptability in pilot trials with blinded assessment of outcome.\n\n. Formally evaluate the outcomes on core features of autism and coexisting difficulties in a large-scale trial, including health economic analysis.\n\n. Conduct a series of smaller trials to determine the elements, length and intensity required to ensure effectiveness of the programme, as well as longer-term outcomes."}
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https://www.nice.org.uk/guidance/cg170
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This guideline covers children and young people with autism spectrum disorder (across the full range of intellectual ability) from birth until their 19th birthday. It covers the different ways that health and social care professionals can provide support, treatment and help for children and young people with autism, and their families and carers, from the early years through to their transition into young adult life.
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cbb66bb83b15fdd7939c8c9b53e2f240ac803fea
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nice
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Ozanimod for treating relapsing–remitting multiple sclerosis
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Ozanimod for treating relapsing–remitting multiple sclerosis
Evidence-based recommendations on ozanimod (Zeposia) for treating relapsing–remitting multiple sclerosis in adults with clinical or imaging features of active disease.
# Recommendations
Ozanimod is not recommended, within its marketing authorisation, for treating relapsing–remitting multiple sclerosis in adults with clinical or imaging features of active disease.
This recommendation is not intended to affect treatment with ozanimod that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Disease-modifying treatments for relapsing–remitting multiple sclerosis include alemtuzumab, beta interferons, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, ocrelizumab and teriflunomide. Treatments aim to reduce the number of relapses, slow the progression of disability and maintain or improve quality of life.
Clinical trial evidence shows that ozanimod reduces the number of relapses and brain lesions compared with interferon beta‑1a. However, ozanimod's effect on the progression of disability is unclear.
The cost-effectiveness estimates are higher than what NICE normally considers an acceptable use of NHS resources. Therefore, ozanimod is not recommended.# Information about ozanimod
# Marketing authorisation indication
Ozanimod (Zeposia, Celgene) is indicated for 'the treatment of adult patients with relapsing remitting multiple sclerosis with active disease as defined by clinical or imaging features'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for ozanimod is £1,373 per maintenance pack of 28 capsules, each containing 1 mg ozanimod hydrochloride (equivalent to 0.92 mg of ozanimod; excluding VAT; BNF online, accessed April 2021). The company has a commercial arrangement, which would have applied if the technology had been recommended.# Committee discussion
The appraisal committee considered evidence submitted by Celgene, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway, population and comparators
## Ozanimod is likely to be used as a first- or second-line treatment for active relapsing–remitting multiple sclerosis
Ozanimod's marketing authorisation is for active disease, as defined by clinical or imaging features. The company explained that the ozanimod clinical trials included people who had active disease, defined as:
at least 1 relapse within the past year or
at least 1 relapse within the last 2 years and evidence of at least 1 gadolinium-enhancing lesion in the last year.The company originally positioned ozanimod as a first-line treatment, stating that it was unlikely to be used for highly active or rapidly evolving severe disease. So, it chose the comparators for this appraisal accordingly (see section 3.3). The ERG agreed with the company's original positioning of ozanimod. At technical engagement the company updated its positioning of ozanimod to:
a first-line treatment when infusion or injectable treatments are not suitable because of administration issues or when oral treatments are preferred and
a second-line treatment when the disease has not responded to 1 or more infusions or injectable treatments.However, highly active multiple sclerosis is often defined as disease that has inadequately responded to disease-modifying therapy. So, at its first meeting, the committee considered that the company's positioning of ozanimod as a second-line treatment implied it would be used for highly active disease. After consultation, the company again updated the positioning of ozanimod; to active rather than highly active disease and only for people who had 2 significant relapses in the last 2 years. It explained that this was based on clinical advice. The company also explained that these people would have ozanimod as a first-line treatment or if they need to switch to another first-line treatment because of tolerability issues. The committee noted that NHS England's treatment algorithm for multiple sclerosis disease-modifying therapies classes second treatments as first line when people switch because of tolerability rather than lack of efficacy. The clinical experts, whose views were sought at the committee's first and second meetings, agreed that ozanimod would be of value as a first-line treatment. However, they were concerned about the company limiting ozanimod to people who have had 2 relapses in the last 2 years. They explained that there are currently no oral first-line treatments for people who have only had 1 relapse in the last 2 years. Ozanimod could benefit this group, so the company's updated positioning was unnecessarily restrictive. The committee agreed with the clinical experts that ozanimod should not be restricted to people who have had 2 relapses in the last 2 years. The clinical experts also recognised that ozanimod would be a useful second-line treatment option to fingolimod, the only sphingosine‑1‑phosphate receptor (S1PR) modulator currently available for relapsing–remitting multiple sclerosis. Ozanimod is also an S1PR modulator, but first-dose cardiac monitoring is only required for people with pre-existing cardiac conditions starting ozanimod, in contrast to all people starting fingolimod. At consultation, patient organisations and patient experts reiterated that having another first- and second-line treatment option would offer people more choice. Also, having a wide range of options is important because of the varied nature of multiple sclerosis. The clinical experts explained that types of multiple sclerosis are not always clearly defined and other clinical factors are considered when helping people choose a treatment. The committee noted the complexity of the pathway, the company's changing position of ozanimod and the clinical experts' opinions. It concluded that ozanimod was likely to be used as a first- or second-line treatment in the NHS for people with active relapsing–remitting multiple sclerosis.
## It is not appropriate to limit the population to people for whom an oral treatment is suitable or who request an oral treatment
The population in the company's original submission was people with relapsing–remitting multiple sclerosis. Later the company restricted this population to include only people with active relapsing–remitting multiple sclerosis for whom an oral treatment is suitable or who request one. The committee accepted that the company added 'active' to define and update the population in line with ozanimod's marketing authorisation, which the European Medicines Agency granted after NICE received the company's submission. The company explained that it restricted the population to people for whom an oral treatment is suitable or who request one because it considered this is how it would be used in practice. It estimated that the oral drugs teriflunomide and dimethyl fumarate account for around half the market share of relapsing–remitting multiple sclerosis treatments, and ozanimod would most likely be used in their place. However, the NHS commissioning expert said that based on the available data, this market share was likely to be a significant overestimate. After consultation, the company provided survey results for the market shares of oral and injectable treatments for active relapsing–remitting multiple sclerosis to support its estimate. It also explained that oral treatments are preferred for active disease and people only have injectable treatments because of historical prescribing habits. The committee considered that if half the people with active disease are having oral treatments, the remaining half must be having injections or infusions. The clinical experts explained that it would be difficult to identify a group of people for whom only oral treatments are suitable. They agreed that many people would choose an oral drug over an injection or infusion, but highlighted that people often switch between treatments with different routes of administration. At consultation, patient organisations and patient experts stressed the benefits of ozanimod's oral route of administration, particularly that it would be easy to take. However, the patient experts also stated that there are many reasons why someone would change their mind about their treatment. People would not want to be excluded from having a treatment because it was an injection or an infusion. But this might happen if the company restricted ozanimod to people for whom an oral treatment is suitable or who prefer one. The ERG had concerns about restricting the population, explaining that it was unclear what is meant by people for whom an oral treatment is suitable or who request one. The committee was concerned that restricting the population would reduce patient choice and exclude potential comparators that are routinely used in the NHS. It concluded that it was not appropriate to limit the population to people for whom an oral treatment is suitable or who request an oral treatment.
## First- and second-line treatments for active relapsing–remitting multiple sclerosis, including ocrelizumab, are comparators
In its submission, the company included beta interferons (1a and 1b), dimethyl fumarate, glatiramer acetate, teriflunomide and peginterferon beta‑1a as comparators. Alemtuzumab and ocrelizumab were included in the scope, but the company excluded them as comparators in its base-case analysis (although it provided analyses with them as comparators in an appendix) because:
a safety review restricted the use of alemtuzumab to highly active disease, and ozanimod is not expected to be used in highly active disease
NICE only recommends ocrelizumab when alemtuzumab is contraindicated or otherwise unsuitable.However, clinical experts advising the ERG and the clinical experts at the meeting confirmed that ocrelizumab is being used as a first-line treatment for relapsing–remitting multiple sclerosis in the NHS. For the restricted population (see section 3.2), the company's comparators were dimethyl fumarate and teriflunomide, the only oral drugs used as first-line treatment for active relapsing–remitting multiple sclerosis. The ERG did not agree with the company restricting the population and limiting the comparators to only dimethyl fumarate and teriflunomide. The committee agreed with the ERG that all the company's original comparators plus ocrelizumab, but excluding alemtuzumab, were relevant comparators for first-line treatment. After consultation and at both committee meetings, the clinical experts explained that ozanimod could also be used as a second-line treatment for relapsing–remitting multiple sclerosis. That is, disease that has not responded to 1 or more disease-modifying treatments, for example as an alternative to fingolimod (see section 3.1). The company had supported this position at technical engagement, but later disagreed at consultation. The committee noted that NHS England's treatment algorithm for multiple sclerosis disease-modifying therapies suggests alemtuzumab, ocrelizumab, cladribine or fingolimod for this group. However, the committee considered that alemtuzumab was not a comparator because it was likely to be used for a population with more severe disease than ozanimod. Also, it has been associated with safety concerns so is only for people who have had a full and adequate course of at least 1 other disease-modifying agent. So, the committee considered ocrelizumab, cladribine and fingolimod to be relevant second-line comparators. The company did not provide comparisons against all relevant first- and second-line treatments after consultation. Instead it maintained that dimethyl fumarate and teriflunomide were the only comparators. The committee concluded that first- and second-line treatments used for active relapsing–remitting multiple sclerosis, including ocrelizumab, were comparators.
# Ozanimod clinical trials
## Baseline characteristics in the trials are generalisable to people in the NHS with active relapsing–remitting multiple sclerosis
The phase 3 trials RADIANCE part B and SUNBEAM compared ozanimod with interferon beta‑1a. The trials had very similar designs, inclusion and exclusion criteria and outcomes, but differed in duration (RADIANCE part B had a 24‑month follow-up period, whereas SUNBEAM had a 12‑month follow-up period). The ERG considered that although the baseline characteristics of people in the trials were broadly generalisable to people having treatment in the NHS, there were some characteristics that may limit generalisability. For example, around 23% of people in the trials had highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and around 30% had already had a disease-modifying therapy. The ERG explained that this was not in line with the company's positioning but would be less of an issue if ozanimod was likely to be used as a second-line treatment. The ERG also highlighted that there was a higher proportion of people with a white family background and from Eastern Europe than in the NHS. The clinical experts advised that the trial populations and the more diverse population in NHS practice were likely to have a similar natural history of relapsing–remitting multiple sclerosis. They therefore considered the baseline characteristics in RADIANCE part B and SUNBEAM to be generalisable to NHS practice. The committee concluded that the baseline characteristics in RADIANCE part B and SUNBEAM were generalisable to people in the NHS with active relapsing–remitting multiple sclerosis.
## Ozanimod reduces relapses and brain lesions compared with interferon beta-1a, but its effects on disability are uncertain
In RADIANCE part B and SUNBEAM, the primary outcome was annualised relapse rate. Key secondary outcomes included:
number of new or enlarging hyperintense T2‑weighted brain MRI lesions
number of gadolinium-enhanced T1 brain MRI lesions and
time to onset of confirmed disability progression (CDP) after 3 months (CDP‑3M) and after 6 months (CDP‑6M).The committee confirmed that in previous appraisals on multiple sclerosis (for example, NICE's technology appraisal guidance on teriflunomide, dimethyl fumarate and beta interferons and glatiramer acetate) it had preferred to use CDP‑6M instead of CDP‑3M. This was because CDP‑6M is less likely to be influenced by relapses so is better at capturing the benefits of treatment. The committee understood that ozanimod was effective at reducing the annualised relapse rate compared with interferon beta‑1a in RADIANCE part B, SUNBEAM and a pre-specified pooled analysis using 12‑month data from each trial. It was also better than interferon beta‑1a for both MRI outcomes. For disability progression, in the pooled analysis the hazard ratio for ozanimod compared with interferon beta‑1a was 0.95 (95% confidence interval 0.68 to 1.33) for CDP‑3M and 1.41 (95% confidence interval 0.92 to 2.17) for CDP‑6M. The company explained that ozanimod's benefits may not have been captured in the results because there were low rates of CDP in both treatment arms in the trials. This meant there was a wide statistical range in the results, and a reduced ability to detect a meaningful difference in CDP between treatments. The committee considered ozanimod to be effective compared with interferon beta‑1a for relapse and MRI outcomes, but understood that the trials did not show a benefit in terms of reducing CDP. The company asked that the CDP results be considered alongside other outcomes for which ozanimod had been shown to be more effective than interferon beta‑1a, that is, annualised relapse rate and brain MRI lesions. The company also highlighted that in RADIANCE part B a significantly higher proportion of people having ozanimod compared with interferon beta‑1a showed no evidence of disease activity (NEDA‑3). The committee understood that NEDA‑3 is a combined measure based on no relapses, no increase in disability and no new or active lesions on MRI. The company suggested these results showed an overall improvement in outcomes for ozanimod compared with interferon beta‑1a. It considered it implausible that ozanimod could be worse than interferon beta‑1a for CDP outcomes but better for relapse and MRI outcomes. It also suggested that CDP was a less important outcome in clinical practice than in clinical trials and cost‑effectiveness models. At consultation, patient organisations highlighted that reduced disability progression is important to people with multiple sclerosis. The ERG highlighted the relative difference in CDP between ozanimod and interferon beta‑1a. It also noted that the rates of CDP‑6M were lower with interferon beta‑1a than with ozanimod in both trials (as shown by a hazard ratio greater than 1 for ozanimod compared with interferon beta‑1a) but the difference was not statistically significant. The clinical experts explained that a treatment that reduced MRI activity and relapses would also be expected to reduce CDP. They considered that the people enrolled in RADIANCE part B and SUNBEAM may have milder relapsing–remitting multiple sclerosis than average. So, they would be less likely to progress in terms of disability over the short duration of the trials. The clinical experts thought it unlikely that ozanimod would be worse than interferon beta‑1a for CDP outcomes. They noted that interferon beta‑1a is usually considered as having lower efficacy than some of the other available treatments. The NHS commissioning expert confirmed this view. The committee considered the statements it heard from the experts, the company's explanation, and the direct evidence from the clinical trial. It acknowledged the company's rationale about why no reduction in CDP‑6M was seen in the trial. The committee considered that it would take this uncertainty into account in its decision making. It concluded that ozanimod was effective at reducing relapses and brain lesions compared with interferon beta‑1a, but its effects on disability were uncertain. This is because it did not improve disability progression outcomes in clinical trials.
# Indirect treatment comparison
## The combined CDP-6M network meta-analysis should account for variability in the relationship between the 3- and 6-month outcomes
In its original submission, the company included a Bayesian network meta-analysis estimating ozanimod's relative effectiveness compared with placebo, interferon beta‑1a, interferon beta‑1b, peginterferon beta‑1a, teriflunomide, glatiramer acetate and dimethyl fumarate. The company modelled annualised relapse rate, CDP‑3M, CDP‑6M, treatment discontinuation, adverse events and serious adverse events. Some older studies did not report CDP‑6M so the company also analysed CDP‑3M and CDP‑6M combined in a single model. This was so that CDP‑6M could be predicted for all comparators (referred to as the CDP‑6M combined outcome). In this analysis it assumed that the hazard ratios for CDP‑6M between treatments were proportional to the hazard ratios for CDP‑3M between treatments. The ERG was satisfied that:
the company's approach to the network meta-analysis was generally appropriate
any heterogeneity or inconsistency did not have an important effect on results.The ERG did, however, highlight that the assumption of a proportional relationship between the CDP‑3M and CDP‑6M hazard ratios for ozanimod appeared to have been violated. It advised caution when drawing conclusions from the company's CDP‑6M combined analysis. The committee noted the ERG's concerns and preferred the CDP‑6M network meta-analysis estimated from the trial data directly, rather than the combined CDP‑6M network meta-analysis that was estimated from the CDP‑3M data. The committee accepted that comparators for which CDP‑6M data was not available were excluded from the network meta-analysis estimated from the trial data directly. The company explained that the proportional relationship between CDP‑3M and CDP‑6M in its combined analysis was assumed to be fixed and to be the same for all studies and treatments. The committee considered it would have preferred the company to have accounted for variability in the relationship between the 3- and 6‑month outcomes in its combined CDP‑6M network meta-analysis. The committee noted that the company did not provide such an analysis at consultation. The ERG identified a potential issue with the glatiramer acetate 40 mg CDP data used in the company's network meta-analysis. It explained that the company may have made an error in data extraction, in which CDP at 12 months may have been extracted as CDP at 12 weeks by mistake. The ERG suspected this data had then been used in the CDP‑6M combined analysis in the company's network meta-analysis. The company did not confirm whether there had been an error in data extraction for glatiramer acetate 40 mg. So, the committee interpreted the results for this comparator with caution. It concluded that the company's network meta-analysis was generally well done. But the combined CDP‑6M network meta-analysis, when used, should have accounted for variability in the relationship between 3‑ and 6‑month outcomes between treatments and studies.
# The company's cost–utility model
## The company's model is generally appropriate and in line with previous models in the disease area
The company's model structure was similar to that of models used in previous multiple sclerosis technology appraisals (for example, NICE's technology appraisal guidance on teriflunomide, dimethyl fumarate, ocrelizumab and peginterferon beta-1a). The model was a Markov transition model consisting of 21 health states (10 Expanded Disability Status Scale states for relapsing–remitting multiple sclerosis, 10 for secondary progressive multiple sclerosis and death). The model used the British Columbia Multiple Sclerosis registry as a source of natural history data. The company obtained treatment effects for ozanimod and all comparators from its network meta-analysis and applied them as:
annualised relapse rates
CDP‑6M (using the combined outcome, see section 3.8)
adverse events and
annualised treatment discontinuation (see section 3.10).The company incorporated a treatment waning effect for all treatments and explained that no treatment switching was allowed in its model. The ERG highlighted that the lack of treatment switching or sequencing in the model may oversimplify what happens in NHS practice. However, it acknowledged that a model simulating treatment switching or treatment sequencing would be complex to construct, and difficult to populate because of limited data. The committee considered that the model did not completely reflect the treatment pathway for relapsing–remitting multiple sclerosis and acknowledged the lack of treatment switching as a limitation. However, the committee concluded that the company's model was generally appropriate and in line with previous models in the disease area and could be used for decision making. In future, the committee would expect a model that more accurately reflected the patient pathway in the NHS. This would include methodological advances in modelling treatment sequences.
## Ozanimod's disability progression hazard ratio is preferred, and a scenario using the interferon beta-1a hazard ratio will be considered
The company explained that it had used the combined CDP‑6M outcome from its network meta-analysis to model the effects of treatments on disability progression. It had advised about the issues with the CDP data in the ozanimod clinical trials (see section 3.5) and noted that these trial results underpinned the network meta-analysis results for ozanimod. The company also explained that it set ozanimod's CDP‑6M hazard ratio as equal to the CDP‑6M hazard ratio for interferon beta‑1a in its model, which it considered to be a conservative assumption. This was because it considered it would be implausible that using interferon beta‑1a could lead to a lower rate of disability progression than ozanimod (see section 3.5). The ERG highlighted that the company had only set ozanimod as equivalent to interferon beta‑1a for CDP‑6M and not for relapses, and this was inconsistent. It further highlighted that the point estimate in the network meta-analysis suggested that ozanimod was not as beneficial as interferon beta‑1a for CDP‑6M. Also, there are other drugs available that have been shown in clinical trials to work better than interferon beta‑1a for this outcome. The committee recognised that the clinical experts suspected the non-statistically significant CDP‑6M results in the ozanimod trials could be because of milder disease and short trial duration. That is, not because ozanimod does not work as well as interferon beta‑1a for this outcome (see section 3.5). However, the committee also understood that the ozanimod trials were of high quality. So, given the uncertainty and for consistency with other outcomes, the committee considered that ozanimod's CDP‑6M hazard ratio from the network meta-analysis should be used. The committee noted that the company did not update its analysis to include this committee preference at consultation. At its first meeting, the committee also considered that the network meta-analysis results estimated directly from the CDP‑6M trial data should be used in the model when possible (see section 3.6). In addition, the CDP‑6M results from the combined outcome estimated from the CDP‑3M data should only be used for treatments that did not have CDP‑6M data available. However, the company did not provide this analysis at consultation. Also, after consultation, the ERG advised that such an analysis cannot be done because the hazard ratios have been generated using different network meta-analysis models that are based on different input data. Therefore, the committee accepted that this analysis could not be done without making strong assumptions. The committee concluded that it would have preferred ozanimod's disability progression hazard ratio from the network meta-analysis to be used in the model. It also acknowledged that it would consider the company's base-case scenario, in which the interferon beta‑1a hazard ratio was used for ozanimod.
## All differences in treatment effects should be modelled regardless of whether they are statistically significant
In its submission the company used the point estimates from its network meta-analysis to model the effects of treatment on disability progression. The ERG originally suggested in its report that if clinical effectiveness results were not statistically significantly different, then a difference in effect should not be modelled. However, before the first committee meeting the ERG clarified its position that the company should use available point estimates from the network meta-analysis. Non-statistically significant results should be explored in probabilistic and scenario analysis. After consultation, the company highlighted the ERG's original position. It suggested that ozanimod should be assumed to be of the same or similar efficacy to its chosen oral comparators because there were no statistically significant differences in the network meta-analysis. The ERG clarified that it had changed its view. It now considered that overlapping or wide confidence intervals were insufficient to conclude that there is no difference in effectiveness between treatments. The ERG also reiterated that it would be inappropriate to assume there are no differences between ozanimod and the comparators. This is because, in some cases, the confidence intervals barely cross 1 and the point estimates are markedly different. In addition, ozanimod has a different mechanism of action to the relevant first-line comparator treatments. The committee considered it would be inappropriate to only model statistically significant differences. Also, the point estimates from the network meta-analysis should be used in the base case as is standard practice in health economic modelling. The committee concluded that all differences in treatment effects should be modelled regardless of whether they were statistically significant.
## Both the company and ERG's approaches to modelling treatment discontinuation have limitations
The company's cost–utility model did not allow people to switch between treatments, so they were assumed to only have 1 disease-modifying treatment. The company took rates of discontinuation for each treatment from its network meta-analysis and assumed that each rate was the same over the entire model time horizon. In addition, people stopped treatment if they reached EDSS state 7 or above, developed secondary progressive multiple sclerosis or died. The ERG preferred a different approach. Its clinical advisers suggested that if no switching of treatments was allowed (as was the case in the model), people would only stop treatment if they were no longer benefitting, even if they still had relapses. Based on this, the ERG used trial treatment discontinuation rates when possible, then assumed everyone stayed on treatment until they reached EDSS state 7 or above, developed secondary progressive multiple sclerosis or died. The clinical experts explained that it was difficult to determine whether the company or ERG's approach better represented NHS practice because people usually switch between several disease-modifying treatments over their lifetime. So, neither approach wholly reflected what would happen in practice. The committee considered the lack of treatment switching to be a limitation of the company's model (see section 3.7). It concluded that both the company and ERG's approaches to modelling treatment discontinuation had limitations.
# Cost-effectiveness estimates
## The most likely cost-effectiveness estimates are higher than what NICE normally considers an acceptable use of NHS resources
For the cost-effectiveness estimates of ozanimod compared with other first-line relapsing–remitting multiple sclerosis treatments, neither the company nor the ERG's analyses reflected the committee's preferred assumptions. The committee would have preferred to see a cost–utility analysis that:
compared ozanimod with all relevant first-line treatments, rather than limiting the comparators to the oral treatments
used ozanimod's CDP‑6M hazard ratio from the network meta-analysis, rather than setting ozanimod as equivalent to interferon beta‑1a
used the trials' CDP‑6M hazard ratios when possible, and only used the combined CDP‑6M hazard ratios for treatments that did not have CDP‑6M data available (glatiramer acetate 40 mg , interferon beta‑1a 22 micrograms and peginterferon beta‑1a)
used combined CDP‑6M hazard ratios, when these are used, from a network meta-analysis that accounts for variability in the relationship between 3- and 6‑month outcomes between treatments and studies.The committee noted that the scenario that most closely resembled its preferences used ozanimod's CDP‑6M hazard ratio from the network meta-analysis. It noted that the cost-effectiveness estimates for ozanimod were higher than what NICE normally considers an acceptable use of NHS resources. It also noted that the cost-effectiveness estimates were higher than acceptable in the company's base case. In the company's base case, the CDP‑6M hazard ratio for ozanimod was set as equal to interferon beta‑1a. This made the company's base case more favourable for ozanimod than when ozanimod's own CDP‑6M hazard ratio was used. Also, including its other preferences was likely to increase the incremental cost-effectiveness ratios. Because of confidential commercial arrangements for ozanimod and comparator treatments, the cost-effectiveness results cannot be reported here.
## A recommendation cannot be made for ozanimod's second-line use
The committee recalled its earlier conclusion that second-line treatments for relapsing–remitting multiple sclerosis were also considered relevant comparators (cladribine, fingolimod and ocrelizumab). It recalled that the company had not presented cost-effectiveness results for these comparisons. Therefore, the committee concluded that it could not make a recommendation for second-line use of ozanimod for treating relapsing–remitting multiple sclerosis.
# Other factors
The committee concluded that ozanimod's benefits were adequately captured in the economic analysis so did not consider it innovative.
|
{'Recommendations': "Ozanimod is not recommended, within its marketing authorisation, for treating relapsing–remitting multiple sclerosis in adults with clinical or imaging features of active disease.\n\nThis recommendation is not intended to affect treatment with ozanimod that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nDisease-modifying treatments for relapsing–remitting multiple sclerosis include alemtuzumab, beta interferons, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, ocrelizumab and teriflunomide. Treatments aim to reduce the number of relapses, slow the progression of disability and maintain or improve quality of life.\n\nClinical trial evidence shows that ozanimod reduces the number of relapses and brain lesions compared with interferon beta‑1a. However, ozanimod's effect on the progression of disability is unclear.\n\nThe cost-effectiveness estimates are higher than what NICE normally considers an acceptable use of NHS resources. Therefore, ozanimod is not recommended.", 'Information about ozanimod': "# Marketing authorisation indication\n\nOzanimod (Zeposia, Celgene) is indicated for 'the treatment of adult patients with relapsing remitting multiple sclerosis with active disease as defined by clinical or imaging features'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for ozanimod is £1,373 per maintenance pack of 28\xa0capsules, each containing 1\xa0mg ozanimod hydrochloride (equivalent to 0.92\xa0mg of ozanimod; excluding VAT; BNF online, accessed April 2021). The company has a commercial arrangement, which would have applied if the technology had been recommended.", 'Committee discussion': "The appraisal committee considered evidence submitted by Celgene, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway, population and comparators\n\n## Ozanimod is likely to be used as a first- or second-line treatment for active relapsing–remitting multiple sclerosis\n\nOzanimod's marketing authorisation is for active disease, as defined by clinical or imaging features. The company explained that the ozanimod clinical trials included people who had active disease, defined as:\n\nat least 1\xa0relapse within the past year or\n\nat least 1\xa0relapse within the last 2\xa0years and evidence of at least 1\xa0gadolinium-enhancing lesion in the last year.The company originally positioned ozanimod as a first-line treatment, stating that it was unlikely to be used for highly active or rapidly evolving severe disease. So, it chose the comparators for this appraisal accordingly (see section\xa03.3). The ERG agreed with the company's original positioning of ozanimod. At technical engagement the company updated its positioning of ozanimod to:\n\na first-line treatment when infusion or injectable treatments are not suitable because of administration issues or when oral treatments are preferred and\n\na second-line treatment when the disease has not responded to 1\xa0or more infusions or injectable treatments.However, highly active multiple sclerosis is often defined as disease that has inadequately responded to disease-modifying therapy. So, at its first meeting, the committee considered that the company's positioning of ozanimod as a second-line treatment implied it would be used for highly active disease. After consultation, the company again updated the positioning of ozanimod; to active rather than highly active disease and only for people who had 2\xa0significant relapses in the last 2\xa0years. It explained that this was based on clinical advice. The company also explained that these people would have ozanimod as a first-line treatment or if they need to switch to another first-line treatment because of tolerability issues. The committee noted that NHS England's treatment algorithm for multiple sclerosis disease-modifying therapies classes second treatments as first line when people switch because of tolerability rather than lack of efficacy. The clinical experts, whose views were sought at the committee's first and second meetings, agreed that ozanimod would be of value as a first-line treatment. However, they were concerned about the company limiting ozanimod to people who have had 2\xa0relapses in the last 2\xa0years. They explained that there are currently no oral first-line treatments for people who have only had 1\xa0relapse in the last 2\xa0years. Ozanimod could benefit this group, so the company's updated positioning was unnecessarily restrictive. The committee agreed with the clinical experts that ozanimod should not be restricted to people who have had 2\xa0relapses in the last 2\xa0years. The clinical experts also recognised that ozanimod would be a useful second-line treatment option to fingolimod, the only sphingosine‑1‑phosphate receptor (S1PR) modulator currently available for relapsing–remitting multiple sclerosis. Ozanimod is also an S1PR modulator, but first-dose cardiac monitoring is only required for people with pre-existing cardiac conditions starting ozanimod, in contrast to all people starting fingolimod. At consultation, patient organisations and patient experts reiterated that having another first- and second-line treatment option would offer people more choice. Also, having a wide range of options is important because of the varied nature of multiple sclerosis. The clinical experts explained that types of multiple sclerosis are not always clearly defined and other clinical factors are considered when helping people choose a treatment. The committee noted the complexity of the pathway, the company's changing position of ozanimod and the clinical experts' opinions. It concluded that ozanimod was likely to be used as a first- or second-line treatment in the NHS for people with active relapsing–remitting multiple sclerosis.\n\n## It is not appropriate to limit the population to people for whom an oral treatment is suitable or who request an oral treatment\n\nThe population in the company's original submission was people with relapsing–remitting multiple sclerosis. Later the company restricted this population to include only people with active relapsing–remitting multiple sclerosis for whom an oral treatment is suitable or who request one. The committee accepted that the company added 'active' to define and update the population in line with ozanimod's marketing authorisation, which the European Medicines Agency granted after NICE received the company's submission. The company explained that it restricted the population to people for whom an oral treatment is suitable or who request one because it considered this is how it would be used in practice. It estimated that the oral drugs teriflunomide and dimethyl fumarate account for around half the market share of relapsing–remitting multiple sclerosis treatments, and ozanimod would most likely be used in their place. However, the NHS commissioning expert said that based on the available data, this market share was likely to be a significant overestimate. After consultation, the company provided survey results for the market shares of oral and injectable treatments for active relapsing–remitting multiple sclerosis to support its estimate. It also explained that oral treatments are preferred for active disease and people only have injectable treatments because of historical prescribing habits. The committee considered that if half the people with active disease are having oral treatments, the remaining half must be having injections or infusions. The clinical experts explained that it would be difficult to identify a group of people for whom only oral treatments are suitable. They agreed that many people would choose an oral drug over an injection or infusion, but highlighted that people often switch between treatments with different routes of administration. At consultation, patient organisations and patient experts stressed the benefits of ozanimod's oral route of administration, particularly that it would be easy to take. However, the patient experts also stated that there are many reasons why someone would change their mind about their treatment. People would not want to be excluded from having a treatment because it was an injection or an infusion. But this might happen if the company restricted ozanimod to people for whom an oral treatment is suitable or who prefer one. The ERG had concerns about restricting the population, explaining that it was unclear what is meant by people for whom an oral treatment is suitable or who request one. The committee was concerned that restricting the population would reduce patient choice and exclude potential comparators that are routinely used in the NHS. It concluded that it was not appropriate to limit the population to people for whom an oral treatment is suitable or who request an oral treatment.\n\n## First- and second-line treatments for active relapsing–remitting multiple sclerosis, including ocrelizumab, are comparators\n\nIn its submission, the company included beta interferons (1a and 1b), dimethyl fumarate, glatiramer acetate, teriflunomide and peginterferon beta‑1a as comparators. Alemtuzumab and ocrelizumab were included in the scope, but the company excluded them as comparators in its base-case analysis (although it provided analyses with them as comparators in an appendix) because:\n\na safety review restricted the use of alemtuzumab to highly active disease, and ozanimod is not expected to be used in highly active disease\n\nNICE only recommends ocrelizumab when alemtuzumab is contraindicated or otherwise unsuitable.However, clinical experts advising the ERG and the clinical experts at the meeting confirmed that ocrelizumab is being used as a first-line treatment for relapsing–remitting multiple sclerosis in the NHS. For the restricted population (see section\xa03.2), the company's comparators were dimethyl fumarate and teriflunomide, the only oral drugs used as first-line treatment for active relapsing–remitting multiple sclerosis. The ERG did not agree with the company restricting the population and limiting the comparators to only dimethyl fumarate and teriflunomide. The committee agreed with the ERG that all the company's original comparators plus ocrelizumab, but excluding alemtuzumab, were relevant comparators for first-line treatment. After consultation and at both committee meetings, the clinical experts explained that ozanimod could also be used as a second-line treatment for relapsing–remitting multiple sclerosis. That is, disease that has not responded to 1\xa0or more disease-modifying treatments, for example as an alternative to fingolimod (see section\xa03.1). The company had supported this position at technical engagement, but later disagreed at consultation. The committee noted that NHS England's treatment algorithm for multiple sclerosis disease-modifying therapies suggests alemtuzumab, ocrelizumab, cladribine or fingolimod for this group. However, the committee considered that alemtuzumab was not a comparator because it was likely to be used for a population with more severe disease than ozanimod. Also, it has been associated with safety concerns so is only for people who have had a full and adequate course of at least 1\xa0other disease-modifying agent. So, the committee considered ocrelizumab, cladribine and fingolimod to be relevant second-line comparators. The company did not provide comparisons against all relevant first- and second-line treatments after consultation. Instead it maintained that dimethyl fumarate and teriflunomide were the only comparators. The committee concluded that first- and second-line treatments used for active relapsing–remitting multiple sclerosis, including ocrelizumab, were comparators.\n\n# Ozanimod clinical trials\n\n## Baseline characteristics in the trials are generalisable to people in the NHS with active relapsing–remitting multiple sclerosis\n\nThe phase\xa03 trials RADIANCE part\xa0B and SUNBEAM compared ozanimod with interferon beta‑1a. The trials had very similar designs, inclusion and exclusion criteria and outcomes, but differed in duration (RADIANCE part\xa0B had a 24‑month follow-up period, whereas SUNBEAM had a 12‑month follow-up period). The ERG considered that although the baseline characteristics of people in the trials were broadly generalisable to people having treatment in the NHS, there were some characteristics that may limit generalisability. For example, around 23% of people in the trials had highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and around 30% had already had a disease-modifying therapy. The ERG explained that this was not in line with the company's positioning but would be less of an issue if ozanimod was likely to be used as a second-line treatment. The ERG also highlighted that there was a higher proportion of people with a white family background and from Eastern Europe than in the NHS. The clinical experts advised that the trial populations and the more diverse population in NHS practice were likely to have a similar natural history of relapsing–remitting multiple sclerosis. They therefore considered the baseline characteristics in RADIANCE part\xa0B and SUNBEAM to be generalisable to NHS practice. The committee concluded that the baseline characteristics in RADIANCE part\xa0B and SUNBEAM were generalisable to people in the NHS with active relapsing–remitting multiple sclerosis.\n\n## Ozanimod reduces relapses and brain lesions compared with interferon beta-1a, but its effects on disability are uncertain\n\nIn RADIANCE part\xa0B and SUNBEAM, the primary outcome was annualised relapse rate. Key secondary outcomes included:\n\nnumber of new or enlarging hyperintense T2‑weighted brain MRI lesions\n\nnumber of gadolinium-enhanced T1 brain MRI lesions and\n\ntime to onset of confirmed disability progression (CDP) after 3\xa0months (CDP‑3M) and after 6\xa0months (CDP‑6M).The committee confirmed that in previous appraisals on multiple sclerosis (for example, NICE's technology appraisal guidance on teriflunomide, dimethyl fumarate and beta interferons and glatiramer acetate) it had preferred to use CDP‑6M instead of CDP‑3M. This was because CDP‑6M is less likely to be influenced by relapses so is better at capturing the benefits of treatment. The committee understood that ozanimod was effective at reducing the annualised relapse rate compared with interferon beta‑1a in RADIANCE part\xa0B, SUNBEAM and a pre-specified pooled analysis using 12‑month data from each trial. It was also better than interferon beta‑1a for both MRI outcomes. For disability progression, in the pooled analysis the hazard ratio for ozanimod compared with interferon beta‑1a was 0.95 (95% confidence interval 0.68 to 1.33) for CDP‑3M and 1.41 (95% confidence interval 0.92 to 2.17) for CDP‑6M. The company explained that ozanimod's benefits may not have been captured in the results because there were low rates of CDP in both treatment arms in the trials. This meant there was a wide statistical range in the results, and a reduced ability to detect a meaningful difference in CDP between treatments. The committee considered ozanimod to be effective compared with interferon beta‑1a for relapse and MRI outcomes, but understood that the trials did not show a benefit in terms of reducing CDP. The company asked that the CDP results be considered alongside other outcomes for which ozanimod had been shown to be more effective than interferon beta‑1a, that is, annualised relapse rate and brain MRI lesions. The company also highlighted that in RADIANCE part\xa0B a significantly higher proportion of people having ozanimod compared with interferon beta‑1a showed no evidence of disease activity (NEDA‑3). The committee understood that NEDA‑3 is a combined measure based on no relapses, no increase in disability and no new or active lesions on MRI. The company suggested these results showed an overall improvement in outcomes for ozanimod compared with interferon beta‑1a. It considered it implausible that ozanimod could be worse than interferon beta‑1a for CDP outcomes but better for relapse and MRI outcomes. It also suggested that CDP was a less important outcome in clinical practice than in clinical trials and cost‑effectiveness models. At consultation, patient organisations highlighted that reduced disability progression is important to people with multiple sclerosis. The ERG highlighted the relative difference in CDP between ozanimod and interferon beta‑1a. It also noted that the rates of CDP‑6M were lower with interferon beta‑1a than with ozanimod in both trials (as shown by a hazard ratio greater than\xa01 for ozanimod compared with interferon beta‑1a) but the difference was not statistically significant. The clinical experts explained that a treatment that reduced MRI activity and relapses would also be expected to reduce CDP. They considered that the people enrolled in RADIANCE part\xa0B and SUNBEAM may have milder relapsing–remitting multiple sclerosis than average. So, they would be less likely to progress in terms of disability over the short duration of the trials. The clinical experts thought it unlikely that ozanimod would be worse than interferon beta‑1a for CDP outcomes. They noted that interferon beta‑1a is usually considered as having lower efficacy than some of the other available treatments. The NHS commissioning expert confirmed this view. The committee considered the statements it heard from the experts, the company's explanation, and the direct evidence from the clinical trial. It acknowledged the company's rationale about why no reduction in CDP‑6M was seen in the trial. The committee considered that it would take this uncertainty into account in its decision making. It concluded that ozanimod was effective at reducing relapses and brain lesions compared with interferon beta‑1a, but its effects on disability were uncertain. This is because it did not improve disability progression outcomes in clinical trials.\n\n# Indirect treatment comparison\n\n## The combined CDP-6M network meta-analysis should account for variability in the relationship between the 3- and 6-month outcomes\n\nIn its original submission, the company included a Bayesian network meta-analysis estimating ozanimod's relative effectiveness compared with placebo, interferon beta‑1a, interferon beta‑1b, peginterferon beta‑1a, teriflunomide, glatiramer acetate and dimethyl fumarate. The company modelled annualised relapse rate, CDP‑3M, CDP‑6M, treatment discontinuation, adverse events and serious adverse events. Some older studies did not report CDP‑6M so the company also analysed CDP‑3M and CDP‑6M combined in a single model. This was so that CDP‑6M could be predicted for all comparators (referred to as the CDP‑6M combined outcome). In this analysis it assumed that the hazard ratios for CDP‑6M between treatments were proportional to the hazard ratios for CDP‑3M between treatments. The ERG was satisfied that:\n\nthe company's approach to the network meta-analysis was generally appropriate\n\nany heterogeneity or inconsistency did not have an important effect on results.The ERG did, however, highlight that the assumption of a proportional relationship between the CDP‑3M and CDP‑6M hazard ratios for ozanimod appeared to have been violated. It advised caution when drawing conclusions from the company's CDP‑6M combined analysis. The committee noted the ERG's concerns and preferred the CDP‑6M network meta-analysis estimated from the trial data directly, rather than the combined CDP‑6M network meta-analysis that was estimated from the CDP‑3M data. The committee accepted that comparators for which CDP‑6M data was not available were excluded from the network meta-analysis estimated from the trial data directly. The company explained that the proportional relationship between CDP‑3M and CDP‑6M in its combined analysis was assumed to be fixed and to be the same for all studies and treatments. The committee considered it would have preferred the company to have accounted for variability in the relationship between the 3- and 6‑month outcomes in its combined CDP‑6M network meta-analysis. The committee noted that the company did not provide such an analysis at consultation. The ERG identified a potential issue with the glatiramer acetate 40\xa0mg CDP data used in the company's network meta-analysis. It explained that the company may have made an error in data extraction, in which CDP at 12\xa0months may have been extracted as CDP at 12\xa0weeks by mistake. The ERG suspected this data had then been used in the CDP‑6M combined analysis in the company's network meta-analysis. The company did not confirm whether there had been an error in data extraction for glatiramer acetate 40\xa0mg. So, the committee interpreted the results for this comparator with caution. It concluded that the company's network meta-analysis was generally well done. But the combined CDP‑6M network meta-analysis, when used, should have accounted for variability in the relationship between 3‑\xa0and 6‑month outcomes between treatments and studies.\n\n# The company's cost–utility model\n\n## The company's model is generally appropriate and in line with previous models in the disease area\n\nThe company's model structure was similar to that of models used in previous multiple sclerosis technology appraisals (for example, NICE's technology appraisal guidance on teriflunomide, dimethyl fumarate, ocrelizumab and peginterferon beta-1a). The model was a Markov transition model consisting of 21\xa0health states (10\xa0Expanded Disability Status Scale [EDSS] states for relapsing–remitting multiple sclerosis, 10\xa0for secondary progressive multiple sclerosis and death). The model used the British Columbia Multiple Sclerosis registry as a source of natural history data. The company obtained treatment effects for ozanimod and all comparators from its network meta-analysis and applied them as:\n\nannualised relapse rates\n\nCDP‑6M (using the combined outcome, see section\xa03.8)\n\nadverse events and\n\nannualised treatment discontinuation (see section\xa03.10).The company incorporated a treatment waning effect for all treatments and explained that no treatment switching was allowed in its model. The ERG highlighted that the lack of treatment switching or sequencing in the model may oversimplify what happens in NHS practice. However, it acknowledged that a model simulating treatment switching or treatment sequencing would be complex to construct, and difficult to populate because of limited data. The committee considered that the model did not completely reflect the treatment pathway for relapsing–remitting multiple sclerosis and acknowledged the lack of treatment switching as a limitation. However, the committee concluded that the company's model was generally appropriate and in line with previous models in the disease area and could be used for decision making. In future, the committee would expect a model that more accurately reflected the patient pathway in the NHS. This would include methodological advances in modelling treatment sequences.\n\n## Ozanimod's disability progression hazard ratio is preferred, and a scenario using the interferon beta-1a hazard ratio will be considered\n\nThe company explained that it had used the combined CDP‑6M outcome from its network meta-analysis to model the effects of treatments on disability progression. It had advised about the issues with the CDP data in the ozanimod clinical trials (see section\xa03.5) and noted that these trial results underpinned the network meta-analysis results for ozanimod. The company also explained that it set ozanimod's CDP‑6M hazard ratio as equal to the CDP‑6M hazard ratio for interferon beta‑1a in its model, which it considered to be a conservative assumption. This was because it considered it would be implausible that using interferon beta‑1a could lead to a lower rate of disability progression than ozanimod (see section\xa03.5). The ERG highlighted that the company had only set ozanimod as equivalent to interferon beta‑1a for CDP‑6M and not for relapses, and this was inconsistent. It further highlighted that the point estimate in the network meta-analysis suggested that ozanimod was not as beneficial as interferon beta‑1a for CDP‑6M. Also, there are other drugs available that have been shown in clinical trials to work better than interferon beta‑1a for this outcome. The committee recognised that the clinical experts suspected the non-statistically significant CDP‑6M results in the ozanimod trials could be because of milder disease and short trial duration. That is, not because ozanimod does not work as well as interferon beta‑1a for this outcome (see section\xa03.5). However, the committee also understood that the ozanimod trials were of high quality. So, given the uncertainty and for consistency with other outcomes, the committee considered that ozanimod's CDP‑6M hazard ratio from the network meta-analysis should be used. The committee noted that the company did not update its analysis to include this committee preference at consultation. At its first meeting, the committee also considered that the network meta-analysis results estimated directly from the CDP‑6M trial data should be used in the model when possible (see section\xa03.6). In addition, the CDP‑6M results from the combined outcome estimated from the CDP‑3M data should only be used for treatments that did not have CDP‑6M data available. However, the company did not provide this analysis at consultation. Also, after consultation, the ERG advised that such an analysis cannot be done because the hazard ratios have been generated using different network meta-analysis models that are based on different input data. Therefore, the committee accepted that this analysis could not be done without making strong assumptions. The committee concluded that it would have preferred ozanimod's disability progression hazard ratio from the network meta-analysis to be used in the model. It also acknowledged that it would consider the company's base-case scenario, in which the interferon beta‑1a hazard ratio was used for ozanimod.\n\n## All differences in treatment effects should be modelled regardless of whether they are statistically significant\n\nIn its submission the company used the point estimates from its network meta-analysis to model the effects of treatment on disability progression. The ERG originally suggested in its report that if clinical effectiveness results were not statistically significantly different, then a difference in effect should not be modelled. However, before the first committee meeting the ERG clarified its position that the company should use available point estimates from the network meta-analysis. Non-statistically significant results should be explored in probabilistic and scenario analysis. After consultation, the company highlighted the ERG's original position. It suggested that ozanimod should be assumed to be of the same or similar efficacy to its chosen oral comparators because there were no statistically significant differences in the network meta-analysis. The ERG clarified that it had changed its view. It now considered that overlapping or wide confidence intervals were insufficient to conclude that there is no difference in effectiveness between treatments. The ERG also reiterated that it would be inappropriate to assume there are no differences between ozanimod and the comparators. This is because, in some cases, the confidence intervals barely cross\xa01 and the point estimates are markedly different. In addition, ozanimod has a different mechanism of action to the relevant first-line comparator treatments. The committee considered it would be inappropriate to only model statistically significant differences. Also, the point estimates from the network meta-analysis should be used in the base case as is standard practice in health economic modelling. The committee concluded that all differences in treatment effects should be modelled regardless of whether they were statistically significant.\n\n## Both the company and ERG's approaches to modelling treatment discontinuation have limitations\n\nThe company's cost–utility model did not allow people to switch between treatments, so they were assumed to only have 1\xa0disease-modifying treatment. The company took rates of discontinuation for each treatment from its network meta-analysis and assumed that each rate was the same over the entire model time horizon. In addition, people stopped treatment if they reached EDSS state\xa07 or above, developed secondary progressive multiple sclerosis or died. The ERG preferred a different approach. Its clinical advisers suggested that if no switching of treatments was allowed (as was the case in the model), people would only stop treatment if they were no longer benefitting, even if they still had relapses. Based on this, the ERG used trial treatment discontinuation rates when possible, then assumed everyone stayed on treatment until they reached EDSS state\xa07 or above, developed secondary progressive multiple sclerosis or died. The clinical experts explained that it was difficult to determine whether the company or ERG's approach better represented NHS practice because people usually switch between several disease-modifying treatments over their lifetime. So, neither approach wholly reflected what would happen in practice. The committee considered the lack of treatment switching to be a limitation of the company's model (see section\xa03.7). It concluded that both the company and ERG's approaches to modelling treatment discontinuation had limitations.\n\n# Cost-effectiveness estimates\n\n## The most likely cost-effectiveness estimates are higher than what NICE normally considers an acceptable use of NHS resources\n\nFor the cost-effectiveness estimates of ozanimod compared with other first-line relapsing–remitting multiple sclerosis treatments, neither the company nor the ERG's analyses reflected the committee's preferred assumptions. The committee would have preferred to see a cost–utility analysis that:\n\ncompared ozanimod with all relevant first-line treatments, rather than limiting the comparators to the oral treatments\n\nused ozanimod's CDP‑6M hazard ratio from the network meta-analysis, rather than setting ozanimod as equivalent to interferon beta‑1a\n\nused the trials' CDP‑6M hazard ratios when possible, and only used the combined CDP‑6M hazard ratios for treatments that did not have CDP‑6M data available (glatiramer acetate 40\xa0mg [if available; see section\xa03.6], interferon beta‑1a 22\xa0micrograms and peginterferon beta‑1a)\n\nused combined CDP‑6M hazard ratios, when these are used, from a network meta-analysis that accounts for variability in the relationship between 3- and 6‑month outcomes between treatments and studies.The committee noted that the scenario that most closely resembled its preferences used ozanimod's CDP‑6M hazard ratio from the network meta-analysis. It noted that the cost-effectiveness estimates for ozanimod were higher than what NICE normally considers an acceptable use of NHS resources. It also noted that the cost-effectiveness estimates were higher than acceptable in the company's base case. In the company's base case, the CDP‑6M hazard ratio for ozanimod was set as equal to interferon beta‑1a. This made the company's base case more favourable for ozanimod than when ozanimod's own CDP‑6M hazard ratio was used. Also, including its other preferences was likely to increase the incremental cost-effectiveness ratios. Because of confidential commercial arrangements for ozanimod and comparator treatments, the cost-effectiveness results cannot be reported here.\n\n## A recommendation cannot be made for ozanimod's second-line use\n\nThe committee recalled its earlier conclusion that second-line treatments for relapsing–remitting multiple sclerosis were also considered relevant comparators (cladribine, fingolimod and ocrelizumab). It recalled that the company had not presented cost-effectiveness results for these comparisons. Therefore, the committee concluded that it could not make a recommendation for second-line use of ozanimod for treating relapsing–remitting multiple sclerosis.\n\n# Other factors\n\nThe committee concluded that ozanimod's benefits were adequately captured in the economic analysis so did not consider it innovative."}
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https://www.nice.org.uk/guidance/ta706
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Evidence-based recommendations on ozanimod (Zeposia) for treating relapsing–remitting multiple sclerosis in adults with clinical or imaging features of active disease.
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ad8b4366067f665adcc370c2b00530fe8630c16b
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nice
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Atezolizumab monotherapy for untreated advanced non-small-cell lung cancer
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Atezolizumab monotherapy for untreated advanced non-small-cell lung cancer
Evidence-based recommendations on atezolizumab (Tecentriq) for treating advanced non-small-cell lung cancer in adults.
# Recommendations
Atezolizumab is recommended, within its marketing authorisation, as an option for untreated metastatic non-small-cell lung cancer (NSCLC) in adults if:
their tumours have PD-L1 expression on at least 50% of tumour cells or 10% of tumour-infiltrating immune cells
their tumours do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations and
the company provides atezolizumab according to the commercial arrangement.
Why the committee made these recommendations
Standard care for untreated metastatic NSCLC tumours with no EGFR or ALK mutations depends on PD-L1 status. If tumours are PD-L1 positive with a score of at least 50%, pembrolizumab monotherapy is offered as standard. Pembrolizumab in combination with chemotherapy may also be offered.
Results from an indirect comparison suggest that atezolizumab is as effective as pembrolizumab in delaying disease progression and in extending life. However, this is uncertain because there is no direct evidence comparing them. Despite the uncertainty in the indirect comparison, the most likely cost-effectiveness estimates for atezolizumab are within what NICE considers an acceptable use of NHS resources. So atezolizumab is recommended.# Information about atezolizumab
# Marketing authorisation indication
Atezolizumab (Tecentriq, Roche) has a marketing authorisation for the 'first-line treatment of adult patients with metastatic non-small-cell lung cancer (NSCLC) whose tumours have a PD-L1 expression ≥ 50% tumour cells (TC) or at least 10% tumour-infiltrating immune cells (IC) and who do not have EGFR mutant or ALK-positive NSCLC'.
# Dosage in the marketing authorisation
The dosage schedule will be available in the summary of product characteristics.
# Price
The list price of atezolizumab is £3,807.69 per 20-ml vial (for the 1,200 mg dose; excluding VAT; BNF online accessed March 2021).The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
it is appropriate for the recommendations to cover both the immune cell 3 (IC3) and tumour cell 3 (TC3) subpopulations
GP and occupational therapist annual home visits were overestimated in the original company submission and should be reduced to align with clinical expert opinion
the company approaches to pembrolizumab time on treatment submitted after technical engagement and using KEYNOTE-042 extrapolations are plausible and suitable for decision making.
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see executive summary of ERG report tables 3, 4 and 5), and took these into account in its decision making. It discussed the following issues (issues 2, 3 and 4), which were outstanding after the technical engagement stage.
# Clinical management
## A new treatment option would benefit people with untreated high PD-L1-expression metastatic non-small-cell lung cancer
People with untreated metastatic non-small-cell lung cancer (NSCLC) whose tumours have high (50% or more) PD-L1 expression and no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations have limited treatment options. Although survival is improving for people with metastatic NSCLC, pembrolizumab is the only immunotherapy medicine available in this indication and so there is still unmet need. Clinical expert input suggested atezolizumab is very similar to pembrolizumab, with no robust differences in toxicity or efficacy. It was also recognised that unlike pembrolizumab, atezolizumab is not subject to a stopping rule and that this could be valuable to people with untreated high PD-L1-expression metastatic NSCLC. The committee concluded that atezolizumab is an important treatment option for people with this condition.
## The main comparator is pembrolizumab monotherapy
The clinical expert explained that most people with untreated high PD-L1-expression metastatic NSCLC have pembrolizumab monotherapy (NICE technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC). A vastly smaller proportion of people had pembrolizumab combination therapy (pembrolizumab with pemetrexed and platinum chemotherapy; NICE technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous NSCLC). The Cancer Drugs Fund clinical lead indicated that real-world evidence from the NHS supported the clinical expert's opinion that pembrolizumab monotherapy is strongly preferred to combination therapy in this population, with the latter typically being reserved for clinical circumstances where a rapid response is needed. Pembrolizumab with carboplatin and paclitaxel is also available for people with squamous NSCLC as part of the Cancer Drugs Fund (NICE technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous NSCLC). However, in line with NICE's position statement on the consideration of products recommended for use in the Cancer Drugs Fund as comparators, pembrolizumab with carboplatin and paclitaxel is not considered to be a comparator in this appraisal. The committee concluded that pembrolizumab monotherapy is the main comparator for atezolizumab.
# Clinical effectiveness
## Only TC3 and IC3 subpopulations of the IMpower110 trial are within scope of this appraisal
The clinical-effectiveness evidence for atezolizumab came from IMpower110. This was an open-label phase 3 randomised controlled trial, comparing atezolizumab with chemotherapy. At screening, people eligible for the study were tested for PD-L1 expression using the SP142 immunohistochemistry assay. Only people whose tumours were PD-L1 positive were enrolled. Tumours were considered PD-L1 positive if they had at least 1% of PD-L1-expressing tumour cells or at least 1% of the tumour area occupied by PD-L1-expressing immune cells. High PD-L1 expression was defined within the IMPower110 study as tumours with PD-L1 expression on at least 50% of their cells (TC3 population) or PD-L1 expressing immune cells being at least 10% of the tumour area (IC3 population). The committee recalled that the marketing authorisation for atezolizumab and the scope of this appraisal was limited to people whose tumours have a PD-L1 expression of at least 50% tumour cells or at least 10% tumour-infiltrating immune cells. Because of this, only data for the TC3 and IC3 subpopulations were considered relevant for this appraisal.
## An indirect comparison is appropriate because there are no head-to-head trials with pembrolizumab
The IMpower110 study demonstrated that atezolizumab improves overall survival (20.2 months compared with 13.1 months) and progression-free survival (8.1 months compared with 5.0 months) compared with chemotherapy. However, there is no evidence directly comparing atezolizumab with pembrolizumab. Therefore, the company did an indirect treatment comparison in the form of a network meta-analysis. This included data from IMpower110 (see section 3.3) and 2 studies comparing pembrolizumab with chemotherapy (KEYNOTE-024 and KEYNOTE-042). Because of an assumption that non-proportional hazards may apply, a fractional polynomial model was also applied using overall survival and progression-free survival data from an exploratory analysis from IMpower110 with longer follow-up duration. This allowed for time-varying hazard ratios to be generated from the network meta-analysis. The committee considered this approach to be acceptable for use in decision making.
## Results from the network meta-analysis show no significant differences between atezolizumab and pembrolizumab
The indirect comparisons from both the standard and the fractional polynomial network meta-analyses imply no significant differences between atezolizumab and pembrolizumab for overall survival, progression-free survival, duration of response and overall-response rate. Results from an exploratory analysis demonstrate a trend in relative hazards moving in favour of pembrolizumab over time (results are considered confidential by the company and cannot be reported here). The trend continues beyond 2 years but with widening credible limits and small sample sizes. In its response to technical engagement, the company explained that these trends are likely to be a result of bias. The company noted that the larger pembrolizumab trial only has follow-up data in line with the earlier IMpower110 data cut. Analyses done during technical engagement demonstrated that using the smaller pembrolizumab study that has longer duration of follow up, within the network meta-analyses improves the hazard ratios slightly for atezolizumab. It was also noted that longer follow-up periods of the IMpower110 study show plateauing in the chemotherapy arm, resulting in hazard ratios for atezolizumab becoming less favourable. It was considered that this is likely because of more people switching from chemotherapy to subsequent lines of cancer therapies. The company explained that these points indicate that differences in follow-up durations between pembrolizumab and atezolizumab studies lead to results being biased in favour of pembrolizumab. The ERG agreed that the points raised by the company may have biased results in favour of pembrolizumab and considered the company base case to reflect the most conservative approach to the analyses. The committee recalled that the clinical expert had considered both products to be comparable. Overall, the committee agreed with the ERG and concluded that the results from the network meta-analysis suggested no significant differences between atezolizumab and pembrolizumab.
## Atezolizumab potentially dominates pembrolizumab in scenario analyses using the 22C3 selected high PD-L1-expression population
People were selected for inclusion in the IMpower110 study using the SP142 assay to measure PD-L1 expression (section 3.3). However, the most frequently used immunohistochemistry assay to assess PD-L1 status in NHS clinical practice is the 22C3 assay, which measures PD-L1 expression based on tumour proportion scores. People included within the pembrolizumab KEYNOTE trials were selected using the 22C3 assay to identify those with tumour proportion scores of at least 50%. The ERG noted that network meta-analyses should be done using populations that are comparable across studies. Because of this, it had concerns about how the different use of assays between the IMpower110 and KEYNOTE studies may impact the network meta-analyses estimates. During the IMpower110 study, the company had done additional analyses of subgroups defined by the 22C3 assay to assess assay comparability. In response to technical engagement, the company submitted a sensitivity analysis using the 22C3 subgroup with a tumour proportion score of at least 50%. The additional analysis showed an improved hazard ratio for atezolizumab compared with the company base case (exact results are considered academic in confidence by the company and cannot be reported here). It was also demonstrated that overall-survival results at the 12- and 24-month landmarks were comparable using the 22C3 or SP142 assays. The company developed several cost-effectiveness scenarios based on the 22C3 assay results. In each of these, atezolizumab was associated with greater quality-adjusted life year (QALY) gains than pembrolizumab. The ERG noted that the 22C3 subgroup represented a double selected population because people had first been selected by the SP142 assay (for inclusion in the IMpower110 trial). This could have biased the 22C3 subgroup analyses in favour of atezolizumab. It was recognised that the data uncertainties could not be fully resolved without long-term comparative data on people selected on the same assay. However, the company was considered to have provided a fair account of the available data. In addition, the clinical expert had indicated that there was overlap between the available assays and NHS England had confirmed that with the approval of atezolizumab, there would be no need for changes in their use in clinical practice. Overall, the committee concluded that the 22C3 scenario analysis demonstrating that atezolizumab potentially dominates pembrolizumab provides further indication that the company may have taken a conservative approach in its base case.
## The duration of treatment effect is uncertain, so various scenarios should be considered
The company base case applied a treatment stopping rule for pembrolizumab at 2 years (in line with the NICE technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC) and assumed that this leads to loss of efficacy relative to chemotherapy 3 years after stopping treatment. For atezolizumab, no stopping rule was relevant, and no loss of efficacy was assumed over the time horizon of the model (that is, a lifetime treatment effect was assumed). The ERG considered the loss of effect for pembrolizumab to be pessimistic. It noted that 5-year data from the KEYNOTE-024 study reported a hazard ratio of 0.62 for pembrolizumab compared with chemotherapy. However, the ERG was also aware that these data included people who had pembrolizumab again after stopping treatment at 2 years. Clinical experts and NHS England confirmed that this would not be allowed within NHS clinical practice and therefore the applicability of the results is questionable. In response to technical engagement, the company submitted further details on its base-case assumptions. For the pembrolizumab assumptions, the company suggested that previous cancer technology appraisals demonstrate a precedent for use of a 5‑year duration of treatment effect (from treatment initiation) with a 2‑year stopping rule. The ERG considered it appropriate to only review previous NSCLC appraisals and found that various durations of treatment effects (including 3-, 5- and 10‑year effects) have been explored in previous NSCLC appraisals. The ERG base case maintained a lifetime duration of treatment effect for atezolizumab and a 5‑year treatment cap for pembrolizumab, consistent with the company base case. However, given the lack of certainty around the duration of treatment effect for pembrolizumab and atezolizumab, the ERG also developed a range of scenarios to demonstrate the impact of alternative durations of treatment effects. The committee noted that previous pembrolizumab appraisals within NSCLC considered treatment effect durations of 3 years and 5 years, and that there would need to be strong justification for longer durations of treatment effect for pembrolizumab. Regarding atezolizumab, it was acknowledged that the issue could not be fully resolved in the absence of long-term follow-up data. However, because of the lack of a stopping rule, atezolizumab could potentially be expected to have a longer treatment effect duration than pembrolizumab, although the extent of this is uncertain. Because of this, the committee agreed it would consider various duration of treatment effect scenario analyses done by the ERG for atezolizumab during its decision making.
# Cost effectiveness
## The company's model structure is suitable for decision making
The company used a partition survival model with 3 mutually exclusive health states: progression-free survival, progressed disease and death. The company explained that the health states reflect the 2 key objectives of treatment for NSCLC: delaying disease progression and prolonging life. In addition, the company noted that this structure directly corresponded with the key endpoints of the IMpower110 study (overall survival and progression-free survival) and therefore allowed full use of the available data. The committee agreed that the model structure is suitable for decision making.
## The company and ERG base cases show atezolizumab is cost saving compared with pembrolizumab
The committee considered both the company's cost-effectiveness and cost-comparison results. Using the confidential discount for atezolizumab and the list price for pembrolizumab, the cost-comparison results showed atezolizumab was associated with an overall lower cost of treatment than pembrolizumab. The company's cost-effectiveness base case estimated atezolizumab was associated with a small loss in QALYs compared with pembrolizumab. It was noted that in situations in which an incremental cost-effectiveness ratio (ICER) is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The company's base-case, cost-effectiveness analysis demonstrated atezolizumab was associated with cost savings per QALY lost. The ERG replicated the company analyses using the confidential discount for pembrolizumab and found that atezolizumab remained cost saving (exact ICERs are confidential and cannot be reported here). The ERG's base case and duration of treatment effect scenarios were also considered. This included consideration of atezolizumab duration of treatment effect capped at 5, 6, 7 and 8 years with treatment stopped from point of efficacy loss. Atezolizumab remained associated with cost savings per QALY lost in the ERG's base case and relevant scenarios described above. Overall, the committee concluded that atezolizumab was a cost-saving treatment option compared with pembrolizumab.
## Considering incremental net health-benefit analyses to compare atezolizumab and pembrolizumab is appropriate for decision making
The company also provided cost-effectiveness results in a net health-benefit framework. The incremental net health benefit of atezolizumab was compared with pembrolizumab at threshold values of £20,000 and £30,000 per QALY gained using the confidential discount for atezolizumab and the list price for pembrolizumab. This resulted in positive incremental net health benefit, indicating that the overall population health is likely to be increased with the availability of atezolizumab. The ERG considered the net health-benefit analyses had been done correctly. It repeated the analyses and included the confidential discount for pembrolizumab. Net health-benefit results were found to remain positive at both the thresholds of £20,000 and £30,000 per QALY gained for the:
company base case
ERG base case
ERG scenarios for atezolizumab treatment effect duration capped at 5, 6, 7 and 8 years with treatment stopped from point of efficacy loss. This confirmed that atezolizumab is cost effective compared with pembrolizumab at the range NICE considers an acceptable use of NHS resources. Given that any differences in QALYs between atezolizumab and pembrolizumab are small, the committee concluded that net health benefit was a useful supplementary analysis to inform cost effectiveness of atezolizumab compared with pembrolizumab.
# Other factors
No equality or social value judgement issues were identified.
# Conclusion
## Atezolizumab is recommended for routine use in the NHS
Evidence suggests that there is no statistically significant difference in the clinical effectiveness of atezolizumab and pembrolizumab. In addition, it was considered that the company may have taken a conservative approach in modelling its cost-effectiveness base case. Each of the plausible analyses resulted in ICERs showing that atezolizumab was associated with cost savings per QALY lost in the range normally considered a cost-effective use of NHS resources. In addition, all plausible net health-benefit results were positive, indicating that the overall population health is likely to be increased with the availability of atezolizumab. Overall, the committee agreed that the likelihood of atezolizumab being cost effective was high. So, it recommended atezolizumab for people with untreated high PD-L1-expression metastatic NSCLC.
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{'Recommendations': 'Atezolizumab is recommended, within its marketing authorisation, as an option for untreated metastatic non-small-cell lung cancer (NSCLC) in adults if:\n\ntheir tumours have PD-L1 expression on at least 50% of tumour cells or 10% of tumour-infiltrating immune cells\n\ntheir tumours do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations and\n\nthe company provides atezolizumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nStandard care for untreated metastatic NSCLC tumours with no EGFR or ALK mutations depends on PD-L1 status. If tumours are PD-L1 positive with a score of at least 50%, pembrolizumab monotherapy is offered as standard. Pembrolizumab in combination with chemotherapy may also be offered.\n\nResults from an indirect comparison suggest that atezolizumab is as effective as pembrolizumab in delaying disease progression and in extending life. However, this is uncertain because there is no direct evidence comparing them. Despite the uncertainty in the indirect comparison, the most likely cost-effectiveness estimates for atezolizumab are within what NICE considers an acceptable use of NHS resources. So atezolizumab is recommended.', 'Information about atezolizumab': "# Marketing authorisation indication\n\nAtezolizumab (Tecentriq, Roche) has a marketing authorisation for the 'first-line treatment of adult patients with metastatic non-small-cell lung cancer (NSCLC) whose tumours have a PD-L1 expression ≥ 50% tumour cells (TC) or at least 10% tumour-infiltrating immune cells (IC) and who do not have EGFR mutant or ALK-positive NSCLC'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule will be available in the summary of product characteristics.\n\n# Price\n\nThe list price of atezolizumab is £3,807.69 per 20-ml vial (for the 1,200\xa0mg dose; excluding VAT; BNF online accessed March 2021).The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nit is appropriate for the recommendations to cover both the immune cell 3 (IC3) and tumour cell 3 (TC3) subpopulations\n\nGP and occupational therapist annual home visits were overestimated in the original company submission and should be reduced to align with clinical expert opinion\n\nthe company approaches to pembrolizumab time on treatment submitted after technical engagement and using KEYNOTE-042 extrapolations are plausible and suitable for decision making.\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see executive summary of ERG report tables 3, 4 and 5), and took these into account in its decision making. It discussed the following issues (issues 2, 3 and 4), which were outstanding after the technical engagement stage.\n\n# Clinical management\n\n## A new treatment option would benefit people with untreated high PD-L1-expression metastatic non-small-cell lung cancer\n\nPeople with untreated metastatic non-small-cell lung cancer (NSCLC) whose tumours have high (50% or more) PD-L1 expression and no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations have limited treatment options. Although survival is improving for people with metastatic NSCLC, pembrolizumab is the only immunotherapy medicine available in this indication and so there is still unmet need. Clinical expert input suggested atezolizumab is very similar to pembrolizumab, with no robust differences in toxicity or efficacy. It was also recognised that unlike pembrolizumab, atezolizumab is not subject to a stopping rule and that this could be valuable to people with untreated high PD-L1-expression metastatic NSCLC. The committee concluded that atezolizumab is an important treatment option for people with this condition.\n\n## The main comparator is pembrolizumab monotherapy\n\nThe clinical expert explained that most people with untreated high PD-L1-expression metastatic NSCLC have pembrolizumab monotherapy (NICE technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC). A vastly smaller proportion of people had pembrolizumab combination therapy (pembrolizumab with pemetrexed and platinum chemotherapy; NICE technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous NSCLC). The Cancer Drugs Fund clinical lead indicated that real-world evidence from the NHS supported the clinical expert's opinion that pembrolizumab monotherapy is strongly preferred to combination therapy in this population, with the latter typically being reserved for clinical circumstances where a rapid response is needed. Pembrolizumab with carboplatin and paclitaxel is also available for people with squamous NSCLC as part of the Cancer Drugs Fund (NICE technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous NSCLC). However, in line with NICE's position statement on the consideration of products recommended for use in the Cancer Drugs Fund as comparators, pembrolizumab with carboplatin and paclitaxel is not considered to be a comparator in this appraisal. The committee concluded that pembrolizumab monotherapy is the main comparator for atezolizumab.\n\n# Clinical effectiveness\n\n## Only TC3 and IC3 subpopulations of the IMpower110 trial are within scope of this appraisal\n\nThe clinical-effectiveness evidence for atezolizumab came from IMpower110. This was an open-label phase\xa03 randomised controlled trial, comparing atezolizumab with chemotherapy. At screening, people eligible for the study were tested for PD-L1 expression using the SP142 immunohistochemistry assay. Only people whose tumours were PD-L1 positive were enrolled. Tumours were considered PD-L1 positive if they had at least 1% of PD-L1-expressing tumour cells or at least 1% of the tumour area occupied by PD-L1-expressing immune cells. High PD-L1 expression was defined within the IMPower110 study as tumours with PD-L1 expression on at least 50% of their cells (TC3 population) or PD-L1 expressing immune cells being at least 10% of the tumour area (IC3 population). The committee recalled that the marketing authorisation for atezolizumab and the scope of this appraisal was limited to people whose tumours have a PD-L1 expression of at least 50% tumour cells or at least 10% tumour-infiltrating immune cells. Because of this, only data for the TC3 and IC3 subpopulations were considered relevant for this appraisal.\n\n## An indirect comparison is appropriate because there are no head-to-head trials with pembrolizumab\n\nThe IMpower110 study demonstrated that atezolizumab improves overall survival (20.2\xa0months compared with 13.1\xa0months) and progression-free survival (8.1\xa0months compared with 5.0\xa0months) compared with chemotherapy. However, there is no evidence directly comparing atezolizumab with pembrolizumab. Therefore, the company did an indirect treatment comparison in the form of a network meta-analysis. This included data from IMpower110 (see section\xa03.3) and 2\xa0studies comparing pembrolizumab with chemotherapy (KEYNOTE-024 and KEYNOTE-042). Because of an assumption that non-proportional hazards may apply, a fractional polynomial model was also applied using overall survival and progression-free survival data from an exploratory analysis from IMpower110 with longer follow-up duration. This allowed for time-varying hazard ratios to be generated from the network meta-analysis. The committee considered this approach to be acceptable for use in decision making.\n\n## Results from the network meta-analysis show no significant differences between atezolizumab and pembrolizumab\n\nThe indirect comparisons from both the standard and the fractional polynomial network meta-analyses imply no significant differences between atezolizumab and pembrolizumab for overall survival, progression-free survival, duration of response and overall-response rate. Results from an exploratory analysis demonstrate a trend in relative hazards moving in favour of pembrolizumab over time (results are considered confidential by the company and cannot be reported here). The trend continues beyond 2\xa0years but with widening credible limits and small sample sizes. In its response to technical engagement, the company explained that these trends are likely to be a result of bias. The company noted that the larger pembrolizumab trial only has follow-up data in line with the earlier IMpower110 data cut. Analyses done during technical engagement demonstrated that using the smaller pembrolizumab study that has longer duration of follow up, within the network meta-analyses improves the hazard ratios slightly for atezolizumab. It was also noted that longer follow-up periods of the IMpower110 study show plateauing in the chemotherapy arm, resulting in hazard ratios for atezolizumab becoming less favourable. It was considered that this is likely because of more people switching from chemotherapy to subsequent lines of cancer therapies. The company explained that these points indicate that differences in follow-up durations between pembrolizumab and atezolizumab studies lead to results being biased in favour of pembrolizumab. The ERG agreed that the points raised by the company may have biased results in favour of pembrolizumab and considered the company base case to reflect the most conservative approach to the analyses. The committee recalled that the clinical expert had considered both products to be comparable. Overall, the committee agreed with the ERG and concluded that the results from the network meta-analysis suggested no significant differences between atezolizumab and pembrolizumab.\n\n## Atezolizumab potentially dominates pembrolizumab in scenario analyses using the 22C3 selected high PD-L1-expression population\n\nPeople were selected for inclusion in the IMpower110 study using the SP142 assay to measure PD-L1 expression (section\xa03.3). However, the most frequently used immunohistochemistry assay to assess PD-L1 status in NHS clinical practice is the 22C3 assay, which measures PD-L1 expression based on tumour proportion scores. People included within the pembrolizumab KEYNOTE trials were selected using the 22C3 assay to identify those with tumour proportion scores of at least 50%. The ERG noted that network meta-analyses should be done using populations that are comparable across studies. Because of this, it had concerns about how the different use of assays between the IMpower110 and KEYNOTE studies may impact the network meta-analyses estimates. During the IMpower110 study, the company had done additional analyses of subgroups defined by the 22C3 assay to assess assay comparability. In response to technical engagement, the company submitted a sensitivity analysis using the 22C3 subgroup with a tumour proportion score of at least 50%. The additional analysis showed an improved hazard ratio for atezolizumab compared with the company base case (exact results are considered academic in confidence by the company and cannot be reported here). It was also demonstrated that overall-survival results at the 12- and 24-month landmarks were comparable using the 22C3 or SP142 assays. The company developed several cost-effectiveness scenarios based on the 22C3 assay results. In each of these, atezolizumab was associated with greater quality-adjusted life year (QALY) gains than pembrolizumab. The ERG noted that the 22C3 subgroup represented a double selected population because people had first been selected by the SP142 assay (for inclusion in the IMpower110 trial). This could have biased the 22C3 subgroup analyses in favour of atezolizumab. It was recognised that the data uncertainties could not be fully resolved without long-term comparative data on people selected on the same assay. However, the company was considered to have provided a fair account of the available data. In addition, the clinical expert had indicated that there was overlap between the available assays and NHS England had confirmed that with the approval of atezolizumab, there would be no need for changes in their use in clinical practice. Overall, the committee concluded that the 22C3 scenario analysis demonstrating that atezolizumab potentially dominates pembrolizumab provides further indication that the company may have taken a conservative approach in its base case.\n\n## The duration of treatment effect is uncertain, so various scenarios should be considered\n\nThe company base case applied a treatment stopping rule for pembrolizumab at 2\xa0years (in line with the NICE technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC) and assumed that this leads to loss of efficacy relative to chemotherapy 3 years after stopping treatment. For atezolizumab, no stopping rule was relevant, and no loss of efficacy was assumed over the time horizon of the model (that is, a lifetime treatment effect was assumed). The ERG considered the loss of effect for pembrolizumab to be pessimistic. It noted that 5-year data from the KEYNOTE-024 study reported a hazard ratio of 0.62 for pembrolizumab compared with chemotherapy. However, the ERG was also aware that these data included people who had pembrolizumab again after stopping treatment at 2\xa0years. Clinical experts and NHS England confirmed that this would not be allowed within NHS clinical practice and therefore the applicability of the results is questionable. In response to technical engagement, the company submitted further details on its base-case assumptions. For the pembrolizumab assumptions, the company suggested that previous cancer technology appraisals demonstrate a precedent for use of a 5‑year duration of treatment effect (from treatment initiation) with a 2‑year stopping rule. The ERG considered it appropriate to only review previous NSCLC appraisals and found that various durations of treatment effects (including 3-, 5- and 10‑year effects) have been explored in previous NSCLC appraisals. The ERG base case maintained a lifetime duration of treatment effect for atezolizumab and a 5‑year treatment cap for pembrolizumab, consistent with the company base case. However, given the lack of certainty around the duration of treatment effect for pembrolizumab and atezolizumab, the ERG also developed a range of scenarios to demonstrate the impact of alternative durations of treatment effects. The committee noted that previous pembrolizumab appraisals within NSCLC considered treatment effect durations of 3\xa0years and 5\xa0years, and that there would need to be strong justification for longer durations of treatment effect for pembrolizumab. Regarding atezolizumab, it was acknowledged that the issue could not be fully resolved in the absence of long-term follow-up data. However, because of the lack of a stopping rule, atezolizumab could potentially be expected to have a longer treatment effect duration than pembrolizumab, although the extent of this is uncertain. Because of this, the committee agreed it would consider various duration of treatment effect scenario analyses done by the ERG for atezolizumab during its decision making.\n\n# Cost effectiveness\n\n## The company's model structure is suitable for decision making\n\nThe company used a partition survival model with 3\xa0mutually exclusive health states: progression-free survival, progressed disease and death. The company explained that the health states reflect the 2\xa0key objectives of treatment for NSCLC: delaying disease progression and prolonging life. In addition, the company noted that this structure directly corresponded with the key endpoints of the IMpower110 study (overall survival and progression-free survival) and therefore allowed full use of the available data. The committee agreed that the model structure is suitable for decision making.\n\n## The company and ERG base cases show atezolizumab is cost saving compared with pembrolizumab\n\nThe committee considered both the company's cost-effectiveness and cost-comparison results. Using the confidential discount for atezolizumab and the list price for pembrolizumab, the cost-comparison results showed atezolizumab was associated with an overall lower cost of treatment than pembrolizumab. The company's cost-effectiveness base case estimated atezolizumab was associated with a small loss in QALYs compared with pembrolizumab. It was noted that in situations in which an incremental cost-effectiveness ratio (ICER) is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The company's base-case, cost-effectiveness analysis demonstrated atezolizumab was associated with cost savings per QALY lost. The ERG replicated the company analyses using the confidential discount for pembrolizumab and found that atezolizumab remained cost saving (exact ICERs are confidential and cannot be reported here). The ERG's base case and duration of treatment effect scenarios were also considered. This included consideration of atezolizumab duration of treatment effect capped at 5, 6, 7 and 8\xa0years with treatment stopped from point of efficacy loss. Atezolizumab remained associated with cost savings per QALY lost in the ERG's base case and relevant scenarios described above. Overall, the committee concluded that atezolizumab was a cost-saving treatment option compared with pembrolizumab.\n\n## Considering incremental net health-benefit analyses to compare atezolizumab and pembrolizumab is appropriate for decision making\n\nThe company also provided cost-effectiveness results in a net health-benefit framework. The incremental net health benefit of atezolizumab was compared with pembrolizumab at threshold values of £20,000 and £30,000 per QALY gained using the confidential discount for atezolizumab and the list price for pembrolizumab. This resulted in positive incremental net health benefit, indicating that the overall population health is likely to be increased with the availability of atezolizumab. The ERG considered the net health-benefit analyses had been done correctly. It repeated the analyses and included the confidential discount for pembrolizumab. Net health-benefit results were found to remain positive at both the thresholds of £20,000 and £30,000 per QALY gained for the:\n\ncompany base case\n\nERG base case\n\nERG scenarios for atezolizumab treatment effect duration capped at 5, 6, 7 and 8\xa0years with treatment stopped from point of efficacy loss. This confirmed that atezolizumab is cost effective compared with pembrolizumab at the range NICE considers an acceptable use of NHS resources. Given that any differences in QALYs between atezolizumab and pembrolizumab are small, the committee concluded that net health benefit was a useful supplementary analysis to inform cost effectiveness of atezolizumab compared with pembrolizumab.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Atezolizumab is recommended for routine use in the NHS\n\nEvidence suggests that there is no statistically significant difference in the clinical effectiveness of atezolizumab and pembrolizumab. In addition, it was considered that the company may have taken a conservative approach in modelling its cost-effectiveness base case. Each of the plausible analyses resulted in ICERs showing that atezolizumab was associated with cost savings per QALY lost in the range normally considered a cost-effective use of NHS resources. In addition, all plausible net health-benefit results were positive, indicating that the overall population health is likely to be increased with the availability of atezolizumab. Overall, the committee agreed that the likelihood of atezolizumab being cost effective was high. So, it recommended atezolizumab for people with untreated high PD-L1-expression metastatic NSCLC."}
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https://www.nice.org.uk/guidance/ta705
|
Evidence-based recommendations on atezolizumab (Tecentriq) for treating advanced non-small-cell lung cancer in adults.
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a395ea8ac7d03971edb1f35ec62d9feecfdda0d1
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nice
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Ex-situ machine perfusion for extracorporeal preservation of lungs (ex-vivo lung perfusion) for transplant
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Ex-situ machine perfusion for extracorporeal preservation of lungs (ex-vivo lung perfusion) for transplant
Evidence-based recommendations on ex-situ machine perfusion for extracorporeal preservation of lungs for transplant. This involves using a machine to deliver an oxygenated solution to a donor lung and keep it at normal body temperature until it can be transplanted.
# Recommendations
Evidence on the safety and efficacy of ex-situ machine perfusion for extracorporeal preservation of lungs for transplant is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Clinicians and centres doing this procedure must follow the relevant regulatory and legal requirements of the Human Tissue Authority.
Clinicians should enter details about all patients having this procedure and details about the device used into the NHS blood and transplant organ donation and transplantation registry.# The condition, current treatments and procedure
# The condition
Lung transplant is usually done in patients with non-malignant advanced or end-stage pulmonary diseases (such as severe pulmonary fibrosis, cystic fibrosis, pulmonary hypertension and obliterative bronchiolitis) that is minimally responsive or unresponsive to treatment and who have a life expectancy of less than a year. This improves patients' quality of life and prolongs survival.
On average, 20% of potential deceased donor lungs in the UK are used for transplant. The rest are considered unsuitable, usually because of complications associated with attempts to save the donor or injury which happens in association with death. Limited availability of deceased donor lungs that meet standard criteria for transplant results in up to 30% of patients clinically deteriorating and dying while waiting for a lung transplant.
# Current treatments
Standard lung transplant protocol involves cold preservation to maintain the donor lungs. Various other strategies are used to increase the available pool of deceased donor lungs and these include brain death donor lungs from extended criteria donors and donors after circulatory death. Living donor lobal or lung transplant is another option.
# The procedure
Ex-situ machine perfusion for extracorporeal preservation of lungs (ex-vivo lung perfusion, EVLP) is a technique of lung preservation that may allow donor lungs to be preserved for longer in better physiologic conditions, and may allow marginal donor lungs or pulmonary grafts which are working poorly to be improved and reconditioned so that they can be used in lung transplant.
Ex-situ machine perfusion for extracorporeal preservation of lungs is done once the lungs have been removed from the donor after cold pulmonary flush using surgical techniques. An adequate donor left atrial cuff and pulmonary artery are preserved to allow anastomosis to the recipients' organs.
After being transferred in cold solution and being ischemic for a period of time, the lungs are placed in a specially designed organ chamber and connected to a modified heart–lung bypass machine, a ventilator and filtration or EVLP system. A specialised nutrient solution (perfusate) is pumped from the filtration or EVLP system through a perfusion circuit (gas exchange membrane, heat exchanger and leukocyte filter) under optimal colloid pressure through the pulmonary artery to the lungs. Pulmonary effluent from the pulmonary veins drains back to the EVLP system and is recirculated. Perfusion flow is then gradually increased, pulmonary artery pressure is carefully monitored, and protective controlled mechanical lung ventilation with low tidal volume and positive end expiratory pressure is started. The lungs are gradually rewarmed to body temperature while reaching a targeted flow. EVLP is possible for a number of hours after removal from the donor. During this period, the lungs can be assessed and, if necessary, treated to remove unwanted fluid, and to re‑expand areas of lung that have collapsed (atelectatic areas). If EVLP-treated lungs recover well enough, they may be considered suitable for transplant in the conventional way.
Ex-situ machine perfusion can be done using different devices or machines and protocols. The perfusate composition, perfusion and ventilation settings (target flow, temperature, pressure) may vary.
|
{'Recommendations': 'Evidence on the safety and efficacy of ex-situ machine perfusion for extracorporeal preservation of lungs for transplant is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians and centres doing this procedure must follow the relevant regulatory and legal requirements of the\xa0Human Tissue Authority.\n\nClinicians should enter details about all patients having this procedure and details about the device used into the\xa0NHS blood and transplant organ donation and transplantation registry.', 'The condition, current treatments and procedure': "# The condition\n\nLung transplant is usually done in patients with non-malignant advanced or end-stage pulmonary diseases (such as severe pulmonary fibrosis, cystic fibrosis, pulmonary hypertension and obliterative bronchiolitis) that is minimally responsive or unresponsive to treatment and who have a life expectancy of less than a year. This improves patients' quality of life and prolongs survival.\n\nOn average, 20% of potential deceased donor lungs in the UK are used for transplant. The rest are considered unsuitable, usually because of complications associated with attempts to save the donor or injury which happens in association with death. Limited availability of deceased donor lungs that meet standard criteria for transplant results in up to 30% of patients clinically deteriorating and dying while waiting for a lung transplant.\n\n# Current treatments\n\nStandard lung transplant protocol involves cold preservation to maintain the donor lungs. Various other strategies are used to increase the available pool of deceased donor lungs and these include brain death donor lungs from extended criteria donors and donors after circulatory death. Living donor lobal or lung transplant is another option.\n\n# The procedure\n\nEx-situ machine perfusion for extracorporeal preservation of lungs (ex-vivo lung perfusion, EVLP) is a technique of lung preservation that may allow donor lungs to be preserved for longer in better physiologic conditions, and may allow marginal donor lungs or pulmonary grafts which are working poorly to be improved and reconditioned so that they can be used in lung transplant.\n\nEx-situ machine perfusion for extracorporeal preservation of lungs is done once the lungs have been removed from the donor after cold pulmonary flush using surgical techniques. An adequate donor left atrial cuff and pulmonary artery are preserved to allow anastomosis to the recipients' organs.\n\nAfter being transferred in cold solution and being ischemic for a period of time, the lungs are placed in a specially designed organ chamber and connected to a modified heart–lung bypass machine, a ventilator and filtration or EVLP system. A specialised nutrient solution (perfusate) is pumped from the filtration or EVLP system through a perfusion circuit (gas exchange membrane, heat exchanger and leukocyte filter) under optimal colloid pressure through the pulmonary artery to the lungs. Pulmonary effluent from the pulmonary veins drains back to the EVLP system and is recirculated. Perfusion flow is then gradually increased, pulmonary artery pressure is carefully monitored, and protective controlled mechanical lung ventilation with low tidal volume and positive end expiratory pressure is started. The lungs are gradually rewarmed to body temperature while reaching a targeted flow. EVLP is possible for a number of hours after removal from the donor. During this period, the lungs can be assessed and, if necessary, treated to remove unwanted fluid, and to re‑expand areas of lung that have collapsed (atelectatic areas). If EVLP-treated lungs recover well enough, they may be considered suitable for transplant in the conventional way.\n\nEx-situ machine perfusion can be done using different devices or machines and protocols. The perfusate composition, perfusion and ventilation settings (target flow, temperature, pressure) may vary."}
|
https://www.nice.org.uk/guidance/ipg695
|
Evidence-based recommendations on ex-situ machine perfusion for extracorporeal preservation of lungs for transplant. This involves using a machine to deliver an oxygenated solution to a donor lung and keep it at normal body temperature until it can be transplanted.
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69deb7f0b19b2c0694cfffb039414678cdfd3285
|
nice
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Transvaginal laser therapy for stress urinary incontinence
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Transvaginal laser therapy for stress urinary incontinence
Evidence-based recommendations on transvaginal laser therapy for urinary stress incontinence. This involves using a laser in the vagina to strengthen the vaginal walls, to help support the bladder and reduce symptoms of urinary stress incontinence.
# Recommendations
The evidence on transvaginal laser therapy for stress urinary incontinence does not show any short-term safety concerns. Evidence on long-term safety and efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should report long-term safety and efficacy outcomes, the type of laser and energy used, treatment protocols, and patient selection including age, menopausal status and severity of stress urinary incontinence.
NICE encourages further research into transvaginal laser therapy for stress urinary incontinence and may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Stress urinary incontinence is the involuntary leakage of urine during exercise or certain movements, such as coughing, sneezing and laughing. In women, it is most commonly associated with previous pregnancy, with or without recognised obstetric trauma. Previous urogynaecological surgery may also result in stress urinary incontinence.
# Current treatments
NICE's guideline on urinary incontinence and pelvic organ prolapse makes recommendations for the management of urinary incontinence in women, accompanied by a patient decision aid to promote shared decision making. Conventional treatment is conservative and includes lifestyle changes, such as weight loss and pelvic floor muscle training. Surgical options are only offered if conservative measures do not help.
# The procedure
Transvaginal laser therapy for stress urinary incontinence is done as an outpatient procedure and can be done without anaesthetic. A laser-probe device is inserted into the vagina to apply laser energy to the vaginal wall. The laser causes a controlled thermal injury, which is claimed to promote tissue remodelling and the production of new collagen. Treatment typically consists of 3 sessions at 4 to 6 weeks apart. The aim is to improve the support to the bladder and reduce the symptoms of stress urinary incontinence.
There are different types of lasers used for this procedure, including CO2 and erbium-doped yttrium aluminium garnet (Er:YAG) lasers. The type of laser and the energy level used have different tissue penetration and can cause different types of thermal injury.
|
{'Recommendations': 'The evidence on transvaginal laser therapy for stress urinary incontinence does not show any short-term safety concerns. Evidence on long-term safety and efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should report long-term safety and efficacy outcomes, the type of laser and energy used, treatment protocols, and patient selection including age, menopausal status and severity of stress urinary incontinence.\n\nNICE encourages further research into transvaginal laser therapy for stress urinary incontinence and may update the guidance on publication of further evidence.', 'The condition, current treatments and procedure': "# The condition\n\nStress urinary incontinence is the involuntary leakage of urine during exercise or certain movements, such as coughing, sneezing and laughing. In women, it is most commonly associated with previous pregnancy, with or without recognised obstetric trauma. Previous urogynaecological surgery may also result in stress urinary incontinence.\n\n# Current treatments\n\nNICE's guideline on urinary incontinence and pelvic organ prolapse makes recommendations for the management of urinary incontinence in women, accompanied by a patient decision aid to promote shared decision making. Conventional treatment is conservative and includes lifestyle changes, such as weight loss and pelvic floor muscle training. Surgical options are only offered if conservative measures do not help.\n\n# The procedure\n\nTransvaginal laser therapy for stress urinary incontinence is done as an outpatient procedure and can be done without anaesthetic. A laser-probe device is inserted into the vagina to apply laser energy to the vaginal wall. The laser causes a controlled thermal injury, which is claimed to promote tissue remodelling and the production of new collagen. Treatment typically consists of 3\xa0sessions at 4\xa0to\xa06\xa0weeks apart. The aim is to improve the support to the bladder and reduce the symptoms of stress urinary incontinence.\n\nThere are different types of lasers used for this procedure, including CO2 and erbium-doped yttrium aluminium garnet (Er:YAG) lasers. The type of laser and the energy level used have different tissue penetration and can cause different types of thermal injury."}
|
https://www.nice.org.uk/guidance/ipg696
|
Evidence-based recommendations on transvaginal laser therapy for urinary stress incontinence. This involves using a laser in the vagina to strengthen the vaginal walls, to help support the bladder and reduce symptoms of urinary stress incontinence.
|
1f75fddf7c2c3ef2e6a6207d0397d08fa6159d43
|
nice
|
Transvaginal laser therapy for urogenital atrophy
|
Transvaginal laser therapy for urogenital atrophy
Evidence-based recommendations on transvaginal laser therapy for urogenital atrophy. This involves using a laser in the vagina to increase its strength and elasticity, to improve symptoms of urogenital atrophy.
# Recommendations
The evidence on transvaginal laser therapy for urogenital atrophy does not show any short-term safety concerns. Evidence on long-term safety and efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should be appropriately powered randomised controlled trials and report details of patient selection, treatment protocols, and long-term safety and efficacy including patient-reported outcomes.
NICE encourages further research into transvaginal laser therapy for urogenital atrophy and may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Urogenital atrophy most often happens during or after the menopause. Lack of the hormone oestrogen leads to thinning of the tissues around the vaginal area and reduction in the number of mucus-producing glands. The most common symptoms affect the vulva and vagina including dryness, pain on sexual intercourse, itching and vaginal discharge. There is increased vulnerability to inflammation, trauma and infection. Urogenital atrophy can also result in urinary symptoms, such as urgency to urinate and urinary tract infections.
# Current treatments
NICE's guideline on diagnosis and management of menopause describes the management of menopausal symptoms. The main treatments for urogenital atrophy are vaginal oestrogen, and non-hormonal lubricants and moisturisers.
# The procedure
Transvaginal laser therapy for urogenital atrophy is done as an outpatient procedure and can be done without anaesthetic. A laser-probe device is inserted into the vagina to apply laser energy to the vaginal wall. The laser causes controlled thermal injury, which is claimed to make the tissue remodel, improve tissue elasticity and stimulate the production of new collagen. Treatment typically consists of 3 sessions at 4 to 6 weeks apart. The aim is to reduce the symptoms of urogenital atrophy.
There are different types of lasers used for this procedure, including CO2 and erbium-doped yttrium aluminium garnet (Er:YAG) lasers. The type of laser and the energy level used have different tissue penetration and can cause different types of thermal injury.
|
{'Recommendations': 'The evidence on transvaginal laser therapy for urogenital atrophy does not show any short-term safety concerns. Evidence on long-term safety and efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should be appropriately powered randomised controlled trials and report details of patient selection, treatment protocols, and long-term safety and efficacy including patient-reported outcomes.\n\nNICE encourages further research into transvaginal laser therapy for urogenital atrophy and may update the guidance on publication of further evidence.', 'The condition, current treatments and procedure': "# The condition\n\nUrogenital atrophy most often happens during or after the menopause. Lack of the hormone oestrogen leads to thinning of the tissues around the vaginal area and reduction in the number of mucus-producing glands. The most common symptoms affect the vulva and vagina including dryness, pain on sexual intercourse, itching and vaginal discharge. There is increased vulnerability to inflammation, trauma and infection. Urogenital atrophy can also result in urinary symptoms, such as urgency to urinate and urinary tract infections.\n\n# Current treatments\n\nNICE's guideline on diagnosis and management of menopause describes the management of menopausal symptoms. The main treatments for urogenital atrophy are vaginal oestrogen, and non-hormonal lubricants and moisturisers.\n\n# The procedure\n\nTransvaginal laser therapy for urogenital atrophy is done as an outpatient procedure and can be done without anaesthetic. A laser-probe device is inserted into the vagina to apply laser energy to the vaginal wall. The laser causes controlled thermal injury, which is claimed to make the tissue remodel, improve tissue elasticity and stimulate the production of new collagen. Treatment typically consists of 3\xa0sessions at 4\xa0to\xa06 weeks apart. The aim is to reduce the symptoms of urogenital atrophy.\n\nThere are different types of lasers used for this procedure, including CO2 and erbium-doped yttrium aluminium garnet (Er:YAG) lasers. The type of laser and the energy level used have different tissue penetration and can cause different types of thermal injury."}
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https://www.nice.org.uk/guidance/ipg697
|
Evidence-based recommendations on transvaginal laser therapy for urogenital atrophy. This involves using a laser in the vagina to increase its strength and elasticity, to improve symptoms of urogenital atrophy.
|
e821073def8fde85f0440b8bfe2e27c9656e10a6
|
nice
|
Electrohydraulic lithotripsy for difficult-to-treat bile duct stones
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Electrohydraulic lithotripsy for difficult-to-treat bile duct stones
Evidence-based recommendations on electrohydraulic lithotripsy for difficult-to-treat bile duct stones in adults. This involves breaking up the stone with soundwaves.
# Recommendations
Evidence on the efficacy of electrohydraulic lithotripsy for difficult-to-treat bile duct stones is adequate. However, evidence on its safety is limited in quantity. Therefore, it should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do electrohydraulic lithotripsy for difficult-to-treat bile duct stones should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
The procedure should only be done in specialised centres with experience of managing difficult-to-treat bile duct stones.
Patient selection should be done by a multidisciplinary team including a hepatobiliary surgeon and clinicians with expertise in endoscopic retrograde cholangiopancreatography.# The condition, current treatments and procedure
# The condition
Bile duct stones that form from cholesterol or bile pigments can block the bile ducts. Difficult-to-treat bile duct stones are defined by their diameter (above 15 mm), number, unusual shape (such as barrel-shaped), location (intrahepatic or cystic duct), stone impaction, narrowing of the bile duct distal to the stone, or the anatomy of the common bile duct (sigmoid-shaped, short distal length or acute distal angulation of less than 135 degrees).
# Current treatments
Diagnosis and management of bile duct stones is described in NICE's guideline on gallstone disease. Treatments for bile duct stones include bile duct clearance and laparoscopic cholecystectomy. Conventional stone extraction involves endoscopic retrograde cholangiopancreatography (ERCP) and a sphincterotomy, then extracting the stones from the ducts using balloon and basket catheters. For difficult-to-treat bile duct stones, treatment options include temporary stenting to allow biliary drainage if the stones cannot be removed or stone fragmentation (lithotripsy).
# The procedure
Electrohydraulic lithotripsy (EHL) aims to fragment bile duct stones that cannot be treated using conventional stone removal techniques.
This procedure is usually done using general anaesthesia and direct visualisation of the stones using an endoscope inserted into the biliary tract. An EHL probe is inserted through the endoscope and the tip of the probe is positioned near the stone. Liquid is then injected around the stone and high-voltage energy from the probe generates shock waves that break the stone into smaller pieces. The procedure is usually done with the endoscope passed orally and through the stomach into the duodenum. However, a percutaneous approach is also possible.
When the stone fragmentation is complete, the fragments are flushed out or removed by standard techniques (such as a basket or balloon catheter). The endoscope is then removed. This procedure takes longer to complete than a standard ERCP, usually about 60 minutes.
|
{'Recommendations': "Evidence on the efficacy of electrohydraulic lithotripsy for difficult-to-treat bile duct stones is adequate. However, evidence on its safety is limited in quantity. Therefore, it should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do electrohydraulic lithotripsy for difficult-to-treat bile duct stones should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThe procedure should only be done in specialised centres with experience of managing difficult-to-treat bile duct stones.\n\nPatient selection should be done by a multidisciplinary team including a hepatobiliary surgeon and clinicians with expertise in endoscopic retrograde cholangiopancreatography.", 'The condition, current treatments and procedure': "# The condition\n\nBile duct stones that form from cholesterol or bile pigments can block the bile ducts. Difficult-to-treat bile duct stones are defined by their diameter (above 15\xa0mm), number, unusual shape (such as barrel-shaped), location (intrahepatic or cystic duct), stone impaction, narrowing of the bile duct distal to the stone, or the anatomy of the common bile duct (sigmoid-shaped, short distal length or acute distal angulation of less than 135\xa0degrees).\n\n# Current treatments\n\nDiagnosis and management of bile duct stones is described in NICE's guideline on gallstone disease. Treatments for bile duct stones include bile duct clearance and laparoscopic cholecystectomy. Conventional stone extraction involves endoscopic retrograde cholangiopancreatography (ERCP) and a sphincterotomy, then extracting the stones from the ducts using balloon and basket catheters. For difficult-to-treat bile duct stones, treatment options include temporary stenting to allow biliary drainage if the stones cannot be removed or stone fragmentation (lithotripsy).\n\n# The procedure\n\nElectrohydraulic lithotripsy (EHL) aims to fragment bile duct stones that cannot be treated using conventional stone removal techniques.\n\nThis procedure is usually done using general anaesthesia and direct visualisation of the stones using an endoscope inserted into the biliary tract. An EHL probe is inserted through the endoscope and the tip of the probe is positioned near the stone. Liquid is then injected around the stone and high-voltage energy from the probe generates shock waves that break the stone into smaller pieces. The procedure is usually done with the endoscope passed orally and through the stomach into the duodenum. However, a percutaneous approach is also possible.\n\nWhen the stone fragmentation is complete, the fragments are flushed out or removed by standard techniques (such as a basket or balloon catheter). The endoscope is then removed. This procedure takes longer to complete than a standard ERCP, usually about 60\xa0minutes."}
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https://www.nice.org.uk/guidance/ipg698
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Evidence-based recommendations on electrohydraulic lithotripsy for difficult-to-treat bile duct stones in adults. This involves breaking up the stone with soundwaves.
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e5d317495336636afb47f2079e991f06f5fc29a8
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nice
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Trastuzumab deruxtecan for treating HER2-positive unresectable or metastatic breast cancer after 2 or more anti-HER2 therapies
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Trastuzumab deruxtecan for treating HER2-positive unresectable or metastatic breast cancer after 2 or more anti-HER2 therapies
Evidence-based recommendations on trastuzumab deruxtecan (Enhertu) for treating HER2-positive unresectable or metastatic breast cancer in adults after 2 or more anti-HER2 therapies.
# Recommendations
Trastuzumab deruxtecan is recommended for use within the Cancer Drugs Fund as an option for treating HER2‑positive unresectable or metastatic breast cancer in adults after 2 or more anti‑HER2 therapies. It is recommended only if the conditions in the managed access agreement are followed.
This recommendation is not intended to affect treatment with trastuzumab deruxtecan that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatment for HER2‑positive unresectable or metastatic breast cancer includes anti‑HER2 therapies. After 2 or more anti‑HER2 therapies, standard care is chemotherapy (such as capecitabine, vinorelbine or eribulin). Trastuzumab deruxtecan is an anti‑HER2 therapy that would be used after 2 or more anti‑HER2 therapies.
Clinical trial evidence is limited. There is a trial of trastuzumab deruxtecan on its own, which means it is not directly compared with any other treatments. Indirect comparisons of trastuzumab deruxtecan with chemotherapy suggest that it may increase how long before disease progresses and how long people live. However, how much longer people live is uncertain because there are differences between trials included in the indirect comparisons, and the final data from the trial of trastuzumab deruxtecan on its own is not available yet. Because of this, the estimates of cost effectiveness are very uncertain and trastuzumab deruxtecan cannot be recommended for routine use in the NHS.
Trastuzumab deruxtecan could be cost effective if further data shows that people live longer with treatment. Another ongoing trial is directly comparing trastuzumab deruxtecan with anti‑HER2 therapies plus chemotherapy. Data from the trials of trastuzumab deruxtecan and from NHS practice would help address the uncertainty about clinical effectiveness. Trastuzumab deruxtecan is therefore recommended for use in the Cancer Drugs Fund.# Information about trastuzumab deruxtecan
# Marketing authorisation indication
Trastuzumab deruxtecan (Enhertu, Daiichi-Sankyo) has a marketing authorisation as 'monotherapy for the treatment of adult patients with unresectable or metastatic HER2‑positive breast cancer who have received two or more prior anti‑HER2‑based regimens'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The company's list price is £1,455 per vial containing 100 mg powder for concentrate for solution for infusion (company's submission). The average cost of a course of treatment at list price is £117,857.55.
The company has a commercial arrangement. This makes trastuzumab deruxtecan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Daiichi-Sankyo, a review of this submission by the evidence review group (ERG) and responses from stakeholders. Ahead of technical engagement, the company submitted new data based on the latest data cut from the trial (June 2020). The evidence and results presented at the committee meeting were based on this data cut. See the committee papers for full details of the evidence.
# Clinical need and treatment pathway
## HER2-positive unresectable or metastatic breast cancer has a high disease burden
Some breast cancer cells have higher levels of a protein called HER2 on their surface, which stimulates them to grow. This is known as HER2‑positive breast cancer and around 1 in 5 unresectable or metastatic breast cancers are HER2‑positive. Patient experts explained that being diagnosed with unresectable or metastatic breast cancer is extremely difficult for people and their family and friends. It can cause considerable anxiety and fear, with the uncertainty being the hardest part for many people. These feelings can negatively affect mental health. People with unresectable or metastatic breast cancer must organise their lives around hospital appointments, which constrains their everyday activities. There is no cure for unresectable or metastatic breast cancer. Treatment aims to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. Treatment is continued for as long as it works. The committee concluded that there is a high disease burden for people with HER2‑positive unresectable or metastatic breast cancer.
## There is a need for anti-HER2 therapies after second-line treatment
Clinical experts explained that people with HER2‑positive unresectable or metastatic breast cancer that has progressed after 2 or more anti‑HER2 therapies have a high symptom burden and their disease is resistant to the previous lines of therapy. First-line treatment of HER2‑positive unresectable or metastatic breast cancer includes anti‑HER2 therapies pertuzumab with trastuzumab and docetaxel, or trastuzumab with paclitaxel (see NICE's technology appraisal guidance on pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer and trastuzumab for the treatment of advanced breast cancer). Trastuzumab emtansine is an anti‑HER2 therapy used as second-line treatment (see NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane). The committee noted that, although some trusts may offer third‑line anti‑HER2 therapy, this is not available across the NHS and cannot be considered standard care. Instead, standard care for people whose disease has progressed on or after 2 anti‑HER2 therapies is non‑targeted chemotherapy, including capecitabine, vinorelbine, or eribulin (see NICE's guideline on advanced breast cancer: diagnosis and treatment and NICE's technology appraisal guidance on eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens). Patient experts explained that chemotherapy has limited efficacy and can cause side effects that are typically more severe than with anti‑HER2 therapies. People having chemotherapy may also experience worse quality of life. Therefore, people want to avoid having chemotherapies for as long as possible. Patient experts highlighted the need for treatments that can extend survival with acceptable tolerability and quality of life. The committee concluded that that there is an unmet need for anti‑HER2 treatment after second-line treatment.
## Relevant comparators for trastuzumab deruxtecan include capecitabine, vinorelbine and eribulin
Current standard care in the NHS for people with HER2‑positive unresectable or metastatic breast cancer that has progressed after 2 or more anti‑HER2 therapies is non-targeted chemotherapy, including capecitabine, vinorelbine, or eribulin. Eribulin is recommended for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens (which may include an anthracycline or a taxane, and capecitabine; see NICE's technology appraisal guidance on eribulin). The clinical experts explained that, in practice, capecitabine or vinorelbine is mostly used as third-line treatment and eribulin is more likely to be used as fourth-line treatment. They confirmed that trastuzumab deruxtecan would replace capecitabine, vinorelbine and eribulin. The committee concluded that capecitabine, vinorelbine and eribulin are all relevant comparators for trastuzumab deruxtecan.
# Clinical evidence
## DESTINY-Breast01 is generalisable to UK clinical practice
The clinical evidence was based on DESTINY-Breast01, a single-arm trial for people with HER2‑positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. Clinical experts explained that DESTINY‑Breast01 is representative of patients in the NHS in terms of characteristics and previous treatment. The committee noted that most people in the trial had 3 or more previous therapies (median 6, range 2 to 24, excluding hormone therapy) and so had more previous treatments than people in the NHS. Clinical experts explained that in people who have had more previous treatments, disease is usually less likely to respond to the next line of treatment. Therefore, trastuzumab deruxtecan efficacy could be higher in the NHS than in the trial. This is supported by a subgroup analysis from DESTINY‑Breast01 (see section 3.5). The committee concluded that DESTINY‑Breast01 is broadly generalisable to clinical practice in the UK.
## Preliminary data for trastuzumab deruxtecan is limited but promising
The primary end point of DESTINY-Breast01 is overall response rate, while overall survival and progression-free survival are secondary endpoints. At the June 2020 data cut-off, overall response rate for trastuzumab deruxtecan was 61.4%. The preliminary median overall survival was 24.6 months (95% confidence interval 23.1 to not evaluable). Median progression-free survival was 19.4 months (95% CI 14.1 to not evaluable). The median follow up was 20.5 months. However, data was immature, with only 35% maturity for overall survival analysis, and a high amount of censoring. The clinical experts explained that although it was a single-arm trial with immature data, the observed results suggested a promising efficacy. They noted an overall response rate of 61.4% in a population who have had a lot of previous treatments, such as in DESTINY‑Breast01, which is much higher than with other available therapies. They explained that response to treatment is usually better with earlier lines of therapy and decreases with subsequent lines of therapy. The pre‑specified subgroup analysis from the DESTINY‑Breast01 trial showed that overall response rate was higher in people who only had 2 previous lines of treatment (76% ), compared with those who had 3 or more previous lines of treatment (59% ). However, this analysis was based on a small number of patients (17 people in the group who had only 2 previous lines) so it is highly uncertain. Clinical experts also explained that in DESTINY‑Breast01, only 21.7% of people had disease response to previous treatment with trastuzumab emtansine. This suggests that a high response rate to trastuzumab deruxtecan is unlikely to be because of patient selection. The clinical experts described randomised controlled trials in people with HER2‑positive metastatic breast cancer who have had at least 2 previous anti‑HER2 therapies (TH3RESA, SOPHIA, NALA, HER2CLIMB). These trials used more intensive treatments as the control arms (chemotherapy plus anti‑HER2 therapy) than chemotherapy alone. This means the efficacy of these control arms is likely to be the same as or higher than for chemotherapy alone. Median progression-free survival in the control arms was between 3.3 months and 5.6 months, and median overall survival between 15.8 months and 19.8 months. This is lower than the lower bound of the confidence interval for overall survival (23.1 months) for trastuzumab deruxtecan from DESTINY‑Breast01. The committee concluded that the preliminary data for trastuzumab deruxtecan suggests a promising efficacy but is limited for decision making.
## Trastuzumab deruxtecan is likely to improve clinical outcomes, including overall survival, but the size of effect is uncertain
Because DESTINY‑Breast01 is a single-arm trial, there is no evidence for the efficacy of trastuzumab deruxtecan directly compared with other treatments. The company therefore did unanchored matching-adjusted indirect comparisons (MAIC) of trastuzumab deruxtecan compared with capecitabine, vinorelbine and eribulin. The MAIC results showed that trastuzumab deruxtecan was associated with improved overall response rate, progression-free survival and overall survival compared with the comparators, but there were major limitations. The committee understood that for an unanchored indirect comparison such as MAIC, population adjustment methods should adjust for all effect modifiers and prognostic variables. But important factors such as HER2 status and previous anti‑HER2 therapy could not be adjusted for, because all patients in DESTINY‑Breast01 had HER2‑positive disease and previous anti‑HER2 therapy. In the eribulin trial (Cortes 2011) used in the comparison, not all patients had HER2‑positive disease or 2 or more previous lines of anti‑HER2 therapy. The company explained that eribulin is not an anti‑HER2 therapy, so additional data is unlikely to become available for the HER2‑positive subgroup. The capecitabine trial (EGF100151 study) was done in a HER2‑positive population who had at least 1 previous line of anti‑HER2 therapy. The ERG explained that this study was more relevant to the population of this appraisal, but there was still some uncertainty in the MAIC of trastuzumab deruxtecan compared with capecitabine. This is because the capecitabine trial was done in a population who had at least 1 previous anti‑HER2 therapy. Also, the analysis only included patients who did not cross over to combination therapy (lapatinib plus capecitabine) after their disease had progressed on capecitabine, which may have introduced selection bias. The vinorelbine (KCSG BR11‑16) trial was done in a population that matched the DESTINY‑Breast01 population. However, clinical experts explained that it was a small study done in South Korea, so the generalisability to UK clinical practice was unclear. The committee understood that the comparative efficacy of trastuzumab deruxtecan was difficult to assess. This was because the trials available for the comparators were quite old and not representative of the latest developments in metastatic breast cancer. The clinical experts mentioned that more meaningful comparisons could be done using control arms from more recent trials for anti‑HER2 therapies, even though they do not represent current NHS practice (see section 3.5). The committee concluded that the company's MAIC has limitations, and the results are uncertain. It also concluded that trastuzumab deruxtecan is likely to improve clinical outcomes, including overall survival, compared with eribulin, capecitabine and vinorelbine. But the size of this effect is uncertain.
## Trastuzumab deruxtecan has an acceptable safety profile
The committee noted that trastuzumab deruxtecan was associated with a relatively high rate of interstitial lung disease (ILD). The clinical experts explained that close monitoring for signs and symptoms of ILD is needed and that, when treated early and adequately, ILD usually resolves without any long-term issues. Also, the clinical experts explained that other treatments approved by NICE can also cause ILD, and clinical teams have experience to manage it adequately. The committee noted that non-targeted chemotherapies have higher rates of grade 3 to 4 adverse events that have a negative effect on patients' quality of life. Also, adverse effects of chemotherapies are a key concern for patients (see section 3.2). The clinical experts also explained that adverse events rates usually increase or stay steady across treatment lines, so trastuzumab deruxtecan is not expected to be tolerated less if it is used as third-line treatment in NHS clinical practice. The committee concluded that trastuzumab deruxtecan is associated with side effects, but its safety profile was acceptable.
# Cost-effectiveness evidence
## The company's economic model is suitable for decision making
The company submitted a partitioned survival model to estimate the cost effectiveness of trastuzumab deruxtecan compared with eribulin, capecitabine and vinorelbine. It had 4 health states: progression-free on treatment, progression-free off treatment, progressed, and death. The committee considered that the partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs and is suitable for decision making.
## The company's modelling of progression-free survival and time to stopping treatment for comparators is uncertain
In the model, progression-free survival and time to stopping treatment for trastuzumab deruxtecan are extrapolated from DESTINY‑Breast01 trial data. The company used the hazard ratios from the MAIC to derive progression-free survival for comparators. The MAIC results were uncertain because some important characteristics could not be adjusted for (see section 3.6). Time to stopping treatment was not available in the studies of comparators, so the company assumed it was the same as progression-free survival. The committee concluded that the modelling of progression-free survival and time to stopping treatment for comparators was uncertain. This was because of the uncertainty in the indirect treatment comparison and using proxy data for time to stopping treatment for comparators.
## The company's modelling of overall survival for trastuzumab deruxtecan relies on data from another treatment and is highly uncertain
In the economic model, overall survival is one of the key drivers of the results. The company explained that overall survival data from DESTINY‑Breast01 is too immature to extrapolate and provide robust long-term overall survival estimates. Therefore, the company used an alternative approach in its base case. It modelled overall survival for trastuzumab deruxtecan by applying a hazard ratio for trastuzumab deruxtecan relative to trastuzumab emtansine to an extrapolated survival curve for trastuzumab emtansine. The hazard ratio was calculated for trastuzumab deruxtecan based on DESTINY‑Breast01 (June 2020 data cut, censored at 20.5 months) relative to trastuzumab emtansine based on TH3RESA. This was calculated using the Cox proportional hazards model in a naive comparison; that is, without adjusting for differences between the populations in the 2 trials. This hazard ratio was then applied to the overall survival curve of trastuzumab emtansine in TH3RESA, extrapolated using the generalised gamma function. The company's approach was based on clinical opinion that the shape of the curve for trastuzumab deruxtecan will be similar to trastuzumab emtansine. This is because both are HER2‑antibody drug conjugates, where a HER2‑antibody is linked to a cytotoxic agent that is released after binding to HER2 on the surface of cancer cells. The company used DESTINY‑Breast01 overall survival data censored at 20.5 months because it considered that the small number of events after this timepoint made the data uninformative. It chose the generalised gamma to extrapolate overall survival of TH3RESA. This was based on clinical opinion that it gave more plausible survival estimates, and better reflected the observed overall survival shape of other anti‑HER2 therapies, than other survival functions. The committee noted that this modelling approach gave an optimistic estimate of overall survival at 20 months (75%), compared with overall survival observed in the DESTINY‑Breast01 trial at the same timepoint (70%). It also noted that it would have been useful to have clinical opinion on the expected hazards for death over time, to help select the most appropriate function to extrapolate overall survival. The company also presented:
Secondary analysis using uncensored DESTINY‑Breast01 overall survival data to calculate the hazard ratio for trastuzumab deruxtecan compared with trastuzumab emtansine (the hazard ratio was higher than in the base case).
Exploratory analysis in response to technical engagement, directly extrapolating overall survival data from DESTINY‑Breast01 trial (June 2020 data cut, censored at 20.5 months). The company used an average of the Weibull and exponential curves. This was based on clinical expert opinion that the Weibull curve was implausibly low and exponential curve was implausibly high. The ERG agreed with the company that the DESTINY‑Breast01 overall survival data is still too immature to extrapolate and provide robust long-term overall survival estimates. It explained that company's base-case approach is not implausible but is highly uncertain. It did not identify any alternative approach to generate more robust analysis, because of evidence limitations. The clinical experts explained that it was difficult to predict the shape of the overall survival curve of trastuzumab deruxtecan in the long term, but that data available indicated considerable survival benefits. The committee noted the high uncertainty in the company's base-case approach for modelling overall survival for trastuzumab deruxtecan. This related to uncertainty in the hazard ratio for overall survival compared with trastuzumab emtansine and long-term extrapolations of overall survival. Therefore, the committee agreed to consider a range of scenario analyses presented by the ERG. These used alternative extrapolation curves for TH3RESA overall survival and, at the same time, varied the hazard ratio for overall survival with trastuzumab deruxtecan relative to trastuzumab emtansine. The committee concluded that the modelling of overall survival was highly uncertain and further data collection was needed to inform trastuzumab deruxtecan overall survival. It also concluded that, once more mature data is available, it would prefer the overall survival data for trastuzumab deruxtecan to be directly extrapolated without relying on data from another treatment.
## The company's modelling of overall survival for comparators is a naive comparison
The company modelled the overall survival for comparators using the Kaplan−Meier data from comparator studies directly (Cortes 2011 for eribulin, EGF100151 for capecitabine and Sim 2019 for vinorelbine) rather than using MAIC results. It explained that this was based on clinical opinion that applying a hazard ratio from the MAIC may not be appropriate. This is because the shape of the overall survival curves is expected to differ between the comparators and trastuzumab deruxtecan, for which a tail may be expected, as seen with other targeted therapies. The committee noted that this approach was a naive comparison; that is, it was not adjusted for differences in patient characteristics between the trials. But, the MAIC also had limitations. There were important differences between DESTINY‑Breast01 and the trials of comparators (see section 3.6) and the committee understood that the direction of the uncertainty was unclear. Therefore, it was impossible to assess whether the relative overall survival with trastuzumab deruxtecan compared with its comparators was overestimated or underestimated in the model. The committee concluded that the relative overall survival benefit for trastuzumab deruxtecan compared with its comparators in the model was uncertain, because it was based on naive comparisons. It also concluded that evidence from a randomised controlled trial was needed to allow a more robust comparison. As a minimum, evidence from such a trial would allow an indirect treatment comparison using a connected network.
## The company's utility values are broadly appropriate
Health-related quality-of-life data were not collected in the DESTINY‑Breast01 trial, so the company used utility values from NICE's technology appraisal guidance for eribulin. The utility values for the 'progression-free on treatment' health state were calculated as a function of the overall response rate for each treatment. Overall response rates for comparators were derived from the MAIC, which was uncertain (see section 3.6). The committee noted that disutility was also applied for adverse events. The clinical expert confirmed that in metastatic breast cancer, there was a clear link between health-related quality of life and objective response rate, progression-free survival, and treatment-emergent adverse events. The committee concluded that the company's approach to utility values is broadly appropriate, but there may be some uncertainty related to limitations of the indirect treatment comparison.
# End of life
## Trastuzumab deruxtecan meets the end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Clinical experts explained that life expectancy after progressing on trastuzumab emtansine was less than 24 months. They also explained that the preliminary overall survival results from the DESTINY‑Breast01 trial were promising, with the likely extension to life of at least 3 months. The ERG agreed that, based on the latest data cut from June 2020, an improvement in overall survival of at least 3 months was plausible. The clinical experts also noted that the end of life criteria were accepted in NICE's technology appraisal guidance on eribulin in third-line treatment and trastuzumab emtansine in second-line treatment. The committee agreed that although the size of the overall survival benefit compared with NHS clinical practice is uncertain, trastuzumab deruxtecan was likely to give an extension to life of at least 3 months. It concluded that, despite the uncertainty in the clinical evidence, trastuzumab deruxtecan likely meets the end of life criteria.
# Cost-effectiveness estimates
## Trastuzumab deruxtecan is not recommended for routine use in the NHS
The committee recalled the high uncertainty in how the relative efficacy of trastuzumab deruxtecan was modelled (see sections 3.9 to 3.12). The ERG did not identify any alternative approach to allow a more robust analysis, because of evidence limitations. The company's base‑case fully incremental analysis produced an incremental cost-effectiveness ratio (ICER) of £47,230 per quality-adjusted life year (QALY) gained relative to capecitabine. The committee considered this ICER was plausible, but highly uncertain. Therefore, the committee considered a range of scenario analyses provided by the ERG. In these, the hazard ratio for overall survival for trastuzumab deruxtecan compared with trastuzumab emtansine and overall survival extrapolation from the TH3RESA trial were varied at the same time (see section 3.10). This gave ICERs of up to £78,142 per QALY gained relative to capecitabine. The committee agreed that this ICER is not implausible, because of the high degree of uncertainty in the relative clinical benefit of trastuzumab deruxtecan compared with its comparators. This is mainly related to the immaturity of the overall survival data and the lack of comparative evidence. The committee concluded that the evidence base was immature and that the ICER could be higher than what NICE normally considers an acceptable use of NHS resources, even considering end of life criteria. Therefore, it concluded that trastuzumab deruxtecan could not be recommended for routine commissioning.
# Cancer Drugs Fund
## Trastuzumab deruxtecan meets the criteria for inclusion in the Cancer Drugs Fund
Having concluded that trastuzumab deruxtecan could not be recommended for routine use, the committee considered if it could be recommended within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It noted that:
The company expressed an interest in trastuzumab deruxtecan being considered for funding through the Cancer Drugs Fund.
The company model is structurally robust for decision making (see section 3.8).
Overall survival is a key driver of the cost-effectiveness results and the key source of uncertainty.
Data from DESTINY‑Breast01 is immature. This single-arm trial is still ongoing and further data could help reduce uncertainties around long-term progression-free survival and overall survival.
Comparative evidence is currently not available. A randomised controlled trial, DESTINY‑Breast02, is ongoing and will provide direct comparative evidence of trastuzumab deruxtecan compared with either trastuzumab plus capecitabine or lapatinib plus capecitabine (treatment is chosen by the investigator). These comparators are not used in NHS clinical practice, but data could be used to inform an indirect treatment comparison using a connected network.
The Systemic Anti-Cancer Therapy dataset could provide meaningful real-world data about time on treatment and overall survival for trastuzumab deruxtecan in the NHS.
Trastuzumab deruxtecan has plausible potential to be cost effective, considering end of life criteria (see sections 3.13 and 3.14) and a confidential patient access scheme (see section 2.4).The committee was satisfied that trastuzumab deruxtecan met the criteria for inclusion in the Cancer Drugs Fund. Therefore, it recommended trastuzumab deruxtecan for use within the Cancer Drugs Fund for people with HER2‑positive unresectable or metastatic breast cancer, after 2 or more anti‑HER2 therapies, if the conditions in the managed access agreement are followed. When the guidance is next reviewed the company should use the committee's preferred assumptions (unless new evidence indicates otherwise), as set out in sections 3.9 to 3.12.
# Innovation
## The model adequately captures the benefits of trastuzumab deruxtecan
The company, patients and clinical experts considered trastuzumab deruxtecan to be innovative. They explained that it would be a step change in improving clinical outcomes and managing HER2‑postive unresectable or metastatic breast cancer after 2 or more anti‑HER2 therapies. The committee concluded that trastuzumab deruxtecan had the potential to give significant benefits for patients, but these benefits have been adequately captured in the model.
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{'Recommendations': 'Trastuzumab deruxtecan is recommended for use within the Cancer Drugs Fund as an option for treating HER2‑positive unresectable or metastatic breast cancer in adults after 2 or more anti‑HER2 therapies. It is recommended only if the conditions in the managed access agreement are followed.\n\nThis recommendation is not intended to affect treatment with trastuzumab deruxtecan that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for HER2‑positive unresectable or metastatic breast cancer includes anti‑HER2 therapies. After 2 or more anti‑HER2 therapies, standard care is chemotherapy (such as capecitabine, vinorelbine or eribulin). Trastuzumab deruxtecan is an anti‑HER2 therapy that would be used after 2 or more anti‑HER2 therapies.\n\nClinical trial evidence is limited. There is a trial of trastuzumab deruxtecan on its own, which means it is not directly compared with any other treatments. Indirect comparisons of trastuzumab deruxtecan with chemotherapy suggest that it may increase how long before disease progresses and how long people live. However, how much longer people live is uncertain because there are differences between trials included in the indirect comparisons, and the final data from the trial of trastuzumab deruxtecan on its own is not available yet. Because of this, the estimates of cost effectiveness are very uncertain and trastuzumab deruxtecan cannot be recommended for routine use in the NHS.\n\nTrastuzumab deruxtecan could be cost effective if further data shows that people live longer with treatment. Another ongoing trial is directly comparing trastuzumab deruxtecan with anti‑HER2 therapies plus chemotherapy. Data from the trials of trastuzumab deruxtecan and from NHS practice would help address the uncertainty about clinical effectiveness. Trastuzumab deruxtecan is therefore recommended for use in the Cancer Drugs Fund.', 'Information about trastuzumab deruxtecan': "# Marketing authorisation indication\n\nTrastuzumab deruxtecan (Enhertu, Daiichi-Sankyo) has a marketing authorisation as 'monotherapy for the treatment of adult patients with unresectable or metastatic HER2‑positive breast cancer who have received two or more prior anti‑HER2‑based regimens'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe company's list price is £1,455 per vial containing 100\xa0mg powder for concentrate for solution for infusion (company's submission). The average cost of a course of treatment at list price is £117,857.55.\n\nThe company has a commercial arrangement. This makes trastuzumab deruxtecan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Daiichi-Sankyo, a review of this submission by the evidence review group (ERG) and responses from stakeholders. Ahead of technical engagement, the company submitted new data based on the latest data cut from the trial (June 2020). The evidence and results presented at the committee meeting were based on this data cut. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## HER2-positive unresectable or metastatic breast cancer has a high disease burden\n\nSome breast cancer cells have higher levels of a protein called HER2 on their surface, which stimulates them to grow. This is known as HER2‑positive breast cancer and around 1 in 5 unresectable or metastatic breast cancers are HER2‑positive. Patient experts explained that being diagnosed with unresectable or metastatic breast cancer is extremely difficult for people and their family and friends. It can cause considerable anxiety and fear, with the uncertainty being the hardest part for many people. These feelings can negatively affect mental health. People with unresectable or metastatic breast cancer must organise their lives around hospital appointments, which constrains their everyday activities. There is no cure for unresectable or metastatic breast cancer. Treatment aims to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. Treatment is continued for as long as it works. The committee concluded that there is a high disease burden for people with HER2‑positive unresectable or metastatic breast cancer.\n\n## There is a need for anti-HER2 therapies after second-line treatment\n\nClinical experts explained that people with HER2‑positive unresectable or metastatic breast cancer that has progressed after 2 or more anti‑HER2 therapies have a high symptom burden and their disease is resistant to the previous lines of therapy. First-line treatment of HER2‑positive unresectable or metastatic breast cancer includes anti‑HER2 therapies pertuzumab with trastuzumab and docetaxel, or trastuzumab with paclitaxel (see NICE's technology appraisal guidance on pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer and trastuzumab for the treatment of advanced breast cancer). Trastuzumab emtansine is an anti‑HER2 therapy used as second-line treatment (see NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane). The committee noted that, although some trusts may offer third‑line anti‑HER2 therapy, this is not available across the NHS and cannot be considered standard care. Instead, standard care for people whose disease has progressed on or after 2 anti‑HER2 therapies is non‑targeted chemotherapy, including capecitabine, vinorelbine, or eribulin (see NICE's guideline on advanced breast cancer: diagnosis and treatment and NICE's technology appraisal guidance on eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens). Patient experts explained that chemotherapy has limited efficacy and can cause side effects that are typically more severe than with anti‑HER2 therapies. People having chemotherapy may also experience worse quality of life. Therefore, people want to avoid having chemotherapies for as long as possible. Patient experts highlighted the need for treatments that can extend survival with acceptable tolerability and quality of life. The committee concluded that that there is an unmet need for anti‑HER2 treatment after second-line treatment.\n\n## Relevant comparators for trastuzumab deruxtecan include capecitabine, vinorelbine and eribulin\n\nCurrent standard care in the NHS for people with HER2‑positive unresectable or metastatic breast cancer that has progressed after 2 or more anti‑HER2 therapies is non-targeted chemotherapy, including capecitabine, vinorelbine, or eribulin. Eribulin is recommended for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens (which may include an anthracycline or a taxane, and capecitabine; see NICE's technology appraisal guidance on eribulin). The clinical experts explained that, in practice, capecitabine or vinorelbine is mostly used as third-line treatment and eribulin is more likely to be used as fourth-line treatment. They confirmed that trastuzumab deruxtecan would replace capecitabine, vinorelbine and eribulin. The committee concluded that capecitabine, vinorelbine and eribulin are all relevant comparators for trastuzumab deruxtecan.\n\n# Clinical evidence\n\n## DESTINY-Breast01 is generalisable to UK clinical practice\n\nThe clinical evidence was based on DESTINY-Breast01, a single-arm trial for people with HER2‑positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. Clinical experts explained that DESTINY‑Breast01 is representative of patients in the NHS in terms of characteristics and previous treatment. The committee noted that most people in the trial had 3 or more previous therapies (median\xa06, range 2 to 24, excluding hormone therapy) and so had more previous treatments than people in the NHS. Clinical experts explained that in people who have had more previous treatments, disease is usually less likely to respond to the next line of treatment. Therefore, trastuzumab deruxtecan efficacy could be higher in the NHS than in the trial. This is supported by a subgroup analysis from DESTINY‑Breast01 (see section\xa03.5). The committee concluded that DESTINY‑Breast01 is broadly generalisable to clinical practice in the UK.\n\n## Preliminary data for trastuzumab deruxtecan is limited but promising\n\nThe primary end point of DESTINY-Breast01 is overall response rate, while overall survival and progression-free survival are secondary endpoints. At the June\xa02020 data cut-off, overall response rate for trastuzumab deruxtecan was 61.4%. The preliminary median overall survival was 24.6\xa0months (95%\xa0confidence interval [CI] 23.1 to not evaluable). Median progression-free survival was 19.4\xa0months (95%\xa0CI 14.1 to not evaluable). The median follow up was 20.5\xa0months. However, data was immature, with only 35% maturity for overall survival analysis, and a high amount of censoring. The clinical experts explained that although it was a single-arm trial with immature data, the observed results suggested a promising efficacy. They noted an overall response rate of 61.4% in a population who have had a lot of previous treatments, such as in DESTINY‑Breast01, which is much higher than with other available therapies. They explained that response to treatment is usually better with earlier lines of therapy and decreases with subsequent lines of therapy. The pre‑specified subgroup analysis from the DESTINY‑Breast01 trial showed that overall response rate was higher in people who only had 2 previous lines of treatment (76% [95%\xa0CI 50% to 93%]), compared with those who had 3 or more previous lines of treatment (59% [95%\xa0CI 51% to 67%]). However, this analysis was based on a small number of patients (17\xa0people in the group who had only 2 previous lines) so it is highly uncertain. Clinical experts also explained that in DESTINY‑Breast01, only 21.7% of people had disease response to previous treatment with trastuzumab emtansine. This suggests that a high response rate to trastuzumab deruxtecan is unlikely to be because of patient selection. The clinical experts described randomised controlled trials in people with HER2‑positive metastatic breast cancer who have had at least 2 previous anti‑HER2 therapies (TH3RESA, SOPHIA, NALA, HER2CLIMB). These trials used more intensive treatments as the control arms (chemotherapy plus anti‑HER2 therapy) than chemotherapy alone. This means the efficacy of these control arms is likely to be the same as or higher than for chemotherapy alone. Median progression-free survival in the control arms was between 3.3\xa0months and 5.6\xa0months, and median overall survival between 15.8\xa0months and 19.8\xa0months. This is lower than the lower bound of the confidence interval for overall survival (23.1\xa0months) for trastuzumab deruxtecan from DESTINY‑Breast01. The committee concluded that the preliminary data for trastuzumab deruxtecan suggests a promising efficacy but is limited for decision making.\n\n## Trastuzumab deruxtecan is likely to improve clinical outcomes, including overall survival, but the size of effect is uncertain\n\nBecause DESTINY‑Breast01 is a single-arm trial, there is no evidence for the efficacy of trastuzumab deruxtecan directly compared with other treatments. The company therefore did unanchored matching-adjusted indirect comparisons (MAIC) of trastuzumab deruxtecan compared with capecitabine, vinorelbine and eribulin. The MAIC results showed that trastuzumab deruxtecan was associated with improved overall response rate, progression-free survival and overall survival compared with the comparators, but there were major limitations. The committee understood that for an unanchored indirect comparison such as MAIC, population adjustment methods should adjust for all effect modifiers and prognostic variables. But important factors such as HER2 status and previous anti‑HER2 therapy could not be adjusted for, because all patients in DESTINY‑Breast01 had HER2‑positive disease and previous anti‑HER2 therapy. In the eribulin trial (Cortes 2011) used in the comparison, not all patients had HER2‑positive disease or 2 or more previous lines of anti‑HER2 therapy. The company explained that eribulin is not an anti‑HER2 therapy, so additional data is unlikely to become available for the HER2‑positive subgroup. The capecitabine trial (EGF100151 study) was done in a HER2‑positive population who had at least 1 previous line of anti‑HER2 therapy. The ERG explained that this study was more relevant to the population of this appraisal, but there was still some uncertainty in the MAIC of trastuzumab deruxtecan compared with capecitabine. This is because the capecitabine trial was done in a population who had at least 1 previous anti‑HER2 therapy. Also, the analysis only included patients who did not cross over to combination therapy (lapatinib plus capecitabine) after their disease had progressed on capecitabine, which may have introduced selection bias. The vinorelbine (KCSG BR11‑16) trial was done in a population that matched the DESTINY‑Breast01 population. However, clinical experts explained that it was a small study done in South Korea, so the generalisability to UK clinical practice was unclear. The committee understood that the comparative efficacy of trastuzumab deruxtecan was difficult to assess. This was because the trials available for the comparators were quite old and not representative of the latest developments in metastatic breast cancer. The clinical experts mentioned that more meaningful comparisons could be done using control arms from more recent trials for anti‑HER2 therapies, even though they do not represent current NHS practice (see section\xa03.5). The committee concluded that the company's MAIC has limitations, and the results are uncertain. It also concluded that trastuzumab deruxtecan is likely to improve clinical outcomes, including overall survival, compared with eribulin, capecitabine and vinorelbine. But the size of this effect is uncertain.\n\n## Trastuzumab deruxtecan has an acceptable safety profile\n\nThe committee noted that trastuzumab deruxtecan was associated with a relatively high rate of interstitial lung disease (ILD). The clinical experts explained that close monitoring for signs and symptoms of ILD is needed and that, when treated early and adequately, ILD usually resolves without any long-term issues. Also, the clinical experts explained that other treatments approved by NICE can also cause ILD, and clinical teams have experience to manage it adequately. The committee noted that non-targeted chemotherapies have higher rates of grade\xa03 to\xa04 adverse events that have a negative effect on patients' quality of life. Also, adverse effects of chemotherapies are a key concern for patients (see section\xa03.2). The clinical experts also explained that adverse events rates usually increase or stay steady across treatment lines, so trastuzumab deruxtecan is not expected to be tolerated less if it is used as third-line treatment in NHS clinical practice. The committee concluded that trastuzumab deruxtecan is associated with side effects, but its safety profile was acceptable.\n\n# Cost-effectiveness evidence\n\n## The company's economic model is suitable for decision making\n\nThe company submitted a partitioned survival model to estimate the cost effectiveness of trastuzumab deruxtecan compared with eribulin, capecitabine and vinorelbine. It had 4 health states: progression-free on treatment, progression-free off treatment, progressed, and death. The committee considered that the partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs and is suitable for decision making.\n\n## The company's modelling of progression-free survival and time to stopping treatment for comparators is uncertain\n\nIn the model, progression-free survival and time to stopping treatment for trastuzumab deruxtecan are extrapolated from DESTINY‑Breast01 trial data. The company used the hazard ratios from the MAIC to derive progression-free survival for comparators. The MAIC results were uncertain because some important characteristics could not be adjusted for (see section\xa03.6). Time to stopping treatment was not available in the studies of comparators, so the company assumed it was the same as progression-free survival. The committee concluded that the modelling of progression-free survival and time to stopping treatment for comparators was uncertain. This was because of the uncertainty in the indirect treatment comparison and using proxy data for time to stopping treatment for comparators.\n\n## The company's modelling of overall survival for trastuzumab deruxtecan relies on data from another treatment and is highly uncertain\n\nIn the economic model, overall survival is one of the key drivers of the results. The company explained that overall survival data from DESTINY‑Breast01 is too immature to extrapolate and provide robust long-term overall survival estimates. Therefore, the company used an alternative approach in its base case. It modelled overall survival for trastuzumab deruxtecan by applying a hazard ratio for trastuzumab deruxtecan relative to trastuzumab emtansine to an extrapolated survival curve for trastuzumab emtansine. The hazard ratio was calculated for trastuzumab deruxtecan based on DESTINY‑Breast01 (June\xa02020 data cut, censored at 20.5\xa0months) relative to trastuzumab emtansine based on TH3RESA. This was calculated using the Cox proportional hazards model in a naive comparison; that is, without adjusting for differences between the populations in the 2 trials. This hazard ratio was then applied to the overall survival curve of trastuzumab emtansine in TH3RESA, extrapolated using the generalised gamma function. The company's approach was based on clinical opinion that the shape of the curve for trastuzumab deruxtecan will be similar to trastuzumab emtansine. This is because both are HER2‑antibody drug conjugates, where a HER2‑antibody is linked to a cytotoxic agent that is released after binding to HER2 on the surface of cancer cells. The company used DESTINY‑Breast01 overall survival data censored at 20.5\xa0months because it considered that the small number of events after this timepoint made the data uninformative. It chose the generalised gamma to extrapolate overall survival of TH3RESA. This was based on clinical opinion that it gave more plausible survival estimates, and better reflected the observed overall survival shape of other anti‑HER2 therapies, than other survival functions. The committee noted that this modelling approach gave an optimistic estimate of overall survival at 20\xa0months (75%), compared with overall survival observed in the DESTINY‑Breast01 trial at the same timepoint (70%). It also noted that it would have been useful to have clinical opinion on the expected hazards for death over time, to help select the most appropriate function to extrapolate overall survival. The company also presented:\n\nSecondary analysis using uncensored DESTINY‑Breast01 overall survival data to calculate the hazard ratio for trastuzumab deruxtecan compared with trastuzumab emtansine (the hazard ratio was higher than in the base case).\n\nExploratory analysis in response to technical engagement, directly extrapolating overall survival data from DESTINY‑Breast01 trial (June\xa02020 data cut, censored at 20.5\xa0months). The company used an average of the Weibull and exponential curves. This was based on clinical expert opinion that the Weibull curve was implausibly low and exponential curve was implausibly high. The ERG agreed with the company that the DESTINY‑Breast01 overall survival data is still too immature to extrapolate and provide robust long-term overall survival estimates. It explained that company's base-case approach is not implausible but is highly uncertain. It did not identify any alternative approach to generate more robust analysis, because of evidence limitations. The clinical experts explained that it was difficult to predict the shape of the overall survival curve of trastuzumab deruxtecan in the long term, but that data available indicated considerable survival benefits. The committee noted the high uncertainty in the company's base-case approach for modelling overall survival for trastuzumab deruxtecan. This related to uncertainty in the hazard ratio for overall survival compared with trastuzumab emtansine and long-term extrapolations of overall survival. Therefore, the committee agreed to consider a range of scenario analyses presented by the ERG. These used alternative extrapolation curves for TH3RESA overall survival and, at the same time, varied the hazard ratio for overall survival with trastuzumab deruxtecan relative to trastuzumab emtansine. The committee concluded that the modelling of overall survival was highly uncertain and further data collection was needed to inform trastuzumab deruxtecan overall survival. It also concluded that, once more mature data is available, it would prefer the overall survival data for trastuzumab deruxtecan to be directly extrapolated without relying on data from another treatment.\n\n## The company's modelling of overall survival for comparators is a naive comparison\n\nThe company modelled the overall survival for comparators using the Kaplan−Meier data from comparator studies directly (Cortes 2011 for eribulin, EGF100151 for capecitabine and Sim 2019 for vinorelbine) rather than using MAIC results. It explained that this was based on clinical opinion that applying a hazard ratio from the MAIC may not be appropriate. This is because the shape of the overall survival curves is expected to differ between the comparators and trastuzumab deruxtecan, for which a tail may be expected, as seen with other targeted therapies. The committee noted that this approach was a naive comparison; that is, it was not adjusted for differences in patient characteristics between the trials. But, the MAIC also had limitations. There were important differences between DESTINY‑Breast01 and the trials of comparators (see section\xa03.6) and the committee understood that the direction of the uncertainty was unclear. Therefore, it was impossible to assess whether the relative overall survival with trastuzumab deruxtecan compared with its comparators was overestimated or underestimated in the model. The committee concluded that the relative overall survival benefit for trastuzumab deruxtecan compared with its comparators in the model was uncertain, because it was based on naive comparisons. It also concluded that evidence from a randomised controlled trial was needed to allow a more robust comparison. As a minimum, evidence from such a trial would allow an indirect treatment comparison using a connected network.\n\n## The company's utility values are broadly appropriate\n\nHealth-related quality-of-life data were not collected in the DESTINY‑Breast01 trial, so the company used utility values from NICE's technology appraisal guidance for eribulin. The utility values for the 'progression-free on treatment' health state were calculated as a function of the overall response rate for each treatment. Overall response rates for comparators were derived from the MAIC, which was uncertain (see section\xa03.6). The committee noted that disutility was also applied for adverse events. The clinical expert confirmed that in metastatic breast cancer, there was a clear link between health-related quality of life and objective response rate, progression-free survival, and treatment-emergent adverse events. The committee concluded that the company's approach to utility values is broadly appropriate, but there may be some uncertainty related to limitations of the indirect treatment comparison.\n\n# End of life\n\n## Trastuzumab deruxtecan meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Clinical experts explained that life expectancy after progressing on trastuzumab emtansine was less than 24\xa0months. They also explained that the preliminary overall survival results from the DESTINY‑Breast01 trial were promising, with the likely extension to life of at least 3\xa0months. The ERG agreed that, based on the latest data cut from June\xa02020, an improvement in overall survival of at least 3\xa0months was plausible. The clinical experts also noted that the end of life criteria were accepted in NICE's technology appraisal guidance on eribulin in third-line treatment and trastuzumab emtansine in second-line treatment. The committee agreed that although the size of the overall survival benefit compared with NHS clinical practice is uncertain, trastuzumab deruxtecan was likely to give an extension to life of at least 3\xa0months. It concluded that, despite the uncertainty in the clinical evidence, trastuzumab deruxtecan likely meets the end of life criteria.\n\n# Cost-effectiveness estimates\n\n## Trastuzumab deruxtecan is not recommended for routine use in the NHS\n\nThe committee recalled the high uncertainty in how the relative efficacy of trastuzumab deruxtecan was modelled (see sections\xa03.9 to\xa03.12). The ERG did not identify any alternative approach to allow a more robust analysis, because of evidence limitations. The company's base‑case fully incremental analysis produced an incremental cost-effectiveness ratio (ICER) of £47,230 per quality-adjusted life year (QALY) gained relative to capecitabine. The committee considered this ICER was plausible, but highly uncertain. Therefore, the committee considered a range of scenario analyses provided by the ERG. In these, the hazard ratio for overall survival for trastuzumab deruxtecan compared with trastuzumab emtansine and overall survival extrapolation from the TH3RESA trial were varied at the same time (see section\xa03.10). This gave ICERs of up to £78,142 per QALY gained relative to capecitabine. The committee agreed that this ICER is not implausible, because of the high degree of uncertainty in the relative clinical benefit of trastuzumab deruxtecan compared with its comparators. This is mainly related to the immaturity of the overall survival data and the lack of comparative evidence. The committee concluded that the evidence base was immature and that the ICER could be higher than what NICE normally considers an acceptable use of NHS resources, even considering end of life criteria. Therefore, it concluded that trastuzumab deruxtecan could not be recommended for routine commissioning.\n\n# Cancer Drugs Fund\n\n## Trastuzumab deruxtecan meets the criteria for inclusion in the Cancer Drugs Fund\n\nHaving concluded that trastuzumab deruxtecan could not be recommended for routine use, the committee considered if it could be recommended within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It noted that:\n\nThe company expressed an interest in trastuzumab deruxtecan being considered for funding through the Cancer Drugs Fund.\n\nThe company model is structurally robust for decision making (see section\xa03.8).\n\nOverall survival is a key driver of the cost-effectiveness results and the key source of uncertainty.\n\nData from DESTINY‑Breast01 is immature. This single-arm trial is still ongoing and further data could help reduce uncertainties around long-term progression-free survival and overall survival.\n\nComparative evidence is currently not available. A randomised controlled trial, DESTINY‑Breast02, is ongoing and will provide direct comparative evidence of trastuzumab deruxtecan compared with either trastuzumab plus capecitabine or lapatinib plus capecitabine (treatment is chosen by the investigator). These comparators are not used in NHS clinical practice, but data could be used to inform an indirect treatment comparison using a connected network.\n\nThe Systemic Anti-Cancer Therapy dataset could provide meaningful real-world data about time on treatment and overall survival for trastuzumab deruxtecan in the NHS.\n\nTrastuzumab deruxtecan has plausible potential to be cost effective, considering end of life criteria (see sections\xa03.13 and\xa03.14) and a confidential patient access scheme (see section\xa02.4).The committee was satisfied that trastuzumab deruxtecan met the criteria for inclusion in the Cancer Drugs Fund. Therefore, it recommended trastuzumab deruxtecan for use within the Cancer Drugs Fund for people with HER2‑positive unresectable or metastatic breast cancer, after 2 or more anti‑HER2 therapies, if the conditions in the managed access agreement are followed. When the guidance is next reviewed the company should use the committee's preferred assumptions (unless new evidence indicates otherwise), as set out in sections\xa03.9 to\xa03.12.\n\n# Innovation\n\n## The model adequately captures the benefits of trastuzumab deruxtecan\n\nThe company, patients and clinical experts considered trastuzumab deruxtecan to be innovative. They explained that it would be a step change in improving clinical outcomes and managing HER2‑postive unresectable or metastatic breast cancer after 2 or more anti‑HER2 therapies. The committee concluded that trastuzumab deruxtecan had the potential to give significant benefits for patients, but these benefits have been adequately captured in the model."}
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https://www.nice.org.uk/guidance/ta704
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Evidence-based recommendations on trastuzumab deruxtecan (Enhertu) for treating HER2-positive unresectable or metastatic breast cancer in adults after 2 or more anti-HER2 therapies.
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c65296f4d00d4d0e3e0d7398eeddfd8dfece3abd
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nice
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Heavy menstrual bleeding: assessment and management
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Heavy menstrual bleeding: assessment and management
This guideline covers assessing and managing heavy menstrual bleeding (menorrhagia). It aims to help healthcare professionals investigate the cause of heavy periods that are affecting a woman’s quality of life and to offer the right treatments, taking into account the woman’s priorities and preferences.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Impact of heavy menstrual bleeding (HMB) on women
Recognise that heavy menstrual bleeding (HMB) has a major impact on a woman's quality of life, and ensure that any intervention aims to improve this rather than focusing on blood loss.
# History, physical examination and laboratory tests
## History
Take a history from the woman that covers:
the nature of the bleeding
related symptoms, such as persistent intermenstrual bleeding, pelvic pain and/or pressure symptoms, that might suggest uterine cavity abnormality, histological abnormality, adenomyosis or fibroids
impact on her quality of life
-ther factors that may affect treatment options (such as comorbidities or previous treatment for HMB).
Take into account the range and natural variability in menstrual cycles and blood loss when diagnosing HMB, and discuss this variation with the woman. If the woman feels that she does not fall within the normal ranges, discuss care options.
If the woman has a history of HMB without other related symptoms (see recommendation 1.2.1), consider pharmacological treatment without carrying out a physical examination (unless the treatment chosen is levonorgestrel-releasing intrauterine system ). Note that this is an off-label use for some LNG-IUSs. See NICE's information on prescribing medicines.
## Physical examination
If the woman has a history of HMB with other related symptoms (see recommendation 1.2.1) offer a physical examination.
Carry out a physical examination before all investigations or LNG-IUS fittings. Note that this is an off-label use for some LNG-IUSs. See NICE's information on prescribing medicines.
## Laboratory tests
Carry out a full blood count test for all women with HMB, in parallel with any HMB treatment offered.
Testing for coagulation disorders (for example, von Willebrand's disease) should be considered for women who:
have had HMB since their periods started and
have a personal or family history suggesting a coagulation disorder.
Do not routinely carry out a serum ferritin test for women with HMB.
Do not carry out female hormone testing for women with HMB.
Do not carry out thyroid hormone testing for women with HMB unless other signs and symptoms of thyroid disease are present.
# Investigations for the cause of HMB
## Before starting investigations
Consider starting pharmacological treatment for HMB without investigating the cause if the woman's history and/or examination suggests a low risk of fibroids, uterine cavity abnormality, histological abnormality or adenomyosis.
If cancer is suspected, see the NICE guideline on suspected cancer: recognition and referral.
## Investigations
Take into account the woman's history and examination when deciding whether to offer hysteroscopy or ultrasound as the first-line investigation.
Offer outpatient hysteroscopy to women with HMB if their history suggests submucosal fibroids, polyps or endometrial pathology because:
they have symptoms such as persistent intermenstrual bleeding or
they have risk factors for endometrial pathology (see recommendation 1.3.10).
Ensure that outpatient hysteroscopy services are organised and the procedure is performed according to best practice, including:
advising women to take oral analgesia before the procedure
vaginoscopy as the standard diagnostic technique, using miniature hysteroscopes (3.5 mm or smaller).
Ensure that hysteroscopy services are organised to enable progression to 'see-and-treat' hysteroscopy in a single setting if feasible.
Explain to women with HMB who are offered outpatient hysteroscopy what the procedure involves and discuss the possible alternatives.
If a woman declines outpatient hysteroscopy, offer hysteroscopy under general or regional anaesthesia.
For women who decline hysteroscopy, consider pelvic ultrasound, explaining the limitations of this technique for detecting uterine cavity causes of HMB.
Consider endometrial biopsy at the time of hysteroscopy for women who are at high risk of endometrial pathology, such as:
women with persistent intermenstrual or persistent irregular bleeding, and women with infrequent heavy bleeding who are obese or have polycystic ovary syndrome
women taking tamoxifen
women for whom treatment for HMB has been unsuccessful.
Obtain an endometrial sample only in the context of diagnostic hysteroscopy. Do not offer 'blind' endometrial biopsy to women with HMB.
Offer pelvic ultrasound to women with HMB if any of the following apply:
their uterus is palpable abdominally
history or examination suggests a pelvic mass
examination is inconclusive or difficult, for example in women who are obese.
Offer transvaginal ultrasound (in preference to transabdominal ultrasound or MRI) to women with HMB who have:
significant dysmenorrhoea (period pain) or
a bulky, tender uterus on examination that suggests adenomyosis.
If a woman declines transvaginal ultrasound or it is not suitable for her, consider transabdominal ultrasound or MRI, explaining the limitations of these techniques.
Be aware that pain associated with HMB may be caused by endometriosis rather than adenomyosis (see NICE's guideline on endometriosis).
## Other diagnostic tools
Do not use saline infusion sonography as a first-line diagnostic tool for HMB.
Do not use MRI as a first-line diagnostic tool for HMB.
Do not use dilatation and curettage alone as a diagnostic tool for HMB.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on investigations for the cause of HMB .
Full details of the evidence and the committee's discussion are in evidence review A: diagnostic test accuracy in investigation for women presenting with heavy menstrual bleeding.
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# Information for women about HMB and treatments
Provide women with information about HMB and its management. Follow the principles in the NICE guidelines on patient experience in adult NHS services and shared decision making in relation to communication, information and shared decision-making.
Provide information about all possible treatment options for HMB and discuss these with the woman (see section 1.5). Discussions should cover:
the benefits and risks of the various options
suitable treatments if she is trying to conceive
whether she wants to retain her fertility and/or her uterus.
## Levonorgestrel-releasing intrauterine system (LNG-IUS)
Explain to women who are offered an LNG-IUS:
about anticipated changes in bleeding pattern, particularly in the first few cycles and maybe lasting longer than 6 months
that it is advisable to wait for at least 6 cycles to see the benefits of the treatment. Note that this is an off-label use for some LNG-IUSs. See NICE's information on prescribing medicines.
## Impact of treatments on fertility
Explain to women about the impact on fertility that any planned surgery or uterine artery embolisation may have, and if a potential treatment (hysterectomy or ablation) involves loss of fertility then opportunities for discussion should be made available.
Explain to women that uterine artery embolisation or myomectomy may potentially allow them to retain their fertility.
## Endometrial ablation
Advise women to avoid subsequent pregnancy and use effective contraception, if needed, after endometrial ablation.
## Hysterectomy
Have a full discussion with all women who are considering hysterectomy about the implications of surgery before a decision is made. The discussion should include:
sexual feelings
impact on fertility
bladder function
need for further treatment
treatment complications
her expectations
alternative surgery
psychological impact.
Inform women about the increased risk of serious complications (such as intraoperative haemorrhage or damage to other abdominal organs) associated with hysterectomy when uterine fibroids are present.
Inform women about the risk of possible loss of ovarian function and its consequences, even if their ovaries are retained during hysterectomy.
# Management of HMB
When agreeing treatment options for HMB with women, take into account:
the woman's preferences
any comorbidities
the presence or absence of fibroids (including size, number and location), polyps, endometrial pathology or adenomyosis
-ther symptoms such as pressure and pain.
## Treatments for women with no identified pathology, fibroids less than 3 cm in diameter, or suspected or diagnosed adenomyosis
Consider an LNG-IUS as the first treatment for HMB in women with:
no identified pathology or
fibroids less than 3 cm in diameter, which are not causing distortion of the uterine cavity or
suspected or diagnosed adenomyosis. Note that this is an off-label use for some LNG-IUSs. See NICE's information on prescribing medicines.
If a woman with HMB declines an LNG-IUS or it is not suitable, consider the following pharmacological treatments:
non-hormonal:
tranexamic acid
NSAIDs (non-steroidal anti-inflammatory drugs)
hormonal:
combined hormonal contraception
cyclical oral progestogens. Note that this is an off-label use for NSAIDs and some combined hormonal contraceptives. See NICE's information on prescribing medicines.
Be aware that progestogen-only contraception may suppress menstruation, which could be beneficial to women with HMB.
If treatment is unsuccessful, the woman declines pharmacological treatment, or symptoms are severe, consider referral to specialist care for:
investigations to diagnose the cause of HMB, if needed (see section 1.3) taking into account any investigations the woman has already had and
alternative treatment choices, including:
pharmacological options not already tried (see recommendations 1.5.2 and 1.5.3)
surgical options:
second-generation endometrial ablation
hysterectomy.
For women with submucosal fibroids, consider hysteroscopic removal.
## Treatments for women with fibroids of 3 cm or more in diameter
Consider referring women to specialist care to undertake additional investigations and discuss treatment options for fibroids of 3 cm or more in diameter.
If pharmacological treatment is needed while investigations and definitive treatment are being organised, offer tranexamic acid and/or NSAIDs. Note that this is an off-label use for NSAIDs. See NICE's information on prescribing medicines.
Advise women to continue using NSAIDs and/or tranexamic acid for as long as they are found to be beneficial. Note that this is an off-label use for NSAIDs. See NICE's information on prescribing medicines.
For women with fibroids of 3 cm or more in diameter, take into account the size, location and number of fibroids, and the severity of the symptoms and consider the following treatments:
pharmacological:
non-hormonal:
tranexamic acid
NSAIDs
hormonal:
LNG-IUS
combined hormonal contraception
cyclical oral progestogens
ulipristal acetate (this is only indicated for some premenopausal women; see recommendations 1.5.11 and 1.5.12 for more information)
uterine artery embolisation for fibroids
surgical:
myomectomy
hysterectomy.Note that this is an off-label use for NSAIDs and some LNG-IUSs. See NICE's information on prescribing medicines.
Only think about ulipristal acetate for the intermittent treatment of moderate to severe symptoms of uterine fibroids in premenopausal women if:
surgery and uterine artery embolisation for fibroids are not suitable, for example, because the risks to a woman outweigh the possible benefits, or
surgery and uterine artery embolisation for fibroids have failed, or
the woman declines surgery and uterine artery embolisation for fibroids.See the MHRA drug safety update on ulipristal acetate.
Discuss with the woman the risks and possible benefits of intermittent treatment with ulipristal acetate.
Advise that ulipristal acetate can be associated with serious liver injury leading to liver failure, and the signs and symptoms to look out for.
Measure liver function before starting ulipristal acetate, monthly for the first 2 courses and once before each new treatment course when clinically indicated.
If there is no underlying liver injury, and surgery and uterine artery embolisation for fibroids are unsuitable or have failed, consider ulipristal acetate 5 mg (up to 4 courses) for premenopausal women with heavy menstrual bleeding and fibroids of 3 cm or more in diameter, particularly if the haemoglobin level is 102 g per litre or below.
If a woman shows signs and symptoms of liver failure, stop ulipristal acetate and perform liver function tests urgently.
Be aware that the effectiveness of pharmacological treatments for HMB may be limited in women with fibroids that are substantially greater than 3 cm in diameter.
Prior to scheduling of uterine artery embolisation or myomectomy, the woman's uterus and fibroid(s) should be assessed by ultrasound. If further information about fibroid position, size, number and vascularity is needed, MRI should be considered.
Consider second-generation endometrial ablation as a treatment option for women with HMB and fibroids of 3 cm or more in diameter who meet the criteria specified in the manufacturers' instructions.
If treatment is unsuccessful:
consider further investigations to reassess the cause of HMB (see section 1.3), taking into account the results of previous investigations and
-ffer alternative treatment with a choice of the options described in recommendation 1.5.10.
Pretreatment with a gonadotrophin-releasing hormone analogue before hysterectomy and myomectomy should be considered if uterine fibroids are causing an enlarged or distorted uterus. Note that this is an off-label use for some gonadotrophin-releasing hormone analogues. See NICE's information on prescribing medicines.
## Route and method of hysterectomy
When discussing the route of hysterectomy (laparoscopy, laparotomy or vaginal) with the woman, carry out an individual assessment and take her preferences into account.
Discuss the options of total hysterectomy (removal of the uterus and the cervix) and subtotal hysterectomy (removal of the uterus and retention of the cervix) with the woman.
## Removal of ovaries (oophorectomy) with hysterectomy
Only remove ovaries with hysterectomy with the express wish and informed consent of the woman, after discussion of all associated risks and benefits.
## Dilatation and curettage
Do not offer dilatation and curettage as a treatment option for HMB.
If dilatation is needed for non-hysteroscopic endometrial ablation:
confirm that there is no evidence of uterine perforation or false passage
use hysteroscopy before inserting the ablation device, to establish the condition of the uterus
ultrasound may be used to ensure correct uterine placement of the ablation device; if the device uses a balloon, keep this inflated during the ultrasound scan.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on management of HMB .
Full details of the evidence and the committee's discussion are in evidence review B: management of heavy menstrual bleeding.
Loading. Please wait.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Hysteroscopy compared with ultrasound or empiric pharmacological treatment in the diagnosis and management of heavy menstrual bleeding (HMB)
Is initial testing using hysteroscopy more effective than testing with pelvic ultrasound or empiric pharmacological treatment in the diagnosis and management of HMB?
## Why this is important
There is no consensus about the best test-and-treat strategy for women with HMB, and empiric pharmacological treatment is often initiated as a first treatment without investigation. Parameters of diagnostic accuracy give useful information about a test's ability to detect a condition (or the absence of a condition). But accurate diagnosis does not automatically result in a better overall outcome for the woman, because this also depends on treatment decisions after the diagnosis is made. However, it is thought that optimal treatment depends on accurate diagnosis of the underlying pathology causing HMB.
In the absence of clinical trials, decision analytical economic models evaluating all possible outpatient testing algorithms have indicated that using ultrasound or hysteroscopy for initial diagnostic testing for women with HMB are the most effective diagnostic strategies. Pelvic ultrasound has been most commonly used because it has been more widely available and is considered less intrusive than hysteroscopy. However, advances in technology mean that the hysteroscopy is well tolerated in the outpatient setting, and it can potentially be performed outside the traditional hospital environment in a community setting. Moreover, in contrast with ultrasound, hysteroscopy allows concomitant treatment of intrauterine pathologies such as submucosal fibroids and endometrial polyps. It also facilitates the fitting of levonorgestrel-releasing intrauterine systems (LNG-IUS).
A test-and-treat randomised controlled trial with cost-effectiveness analysis could help to answer the crucial question of whether hysteroscopy improves outcomes for women and results in more effective use of NHS resources.
# Effectiveness of the progestogen-only pill, injectable progestogens, or progestogen implants in alleviating HMB
How effective are the progestogen-only pill, injectable progestogens or progestogen implants in alleviating HMB?
## Why this is important
Many women use LNG-IUS as the first-line pharmacological treatment for HMB, but it is not acceptable to all women. Combined oral contraceptives have also been shown to be effective for treating HMB, but their use is contraindicated in some women. Other progestogens used for contraception have far fewer contraindications than combined contraceptives, but their effectiveness as a treatment for HMB has not been studied.
A randomised controlled trial or cohort prospective observational study could compare the effectiveness of progestogens with other pharmacological treatments for HMB.
# Long-term outcomes of pharmacological and uterine-sparing surgical treatments for HMB associated with adenomyosis
What are the long-term clinical outcomes of pharmacological and uterine-sparing surgical treatments in women with HMB associated with adenomyosis?
## Why this is important
Adenomyosis is common, and the symptoms cause significant morbidity, including restriction of daily activities. A wide range of incidences have been suggested, but most studies report a prevalence of between 20 and 35%. Despite this, there is little evidence about the impact of adenomyosis on symptoms of HMB or the best treatment for this condition. Optimising treatment can lead to better patient satisfaction and the avoidance of unnecessary investigations and treatments. In order to do this, a better understanding of the impact of adenomyosis in causing HMB, pain and subfertility is needed.
A prospective clinical registry would allow long-term clinical outcomes such as patient satisfaction and re-intervention for refractory symptoms, to be recorded after pharmacological and uterine-sparing surgical treatments for women with adenomyosis.
# Hysteroscopic removal of submucosal fibroids compared with other uterine-sparing treatments for HMB
Is hysteroscopic removal of submucosal fibroids more effective and cost-effective than other uterine-sparing treatments for the management of HMB?
## Why this is important
HMB is thought to be caused by submucosal fibroids in around 15% of women. Such fibroids are amenable to minimally invasive surgical removal ('hysteroscopic myomectomy'), avoiding the need for surgical incision. Non-comparative data have reported improvement in HMB symptoms and the avoidance of further pharmacological or surgical treatment in 70 to 80% of women treated with hysteroscopic myomectomy.
Specific hysteroscopic surgical skills are necessary to optimise surgical success and minimise complications. However, recent advances in endoscopic technologies have made hysteroscopic myomectomy potentially safer and more feasible.
A randomised controlled trial comparing this technique with long-term pharmacological therapy or more invasive surgical intervention would provide information on long-term outcomes.
# Second-generation endometrial ablation for HMB associated with myometrial pathology
Are outcomes after second-generation endometrial ablation for women with HMB associated with myometrial pathology (adenomyosis and/or uterine fibroids) equivalent to those for women without myometrial pathology?
## Why this is important
With the wider availability of high-resolution transvaginal pelvic ultrasound, adenomyosis and fibroids have been recognised as 2 of the most common uterine pathologies in women presenting with HMB. Pharmacological treatments appear to be less effective in the presence of these conditions, making referral to specialist care for surgery more likely.
Second-generation endometrial ablation is a minimally invasive, uterine-sparing surgical procedure, but its effectiveness in women with adenomyosis or uterine fibroids is unclear. Thus women with these conditions may be denied second-generation endometrial ablation and undergo unnecessary invasive surgery such as hysterectomy. On the other hand, women may be subjected to ineffective second-generation endometrial ablation that delays more effective treatment such as hysterectomy. It is therefore important to evaluate the effectiveness of second-generation endometrial ablation in women with these conditions, and a cohort controlled study is suggested as the best approach for doing this.# Rationale and impact
# Investigations for the cause of HMB
Recommendations 1.3.1 to 1.3.14
## Why the committee made the recommendations
The committee agreed that investigation is not necessary before starting treatment when history and examination do not suggest structural abnormalities or endometrial pathology.
The choice of first-line investigation should depend on the woman's history and examination findings. The committee made recommendations for using hysteroscopy or ultrasound that were based on the available evidence for diagnostic accuracy.
Outpatient hysteroscopy is recommended for women with HMB if uterine cavity abnormalities or endometrial pathology are suspected because:
the evidence showed that it is more accurate (higher sensitivity and specificity) in identifying them than pelvic ultrasound
it is safe and has a low risk of complications
it is acceptable to women if done according to best practice guidelines
women can have submucosal fibroids and polyps removed during the procedure, and targeted biopsy if needed
it is cost-effective as part of a diagnosis and treatment strategy.
For women who decline outpatient hysteroscopy, the committee agreed that hysteroscopy under general or regional anaesthetic should be offered, because the benefits of accurate identification outweigh the risks of anaesthesia.
Pelvic ultrasound can be considered for women who decline hysteroscopy, provided that they understand and accept that it is less accurate in detecting uterine cavity abnormalities and endometrial pathology.
Endometrial biopsy should only be taken in the context of hysteroscopy and only from women who a have a high risk of endometrial pathology, to avoid unnecessary and painful biopsies. 'Blind' endometrial biopsy is not recommended because it may not identify treatable lesions.
Hysteroscopy is not able to detect abnormalities outside the uterine cavity, such as subserous or intramural fibroids, or adenomyosis. If an examination suggests a large fibroid or several fibroids, pelvic ultrasound (transvaginal or transabdominal) is recommended instead of hysteroscopy and is likely to be particularly cost-effective in this context.
The committee agreed that if abdominal or vaginal examination is difficult to perform or inconclusive (for example, because the woman is obese), pelvic ultrasound would be helpful to identify any abnormalities that might have otherwise been suggested by examination.
The evidence showed that transvaginal ultrasound is more accurate than transabdominal ultrasound or MRI for detecting adenomyosis. Although transvaginal ultrasound is more intrusive than the other investigations, the committee's experience suggests that many women find it acceptable. It is also widely available in secondary care, and sometimes in primary care.
Transvaginal ultrasound may not be acceptable to or suitable for some women, such as women who have not been sexually active or women with female genital mutilation. The committee agreed that transabdominal ultrasound or MRI can be considered for these women, provided that they understand and accept that they are less accurate for detecting adenomyosis.
## How the 2018 recommendations might affect practice
Hysteroscopy, in preference to pelvic ultrasound, is recommended for women with HMB who are suspected of having submucosal fibroids, polyps or endometrial pathology based on their history and examination. This change in practice will have a resource impact on service organisation and training.
Ultrasound is available through direct booking in primary care, whereas hysteroscopy is not. Changes to services will be needed to allow direct access booking into one-stop hysteroscopy services and ideally to increase delivery in community-based clinics. Specialists could offer more services in the community, or GPs and nurses could be trained to perform hysteroscopy in primary care. However, there should be ongoing savings because the number of unnecessary investigations is reduced and women are offered effective treatment as a result of more accurate diagnosis.
To ensure that outpatient hysteroscopy is acceptable to women, it is essential that the procedure is done according to best practice guidelines, including techniques and equipment to minimise discomfort and pain in women; adequately sized, equipped, and staffed facilities; staff with necessary training, skills and expertise; and the need for audit and benchmarking of outcomes.
Transvaginal and transabdominal ultrasound are already widely available in secondary care and sometimes in primary care.
The committee noted that clinicians might need additional training and experience in interpreting transvaginal ultrasound scans to identify signs of adenomyosis.
For full details of the evidence and the committee's discussion see evidence review A: diagnostic test accuracy in investigation for women presenting with heavy menstrual bleeding.
# Management of HMB
Recommendations 1.5.1 to 1.5.15
## Why the committee made the recommendations
The committee emphasised the importance of talking to the woman about her needs and preferences when deciding on treatments for HMB. This includes any plans for pregnancy and whether she wants to retain her uterus or fertility. The committee also highlighted that the cause of HMB and other symptoms should be taken into account. This is to ensure that the most appropriate management strategy is offered to the woman.
In current practice LNG-IUS is a first-line treatment for HMB in these women. Evidence supported this, showing that it is as effective as, or more effective than, other treatments in improving health-related quality of life and satisfaction with treatment. It also offered the best balance of benefits and costs. However, the committee agreed that more research is needed to determine the benefit to women of investigations before treatment with LNG-IUS as a management strategy (see research recommendation 1).
The available evidence did not show clinically important differences in effectiveness and acceptability among the other pharmacological treatments, so there are several options that may be considered if a woman declines LNG-IUS or it is not suitable.
For women with severe symptoms and those for whom initial treatment is unsuccessful, the committee agreed that referral to specialist care may be considered, because some women may benefit from further investigations (in particular those who started treatment without investigations) or from specialist management.
There was a lack of evidence about second-line treatment, so a choice of pharmacological and surgical options can be considered.
The committee agreed that women who decline pharmacological treatment and ask for surgery as a first treatment may be referred to specialist care for consideration of further investigations and surgical treatment. The evidence showed that reduction in blood loss and satisfaction with treatment was greater for hysterectomy and second-generation endometrial ablation techniques than for first-generation endometrial ablation.
No evidence was found about hysteroscopic removal of submucosal fibroids, but the committee agreed that it is an effective treatment that is acceptable to many women. It can be done at the same time as diagnostic hysteroscopy if facilities are available.
The committee emphasised the importance of taking into account the size, number and location of fibroids, and severity of symptoms, when treating fibroids of 3 cm or more in diameter. This is because women with fibroids that are substantially greater than 3 cm in diameter may benefit from more invasive treatment, such as uterine artery embolisation or surgery. Therefore, referral to specialist care to discuss all treatment options with the woman should be considered.
There was limited evidence that did not favour any one treatment over others for women with fibroids of 3 cm or more in diameter. However, the evidence for pharmacological treatment options was mainly for fibroids not substantially greater than 3 cm in diameter, whereas the evidence for interventional or surgical treatments was mainly for fibroids substantially greater than 3 cm in diameter. The committee agreed that pharmacological treatment is not always the best option for fibroids that are substantially greater than 3 cm in diameter because of their physical effect on the uterine cavity. In addition, some women may prefer not to have pharmacological treatment. Therefore uterine artery embolisation and surgery are included as first-line treatment options.
Evidence on ulipristal acetate was not reviewed as part of this guideline update, but the committee agreed that it is an option for these women.
The committee agreed that second-generation endometrial ablation may be suitable for some women with fibroids that are substantially greater than 3 cm in diameter in the absence of associated pressure-related fibroid symptoms. They were unable to define criteria for eligibility, because these differ for the different techniques (in terms of the size, shape, uniformity and integrity of the uterine cavity) and are specified by the manufacturers.
There was a lack of evidence about specific second-line treatments, so the committee agreed that alternative pharmacological and surgical options should be considered if initial treatment is unsuccessful, after reviewing whether further investigation is needed.
## How the 2018 recommendations might affect practice
The committee noted that the recommendations should reinforce current best practice and help to reduce variation in clinical practice for the treatment of HMB.
In current practice, hysterectomy is a second-line treatment strategy for heavy menstrual bleeding, for which women need to have tried first-line treatment strategies, and for these to be unsuccessful, before being offered a hysterectomy. Offering hysterectomy as a first-line treatment option may result in an increase in hysterectomies. However, only a small group of women are expected to choose the procedure as first-line treatment.
For full details of the evidence and the committee's discussion see evidence review B: management of heavy menstrual bleeding.# Context
Heavy menstrual bleeding (HMB) is defined as excessive menstrual blood loss which interferes with a woman's physical, social, emotional and/or material quality of life. It can occur alone or in combination with other symptoms.
HMB is one of the most common reasons for gynaecological consultations in both primary and secondary care. About 1 in 20 women aged between 30 and 49 years consult their GP each year because of heavy periods or menstrual problems, and menstrual disorders comprise 12% of all referrals to gynaecology services.
The focus of this guideline is on women of reproductive age (after puberty and before the menopause) with HMB, including women with suspected or confirmed fibroids, and women with suspected or confirmed adenomyosis. The guideline does not primarily cover women with gynaecological bleeding other than HMB (for example, intermenstrual bleeding or postcoital bleeding) or with gynaecological conditions in which HMB is not the main symptom (such as endometriosis).
Since the publication of the original guideline in 2007, equipment and software for transvaginal ultrasound have improved. Outpatient hysteroscopy has become more widely available, and is more acceptable to women with the advent of modern equipment such as miniature hysteroscopes. Therefore the relative clinical and cost effectiveness of diagnostic strategies have changed. Improvements in diagnostic imaging in recent years have resulted in an increase in the reported prevalence of adenomyosis. Adenomyosis, which is associated with abnormal uterine bleeding, pelvic pain and infertility, was not included in the previous version of the guideline.
This guideline makes recommendations on a range of pharmacological and surgical treatment options for HMB. Outpatient management comprising insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) has increased in popularity in recent years, and there has been a reduction in surgical procedures. However, some endometrial ablation techniques (such as microwave endometrial ablation) are no longer available in the UK.
The guideline aims to help healthcare professionals advise each woman with HMB about the treatments that are right for her, with a clear focus on the woman's choice. It should be borne in mind that it is the woman herself who decides whether a treatment has been successful.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Impact of heavy menstrual bleeding (HMB) on women\n\nRecognise that heavy menstrual bleeding (HMB) has a major impact on a woman's quality of life, and ensure that any intervention aims to improve this rather than focusing on blood loss. \n\n# History, physical examination and laboratory tests\n\n## History\n\nTake a history from the woman that covers:\n\nthe nature of the bleeding\n\nrelated symptoms, such as persistent intermenstrual bleeding, pelvic pain and/or pressure symptoms, that might suggest uterine cavity abnormality, histological abnormality, adenomyosis or fibroids\n\nimpact on her quality of life\n\nother factors that may affect treatment options (such as comorbidities or previous treatment for HMB). [2007, amended 2018]\n\nTake into account the range and natural variability in menstrual cycles and blood loss when diagnosing HMB, and discuss this variation with the woman. If the woman feels that she does not fall within the normal ranges, discuss care options. \n\nIf the woman has a history of HMB without other related symptoms (see recommendation 1.2.1), consider pharmacological treatment without carrying out a physical examination (unless the treatment chosen is levonorgestrel-releasing intrauterine system [LNG IUS]). [2007, amended 2018] Note that this is an off-label use for some LNG-IUSs. See NICE's information on prescribing medicines.\n\n## Physical examination\n\nIf the woman has a history of HMB with other related symptoms (see recommendation 1.2.1) offer a physical examination. [2007, amended 2018]\n\nCarry out a physical examination before all investigations or LNG-IUS fittings. Note that this is an off-label use for some LNG-IUSs. See NICE's information on prescribing medicines.\n\n## Laboratory tests\n\nCarry out a full blood count test for all women with HMB, in parallel with any HMB treatment offered. \n\nTesting for coagulation disorders (for example, von Willebrand's disease) should be considered for women who:\n\nhave had HMB since their periods started and\n\nhave a personal or family history suggesting a coagulation disorder. \n\nDo not routinely carry out a serum ferritin test for women with HMB. \n\nDo not carry out female hormone testing for women with HMB. \n\nDo not carry out thyroid hormone testing for women with HMB unless other signs and symptoms of thyroid disease are present. \n\n# Investigations for the cause of HMB\n\n## Before starting investigations\n\nConsider starting pharmacological treatment for HMB without investigating the cause if the woman's history and/or examination suggests a low risk of fibroids, uterine cavity abnormality, histological abnormality or adenomyosis. \n\nIf cancer is suspected, see the NICE guideline on suspected cancer: recognition and referral. \n\n## Investigations\n\nTake into account the woman's history and examination when deciding whether to offer hysteroscopy or ultrasound as the first-line investigation. \n\nOffer outpatient hysteroscopy to women with HMB if their history suggests submucosal fibroids, polyps or endometrial pathology because:\n\nthey have symptoms such as persistent intermenstrual bleeding or\n\nthey have risk factors for endometrial pathology (see recommendation 1.3.10). \n\nEnsure that outpatient hysteroscopy services are organised and the procedure is performed according to best practice, including:\n\nadvising women to take oral analgesia before the procedure\n\nvaginoscopy as the standard diagnostic technique, using miniature hysteroscopes (3.5\xa0mm or smaller). \n\nEnsure that hysteroscopy services are organised to enable progression to 'see-and-treat' hysteroscopy in a single setting if feasible. \n\nExplain to women with HMB who are offered outpatient hysteroscopy what the procedure involves and discuss the possible alternatives. \n\nIf a woman declines outpatient hysteroscopy, offer hysteroscopy under general or regional anaesthesia. \n\nFor women who decline hysteroscopy, consider pelvic ultrasound, explaining the limitations of this technique for detecting uterine cavity causes of HMB. \n\nConsider endometrial biopsy at the time of hysteroscopy for women who are at high risk of endometrial pathology, such as:\n\nwomen with persistent intermenstrual or persistent irregular bleeding, and women with infrequent heavy bleeding who are obese or have polycystic ovary syndrome\n\nwomen taking tamoxifen\n\nwomen for whom treatment for HMB has been unsuccessful. [2007, amended 2018]\n\nObtain an endometrial sample only in the context of diagnostic hysteroscopy. Do not offer 'blind' endometrial biopsy to women with HMB. \n\nOffer pelvic ultrasound to women with HMB if any of the following apply:\n\ntheir uterus is palpable abdominally\n\nhistory or examination suggests a pelvic mass\n\nexamination is inconclusive or difficult, for example in women who are obese. \n\nOffer transvaginal ultrasound (in preference to transabdominal ultrasound or MRI) to women with HMB who have:\n\nsignificant dysmenorrhoea (period pain) or\n\na bulky, tender uterus on examination that suggests adenomyosis. \n\nIf a woman declines transvaginal ultrasound or it is not suitable for her, consider transabdominal ultrasound or MRI, explaining the limitations of these techniques. \n\nBe aware that pain associated with HMB may be caused by endometriosis rather than adenomyosis (see NICE's guideline on endometriosis). \n\n## Other diagnostic tools\n\nDo not use saline infusion sonography as a first-line diagnostic tool for HMB. \n\nDo not use MRI as a first-line diagnostic tool for HMB. \n\nDo not use dilatation and curettage alone as a diagnostic tool for HMB. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on investigations for the cause of HMB\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diagnostic test accuracy in investigation for women presenting with heavy menstrual bleeding.\n\nLoading. Please wait.\n\n# Information for women about HMB and treatments\n\nProvide women with information about HMB and its management. Follow the principles in the NICE guidelines on patient experience in adult NHS services and shared decision making in relation to communication, information and shared decision-making. \n\nProvide information about all possible treatment options for HMB and discuss these with the woman (see section 1.5). Discussions should cover:\n\nthe benefits and risks of the various options\n\nsuitable treatments if she is trying to conceive\n\nwhether she wants to retain her fertility and/or her uterus. \n\n## Levonorgestrel-releasing intrauterine system (LNG-IUS)\n\nExplain to women who are offered an LNG-IUS:\n\nabout anticipated changes in bleeding pattern, particularly in the first few cycles and maybe lasting longer than 6\xa0months\n\nthat it is advisable to wait for at least 6\xa0cycles to see the benefits of the treatment. Note that this is an off-label use for some LNG-IUSs. See NICE's information on prescribing medicines.\n\n## Impact of treatments on fertility\n\nExplain to women about the impact on fertility that any planned surgery or uterine artery embolisation may have, and if a potential treatment (hysterectomy or ablation) involves loss of fertility then opportunities for discussion should be made available. \n\nExplain to women that uterine artery embolisation or myomectomy may potentially allow them to retain their fertility. \n\n## Endometrial ablation\n\nAdvise women to avoid subsequent pregnancy and use effective contraception, if needed, after endometrial ablation. \n\n## Hysterectomy\n\nHave a full discussion with all women who are considering hysterectomy about the implications of surgery before a decision is made. The discussion should include:\n\nsexual feelings\n\nimpact on fertility\n\nbladder function\n\nneed for further treatment\n\ntreatment complications\n\nher expectations\n\nalternative surgery\n\npsychological impact. \n\nInform women about the increased risk of serious complications (such as intraoperative haemorrhage or damage to other abdominal organs) associated with hysterectomy when uterine fibroids are present. \n\nInform women about the risk of possible loss of ovarian function and its consequences, even if their ovaries are retained during hysterectomy. \n\n# Management of HMB\n\nWhen agreeing treatment options for HMB with women, take into account:\n\nthe woman's preferences\n\nany comorbidities\n\nthe presence or absence of fibroids (including size, number and location), polyps, endometrial pathology or adenomyosis\n\nother symptoms such as pressure and pain. \n\n## Treatments for women with no identified pathology, fibroids less than 3\xa0cm in diameter, or suspected or diagnosed adenomyosis\n\nConsider an LNG-IUS as the first treatment for HMB in women with:\n\nno identified pathology or\n\nfibroids less than 3\xa0cm in diameter, which are not causing distortion of the uterine cavity or\n\nsuspected or diagnosed adenomyosis. Note that this is an off-label use for some LNG-IUSs. See NICE's information on prescribing medicines.\n\nIf a woman with HMB declines an LNG-IUS or it is not suitable, consider the following pharmacological treatments:\n\nnon-hormonal:\n\n\n\ntranexamic acid\n\nNSAIDs (non-steroidal anti-inflammatory drugs)\n\n\n\nhormonal:\n\n\n\ncombined hormonal contraception\n\ncyclical oral progestogens. Note that this is an off-label use for NSAIDs and some combined hormonal contraceptives. See NICE's information on prescribing medicines.\n\n\n\nBe aware that progestogen-only contraception may suppress menstruation, which could be beneficial to women with HMB. \n\nIf treatment is unsuccessful, the woman declines pharmacological treatment, or symptoms are severe, consider referral to specialist care for:\n\ninvestigations to diagnose the cause of HMB, if needed (see section 1.3) taking into account any investigations the woman has already had and\n\nalternative treatment choices, including:\n\n\n\npharmacological options not already tried (see recommendations 1.5.2 and 1.5.3)\n\nsurgical options:\n\n\n\nsecond-generation endometrial ablation\n\nhysterectomy. \n\n\n\n\n\nFor women with submucosal fibroids, consider hysteroscopic removal. \n\n## Treatments for women with fibroids of 3\xa0cm or more in diameter\n\nConsider referring women to specialist care to undertake additional investigations and discuss treatment options for fibroids of 3\xa0cm or more in diameter. \n\nIf pharmacological treatment is needed while investigations and definitive treatment are being organised, offer tranexamic acid and/or NSAIDs. Note that this is an off-label use for NSAIDs. See NICE's information on prescribing medicines.\n\nAdvise women to continue using NSAIDs and/or tranexamic acid for as long as they are found to be beneficial. Note that this is an off-label use for NSAIDs. See NICE's information on prescribing medicines.\n\nFor women with fibroids of 3\xa0cm or more in diameter, take into account the size, location and number of fibroids, and the severity of the symptoms and consider the following treatments:\n\npharmacological:\n\n\n\nnon-hormonal:\n\n\n\ntranexamic acid\n\nNSAIDs\n\n\n\nhormonal:\n\n\n\nLNG-IUS\n\ncombined hormonal contraception\n\ncyclical oral progestogens\n\nulipristal acetate (this is only indicated for some premenopausal women; see recommendations 1.5.11 and 1.5.12 for more information) [amended 2021]\n\n\n\n\n\nuterine artery embolisation for fibroids\n\nsurgical:\n\n\n\nmyomectomy\n\nhysterectomy.Note that this is an off-label use for NSAIDs and some LNG-IUSs. See NICE's information on prescribing medicines. \n\n\n\nOnly think about ulipristal acetate for the intermittent treatment of moderate to severe symptoms of uterine fibroids in premenopausal women if:\n\nsurgery and uterine artery embolisation for fibroids are not suitable, for example, because the risks to a woman outweigh the possible benefits, or\n\nsurgery and uterine artery embolisation for fibroids have failed, or\n\nthe woman declines surgery and uterine artery embolisation for fibroids.See the MHRA drug safety update on ulipristal acetate. \n\nDiscuss with the woman the risks and possible benefits of intermittent treatment with ulipristal acetate.\n\nAdvise that ulipristal acetate can be associated with serious liver injury leading to liver failure, and the signs and symptoms to look out for.\n\nMeasure liver function before starting ulipristal acetate, monthly for the first 2 courses and once before each new treatment course when clinically indicated.\n\nIf there is no underlying liver injury, and surgery and uterine artery embolisation for fibroids are unsuitable or have failed, consider ulipristal acetate 5\xa0mg (up to 4 courses) for premenopausal women with heavy menstrual bleeding and fibroids of 3\xa0cm or more in diameter, particularly if the haemoglobin level is 102\xa0g per litre or below.\n\nIf a woman shows signs and symptoms of liver failure, stop ulipristal acetate and perform liver function tests urgently. \n\nBe aware that the effectiveness of pharmacological treatments for HMB may be limited in women with fibroids that are substantially greater than 3\xa0cm in diameter. [2018, amended 2020]\n\nPrior to scheduling of uterine artery embolisation or myomectomy, the woman's uterus and fibroid(s) should be assessed by ultrasound. If further information about fibroid position, size, number and vascularity is needed, MRI should be considered. \n\nConsider second-generation endometrial ablation as a treatment option for women with HMB and fibroids of 3\xa0cm or more in diameter who meet the criteria specified in the manufacturers' instructions. \n\nIf treatment is unsuccessful:\n\nconsider further investigations to reassess the cause of HMB (see section 1.3), taking into account the results of previous investigations and\n\noffer alternative treatment with a choice of the options described in recommendation 1.5.10. \n\nPretreatment with a gonadotrophin-releasing hormone analogue before hysterectomy and myomectomy should be considered if uterine fibroids are causing an enlarged or distorted uterus. [2007, amended 2020]Note that this is an off-label use for some gonadotrophin-releasing hormone analogues. See NICE's information on prescribing medicines.\n\n## Route and method of hysterectomy\n\nWhen discussing the route of hysterectomy (laparoscopy, laparotomy or vaginal) with the woman, carry out an individual assessment and take her preferences into account. [2007, amended 2018]\n\nDiscuss the options of total hysterectomy (removal of the uterus and the cervix) and subtotal hysterectomy (removal of the uterus and retention of the cervix) with the woman. [2007, amended 2018]\n\n## Removal of ovaries (oophorectomy) with hysterectomy\n\nOnly remove ovaries with hysterectomy with the express wish and informed consent of the woman, after discussion of all associated risks and benefits. [2007, amended 2018]\n\n## Dilatation and curettage\n\nDo not offer dilatation and curettage as a treatment option for HMB. \n\nIf dilatation is needed for non-hysteroscopic endometrial ablation:\n\nconfirm that there is no evidence of uterine perforation or false passage\n\nuse hysteroscopy before inserting the ablation device, to establish the condition of the uterus\n\nultrasound may be used to ensure correct uterine placement of the ablation device; if the device uses a balloon, keep this inflated during the ultrasound scan. [2007, amended 2018]\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on management of HMB\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: management of heavy menstrual bleeding.\n\nLoading. Please wait.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Hysteroscopy compared with ultrasound or empiric pharmacological treatment in the diagnosis and management of heavy menstrual bleeding (HMB)\n\nIs initial testing using hysteroscopy more effective than testing with pelvic ultrasound or empiric pharmacological treatment in the diagnosis and management of HMB?\n\n## Why this is important\n\nThere is no consensus about the best test-and-treat strategy for women with HMB, and empiric pharmacological treatment is often initiated as a first treatment without investigation. Parameters of diagnostic accuracy give useful information about a test's ability to detect a condition (or the absence of a condition). But accurate diagnosis does not automatically result in a better overall outcome for the woman, because this also depends on treatment decisions after the diagnosis is made. However, it is thought that optimal treatment depends on accurate diagnosis of the underlying pathology causing HMB.\n\nIn the absence of clinical trials, decision analytical economic models evaluating all possible outpatient testing algorithms have indicated that using ultrasound or hysteroscopy for initial diagnostic testing for women with HMB are the most effective diagnostic strategies. Pelvic ultrasound has been most commonly used because it has been more widely available and is considered less intrusive than hysteroscopy. However, advances in technology mean that the hysteroscopy is well tolerated in the outpatient setting, and it can potentially be performed outside the traditional hospital environment in a community setting. Moreover, in contrast with ultrasound, hysteroscopy allows concomitant treatment of intrauterine pathologies such as submucosal fibroids and endometrial polyps. It also facilitates the fitting of levonorgestrel-releasing intrauterine systems (LNG-IUS).\n\nA test-and-treat randomised controlled trial with cost-effectiveness analysis could help to answer the crucial question of whether hysteroscopy improves outcomes for women and results in more effective use of NHS resources.\n\n# Effectiveness of the progestogen-only pill, injectable progestogens, or progestogen implants in alleviating HMB\n\nHow effective are the progestogen-only pill, injectable progestogens or progestogen implants in alleviating HMB?\n\n## Why this is important\n\nMany women use LNG-IUS as the first-line pharmacological treatment for HMB, but it is not acceptable to all women. Combined oral contraceptives have also been shown to be effective for treating HMB, but their use is contraindicated in some women. Other progestogens used for contraception have far fewer contraindications than combined contraceptives, but their effectiveness as a treatment for HMB has not been studied.\n\nA randomised controlled trial or cohort prospective observational study could compare the effectiveness of progestogens with other pharmacological treatments for HMB.\n\n# Long-term outcomes of pharmacological and uterine-sparing surgical treatments for HMB associated with adenomyosis\n\nWhat are the long-term clinical outcomes of pharmacological and uterine-sparing surgical treatments in women with HMB associated with adenomyosis?\n\n## Why this is important\n\nAdenomyosis is common, and the symptoms cause significant morbidity, including restriction of daily activities. A wide range of incidences have been suggested, but most studies report a prevalence of between 20 and 35%. Despite this, there is little evidence about the impact of adenomyosis on symptoms of HMB or the best treatment for this condition. Optimising treatment can lead to better patient satisfaction and the avoidance of unnecessary investigations and treatments. In order to do this, a better understanding of the impact of adenomyosis in causing HMB, pain and subfertility is needed.\n\nA prospective clinical registry would allow long-term clinical outcomes such as patient satisfaction and re-intervention for refractory symptoms, to be recorded after pharmacological and uterine-sparing surgical treatments for women with adenomyosis.\n\n# Hysteroscopic removal of submucosal fibroids compared with other uterine-sparing treatments for HMB\n\nIs hysteroscopic removal of submucosal fibroids more effective and cost-effective than other uterine-sparing treatments for the management of HMB?\n\n## Why this is important\n\nHMB is thought to be caused by submucosal fibroids in around 15% of women. Such fibroids are amenable to minimally invasive surgical removal ('hysteroscopic myomectomy'), avoiding the need for surgical incision. Non-comparative data have reported improvement in HMB symptoms and the avoidance of further pharmacological or surgical treatment in 70 to 80% of women treated with hysteroscopic myomectomy.\n\nSpecific hysteroscopic surgical skills are necessary to optimise surgical success and minimise complications. However, recent advances in endoscopic technologies have made hysteroscopic myomectomy potentially safer and more feasible.\n\nA randomised controlled trial comparing this technique with long-term pharmacological therapy or more invasive surgical intervention would provide information on long-term outcomes.\n\n# Second-generation endometrial ablation for HMB associated with myometrial pathology\n\nAre outcomes after second-generation endometrial ablation for women with HMB associated with myometrial pathology (adenomyosis and/or uterine fibroids) equivalent to those for women without myometrial pathology?\n\n## Why this is important\n\nWith the wider availability of high-resolution transvaginal pelvic ultrasound, adenomyosis and fibroids have been recognised as 2 of the most common uterine pathologies in women presenting with HMB. Pharmacological treatments appear to be less effective in the presence of these conditions, making referral to specialist care for surgery more likely.\n\nSecond-generation endometrial ablation is a minimally invasive, uterine-sparing surgical procedure, but its effectiveness in women with adenomyosis or uterine fibroids is unclear. Thus women with these conditions may be denied second-generation endometrial ablation and undergo unnecessary invasive surgery such as hysterectomy. On the other hand, women may be subjected to ineffective second-generation endometrial ablation that delays more effective treatment such as hysterectomy. It is therefore important to evaluate the effectiveness of second-generation endometrial ablation in women with these conditions, and a cohort controlled study is suggested as the best approach for doing this.", 'Rationale and impact': "# Investigations for the cause of HMB\n\nRecommendations 1.3.1 to 1.3.14\n\n## Why the committee made the recommendations\n\nThe committee agreed that investigation is not necessary before starting treatment when history and examination do not suggest structural abnormalities or endometrial pathology.\n\nThe choice of first-line investigation should depend on the woman's history and examination findings. The committee made recommendations for using hysteroscopy or ultrasound that were based on the available evidence for diagnostic accuracy.\n\nOutpatient hysteroscopy is recommended for women with HMB if uterine cavity abnormalities or endometrial pathology are suspected because:\n\nthe evidence showed that it is more accurate (higher sensitivity and specificity) in identifying them than pelvic ultrasound\n\nit is safe and has a low risk of complications\n\nit is acceptable to women if done according to best practice guidelines\n\nwomen can have submucosal fibroids and polyps removed during the procedure, and targeted biopsy if needed\n\nit is cost-effective as part of a diagnosis and treatment strategy.\n\nFor women who decline outpatient hysteroscopy, the committee agreed that hysteroscopy under general or regional anaesthetic should be offered, because the benefits of accurate identification outweigh the risks of anaesthesia.\n\nPelvic ultrasound can be considered for women who decline hysteroscopy, provided that they understand and accept that it is less accurate in detecting uterine cavity abnormalities and endometrial pathology.\n\nEndometrial biopsy should only be taken in the context of hysteroscopy and only from women who a have a high risk of endometrial pathology, to avoid unnecessary and painful biopsies. 'Blind' endometrial biopsy is not recommended because it may not identify treatable lesions.\n\nHysteroscopy is not able to detect abnormalities outside the uterine cavity, such as subserous or intramural fibroids, or adenomyosis. If an examination suggests a large fibroid or several fibroids, pelvic ultrasound (transvaginal or transabdominal) is recommended instead of hysteroscopy and is likely to be particularly cost-effective in this context.\n\nThe committee agreed that if abdominal or vaginal examination is difficult to perform or inconclusive (for example, because the woman is obese), pelvic ultrasound would be helpful to identify any abnormalities that might have otherwise been suggested by examination.\n\nThe evidence showed that transvaginal ultrasound is more accurate than transabdominal ultrasound or MRI for detecting adenomyosis. Although transvaginal ultrasound is more intrusive than the other investigations, the committee's experience suggests that many women find it acceptable. It is also widely available in secondary care, and sometimes in primary care.\n\nTransvaginal ultrasound may not be acceptable to or suitable for some women, such as women who have not been sexually active or women with female genital mutilation. The committee agreed that transabdominal ultrasound or MRI can be considered for these women, provided that they understand and accept that they are less accurate for detecting adenomyosis.\n\n## How the 2018 recommendations might affect practice\n\nHysteroscopy, in preference to pelvic ultrasound, is recommended for women with HMB who are suspected of having submucosal fibroids, polyps or endometrial pathology based on their history and examination. This change in practice will have a resource impact on service organisation and training.\n\nUltrasound is available through direct booking in primary care, whereas hysteroscopy is not. Changes to services will be needed to allow direct access booking into one-stop hysteroscopy services and ideally to increase delivery in community-based clinics. Specialists could offer more services in the community, or GPs and nurses could be trained to perform hysteroscopy in primary care. However, there should be ongoing savings because the number of unnecessary investigations is reduced and women are offered effective treatment as a result of more accurate diagnosis.\n\nTo ensure that outpatient hysteroscopy is acceptable to women, it is essential that the procedure is done according to best practice guidelines, including techniques and equipment to minimise discomfort and pain in women; adequately sized, equipped, and staffed facilities; staff with necessary training, skills and expertise; and the need for audit and benchmarking of outcomes.\n\nTransvaginal and transabdominal ultrasound are already widely available in secondary care and sometimes in primary care.\n\nThe committee noted that clinicians might need additional training and experience in interpreting transvaginal ultrasound scans to identify signs of adenomyosis.\n\nFor full details of the evidence and the committee's discussion see evidence review A: diagnostic test accuracy in investigation for women presenting with heavy menstrual bleeding.\n\n# Management of HMB\n\nRecommendations 1.5.1 to 1.5.15\n\n## Why the committee made the recommendations\n\nThe committee emphasised the importance of talking to the woman about her needs and preferences when deciding on treatments for HMB. This includes any plans for pregnancy and whether she wants to retain her uterus or fertility. The committee also highlighted that the cause of HMB and other symptoms should be taken into account. This is to ensure that the most appropriate management strategy is offered to the woman.\n\nIn current practice LNG-IUS is a first-line treatment for HMB in these women. Evidence supported this, showing that it is as effective as, or more effective than, other treatments in improving health-related quality of life and satisfaction with treatment. It also offered the best balance of benefits and costs. However, the committee agreed that more research is needed to determine the benefit to women of investigations before treatment with LNG-IUS as a management strategy (see research recommendation 1).\n\nThe available evidence did not show clinically important differences in effectiveness and acceptability among the other pharmacological treatments, so there are several options that may be considered if a woman declines LNG-IUS or it is not suitable.\n\nFor women with severe symptoms and those for whom initial treatment is unsuccessful, the committee agreed that referral to specialist care may be considered, because some women may benefit from further investigations (in particular those who started treatment without investigations) or from specialist management.\n\nThere was a lack of evidence about second-line treatment, so a choice of pharmacological and surgical options can be considered.\n\nThe committee agreed that women who decline pharmacological treatment and ask for surgery as a first treatment may be referred to specialist care for consideration of further investigations and surgical treatment. The evidence showed that reduction in blood loss and satisfaction with treatment was greater for hysterectomy and second-generation endometrial ablation techniques than for first-generation endometrial ablation.\n\nNo evidence was found about hysteroscopic removal of submucosal fibroids, but the committee agreed that it is an effective treatment that is acceptable to many women. It can be done at the same time as diagnostic hysteroscopy if facilities are available.\n\nThe committee emphasised the importance of taking into account the size, number and location of fibroids, and severity of symptoms, when treating fibroids of 3\xa0cm or more in diameter. This is because women with fibroids that are substantially greater than 3\xa0cm in diameter may benefit from more invasive treatment, such as uterine artery embolisation or surgery. Therefore, referral to specialist care to discuss all treatment options with the woman should be considered.\n\nThere was limited evidence that did not favour any one treatment over others for women with fibroids of 3\xa0cm or more in diameter. However, the evidence for pharmacological treatment options was mainly for fibroids not substantially greater than 3\xa0cm in diameter, whereas the evidence for interventional or surgical treatments was mainly for fibroids substantially greater than 3\xa0cm in diameter. The committee agreed that pharmacological treatment is not always the best option for fibroids that are substantially greater than 3\xa0cm in diameter because of their physical effect on the uterine cavity. In addition, some women may prefer not to have pharmacological treatment. Therefore uterine artery embolisation and surgery are included as first-line treatment options.\n\nEvidence on ulipristal acetate was not reviewed as part of this guideline update, but the committee agreed that it is an option for these women.\n\nThe committee agreed that second-generation endometrial ablation may be suitable for some women with fibroids that are substantially greater than 3\xa0cm in diameter in the absence of associated pressure-related fibroid symptoms. They were unable to define criteria for eligibility, because these differ for the different techniques (in terms of the size, shape, uniformity and integrity of the uterine cavity) and are specified by the manufacturers.\n\nThere was a lack of evidence about specific second-line treatments, so the committee agreed that alternative pharmacological and surgical options should be considered if initial treatment is unsuccessful, after reviewing whether further investigation is needed.\n\n## How the 2018 recommendations might affect practice\n\nThe committee noted that the recommendations should reinforce current best practice and help to reduce variation in clinical practice for the treatment of HMB.\n\nIn current practice, hysterectomy is a second-line treatment strategy for heavy menstrual bleeding, for which women need to have tried first-line treatment strategies, and for these to be unsuccessful, before being offered a hysterectomy. Offering hysterectomy as a first-line treatment option may result in an increase in hysterectomies. However, only a small group of women are expected to choose the procedure as first-line treatment.\n\nFor full details of the evidence and the committee's discussion see evidence review B: management of heavy menstrual bleeding.", 'Context': "Heavy menstrual bleeding (HMB) is defined as excessive menstrual blood loss which interferes with a woman's physical, social, emotional and/or material quality of life. It can occur alone or in combination with other symptoms.\n\nHMB is one of the most common reasons for gynaecological consultations in both primary and secondary care. About 1 in 20 women aged between 30 and 49 years consult their GP each year because of heavy periods or menstrual problems, and menstrual disorders comprise 12% of all referrals to gynaecology services.\n\nThe focus of this guideline is on women of reproductive age (after puberty and before the menopause) with HMB, including women with suspected or confirmed fibroids, and women with suspected or confirmed adenomyosis. The guideline does not primarily cover women with gynaecological bleeding other than HMB (for example, intermenstrual bleeding or postcoital bleeding) or with gynaecological conditions in which HMB is not the main symptom (such as endometriosis).\n\nSince the publication of the original guideline in 2007, equipment and software for transvaginal ultrasound have improved. Outpatient hysteroscopy has become more widely available, and is more acceptable to women with the advent of modern equipment such as miniature hysteroscopes. Therefore the relative clinical and cost effectiveness of diagnostic strategies have changed. Improvements in diagnostic imaging in recent years have resulted in an increase in the reported prevalence of adenomyosis. Adenomyosis, which is associated with abnormal uterine bleeding, pelvic pain and infertility, was not included in the previous version of the guideline.\n\nThis guideline makes recommendations on a range of pharmacological and surgical treatment options for HMB. Outpatient management comprising insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) has increased in popularity in recent years, and there has been a reduction in surgical procedures. However, some endometrial ablation techniques (such as microwave endometrial ablation) are no longer available in the UK.\n\nThe guideline aims to help healthcare professionals advise each woman with HMB about the treatments that are right for her, with a clear focus on the woman's choice. It should be borne in mind that it is the woman herself who decides whether a treatment has been successful."}
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https://www.nice.org.uk/guidance/ng88
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This guideline covers assessing and managing heavy menstrual bleeding (menorrhagia). It aims to help healthcare professionals investigate the cause of heavy periods that are affecting a woman’s quality of life and to offer the right treatments, taking into account the woman’s priorities and preferences.
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1ec0f8feffcfe4d950a6b75de4e5e137120c0c7e
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nice
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HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography
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HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography
Evidence-based recommendations on HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography.
# Recommendations
The case for adopting HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography (CCTA) is supported by the evidence. The technology is non-invasive and safe, and has a high level of diagnostic accuracy.
HeartFlow FFRCT should be considered as an option for patients with stable, recent-onset chest pain who are offered CCTA in line with the NICE guideline on chest pain. Using HeartFlow FFRCT may avoid the need for invasive coronary angiography and revascularisation. For correct use, HeartFlow FFRCT requires access to 64‑slice (or above) CCTA facilities.
Based on the current evidence and assuming there is access to appropriate CCTA facilities, using HeartFlow FFRCT may lead to cost savings of £391 per patient . By adopting this technology, the NHS in England may save a minimum of £9.4 million by 2022 through avoiding invasive investigation and treatment .# The technology
# Description of the technology
HeartFlow FFRCT (developed by HeartFlow) is coronary physiology simulation software used for the qualitative and quantitative analysis of previously acquired computerised tomography DICOM data. The software provides a non-invasive method of estimating fractional flow reserve (FFR) using standard coronary CT angiography (CCTA) image data. FFR is the ratio between the maximum blood flow in a narrowed artery and the maximum blood flow in a normal artery. FFR is currently measured invasively using a pressure wire placed across a narrowed artery.
After a clinician decides to request a HeartFlow test, anonymised data from a CCTA scan (of at least 64 slices) are sent from the local imaging system, by secure data transfer to HeartFlow's central processing centre in the US. A case analyst employed by the company then uses the image data to create 3D computer models of the coronary arteries, incorporating coronary flow characteristics. The results are presented in a report which is sent, by secure data transfer, to the referring clinician within 48 hours. The report includes both 3D images of the coronary anatomy and calculated functional information, including the estimated FFR values (known as FFRCT values). Clinicians can then use the report to help guide the management of suspected coronary artery disease.
HeartFlow FFRCT is intended for use in patients with stable, recent-onset chest pain and suspected angina. Because the safety and effectiveness of FFRCT analysis has not been evaluated in other patient subgroups, HeartFlow FFRCT is not recommended in patients who have an acute coronary syndrome or have had a coronary stent, coronary bypass surgery or myocardial infarction in the past month.
The company first received a CE mark in July 2011, covering all 1.X versions of the technology, including the current version, 1.7.
HeartFlow FFRCT costs £700 per test. A higher price of £888 is used in the company submission and assessment report. The cost was reduced in May 2015.
The claimed benefits of HeartFlow FFRCT in the case for adoption presented by the company were as follows:
Analysis is done using standard CCTA scans, without the need for additional imaging, radiation or medication.
It provides the same accuracy in excluding coronary artery disease as CCTA, and characterises the coronary arteries from both functional and anatomical perspectives, differentiating between ischaemic and non-ischaemic vessels in a way that CCTA cannot.
It allows physicians to evaluate anatomical coronary artery disease and accurately determine which coronary lesions are responsible for myocardial ischaemia, avoiding unnecessary invasive diagnostic or therapeutic procedures and related complications.
It reduces the need for revascularisation in patients after identifying anatomical stenosis by invasive coronary angiography (ICA) alone, by more accurately identifying if those stenoses are ischaemic.
It improves the diagnostic accuracy for coronary artery disease compared with CCTA alone against the gold standard of invasive FFR, and provides both functional and anatomical assessment of coronary arteries.
It has better diagnostic performance than CCTA alone, or other non-invasive or invasive tests (such as nuclear myocardial perfusion, magnetic resonance perfusion, stress echocardiography, exercise treadmill testing, invasive angiography or intravascular ultrasound) for detecting and excluding coronary artery lesions that cause ischaemia.
It reduces costs arising from inconclusive or inaccurate diagnostic tests.
It avoids staff and procedure costs for unnecessary ICAs.
It avoids staff and procedure costs for unnecessary interventions (such as angioplasty).
It provides a more effective use of high-cost invasive procedure suites, providing the opportunity to reduce waiting times for these facilities and increase patient turnaround.
# Current management
The NICE guideline on chest pain recommends diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone.
The guideline recommends offering 64‑slice (or above) CCTA as the first-line diagnosis test when clinical assessment indicates typical or atypical angina; or non-anginal chest pain but 12‑lead resting ECG has been done and indicates ST‑T changes or Q waves.
Subsequent diagnostic tests can be requested dependent on the CCTA results. The guideline recommends offering non-invasive functional imaging for myocardial ischaemia if 64‑slice (or above) CCTA has shown coronary artery disease of uncertain functional significance, or is non-diagnostic. Non-invasive functional imaging includes:
myocardial perfusion scintigraphy with single-photon emission CT (MPS with SPECT)
stress echocardiography
first-pass contrast-enhanced MR perfusion
MR imaging for stress-induced wall motion abnormalities.ICA should be offered as a second-line investigation when the results of non-invasive functional imaging are inconclusive.
When ICA is used to determine the presence and severity of coronary stenosis, it may be combined with the invasive measurement of FFR using a pressure wire. Although the NICE guideline on chest pain does not consider FFR, other guidelines (such as those of the European Society of Cardiology and American College of Cardiology) state that lesions with an FFR of 0.80 or less are functionally significant and revascularisation may be considered.# Clinical evidence
The key clinical outcomes for HeartFlow FFRCT presented in the decision problem were:
measures of diagnostic accuracy (sensitivity and specificity, positive and negative likelihood ratios, area-under curve) using invasive fractional flow reserve (FFR) as the reference standard
rates of diagnostic coronary angiography, percutaneous coronary intervention and coronary artery bypass surgery
adverse events (test-related, major adverse cardiac events, radiation exposure and so on)
quality of life
mortality.
# Summary of diagnostic accuracy evidence
The company conducted a literature search on the diagnostic accuracy of FFRCT and the existing tests in the current treatment pathway for patients with a 10% to 90% pre-test likelihood of coronary artery disease, against a reference standard of invasive FFR testing. This review identified 5 relevant meta-analysis studies and 23 individual studies, 1 of which was unpublished. Based on the 22 published studies, and using FFR as the reference standard, the company presented diagnostic accuracy per-patient results for HeartFlow FFRCT compared with:
invasive coronary angiography (ICA)
single-photon emission CT (SPECT)
stress echocardiogram (ECHO)
magnetic resonance imaging (MRI)
coronary CT angiography (CCTA). If there were multiple studies for a test, the company conducted a meta-analysis; for example, 3 studies were included in the meta-analysis for HeartFlow FFRCT (Koo et al. 2011, Min et al. 2012 and Nørgaard et al. 2014). The methodology and results of the meta-analyses are reported as academic in confidence.
The external assessment centre (EAC) reviewed the company's selection of studies and considered that although they addressed the scope in terms of the comparators, reference test and outcomes, most included a mixture of patients with both high (over 90%) and intermediate (10% to 90%) pre-test likelihoods of disease. It also disagreed with the company's decision only to include studies that provided FFR measurements in more than 75% of blood vessels. The EAC considered this criterion not to be reflective of clinical practice, where visual assessment is sometimes used before proceeding with FFR measurements. The EAC also noted that this criterion did not reflect the company's proposed changes to the clinical pathway, where CCTA would be used to decide if HeartFlow FFRCT should be used.
To address these concerns, the EAC conducted a diagnostic literature search using extra keywords related to comparators and outcomes. It included only studies in which most patients had an intermediate pre-test likelihood of disease. The EAC identified 7 diagnostic studies, including 3 presented by the company (Bernhardt et al. 2012, Nørgaard et al. 2014 and Stuijfzand et al. 2014) and 3 that the company had identified but excluded (Danad et al. 2013, Kajander et al. 2010 and Ponte et al. 2014). Only 1 of these, Nørgaard et al. 2014, involved HeartFlow FFRCT.
Nørgaard et al. (2014) reported on a multicentre study (the NXT trial) involving 2 UK centres, which compared HeartFlow FFRCT (v1.4) with CCTA for diagnosing myocardial ischaemia in 254 patients with suspected stable coronary artery disease scheduled to have ICA. Most patients in the study (87%) were considered to have an intermediate likelihood of coronary artery disease. Invasive FFR was measured in all vessels (n=484). The study reported the diagnostic performance of HeartFlow FFRCT and CCTA for diagnosing ischaemia compared with FFR measured during ICA as the reference standard. The diagnostic accuracy of each test was presented on a per-patient and a per-vessel basis compared with the reference standard, an FFR value of ≤0.80. Per-vessel FFRCT was correlated to FFR (Pearson's correlation coefficient 0.82, p>0.001), with a slight underestimation of FFRCT compared with FFR. The authors concluded that HeartFlow FFRCT can identify functionally significant coronary artery disease with high sensitivity and specificity. Furthermore, adding FFRCT measurements to CCTA led to a marked increase in specificity.
The EAC identified 6 studies which both used the comparator tests and included patients with an intermediate likelihood of coronary artery disease. Bernhardt et al. (2012) compared the diagnostic performance of 1.5 T and 3 T MRI scanners using FFR as a reference standard in 34 patients with stable angina and suspected or known coronary artery disease. The authors studied an intermediate-risk population with a mean PROCAM score of 42.7 (a risk assessment metric which estimates the 10‑year risk of developing a coronary event). Ponte et al. (2014) compared the diagnostic accuracy of CCTA and MRI for detecting functionally significant coronary artery disease in patients referred with suspected coronary artery disease, using ICA with FFR as the reference standard. The study included 95 patients with a 15% to 85% pre-test likelihood of coronary artery disease. Stuijfzand et al. (2014) evaluated CCTA and transluminal attenuation gradient compared with CCTA alone for diagnosing functionally significant lesions, using invasive FFR as the reference standard. The study included 85 patients (253 vessels) with an intermediate likelihood of coronary artery disease. Neglia et al. (2015) assessed the accuracy of several imaging techniques – CCTA, SPECT and ECHO – in 475 patients with an intermediate likelihood of coronary artery disease. Danad et al. (2013) evaluated the diagnostic accuracy of CCTA in 120 patients with suspected coronary artery disease who had cardiac positron emission topography (PET), CCTA and ICA. CCTA was done using a hybrid PET/CT scanner. Kajander et al. (2010) evaluated the diagnostic accuracy of PET and CCTA in 107 patients with a history of stable chest pain and a 30% to 70% pre-test likelihood of coronary artery disease. All patients had ICA independently of the non-invasive imaging results, and treatment decisions were based on both ICA and FFR.
Table 1 summarises the EAC's analysis of diagnostic accuracy for HeartFlow FFRCT and its comparators at both per-vessel and per-patient levels, as shown in table 1. When there was more than 1 diagnostic accuracy study available, the EAC conducted a meta-analysis.
Type of analysis
Index test
N
Sensitivity
(95% CI)
Specificity
(95% CI)
Positive likelihood ratio
(95% CI)
Negative likelihood ratio
(95% CI)
Patient based
HeartFlow FFR
CT
(Nørgaard, 2014: NXT trial)
to 0.93
to 0.85
to 5.49
to 0.31
Patient based
CCTA
(6 studies)
to 0.97
to 0.71
to 6.47
to 0.16
Patient based
ECHO
(Neglia, 2015)
to 0.57
to 0.94
to 7.45
to 0.76
Patient based
ICA
(Nørgaard, 2014)
to 0.74
to 0.88
to 5.33
to 0.59
Patient based
MRI
(2 studies)
to 0.95
to 0.97
to 17.9
to 0.26
Patient based
SPECT
(Neglia, 2015)
to 0.81
to 0.74
to 2.79
to 0.57
Vessel based
HeartFlow FFR
CT
(Nørgaard, 2014)
to 0.91
to 0.89
to 7.75
to 0.29
Vessel based
CCTA
(4 studies)
to 0.89
to 0.77
to 7.23
to 0.32
Vessel based
ICA
(Nørgaard, 2014)
to 0.65
to 0.93
to 7.89
to 0.62
Vessel based
MRI
(Bernhardt, 2012)
to 0.96
to 1.00
to 390
to 0.30
Abbreviations: CCTA, coronary CT angiography; CI, confidence interval; ECHO, stress echocardiogram; FFRCT, fractional flow reserve CT; ICA, invasive coronary angiography; MRI, magnetic resonance imaging; SPECT, single-photon emission CT.
The EAC considered that despite the limitations associated with patients having a different reference test in some studies, all contributed to the decision problem and provided data for synthesis. It judged that the Nørgaard (2014) study had a low risk of bias for flow and timing, index and reference test. It noted that there was a risk of patient selection bias because an inclusion criterion was that patients had to have been referred for ICA, but it noted no other risks of bias or applicability concerns. Although it acknowledged that there were no studies directly comparing all the tests, it concluded that HeartFlow FFRCT has:
similar sensitivity but higher specificity compared with CCTA
higher sensitivity but lower specificity compared with ECHO
similar sensitivity but lower specificity compared with MRI
higher sensitivity and specificity compared with SPECT.
# Summary of clinical-effectiveness evidence
The company conducted a literature search for evidence on the clinical outcomes specified in the decision problem for HeartFlow FFRCT, and the existing treatments, against any comparator. It identified 16 studies of which 5 included HeartFlow FFRCT, 1 published (Guar et al. 2014) and 4 unpublished (PLATFORM, Radiation FFRCT, Real World Usage FFRCT and FFRCT RIPCORD).
The EAC included extra intervention and comparator keywords and identified 11 studies, 4 of which had already been identified by the company: 2 published studies (Hachamovitch et al. 2012 and Douglas et al. 2015) and 2 unpublished studies. The EAC noted that only the 2 unpublished studies fully matched the population, intervention, comparators and outcomes defined in the scope; the other 9 included various comparators but not HeartFlow FFRCT. The 2 unpublished studies including HeartFlow FFRCT were PLATFORM (see section 3.18) and Radiation FFRCT; the company provided both in the form of interim results for the former and an abstract for the latter. Two studies (Real World Usage FFRCT and FFRCT RIPCORD) included HeartFlow FFRCT but were excluded because they did not provide information on patients' pre-test likelihood of coronary artery disease.
Radiation FFRCT is a single-centre modelling study, based in Canada, investigating the potential effect of HeartFlow FFRCT on radiation dose exposure and downstream clinical event rate. In the modelling, a clinical pathway in which CCTA plus FFRCT was the initial diagnostic test was compared with 3 clinical pathways instead utilising SPECT, ECHO or CCTA as initial diagnostic tests. The model included 100 patients with suspected coronary artery disease, 34% of whom had intermediate disease. Patients were stratified into 3 categories of likelihood of disease: 50% low, 40% moderate and 10% high. No clinical outcomes were measured in this modelled population. The primary outcome was the estimated radiation dose and the secondary outcome was death or myocardial infarction estimates at 1 year after the test. Of the 4 diagnostic pathways studied, ECHO had the lowest radiation dose (5.3 mSv) but had a higher clinical event rate related to both false-positive and false-negative findings. The FFRCT pathway had lower cumulative radiation exposure (9.4 mSv) than SPECT (26.4 mSv) or CCTA (13.9 mSv) and also had the lowest clinical adverse event rate for low and intermediate-risk patients. For high-risk patients, the lowest clinical event rate was with ICA.
The PROMISE study (Douglas et al. 2015) is a US‑based multicentre randomised controlled trial involving over 10,000 patients, with a median follow‑up of 25 months. Although the study did not include FFRCT, the EAC considered it relevant to the decision problem because it provides further evidence on a diagnostic pathway based on CCTA. Patients with a mean pre-test likelihood of coronary artery disease of 53.3±21.4% were randomly assigned to either CCTA or functional imaging as a first-line diagnostic test. The composite primary end point was death, myocardial infarction, hospitalisation for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterisation that did not show obstructive coronary artery disease and radiation exposure. Results showed that 164 of 4,996 (3.3%) patients in the CCTA group and in 151 of 5,007 (3.0%) in the functional testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; p=0.75) achieved the primary end point. CCTA was associated with fewer catheterisations showing no obstructive coronary artery disease than functional imaging (3.4% compared with 4.3%, p=0.02), although more patients in the CCTA group had catheterisation within 90 days of randomisation (12.2% compared with 8.1%). The median cumulative radiation exposure per patient was lower in the CCTA group than in the functional testing group (10.0 mSv compared with 11.3 mSv), but 32.6% of the patients in the functional testing group had no exposure. As such, overall exposure was higher in the CCTA group (mean 12.0 mSv compared with 10.1 mSv; p<0.001).
The EAC identified 9 published studies containing information on clinical outcomes in comparator diagnostic technologies. Further information about these studies can be found in the assessment report.
## Chest pain guideline update: second literature search
During the assessment of HeartFlow FFRCT for this guidance, NICE updated its guideline on chest pain. Because this included new recommendations for investigating chest pain, it became necessary to update the evidence and cost modelling for the HeartFlow FFRCT assessment. The EAC repeated the evidence searches up to February 2016 and asked the company to identify any recent and ongoing studies. In total, the EAC assessed 7 new studies, 6 of which included HeartFlow FFRCT.
Tanaka et al. (2016) is a technical study on a subgroup of the NXT study investigating the association between FFRCT and invasive FFR in coronary arteries with serial lesions. The authors investigated patients (n=18 patients and 18 vessels) with stable angina and clinically suspected coronary artery disease. There was no clinical follow‑up. The primary outcome was the per-segment correlation between FFRCT and invasive FFR values, expressed as translesional delta (the difference between the proximal and distal FFR measurement of all sequential lesions). Values of translesional delta for FFR and FFRCT were 0.10±0.09 and 0.09±0.10 in distal segments, and 0.17±0.10 and 0.22±0.13 in proximal segments respectively. The coefficient of correlation between translesional delta FFR and FFRCT in each segment was 0.92 (p<0.001). The authors concluded that translesional delta FFR is highly correlated with FFRCT.
Thompson et al. (2015) investigated the diagnostic performance of FFRCT in relation to patients' sex and age, using invasive FFR measurements as the reference standard for a subgroup of the DeFACTO study. Previous evidence from DeFACTO was not considered eligible because it included patients with a high pre-test likelihood of coronary artery disease (Min et al. 2012). Thompson et al. (2015) was included because it reports results based on subgroup analyses for age and sex. The baseline pre-test likelihood did not differ in statistical significance within these subgroups, so it is not expected to bias the results. The authors investigated 252 patients (407 vessels) with stable angina, clinically suspected coronary artery disease and at least 1 coronary stenosis of 30% to 90%. For their analysis, the authors used a clinical rule that included all vessels of diameter ≥2 mm and assigned an FFR value of 0.90 for vessels with stenoses 90%. There was no clinical follow‑up. The primary outcome was per-patient and vessel diagnostic performance of FFRCT. Using this clinical rule, diagnostic performance improved in both sexes with no statistically significant differences between them. There were no differences in the discrimination of FFRCT after application of the clinical use rule when stratified by age ≥65 or <65 years. The authors concluded that FFRCT had similar diagnostic accuracy and discriminatory power to FFR for ischaemia detection in men and women irrespective of age using a cut‑off point of 65 years.
The other 4 studies on HeartFlow FFRCT looked at clinical outcomes. The PLATFORM study (Douglas et al. 2015b and 2016) was presented to the committee as academic in confidence in June 2015 (Douglas et al. 2015a). The study included 584 patients recruited at 11 international centres. They were prospectively assigned to have either functional imaging (n=287) or CCTA/FFRCT (n=297). Each cohort was subdivided into 2 groups based on the evaluation plan decided before enrolment in the study: non-invasive testing (any form of stress testing or CCTA without FFRCT) or ICA (invasive testing).
Douglas et al. (2015b) report the study results at 3‑month follow‑up. The primary end point was the percentage of patients with planned ICA in whom no significant obstructive coronary artery disease (no stenosis ≥50% by core laboratory quantitative analysis or invasive FFR <0.80) was found at ICA within 90 days. Secondary end points included a composite measure of major adverse cardiac events consisting of death, myocardial infarction and unplanned revascularisation, all of which were independently and blindly assessed. Among patients with intended ICA (CCTA/FFRCT=193; functional imaging=187), no obstructive coronary artery disease was found with ICA in 24 patients (12%) in the CCTA/FFRCT arm and 137 patients (73%) in the functional imaging arm (risk difference 61%, 95% CI 53 to 69, p<0.0001). Among patients intended for non-invasive testing, the rates of finding no obstructive coronary artery disease with ICA were 13% in the CCTA/FFRCT arm and 6% in the functional imaging arm (p=0.95). ICA was cancelled in 61% of patients after reviewing the CCTA/FFRCT results. There were low numbers of MACE and vascular complications in all groups.
Douglas et al. (2016) report outcomes from the same study at 1 year. The clinical end points measured were MACE and MACE plus vascular events within 14 days of procedure. Quality of life and resource use outcomes were also collected. There were 2 MACE events in each arm of the planned invasive group (risk difference -0.03 ) and 1 in the planned non-invasive group (risk difference -1.00 ). Cumulative 1‑year radiation exposure in patients in the intended invasive evaluation cohort was similar between the usual care strategy (mean: 10.4±6.7 mSv) and CCTA/FFRCT-guided strategy (mean: 10.7±9.6 mSv; p=0.21), whereas in the non-invasive testing cohort it was higher in patients with a CCTA/FFRCT-guided strategy than usual care strategy (mean: 9.6±10.6 mSv compared with 6.4±7.6 mSv, p<0.001). Functional status and quality of life improved from baseline to 1‑year follow‑up in the planned non-invasive group (p<0.001 for all measures), with greater improvements on the EQ‑5D in patients having CCTA/FFRCT compared with patients having functional imaging (mean change: 0.12 for CCTA/FFRCT compared with 0.07 for functional imaging, p=0.02).
Lu et al. (2015) used a subgroup analysis of the PROMISE trial (n=181) to investigate the added value of FFRCT compared with CCTA in improving efficiency of referral to ICA. End points for the subgroup analysis were rate of revascularisation and ICA that did not show obstructive coronary artery disease and MACE. Over a median follow‑up of 25 months, the addition of FFRCT increased the rate of ICA with revascularisation from 49% to 61%. The rate of angiography without obstructive disease decreased from 27% to 11%. No patient with FFRCT >0.80 had an adverse event which ICA would have prevented.
Nørgaard (2016) reports on the real-world experience of using CCTA with FFRCT as gatekeeper to ICA in patients with stable coronary artery disease and intermediate-range coronary lesions (n=189). Patients were followed up for a median of 12 months. The primary end point was the impact of FFRCT on further downstream diagnostic testing. Other end points were the agreement between FFRCT and invasive FFR, and the short-term clinical outcome after FFRCT testing defined as the occurrence of MACE (death and acute myocardial infarction) or an angina episode leading to hospital admission or visit in the outpatient clinic. The authors concluded that FFRCT testing is feasible in real-world scenarios involving patients with intermediate-range coronary stenosis determined by CCTA. They also concluded that implementing FFRCT for clinical decision-making may influence the downstream diagnostic workflow, and patients with an FFRCT >0.80 who are not referred for ICA have a favourable short-term prognosis. The authors highlight that in patients with FFRCT ranging between 0.76 and 0.80, a non-negligible number of false-positive results may be expected.
The EAC considered that the 1‑year follow‑up data from the PLATFORM study supported the company's claims about resource use, rates of ICA and percutaneous coronary intervention, and quality of life with HeartFlow FFRCT. Additionally, the 1‑year follow‑up evidence from the PLATFORM supports the company's claim that MACE outcomes are equivalent between the current pathway and one that uses FFRCT, whereas the PROMISE study showed that MACE outcomes at 1 year were equivalent between CCTA alone and functional testing. The EAC also considered that the evidence from the PLATFORM study showed higher 1‑year radiation exposure in the HeartFlow FFRCT group in patients intended for non-invasive evaluation. However, this is to be expected because many patients in the non-invasive evaluation had a non-invasive test which did not need the use of radiation. The EAC concluded that the submitted evidence on clinical outcomes supports the value proposition of an FFRCT-guided strategy compared with standard of care, mainly in patients with planned invasive investigation, with equivalent results between FFRCT and functional imaging in the non-invasive group.
## Committee considerations
The committee considered that the evidence showed high diagnostic accuracy and increased specificity with HeartFlow FFRCT compared with CCTA alone. It also noted promising results from the PLATFORM study, in a population which closely matches that in the scope. The evidence was sufficient to conclude that HeartFlow FFRCT has a high diagnostic accuracy for coronary artery disease, and that its use has the potential to reduce the need for invasive coronary investigations.
The committee considered the technology to be innovative and understood that its adoption may serve to simplify a complex patient pathway. The committee heard from clinical experts that they had confidence in the diagnostic accuracy of HeartFlow FFRCT, and that it could provide an effective early rule-out test for coronary artery disease. This would reduce the need for ICA and invasive FFR measurement, and potentially reduce radiation exposure.
The committee understood that there are differences in the local implementation of the patient pathway for diagnosing coronary artery disease. It was advised by clinical experts that the choice of functional imaging test depends on local access, available expertise and clinician preference. It heard that although HeartFlow FFRCT has the potential to reduce the number of tests that are done, the other non-invasive functional imaging tests that are part of the current patient pathway offer different functionality and in some cases provide additional information. Overall, the committee concluded that HeartFlow FFRCT should be considered for use as a non-invasive investigation for diagnosing angina in patients with stable, recent-onset chest pain of suspected cardiac origin, and that it provides the clinician with additional functional information to determine which coronary lesions are responsible for myocardial ischaemia. The committee considered that further clinical studies would be helpful to clarify the wider applicability of HeartFlow FFRCT in routine clinical practice.
The committee considered the evidence from the PLATFORM study to be most relevant to the decision problem. It considered that the results demonstrate the potential of FFRCT to avoid ICA and improve quality of life.
The committee discussed the relative importance of a per-patient or a per-vessel diagnosis. It heard from experts that per-patient diagnostic accuracy was more important for initial diagnosis, and that a per-vessel assessment provides additional information to inform patient management. The committee concluded that per-patient level figures were the most reliable and relevant to the diagnosis of coronary artery disease.# NHS considerations
# System impact
The company's claimed system benefits included reduced costs from fewer inconclusive or inaccurate diagnostic tests and avoidance of unnecessary staff and procedure costs. It claimed that this would lead to more effective use of invasive procedure suites.
The company confirmed that, with specific reference to the updated NICE guideline on chest pain, the proposed place in the diagnostic pathway for HeartFlow FFRCT (to inform management following a positive coronary CT angiography result) was unchanged.
Conservative estimates by the NICE resource impact assessment team suggest that by 2021/22, when fully implemented, HeartFlow FFRCT will potentially be used in around 40,000 patients a year. This would equate to national savings of at least £9.1 million a year.
During selection and routing, the committee asked for additional information on compliance with data protection legislation, and the reproducibility of HeartFlow FFRCT analysis, especially in the face of an increasing workload which might be expected to arise from adoption of the technology in the NHS. The external assessment centre (EAC) produced a technical report that concluded:
The company has a quality assurance process in place that fulfils data quality needs. This includes checks by different team members, and the separation of tasks to ensure that no single analyst is fully responsible for a diagnosis. After the procedure, a more experienced analyst reviews the process, focusing mainly on areas of stenosis. Expert clinician advice is also available should it be needed.
Although the analytical process is largely automated, any part of it can be manually changed by the analyst. This may affect the fractional flow reserve CT (FFRCT) estimate. Manual editing is part of the quality assurance process, negating the risk of spurious results generated from the automated analysis. Gaur et al. (2014) suggest that reproducibility is within acceptable 95% confidence interval limits of agreement. FFRCT reproducibility was found to be equivalent to invasive FFR reproducibility.
The reproducibility of outlining the coronary artery lumen, part of the FFRCT computation analysis, decreases in the distal portion of the vessel (Gage repeatability and reproducibility=29.4%). This could be a result of different factors including lower CT quality, lower CT resolution, smaller vessel diameter at the distal end and higher disease burden.
The company monitors FFRCT reproducibility by re-processing 5% of its case volume on a weekly basis. The company has confirmed that this has shown a reproducibility rate consistent with the literature (Gaur et al. 2014).
The company fulfils regulatory approval standards for data confidentiality and integrity protection for remote processing. It offers NHS customers the option to upload fully anonymised DICOM data to comply with UK data protection law.
## Committee considerations
The committee was satisfied with the EAC's conclusions on reproducibility (see section 4.4). It accepted that the company has protocols in place to manage an increased demand for HeartFlow FFRCT.
The committee considered the protection and oversight of data transferred during the administration of HeartFlow FFRCT to be an important factor in the device's adoption. The committee was satisfied, on the basis of the information available, that the company's data transfer protocols meet regulatory requirements. The committee noted that patients should be informed when sending personal data outside the European Economic Area with HeartFlow FFRCT, and that it may be necessary to obtain written consent.
The committee considered the availability of CCTA facilities. It understood that the cost model assumed access to CCTA facilities, but heard from experts that access to CCTA varies across the NHS despite recommendations in NICE's previous guideline on chest pain. Furthermore, because CT scanners are used for many purposes, a constraint currently exists with regard to both the availability of scanners and scanning time. The committee heard from experts that a sizable investment would be needed for the wider implementation of HeartFlow FFRCT, but acknowledged that this consideration was beyond the scope of the current assessment. It understood that adopting 64‑slice CCTA was ongoing in the NHS, in line with the recommendations in the previous NICE guideline on chest pain.# Cost considerations
# Cost evidence
The company conducted a search of the health economics literature on HeartFlow FFRCT and the comparators specified in the decision problem. They identified a total of 174 studies, 24 of which it considered relevant to the decision problem.
The external assessment centre (EAC) reviewed this search, and considered that most of the studies included neither an appropriate patient population nor a treatment pathway. Only 1 published study, Rajani et al. (2015), was considered by the EAC to be relevant to the decision problem. It conducted a further review of the literature up to February 2016 and identified an additional relevant published study, Hlatky et al. (2015).
Rajani et al. (2015) was a single-centre retrospective cost analysis of 410 patients referred to a rapid-access chest pain clinic in Guy's and St Thomas' Hospital, London, from April 2012 to March 2013. Patients were grouped into pre-test likelihood categories and diagnostic imaging was done based on standardised protocols as recommended in the previous NICE guideline on chest pain. A standardised unit cost for each test and procedure was taken from the NHS National Tariff 2013/14. A decision-tree economic model was used to evaluate the cost of 1,000 patients passing through the current treatment pathway compared with the same 1,000 patients after incorporating HeartFlow FFRCT. The authors found that introducing HeartFlow FFRCT to the pathway resulted in cost savings of £200 per patient. The EAC noted that although the derivation of costs in the study is explicit, details of the decision model structure are unclear.
Hlatky et al. (2015) investigated the quality-of-life and economic outcomes of fractional flow reserve CT (FFRCT) in the PLATFORM study (see section 3.17). Cumulative medical costs were measured over 90 days for each patient by multiplying a standardised cost weight for each medical resource by the number of resources used by the patient. Medicare reimbursement rates (the national average of technical and professional fees in the US) from 2015 were applied because cost weights and online pharmacy costs were used for drugs. Patients were prospectively assigned to either functional imaging (usual care, n=287) or coronary CT angiography (CCTA)/HeartFlow FFRCT (n=297). In the planed invasive group, mean costs were $7,343 among the CCTA/FFRCT patients and $10,734 among functional imaging patients (p<0.0001). In the planned non-invasive group, mean costs were not significantly different (p=0.26) between the CCTA/FFRCT patients ($2,679) and the functional imaging patients ($2,137). Overall, each quality-of-life (EQ‑5D) score improved at 90 days compared with baseline in the study population (p<0.0001), and scores improved more in CCTA/FFRCT patients than in functional imaging patients. In the invasive group, quality-of-life improvements were similar in both arms.
Douglas et al. (2016) published data on the 1‑year economic outcomes of FFRCT in the PLATFORM study. Costs were calculated in the same manner as the 90‑day results in Hlatky et al. (2015). In the planned invasive arm, the mean per-patient cost was $8,127 in FFRCT patients and $12,145 for usual care patients (p<0.0001). The cost savings at 1 year increased by 1.5% from the cost savings at 90 days. In the non-invasive arm, mean costs were not significantly different (p=0.82) between the FFRCT patients ($3,049) and the usual care patients ($2,579).
## Economic model
The company presented a decision-tree model based on integrating HeartFlow FFRCT into the existing diagnostic pathway at the time of its submission. A theoretical population of 1,000 patients with suspected coronary artery disease was allocated to either the current treatment pathway (based on the previous NICE guideline on chest pain) or the company's revised pathway, which included HeartFlow FFRCT. The cost consequences of the treatment pathways were compared based on the mix of diagnostic technologies used in each. The model had a 1‑year time horizon, included the impact of different testing strategies, and relevant clinical outcomes.
The proportion of patients eligible for CCTA as a first-line test and their probability of having coronary artery disease were taken from Rajani et al. (2015). In the model, 10% of patients were assumed to be ineligible for invasive coronary angiography (ICA), have an inconclusive CCTA result and have an uncertain single-photon emission CT (SPECT) result.
The diagnostic accuracy of HeartFlow FFRCT and its comparators in the company's model were based on per-patient level results reported in selected papers, as follows:
HeartFlow FFRCT: sensitivity 86%, specificity 79% (Nørgaard et al. 2014)
SPECT: sensitivity 76%, specificity 38% (Melikian et al. 2010)
CCTA: sensitivity 94%, specificity 48% (Meijboom et al. 2008)
ICA: sensitivity 69%, specificity 67% (Meijboom et al. 2008).The cost of HeartFlow FFRCT (£888) was based on the company's original list price. Costs for comparator tests were based on 2014/15 hospital resource group (HRG) tariffs, as follows:
SPECT: £220 (HRG code RA37Z, nuclear medicine category 3)
CCTA: £136 (HRG code RA14Z, CT scan, more than 3 areas)
Calcium scoring: £77 (HRG code RA08Z, CT scan, 1 area, no contrast)
ICA: £1,241 (HRG code EA36A, catheter 19 years and over)
Percutaneous coronary intervention (PCI): £2,832 (weighted average of 2 tariffs, assuming that 25% of patients needing PCI will need more than 2 stents. HRG codes EA31Z and EA49Z ).
The company's base-case results reported an average per-patient cost of £2,239 using the current pathway and £2,080 using the adapted pathway with HeartFlow FFRCT, representing an average saving of £159 per patient.
The company conducted 1‑way sensitivity analyses on the sensitivity and specificity of HeartFlow FFRCT and the comparator tests, as well as the costs of HeartFlow FFRCT. The analyses showed that HeartFlow FFRCT continued to be cost saving until its price reached £1,126. With regard to changes in the sensitivity and specificity, HeartFlow FFRCT remained cost saving for nearly all the values tested when considered in the context of the entire patient population.
## Revisions by the external assessment centre
The EAC incorporated the changes to the updated NICE guideline on chest pain in the company economic model. In this context, the EAC assumed that HeartFlow FFRCT would be used following an initial CCTA, and that non-invasive functional imaging tests would subsequently be used only if the CCTA result were uncertain or non-diagnostic. The EAC reviewed the parameters and costs used in the company's model. It revised the company's sensitivity and specificity parameters for the comparator diagnostic tests, based on its own analyses of diagnostic accuracy (see table 1).
The EAC used the company's revised list price of £700 for HeartFlow FFRCT, instead of £888 as used in the company's model.
The EAC used the updated NICE guideline on chest pain to determine the costs of all comparator tests except MRI, to ensure that they were consistent with 2014/15 reference costs. The cost of MRI was taken from the Payment by Results tariff, because the chest pain guideline committee determined this to be more representative of the true cost. These costs were as follows:
SPECT: £367 (RN21Z, myocardial perfusion scan, stress only )
CCTA: £122 (RD28Z, complex CT scan)
ECHO: £271 (EY50Z, complex echocardiogram)
ICA: £1,685 (EY43A to EY43F, standard cardiac catheterisation)
MRI: £515 (RA67Z, cardiac MRI scan, pre and post contrast)
PCI: £2,865 (weighted average of 2 tariffs, assuming that 25% of patients needing PCI will need more than 2 stents. HRG codes EA31Z and EA49Z ). Includes an estimated annual cost of £33 for medication following a PCI .
The EAC noted that the company's model did not include costs of drug therapy for patients having PCI. It consulted the NICE guideline on stable angina and estimated an annual drug treatment cost for these patients of £33 based on British national formulary (2015) prescription costs for aspirin and clopidogrel, and used a cost of £2,865 (PCI tariff with drug costs) in its revised model.
The EAC included a cost for optimal medical therapy. It obtained expert advice that optimal medical therapy usually consists of aspirin, statins, nitrates and beta blockers. Based on this information it estimated an annual cost of £84 (aspirin, simvastatin, glyceryl trinitrate and propranolol hydrochloride) from the British national formulary (2015) and used it in the revised model.
Using these updated assumptions, the EAC found a base-case cost saving of £214 per patient for HeartFlow FFRCT compared with the current treatment pathway for all functional imaging tests (SPECT, MRI and ECHO).
The EAC ran a number of sensitivity analyses, varying: the price of HeartFlow FFRCT; the diagnostic accuracy of the functional imaging tests, HeartFlow FFRCT, ICA and CCTA; and the proportion of uncertain CCTA and functional imaging tests. It also used estimates of diagnostic accuracy for CCTA and ICA from the updated NICE guideline on chest pain. In all instances, HeartFlow FFRCT remained cost saving.
## Committee considerations
The committee considered the cost modelling done by the EAC to be both appropriate and plausible. The committee heard from experts that percutaneous or surgical revascularisation is only offered to patients following ICA, and sometimes a confirmatory invasive FFR. The availability of data from HeartFlow FFRCT may help to plan treatment in individual vessels and patients.
For the guidance review, the EAC revised the model to reflect 2021 costs. There were no changes to the cost of the technology. The main parameter change was the cost of comparator tests. Further details of the 2021 revised model are in the cost update in the review decision.
Based on the 2021 guidance review updated cost model, the EAC found a base-case cost saving of £391 per patient for HeartFlow FFRCT compared with the current treatment pathway for all functional imaging tests (SPECT, MRI and ECHO). This cost saving will increase if the cost of HeartFlow FFRCT is reduced.# Conclusions
The committee concluded that the evidence suggests that HeartFlow FFRCT is safe, has high diagnostic accuracy, and that its use may avoid the need for invasive investigations.
The committee concluded that cost savings of £214 per patient are plausible and likely to be realised in practice, providing that sites adopting HeartFlow FFRCT have access to 64‑slice (or above) coronary CT angiography.
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{'Recommendations': 'The case for adopting HeartFlow\xa0FFRCT for estimating fractional flow reserve from coronary CT angiography (CCTA) is supported by the evidence. The technology is non-invasive and safe, and has a high level of diagnostic accuracy.\n\nHeartFlow\xa0FFRCT should be considered as an option for patients with stable, recent-onset chest pain who are offered CCTA in line with the NICE guideline on chest pain. Using HeartFlow\xa0FFRCT may avoid the need for invasive coronary angiography and revascularisation. For correct use, HeartFlow\xa0FFRCT requires access to 64‑slice (or above) CCTA facilities.\n\nBased on the current evidence and assuming there is access to appropriate CCTA facilities, using HeartFlow\xa0FFRCT may lead to cost savings of £391 per patient . By adopting this technology, the NHS in England may save a minimum of £9.4\xa0million by 2022 through avoiding invasive investigation and treatment .', 'The technology': "# Description of the technology\n\nHeartFlow\xa0FFRCT (developed by HeartFlow) is coronary physiology simulation software used for the qualitative and quantitative analysis of previously acquired computerised tomography DICOM data. The software provides a non-invasive method of estimating fractional flow reserve (FFR) using standard coronary CT angiography (CCTA) image data. FFR is the ratio between the maximum blood flow in a narrowed artery and the maximum blood flow in a normal artery. FFR is currently measured invasively using a pressure wire placed across a narrowed artery.\n\nAfter a clinician decides to request a HeartFlow test, anonymised data from a CCTA scan (of at least 64\xa0slices) are sent from the local imaging system, by secure data transfer to HeartFlow's central processing centre in the US. A case analyst employed by the company then uses the image data to create 3D computer models of the coronary arteries, incorporating coronary flow characteristics. The results are presented in a report which is sent, by secure data transfer, to the referring clinician within 48\xa0hours. The report includes both 3D images of the coronary anatomy and calculated functional information, including the estimated FFR values (known as FFRCT values). Clinicians can then use the report to help guide the management of suspected coronary artery disease.\n\nHeartFlow\xa0FFRCT is intended for use in patients with stable, recent-onset chest pain and suspected angina. Because the safety and effectiveness of FFRCT analysis has not been evaluated in other patient subgroups, HeartFlow\xa0FFRCT is not recommended in patients who have an acute coronary syndrome or have had a coronary stent, coronary bypass surgery or myocardial infarction in the past month.\n\nThe company first received a CE mark in July 2011, covering all 1.X\xa0versions of the technology, including the current version,\xa01.7.\n\nHeartFlow\xa0FFRCT costs £700 per test. A higher price of £888 is used in the company submission and assessment report. The cost was reduced in May\xa02015.\n\nThe claimed benefits of HeartFlow\xa0FFRCT in the case for adoption presented by the company were as follows:\n\nAnalysis is done using standard CCTA scans, without the need for additional imaging, radiation or medication.\n\nIt provides the same accuracy in excluding coronary artery disease as CCTA, and characterises the coronary arteries from both functional and anatomical perspectives, differentiating between ischaemic and non-ischaemic vessels in a way that CCTA cannot.\n\nIt allows physicians to evaluate anatomical coronary artery disease and accurately determine which coronary lesions are responsible for myocardial ischaemia, avoiding unnecessary invasive diagnostic or therapeutic procedures and related complications.\n\nIt reduces the need for revascularisation in patients after identifying anatomical stenosis by invasive coronary angiography (ICA) alone, by more accurately identifying if those stenoses are ischaemic.\n\nIt improves the diagnostic accuracy for coronary artery disease compared with CCTA alone against the gold standard of invasive FFR, and provides both functional and anatomical assessment of coronary arteries.\n\nIt has better diagnostic performance than CCTA alone, or other non-invasive or invasive tests (such as nuclear myocardial perfusion, magnetic resonance perfusion, stress echocardiography, exercise treadmill testing, invasive angiography or intravascular ultrasound) for detecting and excluding coronary artery lesions that cause ischaemia.\n\nIt reduces costs arising from inconclusive or inaccurate diagnostic tests.\n\nIt avoids staff and procedure costs for unnecessary ICAs.\n\nIt avoids staff and procedure costs for unnecessary interventions (such as angioplasty).\n\nIt provides a more effective use of high-cost invasive procedure suites, providing the opportunity to reduce waiting times for these facilities and increase patient turnaround.\n\n# Current management\n\nThe NICE guideline on chest pain recommends diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone.\n\nThe guideline recommends offering 64‑slice (or above) CCTA as the first-line diagnosis test when clinical assessment indicates typical or atypical angina; or non-anginal chest pain but 12‑lead resting ECG has been done and indicates ST‑T\xa0changes or Q\xa0waves.\n\nSubsequent diagnostic tests can be requested dependent on the CCTA results. The guideline recommends offering non-invasive functional imaging for myocardial ischaemia if 64‑slice (or above) CCTA has shown coronary artery disease of uncertain functional significance, or is non-diagnostic. Non-invasive functional imaging includes:\n\nmyocardial perfusion scintigraphy with single-photon emission CT (MPS with SPECT)\n\nstress echocardiography\n\nfirst-pass contrast-enhanced MR perfusion\n\nMR imaging for stress-induced wall motion abnormalities.ICA should be offered as a second-line investigation when the results of non-invasive functional imaging are inconclusive.\n\nWhen ICA is used to determine the presence and severity of coronary stenosis, it may be combined with the invasive measurement of FFR using a pressure wire. Although the NICE guideline on chest pain does not consider FFR, other guidelines (such as those of the European Society of Cardiology and American College of Cardiology) state that lesions with an FFR of\xa00.80 or less are functionally significant and revascularisation may be considered.", 'Clinical evidence': "The key clinical outcomes for HeartFlow\xa0FFRCT presented in the decision problem were:\n\nmeasures of diagnostic accuracy (sensitivity and specificity, positive and negative likelihood ratios, area-under curve) using invasive fractional flow reserve (FFR) as the reference standard\n\nrates of diagnostic coronary angiography, percutaneous coronary intervention and coronary artery bypass surgery\n\nadverse events (test-related, major adverse cardiac events, radiation exposure and so on)\n\nquality of life\n\nmortality.\n\n# Summary of diagnostic accuracy evidence\n\nThe company conducted a literature search on the diagnostic accuracy of FFRCT and the existing tests in the current treatment pathway for patients with a 10% to 90% pre-test likelihood of coronary artery disease, against a reference standard of invasive FFR testing. This review identified 5\xa0relevant meta-analysis studies and 23\xa0individual studies, 1\xa0of which was unpublished. Based on the 22\xa0published studies, and using FFR as the reference standard, the company presented diagnostic accuracy per-patient results for HeartFlow\xa0FFRCT compared with:\n\ninvasive coronary angiography (ICA)\n\nsingle-photon emission CT (SPECT)\n\nstress echocardiogram (ECHO)\n\nmagnetic resonance imaging (MRI)\n\ncoronary CT angiography (CCTA). If there were multiple studies for a test, the company conducted a meta-analysis; for example, 3\xa0studies were included in the meta-analysis for HeartFlow\xa0FFRCT (Koo et al. 2011, Min et al. 2012 and Nørgaard et al. 2014). The methodology and results of the meta-analyses are reported as academic in confidence.\n\nThe external assessment centre (EAC) reviewed the company's selection of studies and considered that although they addressed the scope in terms of the comparators, reference test and outcomes, most included a mixture of patients with both high (over 90%) and intermediate (10% to 90%) pre-test likelihoods of disease. It also disagreed with the company's decision only to include studies that provided FFR measurements in more than 75% of blood vessels. The EAC considered this criterion not to be reflective of clinical practice, where visual assessment is sometimes used before proceeding with FFR measurements. The EAC also noted that this criterion did not reflect the company's proposed changes to the clinical pathway, where CCTA would be used to decide if HeartFlow\xa0FFRCT should be used.\n\nTo address these concerns, the EAC conducted a diagnostic literature search using extra keywords related to comparators and outcomes. It included only studies in which most patients had an intermediate pre-test likelihood of disease. The EAC identified 7\xa0diagnostic studies, including 3\xa0presented by the company (Bernhardt et al. 2012, Nørgaard et al. 2014 and Stuijfzand et al. 2014) and 3\xa0that the company had identified but excluded (Danad et al. 2013, Kajander et al. 2010 and Ponte et al. 2014). Only 1\xa0of these, Nørgaard et al. 2014, involved HeartFlow\xa0FFRCT.\n\nNørgaard et al. (2014) reported on a multicentre study (the NXT trial) involving 2\xa0UK centres, which compared HeartFlow\xa0FFRCT (v1.4) with CCTA for diagnosing myocardial ischaemia in 254\xa0patients with suspected stable coronary artery disease scheduled to have ICA. Most patients in the study (87%) were considered to have an intermediate likelihood of coronary artery disease. Invasive FFR was measured in all vessels (n=484). The study reported the diagnostic performance of HeartFlow\xa0FFRCT and CCTA for diagnosing ischaemia compared with FFR measured during ICA as the reference standard. The diagnostic accuracy of each test was presented on a per-patient and a per-vessel basis compared with the reference standard, an FFR value of ≤0.80. Per-vessel FFRCT was correlated to FFR (Pearson's correlation coefficient 0.82, p>0.001), with a slight underestimation of FFRCT compared with FFR. The authors concluded that HeartFlow\xa0FFRCT can identify functionally significant coronary artery disease with high sensitivity and specificity. Furthermore, adding FFRCT measurements to CCTA led to a marked increase in specificity.\n\nThe EAC identified 6\xa0studies which both used the comparator tests and included patients with an intermediate likelihood of coronary artery disease. Bernhardt et al. (2012) compared the diagnostic performance of 1.5\xa0T and 3\xa0T\xa0MRI scanners using FFR as a reference standard in 34\xa0patients with stable angina and suspected or known coronary artery disease. The authors studied an intermediate-risk population with a mean PROCAM score of\xa042.7 (a risk assessment metric which estimates the 10‑year risk of developing a coronary event). Ponte et al. (2014) compared the diagnostic accuracy of CCTA and MRI for detecting functionally significant coronary artery disease in patients referred with suspected coronary artery disease, using ICA with FFR as the reference standard. The study included 95\xa0patients with a 15% to 85% pre-test likelihood of coronary artery disease. Stuijfzand et al. (2014) evaluated CCTA and transluminal attenuation gradient compared with CCTA alone for diagnosing functionally significant lesions, using invasive FFR as the reference standard. The study included 85\xa0patients (253\xa0vessels) with an intermediate likelihood of coronary artery disease. Neglia et al. (2015) assessed the accuracy of several imaging techniques – CCTA, SPECT and ECHO – in 475\xa0patients with an intermediate likelihood of coronary artery disease. Danad et al. (2013) evaluated the diagnostic accuracy of CCTA in 120\xa0patients with suspected coronary artery disease who had cardiac positron emission topography (PET), CCTA and ICA. CCTA was done using a hybrid PET/CT scanner. Kajander et al. (2010) evaluated the diagnostic accuracy of PET and CCTA in 107\xa0patients with a history of stable chest pain and a 30% to 70% pre-test likelihood of coronary artery disease. All patients had ICA independently of the non-invasive imaging results, and treatment decisions were based on both ICA and FFR.\n\nTable\xa01 summarises the EAC's analysis of diagnostic accuracy for HeartFlow\xa0FFRCT and its comparators at both per-vessel and per-patient levels, as shown in table\xa01. When there was more than 1\xa0diagnostic accuracy study available, the EAC conducted a meta-analysis.\n\nType of analysis\n\nIndex test\n\nN\n\nSensitivity\n\n(95% CI)\n\nSpecificity\n\n(95% CI)\n\nPositive likelihood ratio\n\n(95% CI)\n\nNegative likelihood ratio\n\n(95% CI)\n\nPatient based\n\nHeartFlow\xa0FFR\n \n CT\n\n(Nørgaard, 2014: NXT trial)\n\n\n\n\n\nto 0.93\n\n\n\nto 0.85\n\n\n\nto 5.49\n\n\n\nto 0.31\n\nPatient based\n\nCCTA\n\n(6\xa0studies)\n\n,136\n\n\n\nto 0.97\n\n\n\nto 0.71\n\n\n\nto 6.47\n\n\n\nto 0.16\n\nPatient based\n\nECHO\n\n(Neglia, 2015)\n\n\n\n\n\nto 0.57\n\n\n\nto 0.94\n\n\n\nto 7.45\n\n\n\nto 0.76\n\nPatient based\n\nICA\n\n(Nørgaard, 2014)\n\n\n\n\n\nto 0.74\n\n\n\nto 0.88\n\n\n\nto 5.33\n\n\n\nto 0.59\n\nPatient based\n\nMRI\n\n(2\xa0studies)\n\n\n\n\n\nto 0.95\n\n\n\nto 0.97\n\n\n\nto 17.9\n\n\n\nto 0.26\n\nPatient based\n\nSPECT\n\n(Neglia, 2015)\n\n\n\n\n\nto 0.81\n\n\n\nto 0.74\n\n\n\nto 2.79\n\n\n\nto 0.57\n\nVessel based\n\nHeartFlow FFR\n \n CT\n\n(Nørgaard, 2014)\n\n\n\n\n\nto 0.91\n\n\n\nto 0.89\n\n\n\nto 7.75\n\n\n\nto 0.29\n\nVessel based\n\nCCTA\n\n(4\xa0studies)\n\n,645\n\n\n\nto 0.89\n\n\n\nto 0.77\n\n\n\nto 7.23\n\n\n\nto 0.32\n\nVessel based\n\nICA\n\n(Nørgaard, 2014)\n\n\n\n\n\nto 0.65\n\n\n\nto 0.93\n\n\n\nto 7.89\n\n\n\nto 0.62\n\nVessel based\n\nMRI\n\n(Bernhardt, 2012)\n\n\n\n\n\nto 0.96\n\n\n\nto 1.00\n\n\n\nto 390\n\n\n\nto 0.30\n\nAbbreviations: CCTA, coronary CT angiography; CI, confidence interval; ECHO, stress echocardiogram; FFRCT, fractional flow reserve CT; ICA, invasive coronary angiography; MRI, magnetic resonance imaging; SPECT, single-photon emission CT.\n\nThe EAC considered that despite the limitations associated with patients having a different reference test in some studies, all contributed to the decision problem and provided data for synthesis. It judged that the Nørgaard (2014) study had a low risk of bias for flow and timing, index and reference test. It noted that there was a risk of patient selection bias because an inclusion criterion was that patients had to have been referred for ICA, but it noted no other risks of bias or applicability concerns. Although it acknowledged that there were no studies directly comparing all the tests, it concluded that HeartFlow\xa0FFRCT has:\n\nsimilar sensitivity but higher specificity compared with CCTA\n\nhigher sensitivity but lower specificity compared with ECHO\n\nsimilar sensitivity but lower specificity compared with MRI\n\nhigher sensitivity and specificity compared with SPECT.\n\n# Summary of clinical-effectiveness evidence\n\nThe company conducted a literature search for evidence on the clinical outcomes specified in the decision problem for HeartFlow\xa0FFRCT, and the existing treatments, against any comparator. It identified 16\xa0studies of which 5\xa0included HeartFlow\xa0FFRCT, 1\xa0published (Guar et al. 2014) and 4\xa0unpublished (PLATFORM, Radiation FFRCT, Real World Usage FFRCT and FFRCT RIPCORD).\n\nThe EAC included extra intervention and comparator keywords and identified 11\xa0studies, 4\xa0of which had already been identified by the company: 2\xa0published studies (Hachamovitch et al. 2012 and Douglas et al. 2015) and 2\xa0unpublished studies. The EAC noted that only the 2\xa0unpublished studies fully matched the population, intervention, comparators and outcomes defined in the scope; the other 9\xa0included various comparators but not HeartFlow\xa0FFRCT. The 2\xa0unpublished studies including HeartFlow\xa0FFRCT were PLATFORM (see section\xa03.18) and Radiation FFRCT; the company provided both in the form of interim results for the former and an abstract for the latter. Two studies (Real World Usage FFRCT and FFRCT RIPCORD) included HeartFlow\xa0FFRCT but were excluded because they did not provide information on patients' pre-test likelihood of coronary artery disease.\n\nRadiation FFRCT is a single-centre modelling study, based in Canada, investigating the potential effect of HeartFlow\xa0FFRCT on radiation dose exposure and downstream clinical event rate. In the modelling, a clinical pathway in which CCTA plus FFRCT was the initial diagnostic test was compared with 3\xa0clinical pathways instead utilising SPECT, ECHO or CCTA as initial diagnostic tests. The model included 100\xa0patients with suspected coronary artery disease, 34% of whom had intermediate disease. Patients were stratified into 3\xa0categories of likelihood of disease: 50% low, 40% moderate and 10% high. No clinical outcomes were measured in this modelled population. The primary outcome was the estimated radiation dose and the secondary outcome was death or myocardial infarction estimates at 1\xa0year after the test. Of the 4\xa0diagnostic pathways studied, ECHO had the lowest radiation dose (5.3\xa0mSv) but had a higher clinical event rate related to both false-positive and false-negative findings. The FFRCT pathway had lower cumulative radiation exposure (9.4\xa0mSv) than SPECT (26.4\xa0mSv) or CCTA (13.9\xa0mSv) and also had the lowest clinical adverse event rate for low and intermediate-risk patients. For high-risk patients, the lowest clinical event rate was with ICA.\n\nThe PROMISE study (Douglas et al. 2015) is a US‑based multicentre randomised controlled trial involving over 10,000\xa0patients, with a median follow‑up of 25\xa0months. Although the study did not include FFRCT, the EAC considered it relevant to the decision problem because it provides further evidence on a diagnostic pathway based on CCTA. Patients with a mean pre-test likelihood of coronary artery disease of 53.3±21.4% were randomly assigned to either CCTA or functional imaging as a first-line diagnostic test. The composite primary end point was death, myocardial infarction, hospitalisation for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterisation that did not show obstructive coronary artery disease and radiation exposure. Results showed that 164\xa0of 4,996 (3.3%) patients in the CCTA group and in 151\xa0of 5,007 (3.0%) in the functional testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; p=0.75) achieved the primary end point. CCTA was associated with fewer catheterisations showing no obstructive coronary artery disease than functional imaging (3.4% compared with 4.3%, p=0.02), although more patients in the CCTA group had catheterisation within 90\xa0days of randomisation (12.2% compared with 8.1%). The median cumulative radiation exposure per patient was lower in the CCTA group than in the functional testing group (10.0\xa0mSv compared with 11.3\xa0mSv), but 32.6% of the patients in the functional testing group had no exposure. As such, overall exposure was higher in the CCTA group (mean 12.0\xa0mSv compared with 10.1\xa0mSv; p<0.001).\n\nThe EAC identified 9\xa0published studies containing information on clinical outcomes in comparator diagnostic technologies. Further information about these studies can be found in the assessment report.\n\n## Chest pain guideline update: second literature search\n\nDuring the assessment of HeartFlow\xa0FFRCT for this guidance, NICE updated its guideline on chest pain. Because this included new recommendations for investigating chest pain, it became necessary to update the evidence and cost modelling for the HeartFlow\xa0FFRCT assessment. The EAC repeated the evidence searches up to February 2016 and asked the company to identify any recent and ongoing studies. In total, the EAC assessed 7\xa0new studies, 6\xa0of which included HeartFlow\xa0FFRCT.\n\nTanaka et al. (2016) is a technical study on a subgroup of the NXT study investigating the association between FFRCT and invasive FFR in coronary arteries with serial lesions. The authors investigated patients (n=18\xa0patients and 18\xa0vessels) with stable angina and clinically suspected coronary artery disease. There was no clinical follow‑up. The primary outcome was the per-segment correlation between FFRCT and invasive FFR values, expressed as translesional delta (the difference between the proximal and distal FFR measurement of all sequential lesions). Values of translesional delta for FFR and FFRCT were 0.10±0.09 and 0.09±0.10 in distal segments, and 0.17±0.10 and 0.22±0.13 in proximal segments respectively. The coefficient of correlation between translesional delta FFR and FFRCT in each segment was 0.92 (p<0.001). The authors concluded that translesional delta FFR is highly correlated with FFRCT.\n\nThompson et al. (2015) investigated the diagnostic performance of FFRCT in relation to patients' sex and age, using invasive FFR measurements as the reference standard for a subgroup of the DeFACTO study. Previous evidence from DeFACTO was not considered eligible because it included patients with a high pre-test likelihood of coronary artery disease (Min et al. 2012). Thompson et al. (2015) was included because it reports results based on subgroup analyses for age and sex. The baseline pre-test likelihood did not differ in statistical significance within these subgroups, so it is not expected to bias the results. The authors investigated 252\xa0patients (407\xa0vessels) with stable angina, clinically suspected coronary artery disease and at least 1\xa0coronary stenosis of 30% to 90%. For their analysis, the authors used a clinical rule that included all vessels of diameter ≥2\xa0mm and assigned an FFR value of\xa00.90 for vessels with stenoses <30% and an FFR value of\xa00.50 for vessels with stenoses >90%. There was no clinical follow‑up. The primary outcome was per-patient and vessel diagnostic performance of FFRCT. Using this clinical rule, diagnostic performance improved in both sexes with no statistically significant differences between them. There were no differences in the discrimination of FFRCT after application of the clinical use rule when stratified by age ≥65 or <65\xa0years. The authors concluded that FFRCT had similar diagnostic accuracy and discriminatory power to FFR for ischaemia detection in men and women irrespective of age using a cut‑off point of 65\xa0years.\n\nThe other 4\xa0studies on HeartFlow\xa0FFRCT looked at clinical outcomes. The PLATFORM study (Douglas et al. 2015b and 2016) was presented to the committee as academic in confidence in June 2015 (Douglas et al. 2015a). The study included 584\xa0patients recruited at 11\xa0international centres. They were prospectively assigned to have either functional imaging (n=287) or CCTA/FFRCT (n=297). Each cohort was subdivided into 2\xa0groups based on the evaluation plan decided before enrolment in the study: non-invasive testing (any form of stress testing or CCTA without FFRCT) or ICA (invasive testing).\n\nDouglas et al. (2015b) report the study results at 3‑month follow‑up. The primary end point was the percentage of patients with planned ICA in whom no significant obstructive coronary artery disease (no stenosis ≥50% by core laboratory quantitative analysis or invasive FFR\xa0<0.80) was found at ICA within 90\xa0days. Secondary end points included a composite measure of major adverse cardiac events consisting of death, myocardial infarction and unplanned revascularisation, all of which were independently and blindly assessed. Among patients with intended ICA (CCTA/FFRCT=193; functional imaging=187), no obstructive coronary artery disease was found with ICA in 24\xa0patients (12%) in the CCTA/FFRCT arm and 137\xa0patients (73%) in the functional imaging arm (risk difference 61%, 95% CI 53 to 69, p<0.0001). Among patients intended for non-invasive testing, the rates of finding no obstructive coronary artery disease with ICA were 13% in the CCTA/FFRCT arm and 6% in the functional imaging arm (p=0.95). ICA was cancelled in 61% of patients after reviewing the CCTA/FFRCT results. There were low numbers of MACE and vascular complications in all groups.\n\nDouglas et al. (2016) report outcomes from the same study at 1\xa0year. The clinical end points measured were MACE and MACE plus vascular events within 14\xa0days of procedure. Quality of life and resource use outcomes were also collected. There were 2\xa0MACE events in each arm of the planned invasive group (risk difference -0.03 [CI -8.6 to 8.5]) and 1\xa0in the planned non-invasive group (risk difference -1.00 [CI -12.7 to 10.7]). Cumulative 1‑year radiation exposure in patients in the intended invasive evaluation cohort was similar between the usual care strategy (mean: 10.4±6.7\xa0mSv) and CCTA/FFRCT-guided strategy (mean: 10.7±9.6\xa0mSv; p=0.21), whereas in the non-invasive testing cohort it was higher in patients with a CCTA/FFRCT-guided strategy than usual care strategy (mean: 9.6±10.6\xa0mSv compared with 6.4±7.6\xa0mSv, p<0.001). Functional status and quality of life improved from baseline to 1‑year follow‑up in the planned non-invasive group (p<0.001 for all measures), with greater improvements on the EQ‑5D in patients having CCTA/FFRCT compared with patients having functional imaging (mean change: 0.12 for CCTA/FFRCT compared with 0.07 for functional imaging, p=0.02).\n\nLu et al. (2015) used a subgroup analysis of the PROMISE trial (n=181) to investigate the added value of FFRCT compared with CCTA in improving efficiency of referral to ICA. End points for the subgroup analysis were rate of revascularisation and ICA that did not show obstructive coronary artery disease and MACE. Over a median follow‑up of 25\xa0months, the addition of FFRCT increased the rate of ICA with revascularisation from 49% to 61%. The rate of angiography without obstructive disease decreased from 27% to 11%. No patient with FFRCT >0.80 had an adverse event which ICA would have prevented.\n\nNørgaard (2016) reports on the real-world experience of using CCTA with FFRCT as gatekeeper to ICA in patients with stable coronary artery disease and intermediate-range coronary lesions (n=189). Patients were followed up for a median of 12\xa0months. The primary end point was the impact of FFRCT on further downstream diagnostic testing. Other end points were the agreement between FFRCT and invasive FFR, and the short-term clinical outcome after FFRCT testing defined as the occurrence of MACE (death and acute myocardial infarction) or an angina episode leading to hospital admission or visit in the outpatient clinic. The authors concluded that FFRCT testing is feasible in real-world scenarios involving patients with intermediate-range coronary stenosis determined by CCTA. They also concluded that implementing FFRCT for clinical decision-making may influence the downstream diagnostic workflow, and patients with an FFRCT >0.80 who are not referred for ICA have a favourable short-term prognosis. The authors highlight that in patients with FFRCT ranging between 0.76 and 0.80, a non-negligible number of false-positive results may be expected.\n\nThe EAC considered that the 1‑year follow‑up data from the PLATFORM study supported the company's claims about resource use, rates of ICA and percutaneous coronary intervention, and quality of life with HeartFlow\xa0FFRCT. Additionally, the 1‑year follow‑up evidence from the PLATFORM supports the company's claim that MACE outcomes are equivalent between the current pathway and one that uses FFRCT, whereas the PROMISE study showed that MACE outcomes at 1\xa0year were equivalent between CCTA alone and functional testing. The EAC also considered that the evidence from the PLATFORM study showed higher 1‑year radiation exposure in the HeartFlow\xa0FFRCT group in patients intended for non-invasive evaluation. However, this is to be expected because many patients in the non-invasive evaluation had a non-invasive test which did not need the use of radiation. The EAC concluded that the submitted evidence on clinical outcomes supports the value proposition of an FFRCT-guided strategy compared with standard of care, mainly in patients with planned invasive investigation, with equivalent results between FFRCT and functional imaging in the non-invasive group.\n\n## Committee considerations\n\nThe committee considered that the evidence showed high diagnostic accuracy and increased specificity with HeartFlow\xa0FFRCT compared with CCTA alone. It also noted promising results from the PLATFORM study, in a population which closely matches that in the scope. The evidence was sufficient to conclude that HeartFlow\xa0FFRCT has a high diagnostic accuracy for coronary artery disease, and that its use has the potential to reduce the need for invasive coronary investigations.\n\nThe committee considered the technology to be innovative and understood that its adoption may serve to simplify a complex patient pathway. The committee heard from clinical experts that they had confidence in the diagnostic accuracy of HeartFlow\xa0FFRCT, and that it could provide an effective early rule-out test for coronary artery disease. This would reduce the need for ICA and invasive FFR measurement, and potentially reduce radiation exposure.\n\nThe committee understood that there are differences in the local implementation of the patient pathway for diagnosing coronary artery disease. It was advised by clinical experts that the choice of functional imaging test depends on local access, available expertise and clinician preference. It heard that although HeartFlow\xa0FFRCT has the potential to reduce the number of tests that are done, the other non-invasive functional imaging tests that are part of the current patient pathway offer different functionality and in some cases provide additional information. Overall, the committee concluded that HeartFlow\xa0FFRCT should be considered for use as a non-invasive investigation for diagnosing angina in patients with stable, recent-onset chest pain of suspected cardiac origin, and that it provides the clinician with additional functional information to determine which coronary lesions are responsible for myocardial ischaemia. The committee considered that further clinical studies would be helpful to clarify the wider applicability of HeartFlow\xa0FFRCT in routine clinical practice.\n\nThe committee considered the evidence from the PLATFORM study to be most relevant to the decision problem. It considered that the results demonstrate the potential of FFRCT to avoid ICA and improve quality of life.\n\nThe committee discussed the relative importance of a per-patient or a per-vessel diagnosis. It heard from experts that per-patient diagnostic accuracy was more important for initial diagnosis, and that a per-vessel assessment provides additional information to inform patient management. The committee concluded that per-patient level figures were the most reliable and relevant to the diagnosis of coronary artery disease.", 'NHS considerations': "# System impact\n\nThe company's claimed system benefits included reduced costs from fewer inconclusive or inaccurate diagnostic tests and avoidance of unnecessary staff and procedure costs. It claimed that this would lead to more effective use of invasive procedure suites.\n\nThe company confirmed that, with specific reference to the updated NICE guideline on chest pain, the proposed place in the diagnostic pathway for HeartFlow\xa0FFRCT (to inform management following a positive coronary CT angiography [CCTA] result) was unchanged.\n\nConservative estimates by the NICE resource impact assessment team suggest that by 2021/22, when fully implemented, HeartFlow\xa0FFRCT will potentially be used in around 40,000\xa0patients a year. This would equate to national savings of at least £9.1\xa0million a year.\n\nDuring selection and routing, the committee asked for additional information on compliance with data protection legislation, and the reproducibility of HeartFlow\xa0FFRCT analysis, especially in the face of an increasing workload which might be expected to arise from adoption of the technology in the NHS. The external assessment centre (EAC) produced a technical report that concluded:\n\nThe company has a quality assurance process in place that fulfils data quality needs. This includes checks by different team members, and the separation of tasks to ensure that no single analyst is fully responsible for a diagnosis. After the procedure, a more experienced analyst reviews the process, focusing mainly on areas of stenosis. Expert clinician advice is also available should it be needed.\n\nAlthough the analytical process is largely automated, any part of it can be manually changed by the analyst. This may affect the fractional flow reserve CT (FFRCT) estimate. Manual editing is part of the quality assurance process, negating the risk of spurious results generated from the automated analysis. Gaur et al. (2014) suggest that reproducibility is within acceptable 95% confidence interval limits of agreement. FFRCT reproducibility was found to be equivalent to invasive FFR reproducibility.\n\nThe reproducibility of outlining the coronary artery lumen, part of the FFRCT computation analysis, decreases in the distal portion of the vessel (Gage repeatability and reproducibility=29.4%). This could be a result of different factors including lower CT quality, lower CT resolution, smaller vessel diameter at the distal end and higher disease burden.\n\nThe company monitors FFRCT reproducibility by re-processing 5% of its case volume on a weekly basis. The company has confirmed that this has shown a reproducibility rate consistent with the literature (Gaur et al.\xa02014).\n\nThe company fulfils regulatory approval standards for data confidentiality and integrity protection for remote processing. It offers NHS customers the option to upload fully anonymised DICOM data to comply with UK data protection law.\n\n## Committee considerations\n\nThe committee was satisfied with the EAC's conclusions on reproducibility (see section\xa04.4). It accepted that the company has protocols in place to manage an increased demand for HeartFlow\xa0FFRCT.\n\nThe committee considered the protection and oversight of data transferred during the administration of HeartFlow\xa0FFRCT to be an important factor in the device's adoption. The committee was satisfied, on the basis of the information available, that the company's data transfer protocols meet regulatory requirements. The committee noted that patients should be informed when sending personal data outside the European Economic Area with HeartFlow\xa0FFRCT, and that it may be necessary to obtain written consent.\n\nThe committee considered the availability of CCTA facilities. It understood that the cost model assumed access to CCTA facilities, but heard from experts that access to CCTA varies across the NHS despite recommendations in NICE's previous guideline on chest pain. Furthermore, because CT scanners are used for many purposes, a constraint currently exists with regard to both the availability of scanners and scanning time. The committee heard from experts that a sizable investment would be needed for the wider implementation of HeartFlow\xa0FFRCT, but acknowledged that this consideration was beyond the scope of the current assessment. It understood that adopting 64‑slice CCTA was ongoing in the NHS, in line with the recommendations in the previous NICE guideline on chest pain.", 'Cost considerations': "# Cost evidence\n\nThe company conducted a search of the health economics literature on HeartFlow\xa0FFRCT and the comparators specified in the decision problem. They identified a total of 174\xa0studies, 24\xa0of which it considered relevant to the decision problem.\n\nThe external assessment centre (EAC) reviewed this search, and considered that most of the studies included neither an appropriate patient population nor a treatment pathway. Only 1\xa0published study, Rajani et al. (2015), was considered by the EAC to be relevant to the decision problem. It conducted a further review of the literature up to February 2016 and identified an additional relevant published study, Hlatky et al.\xa0(2015).\n\nRajani et al. (2015) was a single-centre retrospective cost analysis of 410\xa0patients referred to a rapid-access chest pain clinic in Guy's and St Thomas' Hospital, London, from April 2012 to March 2013. Patients were grouped into pre-test likelihood categories and diagnostic imaging was done based on standardised protocols as recommended in the previous NICE guideline on chest pain. A standardised unit cost for each test and procedure was taken from the NHS National Tariff 2013/14. A decision-tree economic model was used to evaluate the cost of 1,000\xa0patients passing through the current treatment pathway compared with the same 1,000\xa0patients after incorporating HeartFlow\xa0FFRCT. The authors found that introducing HeartFlow\xa0FFRCT to the pathway resulted in cost savings of £200 per patient. The EAC noted that although the derivation of costs in the study is explicit, details of the decision model structure are unclear.\n\nHlatky et al. (2015) investigated the quality-of-life and economic outcomes of fractional flow reserve CT (FFRCT) in the PLATFORM study (see section\xa03.17). Cumulative medical costs were measured over 90\xa0days for each patient by multiplying a standardised cost weight for each medical resource by the number of resources used by the patient. Medicare reimbursement rates (the national average of technical and professional fees in the US) from 2015 were applied because cost weights and online pharmacy costs were used for drugs. Patients were prospectively assigned to either functional imaging (usual care, n=287) or coronary CT angiography (CCTA)/HeartFlow FFRCT (n=297). In the planed invasive group, mean costs were $7,343 among the CCTA/FFRCT patients and $10,734 among functional imaging patients (p<0.0001). In the planned non-invasive group, mean costs were not significantly different (p=0.26) between the CCTA/FFRCT patients ($2,679) and the functional imaging patients ($2,137). Overall, each quality-of-life (EQ‑5D) score improved at 90\xa0days compared with baseline in the study population (p<0.0001), and scores improved more in CCTA/FFRCT patients than in functional imaging patients. In the invasive group, quality-of-life improvements were similar in both arms.\n\nDouglas et al. (2016) published data on the 1‑year economic outcomes of FFRCT in the PLATFORM study. Costs were calculated in the same manner as the 90‑day results in Hlatky et al. (2015). In the planned invasive arm, the mean per-patient cost was $8,127 in FFRCT patients and $12,145 for usual care patients (p<0.0001). The cost savings at 1\xa0year increased by 1.5% from the cost savings at 90\xa0days. In the non-invasive arm, mean costs were not significantly different (p=0.82) between the FFRCT patients ($3,049) and the usual care patients ($2,579).\n\n## Economic model\n\nThe company presented a decision-tree model based on integrating HeartFlow\xa0FFRCT into the existing diagnostic pathway at the time of its submission. A theoretical population of 1,000\xa0patients with suspected coronary artery disease was allocated to either the current treatment pathway (based on the previous NICE guideline on chest pain) or the company's revised pathway, which included HeartFlow\xa0FFRCT. The cost consequences of the treatment pathways were compared based on the mix of diagnostic technologies used in each. The model had a 1‑year time horizon, included the impact of different testing strategies, and relevant clinical outcomes.\n\nThe proportion of patients eligible for CCTA as a first-line test and their probability of having coronary artery disease were taken from Rajani et al. (2015). In the model, 10% of patients were assumed to be ineligible for invasive coronary angiography (ICA), have an inconclusive CCTA result and have an uncertain single-photon emission CT (SPECT) result.\n\nThe diagnostic accuracy of HeartFlow\xa0FFRCT and its comparators in the company's model were based on per-patient level results reported in selected papers, as follows:\n\nHeartFlow\xa0FFRCT: sensitivity 86%, specificity 79% (Nørgaard et al.\xa02014)\n\nSPECT: sensitivity 76%, specificity 38% (Melikian et al.\xa02010)\n\nCCTA: sensitivity 94%, specificity 48% (Meijboom et al.\xa02008)\n\nICA: sensitivity 69%, specificity 67% (Meijboom et al.\xa02008).The cost of HeartFlow\xa0FFRCT (£888) was based on the company's original list price. Costs for comparator tests were based on 2014/15 hospital resource group (HRG) tariffs, as follows:\n\nSPECT: £220 (HRG code RA37Z, nuclear medicine category\xa03)\n\nCCTA: £136 (HRG code RA14Z, CT scan, more than 3\xa0areas)\n\nCalcium scoring: £77 (HRG code RA08Z, CT scan, 1\xa0area, no contrast)\n\nICA: £1,241 (HRG code EA36A, catheter 19\xa0years and over)\n\nPercutaneous coronary intervention (PCI): £2,832 (weighted average of 2\xa0tariffs, assuming that 25% of patients needing PCI will need more than 2\xa0stents. HRG codes EA31Z [£2,704] and EA49Z [£3,216]).\n\nThe company's base-case results reported an average per-patient cost of £2,239 using the current pathway and £2,080 using the adapted pathway with HeartFlow\xa0FFRCT, representing an average saving of £159 per patient.\n\nThe company conducted 1‑way sensitivity analyses on the sensitivity and specificity of HeartFlow\xa0FFRCT and the comparator tests, as well as the costs of HeartFlow\xa0FFRCT. The analyses showed that HeartFlow\xa0FFRCT continued to be cost saving until its price reached £1,126. With regard to changes in the sensitivity and specificity, HeartFlow\xa0FFRCT remained cost saving for nearly all the values tested when considered in the context of the entire patient population.\n\n## Revisions by the external assessment centre\n\nThe EAC incorporated the changes to the updated NICE guideline on chest pain in the company economic model. In this context, the EAC assumed that HeartFlow\xa0FFRCT would be used following an initial CCTA, and that non-invasive functional imaging tests would subsequently be used only if the CCTA result were uncertain or non-diagnostic. The EAC reviewed the parameters and costs used in the company's model. It revised the company's sensitivity and specificity parameters for the comparator diagnostic tests, based on its own analyses of diagnostic accuracy (see table\xa01).\n\nThe EAC used the company's revised list price of £700 for HeartFlow\xa0FFRCT, instead of £888 as used in the company's model.\n\nThe EAC used the updated NICE guideline on chest pain to determine the costs of all comparator tests except MRI, to ensure that they were consistent with 2014/15 reference costs. The cost of MRI was taken from the Payment by Results tariff, because the chest pain guideline committee determined this to be more representative of the true cost. These costs were as follows:\n\nSPECT: £367 (RN21Z, myocardial perfusion scan, stress only )\n\nCCTA: £122 (RD28Z, complex CT scan)\n\nECHO: £271 (EY50Z, complex echocardiogram)\n\nICA: £1,685 (EY43A to EY43F, standard cardiac catheterisation)\n\nMRI: £515 (RA67Z, cardiac MRI scan, pre and post contrast)\n\nPCI: £2,865 (weighted average of 2\xa0tariffs, assuming that 25% of patients needing PCI will need more than 2\xa0stents. HRG codes EA31Z [£2,704] and EA49Z [£3,216]). Includes an estimated annual cost of £33 for medication following a PCI [aspirin and clopidogrel, British national formulary (2015)].\n\nThe EAC noted that the company's model did not include costs of drug therapy for patients having PCI. It consulted the NICE guideline on stable angina and estimated an annual drug treatment cost for these patients of £33 based on British national formulary (2015) prescription costs for aspirin and clopidogrel, and used a cost of £2,865 (PCI tariff with drug costs) in its revised model.\n\nThe EAC included a cost for optimal medical therapy. It obtained expert advice that optimal medical therapy usually consists of aspirin, statins, nitrates and beta blockers. Based on this information it estimated an annual cost of £84 (aspirin, simvastatin, glyceryl trinitrate and propranolol hydrochloride) from the British national formulary (2015) and used it in the revised model.\n\nUsing these updated assumptions, the EAC found a base-case cost saving of £214 per patient for HeartFlow\xa0FFRCT compared with the current treatment pathway for all functional imaging tests (SPECT, MRI and ECHO).\n\nThe EAC ran a number of sensitivity analyses, varying: the price of HeartFlow\xa0FFRCT; the diagnostic accuracy of the functional imaging tests, HeartFlow\xa0FFRCT, ICA and CCTA; and the proportion of uncertain CCTA and functional imaging tests. It also used estimates of diagnostic accuracy for CCTA and ICA from the updated NICE guideline on chest pain. In all instances, HeartFlow\xa0FFRCT remained cost saving.\n\n## Committee considerations\n\nThe committee considered the cost modelling done by the EAC to be both appropriate and plausible. The committee heard from experts that percutaneous or surgical revascularisation is only offered to patients following ICA, and sometimes a confirmatory invasive FFR. The availability of data from HeartFlow\xa0FFRCT may help to plan treatment in individual vessels and patients.\n\nFor the guidance review, the EAC revised the model to reflect 2021 costs. There were no changes to the cost of the technology. The main parameter change was the cost of comparator tests. Further details of the 2021 revised model are in the cost update in the review decision.\n\nBased on the 2021 guidance review updated cost model, the EAC found a base-case cost saving of £391 per patient for HeartFlow FFRCT compared with the current treatment pathway for all functional imaging tests (SPECT, MRI and ECHO). This cost saving will increase if the cost of HeartFlow FFRCT is reduced.", 'Conclusions': 'The committee concluded that the evidence suggests that HeartFlow\xa0FFRCT is safe, has high diagnostic accuracy, and that its use may avoid the need for invasive investigations.\n\nThe committee concluded that cost savings of £214 per patient are plausible and likely to be realised in practice, providing that sites adopting HeartFlow\xa0FFRCT have access to 64‑slice (or above) coronary CT angiography.'}
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https://www.nice.org.uk/guidance/mtg32
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Evidence-based recommendations on HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography.
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0f2e2973bd2cb1918e826f6b8a6e1ce91c1a874e
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nice
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Parafricta Bootees and Undergarments to reduce skin breakdown in people with or at risk of pressure ulcers
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Parafricta Bootees and Undergarments to reduce skin breakdown in people with or at risk of pressure ulcers
Evidence-based recommendations on Parafricta Bootees and Undergarments to reduce skin breakdown in people with or at risk of pressure ulcers.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. The medical technology guidance on 'Parafricta Bootees and Undergarments' recommends further research. This recommendation is not intended to preclude the use of the technology in the NHS but to identify further evidence which, after evaluation, could support a recommendation for wider adoption.
Parafricta Bootees and Undergarments show potential to reduce the development and progression of skin damage caused by friction and shear in people with, or at risk of, pressure ulcers. However, more evidence for their effectiveness in clinical practice is needed to support the case for routine adoption of Parafricta Bootees and Undergarments in the NHS.
Research is recommended to address uncertainties about the claimed patient and system benefits of using Parafricta Bootees and Undergarments. This should take the form of comparative research against standard care, preferably carried out in a hospital. The research should include development of criteria to recognise people who would most benefit from the technology in both hospitals and community care. NICE will explore the development of appropriate further evidence, in collaboration with the technology sponsor and with clinical and academic partners, and will update this guidance if and when substantive new evidence becomes available.# The technology
# Description of the technology
Parafricta Bootees and Undergarments (APA Parafricta) are intended to reduce the potential for both the development and the progression of skin damage caused by friction and shear in people who have, or are at risk of developing, pressure ulcers, and in people with frail skin or those who have medical conditions in which skin frailty is a primary factor. Bootees provide protection for the heel and ankle, and Undergarments provide protection for the sacrum, buttocks and hips. The items are made from proprietary Parafricta fabric which is designed to reduce the shear stress and friction associated with movement. It has a friction coefficient value of 0.2, whereas most textiles typically range from 0.3 to 0.7. Parafricta fabric has no stiction, which is the additional force needed to overcome skin sticking to a surface before sliding. Because of this, it reduces the 'jerk' effect on skin when movement occurs. The lower the friction and stiction, the less likely it is that shear forces will develop and break the skin down, thereby reducing the risk of pressure ulcers. This mechanism of action is different from current methods of pressure ulcer management or prevention, which aim to manage or prevent pressure ulcers by reducing or redistributing pressure.
Parafricta fabric is used to protect the skin in areas most at risk. Both Parafricta Bootees and Undergarments have non‑slip areas to help patient positioning, and Velcro fastenings for easy application and removal. The positioning of the Velcro fasteners and the garments' flat seams are designed to minimise skin creasing or damage. The Bootee is supplied singly and is available in a range of adult sizes (starting from an adult size 2). They come in 2 types – with slip‑on or Velcro fasteners – and have non‑slip soles. The Undergarment is available in several sizes as a slip‑on garment or with Velcro fasteners, and as briefs or boxer shorts. Parafricta fabric is described as breathable but durable. The products are reusable after washing in accordance with garments for NHS use.
The cost of each Parafricta Bootee stated in the sponsor's submission is £35.14 (excluding VAT). The cost of the Parafricta Undergarment stated in the sponsor's submission is also £35.14 (excluding VAT). Parafricta garments are prescribable on a standard FP10 prescription.
The sponsor's claimed patient and healthcare benefits for Parafricta Bootees and Undergarments are as follows:
A reduction in pressure ulcer incidence and severity in people who are at high risk of pressure ulcers following assessment, thereby reducing or avoiding adverse impact on quality of life, pain, discomfort, hospital length of stay, morbidity and mortality.
Protection of susceptible skin in people in whom a repetitive, rubbing motion – due to an underlying neurological or other medical condition – can break down the skin.
Ease of use for patients and carers, combined with a familiarity with the type of products in older people or those with cognitive impairment, may lead to greater compliance with pressure ulcer preventative measures.
The products can be used in the home or in community care or hospitals, enabling the patient to easily transition between these settings.
The ease of use and practicality of Parafricta garments imply that the technology may be implemented easily in the community, and could be used as a long‑term care strategy to improve people's quality of life.
Prevention of pressure ulcer formation and reduced pressure ulcer incidence would shorten stays in hospital and may allow people to be transferred to lower cost community care. Hospital‑acquired pressure ulcers result in lengthened hospital stays and increased complications.
Reduction in NHS costs including but not limited to:
quicker return of people to the community or community long‑term care
reduced pressure ulcer incidence resulting in lower costs of nursing care, dressings and rehabilitation
the reusable nature of the garments.
# Current management
Current options to reduce breakdown of frail skin and to prevent and manage pressure ulcers focus on the reduction or redistribution of pressure. They include: dynamic or static high‑specification pressure‑relieving or pressure‑redistributing beds, mattresses, overlays and cushions; and sheepskin or pressure‑relieving bootees or silicone gel pads (numerous products, shapes and sizes are available).
NICE's guideline on pressure ulcers states that there is overlap between ulcers caused mainly by moisture and those caused by shear stresses or friction rather than pressure alone. This can cause some confusion in classification. In reality, however, pressure, shear, friction and moisture may all contribute in varying degrees to the development of an ulcer. The guideline recommends that when a person presents with or is at increased risk of developing a pressure ulcer, risk should be assessed and documented and then reassessed regularly.
NICE's guideline on pressure ulcers recommends that risk assessment should be followed by consideration of mobilising, positioning and repositioning interventions to prevent or minimise skin damage. When indicated, the recommended minimum provision is a high‑specification foam pressure‑relieving mattress or high‑specification foam mattress with an alternating pressure overlay, or a sophisticated continuous low pressure system. Any ulcer should be closely observed for deterioration.# Clinical evidence
# Summary of clinical evidence
Full details of all clinical outcomes considered by the committee are available in the assessment report overview.
The key clinical outcomes for Parafricta Bootees and Undergarments presented in the decision problem were:
incidence and severity of pressure ulcers or skin breakdown
length of hospital stay
time to healing for those with an existing pressure ulcer
compliance with pressure ulcer management
the person's comfort (including ability to move and self‑reposition in bed)
quality of life
device‑related adverse events.
The clinical evidence for Parafricta Bootees and Undergarments presented by the sponsor was 4 published multiple‑patient case‑series reports, 3 of which were peer‑reviewed papers (1 with historical controls) and 1 poster. These were Hampton et al. (2009), Loehne (2013; poster), Smith and Ingram (2010; with historical controls) and Stephen‑Haynes and Callaghan (2011). The sponsor also identified 3 single case studies but these were not presented. Independent searches by the external assessment centre (EAC) found no additional relevant studies. Data from an unpublished audit (Gleeson 2014) were sent to the EAC by the sponsor during the evaluation.
## Multiple‑patient case series: peer‑reviewed papers
A case series of 25 nursing home residents by Hampton et al. (2009) evaluated whether using a Parafricta Bootee or Undergarment could reduce oedema and inflammation associated with pressure ulcers. All residents had restricted mobility and each had redness and a 'boggy' feel to the tissues, either over the sacrum or 1 or 2 heels. A total of 28 pressure ulcers of grade 1 or above were analysed, all of which were related to friction or shear. Ten people used a Parafricta Bootee on the right heel (the left heel without the Bootee was used as a comparator) and 18 used a Parafricta Undergarment ('normal' skin adjacent to the sacrum was used as a comparator). The degree of oedema and inflammation of the pressure ulcers was measured using 3 methods: high‑frequency ultrasound scan data, colour photographs and tissue assessment by a tissue viability nurse. Statistical analysis of the high‑frequency ultrasound data was conducted using the Kolmogorov–Smirnov 2‑sample test. For this analysis, the skin profile of each heel (treated and control) was compared with a 'normal' heel profile (a standard heel with no pressure ulcer or redness). At the start of the study, results showed that both the treated heel (p<0.001) and the control heel (p<0.001) were statistically significantly different from the normal heel. At the end of 4 weeks, the difference between the treated heel and the 'normal' heel had reduced (p=0.2), whereas the difference between the control heel and the 'normal' heel was still statistically significant (p<0.001). Analysis of the treated heel results at week 0 compared with week 4 showed an improvement with a statistically significant difference (p<0.001). Based on these results, the authors concluded that the heel treated with a Parafricta Bootee became more similar to the 'normal' heel, and that Parafricta garments were effective in reducing oedema. The tissue viability nurse assessment found that bogginess and redness were reduced in the treated heels of all 10 residents but there was no change in the control heels. Results from the analysis of the high‑frequency ultrasound data for the sacral area showed a statistically significant difference between baseline and week 4 (p=0.006). Bogginess and redness were reduced in all 18 residents treated with a Parafricta Undergarment. The colour photographs for both the heels and the sacral areas were not considered clear enough by the researchers to validate the results. The ultrasound data were deemed to be more objective and reliable than either the colour photographs or the visual assessment.
The case series by Loehne (2013; poster) evaluated the use of Parafricta Bootees to prevent pressure ulcers in nursing home residents who were at risk of developing heel pressure ulcers as a result of friction and shear. Although the poster did not report how many residents were involved, the sponsor submission stated that the study included 6 residents and the intervention was a standard pressure‑reducing surface plus a Parafricta Bootee. After 30 days, none of the residents had developed a pressure ulcer or had any healed ulcers recurring. This included 1 person who had had a recurrent pressure ulcer for 2 years.
Smith and Ingram (2010) investigated the effectiveness of Parafricta garments in reducing the incidence and prevalence of pressure ulcers in hospital. The study incidence data were collected from 2 medical wards and 1 orthopaedic ward over 6 consecutive months. The first 3 months provided the data for group 1 (n=204) and the next 3 months were used for group 2 (n=165). People in both groups had identical care using the hospital's standard pressure ulcer prevention protocol, except that those in group 2 were also given a Parafricta Bootee or Undergarment. It was not clear how many had a Bootee or an Undergarment or both. Analysis of Waterlow scores suggested that they did not differ between the 2 groups. The authors reported the results as percentage differences in incidence of pressure ulcers between the groups. For additional ease of interpretation, the EAC recalculated the results as relative risks. The results showed that at‑risk people who were admitted to hospital without a pressure ulcer were more likely to develop a pressure ulcer in the no Parafricta group than in the Parafricta group (relative risk 1.64, 95% confidence interval 1.05 to 2.59). For at‑risk people admitted without a pressure ulcer who then developed one, those in the no Parafricta group were more likely to have an ulcer that deteriorated or did not improve compared with those in the Parafricta group (RR 2.53, 95% CI 1.16 to 5.52). A similar result was found for people who were admitted with an existing pressure ulcer: risk of deterioration was more likely in the no Parafricta group than in the Parafricta group (RR 4.90, 95% CI 1.75 to 13.75). There was no statistically significant difference between the groups in the risk of developing an additional ulcer in people who were admitted with one (RR 1.55, 95% CI 0.87 to 2.75). The Smith and Ingram (2010) study reported median lengths of stay. The EAC obtained the study data from the sponsor and reanalysed it to calculate mean lengths of stay for each group as a more appropriate parameter for use in the economic model. The average length of stay was calculated by weighting the length of stay in each treatment group by the proportion of people in the group. Results showed a weighted mean length of stay of 20.31 days for the no Parafricta group and 16.27 days for the Parafricta group, a statistically significant difference of 4.05 days (p=0.019). The EAC also used the limited information on confounding factors to estimate adjusted length of stay values, which took into account reported baseline characteristics between the groups. Results showed a weighted mean length of stay of 14.94 days for the no Parafricta group and 12.47 days for the Parafricta group, a difference of 2.47 days. No demographic characteristics were reported for either group.
Stephen‑Haynes and Callaghan (2011) described a case series of 25 nursing home residents who used Parafricta Bootees and Undergarments in addition to the standard approach for ulcer prevention and management as outlined in NICE's guideline on pressure ulcers. At the start of the study, 20 residents had an existing pressure ulcer of category 2 or below and 5 had intact skin. Those with intact skin were considered at risk of developing a pressure ulcer through friction due to repetitive movements caused by their medical condition. The outcomes that were considered included skin improvement, ease of use, garment retention and patient comfort. No information about the timescale of the study was provided. There was skin improvement in 76% (n=19) of residents, whereas 24% (n=6) remained the same. Clinicians found the garments very easy to use for most people (64%, n=16), and 88% (n=22) of clinicians stated that Parafricta garments had a positive impact on clinical outcomes. All residents in the study found the garment comfortable (24%, n=6) or very comfortable (76%, n=19). Almost half (48%; n=12) of clinicians reported that it was very easy to keep the garments in place, and 16% (n=4) did not find it easy. This was an uncontrolled study so it was difficult to tell whether any improvement in pressure ulceration or skin improvement was temporary or prolonged, or even whether any improvement was because of Parafricta garments.
The unpublished clinical audit by Gleeson (2014) evaluated the use of Parafricta Bootees in people at high risk of pressure ulcers on 6 hospital wards in the St. Helen's and Knowsley Teaching Hospitals NHS Trust over a 12‑month period (January to December 2012). The author reported a 32% reduction in hospital‑acquired grade 2 pressure ulcers compared with the previous year. Other details were made available to the committee on an academic‑in‑confidence basis and the author supplied additional academic‑in‑confidence information during the consultation, although details cannot be reported here. The EAC considered it unclear how much of the reduction in pressure ulcers reported was because of the use of Parafricta Bootees, and how much was caused by other pressure ulcer prevention initiatives taking place at the NHS trust.
## Adverse events
The sponsor found no adverse event reports relating to Parafricta garments. No alerts have been issued, and no information was found in a search of the Medicines and Healthcare products Regulatory Agency website.
## Committee considerations
The committee noted that the clinical evidence base for Parafricta garments was 4 published multiple‑patient case series and 1 unpublished audit. The committee agreed with the EAC's conclusions that there was a lack of good quality comparative evidence against standard care. The committee recognised that there is often only limited evidence for products used in pressure ulcer prevention and management , but considered it possible to conduct comparative research of good quality to assess the clinical effectiveness of this technology.
The committee accepted the EAC's critique of the Smith and Ingram (2010) study and agreed that because of potential confounding factors, it is not clear that any change in the pressure ulcer incidence or severity was due to Parafricta garments. The committee also agreed with the concerns raised by the EAC about the unpublished Gleeson audit (2014), including the additional data submitted during consultation, and it was not convinced that the reduction in heel pressure ulcers documented in the audit was solely because of the Parafricta Bootees.
Based on the existing evidence base and expert advice, the committee considered that Parafricta garments may indeed reduce pressure ulcer incidence and severity, and so provide potential benefits for patients. The committee was aware that older people and those with frail skin are more susceptible to pressure ulcers as a result of friction or shear, and it considered that Parafricta garments may be particularly beneficial to these people. However, it judged that the case for routine adoption in the NHS could not currently be supported because there are too many uncertainties in the evidence base.
The committee wished to encourage comparative research in hospitals (for ease and speed of generating findings) to investigate the clinical effectiveness of Parafricta garments as an adjunct to standard care compared with standard care alone in reducing skin breakdown in people with or at risk of pressure ulcers. The study should be randomised and the assessors blinded to minimise bias in the results. The committee specified that the research should focus on determining relative effectiveness compared with standard care when biases were carefully controlled for, and on developing criteria to identify patients for whom Parafricta garments are most likely to be effective.
The committee recognised that there is great potential for the use of Parafricta garments in the community. It considered that they could be beneficial to patients with long‑term conditions where pressure ulcers are a significant problem. However, it was advised of the significant challenges of conducting comparative research in the community. The committee considered that the results obtained in hospitals could plausibly be generalisable , and advised that the need for the findings from a hospital setting to be generalised to community‑based settings should be factored into the design of the research studies.
The committee discussed outcomes of special importance to patients. It noted the results from the Stephen‑Haynes and Callaghan (2011) case series which suggested that the garments were easy to use and that patients found them comfortable. Expert advice to the committee was that the fastenings ensure the garments remain in place, and that they have proven popular with patients. No adverse events were identified as a result of their use. The committee concluded that Parafricta Bootees and Undergarments are convenient, easy to use and well tolerated by patients, but considered that a record of patient experience would be useful to incorporate in future research studies.
For the guidance review, the EAC reviewed evidence published since November 2014. There were 3 publications of 2 single-arm studies on the technology. No new evidence compared Parafricta bootees or undergarments with standard care. In 1 study heel ulcer incidence reduced by 84% after Parafricta bootees were introduced. This was across all wards in 2 hospitals over 5 years of follow up (Gleeson 2015 and 2016). Another study reported on 15 people who used the Parafricta bootees. It reported a significant reduction in peak pressure on heels and other areas of the feet in direct contact with a surface. People rated the technology as 'excellent' or 'good' (Schofield 2018). The EAC considered that the new evidence did not answer the uncertainties that led to the recommendation for research in this guidance. # NHS considerations
# System impact
The Smith and Ingram (2010) study described in section 3.6 provides information on the incidence of pressure ulcers in an NHS hospital and on lengths of stay in hospital. During the selection of Parafricta Bootees and Undergarments, the committee heard expert advice, based on this study and from 3 years' clinical use, that the routine management of washing the garments, educational support, and ensuring that appropriate decision‑making protocols are used to identify the correct piece of equipment for at‑risk patients were issues in the adoption of Parafricta garments.
Additional information on the impact of introducing Parafricta Bootees into another NHS hospital trust was provided by an audit at St. Helen's and Knowsley Teaching Hospitals NHS Trust, described by Gleeson (2014; see section 3.8). Expert advisers who used Parafricta garments confirmed that locally developed pressure ulcer risk protocols were used to identify at‑risk patients who could most benefit. An example of patients at risk of heel pressure ulcers as developed at St. Helen's and Knowsley Teaching hospital NHS Trust was presented to the committee.
## Committee considerations
The committee recognised that pressure ulcers are an important problem facing the NHS, both in hospitals and in the community.
The committee was advised that recent progress in pressure ulcer care has focused on the use of pressure‑reducing and pressure‑redistributing devices, but that many patients remain at risk of a pressure ulcer caused by friction and shear. Experts who use Parafricta garments both in the community and in hospitals informed the committee that they use locally developed protocols to identify people at high risk of developing pressure ulcers due to friction and shear. The committee considered that there needs to be a way of clearly identifying patients who would benefit from the use of Parafricta Bootees and Undergarments and this should be considered in designing further research.
The committee heard from expert advisers about their experiences of using Parafricta garments in both hospital and community care. The experts described the positive effect of the technology on the prevention and management of pressure ulcers in certain patients, and good levels of acceptance among staff and patients.
A reduction in the length of stay was the key driver of the cost saving identified by the sponsor's model, but the committee was unconvinced that this was the most reliable way to capture the benefits of Parafricta garments in a cost analysis. It considered that many patients who use Parafricta garments are likely to have comorbidities, which may indirectly influence the length of stay. Experts also advised the committee that the pressure ulcers that are generally associated with longer hospital stays (grade 3 or 4) are relatively uncommon, and it is less likely that the development of more common grade 1 or 2 ulcers would prolong the length of hospital stay. The committee concluded that collection of detailed resource use information on managing pressure ulcers in hospital was needed to inform a more appropriate cost analysis.
The committee considered the logistics of providing Parafricta garments in hospital. It heard expert advice that the garments can be easily managed in this setting: patients are identified using a locally developed protocol before being issued with the garments from a central pool. Parafricta garments are cleaned in the same way as hospital mattresses and have proved to be very durable; in some cases, the garments have withstood more than 100 washes. A small number of Bootees are disposed of every month, based on an inspection by a clinician, usually because of worn non‑slip soles or fraying at the seams. The committee concluded that the estimates in the cost model of using each Parafricta garment only 6 times were likely to be conservative.
In response to questions about the possibility of cross‑infection, the committee heard expert advice based on experience of using Parafricta Bootees in an NHS hospital trust over 2 years. There had been no occurrences of infection attributable to the Bootee.
With regard to use in the community, the committee was told by an expert about a locally defined protocol used to identify people at risk of developing a pressure ulcer caused by friction and shear in a community setting. Having received the garments on prescription, patients are responsible for their own laundry. The committee heard expert advice that people are happy to use these garments as a long‑term care strategy to prevent and manage pressure ulcers. The committee considered that if further research confirms the effectiveness of Parafricta garments in decreasing incidence and severity of pressure ulcers in hospital, the technology could have a positive effect on patients in the community.# Cost considerations
# Cost evidence
## Published evidence
The sponsor identified 1 relevant study (Smith and Ingram, 2010). The external assessment centre (EAC) agreed with its inclusion and did not identify any further studies. The study considered the cost effectiveness of Parafricta garments to see if any reduction in treatment costs outweighed the initial item cost. Costs were calculated for each treatment pathway, and it was estimated that Parafricta garments could save more than £63,000 per 100 at‑risk people.
## Sponsor's cost model
The sponsor submitted a de novo cost analysis to assess potential cost savings when using Parafricta Bootees and Undergarments as an adjunct to current clinical care. Full details of all cost evidence and modelling considered by the committee are available in the assessment report overview.
The sponsor submitted a base‑case analysis for 1 hospital and 1 community setting. The population was people in the community or in hospital who:
had a grade 1 or 2 pressure ulcer and were at risk of progressing to a grade 3 or 4 pressure ulcer
did not have a pressure ulcer but were at risk of developing pressure ulcers caused by friction and shear
had medical conditions in which frail skin is a primary factor and friction and shear could cause skin damage.Separate analyses were conducted to reflect the garments' use in hospital or in the community. In hospital, potential cost savings were based on expected reductions in length of stay for people using Parafricta garments. In the community, potential cost savings were based on a reduced prevalence rate among those using Parafricta garments. No distinction was made between adults and children, or between the different pressure ulcer grades.
The sponsor explored the uncertainty around the model parameters and the effect this had on the incremental cost using deterministic and probabilistic sensitivity analyses for both the hospital and community models.
The sponsor's hospital model base case included several key assumptions. These were as follows:
A time horizon of 1 year.
Five potential pathways for at‑risk people.
The cost of treating people in each of the 5 pathways was calculated by applying the appropriate day costs to the relevant weighted length of stay.
The only additional daily cost for people with a pressure ulcer compared with those without a pressure ulcer was an additional dressing cost of £0.74.
Each person was allocated 6 garments.
Each garment was washed on average twice over the person's length of stay.
Each set of 6 garments was used by an average of 3 different people over the garments' lifetime.
The base‑case results for the hospital model showed that using Parafricta garments saved £757 per at‑risk person, based on costs of £5,307 per at‑risk person when the garments were not used and £4,550 per at‑risk person when they were. This was based on the cost of each Parafricta garment being £35.14 and an assumed laundry cost of £0.50 per wash, per garment. The weighted median length of stay was 13.7 days for the Parafricta group and 16.2 days for the no Parafricta group. The general hospital costs were £326.53 per day, comprising a bed day cost of £325, a £0.59 per‑day mattress cost and a £0.74 general dressing cost. The additional dressing cost applicable to days with a pressure ulcer was £0.74.
The results from the sponsor's multi‑way deterministic sensitivity analyses confirmed that the modelled cost savings were most sensitive to the weighted length of stay values used. In these results, Parafricta garments were cost saving in all cases, except when the median weighted length of stay without Parafricta garments was 14.8 days and when the median weighted length of stay with Parafricta garments was 14.9 days. In the sensitivity analysis the cost savings were greatest when the median weighted length of stay without Parafricta garments was 17.7 days and when the median length of stay with Parafricta garments was 12.5 days.
The sponsor's community model base case included several key assumptions. These were as follows:
A time horizon of 1 year.
For every person in the community with a pressure ulcer, there were 2 other at‑risk people without a pressure ulcer.
Costs in the community model were based solely on the annual cost of Parafricta garments and the costs associated with nurse visits.
All people with pressure ulcers were assumed to need nurse visits.
The difference between median length of stay when a pressure ulcer developed and time to develop a pressure ulcer was used as a proxy for pressure ulcer duration.
The incidence per at‑risk person and the pressure ulcer duration were used to calculate a point prevalence in Parafricta and no Parafricta groups.
The base‑case results for the community model showed an annual cost saving of £3,455 per person with a pressure ulcer. The base‑case calculation for treating a person with a pressure ulcer in the community was £5,900, based on 1.86 nurse visits a week at £61 per visit for 52 weeks. Treating a pressure ulcer with Parafricta garments was estimated at £2,445, based on a prevalence ratio of 0.37 and an annual cost of £240 per person with a pressure ulcer.
Results from the deterministic sensitivity analysis always favoured the use of Parafricta garments and suggested cost savings of approximately £1,500 to £4,500. The lowest cost savings were obtained with a reduction in the effectiveness of Parafricta garments – by increasing the prevalence ratio to 0.685. Results from the probabilistic sensitivity analysis suggested that there is very little uncertainty and that Parafricta garments are always cost saving.
## EAC revisions to the hospital cost model
The EAC did not consider that all of the assumptions in the sponsor's hospital cost model were optimum. The EAC's revisions included a simplified structure based on 3 pathways, which avoided the small patient numbers in some pathways and also calculated mean lengths of stay adjusted with the limited baseline patient characteristics.
The EAC also amended some of the costs in the model, the most noteworthy of which was the revision of the bed‑day cost. A weighted cost using excess bed‑day cost across a range of wards was used to obtain an estimate of £234 per day. The EAC used a cost of £328 as an upper limit in the sensitivity analysis.
The revised hospital model base‑case results suggested that use of Parafricta garments saved £595 per at‑risk person. This was based on costs of £3,556 per at‑risk person if Parafricta garments are not used and £2,960 per at‑risk person if the garments are used. In a one‑way sensitivity analysis with a bed day costing £328, the cost savings were increased to £863.
The EAC also conducted a probabilistic sensitivity analysis which suggested that the use of Parafricta garments resulted in cost savings nearly 80% of the time. Most iterations suggested that Parafricta garments were cost saving, with maximum savings of about £6,000 per at‑risk person. However, there were some iterations in which the garments added costs, reflecting the uncertainty in length of stay data.
## EAC revisions to the community cost model
The EAC recalculated a prevalence ratio based on the adjusted mean length of stay data and obtained a value of 0.53. No other changes were made to the model.
The base‑case results for the revised community model were estimated at £2,510 per person with a pressure ulcer, based on an unchanged cost per person with a pressure ulcer of £5,900 without Parafricta garments and £3,390 with them. Deterministic sensitivity analysis varying the length of stay data based on lower and upper limits of 95% confidence intervals suggested that the cost savings could be between £2,295 and £2,799.
## Committee considerations
The committee considered that the hospital cost model structure was appropriate and that the sponsor had addressed some of the uncertainties in the cost model through sensitivity analyses. However, it noted that the model included very limited information on the resource implications of having a pressure ulcer, and did not consider pressure ulcer grade. The committee noted that the EAC's revisions simplified the treatment pathways and included weighted mean lengths of stay rather than median values. It considered that analysis based on these revisions was more appropriate, in the context of the data available.
The committee accepted that the mean length of stay values calculated by the EAC – adjusted to account for differences in patient characteristics between the groups – were appropriate. However, the committee noted that the calculated adjusted mean length of stay values were inconsistent, due to the limited information available on patient characteristics. The committee acknowledged that the relationship between length of stay and pressure ulcer incidence and severity is not straightforward and there are many other factors that can influence length of stay. The committee concluded that further research would be necessary to determine the system impact of using Parafricta Bootees and Undergarments in hospital. It considered that more detailed information on the length of stay, severity of pressure ulcers, the costs of treating them, pressure ulcer status and where a patient is cared for after discharge could be used to inform a more robust cost analysis.
The committee noted that a very simple approach was adopted for the cost analysis in the community model. It was aware that the only data available were those from the Smith and Ingram (2011) study that was conducted in hospital. The committee considered that the cost savings from the community model were uncertain, but it nevertheless acknowledged the potential for significant cost savings with the use of Parafricta garments in the community if further research demonstrates their effectiveness in reducing the incidence and severity of pressure ulcers in hospital.# Conclusions
The committee concluded that Parafricta Bootees and Undergarments are a promising technology with the potential to reduce skin damage and the incidence and severity of pressure ulcers in both hospitals and the community. However, the committee considered that more evidence about the clinical benefits of using the garments is needed to support the case for more widespread, routine adoption.
The committee recommended that further research into clinical outcomes with Parafricta Bootees and Undergarments would be beneficial. It considered that comparative research against standard care could determine whether using Parafricta garments prevents skin damage and the development of pressure ulcers, and whether it benefits patients with existing pressure ulcers of all grades. The committee considered that in order for the garments to be used in those most in need, research should address how best to identify patients at risk of pressure ulcers due to friction and shear, for whom the use of Parafricta garments would offer most benefit.
The committee considered that research could be completed relatively quickly, especially in the NHS centres that are already using the technology. Of the outcomes defined in the scope, it considered that the reduction in pressure ulcer incidence and severity, length of hospital stay, ease of use and patient comfort would be particularly important in any research or data analysis.
|
{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. The medical technology guidance on 'Parafricta Bootees and Undergarments' recommends further research. This recommendation is not intended to preclude the use of the technology in the NHS but to identify further evidence which, after evaluation, could support a recommendation for wider adoption.\n\nParafricta Bootees and Undergarments show potential to reduce the development and progression of skin damage caused by friction and shear in people with, or at risk of, pressure ulcers. However, more evidence for their effectiveness in clinical practice is needed to support the case for routine adoption of Parafricta Bootees and Undergarments in the NHS.\n\nResearch is recommended to address uncertainties about the claimed patient and system benefits of using Parafricta Bootees and Undergarments. This should take the form of comparative research against standard care, preferably carried out in a hospital. The research should include development of criteria to recognise people who would most benefit from the technology in both hospitals and community care. NICE will explore the development of appropriate further evidence, in collaboration with the technology sponsor and with clinical and academic partners, and will update this guidance if and when substantive new evidence becomes available.", 'The technology': "# Description of the technology\n\nParafricta Bootees and Undergarments (APA Parafricta) are intended to reduce the potential for both the development and the progression of skin damage caused by friction and shear in people who have, or are at risk of developing, pressure ulcers, and in people with frail skin or those who have medical conditions in which skin frailty is a primary factor. Bootees provide protection for the heel and ankle, and Undergarments provide protection for the sacrum, buttocks and hips. The items are made from proprietary Parafricta fabric which is designed to reduce the shear stress and friction associated with movement. It has a friction coefficient value of 0.2, whereas most textiles typically range from 0.3 to 0.7. Parafricta fabric has no stiction, which is the additional force needed to overcome skin sticking to a surface before sliding. Because of this, it reduces the 'jerk' effect on skin when movement occurs. The lower the friction and stiction, the less likely it is that shear forces will develop and break the skin down, thereby reducing the risk of pressure ulcers. This mechanism of action is different from current methods of pressure ulcer management or prevention, which aim to manage or prevent pressure ulcers by reducing or redistributing pressure.\n\nParafricta fabric is used to protect the skin in areas most at risk. Both Parafricta Bootees and Undergarments have non‑slip areas to help patient positioning, and Velcro fastenings for easy application and removal. The positioning of the Velcro fasteners and the garments' flat seams are designed to minimise skin creasing or damage. The Bootee is supplied singly and is available in a range of adult sizes (starting from an adult size\xa02). They come in 2 types – with slip‑on or Velcro fasteners – and have non‑slip soles. The Undergarment is available in several sizes as a slip‑on garment or with Velcro fasteners, and as briefs or boxer shorts. Parafricta fabric is described as breathable but durable. The products are reusable after washing in accordance with garments for NHS use.\n\nThe cost of each Parafricta Bootee stated in the sponsor's submission is £35.14 (excluding VAT). The cost of the Parafricta Undergarment stated in the sponsor's submission is also £35.14 (excluding VAT). Parafricta garments are prescribable on a standard FP10 prescription.\n\nThe sponsor's claimed patient and healthcare benefits for Parafricta Bootees and Undergarments are as follows:\n\nA reduction in pressure ulcer incidence and severity in people who are at high risk of pressure ulcers following assessment, thereby reducing or avoiding adverse impact on quality of life, pain, discomfort, hospital length of stay, morbidity and mortality.\n\nProtection of susceptible skin in people in whom a repetitive, rubbing motion – due to an underlying neurological or other medical condition – can break down the skin.\n\nEase of use for patients and carers, combined with a familiarity with the type of products in older people or those with cognitive impairment, may lead to greater compliance with pressure ulcer preventative measures.\n\nThe products can be used in the home or in community care or hospitals, enabling the patient to easily transition between these settings.\n\nThe ease of use and practicality of Parafricta garments imply that the technology may be implemented easily in the community, and could be used as a long‑term care strategy to improve people's quality of life.\n\nPrevention of pressure ulcer formation and reduced pressure ulcer incidence would shorten stays in hospital and may allow people to be transferred to lower cost community care. Hospital‑acquired pressure ulcers result in lengthened hospital stays and increased complications.\n\nReduction in NHS costs including but not limited to:\n\n\n\nquicker return of people to the community or community long‑term care\n\nreduced pressure ulcer incidence resulting in lower costs of nursing care, dressings and rehabilitation\n\nthe reusable nature of the garments.\n\n\n\n# Current management\n\nCurrent options to reduce breakdown of frail skin and to prevent and manage pressure ulcers focus on the reduction or redistribution of pressure. They include: dynamic or static high‑specification pressure‑relieving or pressure‑redistributing beds, mattresses, overlays and cushions; and sheepskin or pressure‑relieving bootees or silicone gel pads (numerous products, shapes and sizes are available).\n\nNICE's guideline on pressure ulcers states that there is overlap between ulcers caused mainly by moisture and those caused by shear stresses or friction rather than pressure alone. This can cause some confusion in classification. In reality, however, pressure, shear, friction and moisture may all contribute in varying degrees to the development of an ulcer. The guideline recommends that when a person presents with or is at increased risk of developing a pressure ulcer, risk should be assessed and documented and then reassessed regularly.\n\nNICE's guideline on pressure ulcers recommends that risk assessment should be followed by consideration of mobilising, positioning and repositioning interventions to prevent or minimise skin damage. When indicated, the recommended minimum provision is a high‑specification foam pressure‑relieving mattress or high‑specification foam mattress with an alternating pressure overlay, or a sophisticated continuous low pressure system. Any ulcer should be closely observed for deterioration.", 'Clinical evidence': "# Summary of clinical evidence\n\nFull details of all clinical outcomes considered by the committee are available in the assessment report overview.\n\nThe key clinical outcomes for Parafricta Bootees and Undergarments presented in the decision problem were:\n\nincidence and severity of pressure ulcers or skin breakdown\n\nlength of hospital stay\n\ntime to healing for those with an existing pressure ulcer\n\ncompliance with pressure ulcer management\n\nthe person's comfort (including ability to move and self‑reposition in bed)\n\nquality of life\n\ndevice‑related adverse events.\n\nThe clinical evidence for Parafricta Bootees and Undergarments presented by the sponsor was 4 published multiple‑patient case‑series reports, 3 of which were peer‑reviewed papers (1 with historical controls) and 1 poster. These were Hampton et al. (2009), Loehne (2013; poster), Smith and Ingram (2010; with historical controls) and Stephen‑Haynes and Callaghan (2011). The sponsor also identified 3 single case studies but these were not presented. Independent searches by the external assessment centre (EAC) found no additional relevant studies. Data from an unpublished audit (Gleeson 2014) were sent to the EAC by the sponsor during the evaluation.\n\n## Multiple‑patient case series: peer‑reviewed papers\n\nA case series of 25 nursing home residents by Hampton et al. (2009) evaluated whether using a Parafricta Bootee or Undergarment could reduce oedema and inflammation associated with pressure ulcers. All residents had restricted mobility and each had redness and a 'boggy' feel to the tissues, either over the sacrum or 1 or 2 heels. A total of 28 pressure ulcers of grade\xa01 or above were analysed, all of which were related to friction or shear. Ten\xa0people used a Parafricta Bootee on the right heel (the left heel [control] without the Bootee was used as a comparator) and 18 used a Parafricta Undergarment ('normal' skin adjacent to the sacrum was used as a comparator). The degree of oedema and inflammation of the pressure ulcers was measured using 3 methods: high‑frequency ultrasound scan data, colour photographs and tissue assessment by a tissue viability nurse. Statistical analysis of the high‑frequency ultrasound data was conducted using the Kolmogorov–Smirnov 2‑sample test. For this analysis, the skin profile of each heel (treated and control) was compared with a 'normal' heel profile (a standard heel with no pressure ulcer or redness). At the start of the study, results showed that both the treated heel (p<0.001) and the control heel (p<0.001) were statistically significantly different from the normal heel. At the end of 4\xa0weeks, the difference between the treated heel and the 'normal' heel had reduced (p=0.2), whereas the difference between the control heel and the 'normal' heel was still statistically significant (p<0.001). Analysis of the treated heel results at week\xa00 compared with week\xa04 showed an improvement with a statistically significant difference (p<0.001). Based on these results, the authors concluded that the heel treated with a Parafricta Bootee became more similar to the 'normal' heel, and that Parafricta garments were effective in reducing oedema. The tissue viability nurse assessment found that bogginess and redness were reduced in the treated heels of all 10\xa0residents but there was no change in the control heels. Results from the analysis of the high‑frequency ultrasound data for the sacral area showed a statistically significant difference between baseline and week\xa04 (p=0.006). Bogginess and redness were reduced in all 18\xa0residents treated with a Parafricta Undergarment. The colour photographs for both the heels and the sacral areas were not considered clear enough by the researchers to validate the results. The ultrasound data were deemed to be more objective and reliable than either the colour photographs or the visual assessment.\n\nThe case series by Loehne (2013; poster) evaluated the use of Parafricta Bootees to prevent pressure ulcers in nursing home residents who were at risk of developing heel pressure ulcers as a result of friction and shear. Although the poster did not report how many residents were involved, the sponsor submission stated that the study included 6\xa0residents and the intervention was a standard pressure‑reducing surface plus a Parafricta Bootee. After 30\xa0days, none of the residents had developed a pressure ulcer or had any healed ulcers recurring. This included 1\xa0person who had had a recurrent pressure ulcer for 2\xa0years.\n\nSmith and Ingram (2010) investigated the effectiveness of Parafricta garments in reducing the incidence and prevalence of pressure ulcers in hospital. The study incidence data were collected from 2 medical wards and 1 orthopaedic ward over 6\xa0consecutive months. The first 3\xa0months provided the data for group\xa01 (n=204) and the next 3\xa0months were used for group\xa02 (n=165). People in both groups had identical care using the hospital's standard pressure ulcer prevention protocol, except that those in group\xa02 were also given a Parafricta Bootee or Undergarment. It was not clear how many had a Bootee or an Undergarment or both. Analysis of Waterlow scores suggested that they did not differ between the 2 groups. The authors reported the results as percentage differences in incidence of pressure ulcers between the groups. For additional ease of interpretation, the EAC recalculated the results as relative risks. The results showed that at‑risk people who were admitted to hospital without a pressure ulcer were more likely to develop a pressure ulcer in the no Parafricta group than in the Parafricta group (relative risk [RR]\xa01.64, 95% confidence interval [CI] 1.05\xa0to\xa02.59). For at‑risk people admitted without a pressure ulcer who then developed one, those in the no Parafricta group were more likely to have an ulcer that deteriorated or did not improve compared with those in the Parafricta group (RR\xa02.53, 95% CI 1.16\xa0to\xa05.52). A similar result was found for people who were admitted with an existing pressure ulcer: risk of deterioration was more likely in the no Parafricta group than in the Parafricta group (RR\xa04.90, 95% CI 1.75\xa0to\xa013.75). There was no statistically significant difference between the groups in the risk of developing an additional ulcer in people who were admitted with one (RR\xa01.55, 95% CI 0.87\xa0to\xa02.75). The Smith and Ingram (2010) study reported median lengths of stay. The EAC obtained the study data from the sponsor and reanalysed it to calculate mean lengths of stay for each group as a more appropriate parameter for use in the economic model. The average length of stay was calculated by weighting the length of stay in each treatment group by the proportion of people in the group. Results showed a weighted mean length of stay of 20.31\xa0days for the no Parafricta group and 16.27\xa0days for the Parafricta group, a statistically significant difference of 4.05\xa0days (p=0.019). The EAC also used the limited information on confounding factors to estimate adjusted length of stay values, which took into account reported baseline characteristics between the groups. Results showed a weighted mean length of stay of 14.94\xa0days for the no Parafricta group and 12.47\xa0days for the Parafricta group, a difference of 2.47\xa0days. No demographic characteristics were reported for either group.\n\nStephen‑Haynes and Callaghan (2011) described a case series of 25 nursing home residents who used Parafricta Bootees and Undergarments in addition to the standard approach for ulcer prevention and management as outlined in NICE's guideline\xa0on pressure ulcers. At the start of the study, 20\xa0residents had an existing pressure ulcer of category\xa02 or below and 5 had intact skin. Those with intact skin were considered at risk of developing a pressure ulcer through friction due to repetitive movements caused by their medical condition. The outcomes that were considered included skin improvement, ease of use, garment retention and patient comfort. No information about the timescale of the study was provided. There was skin improvement in 76% (n=19) of residents, whereas 24% (n=6) remained the same. Clinicians found the garments very easy to use for most people (64%, n=16), and 88% (n=22) of clinicians stated that Parafricta garments had a positive impact on clinical outcomes. All residents in the study found the garment comfortable (24%, n=6) or very comfortable (76%, n=19). Almost half (48%; n=12) of clinicians reported that it was very easy to keep the garments in place, and 16% (n=4) did not find it easy. This was an uncontrolled study so it was difficult to tell whether any improvement in pressure ulceration or skin improvement was temporary or prolonged, or even whether any improvement was because of Parafricta garments.\n\nThe unpublished clinical audit by Gleeson (2014) evaluated the use of Parafricta Bootees in people at high risk of pressure ulcers on 6 hospital wards in the St. Helen's and Knowsley Teaching Hospitals NHS Trust over a 12‑month period (January to December 2012). The author reported a 32% reduction in hospital‑acquired grade\xa02 pressure ulcers compared with the previous year. Other details were made available to the committee on an academic‑in‑confidence basis and the author supplied additional academic‑in‑confidence information during the consultation, although details cannot be reported here. The EAC considered it unclear how much of the reduction in pressure ulcers reported was because of the use of Parafricta Bootees, and how much was caused by other pressure ulcer prevention initiatives taking place at the NHS trust.\n\n## Adverse events\n\nThe sponsor found no adverse event reports relating to Parafricta garments. No alerts have been issued, and no information was found in a search of the Medicines and Healthcare products Regulatory Agency website.\n\n## Committee considerations\n\nThe committee noted that the clinical evidence base for Parafricta garments was 4 published multiple‑patient case series and 1 unpublished audit. The committee agreed with the EAC's conclusions that there was a lack of good quality comparative evidence against standard care. The committee recognised that there is often only limited evidence for products used in pressure ulcer prevention and management , but considered it possible to conduct comparative research of good quality to assess the clinical effectiveness of this technology.\n\nThe committee accepted the EAC's critique of the Smith and Ingram (2010) study and agreed that because of potential confounding factors, it is not clear that any change in the pressure ulcer incidence or severity was due to Parafricta garments. The committee also agreed with the concerns raised by the EAC about the unpublished Gleeson audit (2014), including the additional data submitted during consultation, and it was not convinced that the reduction in heel pressure ulcers documented in the audit was solely because of the Parafricta Bootees.\n\nBased on the existing evidence base and expert advice, the committee considered that Parafricta garments may indeed reduce pressure ulcer incidence and severity, and so provide potential benefits for patients. The committee was aware that older people and those with frail skin are more susceptible to pressure ulcers as a result of friction or shear, and it considered that Parafricta garments may be particularly beneficial to these people. However, it judged that the case for routine adoption in the NHS could not currently be supported because there are too many uncertainties in the evidence base.\n\nThe committee wished to encourage comparative research in hospitals (for ease and speed of generating findings) to investigate the clinical effectiveness of Parafricta garments as an adjunct to standard care compared with standard care alone in reducing skin breakdown in people with or at risk of pressure ulcers. The study should be randomised and the assessors blinded to minimise bias in the results. The committee specified that the research should focus on determining relative effectiveness compared with standard care when biases were carefully controlled for, and on developing criteria to identify patients for whom Parafricta garments are most likely to be effective.\n\nThe committee recognised that there is great potential for the use of Parafricta garments in the community. It considered that they could be beneficial to patients with long‑term conditions where pressure ulcers are a significant problem. However, it was advised of the significant challenges of conducting comparative research in the community. The committee considered that the results obtained in hospitals could plausibly be generalisable , and advised that the need for the findings from a hospital setting to be generalised to community‑based settings should be factored into the design of the research studies.\n\nThe committee discussed outcomes of special importance to patients. It noted the results from the Stephen‑Haynes and Callaghan (2011) case series which suggested that the garments were easy to use and that patients found them comfortable. Expert advice to the committee was that the fastenings ensure the garments remain in place, and that they have proven popular with patients. No adverse events were identified as a result of their use. The committee concluded that Parafricta Bootees and Undergarments are convenient, easy to use and well tolerated by patients, but considered that a record of patient experience would be useful to incorporate in future research studies.\n\nFor the guidance review, the EAC reviewed evidence published since November 2014. There were 3 publications of 2 single-arm studies on the technology. No new evidence compared Parafricta bootees or undergarments with standard care. In 1 study heel ulcer incidence reduced by 84% after Parafricta bootees were introduced. This was across all wards in 2 hospitals over 5 years of follow up (Gleeson 2015 and 2016). Another study reported on 15 people who used the Parafricta bootees. It reported a significant reduction in peak pressure on heels and other areas of the feet in direct contact with a surface. People rated the technology as 'excellent' or 'good' (Schofield 2018). The EAC considered that the new evidence did not answer the uncertainties that led to the recommendation for research in this guidance. ", 'NHS considerations': "# System impact\n\nThe Smith and Ingram (2010) study described in section\xa03.6 provides information on the incidence of pressure ulcers in an NHS hospital and on lengths of stay in hospital. During the selection of Parafricta Bootees and Undergarments, the committee heard expert advice, based on this study and from 3\xa0years' clinical use, that the routine management of washing the garments, educational support, and ensuring that appropriate decision‑making protocols are used to identify the correct piece of equipment for at‑risk patients were issues in the adoption of Parafricta garments.\n\nAdditional information on the impact of introducing Parafricta Bootees into another NHS hospital trust was provided by an audit at St. Helen's and Knowsley Teaching Hospitals NHS Trust, described by Gleeson (2014; see section\xa03.8). Expert advisers who used Parafricta garments confirmed that locally developed pressure ulcer risk protocols were used to identify at‑risk patients who could most benefit. An example of patients at risk of heel pressure ulcers as developed at St. Helen's and Knowsley Teaching hospital NHS Trust was presented to the committee.\n\n## Committee considerations\n\nThe committee recognised that pressure ulcers are an important problem facing the NHS, both in hospitals and in the community.\n\nThe committee was advised that recent progress in pressure ulcer care has focused on the use of pressure‑reducing and pressure‑redistributing devices, but that many patients remain at risk of a pressure ulcer caused by friction and shear. Experts who use Parafricta garments both in the community and in hospitals informed the committee that they use locally developed protocols to identify people at high risk of developing pressure ulcers due to friction and shear. The committee considered that there needs to be a way of clearly identifying patients who would benefit from the use of Parafricta Bootees and Undergarments and this should be considered in designing further research.\n\nThe committee heard from expert advisers about their experiences of using Parafricta garments in both hospital and community care. The experts described the positive effect of the technology on the prevention and management of pressure ulcers in certain patients, and good levels of acceptance among staff and patients.\n\nA reduction in the length of stay was the key driver of the cost saving identified by the sponsor's model, but the committee was unconvinced that this was the most reliable way to capture the benefits of Parafricta garments in a cost analysis. It considered that many patients who use Parafricta garments are likely to have comorbidities, which may indirectly influence the length of stay. Experts also advised the committee that the pressure ulcers that are generally associated with longer hospital stays (grade\xa03 or\xa04) are relatively uncommon, and it is less likely that the development of more common grade\xa01 or\xa02 ulcers would prolong the length of hospital stay. The committee concluded that collection of detailed resource use information on managing pressure ulcers in hospital was needed to inform a more appropriate cost analysis.\n\nThe committee considered the logistics of providing Parafricta garments in hospital. It heard expert advice that the garments can be easily managed in this setting: patients are identified using a locally developed protocol before being issued with the garments from a central pool. Parafricta garments are cleaned in the same way as hospital mattresses and have proved to be very durable; in some cases, the garments have withstood more than 100\xa0washes. A small number of Bootees are disposed of every month, based on an inspection by a clinician, usually because of worn non‑slip soles or fraying at the seams. The committee concluded that the estimates in the cost model of using each Parafricta garment only 6\xa0times were likely to be conservative.\n\nIn response to questions about the possibility of cross‑infection, the committee heard expert advice based on experience of using Parafricta Bootees in an NHS hospital trust over 2\xa0years. There had been no occurrences of infection attributable to the Bootee.\n\nWith regard to use in the community, the committee was told by an expert about a locally defined protocol used to identify people at risk of developing a pressure ulcer caused by friction and shear in a community setting. Having received the garments on prescription, patients are responsible for their own laundry. The committee heard expert advice that people are happy to use these garments as a long‑term care strategy to prevent and manage pressure ulcers. The committee considered that if further research confirms the effectiveness of Parafricta garments in decreasing incidence and severity of pressure ulcers in hospital, the technology could have a positive effect on patients in the community.", 'Cost considerations': "# Cost evidence\n\n## Published evidence\n\nThe sponsor identified 1 relevant study (Smith and Ingram, 2010). The external assessment centre (EAC) agreed with its inclusion and did not identify any further studies. The study considered the cost effectiveness of Parafricta garments to see if any reduction in treatment costs outweighed the initial item cost. Costs were calculated for each treatment pathway, and it was estimated that Parafricta garments could save more than £63,000 per 100 at‑risk people.\n\n## Sponsor's cost model\n\nThe sponsor submitted a de novo cost analysis to assess potential cost savings when using Parafricta Bootees and Undergarments as an adjunct to current clinical care. Full details of all cost evidence and modelling considered by the committee are available in the assessment report overview.\n\nThe sponsor submitted a base‑case analysis for 1 hospital and 1 community setting. The population was people in the community or in hospital who:\n\n\n\nhad a grade\xa01 or\xa02 pressure ulcer and were at risk of progressing to a grade\xa03 or\xa04 pressure ulcer\n\ndid not have a pressure ulcer but were at risk of developing pressure ulcers caused by friction and shear\n\n\n\nhad medical conditions in which frail skin is a primary factor and friction and shear could cause skin damage.Separate analyses were conducted to reflect the garments' use in hospital or in the community. In hospital, potential cost savings were based on expected reductions in length of stay for people using Parafricta garments. In the community, potential cost savings were based on a reduced prevalence rate among those using Parafricta garments. No distinction was made between adults and children, or between the different pressure ulcer grades.\n\nThe sponsor explored the uncertainty around the model parameters and the effect this had on the incremental cost using deterministic and probabilistic sensitivity analyses for both the hospital and community models.\n\nThe sponsor's hospital model base case included several key assumptions. These were as follows:\n\nA time horizon of 1\xa0year.\n\nFive potential pathways for at‑risk people.\n\nThe cost of treating people in each of the 5 pathways was calculated by applying the appropriate day costs to the relevant weighted length of stay.\n\nThe only additional daily cost for people with a pressure ulcer compared with those without a pressure ulcer was an additional dressing cost of £0.74.\n\nEach person was allocated 6 garments.\n\nEach garment was washed on average twice over the person's length of stay.\n\nEach set of 6 garments was used by an average of 3 different people over the garments' lifetime.\n\nThe base‑case results for the hospital model showed that using Parafricta garments saved £757 per at‑risk person, based on costs of £5,307 per at‑risk person when the garments were not used and £4,550 per at‑risk person when they were. This was based on the cost of each Parafricta garment being £35.14 and an assumed laundry cost of £0.50 per wash, per garment. The weighted median length of stay was 13.7\xa0days for the Parafricta group and 16.2\xa0days for the no Parafricta group. The general hospital costs were £326.53 per day, comprising a bed day cost of £325, a £0.59 per‑day mattress cost and a £0.74 general dressing cost. The additional dressing cost applicable to days with a pressure ulcer was £0.74.\n\nThe results from the sponsor's multi‑way deterministic sensitivity analyses confirmed that the modelled cost savings were most sensitive to the weighted length of stay values used. In these results, Parafricta garments were cost saving in all cases, except when the median weighted length of stay without Parafricta garments was 14.8\xa0days and when the median weighted length of stay with Parafricta garments was 14.9\xa0days. In the sensitivity analysis the cost savings were greatest when the median weighted length of stay without Parafricta garments was 17.7\xa0days and when the median length of stay with Parafricta garments was 12.5\xa0days.\n\nThe sponsor's community model base case included several key assumptions. These were as follows:\n\nA time horizon of 1\xa0year.\n\nFor every person in the community with a pressure ulcer, there were 2 other at‑risk people without a pressure ulcer.\n\nCosts in the community model were based solely on the annual cost of Parafricta garments and the costs associated with nurse visits.\n\nAll people with pressure ulcers were assumed to need nurse visits.\n\nThe difference between median length of stay when a pressure ulcer developed and time to develop a pressure ulcer was used as a proxy for pressure ulcer duration.\n\nThe incidence per at‑risk person and the pressure ulcer duration were used to calculate a point prevalence in Parafricta and no Parafricta groups.\n\nThe base‑case results for the community model showed an annual cost saving of £3,455 per person with a pressure ulcer. The base‑case calculation for treating a person with a pressure ulcer in the community was £5,900, based on 1.86 nurse visits a week at £61 per visit for 52\xa0weeks. Treating a pressure ulcer with Parafricta garments was estimated at £2,445, based on a prevalence ratio of 0.37 and an annual cost of £240 per person with a pressure ulcer.\n\nResults from the deterministic sensitivity analysis always favoured the use of Parafricta garments and suggested cost savings of approximately £1,500 to £4,500. The lowest cost savings were obtained with a reduction in the effectiveness of Parafricta garments – by increasing the prevalence ratio to 0.685. Results from the probabilistic sensitivity analysis suggested that there is very little uncertainty and that Parafricta garments are always cost saving.\n\n## EAC revisions to the hospital cost model\n\nThe EAC did not consider that all of the assumptions in the sponsor's hospital cost model were optimum. The EAC's revisions included a simplified structure based on 3 pathways, which avoided the small patient numbers in some pathways and also calculated mean lengths of stay adjusted with the limited baseline patient characteristics.\n\nThe EAC also amended some of the costs in the model, the most noteworthy of which was the revision of the bed‑day cost. A weighted cost using excess bed‑day cost across a range of wards was used to obtain an estimate of £234 per day. The EAC used a cost of £328 as an upper limit in the sensitivity analysis.\n\nThe revised hospital model base‑case results suggested that use of Parafricta garments saved £595 per at‑risk person. This was based on costs of £3,556 per at‑risk person if Parafricta garments are not used and £2,960 per at‑risk person if the garments are used. In a one‑way sensitivity analysis with a bed day costing £328, the cost savings were increased to £863.\n\nThe EAC also conducted a probabilistic sensitivity analysis which suggested that the use of Parafricta garments resulted in cost savings nearly 80% of the time. Most iterations suggested that Parafricta garments were cost saving, with maximum savings of about £6,000 per at‑risk person. However, there were some iterations in which the garments added costs, reflecting the uncertainty in length of stay data.\n\n## EAC revisions to the community cost model\n\nThe EAC recalculated a prevalence ratio based on the adjusted mean length of stay data and obtained a value of 0.53. No other changes were made to the model.\n\nThe base‑case results for the revised community model were estimated at £2,510 per person with a pressure ulcer, based on an unchanged cost per person with a pressure ulcer of £5,900 without Parafricta garments and £3,390 with them. Deterministic sensitivity analysis varying the length of stay data based on lower and upper limits of 95% confidence intervals suggested that the cost savings could be between £2,295 and £2,799.\n\n## Committee considerations\n\nThe committee considered that the hospital cost model structure was appropriate and that the sponsor had addressed some of the uncertainties in the cost model through sensitivity analyses. However, it noted that the model included very limited information on the resource implications of having a pressure ulcer, and did not consider pressure ulcer grade. The committee noted that the EAC's revisions simplified the treatment pathways and included weighted mean lengths of stay rather than median values. It considered that analysis based on these revisions was more appropriate, in the context of the data available.\n\nThe committee accepted that the mean length of stay values calculated by the EAC – adjusted to account for differences in patient characteristics between the groups – were appropriate. However, the committee noted that the calculated adjusted mean length of stay values were inconsistent, due to the limited information available on patient characteristics. The committee acknowledged that the relationship between length of stay and pressure ulcer incidence and severity is not straightforward and there are many other factors that can influence length of stay. The committee concluded that further research would be necessary to determine the system impact of using Parafricta Bootees and Undergarments in hospital. It considered that more detailed information on the length of stay, severity of pressure ulcers, the costs of treating them, pressure ulcer status and where a patient is cared for after discharge could be used to inform a more robust cost analysis.\n\nThe committee noted that a very simple approach was adopted for the cost analysis in the community model. It was aware that the only data available were those from the Smith and Ingram (2011) study that was conducted in hospital. The committee considered that the cost savings from the community model were uncertain, but it nevertheless acknowledged the potential for significant cost savings with the use of Parafricta garments in the community if further research demonstrates their effectiveness in reducing the incidence and severity of pressure ulcers in hospital.", 'Conclusions': 'The committee concluded that Parafricta Bootees and Undergarments are a promising technology with the potential to reduce skin damage and the incidence and severity of pressure ulcers in both hospitals and the community. However, the committee considered that more evidence about the clinical benefits of using the garments is needed to support the case for more widespread, routine adoption.\n\nThe committee recommended that further research into clinical outcomes with Parafricta Bootees and Undergarments would be beneficial. It considered that comparative research against standard care could determine whether using Parafricta garments prevents skin damage and the development of pressure ulcers, and whether it benefits patients with existing pressure ulcers of all grades. The committee considered that in order for the garments to be used in those most in need, research should address how best to identify patients at risk of pressure ulcers due to friction and shear, for whom the use of Parafricta garments would offer most benefit.\n\nThe committee considered that research could be completed relatively quickly, especially in the NHS centres that are already using the technology. Of the outcomes defined in the scope, it considered that the reduction in pressure ulcer incidence and severity, length of hospital stay, ease of use and patient comfort would be particularly important in any research or data analysis.'}
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https://www.nice.org.uk/guidance/mtg20
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Evidence-based recommendations on Parafricta Bootees and Undergarments to reduce skin breakdown in people with or at risk of pressure ulcers.
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d9dfac74f8a198136164cd80f25262aae29349a8
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nice
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Ofatumumab for treating relapsing multiple sclerosis
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Ofatumumab for treating relapsing multiple sclerosis
Evidence-based recommendations on ofatumumab (Kesimpta) for treating relapsing–remitting multiple sclerosis in adults with active disease defined by clinical or imaging features.
# Recommendations
Ofatumumab is recommended as an option for treating relapsing–remitting multiple sclerosis in adults with active disease defined by clinical or imaging features. This is only if the company provides ofatumumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with ofatumumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
NHS treatments for relapsing–remitting multiple sclerosis include alemtuzumab, beta interferons, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, ocrelizumab and teriflunomide.
Clinical trial evidence shows that, in people with relapsing–remitting multiple sclerosis, ofatumumab reduces the number of relapses and slows disease progression when compared with teriflunomide. There is no evidence directly comparing ofatumumab with the other treatments listed. But indirect comparisons suggest that ofatumumab reduces the number of relapses and slows disability progression compared with beta interferons, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate and teriflunomide. They also suggest it is as effective as alemtuzumab, natalizumab and ocrelizumab.
The most likely cost-effectiveness estimates suggest ofatumumab is cost effective and an acceptable use of NHS resources, so it is recommended.# Information about ofatumumab
# Marketing authorisation indication
Ofatumumab (Kesimpta, Novartis) is indicated for the treatment of relapsing forms of multiple sclerosis in adults with active disease defined by clinical or imaging features.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for ofatumumab is £1,492.50 (excluding VAT) per unit pack (prefilled autoinjector pen). The company has a commercial arrangement. This makes ofatumumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Novartis, and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The ASCLEPIOS data from 2 multicentre international phase 3 randomised controlled trials in people with relapsing multiple sclerosis was generalisable to UK clinical practice.
Including data from trials that were originally omitted from the company's base‑case network meta‑analysis had only a minor impact on its findings. It did not materially change the clinical-effectiveness findings for the reduction in relapse rates for ofatumumab.
# The condition and current treatment pathway
## People with multiple sclerosis would value a treatment that can be self-administered at home as a subcutaneous monthly injection
The clinical and patient experts said that multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that symptoms of relapsing multiple sclerosis and the adverse effects from treatment can limit people's ability to work, and to engage in social and family life. The dosing frequency and monitoring needs of some treatments can disrupt people's lives and careers. The committee noted that ofatumumab is self-administered at home. It heard that a treatment that could be self-administered monthly is less disruptive to people's lives than treatments administered by intravenous infusions in hospital, so would be valued by people with multiple sclerosis.
## Ofatumumab could be used first line or after other treatments
The clinical experts said that ofatumumab would be offered as a first-line therapy or after other treatments. The committee agreed that, because ofatumumab is an anti‑CD20 monoclonal antibody, it should be in a similar position in the treatment pathway to ocrelizumab. Ocrelizumab is also an anti‑CD20 monoclonal antibody recommended first line or after other treatments. The clinical experts noted that there are no clear rules for sequencing of treatments. However, in practice, clinicians generally offer a different disease-modifying treatment for relapsing–remitting multiple sclerosis when the patient's current treatment no longer prevents disease relapses. The clinical experts said that pregnancy planning can also be an important factor in choosing to change treatments for relapsing–remitting multiple sclerosis. They also recommend stopping all treatments when people can no longer walk or when they develop secondary progressive multiple sclerosis. The committee concluded that ofatumumab was likely to be used first line or after other treatments in people who have active relapsing–remitting multiple sclerosis.
## The company limited its submission to relapsing–remitting multiple sclerosis
The company limited its submission to relapsing–remitting multiple sclerosis rather than all relapsing forms of multiple sclerosis, as specified in its proposed marketing authorisation. The clinical experts agreed that this was reasonable.
## Patient preference is an important consideration when making shared decisions about treatment
Various treatment options are available, with different methods and schedules of administration, and the committee noted that people have different preferences. The patient expert confirmed that ofatumumab could be self‑administered relatively easily monthly at home, after initial training from a health professional. The committee concluded that differences in dosing schedule, adverse effects and monitoring requirements between ofatumumab and other treatments may influence patient choice. It agreed that it is important to take these into account when making decisions about treatment.
# Clinical evidence
## The trial evidence is generalisable to people in the NHS with active relapsing–remitting multiple sclerosis
The main evidence for the clinical effectiveness of ofatumumab compared with teriflunomide came from 2 trials, ASCLEPIOS I (n=927) and ASCLEPIOS II (n=955). These were phase 3 randomised controlled trials in adults with relapsing multiple sclerosis. The main purpose of these trials was to consider if patients who had ofatumumab had fewer relapses and slower disease progression compared with patients who had teriflunomide. Participants had had at least 1 relapse in the past year, 2 relapses in the last 2 years, or a positive gadolinium-enhancing MRI scan in the last year. Few patients in each trial were from the UK, but the clinical experts and ERG noted that there were no major concerns about the generalisability of the evidence. The committee accepted that the baseline characteristics of the patients in ASCLEPIOS I and II reflected people with relapsing–remitting multiple sclerosis having treatment in the NHS. It concluded that the results of the clinical trials were generalisable to NHS clinical practice.
## Highly active and rapidly evolving severe multiple sclerosis subgroup analysis is not suitable for decision making
The company carried out 2 post-hoc analyses of the ASCLEPIOS trials data for the 2 subgroups: patients with highly active disease or with rapidly evolving severe disease. These subgroups had been defined in the NICE scope for this appraisal. The highly active subgroup was defined as people in the ASCLEPIOS relapsing–remitting multiple sclerosis population who had previously had any disease-modifying treatment and stopped their last treatment because of lack of efficacy. The rapidly evolving severe subgroup were people with relapsing–remitting multiple sclerosis, who had had at least 2 relapses in the last year and at least one T1 gadolinium-enhancing lesion on baseline brain MRI. The company was not able to carry out a network meta-analysis for these subgroups because of a lack of published comparator trial data. The committee noted that there was limited evidence for these subgroups and that the company had included them because previous appraisals had considered them. The clinical experts said that clinicians are more likely to use categories that describe treatment and relapse history and, in practice, these subgroups would not be used. The committee concluded that the evidence was not robust enough for them to be considered separately, and the relapsing–remitting multiple sclerosis population would be considered as a whole in this appraisal.
## Ofatumumab reduces relapse and slows disability progression compared with teriflunomide
The ASCLEPIOS trials showed that ofatumumab is more effective than teriflunomide for all main clinical outcomes and had no unexpected safety concerns. Ofatumumab reduced annualised relapse rate compared with teriflunomide with an annual relapse rate ratio of 0.50 (95% confidence interval 0.37 to 0.65) in ASCLEPIOS I and 0.42 (95% confidence interval 0.31 to 0.56) in ASCLEPIOS II. Fewer patients had confirmed disability worsening at 3 months and 6 months for ofatumumab compared with teriflunomide. The hazard ratio for ofatumumab compared with teriflunomide was 0.68 (95% confidence interval 0.50 to 0.92) for confirmed disability worsening at 6 months for the prespecified pooled ASCLEPIOS population (because both trials had the same design and were carried out at the same time). The committee concluded that ofatumumab was clinically effective compared with teriflunomide.
# Mixed treatment comparison
## Ofatumumab reduces annualised relapse rates compared with most comparators in the relapsing–remitting multiple sclerosis population
Because the company had direct comparative evidence only for ofatumumab and teriflunomide, it provided a network meta-analysis to estimate ofatumumab's effectiveness compared with the other comparators in the scope. The company chose 31 studies to inform its mixed treatment comparison for annualised relapse rates in the relapsing–remitting multiple sclerosis population. There was uncertainty in the results because most comparisons were informed by a single trial, and many of the comparators were indirectly compared with ofatumumab by 1 or more intermediate comparator. However, the committee concluded that there was a lower annualised relapse rate for ofatumumab in the whole population compared with most comparators, except the monoclonal antibodies (alemtuzumab, natalizumab and ocrelizumab) and cladribine.
## Ofatumumab may slow disability progression compared with most comparators except the other monoclonal antibodies in the relapsing–remitting multiple sclerosis population
The company chose 21 studies for confirmed disability worsening at 3 months and 20 studies for confirmed disability worsening at 6 months in its base-case analyses. The ASCLEPIOS trials used a different definition of disability worsening from the one commonly used in other trials, based on Expanded Disability Status Scale (EDSS) changes from baseline. The EDSS is used to measure how much someone is affected by their multiple sclerosis. To account for using a different definition, the company carried out additional analyses on the 3‑month and 6‑month data from the ASCLEPIOS trials using 'aligned criteria'. The company also carried out another analysis of the ASCLEPIOS trial data according to the methods set out in the protocol of OPERA trials, which were the pivotal trials for ocrelizumab in people with relapsing multiple sclerosis. The committee considered the evidence for confirmed disability progression at 3 months and 6 months. It noted that the point estimates for hazard ratios measuring ofatumumab against comparators for confirmed disability progression (aligned criteria) at 6 months were below 1 for the comparators except alemtuzumab, natalizumab and ocrelizumab, and that the 95% credible intervals crossed 1 for all the comparators except teriflunomide. This suggested that there was a statistically significant difference between treatment with ofatumumab compared with teriflunomide for most comparators except the other monoclonal antibodies. The committee concluded that ofatumumab may slow confirmed disability progression more than most comparators except the monoclonal antibodies alemtuzumab, natalizumab and ocrelizumab.
# The company's cost–utility model
## The company's model is generally appropriate and aligns with previous models in the disease area
The company's model structure was similar to that of models used in previous appraisals of multiple sclerosis technologies. The model was a Markov transition model consisting of 21 health states based on the EDSS. The EDSS has 10 functional states, with higher numbers reflecting a greater functional impact. The company's model consisted of 10 EDSS states for relapsing–remitting multiple sclerosis, 10 states for secondary progressive multiple sclerosis and death. The model used natural history data from the British Columbia multiple sclerosis registry for transitions between relapsing–remitting multiple sclerosis health states. It used the London Ontario multiple sclerosis registry (as used in NICE's technology appraisal guidance on fingolimod for highly active relapsing–remitting multiple sclerosis) to model transitions from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis health states. And it used data from the London Ontario registry supplemented by data from EXPAND (as used in NICE's technology appraisal guidance on siponimod for secondary progressive multiple sclerosis) as sources of natural history data between secondary progressive multiple sclerosis health states. The company sourced treatment effects for ofatumumab and all comparators from the company's network meta-analysis and applied them as:
annualised relapse rates
confirmed disability worsening at 6 months
adverse events and
treatment discontinuation.The company assumed that the treatment effect with ofatumumab and all comparators was constant and was not expected to wane over time (see section 3.15). The committee considered that the model did not completely reflect the treatment pathway for relapsing–remitting multiple sclerosis. For example, the model did not capture treatment sequencing, which will happen because there are a lot of treatments available. Although these variations in practice were not identified in the model, the committee concluded that the company's model was generally appropriate and in line with previous models in the disease area and could be used for decision making. However, in future, the committee would expect a model that more accurately reflected the patient pathway in the NHS, which would include methodological advances in modelling treatment sequences.
## It is appropriate to include disease management costs associated with treating secondary progressive multiple sclerosis
The company's original base case included direct medical disease management costs for each EDSS status score (the system used to classify the severity and progression of multiple sclerosis). But it used the same disease management costs for each EDSS health state for both relapsing–remitting multiple sclerosis and secondary progressive multiple sclerosis. The ERG commented that the economic analysis should include different disease management costs for people with secondary progressive multiple sclerosis and relapsing–remitting multiple sclerosis to better reflect that the costs of management and care changes over time. After technical engagement, the company agreed and updated its base case in line with the ERG's preferred assumptions. The committee noted that including disease management costs specifically for people with secondary progressive multiple sclerosis had a minor impact on the incremental cost-effectiveness ratio (ICER). But it was satisfied that the company's updated base case better reflected the natural history of multiple sclerosis.
## Annual relapse rates decrease as EDSS levels increase
The values the company chose in its original base case show that for relapsing–remitting multiple sclerosis, there is a steady decrease in annual relapse rates. For secondary progressive multiple sclerosis, relapse happened more often at some higher EDSS scores than at some lower EDSS scores. The ERG preferred an alternative approach, decreasing annual relapse rates as EDSS levels increase. After technical engagement, the company agreed with the approach taken by the ERG and updated its base case accordingly. The committee heard from the clinical experts that, because of the natural course of multiple sclerosis, relapse rates were unlikely to increase as EDSS score increased. The committee concluded that the approach taken in the company's updated analyses was appropriate.
## The probability of progressing to secondary progressive multiple sclerosis should only take account of active forms of relapsing multiple sclerosis
The company's economic model used the EDSS scale to show how people move between the different health states: from no disability from their multiple sclerosis to mild, moderate and severe disability. There were no placebo-arm data from ASCLEPIOS I and II to inform the probability of progressing from one health state to another. So the company used transition matrices from the British Columbia longitudinal multiple sclerosis dataset to model transitions between relapsing–remitting multiple sclerosis health states. The company and ERG used different transition matrices for progressing from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis. The ERG preferred to use transition matrices from 1 analysis of the London Ontario multiple sclerosis dataset from NICE's technology appraisal guidance on peginterferon beta-1a for relapsing–remitting multiple sclerosis (from now on referred to as TA624). The company explained that it used a different analysis of the London Ontario dataset from NICE's technology appraisal guidance on fingolimod for highly active relapsing–remitting multiple sclerosis (from now on referred to as TA254) because the transition probabilities used by the London Ontario dataset from TA624 had not adjusted for active or benign forms of relapsing multiple sclerosis. The London Ontario dataset from TA254 excluded people with less progressive relapsing multiple sclerosis and therefore fully represented eligible people. The committee heard from the clinical experts that it was uncommon for people with secondary progressive multiple sclerosis disease symptoms to improve, but noted that the alternative sources had a minimal impact on cost effectiveness. The committee concluded that in this case, the probability of progressing to secondary progressive multiple sclerosis should take account of only active forms of relapsing multiple sclerosis.
# Health state utility values
## Quality of life reduces as disability progresses
If direct trial data were not available for health state utility values, the company used data from alternative sources. In the secondary progressive multiple sclerosis health states, data from the EXPAND trial (a trial including people with secondary progressive multiple sclerosis) were supplemented by data from Orme et al. (2007) to inform health state utility values for an EDSS status of 7 or more. The company's rationale for this was that values taken from the EXPAND trial consistently decrease with each progressive EDSS state, and this aligns with a clinical expectation of reduced quality of life with disability progression. The ERG preferred to use the data taken directly from Orme et al. (2007). But the company noted that utility values at EDSS health state 3 were lower than at EDSS health state 4, suggesting a better quality of life in people with greater disability. The committee noted that there were negative utility values at higher EDSS states. The clinical experts said that this can be because of the limitations people experience as their multiple sclerosis disability progresses. But overall the committee concluded that as disability progresses, quality of life will reduce.
## All-cause discontinuation can be considered a proxy for waning of treatment efficacy
The company assumed in its base case that the treatment effect of ofatumumab and its comparators did not wane over time, but that any waning in the model would be captured by all‑cause discontinuation (stopping for any reason, including perceived lack of efficacy). In the company's response to technical engagement, it analysed the outcomes of disease worsening and rates of relapse considered in the ASCLEPIOS trials. This showed that over the 27‑month data period, there was no evidence of waning of treatment effect. The ERG was satisfied that the analyses carried out by the company showed that there was no evidence of treatment effect waning in the ASCLEPIOS trials. But because the data were short term, the ERG suggested it would be appropriate to assume a waning of treatment effect for all disease-modifying multiple sclerosis treatments, as seen in previous multiple sclerosis appraisals. The company provided 2 scenario analyses considering the waning of treatment effect:
an 'extremely conservative' scenario applying a 50% reduction in effectiveness after 5 years
a 'conservative' scenario applying a 25% reduction after 5 years, then a 50% reduction after 8 years.
In its response to technical engagement, the company maintained that it did not think it was valid to include treatment effect waning in the base case. The ERG viewed including treatment effect waning as a precaution, with the expectation that the effect of all multiple sclerosis treatments was likely to wane over time eventually. This was consistent with some other multiple sclerosis appraisals. For this reason, the ERG preferred to use a conservative assumption of waning, with a 25% reduction in effectiveness after 5 years, and a 50% reduction after 8 years. The committee considered both approaches as well as considering the approaches taken in other technology appraisals for disease-modifying multiple sclerosis treatments. It noted that there had been no clear consistent approach to waning in the technology appraisals of other disease-modifying multiple sclerosis treatments.
The network meta-analyses showed that ofatumumab had similar efficacy to other monoclonal antibodies. The clinical experts said that because monoclonal antibodies generally have a higher efficacy than other drugs for relapsing multiple sclerosis, they would be expected to have less waning of treatment effect over time. The committee noted that discontinuation and waning were connected, but also noted that the ASCLEPIOS trials were too short to predict long-term discontinuation rates. The clinical experts explained that other monoclonal antibodies such as natalizumab had maintained efficacy over a long period of time. They said that all-cause discontinuation showed that people may choose to discontinue for reasons other than efficacy waning (for example, treatment fatigue or pregnancy). The committee recognised that, because ofatumumab and ocrelizumab were both anti‑CD20 monoclonal antibodies, it was reasonable to consider ocrelizumab the closest comparator to ofatumumab. The committee noted that in NICE's technology appraisal guidance on ocrelizumab for relapsing–remitting multiple sclerosis, all-cause treatment discontinuation was accepted as a proxy for treatment waning in the absence of evidence for a waning effect. But it also noted that scenarios that included waning were also relevant for consideration. The committee recognised that this was a difficult area with limited data and concluded that in this case treatment discontinuation could be considered a proxy for waning.
# Cost-effectiveness estimates
## Ofatumumab can be considered cost effective for treating relapsing–remitting multiple sclerosis
NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered the probabilistic and deterministic cost-effectiveness estimates presented by the company and ERG. Its preferred assumptions included:
secondary progressive multiple sclerosis-specific disease management costs
transition matrices from the British Columbia longitudinal multiple sclerosis dataset for transitions between relapsing–remitting multiple sclerosis and transition probabilities from the TA254 analysis of the London Ontario multiple sclerosis dataset for progressing from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis
annualised relapse rates that decrease as EDSS scores increase
health state utility values showing that as disability progresses, quality of life reduces
no waning of treatment effect; all-cause discontinuation considered a proxy for treatment waning. The committee considered the impact of the various assumptions on the ICER. The committee noted that the ICERs it was using for decision making included commercial arrangements for ofatumumab and each comparator drug. These ICERs are confidential and the exact values cannot be reported here but were within what NICE considers a cost-effective use of NHS resources. The committee noted that, with the exception of waning of treatment effect, changes to each assumption had a minor impact on the base-case ICER. The committee concluded that it could recommend ofatumumab as an additional treatment option for relapsing–remitting multiple sclerosis.
# Other factors
No equality or social value judgements were identified.
NICE's advice about life-extending treatments for people with a short life expectancy did not apply.
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{'Recommendations': 'Ofatumumab is recommended as an option for treating relapsing–remitting multiple sclerosis in adults with active disease defined by clinical or imaging features. This is only if the company provides ofatumumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with ofatumumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nNHS treatments for relapsing–remitting multiple sclerosis include alemtuzumab, beta interferons, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, ocrelizumab and teriflunomide.\n\nClinical trial evidence shows that, in people with relapsing–remitting multiple sclerosis, ofatumumab reduces the number of relapses and slows disease progression when compared with teriflunomide. There is no evidence directly comparing ofatumumab with the other treatments listed. But indirect comparisons suggest that ofatumumab reduces the number of relapses and slows disability progression compared with beta interferons, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate and teriflunomide. They also suggest it is as effective as alemtuzumab, natalizumab and ocrelizumab.\n\nThe most likely cost-effectiveness estimates suggest ofatumumab is cost effective and an acceptable use of NHS resources, so it is recommended.', 'Information about ofatumumab': "# Marketing authorisation indication\n\nOfatumumab (Kesimpta, Novartis) is indicated for the treatment of relapsing forms of multiple sclerosis in adults with active disease defined by clinical or imaging features.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for ofatumumab is £1,492.50 (excluding VAT) per unit pack (prefilled autoinjector pen). The company has a commercial arrangement. This makes ofatumumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis, and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe ASCLEPIOS data from 2 multicentre international phase\xa03 randomised controlled trials in people with relapsing multiple sclerosis was generalisable to UK clinical practice.\n\nIncluding data from trials that were originally omitted from the company's base‑case network meta‑analysis had only a minor impact on its findings. It did not materially change the clinical-effectiveness findings for the reduction in relapse rates for ofatumumab.\n\n# The condition and current treatment pathway\n\n## People with multiple sclerosis would value a treatment that can be self-administered at home as a subcutaneous monthly injection\n\nThe clinical and patient experts said that multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that symptoms of relapsing multiple sclerosis and the adverse effects from treatment can limit people's ability to work, and to engage in social and family life. The dosing frequency and monitoring needs of some treatments can disrupt people's lives and careers. The committee noted that ofatumumab is self-administered at home. It heard that a treatment that could be self-administered monthly is less disruptive to people's lives than treatments administered by intravenous infusions in hospital, so would be valued by people with multiple sclerosis.\n\n## Ofatumumab could be used first line or after other treatments\n\nThe clinical experts said that ofatumumab would be offered as a first-line therapy or after other treatments. The committee agreed that, because ofatumumab is an anti‑CD20 monoclonal antibody, it should be in a similar position in the treatment pathway to ocrelizumab. Ocrelizumab is also an anti‑CD20 monoclonal antibody recommended first line or after other treatments. The clinical experts noted that there are no clear rules for sequencing of treatments. However, in practice, clinicians generally offer a different disease-modifying treatment for relapsing–remitting multiple sclerosis when the patient's current treatment no longer prevents disease relapses. The clinical experts said that pregnancy planning can also be an important factor in choosing to change treatments for relapsing–remitting multiple sclerosis. They also recommend stopping all treatments when people can no longer walk or when they develop secondary progressive multiple sclerosis. The committee concluded that ofatumumab was likely to be used first line or after other treatments in people who have active relapsing–remitting multiple sclerosis.\n\n## The company limited its submission to relapsing–remitting multiple sclerosis\n\nThe company limited its submission to relapsing–remitting multiple sclerosis rather than all relapsing forms of multiple sclerosis, as specified in its proposed marketing authorisation. The clinical experts agreed that this was reasonable.\n\n## Patient preference is an important consideration when making shared decisions about treatment\n\nVarious treatment options are available, with different methods and schedules of administration, and the committee noted that people have different preferences. The patient expert confirmed that ofatumumab could be self‑administered relatively easily monthly at home, after initial training from a health professional. The committee concluded that differences in dosing schedule, adverse effects and monitoring requirements between ofatumumab and other treatments may influence patient choice. It agreed that it is important to take these into account when making decisions about treatment.\n\n# Clinical evidence\n\n## The trial evidence is generalisable to people in the NHS with active relapsing–remitting multiple sclerosis\n\nThe main evidence for the clinical effectiveness of ofatumumab compared with teriflunomide came from 2 trials, ASCLEPIOS\xa0I (n=927) and ASCLEPIOS\xa0II (n=955). These were phase\xa03 randomised controlled trials in adults with relapsing multiple sclerosis. The main purpose of these trials was to consider if patients who had ofatumumab had fewer relapses and slower disease progression compared with patients who had teriflunomide. Participants had had at least 1\xa0relapse in the past year, 2\xa0relapses in the last 2\xa0years, or a positive gadolinium-enhancing MRI scan in the last year. Few patients in each trial were from the UK, but the clinical experts and ERG noted that there were no major concerns about the generalisability of the evidence. The committee accepted that the baseline characteristics of the patients in ASCLEPIOS\xa0I and\xa0II reflected people with relapsing–remitting multiple sclerosis having treatment in the NHS. It concluded that the results of the clinical trials were generalisable to NHS clinical practice.\n\n## Highly active and rapidly evolving severe multiple sclerosis subgroup analysis is not suitable for decision making\n\nThe company carried out 2\xa0post-hoc analyses of the ASCLEPIOS trials data for the 2 subgroups: patients with highly active disease or with rapidly evolving severe disease. These subgroups had been defined in the NICE scope for this appraisal. The highly active subgroup was defined as people in the ASCLEPIOS relapsing–remitting multiple sclerosis population who had previously had any disease-modifying treatment and stopped their last treatment because of lack of efficacy. The rapidly evolving severe subgroup were people with relapsing–remitting multiple sclerosis, who had had at least 2 relapses in the last year and at least one T1 gadolinium-enhancing lesion on baseline brain MRI. The company was not able to carry out a network meta-analysis for these subgroups because of a lack of published comparator trial data. The committee noted that there was limited evidence for these subgroups and that the company had included them because previous appraisals had considered them. The clinical experts said that clinicians are more likely to use categories that describe treatment and relapse history and, in practice, these subgroups would not be used. The committee concluded that the evidence was not robust enough for them to be considered separately, and the relapsing–remitting multiple sclerosis population would be considered as a whole in this appraisal.\n\n## Ofatumumab reduces relapse and slows disability progression compared with teriflunomide\n\nThe ASCLEPIOS trials showed that ofatumumab is more effective than teriflunomide for all main clinical outcomes and had no unexpected safety concerns. Ofatumumab reduced annualised relapse rate compared with teriflunomide with an annual relapse rate ratio of 0.50 (95%\xa0confidence interval 0.37 to 0.65) in ASCLEPIOS\xa0I and 0.42 (95%\xa0confidence interval 0.31 to 0.56) in ASCLEPIOS\xa0II. Fewer patients had confirmed disability worsening at 3\xa0months and 6\xa0months for ofatumumab compared with teriflunomide. The hazard ratio for ofatumumab compared with teriflunomide was 0.68 (95%\xa0confidence interval 0.50\xa0to 0.92) for confirmed disability worsening at 6\xa0months for the prespecified pooled ASCLEPIOS population (because both trials had the same design and were carried out at the same time). The committee concluded that ofatumumab was clinically effective compared with teriflunomide.\n\n# Mixed treatment comparison\n\n## Ofatumumab reduces annualised relapse rates compared with most comparators in the relapsing–remitting multiple sclerosis population\n\nBecause the company had direct comparative evidence only for ofatumumab and teriflunomide, it provided a network meta-analysis to estimate ofatumumab's effectiveness compared with the other comparators in the scope. The company chose 31\xa0studies to inform its mixed treatment comparison for annualised relapse rates in the relapsing–remitting multiple sclerosis population. There was uncertainty in the results because most comparisons were informed by a single trial, and many of the comparators were indirectly compared with ofatumumab by 1\xa0or more intermediate comparator. However, the committee concluded that there was a lower annualised relapse rate for ofatumumab in the whole population compared with most comparators, except the monoclonal antibodies (alemtuzumab, natalizumab and ocrelizumab) and cladribine.\n\n## Ofatumumab may slow disability progression compared with most comparators except the other monoclonal antibodies in the relapsing–remitting multiple sclerosis population\n\nThe company chose 21\xa0studies for confirmed disability worsening at 3\xa0months and 20\xa0studies for confirmed disability worsening at 6\xa0months in its base-case analyses. The ASCLEPIOS trials used a different definition of disability worsening from the one commonly used in other trials, based on Expanded Disability Status Scale (EDSS) changes from baseline. The EDSS is used to measure how much someone is affected by their multiple sclerosis. To account for using a different definition, the company carried out additional analyses on the 3‑month and 6‑month data from the ASCLEPIOS trials using 'aligned criteria'. The company also carried out another analysis of the ASCLEPIOS trial data according to the methods set out in the protocol of OPERA trials, which were the pivotal trials for ocrelizumab in people with relapsing multiple sclerosis. The committee considered the evidence for confirmed disability progression at 3\xa0months\xa0and 6\xa0months. It noted that the point estimates for hazard ratios measuring ofatumumab against comparators for confirmed disability progression (aligned criteria) at 6\xa0months were below\xa01 for the comparators except alemtuzumab, natalizumab and ocrelizumab, and that the 95%\xa0credible intervals crossed 1 for all the comparators except teriflunomide. This suggested that there was a statistically significant difference between treatment with ofatumumab compared with teriflunomide for most comparators except the other monoclonal antibodies. The committee concluded that ofatumumab may slow confirmed disability progression more than most comparators except the monoclonal antibodies alemtuzumab, natalizumab and ocrelizumab.\n\n# The company's cost–utility model\n\n## The company's model is generally appropriate and aligns with previous models in the disease area\n\nThe company's model structure was similar to that of models used in previous appraisals of multiple sclerosis technologies. The model was a Markov transition model consisting of 21 health states based on the EDSS. The EDSS has 10\xa0functional states, with higher numbers reflecting a greater functional impact. The company's model consisted of 10\xa0EDSS states for relapsing–remitting multiple sclerosis, 10 states for secondary progressive multiple sclerosis and death. The model used natural history data from the British Columbia multiple sclerosis registry for transitions between relapsing–remitting multiple sclerosis health states. It used the London Ontario multiple sclerosis registry (as used in NICE's technology appraisal guidance on fingolimod for highly active relapsing–remitting multiple sclerosis) to model transitions from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis health states. And it used data from the London Ontario registry supplemented by data from EXPAND (as used in NICE's technology appraisal guidance on siponimod for secondary progressive multiple sclerosis) as sources of natural history data between secondary progressive multiple sclerosis health states. The company sourced treatment effects for ofatumumab and all comparators from the company's network meta-analysis and applied them as:\n\nannualised relapse rates\n\nconfirmed disability worsening at 6\xa0months\n\nadverse events and\n\ntreatment discontinuation.The company assumed that the treatment effect with ofatumumab and all comparators was constant and was not expected to wane over time (see section\xa03.15). The committee considered that the model did not completely reflect the treatment pathway for relapsing–remitting multiple sclerosis. For example, the model did not capture treatment sequencing, which will happen because there are a lot of treatments available. Although these variations in practice were not identified in the model, the committee concluded that the company's model was generally appropriate and in line with previous models in the disease area and could be used for decision making. However, in future, the committee would expect a model that more accurately reflected the patient pathway in the NHS, which would include methodological advances in modelling treatment sequences.\n\n## It is appropriate to include disease management costs associated with treating secondary progressive multiple sclerosis\n\nThe company's original base case included direct medical disease management costs for each EDSS status score (the system used to classify the severity and progression of multiple sclerosis). But it used the same disease management costs for each EDSS health state for both relapsing–remitting multiple sclerosis and secondary progressive multiple sclerosis. The ERG commented that the economic analysis should include different disease management costs for people with secondary progressive multiple sclerosis and relapsing–remitting multiple sclerosis to better reflect that the costs of management and care changes over time. After technical engagement, the company agreed and updated its base case in line with the ERG's preferred assumptions. The committee noted that including disease management costs specifically for people with secondary progressive multiple sclerosis had a minor impact on the incremental cost-effectiveness ratio (ICER). But it was satisfied that the company's updated base case better reflected the natural history of multiple sclerosis.\n\n## Annual relapse rates decrease as EDSS levels increase\n\nThe values the company chose in its original base case show that for relapsing–remitting multiple sclerosis, there is a steady decrease in annual relapse rates. For secondary progressive multiple sclerosis, relapse happened more often at some higher EDSS scores than at some lower EDSS scores. The ERG preferred an alternative approach, decreasing annual relapse rates as EDSS levels increase. After technical engagement, the company agreed with the approach taken by the ERG and updated its base case accordingly. The committee heard from the clinical experts that, because of the natural course of multiple sclerosis, relapse rates were unlikely to increase as EDSS score increased. The committee concluded that the approach taken in the company's updated analyses was appropriate.\n\n## The probability of progressing to secondary progressive multiple sclerosis should only take account of active forms of relapsing multiple sclerosis\n\nThe company's economic model used the EDSS scale to show how people move between the different health states: from no disability from their multiple sclerosis to mild, moderate and severe disability. There were no placebo-arm data from ASCLEPIOS\xa0I and\xa0II to inform the probability of progressing from one health state to another. So the company used transition matrices from the British Columbia longitudinal multiple sclerosis dataset to model transitions between relapsing–remitting multiple sclerosis health states. The company and ERG used different transition matrices for progressing from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis. The ERG preferred to use transition matrices from 1\xa0analysis of the London Ontario multiple sclerosis dataset from NICE's technology appraisal guidance on peginterferon beta-1a for relapsing–remitting multiple sclerosis (from now on referred to as TA624). The company explained that it used a different analysis of the London Ontario dataset from NICE's technology appraisal guidance on fingolimod for highly active relapsing–remitting multiple sclerosis (from now on referred to as TA254) because the transition probabilities used by the London Ontario dataset from TA624 had not adjusted for active or benign forms of relapsing multiple sclerosis. The London Ontario dataset from TA254 excluded people with less progressive relapsing multiple sclerosis and therefore fully represented eligible people. The committee heard from the clinical experts that it was uncommon for people with secondary progressive multiple sclerosis disease symptoms to improve, but noted that the alternative sources had a minimal impact on cost effectiveness. The committee concluded that in this case, the probability of progressing to secondary progressive multiple sclerosis should take account of only active forms of relapsing multiple sclerosis.\n\n# Health state utility values\n\n## Quality of life reduces as disability progresses\n\nIf direct trial data were not available for health state utility values, the company used data from alternative sources. In the secondary progressive multiple sclerosis health states, data from the EXPAND trial (a trial including people with secondary progressive multiple sclerosis) were supplemented by data from Orme et al. (2007) to inform health state utility values for an EDSS status of 7 or more. The company's rationale for this was that values taken from the EXPAND trial consistently decrease with each progressive EDSS state, and this aligns with a clinical expectation of reduced quality of life with disability progression. The ERG preferred to use the data taken directly from Orme et al. (2007). But the company noted that utility values at EDSS health state\xa03 were lower than at EDSS health state\xa04, suggesting a better quality of life in people with greater disability. The committee noted that there were negative utility values at higher EDSS states. The clinical experts said that this can be because of the limitations people experience as their multiple sclerosis disability progresses. But overall the committee concluded that as disability progresses, quality of life will reduce.\n\n## All-cause discontinuation can be considered a proxy for waning of treatment efficacy\n\nThe company assumed in its base case that the treatment effect of ofatumumab and its comparators did not wane over time, but that any waning in the model would be captured by all‑cause discontinuation (stopping for any reason, including perceived lack of efficacy). In the company's response to technical engagement, it analysed the outcomes of disease worsening and rates of relapse considered in the ASCLEPIOS trials. This showed that over the 27‑month data period, there was no evidence of waning of treatment effect. The ERG was satisfied that the analyses carried out by the company showed that there was no evidence of treatment effect waning in the ASCLEPIOS trials. But because the data were short term, the ERG suggested it would be appropriate to assume a waning of treatment effect for all disease-modifying multiple sclerosis treatments, as seen in previous multiple sclerosis appraisals. The company provided 2 scenario analyses considering the waning of treatment effect:\n\nan 'extremely conservative' scenario applying a 50% reduction in effectiveness after 5\xa0years\n\na 'conservative' scenario applying a 25% reduction after 5\xa0years, then a 50% reduction after 8\xa0years.\n\nIn its response to technical engagement, the company maintained that it did not think it was valid to include treatment effect waning in the base case. The ERG viewed including treatment effect waning as a precaution, with the expectation that the effect of all multiple sclerosis treatments was likely to wane over time eventually. This was consistent with some other multiple sclerosis appraisals. For this reason, the ERG preferred to use a conservative assumption of waning, with a 25% reduction in effectiveness after 5\xa0years, and a 50% reduction after 8\xa0years. The committee considered both approaches as well as considering the approaches taken in other technology appraisals for disease-modifying multiple sclerosis treatments. It noted that there had been no clear consistent approach to waning in the technology appraisals of other disease-modifying multiple sclerosis treatments.\n\nThe network meta-analyses showed that ofatumumab had similar efficacy to other monoclonal antibodies. The clinical experts said that because monoclonal antibodies generally have a higher efficacy than other drugs for relapsing multiple sclerosis, they would be expected to have less waning of treatment effect over time. The committee noted that discontinuation and waning were connected, but also noted that the ASCLEPIOS trials were too short to predict long-term discontinuation rates. The clinical experts explained that other monoclonal antibodies such as natalizumab had maintained efficacy over a long period of time. They said that all-cause discontinuation showed that people may choose to discontinue for reasons other than efficacy waning (for example, treatment fatigue or pregnancy). The committee recognised that, because ofatumumab and ocrelizumab were both anti‑CD20 monoclonal antibodies, it was reasonable to consider ocrelizumab the closest comparator to ofatumumab. The committee noted that in NICE's technology appraisal guidance on ocrelizumab for relapsing–remitting multiple sclerosis, all-cause treatment discontinuation was accepted as a proxy for treatment waning in the absence of evidence for a waning effect. But it also noted that scenarios that included waning were also relevant for consideration. The committee recognised that this was a difficult area with limited data and concluded that in this case treatment discontinuation could be considered a proxy for waning.\n\n# Cost-effectiveness estimates\n\n## Ofatumumab can be considered cost effective for treating relapsing–remitting multiple sclerosis\n\nNICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered the probabilistic and deterministic cost-effectiveness estimates presented by the company and ERG. Its preferred assumptions included:\n\nsecondary progressive multiple sclerosis-specific disease management costs\n\ntransition matrices from the British Columbia longitudinal multiple sclerosis dataset for transitions between relapsing–remitting multiple sclerosis and transition probabilities from the TA254 analysis of the London Ontario multiple sclerosis dataset for progressing from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis\n\nannualised relapse rates that decrease as EDSS scores increase\n\nhealth state utility values showing that as disability progresses, quality of life reduces\n\nno waning of treatment effect; all-cause discontinuation considered a proxy for treatment waning. The committee considered the impact of the various assumptions on the ICER. The committee noted that the ICERs it was using for decision making included commercial arrangements for ofatumumab and each comparator drug. These ICERs are confidential and the exact values cannot be reported here but were within what NICE considers a cost-effective use of NHS resources. The committee noted that, with the exception of waning of treatment effect, changes to each assumption had a minor impact on the base-case ICER. The committee concluded that it could recommend ofatumumab as an additional treatment option for relapsing–remitting multiple sclerosis.\n\n# Other factors\n\nNo equality or social value judgements were identified.\n\nNICE's advice about life-extending treatments for people with a short life expectancy did not apply."}
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https://www.nice.org.uk/guidance/ta699
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Evidence-based recommendations on ofatumumab (Kesimpta) for treating relapsing–remitting multiple sclerosis in adults with active disease defined by clinical or imaging features.
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8b69a8de03dfb19aa9c8b8b62726a5687cd7727c
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nice
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Ravulizumab for treating paroxysmal nocturnal haemoglobinuria
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Ravulizumab for treating paroxysmal nocturnal haemoglobinuria
Evidence-based recommendations on ravulizumab (Ultomiris) for treating paroxysmal nocturnal haemoglobinuria in adults.
# Recommendations
Ravulizumab is recommended, within its marketing authorisation, as an option for treating paroxysmal nocturnal haemoglobinuria in adults:
with haemolysis with clinical symptoms suggesting high disease activity, or
whose disease is clinically stable after having eculizumab for at least 6 months, and
the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Paroxysmal nocturnal haemoglobinuria is currently treated with eculizumab infusions every 2 weeks.
Clinical trial evidence shows that ravulizumab is similarly as effective as eculizumab and is just as safe. Ravulizumab is given less often than eculizumab so there is some benefit on quality of life. Also, it may save costs because people need to have it less often.
Ravulizumab is as effective and costs less than eculizumab so it is recommended as an option for treating paroxysmal nocturnal haemoglobinuria.# Information about ravulizumab
# Marketing authorisation indication
Ravulizumab (Ultomiris, Alexion Pharmaceuticals) is indicated for 'the treatment of adult patients with paroxysmal nocturnal haemoglobinuria:
in patients with haemolysis with clinical symptom(s) indicative of high disease activity
in patients who are clinically stable after having been treated with eculizumab for at least the past 6 months'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £4,533 per 300 mg/3 ml concentrate for solution for infusion vial; £16,621 per 1,100 mg/11 ml concentrate for solution for infusion vial (excluding VAT; company submission).
The company has a commercial arrangement. This makes ravulizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Alexion Pharmaceuticals, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 2 issues were resolved during the technical engagement stage, and agreed that:
the trial populations are generalisable to people seen in clinical practice in England
the effectiveness of ravulizumab is maintained for as long as the treatment is given.It recognised that there were remaining areas of uncertainty associated with the analyses presented (ERG report, tables 1.1 to 1.10, pages 10 to 15), and took these into account in its decision making. It discussed the issues, which were outstanding after the technical engagement stage.
# New treatment option
## People with paroxysmal nocturnal haemoglobinuria would welcome a new treatment option
The patient and clinical experts explained that there is an unmet need for people with paroxysmal nocturnal haemoglobinuria. Current treatment is eculizumab which must be given by intravenous infusion every other week. The patient experts explained that the fortnightly infusions make it difficult for people to work, socialise and join in with family life. They also highlighted the psychological effect of the fortnightly infusions because they are constantly reminded that they have an incurable disease. Also, there is the logistical challenge of arranging infusions, frequent visits from nurses and the frequent canulations can lead to scarring of the veins. Ravulizumab is given by intravenous infusion every 8 weeks. The committee accepted that people with paroxysmal nocturnal haemoglobinuria would welcome a new option that has a longer time between treatments.
# Treatment pathway
## Eculizumab is the standard therapy for people with paroxysmal nocturnal haemoglobinuria
In England, people with paroxysmal nocturnal haemoglobinuria (PNH) are managed by the PNH National Service, consisting of 2 centres and 8 outreach clinics, and their local haematologist through a shared care agreement. The severity of symptoms varies between people and over time, which means that not everyone with paroxysmal nocturnal haemoglobinuria needs treatment. The clinical experts explained that people with high disease activity will be offered eculizumab as laid out by the PNH National Service's indications for treatment with eculizumab. Eculizumab is given by intravenous infusion every 2 weeks and most people choose to get their infusions at home. Most people's disease is well controlled with the licenced dose of 900 mg of eculizumab but some people experience breakthrough haemolysis caused by incomplete C5 inhibition. These people will get a higher dose of eculizumab (1,200 mg) which can also be given more frequently. The committee concluded that eculizumab is the standard treatment for people with paroxysmal nocturnal haemoglobinuria.
## People would prefer ravulizumab because of the lower treatment frequency
The patient experts explained that people prefer ravulizumab instead of eculizumab because it is given every 8 weeks rather than every 2 weeks. They noted that longer treatment breaks reduce the treatment burden and therefore people who have ravulizumab have better health‑related quality of life than those who have eculizumab. They also noted that they can return to work and arrange holidays. Results from a patient and carer survey by PNH Support showed that ravulizumab had a positive effect on quality of life. It improved people's independence because of the increased ability to work and had a psychological benefit for individuals and their families because they were able to forget their incurable chronic disease for 8 weeks at a time. In the survey, patients also mentioned that symptom control was as good or better with ravulizumab compared with eculizumab. The clinical experts commented that the reduced frequency of infusions reduces the number of nurse visits which allows them to do other things. They also explained that breakthrough haemolysis from incomplete C5 inhibition is rare with ravulizumab because the C5 inhibition is more complete compared with eculizumab. Having fewer episodes of breakthrough haemolysis reduces the number of hospital admissions and the need for blood transfusions. The committee concluded that people would most likely prefer ravulizumab over eculizumab because of the lower treatment frequency and associated positive effect on quality of life.
## Ravulizumab could be considered for people with stable disease who are having eculizumab and people with untreated disease
Ravulizumab is indicated for treating disease that is stable after 6 months of treatment with eculizumab. The committee understood that clinicians could offer ravulizumab to people who did not experience breakthrough haemolysis and whose disease symptoms did not worsen during 6 months of having eculizumab. Ravulizumab is also indicated for untreated disease with haemolysis and 1 or more symptoms suggestive of high disease activity. High disease activity is not clearly defined, and depends on a number of factors. The committee understood that in the NHS the criteria for using ravulizumab may be similar to those outlined for eculizumab in the PNH National Service's indication for treatment with eculizumab and that these were reasonable. The criteria for eculizumab are:
thrombosis related to paroxysmal nocturnal haemoglobinuria
complications associated with haemolysis:
renal failure
pulmonary hypertension
pregnancy (and for at least 3 months post-partum)
haemolytic symptomatic paroxysmal nocturnal haemoglobinuria.
# Clinical effectiveness
## Ravulizumab and eculizumab are similarly effective
The company presented data from 2 non-inferiority phase 3 trials comparing the safety and effectiveness of ravulizumab with eculizumab. ALXN1210‑PNH‑301 included adults with paroxysmal nocturnal haemoglobinuria who were complement‑inhibitor naive and ALXN1210‑PNH‑302 included adults with paroxysmal nocturnal haemoglobinuria whose disease was clinically stable following at least 6 months of treatment with eculizumab. Both trials included a 26‑week randomised period followed by an extension period of up to 2 years when all patients got ravulizumab. The primary outcomes for ALXN1210‑PNH‑301 were normalisation of lactate dehydrogenase and achieved transfusion avoidance, and for ALXN1210‑PNH‑302 was percentage change lactate dehydrogenase from baseline to day 183. The ALXN1210‑PNH‑301 results showed that the odds ratio in lactate dehydrogenase-normalisation rate was 1.19 (95% confidence interval 0.80 to 1.77) and the difference in achieved transfusion avoidance was 6.8% (95% CI ‑4.66% to 18.14%). The ALXN1210‑PNH‑301 results showed that the percentage change in lactate dehydrogenase was 9.21% (95% CI ‑0.42% to 18.8%) and the difference in achieved transfusion avoidance was 5.5% (95% CI ‑4.3% to 15.7%). The committee noted the point estimates were in favour of ravulizumab but there was no statistically significant difference between ravulizumab and eculizumab for any of the reported clinical outcomes in either trial. It concluded that ravulizumab and eculizumab are similarly effective.
## Adverse events with ravulizumab are likely to be similar to those with eculizumab
ALXN1210‑PNH‑301 and ALXN1210‑PNH‑302 showed no difference in adverse events between ravulizumab and eculizumab. The clinical experts explained that from clinical experience over 4.5 years, there were no differences in adverse events between the treatments. The committee acknowledged that the European Medicines Agency concluded that the safety profile of ravulizumab appeared to be similar to that of eculizumab. It concluded that adverse events with ravulizumab are likely to be similar to eculizumab.
## Trial results are generalisable to clinical practice in England
In clinical practice some people need an increase in the eculizumab dose after an inadequate disease response or breakthrough haemolysis. This was not allowed in ALXN1210‑PNH‑301 and ALXN1210‑PNH‑302. The clinical experts explained that most people do not need a dose increase of eculizumab. They confirmed that clinical outcomes in the trial would have been similar if a dose increase had been permitted. The committee concluded that the results from the trials were generalisable to clinical practice in England.
# The company's economic model
## The company's model is suitable for decision making
The company presented a state transition model with 8 breakthrough haemolysis‑related health states, 1 mortality‑related health state, and a spontaneous‑remission health state. The breakthrough haemolysis‑related health states were characterised by previous treatment (treatment naive or previously received eculizumab) and breakthrough haemolysis events (no breakthrough haemolysis event, incomplete C5 inhibitor‑related breakthrough haemolysis event and complement amplifying condition‑related breakthrough haemolysis event). The committee concluded that the company's model was suitable for decision making.
## The proportion of people getting a higher dose of eculizumab in the model should be similar to that seen in clinical practice in England
In the trials only the licenced dose of 900 mg of eculizumab was allowed and a dose increase of eculizumab after breakthrough haemolysis or inadequate response was not permitted. In clinical practice in England, people can get higher doses of eculizumab, typically 1,200 mg, after breakthrough haemolysis and an inadequate disease response. The company included up‑dosing in the model using a similar proportion to that seen in clinical practice in England. The ERG cautioned that up‑dosing would affect both the costs and the effectiveness of eculizumab and suggested that up‑dosing should be excluded from the model to align with the clinical trial. The committee recalled that up‑dosing of eculizumab might not affect clinical outcomes (see section 3.7). It concluded that the proportion of people who get a higher eculizumab dose in the model should be similar to that seen in clinical practice in England.
## The utility values in the base-case model should be based on EQ-5D without an additional utility increment
The committee recalled that people would most likely prefer ravulizumab because of less frequent infusions (see section 3.3). In the trials, health‑related quality of life was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC‑QLQ‑C‑30) and the results were mapped to EQ‑5D‑3L. In the model, utilities from a mixed‑effects regression model were used. The company included a treatment effect coefficient to capture quality of life benefit of ravulizumab because of reduced treatment frequency. Results favoured ravulizumab but there was no statistically significant difference in health‑related quality of life between ravulizumab and eculizumab. The company reasoned that the effect of ravulizumab on treatment burden could not be fully captured in the trial because patients still needed to attend the research site for other trial protocol reasons. So, the company applied an additional utility value of 0.057 for fewer visits for ravulizumab. The ERG preferred using the non‑significant treatment effect from the mixed‑effects models using EQ‑5D data because this already included the reduced infusion frequency. The committee agreed that the utility increment proposed by the company was high when compared with the values from the EQ‑5D data. It also agreed that the benefit of lower infusion frequency was captured by the EQ‑5D data. It acknowledged that changes in utility values would have no effect on the overall outcome of the cost‑effectiveness analysis. It concluded that utility values in the model should be based on EQ‑5D data.
# Cost-effectiveness estimates
## Ravulizumab is a cost-effective use of NHS resources for paroxysmal nocturnal haemoglobinuria
The committee agreed that its preferred approach to modelling would:
include the sustained effectiveness of ravulizumab (resolved at technical engagement)
include a dose increase of eculizumab (see section 3.9)
base utility values on EQ‑5D data and not include a utility increment for ravulizumab from the discrete choice experiment (see section 3.10).Using the committee's preferred assumptions and including the confidential discount for ravulizumab, ravulizumab was more effective and less costly than eculizumab in all scenario analyses presented. Exact results are confidential and cannot be reported here. The committee concluded that ravulizumab when compared with eculizumab is a cost‑effective use of NHS resources.
# Equality considerations
## There are no equality issues relevant to the recommendations
People under the age of 18 and pregnant people were excluded from the main trials of ravulizumab. Age and pregnancy are protected characteristics which need to be considered. The committee considered issues relating to people included within the marketing authorisation and noted that people under the age of 18 are not included within the marketing authorisation. The committee acknowledged that the use of ravulizumab may be considered for pregnant people after an assessment of the risks and benefits. The committee concluded that there were no relevant equality issues.
# Conclusion
## Ravulizumab is recommended for routine commissioning
In the committee's preferred analysis and all the other cost‑effectiveness analyses, ravulizumab was more effective and less costly than eculizumab. Therefore, ravulizumab is recommended as a treatment option for paroxysmal nocturnal haemoglobinuria.
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{'Recommendations': 'Ravulizumab is recommended, within its marketing authorisation, as an option for treating paroxysmal nocturnal haemoglobinuria in adults:\n\nwith haemolysis with clinical symptoms suggesting high disease activity, or\n\nwhose disease is clinically stable after having eculizumab for at least 6\xa0months, and\n\nthe company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nParoxysmal nocturnal haemoglobinuria is currently treated with eculizumab infusions every 2\xa0weeks.\n\nClinical trial evidence shows that ravulizumab is similarly as effective as eculizumab and is just as safe. Ravulizumab is given less often than eculizumab so there is some benefit on quality of life. Also, it may save costs because people need to have it less often.\n\nRavulizumab is as effective and costs less than eculizumab so it is recommended as an option for treating paroxysmal nocturnal haemoglobinuria.', 'Information about ravulizumab': "# Marketing authorisation indication\n\nRavulizumab (Ultomiris, Alexion Pharmaceuticals) is indicated for 'the treatment of adult patients with paroxysmal nocturnal haemoglobinuria:\n\nin patients with haemolysis with clinical symptom(s) indicative of high disease activity\n\nin patients who are clinically stable after having been treated with eculizumab for at least the past 6\xa0months'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £4,533 per 300\xa0mg/3\xa0ml concentrate for solution for infusion vial; £16,621 per 1,100\xa0mg/11\xa0ml concentrate for solution for infusion vial (excluding VAT; company submission).\n\nThe company has a commercial arrangement. This makes ravulizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Alexion Pharmaceuticals, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 2\xa0issues were resolved during the technical engagement stage, and agreed that:\n\nthe trial populations are generalisable to people seen in clinical practice in England\n\nthe effectiveness of ravulizumab is maintained for as long as the treatment is given.It recognised that there were remaining areas of uncertainty associated with the analyses presented (ERG report, tables\xa01.1 to\xa01.10, pages\xa010 to\xa015), and took these into account in its decision making. It discussed the issues, which were outstanding after the technical engagement stage.\n\n# New treatment option\n\n## People with paroxysmal nocturnal haemoglobinuria would welcome a new treatment option\n\nThe patient and clinical experts explained that there is an unmet need for people with paroxysmal nocturnal haemoglobinuria. Current treatment is eculizumab which must be given by intravenous infusion every other week. The patient experts explained that the fortnightly infusions make it difficult for people to work, socialise and join in with family life. They also highlighted the psychological effect of the fortnightly infusions because they are constantly reminded that they have an incurable disease. Also, there is the logistical challenge of arranging infusions, frequent visits from nurses and the frequent canulations can lead to scarring of the veins. Ravulizumab is given by intravenous infusion every 8\xa0weeks. The committee accepted that people with paroxysmal nocturnal haemoglobinuria would welcome a new option that has a longer time between treatments.\n\n# Treatment pathway\n\n## Eculizumab is the standard therapy for people with paroxysmal nocturnal haemoglobinuria\n\nIn England, people with paroxysmal nocturnal haemoglobinuria (PNH) are managed by the PNH National Service, consisting of 2\xa0centres and 8\xa0outreach clinics, and their local haematologist through a shared care agreement. The severity of symptoms varies between people and over time, which means that not everyone with paroxysmal nocturnal haemoglobinuria needs treatment. The clinical experts explained that people with high disease activity will be offered eculizumab as laid out by the PNH National Service's indications for treatment with eculizumab. Eculizumab is given by intravenous infusion every 2\xa0weeks and most people choose to get their infusions at home. Most people's disease is well controlled with the licenced dose of 900\xa0mg of eculizumab but some people experience breakthrough haemolysis caused by incomplete C5\xa0inhibition. These people will get a higher dose of eculizumab (1,200\xa0mg) which can also be given more frequently. The committee concluded that eculizumab is the standard treatment for people with paroxysmal nocturnal haemoglobinuria.\n\n## People would prefer ravulizumab because of the lower treatment frequency\n\nThe patient experts explained that people prefer ravulizumab instead of eculizumab because it is given every 8\xa0weeks rather than every 2\xa0weeks. They noted that longer treatment breaks reduce the treatment burden and therefore people who have ravulizumab have better health‑related quality of life than those who have eculizumab. They also noted that they can return to work and arrange holidays. Results from a patient and carer survey by PNH Support showed that ravulizumab had a positive effect on quality of life. It improved people's independence because of the increased ability to work and had a psychological benefit for individuals and their families because they were able to forget their incurable chronic disease for 8\xa0weeks at a time. In the survey, patients also mentioned that symptom control was as good or better with ravulizumab compared with eculizumab. The clinical experts commented that the reduced frequency of infusions reduces the number of nurse visits which allows them to do other things. They also explained that breakthrough haemolysis from incomplete C5\xa0inhibition is rare with ravulizumab because the C5\xa0inhibition is more complete compared with eculizumab. Having fewer episodes of breakthrough haemolysis reduces the number of hospital admissions and the need for blood transfusions. The committee concluded that people would most likely prefer ravulizumab over eculizumab because of the lower treatment frequency and associated positive effect on quality of life.\n\n## Ravulizumab could be considered for people with stable disease who are having eculizumab and people with untreated disease\n\nRavulizumab is indicated for treating disease that is stable after 6\xa0months of treatment with eculizumab. The committee understood that clinicians could offer ravulizumab to people who did not experience breakthrough haemolysis and whose disease symptoms did not worsen during 6\xa0months of having eculizumab. Ravulizumab is also indicated for untreated disease with haemolysis and 1\xa0or\xa0more symptoms suggestive of high disease activity. High disease activity is not clearly defined, and depends on a number of factors. The committee understood that in the NHS the criteria for using ravulizumab may be similar to those outlined for eculizumab in the PNH National Service's indication for treatment with eculizumab and that these were reasonable. The criteria for eculizumab are:\n\nthrombosis related to paroxysmal nocturnal haemoglobinuria\n\ncomplications associated with haemolysis:\n\n\n\nrenal failure\n\npulmonary hypertension\n\n\n\npregnancy (and for at least 3\xa0months post-partum)\n\nhaemolytic symptomatic paroxysmal nocturnal haemoglobinuria.\n\n# Clinical effectiveness\n\n## Ravulizumab and eculizumab are similarly effective\n\nThe company presented data from 2\xa0non-inferiority phase\xa03 trials comparing the safety and effectiveness of ravulizumab with eculizumab. ALXN1210‑PNH‑301 included adults with paroxysmal nocturnal haemoglobinuria who were complement‑inhibitor naive and ALXN1210‑PNH‑302 included adults with paroxysmal nocturnal haemoglobinuria whose disease was clinically stable following at least 6\xa0months of treatment with eculizumab. Both trials included a 26‑week randomised period followed by an extension period of up to 2\xa0years when all patients got ravulizumab. The primary outcomes for ALXN1210‑PNH‑301 were normalisation of lactate dehydrogenase and achieved transfusion avoidance, and for ALXN1210‑PNH‑302 was percentage change lactate dehydrogenase from baseline to day\xa0183. The ALXN1210‑PNH‑301 results showed that the odds ratio in lactate dehydrogenase-normalisation rate was 1.19 (95% confidence interval [CI] 0.80 to 1.77) and the difference in achieved transfusion avoidance was 6.8% (95% CI ‑4.66% to 18.14%). The ALXN1210‑PNH‑301 results showed that the percentage change in lactate dehydrogenase was 9.21% (95% CI ‑0.42% to 18.8%) and the difference in achieved transfusion avoidance was 5.5% (95% CI ‑4.3% to 15.7%). The committee noted the point estimates were in favour of ravulizumab but there was no statistically significant difference between ravulizumab and eculizumab for any of the reported clinical outcomes in either trial. It concluded that ravulizumab and eculizumab are similarly effective.\n\n## Adverse events with ravulizumab are likely to be similar to those with eculizumab\n\nALXN1210‑PNH‑301 and ALXN1210‑PNH‑302 showed no difference in adverse events between ravulizumab and eculizumab. The clinical experts explained that from clinical experience over 4.5\xa0years, there were no differences in adverse events between the treatments. The committee acknowledged that the European Medicines Agency concluded that the safety profile of ravulizumab appeared to be similar to that of eculizumab. It concluded that adverse events with ravulizumab are likely to be similar to eculizumab.\n\n## Trial results are generalisable to clinical practice in England\n\nIn clinical practice some people need an increase in the eculizumab dose after an inadequate disease response or breakthrough haemolysis. This was not allowed in ALXN1210‑PNH‑301 and ALXN1210‑PNH‑302. The clinical experts explained that most people do not need a dose increase of eculizumab. They confirmed that clinical outcomes in the trial would have been similar if a dose increase had been permitted. The committee concluded that the results from the trials were generalisable to clinical practice in England.\n\n# The company's economic model\n\n## The company's model is suitable for decision making\n\nThe company presented a state transition model with 8\xa0breakthrough haemolysis‑related health states, 1\xa0mortality‑related health state, and a spontaneous‑remission health state. The breakthrough haemolysis‑related health states were characterised by previous treatment (treatment naive or previously received eculizumab) and breakthrough haemolysis events (no breakthrough haemolysis event, incomplete C5\xa0inhibitor‑related breakthrough haemolysis event and complement amplifying condition‑related breakthrough haemolysis event). The committee concluded that the company's model was suitable for decision making.\n\n## The proportion of people getting a higher dose of eculizumab in the model should be similar to that seen in clinical practice in England\n\nIn the trials only the licenced dose of 900\xa0mg of eculizumab was allowed and a dose increase of eculizumab after breakthrough haemolysis or inadequate response was not permitted. In clinical practice in England, people can get higher doses of eculizumab, typically 1,200\xa0mg, after breakthrough haemolysis and an inadequate disease response. The company included up‑dosing in the model using a similar proportion to that seen in clinical practice in England. The ERG cautioned that up‑dosing would affect both the costs and the effectiveness of eculizumab and suggested that up‑dosing should be excluded from the model to align with the clinical trial. The committee recalled that up‑dosing of eculizumab might not affect clinical outcomes (see section\xa03.7). It concluded that the proportion of people who get a higher eculizumab dose in the model should be similar to that seen in clinical practice in England.\n\n## The utility values in the base-case model should be based on EQ-5D without an additional utility increment\n\nThe committee recalled that people would most likely prefer ravulizumab because of less frequent infusions (see section\xa03.3). In the trials, health‑related quality of life was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC‑QLQ‑C‑30) and the results were mapped to EQ‑5D‑3L. In the model, utilities from a mixed‑effects regression model were used. The company included a treatment effect coefficient to capture quality of life benefit of ravulizumab because of reduced treatment frequency. Results favoured ravulizumab but there was no statistically significant difference in health‑related quality of life between ravulizumab and eculizumab. The company reasoned that the effect of ravulizumab on treatment burden could not be fully captured in the trial because patients still needed to attend the research site for other trial protocol reasons. So, the company applied an additional utility value of 0.057 for fewer visits for ravulizumab. The ERG preferred using the non‑significant treatment effect from the mixed‑effects models using EQ‑5D data because this already included the reduced infusion frequency. The committee agreed that the utility increment proposed by the company was high when compared with the values from the EQ‑5D data. It also agreed that the benefit of lower infusion frequency was captured by the EQ‑5D data. It acknowledged that changes in utility values would have no effect on the overall outcome of the cost‑effectiveness analysis. It concluded that utility values in the model should be based on EQ‑5D data.\n\n# Cost-effectiveness estimates\n\n## Ravulizumab is a cost-effective use of NHS resources for paroxysmal nocturnal haemoglobinuria\n\nThe committee agreed that its preferred approach to modelling would:\n\ninclude the sustained effectiveness of ravulizumab (resolved at technical engagement)\n\ninclude a dose increase of eculizumab (see section\xa03.9)\n\nbase utility values on EQ‑5D data and not include a utility increment for ravulizumab from the discrete choice experiment (see section\xa03.10).Using the committee's preferred assumptions and including the confidential discount for ravulizumab, ravulizumab was more effective and less costly than eculizumab in all scenario analyses presented. Exact results are confidential and cannot be reported here. The committee concluded that ravulizumab when compared with eculizumab is a cost‑effective use of NHS resources.\n\n# Equality considerations\n\n## There are no equality issues relevant to the recommendations\n\nPeople under the age of 18 and pregnant people were excluded from the main trials of ravulizumab. Age and pregnancy are protected characteristics which need to be considered. The committee considered issues relating to people included within the marketing authorisation and noted that people under the age of 18 are not included within the marketing authorisation. The committee acknowledged that the use of ravulizumab may be considered for pregnant people after an assessment of the risks and benefits. The committee concluded that there were no relevant equality issues.\n\n# Conclusion\n\n## Ravulizumab is recommended for routine commissioning\n\nIn the committee's preferred analysis and all the other cost‑effectiveness analyses, ravulizumab was more effective and less costly than eculizumab. Therefore, ravulizumab is recommended as a treatment option for paroxysmal nocturnal haemoglobinuria."}
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https://www.nice.org.uk/guidance/ta698
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Evidence-based recommendations on ravulizumab (Ultomiris) for treating paroxysmal nocturnal haemoglobinuria in adults.
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7f8055bfaa72dc07e13ca74e419dea1c110008b5
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nice
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Tafamidis for treating transthyretin amyloidosis with cardiomyopathy
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Tafamidis for treating transthyretin amyloidosis with cardiomyopathy
Evidence-based recommendations on tafamidis (Vyndaqel) for treating transthyretin amyloidosis with cardiomyopathy in adults.
# Recommendations
Tafamidis is not recommended, within its marketing authorisation, for treating wild-type or hereditary transthyretin amyloidosis with cardiomyopathy (ATTR‑CM) in adults.
This recommendation is not intended to affect treatment with tafamidis that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
ATTR-CM can lead to heart failure, but treatment options are limited to managing symptoms and best supportive care. Awareness of ATTR-CM has improved, but accurately diagnosing ATTR-CM can be challenging and can take a long time.
Tafamidis is the first treatment for ATTR-CM that aims to treat the disease. Evidence from clinical trials shows that it reduces deaths and hospitalisation from conditions affecting the heart and blood vessels compared with placebo. But clinical benefit varies across different types and stages of ATTR-CM. Also, the measure used to assess how severe ATTR‑CM is has limitations. This makes it difficult to clearly identify who benefits from tafamidis and whether they should continue treatment.
The cost-effectiveness estimates are higher than what NICE normally considers an acceptable use of NHS resources. This is because there is not enough evidence that recommending tafamidis would reduce diagnosis delays and uncertainty about how long the treatment works after it is stopped. So, tafamidis is not recommended.# Information about tafamidis
# Marketing authorisation indication
Tafamidis (Vyndaqel, Pfizer) is indicated for 'the treatment of wild‑type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM)'. Before the marketing authorisation was granted, tafamidis was available in the NHS through the early access to medicines scheme.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The price of tafamidis is £10,685.00 per 30‑capsule pack of 61 mg capsules (excluding VAT; company submission) giving an annual cost of £130,089.88. The company has a commercial arrangement, which would have applied if the technology had been recommended.# Committee discussion
The appraisal committee considered evidence submitted by Pfizer, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
In the economic model, people whose disease is classed as New York Heart Association (NYHA) 1 to 3 should be assumed to remain on treatment (issue 2, see technical report pages 14 to 15).
Utility values for best supportive care should be applied to everyone in the NYHA 4 model health state (issue 3, see technical report pages 15 to 18).
In the model it is acceptable that an age adjustment is applied to health state utility values after the observed trial period (issue 3, see technical report pages 15 to 18).It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, pages 22 to 23), and took these into account in its decision making. It discussed the following issues (issues 1, 2, 4 and 5), which were outstanding after the technical engagement stage.
# The condition
## ATTR-CM can lead to heart failure and sudden death
There are 2 types of transthyretin amyloidosis with cardiomyopathy (ATTR‑CM):
Wild-type ATTR-CM, which is more common. It mostly affects older people and is more common in men.
Hereditary ATTR-CM (also known as familial amyloid cardiomyopathy), which affects people born with inherited mutations in the transthyretin (TTR) gene.The clinical experts explained that ATTR-CM is a progressive disease. Symptoms usually start after age 70 in people with wild-type ATTR‑CM or after age 60 in people with hereditary ATTR-CM. It can cause shortness of breath, palpitations and abnormal heart rhythms such as atrial fibrillation or atrial flutter, ankle swelling, fatigue, fainting and chest pain. They noted that death in most people with ATTR-CM is from sudden death and progressive heart failure. The committee concluded that ATTR-CM can lead to heart failure and sudden death.
## ATTR-CM significantly affects mental and physical wellbeing
The patient experts explained that ATTR-CM significantly affected their physical ability. For example, one noted that walking even short distances could be challenging, while another stated that they were no longer able to do their daily physical activities. Another patient expert explained that ATTR-CM made them feel older than they should and limited them to mostly staying seated. The patient experts noted that ATTR-CM also affected psychological wellbeing, for example, symptoms of breathlessness leading to anxiety. Loss of independence and an increased reliance on caregivers was also highlighted as a cause of depression related to the condition. The patient experts explained that psychological effects can be exacerbated for people with hereditary ATTR‑CM because it can affect multiple members of a family across different generations, and there was anxiety about passing it on to children. The committee concluded that ATTR-CM is a debilitating disease which significantly affects mental and physical wellbeing.
# Clinical management
## Awareness of ATTR-CM has improved but diagnosis can still take a long time
The patient experts explained that getting an accurate diagnosis for ATTR-CM could be challenging. They noted that awareness of the condition, and the type of ATTR-CM a person has (see section 3.1), can vary and lead to delays to diagnosis. One patient expert explained that they waited more than 4 years for an accurate diagnosis, highlighting a general lack of understanding about the condition outside of specialist centres. The company highlighted National Amyloidosis Centre (NAC) data showing that, on average, it took 3 years or more for a person to be accurately diagnosed with ATTR-CM. Two of the clinical experts agreed that there were challenges in diagnosing ATTR‑CM accurately, but noted the developments in recent years. Radionuclide imaging (DPD scan), a test usually used to detect bone abnormalities, is increasingly being used to diagnose ATTR-CM. It is very sensitive to detecting amyloid deposits in the heart. This has improved awareness of ATTR‑CM and increased diagnoses. Two of the clinical experts highlighted that the low cost of DPD scanning meant most hospitals would be able to do them. So, they expected further increases in ATTR‑CM diagnoses. They also noted increased awareness of ATTR‑CM after NICE's highly specialised technologies guidance recommended inotersen and patisiran for treating hereditary transthyretin amyloidosis with polyneuropathy (see section 3.5). The committee concluded that the availability of new diagnostic tests and treatments for the disease had improved awareness of ATTR-CM, but recognised that diagnosis can still take a long time.
## It is unclear if increased availability of DPD scans will lead to an increase in diagnosing amyloidosis or ATTR-CM
Two of the clinical experts explained that transthyretin amyloid deposits are often an incidental finding in people having DPD scans and may not necessarily be associated with a diagnosis of ATTR-CM. They explained that the population they see in practice has a range of amyloid deposits, sometimes because of older age, for example. Also, there is no defined point at which amyloid deposits become amyloidosis. So, it is unclear why some amyloid deposits progress to amyloidosis and others do not. In addition, because other common comorbidities can lead to increased breathlessness and decreased mobility, reaching a definitive ATTR-CM diagnosis is challenging. At consultation, the company commented that the NAC published a non-invasive diagnostic pathway for ATTR-CM in 2016. It explained that the pathway had been validated and implemented at 17 early access to medicines scheme (EAMS) sites. It further explained that based on this pathway, only people with symptoms and certain clinical features are eligible for DPD scans. So, amyloid deposits identified through the pathway are not incidental. It highlighted that, because of this, amyloid deposits found when doing DPD scans for another condition would not result in a diagnosis of amyloidosis. At the second committee meeting one of the clinical experts confirmed that incidental amyloid deposits would not result in an increase in amyloidosis diagnoses, because other clinical features outlined in the ATTR-CM diagnostic pathway would be taken into account. The committee questioned whether everybody with heart failure and an abnormal DPD scan would be diagnosed with amyloidosis. One clinical expert explained that not everyone with heart failure would have a DPD scan, and only those with cardiac symptoms specific to ATTR-CM (such as thickening of the heart muscle) would be tested. They further explained that people diagnosed with ATTR-CM and having treatment in clinical practice would likely reflect the population from the ATTR-ACT pivotal trial (see section 3.9) although in the trial a biopsy was required. The clinical experts and the NHS England representative explained that when amyloidosis is suspected people are referred to the NAC for more rigorous testing. The committee was aware that the European public assessment report for tafamidis states that there are difficulties in diagnosing people with ATTR‑CM in NHYA class 1, particularly if they do not have heart failure. It also states that an accurate diagnosis cannot be formally established without a number of procedures (such as biopsy and scintigraphy). The committee acknowledged this and agreed that even with DPD scans and a diagnostic pathway, there would still be challenges in diagnosing ATTR‑CM. The committee concluded that it was unclear if the increased availability of DPD scans would lead to an increase in diagnosing amyloidosis or ATTR‑CM.
## Best supportive care is the relevant comparator
Treatment options for ATTR-CM are limited to managing symptoms and supportive care, such as diuretics. A small proportion of people with ATTR-CM also have polyneuropathy (mixed clinical features). NICE has recommended 2 treatments for polyneuropathy:
NICE highly specialised technologies guidance on inotersen for treating hereditary transthyretin amyloidosis
NICE highly specialised technologies guidance on patisiran for treating hereditary transthyretin amyloidosis.NICE's final scope included inotersen and patisiran as comparators to tafamidis. The committee noted that the company had not included these treatments as comparators in its submission because neither had been evaluated in people with ATTR-CM. The committee noted that the marketing authorisation for tafamidis 61 mg did not specifically mention people with polyneuropathy. It acknowledged that because it is rare for people to have ATTR-CM and polyneuropathy, there would not be enough evidence to consider it separately. So, it agreed that inotersen and patisiran could not be considered as comparators to tafamidis. The committee also noted that liver or heart transplantation are options for some people with ATTR-CM and a specific genetic mutation. But it recognised that because this mutation is uncommon in England, and transplantation can only take place early in the course of the disease, transplants are rarely done. The committee agreed that transplantation was not an appropriate comparator for tafamidis and concluded that best supportive care was the appropriate comparator.
## Measuring ATTR-CM severity using NYHA classification has limitations but there is insufficient trial evidence to consider an alternative
The NYHA functional classification system is commonly used in clinical practice to assess heart failure, and is sometimes used to measure the severity of ATTR‑CM. It groups symptoms into 1 of 4 classes depending on how limited a person's physical activity is. A person whose disease was classed as NYHA 1 would be able to do ordinary physical activity. But someone whose disease was classed as NYHA 4 would be unable to do physical activity without feeling discomfort. The clinical experts explained that although NYHA classification is used in clinical practice, it has limitations. Because it is a patient-reported measure it can vary from day to day, and there can be inconsistencies in people's symptoms. For example, people with the same activity tolerance may classify their level of heart failure differently. One clinical expert noted that variability in how people classify themselves was a common issue with all symptom-based measures. They also highlighted that the NYHA classification system is used as an entry criterion in most heart failure trials. The clinical experts commented that it was difficult to identify whether movement between the NYHA classes was a result of ATTR-CM progressing or changes in other comorbidities. One of the clinical experts suggested that a measure based on cardiac markers such as B-type natriuretic peptide and glomerular filtration rate had potential to identify disease stage and who is benefiting from treatment, but evidence of its use in ATTR-CM in clinical practice was limited. The ERG explained that there were merits to assessing disease severity using objective measures such as cardiac markers. But it commented that in the ATTR-ACT pivotal trial (see section 3.9), unlike the NYHA classification which was measured every 6 months, these cardiac markers were only measured at baseline, month 12, and after stopping treatment. So, they were not measured frequently enough to accurately characterise the disease. The committee concluded that using the NYHA classification in ATTR-CM had limitations, but acknowledged that there was insufficient trial evidence available to consider an alternative. This was because cardiac markers, which could have been used to identify disease stage and who would benefit from treatment, were not measured frequently enough in the trial.
## It is not appropriate to define starting and stopping rules for tafamidis based on the NYHA classification system
The marketing authorisation for tafamidis does not specify starting and stopping rules for tafamidis based on the NYHA classification system. The company highlighted that NYHA classifications have been incorporated in previous NICE recommendations to define populations eligible for treatment with heart failure therapies. The committee noted that the marketing authorisation states that tafamidis should be 'started as early as possible in the disease course when the clinical benefit on disease progression could be more evident. Conversely, when amyloid-related cardiac damage is more advanced, such as in NYHA class 3, the decision to start or maintain treatment should be taken at the discretion of a physician knowledgeable in the management of patients with amyloidosis or cardiomyopathy'. The committee recalled that NYHA class 1 means that people can do ordinary physical activity (see section 3.6). It considered if tafamidis would be used for people who are easily able to do the activities of daily living (no functional limitations). The clinical experts explained that they would have reservations about offering treatment to people whose disease is classed as NYHA 1 because they have no functional limitations and might not benefit from treatment. At consultation, the company highlighted that this contradicted tafamidis' marketing authorisation, which states that treatment should be started as soon as possible. The company proposed a stopping rule in which people would stop tafamidis if their disease progressed to NYHA class 4. It explained that there was limited evidence to support using tafamidis in people whose disease was NYHA class 4, who had severe heart failure symptoms, because they were excluded from the ATTR-ACT pivotal trial. Also, the company highlighted that its proposed stopping rule reflected treatment stopping in ATTR-ACT, in which most people stopped tafamidis quickly after progressing to NYHA class 4. It also noted that because tafamidis does not improve symptoms caused by ATTR-CM it would be clinically appropriate to stop treatment when a person's disease is classed as NYHA 4. A clinical expert noted that stopping treatments when the disease progresses to NYHA class 4 was common because at this stage people are very unwell. They explained that people would be unable to travel for treatment, so treatment would likely be stopped and best supportive care offered. Comments from the patient organisation supported this view, stating that making decisions about stopping treatment in advanced disease stages were not uncommon. Conversely, 2 of the clinical experts noted that it would be challenging to stop treatment when disease progressed to NYHA class 4 because no alternative treatments were available. These 2 clinical experts also explained that people's disease often varies between NYHA class 3 and 4 and that this was typical of ATTR-CM. They noted that some people whose disease was classed as NYHA 4 could improve, so could change to NYHA class 3 or better. The ERG noted that improvements shown by changes in NYHA class were also seen in ATTR-ACT. The committee recalled that the company's proposed stopping rule was not specified in tafamidis' marketing authorisation. It agreed, that on balance, it would be difficult for clinicians to implement a stopping rule for tafamidis. This was because the disease can often vary between NYHA class 3 and 4 and the lack of alternative treatments for NYHA class 4 disease meant people would likely prefer to keep taking tafamidis. The committee concluded that using the NYHA classification alone to accurately define the population who were eligible to have tafamidis had limitations. So, it also concluded that it would not consider starting and stopping rules for tafamidis based on the NYHA classification system in its decision making.
## There is not enough evidence that tafamidis would reduce delays in diagnosis times
At technical engagement, the company highlighted that introducing tafamidis reduced delays to ATTR-CM diagnoses. It noted that the availability of tafamidis would result in ATTR-CM being detected earlier because of more awareness among cardiologists. The company also noted that since tafamidis became available in the EAMS, the proportion of people whose disease was diagnosed in NYHA class 1 or 2 has increased from 75% to 86%. The committee understood that the short-term observational EAMS data were presented to support the assumption that introducing tafamidis could reduce diagnosis delays. It acknowledged that although the EAMS data were informative, they can only show that diagnosis delays were reducing when tafamidis was available. They cannot show that the delays were reducing because of tafamidis. A statement from NHS England suggested that if NICE recommended tafamidis, and awareness was increased through educational campaigns, diagnosis rates may improve further. The committee recalled that average time to diagnosis at the NAC was 3 years or more (see section 3.3). The company noted that 1 in 3 patients were diagnosed in less than 6 months, while 40% waited for 4 years or more. The committee acknowledged that reducing the average time to diagnosis to less than 6 months would represent a substantial improvement. But, it recognised these diagnoses were made at a specialist centre and questioned if such reductions could be achieved at other centres in clinical practice. The ERG highlighted that the trend of earlier diagnosis seen in the EAMS could be explained by improvements in diagnostic tools since the ATTR-ACT pivotal trial (see section 3.3). It noted that when ATTR-CM is suspected the diagnostic pathway may lead to quicker diagnoses, but when it is not suspected, substantial diagnosis delays may still occur. The committee acknowledged this, and agreed it was not possible to attribute reductions in diagnosis times at EAMS sites to the availability of tafamidis. It also noted web comments at consultation which highlighted evidence of an increasing number of ATTR-CM diagnoses at the NAC before tafamidis was available through EAMS. There were also comments from the EAMS centres' cardiac group that a major contributor to the shorter diagnosis times was the changes in diagnostic tools and algorithms. The committee also recalled that awareness of ATTR-CM had increased (see section 3.3) and questioned whether recommending tafamidis would further increase awareness and reduce diagnosis times. The committee concluded that there was not enough evidence provided to support the assumption that introducing tafamidis would reduce ATTR-CM diagnosis delays.
# Clinical evidence
## The ATTR-ACT trials are appropriate for decision making
The clinical evidence came from 2 trials:
ATTR-ACT (pivotal): a 30‑month, phase 3 double-blind randomised controlled trial. It evaluated how effective, safe, and tolerable tafamidis was compared with placebo in adults with wild-type or hereditary ATTR-CM, whose disease was classed as NYHA 1 to 3 (n=441).
ATTR-ACT extension study: an open-label extension of ATTR-ACT including patients from ATTR-ACT and others with ATTR-CM who did not take part in ATTR-ACT (ongoing; number of patients not reported).The ATTR-ACT pivotal trial randomised patients to have 80 mg of tafamidis meglumine (n=176), 20 mg of tafamidis meglumine (n=88) or placebo (n=177) using a ratio of 2:1:2. Everyone who had treatment in the ATTR‑ACT extension had tafamidis 61 mg, or tafamidis meglumine 80 mg if 61 mg was not available. The committee noted that the dose of tafamidis used in ATTR-ACT was different to the dose in the marketing authorisation for tafamidis, which is 61 mg. But, the marketing authorisation states that the relative bioavailability of tafamidis 61 mg is similar to tafamidis meglumine 80 mg at a steady state. So, the committee concluded that the ATTR-ACT trials were appropriate for decision making.
## Tafamidis is more effective than placebo in clinical trial results
The primary analysis from the ATTR-ACT pivotal trial compared the results of a pooled tafamidis (20 mg and 80 mg doses) treatment group with the placebo group. The primary outcome, a combined measure of all-cause mortality and cardiovascular-related hospitalisations, was assessed in a hierarchical analysis using the Finkelstein-Schoenfeld method. At month 30, 186 people (70.5%) were alive in the tafamidis group compared with 101 people (57.1%) in the placebo group. Of those alive at month 30, people who had tafamidis had fewer annual cardiovascular-related hospitalisations (0.297) on average than those who had placebo (0.455). Tafamidis statistically significantly reduced all-cause mortality and frequency of cardiovascular-related hospitalisations compared with placebo. The committee considered that although the parts of the primary outcome were clinically relevant to patients and clinicians, it questioned whether the combined measure would be considered in clinical practice. It also considered the secondary outcome results from ATTR-ACT and noted that at month 30 compared with placebo, tafamidis was associated with statistically significant reductions in:
cardiovascular-related mortality
cardiovascular-related hospitalisations
mobility decline (assessed using the 6‑minute walk test).The committee concluded that tafamidis could be considered more effective than placebo based on the evidence presented.
## The subgroup results are not suitable for decision making
The committee considered the predefined subgroup analyses from the ATTR‑ACT pivotal trial, specifically those examining the effectiveness and safety of tafamidis in:
hereditary and wild-type ATTR-CM (see section 3.1) and
either NYHA class 1 or 2 or NYHA class 3 disease.The analyses of hereditary and wild-type ATTR-CM found that the observed benefit of tafamidis compared with placebo for the primary outcome was driven by wild-type ATTR‑CM (the results are considered confidential by the company and cannot be reported here). But when the parts of the primary outcome were analysed separately different results were seen. For all-cause mortality, the hazard ratios favoured tafamidis over placebo, but the differences were not statistically significant in either wild-type (hazard ratio 0.71 ) or hereditary ATTR-CM (hazard ratio 0.69 ). Forest plots included in the summary of product characteristics for tafamidis showed that there were statistically significant reductions in hospitalisations for people with wild-type ATTR-CM who had tafamidis. But, no statistically significant differences were seen in people with hereditary ATTR-CM (relative risk ratios are considered confidential by the company and cannot be reported here). The same forest plots showed tafamidis statistically significantly reduced cardiovascular-related mortality and the rate of cardiovascular hospitalisations if a person's disease was classed as NYHA 1 or 2, but not if it was classed as NYHA 3. Two of the clinical experts suggested that the subgroup results could mean that a large proportion of people with ATTR-CM would not benefit from tafamidis. The company highlighted that the relatively small number of people included in the subgroup analyses from ATTR-ACT meant it was inappropriate to place too much weight on the statistical significance of the comparisons. The committee accepted the company's point about a lack of statistical power in the subgroup analyses, recognising that ATTR‑ACT was powered on the primary outcome measure (see section 3.10). But, it agreed that the subgroup results added to the uncertainty about the effectiveness of tafamidis in people with hereditary ATTR-CM and in people with ATTR-CM classed as NYHA 3. One of the clinical experts highlighted that cardiovascular-related mortality reduced for people whose disease was classed as NYHA 3. Although the reduction was not as large as in those whose disease was classed as NYHA 1 or 2, it was encouraging for a subgroup of people with a poor prognosis. The committee agreed that although the subgroup results added a degree of uncertainty around tafamidis' clinical effectiveness it accepted they were underpowered. So, it concluded they would not be considered in its decision making.
# Quality of life
## Tafamidis is more effective than placebo in slowing the decline in quality of life
Quality of life was measured in the ATTR-ACT pivotal trial using 3 scales: the Kansas City Cardiomyopathy Questionnaire (KCCQ), EQ‑5D‑3L and EQ‑5D visual analogue scale. The company explained that the KCCQ is a valid and reliable measure of health status for people with heart failure. It measures physical function, symptoms (frequency and severity), social function and quality-of-life domains, and calculates an overall summary score with lower scores showing worse impairment. The committee noted that the KCCQ overall summary score results from ATTR-ACT showed that from baseline to month 30, people taking tafamidis had a slower decline in quality of life than people taking placebo (least squares mean difference compared with placebo, 13.65 ). The committee also noted the results measured by the EQ‑5D‑3L and EQ‑5D visual analogue score (these are considered confidential by the company and cannot be reported here). The committee concluded that compared with placebo, tafamidis slowed the decline in quality of life for people with ATTR-CM.
# Adverse events
## Tafamidis is a safe and well-tolerated treatment
Most of the adverse events of treatment seen in the ATTR-ACT pivotal trial were mild to moderate in severity, with fewer in the tafamidis treatment groups. The company highlighted that the proportion of people reporting serious events was higher in the placebo group. The committee concluded that tafamidis was generally safe and well tolerated.
# The company's economic model
## The company's economic model can be considered for decision making because no alternative to NYHA health states is available
The company modelled the costs and benefits for tafamidis using a cohort-level Markov state‑transition model. To capture the natural disease progression of ATTR-CM, model health states were based on the NYHA classification system (see section 3.6). The model included 5 health states, 4 defined by NYHA classes (1, 2, 3, and 4) and 5 being death. People could move to a more severe health state (decline) or to a less severe one (improve). The company explained that because NYHA classification captured aspects of functional limitation and symptom severity it was suitable to model changes in ATTR-CM. It also highlighted that NYHA classification predicted health‑related quality of life and survival well, and it had been widely used in cost‑effectiveness models. The committee recalled its concerns about the NYHA classification system (see section 3.6), but concluded that because there was no available alternative the company's model could be considered for decision making.
# Assumptions in the economic model
## A stopping rule for tafamidis based on NYHA classification should not be included in the economic model
Both the company's and ERG's analyses after technical engagement included a stopping rule for tafamidis, which assumed that people would stop treatment if their disease progressed to NYHA class 4. The committee noted the limitations of using the NYHA classification system in clinical practice and the lack of evidence about tafamidis' effectiveness beyond NYHA class 1 and 2 (see sections 3.6, 3.7 and 3.11). The committee recalled that the NYHA classification is widely used to define populations eligible for heart failure treatments and has been used in previous NICE recommendations (see section 3.7). But, it noted that although the tafamidis marketing authorisation states that there were limited clinical data in patients whose disease was classed as NYHA 4, it did not specify that it should be stopped (see section 3.7). The committee also recalled that it would be difficult for clinicians to implement a stopping rule for tafamidis. This was because the disease can often vary between NYHA class 3 and 4 and the lack of alternative treatments for NYHA class 4 disease meant people would likely prefer to keep taking tafamidis (see section 3.7). The committee was aware that when considering treatment continuation rules, it needed to take additional factors into account as well as the cost-effectiveness estimates based on continuing treatment only in those whose disease had a specified response (see NICE's guide to the methods of technology appraisal). These factors include:
the robustness and plausibility of the endpoint on which the rule is based
whether the rule can be incorporated into routine clinical practice
considerations of fairness with regard to withdrawal of treatment from people whose condition does not respond to treatment.The committee concluded that although there were limited clinical data in patients whose disease was classed as NYHA 4, it was not appropriate to model a stopping rule based on the NYHA classification. This was because of the limitations of using the NYHA classification system in ATTR-CM. Also, a stopping rule was not specified in the marketing authorisation and stopping treatment based on NYHA classification could be challenging to do in clinical practice.
## It is unrealistic to assume continued treatment benefits without a cost
After technical engagement, the company included a treatment stopping rule for people in the NYHA class 1 to 3 health states. During technical engagement, a clinical expert explained that it was unlikely people would stop tafamidis in NYHA class 1, 2, or 3. This was because it was unclear when a person's disease changes from one NYHA class to another, and that people usually prefer to remain on treatment if there are no alternatives. Also, because tafamidis is well tolerated and easy to take, a high rate of adherence would be expected. After technical engagement, the company acknowledged this, but included a treatment stopping rule for people in the NYHA class 1 to 3 health states in its revised analysis. The ERG explained that in the economic model, people in the NYHA class 1 to 3 health states who stop treatment with tafamidis are assumed to benefit from treatment indefinitely without any treatment costs. The clinical experts who responded to technical engagement suggested it was unreasonable to assume that treatment benefits would be maintained indefinitely after treatment stops. A clinical expert at the second committee meeting also noted that no evidence was available to support such an assumption. The company noted that the relative treatment effect for tafamidis was estimated from the ATTR-ACT pivotal trial and incorporated the treatment effects for people who remained on treatment and those who stopped. So the effect of stopping treatment is already accounted for in its treatment effectiveness estimates. It also suggested that it is clinically plausible for benefits to continue after treatment stops because tafamidis' mechanism of action reduces cumulative amyloid exposure. So, the longer a person is on treatment, the more their cumulative exposure is reduced. Research group comments received at consultation suggested that ATTR-ACT had not revealed anything about how tafamidis works. The group stated that a recent publication had shown that disease stabilisation does not necessarily inhibit amyloid formation, so the mechanism underlying tafamidis' proposed benefit is unclear. The ERG reiterated that the limitations of the company's approach were acknowledged at technical engagement. It highlighted that the company failed to make use of longer-term data in its extrapolation of treatment stopping. The committee concluded that assuming continued treatment benefits without a cost was overly optimistic and would lead to an underestimated incremental cost‑effectiveness ratio (ICER).
## The ERG's continued treatment benefit analyses are suitable for consideration
The ERG presented 2 alternative analyses that used different assumptions about continued treatment benefits in the NYHA class 1 to 3 health states:
The first analysis continued to model treatment stopping in NYHA class 1 to 3 health states during the observed clinical trial period. But after the clinical trial period finished it assumed that all people having tafamidis would remain on treatment, and treatment benefits and costs would continue.
The second analysis assumed that people having tafamidis in NYHA class 1 to 3 health states would stop treatment at the same rate assumed in the company's analysis (see section 3.15). But after stopping tafamidis, costs and outcomes would revert to those of best supportive care. In the company's analysis people still benefited from tafamidis after stopping treatment.In both analyses, when disease progressed to NYHA class 4, everyone would stop tafamidis and have best supportive care. The committee recalled that it would not consider a stopping rule based on the NYHA classification (see section 3.15), but agreed it would consider the ERG's alternative continued treatment benefit analyses. It considered that some people would likely stop tafamidis for reasons other than disease progression or death, for example adverse events or older age. So, it agreed it was implausible to assume that everyone in the NYHA class 1 to 3 health states would remain on treatment indefinitely after the clinical trial period. It also acknowledged that reverting to best supportive care outcomes after stopping treatment would be conservative. This was because the estimates of tafamidis' treatment effects already included people who stopped treatment during the trial period (see section 3.16). But, the committee agreed that people stopping tafamidis would go on to have best supportive care and that these costs should be included in the model. The company commented that, unlike its approach of extrapolating the observed trial data, the ERG's analyses introduced unnecessary assumptions. On balance, the committee recognised that both of the ERG's alternative analyses had limitations, but agreed they provided realistic alternatives to the company's overly optimistic analyses. The committee concluded that the ERG's analyses were appropriate for decision making, but agreed that a stopping rule should not be included.
## Overall survival beyond the observed trial period should be estimated using a log-normal extrapolation function
After technical engagement the company modelled overall survival beyond the observed trial period, using generalised gamma extrapolation functions for tafamidis and best supportive care. The ERG explained that the company had changed the extrapolation function it used from log‑normal to generalised gamma, which had more favourable results for tafamidis. The ERG highlighted that although the company acknowledged that the extrapolations based on generalised gamma were optimistic, it had not given a reason for revising this aspect of its analysis at technical engagement (for example, statistical goodness‑of‑fit or external clinical validation). At consultation the company changed the extrapolation to reflect a new ATTR-ACT extension study data cut, which suggested that survival benefits increased the longer people were on tafamidis. It explained that because the estimated survival benefits from the ATTR‑ACT extension study included people who had swapped from placebo to tafamidis, mortality benefits were likely to be underestimated. So, because of this, and because the 2 extrapolation functions were similar in statistical and visual fit, it suggested it was appropriate to use the more optimistic of the two. The ERG noted that according to the Bayesian information criterion the generalised gamma extrapolation function used by the company was the worst fit. The committee concluded that modelling overall survival using generalised gamma extrapolation functions was not fully justified. It agreed to consider only the log‑normal extrapolation functions in its decision making.
## The company's early diagnosis assumptions are not appropriate for decision making
After technical engagement, the company provided analyses that used 3 new assumptions about early ATTR-CM diagnosis. It assumed that introducing tafamidis:
reduced the average age of starting treatment by 2.50 years to 71.95 years
avoided £20,000 of healthcare costs that would be incurred during the time people waited for a correct diagnosis
avoided anxiety and depression because of diagnosis delays.The committee recalled that there was not enough evidence provided to support the assumption that introducing tafamidis would reduce ATTR-CM diagnosis delays (see section 3.8). The ERG highlighted that it was unclear how the company had estimated that diagnosis delays could be reduced by 2.5 years and how potential cost savings of £20,000 had been estimated. The company explained that 1 in 3 people in the EAMS had an accurate diagnosis 2.5 years earlier (within 6 months) than the historical average (3 years or more; see section 3.3). It noted that if other centres had access to the same tests used in the EAMS, diagnosis times of 6 months or less could be replicated for all patients. The committee agreed it was unlikely that delays could be reduced by 2.5 years for all patients and that it was difficult to predict how the diagnosis times might change in the future. It was also aware that reducing the average age of starting treatment by 2.5 years had a modest effect on the cost-effectiveness results compared with the other early diagnosis assumptions. Also, if only a proportion of patients had a shorter time to diagnosis, then the effect on cost effectiveness would be small. The company also explained that the cost-saving estimate of £20,000 resulting from earlier diagnosis was calculated based on NAC data, which reported resource use during a 3‑year diagnosis delay. It acknowledged that empirical estimates for reduced hospital, primary care and imaging resource use could not be provided. But, it noted that the cost-saving assumption showed that earlier diagnosis of ATTR-CM could affect cost‑effectiveness estimates. The committee acknowledged that some of the costs incurred during diagnosis delays could be avoided. But, it agreed that because there was insufficient evidence to support the assumption that introducing tafamidis would reduce ATTR‑CM diagnosis delays, it was highly uncertain if any costs could be avoided. The company also derived an anxiety- and depression-related disutility value using EQ‑5D‑3L and highlighted that this disutility could be avoided if ATTR‑CM diagnosis delays were reduced. It acknowledged that not everyone would have depression, but the analysis showed the potential effect of earlier diagnosis on people's quality of life. The ERG considered that applying a quality-adjusted life year (QALY) gain for reduced anxiety or depression for all patients was not a reasonable approach because it was not supported by any evidence. The committee considered if being diagnosed with a serious cardiac condition could negatively affect a person's mental wellbeing and acknowledged it may change the way they view themselves, and how their families perceive them. The company explained that it had not investigated the effects of a diagnosis of ATTR-CM on psychological wellbeing. The committee agreed that there was insufficient evidence to support the assumption that introducing tafamidis would reduce ATTR-CM diagnosis delays (see section 3.8). It also agreed that it was highly uncertain whether any additional cost savings or quality-of-life benefits resulting from earlier diagnosis could be attributed to tafamidis. So, it concluded that the company's early diagnosis assumptions in the model were not appropriate for decision making because there was not enough evidence to support them.
## Including drug wastage costs is appropriate
After technical engagement, the ERG included potential tafamidis drug wastage in its estimate of costs. The committee considered if drug wastage would be substantial for tafamidis. The NHS England representative explained that they did not have any data on tafamidis wastage, so did not know whether it would be significant or not. The committee agreed with including drug wastage in the analysis and acknowledged that including it had little effect on the cost‑effectiveness estimates. So, the committee concluded that it was appropriate to include drug wastage costs in its preferred analysis because some wastage was likely to happen in clinical practice.
# Utility values
## NYHA health state utility values are appropriate for decision making
The company derived health state utility values using EQ‑5D‑3L data from the ATTR-ACT pivotal trial. The committee recalled that the company had also collected quality-of-life data using the KCCQ measure, which included function domains (see section 3 12). However, it agreed that the EQ‑5D‑3L data were more suitable for the economic model because they were in line with the reference case. The committee recalled its concerns about using health states based on NYHA classes in the model, but agreed that they could be considered because there was no available alternative (see section 3.14). The committee concluded that the company's health state utility values were appropriate for decision making.
## Utility values should be adjusted for age after the observed trial period
Before technical engagement, the company's analysis did not adjust health state utility values to account for the effect of increasing age. The ERG highlighted that this meant utility values for tafamidis and best supportive care were better than for the age-equivalent general population. The clinical experts involved in technical engagement explained that it was not plausible that someone with ATTR-CM could have a better quality of life than someone of a similar age and sex from the general population. The company adjusted its utility values to take account of increasing age after the observed trial period in its revised analyses after technical engagement. The committee concluded that using age-adjusted utility values was appropriate.
## Best supportive care utility values should be applied in the NYHA class 4 health state
The company estimated health state utility values separately for each NYHA class (see section 3.21) and treatment included in the model. It explained that different health state utility values between tafamidis and best supportive care may reflect differences in hospitalisations and adverse events associated with each treatment. The committee recalled that the NYHA classification system was unlikely to be sensitive to changes in ATTR-CM (see section 3.6). The ERG noted that the company modelled substantially different on- and off-treatment utility values in the NYHA class 4 health state. It also explained that estimates of NYHA class 4 utility values were based on very few observations. The company highlighted that the health state utility values were derived from EQ‑5D‑3L data from the ATTR-ACT pivotal trial and were the most appropriate data for the economic analysis. The ERG noted that in ATTR-ACT quality-of-life data were collected only during the on-treatment period, and that in the trial, most people stopped treatment before their disease progressed to NYHA class 4. The ERG explained that the estimated NYHA class 4 utility value for tafamidis could be affected by informative censoring, because the quality of life of anyone who stopped tafamidis in NYHA class 4 was not captured. To account for this, the ERG's analysis after technical engagement assumed that the estimated best supportive care utility value applied to everyone in the NYHA class 4 health state. After technical engagement the company accepted that it was appropriate to apply the best supportive care utility value in NYHA class 4 and it used this assumption in its revised analysis. The committee agreed that it had concerns about using treatment-dependent health state utility values from relatively few observations and the potential for informative censoring to bias these estimates. It concluded that the treatment-dependent utility values were reasonable in NYHA class 1 to 3, and that the best supportive care utility value should be applied in the NYHA class 4 health state.
# Cost-effectiveness estimates
## Tafamidis is not a cost-effective use of NHS resources
The company's preferred analysis estimated that the ICER for tafamidis compared with best supportive care, in the full population, was less than £30,000 per QALY gained (including the company's confidential commercial arrangement). It included the following assumptions:
a stopping treatment rule for tafamidis in NYHA health states 1, 2 and 3 (see section 3.16)
using a generalised gamma extrapolation function to model overall survival (see section 3.18)
a stopping treatment rule for tafamidis if disease progressed to NYHA class 4 (see section 3.15)
an earlier treatment starting age and estimated cost savings and benefits associated with earlier diagnosis of ATTR-CM (see sections 3.8 and 3.19)
health state utility values adjusted for age (see section 3.22)
treatment-independent health state utility values in NYHA 4 equal to best supportive care values (see section 3.23).The committee agreed that the company's analysis did not include all of its preferred assumptions. It noted that the ERG's preferred analysis was different from the company's preferred analysis, and more in line with the committee's preferred assumptions. Specifically, the committee agreed with the following changes in the ERG's analysis:
assuming people in NYHA health states 1, 2 and 3 keep taking tafamidis and associated costs and treatment benefits continue after the observed trial period (see section 3.16)
using a log-normal extrapolation function to model overall survival (see section 3.18)
assuming introducing tafamidis would not reduce diagnosis delays and excluding estimated benefits and cost savings associated with earlier diagnosis of ATTR-CM (see sections 3.8 and 3.19)
including drug wastage in cost estimates (see section 3.20).These changes resulted in an ICER that was substantially above £30,000 per QALY gained. The committee recalled that it would consider the ERG's 2 approaches to model treatment stopping in NYHA health states 1, 2 and 3 and that it was not appropriate to model a stopping rule based on the NYHA classification system (see sections 3.15 and 3.17). Using these assumptions in its preferred analysis increased the ICER even more. Considering all these factors, the committee's most plausible ICER for tafamidis compared with best supportive care, in the full population, was substantially above the range that NICE usually considers an acceptable use of NHS resources. It concluded that tafamidis was not a cost‑effective use of NHS resources for treating ATTR-CM.
# Other factors
## There are no equalities issues that can be addressed in the guidance
The most common transthyretin variants associated with hereditary ATTR-CM are Val122Ile, which is common in people of African and Caribbean family origin, and Thr60Ala, which is common in people with Irish ancestry. The committee acknowledged that ATTR-CM disproportionally affected people from certain ethnic groups, but agreed this was not something that could be addressed in its recommendation. A statement received at consultation noted that the recommendation would deny older people with ATTR-CM access to tafamidis, which could maintain their health and reduce morbidity, while those in the EAMS could have tafamidis. The committee was also aware that evidence suggested ATTR-CM prevalence in women may be underestimated, because women may be less likely to have the red flag symptoms that trigger referral. The committee considered that its recommendation did not disproportionately disadvantage women or certain age groups, and that access to tafamidis through the EAMS was not in the scope of their recommendation.
## The benefits of tafamidis are captured in the economic model
The company considered that tafamidis is a breakthrough treatment for ATTR‑CM. It noted that it is a step change in managing the condition, and that it will benefit people with ATTR-CM and their carers. It also highlighted that it was the first treatment for ATTR-CM to reduce mortality and morbidity and reduce cardiovascular-related hospitalisations. It suggested that the high QALY gains seen in the cost-effectiveness analysis represented a major change in managing ATTR-CM. The clinical expert explained that new research had changed their understanding of the way that tafamidis treats ATTR-CM. The committee recalled that a recent publication had shown that disease stabilisation does not necessarily inhibit amyloid formation, so the mechanism underlying tafamidis' proposed benefit is unclear (see section 3.16). The committee acknowledged that there is an unmet need for an effective treatment for ATTR-CM, but considered that the relevant benefits of tafamidis were captured in the economic model.
# Conclusion
## Tafamidis is not recommended
The committee recognised that ATTR-CM is a debilitating and progressive condition which has a substantial effect on a person's quality of life (see sections 3.1 and 3.2). It noted that awareness of ATTR-CM was improving but getting a definitive diagnosis was complicated and can take a long time (see section 3.3). Without validated and objective measures for assessing ATTR-CM, identifying people who need treatment and those who are benefiting from treatment will continue to be a challenge (see section 3.6). It acknowledged that tafamidis was more effective than placebo in the outcomes assessed in the ATTR-ACT pivotal trial. It recalled that there was considerable uncertainty about the modelling of stopping tafamidis and if treatment effects continue after this (see sections 3.15 and 3.16). It also recalled that there was a high degree of uncertainty about whether introducing tafamidis would reduce diagnosis delays and result in any additional benefits or cost savings that could be attributed to tafamidis (see sections 3.8 and 3.19). All this considered, the committee's most plausible range of ICERs was substantially above the range that NICE usually considers an acceptable use of NHS resources (see section 3.24). So, the committee did not recommend using tafamidis in the NHS for treating ATTR-CM.
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{'Recommendations': 'Tafamidis is not recommended, within its marketing authorisation, for treating wild-type or hereditary transthyretin amyloidosis with cardiomyopathy (ATTR‑CM) in adults.\n\nThis recommendation is not intended to affect treatment with tafamidis that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nATTR-CM can lead to heart failure, but treatment options are limited to managing symptoms and best supportive care. Awareness of ATTR-CM has improved, but accurately diagnosing ATTR-CM can be challenging and can take a long time.\n\nTafamidis is the first treatment for ATTR-CM that aims to treat the disease. Evidence from clinical trials shows that it reduces deaths and hospitalisation from conditions affecting the heart and blood vessels compared with placebo. But clinical benefit varies across different types and stages of ATTR-CM. Also, the measure used to assess how severe ATTR‑CM is has limitations. This makes it difficult to clearly identify who benefits from tafamidis and whether they should continue treatment.\n\nThe cost-effectiveness estimates are higher than what NICE normally considers an acceptable use of NHS resources. This is because there is not enough evidence that recommending tafamidis would reduce diagnosis delays and uncertainty about how long the treatment works after it is stopped. So, tafamidis is not recommended.', 'Information about tafamidis': "# Marketing authorisation indication\n\nTafamidis (Vyndaqel, Pfizer) is indicated for 'the treatment of wild‑type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM)'. Before the marketing authorisation was granted, tafamidis was available in the NHS through the early access to medicines scheme.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe price of tafamidis is £10,685.00 per 30‑capsule pack of 61\xa0mg capsules (excluding VAT; company submission) giving an annual cost of £130,089.88. The company has a commercial arrangement, which would have applied if the technology had been recommended.", 'Committee discussion': "The appraisal committee considered evidence submitted by Pfizer, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nIn the economic model, people whose disease is classed as New York Heart Association (NYHA)\xa01 to\xa03 should be assumed to remain on treatment (issue\xa02, see technical report pages 14 to 15).\n\nUtility values for best supportive care should be applied to everyone in the NYHA\xa04 model health state (issue\xa03, see technical report pages 15 to 18).\n\nIn the model it is acceptable that an age adjustment is applied to health state utility values after the observed trial period (issue\xa03, see technical report pages 15 to 18).It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, pages 22 to 23), and took these into account in its decision making. It discussed the following issues (issues\xa01, 2, 4 and 5), which were outstanding after the technical engagement stage.\n\n# The condition\n\n## ATTR-CM can lead to heart failure and sudden death\n\nThere are 2\xa0types of transthyretin amyloidosis with cardiomyopathy (ATTR‑CM):\n\nWild-type ATTR-CM, which is more common. It mostly affects older people and is more common in men.\n\nHereditary ATTR-CM (also known as familial amyloid cardiomyopathy), which affects people born with inherited mutations in the transthyretin (TTR) gene.The clinical experts explained that ATTR-CM is a progressive disease. Symptoms usually start after age 70 in people with wild-type ATTR‑CM or after age 60 in people with hereditary ATTR-CM. It can cause shortness of breath, palpitations and abnormal heart rhythms such as atrial fibrillation or atrial flutter, ankle swelling, fatigue, fainting and chest pain. They noted that death in most people with ATTR-CM is from sudden death and progressive heart failure. The committee concluded that ATTR-CM can lead to heart failure and sudden death.\n\n## ATTR-CM significantly affects mental and physical wellbeing\n\nThe patient experts explained that ATTR-CM significantly affected their physical ability. For example, one noted that walking even short distances could be challenging, while another stated that they were no longer able to do their daily physical activities. Another patient expert explained that ATTR-CM made them feel older than they should and limited them to mostly staying seated. The patient experts noted that ATTR-CM also affected psychological wellbeing, for example, symptoms of breathlessness leading to anxiety. Loss of independence and an increased reliance on caregivers was also highlighted as a cause of depression related to the condition. The patient experts explained that psychological effects can be exacerbated for people with hereditary ATTR‑CM because it can affect multiple members of a family across different generations, and there was anxiety about passing it on to children. The committee concluded that ATTR-CM is a debilitating disease which significantly affects mental and physical wellbeing.\n\n# Clinical management\n\n## Awareness of ATTR-CM has improved but diagnosis can still take a long time\n\nThe patient experts explained that getting an accurate diagnosis for ATTR-CM could be challenging. They noted that awareness of the condition, and the type of ATTR-CM a person has (see section\xa03.1), can vary and lead to delays to diagnosis. One patient expert explained that they waited more than 4\xa0years for an accurate diagnosis, highlighting a general lack of understanding about the condition outside of specialist centres. The company highlighted National Amyloidosis Centre (NAC) data showing that, on average, it took 3\xa0years or more for a person to be accurately diagnosed with ATTR-CM. Two of the clinical experts agreed that there were challenges in diagnosing ATTR‑CM accurately, but noted the developments in recent years. Radionuclide imaging (DPD scan), a test usually used to detect bone abnormalities, is increasingly being used to diagnose ATTR-CM. It is very sensitive to detecting amyloid deposits in the heart. This has improved awareness of ATTR‑CM and increased diagnoses. Two of the clinical experts highlighted that the low cost of DPD scanning meant most hospitals would be able to do them. So, they expected further increases in ATTR‑CM diagnoses. They also noted increased awareness of ATTR‑CM after NICE's highly specialised technologies guidance recommended inotersen and patisiran for treating hereditary transthyretin amyloidosis with polyneuropathy (see section\xa03.5). The committee concluded that the availability of new diagnostic tests and treatments for the disease had improved awareness of ATTR-CM, but recognised that diagnosis can still take a long time.\n\n## It is unclear if increased availability of DPD scans will lead to an increase in diagnosing amyloidosis or ATTR-CM\n\nTwo of the clinical experts explained that transthyretin amyloid deposits are often an incidental finding in people having DPD scans and may not necessarily be associated with a diagnosis of ATTR-CM. They explained that the population they see in practice has a range of amyloid deposits, sometimes because of older age, for example. Also, there is no defined point at which amyloid deposits become amyloidosis. So, it is unclear why some amyloid deposits progress to amyloidosis and others do not. In addition, because other common comorbidities can lead to increased breathlessness and decreased mobility, reaching a definitive ATTR-CM diagnosis is challenging. At consultation, the company commented that the NAC published a non-invasive diagnostic pathway for ATTR-CM in 2016. It explained that the pathway had been validated and implemented at 17\xa0early access to medicines scheme (EAMS) sites. It further explained that based on this pathway, only people with symptoms and certain clinical features are eligible for DPD scans. So, amyloid deposits identified through the pathway are not incidental. It highlighted that, because of this, amyloid deposits found when doing DPD scans for another condition would not result in a diagnosis of amyloidosis. At the second committee meeting one of the clinical experts confirmed that incidental amyloid deposits would not result in an increase in amyloidosis diagnoses, because other clinical features outlined in the ATTR-CM diagnostic pathway would be taken into account. The committee questioned whether everybody with heart failure and an abnormal DPD scan would be diagnosed with amyloidosis. One clinical expert explained that not everyone with heart failure would have a DPD scan, and only those with cardiac symptoms specific to ATTR-CM (such as thickening of the heart muscle) would be tested. They further explained that people diagnosed with ATTR-CM and having treatment in clinical practice would likely reflect the population from the ATTR-ACT pivotal trial (see section\xa03.9) although in the trial a biopsy was required. The clinical experts and the NHS England representative explained that when amyloidosis is suspected people are referred to the NAC for more rigorous testing. The committee was aware that the European public assessment report for tafamidis states that there are difficulties in diagnosing people with ATTR‑CM in NHYA class\xa01, particularly if they do not have heart failure. It also states that an accurate diagnosis cannot be formally established without a number of procedures (such as biopsy and scintigraphy). The committee acknowledged this and agreed that even with DPD scans and a diagnostic pathway, there would still be challenges in diagnosing ATTR‑CM. The committee concluded that it was unclear if the increased availability of DPD scans would lead to an increase in diagnosing amyloidosis or ATTR‑CM.\n\n## Best supportive care is the relevant comparator\n\nTreatment options for ATTR-CM are limited to managing symptoms and supportive care, such as diuretics. A small proportion of people with ATTR-CM also have polyneuropathy (mixed clinical features). NICE has recommended 2\xa0treatments for polyneuropathy:\n\nNICE highly specialised technologies guidance on inotersen for treating hereditary transthyretin amyloidosis\n\nNICE highly specialised technologies guidance on patisiran for treating hereditary transthyretin amyloidosis.NICE's final scope included inotersen and patisiran as comparators to tafamidis. The committee noted that the company had not included these treatments as comparators in its submission because neither had been evaluated in people with ATTR-CM. The committee noted that the marketing authorisation for tafamidis 61\xa0mg did not specifically mention people with polyneuropathy. It acknowledged that because it is rare for people to have ATTR-CM and polyneuropathy, there would not be enough evidence to consider it separately. So, it agreed that inotersen and patisiran could not be considered as comparators to tafamidis. The committee also noted that liver or heart transplantation are options for some people with ATTR-CM and a specific genetic mutation. But it recognised that because this mutation is uncommon in England, and transplantation can only take place early in the course of the disease, transplants are rarely done. The committee agreed that transplantation was not an appropriate comparator for tafamidis and concluded that best supportive care was the appropriate comparator.\n\n## Measuring ATTR-CM severity using NYHA classification has limitations but there is insufficient trial evidence to consider an alternative\n\nThe NYHA functional classification system is commonly used in clinical practice to assess heart failure, and is sometimes used to measure the severity of ATTR‑CM. It groups symptoms into 1 of 4\xa0classes depending on how limited a person's physical activity is. A person whose disease was classed as NYHA\xa01 would be able to do ordinary physical activity. But someone whose disease was classed as NYHA\xa04 would be unable to do physical activity without feeling discomfort. The clinical experts explained that although NYHA classification is used in clinical practice, it has limitations. Because it is a patient-reported measure it can vary from day to day, and there can be inconsistencies in people's symptoms. For example, people with the same activity tolerance may classify their level of heart failure differently. One clinical expert noted that variability in how people classify themselves was a common issue with all symptom-based measures. They also highlighted that the NYHA classification system is used as an entry criterion in most heart failure trials. The clinical experts commented that it was difficult to identify whether movement between the NYHA classes was a result of ATTR-CM progressing or changes in other comorbidities. One of the clinical experts suggested that a measure based on cardiac markers such as B-type natriuretic peptide and glomerular filtration rate had potential to identify disease stage and who is benefiting from treatment, but evidence of its use in ATTR-CM in clinical practice was limited. The ERG explained that there were merits to assessing disease severity using objective measures such as cardiac markers. But it commented that in the ATTR-ACT pivotal trial (see section\xa03.9), unlike the NYHA classification which was measured every 6\xa0months, these cardiac markers were only measured at baseline, month\xa012, and after stopping treatment. So, they were not measured frequently enough to accurately characterise the disease. The committee concluded that using the NYHA classification in ATTR-CM had limitations, but acknowledged that there was insufficient trial evidence available to consider an alternative. This was because cardiac markers, which could have been used to identify disease stage and who would benefit from treatment, were not measured frequently enough in the trial.\n\n## It is not appropriate to define starting and stopping rules for tafamidis based on the NYHA classification system\n\nThe marketing authorisation for tafamidis does not specify starting and stopping rules for tafamidis based on the NYHA classification system. The company highlighted that NYHA classifications have been incorporated in previous NICE recommendations to define populations eligible for treatment with heart failure therapies. The committee noted that the marketing authorisation states that tafamidis should be 'started as early as possible in the disease course when the clinical benefit on disease progression could be more evident. Conversely, when amyloid-related cardiac damage is more advanced, such as in NYHA class\xa03, the decision to start or maintain treatment should be taken at the discretion of a physician knowledgeable in the management of patients with amyloidosis or cardiomyopathy'. The committee recalled that NYHA class\xa01 means that people can do ordinary physical activity (see section\xa03.6). It considered if tafamidis would be used for people who are easily able to do the activities of daily living (no functional limitations). The clinical experts explained that they would have reservations about offering treatment to people whose disease is classed as NYHA\xa01 because they have no functional limitations and might not benefit from treatment. At consultation, the company highlighted that this contradicted tafamidis' marketing authorisation, which states that treatment should be started as soon as possible. The company proposed a stopping rule in which people would stop tafamidis if their disease progressed to NYHA class\xa04. It explained that there was limited evidence to support using tafamidis in people whose disease was NYHA class\xa04, who had severe heart failure symptoms, because they were excluded from the ATTR-ACT pivotal trial. Also, the company highlighted that its proposed stopping rule reflected treatment stopping in ATTR-ACT, in which most people stopped tafamidis quickly after progressing to NYHA class\xa04. It also noted that because tafamidis does not improve symptoms caused by ATTR-CM it would be clinically appropriate to stop treatment when a person's disease is classed as NYHA\xa04. A clinical expert noted that stopping treatments when the disease progresses to NYHA class\xa04 was common because at this stage people are very unwell. They explained that people would be unable to travel for treatment, so treatment would likely be stopped and best supportive care offered. Comments from the patient organisation supported this view, stating that making decisions about stopping treatment in advanced disease stages were not uncommon. Conversely, 2\xa0of the clinical experts noted that it would be challenging to stop treatment when disease progressed to NYHA class\xa04 because no alternative treatments were available. These 2\xa0clinical experts also explained that people's disease often varies between NYHA class\xa03 and\xa04 and that this was typical of ATTR-CM. They noted that some people whose disease was classed as NYHA\xa04 could improve, so could change to NYHA class\xa03 or better. The ERG noted that improvements shown by changes in NYHA class were also seen in ATTR-ACT. The committee recalled that the company's proposed stopping rule was not specified in tafamidis' marketing authorisation. It agreed, that on balance, it would be difficult for clinicians to implement a stopping rule for tafamidis. This was because the disease can often vary between NYHA class\xa03 and\xa04 and the lack of alternative treatments for NYHA class\xa04 disease meant people would likely prefer to keep taking tafamidis. The committee concluded that using the NYHA classification alone to accurately define the population who were eligible to have tafamidis had limitations. So, it also concluded that it would not consider starting and stopping rules for tafamidis based on the NYHA classification system in its decision making.\n\n## There is not enough evidence that tafamidis would reduce delays in diagnosis times\n\nAt technical engagement, the company highlighted that introducing tafamidis reduced delays to ATTR-CM diagnoses. It noted that the availability of tafamidis would result in ATTR-CM being detected earlier because of more awareness among cardiologists. The company also noted that since tafamidis became available in the EAMS, the proportion of people whose disease was diagnosed in NYHA class\xa01 or\xa02 has increased from 75% to 86%. The committee understood that the short-term observational EAMS data were presented to support the assumption that introducing tafamidis could reduce diagnosis delays. It acknowledged that although the EAMS data were informative, they can only show that diagnosis delays were reducing when tafamidis was available. They cannot show that the delays were reducing because of tafamidis. A statement from NHS England suggested that if NICE recommended tafamidis, and awareness was increased through educational campaigns, diagnosis rates may improve further. The committee recalled that average time to diagnosis at the NAC was 3\xa0years or more (see section\xa03.3). The company noted that 1\xa0in\xa03 patients were diagnosed in less than 6\xa0months, while 40% waited for 4\xa0years or more. The committee acknowledged that reducing the average time to diagnosis to less than 6\xa0months would represent a substantial improvement. But, it recognised these diagnoses were made at a specialist centre and questioned if such reductions could be achieved at other centres in clinical practice. The ERG highlighted that the trend of earlier diagnosis seen in the EAMS could be explained by improvements in diagnostic tools since the ATTR-ACT pivotal trial (see section\xa03.3). It noted that when ATTR-CM is suspected the diagnostic pathway may lead to quicker diagnoses, but when it is not suspected, substantial diagnosis delays may still occur. The committee acknowledged this, and agreed it was not possible to attribute reductions in diagnosis times at EAMS sites to the availability of tafamidis. It also noted web comments at consultation which highlighted evidence of an increasing number of ATTR-CM diagnoses at the NAC before tafamidis was available through EAMS. There were also comments from the EAMS centres' cardiac group that a major contributor to the shorter diagnosis times was the changes in diagnostic tools and algorithms. The committee also recalled that awareness of ATTR-CM had increased (see section\xa03.3) and questioned whether recommending tafamidis would further increase awareness and reduce diagnosis times. The committee concluded that there was not enough evidence provided to support the assumption that introducing tafamidis would reduce ATTR-CM diagnosis delays.\n\n# Clinical evidence\n\n## The ATTR-ACT trials are appropriate for decision making\n\nThe clinical evidence came from 2\xa0trials:\n\nATTR-ACT (pivotal): a 30‑month, phase\xa03 double-blind randomised controlled trial. It evaluated how effective, safe, and tolerable tafamidis was compared with placebo in adults with wild-type or hereditary ATTR-CM, whose disease was classed as NYHA\xa01 to 3 (n=441).\n\nATTR-ACT extension study: an open-label extension of ATTR-ACT including patients from ATTR-ACT and others with ATTR-CM who did not take part in ATTR-ACT (ongoing; number of patients not reported).The ATTR-ACT pivotal trial randomised patients to have 80\xa0mg of tafamidis meglumine (n=176), 20\xa0mg of tafamidis meglumine (n=88) or placebo (n=177) using a ratio of 2:1:2. Everyone who had treatment in the ATTR‑ACT extension had tafamidis 61\xa0mg, or tafamidis meglumine 80\xa0mg if 61\xa0mg was not available. The committee noted that the dose of tafamidis used in ATTR-ACT was different to the dose in the marketing authorisation for tafamidis, which is 61\xa0mg. But, the marketing authorisation states that the relative bioavailability of tafamidis 61\xa0mg is similar to tafamidis meglumine 80\xa0mg at a steady state. So, the committee concluded that the ATTR-ACT trials were appropriate for decision making.\n\n## Tafamidis is more effective than placebo in clinical trial results\n\nThe primary analysis from the ATTR-ACT pivotal trial compared the results of a pooled tafamidis (20\xa0mg and 80\xa0mg doses) treatment group with the placebo group. The primary outcome, a combined measure of all-cause mortality and cardiovascular-related hospitalisations, was assessed in a hierarchical analysis using the Finkelstein-Schoenfeld method. At month\xa030, 186\xa0people (70.5%) were alive in the tafamidis group compared with 101\xa0people (57.1%) in the placebo group. Of those alive at month\xa030, people who had tafamidis had fewer annual cardiovascular-related hospitalisations (0.297) on average than those who had placebo (0.455). Tafamidis statistically significantly reduced all-cause mortality and frequency of cardiovascular-related hospitalisations compared with placebo. The committee considered that although the parts of the primary outcome were clinically relevant to patients and clinicians, it questioned whether the combined measure would be considered in clinical practice. It also considered the secondary outcome results from ATTR-ACT and noted that at month\xa030 compared with placebo, tafamidis was associated with statistically significant reductions in:\n\ncardiovascular-related mortality\n\ncardiovascular-related hospitalisations\n\nmobility decline (assessed using the 6‑minute walk test).The committee concluded that tafamidis could be considered more effective than placebo based on the evidence presented.\n\n## The subgroup results are not suitable for decision making\n\nThe committee considered the predefined subgroup analyses from the ATTR‑ACT pivotal trial, specifically those examining the effectiveness and safety of tafamidis in:\n\nhereditary and wild-type ATTR-CM (see section\xa03.1) and\n\neither NYHA class\xa01 or\xa02 or NYHA class\xa03 disease.The analyses of hereditary and wild-type ATTR-CM found that the observed benefit of tafamidis compared with placebo for the primary outcome was driven by wild-type ATTR‑CM (the results are considered confidential by the company and cannot be reported here). But when the parts of the primary outcome were analysed separately different results were seen. For all-cause mortality, the hazard ratios favoured tafamidis over placebo, but the differences were not statistically significant in either wild-type (hazard ratio 0.71 [95%\xa0confidence interval 0.47 to 1.05]) or hereditary ATTR-CM (hazard ratio\xa00.69 [95%\xa0confidence interval 0.41 to 1.17]). Forest plots included in the summary of product characteristics for tafamidis showed that there were statistically significant reductions in hospitalisations for people with wild-type ATTR-CM who had tafamidis. But, no statistically significant differences were seen in people with hereditary ATTR-CM (relative risk ratios are considered confidential by the company and cannot be reported here). The same forest plots showed tafamidis statistically significantly reduced cardiovascular-related mortality and the rate of cardiovascular hospitalisations if a person's disease was classed as NYHA\xa01 or 2, but not if it was classed as NYHA\xa03. Two of the clinical experts suggested that the subgroup results could mean that a large proportion of people with ATTR-CM would not benefit from tafamidis. The company highlighted that the relatively small number of people included in the subgroup analyses from ATTR-ACT meant it was inappropriate to place too much weight on the statistical significance of the comparisons. The committee accepted the company's point about a lack of statistical power in the subgroup analyses, recognising that ATTR‑ACT was powered on the primary outcome measure (see section\xa03.10). But, it agreed that the subgroup results added to the uncertainty about the effectiveness of tafamidis in people with hereditary ATTR-CM and in people with ATTR-CM classed as NYHA\xa03. One of the clinical experts highlighted that cardiovascular-related mortality reduced for people whose disease was classed as NYHA\xa03. Although the reduction was not as large as in those whose disease was classed as NYHA\xa01 or\xa02, it was encouraging for a subgroup of people with a poor prognosis. The committee agreed that although the subgroup results added a degree of uncertainty around tafamidis' clinical effectiveness it accepted they were underpowered. So, it concluded they would not be considered in its decision making.\n\n# Quality of life\n\n## Tafamidis is more effective than placebo in slowing the decline in quality of life\n\nQuality of life was measured in the ATTR-ACT pivotal trial using 3\xa0scales: the Kansas City Cardiomyopathy Questionnaire (KCCQ), EQ‑5D‑3L and EQ‑5D visual analogue scale. The company explained that the KCCQ is a valid and reliable measure of health status for people with heart failure. It measures physical function, symptoms (frequency and severity), social function and quality-of-life domains, and calculates an overall summary score with lower scores showing worse impairment. The committee noted that the KCCQ overall summary score results from ATTR-ACT showed that from baseline to month\xa030, people taking tafamidis had a slower decline in quality of life than people taking placebo (least squares mean difference compared with placebo, 13.65 [p<0.0001]). The committee also noted the results measured by the EQ‑5D‑3L and EQ‑5D visual analogue score (these are considered confidential by the company and cannot be reported here). The committee concluded that compared with placebo, tafamidis slowed the decline in quality of life for people with ATTR-CM.\n\n# Adverse events\n\n## Tafamidis is a safe and well-tolerated treatment\n\nMost of the adverse events of treatment seen in the ATTR-ACT pivotal trial were mild to moderate in severity, with fewer in the tafamidis treatment groups. The company highlighted that the proportion of people reporting serious events was higher in the placebo group. The committee concluded that tafamidis was generally safe and well tolerated.\n\n# The company's economic model\n\n## The company's economic model can be considered for decision making because no alternative to NYHA health states is available\n\nThe company modelled the costs and benefits for tafamidis using a cohort-level Markov state‑transition model. To capture the natural disease progression of ATTR-CM, model health states were based on the NYHA classification system (see section\xa03.6). The model included 5\xa0health states, 4 defined by NYHA classes (1, 2, 3, and 4) and 5 being death. People could move to a more severe health state (decline) or to a less severe one (improve). The company explained that because NYHA classification captured aspects of functional limitation and symptom severity it was suitable to model changes in ATTR-CM. It also highlighted that NYHA classification predicted health‑related quality of life and survival well, and it had been widely used in cost‑effectiveness models. The committee recalled its concerns about the NYHA classification system (see section\xa03.6), but concluded that because there was no available alternative the company's model could be considered for decision making.\n\n# Assumptions in the economic model\n\n## A stopping rule for tafamidis based on NYHA classification should not be included in the economic model\n\nBoth the company's and ERG's analyses after technical engagement included a stopping rule for tafamidis, which assumed that people would stop treatment if their disease progressed to NYHA class\xa04. The committee noted the limitations of using the NYHA classification system in clinical practice and the lack of evidence about tafamidis' effectiveness beyond NYHA class\xa01 and\xa02 (see sections\xa03.6, 3.7 and 3.11). The committee recalled that the NYHA classification is widely used to define populations eligible for heart failure treatments and has been used in previous NICE recommendations (see section\xa03.7). But, it noted that although the tafamidis marketing authorisation states that there were limited clinical data in patients whose disease was classed as NYHA\xa04, it did not specify that it should be stopped (see section\xa03.7). The committee also recalled that it would be difficult for clinicians to implement a stopping rule for tafamidis. This was because the disease can often vary between NYHA class\xa03 and 4 and the lack of alternative treatments for NYHA class\xa04 disease meant people would likely prefer to keep taking tafamidis (see section\xa03.7). The committee was aware that when considering treatment continuation rules, it needed to take additional factors into account as well as the cost-effectiveness estimates based on continuing treatment only in those whose disease had a specified response (see NICE's guide to the methods of technology appraisal). These factors include:\n\nthe robustness and plausibility of the endpoint on which the rule is based\n\nwhether the rule can be incorporated into routine clinical practice\n\nconsiderations of fairness with regard to withdrawal of treatment from people whose condition does not respond to treatment.The committee concluded that although there were limited clinical data in patients whose disease was classed as NYHA\xa04, it was not appropriate to model a stopping rule based on the NYHA classification. This was because of the limitations of using the NYHA classification system in ATTR-CM. Also, a stopping rule was not specified in the marketing authorisation and stopping treatment based on NYHA classification could be challenging to do in clinical practice.\n\n## It is unrealistic to assume continued treatment benefits without a cost\n\nAfter technical engagement, the company included a treatment stopping rule for people in the NYHA class\xa01 to 3 health states. During technical engagement, a clinical expert explained that it was unlikely people would stop tafamidis in NYHA class\xa01, 2, or 3. This was because it was unclear when a person's disease changes from one NYHA class to another, and that people usually prefer to remain on treatment if there are no alternatives. Also, because tafamidis is well tolerated and easy to take, a high rate of adherence would be expected. After technical engagement, the company acknowledged this, but included a treatment stopping rule for people in the NYHA class\xa01 to\xa03 health states in its revised analysis. The ERG explained that in the economic model, people in the NYHA class\xa01 to\xa03 health states who stop treatment with tafamidis are assumed to benefit from treatment indefinitely without any treatment costs. The clinical experts who responded to technical engagement suggested it was unreasonable to assume that treatment benefits would be maintained indefinitely after treatment stops. A clinical expert at the second committee meeting also noted that no evidence was available to support such an assumption. The company noted that the relative treatment effect for tafamidis was estimated from the ATTR-ACT pivotal trial and incorporated the treatment effects for people who remained on treatment and those who stopped. So the effect of stopping treatment is already accounted for in its treatment effectiveness estimates. It also suggested that it is clinically plausible for benefits to continue after treatment stops because tafamidis' mechanism of action reduces cumulative amyloid exposure. So, the longer a person is on treatment, the more their cumulative exposure is reduced. Research group comments received at consultation suggested that ATTR-ACT had not revealed anything about how tafamidis works. The group stated that a recent publication had shown that disease stabilisation does not necessarily inhibit amyloid formation, so the mechanism underlying tafamidis' proposed benefit is unclear. The ERG reiterated that the limitations of the company's approach were acknowledged at technical engagement. It highlighted that the company failed to make use of longer-term data in its extrapolation of treatment stopping. The committee concluded that assuming continued treatment benefits without a cost was overly optimistic and would lead to an underestimated incremental cost‑effectiveness ratio (ICER).\n\n## The ERG's continued treatment benefit analyses are suitable for consideration\n\nThe ERG presented 2\xa0alternative analyses that used different assumptions about continued treatment benefits in the NYHA class\xa01 to 3 health states:\n\nThe first analysis continued to model treatment stopping in NYHA class\xa01 to\xa03 health states during the observed clinical trial period. But after the clinical trial period finished it assumed that all people having tafamidis would remain on treatment, and treatment benefits and costs would continue.\n\nThe second analysis assumed that people having tafamidis in NYHA class\xa01 to\xa03 health states would stop treatment at the same rate assumed in the company's analysis (see section\xa03.15). But after stopping tafamidis, costs and outcomes would revert to those of best supportive care. In the company's analysis people still benefited from tafamidis after stopping treatment.In both analyses, when disease progressed to NYHA class\xa04, everyone would stop tafamidis and have best supportive care. The committee recalled that it would not consider a stopping rule based on the NYHA classification (see section\xa03.15), but agreed it would consider the ERG's alternative continued treatment benefit analyses. It considered that some people would likely stop tafamidis for reasons other than disease progression or death, for example adverse events or older age. So, it agreed it was implausible to assume that everyone in the NYHA class\xa01 to 3 health states would remain on treatment indefinitely after the clinical trial period. It also acknowledged that reverting to best supportive care outcomes after stopping treatment would be conservative. This was because the estimates of tafamidis' treatment effects already included people who stopped treatment during the trial period (see section\xa03.16). But, the committee agreed that people stopping tafamidis would go on to have best supportive care and that these costs should be included in the model. The company commented that, unlike its approach of extrapolating the observed trial data, the ERG's analyses introduced unnecessary assumptions. On balance, the committee recognised that both of the ERG's alternative analyses had limitations, but agreed they provided realistic alternatives to the company's overly optimistic analyses. The committee concluded that the ERG's analyses were appropriate for decision making, but agreed that a stopping rule should not be included.\n\n## Overall survival beyond the observed trial period should be estimated using a log-normal extrapolation function\n\nAfter technical engagement the company modelled overall survival beyond the observed trial period, using generalised gamma extrapolation functions for tafamidis and best supportive care. The ERG explained that the company had changed the extrapolation function it used from log‑normal to generalised gamma, which had more favourable results for tafamidis. The ERG highlighted that although the company acknowledged that the extrapolations based on generalised gamma were optimistic, it had not given a reason for revising this aspect of its analysis at technical engagement (for example, statistical goodness‑of‑fit or external clinical validation). At consultation the company changed the extrapolation to reflect a new ATTR-ACT extension study data cut, which suggested that survival benefits increased the longer people were on tafamidis. It explained that because the estimated survival benefits from the ATTR‑ACT extension study included people who had swapped from placebo to tafamidis, mortality benefits were likely to be underestimated. So, because of this, and because the 2\xa0extrapolation functions were similar in statistical and visual fit, it suggested it was appropriate to use the more optimistic of the two. The ERG noted that according to the Bayesian information criterion the generalised gamma extrapolation function used by the company was the worst fit. The committee concluded that modelling overall survival using generalised gamma extrapolation functions was not fully justified. It agreed to consider only the log‑normal extrapolation functions in its decision making.\n\n## The company's early diagnosis assumptions are not appropriate for decision making\n\nAfter technical engagement, the company provided analyses that used 3\xa0new assumptions about early ATTR-CM diagnosis. It assumed that introducing tafamidis:\n\nreduced the average age of starting treatment by 2.50\xa0years to 71.95\xa0years\n\navoided £20,000 of healthcare costs that would be incurred during the time people waited for a correct diagnosis\n\navoided anxiety and depression because of diagnosis delays.The committee recalled that there was not enough evidence provided to support the assumption that introducing tafamidis would reduce ATTR-CM diagnosis delays (see section\xa03.8). The ERG highlighted that it was unclear how the company had estimated that diagnosis delays could be reduced by 2.5\xa0years and how potential cost savings of £20,000 had been estimated. The company explained that 1\xa0in\xa03 people in the EAMS had an accurate diagnosis 2.5\xa0years earlier (within 6\xa0months) than the historical average (3\xa0years or more; see section\xa03.3). It noted that if other centres had access to the same tests used in the EAMS, diagnosis times of 6\xa0months or less could be replicated for all patients. The committee agreed it was unlikely that delays could be reduced by 2.5\xa0years for all patients and that it was difficult to predict how the diagnosis times might change in the future. It was also aware that reducing the average age of starting treatment by 2.5\xa0years had a modest effect on the cost-effectiveness results compared with the other early diagnosis assumptions. Also, if only a proportion of patients had a shorter time to diagnosis, then the effect on cost effectiveness would be small. The company also explained that the cost-saving estimate of £20,000 resulting from earlier diagnosis was calculated based on NAC data, which reported resource use during a 3‑year diagnosis delay. It acknowledged that empirical estimates for reduced hospital, primary care and imaging resource use could not be provided. But, it noted that the cost-saving assumption showed that earlier diagnosis of ATTR-CM could affect cost‑effectiveness estimates. The committee acknowledged that some of the costs incurred during diagnosis delays could be avoided. But, it agreed that because there was insufficient evidence to support the assumption that introducing tafamidis would reduce ATTR‑CM diagnosis delays, it was highly uncertain if any costs could be avoided. The company also derived an anxiety- and depression-related disutility value using EQ‑5D‑3L and highlighted that this disutility could be avoided if ATTR‑CM diagnosis delays were reduced. It acknowledged that not everyone would have depression, but the analysis showed the potential effect of earlier diagnosis on people's quality of life. The ERG considered that applying a quality-adjusted life year (QALY) gain for reduced anxiety or depression for all patients was not a reasonable approach because it was not supported by any evidence. The committee considered if being diagnosed with a serious cardiac condition could negatively affect a person's mental wellbeing and acknowledged it may change the way they view themselves, and how their families perceive them. The company explained that it had not investigated the effects of a diagnosis of ATTR-CM on psychological wellbeing. The committee agreed that there was insufficient evidence to support the assumption that introducing tafamidis would reduce ATTR-CM diagnosis delays (see section\xa03.8). It also agreed that it was highly uncertain whether any additional cost savings or quality-of-life benefits resulting from earlier diagnosis could be attributed to tafamidis. So, it concluded that the company's early diagnosis assumptions in the model were not appropriate for decision making because there was not enough evidence to support them.\n\n## Including drug wastage costs is appropriate\n\nAfter technical engagement, the ERG included potential tafamidis drug wastage in its estimate of costs. The committee considered if drug wastage would be substantial for tafamidis. The NHS England representative explained that they did not have any data on tafamidis wastage, so did not know whether it would be significant or not. The committee agreed with including drug wastage in the analysis and acknowledged that including it had little effect on the cost‑effectiveness estimates. So, the committee concluded that it was appropriate to include drug wastage costs in its preferred analysis because some wastage was likely to happen in clinical practice.\n\n# Utility values\n\n## NYHA health state utility values are appropriate for decision making\n\nThe company derived health state utility values using EQ‑5D‑3L data from the ATTR-ACT pivotal trial. The committee recalled that the company had also collected quality-of-life data using the KCCQ measure, which included function domains (see section 3\xa012). However, it agreed that the EQ‑5D‑3L data were more suitable for the economic model because they were in line with the reference case. The committee recalled its concerns about using health states based on NYHA classes in the model, but agreed that they could be considered because there was no available alternative (see section\xa03.14). The committee concluded that the company's health state utility values were appropriate for decision making.\n\n## Utility values should be adjusted for age after the observed trial period\n\nBefore technical engagement, the company's analysis did not adjust health state utility values to account for the effect of increasing age. The ERG highlighted that this meant utility values for tafamidis and best supportive care were better than for the age-equivalent general population. The clinical experts involved in technical engagement explained that it was not plausible that someone with ATTR-CM could have a better quality of life than someone of a similar age and sex from the general population. The company adjusted its utility values to take account of increasing age after the observed trial period in its revised analyses after technical engagement. The committee concluded that using age-adjusted utility values was appropriate.\n\n## Best supportive care utility values should be applied in the NYHA class\xa04 health state\n\nThe company estimated health state utility values separately for each NYHA class (see section\xa03.21) and treatment included in the model. It explained that different health state utility values between tafamidis and best supportive care may reflect differences in hospitalisations and adverse events associated with each treatment. The committee recalled that the NYHA classification system was unlikely to be sensitive to changes in ATTR-CM (see section\xa03.6). The ERG noted that the company modelled substantially different on- and off-treatment utility values in the NYHA class\xa04 health state. It also explained that estimates of NYHA class\xa04 utility values were based on very few observations. The company highlighted that the health state utility values were derived from EQ‑5D‑3L data from the ATTR-ACT pivotal trial and were the most appropriate data for the economic analysis. The ERG noted that in ATTR-ACT quality-of-life data were collected only during the on-treatment period, and that in the trial, most people stopped treatment before their disease progressed to NYHA class\xa04. The ERG explained that the estimated NYHA class\xa04 utility value for tafamidis could be affected by informative censoring, because the quality of life of anyone who stopped tafamidis in NYHA class\xa04 was not captured. To account for this, the ERG's analysis after technical engagement assumed that the estimated best supportive care utility value applied to everyone in the NYHA class\xa04 health state. After technical engagement the company accepted that it was appropriate to apply the best supportive care utility value in NYHA class\xa04 and it used this assumption in its revised analysis. The committee agreed that it had concerns about using treatment-dependent health state utility values from relatively few observations and the potential for informative censoring to bias these estimates. It concluded that the treatment-dependent utility values were reasonable in NYHA class\xa01 to 3, and that the best supportive care utility value should be applied in the NYHA class\xa04 health state.\n\n# Cost-effectiveness estimates\n\n## Tafamidis is not a cost-effective use of NHS resources\n\nThe company's preferred analysis estimated that the ICER for tafamidis compared with best supportive care, in the full population, was less than £30,000 per QALY gained (including the company's confidential commercial arrangement). It included the following assumptions:\n\na stopping treatment rule for tafamidis in NYHA health states 1, 2 and 3 (see section\xa03.16)\n\nusing a generalised gamma extrapolation function to model overall survival (see section\xa03.18)\n\na stopping treatment rule for tafamidis if disease progressed to NYHA class\xa04 (see section\xa03.15)\n\nan earlier treatment starting age and estimated cost savings and benefits associated with earlier diagnosis of ATTR-CM (see sections\xa03.8 and 3.19)\n\nhealth state utility values adjusted for age (see section\xa03.22)\n\ntreatment-independent health state utility values in NYHA\xa04 equal to best supportive care values (see section\xa03.23).The committee agreed that the company's analysis did not include all of its preferred assumptions. It noted that the ERG's preferred analysis was different from the company's preferred analysis, and more in line with the committee's preferred assumptions. Specifically, the committee agreed with the following changes in the ERG's analysis:\n\nassuming people in NYHA health states 1, 2 and 3 keep taking tafamidis and associated costs and treatment benefits continue after the observed trial period (see section\xa03.16)\n\nusing a log-normal extrapolation function to model overall survival (see section\xa03.18)\n\nassuming introducing tafamidis would not reduce diagnosis delays and excluding estimated benefits and cost savings associated with earlier diagnosis of ATTR-CM (see sections\xa03.8 and 3.19)\n\nincluding drug wastage in cost estimates (see section\xa03.20).These changes resulted in an ICER that was substantially above £30,000 per QALY gained. The committee recalled that it would consider the ERG's 2\xa0approaches to model treatment stopping in NYHA health states 1, 2 and 3 and that it was not appropriate to model a stopping rule based on the NYHA classification system (see sections\xa03.15 and 3.17). Using these assumptions in its preferred analysis increased the ICER even more. Considering all these factors, the committee's most plausible ICER for tafamidis compared with best supportive care, in the full population, was substantially above the range that NICE usually considers an acceptable use of NHS resources. It concluded that tafamidis was not a cost‑effective use of NHS resources for treating ATTR-CM.\n\n# Other factors\n\n## There are no equalities issues that can be addressed in the guidance\n\nThe most common transthyretin variants associated with hereditary ATTR-CM are Val122Ile, which is common in people of African and Caribbean family origin, and Thr60Ala, which is common in people with Irish ancestry. The committee acknowledged that ATTR-CM disproportionally affected people from certain ethnic groups, but agreed this was not something that could be addressed in its recommendation. A statement received at consultation noted that the recommendation would deny older people with ATTR-CM access to tafamidis, which could maintain their health and reduce morbidity, while those in the EAMS could have tafamidis. The committee was also aware that evidence suggested ATTR-CM prevalence in women may be underestimated, because women may be less likely to have the red flag symptoms that trigger referral. The committee considered that its recommendation did not disproportionately disadvantage women or certain age groups, and that access to tafamidis through the EAMS was not in the scope of their recommendation.\n\n## The benefits of tafamidis are captured in the economic model\n\nThe company considered that tafamidis is a breakthrough treatment for ATTR‑CM. It noted that it is a step change in managing the condition, and that it will benefit people with ATTR-CM and their carers. It also highlighted that it was the first treatment for ATTR-CM to reduce mortality and morbidity and reduce cardiovascular-related hospitalisations. It suggested that the high QALY gains seen in the cost-effectiveness analysis represented a major change in managing ATTR-CM. The clinical expert explained that new research had changed their understanding of the way that tafamidis treats ATTR-CM. The committee recalled that a recent publication had shown that disease stabilisation does not necessarily inhibit amyloid formation, so the mechanism underlying tafamidis' proposed benefit is unclear (see section\xa03.16). The committee acknowledged that there is an unmet need for an effective treatment for ATTR-CM, but considered that the relevant benefits of tafamidis were captured in the economic model.\n\n# Conclusion\n\n## Tafamidis is not recommended\n\nThe committee recognised that ATTR-CM is a debilitating and progressive condition which has a substantial effect on a person's quality of life (see sections\xa03.1 and 3.2). It noted that awareness of ATTR-CM was improving but getting a definitive diagnosis was complicated and can take a long time (see section\xa03.3). Without validated and objective measures for assessing ATTR-CM, identifying people who need treatment and those who are benefiting from treatment will continue to be a challenge (see section\xa03.6). It acknowledged that tafamidis was more effective than placebo in the outcomes assessed in the ATTR-ACT pivotal trial. It recalled that there was considerable uncertainty about the modelling of stopping tafamidis and if treatment effects continue after this (see sections\xa03.15 and 3.16). It also recalled that there was a high degree of uncertainty about whether introducing tafamidis would reduce diagnosis delays and result in any additional benefits or cost savings that could be attributed to tafamidis (see sections\xa03.8 and 3.19). All this considered, the committee's most plausible range of ICERs was substantially above the range that NICE usually considers an acceptable use of NHS resources (see section\xa03.24). So, the committee did not recommend using tafamidis in the NHS for treating ATTR-CM."}
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https://www.nice.org.uk/guidance/ta696
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Evidence-based recommendations on tafamidis (Vyndaqel) for treating transthyretin amyloidosis with cardiomyopathy in adults.
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9d91387547f1ec8e37ecb3ff48b82fe30332975a
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nice
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Andexanet alfa for reversing anticoagulation from apixaban or rivaroxaban
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Andexanet alfa for reversing anticoagulation from apixaban or rivaroxaban
Evidence-based recommendations on andexanet alfa (Ondexxya) for reversing anticoagulation form apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding.
# Recommendations
Andexanet alfa is recommended as an option for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding, only if:
the bleed is in the gastrointestinal tract, and
the company provides andexanet alfa according to the commercial arrangement.
Andexanet alfa is recommended only in research for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding in the skull (intracranial haemorrhage; ICH), in the form of an ongoing randomised trial mandated by the regulator.
Why the committee made these recommendations
Apixaban and rivaroxaban are anticoagulants used for preventing and treating thromboembolism (blood clots). They can increase the risk of major bleeding, which may be life-threatening. If someone has a major bleed the anticoagulation effects need to be reversed. Andexanet alfa aims to reverse the effects of apixaban and rivaroxaban, in case of uncontrolled or life-threatening bleeding.
There is no clinical trial evidence directly comparing andexanet alfa with existing treatments, including prothrombin complex concentrate. An indirect comparison suggests that andexanet alfa improves survival in people with gastrointestinal bleeding or ICH, but lowers survival for people with bleeds in other parts of the body. However, there are differences between the populations in the 2 studies, so the results of the indirect comparison are uncertain. There is no robust evidence that andexanet alfa reduces long-term disability in ICH.
Because of the limitations of the clinical evidence, the cost-effectiveness estimates for andexanet alfa are uncertain. They are likely to be within what NICE considers a cost-effective use of NHS resources for gastrointestinal bleeding, but not for ICH or bleeds in other parts of the body. Therefore, andexanet alfa for reversing anticoagulation is recommended for routine use only in gastrointestinal bleeding. It is recommended only in research in ICH.# Information about andexanet alfa
# Marketing authorisation indication
Andexanet alfa (Ondexxya, Alexion) has a conditional marketing authorisation for 'adult patients treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for andexanet alfa is £11,100 per 4-vial pack of 200 mg of powder for solution for infusion (excluding VAT, BNF online accessed March 2021). The average cost of a course of treatment at list price is £15,000 per patient.
The company has a commercial arrangement. This makes andexanet alfa available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Portola Pharmaceuticals, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
In March 2020, the appraisal committee decided not to recommend andexanet alfa within its marketing authorisation. In June 2020 and February 2021 the committee discussed the following issues, some of which were new issues that were not included in the first appraisal consultation document.
# Treatment pathway and clinical need
## Direct anticoagulants are associated with a serious risk of major bleeding
Direct anticoagulants such as apixaban and rivaroxaban are used for preventing and treating thromboembolism in conditions such as deep vein thrombosis and pulmonary embolism, and for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation. Although anticoagulants have a greater overall benefit than risk, major bleeding is a serious risk. People with a major bleed are at an increased risk of death and an increased risk of subsequent thrombotic events when anticoagulation is interrupted. The patient experts explained that thrombotic events can have a substantial physical and psychological effect on people's lives. Treatment for a thrombosis can affect employment, family planning, travel and social life. Also, many people fear having further blood clots. Anticoagulants therefore are of benefit to people, but they increase the risk of a major bleeding event. The committee concluded that direct anticoagulants are associated with a risk of major bleeding events.
## There is a clinical need for effective anticoagulation reversal agents
The patient experts explained that anticoagulation treatments are accepted by people because they are lifesaving, but there are concerns about safely managing anticoagulation if a major bleed happens. If bleeding is life-threatening then anticoagulation needs to be reversed. Treatment is challenging if there is no reversal agent and relies on treating symptoms until the effects of the anticoagulant stop, in line with the normal half-life of the drug. The clinical experts explained that established clinical management often includes prothrombin complex concentrate (PCC), which is used outside of its marketing authorisation to reverse a major bleed. However, there is limited clinical evidence to support its use. The patient experts explained that there is an unmet need for a safe reversal agent for direct factor Xa anticoagulants such as apixaban and rivaroxaban. The committee concluded that the availability of an effective reversal agent would be greatly valued by people and healthcare professionals.
## Clinical need is increasing because of changes in clinical practice
The patient experts explained that the recently published NICE guideline on venous thromboembolic diseases recommends offering apixaban or rivaroxaban as first choice for anticoagulation, including for people with cancer-associated thrombosis. Also, NHS England's clinical guide for managing anticoagulation services has been updated for the COVID-19 pandemic. This has resulted in more people starting or switching treatment to a direct oral anticoagulant. The patient experts explained that anxiety will be high because of COVID-19 and a reversal agent not being available would increase people's concerns. The committee concluded that because more people are having direct oral anticoagulants there is an increased need for a specific reversal agent.
# Most relevant population
## It is not appropriate to combine all bleed types for decision making
The clinical evidence came from ANNEXA-4, a single-arm trial of andexanet alfa in people taking a direct factor Xa inhibitor who had an acute major bleed. Initially, the company submitted results for 3 groups: the whole trial population, a cohort of people with intracranial haemorrhage (ICH) and severe gastrointestinal bleeds, and a cohort of people with ICH alone. After technical engagement, the company also provided results for a cohort of people with severe gastrointestinal bleeds alone. The clinical experts explained that different types of bleeds should be considered separately because the nature of the bleeds, their treatment and outcomes vary. The clinical experts explained that most gastrointestinal bleeds can be managed using measures such as endoscopy, embolisation or surgery. The committee noted that ICH may happen within the brain tissue (intracerebral) or outside the brain (subdural or subarachnoid) and can lead to mortality and long-term disability. They differ from gastrointestinal bleeds in that they happen into a closed rigid structure, the skull, rather than into an air-containing space like the gastrointestinal tract. Treatment options are very limited for ICH, particularly if the bleed is in the brain tissue where damage happens at the time of the bleed and surgery is not usually feasible. The clinical experts explained that outcomes and risk of further bleeding after initial treatment varies depending on the location and cause of an ICH. The effect of bleeding at sites of the body other than intracranial or the gastrointestinal tract would vary considerably, depending on where the bleed happened. For example, a bleed into the eye could lead to blindness in that eye. The committee concluded that different types of bleeds should be considered separately for decision making.
# Clinical evidence
## The evidence on clinical events is limited to 30-day mortality
The committee noted that the 2 primary outcomes in the trial were both haematological: change in 'anti-factor Xa activity' and haemostatic efficacy. The only outcome related to clinical events was the safety end point of 30-day mortality. However, the trial excluded all patients with an expected lifespan of less than 1 month. For ICH there were additional exclusions related to larger bleeds (volume over 60 ml) and reduced consciousness (a Glasgow Coma Score below 7). Therefore, the generalisability of the 30-day mortality data from ANNEXA-4 to routine NHS practice is questionable, particularly for ICH. In their response to technical engagement, the clinical experts also questioned the definitions of haemostatic efficacy in relation to intracerebral haemorrhage (ICH). A poor outcome was defined in ANNEXA-4 as more than 35% increase in haematoma volume. The experts considered that haemostatic efficacy as defined in the trial could not be considered directly predictive of clinical outcomes. The clinical expert explained that ICH types are heterogenous and have different management strategies and outcomes. They noted that outcomes after ICH are related to bleed volume. A large bleed volume at first presentation is a poor prognostic sign, and patients with large bleeds were excluded from ANNEXA-4. At the first committee meeting, the clinical experts stated that not all bleeds increase in size. However, at the third committee meeting, 1 expert stated that an increase in bleed size would be likely for people taking an anticoagulant. The committee noted that no data on ICH growth was available for people on anticoagulants not treated with andexanet alfa. The clinical experts agreed that it is difficult to say that an increase of less than 35% for ICH can be considered a positive outcome or good haemostatic efficacy as defined in the trial. At the second consultation, the company submitted the results of a Delphi panel survey of clinical experts that supported the assumption that limiting haematoma expansion would improve morbidity and quality-of-life outcomes. The company noted that this was in line with results from a meta-analysis from Davis et al. (2006). However, the committee agreed that the Delphi panel represented opinion rather than offering robust evidence on key areas of uncertainty, and that the results should be interpreted with caution. The committee concluded that the clinical evidence available for andexanet alfa was limited to only 30-day mortality in a trial that had several potentially relevant exclusion criteria.
## There is no evidence directly comparing andexanet alfa with established clinical management and the indirect comparison has limitations
Because ANNEXA-4 is a single-arm trial there is no direct evidence for the efficacy of andexanet alfa compared with other treatments, which added to the uncertainty about its benefit in clinical practice. The company used the ORANGE study for the comparison with established clinical management. ORANGE was a UK observational study in people taking anticoagulants who were admitted to hospital with a major bleed. The company used a subgroup from the ORANGE study who had had PCC, which the company considered included people with severe enough bleeds to have andexanet alpha in clinical practice. These data were used in an indirect treatment comparison with andexanet alpha. ORANGE did not exclude patients with an expected survival less than 1 month, or those with the most severe intracranial bleeds, that is an intracerebral bleed volume of more than 60 ml or a Glasgow Coma Score lower than 7, which were exclusion criteria for ANNEXA-4. The committee noted that this could affect the comparability of results for 30-day mortality, particularly in the case of intracerebral bleeds for which there were added exclusion criteria. The company explained that the proportion of patients excluded based on the 30-day survival criterion was extremely low. However, the committee noted that some patients may not have been screened for inclusion if the clinicians considered that they were too ill to meet the criteria or the intracerebral bleed was too severe. The clinical expert pointed out that every patient with a life-threatening gastrointestinal bleed should have been screened for inclusion unless they were on a known end-of-life pathway. The committee concluded that the 30-day mortality evidence for andexanet alfa compared with established clinical management using PCC had limitations.
## The indirect treatment comparison predicts a reduced 30-day mortality with andexanet alfa compared with established clinical management including PCC, but the results are uncertain
The company did a propensity score matching analysis to compare 30-day mortality rates from ANNEXA-4 and ORANGE. The results showed a reduced 30-day mortality with andexanet alfa compared with PCC for the gastrointestinal cohort and the ICH cohort but not for the 'other major bleeds' cohort (pericardial, retroperitoneal, intraspinal and intraocular bleeds), where the 30-day mortality was higher. The committee understood that important prognostic factors such as severity and volume of the bleed could not be included as covariates, because these were not collected in ORANGE. It also noted that 30-day mortality was a key driver of the economic model. The company explained that only patients from ORANGE who had PCC were matched to patients in ANNEXA-4. The company assumed that patients who had PCC in ORANGE were a good proxy for those with more severe bleeds, because PCC is used off-label and would be reserved for more severely affected patients. The clinical experts explained that severity and volume of bleeds are the primary prognostic factors for bleed-related mortality. The committee considered that without key prognostic factors accounted for, the results of the propensity score matching analysis were uncertain. The committee also noted that for gastrointestinal bleeds, no comparative data were available on what other treatments people had in the 2 studies, particularly endoscopic therapy. The clinical experts explained that in the absence of a randomised controlled trial it was very difficult to reach any conclusion about the clinical benefit of andexanet alfa compared with established management, including PCC. The committee considered that the propensity score matching analysis predicted a reduced 30-day mortality for the gastrointestinal cohort and the ICH cohort, but the results were uncertain.
## Andexanet alfa is likely to reduce 30-day mortality for people with gastrointestinal bleeds
The committee had concerns about the effect of andexanet alfa on 30-day mortality for gastrointestinal bleeds, because the ANNEXA-4 trial excluded patients with an expected survival of less than 1 month. In its response to the first appraisal consultation document, the company submitted an analysis of in-hospital mortality results from a US multicentre real-world study of patients who had andexanet alfa within its licensed indication. The study did not exclude patients with an expected survival of less than 1 month, unlike ANNEXA-4. However, the criteria for who had treatment in the study and what other treatments the patients had were not clear. The committee noted that in-hospital mortality in the real-world study was lower than in ANNEXA-4, even though an exclusion criterion based on expected survival was not applied. The committee considered that this potentially supported the generalisability of the trial outcomes to a broader population. The committee also considered the Rockall score submitted by the company for patients with gastrointestinal bleeds in ANNEXA-4. The clinical expert explained that the Rockall score is a validated predictor of mortality. In ANNEXA-4, patients had a lower mortality rate than predicted by the Rockall score, suggesting that andexanet alfa reduces mortality. The clinical expert noted that this data increased confidence about the benefit of andexanet alfa. The committee noted that the Rockall score was not developed in an anticoagulated population. However, it considered that the Rockall score submitted by the company was broadly supportive of andexanet alfa reducing 30-day mortality in patients with gastrointestinal bleeds. Nevertheless, in the absence of any direct evidence, there were still some uncertainties around the efficacy of andexanet alfa in gastrointestinal bleeds. This is particularly because other treatments are available and andexanet alfa itself carries a risk of thrombosis. The clinical expert noted that andexanet alfa would be best used as part of a major gastrointestinal bleed protocol, in line with its use in ANNEXA-4. The committee concluded that andexanet alfa is likely to reduce 30-day mortality for people with life-threatening or uncontrolled gastrointestinal bleeds.
## The extent that andexanet alfa reduces mortality in ICH is unclear
The indirect treatment comparison predicted that andexanet alfa reduces mortality in people with ICH. The committee considered this to be plausible but recalled its concern that the 30-day mortality data for andexanet alfa came from a trial that excluded people with a predicted life expectancy of less than 30 days, and also excluded people with the largest bleed volumes. The Delphi panel reached consensus that for intracerebral bleeds, the population that would be offered treatment should be similar to the clinical trial population. This means that some people with major intracranial bleeds would not be treated in clinical practice, based on a projected life expectancy, bleed volume and clinical judgements about their prognosis, even though the marketing authorisation did not exclude these people. However, the clinical experts emphasised the difficulty in deciding when not to use andexanet alfa in clinical practice, because treatment should be given as soon as possible, and the decision may fall to relatively inexperienced doctors. For this reason, it is likely that all people would be treated in the NHS, rather than the selected group in ANNEXA-4 which excluded people with a life expectancy under 1 month, larger bleed volumes and a Glasgow Coma Score below 7. The committee noted that, by excluding these people, a lower 30-day mortality would have been expected in ANNEXA-4 compared with the population seen in clinical practice. Therefore, the generalisability of the ANNEXA-4 results, and the size of any mortality benefit for andexanet alfa when used in routine clinical practice is unclear. The committee concluded that it is uncertain whether or to what extent andexanet alfa would reduce mortality in ICH.
## The benefit of andexanet alfa on disability after an ICH is unproven
The company assumed that andexanet alfa would reduce the severity of long-term disability in people who had had an ICH, compared with conventional treatment including PCC. This assumption had a large effect on the incremental cost-effectiveness ratio (ICER). However, the committee was concerned by comments received at consultation from the British Association of Stroke Physicians, stating that it was unclear if andexanet alfa improves 'very disabled survival in people who would otherwise die, or is improving the number of people with excellent recovery'. This uncertainty would make treatment decisions difficult and might involve discussions with relatives about whether to use andexanet alfa for ICH. The British Association of Stroke Physicians commented at consultation that it was 'difficult to estimate any effect of this treatment on quality of life or recovery as the size of any beneficial treatment effect is unclear'. Disability after ICH is assessed using the modified Rankin scale (mRS) score, and in the economic model these affected mortality risk, costs and utilities. The company used 2 different sources for mRS scores. For andexanet alfa, it used data from ANNEXA‑4. For established management with PCC it used data from Øie et al. (2018), a study that included patients with ICH only and excluded those with other intracranial bleeds. The ERG and the clinical experts explained that ICH is the most severe type of ICH and therefore the company's comparison potentially overestimated the severity of disability and mRS scores for established management, including PCC. The committee also recalled that ANNEXA-4 excluded people with the worst prognoses. The committee noted that there was no direct evidence that people would have better mRS scores and less disability after andexanet alfa than other treatments including PCC, and that the company's assumption was based on a naive comparison of data from ANNEXA-4 and Øie et al. The clinical experts noted that without evidence from a study, it was impossible to predict a benefit in long-term disability. One clinical expert explained that around 80% of people who survive an ICH are on the dependent scale of mRS (scores of 3 or higher) and that evidence would need to show a clear shift in mRS scores to prove an improvement in disability. Another clinical expert stated that for an effective intervention that improves mortality, all people with an ICH would be expected to have an improved level of disability on their baseline. Consensus statements from the Delphi panel also supported an improvement in long-term morbidity after treatment with andexanet alfa. However the committee recalled its earlier conclusions that any mortality benefit with andexanet alfa was uncertain and that the Delphi panel results were based on clinical assumptions. The committee concluded that a benefit from andexanet alfa on long-term disability is unproven.
## Additional data collection is needed on neurological outcomes compared with established clinical management
The committee noted that the marketing authorisation for andexanet alfa was on a conditional basis, with a need for a randomised controlled trial being completed in people with ICH to further explore the benefits and risks in this indication. The committee noted that the clinical outcome in this randomised controlled trial is neurological disability measured up to 24 hours from baseline, comparing andexanet alfa with standard care. The committee recognised that data from the randomised controlled trial will provide stronger evidence of haemostatic efficacy and short-term mortality and neurological outcomes, and it has been mandated by the regulator. It acknowledged that the trial will not resolve the uncertainty about long-term morbidity or mortality. However, it will address the key clinical question of whether having had the infusion, people were more likely to be alive and in a better neurological state than if they had not had it. The committee concluded that additional data collection is needed on neurological outcomes compared with established clinical management.
## The evidence in 'other major bleeds' is too unreliable for decision making
The committee noted that the indirect treatment comparison results for 'other major bleeds' showed that 30-day mortality was worse with andexanet alfa than established care in combination with PCC. The committee appreciated that the analysis was done with a very small sample size, however it considered it would be unreasonable to ignore these results. The company stated that it expected andexanet alfa treatment to be beneficial in this population. However, the committee concluded that andexanet alfa reducing mortality in 'other major bleeds' had not been shown or quantified.
# Cost effectiveness
## The company's economic model is suitable for decision making
The company submitted a decision tree followed by a Markov model to estimate the cost effectiveness of andexanet alfa compared with PCC. The committee considered that the model was suitable for decision making.
## The company's assumptions about 'other major bleeds' are not well justified
The propensity score matching analysis was based on a small number of patients for bleeds classified as 'other major bleeds' (pericardial, retroperitoneal, intraspinal and intraocular bleeds). The analysis results for these bleeds did not favour andexanet alfa compared with established clinical management with PCC, so the company considered it was counterintuitive and several assumptions were made to model these bleeds. The company assumed that andexanet alfa would lead to a 25% relative reduction in mortality for pericardial and retroperitoneal bleeds, and it set the mortality to 0 for intraspinal and intraocular bleeds. The company also assumed that andexanet alfa would reduce paralysis and blindness by 25% after intraspinal and intraocular bleeds, which reduced the long-term management costs and improved the long-term utilities. These assumptions were based on clinical opinion only. The clinical experts explained that the evidence was too scarce to make assumptions of 25% relative reduction in mortality, paralysis and blindness and that the ERG's assumption of 0% relative reduction was more reasonable in the absence of robust evidence. At consultation, the company agreed that its assumptions were uncertain because of the limited evidence available. The committee concluded that the company's assumptions were not supported by evidence.
## The long-term outcomes and utilities after ICH are highly uncertain
The committee noted that there was no direct evidence that people who had an ICH had better long-term outcomes with andexanet alfa than if they had PCC (see section 3.10). Differences in mRS scores affected the long-term mortality risk, costs and utilities in the model. The long-term utility value for people who had an ICH in the established clinical management arm (using PCC as a proxy) in the company's model was 0.61. This was obtained from a 3-month post-acute care utility value for people who had an ICH, which was used in NICE's guidance on apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. The company calculated that andexanet alfa increased the long-term utility of people who had an ICH by 0.11 compared with PCC, based on the difference in mRS scores between ANNEXA-4 and Øie et al. (2018). This resulted in a long-term utility of 0.72 after an ICH for people who had andexanet alfa. The ERG was concerned that a utility of 0.72 is not plausible because it is only 0.01 lower than the UK general population aged 75 and over. Also, the differences in long-term outcomes were driven by the naive comparison of mRS scores from ANNEXA-4 and Øie et al. The ERG's preferred scenario was to use the mRS scores from Øie et al. only in people who had an ICH in ANNEXA-4, or alternatively to use the ANNEXA-4 mRS scores for both treatments (assuming no benefit in mRS scores). In its updated base case, the ERG's preferred scenario was to assume no benefit in morbidity and to use the same mRS scores from the trial. At the second consultation, the company provided scenarios with varying utility benefits for andexanet alfa compared with PCC. It presented results using baseline utility values mapped from ANNEXA-4 and results using baseline utility values from NICE's guidance on apixaban. The committee recalled that the Delphi panel consensus supported an improvement in morbidity after treatment with andexanet alfa. However, it was concerned that any increase in benefit was uncertain, as was the size of the benefit. It noted the company had included a utility benefit in its base case that was higher than any predicted by individual experts or in the consensus statement from the Delphi panel. One clinical expert advised that a specific recommendation should be made for people having surgery, in which there is an unmet need. The committee recognised that theoretically a specific reversal agent would be useful. But it agreed there was as yet no evidence that in the situation of surgery andexanet alfa would be better than established clinical management including PCC, so it could not justify a specific recommendation for this situation. The committee concluded that differences in the long-term outcomes and utilities for people after an ICH, depending on the treatment they had, are highly uncertain.
# Cost-effectiveness estimates
## Andexanet alfa is likely to be cost effective compared with established clinical management including PCC in gastrointestinal bleeds
The committee considered the company's and the ERG's ICERs for the gastrointestinal cohort, which were very similar. Although associated with some uncertainty, the ICERs from the company and ERG were at a level that included a margin to accommodate uncertainty about mortality benefit. The committee concluded that the ICERs for the gastrointestinal cohort are likely to be within what NICE considers a cost-effective use of NHS resources.
## Andexanet alfa has not been shown to be cost effective compared with established clinical management including PCC in ICH
The committee noted that the extent of the clinical benefit for ICH was uncertain. Therefore, the most plausible ICER for ICH was uncertain. One company scenario included the mortality benefit from the indirect comparison and the modal utility benefit predicted by the Delphi panel in their individual responses. This was within the range NICE normally considers a cost-effective use of NHS resources. However, the committee was concerned that the 30-day mortality benefit from andexanet alpha in this population is highly uncertain because ANNEXA-4 excluded both those with a life expectancy of less than 30 days, and those with the most severe intracranial bleeds, and clinical experts explained that these people would not be excluded from treatment in an emergency situation in clinical practice. The committee also had concerns about the assumption of a benefit from andexanet alfa on long-term disability. The committee further considered the ERG's updated base case and scenarios modelling different utility benefits for andexanet alfa for the ICH cohort, all of which used baseline utility values mapped from ANNEXA-4, which the committee considered was appropriate, because it came directly from the trial in question. The ICERs which all included the 30-day mortality benefit from the indirect comparison, either with no utility benefit, as preferred by the ERG, or the modal benefit as suggested by the Delphi panel, were above what NICE normally considers a cost-effective use of NHS resources. The committee recalled that the extent to which andexanet alfa reduces mortality is uncertain and that reducing the 30-day mortality benefit for andexanet alfa compared with established clinical management including PCC would further increase the ICER. Therefore, the committee was not confident that any of the ICERs for ICH were robust, and those presented may well be underestimates. It recognised the need for an effective reversal agent for direct factor Xa inhibitors, such as apixaban and rivaroxaban, in people with uncontrolled or life-threatening ICH. However, it concluded that andexanet alfa had not been shown to be a cost-effective use of NHS resources for ICH. Therefore it could not recommend it for routine use in the NHS, pending further research as mandated by the regulator.
## Andexanet alfa has not been shown to be cost effective compared with established clinical management for 'other major bleeds'
The committee noted that the indirect treatment comparison for 'other major bleeds' showed that mortality was worse with andexanet alfa than PCC. Also, the company's assumptions on a potential morbidity benefit were not supported by evidence. Therefore, the committee considered that the ICERs for 'other major bleeds' were very uncertain and that andexanet alfa had not been shown to be a cost-effective use of NHS resources for 'other major bleeds'.
# Other considerations
## Equalities
The committee noted an equality concern. Some people do not accept blood products, so would be unable to have PCC as part of their standard care. The committee noted that PCC is not an established treatment for reversing anticoagulation with apixaban or rivaroxaban and is used outside of its marketing authorisation. The committee was aware that people who would not be able to have PCC would have alternative clinical management. In the ORANGE study, 39% of patients had PCC, 41% had a blood transfusion and 28% had tranexamic acid. It noted that no data had been presented that compared established clinical management outcomes with and without blood products. The committee noted that data from the ongoing randomised controlled trial might reduce this uncertainty in ICH, because it compares andexanet alfa with standard care, which is not limited to PCC. However, the committee concluded that the effectiveness of andexanet alfa in ICH and other bleeds was still highly uncertain for people who could and could not have blood products. Therefore, there was no need to alter its recommendation. During the second consultation, stakeholders and clinical experts noted a further equality concern that there would be national variation in access to andexanet alfa if recommended only in research. However, the committee understood that any variation in access is governed by entry to a randomised controlled trial which had been mandated by the regulator. It concluded that the ability to take part in this research was not an issue that needed its recommendation to be altered.
# Conclusion
## Andexanet alfa is recommended for reversing anticoagulation in life‑threatening or uncontrolled bleeding in gastrointestinal bleeds
Andexanet alfa is likely to reduce 30-day mortality for people with gastrointestinal bleeds. Despite the uncertainty, the committee concluded that the ICER for the gastrointestinal cohort is likely to be within what NICE considers a cost-effective use of NHS resources. Therefore, it concluded that andexanet alfa is recommended in gastrointestinal bleeds as defined in the ANNEXA-4 trial and used as part of a major gastrointestinal bleed protocol.
## Andexanet alfa is recommended only in research for reversing anticoagulation in life-threatening or uncontrolled bleeding in ICH bleeds
The extent of benefits in terms of mortality and long-term disability from andexanet alfa in ICH are unclear and the committee was not confident that the cost-effectiveness results for ICH were robust. There is a need for an effective reversal agent for direct factor Xa inhibitors, such as apixaban and rivaroxaban, in people with uncontrolled or life-threatening bleeding in ICH. However, the committee was not convinced that andexanet alfa had been shown to be a cost-effective use of NHS resources in ICH. Therefore, andexanet alfa should be used only in research in ICH as part of the trial mandated by the regulator.
## Andexanet alfa is not recommended for reversing anticoagulation in life-threatening or uncontrolled bleeding in 'other major bleeds'
The potential benefits of andexanet alfa in the 'other major bleeds' cohort were not supported by evidence and the cost-effectiveness estimates were very uncertain. Therefore, andexanet alfa is not recommended for reversing anticoagulation in life-threatening or uncontrolled bleeding in 'other major bleeds'.# Recommendations for research
The committee noted an ongoing randomised controlled trial of the effectiveness of andexanet alfa compared with standard care in people with intracranial haemorrhage. The main outcomes of interest are haemostatic efficacy and short-term mortality and neurological outcomes.
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{'Recommendations': 'Andexanet alfa is recommended as an option for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding, only if:\n\nthe bleed is in the gastrointestinal tract, and\n\nthe company provides andexanet alfa according to the commercial arrangement.\n\nAndexanet alfa is recommended only in research for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding in the skull (intracranial haemorrhage; ICH), in the form of an ongoing randomised trial mandated by the regulator.\n\nWhy the committee made these recommendations\n\nApixaban and rivaroxaban are anticoagulants used for preventing and treating thromboembolism (blood clots). They can increase the risk of major bleeding, which may be life-threatening. If someone has a major bleed the anticoagulation effects need to be reversed. Andexanet alfa aims to reverse the effects of apixaban and rivaroxaban, in case of uncontrolled or life-threatening bleeding.\n\nThere is no clinical trial evidence directly comparing andexanet alfa with existing treatments, including prothrombin complex concentrate. An indirect comparison suggests that andexanet alfa improves survival in people with gastrointestinal bleeding or ICH, but lowers survival for people with bleeds in other parts of the body. However, there are differences between the populations in the 2\xa0studies, so the results of the indirect comparison are uncertain. There is no robust evidence that andexanet alfa reduces long-term disability in ICH.\n\nBecause of the limitations of the clinical evidence, the cost-effectiveness estimates for andexanet alfa are uncertain. They are likely to be within what NICE considers a cost-effective use of NHS resources for gastrointestinal bleeding, but not for ICH or bleeds in other parts of the body. Therefore, andexanet alfa for reversing anticoagulation is recommended for routine use only in gastrointestinal bleeding. It is recommended only in research in ICH.', 'Information about andexanet alfa': "# Marketing authorisation indication\n\nAndexanet alfa (Ondexxya, Alexion) has a conditional marketing authorisation for 'adult patients treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for andexanet alfa is £11,100 per 4-vial pack of 200\xa0mg of powder for solution for infusion (excluding VAT, BNF online accessed March 2021). The average cost of a course of treatment at list price is £15,000 per patient.\n\nThe company has a commercial arrangement. This makes andexanet alfa available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Portola Pharmaceuticals, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nIn March\xa02020, the appraisal committee decided not to recommend andexanet alfa within its marketing authorisation. In June\xa02020 and February\xa02021 the committee discussed the following issues, some of which were new issues that were not included in the first appraisal consultation document.\n\n# Treatment pathway and clinical need\n\n## Direct anticoagulants are associated with a serious risk of major bleeding\n\nDirect anticoagulants such as apixaban and rivaroxaban are used for preventing and treating thromboembolism in conditions such as deep vein thrombosis and pulmonary embolism, and for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation. Although anticoagulants have a greater overall benefit than risk, major bleeding is a serious risk. People with a major bleed are at an increased risk of death and an increased risk of subsequent thrombotic events when anticoagulation is interrupted. The patient experts explained that thrombotic events can have a substantial physical and psychological effect on people's lives. Treatment for a thrombosis can affect employment, family planning, travel and social life. Also, many people fear having further blood clots. Anticoagulants therefore are of benefit to people, but they increase the risk of a major bleeding event. The committee concluded that direct anticoagulants are associated with a risk of major bleeding events.\n\n## There is a clinical need for effective anticoagulation reversal agents\n\nThe patient experts explained that anticoagulation treatments are accepted by people because they are lifesaving, but there are concerns about safely managing anticoagulation if a major bleed happens. If bleeding is life-threatening then anticoagulation needs to be reversed. Treatment is challenging if there is no reversal agent and relies on treating symptoms until the effects of the anticoagulant stop, in line with the normal half-life of the drug. The clinical experts explained that established clinical management often includes prothrombin complex concentrate (PCC), which is used outside of its marketing authorisation to reverse a major bleed. However, there is limited clinical evidence to support its use. The patient experts explained that there is an unmet need for a safe reversal agent for direct factor Xa anticoagulants such as apixaban and rivaroxaban. The committee concluded that the availability of an effective reversal agent would be greatly valued by people and healthcare professionals.\n\n## Clinical need is increasing because of changes in clinical practice\n\nThe patient experts explained that the recently published NICE guideline on venous thromboembolic diseases recommends offering apixaban or rivaroxaban as first choice for anticoagulation, including for people with cancer-associated thrombosis. Also, NHS England's clinical guide for managing anticoagulation services has been updated for the COVID-19 pandemic. This has resulted in more people starting or switching treatment to a direct oral anticoagulant. The patient experts explained that anxiety will be high because of COVID-19 and a reversal agent not being available would increase people's concerns. The committee concluded that because more people are having direct oral anticoagulants there is an increased need for a specific reversal agent.\n\n# Most relevant population\n\n## It is not appropriate to combine all bleed types for decision making\n\nThe clinical evidence came from ANNEXA-4, a single-arm trial of andexanet alfa in people taking a direct factor Xa inhibitor who had an acute major bleed. Initially, the company submitted results for 3\xa0groups: the whole trial population, a cohort of people with intracranial haemorrhage (ICH) and severe gastrointestinal bleeds, and a cohort of people with ICH alone. After technical engagement, the company also provided results for a cohort of people with severe gastrointestinal bleeds alone. The clinical experts explained that different types of bleeds should be considered separately because the nature of the bleeds, their treatment and outcomes vary. The clinical experts explained that most gastrointestinal bleeds can be managed using measures such as endoscopy, embolisation or surgery. The committee noted that ICH may happen within the brain tissue (intracerebral) or outside the brain (subdural or subarachnoid) and can lead to mortality and long-term disability. They differ from gastrointestinal bleeds in that they happen into a closed rigid structure, the skull, rather than into an air-containing space like the gastrointestinal tract. Treatment options are very limited for ICH, particularly if the bleed is in the brain tissue where damage happens at the time of the bleed and surgery is not usually feasible. The clinical experts explained that outcomes and risk of further bleeding after initial treatment varies depending on the location and cause of an ICH. The effect of bleeding at sites of the body other than intracranial or the gastrointestinal tract would vary considerably, depending on where the bleed happened. For example, a bleed into the eye could lead to blindness in that eye. The committee concluded that different types of bleeds should be considered separately for decision making.\n\n# Clinical evidence\n\n## The evidence on clinical events is limited to 30-day mortality\n\nThe committee noted that the 2\xa0primary outcomes in the trial were both haematological: change in 'anti-factor\xa0Xa activity' and haemostatic efficacy. The only outcome related to clinical events was the safety end point of 30-day mortality. However, the trial excluded all patients with an expected lifespan of less than 1\xa0month. For ICH there were additional exclusions related to larger bleeds (volume over 60\xa0ml) and reduced consciousness (a Glasgow Coma Score below 7). Therefore, the generalisability of the 30-day mortality data from ANNEXA-4 to routine NHS practice is questionable, particularly for ICH. In their response to technical engagement, the clinical experts also questioned the definitions of haemostatic efficacy in relation to intracerebral haemorrhage (ICH). A poor outcome was defined in ANNEXA-4 as more than 35% increase in haematoma volume. The experts considered that haemostatic efficacy as defined in the trial could not be considered directly predictive of clinical outcomes. The clinical expert explained that ICH types are heterogenous and have different management strategies and outcomes. They noted that outcomes after ICH are related to bleed volume. A large bleed volume at first presentation is a poor prognostic sign, and patients with large bleeds were excluded from ANNEXA-4. At the first committee meeting, the clinical experts stated that not all bleeds increase in size. However, at the third committee meeting, 1\xa0expert stated that an increase in bleed size would be likely for people taking an anticoagulant. The committee noted that no data on ICH growth was available for people on anticoagulants not treated with andexanet alfa. The clinical experts agreed that it is difficult to say that an increase of less than 35% for ICH can be considered a positive outcome or good haemostatic efficacy as defined in the trial. At the second consultation, the company submitted the results of a Delphi panel survey of clinical experts that supported the assumption that limiting haematoma expansion would improve morbidity and quality-of-life outcomes. The company noted that this was in line with results from a meta-analysis from Davis et al. (2006). However, the committee agreed that the Delphi panel represented opinion rather than offering robust evidence on key areas of uncertainty, and that the results should be interpreted with caution. The committee concluded that the clinical evidence available for andexanet alfa was limited to only 30-day mortality in a trial that had several potentially relevant exclusion criteria.\n\n## There is no evidence directly comparing andexanet alfa with established clinical management and the indirect comparison has limitations\n\nBecause ANNEXA-4 is a single-arm trial there is no direct evidence for the efficacy of andexanet alfa compared with other treatments, which added to the uncertainty about its benefit in clinical practice. The company used the ORANGE study for the comparison with established clinical management. ORANGE was a UK observational study in people taking anticoagulants who were admitted to hospital with a major bleed. The company used a subgroup from the ORANGE study who had had PCC, which the company considered included people with severe enough bleeds to have andexanet alpha in clinical practice. These data were used in an indirect treatment comparison with andexanet alpha. ORANGE did not exclude patients with an expected survival less than 1\xa0month, or those with the most severe intracranial bleeds, that is an intracerebral bleed volume of more than 60\xa0ml or a Glasgow Coma Score lower than 7, which were exclusion criteria for ANNEXA-4. The committee noted that this could affect the comparability of results for 30-day mortality, particularly in the case of intracerebral bleeds for which there were added exclusion criteria. The company explained that the proportion of patients excluded based on the 30-day survival criterion was extremely low. However, the committee noted that some patients may not have been screened for inclusion if the clinicians considered that they were too ill to meet the criteria or the intracerebral bleed was too severe. The clinical expert pointed out that every patient with a life-threatening gastrointestinal bleed should have been screened for inclusion unless they were on a known end-of-life pathway. The committee concluded that the 30-day mortality evidence for andexanet alfa compared with established clinical management using PCC had limitations.\n\n## The indirect treatment comparison predicts a reduced 30-day mortality with andexanet alfa compared with established clinical management including PCC, but the results are uncertain\n\nThe company did a propensity score matching analysis to compare 30-day mortality rates from ANNEXA-4 and ORANGE. The results showed a reduced 30-day mortality with andexanet alfa compared with PCC for the gastrointestinal cohort and the ICH cohort but not for the 'other major bleeds' cohort (pericardial, retroperitoneal, intraspinal and intraocular bleeds), where the 30-day mortality was higher. The committee understood that important prognostic factors such as severity and volume of the bleed could not be included as covariates, because these were not collected in ORANGE. It also noted that 30-day mortality was a key driver of the economic model. The company explained that only patients from ORANGE who had PCC were matched to patients in ANNEXA-4. The company assumed that patients who had PCC in ORANGE were a good proxy for those with more severe bleeds, because PCC is used off-label and would be reserved for more severely affected patients. The clinical experts explained that severity and volume of bleeds are the primary prognostic factors for bleed-related mortality. The committee considered that without key prognostic factors accounted for, the results of the propensity score matching analysis were uncertain. The committee also noted that for gastrointestinal bleeds, no comparative data were available on what other treatments people had in the 2\xa0studies, particularly endoscopic therapy. The clinical experts explained that in the absence of a randomised controlled trial it was very difficult to reach any conclusion about the clinical benefit of andexanet alfa compared with established management, including PCC. The committee considered that the propensity score matching analysis predicted a reduced 30-day mortality for the gastrointestinal cohort and the ICH cohort, but the results were uncertain.\n\n## Andexanet alfa is likely to reduce 30-day mortality for people with gastrointestinal bleeds\n\nThe committee had concerns about the effect of andexanet alfa on 30-day mortality for gastrointestinal bleeds, because the ANNEXA-4 trial excluded patients with an expected survival of less than 1\xa0month. In its response to the first appraisal consultation document, the company submitted an analysis of in-hospital mortality results from a US multicentre real-world study of patients who had andexanet alfa within its licensed indication. The study did not exclude patients with an expected survival of less than 1\xa0month, unlike ANNEXA-4. However, the criteria for who had treatment in the study and what other treatments the patients had were not clear. The committee noted that in-hospital mortality in the real-world study was lower than in ANNEXA-4, even though an exclusion criterion based on expected survival was not applied. The committee considered that this potentially supported the generalisability of the trial outcomes to a broader population. The committee also considered the Rockall score submitted by the company for patients with gastrointestinal bleeds in ANNEXA-4. The clinical expert explained that the Rockall score is a validated predictor of mortality. In ANNEXA-4, patients had a lower mortality rate than predicted by the Rockall score, suggesting that andexanet alfa reduces mortality. The clinical expert noted that this data increased confidence about the benefit of andexanet alfa. The committee noted that the Rockall score was not developed in an anticoagulated population. However, it considered that the Rockall score submitted by the company was broadly supportive of andexanet alfa reducing 30-day mortality in patients with gastrointestinal bleeds. Nevertheless, in the absence of any direct evidence, there were still some uncertainties around the efficacy of andexanet alfa in gastrointestinal bleeds. This is particularly because other treatments are available and andexanet alfa itself carries a risk of thrombosis. The clinical expert noted that andexanet alfa would be best used as part of a major gastrointestinal bleed protocol, in line with its use in ANNEXA-4. The committee concluded that andexanet alfa is likely to reduce 30-day mortality for people with life-threatening or uncontrolled gastrointestinal bleeds.\n\n## The extent that andexanet alfa reduces mortality in ICH is unclear\n\nThe indirect treatment comparison predicted that andexanet alfa reduces mortality in people with ICH. The committee considered this to be plausible but recalled its concern that the 30-day mortality data for andexanet alfa came from a trial that excluded people with a predicted life expectancy of less than 30\xa0days, and also excluded people with the largest bleed volumes. The Delphi panel reached consensus that for intracerebral bleeds, the population that would be offered treatment should be similar to the clinical trial population. This means that some people with major intracranial bleeds would not be treated in clinical practice, based on a projected life expectancy, bleed volume and clinical judgements about their prognosis, even though the marketing authorisation did not exclude these people. However, the clinical experts emphasised the difficulty in deciding when not to use andexanet alfa in clinical practice, because treatment should be given as soon as possible, and the decision may fall to relatively inexperienced doctors. For this reason, it is likely that all people would be treated in the NHS, rather than the selected group in ANNEXA-4 which excluded people with a life expectancy under 1\xa0month, larger bleed volumes and a Glasgow Coma Score below 7. The committee noted that, by excluding these people, a lower 30-day mortality would have been expected in ANNEXA-4 compared with the population seen in clinical practice. Therefore, the generalisability of the ANNEXA-4 results, and the size of any mortality benefit for andexanet alfa when used in routine clinical practice is unclear. The committee concluded that it is uncertain whether or to what extent andexanet alfa would reduce mortality in ICH.\n\n## The benefit of andexanet alfa on disability after an ICH is unproven\n\nThe company assumed that andexanet alfa would reduce the severity of long-term disability in people who had had an ICH, compared with conventional treatment including PCC. This assumption had a large effect on the incremental cost-effectiveness ratio (ICER). However, the committee was concerned by comments received at consultation from the British Association of Stroke Physicians, stating that it was unclear if andexanet alfa improves 'very disabled survival in people who would otherwise die, or is improving the number of people with excellent recovery'. This uncertainty would make treatment decisions difficult and might involve discussions with relatives about whether to use andexanet alfa for ICH. The British Association of Stroke Physicians commented at consultation that it was 'difficult to estimate any effect of this treatment on quality of life or recovery as the size of any beneficial treatment effect is unclear'. Disability after ICH is assessed using the modified Rankin scale (mRS) score, and in the economic model these affected mortality risk, costs and utilities. The company used 2\xa0different sources for mRS scores. For andexanet alfa, it used data from ANNEXA‑4. For established management with PCC it used data from Øie et al. (2018), a study that included patients with ICH only and excluded those with other intracranial bleeds. The ERG and the clinical experts explained that ICH is the most severe type of ICH and therefore the company's comparison potentially overestimated the severity of disability and mRS scores for established management, including PCC. The committee also recalled that ANNEXA-4 excluded people with the worst prognoses. The committee noted that there was no direct evidence that people would have better mRS scores and less disability after andexanet alfa than other treatments including PCC, and that the company's assumption was based on a naive comparison of data from ANNEXA-4 and Øie et al. The clinical experts noted that without evidence from a study, it was impossible to predict a benefit in long-term disability. One clinical expert explained that around 80% of people who survive an ICH are on the dependent scale of mRS (scores of 3 or higher) and that evidence would need to show a clear shift in mRS scores to prove an improvement in disability. Another clinical expert stated that for an effective intervention that improves mortality, all people with an ICH would be expected to have an improved level of disability on their baseline. Consensus statements from the Delphi panel also supported an improvement in long-term morbidity after treatment with andexanet alfa. However the committee recalled its earlier conclusions that any mortality benefit with andexanet alfa was uncertain and that the Delphi panel results were based on clinical assumptions. The committee concluded that a benefit from andexanet alfa on long-term disability is unproven.\n\n## Additional data collection is needed on neurological outcomes compared with established clinical management\n\nThe committee noted that the marketing authorisation for andexanet alfa was on a conditional basis, with a need for a randomised controlled trial being completed in people with ICH to further explore the benefits and risks in this indication. The committee noted that the clinical outcome in this randomised controlled trial is neurological disability measured up to 24\xa0hours from baseline, comparing andexanet alfa with standard care. The committee recognised that data from the randomised controlled trial will provide stronger evidence of haemostatic efficacy and short-term mortality and neurological outcomes, and it has been mandated by the regulator. It acknowledged that the trial will not resolve the uncertainty about long-term morbidity or mortality. However, it will address the key clinical question of whether having had the infusion, people were more likely to be alive and in a better neurological state than if they had not had it. The committee concluded that additional data collection is needed on neurological outcomes compared with established clinical management.\n\n## The evidence in 'other major bleeds' is too unreliable for decision making\n\nThe committee noted that the indirect treatment comparison results for 'other major bleeds' showed that 30-day mortality was worse with andexanet alfa than established care in combination with PCC. The committee appreciated that the analysis was done with a very small sample size, however it considered it would be unreasonable to ignore these results. The company stated that it expected andexanet alfa treatment to be beneficial in this population. However, the committee concluded that andexanet alfa reducing mortality in 'other major bleeds' had not been shown or quantified.\n\n# Cost effectiveness\n\n## The company's economic model is suitable for decision making\n\nThe company submitted a decision tree followed by a Markov model to estimate the cost effectiveness of andexanet alfa compared with PCC. The committee considered that the model was suitable for decision making.\n\n## The company's assumptions about 'other major bleeds' are not well justified\n\nThe propensity score matching analysis was based on a small number of patients for bleeds classified as 'other major bleeds' (pericardial, retroperitoneal, intraspinal and intraocular bleeds). The analysis results for these bleeds did not favour andexanet alfa compared with established clinical management with PCC, so the company considered it was counterintuitive and several assumptions were made to model these bleeds. The company assumed that andexanet alfa would lead to a 25% relative reduction in mortality for pericardial and retroperitoneal bleeds, and it set the mortality to 0 for intraspinal and intraocular bleeds. The company also assumed that andexanet alfa would reduce paralysis and blindness by 25% after intraspinal and intraocular bleeds, which reduced the long-term management costs and improved the long-term utilities. These assumptions were based on clinical opinion only. The clinical experts explained that the evidence was too scarce to make assumptions of 25% relative reduction in mortality, paralysis and blindness and that the ERG's assumption of 0% relative reduction was more reasonable in the absence of robust evidence. At consultation, the company agreed that its assumptions were uncertain because of the limited evidence available. The committee concluded that the company's assumptions were not supported by evidence.\n\n## The long-term outcomes and utilities after ICH are highly uncertain\n\nThe committee noted that there was no direct evidence that people who had an ICH had better long-term outcomes with andexanet alfa than if they had PCC (see section\xa03.10). Differences in mRS scores affected the long-term mortality risk, costs and utilities in the model. The long-term utility value for people who had an ICH in the established clinical management arm (using PCC as a proxy) in the company's model was 0.61. This was obtained from a 3-month post-acute care utility value for people who had an ICH, which was used in NICE's guidance on apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. The company calculated that andexanet alfa increased the long-term utility of people who had an ICH by 0.11 compared with PCC, based on the difference in mRS scores between ANNEXA-4 and Øie et al. (2018). This resulted in a long-term utility of 0.72 after an ICH for people who had andexanet alfa. The ERG was concerned that a utility of 0.72 is not plausible because it is only 0.01 lower than the UK general population aged 75 and over. Also, the differences in long-term outcomes were driven by the naive comparison of mRS scores from ANNEXA-4 and Øie et al. The ERG's preferred scenario was to use the mRS scores from Øie et al. only in people who had an ICH in ANNEXA-4, or alternatively to use the ANNEXA-4 mRS scores for both treatments (assuming no benefit in mRS scores). In its updated base case, the ERG's preferred scenario was to assume no benefit in morbidity and to use the same mRS scores from the trial. At the second consultation, the company provided scenarios with varying utility benefits for andexanet alfa compared with PCC. It presented results using baseline utility values mapped from ANNEXA-4 and results using baseline utility values from NICE's guidance on apixaban. The committee recalled that the Delphi panel consensus supported an improvement in morbidity after treatment with andexanet alfa. However, it was concerned that any increase in benefit was uncertain, as was the size of the benefit. It noted the company had included a utility benefit in its base case that was higher than any predicted by individual experts or in the consensus statement from the Delphi panel. One clinical expert advised that a specific recommendation should be made for people having surgery, in which there is an unmet need. The committee recognised that theoretically a specific reversal agent would be useful. But it agreed there was as yet no evidence that in the situation of surgery andexanet alfa would be better than established clinical management including PCC, so it could not justify a specific recommendation for this situation. The committee concluded that differences in the long-term outcomes and utilities for people after an ICH, depending on the treatment they had, are highly uncertain.\n\n# Cost-effectiveness estimates\n\n## Andexanet alfa is likely to be cost effective compared with established clinical management including PCC in gastrointestinal bleeds\n\nThe committee considered the company's and the ERG's ICERs for the gastrointestinal cohort, which were very similar. Although associated with some uncertainty, the ICERs from the company and ERG were at a level that included a margin to accommodate uncertainty about mortality benefit. The committee concluded that the ICERs for the gastrointestinal cohort are likely to be within what NICE considers a cost-effective use of NHS resources.\n\n## Andexanet alfa has not been shown to be cost effective compared with established clinical management including PCC in ICH\n\nThe committee noted that the extent of the clinical benefit for ICH was uncertain. Therefore, the most plausible ICER for ICH was uncertain. One company scenario included the mortality benefit from the indirect comparison and the modal utility benefit predicted by the Delphi panel in their individual responses. This was within the range NICE normally considers a cost-effective use of NHS resources. However, the committee was concerned that the 30-day mortality benefit from andexanet alpha in this population is highly uncertain because ANNEXA-4 excluded both those with a life expectancy of less than 30\xa0days, and those with the most severe intracranial bleeds, and clinical experts explained that these people would not be excluded from treatment in an emergency situation in clinical practice. The committee also had concerns about the assumption of a benefit from andexanet alfa on long-term disability. The committee further considered the ERG's updated base case and scenarios modelling different utility benefits for andexanet alfa for the ICH cohort, all of which used baseline utility values mapped from ANNEXA-4, which the committee considered was appropriate, because it came directly from the trial in question. The ICERs which all included the 30-day mortality benefit from the indirect comparison, either with no utility benefit, as preferred by the ERG, or the modal benefit as suggested by the Delphi panel, were above what NICE normally considers a cost-effective use of NHS resources. The committee recalled that the extent to which andexanet alfa reduces mortality is uncertain and that reducing the 30-day mortality benefit for andexanet alfa compared with established clinical management including PCC would further increase the ICER. Therefore, the committee was not confident that any of the ICERs for ICH were robust, and those presented may well be underestimates. It recognised the need for an effective reversal agent for direct factor\xa0Xa inhibitors, such as apixaban and rivaroxaban, in people with uncontrolled or life-threatening ICH. However, it concluded that andexanet alfa had not been shown to be a cost-effective use of NHS resources for ICH. Therefore it could not recommend it for routine use in the NHS, pending further research as mandated by the regulator.\n\n## Andexanet alfa has not been shown to be cost effective compared with established clinical management for 'other major bleeds'\n\nThe committee noted that the indirect treatment comparison for 'other major bleeds' showed that mortality was worse with andexanet alfa than PCC. Also, the company's assumptions on a potential morbidity benefit were not supported by evidence. Therefore, the committee considered that the ICERs for 'other major bleeds' were very uncertain and that andexanet alfa had not been shown to be a cost-effective use of NHS resources for 'other major bleeds'.\n\n# Other considerations\n\n## Equalities\n\nThe committee noted an equality concern. Some people do not accept blood products, so would be unable to have PCC as part of their standard care. The committee noted that PCC is not an established treatment for reversing anticoagulation with apixaban or rivaroxaban and is used outside of its marketing authorisation. The committee was aware that people who would not be able to have PCC would have alternative clinical management. In the ORANGE study, 39% of patients had PCC, 41% had a blood transfusion and 28% had tranexamic acid. It noted that no data had been presented that compared established clinical management outcomes with and without blood products. The committee noted that data from the ongoing randomised controlled trial might reduce this uncertainty in ICH, because it compares andexanet alfa with standard care, which is not limited to PCC. However, the committee concluded that the effectiveness of andexanet alfa in ICH and other bleeds was still highly uncertain for people who could and could not have blood products. Therefore, there was no need to alter its recommendation. During the second consultation, stakeholders and clinical experts noted a further equality concern that there would be national variation in access to andexanet alfa if recommended only in research. However, the committee understood that any variation in access is governed by entry to a randomised controlled trial which had been mandated by the regulator. It concluded that the ability to take part in this research was not an issue that needed its recommendation to be altered.\n\n# Conclusion\n\n## Andexanet alfa is recommended for reversing anticoagulation in life‑threatening or uncontrolled bleeding in gastrointestinal bleeds\n\nAndexanet alfa is likely to reduce 30-day mortality for people with gastrointestinal bleeds. Despite the uncertainty, the committee concluded that the ICER for the gastrointestinal cohort is likely to be within what NICE considers a cost-effective use of NHS resources. Therefore, it concluded that andexanet alfa is recommended in gastrointestinal bleeds as defined in the ANNEXA-4 trial and used as part of a major gastrointestinal bleed protocol.\n\n## Andexanet alfa is recommended only in research for reversing anticoagulation in life-threatening or uncontrolled bleeding in ICH bleeds\n\nThe extent of benefits in terms of mortality and long-term disability from andexanet alfa in ICH are unclear and the committee was not confident that the cost-effectiveness results for ICH were robust. There is a need for an effective reversal agent for direct factor Xa inhibitors, such as apixaban and rivaroxaban, in people with uncontrolled or life-threatening bleeding in ICH. However, the committee was not convinced that andexanet alfa had been shown to be a cost-effective use of NHS resources in ICH. Therefore, andexanet alfa should be used only in research in ICH as part of the trial mandated by the regulator.\n\n## Andexanet alfa is not recommended for reversing anticoagulation in life-threatening or uncontrolled bleeding in 'other major bleeds'\n\nThe potential benefits of andexanet alfa in the 'other major bleeds' cohort were not supported by evidence and the cost-effectiveness estimates were very uncertain. Therefore, andexanet alfa is not recommended for reversing anticoagulation in life-threatening or uncontrolled bleeding in 'other major bleeds'.", 'Recommendations for research': 'The committee noted an ongoing randomised controlled trial of the effectiveness of andexanet alfa compared with standard care in people with intracranial haemorrhage. The main outcomes of interest are haemostatic efficacy and short-term mortality and neurological outcomes.'}
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https://www.nice.org.uk/guidance/ta697
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Evidence-based recommendations on andexanet alfa (Ondexxya) for reversing anticoagulation form apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding.
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4f84b0dd5e69814a80a73f7fbcb02f639ed000d0
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nice
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Permanent His-bundle pacemaker implantation for treating heart failure
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Permanent His-bundle pacemaker implantation for treating heart failure
Evidence-based recommendations on permanent His-bundle pacemaker implantation for treating heart failure. This involves attaching a wire to the heart’s electrical conduction pathway (through a vein). The wire is connected to a pacemaker under the surface of the skin, to help the heart pump blood more efficiently.
# Recommendations
Evidence on the safety and efficacy of permanent His-bundle pacemaker implantation for treating heart failure is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
This is a technically challenging procedure and experience in cardiac electrophysiology is needed. It should only be done in specialist centres with experience of cardiac pacing.
Further research should be in the form of randomised controlled trials or registry data. It should report details of patient selection. Outcomes should include quality of life using relevant and validated measures, including the New York Heart Association classification, survival and the need for hospital admissions.# The condition, current treatments and procedure
# The condition
Heart failure is a complex clinical syndrome of symptoms and signs that happen when the heart is not working well enough. It leads to reduced blood flow to body tissues and can cause oedema in the lungs (causing breathlessness) and swelling of the legs. Other symptoms include reduced ability to exercise, fatigue and malaise. Heart failure can be caused by structural or functional abnormalities of the heart.
# Current treatments
Treatments for heart failure are described in NICE's guideline on diagnosing and managing chronic heart failure in adults. Initial treatments include drugs to improve heart function. However, as heart failure becomes more severe, it can become unresponsive to drugs alone. Implantation of specific devices to sense and stimulate the heart chambers might then be recommended as an adjunctive treatment. This is known as cardiac resynchronisation therapy (CRT) which may also include inserting a defibrillator (CRT‑D) or pacing (CRT‑P).
Other treatments include cardiac rehabilitation, coronary revascularisation (when there is coronary artery narrowing), a heart transplant and palliative care. Permanent His-bundle pacemaker implantation may be another option for people with advanced heart failure.
# The procedure
The aim of implanting a permanent pacemaker at the His bundle is to produce normal physiological ventricular activation via the His-Purkinje system.
The procedure is usually done under local anaesthesia, with or without sedation, in a cardiac catheterisation laboratory. A pacemaker generator is implanted under the skin near the collarbone, usually on the left side of the chest (although the right side is possible). A standard or dedicated pacing lead is inserted through the subclavian, cephalic or axillary vein into the heart. This is done under fluoroscopic guidance and continuous electrocardiogram monitoring or mapping, and using a standard or specially designed His-delivery sheath. It is then positioned and secured to the His bundle, where it can directly stimulate the His-bundle fibres. An electrogram from the tip of the lead is used to ensure a His signal and that the pacing lead is correctly placed. The pacemaker generator is securely connected to the His-bundle lead. The generator can be adjusted transcutaneously to ensure optimum His-bundle pacing.
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{'Recommendations': 'Evidence on the safety and efficacy of permanent His-bundle pacemaker implantation for treating heart failure is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nThis is a technically challenging procedure and experience in cardiac electrophysiology is needed. It should only be done in specialist centres with experience of cardiac pacing.\n\nFurther research should be in the form of randomised controlled trials or registry data. It should report details of patient selection. Outcomes should include quality of life using relevant and validated measures, including the New York Heart Association classification, survival and the need for hospital admissions.', 'The condition, current treatments and procedure': "# The condition\n\nHeart failure is a complex clinical syndrome of symptoms and signs that happen when the heart is not working well enough. It leads to reduced blood flow to body tissues and can cause oedema in the lungs (causing breathlessness) and swelling of the legs. Other symptoms include reduced ability to exercise, fatigue and malaise. Heart failure can be caused by structural or functional abnormalities of the heart.\n\n# Current treatments\n\nTreatments for heart failure are described in NICE's guideline on diagnosing and managing chronic heart failure in adults. Initial treatments include drugs to improve heart function. However, as heart failure becomes more severe, it can become unresponsive to drugs alone. Implantation of specific devices to sense and stimulate the heart chambers might then be recommended as an adjunctive treatment. This is known as cardiac resynchronisation therapy (CRT) which may also include inserting a defibrillator (CRT‑D) or pacing (CRT‑P).\n\nOther treatments include cardiac rehabilitation, coronary revascularisation (when there is coronary artery narrowing), a heart transplant and palliative care. Permanent His-bundle pacemaker implantation may be another option for people with advanced heart failure.\n\n# The procedure\n\nThe aim of implanting a permanent pacemaker at the His bundle is to produce normal physiological ventricular activation via the His-Purkinje system.\n\nThe procedure is usually done under local anaesthesia, with or without sedation, in a cardiac catheterisation laboratory. A pacemaker generator is implanted under the skin near the collarbone, usually on the left side of the chest (although the right side is possible). A standard or dedicated pacing lead is inserted through the subclavian, cephalic or axillary vein into the heart. This is done under fluoroscopic guidance and continuous electrocardiogram monitoring or mapping, and using a standard or specially designed His-delivery sheath. It is then positioned and secured to the His bundle, where it can directly stimulate the His-bundle fibres. An electrogram from the tip of the lead is used to ensure a His signal and that the pacing lead is correctly placed. The pacemaker generator is securely connected to the His-bundle lead. The generator can be adjusted transcutaneously to ensure optimum His-bundle pacing."}
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https://www.nice.org.uk/guidance/ipg694
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Evidence-based recommendations on permanent His-bundle pacemaker implantation for treating heart failure. This involves attaching a wire to the heart’s electrical conduction pathway (through a vein). The wire is connected to a pacemaker under the surface of the skin, to help the heart pump blood more efficiently.
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7fe481972345d1ab277fa8a4c97ad6a24c16cb4d
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nice
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UroLift for treating lower urinary tract symptoms of benign prostatic hyperplasia
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UroLift for treating lower urinary tract symptoms of benign prostatic hyperplasia
Evidence-based recommendations on UroLift for treating lower urinary tract symptoms of benign prostatic hyperplasia.
# Recommendations
Evidence supports the case for adopting the UroLift System for treating lower urinary tract symptoms of benign prostatic hyperplasia. The UroLift System relieves lower urinary tract symptoms, avoids risk to sexual function, and improves quality of life.
The UroLift System is a minimally invasive procedure, which should be considered as an alternative to transurethral resection of the prostate (TURP) and holmium laser enucleation of the prostate (HoLEP). It can be done as a day-case or outpatient procedure for people aged 50 and older with a prostate volume between 30 and 80 ml.
Cost modelling shows that the UroLift System is likely to be cost saving compared with standard treatments, because of reduced length of stay and procedure time. Over 5 years, if done as a day‑case procedure, UroLift is estimated to save, per person:
£981 compared with bipolar TURP
£1,242 compared with monopolar TURP
£1,230 compared with HoLEP.Cost savings are uncertain compared with transurethral water vapour therapy using Rezum and when UroLift is used for treating an obstructive median lobe.
Why the committee made these recommendations
The UroLift System inserts implants using a minimally invasive procedure. The implants hold obstructing prostate tissue away from the urethra so that it is not blocked. The aim is to relieve lower urinary tract symptoms such as difficulty urinating.
New clinical evidence available since the original guidance was published in 2015 shows that UroLift relieves lower urinary tract symptoms for up to 5 years. It also shows that UroLift improves quality of life and avoids risk to sexual function.
Cost analyses suggest that using UroLift instead of TURP or HoLEP is likely to be cost saving. This is because UroLift is done as day surgery with reduced operating and recovery costs. Compared with Rezum, cost savings for UroLift are uncertain and depend on whether flexible cystoscopy is used before the procedure and the number of implants needed for UroLift. The additional implants needed when UroLift is used for obstructive median lobe treatment mean that there may be additional costs when compared with Rezum.# The technology
# Technology
The UroLift System (Teleflex Inc.) is used to do a prostatic urethral lift, a procedure that relieves lower urinary tract symptoms. It uses implants to pull excess prostatic tissue away from the urethra so that it does not narrow or block the urethra. The system comprises 2 single-use components: a delivery device and an implant. The delivery device consists of a hand-held pistol grip with a needle-shaped probe attached. Each UroLift implant consists of a superelastic nitinol capsular tab (a piece of metal holding 1 side of the suture), a polyethylene terephthalate monofilament suture, and a stainless-steel urethral end-piece. The surgeon inserts the probe into the urethra until it reaches the prostatic urethra (the widest part of the urethral canal). A fine needle at the end of the probe deploys and secures an implant in a lobe of the prostate. One end of the implant is anchored to the firm outer surface of the prostatic capsule, while the other is on the inside of the urethra. When the device is tightened, the prostatic tissue is pulled away from the urethra. This is repeated on the other lobe of the prostate. Typically, about 4 implants are used to widen the urethra. The procedure is done under local or general anaesthesia and usually as a day‑case or outpatient procedure. Sometimes UroLift is done as an inpatient treatment depending on the person's circumstances. For example, if they have comorbidities or no home support.
# Innovative aspects
Treatment with UroLift does not involve cutting or removing tissue. The implants can be partially removed, so the procedure is reversible, and people can have other surgical treatments later if needed. UroLift is less invasive than standard treatments and may reduce the need for postoperative catheterisation and catheterisation time. UroLift is a quick procedure that can be done as a day-case or outpatient procedure, so it may reduce the need to stay in hospital.
# Intended use
UroLift is intended for treating symptoms caused by urinary outflow obstruction secondary to benign prostatic hyperplasia affecting the lateral and median lobes, in people aged 50 and older. This indication was updated in 2020. According to the UK instructions for use, UroLift should not be used if prostate volume is more than 100 ml or if people have a urinary tract infection. Clinical experts also advised that people need to be assessed on an individual basis to check if the procedure is suitable for them. This is because some clinicians may consider that other conditions, such as chronic urinary retention, are contraindications. The company states that UroLift treatment can be done under local anaesthetic, with light sedation if needed.
# Relevant pathway
The NICE Pathway for managing lower urinary tract symptoms in men is relevant and is described in the decision problem for UroLift.
# Costs
The cost of the UroLift System (comprising 1 delivery device and 1 implant) stated in the company's submission is £400 (excluding VAT).# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence from the original guidance
## Relevant evidence comes from 1 systematic review and 1 English language translation of an uncontrolled case series
In the original UroLift medical technologies guidance, the EAC considered:
-ne systematic review summarising 9 studies (reporting outcomes for 452 to 680 people, depending on the outcome)
-ne uncontrolled case series (reporting outcomes from 20 people).The EAC identified no further evidence. The studies relevant to the decision problem in the scope were:
nine studies in the systematic review including 2 papers on a randomised controlled trial (RCT; the LIFT study; McVary et al. 2014; Roehrborn et al. 2013) and 7 uncontrolled before‑and‑after studies (Cantwell et al. 2014; Chin et al. 2012; Delongchamps et al. 2012; McNicholas et al. 2013; Shore et al. 2014; Woo et al. 2011 and 2012)
-ne English language translation of an uncontrolled case series (Abad et al. 2013).For full details of the clinical evidence, see section 3 of the assessment report in supporting documentation.
## There is no published comparison of UroLift with HoLEP
In the original guidance, there was no published evidence directly comparing the UroLift System with the comparator technologies highlighted in the scope. So, the EAC did an evidence synthesis of the outcomes in the UroLift studies. It compared them with those reported with transurethral resection of the prostate (TURP) and holmium laser enucleation of the prostate (HoLEP) in a systematic review (Li et al. 2014). During the consultation period, initial results from the BPH6 RCT comparing UroLift with TURP became available.
## UroLift improves symptoms of benign prostatic hyperplasia, but not as much as TURP or HoLEP
The EAC's evidence synthesis showed that both TURP and HoLEP were associated with greater improvements in International Prostate Symptom Score (IPSS) than UroLift at all time points. Overall changes within a 2‑year period ranged from -17.34 to -19.7 with TURP and -17.68 to -20.88 with HoLEP, compared with -9.22 to -11.82 with UroLift. Maximum urinary flow (Qmax) and post-void residual improvements were also greater with TURP and HoLEP.
## UroLift improves quality of life, but not as much as TURP or HoLEP
The EAC's evidence synthesis reported that the IPSS quality-of-life score improved by 2.22 to 2.48 points for people having UroLift treatment. However, this was less than the improvement after TURP (2.99 to 3.18 points) and HoLEP (2.64 to 3.24 points). An increase of 1 to 3 points is generally considered to represent a minimum important change.
## UroLift does not damage sexual function
The EAC's evidence synthesis showed that sexual function is not negatively affected after using UroLift. In fact, small, statistically significant improvements (0.3 to 0.4 points, based on combined sexual health scores reported in the meta-analysis) were reported. Changes in sexual function were poorly reported in the TURP and HoLEP studies, which made it difficult to accurately assess the effect of these technologies. Expert advice was that deterioration in sexual function was well described and seen in practice in some people having TURP or HoLEP.
# New clinical evidence
## New relevant evidence comes from 12 publications, including 2 RCTs, and 6 NICE shared learning case studies
For the guidance update, the EAC considered a total of 12 new studies (1,938 people) and 6 NICE shared learning case studies relevant to the decision problem in the scope. These were published after the original guidance was published. The scope for the guidance update included 1 additional comparator, Rezum. One study was found comparing Rezum with UroLift (Tutrone and Schiff, 2020), which was included in the EAC's evaluation of the evidence. The studies relevant to the updated scope were:
two RCTs reported in 5 papers: The LIFT study (reported in Roehrborn et al. 2015, with Rukstalis et al. 2016 and Roehrborn et al. 2017 reporting trial follow-up data) and the full published results of the BPH6 study (reported by Sonksen et al. 2015; Gratzke et al. 2016)
two non-randomised, comparative, prospective studies (Tutrone and Schiff 2020; Rukstalis et al. 2018)
two non-comparative, prospective, multicentre studies (Sievert et al. 2019; Rubio et al. 2019)
-ne retrospective non-comparative study (Bozkurt et al. 2016)
-ne single-centre, single-surgeon retrospective note analysis (Bardoli et al. 2017)
-ne retrospective multicentre chart analysis (Eure et al. 2019)
six NICE shared learning case studies (Royal Devon and Exeter NHS Trust 2020; Northampton NHS Trust 2020; Norfolk and Norwich NHS Trust 2019; NHS Fife 2020; St Helens and Knowsley NHS Trust 2016; Frimley Park NHS Trust 2016).For full details of the clinical evidence, see section 3 of the assessment report update in supporting documentation.
## UroLift significantly improves long-term symptoms of benign prostatic hyperplasia
In 7 studies there were statistically significant improvements in symptom severity (IPSS score) and in 4 studies there were improvements in Benign Prostatic Hyperplasia Impact Index (BPHII) score up to 5 years after the UroLift procedure. These studies were Roehrborn et al. 2015; Bozkurt et al. 2016; Rukstalis et al. 2016; Bardoli et al. 2017; Roehrborn et al. 2017; Sievert et al. 2018; Eure et al. 2019 and Rubio et al. 2019; Rukstalis et al. 2018.
## UroLift improves symptoms of benign prostatic hyperplasia compared with TURP and Rezum
Compared with TURP, people having UroLift reported smaller improvements in IPSS scores up to 12 months after the procedure (Sonksen et al. 2015; Gratzke et al. 2016). Compared with Rezum, people having UroLift reported greater improvements in IPSS scores at 30 days after the procedure (Tutrone and Schiff, 2020).
## UroLift improves urinary flow and retention symptoms over time
Qmax improved up to 5 years after UroLift treatment in most studies (Roehrborn et al. 2015; Bozkurt et al. 2016; Rukstalis et al. 2016; Roehrborn et al. 2017; Sievert et al. 2018; Rubio et al. 2019; Rukstalis et al. 2018). However, in Eure et al. (2019) Qmax decreased up to 6 months after the procedure and no significant difference in Qmax was reported by Bardoli et al. (2017).
In 4 studies there was a statistically significant improvement (up to 12 months) in post-urination residual volume (Bozkurt et al. 2016; Rukstalis et al. 2016; Bardoli et al. 2017; Sievert et al. 2018). In Gratzke et al. (2016) Incontinence Severity Index scores remained unchanged up to 2 years after UroLift treatment.
TURP produced greater improvements in Qmax and post-urination residual volume up to 24 months after the procedure compared with UroLift (Sonksen et al. 2015; Gratzke et al. 2016).
## UroLift does not negatively affect sexual function
In most studies, the UroLift procedure did not result in statistically significant changes in erectile dysfunction. This was assessed using the International Index of Erectile Function and the Sexual Health Inventory for Men (SHIM) questionnaires (Bozkurt et al. 2016; Rukstalis et al. 2016; Rubio et al. 2019). However, in people with obstructive median lobes, there were improvements in both measures up to 12 months after the procedure (Rukstalis et al. 2018). The amount of change in SHIM scores did not differ much between UroLift and TURP (Sonksen et al. 2015; Gratzke et al. 2016) but was statistically significantly better with UroLift than Rezum (Tutrone and Schiff, 2020).
In 5 studies, Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MSHQ-EjD) scores after UroLift and other treatments were reported. In 2 of these, there were improvements over time after UroLift (Roehrborn et al. 2015; Rukstalis et al. 2018). In 2 other studies improvements over time with UroLift compared with TURP were not statistically significant (Sonksen et al. 2015; Gratze et al. 2016). In 1 study the difference in scores between people who had UroLift or Rezum was not statistically significant at 30 days follow up (Tutrone and Schiff, 2020).
## UroLift reduces the rate and duration of postoperative catheterisation compared with TURP and Rezum
After TURP 74% of people needed catheterisation for more than 24 hours compared with 45% after UroLift (Sonksen et al. 2015). After UroLift 57% of people needed post-procedure catheterisation compared with 87% after Rezum (Tutrone and Schiff, 2020). Catheterisation time after UroLift was statistically significantly shorter than with Rezum (1.2 days compared with 4.5 days; Tutrone and Schiff, 2020).
## UroLift improves quality of life
Eleven studies measured quality of life, with 8 showing a statistically significant improvement up to 5 years after UroLift treatment. Quality-of-life scores for people having UroLift were statistically significantly better than for people having Rezum (Tutrone and Schiff, 2020). In Sonksen et al. 2015 and Gratzke et al. 2016 there were no statistically significant differences between quality-of-life scores after TURP and UroLift at up to 12 and 24 months, respectively.
## UroLift reduces the length of hospital stay compared with TURP
In 1 study (Sonksen et al. 2015) hospitalisation times were reduced for UroLift (time to discharge 1.0 days) compared with TURP (1.9 days).
## UroLift is effective for treating benign prostatic hyperplasia with an obstructive median lobe
One small study (Rukstalis et al. 2018) including 45 people described the clinical effectiveness of using UroLift in people with an obstructive median lobe. UroLift reduced BPHII and IPSS scores of symptom severity and improved sexual function (MSHQ-EjD score), quality-of-life measures and urological outcomes (Qmax values). The changes were statistically significant.
## Case studies show that UroLift is beneficial when used in the NHS
All 6 NICE shared learning case studies suggested that UroLift was beneficial when used in the NHS, resulting in improved IPSS and quality-of-life scores, reduced surgery times and reduced hospital stay. In 1 case study, the use of either general or local anaesthetic was compared, and no statistically significant differences were reported in IPSS, quality-of-life and pain scores after the procedure (NHS Fife, 2020).
# Cost evidence
## The company's updated cost model is based on the original model but Rezum is a comparator and median lobe treatment is included
The company updated the original economic model to include Rezum as a comparator and median lobe treatment. Clinical parameters for UroLift were based on the LIFT study, using 5‑year post-procedure data (Roehrborn et al. 2017). The original guidance was based on clinical parameters from the same trial at 1 and 2 years after the procedure (Roehrborn et al. 2013 and 2014). For full details of the cost evidence, see section 4 of the assessment report update.
## The EAC adjusts assumptions in the cost model
The EAC updated some of the model's parameters, including the cost of incontinence to cover the 5‑year time horizon, the consumables costs for TURP procedures and the NHS reference costs.
## The updated costs include a reduced number of implants used per surgery and reduced theatre time
The overall cost of UroLift was reduced by £200 per surgery because of adjustments in the number of devices implanted and the duration of surgery. The number of implants per surgery was reduced from 4 to 3.5 and theatre time was decreased from 30 minutes to 14 minutes based on submitted audit data. These data were collected from NHS trusts over the past 3 years for 552 people who had treatment. The findings were supported by local audits carried out in NHS trusts and described in NICE shared learning case studies (NHS Fife 2020; Natarajan 2020; Dhanasekaran 2020b; Royal Devon and Exeter NHS Trust 2020; Norfolk and Norwich NHS Trust 2019).
## Surgery follow up is changed to a telephone consultation
Changing the follow up for UroLift surgery from a face-to-face consultation to a telephone consultation reduced the cost by £72.33 per consultation. This was based on an EAC cost of £37.00 for 20 minutes of band 6 nurse time.
## Costs increase for bipolar TURP, monopolar TURP and HoLEP compared with the original guidance
In the model update the costs of bipolar TURP and monopolar TURP increased compared with the original guidance. This was because of an increase in consumable costs for bipolar TURP, and to a lesser extent for monopolar TURP. The cost of managing incontinence was also applied to the whole population who have treatment instead of only when treatment has failed.
## The revised EAC base-case analysis shows that UroLift is cost saving when compared with all comparators
The EAC's revised base-case analysis showed that when UroLift is done as an outpatient procedure, UroLift is cost saving, per person, by:
£121 compared with Rezum
£1,006 compared with bipolar TURP
£1,267 compared with monopolar TURP and
£1,255 compared with HoLEP.When UroLift is done as a day-case procedure, it is cost saving, per person, by:
£96 compared with Rezum
£981 compared with bipolar TURP
£1,242 compared with monopolar TURP and
£1,230 compared with HoLEP.The EAC concluded that UroLift is cost saving compared with monopolar TURP, bipolar TURP and HoLEP in the base case and in the company's and EAC's scenarios.
## There is uncertainty as to whether UroLift is cost saving compared with Rezum
The UroLift economic model was compared with the model used in NICE's medical technologies guidance on Rezum. The committee concluded that there were too many uncertainties to draw firm conclusions about the costs of using Rezum compared with the costs of using UroLift. However, the Rezum base-case model results showed that Rezum was cost saving when compared with UroLift. The key parameters that were changed in the UroLift model were theatre time, length of stay and type of consultation after UroLift. If length of hospital stay were the same for Rezum and UroLift, Rezum would be cost saving compared with UroLift. However, the EAC's sensitivity analysis concluded that UroLift was only cost saving compared with Rezum if theatre time for the procedure was less than 16.7 minutes.# Committee discussion
# Clinical-effectiveness overview
## UroLift is effective with sustained clinical benefits, and the procedure is minimally invasive
The committee concluded that UroLift is clinically effective, with sustained relief of lower urinary tract symptoms up to 5 years after treatment. It is implanted using a minimally invasive procedure. The clinical experts confirmed that in their practice, UroLift is an effective treatment that is well tolerated.
## The UroLift procedure avoids the development of sexual dysfunction
The committee concluded that there was no evidence to suggest the UroLift procedure increases the risk of developing sexual dysfunction. The clinical experts explained that during the procedure there is no resection or ablation of prostate tissue. This is an important difference between UroLift and other invasive treatments for benign prostatic hyperplasia. Therefore, the committee considered that the reduced incidence of sexual dysfunction with UroLift, compared with comparator treatments, was plausible.
## The person's preference is important in choosing an appropriate treatment for benign prostatic hyperplasia
The clinical experts explained that there are several invasive treatments for managing benign prostatic hyperplasia symptoms when drug treatment has not worked. Also, they explained that treatment is guided by what the person prefers because there is no definitive evidence that one treatment is better than another for all clinical outcomes. The committee noted that the updated evidence allowed direct comparison of UroLift with transurethral resection of the prostate (TURP). This evidence suggested that although the improvement in lower urinary tract symptoms may be greater after TURP the incidence of sexual dysfunction was lower with UroLift. The clinical experts explained that people for whom UroLift is considered suitable are also able to have Rezum treatment. The committee noted that there is only 1 study comparing Rezum with UroLift, with a follow-up period of 30 days. This showed that UroLift was better than Rezum for the short-term relief of lower urinary tract symptoms and for improving erectile dysfunction, but any comparative benefits beyond 30 days were uncertain. The committee concluded that the evidence supported the use of UroLift. But, deciding whether to use UroLift or other technologies should be guided by clinical expertise and counselling for the person having the procedure.
## The evidence for using UroLift for people with an obstructive median lobe is limited but shows promising clinical effectiveness
The clinical evidence for using UroLift for people with an obstructive median lobe consisted of 1 small study of 45 people with a 12‑month follow-up period. The results showed a statistically significant improvement in lower urinary tract symptoms and quality of life after UroLift without the development of sexual dysfunction. The clinical experts explained that they have successfully used UroLift to treat an obstructive median lobe. The committee concluded that the evidence was limited but promising for using UroLift to treat an obstructive median lobe.
# Side effects and adverse events
## Urinary tract infection is not a common complication after UroLift
The urinary tract infection rate after UroLift was 2.9% (Roehrborn et al. 2013). The clinical experts explained that the risk of urinary tract infection was, in their experience, lower with UroLift than with other procedures. This was likely to be because of the reduced need for urinary catheterisation after the procedure.
## The treatment failure rate is low with UroLift
The clinical experts explained that UroLift has a good success rate in adequately relieving lower urinary tract symptoms, with an early failure rate of less than 5%. However, they considered that people may need further treatment, for example if the prostate enlarges further, so should expect a reintervention rate of up to 20%. The clinical evidence from the LIFT study showed a 13.6% reintervention rate at 5 years after the procedure. This reintervention rate was used in the economic model for UroLift.
# Relevance to the NHS
## UroLift is an option for treating lower urinary tract symptoms caused by benign prostatic hyperplasia in the NHS
A clinical expert confirmed that UroLift is widely used in the NHS since the publication of the original NICE guidance. However, there are now other minimally invasive procedures available to treat the condition in the same population, such as Rezum.
# NHS considerations overview
## UroLift can be done using general anaesthesia, or local anaesthesia with or without sedation
The clinical experts stated that in clinical practice, UroLift is done under either general anaesthesia or local anaesthesia (with or without sedation). The method of anaesthesia is tailored to the needs of the person having the procedure. If light sedation is needed with local anaesthesia, the clinical experts emphasised that it is important to have an appropriately trained professional, other than the surgeon, monitoring the person during and after the procedure. They also explained that doing flexible cystoscopy in the outpatient clinic to plan treatment is a good opportunity to assess tolerance and suitability for doing the procedure under local anaesthesia.
## UroLift can be done as an outpatient procedure if appropriate facilities are available
The clinical experts explained that they do not currently offer UroLift as an outpatient treatment themselves but were aware that some clinicians do. UroLift procedures are offered in a small number of NHS trusts with outpatient facilities equipped for implant procedures and with recovery space to monitor people after the procedure. The clinical experts stated that if such facilities were available in their own centres they would also consider doing UroLift as an outpatient procedure.
## Consider prostate volume when assessing whether UroLift is suitable
There is limited clinical evidence on using UroLift for prostates over 80 ml in volume. The clinical experts confirmed that in their own practice, they consider UroLift is most appropriate for prostates under 80 ml. They explained their experience that if UroLift is done on prostates over 80 ml, more implants are needed. Also, the results are not likely to be as good and symptoms may recur. Clinical decision making is best supported by measuring prostate size objectively using transrectal ultrasound or MRI, but it can also be estimated from preoperative cystoscopy.
## The proportion of flexible cystoscopies routinely carried out before a UroLift procedure is uncertain
Two of the clinical experts stated that they did flexible cystoscopy routinely before deciding whether to offer UroLift. This allowed them to see whether there is an obstructive median lobe and estimate the number of implants needed. They could also assess whether there are any other conditions, including bladder stones or bladder cancer, which might affect whether the procedure is done. One expert stated that they do not routinely do flexible cystoscopy before UroLift because of the added time and cost implications. There is uncertainty about the proportion of flexible cystoscopies routinely carried out before the procedure.
## The procedure time and length of hospital stay for UroLift can vary
The clinical experts agreed that on average, the UroLift procedure takes 10 to 15 minutes per person to do. However, they noted that this does not take into account variations in time taken for the administration of local or general anaesthetic or for changeover time between procedures. The clinical experts also noted that the length of hospital stay can vary. This is because of local hospital procedures, the time taken to recover from the anaesthetic and for the person to empty their bladder (a requirement for leaving hospital).
## Telephone follow up is routinely used
Telephone follow up by a nurse was now routine with UroLift, Rezum, TURP and holmium laser enucleation of the prostate (HoLEP). People having Rezum, TURP or HoLEP also need to have a trial period without the urinary catheter in place, but the clinical experts explained that this was usually done in the community. The clinical experts also explained that people may return a few months after their procedure for objective tests to assess clinical outcomes such as flow rate and International Prostate Symptom Score.
## UroLift is a minimally invasive procedure but may not be suitable for everyone
The clinical experts explained that TURP and HoLEP are unsuitable for some people with lower urinary tract symptoms, because of frailty or comorbidities. Although UroLift is minimally invasive, they considered that it may be unsuitable for some people in poor health and those who do not wish to have implants in their bodies. The decision to use UroLift should be made on an individual basis. The clinical experts noted that the implants can sometimes leave traces on MRI scans, which may be confusing if people are being investigated for possible prostate cancer. But if the radiologists interpreting the scans are aware that the person has UroLift implants, this should not be a problem.
# Equality considerations
## People who identify as women have had UroLift
Eight people who identify as women have had UroLift treatment. One of these procedures was done in the NHS. The clinical experts stated that doing a UroLift procedure in people who have had gender reassignment surgery did seem possible. Gender reassignment is a protected characteristic under the Equality Act 2010.
# Cost modelling overview
## UroLift is cost saving compared with standard treatments
The external assessment centre (EAC) revised the company's base case and showed that UroLift remained cost saving compared with the standard treatments, TURP and HoLEP. The committee accepted the EAC's conclusions. It noted that using UroLift was estimated to save, per person, £981 compared with bipolar TURP, £1,242 compared with monopolar TURP and £1,230 compared with HoLEP. This was over a 5‑year time horizon and if UroLift was done as a day-case procedure.
## Follow-up care for comparators affects UroLift's cost case
Further analysis was done to look at the use of telephone follow up for all treatments and a trial without a catheter in the community for Rezum. UroLift remained cost saving when all treatments had a telephone follow up instead of an outpatient appointment. Rezum and UroLift were cost neutral when there was a trial without a catheter in the community, instead of as an outpatient, after Rezum. The committee considered that it was unclear which assumptions on follow-up care most closely resembled routine NHS practice. It concluded that this introduced some uncertainty in the cost case between UroLift and Rezum.
## The number of implants used affects UroLift's cost case
The economic analysis included an assumption that an average of 3.5 implants were used per person with UroLift treatment. The clinical experts thought this was an underestimate and that an average of 4 implants was more appropriate, with a range of between 2 and 6 implants depending on prostate size. There was a learning curve associated with accurately judging the number of implants needed and usually after 15 to 25 procedures a surgeon can confidently do this. The committee acknowledged that the economic model was sensitive to the cost and number of implants used. But varying the number of implants used was unlikely to affect the cost savings when compared with TURP and with HoLEP. It concluded, however, that the cost case compared with Rezum was less certain if the number of implants varied. The clinical experts commented that this may mean that using UroLift for smaller prostates, with no obstructive median lobe, might be cost saving when compared with Rezum.
## It is uncertain whether UroLift is cost saving compared with Rezum
UroLift (if done as an outpatient procedure) was cost saving in the base case by £121 compared with Rezum for everyone who had treatment, over a 5‑year time horizon. However, the EAC's sensitivity analysis showed that Rezum would be cheaper if several parameters were changed individually, including:
if the procedure time was the same for both procedures
if the average number of UroLift implants exceeded 3.61.Further economic analysis showed that Rezum was likely to be cost saving if flexible cystoscopy was done before UroLift treatment. However, there was uncertainty around whether only people being considered for UroLift would have flexible cystoscopy. The clinical experts stated that they sometimes use flexible cystoscopy in assessing suitability for procedures other than UroLift.
## The cost case for UroLift when treating an obstructive median lobe is uncertain because of the increasing number of implants
Between 5% and 20% of people with lower urinary tract symptoms of benign prostatic hyperplasia have an obstructive median lobe, which may not be identified before the procedure. The committee discussed that having an obstructive median lobe made UroLift's potential case for cost savings for the full population uncertain. The base case assumed that 5.3% of people have an obstructive median lobe, which means on average, 1.3 additional implants per procedure. The clinical experts stated that in their practice, the average is more likely to be 2 additional implants. This led to increasing uncertainty in the cost case for UroLift compared with Rezum. Rezum's cost is not affected by the presence of an obstructive median lobe.
# Further research
## The efficacy of UroLift compared with Rezum needs further research
Further evidence to address uncertainties about the relative clinical and cost effectiveness of UroLift compared with Rezum, especially in the NHS, would be welcome. This should include:
exploring long-term clinical outcomes and reintervention rates after UroLift
assessing the suitability of UroLift for prostates larger than 80 ml and for those with an obstructive median lobe.This evidence could be generated by collating UK registry data and including the number of implants used, the length of the procedure and procedural outcomes.
|
{'Recommendations': 'Evidence supports the case for adopting the UroLift System for treating lower urinary tract symptoms of benign prostatic hyperplasia. The UroLift System relieves lower urinary tract symptoms, avoids risk to sexual function, and improves quality of life.\n\nThe UroLift System is a minimally invasive procedure, which should be considered as an alternative to transurethral resection of the prostate (TURP) and holmium laser enucleation of the prostate (HoLEP). It can be done as a day-case or outpatient procedure for people aged 50\xa0and older with a prostate volume between 30\xa0and 80\xa0ml.\n\nCost modelling shows that the UroLift System is likely to be cost saving compared with standard treatments, because of reduced length of stay and procedure time. Over 5\xa0years, if done as a day‑case procedure, UroLift is estimated to save, per person:\n\n£981 compared with bipolar TURP\n\n£1,242 compared with monopolar TURP\n\n£1,230 compared with HoLEP.Cost savings are uncertain compared with transurethral water vapour therapy using Rezum and when UroLift is used for treating an obstructive median lobe.\n\nWhy the committee made these recommendations\n\nThe UroLift System inserts implants using a minimally invasive procedure. The implants hold obstructing prostate tissue away from the urethra so that it is not blocked. The aim is to relieve lower urinary tract symptoms such as difficulty urinating.\n\nNew clinical evidence available since the original guidance was published in 2015 shows that UroLift relieves lower urinary tract symptoms for up to 5\xa0years. It also shows that UroLift improves quality of life and avoids risk to sexual function.\n\nCost analyses suggest that using UroLift instead of TURP or HoLEP is likely to be cost saving. This is because UroLift is done as day surgery with reduced operating and recovery costs. Compared with Rezum, cost savings for UroLift are uncertain and depend on whether flexible cystoscopy is used before the procedure and the number of implants needed for UroLift. The additional implants needed when UroLift is used for obstructive median lobe treatment mean that there may be additional costs when compared with Rezum.', 'The technology': "# Technology\n\nThe UroLift System (Teleflex Inc.) is used to do a prostatic urethral lift, a procedure that relieves lower urinary tract symptoms. It uses implants to pull excess prostatic tissue away from the urethra so that it does not narrow or block the urethra. The system comprises 2\xa0single-use components: a delivery device and an implant. The delivery device consists of a hand-held pistol grip with a needle-shaped probe attached. Each UroLift implant consists of a superelastic nitinol capsular tab (a piece of metal holding 1\xa0side of the suture), a polyethylene terephthalate monofilament suture, and a stainless-steel urethral end-piece. The surgeon inserts the probe into the urethra until it reaches the prostatic urethra (the widest part of the urethral canal). A fine needle at the end of the probe deploys and secures an implant in a lobe of the prostate. One end of the implant is anchored to the firm outer surface of the prostatic capsule, while the other is on the inside of the urethra. When the device is tightened, the prostatic tissue is pulled away from the urethra. This is repeated on the other lobe of the prostate. Typically, about 4\xa0implants are used to widen the urethra. The procedure is done under local or general anaesthesia and usually as a day‑case or outpatient procedure. Sometimes UroLift is done as an inpatient treatment depending on the person's circumstances. For example, if they have comorbidities or no home support.\n\n# Innovative aspects\n\nTreatment with UroLift does not involve cutting or removing tissue. The implants can be partially removed, so the procedure is reversible, and people can have other surgical treatments later if needed. UroLift is less invasive than standard treatments and may reduce the need for postoperative catheterisation and catheterisation time. UroLift is a quick procedure that can be done as a day-case or outpatient procedure, so it may reduce the need to stay in hospital.\n\n# Intended use\n\nUroLift is intended for treating symptoms caused by urinary outflow obstruction secondary to benign prostatic hyperplasia affecting the lateral and median lobes, in people aged 50\xa0and older. This indication was updated in 2020. According to the UK instructions for use, UroLift should not be used if prostate volume is more than 100\xa0ml or if people have a urinary tract infection. Clinical experts also advised that people need to be assessed on an individual basis to check if the procedure is suitable for them. This is because some clinicians may consider that other conditions, such as chronic urinary retention, are contraindications. The company states that UroLift treatment can be done under local anaesthetic, with light sedation if needed.\n\n# Relevant pathway\n\nThe NICE Pathway for managing lower urinary tract symptoms in men is relevant and is described in the decision problem for UroLift.\n\n# Costs\n\nThe cost of the UroLift System (comprising 1\xa0delivery device and 1\xa0implant) stated in the company's submission is £400 (excluding VAT).", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence from the original guidance\n\n## Relevant evidence comes from 1\xa0systematic review and 1\xa0English language translation of an uncontrolled case series\n\nIn the original UroLift medical technologies guidance, the EAC considered:\n\none\xa0systematic review summarising 9\xa0studies (reporting outcomes for 452\xa0to 680\xa0people, depending on the outcome)\n\none\xa0uncontrolled case series (reporting outcomes from 20\xa0people).The EAC identified no further evidence. The studies relevant to the decision problem in the scope were:\n\nnine\xa0studies in the systematic review including 2\xa0papers on a randomised controlled trial (RCT; the LIFT study; McVary et al. 2014; Roehrborn et al. 2013) and 7\xa0uncontrolled before‑and‑after studies (Cantwell et al. 2014; Chin et al. 2012; Delongchamps et al. 2012; McNicholas et al. 2013; Shore et al. 2014; Woo et al. 2011 and 2012)\n\none\xa0English language translation of an uncontrolled case series (Abad et al. 2013).For full details of the clinical evidence, see section\xa03 of the assessment report in supporting documentation.\n\n## There is no published comparison of UroLift with HoLEP\n\nIn the original guidance, there was no published evidence directly comparing the UroLift System with the comparator technologies highlighted in the scope. So, the EAC did an evidence synthesis of the outcomes in the UroLift studies. It compared them with those reported with transurethral resection of the prostate (TURP) and holmium laser enucleation of the prostate (HoLEP) in a systematic review (Li et al. 2014). During the consultation period, initial results from the BPH6 RCT comparing UroLift with TURP became available.\n\n## UroLift improves symptoms of benign prostatic hyperplasia, but not as much as TURP or HoLEP\n\nThe EAC's evidence synthesis showed that both TURP and HoLEP were associated with greater improvements in International Prostate Symptom Score (IPSS) than UroLift at all time points. Overall changes within a 2‑year period ranged from -17.34\xa0to\xa0-19.7 with TURP and -17.68\xa0to\xa0-20.88 with HoLEP, compared with -9.22\xa0to\xa0-11.82 with UroLift. Maximum urinary flow (Qmax) and post-void residual improvements were also greater with TURP and HoLEP.\n\n## UroLift improves quality of life, but not as much as TURP or HoLEP\n\nThe EAC's evidence synthesis reported that the IPSS quality-of-life score improved by 2.22\xa0to 2.48\xa0points for people having UroLift treatment. However, this was less than the improvement after TURP (2.99\xa0to 3.18\xa0points) and HoLEP (2.64\xa0to 3.24\xa0points). An increase of 1\xa0to 3\xa0points is generally considered to represent a minimum important change.\n\n## UroLift does not damage sexual function\n\nThe EAC's evidence synthesis showed that sexual function is not negatively affected after using UroLift. In fact, small, statistically significant improvements (0.3\xa0to 0.4\xa0points, based on combined sexual health scores reported in the meta-analysis) were reported. Changes in sexual function were poorly reported in the TURP and HoLEP studies, which made it difficult to accurately assess the effect of these technologies. Expert advice was that deterioration in sexual function was well described and seen in practice in some people having TURP or HoLEP.\n\n# New clinical evidence\n\n## New relevant evidence comes from 12\xa0publications, including 2\xa0RCTs, and 6\xa0NICE shared learning case studies\n\nFor the guidance update, the EAC considered a total of 12\xa0new studies (1,938\xa0people) and 6\xa0NICE shared learning case studies relevant to the decision problem in the scope. These were published after the original guidance was published. The scope for the guidance update included 1\xa0additional comparator, Rezum. One study was found comparing Rezum with UroLift (Tutrone and Schiff, 2020), which was included in the EAC's evaluation of the evidence. The studies relevant to the updated scope were:\n\ntwo\xa0RCTs reported in 5\xa0papers: The LIFT study (reported in Roehrborn et al. 2015, with Rukstalis et al. 2016 and Roehrborn et al. 2017 reporting trial follow-up data) and the full published results of the BPH6 study (reported by Sonksen et al. 2015; Gratzke et al. 2016)\n\ntwo\xa0non-randomised, comparative, prospective studies (Tutrone and Schiff 2020; Rukstalis et al. 2018)\n\ntwo\xa0non-comparative, prospective, multicentre studies (Sievert et al. 2019; Rubio et al. 2019)\n\none\xa0retrospective non-comparative study (Bozkurt et al. 2016)\n\none\xa0single-centre, single-surgeon retrospective note analysis (Bardoli et al. 2017)\n\none\xa0retrospective multicentre chart analysis (Eure et al. 2019)\n\nsix\xa0NICE shared learning case studies (Royal Devon and Exeter NHS Trust 2020; Northampton NHS Trust 2020; Norfolk and Norwich NHS Trust 2019; NHS Fife 2020; St Helens and Knowsley NHS Trust 2016; Frimley Park NHS Trust 2016).For full details of the clinical evidence, see section\xa03 of the assessment report update in supporting documentation.\n\n## UroLift significantly improves long-term symptoms of benign prostatic hyperplasia\n\nIn 7\xa0studies there were statistically significant improvements in symptom severity (IPSS score) and in 4\xa0studies there were improvements in Benign Prostatic Hyperplasia Impact Index (BPHII) score up to 5\xa0years after the UroLift procedure. These studies were Roehrborn et al. 2015; Bozkurt et al. 2016; Rukstalis et al. 2016; Bardoli et al. 2017; Roehrborn et al. 2017; Sievert et al. 2018; Eure et al. 2019 and Rubio et al. 2019; Rukstalis et al. 2018.\n\n## UroLift improves symptoms of benign prostatic hyperplasia compared with TURP and Rezum\n\nCompared with TURP, people having UroLift reported smaller improvements in IPSS scores up to 12\xa0months after the procedure (Sonksen et al. 2015; Gratzke et al. 2016). Compared with Rezum, people having UroLift reported greater improvements in IPSS scores at 30\xa0days after the procedure (Tutrone and Schiff, 2020).\n\n## UroLift improves urinary flow and retention symptoms over time\n\nQmax improved up to 5\xa0years after UroLift treatment in most studies (Roehrborn et al. 2015; Bozkurt et al. 2016; Rukstalis et al. 2016; Roehrborn et al. 2017; Sievert et al. 2018; Rubio et al. 2019; Rukstalis et al. 2018). However, in Eure et al. (2019) Qmax decreased up to 6\xa0months after the procedure and no significant difference in Qmax was reported by Bardoli et al. (2017).\n\nIn 4\xa0studies there was a statistically significant improvement (up to 12\xa0months) in post-urination residual volume (Bozkurt et al. 2016; Rukstalis et al. 2016; Bardoli et al. 2017; Sievert et al. 2018). In Gratzke et al. (2016) Incontinence Severity Index scores remained unchanged up to 2\xa0years after UroLift treatment.\n\nTURP produced greater improvements in Qmax and post-urination residual volume up to 24\xa0months after the procedure compared with UroLift (Sonksen et al. 2015; Gratzke et al. 2016).\n\n## UroLift does not negatively affect sexual function\n\nIn most studies, the UroLift procedure did not result in statistically significant changes in erectile dysfunction. This was assessed using the International Index of Erectile Function and the Sexual Health Inventory for Men (SHIM) questionnaires (Bozkurt et al. 2016; Rukstalis et al. 2016; Rubio et al. 2019). However, in people with obstructive median lobes, there were improvements in both measures up to 12\xa0months after the procedure (Rukstalis et al. 2018). The amount of change in SHIM scores did not differ much between UroLift and TURP (Sonksen et al. 2015; Gratzke et al. 2016) but was statistically significantly better with UroLift than Rezum (Tutrone and Schiff, 2020).\n\nIn 5\xa0studies, Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MSHQ-EjD) scores after UroLift and other treatments were reported. In 2\xa0of these, there were improvements over time after UroLift (Roehrborn et al. 2015; Rukstalis et al. 2018). In 2\xa0other studies improvements over time with UroLift compared with TURP were not statistically significant (Sonksen et al. 2015; Gratze et al. 2016). In 1\xa0study the difference in scores between people who had UroLift or Rezum was not statistically significant at 30\xa0days follow up (Tutrone and Schiff, 2020).\n\n## UroLift reduces the rate and duration of postoperative catheterisation compared with TURP and Rezum\n\nAfter TURP 74% of people needed catheterisation for more than 24\xa0hours compared with 45% after UroLift (Sonksen et al. 2015). After UroLift 57% of people needed post-procedure catheterisation compared with 87% after Rezum (Tutrone and Schiff, 2020). Catheterisation time after UroLift was statistically significantly shorter than with Rezum (1.2\xa0days compared with 4.5\xa0days; Tutrone and Schiff, 2020).\n\n## UroLift improves quality of life\n\nEleven studies measured quality of life, with 8\xa0showing a statistically significant improvement up to 5\xa0years after UroLift treatment. Quality-of-life scores for people having UroLift were statistically significantly better than for people having Rezum (Tutrone and Schiff, 2020). In Sonksen et al. 2015 and Gratzke et al. 2016 there were no statistically significant differences between quality-of-life scores after TURP and UroLift at up to 12\xa0and 24\xa0months, respectively.\n\n## UroLift reduces the length of hospital stay compared with TURP\n\nIn 1\xa0study (Sonksen et al. 2015) hospitalisation times were reduced for UroLift (time to discharge 1.0\xa0days) compared with TURP (1.9\xa0days).\n\n## UroLift is effective for treating benign prostatic hyperplasia with an obstructive median lobe\n\nOne small study (Rukstalis et al. 2018) including 45\xa0people described the clinical effectiveness of using UroLift in people with an obstructive median lobe. UroLift reduced BPHII and IPSS scores of symptom severity and improved sexual function (MSHQ-EjD score), quality-of-life measures and urological outcomes (Qmax values). The changes were statistically significant.\n\n## Case studies show that UroLift is beneficial when used in the NHS\n\nAll 6\xa0NICE shared learning case studies suggested that UroLift was beneficial when used in the NHS, resulting in improved IPSS and quality-of-life scores, reduced surgery times and reduced hospital stay. In 1\xa0case study, the use of either general or local anaesthetic was compared, and no statistically significant differences were reported in IPSS, quality-of-life and pain scores after the procedure (NHS Fife, 2020).\n\n# Cost evidence\n\n## The company's updated cost model is based on the original model but Rezum is a comparator and median lobe treatment is included\n\nThe company updated the original economic model to include Rezum as a comparator and median lobe treatment. Clinical parameters for UroLift were based on the LIFT study, using 5‑year post-procedure data (Roehrborn et al. 2017). The original guidance was based on clinical parameters from the same trial at 1\xa0and 2\xa0years after the procedure (Roehrborn et al. 2013 and 2014). For full details of the cost evidence, see section\xa04 of the assessment report update.\n\n## The EAC adjusts assumptions in the cost model\n\nThe EAC updated some of the model's parameters, including the cost of incontinence to cover the 5‑year time horizon, the consumables costs for TURP procedures and the NHS reference costs.\n\n## The updated costs include a reduced number of implants used per surgery and reduced theatre time\n\nThe overall cost of UroLift was reduced by £200 per surgery because of adjustments in the number of devices implanted and the duration of surgery. The number of implants per surgery was reduced from 4\xa0to\xa03.5 and theatre time was decreased from 30\xa0minutes to 14\xa0minutes based on submitted audit data. These data were collected from NHS trusts over the past 3\xa0years for 552\xa0people who had treatment. The findings were supported by local audits carried out in NHS trusts and described in NICE shared learning case studies (NHS Fife 2020; Natarajan 2020; Dhanasekaran 2020b; Royal Devon and Exeter NHS Trust 2020; Norfolk and Norwich NHS Trust 2019).\n\n## Surgery follow up is changed to a telephone consultation\n\nChanging the follow up for UroLift surgery from a face-to-face consultation to a telephone consultation reduced the cost by £72.33 per consultation. This was based on an EAC cost of £37.00 for 20\xa0minutes of band\xa06 nurse time.\n\n## Costs increase for bipolar TURP, monopolar TURP and HoLEP compared with the original guidance\n\nIn the model update the costs of bipolar TURP and monopolar TURP increased compared with the original guidance. This was because of an increase in consumable costs for bipolar TURP, and to a lesser extent for monopolar TURP. The cost of managing incontinence was also applied to the whole population who have treatment instead of only when treatment has failed.\n\n## The revised EAC base-case analysis shows that UroLift is cost saving when compared with all comparators\n\nThe EAC's revised base-case analysis showed that when UroLift is done as an outpatient procedure, UroLift is cost saving, per person, by:\n\n£121 compared with Rezum\n\n£1,006 compared with bipolar TURP\n\n£1,267 compared with monopolar TURP and\n\n£1,255 compared with HoLEP.When UroLift is done as a day-case procedure, it is cost saving, per person, by:\n\n£96 compared with Rezum\n\n£981 compared with bipolar TURP\n\n£1,242 compared with monopolar TURP and\n\n£1,230 compared with HoLEP.The EAC concluded that UroLift is cost saving compared with monopolar TURP, bipolar TURP and HoLEP in the base case and in the company's and EAC's scenarios.\n\n## There is uncertainty as to whether UroLift is cost saving compared with Rezum\n\nThe UroLift economic model was compared with the model used in NICE's medical technologies guidance on Rezum. The committee concluded that there were too many uncertainties to draw firm conclusions about the costs of using Rezum compared with the costs of using UroLift. However, the Rezum base-case model results showed that Rezum was cost saving when compared with UroLift. The key parameters that were changed in the UroLift model were theatre time, length of stay and type of consultation after UroLift. If length of hospital stay were the same for Rezum and UroLift, Rezum would be cost saving compared with UroLift. However, the EAC's sensitivity analysis concluded that UroLift was only cost saving compared with Rezum if theatre time for the procedure was less than 16.7\xa0minutes.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## UroLift is effective with sustained clinical benefits, and the procedure is minimally invasive\n\nThe committee concluded that UroLift is clinically effective, with sustained relief of lower urinary tract symptoms up to 5\xa0years after treatment. It is implanted using a minimally invasive procedure. The clinical experts confirmed that in their practice, UroLift is an effective treatment that is well tolerated.\n\n## The UroLift procedure avoids the development of sexual dysfunction\n\nThe committee concluded that there was no evidence to suggest the UroLift procedure increases the risk of developing sexual dysfunction. The clinical experts explained that during the procedure there is no resection or ablation of prostate tissue. This is an important difference between UroLift and other invasive treatments for benign prostatic hyperplasia. Therefore, the committee considered that the reduced incidence of sexual dysfunction with UroLift, compared with comparator treatments, was plausible.\n\n## The person's preference is important in choosing an appropriate treatment for benign prostatic hyperplasia\n\nThe clinical experts explained that there are several invasive treatments for managing benign prostatic hyperplasia symptoms when drug treatment has not worked. Also, they explained that treatment is guided by what the person prefers because there is no definitive evidence that one treatment is better than another for all clinical outcomes. The committee noted that the updated evidence allowed direct comparison of UroLift with transurethral resection of the prostate (TURP). This evidence suggested that although the improvement in lower urinary tract symptoms may be greater after TURP the incidence of sexual dysfunction was lower with UroLift. The clinical experts explained that people for whom UroLift is considered suitable are also able to have Rezum treatment. The committee noted that there is only 1\xa0study comparing Rezum with UroLift, with a follow-up period of 30\xa0days. This showed that UroLift was better than Rezum for the short-term relief of lower urinary tract symptoms and for improving erectile dysfunction, but any comparative benefits beyond 30\xa0days were uncertain. The committee concluded that the evidence supported the use of UroLift. But, deciding whether to use UroLift or other technologies should be guided by clinical expertise and counselling for the person having the procedure.\n\n## The evidence for using UroLift for people with an obstructive median lobe is limited but shows promising clinical effectiveness\n\nThe clinical evidence for using UroLift for people with an obstructive median lobe consisted of 1\xa0small study of 45\xa0people with a 12‑month follow-up period. The results showed a statistically significant improvement in lower urinary tract symptoms and quality of life after UroLift without the development of sexual dysfunction. The clinical experts explained that they have successfully used UroLift to treat an obstructive median lobe. The committee concluded that the evidence was limited but promising for using UroLift to treat an obstructive median lobe.\n\n# Side effects and adverse events\n\n## Urinary tract infection is not a common complication after UroLift\n\nThe urinary tract infection rate after UroLift was 2.9% (Roehrborn et al. 2013). The clinical experts explained that the risk of urinary tract infection was, in their experience, lower with UroLift than with other procedures. This was likely to be because of the reduced need for urinary catheterisation after the procedure.\n\n## The treatment failure rate is low with UroLift\n\nThe clinical experts explained that UroLift has a good success rate in adequately relieving lower urinary tract symptoms, with an early failure rate of less than 5%. However, they considered that people may need further treatment, for example if the prostate enlarges further, so should expect a reintervention rate of up to 20%. The clinical evidence from the LIFT study showed a 13.6% reintervention rate at 5\xa0years after the procedure. This reintervention rate was used in the economic model for UroLift.\n\n# Relevance to the NHS\n\n## UroLift is an option for treating lower urinary tract symptoms caused by benign prostatic hyperplasia in the NHS\n\nA clinical expert confirmed that UroLift is widely used in the NHS since the publication of the original NICE guidance. However, there are now other minimally invasive procedures available to treat the condition in the same population, such as Rezum.\n\n# NHS considerations overview\n\n## UroLift can be done using general anaesthesia, or local anaesthesia with or without sedation\n\nThe clinical experts stated that in clinical practice, UroLift is done under either general anaesthesia or local anaesthesia (with or without sedation). The method of anaesthesia is tailored to the needs of the person having the procedure. If light sedation is needed with local anaesthesia, the clinical experts emphasised that it is important to have an appropriately trained professional, other than the surgeon, monitoring the person during and after the procedure. They also explained that doing flexible cystoscopy in the outpatient clinic to plan treatment is a good opportunity to assess tolerance and suitability for doing the procedure under local anaesthesia.\n\n## UroLift can be done as an outpatient procedure if appropriate facilities are available\n\nThe clinical experts explained that they do not currently offer UroLift as an outpatient treatment themselves but were aware that some clinicians do. UroLift procedures are offered in a small number of NHS trusts with outpatient facilities equipped for implant procedures and with recovery space to monitor people after the procedure. The clinical experts stated that if such facilities were available in their own centres they would also consider doing UroLift as an outpatient procedure.\n\n## Consider prostate volume when assessing whether UroLift is suitable\n\nThere is limited clinical evidence on using UroLift for prostates over 80\xa0ml in volume. The clinical experts confirmed that in their own practice, they consider UroLift is most appropriate for prostates under 80\xa0ml. They explained their experience that if UroLift is done on prostates over 80\xa0ml, more implants are needed. Also, the results are not likely to be as good and symptoms may recur. Clinical decision making is best supported by measuring prostate size objectively using transrectal ultrasound or MRI, but it can also be estimated from preoperative cystoscopy.\n\n## The proportion of flexible cystoscopies routinely carried out before a UroLift procedure is uncertain\n\nTwo of the clinical experts stated that they did flexible cystoscopy routinely before deciding whether to offer UroLift. This allowed them to see whether there is an obstructive median lobe and estimate the number of implants needed. They could also assess whether there are any other conditions, including bladder stones or bladder cancer, which might affect whether the procedure is done. One expert stated that they do not routinely do flexible cystoscopy before UroLift because of the added time and cost implications. There is uncertainty about the proportion of flexible cystoscopies routinely carried out before the procedure.\n\n## The procedure time and length of hospital stay for UroLift can vary\n\nThe clinical experts agreed that on average, the UroLift procedure takes 10\xa0to 15\xa0minutes per person to do. However, they noted that this does not take into account variations in time taken for the administration of local or general anaesthetic or for changeover time between procedures. The clinical experts also noted that the length of hospital stay can vary. This is because of local hospital procedures, the time taken to recover from the anaesthetic and for the person to empty their bladder (a requirement for leaving hospital).\n\n## Telephone follow up is routinely used\n\nTelephone follow up by a nurse was now routine with UroLift, Rezum, TURP and holmium laser enucleation of the prostate (HoLEP). People having Rezum, TURP or HoLEP also need to have a trial period without the urinary catheter in place, but the clinical experts explained that this was usually done in the community. The clinical experts also explained that people may return a few months after their procedure for objective tests to assess clinical outcomes such as flow rate and International Prostate Symptom Score.\n\n## UroLift is a minimally invasive procedure but may not be suitable for everyone\n\nThe clinical experts explained that TURP and HoLEP are unsuitable for some people with lower urinary tract symptoms, because of frailty or comorbidities. Although UroLift is minimally invasive, they considered that it may be unsuitable for some people in poor health and those who do not wish to have implants in their bodies. The decision to use UroLift should be made on an individual basis. The clinical experts noted that the implants can sometimes leave traces on MRI scans, which may be confusing if people are being investigated for possible prostate cancer. But if the radiologists interpreting the scans are aware that the person has UroLift implants, this should not be a problem.\n\n# Equality considerations\n\n## People who identify as women have had UroLift\n\nEight people who identify as women have had UroLift treatment. One of these procedures was done in the NHS. The clinical experts stated that doing a UroLift procedure in people who have had gender reassignment surgery did seem possible. Gender reassignment is a protected characteristic under the Equality Act 2010.\n\n# Cost modelling overview\n\n## UroLift is cost saving compared with standard treatments\n\nThe external assessment centre (EAC) revised the company's base case and showed that UroLift remained cost saving compared with the standard treatments, TURP and HoLEP. The committee accepted the EAC's conclusions. It noted that using UroLift was estimated to save, per person, £981 compared with bipolar TURP, £1,242 compared with monopolar TURP and £1,230 compared with HoLEP. This was over a 5‑year time horizon and if UroLift was done as a day-case procedure.\n\n## Follow-up care for comparators affects UroLift's cost case\n\nFurther analysis was done to look at the use of telephone follow up for all treatments and a trial without a catheter in the community for Rezum. UroLift remained cost saving when all treatments had a telephone follow up instead of an outpatient appointment. Rezum and UroLift were cost neutral when there was a trial without a catheter in the community, instead of as an outpatient, after Rezum. The committee considered that it was unclear which assumptions on follow-up care most closely resembled routine NHS practice. It concluded that this introduced some uncertainty in the cost case between UroLift and Rezum.\n\n## The number of implants used affects UroLift's cost case\n\nThe economic analysis included an assumption that an average of 3.5\xa0implants were used per person with UroLift treatment. The clinical experts thought this was an underestimate and that an average of 4\xa0implants was more appropriate, with a range of between 2\xa0and 6\xa0implants depending on prostate size. There was a learning curve associated with accurately judging the number of implants needed and usually after 15\xa0to 25\xa0procedures a surgeon can confidently do this. The committee acknowledged that the economic model was sensitive to the cost and number of implants used. But varying the number of implants used was unlikely to affect the cost savings when compared with TURP and with HoLEP. It concluded, however, that the cost case compared with Rezum was less certain if the number of implants varied. The clinical experts commented that this may mean that using UroLift for smaller prostates, with no obstructive median lobe, might be cost saving when compared with Rezum.\n\n## It is uncertain whether UroLift is cost saving compared with Rezum\n\nUroLift (if done as an outpatient procedure) was cost saving in the base case by £121 compared with Rezum for everyone who had treatment, over a 5‑year time horizon. However, the EAC's sensitivity analysis showed that Rezum would be cheaper if several parameters were changed individually, including:\n\nif the procedure time was the same for both procedures\n\nif the average number of UroLift implants exceeded\xa03.61.Further economic analysis showed that Rezum was likely to be cost saving if flexible cystoscopy was done before UroLift treatment. However, there was uncertainty around whether only people being considered for UroLift would have flexible cystoscopy. The clinical experts stated that they sometimes use flexible cystoscopy in assessing suitability for procedures other than UroLift.\n\n## The cost case for UroLift when treating an obstructive median lobe is uncertain because of the increasing number of implants\n\nBetween 5% and 20% of people with lower urinary tract symptoms of benign prostatic hyperplasia have an obstructive median lobe, which may not be identified before the procedure. The committee discussed that having an obstructive median lobe made UroLift's potential case for cost savings for the full population uncertain. The base case assumed that 5.3% of people have an obstructive median lobe, which means on average, 1.3\xa0additional implants per procedure. The clinical experts stated that in their practice, the average is more likely to be 2\xa0additional implants. This led to increasing uncertainty in the cost case for UroLift compared with Rezum. Rezum's cost is not affected by the presence of an obstructive median lobe.\n\n# Further research\n\n## The efficacy of UroLift compared with Rezum needs further research\n\nFurther evidence to address uncertainties about the relative clinical and cost effectiveness of UroLift compared with Rezum, especially in the NHS, would be welcome. This should include:\n\nexploring long-term clinical outcomes and reintervention rates after UroLift\n\nassessing the suitability of UroLift for prostates larger than 80\xa0ml and for those with an obstructive median lobe.This evidence could be generated by collating UK registry data and including the number of implants used, the length of the procedure and procedural outcomes."}
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https://www.nice.org.uk/guidance/mtg58
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Evidence-based recommendations on UroLift for treating lower urinary tract symptoms of benign prostatic hyperplasia.
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98718603dbe39453edd5f49d2191cc5a8fdb7954
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nice
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Repetitive short-pulse transscleral cyclophotocoagulation for glaucoma
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Repetitive short-pulse transscleral cyclophotocoagulation for glaucoma
Evidence-based recommendations on short-pulse transscleral cyclophotocoagulation for glaucoma. This involves using repeated short pulses of laser energy to destroy some of the cells in the eye that produce fluid. The aim is to reduce fluid, and so pressure, in the eye.
# Recommendations
Evidence on the safety of repetitive short-pulse transscleral cyclophotocoagulation for glaucoma shows no major safety concerns. Evidence on efficacy is inadequate in quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.
Further research should ideally be in the form of randomised controlled trials comparing the procedure with standard care. It should report details of patient selection, particularly whether the glaucoma is refractory or non-refractory. Outcomes should include duration of effect.# The condition, current treatments and procedure
# The condition
Glaucoma is usually a chronic condition associated with raised intraocular pressure. The most common type of glaucoma in the UK is primary (or chronic) open-angle glaucoma. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic. But, as the condition progresses, it causes visual impairment and, if untreated, blindness.
# Current treatments
NICE's guideline on glaucoma describes its diagnosis and management. Treatment is usually eye drops containing drugs that either reduce aqueous humor production or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy, laser trabeculoplasty and cyclodiode laser treatment may also be used.
# The procedure
Repetitive short-pulse transscleral cyclophotocoagulation (commonly known as micropulse transscleral cytophotocoagulation) uses a laser to target the same tissue as conventional cyclodiode laser treatment but it is delivered in pulses lasting microseconds. This allows the tissue to cool between pulses, with the aim of reducing collateral damage.
The procedure is normally done under local or general anaesthesia and usually takes 10 to 20 minutes. A probe is applied to the surface of the eye with firm pressure and moved in a continuous sliding motion over the upper or lower limbus of the eye, or both. To prevent ciliary neurovascular injury, the 3 and 9 o'clock positions are avoided. The device is set to deliver repetitive short-pulse (micropulse) laser energy with specified 'on' and 'off' times. Lower laser settings are used for patients with higher pigments to avoid overtreatment and inflammation. The laser treatment usually lasts between 100 seconds and 360 seconds per session. After the procedure, patients may need to wear an eye patch over the treated eye for about 24 hours and may be prescribed topical corticosteroids and antibiotics.
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{'Recommendations': 'Evidence on the safety of repetitive short-pulse transscleral cyclophotocoagulation for glaucoma shows no major safety concerns. Evidence on efficacy is inadequate in quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.\n\nFurther research should ideally be in the form of randomised controlled trials comparing the procedure with standard care. It should report details of patient selection, particularly whether the glaucoma is refractory or non-refractory. Outcomes should include duration of effect.', 'The condition, current treatments and procedure': "# The condition\n\nGlaucoma is usually a chronic condition associated with raised intraocular pressure. The most common type of glaucoma in the UK is primary (or chronic) open-angle glaucoma. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic. But, as the condition progresses, it causes visual impairment and, if untreated, blindness.\n\n# Current treatments\n\nNICE's guideline on glaucoma describes its diagnosis and management. Treatment is usually eye drops containing drugs that either reduce aqueous humor production or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy, laser trabeculoplasty and cyclodiode laser treatment may also be used.\n\n# The procedure\n\nRepetitive short-pulse transscleral cyclophotocoagulation (commonly known as micropulse transscleral cytophotocoagulation) uses a laser to target the same tissue as conventional cyclodiode laser treatment but it is delivered in pulses lasting microseconds. This allows the tissue to cool between pulses, with the aim of reducing collateral damage.\n\nThe procedure is normally done under local or general anaesthesia and usually takes 10\xa0to 20\xa0minutes. A probe is applied to the surface of the eye with firm pressure and moved in a continuous sliding motion over the upper or lower limbus of the eye, or both. To prevent ciliary neurovascular injury, the 3\xa0and 9\xa0o'clock positions are avoided. The device is set to deliver repetitive short-pulse (micropulse) laser energy with specified 'on' and 'off' times. Lower laser settings are used for patients with higher pigments to avoid overtreatment and inflammation. The laser treatment usually lasts between 100\xa0seconds and 360\xa0seconds per session. After the procedure, patients may need to wear an eye patch over the treated eye for about 24\xa0hours and may be prescribed topical corticosteroids and antibiotics."}
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https://www.nice.org.uk/guidance/ipg692
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Evidence-based recommendations on short-pulse transscleral cyclophotocoagulation for glaucoma. This involves using repeated short pulses of laser energy to destroy some of the cells in the eye that produce fluid. The aim is to reduce fluid, and so pressure, in the eye.
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20c673e1dadab501ed97d05da66bdae2403bec05
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nice
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Deep brain stimulation for chronic, severe, treatment-resistant obsessive-compulsive disorder in adults
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Deep brain stimulation for chronic, severe, treatment-resistant obsessive-compulsive disorder in adults
Evidence-based recommendations on deep brain stimulation for chronic, severe, treatment-resistant obsessive-compulsive disorder in adults. This involves implanting an electrode in the brain and an electrical stimulator under the skin on the chest.
# Recommendations
Evidence on the safety and efficacy of deep brain stimulation for chronic, severe, treatment-resistant obsessive-compulsive disorder (OCD) in adults is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Patient selection should be done by a multidisciplinary team experienced in managing OCD. It should include experts in psychiatry, neuropsychiatry, clinical psychology, neurology, neurosurgery and deep brain stimulation.
The procedure should only be done in centres with expertise in deep brain stimulation and experience in managing OCD.
Further research should primarily be randomised controlled trials. It should clearly define the area of the brain that should be targeted in this procedure. It should also describe details of patient selection, comorbidities, and use of adjunctive therapies. Outcomes should include reduction in OCD symptoms, improvement in quality of life and any neuropsychiatric and cognitive effects.# The condition, current treatments and procedure
# The condition
Obsessive-compulsive disorder (OCD) is a mental health condition in which a person has obsessive thoughts (repeated, unwanted and unpleasant thoughts, images or urges). The person feels compelled to carry out compulsive (repetitive) behaviours to try to relieve the unpleasant feelings brought on by the obsessive thoughts.
# Current treatments
NICE's guideline on obsessive-compulsive disorder and body dysmorphic disorder describes the treatment of OCD. Treatment options include psychological interventions and drug treatment (usually selective serotonin reuptake inhibitors).
# The procedure
Deep brain stimulation for OCD is done under general or local anaesthesia. A stereotactic frame may be used. MRI or CT imaging, or both, are used to identify the target area of the brain (commonly, the anterior limb of the internal capsule). Two small holes are drilled in the skull and electrodes are implanted into the target area. The electrodes are connected to an implantable neurostimulator by leads, which are tunnelled under the skin of the neck and scalp. The neurostimulator is surgically placed into a subcutaneous pocket below the clavicle. Postoperative imaging is usually used to confirm the location of the electrodes. A handheld remote-control programming unit is used to turn the neurostimulator on or off and adjust stimulation parameters to find the right level of stimulation.
Although the mechanisms of action of deep brain stimulation are not fully understood, the aim of the procedure is to reduce the obsessive-compulsive thoughts and behaviours. A potential advantage of the procedure is that the stimulation can be adjusted according to the clinical effect and if necessary, stopped completely. It can be used as an adjunct to medication and as an alternative to neurosurgery for treatment-resistant OCD.
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{'Recommendations': 'Evidence on the safety and efficacy of deep brain stimulation for chronic, severe, treatment-resistant obsessive-compulsive disorder (OCD) in adults is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a multidisciplinary team experienced in managing OCD. It should include experts in psychiatry, neuropsychiatry, clinical psychology, neurology, neurosurgery and deep brain stimulation.\n\nThe procedure should only be done in centres with expertise in deep brain stimulation and experience in managing OCD.\n\nFurther research should primarily be randomised controlled trials. It should clearly define the area of the brain that should be targeted in this procedure. It should also describe details of patient selection, comorbidities, and use of adjunctive therapies. Outcomes should include reduction in OCD symptoms, improvement in quality of life and any neuropsychiatric and cognitive effects.', 'The condition, current treatments and procedure': "# The condition\n\nObsessive-compulsive disorder (OCD) is a mental health condition in which a person has obsessive thoughts (repeated, unwanted and unpleasant thoughts, images or urges). The person feels compelled to carry out compulsive (repetitive) behaviours to try to relieve the unpleasant feelings brought on by the obsessive thoughts.\n\n# Current treatments\n\nNICE's guideline on obsessive-compulsive disorder and body dysmorphic disorder describes the treatment of OCD. Treatment options include psychological interventions and drug treatment (usually selective serotonin reuptake inhibitors).\n\n# The procedure\n\nDeep brain stimulation for OCD is done under general or local anaesthesia. A stereotactic frame may be used. MRI or CT imaging, or both, are used to identify the target area of the brain (commonly, the anterior limb of the internal capsule). Two small holes are drilled in the skull and electrodes are implanted into the target area. The electrodes are connected to an implantable neurostimulator by leads, which are tunnelled under the skin of the neck and scalp. The neurostimulator is surgically placed into a subcutaneous pocket below the clavicle. Postoperative imaging is usually used to confirm the location of the electrodes. A handheld remote-control programming unit is used to turn the neurostimulator on or off and adjust stimulation parameters to find the right level of stimulation.\n\nAlthough the mechanisms of action of deep brain stimulation are not fully understood, the aim of the procedure is to reduce the obsessive-compulsive thoughts and behaviours. A potential advantage of the procedure is that the stimulation can be adjusted according to the clinical effect and if necessary, stopped completely. It can be used as an adjunct to medication and as an alternative to neurosurgery for treatment-resistant OCD."}
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https://www.nice.org.uk/guidance/ipg693
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Evidence-based recommendations on deep brain stimulation for chronic, severe, treatment-resistant obsessive-compulsive disorder in adults. This involves implanting an electrode in the brain and an electrical stimulator under the skin on the chest.
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bc205da176a7307bfeb33a7b085bff08a49cf5b5
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nice
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Pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy
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Pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy
Evidence-based recommendations on pembrolizumab (Keytruda) for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy in adults.
# Recommendations
Pembrolizumab is not recommended, within its marketing authorisation, for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy.
This recommendation is not intended to affect treatment with pembrolizumab that was started in the Cancer Drugs Fund before this guidance was published. For those people, pembrolizumab will be funded by the company until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment for previously treated locally advanced or metastatic urothelial carcinoma includes docetaxel or paclitaxel. Clinical trial evidence shows that pembrolizumab significantly improves overall survival compared with docetaxel and paclitaxel. Some evidence has also been collected through the Cancer Drugs Fund.
Atezolizumab is now also a possible treatment. But it was not established clinical practice in the NHS at the time of the original appraisal, so is not included in the scope for this review.
If an active treatment is not tolerated or people choose not to have it, best supportive care is given. No clinical or cost-effectiveness evidence was available for pembrolizumab compared with best supportive care.
Pembrolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The most likely cost-effectiveness estimate for pembrolizumab is uncertain. This is because it is not clear which model of overall survival is most appropriate or how long the treatment benefit of pembrolizumab should continue. Even when pembrolizumab is offered with its agreed discount, the most plausible cost‑effectiveness estimate remains higher than what NICE normally considers acceptable for end‑of‑life treatments. Therefore, pembrolizumab is not recommended.# Information about pembrolizumab
# Marketing authorisation indication
Pembrolizumab (Keytruda, Merck Sharp & Dohme) has a marketing authorisation for 'the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
£2,630 per 100‑mg vial (excluding VAT; company submission).
The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The committee recognised that there were remaining areas of uncertainty in the analyses presented (see technical report, table 2, page 37) and took these into account in its decision making. It discussed issues 1 to 5 from the technical report, which were not resolved after technical engagement:
choice of extrapolation for progression-free survival
treatment switching
choice of extrapolation curve and cut-off point for overall survival
treatment effect duration
PD-L1 expression subgroups.
# The condition
## Locally advanced or metastatic urothelial carcinoma substantially decreases quality of life
Urothelial carcinoma causes a number of symptoms, including haematuria (blood in the urine) and increased frequency, urgency and pain associated with urination. Surgical treatments such as urostomy can have a substantial effect on quality of life and restrict daily activities. The patient experts explained that chemotherapy is associated with unpleasant side effects such as fatigue, nausea and vomiting and puts people at a greater risk of infection. The committee was aware that many people with locally advanced or metastatic urothelial carcinoma are older and may have comorbidities, which can affect treatment decisions. It recognised that locally advanced or metastatic urothelial carcinoma has a significant impact on quality of life.
# Current treatments and comparators
## Paclitaxel, docetaxel and best supportive care are the relevant comparators for this appraisal
The committee was aware that the treatment pathway for locally advanced or metastatic urothelial carcinoma had changed since the original appraisal of pembrolizumab for this indication. This is because of NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy (from now, TA525). Atezolizumab was not established clinical practice in the NHS when the final scope for the original appraisal of pembrolizumab was issued. In a review of a drug funded by the Cancer Drugs Fund, no changes to the final scope of the original appraisal are allowed, so atezolizumab could not be included as a comparator (see section 6.25 of the NICE guide to the processes of technology appraisal). At the time of the original appraisal of pembrolizumab, first-line treatment for locally advanced or metastatic disease was usually a platinum‑containing chemotherapy regimen. For people who were not well enough or chose not to have this, best supportive care was offered. Retreatment with a first-line chemotherapy was also included in the scope for the original appraisal of pembrolizumab. However, it was not established clinical practice then, because retreatment was used before a second-line treatment option was available. Also, most clinicians would have used a taxane (paclitaxel and docetaxel). The committee agreed that treatment options for people with disease progression after platinum-containing chemotherapy at that time included docetaxel, paclitaxel or best supportive care. The committee concluded for the original appraisal that the most relevant comparators were paclitaxel, docetaxel and best supportive care.
## The KEYNOTE-045 post-hoc subgroup results are most appropriate for decision making
The clinical-effectiveness evidence for pembrolizumab came from KEYNOTE‑045, an open-label, randomised controlled trial. It included people with disease progression or recurrence of urothelial cancer after treatment with a platinum-containing regimen (cisplatin or carboplatin). The comparator arm in the trial was the investigator's choice of paclitaxel, docetaxel or vinflunine. The company recognised that vinflunine is not used in clinical practice in the UK and did a post-hoc subgroup analysis. This included:
people randomised to have pembrolizumab
people randomised to have the investigator's choice of paclitaxel or docetaxel (referred to as the 'UK standard of care ' control arm).The committee concluded that the trial was good quality and the results were informative for decision making. It was aware that using post-hoc subgroup analyses introduced the risk of bias and that excluding the vinflunine data reduces the statistical power of the trial. But the committee concluded that the post-hoc subgroup best reflects UK clinical practice and is the most appropriate evidence for decision making.
## Pembrolizumab improves overall survival compared with docetaxel or paclitaxel
In KEYNOTE-045, progression-free survival and overall survival were co‑primary end points. In the latest data cut of KEYNOTE‑045, the median overall survival for pembrolizumab was 10.1 months (95% confidence interval 7.6 to 12.9) compared with 6.2 months (95% CI 5.2 to 7.4) for the UK SoC arm with a hazard ratio of 0.64 (95% CI 0.49 to 0.81). This suggests that pembrolizumab improves overall survival compared with docetaxel or paclitaxel. However, the median progression-free survival for pembrolizumab was 2.1 months (95% CI 2.0 to 2.2) compared with 3.3 months (95% CI 2.3 to 3.5) in the UK SoC arm, with a hazard ratio of 0.95 (95% CI 0.76 to 1.19). The committee concluded that pembrolizumab improves overall survival but does not appear to improve progression-free survival. The additional clinical data collected by Public Health England as part of the Systemic Anti-Cancer Therapy dataset while pembrolizumab was in the Cancer Drugs Fund did not contribute to this review.
## The 2-stage method for subsequent immunotherapy in KEYNOTE-045 is appropriate in the original appraisal
If their disease progressed, people in the trial could have subsequent anti‑PD‑L1 or PD‑1 treatment. This included atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab. The company adjusted overall survival in the UK SoC arm to account for these treatments using the 2‑stage method to adjust for treatment switching. The 2‑stage method used an acceleration factor (a ratio of the survivor function for the pembrolizumab and UK SoC treatment arms). This was to shrink the survival time of patients who had UK SoC, were eligible for subsequent therapy, and who then had anti-PD‑L1 or PD‑1 therapy. The ERG believed that the 2‑stage method had disadvantages, but overall was the most appropriate. The committee concluded that the company's 2‑stage method was appropriate for decision making in the original appraisal.
## New KEYNOTE-045 data shows that the 2-stage method may not be appropriate, and the unadjusted method should also be taken into account
The November 2018 data cut from KEYNOTE‑045 showed that the acceleration factor was larger and applied to more people in the trial. This meant the 2‑stage adjustment had a greater influence on overall survival than it did in the original appraisal. The acceleration factor was 5.37 (95% CI 3.23 to 10.09; based on 25 patients) after the November 2018 data cut, compared with 3.86 (95% CI 1.79 to 11.68; based on 14 patients) using previous data. The ERG considered that both the 2‑stage adjusted analyses and analyses without this adjustment for treatment switching should be carefully considered. It advised that the true overall survival benefit would be somewhere between the result of the 2 approaches. Using an approach without the adjustment might overestimate survival time in the UK SoC arm, but the 2‑stage method might underestimate survival time in this arm too much. The ERG advised that the main uncertainties with the 2‑stage adjustment were:
The wide confidence interval around the acceleration factor showed a high degree of uncertainty.
The adjustment method assumed an average adjustment for all people switching to anti‑PD‑L1 or PD‑1 therapy. The ERG considered it unlikely that all patients who switched benefited equally from the anti‑PD‑L1 or PD‑1 treatment. This was because evidence from KEYNOTE‑045 suggested pembrolizumab had less benefit than UK SoC for the first 3 months of follow up, and because immunotherapies have not been shown to benefit everyone.
With the adjustment, the benefit would have been the same as if patients had anti‑PD‑L1 or PD‑1 therapy earlier in their disease pathway. The KEYNOTE‑045 trial data did not support this.
There was potential for selection bias related to switching and unmeasured prognostic factors could affect the data. In response to the appraisal consultation document, the company advised that it considered the updated acceleration factor to be more reliable than the original acceleration factor. This was because it was calculated from a larger sample size and the confidence intervals were narrower and within the range of the originally calculated confidence intervals. The ERG stated that the main concern was not the size of the acceleration factor, but that the increased size meant the adjustment had more influence and so the existing uncertainties associated with the 2‑stage method were more important. With the most up-to-date data from November 2018, 40 people on the UK SoC arm of the trial switched to an anti‑PD‑L1 or PD‑1 treatment. The acceleration factor was calculated from the 25 people who switched when progression of their disease was documented. The acceleration factor was not applied to the overall survival time of 15 patients who switched at different times. The ERG stated that the company had not provided an established rule for switching. In response to consultation, the company provided a sensitivity analysis applying the acceleration factor to all 40 patients. In this, the hazard ratio for pembrolizumab compared with UK SoC was 0.55. However, the calculation of the acceleration factor was not adjusted to include these 15 patients. The committee considered that using the 2‑stage adjustment for treatment switching likely underestimated the incremental cost‑effectiveness ratios (ICERs) but using no adjustment would overestimate the ICERs. It concluded that the true overall survival benefit was probably between that seen with an adjustment for treatment switching and that without an adjustment. The committee considered this issue further after an appeal (see sections 3.23 and 3.26).
## PD-L1-positive subgroups are not clinically distinct
The company defined PD‑L1 expression in KEYNOTE‑045 by combined proportion score, which includes PD‑L1 expression in both the solid tumour and the infiltrating immune cells. The company did not present an analysis showing the interaction between treatment effect and PD‑L1 status, or results for the PD‑L1-negative subgroup using data from the November 2018 cut-off. The committee agreed there was inherent uncertainty when considering estimates of effectiveness based on any subgroup data. The clinical expert explained that PD‑L1 is not a predictive biomarker for pembrolizumab after platinum‑containing chemotherapy, but it is more relevant for pembrolizumab for people when cisplatin is unsuitable. This is reflected in the marketing authorisation for pembrolizumab in the first-line indication for people when cisplatin is unsuitable, because it specifies PD‑L1 expression through combined proportion score level. The clinical expert advised that diagnostic tissue samples for combined proportion score testing are taken before first-line treatment, and combined proportion score may change after platinum-based chemotherapy. This means combined proportion score and PD‑L1 expression are not predictive biomarkers in this post-chemotherapy population. The committee agreed that PD‑L1-positive subgroups were not clinically distinct subgroups for this indication. It concluded to not consider PD‑L1 subgroups in its decision making.
# Comparison with best supportive care
## No evidence is available comparing pembrolizumab with best supportive care
The committee considered best supportive care as a relevant comparator, because a few people would have best supportive care if an active treatment was not tolerated or they chose not to have it (see section 3.2). There was no direct trial evidence comparing pembrolizumab with best supportive care. The company did not consider best supportive care a relevant comparator and, in the original appraisal, did not present any new clinical or cost-effectiveness evidence comparing pembrolizumab with best supportive care. Therefore, the committee concluded it was unable to make a recommendation on this and agreed not to consider it further.
# Adverse events
## Pembrolizumab is well tolerated in clinical practice
Pembrolizumab is associated with some rare but unpleasant, and potentially serious, adverse events that are specific to immunotherapy. The committee understood that pembrolizumab was well tolerated and that patients considered it to have fewer severe adverse events than chemotherapy. The patient experts explained that although pembrolizumab does have side effects, these are typically less than for chemotherapy for this indication. They suggested that pembrolizumab did not interfere with everyday activities as much. The committee concluded that pembrolizumab was well tolerated.
# Assumptions used in the economic model
## A 2-year stopping rule for pembrolizumab is appropriate
In the KEYNOTE‑045 protocol, the maximum pembrolizumab treatment duration was 2 years from the first dose, when treatment must be stopped. This was not reflected in the summary of product characteristics, which states that treatment should continue until disease progression or unacceptable toxicity. For pembrolizumab for other indications, and in TA525, a 2‑year stopping rule was applied. The committee noted that the 2‑year stopping rule was included in company's economic model and concluded that it was appropriate.
## A Weibull curve is the most appropriate to model progression-free survival in both treatment arms
In the original appraisal, the committee concluded that the Weibull curve for progression-free survival was appropriate. The committee noted that, for the review, the company still extrapolated progression-free survival from 21 weeks, but preferred a log-normal curve for the pembrolizumab arm. This was based on statistical and visual fit to the KEYNOTE‑045 data, and then was used for the UK SoC arm to be consistent. The ERG considered it appropriate to extrapolate from 21 weeks, but only found the Weibull curve to consistently be among the best fitting curves for both the pembrolizumab and the UK SoC arms. This was according to the Akaike information criterion and the Bayesian information criterion. The ERG explained that NICE's technical support document 14 advises that when parametric models are fitted separately to individual treatment arms, the same extrapolation should be used for both arms. Otherwise, substantial justification would be needed to use different extrapolation models. The committee considered the Weibull curve to fit well to the almost-complete data for the UK SoC arm, and also to the 2 to 3‑year progression-free survival data for pembrolizumab (the benefit is very uncertain beyond that). The Weibull curve was most consistent with the Kaplan−Meier data seen at 2 and 3 years in both arms of the KEYNOTE‑045 trial, and was also a good visual fit. The committee concluded that the Weibull curve was the most appropriate curve to model progression-free survival and that it should be used for both the pembrolizumab and UK SoC arms.
## A piecewise model is appropriate to model overall survival, and the best time to switch to a parametric curve is at 24 weeks
The company used a piecewise approach to model overall survival, in which Kaplan−Meier data are used first before switching to a parametric curve. This is because the cumulative hazard plot showed that the hazards crossed and therefore the proportional hazards assumption did not hold. The company incorporated switching to a parametric curve at week 24 in its base-case analysis because the cumulative hazard curves started separating from week 24. The committee agreed that the company's piecewise model was appropriate to model overall survival and the best time for switching to a parametric curve was at 24 weeks.
## The long-term effect of a stopping rule on the duration of treatment effect is unknown for immunotherapies, but a lifetime treatment effect is implausible
A 2-year stopping rule was appropriate for pembrolizumab (see section 3.10). The duration of continued treatment effect after implementation of a stopping rule is an area of uncertainty for all immunotherapies. Before this review, there were no data from KEYNOTE‑045 on the effect of implementing the stopping rule, because the longest follow up was only 20.8 months. In the original appraisal, the committee concluded that a lifetime treatment effect was implausible. While a small number of patients could have 'immune memory' after the 2‑year stopping point for treatment with pembrolizumab, this was uncertain. The clinical expert explained that the long-term effect of stopping immunotherapy at 2 years was still unknown for any disease.
## Evidence of treatment effect duration from other pembrolizumab trials is not appropriate for decision making
The company highlighted that data supporting a long-term survival benefit was available across the pembrolizumab clinical study programme, particularly from KEYNOTE‑001 (melanoma, non‑small‑cell lung cancer), KEYNOTE‑006 (melanoma) and KEYNOTE‑024 (non‑small‑cell lung cancer). The committee was aware that melanoma and non-small-cell lung cancer trials for pembrolizumab had some of the strongest evidence for a sustained response in a small number of patients. However, it recognised that the evidence suggests that treatment effect duration varies in different types of cancers. It therefore agreed that the results from those trials were not generalisable to urothelial carcinoma.
## There is no strong evidence to support the 5-year duration of treatment effect from the start of pembrolizumab treatment in the company's base case
For this review, the company used a 5‑year treatment effect duration from the start of treatment with pembrolizumab in its base case, and 3 years and 10 years of treatment effect from the start of treatment in its scenario analyses. It supported its choice of a 5‑year treatment effect duration in its base case by showing that the hazard ratio for overall survival for pembrolizumab compared with the UK SoC arm (using its preferred 2‑stage adjustment, see section 3.4) had improved with additional follow-up data (median follow up 40.9 months, range 36.6 to 48.9 months). The comparison with the data from the original appraisal cannot be shown here as the hazard ratio is academic in confidence. The company explained that this trend was seen with the full trial population in the comparator arm of KEYNOTE‑045 and when data for the UK SoC arm (unadjusted for treatment switching) was used. The company considered that a 2‑year or 3‑year cap on the duration of treatment effect from the start of treatment was inappropriate. This was because any longer-term benefit of pembrolizumab would not be taken into consideration, and extrapolation in the pembrolizumab arm did not fit well to the Kaplan−Meier overall survival data from the November 2018 data cut-off. The company indicated that with its preferred log-logistic curve for extrapolation of overall survival (see section 3.20), 4.5% of people having pembrolizumab were modelled to still be alive 10 years after starting treatment. Around 50% of patients in KEYNOTE‑045 stopped pembrolizumab 6 months after starting treatment. The clinical expert found it plausible that 5% to 10% of people having pembrolizumab might survive to 10 years after starting treatment (with a 2‑year stopping rule). A patient expert and the Cancer Drugs Fund clinical lead agreed that there was uncertainty about how long people might survive after having pembrolizumab. This is because people with urothelial cancer tend to be older, with other comorbidities, so those people whose cancer responds to treatment could die from another cause before 10 years after starting treatment. The committee agreed that there was no strong evidence to support a 5‑year or longer treatment effect, and no more than 5% of people treated with pembrolizumab might be alive after 10 years.
## Based on the available evidence, a 3-year duration of treatment effect from the start of pembrolizumab is plausible
The ERG suggested that the improved hazard ratio for overall survival for pembrolizumab with the extended follow up could be explained by greater data completeness (patients in the trial progressing or dying in the longer follow-up period). The ERG preferred to use a 3‑year duration of treatment effect in its exploratory base case, because it thought there was reasonably robust evidence of an effect up until 2 years from starting treatment, but limited support for an effect beyond 3 years. This was because after 3 years, there was only 1 death in the unadjusted (see section 3.5) UK SoC arm and none in the adjusted population. Although the ERG accepted that there was some evidence of sustained response for pembrolizumab, it also considered that the same was true for the UK SoC arm, with no evidence to suggest the hazard rate for long‑term response was different across treatment arms after 2 years. The clinical expert advised that the sustained response from pembrolizumab was greater than that for the UK SoC arm. They stated that there was a small group of people who had pembrolizumab supporting at least a 3‑year duration of treatment effect from the start of treatment. The clinical expert explained that this was not the case for people who had chemotherapy, because very few people survive beyond 2 years. The committee considered that there was robust evidence to support a 3‑year treatment effect after starting pembrolizumab (2 years of treatment plus 1 year of follow up). It concluded that, although the effect duration was uncertain, based on the available evidence a 3‑year duration treatment from the start of pembrolizumab was plausible.
## The company's new scenario analyses on duration of treatment effect are not appropriate for the model
In response to consultation, the company highlighted that 38.5% of people in the pembrolizumab arm had a best overall response of disease control. It presented several scenario analyses in which 38.5% of people continued to benefit from pembrolizumab for their lifetime, while the rest had the same benefit as the UK SoC arm after either 3 or 5 years. The ERG highlighted that the company had assumed the same level of response to pembrolizumab for people whose disease responded and people whose disease did not respond for the first 3 or 5 years of the model. It considered that the 2 groups would be likely to have quite different survival outcomes. The committee considered that it was arbitrary to split the pembrolizumab arm at 3 or 5 years and that a split at baseline with a different statistical analysis may have been more plausible. It also noted that the analysis was not applied to the UK SoC arm although there were people in the UK SoC arm whose disease also became stable. The committee concluded that the company's new scenario analyses were not appropriate for the model.
## A 3-year to 5-year duration of treatment effect from the start of pembrolizumab treatment could be plausible
In response to consultation, the company also presented a summary of response rates from KEYNOTE‑045. It highlighted that the median duration of response for responders was 29.7 months in the pembrolizumab arm and 4.4 months in the UK SoC arm. The 36‑month overall survival rate was 20.7% in the pembrolizumab arm and 11.0% in the UK SoC arm. The proportion of responses lasting 24 months or more was 56.8% in the pembrolizumab arm and 28.3% in the UK SoC arm. The company also stated that the trial was not designed to show a treatment benefit beyond 3 years. At consultation, professional groups also highlighted these figures and stated that they were consistent with more positive long-term survival estimates than those previously assumed by the committee. The committee agreed that the Kaplan‒Meier evidence did not suggest a long-term difference in hazard rates between the 2 treatment arms. It considered that there was robust evidence to support a 3‑year treatment effect after starting pembrolizumab (see section 3.16). However, it also considered that the new figures suggested the relative treatment effect of pembrolizumab might continue beyond 3 years. The committee recalled that in the NICE technology appraisal guidance on atezolizumab (TA525) analyses with a treatment effect cap at 3 years after stopping were taken into account in its decision making but there was not enough evidence to support a specific duration of benefit. The committee agreed that the treatment effect duration was uncertain. It concluded that a 3‑year to 5‑year treatment effect from start of pembrolizumab treatment could be plausible. The committee considered this issue further after an appeal (see sections 3.23 and 3.24).
## The costs of pembrolizumab are likely underestimated in the model
The NHS England commissioning expert highlighted that in KEYNOTE‑045, people in the pembrolizumab arm who stopped taking pembrolizumab because they had a complete response or after the 2‑year stopping rule could restart pembrolizumab for up to 1 year if their disease progressed. The company explained that 10 people out of 188 in the pembrolizumab arm had retreatment with pembrolizumab and that the costs of this were not included in the model. It explained that it was difficult to separate out the benefit these people may have had with retreatment from the overall benefit of taking pembrolizumab. The committee concluded that although only a small proportion of patients had retreatment, the costs of pembrolizumab were likely underestimated in the model. The committee considered this issue further after an appeal (see sections 3.23 and 3.25).
## There are 3 plausible overall survival extrapolation curves
In its base case, the company preferred the log-logistic extrapolation for overall survival. This choice was based on statistical and visual fit to the updated overall survival data from KEYNOTE‑045 (see section 3.6). The company highlighted that the log-logistic curve gave a 3.2% 5‑year survival rate for the UK SoC arm, consistent with the 2% to 3% figure given by the ERG's clinical expert in the original appraisal. The ERG preferred a log-logistic curve in its exploratory base case. But, it also considered the log-normal and generalised gamma plausible if some patients experienced the long-term survival benefit for pembrolizumab suggested by the company (with generalised gamma being the most optimistic). If no patients experienced this long-term survival benefit, then the ERG advised that the Weibull extrapolation would be plausible. The ERG explained that the company's preferred curve and anticipated long-tailed survival profile for pembrolizumab in the long term were plausible, but unsupported by evidence (see section 3.15). The committee acknowledged that there were a number of plausible overall survival extrapolation curves. Because a small number of people having pembrolizumab may survive to 10 years after starting treatment (see section 3.15), the committee agreed that the Weibull extrapolation would penalise overall survival too harshly. But, the log-logistic, log-normal and generalised gamma were plausible if there were any survivors at 10 years. However, there was a high degree of uncertainty around long-term overall survival for pembrolizumab and all immunotherapies at 10 years because of a lack of data. So, the committee concluded that log-logistic, log-normal and generalised gamma were all plausible and that all 3 should be taken into account in decision making.
## The company's utility value estimates are appropriate
EQ‑5D data were collected directly in KEYNOTE‑045; these data are the preferred measure of health-related quality of life in adults. In the company's base case, vinflunine data was not included in the utility estimates because vinflunine is not used in UK clinical practice and is not included in the survival data (see sections 3.3 and 3.6). The company based the utility values on progression state and used the most recent age-related disutility algorithm. It also pooled the utility estimates across treatment arms. The committee agreed with the utility values estimates used in the company's economic model.
# The cost-effectiveness estimates before the appeal
## The most plausible ICER for pembrolizumab compared with docetaxel and paclitaxel is likely to be over £50,000 per QALY gained
The company's base-case deterministic ICER for pembrolizumab was £47,123 per quality-adjusted life year (QALY) gained compared with docetaxel or paclitaxel. This was based on the following assumptions: log-normal extrapolation for progression-free survival from 21 weeks; log-logistic extrapolation for overall survival from 24 weeks; a 5‑year treatment effect duration from the start of treatment with pembrolizumab; 2‑stage adjustment for treatment switching applied to the UK SoC arm. The committee noted that without the 2‑stage adjustment for switching (see section 3.5) the company's ICER increased to £56,422 per QALY gained. The ERG changed the company's base case to use a Weibull extrapolation for progression-free survival from 21 weeks, which was the committee's preferred assumption (see section 3.11). This increased the ICER for pembrolizumab to £48,518 per QALY gained, and to £58,850 per QALY gained without the 2‑stage adjustment for treatment switching (both ICERs including a 5‑year treatment duration effect). The ERG then also included a 3‑year treatment effect duration, which the committee agreed was plausible (see section 3.18). The ICER for pembrolizumab increased to £53,678 per QALY gained with the 2‑stage adjustment for treatment switching and to £65,469 per QALY gained without the 2-stage adjustment. Considering all 3 plausible options for the extrapolation of overall survival (log‑logistic, log-normal and generalised gamma, see section 3.20), with the 2‑stage adjustment for treatment switching, the Weibull extrapolation for progression‑free survival and the 3‑year treatment effect duration, the ICER ranged from £53,678 to £58,705 per QALY gained. The equivalent ICERs without the 2‑stage adjustment ranged from £61,653 to £70,520 per QALY gained. The committee agreed the most plausible ICERs were somewhere between those with the 2‑stage adjustment for treatment switching in the UK SoC arm and those without the adjustment (see section 3.5). It also agreed that the ICER of £48,518 per QALY gained was at the lowest end of the range of plausible ICERs, but it was unlikely to be the most plausible because it was based on the most optimistic of the committee's preferred assumptions. When taking into account the uncertainty about the 2‑stage adjustment, the uncertainty around the plausible treatment effect duration (3 to 5 years, see section 3.18) and the 3 plausible overall survival extrapolations (see section 3.20), the committee noted that the ICER could be as high as £70,520 per QALY gained. This was also unlikely to be the most plausible ICER because it was based on the most pessimistic of the committee's preferred assumptions. The committee also considered that the costs of pembrolizumab could be underestimated in the model (see section 3.19) and that increasing the costs of pembrolizumab would increase the ICERs. Considering all these factors, the committee concluded that the most plausible ICER for pembrolizumab compared with docetaxel and paclitaxel was likely to be over £50,000 per QALY gained.
# After the appeal
At the third appraisal committee meeting, the committee considered the appeal panel's decision to uphold 3 appeal points and refer these back to the appraisal committee for further consideration. These were:
The committee needs to clearly explain its rationale for accepting a different approach to the duration of treatment effect than TA525 (see section 3.24).
The committee should allow the company an opportunity to respond to the issue of retreatment costs (see section 3.25).
The committee should consider a range of acceleration factors for the 2‑stage method to adjust for treatment switching. Also, it should reconsider whether it is appropriate to give equal weight to analyses that did not adjust for treatment switching (see section 3.26).The committee considered the company's updated analyses including a revised patient access scheme.
## Differences in the clinical and economic evidence between this appraisal and TA525 mean it is appropriate to consider different treatment effect durations
The committee considered the first upheld appeal point (see section 3.23). It discussed the reasoning behind its previous conclusion to consider 3‑year and 5‑year treatment effect durations after starting pembrolizumab for decision making (see section 3.18). In TA525 all analyses that varied the treatment effect duration, from a lifetime effect to a 3‑year effect after stopping atezolizumab, had ICERs that were comfortably within the range normally considered cost effective for end-of-life technologies. The exact ICERs are confidential and cannot be reported here. The committee noted several other differences between the 2 appraisals:
The 5‑year treatment effect duration used in TA525 was not supported by robust evidence because the IMvigor211 trial had a maximum follow up of 25 months. However, extended follow-up data from KEYNOTE‑045 were available. Those data suggested that the treatment benefit with pembrolizumab was unlikely to be sustained after 3 years (see section 3.16).
Pembrolizumab treatment was only given for 2 years in KEYNOTE‑045 but there was no treatment cap for atezolizumab in IMvigor211.
In IMvigor211, patients continued taking atezolizumab until unmanageable toxicity or lack of clinical efficacy. This means that some people continued taking atezolizumab after their disease progressed. So, any treatment benefit may have lasted for longer than if treatment was stopped after disease progression (as in KEYNOTE‑045).
In KEYNOTE‑045, 10 patients had retreatment with pembrolizumab after disease progression (see sections 3.19 and 3.25). These patients being offered a second course of pembrolizumab suggests that a long‑term treatment effect after their initial course was not expected. In TA525, there was no evidence of retreatment with atezolizumab.
In the model, the proportion of patients alive at 2 years still having treatment was lower for pembrolizumab than for atezolizumab.
The company for atezolizumab did not provide analyses assuming a 3‑year treatment effect duration from starting treatment.The committee carefully considered these differences. It reiterated that there was no robust evidence to support a 5‑year treatment effect, but acknowledged that it could be plausible (see section 3.18). In TA525, although it had not seen analyses assuming a 3‑year treatment effect duration from starting treatment, all ICERs were comfortably cost effective. This meant the committee was confident a 3‑year treatment effect analysis would also have had a cost-effective ICER. It concluded that its rationale for considering analyses using 3‑year and 5‑year treatment effect durations from the start of pembrolizumab treatment was reasonable, based primarily on the difference in cost-effectiveness estimates between this appraisal and TA525, and supported by the differences in the evidence.
## The cost of retreatment should be included at 3 years
The committee considered the second upheld appeal point (see section 3.23). After the appeal, the company submitted scenario analyses that included the costs of pembrolizumab retreatment for the 10 patients that had it. The company and ERG had different preferences about when to apply this cost in the model. The committee agreed that the ERG's preference (3 years) was more consistent with the data, but acknowledged the timing had negligible impact on cost-effectiveness results. The company could have provided analyses that removed potential survival benefit from retreatment instead of adding the costs, but it did not do so. The company advised that pembrolizumab retreatment has uncertain clinical benefit and does not reflect clinical practice in the NHS in England. So, it considered that its preferred analysis without the costs remained appropriate for decision making. The committee found it inconsistent to include the potential benefits of retreatment without the costs, so both should either be included or excluded. In the absence of an analysis removing the benefits of retreatment, it concluded that the costs should be applied at 3 years.
## Unadjusted analyses are not suitable for decision making
The committee considered the third upheld appeal point (see section 3.23). It previously concluded that analyses that did not attempt to adjust for treatment switching method should be taken into account (see section 3.6). After the appeal, both the company and ERG agreed that the unadjusted analyses were not appropriate for decision making. The committee agreed that the unadjusted analyses would be less robust than the 2‑stage adjustment method. It concluded that unadjusted analyses were not suitable for decision making.
## The ERG's analysis of post-progression survival times is suitable for decision making
Having concluded that analyses based on the 2‑stage adjustment for treatment switching were appropriate for decision making, the committee discussed the acceleration factor used in the adjustment. The company's base case remained unchanged and used the point estimate of 5.37, but it provided a scenario analysis using the lower bound of the 95% confidence interval (3.23). The company submitted 3 additional analyses exploring the effect of different acceleration factors. The ERG described the limitations of those analyses:
Including recensoring led to much less follow up and considerably less information on the control arm. This made it unlikely to be useful for decision making.
Using an acceleration factor of 5.32 included people who had vinflunine, which is not licensed in England.
Applying an acceleration factor of 5.37 (calculated based on 25 patients who switched after disease progression) to all 40 patients that switched, including 15 who switched at different times, was discussed previously (see section 3.6). The company did not provide more information on the characteristics of these patients.The committee agreed that only the 5.37 and 3.23 acceleration factors were relevant to the decision, because the company's additional analyses had important limitations. At the clarification stage, the ERG asked the company to provide the patient-level data and code needed to reproduce and explore the acceleration factor. The company provided the code but not the patient-level data. So, the ERG approximated progression and survival data using outputs from the model, to examine how different acceleration factors affected post‑progression survival. The ERG's analysis predicted how long patients who switched treatment would have lived for if they had not switched treatment (the counterfactual). The company considered that the ERG's comparison of post-progression survival estimates was flawed, because it did not adjust the full standard care arm for the 15 patients who switched to an active treatment at different times. The committee would have liked to have seen a comparison of the characteristics of those 15 patients with the 25 who switched after disease progression, but the company did not provide those data. Therefore, it agreed that it was appropriate to consider the ERG's analyses in its decision making.
## An acceleration factor of 5.37 is not plausible, and although 3.23 is more appropriate the most plausible value is very uncertain and may be lower
Using the company's preferred acceleration factor of 5.37, the ERG's analysis (see section 3.27) predicted that patients who switched would otherwise have had shorter post-progression survival than the average patient in the standard care arm. The exact data are confidential and cannot be reported here. Using the lower bound acceleration factor of 3.23, the ERG predicted that patients who switched would otherwise have had similar post-progression survival to the average patient in the standard care arm. It advised that this suggests the company's preferred acceleration factor (5.37) was adjusting survival on the standard care arm too much. This was because it attributed too much post‑progression survival benefit to the effect of the new treatment and too little to potential confounding factors. The company provided analyses that adjusted for several potential confounders such as age, gender and ECOG performance status, but did not provide enough information to allow the ERG to validate these analyses. Therefore, the ERG's preferred analysis used the lower bound acceleration factor (3.23), which was closer to the original acceleration factor applied in the original appraisal (3.86). The committee considered that patients who were offered and accepted a treatment switch were likely to have a relatively good prognosis and post‑progression survival compared with the average patient having standard care. Therefore, it agreed that the company's preferred acceleration factor (5.37) produced clinically implausible results in the ERG's analysis, while the ERG's preferred acceleration factor (3.23) produced more plausible results. It acknowledged that 3.23 is closer to the value that was accepted in the original appraisal (3.86). The committee agreed that 5.37 adjusted survival on the standard care arm too much. It recalled the limitations of the 2‑stage method (see section 3.6) and noted that the ERG had not been provided with the data to validate the company's 2‑stage adjustment in detail. This meant the point estimate acceleration factor (5.37) and its lower bound (3.23) were both subject to the same methodological uncertainties. It also noted that 3.23 was an arbitrary value to use, presented only because it is the confidence interval's lower bound. Therefore, the committee agreed that neither value was robust, but the most plausible acceleration factor is likely to be closer to 3.23 than 5.37, and it could plausibly be even lower than 3.23. It concluded that it would consider analyses using both acceleration factors in its decision making, but would be mindful that 3.23 was likely to be more plausible than 5.37 and the most plausible value could be even lower.
# End of life
## Life expectancy for people with urothelial carcinoma is less than 24 months
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. For people with locally advanced or metastatic disease who have had platinum-containing chemotherapy, data from the company's model and from the literature showed that median overall survival was much less than 24 months for people having treatment with UK standard care. The clinical experts also agreed that they would expect people with locally advanced or metastatic urothelial carcinoma to live for less than 24 months. The committee concluded that the short life expectancy criterion was met.
## Pembrolizumab extends life by at least 3 months, and meets the criteria for end-of-life treatments
The median overall survival for pembrolizumab in KEYNOTE‑045 using the November 2018 cut‑off was 10.1 months (95% CI 7.6 to 12.9) compared with 6.2 months (95% CI 5.2 to 7.4) for UK SoC (using a 2‑stage method for adjustment). The committee concluded that pembrolizumab would extend life by more than 3 months, and therefore met the end-of-life criteria.
# Cost-effectiveness estimates after the appeal
## The most plausible ICER for pembrolizumab compared with docetaxel and paclitaxel is likely to be over £50,000 per QALY gained
After the appeal, the company's base-case deterministic ICER was £43,181 per QALY gained with the revised patient access scheme. The committee noted that the company's preferred assumptions had not changed after the appeal (see section 3.22). The committee took into account its preferred assumptions of:
considering both the 3‑year and 5‑year treatment effect durations from the start of pembrolizumab (see section 3.24)
adding retreatment costs at 3 years (see section 3.25)
considering analyses using the 2-stage method with acceleration factors of 3.23 and 5.37 to adjust for treatment switching, noting that 3.23 was more likely to be plausible than 5.37 (see sections 3.27 and 3.28).The committee found the log-logistic, log-normal and generalised gamma overall survival functions all plausible (see section 3.20). Therefore, the ICERs considered for decision making ranged from £44,903 to £58,323 per QALY gained. The committee noted that the higher ICERs in this range were associated with an acceleration factor of 3.23, which it reiterated was more plausible than 5.37 and the most appropriate acceleration factor could be even lower. It concluded that the most plausible ICER was likely to be over £50,000 per QALY gained. It also agreed that most ICERs considered would need to be comfortably below £50,000 per QALY gained for it to be confident that pembrolizumab was cost effective, given the substantial uncertainty in the value of the acceleration factor and treatment effect duration.
# Cancer Drugs Fund
## Pembrolizumab cannot be recommended in the Cancer Drugs Fund
The aim of a Cancer Drugs Fund guidance review is to decide whether or not the drug can be recommended for routine use. Pembrolizumab for locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy will not remain in the Cancer Drugs Fund once the guidance review has been completed (see NICE's guide to the processes of technology appraisal).
# Conclusion
## Pembrolizumab is not recommended for routine use
The committee considered that the most plausible ICER was above the range that NICE normally considers a cost-effective use of NHS resources for a life‑extending treatment at the end of life. It agreed that there is uncertainty surrounding the acceleration factor estimates (more likely to be 3.23 than 5.37, but may be even lower) and therefore the cost-effectiveness results. So, most ICERs in the range considered for decision making should be substantially below £50,000 per QALY gained (that is, the maximum weight of 1.7 applied to the normal range of maximum acceptable ICERs). Based on the range of ICERs considered in decision making, it concluded not to recommend pembrolizumab for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy.
# Other factors
No equality issues were identified.
The company did not highlight any additional benefits that had not been captured in the QALY calculations.
|
{'Recommendations': "Pembrolizumab is not recommended, within its marketing authorisation, for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy.\n\nThis recommendation is not intended to affect treatment with pembrolizumab that was started in the Cancer Drugs Fund before this guidance was published. For those people, pembrolizumab will be funded by the company until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for previously treated locally advanced or metastatic urothelial carcinoma includes docetaxel or paclitaxel. Clinical trial evidence shows that pembrolizumab significantly improves overall survival compared with docetaxel and paclitaxel. Some evidence has also been collected through the Cancer Drugs Fund.\n\nAtezolizumab is now also a possible treatment. But it was not established clinical practice in the NHS at the time of the original appraisal, so is not included in the scope for this review.\n\nIf an active treatment is not tolerated or people choose not to have it, best supportive care is given. No clinical or cost-effectiveness evidence was available for pembrolizumab compared with best supportive care.\n\nPembrolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The most likely cost-effectiveness estimate for pembrolizumab is uncertain. This is because it is not clear which model of overall survival is most appropriate or how long the treatment benefit of pembrolizumab should continue. Even when pembrolizumab is offered with its agreed discount, the most plausible cost‑effectiveness estimate remains higher than what NICE normally considers acceptable for end‑of‑life treatments. Therefore, pembrolizumab is not recommended.", 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp & Dohme) has a marketing authorisation for 'the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\n£2,630 per 100‑mg vial (excluding VAT; company submission).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe committee recognised that there were remaining areas of uncertainty in the analyses presented (see technical report, table\xa02, page\xa037) and took these into account in its decision making. It discussed issues\xa01 to 5 from the technical report, which were not resolved after technical engagement:\n\nchoice of extrapolation for progression-free survival\n\ntreatment switching\n\nchoice of extrapolation curve and cut-off point for overall survival\n\ntreatment effect duration\n\nPD-L1 expression subgroups.\n\n# The condition\n\n## Locally advanced or metastatic urothelial carcinoma substantially decreases quality of life\n\nUrothelial carcinoma causes a number of symptoms, including haematuria (blood in the urine) and increased frequency, urgency and pain associated with urination. Surgical treatments such as urostomy can have a substantial effect on quality of life and restrict daily activities. The patient experts explained that chemotherapy is associated with unpleasant side effects such as fatigue, nausea and vomiting and puts people at a greater risk of infection. The committee was aware that many people with locally advanced or metastatic urothelial carcinoma are older and may have comorbidities, which can affect treatment decisions. It recognised that locally advanced or metastatic urothelial carcinoma has a significant impact on quality of life.\n\n# Current treatments and comparators\n\n## Paclitaxel, docetaxel and best supportive care are the relevant comparators for this appraisal\n\nThe committee was aware that the treatment pathway for locally advanced or metastatic urothelial carcinoma had changed since the original appraisal of pembrolizumab for this indication. This is because of NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy (from now, TA525). Atezolizumab was not established clinical practice in the NHS when the final scope for the original appraisal of pembrolizumab was issued. In a review of a drug funded by the Cancer Drugs Fund, no changes to the final scope of the original appraisal are allowed, so atezolizumab could not be included as a comparator (see section\xa06.25 of the NICE guide to the processes of technology appraisal). At the time of the original appraisal of pembrolizumab, first-line treatment for locally advanced or metastatic disease was usually a platinum‑containing chemotherapy regimen. For people who were not well enough or chose not to have this, best supportive care was offered. Retreatment with a first-line chemotherapy was also included in the scope for the original appraisal of pembrolizumab. However, it was not established clinical practice then, because retreatment was used before a second-line treatment option was available. Also, most clinicians would have used a taxane (paclitaxel and docetaxel). The committee agreed that treatment options for people with disease progression after platinum-containing chemotherapy at that time included docetaxel, paclitaxel or best supportive care. The committee concluded for the original appraisal that the most relevant comparators were paclitaxel, docetaxel and best supportive care.\n\n## The KEYNOTE-045 post-hoc subgroup results are most appropriate for decision making\n\nThe clinical-effectiveness evidence for pembrolizumab came from KEYNOTE‑045, an open-label, randomised controlled trial. It included people with disease progression or recurrence of urothelial cancer after treatment with a platinum-containing regimen (cisplatin or carboplatin). The comparator arm in the trial was the investigator's choice of paclitaxel, docetaxel or vinflunine. The company recognised that vinflunine is not used in clinical practice in the UK and did a post-hoc subgroup analysis. This included:\n\npeople randomised to have pembrolizumab\n\npeople randomised to have the investigator's choice of paclitaxel or docetaxel (referred to as the 'UK standard of care [UK SoC]' control arm).The committee concluded that the trial was good quality and the results were informative for decision making. It was aware that using post-hoc subgroup analyses introduced the risk of bias and that excluding the vinflunine data reduces the statistical power of the trial. But the committee concluded that the post-hoc subgroup best reflects UK clinical practice and is the most appropriate evidence for decision making.\n\n## Pembrolizumab improves overall survival compared with docetaxel or paclitaxel\n\nIn KEYNOTE-045, progression-free survival and overall survival were co‑primary end points. In the latest data cut of KEYNOTE‑045, the median overall survival for pembrolizumab was 10.1\xa0months (95% confidence interval [CI] 7.6 to 12.9) compared with 6.2\xa0months (95% CI 5.2 to 7.4) for the UK SoC arm with a hazard ratio of 0.64 (95% CI 0.49 to 0.81). This suggests that pembrolizumab improves overall survival compared with docetaxel or paclitaxel. However, the median progression-free survival for pembrolizumab was 2.1\xa0months (95% CI 2.0 to 2.2) compared with 3.3\xa0months (95% CI 2.3 to 3.5) in the UK SoC arm, with a hazard ratio of 0.95 (95% CI 0.76 to 1.19). The committee concluded that pembrolizumab improves overall survival but does not appear to improve progression-free survival. The additional clinical data collected by Public Health England as part of the Systemic Anti-Cancer Therapy dataset while pembrolizumab was in the Cancer Drugs Fund did not contribute to this review.\n\n## The 2-stage method for subsequent immunotherapy in KEYNOTE-045 is appropriate in the original appraisal\n\nIf their disease progressed, people in the trial could have subsequent anti‑PD‑L1 or PD‑1 treatment. This included atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab. The company adjusted overall survival in the UK SoC arm to account for these treatments using the 2‑stage method to adjust for treatment switching. The 2‑stage method used an acceleration factor (a ratio of the survivor function for the pembrolizumab and UK SoC treatment arms). This was to shrink the survival time of patients who had UK SoC, were eligible for subsequent therapy, and who then had anti-PD‑L1 or PD‑1 therapy. The ERG believed that the 2‑stage method had disadvantages, but overall was the most appropriate. The committee concluded that the company's 2‑stage method was appropriate for decision making in the original appraisal.\n\n## New KEYNOTE-045 data shows that the 2-stage method may not be appropriate, and the unadjusted method should also be taken into account\n\nThe November 2018 data cut from KEYNOTE‑045 showed that the acceleration factor was larger and applied to more people in the trial. This meant the 2‑stage adjustment had a greater influence on overall survival than it did in the original appraisal. The acceleration factor was 5.37 (95% CI 3.23 to 10.09; based on 25\xa0patients) after the November 2018 data cut, compared with 3.86 (95%\xa0CI 1.79 to 11.68; based on 14\xa0patients) using previous data. The ERG considered that both the 2‑stage adjusted analyses and analyses without this adjustment for treatment switching should be carefully considered. It advised that the true overall survival benefit would be somewhere between the result of the 2\xa0approaches. Using an approach without the adjustment might overestimate survival time in the UK SoC arm, but the 2‑stage method might underestimate survival time in this arm too much. The ERG advised that the main uncertainties with the 2‑stage adjustment were:\n\nThe wide confidence interval around the acceleration factor showed a high degree of uncertainty.\n\nThe adjustment method assumed an average adjustment for all people switching to anti‑PD‑L1 or PD‑1 therapy. The ERG considered it unlikely that all patients who switched benefited equally from the anti‑PD‑L1 or PD‑1 treatment. This was because evidence from KEYNOTE‑045 suggested pembrolizumab had less benefit than UK SoC for the first 3\xa0months of follow up, and because immunotherapies have not been shown to benefit everyone.\n\nWith the adjustment, the benefit would have been the same as if patients had anti‑PD‑L1 or PD‑1 therapy earlier in their disease pathway. The KEYNOTE‑045 trial data did not support this.\n\nThere was potential for selection bias related to switching and unmeasured prognostic factors could affect the data. In response to the appraisal consultation document, the company advised that it considered the updated acceleration factor to be more reliable than the original acceleration factor. This was because it was calculated from a larger sample size and the confidence intervals were narrower and within the range of the originally calculated confidence intervals. The ERG stated that the main concern was not the size of the acceleration factor, but that the increased size meant the adjustment had more influence and so the existing uncertainties associated with the 2‑stage method were more important. With the most up-to-date data from November 2018, 40\xa0people on the UK SoC arm of the trial switched to an anti‑PD‑L1 or PD‑1 treatment. The acceleration factor was calculated from the 25\xa0people who switched when progression of their disease was documented. The acceleration factor was not applied to the overall survival time of 15\xa0patients who switched at different times. The ERG stated that the company had not provided an established rule for switching. In response to consultation, the company provided a sensitivity analysis applying the acceleration factor to all 40\xa0patients. In this, the hazard ratio for pembrolizumab compared with UK SoC was 0.55. However, the calculation of the acceleration factor was not adjusted to include these 15\xa0patients. The committee considered that using the 2‑stage adjustment for treatment switching likely underestimated the incremental cost‑effectiveness ratios (ICERs) but using no adjustment would overestimate the ICERs. It concluded that the true overall survival benefit was probably between that seen with an adjustment for treatment switching and that without an adjustment. The committee considered this issue further after an appeal (see sections\xa03.23 and\xa03.26).\n\n## PD-L1-positive subgroups are not clinically distinct\n\nThe company defined PD‑L1 expression in KEYNOTE‑045 by combined proportion score, which includes PD‑L1 expression in both the solid tumour and the infiltrating immune cells. The company did not present an analysis showing the interaction between treatment effect and PD‑L1 status, or results for the PD‑L1-negative subgroup using data from the November 2018 cut-off. The committee agreed there was inherent uncertainty when considering estimates of effectiveness based on any subgroup data. The clinical expert explained that PD‑L1 is not a predictive biomarker for pembrolizumab after platinum‑containing chemotherapy, but it is more relevant for pembrolizumab for people when cisplatin is unsuitable. This is reflected in the marketing authorisation for pembrolizumab in the first-line indication for people when cisplatin is unsuitable, because it specifies PD‑L1 expression through combined proportion score level. The clinical expert advised that diagnostic tissue samples for combined proportion score testing are taken before first-line treatment, and combined proportion score may change after platinum-based chemotherapy. This means combined proportion score and PD‑L1 expression are not predictive biomarkers in this post-chemotherapy population. The committee agreed that PD‑L1-positive subgroups were not clinically distinct subgroups for this indication. It concluded to not consider PD‑L1 subgroups in its decision making.\n\n# Comparison with best supportive care\n\n## No evidence is available comparing pembrolizumab with best supportive care\n\nThe committee considered best supportive care as a relevant comparator, because a few people would have best supportive care if an active treatment was not tolerated or they chose not to have it (see section\xa03.2). There was no direct trial evidence comparing pembrolizumab with best supportive care. The company did not consider best supportive care a relevant comparator and, in the original appraisal, did not present any new clinical or cost-effectiveness evidence comparing pembrolizumab with best supportive care. Therefore, the committee concluded it was unable to make a recommendation on this and agreed not to consider it further.\n\n# Adverse events\n\n## Pembrolizumab is well tolerated in clinical practice\n\nPembrolizumab is associated with some rare but unpleasant, and potentially serious, adverse events that are specific to immunotherapy. The committee understood that pembrolizumab was well tolerated and that patients considered it to have fewer severe adverse events than chemotherapy. The patient experts explained that although pembrolizumab does have side effects, these are typically less than for chemotherapy for this indication. They suggested that pembrolizumab did not interfere with everyday activities as much. The committee concluded that pembrolizumab was well tolerated.\n\n# Assumptions used in the economic model\n\n## A 2-year stopping rule for pembrolizumab is appropriate\n\nIn the KEYNOTE‑045 protocol, the maximum pembrolizumab treatment duration was 2\xa0years from the first dose, when treatment must be stopped. This was not reflected in the summary of product characteristics, which states that treatment should continue until disease progression or unacceptable toxicity. For pembrolizumab for other indications, and in TA525, a 2‑year stopping rule was applied. The committee noted that the 2‑year stopping rule was included in company's economic model and concluded that it was appropriate.\n\n## A Weibull curve is the most appropriate to model progression-free survival in both treatment arms\n\nIn the original appraisal, the committee concluded that the Weibull curve for progression-free survival was appropriate. The committee noted that, for the review, the company still extrapolated progression-free survival from 21\xa0weeks, but preferred a log-normal curve for the pembrolizumab arm. This was based on statistical and visual fit to the KEYNOTE‑045 data, and then was used for the UK SoC arm to be consistent. The ERG considered it appropriate to extrapolate from 21\xa0weeks, but only found the Weibull curve to consistently be among the best fitting curves for both the pembrolizumab and the UK SoC arms. This was according to the Akaike information criterion and the Bayesian information criterion. The ERG explained that NICE's technical support document\xa014 advises that when parametric models are fitted separately to individual treatment arms, the same extrapolation should be used for both arms. Otherwise, substantial justification would be needed to use different extrapolation models. The committee considered the Weibull curve to fit well to the almost-complete data for the UK SoC arm, and also to the 2\xa0to 3‑year progression-free survival data for pembrolizumab (the benefit is very uncertain beyond that). The Weibull curve was most consistent with the Kaplan−Meier data seen at\xa02 and 3\xa0years in both arms of the KEYNOTE‑045 trial, and was also a good visual fit. The committee concluded that the Weibull curve was the most appropriate curve to model progression-free survival and that it should be used for both the pembrolizumab and UK SoC arms.\n\n## A piecewise model is appropriate to model overall survival, and the best time to switch to a parametric curve is at 24\xa0weeks\n\nThe company used a piecewise approach to model overall survival, in which Kaplan−Meier data are used first before switching to a parametric curve. This is because the cumulative hazard plot showed that the hazards crossed and therefore the proportional hazards assumption did not hold. The company incorporated switching to a parametric curve at week\xa024 in its base-case analysis because the cumulative hazard curves started separating from week\xa024. The committee agreed that the company's piecewise model was appropriate to model overall survival and the best time for switching to a parametric curve was at 24\xa0weeks.\n\n## The long-term effect of a stopping rule on the duration of treatment effect is unknown for immunotherapies, but a lifetime treatment effect is implausible\n\nA 2-year stopping rule was appropriate for pembrolizumab (see section\xa03.10). The duration of continued treatment effect after implementation of a stopping rule is an area of uncertainty for all immunotherapies. Before this review, there were no data from KEYNOTE‑045 on the effect of implementing the stopping rule, because the longest follow up was only 20.8\xa0months. In the original appraisal, the committee concluded that a lifetime treatment effect was implausible. While a small number of patients could have 'immune memory' after the 2‑year stopping point for treatment with pembrolizumab, this was uncertain. The clinical expert explained that the long-term effect of stopping immunotherapy at 2\xa0years was still unknown for any disease.\n\n## Evidence of treatment effect duration from other pembrolizumab trials is not appropriate for decision making\n\nThe company highlighted that data supporting a long-term survival benefit was available across the pembrolizumab clinical study programme, particularly from KEYNOTE‑001 (melanoma, non‑small‑cell lung cancer), KEYNOTE‑006 (melanoma) and KEYNOTE‑024 (non‑small‑cell lung cancer). The committee was aware that melanoma and non-small-cell lung cancer trials for pembrolizumab had some of the strongest evidence for a sustained response in a small number of patients. However, it recognised that the evidence suggests that treatment effect duration varies in different types of cancers. It therefore agreed that the results from those trials were not generalisable to urothelial carcinoma.\n\n## There is no strong evidence to support the 5-year duration of treatment effect from the start of pembrolizumab treatment in the company's base case\n\nFor this review, the company used a 5‑year treatment effect duration from the start of treatment with pembrolizumab in its base case, and 3\xa0years and 10\xa0years of treatment effect from the start of treatment in its scenario analyses. It supported its choice of a 5‑year treatment effect duration in its base case by showing that the hazard ratio for overall survival for pembrolizumab compared with the UK SoC arm (using its preferred 2‑stage adjustment, see section\xa03.4) had improved with additional follow-up data (median follow up 40.9\xa0months, range 36.6 to 48.9\xa0months). The comparison with the data from the original appraisal cannot be shown here as the hazard ratio is academic in confidence. The company explained that this trend was seen with the full trial population in the comparator arm of KEYNOTE‑045 and when data for the UK SoC arm (unadjusted for treatment switching) was used. The company considered that a 2‑year or 3‑year cap on the duration of treatment effect from the start of treatment was inappropriate. This was because any longer-term benefit of pembrolizumab would not be taken into consideration, and extrapolation in the pembrolizumab arm did not fit well to the Kaplan−Meier overall survival data from the November 2018 data cut-off. The company indicated that with its preferred log-logistic curve for extrapolation of overall survival (see section\xa03.20), 4.5% of people having pembrolizumab were modelled to still be alive 10\xa0years after starting treatment. Around 50% of patients in KEYNOTE‑045 stopped pembrolizumab 6\xa0months after starting treatment. The clinical expert found it plausible that 5% to 10% of people having pembrolizumab might survive to 10\xa0years after starting treatment (with a 2‑year stopping rule). A patient expert and the Cancer Drugs Fund clinical lead agreed that there was uncertainty about how long people might survive after having pembrolizumab. This is because people with urothelial cancer tend to be older, with other comorbidities, so those people whose cancer responds to treatment could die from another cause before 10\xa0years after starting treatment. The committee agreed that there was no strong evidence to support a 5‑year or longer treatment effect, and no more than 5% of people treated with pembrolizumab might be alive after 10\xa0years.\n\n## Based on the available evidence, a 3-year duration of treatment effect from the start of pembrolizumab is plausible\n\nThe ERG suggested that the improved hazard ratio for overall survival for pembrolizumab with the extended follow up could be explained by greater data completeness (patients in the trial progressing or dying in the longer follow-up period). The ERG preferred to use a 3‑year duration of treatment effect in its exploratory base case, because it thought there was reasonably robust evidence of an effect up until 2\xa0years from starting treatment, but limited support for an effect beyond 3\xa0years. This was because after 3\xa0years, there was only 1\xa0death in the unadjusted (see section\xa03.5) UK SoC arm and none in the adjusted population. Although the ERG accepted that there was some evidence of sustained response for pembrolizumab, it also considered that the same was true for the UK SoC arm, with no evidence to suggest the hazard rate for long‑term response was different across treatment arms after 2\xa0years. The clinical expert advised that the sustained response from pembrolizumab was greater than that for the UK SoC arm. They stated that there was a small group of people who had pembrolizumab supporting at least a 3‑year duration of treatment effect from the start of treatment. The clinical expert explained that this was not the case for people who had chemotherapy, because very few people survive beyond 2\xa0years. The committee considered that there was robust evidence to support a 3‑year treatment effect after starting pembrolizumab (2\xa0years of treatment plus 1\xa0year of follow up). It concluded that, although the effect duration was uncertain, based on the available evidence a 3‑year duration treatment from the start of pembrolizumab was plausible.\n\n## The company's new scenario analyses on duration of treatment effect are not appropriate for the model\n\nIn response to consultation, the company highlighted that 38.5% of people in the pembrolizumab arm had a best overall response of disease control. It presented several scenario analyses in which 38.5% of people continued to benefit from pembrolizumab for their lifetime, while the rest had the same benefit as the UK SoC arm after either 3\xa0or 5\xa0years. The ERG highlighted that the company had assumed the same level of response to pembrolizumab for people whose disease responded and people whose disease did not respond for the first 3\xa0or 5\xa0years of the model. It considered that the 2\xa0groups would be likely to have quite different survival outcomes. The committee considered that it was arbitrary to split the pembrolizumab arm at 3\xa0or 5\xa0years and that a split at baseline with a different statistical analysis may have been more plausible. It also noted that the analysis was not applied to the UK SoC arm although there were people in the UK SoC arm whose disease also became stable. The committee concluded that the company's new scenario analyses were not appropriate for the model.\n\n## A 3-year to 5-year duration of treatment effect from the start of pembrolizumab treatment could be plausible\n\nIn response to consultation, the company also presented a summary of response rates from KEYNOTE‑045. It highlighted that the median duration of response for responders was 29.7\xa0months in the pembrolizumab arm and 4.4\xa0months in the UK SoC arm. The 36‑month overall survival rate was 20.7% in the pembrolizumab arm and 11.0% in the UK SoC arm. The proportion of responses lasting 24\xa0months or more was 56.8% in the pembrolizumab arm and 28.3% in the UK SoC arm. The company also stated that the trial was not designed to show a treatment benefit beyond 3\xa0years. At consultation, professional groups also highlighted these figures and stated that they were consistent with more positive long-term survival estimates than those previously assumed by the committee. The committee agreed that the Kaplan‒Meier evidence did not suggest a long-term difference in hazard rates between the 2\xa0treatment arms. It considered that there was robust evidence to support a 3‑year treatment effect after starting pembrolizumab (see section\xa03.16). However, it also considered that the new figures suggested the relative treatment effect of pembrolizumab might continue beyond 3\xa0years. The committee recalled that in the NICE technology appraisal guidance on atezolizumab (TA525) analyses with a treatment effect cap at 3\xa0years after stopping were taken into account in its decision making but there was not enough evidence to support a specific duration of benefit. The committee agreed that the treatment effect duration was uncertain. It concluded that a 3‑year to 5‑year treatment effect from start of pembrolizumab treatment could be plausible. The committee considered this issue further after an appeal (see sections\xa03.23 and\xa03.24).\n\n## The costs of pembrolizumab are likely underestimated in the model\n\nThe NHS England commissioning expert highlighted that in KEYNOTE‑045, people in the pembrolizumab arm who stopped taking pembrolizumab because they had a complete response or after the 2‑year stopping rule could restart pembrolizumab for up to 1\xa0year if their disease progressed. The company explained that 10\xa0people out of\xa0188 in the pembrolizumab arm had retreatment with pembrolizumab and that the costs of this were not included in the model. It explained that it was difficult to separate out the benefit these people may have had with retreatment from the overall benefit of taking pembrolizumab. The committee concluded that although only a small proportion of patients had retreatment, the costs of pembrolizumab were likely underestimated in the model. The committee considered this issue further after an appeal (see sections\xa03.23 and\xa03.25).\n\n## There are 3 plausible overall survival extrapolation curves\n\nIn its base case, the company preferred the log-logistic extrapolation for overall survival. This choice was based on statistical and visual fit to the updated overall survival data from KEYNOTE‑045 (see section\xa03.6). The company highlighted that the log-logistic curve gave a 3.2% 5‑year survival rate for the UK SoC arm, consistent with the 2% to 3% figure given by the ERG's clinical expert in the original appraisal. The ERG preferred a log-logistic curve in its exploratory base case. But, it also considered the log-normal and generalised gamma plausible if some patients experienced the long-term survival benefit for pembrolizumab suggested by the company (with generalised gamma being the most optimistic). If no patients experienced this long-term survival benefit, then the ERG advised that the Weibull extrapolation would be plausible. The ERG explained that the company's preferred curve and anticipated long-tailed survival profile for pembrolizumab in the long term were plausible, but unsupported by evidence (see section\xa03.15). The committee acknowledged that there were a number of plausible overall survival extrapolation curves. Because a small number of people having pembrolizumab may survive to 10\xa0years after starting treatment (see section\xa03.15), the committee agreed that the Weibull extrapolation would penalise overall survival too harshly. But, the log-logistic, log-normal and generalised gamma were plausible if there were any survivors at 10\xa0years. However, there was a high degree of uncertainty around long-term overall survival for pembrolizumab and all immunotherapies at 10\xa0years because of a lack of data. So, the committee concluded that log-logistic, log-normal and generalised gamma were all plausible and that all\xa03 should be taken into account in decision making.\n\n## The company's utility value estimates are appropriate\n\nEQ‑5D data were collected directly in KEYNOTE‑045; these data are the preferred measure of health-related quality of life in adults. In the company's base case, vinflunine data was not included in the utility estimates because vinflunine is not used in UK clinical practice and is not included in the survival data (see sections\xa03.3 and\xa03.6). The company based the utility values on progression state and used the most recent age-related disutility algorithm. It also pooled the utility estimates across treatment arms. The committee agreed with the utility values estimates used in the company's economic model.\n\n# The cost-effectiveness estimates before the appeal\n\n## The most plausible ICER for pembrolizumab compared with docetaxel and paclitaxel is likely to be over £50,000 per QALY gained\n\nThe company's base-case deterministic ICER for pembrolizumab was £47,123 per quality-adjusted life year (QALY) gained compared with docetaxel or paclitaxel. This was based on the following assumptions: log-normal extrapolation for progression-free survival from 21\xa0weeks; log-logistic extrapolation for overall survival from 24\xa0weeks; a 5‑year treatment effect duration from the start of treatment with pembrolizumab; 2‑stage adjustment for treatment switching applied to the UK SoC arm. The committee noted that without the 2‑stage adjustment for switching (see section\xa03.5) the company's ICER increased to £56,422 per QALY gained. The ERG changed the company's base case to use a Weibull extrapolation for progression-free survival from 21\xa0weeks, which was the committee's preferred assumption (see section\xa03.11). This increased the ICER for pembrolizumab to £48,518 per QALY gained, and to £58,850 per QALY gained without the 2‑stage adjustment for treatment switching (both ICERs including a 5‑year treatment duration effect). The ERG then also included a 3‑year treatment effect duration, which the committee agreed was plausible (see section\xa03.18). The ICER for pembrolizumab increased to £53,678 per QALY gained with the 2‑stage adjustment for treatment switching and to £65,469 per QALY gained without the 2-stage adjustment. Considering all 3 plausible options for the extrapolation of overall survival (log‑logistic, log-normal and generalised gamma, see section\xa03.20), with the 2‑stage adjustment for treatment switching, the Weibull extrapolation for progression‑free survival and the 3‑year treatment effect duration, the ICER ranged from £53,678 to £58,705 per QALY gained. The equivalent ICERs without the 2‑stage adjustment ranged from £61,653 to £70,520 per QALY gained. The committee agreed the most plausible ICERs were somewhere between those with the 2‑stage adjustment for treatment switching in the UK SoC arm and those without the adjustment (see section\xa03.5). It also agreed that the ICER of £48,518 per QALY gained was at the lowest end of the range of plausible ICERs, but it was unlikely to be the most plausible because it was based on the most optimistic of the committee's preferred assumptions. When taking into account the uncertainty about the 2‑stage adjustment, the uncertainty around the plausible treatment effect duration (3\xa0to 5\xa0years, see section\xa03.18) and the 3\xa0plausible overall survival extrapolations (see section\xa03.20), the committee noted that the ICER could be as high as £70,520 per QALY gained. This was also unlikely to be the most plausible ICER because it was based on the most pessimistic of the committee's preferred assumptions. The committee also considered that the costs of pembrolizumab could be underestimated in the model (see section\xa03.19) and that increasing the costs of pembrolizumab would increase the ICERs. Considering all these factors, the committee concluded that the most plausible ICER for pembrolizumab compared with docetaxel and paclitaxel was likely to be over £50,000 per QALY gained.\n\n# After the appeal\n\nAt the third appraisal committee meeting, the committee considered the appeal panel's decision to uphold 3\xa0appeal points and refer these back to the appraisal committee for further consideration. These were:\n\nThe committee needs to clearly explain its rationale for accepting a different approach to the duration of treatment effect than TA525 (see section\xa03.24).\n\nThe committee should allow the company an opportunity to respond to the issue of retreatment costs (see section\xa03.25).\n\nThe committee should consider a range of acceleration factors for the 2‑stage method to adjust for treatment switching. Also, it should reconsider whether it is appropriate to give equal weight to analyses that did not adjust for treatment switching (see section\xa03.26).The committee considered the company's updated analyses including a revised patient access scheme.\n\n## Differences in the clinical and economic evidence between this appraisal and TA525 mean it is appropriate to consider different treatment effect durations\n\nThe committee considered the first upheld appeal point (see section\xa03.23). It discussed the reasoning behind its previous conclusion to consider 3‑year and 5‑year treatment effect durations after starting pembrolizumab for decision making (see section\xa03.18). In TA525 all analyses that varied the treatment effect duration, from a lifetime effect to a 3‑year effect after stopping atezolizumab, had ICERs that were comfortably within the range normally considered cost effective for end-of-life technologies. The exact ICERs are confidential and cannot be reported here. The committee noted several other differences between the 2\xa0appraisals:\n\nThe 5‑year treatment effect duration used in TA525 was not supported by robust evidence because the IMvigor211 trial had a maximum follow up of 25\xa0months. However, extended follow-up data from KEYNOTE‑045 were available. Those data suggested that the treatment benefit with pembrolizumab was unlikely to be sustained after 3\xa0years (see section\xa03.16).\n\nPembrolizumab treatment was only given for 2\xa0years in KEYNOTE‑045 but there was no treatment cap for atezolizumab in IMvigor211.\n\nIn IMvigor211, patients continued taking atezolizumab until unmanageable toxicity or lack of clinical efficacy. This means that some people continued taking atezolizumab after their disease progressed. So, any treatment benefit may have lasted for longer than if treatment was stopped after disease progression (as in KEYNOTE‑045).\n\nIn KEYNOTE‑045, 10\xa0patients had retreatment with pembrolizumab after disease progression (see sections\xa03.19 and\xa03.25). These patients being offered a second course of pembrolizumab suggests that a long‑term treatment effect after their initial course was not expected. In TA525, there was no evidence of retreatment with atezolizumab.\n\nIn the model, the proportion of patients alive at 2\xa0years still having treatment was lower for pembrolizumab than for atezolizumab.\n\nThe company for atezolizumab did not provide analyses assuming a 3‑year treatment effect duration from starting treatment.The committee carefully considered these differences. It reiterated that there was no robust evidence to support a 5‑year treatment effect, but acknowledged that it could be plausible (see section\xa03.18). In TA525, although it had not seen analyses assuming a 3‑year treatment effect duration from starting treatment, all ICERs were comfortably cost effective. This meant the committee was confident a 3‑year treatment effect analysis would also have had a cost-effective ICER. It concluded that its rationale for considering analyses using 3‑year and 5‑year treatment effect durations from the start of pembrolizumab treatment was reasonable, based primarily on the difference in cost-effectiveness estimates between this appraisal and TA525, and supported by the differences in the evidence.\n\n## The cost of retreatment should be included at 3 years\n\nThe committee considered the second upheld appeal point (see section\xa03.23). After the appeal, the company submitted scenario analyses that included the costs of pembrolizumab retreatment for the 10\xa0patients that had it. The company and ERG had different preferences about when to apply this cost in the model. The committee agreed that the ERG's preference (3\xa0years) was more consistent with the data, but acknowledged the timing had negligible impact on cost-effectiveness results. The company could have provided analyses that removed potential survival benefit from retreatment instead of adding the costs, but it did not do so. The company advised that pembrolizumab retreatment has uncertain clinical benefit and does not reflect clinical practice in the NHS in England. So, it considered that its preferred analysis without the costs remained appropriate for decision making. The committee found it inconsistent to include the potential benefits of retreatment without the costs, so both should either be included or excluded. In the absence of an analysis removing the benefits of retreatment, it concluded that the costs should be applied at 3\xa0years.\n\n## Unadjusted analyses are not suitable for decision making\n\nThe committee considered the third upheld appeal point (see section\xa03.23). It previously concluded that analyses that did not attempt to adjust for treatment switching method should be taken into account (see section\xa03.6). After the appeal, both the company and ERG agreed that the unadjusted analyses were not appropriate for decision making. The committee agreed that the unadjusted analyses would be less robust than the 2‑stage adjustment method. It concluded that unadjusted analyses were not suitable for decision making.\n\n## The ERG's analysis of post-progression survival times is suitable for decision making\n\nHaving concluded that analyses based on the 2‑stage adjustment for treatment switching were appropriate for decision making, the committee discussed the acceleration factor used in the adjustment. The company's base case remained unchanged and used the point estimate of 5.37, but it provided a scenario analysis using the lower bound of the 95%\xa0confidence interval (3.23). The company submitted 3\xa0additional analyses exploring the effect of different acceleration factors. The ERG described the limitations of those analyses:\n\nIncluding recensoring led to much less follow up and considerably less information on the control arm. This made it unlikely to be useful for decision making.\n\nUsing an acceleration factor of 5.32 included people who had vinflunine, which is not licensed in England.\n\nApplying an acceleration factor of 5.37 (calculated based on 25\xa0patients who switched after disease progression) to all 40\xa0patients that switched, including 15 who switched at different times, was discussed previously (see section\xa03.6). The company did not provide more information on the characteristics of these patients.The committee agreed that only the 5.37 and 3.23 acceleration factors were relevant to the decision, because the company's additional analyses had important limitations. At the clarification stage, the ERG asked the company to provide the patient-level data and code needed to reproduce and explore the acceleration factor. The company provided the code but not the patient-level data. So, the ERG approximated progression and survival data using outputs from the model, to examine how different acceleration factors affected post‑progression survival. The ERG's analysis predicted how long patients who switched treatment would have lived for if they had not switched treatment (the counterfactual). The company considered that the ERG's comparison of post-progression survival estimates was flawed, because it did not adjust the full standard care arm for the 15\xa0patients who switched to an active treatment at different times. The committee would have liked to have seen a comparison of the characteristics of those 15\xa0patients with the 25 who switched after disease progression, but the company did not provide those data. Therefore, it agreed that it was appropriate to consider the ERG's analyses in its decision making.\n\n## An acceleration factor of 5.37 is not plausible, and although 3.23 is more appropriate the most plausible value is very uncertain and may be lower\n\nUsing the company's preferred acceleration factor of 5.37, the ERG's analysis (see section\xa03.27) predicted that patients who switched would otherwise have had shorter post-progression survival than the average patient in the standard care arm. The exact data are confidential and cannot be reported here. Using the lower bound acceleration factor of 3.23, the ERG predicted that patients who switched would otherwise have had similar post-progression survival to the average patient in the standard care arm. It advised that this suggests the company's preferred acceleration factor (5.37) was adjusting survival on the standard care arm too much. This was because it attributed too much post‑progression survival benefit to the effect of the new treatment and too little to potential confounding factors. The company provided analyses that adjusted for several potential confounders such as age, gender and ECOG performance status, but did not provide enough information to allow the ERG to validate these analyses. Therefore, the ERG's preferred analysis used the lower bound acceleration factor (3.23), which was closer to the original acceleration factor applied in the original appraisal (3.86). The committee considered that patients who were offered and accepted a treatment switch were likely to have a relatively good prognosis and post‑progression survival compared with the average patient having standard care. Therefore, it agreed that the company's preferred acceleration factor (5.37) produced clinically implausible results in the ERG's analysis, while the ERG's preferred acceleration factor (3.23) produced more plausible results. It acknowledged that 3.23 is closer to the value that was accepted in the original appraisal (3.86). The committee agreed that 5.37 adjusted survival on the standard care arm too much. It recalled the limitations of the 2‑stage method (see section\xa03.6) and noted that the ERG had not been provided with the data to validate the company's 2‑stage adjustment in detail. This meant the point estimate acceleration factor (5.37) and its lower bound (3.23) were both subject to the same methodological uncertainties. It also noted that 3.23 was an arbitrary value to use, presented only because it is the confidence interval's lower bound. Therefore, the committee agreed that neither value was robust, but the most plausible acceleration factor is likely to be closer to 3.23 than 5.37, and it could plausibly be even lower than 3.23. It concluded that it would consider analyses using both acceleration factors in its decision making, but would be mindful that 3.23 was likely to be more plausible than 5.37 and the most plausible value could be even lower.\n\n# End of life\n\n## Life expectancy for people with urothelial carcinoma is less than 24\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. For people with locally advanced or metastatic disease who have had platinum-containing chemotherapy, data from the company's model and from the literature showed that median overall survival was much less than 24\xa0months for people having treatment with UK standard care. The clinical experts also agreed that they would expect people with locally advanced or metastatic urothelial carcinoma to live for less than 24\xa0months. The committee concluded that the short life expectancy criterion was met.\n\n## Pembrolizumab extends life by at least 3\xa0months, and meets the criteria for end-of-life treatments\n\nThe median overall survival for pembrolizumab in KEYNOTE‑045 using the November 2018 cut‑off was 10.1\xa0months (95% CI 7.6 to 12.9) compared with 6.2\xa0months (95% CI 5.2 to 7.4) for UK SoC (using a 2‑stage method for adjustment). The committee concluded that pembrolizumab would extend life by more than 3\xa0months, and therefore met the end-of-life criteria.\n\n# Cost-effectiveness estimates after the appeal\n\n## The most plausible ICER for pembrolizumab compared with docetaxel and paclitaxel is likely to be over £50,000 per QALY gained\n\nAfter the appeal, the company's base-case deterministic ICER was £43,181 per QALY gained with the revised patient access scheme. The committee noted that the company's preferred assumptions had not changed after the appeal (see section\xa03.22). The committee took into account its preferred assumptions of:\n\nconsidering both the 3‑year and 5‑year treatment effect durations from the start of pembrolizumab (see section\xa03.24)\n\nadding retreatment costs at 3\xa0years (see section\xa03.25)\n\nconsidering analyses using the 2-stage method with acceleration factors of 3.23 and 5.37 to adjust for treatment switching, noting that 3.23 was more likely to be plausible than 5.37 (see sections\xa03.27 and\xa03.28).The committee found the log-logistic, log-normal and generalised gamma overall survival functions all plausible (see section\xa03.20). Therefore, the ICERs considered for decision making ranged from £44,903 to £58,323 per QALY gained. The committee noted that the higher ICERs in this range were associated with an acceleration factor of 3.23, which it reiterated was more plausible than 5.37 and the most appropriate acceleration factor could be even lower. It concluded that the most plausible ICER was likely to be over £50,000 per QALY gained. It also agreed that most ICERs considered would need to be comfortably below £50,000 per QALY gained for it to be confident that pembrolizumab was cost effective, given the substantial uncertainty in the value of the acceleration factor and treatment effect duration.\n\n# Cancer Drugs Fund\n\n## Pembrolizumab cannot be recommended in the Cancer Drugs Fund\n\nThe aim of a Cancer Drugs Fund guidance review is to decide whether or not the drug can be recommended for routine use. Pembrolizumab for locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy will not remain in the Cancer Drugs Fund once the guidance review has been completed (see NICE's guide to the processes of technology appraisal).\n\n# Conclusion\n\n## Pembrolizumab is not recommended for routine use\n\nThe committee considered that the most plausible ICER was above the range that NICE normally considers a cost-effective use of NHS resources for a life‑extending treatment at the end of life. It agreed that there is uncertainty surrounding the acceleration factor estimates (more likely to be 3.23 than 5.37, but may be even lower) and therefore the cost-effectiveness results. So, most ICERs in the range considered for decision making should be substantially below £50,000 per QALY gained (that is, the maximum weight of 1.7 applied to the normal range of maximum acceptable ICERs). Based on the range of ICERs considered in decision making, it concluded not to recommend pembrolizumab for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy.\n\n# Other factors\n\nNo equality issues were identified.\n\nThe company did not highlight any additional benefits that had not been captured in the QALY calculations."}
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https://www.nice.org.uk/guidance/ta692
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Evidence-based recommendations on pembrolizumab (Keytruda) for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy in adults.
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a9b3f174f082e2bddbd4df6dd89f6579f9598677
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nice
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Olaparib plus bevacizumab for maintenance treatment of advanced ovarian, fallopian tube or primary peritoneal cancer
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Olaparib plus bevacizumab for maintenance treatment of advanced ovarian, fallopian tube or primary peritoneal cancer
Evidence-based recommendations on olaparib (Lynparza) plus bevacizumab (Avastin) for maintenance treatment of advanced ovarian, fallopian tube or primary peritoneal cancer in adults.
# Recommendations
Olaparib plus bevacizumab is recommended for use within the Cancer Drugs Fund as an option for maintenance treatment of advanced (International Federation of Gynecology and Obstetrics stages 3 and 4) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer in adults when:
there has been a complete or partial response after first-line platinum-based chemotherapy plus bevacizumab, and
the cancer is associated with homologous recombination deficiency (HRD).It is recommended only if the conditions in the managed access agreement for olaparib are followed.
This recommendation is not intended to affect treatment with olaparib plus bevacizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There is an ongoing clinical trial comparing maintenance treatment with olaparib plus bevacizumab with placebo plus bevacizumab in people whose cancer has responded to first-line platinum-based chemotherapy plus bevacizumab. Early results suggest that it improves how long people live without their cancer getting worse. The evidence suggests that the treatment effect is bigger in people whose disease is HRD-positive. However, there is uncertainty about how olaparib plus bevacizumab affects the length of time people live.
The uncertainty in the clinical evidence means that the cost-effectiveness estimates are very uncertain, so the treatment is not recommended for routine use in the NHS.
If the treatment does increase the length of time people live, it has the potential to be cost effective. Further trial results will help to address the uncertainties in the clinical-and cost-effectiveness estimates. Therefore, olaparib plus bevacizumab maintenance treatment is recommended for use within the Cancer Drugs Fund while further data are collected.# Information about olaparib
# Marketing authorisation indication
Olaparib (Lynparza, Astra Zeneca) plus bevacizumab (Avastin, Roche) is indicated for 'the maintenance treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics stages 3 and 4) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a BRCA1/2 mutation and/or genomic instability'.
# Dosage in the marketing authorisation
The dosage schedule for olaparib is available in its summary of product characteristics. The dosage schedule for bevacizumab is available in its summary of product characteristics.
# Price
The list price for olaparib tablets is £2,317.50 for 56 × 150 mg tablets (excluding VAT; BNF online accessed September 2020).The company has a commercial arrangement for olaparib tablets. The commercial arrangement additionally forms part of the managed access agreement for use of olaparib tablets in the Cancer Drugs Fund. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), NICE's technical report and responses from stakeholders. See the committee papers for full details of the evidence.
# Ovarian cancer treatment pathway and scope of the appraisal
## Olaparib plus bevacizumab maintenance treatment should be appraised in sequence with first-line treatment
In routine practice, first-line treatment for advanced ovarian cancer is surgery and platinum-based chemotherapy, followed by routine surveillance until the cancer progresses or comes back. Bevacizumab (15 mg/kg) is licenced for first-line treatment with platinum plus paclitaxel, but this is not recommended in NICE's technology appraisal guidance on bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer. Bevacizumab, at a dose lower (7.5 mg/kg) than the marketing authorisation may be used first line with platinum-based chemotherapy and as a subsequent maintenance treatment through the Cancer Drugs Fund when 1 or more of the following eligibility criteria apply:
International Federation of Gynecology and Obstetrics (FIGO) stage 3 debulked but residual disease of more than 1 cm
stage 4 disease
stage 3 disease at presentation and needing neo-adjuvant chemotherapy.Olaparib monotherapy is also available through the Cancer Drugs Fund as a maintenance treatment for cancer that has responded to first-line platinum-based chemotherapy, but only if there are BRCA mutations (see NICE's technology appraisal guidance on olaparib monotherapy). The treatment under appraisal here is olaparib plus bevacizumab maintenance treatment for all stage 3 and 4 cancer that:
has responded to first-line platinum-based chemotherapy plus bevacizumab and
is associated with homologous recombination deficiency (HRD) positive status defined by either a BRCA1 or 2 mutation or genomic instability (from now, referred to as HRD-positive disease).Implementing olaparib plus bevacizumab maintenance treatment in the NHS would therefore need changes to be made to the first-line treatment pathway. Specifically, all patients with stage 3 and 4 HRD-positive disease would have to be offered first-line bevacizumab plus platinum chemotherapy. The committee noted that the change to first-line treatment would be associated with increased costs. Also, it noted that the consequences in terms of the clinical outcomes with additional first-line treatments were unclear. The committee concluded that, in line with the appraisal scope, olaparib plus bevacizumab maintenance treatment needs to be appraised as part of a treatment sequence that includes first-line platinum-based chemotherapy plus bevacizumab.
## Both comparators in the scope are relevant
The comparator in the scope was first-line platinum-based chemotherapy followed by routine surveillance. In addition, for people having bevacizumab through the Cancer Drugs Fund (see section 3.1), the scope included first-line platinum-based chemotherapy plus bevacizumab (7.5 mg/kg every 3 weeks), followed by bevacizumab maintenance therapy at the same dose, as another comparator. The committee considered whether both comparators were relevant. It noted that treatments in the Cancer Drugs Fund are not normally included as comparators. Also, NICE's position statement on appraising new cancer products states that products recommended for use in the Cancer Drugs Fund after 1 April 2016 should not be considered as comparators. The committee heard from the Cancer Drugs Fund clinical lead that bevacizumab 7.5 mg/kg has been available through the Cancer Drugs Fund since at least 2012. He also stated that it is widely used and provides benefits to the high-risk group for whom it is available. The committee acknowledged that the NICE position statement did not apply to technologies in the Cancer Drugs Fund before 2016. It concluded that both comparators were relevant because they were established in NHS clinical practice.
## HRD testing is potentially implementable in the NHS
As noted in section 3.1, the marketing authorisation for olaparib plus bevacizumab is specific to people with HRD-positive disease. Therefore, HRD testing would be needed before olaparib plus bevacizumab maintenance treatment is started. HRD testing is not routinely done in the NHS. The only available validated test is the Myriad myChoice test, for which samples need to be sent to the US. The clinical experts supported implementing HRD testing in routine NHS practice because genetic mutations can be an important factor in determining treatment decisions and in prognosis. They considered that implementation was potentially feasible, given the similarities with the somatic (tumour) BRCA testing pathway. They also agreed with the company's comment at technical engagement that the availability of new treatments that need specific tests have previously provided an incentive for test development and introduction. They noted that HRD and somatic BRCA testing should be done at the same time, so that tissue biopsy could be aligned to maximise the chance of enough tissue being available for accurate testing. They also considered using the Myriad myChoice test processing facilities in the US to be a reasonable interim option until an NHS-specific pathway could be set up. The committee concluded that routine HRD testing could be developed and implemented in the NHS.
# Clinical need for new treatments
## People would welcome new treatments that prolong life and reduce the need for further chemotherapy
The patient experts explained that advanced ovarian cancer is a devastating condition with a poor prognosis. Most people are diagnosed after it is already advanced and, even when initial treatment is successful, the cancer usually comes back. Living under its shadow and not knowing when it will recur can be very traumatic for patients and their families. Given the effect of the condition on life expectancy, people would welcome new treatments. This clinical need is made greater by the effects of the current treatments on quality of life. For most people, a diagnosis of advanced ovarian cancer means multiple rounds of chemotherapy and having to endure its potentially gruelling side effects. Chemotherapy also has to be delivered in hospital, so it can severely disrupt daily life and work. It can also negatively affect quality of life, family and social relationships. The interval between rounds of chemotherapy can be very short. One expert described her personal experience of having 3 rounds of chemotherapy treatment over 3 years. An added benefit of olaparib is that it can be taken orally. Also, both olaparib and bevacizumab have side effects that are more manageable than those associated with chemotherapy. The committee concluded that there is a high unmet need for new treatments to delay or prevent recurrence of advanced ovarian cancer.
## Using PARP inhibitors early in the treatment pathway is likely to maximise the potential benefits of these treatments
The clinical and patient experts agreed that introducing poly-ADP-ribose polymerase (PARP) inhibitors, such as olaparib, for ovarian cancer has been a significant advance in treating the condition. The patient expert, who had started taking olaparib after surgery and 4 lines of chemotherapy, described olaparib as transformative. She explained that it had prolonged her life and allowed her to live an almost normal life after years of debilitating chemotherapy. She also explained that, before olaparib, bevacizumab had been an effective and manageable treatment in her experience, so it seemed logical to use both drugs as early as possible. The clinical experts noted that the patient's personal testimony was reflective of their clinical experience. They also stressed that using effective treatments as early as possible is important. This is because treatments given first line can make a dramatic difference to survival and quality of life, whereas the possibility of a cure is very low after subsequent lines of treatment. Also, if treatment is delayed, people may die before becoming eligible to have it, or may not meet the eligibility criteria for having a PARP inhibitor. The committee concluded that there are compelling reasons for using therapies such as olaparib and bevacizumab early in the ovarian cancer treatment pathway when the possibility of a cure is greatest.
# Clinical evidence
## The clinical trial does not fully reflect the scope
The clinical evidence presented by the company comes from PAOLA‑1, a randomised controlled trial in 806 people with advanced (stages 3 and 4) ovarian cancer. The trial compared the efficacy of olaparib (300 mg twice daily) for up to 2 years (n=537) with a matching placebo (n=269). Everyone also had bevacizumab (15 mg/kg every 3 weeks) as maintenance treatment for up to 15 months. People with HRD-positive disease were a prespecified subgroup, amounting to 48.0% of the intention-to-treat population. HRD testing was done after randomisation. A similar proportion of people were HRD-positive in each arm (47.5% in the olaparib plus bevacizumab arm and 49.1% in the placebo plus bevacizumab arm). The committee noted that the trial did not include anyone from the UK and did not fully reflect the scope in terms of the population, intervention or comparators of interest. Specifically:
The people in PAOLA‑1 had cancer that had already responded to first-line platinum-taxane chemotherapy plus bevacizumab whereas the population in the scope was people with newly diagnosed advanced ovarian cancer.
The intervention in the trial was olaparib plus bevacizumab maintenance treatment, whereas the intervention in the scope included first-line treatment (see section 3.1).
The comparator in the trial was bevacizumab monotherapy (15 mg/kg every 3 weeks) maintenance treatment, whereas the 2 comparators in the scope were platinum-based chemotherapy followed by routine surveillance and platinum-based chemotherapy plus bevacizumab (7.5 mg/kg every 3 weeks) followed by bevacizumab maintenance treatment (see section 3.2).The committee concluded that PAOLA‑1 provided the best available evidence for use in the appraisal, but the results did not directly reflect the decision problem. It considered this a significant limitation of the evidence base that would need to be addressed in the modelling to ensure that the cost-effectiveness estimates were relevant to the NHS.
## Olaparib plus bevacizumab maintenance treatment improves progression-free survival in people with HRD-positive ovarian cancer
The primary end point in PAOLA‑1 was investigator-assessed progression-free survival (PFS). In the intention-to-treat population, people who had olaparib plus bevacizumab had longer median PFS than people who had placebo plus bevacizumab (22.1 months compared with 16.6 months). The difference between the groups was statistically significant (hazard ratio 0.59, 95% confidence interval 0.49 to 0.72; p<0.0001). A PFS benefit was also seen in the HRD-positive subgroup and the effect size was bigger than in the intention-to-treat population (median PFS 37.2 months compared with 17.7 months, unstratified HR 0.33, 95% CI 0.25 to 0.45). In contrast, no difference in PFS was found between the treatment arms in the HRD-negative subgroup (median PFS 16.9 months compared with 16.0 months, unstratified HR 0.92, 95% CI 0.72 to 1.17). The clinical experts noted that the PFS results provide compelling evidence that olaparib plus bevacizumab is more effective in people with HRD-positive disease than in those with HRD-negative disease. The committee agreed with the clinical experts. It concluded that olaparib plus bevacizumab maintenance treatment improves PFS in people with HRD-positive ovarian cancer that has completely or partially responded after first-line platinum-taxane chemotherapy plus bevacizumab.
## The overall-survival data are promising but uncertain
Overall survival is a secondary end point in PAOLA‑1. The company submission included early results for the HRD-positive subgroup based on the number of events that had occurred at the time of the primary PFS analysis. These estimates favoured olaparib plus bevacizumab maintenance treatment (the results, including the number of events that had occurred at the time of the analysis, cannot be reported because they are not yet in the public domain). The clinical experts acknowledged the uncertainty in the current estimates given the data maturity. However, they stated that the more mature data from SOLO1 on using olaparib monotherapy in the first-line maintenance setting provided some reassurance that the PFS benefit observed in PAOLA‑1 may translate into an overall-survival benefit in the long term. The committee agreed that the current overall-survival data are promising but concluded that the survival benefit remains uncertain.
## It is unclear whether olaparib plus bevacizumab maintenance treatment is curative
The committee recognised that a key consideration for the appraisal is whether olaparib plus bevacizumab maintenance treatment is likely to prevent recurrence or only delay it. The clinical experts noted that survival outcomes are heterogenous in the population of interest (they cited ICON5, CHORUS and ICON7 as reporting outcomes after first-line treatment that support this observation). They explained that, based on previous studies and experience of using PARP inhibitors, any potential overall-survival benefit is likely to be driven by a subgroup with particularly good treatment outcomes. The clinical experts anticipate that olaparib plus bevacizumab will increase the proportion of people who have long-term PFS and overall survival. They also explained that maintaining PFS for 5 years is widely considered to be a good indicator of long-term survival. The cancer will progress after 5 to 10 years in only a small proportion of people who are progression free at 5 years. The clinical experts noted that they do not tell people after 5 years of PFS that they are 'cured', but tell them that their cancer is very unlikely to come back. This is reflected in the British Gynaecological Cancer Society ovarian cancer guidelines, which recommend stopping follow up if the cancer has not come back within 5 years. The committee noted that the clinical experts' comments were consistent with those made by clinical experts for NICE's technology appraisal guidance on olaparib for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy. The experts for that appraisal made the following comments in relation to a trial of olaparib for relapsed ovarian cancer (Study 19):
After 10 years, 10% of people are disease free (indicating a cure).
This 10% are more likely to be people whose cancer had a complete response to platinum-based chemotherapy.The committee considered that other olaparib studies and the trials of other PARP inhibitors provided useful clinical context, and showed that a long-term treatment effect that could be indicative of cure is plausible. However, the committee also noted that although median PFS has been reached in PAOLA‑1, the median length of follow up in the olaparib plus bevacizumab arm was 22.7 months (less than 2 years), and the treatment was given for up to only 15.0 months. The limited follow up means that there are insufficient data to show whether the treatment can maintain remission up to the clinically important 5‑year threshold. It also noted there was no obvious plateau in the intervention arm of the Kaplan–Meier plot to confirm a levelling off of the risk of progression and, given the numbers remaining at risk of progression, this was unlikely to be observed in future. The committee concluded that it is unclear whether olaparib plus bevacizumab maintenance treatment can cure ovarian cancer.
# Cost effectiveness
## The company's maintenance-only analysis is not appropriate
The company presented a 4‑state partitioned survival model to estimate the cost effectiveness of olaparib plus bevacizumab (15 mg/kg) maintenance treatment in people with HRD-positive disease whose cancer had responded to first-line platinum-based chemotherapy plus bevacizumab (15 mg/kg). The company presented 2 analyses, a maintenance-only analysis and an extended-regimen analysis (see section 3.11). In the maintenance model, the company compared olaparib plus bevacizumab (15 mg/kg) maintenance treatment with routine surveillance and bevacizumab (7.5 mg/kg). It also included bevacizumab (15 mg/kg) alone as a comparator. However, this was not in the scope and is not a standard treatment in the UK, so this comparison is not discussed further. The committee considered that the company's maintenance analysis did not address the full appraisal question in the scope because it focused on the maintenance period only. It did not consider the associated costs or clinical outcomes of having bevacizumab (15 mg/kg) plus platinum-based chemotherapy first line (see section 3.1). Therefore, the committee concluded that this analysis was not appropriate.
## The extended-regimen analysis is appropriate
The company's extended-regimen analysis compared first-line platinum-based chemotherapy plus bevacizumab (15 mg/kg) followed by olaparib plus bevacizumab (15 mg/kg) maintenance treatment for people whose cancer had responded with:
first-line platinum-based chemotherapy followed by routine surveillance
first-line platinum-based chemotherapy plus bevacizumab (7.5 mg/kg) followed by bevacizumab (7.5 mg/kg) as maintenance treatment for people whose cancer had responded
first-line platinum-based chemotherapy plus bevacizumab (15 mg/kg) followed by bevacizumab (15 mg/kg) as maintenance treatment for people whose cancer had responded (which was not in the scope and is not routine treatment in the UK, so is not discussed further).The company included the cost of having bevacizumab (15 mg/kg) plus first-line platinum-based chemotherapy but assumed that all the first-line treatment options were equally effective. The ERG identified some errors in the company's extended-regimen analyses. It considered that the analysis did not capture the full costs or the clinical outcomes of first-line treatment. The ERG included the additional costs and the outcomes in its own exploratory analyses. This analysis assumed that, in 69% of people, the cancer had completely or partially responded after first-line treatment, was stable in 23% and would progress in 8%. The clinical experts considered that these assumptions were clinically plausible. The committee agreed with the ERG that the company's extended-regimen analysis was limited because it did not capture the full costs or the health benefits of first-line treatment. It concluded that the ERG's extended-regimen analysis was more appropriate because it included both of these.
## A mixture cure model is not justified and may overestimate survival gain
The company and the ERG used different methods to model survival. This was the key driver of the cost-effectiveness results. The company used a mixture cure model to estimate long-term survival. This assumed that the model population consisted of 2 groups: a 'cured' population and a population whose cancer would progress. People predicted to be progression free at 5 years were considered 'cured' and were assumed to have the same mortality as the UK general population. To predict overall survival, the company used standard parametric models up to 5 to 6 years and then overall survival was set to equal PFS. The ERG had several concerns about the company's modelling approach. It disagreed with using the mixture cure model in principle because PAOLA‑1 data are not mature enough to show a cure effect. It noted that a wide range of cure fractions had been reported across the different mixture cure models tested by the company. It also noted that the difference in the cure fractions used by the company in its base case, combined with its decision to set overall survival to equal PFS, resulted in a large and very long predicted overall-survival effect for olaparib plus bevacizumab. The ERG considered the company's approach of setting the overall-survival curves equal to the PFS curves methodologically flawed and to have a major effect on the relative effectiveness of the treatments. The committee agreed with the ERG's concerns. It noted that, at present, PAOLA‑1 does not provide sufficient evidence to support the company's assumption that a proportion of patients would be cured at 5 years. This is because there are only 3 years of PFS data. The specific cure fractions used in the company's mixture cure model are therefore not supported by the trial data. The committee was also concerned about the lack of a plateau in the Kaplan–Meier curve for PFS, which would be expected for a curative treatment. It appreciated that clinical trials for other PARP inhibitors have shown a plateau in the curves and that a subgroup are cancer free after 10 years, indicating a cure. However, this has so far not been proven for olaparib plus bevacizumab. It also noted that the small proportion of people whose cancer progresses between 5 and 10 years (see section 3.9) are not accounted for in the company's mixture cure model. The committee considered that these points undermined the company's justification for using a mixture cure model. It agreed that using a mixture cure model, and the specific cure fractions preferred by the company, may have overestimated the survival gain for olaparib plus bevacizumab. It concluded that it is not possible to resolve the uncertainties about overall survival until further data are available from PAOLA‑1.
## The ERG's exploratory analyses show the high uncertainty in the survival modelling
The ERG initially preferred to use standard parametric models to estimate long-term PFS and overall survival. However, it updated its approach after the clinical experts suggested at technical engagement that the PFS projections were not plausible. The ERG's updated modelling used the company's mixture cure model to estimate PFS, but predicted the survival trajectory from the overall-survival data rather than the PFS data. The clinical experts explained that the overall-survival projections for the routine surveillance arm were much higher than in clinical studies. The ERG acknowledged that the absolute overall-survival values were optimistic in both arms of the model and that its updated analysis had included some simplified modelling techniques. It explained that the aims of its updated approach were to:
show the substantial effect of using different survival modelling approaches on the cost-effectiveness results
provide an estimate of the relative survival benefit associated with olaparib plus bevacizumab maintenance treatment, which could be considered more realistic than the company's.The committee appreciated that the ERG's updated analysis was an exploratory analysis designed to show the uncertainty in the company's approach. It noted that the incremental cost-effectiveness ratios (ICERs) increased substantially when the ERG's original and updated survival modelling approaches were used. The committee concluded that the ERG's analyses showed the high level of uncertainty in the survival modelling.
## Subsequent treatment costs should reflect routine NHS practice
The company and ERG used different treatment costs in their modelling, and this was also a driver of cost effectiveness. The company incorporated a hypothetical 50% discount to the bevacizumab list price to reflect the loss of exclusivity in 2020. The committee was aware that a confidential discount for bevacizumab had been agreed in a patient access scheme, and that the correct discounted price would be used in its decision making. The committee noted that the company and ERG also had different approaches to costing subsequent treatments. The company's approach was a hybrid between reflecting the treatments given in PAOLA‑1 and what is available routinely in UK clinical practice and through the Cancer Drugs Fund. By contrast, the ERG's costs were matched to NHS routine practice, whereby routinely commissioned treatments were included but not those available through the Cancer Drugs Fund. The committee noted the NICE position statement on consideration of products recommended for use in the Cancer Drugs Fund as comparators, or in a treatment sequence, in the appraisal of a new cancer product. The committee agreed that the costing of subsequent treatments should reflect routine NHS practice in line with the position statement. It therefore considered that the ERG's approach was more appropriate.
## HRD-testing costs should be included in the modelling
The company did not include HRD-testing costs in its analyses. The ERG's exploratory analyses showed that including the costs of HRD testing would increase the cost-effectiveness estimate by around £5,000 per quality-adjusted life year (QALY) gained. The committee was aware that HRD testing is not standard practice, so an uplift in resources directly related to using olaparib plus bevacizumab would be needed to introduce it into the NHS. The committee concluded that HRD-testing costs should be included in the cost-effectiveness modelling.
## The choice of utilities has a small effect on the cost-effectiveness results
The company and ERG used different utility values in their analyses. The company's utilities were derived from EQ‑5D‑5L data from PAOLA‑1 (mapped to EQ‑5D‑3L) for the PFS and first disease-progression health states. There were different values for PFS on and off treatment. The ERG was concerned about the appropriateness of having different utilities for PFS on and off treatment, and about the methods used to estimate the utilities. Therefore, the ERG preferred to use mapped EQ‑5D‑3L values from NICE's technology appraisal guidance on olaparib monotherapy maintenance treatment in its own analyses. The committee noted that the choice of utilities had a very small effect on the cost-effectiveness results and did not discuss this further.
# Cost-effectiveness estimate
## Olaparib plus bevacizumab maintenance treatment cannot be recommended for routine commissioning
The company's ICERs, using its extended-regimen analysis, for first-line platinum-based chemotherapy plus bevacizumab (15 mg/kg) followed by olaparib plus bevacizumab maintenance treatment for people whose cancer had responded were:
£26,268 per QALY gained compared with platinum-based chemotherapy followed by routine surveillance
£19,925 per QALY gained compared with first-line platinum-based chemotherapy plus bevacizumab (7.5 mg/kg) followed by bevacizumab maintenance treatment for people whose cancer had responded.Using the company's analysis, but incorporating the ERG's changes to the extended-regimen analysis in line with the committee's preference (see section 3.11), the ICERs were £34,165 per QALY gained for the routine surveillance arm and £24,726 per QALY gained for the bevacizumab (7.5 mg/kg) arm. All the ICERs are lower when the confidential patient access scheme for bevacizumab is included. The committee noted that the ICERs were based on the company's survival modelling approach and could have substantially overestimated the survival gain for the olaparib plus bevacizumab arm (see section 3.12). Because of the high level of uncertainty in the survival modelling, the committee considered that the ICERs could be much higher. It noted that using the ERG's survival modelling updated after technical engagement, and including other preferred assumptions (see sections 3.14 to 3.16), increased the ICER to £93,350 per QALY gained compared with the routine surveillance arm and £75,476 per QALY gained compared with the bevacizumab (7.5 mg/kg) arm. The committee considered that the ERG's exploratory analyses showed the substantial effect on the ICERs of using different survival modelling. Therefore, the committee could not state with any certainty a most plausible ICER. It concluded that, because of the high level of uncertainty, the ICER had not been shown to be within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained). Therefore, it could not recommend olaparib plus bevacizumab maintenance treatment for routine NHS use.
# Cancer Drugs Fund
## Further data from PAOLA‑1 would help to resolve the uncertainties in the clinical- and cost-effectiveness evidence
Having concluded that olaparib plus bevacizumab maintenance treatment could not be recommended for routine NHS use, the committee considered whether it could be recommended within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee recognised that olaparib plus bevacizumab maintenance treatment is an innovative treatment for advanced ovarian cancer and that there is a high unmet need in this disease area. It therefore considered whether clinical uncertainty associated with the treatment could be addressed through collection of additional data from PAOLA‑1. The company explained that further data collection is expected within the next 2 years, including data on PFS, PFS2 and interim overall-survival data. The committee agreed that further data would be a valuable addition to the clinical evidence base and would help to resolve the major uncertainties.
## Olaparib plus bevacizumab maintenance treatment meets the Cancer Drugs Fund inclusion criteria
The committee recalled that, using the company's analysis but incorporating the ERG's changes to the extended-regimen analysis in line with its preference (see section 3.11), the ICERs were £34,165 per QALY gained compared with the routine surveillance arm and £24,726 per QALY gained compared with the bevacizumab (7.5 mg/kg) arm. It also recalled that the ICERs were lower when the confidential patient access scheme for bevacizumab was included. The company's base case assumed that people will be cured from ovarian cancer if they are progression free at 5 years. Although the clinical experts had explained that a cure is possible, the committee noted that there were only 3 years of PFS data from PAOLA‑1 and the overall-survival data were immature (see section 3.8). Therefore, the committee considered that the company's base-case ICER may be an optimistic estimate of cost effectiveness (see section 3.17). It thought that it was plausible the ICER could be much higher, exceeding the range that is usually considered a cost-effective use of NHS resources. The committee accepted that the upper bound of the range of plausible ICERs was highly uncertain. However, it considered that, pending the results from PAOLA‑1, there was plausible potential for platinum-based chemotherapy with bevacizumab 15 mg/kg followed by olaparib plus bevacizumab maintenance treatment to be cost effective in routine NHS use. Therefore, it concluded that the treatment meets the criteria for inclusion in the Cancer Drugs Fund for treating HRD-positive advanced ovarian, fallopian tube or primary peritoneal cancer.
# Conclusion
## Olaparib plus bevacizumab maintenance treatment is recommended for the Cancer Drugs Fund
Early results from PAOLA‑1 suggest that maintenance treatment with olaparib plus bevacizumab in people with HRD-positive disease that has responded to first-line platinum-based chemotherapy plus bevacizumab (15 mg/kg) improves PFS compared with maintenance treatment with placebo plus bevacizumab. However, mature overall-survival data are not available and the extent to which the PFS benefit will translate into an overall-survival benefit is unclear. Because of the uncertainty about the overall-survival benefit, the estimates of cost effectiveness are very uncertain, and the treatment cannot be recommended for routine use in the NHS. If the treatment does increase survival, it has the potential to be cost effective. Further data from PAOLA‑1 will help to address the uncertainties in the clinical and cost effectiveness. Olaparib plus bevacizumab maintenance treatment is therefore recommended as an option within the Cancer Drugs Fund while further data are collected.
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{'Recommendations': 'Olaparib plus bevacizumab is recommended for use within the Cancer Drugs Fund as an option for maintenance treatment of advanced (International Federation of Gynecology and Obstetrics [FIGO] stages\xa03 and\xa04) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer in adults when:\n\nthere has been a complete or partial response after first-line platinum-based chemotherapy plus bevacizumab, and\n\nthe cancer is associated with homologous recombination deficiency (HRD).It is recommended only if the conditions in the managed access agreement for olaparib are followed.\n\nThis recommendation is not intended to affect treatment with olaparib plus bevacizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere is an ongoing clinical trial comparing maintenance treatment with olaparib plus bevacizumab with placebo plus bevacizumab in people whose cancer has responded to first-line platinum-based chemotherapy plus bevacizumab. Early results suggest that it improves how long people live without their cancer getting worse. The evidence suggests that the treatment effect is bigger in people whose disease is HRD-positive. However, there is uncertainty about how olaparib plus bevacizumab affects the length of time people live.\n\nThe uncertainty in the clinical evidence means that the cost-effectiveness estimates are very uncertain, so the treatment is not recommended for routine use in the NHS.\n\nIf the treatment does increase the length of time people live, it has the potential to be cost effective. Further trial results will help to address the uncertainties in the clinical-and cost-effectiveness estimates. Therefore, olaparib plus bevacizumab maintenance treatment is recommended for use within the Cancer Drugs Fund while further data are collected.', 'Information about olaparib': "# Marketing authorisation indication\n\nOlaparib (Lynparza, Astra Zeneca) plus bevacizumab (Avastin, Roche) is indicated for 'the maintenance treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics [FIGO] stages\xa03 and\xa04) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a BRCA1/2 mutation and/or genomic instability'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule for olaparib is available in its summary of product characteristics. The dosage schedule for bevacizumab is available in its summary of product characteristics.\n\n# Price\n\nThe list price for olaparib tablets is £2,317.50 for 56\xa0×\xa0150\xa0mg tablets (excluding VAT; BNF online accessed September 2020).The company has a commercial arrangement for olaparib tablets. The commercial arrangement additionally forms part of the managed access agreement for use of olaparib tablets in the Cancer Drugs Fund. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), NICE's technical report and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Ovarian cancer treatment pathway and scope of the appraisal\n\n## Olaparib plus bevacizumab maintenance treatment should be appraised in sequence with first-line treatment\n\nIn routine practice, first-line treatment for advanced ovarian cancer is surgery and platinum-based chemotherapy, followed by routine surveillance until the cancer progresses or comes back. Bevacizumab (15\xa0mg/kg) is licenced for first-line treatment with platinum plus paclitaxel, but this is not recommended in NICE's technology appraisal guidance on bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer. Bevacizumab, at a dose lower (7.5\xa0mg/kg) than the marketing authorisation may be used first line with platinum-based chemotherapy and as a subsequent maintenance treatment through the Cancer Drugs Fund when 1\xa0or more of the following eligibility criteria apply:\n\nInternational Federation of Gynecology and Obstetrics (FIGO) stage\xa03 debulked but residual disease of more than 1\xa0cm\n\nstage\xa04 disease\n\nstage\xa03 disease at presentation and needing neo-adjuvant chemotherapy.Olaparib monotherapy is also available through the Cancer Drugs Fund as a maintenance treatment for cancer that has responded to first-line platinum-based chemotherapy, but only if there are BRCA mutations (see NICE's technology appraisal guidance on olaparib monotherapy). The treatment under appraisal here is olaparib plus bevacizumab maintenance treatment for all stage\xa03 and\xa04 cancer that:\n\nhas responded to first-line platinum-based chemotherapy plus bevacizumab and\n\nis associated with homologous recombination deficiency (HRD) positive status defined by either a BRCA1 or\xa02 mutation or genomic instability (from now, referred to as HRD-positive disease).Implementing olaparib plus bevacizumab maintenance treatment in the NHS would therefore need changes to be made to the first-line treatment pathway. Specifically, all patients with stage\xa03 and\xa04 HRD-positive disease would have to be offered first-line bevacizumab plus platinum chemotherapy. The committee noted that the change to first-line treatment would be associated with increased costs. Also, it noted that the consequences in terms of the clinical outcomes with additional first-line treatments were unclear. The committee concluded that, in line with the appraisal scope, olaparib plus bevacizumab maintenance treatment needs to be appraised as part of a treatment sequence that includes first-line platinum-based chemotherapy plus bevacizumab.\n\n## Both comparators in the scope are relevant\n\nThe comparator in the scope was first-line platinum-based chemotherapy followed by routine surveillance. In addition, for people having bevacizumab through the Cancer Drugs Fund (see section\xa03.1), the scope included first-line platinum-based chemotherapy plus bevacizumab (7.5\xa0mg/kg every 3\xa0weeks), followed by bevacizumab maintenance therapy at the same dose, as another comparator. The committee considered whether both comparators were relevant. It noted that treatments in the Cancer Drugs Fund are not normally included as comparators. Also, NICE's position statement on appraising new cancer products states that products recommended for use in the Cancer Drugs Fund after 1\xa0April 2016 should not be considered as comparators. The committee heard from the Cancer Drugs Fund clinical lead that bevacizumab 7.5\xa0mg/kg has been available through the Cancer Drugs Fund since at least 2012. He also stated that it is widely used and provides benefits to the high-risk group for whom it is available. The committee acknowledged that the NICE position statement did not apply to technologies in the Cancer Drugs Fund before 2016. It concluded that both comparators were relevant because they were established in NHS clinical practice.\n\n## HRD testing is potentially implementable in the NHS\n\nAs noted in section\xa03.1, the marketing authorisation for olaparib plus bevacizumab is specific to people with HRD-positive disease. Therefore, HRD testing would be needed before olaparib plus bevacizumab maintenance treatment is started. HRD testing is not routinely done in the NHS. The only available validated test is the Myriad myChoice test, for which samples need to be sent to the US. The clinical experts supported implementing HRD testing in routine NHS practice because genetic mutations can be an important factor in determining treatment decisions and in prognosis. They considered that implementation was potentially feasible, given the similarities with the somatic (tumour) BRCA testing pathway. They also agreed with the company's comment at technical engagement that the availability of new treatments that need specific tests have previously provided an incentive for test development and introduction. They noted that HRD and somatic BRCA testing should be done at the same time, so that tissue biopsy could be aligned to maximise the chance of enough tissue being available for accurate testing. They also considered using the Myriad myChoice test processing facilities in the US to be a reasonable interim option until an NHS-specific pathway could be set up. The committee concluded that routine HRD testing could be developed and implemented in the NHS.\n\n# Clinical need for new treatments\n\n## People would welcome new treatments that prolong life and reduce the need for further chemotherapy\n\nThe patient experts explained that advanced ovarian cancer is a devastating condition with a poor prognosis. Most people are diagnosed after it is already advanced and, even when initial treatment is successful, the cancer usually comes back. Living under its shadow and not knowing when it will recur can be very traumatic for patients and their families. Given the effect of the condition on life expectancy, people would welcome new treatments. This clinical need is made greater by the effects of the current treatments on quality of life. For most people, a diagnosis of advanced ovarian cancer means multiple rounds of chemotherapy and having to endure its potentially gruelling side effects. Chemotherapy also has to be delivered in hospital, so it can severely disrupt daily life and work. It can also negatively affect quality of life, family and social relationships. The interval between rounds of chemotherapy can be very short. One expert described her personal experience of having 3\xa0rounds of chemotherapy treatment over 3\xa0years. An added benefit of olaparib is that it can be taken orally. Also, both olaparib and bevacizumab have side effects that are more manageable than those associated with chemotherapy. The committee concluded that there is a high unmet need for new treatments to delay or prevent recurrence of advanced ovarian cancer.\n\n## Using PARP inhibitors early in the treatment pathway is likely to maximise the potential benefits of these treatments\n\nThe clinical and patient experts agreed that introducing poly-ADP-ribose polymerase (PARP) inhibitors, such as olaparib, for ovarian cancer has been a significant advance in treating the condition. The patient expert, who had started taking olaparib after surgery and 4\xa0lines of chemotherapy, described olaparib as transformative. She explained that it had prolonged her life and allowed her to live an almost normal life after years of debilitating chemotherapy. She also explained that, before olaparib, bevacizumab had been an effective and manageable treatment in her experience, so it seemed logical to use both drugs as early as possible. The clinical experts noted that the patient's personal testimony was reflective of their clinical experience. They also stressed that using effective treatments as early as possible is important. This is because treatments given first line can make a dramatic difference to survival and quality of life, whereas the possibility of a cure is very low after subsequent lines of treatment. Also, if treatment is delayed, people may die before becoming eligible to have it, or may not meet the eligibility criteria for having a PARP inhibitor. The committee concluded that there are compelling reasons for using therapies such as olaparib and bevacizumab early in the ovarian cancer treatment pathway when the possibility of a cure is greatest.\n\n# Clinical evidence\n\n## The clinical trial does not fully reflect the scope\n\nThe clinical evidence presented by the company comes from PAOLA‑1, a randomised controlled trial in 806\xa0people with advanced (stages\xa03 and\xa04) ovarian cancer. The trial compared the efficacy of olaparib (300\xa0mg twice daily) for up to 2\xa0years (n=537) with a matching placebo (n=269). Everyone also had bevacizumab (15\xa0mg/kg every 3\xa0weeks) as maintenance treatment for up to 15\xa0months. People with HRD-positive disease were a prespecified subgroup, amounting to 48.0% of the intention-to-treat population. HRD testing was done after randomisation. A similar proportion of people were HRD-positive in each arm (47.5% in the olaparib plus bevacizumab arm and 49.1% in the placebo plus bevacizumab arm). The committee noted that the trial did not include anyone from the UK and did not fully reflect the scope in terms of the population, intervention or comparators of interest. Specifically:\n\nThe people in PAOLA‑1 had cancer that had already responded to first-line platinum-taxane chemotherapy plus bevacizumab whereas the population in the scope was people with newly diagnosed advanced ovarian cancer.\n\nThe intervention in the trial was olaparib plus bevacizumab maintenance treatment, whereas the intervention in the scope included first-line treatment (see section\xa03.1).\n\nThe comparator in the trial was bevacizumab monotherapy (15\xa0mg/kg every 3\xa0weeks) maintenance treatment, whereas the 2\xa0comparators in the scope were platinum-based chemotherapy followed by routine surveillance and platinum-based chemotherapy plus bevacizumab (7.5\xa0mg/kg every 3\xa0weeks) followed by bevacizumab maintenance treatment (see section\xa03.2).The committee concluded that PAOLA‑1 provided the best available evidence for use in the appraisal, but the results did not directly reflect the decision problem. It considered this a significant limitation of the evidence base that would need to be addressed in the modelling to ensure that the cost-effectiveness estimates were relevant to the NHS.\n\n## Olaparib plus bevacizumab maintenance treatment improves progression-free survival in people with HRD-positive ovarian cancer\n\nThe primary end point in PAOLA‑1 was investigator-assessed progression-free survival (PFS). In the intention-to-treat population, people who had olaparib plus bevacizumab had longer median PFS than people who had placebo plus bevacizumab (22.1\xa0months compared with 16.6\xa0months). The difference between the groups was statistically significant (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.49\xa0to\xa00.72; p<0.0001). A PFS benefit was also seen in the HRD-positive subgroup and the effect size was bigger than in the intention-to-treat population (median PFS 37.2\xa0months compared with 17.7\xa0months, unstratified HR\xa00.33, 95%\xa0CI 0.25\xa0to\xa00.45). In contrast, no difference in PFS was found between the treatment arms in the HRD-negative subgroup (median PFS 16.9\xa0months compared with 16.0\xa0months, unstratified HR\xa00.92, 95%\xa0CI 0.72\xa0to\xa01.17). The clinical experts noted that the PFS results provide compelling evidence that olaparib plus bevacizumab is more effective in people with HRD-positive disease than in those with HRD-negative disease. The committee agreed with the clinical experts. It concluded that olaparib plus bevacizumab maintenance treatment improves PFS in people with HRD-positive ovarian cancer that has completely or partially responded after first-line platinum-taxane chemotherapy plus bevacizumab.\n\n## The overall-survival data are promising but uncertain\n\nOverall survival is a secondary end point in PAOLA‑1. The company submission included early results for the HRD-positive subgroup based on the number of events that had occurred at the time of the primary PFS analysis. These estimates favoured olaparib plus bevacizumab maintenance treatment (the results, including the number of events that had occurred at the time of the analysis, cannot be reported because they are not yet in the public domain). The clinical experts acknowledged the uncertainty in the current estimates given the data maturity. However, they stated that the more mature data from SOLO1 on using olaparib monotherapy in the first-line maintenance setting provided some reassurance that the PFS benefit observed in PAOLA‑1 may translate into an overall-survival benefit in the long term. The committee agreed that the current overall-survival data are promising but concluded that the survival benefit remains uncertain.\n\n## It is unclear whether olaparib plus bevacizumab maintenance treatment is curative\n\nThe committee recognised that a key consideration for the appraisal is whether olaparib plus bevacizumab maintenance treatment is likely to prevent recurrence or only delay it. The clinical experts noted that survival outcomes are heterogenous in the population of interest (they cited ICON5, CHORUS and ICON7 as reporting outcomes after first-line treatment that support this observation). They explained that, based on previous studies and experience of using PARP inhibitors, any potential overall-survival benefit is likely to be driven by a subgroup with particularly good treatment outcomes. The clinical experts anticipate that olaparib plus bevacizumab will increase the proportion of people who have long-term PFS and overall survival. They also explained that maintaining PFS for 5\xa0years is widely considered to be a good indicator of long-term survival. The cancer will progress after 5\xa0to 10\xa0years in only a small proportion of people who are progression free at 5\xa0years. The clinical experts noted that they do not tell people after 5\xa0years of PFS that they are 'cured', but tell them that their cancer is very unlikely to come back. This is reflected in the British Gynaecological Cancer Society ovarian cancer guidelines, which recommend stopping follow up if the cancer has not come back within 5\xa0years. The committee noted that the clinical experts' comments were consistent with those made by clinical experts for NICE's technology appraisal guidance on olaparib for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy. The experts for that appraisal made the following comments in relation to a trial of olaparib for relapsed ovarian cancer (Study\xa019):\n\nAfter 10\xa0years, 10% of people are disease free (indicating a cure).\n\nThis 10% are more likely to be people whose cancer had a complete response to platinum-based chemotherapy.The committee considered that other olaparib studies and the trials of other PARP inhibitors provided useful clinical context, and showed that a long-term treatment effect that could be indicative of cure is plausible. However, the committee also noted that although median PFS has been reached in PAOLA‑1, the median length of follow up in the olaparib plus bevacizumab arm was 22.7\xa0months (less than 2\xa0years), and the treatment was given for up to only 15.0\xa0months. The limited follow up means that there are insufficient data to show whether the treatment can maintain remission up to the clinically important 5‑year threshold. It also noted there was no obvious plateau in the intervention arm of the Kaplan–Meier plot to confirm a levelling off of the risk of progression and, given the numbers remaining at risk of progression, this was unlikely to be observed in future. The committee concluded that it is unclear whether olaparib plus bevacizumab maintenance treatment can cure ovarian cancer.\n\n# Cost effectiveness\n\n## The company's maintenance-only analysis is not appropriate\n\nThe company presented a 4‑state partitioned survival model to estimate the cost effectiveness of olaparib plus bevacizumab (15\xa0mg/kg) maintenance treatment in people with HRD-positive disease whose cancer had responded to first-line platinum-based chemotherapy plus bevacizumab (15\xa0mg/kg). The company presented 2\xa0analyses, a maintenance-only analysis and an extended-regimen analysis (see section\xa03.11). In the maintenance model, the company compared olaparib plus bevacizumab (15\xa0mg/kg) maintenance treatment with routine surveillance and bevacizumab (7.5\xa0mg/kg). It also included bevacizumab (15\xa0mg/kg) alone as a comparator. However, this was not in the scope and is not a standard treatment in the UK, so this comparison is not discussed further. The committee considered that the company's maintenance analysis did not address the full appraisal question in the scope because it focused on the maintenance period only. It did not consider the associated costs or clinical outcomes of having bevacizumab (15\xa0mg/kg) plus platinum-based chemotherapy first line (see section\xa03.1). Therefore, the committee concluded that this analysis was not appropriate.\n\n## The extended-regimen analysis is appropriate\n\nThe company's extended-regimen analysis compared first-line platinum-based chemotherapy plus bevacizumab (15\xa0mg/kg) followed by olaparib plus bevacizumab (15\xa0mg/kg) maintenance treatment for people whose cancer had responded with:\n\nfirst-line platinum-based chemotherapy followed by routine surveillance\n\nfirst-line platinum-based chemotherapy plus bevacizumab (7.5\xa0mg/kg) followed by bevacizumab (7.5\xa0mg/kg) as maintenance treatment for people whose cancer had responded\n\nfirst-line platinum-based chemotherapy plus bevacizumab (15\xa0mg/kg) followed by bevacizumab (15\xa0mg/kg) as maintenance treatment for people whose cancer had responded (which was not in the scope and is not routine treatment in the UK, so is not discussed further).The company included the cost of having bevacizumab (15\xa0mg/kg) plus first-line platinum-based chemotherapy but assumed that all the first-line treatment options were equally effective. The ERG identified some errors in the company's extended-regimen analyses. It considered that the analysis did not capture the full costs or the clinical outcomes of first-line treatment. The ERG included the additional costs and the outcomes in its own exploratory analyses. This analysis assumed that, in 69% of people, the cancer had completely or partially responded after first-line treatment, was stable in 23% and would progress in 8%. The clinical experts considered that these assumptions were clinically plausible. The committee agreed with the ERG that the company's extended-regimen analysis was limited because it did not capture the full costs or the health benefits of first-line treatment. It concluded that the ERG's extended-regimen analysis was more appropriate because it included both of these.\n\n## A mixture cure model is not justified and may overestimate survival gain\n\nThe company and the ERG used different methods to model survival. This was the key driver of the cost-effectiveness results. The company used a mixture cure model to estimate long-term survival. This assumed that the model population consisted of 2\xa0groups: a 'cured' population and a population whose cancer would progress. People predicted to be progression free at 5\xa0years were considered 'cured' and were assumed to have the same mortality as the UK general population. To predict overall survival, the company used standard parametric models up to 5\xa0to 6\xa0years and then overall survival was set to equal PFS. The ERG had several concerns about the company's modelling approach. It disagreed with using the mixture cure model in principle because PAOLA‑1 data are not mature enough to show a cure effect. It noted that a wide range of cure fractions had been reported across the different mixture cure models tested by the company. It also noted that the difference in the cure fractions used by the company in its base case, combined with its decision to set overall survival to equal PFS, resulted in a large and very long predicted overall-survival effect for olaparib plus bevacizumab. The ERG considered the company's approach of setting the overall-survival curves equal to the PFS curves methodologically flawed and to have a major effect on the relative effectiveness of the treatments. The committee agreed with the ERG's concerns. It noted that, at present, PAOLA‑1 does not provide sufficient evidence to support the company's assumption that a proportion of patients would be cured at 5\xa0years. This is because there are only 3\xa0years of PFS data. The specific cure fractions used in the company's mixture cure model are therefore not supported by the trial data. The committee was also concerned about the lack of a plateau in the Kaplan–Meier curve for PFS, which would be expected for a curative treatment. It appreciated that clinical trials for other PARP inhibitors have shown a plateau in the curves and that a subgroup are cancer free after 10\xa0years, indicating a cure. However, this has so far not been proven for olaparib plus bevacizumab. It also noted that the small proportion of people whose cancer progresses between 5\xa0and 10\xa0years (see section\xa03.9) are not accounted for in the company's mixture cure model. The committee considered that these points undermined the company's justification for using a mixture cure model. It agreed that using a mixture cure model, and the specific cure fractions preferred by the company, may have overestimated the survival gain for olaparib plus bevacizumab. It concluded that it is not possible to resolve the uncertainties about overall survival until further data are available from PAOLA‑1.\n\n## The ERG's exploratory analyses show the high uncertainty in the survival modelling\n\nThe ERG initially preferred to use standard parametric models to estimate long-term PFS and overall survival. However, it updated its approach after the clinical experts suggested at technical engagement that the PFS projections were not plausible. The ERG's updated modelling used the company's mixture cure model to estimate PFS, but predicted the survival trajectory from the overall-survival data rather than the PFS data. The clinical experts explained that the overall-survival projections for the routine surveillance arm were much higher than in clinical studies. The ERG acknowledged that the absolute overall-survival values were optimistic in both arms of the model and that its updated analysis had included some simplified modelling techniques. It explained that the aims of its updated approach were to:\n\nshow the substantial effect of using different survival modelling approaches on the cost-effectiveness results\n\nprovide an estimate of the relative survival benefit associated with olaparib plus bevacizumab maintenance treatment, which could be considered more realistic than the company's.The committee appreciated that the ERG's updated analysis was an exploratory analysis designed to show the uncertainty in the company's approach. It noted that the incremental cost-effectiveness ratios (ICERs) increased substantially when the ERG's original and updated survival modelling approaches were used. The committee concluded that the ERG's analyses showed the high level of uncertainty in the survival modelling.\n\n## Subsequent treatment costs should reflect routine NHS practice\n\nThe company and ERG used different treatment costs in their modelling, and this was also a driver of cost effectiveness. The company incorporated a hypothetical 50% discount to the bevacizumab list price to reflect the loss of exclusivity in 2020. The committee was aware that a confidential discount for bevacizumab had been agreed in a patient access scheme, and that the correct discounted price would be used in its decision making. The committee noted that the company and ERG also had different approaches to costing subsequent treatments. The company's approach was a hybrid between reflecting the treatments given in PAOLA‑1 and what is available routinely in UK clinical practice and through the Cancer Drugs Fund. By contrast, the ERG's costs were matched to NHS routine practice, whereby routinely commissioned treatments were included but not those available through the Cancer Drugs Fund. The committee noted the NICE position statement on consideration of products recommended for use in the Cancer Drugs Fund as comparators, or in a treatment sequence, in the appraisal of a new cancer product. The committee agreed that the costing of subsequent treatments should reflect routine NHS practice in line with the position statement. It therefore considered that the ERG's approach was more appropriate.\n\n## HRD-testing costs should be included in the modelling\n\nThe company did not include HRD-testing costs in its analyses. The ERG's exploratory analyses showed that including the costs of HRD testing would increase the cost-effectiveness estimate by around £5,000 per quality-adjusted life year (QALY) gained. The committee was aware that HRD testing is not standard practice, so an uplift in resources directly related to using olaparib plus bevacizumab would be needed to introduce it into the NHS. The committee concluded that HRD-testing costs should be included in the cost-effectiveness modelling.\n\n## The choice of utilities has a small effect on the cost-effectiveness results\n\nThe company and ERG used different utility values in their analyses. The company's utilities were derived from EQ‑5D‑5L data from PAOLA‑1 (mapped to EQ‑5D‑3L) for the PFS and first disease-progression health states. There were different values for PFS on and off treatment. The ERG was concerned about the appropriateness of having different utilities for PFS on and off treatment, and about the methods used to estimate the utilities. Therefore, the ERG preferred to use mapped EQ‑5D‑3L values from NICE's technology appraisal guidance on olaparib monotherapy maintenance treatment in its own analyses. The committee noted that the choice of utilities had a very small effect on the cost-effectiveness results and did not discuss this further.\n\n# Cost-effectiveness estimate\n\n## Olaparib plus bevacizumab maintenance treatment cannot be recommended for routine commissioning\n\nThe company's ICERs, using its extended-regimen analysis, for first-line platinum-based chemotherapy plus bevacizumab (15\xa0mg/kg) followed by olaparib plus bevacizumab maintenance treatment for people whose cancer had responded were:\n\n£26,268 per QALY gained compared with platinum-based chemotherapy followed by routine surveillance\n\n£19,925 per QALY gained compared with first-line platinum-based chemotherapy plus bevacizumab (7.5\xa0mg/kg) followed by bevacizumab maintenance treatment for people whose cancer had responded.Using the company's analysis, but incorporating the ERG's changes to the extended-regimen analysis in line with the committee's preference (see section\xa03.11), the ICERs were £34,165 per QALY gained for the routine surveillance arm and £24,726 per QALY gained for the bevacizumab (7.5\xa0mg/kg) arm. All the ICERs are lower when the confidential patient access scheme for bevacizumab is included. The committee noted that the ICERs were based on the company's survival modelling approach and could have substantially overestimated the survival gain for the olaparib plus bevacizumab arm (see section\xa03.12). Because of the high level of uncertainty in the survival modelling, the committee considered that the ICERs could be much higher. It noted that using the ERG's survival modelling updated after technical engagement, and including other preferred assumptions (see sections\xa03.14 to 3.16), increased the ICER to £93,350 per QALY gained compared with the routine surveillance arm and £75,476 per QALY gained compared with the bevacizumab (7.5\xa0mg/kg) arm. The committee considered that the ERG's exploratory analyses showed the substantial effect on the ICERs of using different survival modelling. Therefore, the committee could not state with any certainty a most plausible ICER. It concluded that, because of the high level of uncertainty, the ICER had not been shown to be within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained). Therefore, it could not recommend olaparib plus bevacizumab maintenance treatment for routine NHS use.\n\n# Cancer Drugs Fund\n\n## Further data from PAOLA‑1 would help to resolve the uncertainties in the clinical- and cost-effectiveness evidence\n\nHaving concluded that olaparib plus bevacizumab maintenance treatment could not be recommended for routine NHS use, the committee considered whether it could be recommended within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee recognised that olaparib plus bevacizumab maintenance treatment is an innovative treatment for advanced ovarian cancer and that there is a high unmet need in this disease area. It therefore considered whether clinical uncertainty associated with the treatment could be addressed through collection of additional data from PAOLA‑1. The company explained that further data collection is expected within the next 2\xa0years, including data on PFS, PFS2 and interim overall-survival data. The committee agreed that further data would be a valuable addition to the clinical evidence base and would help to resolve the major uncertainties.\n\n## Olaparib plus bevacizumab maintenance treatment meets the Cancer Drugs Fund inclusion criteria\n\nThe committee recalled that, using the company's analysis but incorporating the ERG's changes to the extended-regimen analysis in line with its preference (see section\xa03.11), the ICERs were £34,165 per QALY gained compared with the routine surveillance arm and £24,726 per QALY gained compared with the bevacizumab (7.5\xa0mg/kg) arm. It also recalled that the ICERs were lower when the confidential patient access scheme for bevacizumab was included. The company's base case assumed that people will be cured from ovarian cancer if they are progression free at 5\xa0years. Although the clinical experts had explained that a cure is possible, the committee noted that there were only 3\xa0years of PFS data from PAOLA‑1 and the overall-survival data were immature (see section\xa03.8). Therefore, the committee considered that the company's base-case ICER may be an optimistic estimate of cost effectiveness (see section\xa03.17). It thought that it was plausible the ICER could be much higher, exceeding the range that is usually considered a cost-effective use of NHS resources. The committee accepted that the upper bound of the range of plausible ICERs was highly uncertain. However, it considered that, pending the results from PAOLA‑1, there was plausible potential for platinum-based chemotherapy with bevacizumab 15 mg/kg followed by olaparib plus bevacizumab maintenance treatment to be cost effective in routine NHS use. Therefore, it concluded that the treatment meets the criteria for inclusion in the Cancer Drugs Fund for treating HRD-positive advanced ovarian, fallopian tube or primary peritoneal cancer.\n\n# Conclusion\n\n## Olaparib plus bevacizumab maintenance treatment is recommended for the Cancer Drugs Fund\n\nEarly results from PAOLA‑1 suggest that maintenance treatment with olaparib plus bevacizumab in people with HRD-positive disease that has responded to first-line platinum-based chemotherapy plus bevacizumab (15\xa0mg/kg) improves PFS compared with maintenance treatment with placebo plus bevacizumab. However, mature overall-survival data are not available and the extent to which the PFS benefit will translate into an overall-survival benefit is unclear. Because of the uncertainty about the overall-survival benefit, the estimates of cost effectiveness are very uncertain, and the treatment cannot be recommended for routine use in the NHS. If the treatment does increase survival, it has the potential to be cost effective. Further data from PAOLA‑1 will help to address the uncertainties in the clinical and cost effectiveness. Olaparib plus bevacizumab maintenance treatment is therefore recommended as an option within the Cancer Drugs Fund while further data are collected."}
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https://www.nice.org.uk/guidance/ta693
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Evidence-based recommendations on olaparib (Lynparza) plus bevacizumab (Avastin) for maintenance treatment of advanced ovarian, fallopian tube or primary peritoneal cancer in adults.
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a44db02baf9e247f6e84c0808686fe33545e9b3a
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nice
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Bempedoic acid with ezetimibe for treating primary hypercholesterolaemia or mixed dyslipidaemia
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Bempedoic acid with ezetimibe for treating primary hypercholesterolaemia or mixed dyslipidaemia
Evidence-based recommendations on bempedoic acid with ezetimibe (Nilemdo and Nustendi) for treating primary hypercholesterolaemia or mixed dyslipidaemia as an adjunct to diet in adults.
# Recommendations
Bempedoic acid with ezetimibe is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults. It is recommended only if:
statins are contraindicated or not tolerated
ezetimibe alone does not control low-density lipoprotein cholesterol well enough and
the company provides bempedoic acid and bempedoic acid with ezetimibe according to the commercial arrangement.Bempedoic acid with ezetimibe can be used as separate tablets or a fixed-dose combination.
This recommendation is not intended to affect treatment with bempedoic acid with ezetimibe that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatment for primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia includes statins for lowering low-density lipoprotein cholesterol (LDL-C) levels. Ezetimibe and either alirocumab or evolocumab may be added when patients' LDL-C levels are not lowered enough with the maximally tolerated dose of statins. Bempedoic acid with ezetimibe would be used when statins are contraindicated or not tolerated, and when ezetimibe alone does not control LDL-C well enough.
Clinical trial evidence suggests that bempedoic acid with ezetimibe may help lower LDL-C levels when other lipid-lowering therapies have not reduced them enough. But, there is no data directly comparing bempedoic acid with ezetimibe with either alirocumab or evolocumab. An indirect comparison of trials suggests that bempedoic acid with ezetimibe may not be as effective at reducing LDL-C levels as alirocumab or evolocumab.
Despite the uncertainty, the cost-effectiveness estimates for bempedoic acid with ezetimibe, when statins are contraindicated or not tolerated, are within what NICE normally considers an acceptable use of NHS resources. So, bempedoic acid with ezetimibe is recommended.# Information about bempedoic acid
# Marketing authorisation indication
## Bempedoic acid
Bempedoic acid (Nilemdo, Daiichi Sankyo) is 'indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:
in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,
alone or in combination with other lipid-lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated'.
## Bempedoic acid–ezetimibe
Bempedoic acid–ezetimibe (Nustendi, Daiichi Sankyo) is 'indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:
in combination with a statin in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibe,
alone in patients who are either statin intolerant or for whom a statin is contraindicated, and are unable to reach LDL-C goals with ezetimibe alone,
in patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets with or without statin'.
# Dosage in the marketing authorisation
The dosage schedule for bempedoic acid is available in the summary of product characteristics.
The dosage schedule for bempedoic acid–ezetimibe is available in the summary of product characteristics.
# Price
Bempedoic acid and bempedoic acid–ezetimibe costs £55.44 per 28‑pack, excluding VAT.
The company has a commercial arrangement (commercial access agreement). This makes bempedoic acid and bempedoic acid–ezetimibe available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Daiichi Sankyo, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Clinical pathway
## People with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia will welcome a new treatment option
People with primary hypercholesterolaemia (heterozygous familial and non‑familial) or mixed dyslipidaemia would welcome a new treatment option. The clinical expert explained that the main aim of treatment is to lower low‑density lipoprotein cholesterol (LDL-C) with a statin. People may also have ezetimibe if the maximum dose of statin is not lowering LDL-C enough. If LDL-C levels stay higher than normal and the person has cardiovascular disease or primary heterozygous familial hypercholesterolaemia, evolocumab or alirocumab are offered. The clinical expert explained that some people experience intolerance to statins. Statin intolerance can be difficult to define in clinical practice however some people experience muscle pains and in rare cases muscle breakdown. The patient expert explained the difficulty in appropriately identifying and offering treatment to people with increased levels of LDL-C because often they have no symptoms. In some people with increased LDL-C but who have not had a cardiovascular event (primary prevention), there can be reluctance to continue treatment with a statin. In people who have had a cardiovascular event (secondary prevention) treatment adherence is usually improved. The patient and clinical expert and responses to the appraisal consultation document noted that uptake of alirocumab and evolocumab in clinical practice is between 65% and 72% lower than expected. The clinical expert suggested this was because people who are eligible are not navigated through the lipid management pathway appropriately. The patient and clinical expert noted that bempedoic acid is an inexpensive, oral preparation that is easy to use and suitable for people who cannot tolerate statins. The committee concluded that a new treatment option for managing cholesterol would be welcomed.
## The company's proposed position of bempedoic acid with ezetimibe in the treatment pathway reflects NHS clinical practice
At the first committee meeting, the company had positioned bempedoic acid with ezetimibe for people when:
statins are contraindicated or not tolerated, and ezetimibe alone does not control LDL‑C well enough and
alirocumab or evolocumab are not appropriate (population 2a)
alirocumab or evolocumab are appropriate (population 2b).
the maximally tolerated statin dose with ezetimibe alone does not control LDL-C well enough and
alirocumab or evolocumab are not appropriate (population 4a)
alirocumab or evolocumab are appropriate (population 4b).The company's proposed position is narrower than the marketing authorisation (which allows bempedoic acid alone or in combination with a statin without ezetimibe), because they did not anticipate bempedoic acid would be used before ezetimibe in the treatment pathway in the NHS.During the appraisal, the company decided that it was no longer seeking a recommendation in the maximally tolerated statin population (populations 4a and 4b), because the incremental cost-effectiveness ratio (ICER) estimates were too high to be recommended for routine use in the NHS.The clinical and patient experts agreed with the position of bempedoic acid proposed by the company and noted it would likely not be used before ezetimibe in NHS clinical practice. The committee concluded that the company's proposed position of bempedoic acid in the treatment pathway reflects NHS clinical practice.
# Previous treatment with ezetimibe
## The network meta-analyses should include only trials in which all patients were having ezetimibe at baseline
The company's pivotal trial evidence for the effectiveness of bempedoic acid included 7 randomised controlled trials comprising 4 trials of bempedoic acid alone, 1 of bempedoic acid with ezetimibe, 1 of bempedoic acid alone or bempedoic acid with ezetimibe, and 1 trial of bempedoic acid–ezetimibe or bempedoic acid alone. Except for CLEAR Tranquility, the bempedoic acid trials included patients who had not previously had treatment with ezetimibe at baseline or who have had a washout period of lipid-lowering therapies. The ERG noted that this is not reflective of clinical practice because patients would be expected to have previously had ezetimibe according to the treatment pathway (see section 3.2). The clinical expert explained that generalising the clinical effectiveness of previous ezetimibe on improving cardiovascular outcomes and lipid levels depends on the length of time that a patient was having ezetimibe and the time since stopping. The clinical expert noted that the length of time that a patient was having ezetimibe will have an effect on cardiovascular outcomes for patients, and the time from stopping will affect the patients lipid profile. Furthermore, a washout period before bempedoic acid therapy may mitigate the effect of previous ezetimibe treatment. At the second committee meeting, the company updated its analysis to include a restricted network of trials, in which all patients were having ezetimibe at baseline (see section 3.8). The updated analysis included all the appropriate data from the CLEAR trials. The company noted that it was not feasible to include a network in which all trials had high background ezetimibe use (80% or more of patients in the trial had previously had ezetimibe). However, if the threshold were relaxed to 60%, 1 trial could be added to populations 2a and 2b (people who were intolerant to statins) network. The committee concluded that, given the proposed positioning of bempedoic acid in the treatment pathway, the network meta-analyses should be restricted to include only patients having ezetimibe at baseline.
# Baseline LDL-C levels in subpopulations not eligible for alirocumab or evolocumab
## Scenario analyses for adjusted baseline LDL-C levels were sufficient for decision making
The company used different mean baseline LDL-C levels in its economic model depending on the position of bempedoic acid in the treatment pathway. In patients who could have alirocumab and evolocumab, the company used mean baseline LDL-C levels from patients having alirocumab and evolocumab treatment in the CLEAR trials. However, in patients who could not have alirocumab and evolocumab, baseline LDL-C levels were taken from all patients in the CLEAR trials and did not distinguish between those who could have alirocumab or evolocumab and those who could not. NICE's technology appraisal guidance on alirocumab and evolocumab recommend treatment for:
primary prevention patients with heterozygous familial hypercholesterolaemia only if LDL-C levels persistently above 5 mmol/L
secondary prevention patients only if high risk for cardiovascular disease and LDL-C persistently above 4 mmol/L
secondary prevention patients only if very high risk for cardiovascular disease and LDL-C persistently above 3.5 mmol/L.The ERG preferred to use LDL-C levels separated by alirocumab or evolocumab eligibility because the baseline LDL-C levels in people not eligible were lower than the levels for those who were eligible. The clinical expert agreed that the baseline LDL-C levels will differ across the subpopulations. The committee agreed with the ERG, and wanted to see results based on the appropriate mean baseline LDL-C levels for the appropriate subpopulations. After the first committee meeting, NICE requested that the company provide results where baseline LDL-C levels reflect the intended positioning for bempedoic acid (that is, from patients who had already had ezetimibe and according to alirocumab or evolocumab eligibility). In response, the company provided an updated analysis which removed 2 trials from the network for populations 2a and 2b to improve similarity and comparability of baseline LDL‑C, but made no adjustment for baseline LDL‑C in patients who could not have alirocumab or evolocumab. The ERG presented results for adjusted baseline LDL‑C levels in population 2a, according to alirocumab and evolocumab eligibility. The company did provide mean baseline LDL-C levels for patients in the CLEAR trials with and without ezetimibe at baseline, however no statistical tests for differences between patients who had previously had ezetimibe and all patients (that is, patients who had and did not have previous ezetimibe) were done. The company also noted that across the bempedoic acid trials, the percentage reduction in LDL-C at 12 weeks was similar for all patients regardless of whether they could have alirocumab or evolocumab or not. The ERG modelled the baseline LDL-C levels to reflect the intended positioning for bempedoic acid (that is, patients who had already had ezetimibe and according to alirocumab and evolocumab eligibility). However, it noted that because of small patient numbers having already had ezetimibe and limited data to determine eligibility to alirocumab or evolocumab, these results are not reliable for decision making. The committee understood the added uncertainty around the results given the limitations of the CLEAR trial informing baseline LDL-C levels. It concluded that cost‑effectiveness results from scenario analyses were sufficient for decision making.
# Subgroup analyses
## Because of trial limitations, subgroup analyses could not be provided by heterozygous familial hypercholesterolaemia and cardiovascular risk status
The final NICE scope specified that subgroup analysis by cardiovascular risk and presence of heterozygous familial hypercholesterolaemia should be considered for the subgroups who were eligible for alirocumab or evolocumab. NICE's technology appraisals guidance for evolocumab and alirocumab made recommendations for these different subgroups (see section 3.4). The company noted that the proportion of patients with heterozygous familial hypercholesterolaemia in its trials were small. It noted that CLEAR Wisdom included the largest group of patients with heterozygous familial hypercholesterolaemia, and subgroup analysis suggested that the treatment effect is consistent with the non‑heterozygous familial hypercholesterolaemia population. At technical engagement, the company presented cost‑effectiveness results in 7 subgroups according to cardiovascular risk and heterozygous familial hypercholesterolaemia. The same treatment effect for bempedoic acid was used in each subgroup based on the assumption that the treatment effect would be similar in patients with and without heterozygous familial hypercholesterolaemia and with and without previous cardiovascular disease. The clinical expert explained that a common treatment effect should not be assumed across subgroups of heterozygous familial hypercholesterolaemia, non-familial hypercholesterolaemia and mixed dyslipidaemia because they each have distinct lipid profiles. The ERG considered that the company's subgroup analyses show the cost effectiveness of bempedoic acid is correlated with the baseline LDL-C level rather than with alirocumab or evolocumab eligibility. Further, the ERG noted that the company's trials had not been designed to detect statistical differences across cardiovascular risk and heterozygous familial hypercholesterolaemia. Also, the subgroup analysis had low patient numbers and was underpowered. The company did not update their subgroup analyses for heterozygous familial hypercholesterolaemia and cardiovascular risk status using their latest network meta-analysis (see section 3.8). The committee acknowledged that because the data needed were not collected in the CLEAR trials, it is not possible to do the appropriate subgroup analyses for heterozygous familial hypercholesterolaemia and cardiovascular risk status. The committee concluded that the company's subgroup analyses for these subgroups were not sufficient for decision making, because a treatment effect was assumed to be the same across patients with and without heterozygous familial hypercholesterolaemia, and with and without previous cardiovascular disease.
# Analyses by primary and secondary prevention population
## Because of trial limitations, analyses based on efficacy data directly related to the primary and secondary prevention populations could not be done
At technical engagement, the ERG noted that efficacy data for bempedoic acid are limited in primary prevention and patients with heterozygous familial hypercholesterolaemia. The clinical expert noted that it is possible to assume a similar treatment effect of bempedoic acid on lipid reduction across primary and secondary prevention status. However, it is not reasonable to assume a similar treatment effect on cardiovascular prevention, because cardiovascular risk is higher in secondary prevention patients. To avoid modelling a mixed prevention cohort, the company accepted the ERG's suggestion to model the subpopulations according to most of the population in the CLEAR trials. The populations were modelled as follows:
subpopulation 2a, primary prevention without heterozygous familial hypercholesterolaemia;
subpopulation 2b, secondary prevention without heterozygous familial hypercholesterolaemia.However, the ERG noted that not all patients in the trials included in the company's original network meta-analysis supporting the data for subpopulation 2b come from trial populations without heterozygous familial hypercholesterolaemia in secondary prevention. Also, not all patients in the network meta-analysis supporting the data for subpopulation 2a come from trial populations without heterozygous familial hypercholesterolaemia in primary prevention. At the second appraisal meeting, NICE requested analyses based on efficacy data directly relevant to the intended subpopulation should be done to provide reliable cost‑effectiveness estimates. The company noted that limiting to primary prevention and secondary prevention trials is challenging, because trials had mixed populations, and reporting of cardiovascular risk and previous cardiovascular events was unclear. As such, the company did not present updated results in response to this request. The committee concluded that the clinical heterogeneity resulting from generalised subgroup efficacy data is unlikely to be resolvable because of the limitations in the data from the CLEAR trials.
## Primary cardiovascular risk and cardiovascular event risk could not be collected from the company's CLEAR trials data
The company's model calculated background cardiovascular risks by converting the SCORE risk algorithm in European Society of Cardiology guidelines for a high-risk population into a QRISK3 risk. The subsequent annual risk was then used to estimate annual risk for the different cardiovascular events based on the relative rates of first events in Ward et al., 2007. The company noted that this approach is consistent with the approach in NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification. The ERG considered that primary cardiovascular risks and cardiovascular event history in the CLEAR trials may be more appropriate to use than other sources. The ERG considered that the true risk for primary cardiovascular events would lie somewhere between the company's base-case analysis (a 10-year risk of around 30% for myocardial infarction, ischemic stroke or cardiovascular death estimated using the SCORE risk) and the company's scenario analysis provided during the clarification stage (a 10-year risk of 20% for myocardial infarction, ischemic stroke or cardiovascular death). After the first committee meeting, NICE requested that the analyses use data from the CLEAR trials to inform baseline cardiovascular risk and event history in the model. The company reiterated that the parameters needed to reliably calculate cardiovascular risks using the QRISK3 algorithm had not been captured in the CLEAR trial datasets and cannot be obtained from published data. Additionally, the company noted that they were unable to use previous cardiovascular events from the CLEAR trials to estimate what previous events would have happened in the model, because these data were also not available from the CLEAR trials. The ERG reported, that in absence of the CLEAR trial data, using Ward et al., to inform the distribution of previous cardiovascular events is a reasonable alternative. At the second committee meeting, the ERG presented the updated scenario analysis from the first committee meeting using the ERG preferred network meta-analysis (see section 3.8) for population 2a (that is, patients who were statin intolerant and not eligible for alirocumab or evolocumab). The committee understood that data on primary cardiovascular risks and cardiovascular event history could not be obtained from the CLEAR trials. They concluded that using data from Ward et al., was a reasonable alternative, and the resulting uncertainty in the cost-effectiveness results could not be resolved.
# Methodological uncertainty
## The ERG's updated network meta-analysis is the most suitable for decision making
The ERG noted that the company's network meta-analysis submitted at technical engagement had high levels of statistical and clinical heterogeneity present. This included differences between trials in terms of baseline cardiovascular risk, statin intensity, proportion of patients having lipid‑lowering therapy for primary prevention, and proportions of patients with heterozygous familial hypercholesterolaemia. It also noted that the high residual deviance implied that the company's network meta-analysis would poorly predict the data from the trials used in the analysis. At the first appraisal meeting, the committee considered the high levels of statistical and clinical heterogeneity present in the company network meta-analysis to be unreliable for decision making. The committee noted that neither the ERG's or company's network meta-analysis were suitable, and preferred to see network meta-analyses with improved statistical fit and reduced clinical heterogeneity. After the first appraisal committee meeting, NICE requested that the company do an analysis which builds upon the network meta-analyses done by the ERG and presented in the first appraisal meeting to reduce statistical and clinical heterogeneity. As part of the analysis, NICE also asked the company to identify any additional trials that meet the following:
People in the trial have had treatment with ezetimibe before randomisation (see section 3.3).
People in the trials have similar unadjusted baseline LDL-C levels (see section 3.4).
Use appropriate trials to inform treatment efficacy for primary prevention (population 2a) and secondary prevention (population 2b) (see section 3.6 and section 3.7).
Trials that have other similar baseline characteristics such as cardiovascular disease risk, heterozygous familial hypercholesterolaemia, type of statin, sex, and ethnicity (see section 3.5).In response, the company presented 2 further network meta-analyses:
An additional network meta-analysis, which included several changes in line with the requests by NICE (see sections 3.3 to 3.7). The committee agreed with the ERG and remained concerned that there was substantial unresolved clinical heterogeneity between the trials included in the company's additional network meta‑analysis, and the results were not suitable for decision making.
An update of the ERG preferred network meta-analysis to include all available data for bempedoic acid in patients having ezetimibe at baseline from the CLEAR trials, to which the ERG did not previously have access to. The ERG considered that the updated ERG analysis met the requests from NICE.The committee concluded that the company's updated ERG network meta-analysis was preferred and the most suitable for decision making. In response to the appraisal consultation document, the company provided updated cost-effectiveness results using the committee's preferred network meta-analysis.
# Long-term treatment effect of bempedoic acid
## There is uncertainty with the evidence informing the long-term treatment effect of bempedoic acid
The primary efficacy outcome of all relevant bempedoic acid trials was percentage change from baseline LDL-C at 12 weeks. The company model assumed that results achieved at 12 weeks were maintained for the duration of the model's time horizon, or until treatment is stopped. The ERG noted that there may be a slight waning of treatment effect with bempedoic acid beyond 12 weeks in the data for CLEAR Tranquility and CLEAR Serenity. In response to the appraisal consultation document, the company highlighted evidence from the CLEAR Harmony open-label extension study which showed a mean LDL-C reduction from baseline in CLEAR Harmony of ‑14.9% and ‑14.4% at 12 and 78 weeks. The ERG noted that the data relate to people who have maximally tolerated statin levels, which is a population that the company is no longer seeking recommendation for, and it also includes people who have not previously had ezetimibe. The ERG considered that there may be a slight waning of treatment effect with bempedoic acid beyond 12 weeks but it did not know if a similar waning would be seen with the comparators. Therefore, the ERG explored 2 scenarios to show what effect a treatment waning effect on LDL-C could have on the cost-effectiveness results using data from CLEAR Serenity (study data directly relating to the statin intolerant population). Clinical experts could not comment on the potential waning effect of bempedoic acid. The company and the ERG noted that treatment waning effects could be because of other factors (for example when people stop following advice on diet and exercise improvements) and not just lipid-lowering drug efficacy. The committee concluded that there is uncertainty in the evidence informing the long-term treatment effect of bempedoic acid.
## Evidence of the direct effect on cardiovascular outcomes is not available
The company noted that it modelled the relationship between LDL-C reduction and cardiovascular risk based on the Cholesterol Treatment Trialist Collaboration meta-analyses of statin studies. The company noted that although bempedoic acid and statins both inhibit cholesterol synthesis in the liver, a differentiating factor is that, unlike statins, bempedoic acid is inactive in skeletal muscle. At the second appraisal meeting, the committee expressed a concern that the link between changes in LDL-C levels and cardiovascular outcomes used in the company model, may not be appropriate for bempedoic acid because the mechanism of action of bempedoic acid is different to that of statins. In response to the appraisal consultation document, the company provided additional information reinforcing that the cardiovascular benefits of LDL-C lowering are independent of the methods by which it is achieved. The committee accepted the association between LDL-C lowering and cardiovascular benefits, but concluded that it would have liked to have seen evidence of the direct impact of bempedoic acid on cardiovascular outcomes.
# Cost-effectiveness results
## The ERG's updated base case includes the committee's preferences
The ERG's revised base case (which is the same as the company's updated ERG preferred network meta-analysis) provided at the second appraisal meeting included the committee's preferred network meta-analysis. The ERG network meta-analysis comprised of restricted networks of trials for populations 2a and 2b (people who were intolerant to statins) in which all patients were having ezetimibe at baseline (see section 3.3), and thus were aligned with the company's proposed positioning of bempedoic acid in the treatment pathway. The results of the ERG's revised base case included the cost of the bempedoic acid–ezetimibe fixed-dose combination tablet only. The committee was aware that this was cheaper than separate tablets for bempedoic acid and ezetimibe. The committee concluded that the revised ERG base case was the most suitable for decision making. In response to the appraisal consultation document, the company provided updated cost-effectiveness results based on the committee's preferred modelling assumptions with a commercial arrangement for bempedoic acid and bempedoic acid–ezetimibe.
## Because of the uncertainty, an acceptable ICER is below £20,000 per quality-adjusted life year (QALY) gained and above £30,000 per QALY lost
The committee recalled that the company was no longer seeking a recommendation in the maximally tolerated statin population (population 4a and 4b) (see section 3.2). For population 2a, the ICER resulted in additional costs and a gain of QALYs. For population 2b, the ICER resulted in cost savings and a loss of QALYs. NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.The committee noted the high level of uncertainty. In particular:
the committee remained uncertain that the results appropriately reflect the intended positioning of bempedoic acid given the limitations of the CLEAR trial informing baseline LDL‑C levels (see section 3.4)
subgroup analyses by cardiovascular risk and heterozygous familial hypercholesterolaemia could not be appropriately done (see section 3.5)
the appropriate analyses based on efficacy data directly related to the primary and secondary prevention populations could not be done (see section 3.6)
that primary cardiovascular risks and cardiovascular event history could not be informed by the CLEAR trial (see section 3.7)
the committee remain uncertain about the evidence provided on the long-term impact of bempedoic acid on cardiovascular outcomes (see section 3.10)Therefore, the committee agreed that conservative thresholds for populations 2a and 2b should be adopted. The committee concluded that an acceptable ICER for population 2a would be below £20,000 per QALY gained, and an acceptable ICER for population 2b would be above £30,000 per QALY lost.
## Bempedoic acid with ezetimibe is recommended as a cost-effective use of NHS resources
Using the committee's preferred assumptions (see section 3.11) the most plausible ICER for population 2a (statins are contraindicated or not tolerated and not eligible for alirocumab or evolocumab) was less than £20,000 per QALY gained for bempedoic acid and bempedoic acid–ezetimibe. Because of the confidential discount for bempedoic acid and bempedoic acid–ezetimibe, the exact ICER for population 2a cannot be reported here.
Using the committee's preferred assumptions (see section 3.11) the most plausible ICER for population 2b (statins are contraindicated or not tolerated and eligible for alirocumab or evolocumab) was more than £30,000 saved per QALY lost for bempedoic acid and bempedoic acid–ezetimibe. Because of the confidential discount for bempedoic acid and bempedoic acid–ezetimibe, the exact ICER for population 2b cannot be reported here.
The committee concluded that bempedoic acid with ezetimibe (both as separate tablets and in a fixed-dose combination) is cost effective for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet in adults for whom statins are contraindicated or not tolerated, and ezetimibe alone does not control LDL-C well enough.
# Other factors
## There are no equalities issues
No equality or social value judgement issues were identified.
## There are no additional benefits not already captured in the economic analysis
The committee understood that there is an unmet need for patients who cannot tolerate statins. The committee was aware that bempedoic acid is an oral preparation compared with alirocumab and evolocumab which are administered subcutaneously and took this into account in its decision making. The committee concluded that there were no additional benefits associated with this treatment that had not been captured in the economic analysis.
# Conclusion
## Bempedoic acid with ezetimibe is recommended
The committee concluded that bempedoic acid with ezetimibe is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet in adults for whom statins are contraindicated or not tolerated, and ezetimibe alone does not control LDL-C well enough. The committee was concerned about the clinical effectiveness of bempedoic acid because of the lack of long-term data on cardiovascular outcomes in the pivotal trials, and that appropriate subgroup analyses relating to cardiovascular risk and heterozygous familial hypercholesterolaemia could not be provided. However, it noted that further data were unlikely to become available. The cost-effectiveness results based on the committee's preferred modelling assumptions with a commercial arrangement for bempedoic acid and bempedoic acid–ezetimibe represent a cost-effective use of NHS resources. The committee therefore concluded that bempedoic acid with ezetimibe be recommended for routine use in the NHS in people for whom statins are contraindicated or not tolerated, and ezetimibe alone does not control LDL-C well enough.
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{'Recommendations': "Bempedoic acid with ezetimibe is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults. It is recommended only if:\n\nstatins are contraindicated or not tolerated\n\nezetimibe alone does not control low-density lipoprotein cholesterol well enough and\n\nthe company provides bempedoic acid and bempedoic acid with ezetimibe according to the commercial arrangement.Bempedoic acid with ezetimibe can be used as separate tablets or a fixed-dose combination.\n\nThis recommendation is not intended to affect treatment with bempedoic acid with ezetimibe that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia includes statins for lowering low-density lipoprotein cholesterol (LDL-C) levels. Ezetimibe and either alirocumab or evolocumab may be added when patients' LDL-C levels are not lowered enough with the maximally tolerated dose of statins. Bempedoic acid with ezetimibe would be used when statins are contraindicated or not tolerated, and when ezetimibe alone does not control LDL-C well enough.\n\nClinical trial evidence suggests that bempedoic acid with ezetimibe may help lower LDL-C levels when other lipid-lowering therapies have not reduced them enough. But, there is no data directly comparing bempedoic acid with ezetimibe with either alirocumab or evolocumab. An indirect comparison of trials suggests that bempedoic acid with ezetimibe may not be as effective at reducing LDL-C levels as alirocumab or evolocumab.\n\nDespite the uncertainty, the cost-effectiveness estimates for bempedoic acid with ezetimibe, when statins are contraindicated or not tolerated, are within what NICE normally considers an acceptable use of NHS resources. So, bempedoic acid with ezetimibe is recommended.", 'Information about bempedoic acid': "# Marketing authorisation indication\n\n## Bempedoic acid\n\nBempedoic acid (Nilemdo, Daiichi Sankyo) is 'indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:\n\nin combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,\n\nalone or in combination with other lipid-lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated'.\n\n## Bempedoic acid–ezetimibe\n\nBempedoic acid–ezetimibe (Nustendi, Daiichi Sankyo) is 'indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:\n\nin combination with a statin in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibe,\n\nalone in patients who are either statin intolerant or for whom a statin is contraindicated, and are unable to reach LDL-C goals with ezetimibe alone,\n\nin patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets with or without statin'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule for bempedoic acid is available in the summary of product characteristics.\n\nThe dosage schedule for bempedoic acid–ezetimibe is available in the summary of product characteristics.\n\n# Price\n\nBempedoic acid and bempedoic acid–ezetimibe costs £55.44 per 28‑pack, excluding VAT.\n\nThe company has a commercial arrangement (commercial access agreement). This makes bempedoic acid and bempedoic acid–ezetimibe available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Daiichi Sankyo, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical pathway\n\n## People with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia will welcome a new treatment option\n\nPeople with primary hypercholesterolaemia (heterozygous familial and non‑familial) or mixed dyslipidaemia would welcome a new treatment option. The clinical expert explained that the main aim of treatment is to lower low‑density lipoprotein cholesterol (LDL-C) with a statin. People may also have ezetimibe if the maximum dose of statin is not lowering LDL-C enough. If LDL-C levels stay higher than normal and the person has cardiovascular disease or primary heterozygous familial hypercholesterolaemia, evolocumab or alirocumab are offered. The clinical expert explained that some people experience intolerance to statins. Statin intolerance can be difficult to define in clinical practice however some people experience muscle pains and in rare cases muscle breakdown. The patient expert explained the difficulty in appropriately identifying and offering treatment to people with increased levels of LDL-C because often they have no symptoms. In some people with increased LDL-C but who have not had a cardiovascular event (primary prevention), there can be reluctance to continue treatment with a statin. In people who have had a cardiovascular event (secondary prevention) treatment adherence is usually improved. The patient and clinical expert and responses to the appraisal consultation document noted that uptake of alirocumab and evolocumab in clinical practice is between 65% and 72% lower than expected. The clinical expert suggested this was because people who are eligible are not navigated through the lipid management pathway appropriately. The patient and clinical expert noted that bempedoic acid is an inexpensive, oral preparation that is easy to use and suitable for people who cannot tolerate statins. The committee concluded that a new treatment option for managing cholesterol would be welcomed.\n\n## The company's proposed position of bempedoic acid with ezetimibe in the treatment pathway reflects NHS clinical practice\n\nAt the first committee meeting, the company had positioned bempedoic acid with ezetimibe for people when:\n\nstatins are contraindicated or not tolerated, and ezetimibe alone does not control LDL‑C well enough and\n\n\n\nalirocumab or evolocumab are not appropriate (population\xa02a)\n\nalirocumab or evolocumab are appropriate (population\xa02b).\n\n\n\nthe maximally tolerated statin dose with ezetimibe alone does not control LDL-C well enough and\n\n\n\nalirocumab or evolocumab are not appropriate (population\xa04a)\n\nalirocumab or evolocumab are appropriate (population 4b).The company's proposed position is narrower than the marketing authorisation (which allows bempedoic acid alone or in combination with a statin without ezetimibe), because they did not anticipate bempedoic acid would be used before ezetimibe in the treatment pathway in the NHS.During the appraisal, the company decided that it was no longer seeking a recommendation in the maximally tolerated statin population (populations\xa04a and\xa04b), because the incremental cost-effectiveness ratio (ICER) estimates were too high to be recommended for routine use in the NHS.The clinical and patient experts agreed with the position of bempedoic acid proposed by the company and noted it would likely not be used before ezetimibe in NHS clinical practice. The committee concluded that the company's proposed position of bempedoic acid in the treatment pathway reflects NHS clinical practice.\n\n\n\n# Previous treatment with ezetimibe\n\n## The network meta-analyses should include only trials in which all patients were having ezetimibe at baseline\n\nThe company's pivotal trial evidence for the effectiveness of bempedoic acid included 7\xa0randomised controlled trials comprising 4\xa0trials of bempedoic acid alone, 1 of bempedoic acid with ezetimibe, 1 of bempedoic acid alone or bempedoic acid with ezetimibe, and 1\xa0trial of bempedoic acid–ezetimibe or bempedoic acid alone. Except for CLEAR Tranquility, the bempedoic acid trials included patients who had not previously had treatment with ezetimibe at baseline or who have had a washout period of lipid-lowering therapies. The ERG noted that this is not reflective of clinical practice because patients would be expected to have previously had ezetimibe according to the treatment pathway (see section\xa03.2). The clinical expert explained that generalising the clinical effectiveness of previous ezetimibe on improving cardiovascular outcomes and lipid levels depends on the length of time that a patient was having ezetimibe and the time since stopping. The clinical expert noted that the length of time that a patient was having ezetimibe will have an effect on cardiovascular outcomes for patients, and the time from stopping will affect the patients lipid profile. Furthermore, a washout period before bempedoic acid therapy may mitigate the effect of previous ezetimibe treatment. At the second committee meeting, the company updated its analysis to include a restricted network of trials, in which all patients were having ezetimibe at baseline (see section\xa03.8). The updated analysis included all the appropriate data from the CLEAR trials. The company noted that it was not feasible to include a network in which all trials had high background ezetimibe use (80% or more of patients in the trial had previously had ezetimibe). However, if the threshold were relaxed to 60%, 1\xa0trial could be added to populations\xa02a and\xa02b (people who were intolerant to statins) network. The committee concluded that, given the proposed positioning of bempedoic acid in the treatment pathway, the network meta-analyses should be restricted to include only patients having ezetimibe at baseline.\n\n# Baseline LDL-C levels in subpopulations not eligible for alirocumab or evolocumab\n\n## Scenario analyses for adjusted baseline LDL-C levels were sufficient for decision making\n\nThe company used different mean baseline LDL-C levels in its economic model depending on the position of bempedoic acid in the treatment pathway. In patients who could have alirocumab and evolocumab, the company used mean baseline LDL-C levels from patients having alirocumab and evolocumab treatment in the CLEAR trials. However, in patients who could not have alirocumab and evolocumab, baseline LDL-C levels were taken from all patients in the CLEAR trials and did not distinguish between those who could have alirocumab or evolocumab and those who could not. NICE's technology appraisal guidance on alirocumab and evolocumab recommend treatment for:\n\nprimary prevention patients with heterozygous familial hypercholesterolaemia only if LDL-C levels persistently above 5\xa0mmol/L\n\nsecondary prevention patients only if high risk for cardiovascular disease and LDL-C persistently above 4\xa0mmol/L\n\nsecondary prevention patients only if very high risk for cardiovascular disease and LDL-C persistently above 3.5\xa0mmol/L.The ERG preferred to use LDL-C levels separated by alirocumab or evolocumab eligibility because the baseline LDL-C levels in people not eligible were lower than the levels for those who were eligible. The clinical expert agreed that the baseline LDL-C levels will differ across the subpopulations. The committee agreed with the ERG, and wanted to see results based on the appropriate mean baseline LDL-C levels for the appropriate subpopulations. After the first committee meeting, NICE requested that the company provide results where baseline LDL-C levels reflect the intended positioning for bempedoic acid (that is, from patients who had already had ezetimibe and according to alirocumab or evolocumab eligibility). In response, the company provided an updated analysis which removed 2 trials from the network for populations\xa02a and\xa02b to improve similarity and comparability of baseline LDL‑C, but made no adjustment for baseline LDL‑C in patients who could not have alirocumab or evolocumab. The ERG presented results for adjusted baseline LDL‑C levels in population 2a, according to alirocumab and evolocumab eligibility. The company did provide mean baseline LDL-C levels for patients in the CLEAR trials with and without ezetimibe at baseline, however no statistical tests for differences between patients who had previously had ezetimibe and all patients (that is, patients who had and did not have previous ezetimibe) were done. The company also noted that across the bempedoic acid trials, the percentage reduction in LDL-C at 12\xa0weeks was similar for all patients regardless of whether they could have alirocumab or evolocumab or not. The ERG modelled the baseline LDL-C levels to reflect the intended positioning for bempedoic acid (that is, patients who had already had ezetimibe and according to alirocumab and evolocumab eligibility). However, it noted that because of small patient numbers having already had ezetimibe and limited data to determine eligibility to alirocumab or evolocumab, these results are not reliable for decision making. The committee understood the added uncertainty around the results given the limitations of the CLEAR trial informing baseline LDL-C levels. It concluded that cost‑effectiveness results from scenario analyses were sufficient for decision making.\n\n# Subgroup analyses\n\n## Because of trial limitations, subgroup analyses could not be provided by heterozygous familial hypercholesterolaemia and cardiovascular risk status\n\nThe final NICE scope specified that subgroup analysis by cardiovascular risk and presence of heterozygous familial hypercholesterolaemia should be considered for the subgroups who were eligible for alirocumab or evolocumab. NICE's technology appraisals guidance for evolocumab and alirocumab made recommendations for these different subgroups (see section\xa03.4). The company noted that the proportion of patients with heterozygous familial hypercholesterolaemia in its trials were small. It noted that CLEAR Wisdom included the largest group of patients with heterozygous familial hypercholesterolaemia, and subgroup analysis suggested that the treatment effect is consistent with the non‑heterozygous familial hypercholesterolaemia population. At technical engagement, the company presented cost‑effectiveness results in 7 subgroups according to cardiovascular risk and heterozygous familial hypercholesterolaemia. The same treatment effect for bempedoic acid was used in each subgroup based on the assumption that the treatment effect would be similar in patients with and without heterozygous familial hypercholesterolaemia and with and without previous cardiovascular disease. The clinical expert explained that a common treatment effect should not be assumed across subgroups of heterozygous familial hypercholesterolaemia, non-familial hypercholesterolaemia and mixed dyslipidaemia because they each have distinct lipid profiles. The ERG considered that the company's subgroup analyses show the cost effectiveness of bempedoic acid is correlated with the baseline LDL-C level rather than with alirocumab or evolocumab eligibility. Further, the ERG noted that the company's trials had not been designed to detect statistical differences across cardiovascular risk and heterozygous familial hypercholesterolaemia. Also, the subgroup analysis had low patient numbers and was underpowered. The company did not update their subgroup analyses for heterozygous familial hypercholesterolaemia and cardiovascular risk status using their latest network meta-analysis (see section\xa03.8). The committee acknowledged that because the data needed were not collected in the CLEAR trials, it is not possible to do the appropriate subgroup analyses for heterozygous familial hypercholesterolaemia and cardiovascular risk status. The committee concluded that the company's subgroup analyses for these subgroups were not sufficient for decision making, because a treatment effect was assumed to be the same across patients with and without heterozygous familial hypercholesterolaemia, and with and without previous cardiovascular disease.\n\n# Analyses by primary and secondary prevention population\n\n## Because of trial limitations, analyses based on efficacy data directly related to the primary and secondary prevention populations could not be done\n\nAt technical engagement, the ERG noted that efficacy data for bempedoic acid are limited in primary prevention and patients with heterozygous familial hypercholesterolaemia. The clinical expert noted that it is possible to assume a similar treatment effect of bempedoic acid on lipid reduction across primary and secondary prevention status. However, it is not reasonable to assume a similar treatment effect on cardiovascular prevention, because cardiovascular risk is higher in secondary prevention patients. To avoid modelling a mixed prevention cohort, the company accepted the ERG's suggestion to model the subpopulations according to most of the population in the CLEAR trials. The populations were modelled as follows:\n\nsubpopulation\xa02a, primary prevention without heterozygous familial hypercholesterolaemia;\n\nsubpopulation\xa02b, secondary prevention without heterozygous familial hypercholesterolaemia.However, the ERG noted that not all patients in the trials included in the company's original network meta-analysis supporting the data for subpopulation\xa02b come from trial populations without heterozygous familial hypercholesterolaemia in secondary prevention. Also, not all patients in the network meta-analysis supporting the data for subpopulation\xa02a come from trial populations without heterozygous familial hypercholesterolaemia in primary prevention. At the second appraisal meeting, NICE requested analyses based on efficacy data directly relevant to the intended subpopulation should be done to provide reliable cost‑effectiveness estimates. The company noted that limiting to primary prevention and secondary prevention trials is challenging, because trials had mixed populations, and reporting of cardiovascular risk and previous cardiovascular events was unclear. As such, the company did not present updated results in response to this request. The committee concluded that the clinical heterogeneity resulting from generalised subgroup efficacy data is unlikely to be resolvable because of the limitations in the data from the CLEAR trials.\n\n## Primary cardiovascular risk and cardiovascular event risk could not be collected from the company's CLEAR trials data\n\nThe company's model calculated background cardiovascular risks by converting the SCORE risk algorithm in European Society of Cardiology guidelines for a high-risk population into a QRISK3\xa0risk. The subsequent annual risk was then used to estimate annual risk for the different cardiovascular events based on the relative rates of first events in Ward et al., 2007. The company noted that this approach is consistent with the approach in NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification. The ERG considered that primary cardiovascular risks and cardiovascular event history in the CLEAR trials may be more appropriate to use than other sources. The ERG considered that the true risk for primary cardiovascular events would lie somewhere between the company's base-case analysis (a 10-year risk of around 30% for myocardial infarction, ischemic stroke or cardiovascular death estimated using the SCORE risk) and the company's scenario analysis provided during the clarification stage (a 10-year risk of 20% for myocardial infarction, ischemic stroke or cardiovascular death). After the first committee meeting, NICE requested that the analyses use data from the CLEAR trials to inform baseline cardiovascular risk and event history in the model. The company reiterated that the parameters needed to reliably calculate cardiovascular risks using the QRISK3 algorithm had not been captured in the CLEAR trial datasets and cannot be obtained from published data. Additionally, the company noted that they were unable to use previous cardiovascular events from the CLEAR trials to estimate what previous events would have happened in the model, because these data were also not available from the CLEAR trials. The ERG reported, that in absence of the CLEAR trial data, using Ward et al., to inform the distribution of previous cardiovascular events is a reasonable alternative. At the second committee meeting, the ERG presented the updated scenario analysis from the first committee meeting using the ERG preferred network meta-analysis (see section\xa03.8) for population\xa02a (that is, patients who were statin intolerant and not eligible for alirocumab or evolocumab). The committee understood that data on primary cardiovascular risks and cardiovascular event history could not be obtained from the CLEAR trials. They concluded that using data from Ward et al., was a reasonable alternative, and the resulting uncertainty in the cost-effectiveness results could not be resolved.\n\n# Methodological uncertainty\n\n## The ERG's updated network meta-analysis is the most suitable for decision making\n\nThe ERG noted that the company's network meta-analysis submitted at technical engagement had high levels of statistical and clinical heterogeneity present. This included differences between trials in terms of baseline cardiovascular risk, statin intensity, proportion of patients having lipid‑lowering therapy for primary prevention, and proportions of patients with heterozygous familial hypercholesterolaemia. It also noted that the high residual deviance implied that the company's network meta-analysis would poorly predict the data from the trials used in the analysis. At the first appraisal meeting, the committee considered the high levels of statistical and clinical heterogeneity present in the company network meta-analysis to be unreliable for decision making. The committee noted that neither the ERG's or company's network meta-analysis were suitable, and preferred to see network meta-analyses with improved statistical fit and reduced clinical heterogeneity. After the first appraisal committee meeting, NICE requested that the company do an analysis which builds upon the network meta-analyses done by the ERG and presented in the first appraisal meeting to reduce statistical and clinical heterogeneity. As part of the analysis, NICE also asked the company to identify any additional trials that meet the following:\n\nPeople in the trial have had treatment with ezetimibe before randomisation (see section\xa03.3).\n\nPeople in the trials have similar unadjusted baseline LDL-C levels (see section\xa03.4).\n\nUse appropriate trials to inform treatment efficacy for primary prevention (population\xa02a) and secondary prevention (population\xa02b) (see section\xa03.6 and\xa0section 3.7).\n\nTrials that have other similar baseline characteristics such as cardiovascular disease risk, heterozygous familial hypercholesterolaemia, type of statin, sex, and ethnicity (see section\xa03.5).In response, the company presented 2 further network meta-analyses:\n\nAn additional network meta-analysis, which included several changes in line with the requests by NICE (see sections\xa03.3 to 3.7). The committee agreed with the ERG and remained concerned that there was substantial unresolved clinical heterogeneity between the trials included in the company's additional network meta‑analysis, and the results were not suitable for decision making.\n\nAn update of the ERG preferred network meta-analysis to include all available data for bempedoic acid in patients having ezetimibe at baseline from the CLEAR trials, to which the ERG did not previously have access to. The ERG considered that the updated ERG analysis met the requests from NICE.The committee concluded that the company's updated ERG network meta-analysis was preferred and the most suitable for decision making. In response to the appraisal consultation document, the company provided updated cost-effectiveness results using the committee's preferred network meta-analysis.\n\n# Long-term treatment effect of bempedoic acid\n\n## There is uncertainty with the evidence informing the long-term treatment effect of bempedoic acid\n\nThe primary efficacy outcome of all relevant bempedoic acid trials was percentage change from baseline LDL-C at 12\xa0weeks. The company model assumed that results achieved at 12\xa0weeks were maintained for the duration of the model's time horizon, or until treatment is stopped. The ERG noted that there may be a slight waning of treatment effect with bempedoic acid beyond 12\xa0weeks in the data for CLEAR Tranquility and CLEAR Serenity. In response to the appraisal consultation document, the company highlighted evidence from the CLEAR Harmony open-label extension study which showed a mean LDL-C reduction from baseline in CLEAR Harmony of ‑14.9% and ‑14.4% at 12 and 78\xa0weeks. The ERG noted that the data relate to people who have maximally tolerated statin levels, which is a population that the company is no longer seeking recommendation for, and it also includes people who have not previously had ezetimibe. The ERG considered that there may be a slight waning of treatment effect with bempedoic acid beyond 12\xa0weeks but it did not know if a similar waning would be seen with the comparators. Therefore, the ERG explored 2 scenarios to show what effect a treatment waning effect on LDL-C could have on the cost-effectiveness results using data from CLEAR Serenity (study data directly relating to the statin intolerant population). Clinical experts could not comment on the potential waning effect of bempedoic acid. The company and the ERG noted that treatment waning effects could be because of other factors (for example when people stop following advice on diet and exercise improvements) and not just lipid-lowering drug efficacy. The committee concluded that there is uncertainty in the evidence informing the long-term treatment effect of bempedoic acid.\n\n## Evidence of the direct effect on cardiovascular outcomes is not available\n\nThe company noted that it modelled the relationship between LDL-C reduction and cardiovascular risk based on the Cholesterol Treatment Trialist Collaboration meta-analyses of statin studies. The company noted that although bempedoic acid and statins both inhibit cholesterol synthesis in the liver, a differentiating factor is that, unlike statins, bempedoic acid is inactive in skeletal muscle. At the second appraisal meeting, the committee expressed a concern that the link between changes in LDL-C levels and cardiovascular outcomes used in the company model, may not be appropriate for bempedoic acid because the mechanism of action of bempedoic acid is different to that of statins. In response to the appraisal consultation document, the company provided additional information reinforcing that the cardiovascular benefits of LDL-C lowering are independent of the methods by which it is achieved. The committee accepted the association between LDL-C lowering and cardiovascular benefits, but concluded that it would have liked to have seen evidence of the direct impact of bempedoic acid on cardiovascular outcomes.\n\n# Cost-effectiveness results\n\n## The ERG's updated base case includes the committee's preferences\n\nThe ERG's revised base case (which is the same as the company's updated ERG preferred network meta-analysis) provided at the second appraisal meeting included the committee's preferred network meta-analysis. The ERG network meta-analysis comprised of restricted networks of trials for populations\xa02a and 2b (people who were intolerant to statins) in which all patients were having ezetimibe at baseline (see section\xa03.3), and thus were aligned with the company's proposed positioning of bempedoic acid in the treatment pathway. The results of the ERG's revised base case included the cost of the bempedoic acid–ezetimibe fixed-dose combination tablet only. The committee was aware that this was cheaper than separate tablets for bempedoic acid and ezetimibe. The committee concluded that the revised ERG base case was the most suitable for decision making. In response to the appraisal consultation document, the company provided updated cost-effectiveness results based on the committee's preferred modelling assumptions with a commercial arrangement for bempedoic acid and bempedoic acid–ezetimibe.\n\n## Because of the uncertainty, an acceptable ICER is below £20,000 per quality-adjusted life year (QALY) gained and above £30,000 per QALY lost\n\nThe committee recalled that the company was no longer seeking a recommendation in the maximally tolerated statin population (population\xa04a and 4b) (see section\xa03.2). For population\xa02a, the ICER resulted in additional costs and a gain of QALYs. For population\xa02b, the ICER resulted in cost savings and a loss of QALYs. NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.The committee noted the high level of uncertainty. In particular:\n\nthe committee remained uncertain that the results appropriately reflect the intended positioning of bempedoic acid given the limitations of the CLEAR trial informing baseline LDL‑C levels (see section\xa03.4)\n\nsubgroup analyses by cardiovascular risk and heterozygous familial hypercholesterolaemia could not be appropriately done (see section\xa03.5)\n\nthe appropriate analyses based on efficacy data directly related to the primary and secondary prevention populations could not be done (see section\xa03.6)\n\nthat primary cardiovascular risks and cardiovascular event history could not be informed by the CLEAR trial (see section\xa03.7)\n\nthe committee remain uncertain about the evidence provided on the long-term impact of bempedoic acid on cardiovascular outcomes (see section\xa03.10)Therefore, the committee agreed that conservative thresholds for populations\xa02a and 2b should be adopted. The committee concluded that an acceptable ICER for population\xa02a would be below £20,000 per QALY gained, and an acceptable ICER for population\xa02b would be above £30,000 per QALY lost.\n\n## Bempedoic acid with ezetimibe is recommended as a cost-effective use of NHS resources\n\nUsing the committee's preferred assumptions (see section\xa03.11) the most plausible ICER for population\xa02a (statins are contraindicated or not tolerated and not eligible for alirocumab or evolocumab) was less than £20,000 per QALY gained for bempedoic acid and bempedoic acid–ezetimibe. Because of the confidential discount for bempedoic acid and bempedoic acid–ezetimibe, the exact ICER for population\xa02a cannot be reported here.\n\nUsing the committee's preferred assumptions (see section\xa03.11) the most plausible ICER for population\xa02b (statins are contraindicated or not tolerated and eligible for alirocumab or evolocumab) was more than £30,000 saved per QALY lost for bempedoic acid and bempedoic acid–ezetimibe. Because of the confidential discount for bempedoic acid and bempedoic acid–ezetimibe, the exact ICER for population\xa02b cannot be reported here.\n\nThe committee concluded that bempedoic acid with ezetimibe (both as separate tablets and in a fixed-dose combination) is cost effective for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet in adults for whom statins are contraindicated or not tolerated, and ezetimibe alone does not control LDL-C well enough.\n\n# Other factors\n\n## There are no equalities issues\n\nNo equality or social value judgement issues were identified.\n\n## There are no additional benefits not already captured in the economic analysis\n\nThe committee understood that there is an unmet need for patients who cannot tolerate statins. The committee was aware that bempedoic acid is an oral preparation compared with alirocumab and evolocumab which are administered subcutaneously and took this into account in its decision making. The committee concluded that there were no additional benefits associated with this treatment that had not been captured in the economic analysis.\n\n# Conclusion\n\n## Bempedoic acid with ezetimibe is recommended\n\nThe committee concluded that bempedoic acid with ezetimibe is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet in adults for whom statins are contraindicated or not tolerated, and ezetimibe alone does not control LDL-C well enough. The committee was concerned about the clinical effectiveness of bempedoic acid because of the lack of long-term data on cardiovascular outcomes in the pivotal trials, and that appropriate subgroup analyses relating to cardiovascular risk and heterozygous familial hypercholesterolaemia could not be provided. However, it noted that further data were unlikely to become available. The cost-effectiveness results based on the committee's preferred modelling assumptions with a commercial arrangement for bempedoic acid and bempedoic acid–ezetimibe represent a cost-effective use of NHS resources. The committee therefore concluded that bempedoic acid with ezetimibe be recommended for routine use in the NHS in people for whom statins are contraindicated or not tolerated, and ezetimibe alone does not control LDL-C well enough."}
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https://www.nice.org.uk/guidance/ta694
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Evidence-based recommendations on bempedoic acid with ezetimibe (Nilemdo and Nustendi) for treating primary hypercholesterolaemia or mixed dyslipidaemia as an adjunct to diet in adults.
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1c833eefdfbf3d2e9b4f6183cbd918c30f5b8573
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nice
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Carfilzomib with dexamethasone and lenalidomide for previously treated multiple myeloma
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Carfilzomib with dexamethasone and lenalidomide for previously treated multiple myeloma
Evidence-based recommendations on carfilzomib (Kyprolis) with dexamethasone and lenalidomide (Revlimid) for previously treated multiple myeloma in adults.
# Recommendations
Carfilzomib plus lenalidomide and dexamethasone is recommended as an option for treating multiple myeloma in adults, only if:
they have had only 1 previous therapy, which included bortezomib, and
the company provides carfilzomib according to the commercial arrangement.
This recommendation is not intended to affect treatment with carfilzomib plus lenalidomide and dexamethasone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Clinical trial evidence shows that carfilzomib plus lenalidomide and dexamethasone gives longer periods of remission and people live longer, compared with lenalidomide plus dexamethasone. This treatment benefit appears to continue for up to 6 years. However, there is uncertainty about how long the benefit lasts after this.
The most likely cost-effectiveness estimates are within what NICE normally considers a cost-effective use of NHS resources. So, carfilzomib plus lenalidomide and dexamethasone is recommended.# Information about carfilzomib
# Marketing authorisation indication
Carfilzomib (Kyprolis, Amgen) 'in combination with daratumumab and dexamethasone, with lenalidomide and dexamethasone, or with dexamethasone alone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of carfilzomib is £1,056 for a 60‑mg vial (excluding VAT; BNF online, accessed January 2021). Multiple courses of treatment may be used in combination with lenalidomide and dexamethasone. The company has a commercial arrangement. This makes carfilzomib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.
The list price of lenalidomide per 21‑capsule pack varies according to capsule size: £3,426.00 (2.5 mg), £3,570.00 (5 mg), £3,675.00 (7.5 mg), £3,780.00 (10 mg), £3,969.00 (15 mg), £4,168.50 (20 mg) and £4,368.00 (25 mg) (excluding VAT; BNF online, accessed January 2021). The company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Amgen, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# New treatment option
## People with previously treated multiple myeloma would welcome a new second-line treatment option
The patient experts explained that multiple myeloma is a relapsing and remitting disease with periods of severe symptoms that need treating. They described how difficult it is not knowing when their disease will relapse and that they have to put their life on hold. Treatment options for multiple myeloma after 1 previous treatment depend on what that treatment was and whether a stem cell transplant is suitable. If a stem cell transplant is suitable, treatment options include daratumumab with bortezomib and dexamethasone (NICE's technology appraisal guidance on daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma). If a stem cell transplant is not suitable, NICE technology appraisal guidance recommends the following treatment options:
bortezomib monotherapy
carfilzomib with dexamethasone
lenalidomide with dexamethasone after 1 previous treatment that included bortezomib
daratumumab with bortezomib and dexamethasone (recommended for use within the Cancer Drugs Fund after 1 previous treatment).The patient experts explained that there is a need for new effective second-line treatments, and the availability of effective combination treatments with different mechanisms of action is important when relapse occurs. They explained that the potential for improved quality of life during prolonged remission is important, as well as the potential for improved survival. The committee concluded that people with multiple myeloma would welcome a new second‑line treatment that gives longer periods of remission and improves survival.
# Comparators
## Lenalidomide and dexamethasone is the only relevant comparator
The clinical evidence came from ASPIRE, an open-label, randomised multicentre trial of carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone. The company submission included a matched-adjusted indirect comparison of carfilzomib plus lenalidomide and dexamethasone against daratumumab with bortezomib and dexamethasone, which is recommended for use within the Cancer Drugs Fund for treating relapsed multiple myeloma after 1 previous treatment (NICE's technology appraisal guidance on daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma). The evidence for this comparison was not presented to the committee because of NICE's position statement on the Cancer Drugs Fund. This states that technologies recommended by NICE for use within the Cancer Drugs Fund cannot be considered established practice and therefore cannot be considered as comparators in new appraisals. The clinical expert explained that many patients have daratumumab plus bortezomib and dexamethasone as second-line treatment, so the comparison with lenalidomide plus dexamethasone does not fully reflect clinical practice. The committee noted that daratumumab plus bortezomib and dexamethasone was recommended for use within the Cancer Drugs Fund because the uncertainties in the clinical evidence and cost-effectiveness estimates were too great to make a recommendation for routine commissioning. The committee also noted that technologies recommended for use within the Cancer Drugs Fund might not subsequently be recommended for routine commissioning. It therefore concluded that based on NICE's position statement on the role of technologies recommended for use in the Cancer Drugs Fund as comparators in appraisals, lenalidomide plus dexamethasone is the only relevant comparator.
# Treatment pathway and positioning
## The relevant population is people who have had only 1 previous treatment containing bortezomib, whether or not a stem cell transplant is suitable
The committee noted that the treatment pathway differs depending on whether a person can have a stem cell transplant. It discussed whether a person who has had a stem cell transplant would have poorer outcomes with carfilzomib plus lenalidomide and dexamethasone than with lenalidomide plus dexamethasone. The clinical expert suggested that there is no clinical reason for carfilzomib to work differently in a person who has had a stem cell transplant compared with someone who has not. The committee understood that the myeloma treatment pathway is continually evolving. It noted that the introduction of carfilzomib plus lenalidomide and dexamethasone as a second-line treatment option would help to address the need for effective therapies with alternative mechanisms of action. It agreed that the company's approach of restricting the population to people who have had 1 previous bortezomib treatment is reasonable. The committee concluded that the population relevant to this appraisal is people who have had only 1 previous treatment containing bortezomib, whether or not a stem cell transplant is suitable.
# Subgroup data
## The subgroup of patients from ASPIRE who had 1 bortezomib treatment and no previous lenalidomide reflects the current treatment pathway
The company presented analyses for a subgroup of patients from ASPIRE who had had 1 previous bortezomib treatment. The company considered that in clinical practice, a small number of patients may have lenalidomide and bortezomib as first-line treatment and would still be considered eligible for carfilzomib plus lenalidomide and dexamethasone. The ERG highlighted that in the company's subgroup, all patients had 1 previous bortezomib treatment, but not all patients had bortezomib as part of their last treatment regimen. Some patients also had lenalidomide at the same time or afterwards (in the same treatment phase). The ERG presented analyses from a post-hoc subgroup that had a stricter definition of first-line therapy. It was based on the current NICE-recommended treatment pathway for multiple myeloma and included patients who only had 1 previous bortezomib treatment and no previous lenalidomide. The committee heard from clinical experts that it is not current standard practice to have bortezomib and lenalidomide as a first-line treatment. The clinical lead for the Cancer Drugs Fund explained that most patients would have bortezomib as induction therapy before a stem cell transplant, and lenalidomide would only be considered if bortezomib did not provide an adequate response. In this situation, it would be unlikely that a triple regimen of carfilzomib plus lenalidomide and dexamethasone would be tolerated as a second-line treatment. The company did not submit new evidence to support its choice of post-hoc subgroup in response to the appraisal consultation document. The committee noted that the first-line treatments in the ERG's subgroup are appropriate for patients who would be offered carfilzomib plus lenalidomide and dexamethasone as second line in the NHS. It concluded that the ERG's subgroup should be the basis of its preferred analyses.
# Overall survival and progression-free survival
## Mature data from ASPIRE show improved progression-free survival and overall survival
Carfilzomib plus lenalidomide and dexamethasone increased median progression-free survival compared with lenalidomide plus dexamethasone from 16.6 months to 26.1 months (hazard ratio 0.659; 95% confidence interval 0.553 to 0.784, p<0.0001) in the intention-to-treat population. Carfilzomib plus lenalidomide and dexamethasone increased median overall survival compared with lenalidomide plus dexamethasone from 40.4 months to 48.3 months (hazard ratio 0.794; 95% confidence interval 0.667 to 0.945, p=0.0045) in the intention-to-treat population. For both its own and the ERG's preferred post-hoc subgroups, the company did an inverse probability weighted analysis to account for imbalances in baseline characteristics in the non-randomised groups. The subgroup results are considered confidential by the company and cannot be reported here, but the results for the ERG's preferred post-hoc subgroup showed a similar size benefit as for the intention-to-treat population. The clinical expert explained that clinical practice focuses on whether progression-free survival will translate into overall survival, and that the combinations available in England tend to show improvements only in progression-free survival and not overall survival. The clinical expert stated that this is the first multiple myeloma trial with a long follow-up period to provide clear evidence of improved progression-free survival and overall survival. The committee welcomed the mature trial data from ASPIRE and concluded that carfilzomib plus lenalidomide and dexamethasone improves progression-free survival and overall survival compared with lenalidomide plus dexamethasone.
# Utility values used in the economic model
## Analyses with and without treatment-specific utility values were considered
From cycle 3 in the company's model, the utility values for the progression-free health state increased from baseline for carfilzomib plus lenalidomide, and dexamethasone and also for lenalidomide plus dexamethasone. However, the increase in utility is greater for carfilzomib plus lenalidomide and dexamethasone. The committee discussed the clinical plausibility of using differential treatment-specific utility values for patients in the same health state. It noted that treatment-specific utility values were included in the company's model, which was accepted in NICE's technology appraisal guidance on carfilzomib with dexamethasone. The company highlighted that the general cancer health-related quality of life (HRQoL) questionnaire (EORTC QLQ‑C30) used in ASPIRE showed a statistically significant difference in the global health status scores between the treatment arms over 18 cycles of treatment. However, the committee noted that there were no significant differences between treatment arms on the other HRQoL domains assessed, including the myeloma-specific EORTC QLQ‑MY20 instrument that was also used to collect quality of life data in ASPIRE. The clinical expert explained that adding carfilzomib to treatment with lenalidomide and dexamethasone would not necessarily improve a person's quality of life. But it increases the effectiveness of controlling the disease, which would improve quality of life. The company did not submit any new evidence to support its approach of using treatment-specific utility values in response to the appraisal consultation document. The company's clinical experts considered that patients in the progression-free health state having carfilzomib treatment are likely to experience reduced symptoms (such as bone pain and fatigue), a higher response rate and a faster response. This would improve their quality of life. The committee noted that the ERG's clinical expert considered there may be a quicker response to treatment for patients having carfilzomib in addition to lenalidomide and dexamethasone. But there is no clinical reason for there to be a treatment-specific utility benefit in addition to the benefit provided by any gains in progression-free survival. The ERG noted that ASPIRE was an open-label trial, and knowing which treatment they were having could have influenced patient's responses to the HRQoL questionnaires. It therefore preferred to use the same utility value for both treatments, with no increase from baseline. The committee considered that it had not been presented with strong evidence to support the company's use of treatment-specific utility values. It noted that using the same values for both treatments may be more clinically plausible because of possible confounding of the treatment-specific values. But it also noted that applying either choice of utility values resulted in carfilzomib plus lenalidomide and dexamethasone being cost effective. The committee concluded that it would consider treatment-specific values and equal values for both treatments in its decision making.
# Extrapolation of overall survival
## Overall survival should be extrapolated from the mature ASPIRE data
The company considered that extrapolating from ASPIRE data may underestimate long-term survival, producing conservative results for the lenalidomide plus dexamethasone arm compared with estimates presented in related technology appraisals. Because of this, to estimate overall survival for both treatment arms, the company used a combination of extrapolated ASPIRE inverse probability weighted overall-survival data and real-world evidence from a French registry (MyelomaToul) of multiple myeloma patients who had lenalidomide as a second-line treatment. The ERG considered that a clinically plausible extrapolation of overall survival for carfilzomib plus lenalidomide and dexamethasone could be estimated entirely from mature ASPIRE data. It noted that the exponential distribution was the best statistical fit for its preferred subgroup. The company did not provide any new evidence to support its preferred overall-survival extrapolations in response to the appraisal consultation document. The committee concluded that it preferred to estimate overall survival for both treatment arms using data from the ASPIRE trial only.
# Stopping rule
## In clinical practice, treatment with carfilzomib would be limited to 18 cycles
In ASPIRE, carfilzomib treatment stopped after 18 cycles. But the marketing authorisation allows for treatment until disease progression or unacceptable toxicity. Carfilzomib's summary of product characteristics states that treatment 'combined with lenalidomide and dexamethasone for longer than 18 cycles should be based on an individual benefit/risk assessment, as the data on the tolerability and toxicity of carfilzomib beyond 18 cycles are limited'. The committee noted that treatment costs for carfilzomib after 18 cycles were not included in the company's economic model. The clinical expert stated that because of lack of evidence of efficacy for carfilzomib treatment beyond 18 months, and the associated toxicity, it would be unlikely for treatment to continue beyond this time period. The clinical lead for the Cancer Drugs Fund advised that NHS England would commission a maximum of 18 cycles of carfilzomib based on the evidence from ASPIRE. The committee noted that many cancer treatments are commissioned for a fixed duration of time and clinicians are familiar with this approach. In particular, carfilzomib with dexamethasone alone is commissioned and used for a maximum of 18 cycles in the NHS. The patient expert highlighted that there may be some patients who wish to continue treatment with carfilzomib beyond 18 cycles, but most patients would be reassured by the availability of other effective subsequent treatment therapies. The committee concluded that treatment with carfilzomib would be not continue beyond 18 cycles because further treatment would not be commissioned by NHS England after this period.
## It is uncertain how long any treatment benefit lasts after stopping treatment
The committee noted that a constant relative treatment effect had been applied to every cycle in the company's model for carfilzomib plus lenalidomide and dexamethasone, beyond the observed ASPIRE data. This is despite the fact that the company proposes carfilzomib is stopped after 18 cycles of treatment. The committee considered that the ERG's exponential model of overall survival also included a treatment benefit for carfilzomib plus lenalidomide and dexamethasone after stopping treatment. However, it accepted that the use of mature data from ASPIRE may have captured some waning of treatment effect. The committee discussed whether there would be better prognosis in people who reached 20‑years survival with carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone. The clinical expert confirmed that people who are alive after 20 years only have a better prognosis because they are able to have further treatment, and not necessarily because they previously had 1 treatment rather than another. The committee agreed it was unclear how long the treatment benefit would last for carfilzomib plus lenalidomide and dexamethasone. It considered that the application of a prolonged treatment benefit may potentially overestimate survival and be favourable to carfilzomib plus lenalidomide and dexamethasone. The company provided some additional analyses in response to the appraisal consultation document that aimed to resolve the committee's concerns that the treatment effect may wane over time. The committee agreed that the new evidence clearly showed that a treatment benefit is maintained for carfilzomib plus lenalidomide and dexamethasone after 18 cycles of carfilzomib treatment (28 days of treatment per cycle) and during the entire trial follow-up period (72 months). However, it was not convinced there was sufficient evidence or clinical rationale to support the assumption of a continued treatment benefit beyond the observed ASPIRE data. Therefore, the committee concluded that it is uncertain how long any treatment benefit with carfilzomib plus lenalidomide and dexamethasone lasts after stopping treatment. It considered that the treatment effect is likely to diminish over time in the extrapolated period. The committee concluded that accepting a constant treatment benefit during this period may result in optimistic cost-effectiveness estimates in favour of carfilzomib.
# Combination therapies
## The costs of lenalidomide with dexamethasone should be included in the model
The company considered that the increase in progression-free survival from adding carfilzomib to lenalidomide and dexamethasone is penalised because lenalidomide and dexamethasone are given until disease progression. This increases the costs associated with these drugs compared with using them without carfilzomib. The company did an exploratory analysis that excluded the additional cost of lenalidomide and dexamethasone in the carfilzomib plus lenalidomide and dexamethasone treatment arm. This improved the cost effectiveness of the carfilzomib regimen. The committee acknowledged that treatments that extend the use of other high-cost drugs (such as lenalidomide) can lead to additional cost associated with those other drugs, and that this has been considered in NICE appraisals of other cancer topics. It concluded that the costs of lenalidomide and dexamethasone are relevant because the NHS would incur those costs in practice, so they should be included in the model.
# Cost-effectiveness estimates
## The committee's preferred incremental cost-effectiveness ratios are likely to be below £30,000 per quality-adjusted life year gained
NICE's guide to the methods of technology appraisal notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.
The company's deterministic base-case ICER for carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone was £43,952 per QALY gained (using the patient access scheme for carfilzomib, which the company revised in response to consultation). The ERG presented analyses combining its preferred assumptions including choice of post-hoc subgroup, using the same pre-progression utility values for both treatment arms and using the exponential distribution to extrapolate overall survival based on the ASPIRE data only. It also presented analyses for its base-case assumptions without the treatment-specific utility values. The ERG's analyses included the confidential commercial arrangements for lenalidomide and for panobinostat and pomalidomide, which are options later in the treatment pathway. The committee considered analyses with and without the treatment-specific utility values (see section 3.6). The ICERs for all scenarios were below £30,000 per QALY gained for carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone. The committee discussed that the cost-effectiveness estimates may be optimistic because some waning of treatment benefit with carfilzomib plus lenalidomide and dexamethasone is likely to occur beyond the observed ASPIRE data. Based on the evidence presented and with the discount agreed in the commercial arrangement, the committee concluded that the most plausible ICERs are within the range that NICE normally considers an acceptable use of NHS resources. Although the committee's preferred analyses were based on the ERG's post-hoc subgroup (see section 3.4), it did not consider it needed to specify that people should not have previously had lenalidomide in the recommendation. This was because it noted the company's argument that this may exclude a small number of people from accessing carfilzomib plus lenalidomide and dexamethasone. It was also aware that recommendations for the comparator in this appraisal, lenalidomide plus dexamethasone, do not specify no previous lenalidomide. Therefore, it recommended carfilzomib plus lenalidomide and dexamethasone for multiple myeloma in adults who have had only 1 previous therapy, which included bortezomib.
# End of life
## Carfilzomib plus lenalidomide and dexamethasone does not meet NICE's end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee considered whether carfilzomib plus lenalidomide and dexamethasone meets the end of life criteria for people with multiple myeloma who have had 1 previous treatment including bortezomib. The committee noted that the model predicted that patients in the comparator arm lived longer than 24 months, and therefore concluded that carfilzomib in this indication did not meet the criterion for life expectancy. Because it did not meet this criterion, the committee concluded that it did not need to discuss the end of life criteria further.
# Other factors
## There are no equality issues relevant to the recommendations
The patient expert advised that they were not aware of any equality issues. The committee concluded that no equality or social value judgements are relevant to its decision.
## The benefits of carfilzomib are captured in the cost-effectiveness analysis
The company and the clinical expert consider carfilzomib plus lenalidomide and dexamethasone to be innovative because it significantly improves progression-free survival and overall survival compared with lenalidomide and dexamethasone. The committee agreed that these are important benefits of carfilzomib plus lenalidomide and dexamethasone. But it concluded that it had not been presented with evidence of any additional benefits that had not been captured in the QALYs.
|
{'Recommendations': 'Carfilzomib plus lenalidomide and dexamethasone is recommended as an option for treating multiple myeloma in adults, only if:\n\nthey have had only 1\xa0previous therapy, which included bortezomib, and\n\nthe company provides carfilzomib according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with carfilzomib plus lenalidomide and dexamethasone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nClinical trial evidence shows that carfilzomib plus lenalidomide and dexamethasone gives longer periods of remission and people live longer, compared with lenalidomide plus dexamethasone. This treatment benefit appears to continue for up to 6\xa0years. However, there is uncertainty about how long the benefit lasts after this.\n\nThe most likely cost-effectiveness estimates are within what NICE normally considers a cost-effective use of NHS resources. So, carfilzomib plus lenalidomide and dexamethasone is recommended.', 'Information about carfilzomib': "# Marketing authorisation indication\n\nCarfilzomib (Kyprolis, Amgen) 'in combination with daratumumab and dexamethasone, with lenalidomide and dexamethasone, or with dexamethasone alone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of carfilzomib is £1,056 for a 60‑mg vial (excluding VAT; BNF online, accessed January\xa02021). Multiple courses of treatment may be used in combination with lenalidomide and dexamethasone. The company has a commercial arrangement. This makes carfilzomib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\nThe list price of lenalidomide per 21‑capsule pack varies according to capsule size: £3,426.00 (2.5\xa0mg), £3,570.00 (5\xa0mg), £3,675.00 (7.5\xa0mg), £3,780.00 (10\xa0mg), £3,969.00 (15\xa0mg), £4,168.50 (20\xa0mg) and £4,368.00 (25\xa0mg) (excluding VAT; BNF online, accessed January\xa02021). The company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Amgen, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with previously treated multiple myeloma would welcome a new second-line treatment option\n\nThe patient experts explained that multiple myeloma is a relapsing and remitting disease with periods of severe symptoms that need treating. They described how difficult it is not knowing when their disease will relapse and that they have to put their life on hold. Treatment options for multiple myeloma after 1\xa0previous treatment depend on what that treatment was and whether a stem cell transplant is suitable. If a stem cell transplant is suitable, treatment options include daratumumab with bortezomib and dexamethasone (NICE's technology appraisal guidance on daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma). If a stem cell transplant is not suitable, NICE technology appraisal guidance recommends the following treatment options:\n\nbortezomib monotherapy\n\ncarfilzomib with dexamethasone\n\nlenalidomide with dexamethasone after 1\xa0previous treatment that included bortezomib\n\ndaratumumab with bortezomib and dexamethasone (recommended for use within the Cancer Drugs Fund after 1\xa0previous treatment).The patient experts explained that there is a need for new effective second-line treatments, and the availability of effective combination treatments with different mechanisms of action is important when relapse occurs. They explained that the potential for improved quality of life during prolonged remission is important, as well as the potential for improved survival. The committee concluded that people with multiple myeloma would welcome a new second‑line treatment that gives longer periods of remission and improves survival.\n\n# Comparators\n\n## Lenalidomide and dexamethasone is the only relevant comparator\n\nThe clinical evidence came from ASPIRE, an open-label, randomised multicentre trial of carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone. The company submission included a matched-adjusted indirect comparison of carfilzomib plus lenalidomide and dexamethasone against daratumumab with bortezomib and dexamethasone, which is recommended for use within the Cancer Drugs Fund for treating relapsed multiple myeloma after 1\xa0previous treatment (NICE's technology appraisal guidance on daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma). The evidence for this comparison was not presented to the committee because of NICE's position statement on the Cancer Drugs Fund. This states that technologies recommended by NICE for use within the Cancer Drugs Fund cannot be considered established practice and therefore cannot be considered as comparators in new appraisals. The clinical expert explained that many patients have daratumumab plus bortezomib and dexamethasone as second-line treatment, so the comparison with lenalidomide plus dexamethasone does not fully reflect clinical practice. The committee noted that daratumumab plus bortezomib and dexamethasone was recommended for use within the Cancer Drugs Fund because the uncertainties in the clinical evidence and cost-effectiveness estimates were too great to make a recommendation for routine commissioning. The committee also noted that technologies recommended for use within the Cancer Drugs Fund might not subsequently be recommended for routine commissioning. It therefore concluded that based on NICE's position statement on the role of technologies recommended for use in the Cancer Drugs Fund as comparators in appraisals, lenalidomide plus dexamethasone is the only relevant comparator.\n\n# Treatment pathway and positioning\n\n## The relevant population is people who have had only 1\xa0previous treatment containing bortezomib, whether or not a stem cell transplant is suitable\n\nThe committee noted that the treatment pathway differs depending on whether a person can have a stem cell transplant. It discussed whether a person who has had a stem cell transplant would have poorer outcomes with carfilzomib plus lenalidomide and dexamethasone than with lenalidomide plus dexamethasone. The clinical expert suggested that there is no clinical reason for carfilzomib to work differently in a person who has had a stem cell transplant compared with someone who has not. The committee understood that the myeloma treatment pathway is continually evolving. It noted that the introduction of carfilzomib plus lenalidomide and dexamethasone as a second-line treatment option would help to address the need for effective therapies with alternative mechanisms of action. It agreed that the company's approach of restricting the population to people who have had 1\xa0previous bortezomib treatment is reasonable. The committee concluded that the population relevant to this appraisal is people who have had only 1\xa0previous treatment containing bortezomib, whether or not a stem cell transplant is suitable.\n\n# Subgroup data\n\n## The subgroup of patients from ASPIRE who had 1\xa0bortezomib treatment and no previous lenalidomide reflects the current treatment pathway\n\nThe company presented analyses for a subgroup of patients from ASPIRE who had had 1\xa0previous bortezomib treatment. The company considered that in clinical practice, a small number of patients may have lenalidomide and bortezomib as first-line treatment and would still be considered eligible for carfilzomib plus lenalidomide and dexamethasone. The ERG highlighted that in the company's subgroup, all patients had 1\xa0previous bortezomib treatment, but not all patients had bortezomib as part of their last treatment regimen. Some patients also had lenalidomide at the same time or afterwards (in the same treatment phase). The ERG presented analyses from a post-hoc subgroup that had a stricter definition of first-line therapy. It was based on the current NICE-recommended treatment pathway for multiple myeloma and included patients who only had 1\xa0previous bortezomib treatment and no previous lenalidomide. The committee heard from clinical experts that it is not current standard practice to have bortezomib and lenalidomide as a first-line treatment. The clinical lead for the Cancer Drugs Fund explained that most patients would have bortezomib as induction therapy before a stem cell transplant, and lenalidomide would only be considered if bortezomib did not provide an adequate response. In this situation, it would be unlikely that a triple regimen of carfilzomib plus lenalidomide and dexamethasone would be tolerated as a second-line treatment. The company did not submit new evidence to support its choice of post-hoc subgroup in response to the appraisal consultation document. The committee noted that the first-line treatments in the ERG's subgroup are appropriate for patients who would be offered carfilzomib plus lenalidomide and dexamethasone as second line in the NHS. It concluded that the ERG's subgroup should be the basis of its preferred analyses.\n\n# Overall survival and progression-free survival\n\n## Mature data from ASPIRE show improved progression-free survival and overall survival\n\nCarfilzomib plus lenalidomide and dexamethasone increased median progression-free survival compared with lenalidomide plus dexamethasone from 16.6\xa0months to 26.1\xa0months (hazard ratio\xa00.659; 95%\xa0confidence interval 0.553 to 0.784, p<0.0001) in the intention-to-treat population. Carfilzomib plus lenalidomide and dexamethasone increased median overall survival compared with lenalidomide plus dexamethasone from 40.4\xa0months to 48.3\xa0months (hazard ratio\xa00.794; 95%\xa0confidence interval 0.667 to 0.945, p=0.0045) in the intention-to-treat population. For both its own and the ERG's preferred post-hoc subgroups, the company did an inverse probability weighted analysis to account for imbalances in baseline characteristics in the non-randomised groups. The subgroup results are considered confidential by the company and cannot be reported here, but the results for the ERG's preferred post-hoc subgroup showed a similar size benefit as for the intention-to-treat population. The clinical expert explained that clinical practice focuses on whether progression-free survival will translate into overall survival, and that the combinations available in England tend to show improvements only in progression-free survival and not overall survival. The clinical expert stated that this is the first multiple myeloma trial with a long follow-up period to provide clear evidence of improved progression-free survival and overall survival. The committee welcomed the mature trial data from ASPIRE and concluded that carfilzomib plus lenalidomide and dexamethasone improves progression-free survival and overall survival compared with lenalidomide plus dexamethasone.\n\n# Utility values used in the economic model\n\n## Analyses with and without treatment-specific utility values were considered\n\nFrom cycle\xa03 in the company's model, the utility values for the progression-free health state increased from baseline for carfilzomib plus lenalidomide, and dexamethasone and also for lenalidomide plus dexamethasone. However, the increase in utility is greater for carfilzomib plus lenalidomide and dexamethasone. The committee discussed the clinical plausibility of using differential treatment-specific utility values for patients in the same health state. It noted that treatment-specific utility values were included in the company's model, which was accepted in NICE's technology appraisal guidance on carfilzomib with dexamethasone. The company highlighted that the general cancer health-related quality of life (HRQoL) questionnaire (EORTC\xa0QLQ‑C30) used in ASPIRE showed a statistically significant difference in the global health status scores between the treatment arms over 18\xa0cycles of treatment. However, the committee noted that there were no significant differences between treatment arms on the other HRQoL domains assessed, including the myeloma-specific EORTC\xa0QLQ‑MY20 instrument that was also used to collect quality of life data in ASPIRE. The clinical expert explained that adding carfilzomib to treatment with lenalidomide and dexamethasone would not necessarily improve a person's quality of life. But it increases the effectiveness of controlling the disease, which would improve quality of life. The company did not submit any new evidence to support its approach of using treatment-specific utility values in response to the appraisal consultation document. The company's clinical experts considered that patients in the progression-free health state having carfilzomib treatment are likely to experience reduced symptoms (such as bone pain and fatigue), a higher response rate and a faster response. This would improve their quality of life. The committee noted that the ERG's clinical expert considered there may be a quicker response to treatment for patients having carfilzomib in addition to lenalidomide and dexamethasone. But there is no clinical reason for there to be a treatment-specific utility benefit in addition to the benefit provided by any gains in progression-free survival. The ERG noted that ASPIRE was an open-label trial, and knowing which treatment they were having could have influenced patient's responses to the HRQoL questionnaires. It therefore preferred to use the same utility value for both treatments, with no increase from baseline. The committee considered that it had not been presented with strong evidence to support the company's use of treatment-specific utility values. It noted that using the same values for both treatments may be more clinically plausible because of possible confounding of the treatment-specific values. But it also noted that applying either choice of utility values resulted in carfilzomib plus lenalidomide and dexamethasone being cost effective. The committee concluded that it would consider treatment-specific values and equal values for both treatments in its decision making.\n\n# Extrapolation of overall survival\n\n## Overall survival should be extrapolated from the mature ASPIRE data\n\nThe company considered that extrapolating from ASPIRE data may underestimate long-term survival, producing conservative results for the lenalidomide plus dexamethasone arm compared with estimates presented in related technology appraisals. Because of this, to estimate overall survival for both treatment arms, the company used a combination of extrapolated ASPIRE inverse probability weighted overall-survival data and real-world evidence from a French registry (MyelomaToul) of multiple myeloma patients who had lenalidomide as a second-line treatment. The ERG considered that a clinically plausible extrapolation of overall survival for carfilzomib plus lenalidomide and dexamethasone could be estimated entirely from mature ASPIRE data. It noted that the exponential distribution was the best statistical fit for its preferred subgroup. The company did not provide any new evidence to support its preferred overall-survival extrapolations in response to the appraisal consultation document. The committee concluded that it preferred to estimate overall survival for both treatment arms using data from the ASPIRE trial only.\n\n# Stopping rule\n\n## In clinical practice, treatment with carfilzomib would be limited to 18\xa0cycles\n\nIn ASPIRE, carfilzomib treatment stopped after\xa018 cycles. But the marketing authorisation allows for treatment until disease progression or unacceptable toxicity. Carfilzomib's summary of product characteristics states that treatment 'combined with lenalidomide and dexamethasone for longer than 18\xa0cycles should be based on an individual benefit/risk assessment, as the data on the tolerability and toxicity of carfilzomib beyond 18\xa0cycles are limited'. The committee noted that treatment costs for carfilzomib after 18\xa0cycles were not included in the company's economic model. The clinical expert stated that because of lack of evidence of efficacy for carfilzomib treatment beyond 18\xa0months, and the associated toxicity, it would be unlikely for treatment to continue beyond this time period. The clinical lead for the Cancer Drugs Fund advised that NHS England would commission a maximum of 18\xa0cycles of carfilzomib based on the evidence from ASPIRE. The committee noted that many cancer treatments are commissioned for a fixed duration of time and clinicians are familiar with this approach. In particular, carfilzomib with dexamethasone alone is commissioned and used for a maximum of 18\xa0cycles in the NHS. The patient expert highlighted that there may be some patients who wish to continue treatment with carfilzomib beyond 18\xa0cycles, but most patients would be reassured by the availability of other effective subsequent treatment therapies. The committee concluded that treatment with carfilzomib would be not continue beyond 18\xa0cycles because further treatment would not be commissioned by NHS England after this period.\n\n## It is uncertain how long any treatment benefit lasts after stopping treatment\n\nThe committee noted that a constant relative treatment effect had been applied to every cycle in the company's model for carfilzomib plus lenalidomide and dexamethasone, beyond the observed ASPIRE data. This is despite the fact that the company proposes carfilzomib is stopped after 18\xa0cycles of treatment. The committee considered that the ERG's exponential model of overall survival also included a treatment benefit for carfilzomib plus lenalidomide and dexamethasone after stopping treatment. However, it accepted that the use of mature data from ASPIRE may have captured some waning of treatment effect. The committee discussed whether there would be better prognosis in people who reached 20‑years survival with carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone. The clinical expert confirmed that people who are alive after 20\xa0years only have a better prognosis because they are able to have further treatment, and not necessarily because they previously had 1\xa0treatment rather than another. The committee agreed it was unclear how long the treatment benefit would last for carfilzomib plus lenalidomide and dexamethasone. It considered that the application of a prolonged treatment benefit may potentially overestimate survival and be favourable to carfilzomib plus lenalidomide and dexamethasone. The company provided some additional analyses in response to the appraisal consultation document that aimed to resolve the committee's concerns that the treatment effect may wane over time. The committee agreed that the new evidence clearly showed that a treatment benefit is maintained for carfilzomib plus lenalidomide and dexamethasone after 18\xa0cycles of carfilzomib treatment (28\xa0days of treatment per cycle) and during the entire trial follow-up period (72\xa0months). However, it was not convinced there was sufficient evidence or clinical rationale to support the assumption of a continued treatment benefit beyond the observed ASPIRE data. Therefore, the committee concluded that it is uncertain how long any treatment benefit with carfilzomib plus lenalidomide and dexamethasone lasts after stopping treatment. It considered that the treatment effect is likely to diminish over time in the extrapolated period. The committee concluded that accepting a constant treatment benefit during this period may result in optimistic cost-effectiveness estimates in favour of carfilzomib.\n\n# Combination therapies\n\n## The costs of lenalidomide with dexamethasone should be included in the model\n\nThe company considered that the increase in progression-free survival from adding carfilzomib to lenalidomide and dexamethasone is penalised because lenalidomide and dexamethasone are given until disease progression. This increases the costs associated with these drugs compared with using them without carfilzomib. The company did an exploratory analysis that excluded the additional cost of lenalidomide and dexamethasone in the carfilzomib plus lenalidomide and dexamethasone treatment arm. This improved the cost effectiveness of the carfilzomib regimen. The committee acknowledged that treatments that extend the use of other high-cost drugs (such as lenalidomide) can lead to additional cost associated with those other drugs, and that this has been considered in NICE appraisals of other cancer topics. It concluded that the costs of lenalidomide and dexamethasone are relevant because the NHS would incur those costs in practice, so they should be included in the model.\n\n# Cost-effectiveness estimates\n\n## The committee's preferred incremental cost-effectiveness ratios are likely to be below £30,000 per quality-adjusted life year gained\n\nNICE's guide to the methods of technology appraisal notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.\n\nThe company's deterministic base-case ICER for carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone was £43,952 per QALY gained (using the patient access scheme for carfilzomib, which the company revised in response to consultation). The ERG presented analyses combining its preferred assumptions including choice of post-hoc subgroup, using the same pre-progression utility values for both treatment arms and using the exponential distribution to extrapolate overall survival based on the ASPIRE data only. It also presented analyses for its base-case assumptions without the treatment-specific utility values. The ERG's analyses included the confidential commercial arrangements for lenalidomide and for panobinostat and pomalidomide, which are options later in the treatment pathway. The committee considered analyses with and without the treatment-specific utility values (see section\xa03.6). The ICERs for all scenarios were below £30,000 per QALY gained for carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone. The committee discussed that the cost-effectiveness estimates may be optimistic because some waning of treatment benefit with carfilzomib plus lenalidomide and dexamethasone is likely to occur beyond the observed ASPIRE data. Based on the evidence presented and with the discount agreed in the commercial arrangement, the committee concluded that the most plausible ICERs are within the range that NICE normally considers an acceptable use of NHS resources. Although the committee's preferred analyses were based on the ERG's post-hoc subgroup (see section\xa03.4), it did not consider it needed to specify that people should not have previously had lenalidomide in the recommendation. This was because it noted the company's argument that this may exclude a small number of people from accessing carfilzomib plus lenalidomide and dexamethasone. It was also aware that recommendations for the comparator in this appraisal, lenalidomide plus dexamethasone, do not specify no previous lenalidomide. Therefore, it recommended carfilzomib plus lenalidomide and dexamethasone for multiple myeloma in adults who have had only 1\xa0previous therapy, which included bortezomib.\n\n# End of life\n\n## Carfilzomib plus lenalidomide and dexamethasone does not meet NICE's end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee considered whether carfilzomib plus lenalidomide and dexamethasone meets the end of life criteria for people with multiple myeloma who have had 1\xa0previous treatment including bortezomib. The committee noted that the model predicted that patients in the comparator arm lived longer than 24\xa0months, and therefore concluded that carfilzomib in this indication did not meet the criterion for life expectancy. Because it did not meet this criterion, the committee concluded that it did not need to discuss the end of life criteria further.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe patient expert advised that they were not aware of any equality issues. The committee concluded that no equality or social value judgements are relevant to its decision.\n\n## The benefits of carfilzomib are captured in the cost-effectiveness analysis\n\nThe company and the clinical expert consider carfilzomib plus lenalidomide and dexamethasone to be innovative because it significantly improves progression-free survival and overall survival compared with lenalidomide and dexamethasone. The committee agreed that these are important benefits of carfilzomib plus lenalidomide and dexamethasone. But it concluded that it had not been presented with evidence of any additional benefits that had not been captured in the QALYs."}
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https://www.nice.org.uk/guidance/ta695
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Evidence-based recommendations on carfilzomib (Kyprolis) with dexamethasone and lenalidomide (Revlimid) for previously treated multiple myeloma in adults.
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513247c374ec99b66d6c86eca46e87805477405a
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nice
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Melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for primary or metastatic cancer in the liver
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Melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for primary or metastatic cancer in the liver
Evidence-based recommendations on melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for primary or metastatic cancer in the liver. This involves diverting the blood flow from the liver to the rest of the body (hepatic vein isolation) while the drug is delivered directly into the liver (percutaneous hepatic artery perfusion). Blood leaving the liver is taken out of the body and filtered to remove the drug, then returned. The aim is to destroy the cancer with a very high dose of the drug (chemosaturation) without causing side effects in the rest of the body.
# Recommendations
Evidence on the safety of melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for cancer or metastases in the liver shows there are serious, well‑recognised complications.
For patients with metastases in the liver from ocular melanoma, there is some evidence of short‑term tumour response. For these patients, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
For patients with primary liver cancer or metastases in the liver that are not from ocular melanoma, evidence of efficacy is inadequate in quality and quantity. For these patients, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Clinicians wishing to do melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for patients with metastases in the liver from ocular melanoma should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
The procedure should only be done in specialist centres by a melanoma multidisciplinary team that includes an interventional radiologist, an anaesthetist, an oncologist and a clinical perfusion scientist trained and experienced in the procedure.
Further research should be in the form of randomised controlled trials against current best practice, including other liver‑directed and systemic therapies. It should report details of patient selection, concurrent therapies and techniques, and adverse events, including those related to chemotherapy.# The condition, current treatments and procedure
# The condition
The most common types of primary liver cancer are hepatocellular carcinoma (also known as hepatoma) and cholangiocarcinoma. However, cancer in the liver has often metastasised from other sites such as the lung, colon, stomach and eye (particularly ocular melanoma, also known as uveal melanoma).
# Current treatments
Treatment for primary or metastatic cancer in the liver depends on the location and stage of the cancer and how much liver function is preserved. Treatment options include surgical resection, thermal ablation, systemic chemotherapy, transarterial chemoembolisation, isolated hepatic perfusion and selective internal radiation therapy. In patients with primary liver cancer, surgical removal with curative intent and liver transplantation may be possible. For most patients with liver metastases, treatment with curative intent is not possible.
# The procedure
Melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation is done under general anaesthesia. A high dose of melphalan chemotherapy is delivered directly into the hepatic artery. Blood leaving the liver is diverted out of the body and filtered to reduce the level of melphalan before being returned to the circulation. The aim is to allow high doses of melphalan chemotherapy to be used, which would otherwise not be tolerated because of severe systemic side effects.
An infusion catheter is inserted into the femoral artery and guided into the hepatic artery. The femoral vein is cannulated and a multi‑lumen, double-balloon catheter is inserted into the inferior vena cava and across the hepatic veins. The balloons are inflated so that all blood leaving the liver through the hepatic veins enters the catheter rather than the systemic circulation. High doses of melphalan are infused directly into the liver through the hepatic artery infusion catheter over about 30 minutes. Blood leaving the liver passes through an extracorporeal filtration system to remove most of the melphalan and is returned to the circulation through a catheter in the internal jugular vein. Full anticoagulation with heparin is needed throughout the procedure.
The procedure causes significant changes in the patient's haemodynamic status, which must be managed by the anaesthetic team with support from a clinical perfusion scientist.
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{'Recommendations': "Evidence on the safety of melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for cancer or metastases in the liver shows there are serious, well‑recognised complications.\n\nFor patients with metastases in the liver from ocular melanoma, there is some evidence of short‑term tumour response. For these patients, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFor patients with primary liver cancer or metastases in the liver that are not from ocular melanoma, evidence of efficacy is inadequate in quality and quantity. For these patients, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wishing to do melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for patients with metastases in the liver from ocular melanoma should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThe procedure should only be done in specialist centres by a melanoma multidisciplinary team that includes an interventional radiologist, an anaesthetist, an oncologist and a clinical perfusion scientist trained and experienced in the procedure.\n\nFurther research should be in the form of randomised controlled trials against current best practice, including other liver‑directed and systemic therapies. It should report details of patient selection, concurrent therapies and techniques, and adverse events, including those related to chemotherapy.", 'The condition, current treatments and procedure': "# The condition\n\nThe most common types of primary liver cancer are hepatocellular carcinoma (also known as hepatoma) and cholangiocarcinoma. However, cancer in the liver has often metastasised from other sites such as the lung, colon, stomach and eye (particularly ocular melanoma, also known as uveal melanoma).\n\n# Current treatments\n\nTreatment for primary or metastatic cancer in the liver depends on the location and stage of the cancer and how much liver function is preserved. Treatment options include surgical resection, thermal ablation, systemic chemotherapy, transarterial chemoembolisation, isolated hepatic perfusion and selective internal radiation therapy. In patients with primary liver cancer, surgical removal with curative intent and liver transplantation may be possible. For most patients with liver metastases, treatment with curative intent is not possible.\n\n# The procedure\n\nMelphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation is done under general anaesthesia. A high dose of melphalan chemotherapy is delivered directly into the hepatic artery. Blood leaving the liver is diverted out of the body and filtered to reduce the level of melphalan before being returned to the circulation. The aim is to allow high doses of melphalan chemotherapy to be used, which would otherwise not be tolerated because of severe systemic side effects.\n\nAn infusion catheter is inserted into the femoral artery and guided into the hepatic artery. The femoral vein is cannulated and a multi‑lumen, double-balloon catheter is inserted into the inferior vena cava and across the hepatic veins. The balloons are inflated so that all blood leaving the liver through the hepatic veins enters the catheter rather than the systemic circulation. High doses of melphalan are infused directly into the liver through the hepatic artery infusion catheter over about 30\xa0minutes. Blood leaving the liver passes through an extracorporeal filtration system to remove most of the melphalan and is returned to the circulation through a catheter in the internal jugular vein. Full anticoagulation with heparin is needed throughout the procedure.\n\nThe procedure causes significant changes in the patient's haemodynamic status, which must be managed by the anaesthetic team with support from a clinical perfusion scientist."}
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https://www.nice.org.uk/guidance/ipg691
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Evidence-based recommendations on melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for primary or metastatic cancer in the liver. This involves diverting the blood flow from the liver to the rest of the body (hepatic vein isolation) while the drug is delivered directly into the liver (percutaneous hepatic artery perfusion). Blood leaving the liver is taken out of the body and filtered to remove the drug, then returned. The aim is to destroy the cancer with a very high dose of the drug (chemosaturation) without causing side effects in the rest of the body.
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917ae4472ac08ccb1e6d9baa96437b1b1849c994
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nice
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Acalabrutinib for treating chronic lymphocytic leukaemia
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Acalabrutinib for treating chronic lymphocytic leukaemia
Evidence-based recommendations on acalabrutinib (Calquence) for treating chronic lymphocytic leukaemia in adults.
# Recommendations
Acalabrutinib as monotherapy is recommended as an option for untreated chronic lymphocytic leukaemia (CLL) in adults, only if:
there is a 17p deletion or TP53 mutation, or
there is no 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR) is unsuitable, and
the company provides the drug according to the commercial arrangement.
Acalabrutinib as monotherapy is recommended, within its marketing authorisation, as an option for previously treated CLL in adults. It is recommended only if the company provides the drug according to the commercial arrangement.
These recommendations are not intended to affect treatment with acalabrutinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
This appraisal looks at the use of acalabrutinib as monotherapy. NICE has not made recommendations on the use of acalabrutinib with obinutuzumab because the company did not submit any data for this combination.
People with untreated CLL that has a 17p deletion or TP53 mutation usually have ibrutinib. For this group, acalabrutinib has not been directly compared with ibrutinib in a clinical trial, and the results of an indirect comparison are uncertain. The company assumed that acalabrutinib is as effective as ibrutinib in a cost‑minimisation analysis. Despite the uncertainties, acalabrutinib is likely to be cost saving compared with ibrutinib. Therefore, acalabrutinib is recommended in this group.
People with untreated CLL without a 17p deletion or TP53 mutation usually have FCR or BR. If FCR or BR is unsuitable, chlorambucil plus obinutuzumab is offered instead. Clinical trial evidence in this group shows that CLL takes longer to progress when treated with acalabrutinib compared with chlorambucil plus obinutuzumab. However, the overall survival benefit is uncertain. The cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources, so acalabrutinib is recommended in this group.
People with previously treated CLL that has relapsed or does not respond to treatment, usually have ibrutinib or venetoclax plus rituximab. For this group, acalabrutinib has not been directly compared with ibrutinib or with venetoclax plus rituximab. The results of an indirect comparison with ibrutinib are uncertain. The company assumed that acalabrutinib was as effective as ibrutinib in the cost‑minimisation analyses. Despite the uncertainty, acalabrutinib is likely to be cost saving compared with ibrutinib. Therefore, acalabrutinib is recommended in this group.# Information about acalabrutinib
# Marketing authorisation indication
Acalabrutinib (Calquence, AstraZeneca) is indicated:
as monotherapy or in combination with obinutuzumab for the 'treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL)', and
as monotherapy for the 'treatment of adult patients with CLL who have received at least one prior therapy.'The company did not submit evidence to support reimbursement for acalabrutinib in combination with obinutuzumab. It also did not provide evidence for adults with previously untreated CLL that is suitable for fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR) therapy (see section 3.5).
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
A 30-day pack of acalabrutinib 100-mg tablets costs £5,059. The company has a commercial arrangement (simple discount patient access scheme). This makes acalabrutinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## Chronic lymphocytic leukaemia has substantial effects on quality of life
Chronic lymphocytic leukaemia (CLL) is a malignant disorder of white blood cells and is the most common type of leukaemia in England. The patient experts explained that the physical and psychological effects of CLL have a debilitating effect on their daily lives. The committee noted the increase in prevalence of CLL with age and the additional effect of the condition on family and carers. It concluded that CLL substantially affects both physical and psychological aspects of quality of life.
# Treatment pathway and comparators
## There is an unmet need for more effective treatments for CLL and a new treatment option would be welcome
The clinical and patient experts noted that people with untreated CLL are a heterogeneous population, with different mutation status and comorbidities. They agreed that there is an unmet need for more effective, targeted treatments with fewer side effects than existing NHS treatments. They considered that this unmet need is particularly high for people with a 17p deletion or TP53 mutation. This is because ibrutinib and idelalisib plus rituximab are the only available treatments, and idelalisib is poorly tolerated and not widely used. However, for people without a 17p deletion or TP53 mutation there is also a need for greater treatment choice. Around one-third of this population are offered fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR), which have many long-term side effects. The patient experts also noted that access to treatments other than these chemo-immunotherapies is limited. Chlorambucil plus obinutuzumab is the only other option, so targeted treatments such as acalabrutinib are needed. The committee acknowledged that for previously treated CLL that has progressed, the treatment options are currently limited to either ibrutinib or venetoclax plus rituximab. The patient experts explained that acalabrutinib is generally well tolerated and causes fewer side effects than current treatments. Also, it is an option when ibrutinib is not suitable for some people with cardiovascular comorbidities. The committee concluded that acalabrutinib would be welcomed as a new treatment option for people with CLL.
## Treatment varies depending on mutation status and comorbidities
The clinical experts confirmed that mutation status and comorbidities affect the treatment options for people with untreated CLL. People without a 17p deletion or TP53 mutation who have comorbidities that make FCR or BR unsuitable for them, would be offered chlorambucil plus obinutuzumab. People with a 17p deletion or TP53 mutation would usually be offered ibrutinib. Idelalisib plus rituximab is rarely used in clinical practice because it has an intensive dosing regimen and is associated with increased infection risk. The clinical experts also stated that ibrutinib is the most used treatment for previously treated CLL that has progressed, but venetoclax plus rituximab is also used. The committee agreed that it was appropriate to model different treatments depending on mutation status and comorbidities.
## For previously treated CLL, venetoclax plus rituximab is a relevant comparator
The company did not present evidence comparing acalabrutinib with venetoclax plus rituximab for the previously treated relapsed or refractory CLL population. It did not consider venetoclax plus rituximab to be a commonly used treatment in this population in the NHS. Instead, it regarded ibrutinib to be the established treatment for relapsed or refractory CLL in the NHS and was the only comparator in its cost-minimisation analysis for this population. The committee noted that a proportion of this population would likely have venetoclax plus rituximab, but the economic analysis did not include costs for this combination. The committee concluded that venetoclax plus rituximab is a relevant comparator for previously treated relapsed or refractory CLL.
## The company does not present any evidence for a population with untreated CLL for which FCR or BR is suitable
The company's submission did not include people with untreated CLL for which FCR or BR is suitable, although this population was in the NICE scope and is included in the marketing authorisation for acalabrutinib. The patient experts suggested that acalabrutinib should have been presented in the company's submission as an alternative to chemo-immunotherapy for this population. However, the company's clinical experts suggested excluding this population from its clinical trial, ELEVATE-TN, in line with expected clinical practice. The company explained that ELEVATE-TN did include people with untreated CLL for which FCR or BR is suitable, but it presented no clinical or cost evidence for this group. The committee acknowledged that the company was not seeking reimbursement for acalabrutinib for this population and that no comparative evidence was presented. It concluded that although people with untreated CLL for which FCR or BR is suitable is an important subgroup, it could not make a recommendation for this group because no evidence had been presented.
# Clinical effectiveness
## The clinical-effectiveness evidence is largely relevant to NHS clinical practice in England
The company presented results for the population with untreated CLL from ELEVATE-TN, an open‑label randomised controlled trial comparing acalabrutinib monotherapy (n=179) with chlorambucil plus obinutuzumab (n=177). ELEVATE-TN included people over 18 years with untreated CLL whose multimorbidities made FCR or BR unsuitable. People in ELEVATE-TN had to have a Cumulative Illness Rating Scale score greater than 6, or a creatinine clearance of less than 70 ml/minute (low creatinine clearance levels indicate serious kidney damage). The company considered that these criteria meant that FCR or BR would be unsuitable for similar patients in NHS clinical practice. ELEVATE-TN also included an acalabrutinib plus obinutuzumab arm, but this was not part of the company's submission and was not considered further. Of the 356 people in ELEVATE-TN, 35 had a 17p deletion or TP53 mutation. For the population with previously treated CLL, the company presented clinical effectiveness evidence from ASCEND. This was an open-label, randomised controlled trial comparing acalabrutinib (n=155) with either idelalisib plus rituximab or BR (n=155). The ERG considered that the population in ELEVATE-TN broadly represented the population with untreated CLL for which FCR or BR was unsuitable as seen in the NHS in England. Also, the population in ASCEND broadly represented the population with previously treated relapsed or refractory CLL who would be eligible for treatment with acalabrutinib. The committee was satisfied that the clinical-effectiveness evidence was largely relevant to NHS clinical practice.
## It is acceptable to use the full trial data from ELEVATE-TN in the untreated CLL model
The company used data from ELEVATE-TN to inform the economic analysis for the populations with untreated CLL. ELEVATE-TN included 35 people with a 17p deletion or TP53 mutation (high-risk CLL). The ERG explained that the company's economic model for untreated CLL used the full population from ELEVATE-TN. Because there is a separate model for people with high‑risk CLL, this resulted in the same population with high‑risk CLL being included in 2 different models with different comparators. The ERG noted that the effect of including the population with high‑risk CLL in the untreated CLL model was uncertain. The clinical experts explained that it was reasonable to assume a similar treatment effect of acalabrutinib for the populations with untreated CLL whether or not they had high-risk CLL. They considered that it was therefore acceptable to include both populations in the same model. The committee agreed and concluded that it was acceptable to use the full trial data from ELEVATE-TN in the untreated CLL model.
## For untreated CLL when FCR or BR is unsuitable, acalabrutinib improves progression-free survival but the overall survival benefit is uncertain
After a median follow up of 28 months, there was a statistically significant increase in progression‑free survival for acalabrutinib compared with chlorambucil plus obinutuzumab (hazard ratio 0.20, 95% confidence interval 0.13 to 0.30, p<0.0001). Median progression‑free survival was not reached in the acalabrutinib arm and was 22.6 months in the chlorambucil plus obinutuzumab arm. Median time to next treatment was not reached in either treatment arm but the trend was towards this being longer with acalabrutinib. Median overall survival was not reached in either treatment arm and there was no difference in overall survival between the 2 arms (HR 0.60, 95% CI 0.28 to 1.27, p=0.1556). The committee concluded that the trial data showed that acalabrutinib increased progression-free survival and time to next treatment compared with chlorambucil plus obinutuzumab. The committee concluded that the benefit of acalabrutinib on overall survival was uncertain, noting the immaturity of the data (that is, the endpoints had not been reached).
## For untreated high-risk CLL, an indirect treatment comparison in a different population is acceptable for decision making
The company's economic model for the population with untreated high-risk CLL used data from an indirect treatment comparison in the population with relapsed or refractory disease (see section 3.10). The company considered that the results from the indirect comparison could apply to the population with high-risk CLL and that acalabrutinib is clinically equivalent to ibrutinib. The ERG explained that because the data did not specifically relate to this population, there was uncertainty in assuming clinical equivalence based on the separate relapsed or refractory CLL population analysis. The clinical experts explained that there was no reason to consider acalabrutinib to be clinically inferior to ibrutinib and that assuming equivalent effectiveness was reasonable. The committee noted that there was no direct evidence presented for the population with high-risk CLL. Although there was uncertainty, it concluded that it was plausible that clinical equivalence between acalabrutinib and ibrutinib could be assumed in both populations and this was acceptable for decision making.
## For previously treated CLL, the company's indirect treatment comparison with ibrutinib is acceptable for decision making
No direct evidence was presented comparing acalabrutinib with ibrutinib for the population with previously treated relapsed or refractory CLL. The company did an unanchored matching adjusted indirect comparison (MAIC) using data from the acalabrutinib arm of ASCEND and the ibrutinib arm of RESONATE. Individual patient data were weighted to match baseline characteristics between arms and all observed effect modifiers and prognostic variables accounted for in the analysis. Kaplan–Meier estimates for progression-free survival and overall survival were found to be similar for both interventions (the exact hazard ratios and statistical values are confidential and cannot be reported here). The results of the MAIC were used to inform the cost-minimisation approach for the population with previously treated relapsed or refractory CLL. The company considered that the results justified the assumption of equivalent efficacy between acalabrutinib and ibrutinib in the populations with previously treated relapsed or refractory CLL and untreated high-risk CLL. The ERG considered that the methods for the indirect comparison were appropriate, concluding that it was reasonable to assume clinical equivalence of acalabrutinib and ibrutinib in the population with previously treated relapsed or refractory CLL. The committee concluded that the indirect treatment comparison was acceptable for decision making.
# Adverse effects
## Acalabrutinib is generally well tolerated compared with current treatments
The results of ELEVATE-TN showed that acalabrutinib had an acceptable tolerability profile compared with chlorambucil plus obinutuzumab. The patient experts highlighted that acalabrutinib was associated with fewer adverse effects and was generally well tolerated. They explained that some people noted reduced adverse effects after changing to acalabrutinib from other treatments. The committee agreed that acalabrutinib was likely to be generally well tolerated compared with current treatments.
# Cost-effectiveness model structure
## The model structure is appropriate for decision making
For the population with untreated CLL, the company submitted a semi-Markov model with 3 states (progression-free, progressed disease and death). The company used data from ELEVATE‑TN to estimate progression-free survival, overall survival and time to next treatment using parametric curves fitted to Kaplan–Meier data. Post-progression survival was estimated from the overall survival data from the MURANO and RESONATE trials in previously treated CLL. Data from the venetoclax plus rituximab arm of MURANO were applied to people whose disease progressed on first-line acalabrutinib. Data from the ibrutinib arm of RESONATE were applied to people whose disease progressed on chlorambucil plus obinutuzumab. Acalabrutinib treatment was assumed to continue until disease progression or death. Chlorambucil plus obinutuzumab was given for 6 cycles or until disease progression or death. Following disease progression after initial treatment, the model included a delay between disease progression and starting subsequent treatment. The ERG highlighted that the model structure did not allow for a second progression event and subsequent treatment costs were applied from the start of the second treatment until death or the maximum treatment duration. The committee noted the uncertainty about the duration of subsequent treatment (see section 3.13 and section 3.14) but concluded that the model structure was appropriate for decision making.
# Subsequent treatment
## For untreated CLL, the distribution of subsequent treatments is uncertain
In the company's untreated CLL model, it assumed that the type of second-line treatment would depend on their first-line treatment. After disease progression, the company assumed that people in the acalabrutinib group would have second-line treatment with venetoclax plus rituximab and people in the chlorambucil plus obinutuzumab group would have ibrutinib. This sequence was assumed because, in clinical practice, it is unlikely that people would have a Bruton's Tyrosine Kinase (BTK) inhibitor such as acalabrutinib after another BTK inhibitor such as ibrutinib. The company considered that ibrutinib was mainly used after chlorambucil plus obinutuzumab in the NHS. The company assumed that in the chlorambucil plus obinutuzumab group, 13% go on to have venetoclax plus rituximab. The ERG highlighted that there was some uncertainty in the proportion of people who would have venetoclax plus rituximab in the chlorambucil plus obinutuzumab group, but it also considered 13% reasonable. In response to consultation, the company provided more evidence to support its initial assumption. The clinical experts explained that venetoclax plus rituximab was a relatively recent treatment option. At the second committee meeting, they agreed that it was likely to currently account for between 13% and 20% of second-line treatment after chlorambucil plus obinutuzumab, but noted this proportion may increase over time. The committee agreed that the distribution of subsequent treatments after disease progression in the untreated CLL model was uncertain and considered scenarios with a range of proportions. It concluded that it was plausible that venetoclax plus rituximab currently accounts for up to 20% of second-line treatment after chlorambucil plus obinutuzumab, but that this may increase over time.
## For untreated CLL, the ERG's model for costing subsequent treatments is appropriate
In the company's original economic model, subsequent treatment and its associated costs were modelled to continue from the start of subsequent treatment until death. However, the ERG highlighted that the model incorrectly applied second-line treatment costs because people would only have second-line treatment until progression. At this point treatment, and costs, would stop. In response to comments submitted by the company as part of their check of the factual accuracy of the ERG report, the ERG developed a second-line treatment costing model. In the ERG's model, mean progression-free survival for second-line ibrutinib treatment was extrapolated from the RESONATE progression-free survival data for 1 to 2 previous lines of treatment. The company agreed with this approach, but disagreed with the ERG on 2 points:
The company preferred a log-normal parametric curve for second-line treatment duration, which estimated a duration of 5.56 years for ibrutinib treatment. The ERG preferred the Weibull curve, which estimated a duration of 4.78 years.
The company assumed that the delay from progressing on first-line treatment through to starting second-line treatment would be 1 cycle. But the ERG used the company's original assumption of a 14-cycle delay.The ERG highlighted that the subsequent treatment costs accounted for a substantial proportion of the overall costs of the chlorambucil plus obinutuzumab comparator group. Therefore, increasing the duration of second-line ibrutinib treatment in the chlorambucil plus obinutuzumab group substantially increased the overall costs compared with the acalabrutinib group. The company considered that the log-normal distribution provided the most clinically realistic second-line ibrutinib treatment duration and provided the best statistical fit to the data. The clinical experts suggested that a second-line treatment duration of about 4.5 years for ibrutinib was reasonable, which corresponded to the ERG's approach. The ERG also highlighted that reducing the delay from progression to second-line treatment led to a much greater increase in the subsequent treatment cost of ibrutinib in the chlorambucil plus obinutuzumab group than in the subsequent treatment cost of venetoclax plus rituximab in the acalabrutinib group. The company explained that the 14-cycle delay was included to account for the assumption that people would have subsequent treatments at different ages depending on when they progressed. The company reduced the delay to 1 cycle because it considered that the ERG's model used a more personalised approach. The company also explained that the 14-cycle delay was based on immature data from ELEVATE‑TN. It discussed this with its clinical advisers who suggested that the 14-cycle delay was not clinically plausible because people would not have to wait for 1 year before starting second-line treatment. The ERG noted that the company's submission did not clearly identify the rationale for assuming a 14-cycle delay and that data from ELEVATE‑TN could be used to determine the mean delay, but those data were not presented. The clinical experts explained that in practice it is sometimes reasonable to wait 1 year before starting second-line treatment after progression with chlorambucil plus obinutuzumab. The committee considered the log-normal parametric model to be plausible but preferred the Weibull model because it was less constrained by overall survival gains. It agreed that the treatment duration with second-line ibrutinib was uncertain, with the most plausible estimate likely to be between that estimated using the log-normal and the Weibull distributions. It noted some uncertainty about the appropriate delay between progression and starting second-line treatment and separate scenarios were considered for the 14-cycle and the 1-cycle delays. The committee also acknowledged the effect of sequencing on costs of subsequent treatments (see section 3.13). It concluded that the ERG's model for costing subsequent treatments was appropriate, but that it would consider scenarios using the log-normal and Weibull distributions.
# Survival extrapolations
## For untreated CLL, the overall survival data are immature, leading to highly uncertain survival estimates
The data from ELEVATE-TN showed a trend towards improved overall survival for acalabrutinib compared with chlorambucil plus obinutuzumab. However, the data were immature, with median follow up at 28 months, and the difference between the groups was not statistically significant. The company estimated overall survival as a function of time to progression, pre-progression mortality and post-progression survival. Parametric survival models were fitted to data from ELEVATE-TN to model time to progression and pre-progression mortality. Post-progression survival in the acalabrutinib arm used overall survival data from the venetoclax plus rituximab arm of the MURANO trial. In the chlorambucil plus obinutuzumab group, data from the ibrutinib arm of RESONATE were used in a similar way but resulted in a lower overall survival rate. The ERG considered this approach favoured the sequence using venetoclax plus rituximab but that it was possible the difference in overall survival was because of confounding due to the unadjusted arm‑based comparison. The company considered that the MURANO and RESONATE trials reflected clinical practice for subsequent treatments as indicated by its clinical advisers. It therefore considered the post-progression survival estimates reasonable. The ERG highlighted that when modelling post-progression survival using MURANO, the overall survival hazard converged with that for the general population. This led to most people having acalabrutinib followed by venetoclax plus rituximab having similar survival to the general population. The ERG preferred to assume equal rates of post-progression survival for the acalabrutinib and chlorambucil plus obinutuzumab groups based on post-progression survival data from RESONATE because this leads to less optimistic projections of overall survival. The clinical experts suggested that overall survival was likely to be longer when starting treatment with acalabrutinib followed by venetoclax plus rituximab. This is because it is more effective and less toxic than chlorambucil plus obinutuzumab followed by ibrutinib. However, long-term data confirming overall survival benefit are lacking at present. They considered it reasonable to use MURANO because it accurately reflects the most likely treatment sequence of acalabrutinib followed by venetoclax plus rituximab. One clinical expert also explained that it was reasonable to expect that many people will reach the life expectancy of the general population after treatment with acalabrutinib and will be functionally cured. The other clinical expert did not consider this plausible. The committee concluded that there was considerable uncertainty in the overall survival estimates for acalabrutinib because of the extrapolation using data from trials for other treatments and the immature data from ELEVATE‑TN.
# Cost-effectiveness results
## For untreated CLL when FCR or BR is unsuitable, the incremental cost-effectiveness ratios are likely to be in the range normally considered acceptable
The incremental cost-effectiveness ratios (ICERs) used by the committee for decision making took account of all available confidential discounts, including those for comparators and follow-up treatments. Because of these confidential discounts, exact results cannot be reported here. The company's revised base-case ICER for acalabrutinib compared with chlorambucil plus obinutuzumab for untreated CLL when FCR or BR is unsuitable was within the range normally considered cost effective. Incorporating the ERG's preferred assumptions on applying a 14-cycle delay and using the Weibull model for subsequent treatment (see section 3.14) and using RESONATE post-progression survival for both treatment arms (see section 3.15) increased the ICER but it remained below £30,000 per quality-adjusted life year (QALY) gained. The committee used the ERG's base case for decision making. However, it also considered that further assumptions should be considered:
The proportion of people having second-line venetoclax plus rituximab was up to 20% (see section 3.13).
Adjusting the overall survival gain for acalabrutinib compared with chlorambucil plus obinutuzumab so that it was 50% lower, reflecting uncertainty about the immature survival data in ELEVATE-TN (see section 3.15).In all the combinations of scenarios the committee considered, the ICER remained below £30,000 per QALY gained, except the combination using the most pessimistic assumptions. The committee recalled that the most plausible duration of subsequent treatment was likely between that estimated by the log-normal and Weibull distributions (see section 3.14) which reduced the ICER considerably. So, it was satisfied that acalabrutinib is likely to be a cost-effective use of NHS resources for untreated CLL that is not high risk and when FCR or BR is unsuitable.
## For people with a 17p deletion or TP53 mutation, acalabrutinib is likely to be cost saving compared with ibrutinib
In the company's base case from its cost-minimisation analysis, costs for acalabrutinib were lower than costs for ibrutinib for people with untreated CLL with a 17p deletion or TP53 mutation (high‑risk CLL). The cost-minimisation analysis considered if the acquisition and management of adverse events costs for acalabrutinib were lower than for ibrutinib. The ERG's analysis made no substantial changes to the company's base case and resulted in mostly unchanged cost savings for acalabrutinib treatment. Final costs considered by the committee took account of all available confidential discounts, including those for comparators. The committee concluded that for people with untreated CLL with a 17p deletion or TP53 mutation, acalabrutinib is likely to be cost saving compared with ibrutinib.
## For previously treated CLL, acalabrutinib is likely to be cost saving compared with ibrutinib
In the company's base case from its cost-minimisation analysis, costs for acalabrutinib were lower than costs for ibrutinib for people with previously treated CLL. The cost-minimisation analysis considered if the acquisition and management of adverse events costs for acalabrutinib were lower than for ibrutinib. The ERG's analysis made no substantial changes to the company's base case and resulted in mostly unchanged cost savings for acalabrutinib treatment. The final costs considered by the committee took account of all available confidential discounts, including those for comparators. The committee concluded that for people with previously treated CLL, acalabrutinib was likely to be cost saving compared with ibrutinib. However, the committee considered that venetoclax plus rituximab was a relevant comparator for this population and because the company did not present a comparison with acalabrutinib, the cost effectiveness is unknown (see section 3.4).
# End of life
## Acalabrutinib does not meet the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered that the short life expectancy criterion of less than 24 months was not met because people with CLL have a life expectancy of more than 2 years. The committee concluded that acalabrutinib does not meet the criteria to be considered a life-extending treatment at the end of life.
# Conclusions
## Acalabrutinib is recommended for untreated CLL that is not high risk and when FCR or BR is unsuitable
The committee considered the uncertainties with distribution of subsequent treatments, subsequent treatment costs and survival estimates. It concluded that, with its preferred assumptions, the ICERs for acalabrutinib would be considered an acceptable use of NHS resources for untreated CLL that is not high risk and when FCR or BR is unsuitable (see section 3.16). The committee concluded that acalabrutinib could be recommended as an option for this population.
## Acalabrutinib is recommended for people with untreated CLL with a 17p deletion or TP53 mutation
The committee considered the uncertainty in the evidence for a population with untreated CLL with a 17p deletion or TP53 mutation. However, it considered the economic model to be appropriate for decision making (see section 3.17). The committee concluded that for people with untreated CLL with a 17p deletion or TP53 mutation, acalabrutinib was likely to be cost saving compared with ibrutinib. Therefore, it could be recommended as an option for this population.
## Acalabrutinib is recommended for previously treated CLL
The committee considered that venetoclax plus rituximab was a relevant comparator for this population but no evidence comparing it with acalabrutinib was presented (see section 3.18). It concluded that the economic model was appropriate to compare acalabrutinib with ibrutinib and acalabrutinib was likely to be cost saving compared with ibrutinib. At the first meeting, the committee concluded that acalabrutinib could be recommended as an option for previously treated CLL but stipulated in the recommendations that it could be used only when ibrutinib is the only suitable treatment option. In response to consultation, several consultees noted that this could inadvertently prevent people from having acalabrutinib because ibrutinib is not suitable because of cardiac issues. The committee agreed that was not the intention of the recommendation, as acalabrutinib would be particularly beneficial for such people. The clinical lead for the Cancer Drugs Fund noted that he understood the rationale behind the committee's recommendation but considered that it would be beneficial to give clinicians flexibility in prescribing. Moreover, if doctors and patients reach the stage of considering a BTK inhibitor (ibrutinib or acalabrutinib) then it is likely that they have already ruled out treatment with venetoclax plus rituximab. Therefore, the committee concluded that the restriction included in the draft recommendations was not necessary.
# Equality considerations
## There are no equality issues relevant to the recommendations
The company's submission did not include people with untreated CLL for which FCR or BR is suitable. Patient submissions highlighted that this would potentially deny younger and fitter people access to a new treatment option that is well tolerated. However, the committee could not make a recommendation about the clinical and cost effectiveness of acalabrutinib for this population because the company did not present any evidence. Therefore, the committee did not consider this an equality issue it could resolve.
# Innovation
## There are no additional benefits that are not captured in the QALY calculations
The company considered acalabrutinib to be an innovative treatment because it is a highly selective BTK inhibitor that addresses a significant unmet need in first-line CLL treatment. Also, it offers an alternative option to the first-generation BTK inhibitor in previously treated CLL. Its targeted mechanism of action means it offers improved safety and tolerability compared with current treatments. The committee concluded that acalabrutinib would be a beneficial additional treatment option. However, it noted that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
|
{'Recommendations': 'Acalabrutinib as monotherapy is recommended as an option for untreated chronic lymphocytic leukaemia (CLL) in adults, only if:\n\nthere is a 17p\xa0deletion or TP53\xa0mutation, or\n\nthere is no 17p\xa0deletion or TP53\xa0mutation, and fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR) is unsuitable, and\n\nthe company provides the drug according to the commercial arrangement.\n\nAcalabrutinib as monotherapy is recommended, within its marketing authorisation, as an option for previously treated CLL in adults. It is recommended only if the company provides the drug according to the commercial arrangement.\n\nThese recommendations are not intended to affect treatment with acalabrutinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThis appraisal looks at the use of acalabrutinib as monotherapy. NICE has not made recommendations on the use of acalabrutinib with obinutuzumab because the company did not submit any data for this combination.\n\nPeople with untreated CLL that has a 17p\xa0deletion or TP53\xa0mutation usually have ibrutinib. For this group, acalabrutinib has not been directly compared with ibrutinib in a clinical trial, and the results of an indirect comparison are uncertain. The company assumed that acalabrutinib is as effective as ibrutinib in a cost‑minimisation analysis. Despite the uncertainties, acalabrutinib is likely to be cost saving compared with ibrutinib. Therefore, acalabrutinib is recommended in this group.\n\nPeople with untreated CLL without a 17p\xa0deletion or TP53\xa0mutation usually have FCR or BR. If FCR or BR is unsuitable, chlorambucil plus obinutuzumab is offered instead. Clinical trial evidence in this group shows that CLL takes longer to progress when treated with acalabrutinib compared with chlorambucil plus obinutuzumab. However, the overall survival benefit is uncertain. The cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources, so acalabrutinib is recommended in this group.\n\nPeople with previously treated CLL that has relapsed or does not respond to treatment, usually have ibrutinib or venetoclax plus rituximab. For this group, acalabrutinib has not been directly compared with ibrutinib or with venetoclax plus rituximab. The results of an indirect comparison with ibrutinib are uncertain. The company assumed that acalabrutinib was as effective as ibrutinib in the cost‑minimisation analyses. Despite the uncertainty, acalabrutinib is likely to be cost saving compared with ibrutinib. Therefore, acalabrutinib is recommended in this group.', 'Information about acalabrutinib': "# Marketing authorisation indication\n\nAcalabrutinib (Calquence, AstraZeneca) is indicated:\n\nas monotherapy or in combination with obinutuzumab for the 'treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL)', and\n\nas monotherapy for the 'treatment of adult patients with CLL who have received at least one prior therapy.'The company did not submit evidence to support reimbursement for acalabrutinib in combination with obinutuzumab. It also did not provide evidence for adults with previously untreated CLL that is suitable for fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR) therapy (see section\xa03.5).\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nA 30-day pack of acalabrutinib 100-mg tablets costs £5,059. The company has a commercial arrangement (simple discount patient access scheme). This makes acalabrutinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Chronic lymphocytic leukaemia has substantial effects on quality of life\n\nChronic lymphocytic leukaemia (CLL) is a malignant disorder of white blood cells and is the most common type of leukaemia in England. The patient experts explained that the physical and psychological effects of CLL have a debilitating effect on their daily lives. The committee noted the increase in prevalence of CLL with age and the additional effect of the condition on family and carers. It concluded that CLL substantially affects both physical and psychological aspects of quality of life.\n\n# Treatment pathway and comparators\n\n## There is an unmet need for more effective treatments for CLL and a new treatment option would be welcome\n\nThe clinical and patient experts noted that people with untreated CLL are a heterogeneous population, with different mutation status and comorbidities. They agreed that there is an unmet need for more effective, targeted treatments with fewer side effects than existing NHS treatments. They considered that this unmet need is particularly high for people with a 17p\xa0deletion or TP53\xa0mutation. This is because ibrutinib and idelalisib plus rituximab are the only available treatments, and idelalisib is poorly tolerated and not widely used. However, for people without a 17p\xa0deletion or TP53\xa0mutation there is also a need for greater treatment choice. Around one-third of this population are offered fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR), which have many long-term side effects. The patient experts also noted that access to treatments other than these chemo-immunotherapies is limited. Chlorambucil plus obinutuzumab is the only other option, so targeted treatments such as acalabrutinib are needed. The committee acknowledged that for previously treated CLL that has progressed, the treatment options are currently limited to either ibrutinib or venetoclax plus rituximab. The patient experts explained that acalabrutinib is generally well tolerated and causes fewer side effects than current treatments. Also, it is an option when ibrutinib is not suitable for some people with cardiovascular comorbidities. The committee concluded that acalabrutinib would be welcomed as a new treatment option for people with CLL.\n\n## Treatment varies depending on mutation status and comorbidities\n\nThe clinical experts confirmed that mutation status and comorbidities affect the treatment options for people with untreated CLL. People without a 17p\xa0deletion or TP53\xa0mutation who have comorbidities that make FCR or BR unsuitable for them, would be offered chlorambucil plus obinutuzumab. People with a 17p\xa0deletion or TP53\xa0mutation would usually be offered ibrutinib. Idelalisib plus rituximab is rarely used in clinical practice because it has an intensive dosing regimen and is associated with increased infection risk. The clinical experts also stated that ibrutinib is the most used treatment for previously treated CLL that has progressed, but venetoclax plus rituximab is also used. The committee agreed that it was appropriate to model different treatments depending on mutation status and comorbidities.\n\n## For previously treated CLL, venetoclax plus rituximab is a relevant comparator\n\nThe company did not present evidence comparing acalabrutinib with venetoclax plus rituximab for the previously treated relapsed or refractory CLL population. It did not consider venetoclax plus rituximab to be a commonly used treatment in this population in the NHS. Instead, it regarded ibrutinib to be the established treatment for relapsed or refractory CLL in the NHS and was the only comparator in its cost-minimisation analysis for this population. The committee noted that a proportion of this population would likely have venetoclax plus rituximab, but the economic analysis did not include costs for this combination. The committee concluded that venetoclax plus rituximab is a relevant comparator for previously treated relapsed or refractory CLL.\n\n## The company does not present any evidence for a population with untreated CLL for which FCR or BR is suitable\n\nThe company's submission did not include people with untreated CLL for which FCR or BR is suitable, although this population was in the NICE scope and is included in the marketing authorisation for acalabrutinib. The patient experts suggested that acalabrutinib should have been presented in the company's submission as an alternative to chemo-immunotherapy for this population. However, the company's clinical experts suggested excluding this population from its clinical trial, ELEVATE-TN, in line with expected clinical practice. The company explained that ELEVATE-TN did include people with untreated CLL for which FCR or BR is suitable, but it presented no clinical or cost evidence for this group. The committee acknowledged that the company was not seeking reimbursement for acalabrutinib for this population and that no comparative evidence was presented. It concluded that although people with untreated CLL for which FCR or BR is suitable is an important subgroup, it could not make a recommendation for this group because no evidence had been presented.\n\n# Clinical effectiveness\n\n## The clinical-effectiveness evidence is largely relevant to NHS clinical practice in England\n\nThe company presented results for the population with untreated CLL from ELEVATE-TN, an open‑label randomised controlled trial comparing acalabrutinib monotherapy (n=179) with chlorambucil plus obinutuzumab (n=177). ELEVATE-TN included people over 18\xa0years with untreated CLL whose multimorbidities made FCR or BR unsuitable. People in ELEVATE-TN had to have a Cumulative Illness Rating Scale score greater than\xa06, or a creatinine clearance of less than 70\xa0ml/minute (low creatinine clearance levels indicate serious kidney damage). The company considered that these criteria meant that FCR or BR would be unsuitable for similar patients in NHS clinical practice. ELEVATE-TN also included an acalabrutinib plus obinutuzumab arm, but this was not part of the company's submission and was not considered further. Of the 356\xa0people in ELEVATE-TN, 35 had a 17p\xa0deletion or TP53\xa0mutation. For the population with previously treated CLL, the company presented clinical effectiveness evidence from ASCEND. This was an open-label, randomised controlled trial comparing acalabrutinib (n=155) with either idelalisib plus rituximab or BR (n=155). The ERG considered that the population in ELEVATE-TN broadly represented the population with untreated CLL for which FCR or BR was unsuitable as seen in the NHS in England. Also, the population in ASCEND broadly represented the population with previously treated relapsed or refractory CLL who would be eligible for treatment with acalabrutinib. The committee was satisfied that the clinical-effectiveness evidence was largely relevant to NHS clinical practice.\n\n## It is acceptable to use the full trial data from ELEVATE-TN in the untreated CLL model\n\nThe company used data from ELEVATE-TN to inform the economic analysis for the populations with untreated CLL. ELEVATE-TN included 35\xa0people with a 17p\xa0deletion or TP53\xa0mutation (high-risk CLL). The ERG explained that the company's economic model for untreated CLL used the full population from ELEVATE-TN. Because there is a separate model for people with high‑risk CLL, this resulted in the same population with high‑risk CLL being included in 2\xa0different models with different comparators. The ERG noted that the effect of including the population with high‑risk CLL in the untreated CLL model was uncertain. The clinical experts explained that it was reasonable to assume a similar treatment effect of acalabrutinib for the populations with untreated CLL whether or not they had high-risk CLL. They considered that it was therefore acceptable to include both populations in the same model. The committee agreed and concluded that it was acceptable to use the full trial data from ELEVATE-TN in the untreated CLL model.\n\n## For untreated CLL when FCR or BR is unsuitable, acalabrutinib improves progression-free survival but the overall survival benefit is uncertain\n\nAfter a median follow up of 28\xa0months, there was a statistically significant increase in progression‑free survival for acalabrutinib compared with chlorambucil plus obinutuzumab (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.13 to 0.30, p<0.0001). Median progression‑free survival was not reached in the acalabrutinib arm and was 22.6\xa0months in the chlorambucil plus obinutuzumab arm. Median time to next treatment was not reached in either treatment arm but the trend was towards this being longer with acalabrutinib. Median overall survival was not reached in either treatment arm and there was no difference in overall survival between the 2\xa0arms (HR\xa00.60, 95%\xa0CI 0.28\xa0to\xa01.27, p=0.1556). The committee concluded that the trial data showed that acalabrutinib increased progression-free survival and time to next treatment compared with chlorambucil plus obinutuzumab. The committee concluded that the benefit of acalabrutinib on overall survival was uncertain, noting the immaturity of the data (that is, the endpoints had not been reached).\n\n## For untreated high-risk CLL, an indirect treatment comparison in a different population is acceptable for decision making\n\nThe company's economic model for the population with untreated high-risk CLL used data from an indirect treatment comparison in the population with relapsed or refractory disease (see section\xa03.10). The company considered that the results from the indirect comparison could apply to the population with high-risk CLL and that acalabrutinib is clinically equivalent to ibrutinib. The ERG explained that because the data did not specifically relate to this population, there was uncertainty in assuming clinical equivalence based on the separate relapsed or refractory CLL population analysis. The clinical experts explained that there was no reason to consider acalabrutinib to be clinically inferior to ibrutinib and that assuming equivalent effectiveness was reasonable. The committee noted that there was no direct evidence presented for the population with high-risk CLL. Although there was uncertainty, it concluded that it was plausible that clinical equivalence between acalabrutinib and ibrutinib could be assumed in both populations and this was acceptable for decision making.\n\n## For previously treated CLL, the company's indirect treatment comparison with ibrutinib is acceptable for decision making\n\nNo direct evidence was presented comparing acalabrutinib with ibrutinib for the population with previously treated relapsed or refractory CLL. The company did an unanchored matching adjusted indirect comparison (MAIC) using data from the acalabrutinib arm of ASCEND and the ibrutinib arm of RESONATE. Individual patient data were weighted to match baseline characteristics between arms and all observed effect modifiers and prognostic variables accounted for in the analysis. Kaplan–Meier estimates for progression-free survival and overall survival were found to be similar for both interventions (the exact hazard ratios and statistical values are confidential and cannot be reported here). The results of the MAIC were used to inform the cost-minimisation approach for the population with previously treated relapsed or refractory CLL. The company considered that the results justified the assumption of equivalent efficacy between acalabrutinib and ibrutinib in the populations with previously treated relapsed or refractory CLL and untreated high-risk CLL. The ERG considered that the methods for the indirect comparison were appropriate, concluding that it was reasonable to assume clinical equivalence of acalabrutinib and ibrutinib in the population with previously treated relapsed or refractory CLL. The committee concluded that the indirect treatment comparison was acceptable for decision making.\n\n# Adverse effects\n\n## Acalabrutinib is generally well tolerated compared with current treatments\n\nThe results of ELEVATE-TN showed that acalabrutinib had an acceptable tolerability profile compared with chlorambucil plus obinutuzumab. The patient experts highlighted that acalabrutinib was associated with fewer adverse effects and was generally well tolerated. They explained that some people noted reduced adverse effects after changing to acalabrutinib from other treatments. The committee agreed that acalabrutinib was likely to be generally well tolerated compared with current treatments.\n\n# Cost-effectiveness model structure\n\n## The model structure is appropriate for decision making\n\nFor the population with untreated CLL, the company submitted a semi-Markov model with 3\xa0states (progression-free, progressed disease and death). The company used data from ELEVATE‑TN to estimate progression-free survival, overall survival and time to next treatment using parametric curves fitted to Kaplan–Meier data. Post-progression survival was estimated from the overall survival data from the MURANO and RESONATE trials in previously treated CLL. Data from the venetoclax plus rituximab arm of MURANO were applied to people whose disease progressed on first-line acalabrutinib. Data from the ibrutinib arm of RESONATE were applied to people whose disease progressed on chlorambucil plus obinutuzumab. Acalabrutinib treatment was assumed to continue until disease progression or death. Chlorambucil plus obinutuzumab was given for 6\xa0cycles or until disease progression or death. Following disease progression after initial treatment, the model included a delay between disease progression and starting subsequent treatment. The ERG highlighted that the model structure did not allow for a second progression event and subsequent treatment costs were applied from the start of the second treatment until death or the maximum treatment duration. The committee noted the uncertainty about the duration of subsequent treatment (see section\xa03.13 and section\xa03.14) but concluded that the model structure was appropriate for decision making.\n\n# Subsequent treatment\n\n## For untreated CLL, the distribution of subsequent treatments is uncertain\n\nIn the company's untreated CLL model, it assumed that the type of second-line treatment would depend on their first-line treatment. After disease progression, the company assumed that people in the acalabrutinib group would have second-line treatment with venetoclax plus rituximab and people in the chlorambucil plus obinutuzumab group would have ibrutinib. This sequence was assumed because, in clinical practice, it is unlikely that people would have a Bruton's Tyrosine Kinase (BTK) inhibitor such as acalabrutinib after another BTK inhibitor such as ibrutinib. The company considered that ibrutinib was mainly used after chlorambucil plus obinutuzumab in the NHS. The company assumed that in the chlorambucil plus obinutuzumab group, 13% go on to have venetoclax plus rituximab. The ERG highlighted that there was some uncertainty in the proportion of people who would have venetoclax plus rituximab in the chlorambucil plus obinutuzumab group, but it also considered 13% reasonable. In response to consultation, the company provided more evidence to support its initial assumption. The clinical experts explained that venetoclax plus rituximab was a relatively recent treatment option. At the second committee meeting, they agreed that it was likely to currently account for between 13% and 20% of second-line treatment after chlorambucil plus obinutuzumab, but noted this proportion may increase over time. The committee agreed that the distribution of subsequent treatments after disease progression in the untreated CLL model was uncertain and considered scenarios with a range of proportions. It concluded that it was plausible that venetoclax plus rituximab currently accounts for up to 20% of second-line treatment after chlorambucil plus obinutuzumab, but that this may increase over time.\n\n## For untreated CLL, the ERG's model for costing subsequent treatments is appropriate\n\nIn the company's original economic model, subsequent treatment and its associated costs were modelled to continue from the start of subsequent treatment until death. However, the ERG highlighted that the model incorrectly applied second-line treatment costs because people would only have second-line treatment until progression. At this point treatment, and costs, would stop. In response to comments submitted by the company as part of their check of the factual accuracy of the ERG report, the ERG developed a second-line treatment costing model. In the ERG's model, mean progression-free survival for second-line ibrutinib treatment was extrapolated from the RESONATE progression-free survival data for 1\xa0to 2\xa0previous lines of treatment. The company agreed with this approach, but disagreed with the ERG on 2\xa0points:\n\nThe company preferred a log-normal parametric curve for second-line treatment duration, which estimated a duration of 5.56\xa0years for ibrutinib treatment. The ERG preferred the Weibull curve, which estimated a duration of 4.78\xa0years.\n\nThe company assumed that the delay from progressing on first-line treatment through to starting second-line treatment would be 1\xa0cycle. But the ERG used the company's original assumption of a 14-cycle delay.The ERG highlighted that the subsequent treatment costs accounted for a substantial proportion of the overall costs of the chlorambucil plus obinutuzumab comparator group. Therefore, increasing the duration of second-line ibrutinib treatment in the chlorambucil plus obinutuzumab group substantially increased the overall costs compared with the acalabrutinib group. The company considered that the log-normal distribution provided the most clinically realistic second-line ibrutinib treatment duration and provided the best statistical fit to the data. The clinical experts suggested that a second-line treatment duration of about 4.5\xa0years for ibrutinib was reasonable, which corresponded to the ERG's approach. The ERG also highlighted that reducing the delay from progression to second-line treatment led to a much greater increase in the subsequent treatment cost of ibrutinib in the chlorambucil plus obinutuzumab group than in the subsequent treatment cost of venetoclax plus rituximab in the acalabrutinib group. The company explained that the 14-cycle delay was included to account for the assumption that people would have subsequent treatments at different ages depending on when they progressed. The company reduced the delay to 1\xa0cycle because it considered that the ERG's model used a more personalised approach. The company also explained that the 14-cycle delay was based on immature data from ELEVATE‑TN. It discussed this with its clinical advisers who suggested that the 14-cycle delay was not clinically plausible because people would not have to wait for 1\xa0year before starting second-line treatment. The ERG noted that the company's submission did not clearly identify the rationale for assuming a 14-cycle delay and that data from ELEVATE‑TN could be used to determine the mean delay, but those data were not presented. The clinical experts explained that in practice it is sometimes reasonable to wait 1\xa0year before starting second-line treatment after progression with chlorambucil plus obinutuzumab. The committee considered the log-normal parametric model to be plausible but preferred the Weibull model because it was less constrained by overall survival gains. It agreed that the treatment duration with second-line ibrutinib was uncertain, with the most plausible estimate likely to be between that estimated using the log-normal and the Weibull distributions. It noted some uncertainty about the appropriate delay between progression and starting second-line treatment and separate scenarios were considered for the 14-cycle and the 1-cycle delays. The committee also acknowledged the effect of sequencing on costs of subsequent treatments (see section\xa03.13). It concluded that the ERG's model for costing subsequent treatments was appropriate, but that it would consider scenarios using the log-normal and Weibull distributions.\n\n# Survival extrapolations\n\n## For untreated CLL, the overall survival data are immature, leading to highly uncertain survival estimates\n\nThe data from ELEVATE-TN showed a trend towards improved overall survival for acalabrutinib compared with chlorambucil plus obinutuzumab. However, the data were immature, with median follow up at 28\xa0months, and the difference between the groups was not statistically significant. The company estimated overall survival as a function of time to progression, pre-progression mortality and post-progression survival. Parametric survival models were fitted to data from ELEVATE-TN to model time to progression and pre-progression mortality. Post-progression survival in the acalabrutinib arm used overall survival data from the venetoclax plus rituximab arm of the MURANO trial. In the chlorambucil plus obinutuzumab group, data from the ibrutinib arm of RESONATE were used in a similar way but resulted in a lower overall survival rate. The ERG considered this approach favoured the sequence using venetoclax plus rituximab but that it was possible the difference in overall survival was because of confounding due to the unadjusted arm‑based comparison. The company considered that the MURANO and RESONATE trials reflected clinical practice for subsequent treatments as indicated by its clinical advisers. It therefore considered the post-progression survival estimates reasonable. The ERG highlighted that when modelling post-progression survival using MURANO, the overall survival hazard converged with that for the general population. This led to most people having acalabrutinib followed by venetoclax plus rituximab having similar survival to the general population. The ERG preferred to assume equal rates of post-progression survival for the acalabrutinib and chlorambucil plus obinutuzumab groups based on post-progression survival data from RESONATE because this leads to less optimistic projections of overall survival. The clinical experts suggested that overall survival was likely to be longer when starting treatment with acalabrutinib followed by venetoclax plus rituximab. This is because it is more effective and less toxic than chlorambucil plus obinutuzumab followed by ibrutinib. However, long-term data confirming overall survival benefit are lacking at present. They considered it reasonable to use MURANO because it accurately reflects the most likely treatment sequence of acalabrutinib followed by venetoclax plus rituximab. One clinical expert also explained that it was reasonable to expect that many people will reach the life expectancy of the general population after treatment with acalabrutinib and will be functionally cured. The other clinical expert did not consider this plausible. The committee concluded that there was considerable uncertainty in the overall survival estimates for acalabrutinib because of the extrapolation using data from trials for other treatments and the immature data from ELEVATE‑TN.\n\n# Cost-effectiveness results\n\n## For untreated CLL when FCR or BR is unsuitable, the incremental cost-effectiveness ratios are likely to be in the range normally considered acceptable\n\nThe incremental cost-effectiveness ratios (ICERs) used by the committee for decision making took account of all available confidential discounts, including those for comparators and follow-up treatments. Because of these confidential discounts, exact results cannot be reported here. The company's revised base-case ICER for acalabrutinib compared with chlorambucil plus obinutuzumab for untreated CLL when FCR or BR is unsuitable was within the range normally considered cost effective. Incorporating the ERG's preferred assumptions on applying a 14-cycle delay and using the Weibull model for subsequent treatment (see section\xa03.14) and using RESONATE post-progression survival for both treatment arms (see section\xa03.15) increased the ICER but it remained below £30,000 per quality-adjusted life year (QALY) gained. The committee used the ERG's base case for decision making. However, it also considered that further assumptions should be considered:\n\nThe proportion of people having second-line venetoclax plus rituximab was up to 20% (see section\xa03.13).\n\nAdjusting the overall survival gain for acalabrutinib compared with chlorambucil plus obinutuzumab so that it was 50% lower, reflecting uncertainty about the immature survival data in ELEVATE-TN (see section\xa03.15).In all the combinations of scenarios the committee considered, the ICER remained below £30,000 per QALY gained, except the combination using the most pessimistic assumptions. The committee recalled that the most plausible duration of subsequent treatment was likely between that estimated by the log-normal and Weibull distributions (see section\xa03.14) which reduced the ICER considerably. So, it was satisfied that acalabrutinib is likely to be a cost-effective use of NHS resources for untreated CLL that is not high risk and when FCR or BR is unsuitable.\n\n## For people with a 17p\xa0deletion or TP53\xa0mutation, acalabrutinib is likely to be cost saving compared with ibrutinib\n\nIn the company's base case from its cost-minimisation analysis, costs for acalabrutinib were lower than costs for ibrutinib for people with untreated CLL with a 17p\xa0deletion or TP53\xa0mutation (high‑risk CLL). The cost-minimisation analysis considered if the acquisition and management of adverse events costs for acalabrutinib were lower than for ibrutinib. The ERG's analysis made no substantial changes to the company's base case and resulted in mostly unchanged cost savings for acalabrutinib treatment. Final costs considered by the committee took account of all available confidential discounts, including those for comparators. The committee concluded that for people with untreated CLL with a 17p\xa0deletion or TP53\xa0mutation, acalabrutinib is likely to be cost saving compared with ibrutinib.\n\n## For previously treated CLL, acalabrutinib is likely to be cost saving compared with ibrutinib\n\nIn the company's base case from its cost-minimisation analysis, costs for acalabrutinib were lower than costs for ibrutinib for people with previously treated CLL. The cost-minimisation analysis considered if the acquisition and management of adverse events costs for acalabrutinib were lower than for ibrutinib. The ERG's analysis made no substantial changes to the company's base case and resulted in mostly unchanged cost savings for acalabrutinib treatment. The final costs considered by the committee took account of all available confidential discounts, including those for comparators. The committee concluded that for people with previously treated CLL, acalabrutinib was likely to be cost saving compared with ibrutinib. However, the committee considered that venetoclax plus rituximab was a relevant comparator for this population and because the company did not present a comparison with acalabrutinib, the cost effectiveness is unknown (see section\xa03.4).\n\n# End of life\n\n## Acalabrutinib does not meet the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered that the short life expectancy criterion of less than 24\xa0months was not met because people with CLL have a life expectancy of more than 2\xa0years. The committee concluded that acalabrutinib does not meet the criteria to be considered a life-extending treatment at the end of life.\n\n# Conclusions\n\n## Acalabrutinib is recommended for untreated CLL that is not high risk and when FCR or BR is unsuitable\n\nThe committee considered the uncertainties with distribution of subsequent treatments, subsequent treatment costs and survival estimates. It concluded that, with its preferred assumptions, the ICERs for acalabrutinib would be considered an acceptable use of NHS resources for untreated CLL that is not high risk and when FCR or BR is unsuitable (see section\xa03.16). The committee concluded that acalabrutinib could be recommended as an option for this population.\n\n## Acalabrutinib is recommended for people with untreated CLL with a 17p\xa0deletion or TP53\xa0mutation\n\nThe committee considered the uncertainty in the evidence for a population with untreated CLL with a 17p\xa0deletion or TP53\xa0mutation. However, it considered the economic model to be appropriate for decision making (see section\xa03.17). The committee concluded that for people with untreated CLL with a 17p\xa0deletion or TP53\xa0mutation, acalabrutinib was likely to be cost saving compared with ibrutinib. Therefore, it could be recommended as an option for this population.\n\n## Acalabrutinib is recommended for previously treated CLL\n\nThe committee considered that venetoclax plus rituximab was a relevant comparator for this population but no evidence comparing it with acalabrutinib was presented (see section\xa03.18). It concluded that the economic model was appropriate to compare acalabrutinib with ibrutinib and acalabrutinib was likely to be cost saving compared with ibrutinib. At the first meeting, the committee concluded that acalabrutinib could be recommended as an option for previously treated CLL but stipulated in the recommendations that it could be used only when ibrutinib is the only suitable treatment option. In response to consultation, several consultees noted that this could inadvertently prevent people from having acalabrutinib because ibrutinib is not suitable because of cardiac issues. The committee agreed that was not the intention of the recommendation, as acalabrutinib would be particularly beneficial for such people. The clinical lead for the Cancer Drugs Fund noted that he understood the rationale behind the committee's recommendation but considered that it would be beneficial to give clinicians flexibility in prescribing. Moreover, if doctors and patients reach the stage of considering a BTK inhibitor (ibrutinib or acalabrutinib) then it is likely that they have already ruled out treatment with venetoclax plus rituximab. Therefore, the committee concluded that the restriction included in the draft recommendations was not necessary.\n\n# Equality considerations\n\n## There are no equality issues relevant to the recommendations\n\nThe company's submission did not include people with untreated CLL for which FCR or BR is suitable. Patient submissions highlighted that this would potentially deny younger and fitter people access to a new treatment option that is well tolerated. However, the committee could not make a recommendation about the clinical and cost effectiveness of acalabrutinib for this population because the company did not present any evidence. Therefore, the committee did not consider this an equality issue it could resolve.\n\n# Innovation\n\n## There are no additional benefits that are not captured in the QALY calculations\n\nThe company considered acalabrutinib to be an innovative treatment because it is a highly selective BTK inhibitor that addresses a significant unmet need in first-line CLL treatment. Also, it offers an alternative option to the first-generation BTK inhibitor in previously treated CLL. Its targeted mechanism of action means it offers improved safety and tolerability compared with current treatments. The committee concluded that acalabrutinib would be a beneficial additional treatment option. However, it noted that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs."}
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https://www.nice.org.uk/guidance/ta689
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Evidence-based recommendations on acalabrutinib (Calquence) for treating chronic lymphocytic leukaemia in adults.
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ba92f98feb0f20dffef57da6ff5213b32fe856c5
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nice
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Avelumab for untreated metastatic Merkel cell carcinoma
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Avelumab for untreated metastatic Merkel cell carcinoma
Evidence-based recommendations on avelumab (Bavencio) for untreated metastatic Merkel cell carcinoma in adults.
# Recommendation
Avelumab is recommended as an option for treating metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease. It is recommended only if the company provides avelumab according to the commercial arrangement.
Why the committee made this recommendation
This appraisal reviews the additional evidence collected in the Cancer Drugs Fund managed access agreement for avelumab for metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease (NICE technology appraisal guidance 517). The new evidence includes data from clinical trials and from people having treatment in the NHS while this treatment was available in the Cancer Drugs Fund in England.
Avelumab is routinely available in the NHS for treating metastatic Merkel cell carcinoma after chemotherapy. Evidence collected while avelumab was in the Cancer Drugs Fund shows that it is an effective treatment for untreated disease. It shows that, compared with chemotherapy, avelumab improves how long people have before their disease progresses and how long they live.
Avelumab is considered to be a life‑extending treatment at the end of life. Cost‑effectiveness estimates for avelumab are within what NICE consider an acceptable use of NHS resources. Therefore, it is recommended.# Information about avelumab
# Marketing authorisation indication
Avelumab (Bavencio, Merck/Pfizer) is indicated as monotherapy for 'the treatment of adult patients with metastatic Merkel cell carcinoma'.
# Dosage in the marketing authorisation
The full dosage schedule is available in the summary of product characteristics.
The licensed dose has changed since NICE's technology appraisal guidance on avelumab for treating metastatic Merkel cell carcinoma. The dosage given in the JAVELIN trial was 10 mg/kg. In November 2019, the approved dose was changed to the dose described in the summary of product characteristics.
# Price
The list price of avelumab is £768 per 200-mg vial (excluding VAT; British National Formulary , accessed January 2021). The company has a commercial arrangement. This makes avelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck, a review of this submission by the evidence review group (ERG), NICE's technical engagement response form, and responses from stakeholders. See the committee papers for full details of the evidence.
# Clinical need and treatment pathway
## Metastatic Merkel cell carcinoma is a rare disease with limited treatment options
Patient groups explained in their written submissions that metastatic Merkel cell carcinoma is an aggressive and frightening cancer for patients. This fear stems from its visibility on the surface of the skin, the potential for disfigurement and rapid observable changes. Because its diagnosis is rare, clinical data and research are limited. This leads people to worry that decision making relating to future treatments and options will be impacted. Merkel cell carcinoma is currently treated with chemotherapy and best supportive care. However, chemotherapy is rarely effective and relapse rates are high with little sustained response. Because of the absence of alternative treatments, people often choose to have chemotherapy despite its limited effectiveness. Avelumab is already routinely used in metastatic Merkel cell carcinoma but only after chemotherapy. Earlier use of avelumab would offer people an alternative to chemotherapy. Benefits include a sustained response, fewer side effects and positive impact on quality of life. The patient expert present at the committee meeting also explained that avelumab makes a huge difference both physically and psychologically to people with metastatic Merkel cell carcinoma and their families. The committee concluded that there is a high unmet need for effective treatments in metastatic Merkel cell carcinoma and that early use of avelumab in the course of the disease would be welcomed by people with the disease and their families.
# Clinical trial evidence from JAVELIN
## Avelumab is an effective treatment for metastatic Merkel cell carcinoma
The clinical-effectiveness evidence came from JAVELIN, a single-arm open-label trial in people with metastatic Merkel cell carcinoma. The trial has 2 parts:
Part A: people with disease relapse after at least 1 line of chemotherapy.
Part B: people who had not had previous systemic therapy for metastatic disease.The first-line cohort (part B) is relevant to this appraisal. The main clinical uncertainties identified by the committee in NICE's technology appraisal guidance on avelumab for treating metastatic Merkel cell carcinoma (from now on, referred to as TA517) were the small numbers of people in the cohort, the short follow up and the immaturity of the progression-free survival (PFS) and overall-survival (OS) data. The committee concluded that more mature OS data from JAVELIN part B would be likely to resolve uncertainty around the treatment effect of avelumab and allow more reliable cost-effectiveness estimates. This appraisal reviews the most recent data from JAVELIN part B, which includes 116 people and has a median follow up of 16 months. The results show a median OS of 20 months, and a median PFS of 4.1 months. OS at 6 months was 75%, decreasing to 60% at 12 months. PFS at 6 months was 41%, decreasing to 31% at 12 months. The committee concluded that the mature data from JAVELIN show that avelumab is an effective treatment for metastatic Merkel cell carcinoma in people who have not had previous systemic therapy for metastatic disease.
## JAVELIN is generalisable to UK clinical practice
The committee discussed the baseline characteristics of people in JAVELIN part B. The ERG's commented that, compared with clinical practice, the population may be slightly younger, and include more men and people with more favourable Eastern Cooperative Oncology Group (ECOG) performance scores. Professional and patient groups at technical engagement also commented that the trial population broadly resembles people in clinical practice, but with more men and a higher than expected proportion of people with an ECOG score of 0 (meaning they are fully active). The clinical experts agreed that the trial population is broadly representative and explained that any differences between the trial and people who have treatment in clinical practice are not unique to metastatic Merkel cell carcinoma. These differences are seen in many cancers, as frailer people are generally excluded from cancer trials. The committee also heard from the company that the efficacy and safety outcomes from JAVELIN are similar to outcomes expected in the clinical setting. The committee concluded that the results from JAVELIN are generalisable to the NHS.
# Clinical evidence from the systemic anticancer therapy (SACT) data
## SACT provides an additional data source to support decision making
Observational data for patients in the Cancer Drugs Fund obtained from the SACT dataset were presented by the company but were not included in its economic analysis. However, the ERG used the SACT dataset in a scenario analysis. The SACT dataset includes 52 people and has a median follow up of 6 months. The results showed a median OS of 11.8 months. OS at 6 months was 58%, decreasing to 50% at 12 months. PFS data were not collected. The committee noted that there were several limitations with the SACT data compared with JAVELIN part B, including a smaller sample size (n=52 versus n=116), data immaturity (median follow up for OS is 6 months versus 16 months), and a reduced number of outcomes collected. The committee concluded that the SACT data are limited by these factors but could be used as an additional data source to support decision making.
# Indirect treatment comparison of avelumab and chemotherapy
## The ERG's adjusted analysis was preferred by the committee
In TA517, the company did a naive (that is, unadjusted) indirect comparison of avelumab against chemotherapy using a retrospective observational study of people with metastatic Merkel cell carcinoma (study 100070‑Obs001). The company did this study specifically to compare avelumab with chemotherapy. For this appraisal, it updated its naive indirect comparison with the 2019 JAVELIN part B data. No new data for chemotherapy were identified. The results of the naive indirect comparison suggest that avelumab improves overall response rates, PFS and OS compared with chemotherapy. However, the ERG was concerned about the methodological robustness of using a naive unadjusted comparison. It noted that by using a naive pooled analysis of multiple chemotherapy studies, the company was likely to introduce unnecessary heterogeneity into the analysis. The ERG considered the use of the immunocompetent subgroup of study 100070‑Obs001 more appropriate for a naive comparison with JAVELIN, as JAVELIN only includes people who are immunocompetent. However, the ERG noted that this approach is still potentially unreliable. At clarification, the ERG requested that the company perform propensity score weighting analysis to compare avelumab with chemotherapy efficacy using JAVELIN part B and study 100070‑Obs001. The ERG's preferred analysis adjusted for age, sex and ECOG performance score and maintained all patients in the analysis while achieving the best balance in baseline characteristics. The committee agreed with the ERG that an adjusted analysis was more appropriate than a naive comparison.
# Cost effectiveness
## The company's updated model uses the committee's preferred assumptions
The committee considered the preferred committee assumptions from TA517. It recalled that the cost-effectiveness estimates were largely dependent on the modelling of PFS and OS, which were uncertain because the trial data were immature. The committee had concluded that there was a plausible potential for avelumab to be cost effective, and that further clinical data from JAVELIN based on a larger number of people with longer follow up could reduce the uncertainty and produce more reliable cost-effectiveness estimates using the original economic model. The ERG explained that the model structure remained the same and was generally in line with the committee's preferred assumptions. The committee was satisfied the company had adhered to the preferred assumptions from TA517.
## The modelling of OS is appropriate
To estimate the expected overall survival for avelumab, the company used a 1‑knot odds spline‑based model. The ERG considered a 1‑knot spline‑based model to be appropriate but preferred the 1‑knot hazard spline. It highlighted that uncertainties in the naive comparison of the treatment effects of avelumab with chemotherapy meant that a more conservative approach using the hazard-based 1‑knot spline was appropriate. After technical engagement, the committee heard from the company that all 3 of the 1‑knot modelling approaches produced estimates in line with clinical advice. Each curve produced was also a near-identical fit to the Kaplan-Meier curve. The company explained that the ERG's preferred 1‑knot hazard spline, when extrapolated, eventually resulted in an estimated hazard of death that exceeds that of the base-case analysis in TA517 for people who have had 1 or more lines of chemotherapy. This does not align with clinical opinion that a treatment-naive population has better outcomes than those who have had chemotherapy. The ERG acknowledged that all 3 of the 1‑knot models presented by the company are very similar and, on its own, the selection of model is unlikely to make a difference to decision making. The committee agreed with the ERG's comments and concluded that the modelling of OS is appropriate for decision making.
## The modelling of PFS is appropriate
To extrapolate PFS for avelumab, the company used a 2‑knot odds spline‑based model. The ERG noted that the 2‑knot odds spline‑based model underestimated the Kaplan-Meier data between 0.5 and 1 year and overestimated the Kaplan-Meier data for the tail. The ERG considered the 3‑knots odds spline to provide a better extrapolation as well as a better fit to the data. After technical engagement, the company commented that there was little evidence to reject one model in favour of the other, and that both models are suitable for decision making with limited impact on the incremental cost-effectiveness ratio (ICER). The committee agreed with these comments and concluded that the modelling of PFS is appropriate for decision making.
## The modelling of time on treatment is appropriate
To extrapolate time on treatment for avelumab, the company used Weibull curves. Extrapolation beyond the minimum follow-up period of 15 months in JAVELIN part B was informed by data from JAVELIN part A (people with relapse after at least 1 line of chemotherapy), in which the minimum follow up was 36 months. Clinical experts advising the company expected most people to stop avelumab within 2 years of initiation, and it was assumed in the model that people remaining on treatment at 5 years would immediately stop. The ERG agreed with this assumption and used it in its preferred analyses. However, the ERG did not agree that the curves fitted to the time‑on‑treatment data should be adjusted using the JAVELIN part A data, as these data are not reflective of a treatment-naive population. The ERG preferred the 3‑knot hazard spline and did not use the JAVELIN part A data in its approach. After technical engagement, the company stated that its approach was taken to supplement the limited data from JAVELIN part B with mature data from JAVELIN part A while maintaining a model based on a treatment-naive population for the earlier part of the curve. The committee noted that both models resulted in similar mean time‑on‑treatment estimates, and the ICER was not impacted substantially. The clinical experts commented that treatment with avelumab beyond 5 years would be unusual, making the assumptions made about discontinuation of treatment correct. The committee concluded that modelling of time on treatment is appropriate for decision making.
# Cost-effectiveness estimate
## Avelumab is cost effective compared with chemotherapy
The company's base-case ICER was £17,947 per quality-adjusted life year (QALY) gained. Using the ERG's preferred propensity score weighting analysis to compare avelumab with chemotherapy (see section 3.5) and the ERG's preferred assumptions for modelling OS, PFS and time on treatment (see sections 3.7 to 3.9), the ICER was £20,780 per QALY gained. These ICERs are either below or within the range normally considered to be an acceptable use of NHS resources (£20,000 to £30,000 per QALY gained). All scenario analyses done by both the company and ERG were also below £25,000 per QALY gained. Therefore, the committee concluded that avelumab is cost effective compared with chemotherapy.
# End of Life
## Avelumab meets the end-of-life criteria
In TA517, the committee concluded that avelumab meets the criteria to be considered a life‑extending end-of-life treatment for first-line treatment of metastatic Merkel cell carcinoma. The committee considered the advice about life‑extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.
# Conclusion
## Avelumab is a clinically- and cost-effective treatment for metastatic Merkel cell carcinoma
The committee was reassured that avelumab is an effective treatment for metastatic Merkel cell carcinoma. Updated evidence from JAVELIN and the indirect treatment comparison showed that avelumab improves overall response rates, PFS and OS compared with chemotherapy. The modelling approaches taken by the company were also considered appropriate. The cost‑effectiveness estimates for avelumab are in the range normally considered to be a cost‑effective use of NHS resources for life‑extending treatments at the end of life. Therefore, the committee recommended avelumab for the treatment of metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease.
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{'Recommendation': 'Avelumab is recommended as an option for treating metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease. It is recommended only if the company provides avelumab according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nThis appraisal reviews the additional evidence collected in the Cancer Drugs Fund managed access agreement for avelumab for metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease (NICE technology appraisal guidance 517). The new evidence includes data from clinical trials and from people having treatment in the NHS while this treatment was available in the Cancer Drugs Fund in England.\n\nAvelumab is routinely available in the NHS for treating metastatic Merkel cell carcinoma after chemotherapy. Evidence collected while avelumab was in the Cancer Drugs Fund shows that it is an effective treatment for untreated disease. It shows that, compared with chemotherapy, avelumab improves how long people have before their disease progresses and how long they live.\n\nAvelumab is considered to be a life‑extending treatment at the end of life. Cost‑effectiveness estimates for avelumab are within what NICE consider an acceptable use of NHS resources. Therefore, it is recommended.', 'Information about avelumab': "# Marketing authorisation indication\n\nAvelumab (Bavencio, Merck/Pfizer) is indicated as monotherapy for 'the treatment of adult patients with metastatic Merkel cell carcinoma'.\n\n# Dosage in the marketing authorisation\n\nThe full dosage schedule is available in the summary of product characteristics.\n\nThe licensed dose has changed since NICE's technology appraisal guidance on avelumab for treating metastatic Merkel cell carcinoma. The dosage given in the JAVELIN trial was 10\xa0mg/kg. In November\xa02019, the approved dose was changed to the dose described in the summary of product characteristics.\n\n# Price\n\nThe list price of avelumab is £768 per 200-mg vial (excluding VAT; British National Formulary [BNF], accessed January\xa02021). The company has a commercial arrangement. This makes avelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck, a review of this submission by the evidence review group (ERG), NICE's technical engagement response form, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## Metastatic Merkel cell carcinoma is a rare disease with limited treatment options\n\nPatient groups explained in their written submissions that metastatic Merkel cell carcinoma is an aggressive and frightening cancer for patients. This fear stems from its visibility on the surface of the skin, the potential for disfigurement and rapid observable changes. Because its diagnosis is rare, clinical data and research are limited. This leads people to worry that decision making relating to future treatments and options will be impacted. Merkel cell carcinoma is currently treated with chemotherapy and best supportive care. However, chemotherapy is rarely effective and relapse rates are high with little sustained response. Because of the absence of alternative treatments, people often choose to have chemotherapy despite its limited effectiveness. Avelumab is already routinely used in metastatic Merkel cell carcinoma but only after chemotherapy. Earlier use of avelumab would offer people an alternative to chemotherapy. Benefits include a sustained response, fewer side effects and positive impact on quality of life. The patient expert present at the committee meeting also explained that avelumab makes a huge difference both physically and psychologically to people with metastatic Merkel cell carcinoma and their families. The committee concluded that there is a high unmet need for effective treatments in metastatic Merkel cell carcinoma and that early use of avelumab in the course of the disease would be welcomed by people with the disease and their families.\n\n# Clinical trial evidence from JAVELIN\n\n## Avelumab is an effective treatment for metastatic Merkel cell carcinoma\n\nThe clinical-effectiveness evidence came from JAVELIN, a single-arm open-label trial in people with metastatic Merkel cell carcinoma. The trial has 2\xa0parts:\n\nPart\xa0A: people with disease relapse after at least 1\xa0line of chemotherapy.\n\nPart\xa0B: people who had not had previous systemic therapy for metastatic disease.The first-line cohort (part\xa0B) is relevant to this appraisal. The main clinical uncertainties identified by the committee in NICE's technology appraisal guidance on avelumab for treating metastatic Merkel cell carcinoma (from now on, referred to as TA517) were the small numbers of people in the cohort, the short follow up and the immaturity of the progression-free survival (PFS) and overall-survival (OS) data. The committee concluded that more mature OS data from JAVELIN part\xa0B would be likely to resolve uncertainty around the treatment effect of avelumab and allow more reliable cost-effectiveness estimates. This appraisal reviews the most recent data from JAVELIN part\xa0B, which includes 116\xa0people and has a median follow up of 16\xa0months. The results show a median OS of 20\xa0months, and a median PFS of 4.1\xa0months. OS at 6\xa0months was 75%, decreasing to 60% at 12\xa0months. PFS at 6\xa0months was 41%, decreasing to 31% at 12\xa0months. The committee concluded that the mature data from JAVELIN show that avelumab is an effective treatment for metastatic Merkel cell carcinoma in people who have not had previous systemic therapy for metastatic disease.\n\n## JAVELIN is generalisable to UK clinical practice\n\nThe committee discussed the baseline characteristics of people in JAVELIN part\xa0B. The ERG's commented that, compared with clinical practice, the population may be slightly younger, and include more men and people with more favourable Eastern Cooperative Oncology Group (ECOG) performance scores. Professional and patient groups at technical engagement also commented that the trial population broadly resembles people in clinical practice, but with more men and a higher than expected proportion of people with an ECOG score of 0 (meaning they are fully active). The clinical experts agreed that the trial population is broadly representative and explained that any differences between the trial and people who have treatment in clinical practice are not unique to metastatic Merkel cell carcinoma. These differences are seen in many cancers, as frailer people are generally excluded from cancer trials. The committee also heard from the company that the efficacy and safety outcomes from JAVELIN are similar to outcomes expected in the clinical setting. The committee concluded that the results from JAVELIN are generalisable to the NHS.\n\n# Clinical evidence from the systemic anticancer therapy (SACT) data\n\n## SACT provides an additional data source to support decision making\n\nObservational data for patients in the Cancer Drugs Fund obtained from the SACT dataset were presented by the company but were not included in its economic analysis. However, the ERG used the SACT dataset in a scenario analysis. The SACT dataset includes 52\xa0people and has a median follow up of 6\xa0months. The results showed a median OS of 11.8\xa0months. OS at 6\xa0months was 58%, decreasing to 50% at 12\xa0months. PFS data were not collected. The committee noted that there were several limitations with the SACT data compared with JAVELIN part\xa0B, including a smaller sample size (n=52 versus n=116), data immaturity (median follow up for OS is 6\xa0months versus 16\xa0months), and a reduced number of outcomes collected. The committee concluded that the SACT data are limited by these factors but could be used as an additional data source to support decision making.\n\n# Indirect treatment comparison of avelumab and chemotherapy\n\n## The ERG's adjusted analysis was preferred by the committee\n\nIn TA517, the company did a naive (that is, unadjusted) indirect comparison of avelumab against chemotherapy using a retrospective observational study of people with metastatic Merkel cell carcinoma (study 100070‑Obs001). The company did this study specifically to compare avelumab with chemotherapy. For this appraisal, it updated its naive indirect comparison with the 2019 JAVELIN part\xa0B data. No new data for chemotherapy were identified. The results of the naive indirect comparison suggest that avelumab improves overall response rates, PFS and OS compared with chemotherapy. However, the ERG was concerned about the methodological robustness of using a naive unadjusted comparison. It noted that by using a naive pooled analysis of multiple chemotherapy studies, the company was likely to introduce unnecessary heterogeneity into the analysis. The ERG considered the use of the immunocompetent subgroup of study 100070‑Obs001 more appropriate for a naive comparison with JAVELIN, as JAVELIN only includes people who are immunocompetent. However, the ERG noted that this approach is still potentially unreliable. At clarification, the ERG requested that the company perform propensity score weighting analysis to compare avelumab with chemotherapy efficacy using JAVELIN part\xa0B and study 100070‑Obs001. The ERG's preferred analysis adjusted for age, sex and ECOG performance score and maintained all patients in the analysis while achieving the best balance in baseline characteristics. The committee agreed with the ERG that an adjusted analysis was more appropriate than a naive comparison.\n\n# Cost effectiveness\n\n## The company's updated model uses the committee's preferred assumptions\n\nThe committee considered the preferred committee assumptions from TA517. It recalled that the cost-effectiveness estimates were largely dependent on the modelling of PFS and OS, which were uncertain because the trial data were immature. The committee had concluded that there was a plausible potential for avelumab to be cost effective, and that further clinical data from JAVELIN based on a larger number of people with longer follow up could reduce the uncertainty and produce more reliable cost-effectiveness estimates using the original economic model. The ERG explained that the model structure remained the same and was generally in line with the committee's preferred assumptions. The committee was satisfied the company had adhered to the preferred assumptions from TA517.\n\n## The modelling of OS is appropriate\n\nTo estimate the expected overall survival for avelumab, the company used a 1‑knot odds spline‑based model. The ERG considered a 1‑knot spline‑based model to be appropriate but preferred the 1‑knot hazard spline. It highlighted that uncertainties in the naive comparison of the treatment effects of avelumab with chemotherapy meant that a more conservative approach using the hazard-based 1‑knot spline was appropriate. After technical engagement, the committee heard from the company that all 3 of the 1‑knot modelling approaches produced estimates in line with clinical advice. Each curve produced was also a near-identical fit to the Kaplan-Meier curve. The company explained that the ERG's preferred 1‑knot hazard spline, when extrapolated, eventually resulted in an estimated hazard of death that exceeds that of the base-case analysis in TA517 for people who have had 1 or more lines of chemotherapy. This does not align with clinical opinion that a treatment-naive population has better outcomes than those who have had chemotherapy. The ERG acknowledged that all 3 of the 1‑knot models presented by the company are very similar and, on its own, the selection of model is unlikely to make a difference to decision making. The committee agreed with the ERG's comments and concluded that the modelling of OS is appropriate for decision making.\n\n## The modelling of PFS is appropriate\n\nTo extrapolate PFS for avelumab, the company used a 2‑knot odds spline‑based model. The ERG noted that the 2‑knot odds spline‑based model underestimated the Kaplan-Meier data between 0.5 and 1\xa0year and overestimated the Kaplan-Meier data for the tail. The ERG considered the 3‑knots odds spline to provide a better extrapolation as well as a better fit to the data. After technical engagement, the company commented that there was little evidence to reject one model in favour of the other, and that both models are suitable for decision making with limited impact on the incremental cost-effectiveness ratio (ICER). The committee agreed with these comments and concluded that the modelling of PFS is appropriate for decision making.\n\n## The modelling of time on treatment is appropriate\n\nTo extrapolate time on treatment for avelumab, the company used Weibull curves. Extrapolation beyond the minimum follow-up period of 15\xa0months in JAVELIN part\xa0B was informed by data from JAVELIN part\xa0A (people with relapse after at least 1\xa0line of chemotherapy), in which the minimum follow up was 36\xa0months. Clinical experts advising the company expected most people to stop avelumab within 2\xa0years of initiation, and it was assumed in the model that people remaining on treatment at 5\xa0years would immediately stop. The ERG agreed with this assumption and used it in its preferred analyses. However, the ERG did not agree that the curves fitted to the time‑on‑treatment data should be adjusted using the JAVELIN part\xa0A data, as these data are not reflective of a treatment-naive population. The ERG preferred the 3‑knot hazard spline and did not use the JAVELIN part\xa0A data in its approach. After technical engagement, the company stated that its approach was taken to supplement the limited data from JAVELIN part\xa0B with mature data from JAVELIN part\xa0A while maintaining a model based on a treatment-naive population for the earlier part of the curve. The committee noted that both models resulted in similar mean time‑on‑treatment estimates, and the ICER was not impacted substantially. The clinical experts commented that treatment with avelumab beyond 5\xa0years would be unusual, making the assumptions made about discontinuation of treatment correct. The committee concluded that modelling of time on treatment is appropriate for decision making.\n\n# Cost-effectiveness estimate\n\n## Avelumab is cost effective compared with chemotherapy\n\nThe company's base-case ICER was £17,947 per quality-adjusted life year (QALY) gained. Using the ERG's preferred propensity score weighting analysis to compare avelumab with chemotherapy (see section\xa03.5) and the ERG's preferred assumptions for modelling OS, PFS and time on treatment (see sections\xa03.7 to\xa03.9), the ICER was £20,780 per QALY gained. These ICERs are either below or within the range normally considered to be an acceptable use of NHS resources (£20,000 to £30,000 per QALY gained). All scenario analyses done by both the company and ERG were also below £25,000 per QALY gained. Therefore, the committee concluded that avelumab is cost effective compared with chemotherapy.\n\n# End of Life\n\n## Avelumab meets the end-of-life criteria\n\nIn TA517, the committee concluded that avelumab meets the criteria to be considered a life‑extending end-of-life treatment for first-line treatment of metastatic Merkel cell carcinoma. The committee considered the advice about life‑extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.\n\n# Conclusion\n\n## Avelumab is a clinically- and cost-effective treatment for metastatic Merkel cell carcinoma\n\nThe committee was reassured that avelumab is an effective treatment for metastatic Merkel cell carcinoma. Updated evidence from JAVELIN and the indirect treatment comparison showed that avelumab improves overall response rates, PFS and OS compared with chemotherapy. The modelling approaches taken by the company were also considered appropriate. The cost‑effectiveness estimates for avelumab are in the range normally considered to be a cost‑effective use of NHS resources for life‑extending treatments at the end of life. Therefore, the committee recommended avelumab for the treatment of metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease."}
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https://www.nice.org.uk/guidance/ta691
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Evidence-based recommendations on avelumab (Bavencio) for untreated metastatic Merkel cell carcinoma in adults.
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Avelumab for treating metastatic Merkel cell carcinoma
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Avelumab for treating metastatic Merkel cell carcinoma
Evidence-based recommendations on avelumab (Bavencio) for metastatic Merkel cell carcinoma in adults.
# Recommendations
Avelumab is recommended as an option for treating metastatic Merkel cell carcinoma in adults who have had 1 or more lines of chemotherapy for metastatic disease. It is recommended only if the company provides avelumab according to the commercial arrangement.
This recommendation has been updated and replaced by avelumab for untreated metastatic Merkel cell carcinoma (NICE technology appraisal 691).
Why the committee made these recommendations
Treatment options for metastatic Merkel cell carcinoma are limited. People are usually offered chemotherapy or best supportive care. Avelumab could potentially be used as a first-line treatment or after chemotherapy.
Clinical trial evidence suggests that avelumab may improve overall survival compared with chemotherapy. But chemotherapy has not been compared directly with avelumab so the results are highly uncertain. The evidence on avelumab is promising, but at the time these recommendations were published the trial included only a small number of people and data were still being collected.
Avelumab as a first-line or second-line treatment meets NICE's criteria to be considered a life-extending end-of-life treatment.
Avelumab is recommended as a second-line treatment after chemotherapy because it is within the range NICE normally considers acceptable for end-of-life treatments. In April 2021 the company submitted updated data from the Cancer Drugs Fund on the use of avelumab as first-line treatment. NICE has therefore published new recommendations on avelumab for untreated Merkel cell carcinoma (see NICE technology appraisal 691) and recommendation 1.2 was removed.# The technology
# Marketing authorisation indication
Avelumab (Bavencio, Merck) is indicated as monotherapy for 'the treatment of adult patients with metastatic Merkel cell carcinoma'.
# Dosage in the marketing authorisation
The dosage given in the JAVELIN trial was 10 mg/kg every 2 weeks by intravenous infusion over 60 minutes. Avelumab should be continued until there is disease progression or unacceptable toxicity. Patients could continue treatment if they have radiological disease progression that is not associated with significant clinical deterioration (defined as no new or worsening symptoms, no change in performance status for more than 2 weeks and no need for salvage therapy). In November 2019, the approved dose was changed to the dose described in the summary of product characteristics.
# Price
The list price of avelumab is £768 per 200-mg vial (excluding VAT; Monthly Index of Medical Specialities online ). The average cost of treatment per patient is £65,086 based on the list price. The company has a commercial arrangement. This makes avelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Merkel cell carcinoma
## People with metastatic Merkel cell carcinoma would welcome avelumab as a treatment option
Merkel cell carcinoma is a rare and aggressive cancer with limited treatment options. There is an unmet clinical need for people with the disease. The patient experts explained that Merkel cell carcinoma often progresses rapidly, and can be frightening for both patients and families. The disease can start off as a small lump and then grow rapidly, spreading to other parts of the body (metastatic disease). Because it affects the surface of the skin, it is a very visible disease that can become oozing and unsightly. When it spreads to other parts of the body, patients are currently offered chemotherapy if they are able to tolerate it. The initial response rates are relatively high, but the disease often relapses quite quickly. The main benefit of avelumab is the potential for both good response rates and longer disease control than is seen with chemotherapy. The patient experts stated that avelumab has shown very rapid responses in some cases, with fewer side effects than chemotherapy. The clinical experts indicated that avelumab could be used either as a first treatment or after chemotherapy, but should ideally be used as early as possible in the treatment pathway for maximum clinical benefit. The committee concluded that avelumab offers a promising treatment option for people with metastatic Merkel cell carcinoma.
## Chemotherapy or best supportive care are appropriate comparators
The committee noted that the marketing authorisation for avelumab does not specify when it should be given in the treatment pathway (as the first treatment in metastatic disease or after chemotherapy). The clinical experts explained that they would like to offer avelumab to patients who have had none or only 1 previous line of therapy. The committee was aware that the final scope of this appraisal includes chemotherapy as a comparator for patients who have not had any treatment for metastatic disease (referred to as first line), and best supportive care for patients who have had 1 previous treatment (referred to as second line). The committee concluded that the appropriate comparator for first-line treatment is chemotherapy. However, it noted that some patients may be unable to have chemotherapy and are offered best supportive care instead. For second-line treatment, the committee concluded that best supportive care is the most appropriate comparator because very few patients would be expected to have chemotherapy again.
# Clinical trial evidence
## Results from the JAVELIN trial should be interpreted with caution
The evidence for avelumab came from JAVELIN. This is a single-arm non-randomised trial of patients with metastatic Merkel cell carcinoma. The trial has 2 parts:
Part A: 88 patients with relapse after at least 1 line of chemotherapy ('second-line and beyond' group).
Part B: 39 patients who had not had previous systemic therapy for metastatic disease (first-line group).The company originally presented interim data from a cut-off date of March 2017, and explained that it is still collecting data for both part A and part B. In response to consultation, and in support of the original analyses, the company presented additional data from a cut-off date of September 2017 (these data are academic in confidence and are not reported here). The committee was concerned that the interim data from part B (first-line group) relies on a very small number of patients with a short follow up (29 patients were followed for 3 months or more, 14 were followed for 6 months or more). Follow up in part A (second-line and beyond group) was 18 months. The committee welcomed the availability of slightly more mature data based on a larger number of patients, but the further data did not overcome the issue that the results were from 1 single-arm non-randomised trial. The committee also noted that the marketing authorisation has been granted conditionally for the first-line group because of the immaturity of the data. The European public assessment report specifies that further data cuts are expected to provide additional evidence on efficacy and toxicity. The committee concluded that the JAVELIN results should be interpreted with caution.
## There are some unanswered questions about the generalisability of the JAVELIN results
The committee discussed the baseline characteristics of patients in the JAVELIN trial:
Patients who were immunosuppressed were excluded from the trial. The clinical experts stated that patients with neuroendocrine tumours are generally responsive to immunotherapies such as avelumab, including those who are immunosuppressed. They stated that the only people who are immunosuppressed who may not be offered avelumab would be patients who have had a transplant, and this would be because of the risk of rejection rather than because avelumab would be less effective. There are some people, for example, with chronic lymphatic leukaemia or on very high doses of corticosteroids, who may not do well on this treatment. However, this would be very few patients and would be assessed on an individual basis. The committee agreed that although patients who were immunosuppressed were excluded from the trial, most could have been offered avelumab.
There were no study sites in England and the median age of the patients in part A was 72.5 years, which is slightly older than that expected in clinical practice in England (70.0 years).
The overall survival data may be confounded by the use of subsequent treatments, and no data on subsequent treatments were recorded as part of the trial.
The Eastern Cooperative Oncology Group (ECOG) performance score of patients was 0 to 1 in the trial. The clinical experts stated that, in clinical practice, they would offer immunotherapy to some patients who have an ECOG score of 2, if this was because of unrelated comorbidities that would not affect their ability to tolerate or benefit from avelumab. The clinical experts also stated that if patients have an ECOG score of 2 because of advanced Merkel cell carcinoma then immunotherapy may not be appropriate because patients need to have a reasonable life expectancy to be able to benefit from immunotherapy.The committee concluded that there were some unanswered questions about the generalisability of the trial to UK clinical practice.
## Clinical-effectiveness results for avelumab in second and further lines of treatment are promising but should be interpreted with caution
JAVELIN showed favourable efficacy outcomes for avelumab when used as a second or subsequent treatment (objective response rate of 33% at 18‑month follow up). The clinical experts explained that avelumab, as an immunotherapy agent, is expected to produce a more durable response than chemotherapy. The committee also heard that this durable progression-free survival should result in longer overall survival. It noted that the median overall survival was 12.6 months, which was higher than would currently be expected for patients with metastatic Merkel cell carcinomas. Even taking into account the later September 2017 data, the committee noted that the overall survival data were still relatively immature. It concluded that, although there were uncertainties, the results for avelumab used in second and further lines were very promising.
## Clinical-effectiveness results for avelumab as a first-line treatment are promising but should be interpreted with caution
The median overall survival for first-line treatment had not been reached, but JAVELIN showed promising response rates for avelumab as a first-line treatment. The clinical expert explained that the first-line response rates in JAVELIN had been high so far (62.11% at 3 months and 71.40% at 6 months for overall objective response rate). Taking into account the September 2017 data, the clinical experts anticipate that the response rate first line should be at least equal to, and possibly slightly better, than in second-line treatment. However, the committee was concerned that the results were from a very small number of patients with a short follow up, and that data on progression-free and overall survival were not adequate for decision-making. It noted that the trial provided no direct comparison with any other treatment and that data collection is ongoing in JAVELIN for first-line use. The committee concluded that the results for first-line use in metastatic Merkel cell carcinoma are highly immature and should be interpreted with caution.
# Naive indirect comparison
## Observational data are appropriate for comparison with JAVELIN
JAVELIN is a single-arm trial with no comparator, so the company did a naive (that is, unadjusted) indirect comparison of avelumab against chemotherapy using a retrospective observational study of patients with metastatic Merkel cell carcinoma (study 100070‑Obs001). The company did this study specifically for the purpose of comparing avelumab with chemotherapy. The study has 2 parts:
Part A, done in the US: 67 patients who had systemic chemotherapy first line, and 20 patients who had systemic chemotherapy after at least 1 line of chemotherapy.
Part B, done in the European Union: 34 patients who had systemic chemotherapy after at least 2 previous lines of chemotherapy.The committee concluded that, given the lack of data for this disease, the 2‑part observational study was appropriate for comparison with JAVELIN.
## The results from the naive indirect comparison are highly uncertain
The naive indirect comparison suggests that, for both first line and second and further lines, avelumab has improved overall response rates, progression-free survival and overall survival compared with chemotherapy. The ERG considered that results from JAVELIN and the 2‑part observational study should have been adjusted for differences in baseline characteristics including immunosuppression, ECOG performance score and age. In its clarification response, the company did regression analyses for the second-line and beyond group, but the ERG still had concerns with these analyses. The committee recalled the immaturity of the data and the small patient numbers, particularly first line. The committee heard from the ERG that, because efficacy data were only from non-randomised single-arm studies, it could not accurately assess how avelumab compares with chemotherapy or best supportive care. The committee concluded that the results from the naive indirect comparison should be interpreted cautiously.
# Adverse events
## Avelumab has an acceptable tolerability profile
The clinical experts explained that immunotherapy agents such as avelumab are generally better tolerated than chemotherapy, but immune-related adverse reactions can occur. The committee noted that no treatment-related deaths were recorded in JAVELIN, but treatment-related adverse event rates were high in both the first-line and second-line groups (71.8% and 75.0% of patients respectively). The committee would have liked to have seen long-term safety data but it appreciated that further data are being collected. The committee concluded that avelumab is generally better tolerated than chemotherapy but it can cause immune-related adverse reactions.
# The company's economic model
## The company's model structure is appropriate for decision-making
The company presented a 3‑state partitioned survival model comparing avelumab with chemotherapy or best supportive care in patients having first-line treatment, and comparing avelumab to best supportive care in patients having second and further lines of treatment. Each model included 3 health states (progression-free disease, progressed disease and death) with 3 sub-health states (greater than 100 days until death, 30 days to 100 days until death, and less than 30 days until death). The sub-health states applied to both the progression-free and progressed disease health states, and accounted for the deterioration in health-related quality of life when a patient approaches death. Although uncommon, the ERG considered this approach to be reasonable to capture the changes in quality of life that patients experience over their lifetime, in addition to the changes experienced after progression of the disease. The committee concluded that the model structure was appropriate for decision-making.
# Progression-free survival and overall survival estimates
## The modelled progression-free and overall survival for second and further lines of treatment is uncertain
The committee first discussed the second and further lines of treatment model, being aware that first-line survival estimates were developed and derived from the second- and further-line modelling. In its second- and further-line model, the company used a spline-based approach (a flexible parametric survival method) to extrapolate progression-free and overall survival estimates for the time horizon of the model. Because the tail observed for progression-free survival was long (suggesting a durable response), the company censored patients at 18‑month follow up. This allowed the progression-free survival estimate not to be overly influenced by a potentially optimistic estimate of durable response. The committee decided that this method was reasonable. However, it noted that the estimates were based on a naive indirect comparison with small numbers of patients (see section 3.7) and an extrapolation from 18 months of follow up to a 40‑year time horizon, and were therefore highly uncertain. Because of the limitations of the naive comparison the ERG preferred a Weibull regression, adjusting for parameter differences (including immunosuppression, age and gender) between study 100070‑Obs001 and JAVELIN. The committee concluded that it was not possible to confidently decide which method produced the more reliable results.
## The survival estimates for first-line treatment are highly uncertain
Because of the very limited data for first-line treatment (see section 3.6), the company considered it was unreliable to use progression-free and overall survival trial data in the first-line model. Instead, it used estimates derived from the second-line and beyond model in its original first-line model. The committee was concerned that the progression-free and overall survival estimates for first-line treatment were based on clinical assumptions, not direct evidence. The ERG considered that it was more appropriate to fit distributions for avelumab to the first-line estimates, rather than generating survival curves dependent on the second-line and beyond estimates and relying on assumptions. The committee was aware that the ERG's preferred survival model did not solve the issue of the uncertainty caused by limited data. The committee heard from the ERG that the company's original cost-effectiveness result for first-line treatment was most sensitive to the hazard ratio chosen for overall survival. The committee concluded that the company's original progression-free and overall survival estimates for first-line treatment with avelumab are highly uncertain.
## The effectiveness of best supportive care is assumed to be equivalent to chemotherapy
The company used patient-level data from the 2‑part observational study 100070‑Obs001 to estimate progression-free and overall survival for chemotherapy. The effectiveness of best supportive care was assumed to be equivalent to chemotherapy. The committee noted that the company used chemotherapy as a proxy for best supportive care in both first-line and second-line and beyond treatment because of a lack of data for best supportive care. In the second-line and beyond population, the company used pooled patient-level data from part A and part B to estimate progression-free and overall survival for chemotherapy. In the first-line population, the company used data from part A to estimate progression-free and overall survival for chemotherapy. The committee noted that there were no direct comparative data, and concluded that, although uncertain, the 2‑part observational study 100070‑Obs001 provided the most appropriate comparator data.
# Time-on-treatment estimates
## The company's assumptions for modelling time-on-treatment are in line with clinical practice
The company assumed that two-thirds of patients would stop treatment after 2 years (and all remaining patients would stop treatment after 5 years). The clinical experts explained that they expect 95% of patients having avelumab to stop treatment by 2 years. They explained that, for many immunotherapies used in other diseases, when there is a durable response and patients remain well, treatment tends to be stopped by 2 years. At this point, many patients would not want to keep coming back for further treatment. The clinical experts stated that there may be patients with a large volume of disease that was continuing to improve, who may wish to continue on treatment beyond 2 years, but this would be very few patients. The ERG noted that this assumption could potentially underestimate treatment costs. It considered the time-on-treatment extrapolation without truncation at 2 years to be more plausible and therefore included this approach in its base case. The committee agreed that the company's assumptions appeared to reflect clinical practice with regard to stopping treatment. However, it concluded that it would consider both the company's and the ERG's assumptions in its decision-making.
# Utility values in the economic model
## The baseline utilities are high
JAVELIN collected health-related quality-of-life data using EQ‑5D‑5L and FACT‑M questionnaires. The company mapped the EQ‑5D‑5L data to EQ‑5D‑3L values using a validated mapping function, in line with NICE's position statement on EQ-5D-5L. The company used a regression model to generate utilities from the mapped EQ‑5D‑5L. The utilities varied across 3 time periods relative to time of death: utility for greater than 100 days until death; utility for 30 days to 100 days until death; and utility for less than 30 days until death. The committee was aware that the utilities included the effect of adverse reactions. The ERG noted that the company did not compare the utilities used in the model with those reported in the literature. The committee heard that the time-to-death and baseline utilities were higher than the age-matched UK population. The committee agreed that these values were implausibly high but it noted that, because the same utilities were applied regardless of treatment group, only the difference between health states mattered. The committee concluded that it could accept the company's utility values but acknowledged that these were very high.
# The company's base case
## The company's revised base-case results for second and further lines of treatment are similar to the ERG's revised base case
The company's original base-case incremental cost-effectiveness ratio (ICER) for avelumab compared with best supportive care was £37,350 per quality-adjusted life year (QALY) gained. However, the company's original base case did not include all of the committee's preferred assumptions, that is:
using Weibull regressions to model progression-free and overall survival (see section 3.11)
adding the cost of premedication (approximately £100).At the request of the committee following the first committee meeting, the ERG submitted a revised base case that included the above assumptions, and incorporated the company's method for modelling time-on-treatment (which predicted 5.4% of patients having treatment with avelumab at 2 years). The ERG's revised base case resulted in an ICER of £37,629 per QALY gained compared with best supportive care. Following the consultation, the company submitted a revised base case with:
added administration costs (approximately £43)
an assumption that only 5.0% of patients have treatment with avelumab at 2 years.The revised base case resulted in an ICER of 37,846 per QALY gained compared with best supportive care. The company explained that no further data collection is planned for part A of JAVELIN, and noted that second and further-line treatment data were mature. The ERG noted minor differences in the estimates for patients still having treatment at 2 years, and in premedication costs. However, the ERG agreed with the company that JAVELIN part A data are mature, and noted that the company's revised ICER of £37,846 was very close to the ERG's revised base case of £37,629 per QALY gained. Despite this, the ERG highlighted that the revised estimate was still based on uncertain clinical parameters. The committee was concerned about the limited follow up on overall survival, and it was unclear why the company did not plan to collect further data. The committee was also concerned about the uncertainties in the clinical data (see section 3.5), particularly the small number of patients and the limitations of the naive comparison (see section 3.7), and about the reliability of the long-term modelling results (see section 3.11). However, the committee concluded that an ICER of around £38,000 per QALY gained was plausible.
## The company's revised first-line base-case results are based on immature data, which are highly uncertain and differ from the ERG's estimate
The company's original base-case ICER for avelumab compared with chemotherapy was £43,553 gained. However, the company's original base case did not include all of the committee's preferred assumptions, that is:
using the parametric curves to model progression-free and overall survival (see section 3.12)
adding the cost of premedication (approximately £100).The ERG submitted a revised base case, as requested by the committee following the first committee meeting. This included the above assumptions and the company's method for modelling time-on-treatment, resulting in 8.5% of patients still having treatment with avelumab at 2 years. The ERG's revised base-case ICER was £72,033 per QALY gained compared with chemotherapy. Following consultation, the company submitted a revised base case in which it:
added administration costs (approximately £43)
corrected an error in the calculation of background mortality
assumed that only 5% of patients have treatment with avelumab at 2 years
adjusted the ERG's progression-free and overall survival modelling because first-line hazards were larger than second and further-line treatment hazards, and the company considered it unlikely that avelumab is less effective first line than when given later in the course of the disease.The revised company base case resulted in an ICER of £58,315 per QALY gained compared with chemotherapy, lower than the ERG's base case of £72,033 per QALY gained. The assumption that only 5% of patients have treatment with avelumab at 2 years (a decrease from 8.5%) resulted in a decrease of approximately £5,000 per QALY gained from the ERG's revised base-case ICER. The ERG reiterated that 5% may be too low and may underestimate the cost of treatment (see section 3.14). The ERG also commented that the cost of premedication included in the company's new base case was less than the committee's estimate of £100. On the issue of first-line hazards, the ERG agreed with the company that the first-line hazards should not be larger than second-line and beyond hazards; that is, the effectiveness of avelumab would not be less when given first line compared with later in the disease. However, the ERG highlighted that the progression-free and overall survival modelling are both highly uncertain because of the lack of clinical data. The committee agreed with the ERG on that point and was very concerned about the lack of clinical data, particularly the very small number of patients in part B of JAVELIN, and the uncertainties around the methods used to generate the survival estimates. It agreed that the most plausible ICER is highly uncertain, and considered that the first-line evidence will be strengthened when the company can present further clinical data based on a larger number of patients with longer follow up. The committee concluded that the most plausible ICER could be between £58,000 and £72,000 per QALY gained, although it could also be above or below this range.
# End-of-life
## Avelumab meets the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods.
The committee noted the evidence presented by the company for first-line treatment. Based on the median overall survival from the US part A observational study (100070‑Obs001), the life expectancy of people with metastatic Merkel cell carcinoma was estimated to be 11.5 months. The modelled mean value was closer to 24.0 months, but it was based on very uncertain extrapolations of overall survival with first-line treatment. The trial evidence showed considerably longer survival with avelumab compared with current NHS treatment. The committee concluded that avelumab meets the criteria to be considered a life-extending end-of-life treatment for first-line treatment of metastatic Merkel cell carcinoma.
The evidence presented by the company indicated that people with metastatic Merkel cell carcinoma on second and further-line treatments have a life expectancy of between 5.1 months and 5.5 months, and that avelumab extends life by at least an additional 3 months compared with current NHS treatment. The committee accepted that avelumab meets the end-of-life criteria for second-line treatment of metastatic Merkel cell carcinoma.
# Cost-effectiveness estimates
## Avelumab can be recommended for routine commissioning for second-line and beyond treatment
The committee considered the company's new base-case ICER of £37,846 per QALY gained, and the ERG's revised base-case ICER of £37,629 per QALY gained. It noted that, although these are within the range that could be considered cost effective for end-of-life treatments, both estimates are uncertain. The committee recalled that no new data are being collected in part A of JAVELIN (see section 3.16) and therefore the uncertainty is unlikely to be resolved further. The committee agreed that avelumab is a promising treatment option for people with metastatic Merkel cell carcinoma, which is a very rare disease (see section 3.1), and heard from the clinical experts that only a very small number of people would be offered avelumab second line, particularly if it were available for first-line use. The committee agreed that a degree of uncertainty was acceptable in these circumstances, and was persuaded that avelumab is a clinically- and cost-effective treatment for people with metastatic Merkel cell carcinoma when used second line and beyond. It therefore recommended avelumab for routine use in the NHS for this population.
## Avelumab cannot be recommended for routine use in the NHS for first-line treatment because the clinical and cost effectiveness is highly uncertain
The committee considered the company's new base-case ICER of £58,315 per QALY gained, and the ERG's revised base-case ICER of £72,033 per QALY gained. It noted that both estimates are above the range that could be considered cost effective for end-of-life treatments. The committee agreed that, because of the uncertainty in the evidence, it was difficult to determine a robust cost-effectiveness estimate. It considered that both the company's and the ERG's revised estimates were potentially plausible, but that both were highly uncertain. The committee concluded that avelumab had not been proven to be a cost-effective treatment for people with metastatic Merkel cell carcinoma when used first line, and it could not currently be recommended for routine commissioning in the NHS.
# Cancer Drugs Fund
## Avelumab is a promising first-line treatment and more data are needed to establish its clinical and cost effectiveness
Having concluded that avelumab could not be recommended for routine first-line use, the committee then considered if it could be recommended for treating metastatic Merkel cell carcinoma first line within the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The company confirmed in its consultation response that it would consider the option of a recommendation in the Cancer Drugs Fund.
## Avelumab is suitable to be recommended for use in the Cancer Drugs Fund, when used first line
The range of ICERs for first-line treatment was £58,315 to £72,033 per QALY gained (see section 3.22). The committee considered that avelumab is a promising treatment, and that early use in the course of disease would be favoured by patients and clinicians. It acknowledged that immature data were used in the model, and that ongoing data collection in JAVELIN part B would reduce the uncertainty about the progression-free and overall survival benefit. There is plausible potential for first-line use of avelumab to be cost effective, if further trial data prove favourable. Therefore, the committee concluded that avelumab is suitable to be recommended for use in the Cancer Drugs Fund, when used first line for people with metastatic Merkel cell carcinoma, while further trial data accrues.
# Innovation
## All potential quality-of-life benefits are accounted for in the committee's decision
The committee noted the company's view that avelumab has the potential to help address the considerable unmet clinical need of people with metastatic Merkel cell carcinoma who currently have limited treatment options available to them at end-of-life. The committee heard from the clinical and patient experts that avelumab is innovative in its potential to have significant and substantial clinical benefits. It understood that avelumab is generally well-tolerated compared with chemotherapy. The committee agreed that avelumab addresses an unmet need for a debilitating condition with few treatment options, but considered that the benefits had been adequately captured in the QALY calculations.# Recommendations for data collection
As a condition of the positive recommendation and the managed access agreement, the company is required to collect efficacy data from the JAVELIN part B trial.
|
{'Recommendations': "Avelumab is recommended as an option for treating metastatic Merkel cell carcinoma in adults who have had 1\xa0or more lines of chemotherapy for metastatic disease. It is recommended only if the company provides avelumab according to the commercial arrangement.\n\nThis recommendation has been updated and replaced by avelumab for untreated metastatic Merkel cell carcinoma (NICE technology appraisal 691).\n\nWhy the committee made these recommendations\n\nTreatment options for metastatic Merkel cell carcinoma are limited. People are usually offered chemotherapy or best supportive care. Avelumab could potentially be used as a first-line treatment or after chemotherapy.\n\nClinical trial evidence suggests that avelumab may improve overall survival compared with chemotherapy. But chemotherapy has not been compared directly with avelumab so the results are highly uncertain. The evidence on avelumab is promising, but at the time these recommendations were published the trial included only a small number of people and data were still being collected.\n\nAvelumab as a first-line or second-line treatment meets NICE's criteria to be considered a life-extending end-of-life treatment.\n\nAvelumab is recommended as a second-line treatment after chemotherapy because it is within the range NICE normally considers acceptable for end-of-life treatments. In April\xa02021 the company submitted updated data from the Cancer Drugs Fund on the use of avelumab as first-line treatment. NICE has therefore published new recommendations on avelumab for untreated Merkel cell carcinoma (see NICE technology appraisal 691) and recommendation 1.2 was removed.", 'The technology': "# Marketing authorisation indication\n\nAvelumab (Bavencio, Merck) is indicated as monotherapy for 'the treatment of adult patients with metastatic Merkel cell carcinoma'.\n\n# Dosage in the marketing authorisation\n\nThe dosage given in the JAVELIN trial was 10\xa0mg/kg every 2\xa0weeks by intravenous infusion over 60\xa0minutes. Avelumab should be continued until there is disease progression or unacceptable toxicity. Patients could continue treatment if they have radiological disease progression that is not associated with significant clinical deterioration (defined as no new or worsening symptoms, no change in performance status for more than 2\xa0weeks and no need for salvage therapy). In November\xa02019, the approved dose was changed to the dose described in the summary of product characteristics.\n\n# Price\n\nThe list price of avelumab is £768 per 200-mg vial (excluding VAT; Monthly Index of Medical Specialities [MIMS] online [accessed January 2018]). The average cost of treatment per patient is £65,086 based on the list price. The company has a commercial arrangement. This makes avelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Merkel cell carcinoma\n\n## People with metastatic Merkel cell carcinoma would welcome avelumab as a treatment option\n\nMerkel cell carcinoma is a rare and aggressive cancer with limited treatment options. There is an unmet clinical need for people with the disease. The patient experts explained that Merkel cell carcinoma often progresses rapidly, and can be frightening for both patients and families. The disease can start off as a small lump and then grow rapidly, spreading to other parts of the body (metastatic disease). Because it affects the surface of the skin, it is a very visible disease that can become oozing and unsightly. When it spreads to other parts of the body, patients are currently offered chemotherapy if they are able to tolerate it. The initial response rates are relatively high, but the disease often relapses quite quickly. The main benefit of avelumab is the potential for both good response rates and longer disease control than is seen with chemotherapy. The patient experts stated that avelumab has shown very rapid responses in some cases, with fewer side effects than chemotherapy. The clinical experts indicated that avelumab could be used either as a first treatment or after chemotherapy, but should ideally be used as early as possible in the treatment pathway for maximum clinical benefit. The committee concluded that avelumab offers a promising treatment option for people with metastatic Merkel cell carcinoma.\n\n## Chemotherapy or best supportive care are appropriate comparators\n\nThe committee noted that the marketing authorisation for avelumab does not specify when it should be given in the treatment pathway (as the first treatment in metastatic disease or after chemotherapy). The clinical experts explained that they would like to offer avelumab to patients who have had none or only 1\xa0previous line of therapy. The committee was aware that the final scope of this appraisal includes chemotherapy as a comparator for patients who have not had any treatment for metastatic disease (referred to as first line), and best supportive care for patients who have had 1\xa0previous treatment (referred to as second line). The committee concluded that the appropriate comparator for first-line treatment is chemotherapy. However, it noted that some patients may be unable to have chemotherapy and are offered best supportive care instead. For second-line treatment, the committee concluded that best supportive care is the most appropriate comparator because very few patients would be expected to have chemotherapy again.\n\n# Clinical trial evidence\n\n## Results from the JAVELIN trial should be interpreted with caution\n\nThe evidence for avelumab came from JAVELIN. This is a single-arm non-randomised trial of patients with metastatic Merkel cell carcinoma. The trial has 2\xa0parts:\n\nPart\xa0A: 88\xa0patients with relapse after at least 1\xa0line of chemotherapy ('second-line and beyond' group).\n\nPart\xa0B: 39\xa0patients who had not had previous systemic therapy for metastatic disease (first-line group).The company originally presented interim data from a cut-off date of March\xa02017, and explained that it is still collecting data for both part\xa0A and part\xa0B. In response to consultation, and in support of the original analyses, the company presented additional data from a cut-off date of September\xa02017 (these data are academic in confidence and are not reported here). The committee was concerned that the interim data from part\xa0B (first-line group) relies on a very small number of patients with a short follow up (29\xa0patients were followed for 3\xa0months or more, 14\xa0were followed for 6\xa0months or more). Follow up in part\xa0A (second-line and beyond group) was 18\xa0months. The committee welcomed the availability of slightly more mature data based on a larger number of patients, but the further data did not overcome the issue that the results were from 1\xa0single-arm non-randomised trial. The committee also noted that the marketing authorisation has been granted conditionally for the first-line group because of the immaturity of the data. The European public assessment report specifies that further data cuts are expected to provide additional evidence on efficacy and toxicity. The committee concluded that the JAVELIN results should be interpreted with caution.\n\n## There are some unanswered questions about the generalisability of the JAVELIN results\n\nThe committee discussed the baseline characteristics of patients in the JAVELIN trial:\n\nPatients who were immunosuppressed were excluded from the trial. The clinical experts stated that patients with neuroendocrine tumours are generally responsive to immunotherapies such as avelumab, including those who are immunosuppressed. They stated that the only people who are immunosuppressed who may not be offered avelumab would be patients who have had a transplant, and this would be because of the risk of rejection rather than because avelumab would be less effective. There are some people, for example, with chronic lymphatic leukaemia or on very high doses of corticosteroids, who may not do well on this treatment. However, this would be very few patients and would be assessed on an individual basis. The committee agreed that although patients who were immunosuppressed were excluded from the trial, most could have been offered avelumab.\n\nThere were no study sites in England and the median age of the patients in part\xa0A was 72.5\xa0years, which is slightly older than that expected in clinical practice in England (70.0\xa0years).\n\nThe overall survival data may be confounded by the use of subsequent treatments, and no data on subsequent treatments were recorded as part of the trial.\n\nThe Eastern Cooperative Oncology Group (ECOG) performance score of patients was 0\xa0to\xa01 in the trial. The clinical experts stated that, in clinical practice, they would offer immunotherapy to some patients who have an ECOG score of\xa02, if this was because of unrelated comorbidities that would not affect their ability to tolerate or benefit from avelumab. The clinical experts also stated that if patients have an ECOG score of\xa02 because of advanced Merkel cell carcinoma then immunotherapy may not be appropriate because patients need to have a reasonable life expectancy to be able to benefit from immunotherapy.The committee concluded that there were some unanswered questions about the generalisability of the trial to UK clinical practice.\n\n## Clinical-effectiveness results for avelumab in second and further lines of treatment are promising but should be interpreted with caution\n\nJAVELIN showed favourable efficacy outcomes for avelumab when used as a second or subsequent treatment (objective response rate of 33% at 18‑month follow up). The clinical experts explained that avelumab, as an immunotherapy agent, is expected to produce a more durable response than chemotherapy. The committee also heard that this durable progression-free survival should result in longer overall survival. It noted that the median overall survival was 12.6\xa0months, which was higher than would currently be expected for patients with metastatic Merkel cell carcinomas. Even taking into account the later September\xa02017 data, the committee noted that the overall survival data were still relatively immature. It concluded that, although there were uncertainties, the results for avelumab used in second and further lines were very promising.\n\n## Clinical-effectiveness results for avelumab as a first-line treatment are promising but should be interpreted with caution\n\nThe median overall survival for first-line treatment had not been reached, but JAVELIN showed promising response rates for avelumab as a first-line treatment. The clinical expert explained that the first-line response rates in JAVELIN had been high so far (62.11% at 3\xa0months and 71.40% at 6\xa0months for overall objective response rate). Taking into account the September\xa02017 data, the clinical experts anticipate that the response rate first line should be at least equal to, and possibly slightly better, than in second-line treatment. However, the committee was concerned that the results were from a very small number of patients with a short follow up, and that data on progression-free and overall survival were not adequate for decision-making. It noted that the trial provided no direct comparison with any other treatment and that data collection is ongoing in JAVELIN for first-line use. The committee concluded that the results for first-line use in metastatic Merkel cell carcinoma are highly immature and should be interpreted with caution.\n\n# Naive indirect comparison\n\n## Observational data are appropriate for comparison with JAVELIN\n\nJAVELIN is a single-arm trial with no comparator, so the company did a naive (that is, unadjusted) indirect comparison of avelumab against chemotherapy using a retrospective observational study of patients with metastatic Merkel cell carcinoma (study 100070‑Obs001). The company did this study specifically for the purpose of comparing avelumab with chemotherapy. The study has 2\xa0parts:\n\nPart\xa0A, done in the US: 67\xa0patients who had systemic chemotherapy first line, and 20\xa0patients who had systemic chemotherapy after at least 1\xa0line of chemotherapy.\n\nPart\xa0B, done in the European Union: 34\xa0patients who had systemic chemotherapy after at least 2\xa0previous lines of chemotherapy.The committee concluded that, given the lack of data for this disease, the 2‑part observational study was appropriate for comparison with JAVELIN.\n\n## The results from the naive indirect comparison are highly uncertain\n\nThe naive indirect comparison suggests that, for both first line and second and further lines, avelumab has improved overall response rates, progression-free survival and overall survival compared with chemotherapy. The ERG considered that results from JAVELIN and the 2‑part observational study should have been adjusted for differences in baseline characteristics including immunosuppression, ECOG performance score and age. In its clarification response, the company did regression analyses for the second-line and beyond group, but the ERG still had concerns with these analyses. The committee recalled the immaturity of the data and the small patient numbers, particularly first line. The committee heard from the ERG that, because efficacy data were only from non-randomised single-arm studies, it could not accurately assess how avelumab compares with chemotherapy or best supportive care. The committee concluded that the results from the naive indirect comparison should be interpreted cautiously.\n\n# Adverse events\n\n## Avelumab has an acceptable tolerability profile\n\nThe clinical experts explained that immunotherapy agents such as avelumab are generally better tolerated than chemotherapy, but immune-related adverse reactions can occur. The committee noted that no treatment-related deaths were recorded in JAVELIN, but treatment-related adverse event rates were high in both the first-line and second-line groups (71.8% and 75.0% of patients respectively). The committee would have liked to have seen long-term safety data but it appreciated that further data are being collected. The committee concluded that avelumab is generally better tolerated than chemotherapy but it can cause immune-related adverse reactions.\n\n# The company's economic model\n\n## The company's model structure is appropriate for decision-making\n\nThe company presented a 3‑state partitioned survival model comparing avelumab with chemotherapy or best supportive care in patients having first-line treatment, and comparing avelumab to best supportive care in patients having second and further lines of treatment. Each model included 3\xa0health states (progression-free disease, progressed disease and death) with 3\xa0sub-health states (greater than 100\xa0days until death, 30\xa0days to 100\xa0days until death, and less than 30\xa0days until death). The sub-health states applied to both the progression-free and progressed disease health states, and accounted for the deterioration in health-related quality of life when a patient approaches death. Although uncommon, the ERG considered this approach to be reasonable to capture the changes in quality of life that patients experience over their lifetime, in addition to the changes experienced after progression of the disease. The committee concluded that the model structure was appropriate for decision-making.\n\n# Progression-free survival and overall survival estimates\n\n## The modelled progression-free and overall survival for second and further lines of treatment is uncertain\n\nThe committee first discussed the second and further lines of treatment model, being aware that first-line survival estimates were developed and derived from the second- and further-line modelling. In its second- and further-line model, the company used a spline-based approach (a flexible parametric survival method) to extrapolate progression-free and overall survival estimates for the time horizon of the model. Because the tail observed for progression-free survival was long (suggesting a durable response), the company censored patients at 18‑month follow up. This allowed the progression-free survival estimate not to be overly influenced by a potentially optimistic estimate of durable response. The committee decided that this method was reasonable. However, it noted that the estimates were based on a naive indirect comparison with small numbers of patients (see section\xa03.7) and an extrapolation from 18\xa0months of follow up to a 40‑year time horizon, and were therefore highly uncertain. Because of the limitations of the naive comparison the ERG preferred a Weibull regression, adjusting for parameter differences (including immunosuppression, age and gender) between study 100070‑Obs001 and JAVELIN. The committee concluded that it was not possible to confidently decide which method produced the more reliable results.\n\n## The survival estimates for first-line treatment are highly uncertain\n\nBecause of the very limited data for first-line treatment (see section\xa03.6), the company considered it was unreliable to use progression-free and overall survival trial data in the first-line model. Instead, it used estimates derived from the second-line and beyond model in its original first-line model. The committee was concerned that the progression-free and overall survival estimates for first-line treatment were based on clinical assumptions, not direct evidence. The ERG considered that it was more appropriate to fit distributions for avelumab to the first-line estimates, rather than generating survival curves dependent on the second-line and beyond estimates and relying on assumptions. The committee was aware that the ERG's preferred survival model did not solve the issue of the uncertainty caused by limited data. The committee heard from the ERG that the company's original cost-effectiveness result for first-line treatment was most sensitive to the hazard ratio chosen for overall survival. The committee concluded that the company's original progression-free and overall survival estimates for first-line treatment with avelumab are highly uncertain.\n\n## The effectiveness of best supportive care is assumed to be equivalent to chemotherapy\n\nThe company used patient-level data from the 2‑part observational study 100070‑Obs001 to estimate progression-free and overall survival for chemotherapy. The effectiveness of best supportive care was assumed to be equivalent to chemotherapy. The committee noted that the company used chemotherapy as a proxy for best supportive care in both first-line and second-line and beyond treatment because of a lack of data for best supportive care. In the second-line and beyond population, the company used pooled patient-level data from part\xa0A and part\xa0B to estimate progression-free and overall survival for chemotherapy. In the first-line population, the company used data from part\xa0A to estimate progression-free and overall survival for chemotherapy. The committee noted that there were no direct comparative data, and concluded that, although uncertain, the 2‑part observational study 100070‑Obs001 provided the most appropriate comparator data.\n\n# Time-on-treatment estimates\n\n## The company's assumptions for modelling time-on-treatment are in line with clinical practice\n\nThe company assumed that two-thirds of patients would stop treatment after 2\xa0years (and all remaining patients would stop treatment after 5\xa0years). The clinical experts explained that they expect 95% of patients having avelumab to stop treatment by 2\xa0years. They explained that, for many immunotherapies used in other diseases, when there is a durable response and patients remain well, treatment tends to be stopped by 2\xa0years. At this point, many patients would not want to keep coming back for further treatment. The clinical experts stated that there may be patients with a large volume of disease that was continuing to improve, who may wish to continue on treatment beyond 2\xa0years, but this would be very few patients. The ERG noted that this assumption could potentially underestimate treatment costs. It considered the time-on-treatment extrapolation without truncation at 2\xa0years to be more plausible and therefore included this approach in its base case. The committee agreed that the company's assumptions appeared to reflect clinical practice with regard to stopping treatment. However, it concluded that it would consider both the company's and the ERG's assumptions in its decision-making.\n\n# Utility values in the economic model\n\n## The baseline utilities are high\n\nJAVELIN collected health-related quality-of-life data using EQ‑5D‑5L and FACT‑M questionnaires. The company mapped the EQ‑5D‑5L data to EQ‑5D‑3L values using a validated mapping function, in line with NICE's position statement on EQ-5D-5L. The company used a regression model to generate utilities from the mapped EQ‑5D‑5L. The utilities varied across 3\xa0time periods relative to time of death: utility for greater than 100\xa0days until death; utility for 30\xa0days to 100\xa0days until death; and utility for less than 30\xa0days until death. The committee was aware that the utilities included the effect of adverse reactions. The ERG noted that the company did not compare the utilities used in the model with those reported in the literature. The committee heard that the time-to-death and baseline utilities were higher than the age-matched UK population. The committee agreed that these values were implausibly high but it noted that, because the same utilities were applied regardless of treatment group, only the difference between health states mattered. The committee concluded that it could accept the company's utility values but acknowledged that these were very high.\n\n# The company's base case\n\n## The company's revised base-case results for second and further lines of treatment are similar to the ERG's revised base case\n\nThe company's original base-case incremental cost-effectiveness ratio (ICER) for avelumab compared with best supportive care was £37,350 per quality-adjusted life year (QALY) gained. However, the company's original base case did not include all of the committee's preferred assumptions, that is:\n\nusing Weibull regressions to model progression-free and overall survival (see section\xa03.11)\n\nadding the cost of premedication (approximately £100).At the request of the committee following the first committee meeting, the ERG submitted a revised base case that included the above assumptions, and incorporated the company's method for modelling time-on-treatment (which predicted 5.4% of patients having treatment with avelumab at 2\xa0years). The ERG's revised base case resulted in an ICER of £37,629 per QALY gained compared with best supportive care. Following the consultation, the company submitted a revised base case with:\n\nadded administration costs (approximately £43)\n\nan assumption that only 5.0% of patients have treatment with avelumab at 2\xa0years.The revised base case resulted in an ICER of 37,846 per QALY gained compared with best supportive care. The company explained that no further data collection is planned for part\xa0A of JAVELIN, and noted that second and further-line treatment data were mature. The ERG noted minor differences in the estimates for patients still having treatment at 2\xa0years, and in premedication costs. However, the ERG agreed with the company that JAVELIN part\xa0A data are mature, and noted that the company's revised ICER of £37,846 was very close to the ERG's revised base case of £37,629 per QALY gained. Despite this, the ERG highlighted that the revised estimate was still based on uncertain clinical parameters. The committee was concerned about the limited follow up on overall survival, and it was unclear why the company did not plan to collect further data. The committee was also concerned about the uncertainties in the clinical data (see section\xa03.5), particularly the small number of patients and the limitations of the naive comparison (see section\xa03.7), and about the reliability of the long-term modelling results (see section\xa03.11). However, the committee concluded that an ICER of around £38,000 per QALY gained was plausible.\n\n## The company's revised first-line base-case results are based on immature data, which are highly uncertain and differ from the ERG's estimate\n\nThe company's original base-case ICER for avelumab compared with chemotherapy was £43,553 gained. However, the company's original base case did not include all of the committee's preferred assumptions, that is:\n\nusing the parametric curves to model progression-free and overall survival (see section\xa03.12)\n\nadding the cost of premedication (approximately £100).The ERG submitted a revised base case, as requested by the committee following the first committee meeting. This included the above assumptions and the company's method for modelling time-on-treatment, resulting in 8.5% of patients still having treatment with avelumab at 2\xa0years. The ERG's revised base-case ICER was £72,033 per QALY gained compared with chemotherapy. Following consultation, the company submitted a revised base case in which it:\n\nadded administration costs (approximately £43)\n\ncorrected an error in the calculation of background mortality\n\nassumed that only 5% of patients have treatment with avelumab at 2\xa0years\n\nadjusted the ERG's progression-free and overall survival modelling because first-line hazards were larger than second and further-line treatment hazards, and the company considered it unlikely that avelumab is less effective first line than when given later in the course of the disease.The revised company base case resulted in an ICER of £58,315 per QALY gained compared with chemotherapy, lower than the ERG's base case of £72,033 per QALY gained. The assumption that only 5% of patients have treatment with avelumab at 2\xa0years (a decrease from 8.5%) resulted in a decrease of approximately £5,000 per QALY gained from the ERG's revised base-case ICER. The ERG reiterated that 5% may be too low and may underestimate the cost of treatment (see section\xa03.14). The ERG also commented that the cost of premedication included in the company's new base case was less than the committee's estimate of £100. On the issue of first-line hazards, the ERG agreed with the company that the first-line hazards should not be larger than second-line and beyond hazards; that is, the effectiveness of avelumab would not be less when given first line compared with later in the disease. However, the ERG highlighted that the progression-free and overall survival modelling are both highly uncertain because of the lack of clinical data. The committee agreed with the ERG on that point and was very concerned about the lack of clinical data, particularly the very small number of patients in part\xa0B of JAVELIN, and the uncertainties around the methods used to generate the survival estimates. It agreed that the most plausible ICER is highly uncertain, and considered that the first-line evidence will be strengthened when the company can present further clinical data based on a larger number of patients with longer follow up. The committee concluded that the most plausible ICER could be between £58,000 and £72,000 per QALY gained, although it could also be above or below this range.\n\n# End-of-life\n\n## Avelumab meets the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods.\n\nThe committee noted the evidence presented by the company for first-line treatment. Based on the median overall survival from the US part\xa0A observational study (100070‑Obs001), the life expectancy of people with metastatic Merkel cell carcinoma was estimated to be 11.5\xa0months. The modelled mean value was closer to 24.0\xa0months, but it was based on very uncertain extrapolations of overall survival with first-line treatment. The trial evidence showed considerably longer survival with avelumab compared with current NHS treatment. The committee concluded that avelumab meets the criteria to be considered a life-extending end-of-life treatment for first-line treatment of metastatic Merkel cell carcinoma.\n\nThe evidence presented by the company indicated that people with metastatic Merkel cell carcinoma on second and further-line treatments have a life expectancy of between 5.1\xa0months and 5.5\xa0months, and that avelumab extends life by at least an additional 3\xa0months compared with current NHS treatment. The committee accepted that avelumab meets the end-of-life criteria for second-line treatment of metastatic Merkel cell carcinoma.\n\n# Cost-effectiveness estimates\n\n## Avelumab can be recommended for routine commissioning for second-line and beyond treatment\n\nThe committee considered the company's new base-case ICER of £37,846 per QALY gained, and the ERG's revised base-case ICER of £37,629 per QALY gained. It noted that, although these are within the range that could be considered cost effective for end-of-life treatments, both estimates are uncertain. The committee recalled that no new data are being collected in part\xa0A of JAVELIN (see section\xa03.16) and therefore the uncertainty is unlikely to be resolved further. The committee agreed that avelumab is a promising treatment option for people with metastatic Merkel cell carcinoma, which is a very rare disease (see section\xa03.1), and heard from the clinical experts that only a very small number of people would be offered avelumab second line, particularly if it were available for first-line use. The committee agreed that a degree of uncertainty was acceptable in these circumstances, and was persuaded that avelumab is a clinically- and cost-effective treatment for people with metastatic Merkel cell carcinoma when used second line and beyond. It therefore recommended avelumab for routine use in the NHS for this population.\n\n## Avelumab cannot be recommended for routine use in the NHS for first-line treatment because the clinical and cost effectiveness is highly uncertain\n\nThe committee considered the company's new base-case ICER of £58,315 per QALY gained, and the ERG's revised base-case ICER of £72,033 per QALY gained. It noted that both estimates are above the range that could be considered cost effective for end-of-life treatments. The committee agreed that, because of the uncertainty in the evidence, it was difficult to determine a robust cost-effectiveness estimate. It considered that both the company's and the ERG's revised estimates were potentially plausible, but that both were highly uncertain. The committee concluded that avelumab had not been proven to be a cost-effective treatment for people with metastatic Merkel cell carcinoma when used first line, and it could not currently be recommended for routine commissioning in the NHS.\n\n# Cancer Drugs Fund\n\n## Avelumab is a promising first-line treatment and more data are needed to establish its clinical and cost effectiveness\n\nHaving concluded that avelumab could not be recommended for routine first-line use, the committee then considered if it could be recommended for treating metastatic Merkel cell carcinoma first line within the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The company confirmed in its consultation response that it would consider the option of a recommendation in the Cancer Drugs Fund.\n\n## Avelumab is suitable to be recommended for use in the Cancer Drugs Fund, when used first line\n\nThe range of ICERs for first-line treatment was £58,315 to £72,033 per QALY gained (see section\xa03.22). The committee considered that avelumab is a promising treatment, and that early use in the course of disease would be favoured by patients and clinicians. It acknowledged that immature data were used in the model, and that ongoing data collection in JAVELIN part\xa0B would reduce the uncertainty about the progression-free and overall survival benefit. There is plausible potential for first-line use of avelumab to be cost effective, if further trial data prove favourable. Therefore, the committee concluded that avelumab is suitable to be recommended for use in the Cancer Drugs Fund, when used first line for people with metastatic Merkel cell carcinoma, while further trial data accrues.\n\n# Innovation\n\n## All potential quality-of-life benefits are accounted for in the committee's decision\n\nThe committee noted the company's view that avelumab has the potential to help address the considerable unmet clinical need of people with metastatic Merkel cell carcinoma who currently have limited treatment options available to them at end-of-life. The committee heard from the clinical and patient experts that avelumab is innovative in its potential to have significant and substantial clinical benefits. It understood that avelumab is generally well-tolerated compared with chemotherapy. The committee agreed that avelumab addresses an unmet need for a debilitating condition with few treatment options, but considered that the benefits had been adequately captured in the QALY calculations.", 'Recommendations for data collection': 'As a condition of the positive recommendation and the managed access agreement, the company is required to collect efficacy data from the JAVELIN part\xa0B trial.'}
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https://www.nice.org.uk/guidance/ta517
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Evidence-based recommendations on avelumab (Bavencio) for metastatic Merkel cell carcinoma in adults.
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244f13f9bfac652990860e32c177654c2962814b
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nice
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Postnatal care
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Postnatal care
This guideline covers the routine postnatal care that women and their babies should receive in the first 8 weeks after the birth. It includes the organisation and delivery of postnatal care, identifying and managing common and serious health problems in women and their babies, how to help parents form strong relationships with their babies, and baby feeding. The recommendations on emotional attachment and baby feeding also cover the antenatal period.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Parents and carers have the right to be involved in planning and making decisions about their baby's health and care, and to be given information and support to enable them to do this, as set out in the NHS Constitution and summarised in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Please note that the Royal College of Obstetricians and Gynaecologists has produced guidance on COVID-19 infection and pregnancy for all midwifery and obstetric services.
This guideline uses the term 'woman' or 'mother' and includes all people who have given birth, even if they may not identify as women or mothers. 'Woman' is generally used but in some instances, 'mother' is used when referring to her in relation to her baby.
This guideline uses the term 'partner' to refer to the woman's chosen supporter. This could be the baby's father, the woman's partner, a family member or friend, or anyone who the woman feels supported by or wishes to involve. The term 'parents' refers to those with the main responsibility for the care of a baby. This will often be the mother and the father, but many other family arrangements exist, including single parents.
# Organisation and delivery of postnatal care
## Principles of care
When caring for a woman who has recently given birth, listen to her and be responsive to her needs and preferences. Also see the NICE guideline on patient experience in adult NHS services.
Be aware that the 2020 MBRRACE-UK reports on maternal and perinatal mortality showed that women and babies from some minority ethnic backgrounds and those who live in deprived areas have an increased risk of death and may need closer monitoring. The reports showed that:
compared with white women (8 per 100,000), the risk of maternal death during pregnancy and up to 6 weeks after birth is:
times higher in black women (34 per 100,000)
times higher in mixed ethnicity women (25 per 100,000)
times higher in Asian women (15 per 100,000; does not include Chinese women)
the neonatal mortality rate is around 50% higher in black and Asian babies compared with white babies (17 compared with 25 per 10,000)
women living in the most deprived areas are more than 2.5 times more likely to die compared with women living in the least deprived areas (6 compared with 15 per 100,000)
the neonatal mortality rate increases according to the level of deprivation in the area the mother lives in, with almost twice as many babies dying in the most deprived areas compared with the least deprived areas (12 compared with 22 per 10,000).
A woman may be supported by her partner in the postnatal period. Involve them according to the woman's wishes.
When caring for a baby, remember that those with parental responsibility have the right be involved in the baby's care, if they choose.
When giving information about postnatal care, use clear language and tailor the timing, content and delivery of information to the woman's needs and preferences. Information should support shared decision making and be:
provided face-to-face and supplemented by virtual discussions and written formats, for example, digital, printed, braille or Easy Read
-ffered throughout the woman's care
individualised and sensitive
supportive and respectful
evidence based and consistent
translated by an appropriate interpreter to overcome language barriers.For more guidance on communication, providing information (including different formats and languages) and shared decision making, see the NICE guidelines on patient experience in adult NHS services and shared decision making, and the NHS Accessible Information Standard.
Check that the woman understands the information she has been given, and how it relates to her. Provide regular opportunities for her to ask questions, and set aside enough time to discuss any concerns.
Follow the principles in the NICE guideline on pregnancy and complex social factors for women who may need additional support, for example:
women who misuse substances
recent migrants, asylum seekers or refugees, or women who have difficulty reading or speaking English
young women aged under 20
women who experience domestic abuse.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on principles of care .
Full details of the evidence and the committee's discussion are in evidence review G: provision of information about the postnatal health of women.
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## Communication between healthcare professionals at transfer of care
Ensure that there is effective and prompt communication between healthcare professionals when women transfer between services, for example, from secondary to primary care, and from midwifery to health visitor care. This should include sharing relevant information about:
the pregnancy, birth, postnatal period and any complications
the plan of ongoing care, including any condition that needs long-term management
problems related to previous pregnancies that may be relevant to current care
previous or current mental health concerns
female genital mutilation (mother or previous child)
who has parental responsibility for the baby, if known
the woman's next of kin
safeguarding issues (also see the NICE guideline on domestic violence and abuse and the NICE guideline on child abuse and neglect)
concerns about the woman's health and care, raised by her, her partner or a healthcare professional
concerns about the baby's health and care, raised by the parents or a healthcare professional
the baby's feeding.
Midwifery services should ensure that:
the transfer of care from midwife to health visitor is clearly communicated between healthcare professionals and
the woman or the parents are informed about the transfer of care from midwife to health visitor.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on communication between healthcare professionals at transfer of care .
Full details of the evidence and the committee's discussion are in evidence review B: information transfer.
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## Transfer to community care
Before transfer from the maternity unit to community care, or before the midwife leaves after a home birth:
assess the woman's health (see recommendations 1.2.2 and 1.2.3)
assess the woman's bladder function by measuring the volume of the first void after giving birth
assess the baby's health (including physical inspection and observation)
if the baby has not passed meconium, advise the parents that if the baby does not do so within 24 hours of birth, they should seek advice from a healthcare professional (also see recommendation 1.3.12)
make sure there is a plan for feeding the baby, which should include observing at least 1 effective feed.
Before transfer from the maternity unit to community care, discuss the timing of transfer to community care with the woman, and ask her about her needs, preferences and support available.
When deciding on the timing of the transfer to community care, take into account the woman's preferences, the factors in recommendations 1.1.10 and 1.1.11 and any concerns, including any safeguarding issues (also see the NICE guideline on domestic violence and abuse).
Before transfer from the maternity unit to community care, or before the midwife leaves after a home birth, give women information about:
the postnatal period and what to expect
the importance of pelvic floor exercises (see the NICE guideline on pelvic floor dysfunction)
what support is available (statutory and voluntary services)
who to contact if any concerns arise at different stages.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on transfer to community care .
Full details of the evidence and the committee's discussion are in evidence review A: length of postpartum stay.
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## First midwife visit after transfer of care from the place of birth or after a home birth
Ensure that the first postnatal visit by a midwife takes place within 36 hours after transfer of care from the place of birth or after a home birth. The visit should be face-to-face and usually at the woman's home, depending on her circumstances and preferences.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on first midwife visit after transfer of care from the place of birth or after a home birth .
Full details of the evidence and the committee's discussion are in evidence review C: timing of first postnatal contact by midwife.
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## First health visitor visit
Consider arranging the first postnatal health visitor home visit to take place between 7 and 14 days after transfer of care from midwifery care so that the timing of postnatal contacts is evenly spread out.
If a woman did not receive an antenatal health visitor visit, consider arranging an additional early postnatal health visitor visit.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on first health visitor visit .
Full details of the evidence and the committee's discussion are in evidence review D: timing of first postnatal contact by health visitor.
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# Postnatal care of the woman
## Assessment and care of the woman
At each postnatal contact, ask the woman about her general health and whether she has any concerns, and assess her general wellbeing. Discuss topics that may be affecting her daily life, and provide information, reassurance and further care as appropriate. Topics to discuss may include:
the postnatal period and what to expect
symptoms and signs of potential postnatal mental health problems and how to seek help
symptoms and signs of potential postnatal physical problems and how to seek help
the importance of pelvic floor exercises, how to do them and when to seek help (see the NICE guideline on pelvic floor dysfunction)
fatigue
factors such as nutrition and diet, physical activity, smoking, alcohol consumption and recreational drug use (also see the NICE guidelines on maternal and child nutrition, weight management before, during and after pregnancy, tobacco and the UK Chief Medical Officer's physical activity guidelines for women after birth)
contraception (see the Faculty of Sexual & Reproductive Healthcare (FSRH) guideline on contraception after pregnancy)
sexual intercourse
safeguarding concerns, including domestic abuse (see the NICE guideline on domestic violence and abuse and the NICE guideline on child abuse and neglect).
At each postnatal contact, assess the woman's psychological and emotional wellbeing. Follow the recommendations on recognising mental health problems in pregnancy and the postnatal period and referral in the NICE guideline on antenatal and postnatal mental health. If there are concerns, arrange for further assessment and follow up.
At each postnatal contact by a midwife, assess the woman's physical health, including the following:
for all women:
symptoms and signs of infection
pain
vaginal discharge and bleeding (see the section on postpartum bleeding)
bladder function
bowel function
nipple and breast discomfort and symptoms of inflammation
symptoms and signs of thromboembolism
symptoms and signs of anaemia
symptoms and signs of pre‑eclampsia
for women who have had a vaginal birth:
perineal healing (see the section on perineal health)
for women who have had a caesarean section (also see the NICE guideline on caesarean birth):
wound healing
symptoms of wound infection.
At the first postnatal midwife contact, inform the woman that the following are symptoms or signs of potentially serious conditions, and she should seek medical advice without delay if any of these occur:
sudden or very heavy vaginal bleeding, or persistent or increased vaginal bleeding, which could indicate retained placental tissue or endometritis
abdominal, pelvic or perineal pain, fever, shivering, or vaginal discharge with an unpleasant smell, which could indicate infection
leg swelling and tenderness, or shortness of breath, which could indicate venous thromboembolism
chest pain, which could indicate venous thromboembolism or cardiac problems
persistent or severe headache, which could indicate hypertension, pre‑eclampsia, postdural-puncture headache, migraine, intracranial pathology or infection
worsening reddening and swelling of breasts persisting for more than 24 hours despite self-management, which could indicate mastitis
symptoms or signs of potentially serious conditions that do not respond to treatment.
At each postnatal contact, give the woman the opportunity to talk about her birth experience, and provide information about relevant support and birth reflection services, if appropriate. See the section on traumatic birth, stillbirth and miscarriage in the NICE guideline on antenatal and postnatal mental health and the NICE guideline on post-traumatic stress disorder.
All healthcare professionals should ensure appropriate referral if there are concerns about the woman's health.
At 6 to 8 weeks after the birth, a GP should:
carry out an assessment including the points in recommendations 1.2.1 to 1.2.5 and taking into account the time since the birth
respond to any concerns, which may include referral to specialist services in either secondary care or other healthcare services such as physiotherapy.
For guidance on care for women with symptoms or signs of sepsis, see the NICE guideline on sepsis. If the woman has confirmed or suspected puerperal sepsis, assess the baby for symptoms or signs of infection.
For postnatal care of women who have had hypertension or pre‑eclampsia in pregnancy, see the NICE guideline on hypertension in pregnancy, in particular:
postnatal investigation, monitoring and treatment:
for women with chronic hypertension
for women with gestational hypertension
for women with pre-eclampsia
antihypertensive treatment during the postnatal period, including when breastfeeding
advice and follow-up at transfer to community care.
For postnatal care of women with pre-existing diabetes or who had gestational diabetes, see the recommendations on postnatal care in the NICE guideline on diabetes in pregnancy.
For guidance on assessing the risk and preventing venous thromboembolism in women who have given birth, see the NICE guideline on venous thromboembolism and the Royal College of Obstetricians and Gynaecologists' guideline on reducing the risk of venous thromboembolism during pregnancy and the puerperium.
For guidance on assessing and managing urinary incontinence and pelvic organ prolapse in women who have given birth, see:
the NICE guideline on urinary incontinence and pelvic organ prolapse in women
the NICE guideline on pelvic floor dysfunction.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on assessment and care of the woman .
Full details of the evidence and the committee's discussion are in:
evidence review F: content of postnatal care contacts
evidence review H: tools for the clinical review of women
evidence review I: assessment of secondary postpartum haemorrhage
evidence review E: timing of comprehensive assessment.
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## Postpartum bleeding
Discuss with women what vaginal bleeding to expect after the birth (lochia), and advise women to seek medical advice if:
the vaginal bleeding is sudden or very heavy
the bleeding increases
they pass clots, placental tissue or membranes
they have symptoms of possible infection, such as abdominal, pelvic or perineal pain, fever, shivering, or vaginal bleeding or discharge has an unpleasant smell
they have concerns about vaginal bleeding after the birth.
If a women seeks medical advice about vaginal bleeding after the birth, assess the severity, and be aware of the risk factors for postpartum haemorrhage in the NICE guideline on intrapartum care for healthy women and babies. Also be aware of the following factors, which may worsen the consequences of secondary postpartum haemorrhage:
anaemia
weight of less than 50 kg at the first appointment with the midwife during pregnancy (booking appointment).
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on postpartum bleeding .
Full details of the evidence and the committee's discussion are in evidence review I: assessment of secondary postpartum haemorrhage.
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## Perineal health
At each postnatal contact, as part of assessing perineal wound healing, ask the woman if she has any concerns and ask about:
pain not resolving or worsening
increasing need for pain relief
discharge that has a strong or unpleasant smell
swelling
wound breakdown.
Advise the woman about the importance of good perineal hygiene, including daily showering of the perineum, frequent changing of sanitary pads, and hand washing before and after doing this.
Consider using a validated pain scale to monitor perineal pain.
If the woman or the healthcare professional has concerns about perineal healing or if the woman asks for reassurance, offer or arrange an examination of the perineum by a midwife or a doctor.
If needed, discuss available pain relief options, taking into account if the woman is breastfeeding.
If the perineal wound breaks down or there are ongoing healing concerns, refer the woman urgently to specialist maternity services (to be seen the same day in the case of a perineal wound breakdown).
Be aware that perineal pain that persists or gets worse within the first few weeks after the birth may be associated with symptoms of depression, long-term perineal pain, problems with daily functioning and psychosexual difficulties.
Be aware of the following risk factors for persistent postnatal perineal pain:
episiotomy, or labial or perineal tear
assisted vaginal birth
wound infection or breakdown
birth experienced as traumatic.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on perineal health .
Full details of the evidence and the committee's discussion are in evidence review J: perineal pain and evidence review H: tools for the clinical review of women.
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# Postnatal care of the baby
## Assessment and care of the baby
At each postnatal contact, ask parents if they have any concerns about their baby's general wellbeing, feeding or development. Review the history and assess the baby's health, including physical inspection and observation. If there are any concerns, take appropriate further action.
Be aware that if the baby has not passed meconium within 24 hours of birth, this may indicate a serious disorder and requires medical advice.
Carry out a complete examination of the baby within 72 hours of the birth and at 6 to 8 weeks after the birth (see the Public Health England newborn and infant physical examination screening programme). This should include checking the baby's:
appearance, including colour, breathing, behaviour, activity and posture
head (including fontanelles), face, nose, mouth (including palate), ears, neck and general symmetry of head and facial features
eyes: opacities, red reflex and colour of sclera
neck and clavicles, limbs, hands, feet and digits; assess proportions and symmetry
heart: position, heart rate, rhythm and sounds, murmurs and femoral pulse volume
lungs: respiratory effort, rate and lung sounds
abdomen: assess shape and palpate to identify any organomegaly; check condition of umbilical cord
genitalia and anus: completeness and patency and undescended testes in boys
spine: inspect and palpate bony structures and check integrity of the skin
skin: colour and texture as well as any birthmarks or rashes
central nervous system: tone, behaviour, movements and posture; check newborn reflexes only if concerned
hips: symmetry of the limbs, Barlow and Ortolani's manoeuvres
cry: assess sound.
At 6 to 8 weeks, assess the baby's social smiling and visual fixing and following.
Measure weight and head circumference of babies in the first week and around 8 weeks, and at other times only if there are concerns. Plot the results on the growth chart.
For advice on identifying and managing jaundice, see the NICE guideline on jaundice in newborn babies under 28 days.
If there are concerns about the baby's growth, see the NICE guideline on faltering growth.
Carry out newborn blood spot screening in line with the NHS newborn blood spot screening programme.
Carry out newborn hearing screening in line with the NHS newborn hearing screening programme.
Give parents information about:
how to bathe their baby and care for their skin
care of the umbilical stump
feeding (see recommendations on planning and supporting babies' feeding)
bonding and emotional attachment (see recommendations on promoting emotional attachment)
how to recognise if the baby is unwell, and how to seek help (see recommendations on symptoms and signs of illness in babies)
established guidance on safer sleeping (including recommendations on bed sharing)
maintaining a smoke-free environment for the baby (see also the NICE guideline on tobacco)
vitamin D supplements for babies in line with the NICE guideline on vitamin D supplement use
immunising the baby in line with Public Health England's routine childhood immunisations schedule.
Consider giving parents information about the Baby Check scoring system and how it may help them to decide whether to seek advice from a healthcare professional if they think their baby might be unwell.
Advise parents to seek advice from a healthcare professional if they think their baby is unwell, and to contact emergency services (call 999) if they think their baby is seriously ill.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on assessment and care of the baby .
Full details of the evidence and the committee's discussion are in evidence review F: content of postnatal care contacts and evidence review L2: scoring systems for illness in babies.
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## Bed sharing
Discuss with parents safer practices for bed sharing, including:
making sure the baby sleeps on a firm, flat mattress, lying face up (rather than face down or on their side)
not sleeping on a sofa or chair with the baby
not having pillows or duvets near the baby
not having other children or pets in the bed when sharing a bed with a baby.
Strongly advise parents not to share a bed with their baby if their baby was low birth weight or if either parent:
has had 2 or more units of alcohol
smokes
has taken medicine that causes drowsiness
has used recreational drugs.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on bed sharing .
Full details of the evidence and the committee's discussion are in evidence review M: benefits and harms of bed sharing and evidence review N: co-sleeping risk factors.
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## Promoting emotional attachment
Before and after the birth, discuss the importance of bonding and emotional attachment with parents, and the approaches that can help them to bond with their baby.
Encourage parents to value the time they spend with their baby as a way of promoting emotional attachment, including:
face-to-face interaction
skin-to-skin contact
responding appropriately to the baby's cues.
Discuss with parents the potentially challenging aspects of the postnatal period that may affect bonding and emotional attachment, including:
the woman's physical and emotional recovery from birth
experience of a traumatic birth or birth complications
fatigue and sleep deprivation
feeding concerns
demands of parenthood.
Recognise that additional support in bonding and emotional attachment may be needed by some parents who, for example:
have been through the care system
have experienced adverse childhood events
have experienced a traumatic birth
have complex psychosocial needs.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on promoting emotional attachment .
Full details of the evidence and the committee's discussion are in evidence review O: emotional attachment.
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# Symptoms and signs of illness in babies
Listen carefully to parents' concerns about their baby's health and treat their concerns as an important indicator of possible serious illness in their baby.
Healthcare professionals should consider using the Baby Check scoring system:
to supplement the clinical assessment of babies for possible illness, particularly as part of a remote assessment and
as a communication aid in conversations with parents to help them describe the baby's condition.
Follow the recommendations in the NICE guideline on neonatal infection on:
assessing and managing the risk of early-onset neonatal infection after birth (within 72 hours of the birth)
risk factors for and clinical indicators of possible late-onset neonatal infection (more than 72 hours after the birth).
Be aware that fever may not be present in young babies with a serious infection.
If the baby has a fever, follow the recommendations in the NICE guideline on fever in under 5s.
If there are concerns about the baby's growth, follow the recommendations in the NICE guideline on faltering growth.
Be aware of the possible significance of a change in the baby's behaviour or signs, such as refusing feeds or a change in the level of responsiveness.
Be aware that the presence or absence of individual symptoms or signs may be of limited value in identifying or ruling out serious illness in a young baby.
Recognise the following as 'red flags' for serious illness in young babies:
appearing ill to a healthcare professional
appearing pale, ashen, mottled or blue (cyanosis)
unresponsive or unrousable
having a weak, abnormally high-pitched or continuous cry
abnormal breathing pattern, such as:
grunting respirations
increased respiratory rate (over 60 breaths/minute)
chest indrawing
temperature of 38°C or over or under 36°C
non-blanching rash
bulging fontanelle
neck stiffness
seizures
focal neurological signs
diarrhoea associated with dehydration
frequent forceful (projectile) vomiting
bilious vomiting (green or yellow-green vomit).See the following sections in other NICE guidelines for more information:
fever in under 5s: clinical assessment of children with fever
neonatal infection: assessing and managing the risk of early-onset neonatal infection after birth and risk factors for and clinical indicators of possible late-onset neonatal infection
sepsis: identifying people with suspected sepsis
meningitis (bacterial) and meningococcal septicaemia in under 16s: symptoms, signs and initial assessment
gastroesophageal reflux disease (GORD) in children and young people: diagnosing and investigating GORD
diarrhoea and vomiting caused by gastroenteritis in under 5s: assessing dehydration and shock
urinary tract infection in under 16s: diagnosis.
If a baby is thought to be seriously unwell based on a 'red flag' (see recommendation 1.4.9) or on an overall assessment of their condition, arrange an immediate assessment with an appropriate emergency service. If the baby's condition is immediately life-threatening, dial 999.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on symptoms and signs of illness in babies .
Full details of the evidence and the committee's discussion are in evidence review L1: signs and symptoms of serious illness in babies and evidence review L2: scoring systems for illness in babies.
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# Planning and supporting babies' feeding
## General principles about babies' feeding
When discussing babies' feeding, follow the recommendations in the section on principles of care, and:
acknowledge the parents' emotional, social, financial and environmental concerns about feeding options
be respectful of parents' choices.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on general principles about babies' feeding .
Full details of the evidence and the committee's discussion are in evidence review T: formula feeding information and support.
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## Giving information about breastfeeding
Before and after the birth, discuss breastfeeding and provide information and breastfeeding support (see the section on supporting women to breastfeed). Topics to discuss may include (see also recommendation 1.5.12):
nutritional benefits for the baby
health benefits for both the baby and the woman
how it can have benefits even if only done for a short time
how it can soothe and comfort the baby.
Give information about how the partner can support the woman to breastfeed, including:
the value of their involvement and support
how they can comfort and bond with the baby.
Inform women that vitamin D supplements are recommended for all breastfeeding women (see the NICE guideline on vitamin D).
Inform women and their partners that under the Equality Act 2010, women have the right to breastfeed in 'any public space'.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on giving information about breastfeeding .
Full details of the evidence and the committee's discussion are in:
evidence review P: breastfeeding interventions
evidence review Q: breastfeeding facilitators and barriers
evidence review S: breastfeeding information and support.
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## Role of the healthcare professional supporting breastfeeding
Healthcare professionals caring for women and babies in the postnatal period should know about:
breast milk production
signs of good attachment at the breast
effective milk transfer
how to encourage and support women with common breastfeeding problems
appropriate resources for safe medicine use and prescribing for breastfeeding women.
Encourage the woman to have early skin-to-skin contact with her baby so that breastfeeding can start when the baby and mother are ready.
Those providing breastfeeding support should:
be respectful of women's personal space, cultural influences, preferences and previous experience of infant feeding
balance the woman's preference for privacy to breastfeed and express milk in hospital with the need to carry out routine observations
-btain consent before offering physical assistance with breastfeeding
recognise the emotional impact of breastfeeding
give women the time, reassurance and encouragement they need to gain confidence in breastfeeding.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on the role of the healthcare professional supporting breastfeeding .
Full details of the evidence and the committee's discussion are in evidence review Q: breastfeeding facilitators and barriers and evidence review S: breastfeeding information and support.
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## Supporting women to breastfeed
Give breastfeeding care that is tailored to the woman's individual needs and provides:
face-to-face support
written, digital or telephone information to supplement (but not replace) face-to-face support
continuity of carer
information about what to do and who to contact if she needs additional support
information for partners about breastfeeding and how best to support breastfeeding women, taking into account the woman's preferences about the partner's involvement
information about opportunities for peer support.
Make face-to-face breastfeeding support integral to the standard postnatal contacts for women who breastfeed. Continue this until breastfeeding is established and any problems have been addressed.
Be aware that younger women and women from a low income or disadvantaged background may need more support and encouragement to start and continue breastfeeding, and that continuity of carer is particularly important for these women.
Provide information, advice and reassurance about breastfeeding, so women (and their partners) know what to expect, and when and how to seek help. Topics to discuss include:
how milk is produced, how much is produced in the early stages, and the supply-and-demand nature of breastfeeding
responsive breastfeeding
how often babies typically need to feed and for how long, taking into account individual variation
feeding positions and how to help the baby attach to the breast
signs of effective feeding so the woman knows her baby is getting enough milk (it is not possible to overfeed a breastfed baby; see also recommendation 1.5.14)
expressing breast milk (by hand or with a breast pump) as part of breastfeeding and how it can be useful; safe storage and preparation of expressed breast milk; and the dangers of 'prop' feeding
normal breast changes during pregnancy and after the birth
pain when breastfeeding and when to seek help
breastfeeding complications (for example, mastitis or breast abscess) and when to seek help
strategies to manage fatigue when breastfeeding
supplementary feeding with formula milk that is sometimes, but not commonly, clinically indicated (also see the NICE guideline on faltering growth)
how breastfeeding can affect the woman's body image and identity
that the information given may change as the baby grows
the possibility of relactation after a gap in breastfeeding
safe medicine use when breastfeeding.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on supporting women to breastfeed .
Full details of the evidence and the committee's discussion are in:
evidence review P: breastfeeding interventions
evidence review Q: breastfeeding facilitators and barriers
evidence review S: breastfeeding information and support.
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## Assessing breastfeeding
A practitioner with skills and competencies in breastfeeding support should assess breastfeeding to identify and address any concerns.
As part of the breastfeeding assessment:
ask about:
any concerns the parents have about their baby's feeding
how often and how long the feeds are
rhythmic sucking and audible swallowing
if the baby is content after the feed
if the baby is waking up for feeds
the baby's weight gain or weight loss
the number of wet and dirty nappies
the condition of the woman's breasts and nipples
-bserve a feed within the first 24 hours after the birth, and at least 1 other feed within the first week.
If there are ongoing concerns, consider:
-bserving additional feeds
-ther actions, such as:
adjusting positioning and attachment to the breast
giving expressed milk
referring to additional support such as a lactation consultation or peer support
assessing for tongue‑tie.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on assessing breastfeeding .
Full details of the evidence and the committee's discussion are in evidence review R: tools for predicting breastfeeding difficulties.
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## Formula feeding
Before and after the birth, discuss formula feeding with parents who are considering or who need to formula feed, taking into account that babies may be partially formula fed alongside breastfeeding or expressed breast milk.
Information about formula feeding should include:
the differences between breast milk and formula milk
that first infant formula is the only formula milk that babies need in the first year of life, unless there are specific medical needs
how to sterilise feeding equipment and prepare formula feeds safely, including a practical demonstration if needed
for women who are trying to establish breastfeeding and considering supplementing with formula feeding, the possible effects on breastfeeding success, and how to maintain adequate milk supply while supplementing.
For parents who formula feed:
have a one-to-one discussion about safe formula feeding
provide face-to-face support
provide written, digital or telephone information to supplement (but not replace) face-to-face support.
Face-to-face formula feeding support should include:
advice about responsive bottle feeding and help to recognise feeding cues
-ffering to observe a feed
positions for holding a baby for bottle feeding and the dangers of 'prop' feeding
advice about how to pace bottle feeding and how to recognise signs that a baby has had enough milk (because it is possible to overfeed a formula-fed baby), and advice about ways other than feeding that can comfort and soothe the baby
how to bond with the baby when bottle feeding, through skin-to-skin contact, eye contact and the potential benefit of minimising the number of people regularly feeding the baby.
For parents who are thinking about supplementing breastfeeding with formula or changing from breastfeeding to formula feeding, support them to make an informed decision.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on formula feeding .
Full details of the evidence and the committee's discussion are in evidence review T: formula feeding information and support.
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## Lactation suppression
Discuss lactation suppression with women if breastfeeding is not started or is stopped, breastfeeding is contraindicated for the baby or the woman, or in the event of the death of a baby. Follow the recommendations in the section on principles of care. Topics to discuss include:
how the body produces milk, what happens when milk production stops, and how long it takes for milk production to stop
self-help advice, such as:
avoiding stimulating the breast
wearing a supportive bra
using ice packs
-ver-the-counter pain relief
sparingly expressing milk to ease engorgement
when to seek help
medicines that can be prescribed to suppress lactation
the advantages and disadvantages of the different methods of lactation suppression
the possibility of becoming a breast milk donor (also see the section on screening and selecting donors in the NICE guideline on donor milk banks).
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on lactation suppression .
Full details of the evidence and the committee's discussion are in evidence review K: information for lactation suppression.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
## Bonding and emotional attachment
Bonding is the positive emotional and psychological connection that the parent develops with the baby.
Emotional attachment refers to the relationship between the baby and parent, driven by innate behaviour and which ensures the baby's proximity to the parent and safety. Its development is a complex and dynamic process dependent on sensitive and emotionally attuned parent interactions supporting healthy infant psychological and social development and a secure attachment. Babies form attachments with a variety of caregivers but the first, and usually most significant of these, will be with the mother and/or father.
## Continuity of carer
Better Births, a report by the National Maternity Review, defines continuity of carer as consistency in the midwifery team (between 4 and 8 individuals) that provides care for the woman and her baby throughout pregnancy, labour and the postnatal period. A named midwife coordinates the care and takes responsibility for ensuring the needs of the woman and her baby are met throughout the antenatal, intrapartum and postnatal periods.
For the purpose of this guideline, the definition of continuity of carer in the Better Births report has been adapted to include not just the midwifery team but any healthcare team involved in the care of the woman and her baby, including the health visitor team. It emphasises the importance of effective information transfer between the individuals within the team. Having continuity of carer means that a trusting relationship can be developed between the woman and the healthcare professional(s) who cares for her. For more information, see the NHS Implementing Better Births: continuity of carer.
## Effective feed
In general, effective feeding includes the baby showing readiness to feed, rhythmic sucking, calmness during the feed and satisfactory weight gain. For a first feed at the breast or with a bottle, effective feeding is shown by the baby latching to the breast or drawing the teat into mouth when offered and showing some rhythmic sucking.
## First infant formula
First infant formula or 'first milk' is the type of formula milk that is suitable for a baby from birth to 12 months.
## Low birth weight
A birth weight of less than 2,500 grams regardless of gestational age.
## Nominal group technique
This is a structured method that uses the opinions of individuals within a group to reach a consensus. It involves anonymous voting with an opportunity to provide comments. Options with low agreement are eliminated and options with high agreement are retained. Using the comments that individuals provide, options with medium agreement are revised and then considered in a second round. For more information, see supplement 1 on methods.
## Parental responsibility
See the government definition of parental responsibility.
## Parents
Parents are those with the main responsibility for the care of a baby. This will often be the mother and the father, but many other family arrangements exist, including single parents.
## Partner
Partner refers to the woman's chosen supporter. This could be the baby's father, the woman's partner, a family member or friend, or anyone who the woman feels supported by or wishes to involve.
## Prop feeding
When a baby's feeding bottle is propped against a pillow or other support, rather than the baby and the bottle being held when feeding.
## Responsive feeding
Responsive feeding means feeding in response to the baby's cues. It recognises that feeds are not just for nutrition, but also for love, comfort and reassurance between the baby and mother (or parent in case of bottle feeding). Responsive breastfeeding also involves a mother responding to her own desire to feed for her comfort or convenience. Responsive bottle feeding involves holding the baby close, pacing the feeds and avoiding forcing the baby to finish the feed by recognising signs that the baby has had enough milk, and to reduce the risk of overfeeding. For more information, see the UNICEF Baby Friendly Initiative (BFI) information sheet on responsive feeding.# Recommendations for research
The guideline committee has made the following key recommendations for research.
# Length of postpartum stay and first midwife visit after transfer of care
How does the length of postpartum stay and the timing of the first midwife visit after transfer of care affect unplanned or emergency health contacts for women and babies?
For a short explanation of why the committee made this recommendation for research, see the rationale section on timing of transfer to community care .
Full details of the recommendation for research are in evidence review A: length of postpartum stay.
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See also the rationale section on first midwife visit after transfer of care from the place of birth or after a home birth .
Full details of the recommendation for research are in evidence review C: timing of first postnatal contact by midwife.
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# Timing of first health visitor visit
What is the most effective timing of the first postnatal contact by a health visitor?
For a short explanation of why the committee made this recommendation for research, see the rationale section on first health visitor visit .
Full details of the recommendation for research are in evidence review D: timing of first postnatal contact by health visitor.
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# Clinical tools to assess women's health
What tools for the clinical review of women (including pain scores) are effective during the first 8 weeks after birth?
For a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and care of the woman .
Full details of the recommendation for research are in evidence review H: tools for the clinical review of women.
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# Perineal pain
What characteristics of perineal pain suggest the need for further evaluation?
For a short explanation of why the committee made this recommendation for research, see the rationale section on perineal health .
Full details of the recommendation for research are in evidence review J: perineal pain.
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# Breastfeeding support for parents with twins or triplets
What support with breastfeeding do parents of twins or triplets find helpful?
For a short explanation of why the committee made this recommendation for research, see the rationale section on supporting women to breastfeed .
Full details of the recommendation for research are in evidence review S: breastfeeding information and support.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Principles of care
Recommendations 1.1.1 to 1.1.7
## Why the committee made the recommendations
The committee agreed that one of the key principles of care in the postnatal period is to listen to women and be responsive to their needs, in line with the findings of the Ockenden report on maternity services at the Shrewsbury and Telford hospital NHS trust. The NICE guideline on patient experience in adult NHS services gives comprehensive guidance on individualised and person-centred care.
The committee also agreed that healthcare professionals should be aware of the disproportionate maternal and neonatal mortality rates among women and babies from black, Asian and minority ethnic backgrounds and those living in deprived areas, as highlighted by the 2020 MBRRACE-UK reports on maternal and perinatal mortality. This increased risk of death indicates that closer monitoring and lower thresholds for further care or admission might be needed. Future research could help understand these disparities and what interventions could improve the outcomes.
The committee recognised that the home and family circumstances for women vary, and it is up to the woman who she may want to involve in her postnatal care. The committee also recognised the role of the baby's father or other parents (or whoever has parental responsibility) in the care of the baby.
There was evidence that information given in the postnatal period is often inconsistent, and this was supported by the committee's experience. There was some evidence that information may need to be repeated at different times by different healthcare professionals. The committee agreed that this is good practice given the number of healthcare professionals that new parents are likely to come into contact with. They discussed concerns about the wide range and varied quality of information available from healthcare professionals, the internet and social media.
The evidence showed that healthcare professionals are a trusted source of information, so the committee agreed that it is important for healthcare professionals to provide evidence-based and consistent information throughout the woman's care. It should also take into consideration the individual needs and preferences of the woman. The evidence suggested that it is helpful to deliver information in different formats, for example, face-to-face discussions and printed or digital materials. The NICE guideline on patient experience in adult NHS services gives more information. The committee discussed the importance of allowing sufficient time for discussions.
The NICE guideline on pregnancy and complex social factors provides guidance for the antenatal period for specific groups. The committee agreed that the principles of care that are not specific to the antenatal period can also be applied to the postnatal period for potentially vulnerable groups of women.
## How the recommendations might affect practice
There is some variation in what information is provided, and the recommendations may result in a change in practice for some centres, involving more training for healthcare professionals, and more time in postnatal appointments. The recommendations are expected to have a positive effect on women's experience of the healthcare service by increasing their confidence in the information provided. This may result in parents being more likely to follow the advice given, which may enable them to react more appropriately to difficulties and thereby reduce morbidity and mortality.
Return to recommendations
# Communication between healthcare professionals at transfer of care
Recommendations 1.1.8 and 1.1.9
## Why the committee made the recommendations
The evidence highlighted issues that should be communicated between healthcare professionals at transfer of care, including the woman's history in relation to her pregnancy and birth experience, and any mental health problems or safeguarding issues. Based on this evidence and their knowledge and experience, the committee agreed the information that should be passed on when women transfer between services, so that healthcare professionals do not miss relevant information and the woman does not always have to repeat the same information to different healthcare professionals. What is relevant and the level of detail needed may vary depending on whether the healthcare professional is a GP, midwife or a health visitor.
The committee also emphasised the importance of seamless transfer of care from midwifery to health visitor care so that there is continuous care provision.
## How the recommendations might affect practice
There is variation in practice regarding what information, if any, is transferred between the different teams. The recommendation should lead to clearer guidance, improve relevant transfer of information and improve care for women and babies.
Return to recommendations
# Transfer to community care
Recommendations 1.1.10 to 1.1.13
## Why the committee made the recommendations
Studies looking at varying transfer timings showed that there was no consistent evidence about the best time to transfer the care of women and their babies to community care. Based on their knowledge and experience, the committee agreed that the timing should depend on the health and wellbeing of the woman and the baby. This also applies to the departure of the midwife in the case of a home birth. This will help to safely manage potential complications, prevent readmissions in the immediate postnatal period, and take into account any safeguarding concerns so that the woman and the baby are not discharged to an unsafe environment.
Assessing the woman's bladder function to rule out urinary retention is important because undetected or unmanaged urinary retention can lead to serious long-term consequences such as urinary incontinence.
Not passing meconium (the baby's first bowel movement) within the first 24 hours can be a sign of bowel obstruction, so it is important that parents know to seek advice from a healthcare professional. This might be for example a midwife, a doctor or, if the baby is thought to be seriously unwell, the emergency services.
Observing at least 1 effective feed (regardless of the method of feeding) is important to establish feeding and lower the chance of feeding problems at home and the need for readmission.
The committee also agreed that in order to reassure women that they and their babies are being taken care of, they should be given information about what happens next, what support is available and who to contact in case of concerns. It is also important to highlight the importance of pelvic floor exercises soon after birth to prevent potentially long-term and serious conditions such as incontinence and pelvic organ prolapse.
No evidence on timing of transfer to home care was identified for twins or triplets, but the committee agreed that the same principles apply for multiple births as for singleton births.
Because of the lack of clear evidence, the committee made a recommendation for research on length of postpartum stay to assess how the length of the hospital stay after giving birth affects unplanned or emergency contacts with primary or secondary care.
## How the recommendations might affect practice
There is wide variation in practice in how long women stay in hospital after giving birth. The committee noted that observing a feed before transfer is already current practice in settings that are UNICEF Baby Friendly Initiative (BFI)-accredited, but many providers in England do not have this accreditation. The recommendations should lead to more consistency. If potential problems are prevented or managed early, this could potentially lead to cost savings because of lower reattendance or readmission.
Return to recommendations
# First midwife visit after transfer of care from the place of birth or after a home birth
Recommendation 1.1.14
## Why the committee made the recommendation
There was little evidence and the committee had low confidence in it, so the committee used their knowledge and experience to agree the timing of the first midwife visit. Having the first visit within 36 hours after transfer of care would usually mean that the visit is not left too long, so that any health or support needs can be identified early.
The committee agreed that the first postnatal visit by the midwifery team should be by a midwife (and not, for example, by a maternity support worker), face-to-face and, depending on the woman's circumstances and preferences, in the home. This should enable a comprehensive assessment of the health and support needs of the woman and her baby.
Because of the lack of evidence, the committee made a recommendation for research on the first midwife visit after discharge to assess how the timing of the first midwife visit after the transfer of care affects unplanned or emergency contacts with primary or secondary care.
## How the recommendation might affect practice
The recommendation should reduce variation in practice and improve care for women. The recommendation might affect practice because a midwife should attend the first postnatal visit, and in current practice this might be a maternity support worker or a student midwife instead. However, no significant resource implications are expected.
Return to recommendations
# First health visitor visit
Recommendations 1.1.15 and 1.1.16
## Why the committee made the recommendations
No evidence was found about when the first postnatal health visitor visit should take place, so the committee used their knowledge and experience to agree the timing. The aim is to involve health visitors when they are most needed, and spread the visits evenly throughout the postnatal period.
According to the Department of Health and Social Care's Healthy Child Programme, there should be 2 health visitor visits in the postnatal period. The first visit is often very soon after transfer of care from midwifery care (which usually takes places 10 to 14 days after birth). This creates a gap of several weeks before the second health visitor visit at around 6 to 8 weeks. The first 2 weeks after birth may be overwhelming for some families, with several visits from both the midwifery team and health visitors. Having the first postnatal health visitor visit 1 to 2 weeks after transfer of care from midwifery care will mean that the visits are more evenly spread out.
Although the Healthy Child Programme includes an antenatal visit by the health visitor, the committee agreed that this does not always happen. If this is the case, an additional early postnatal visit by the health visitor to replace the missed antenatal visit could be considered to enable the health visitor to get to know the family and their circumstances early on.
Because of the lack of evidence, the committee made a recommendation for research on the most effective timing of the first postnatal visit by a health visitor.
## How the recommendations might affect practice
There is variation in when the first postnatal health visitor visit takes place. However, 1 of the key performance indicators of the Healthy Child Programme is that the first postnatal health visitor visit takes place between 10 and 14 days after birth, so the recommendation would mean a change in practice. The recommendation aims to reduce variation in practice and improve care for women and their babies. Some additional resources may be needed to organise an additional early postnatal visit by a health visitor in the exceptional circumstance when a mandated antenatal health visitor visit has not taken place; however, the resource impact of this is not considered to be large, and is likely outweighed by the potential benefits.
Return to recommendations
# Assessment and care of the woman
Recommendations 1.2.1 to 1.2.12
## Why the committee made the recommendations
The recommendations were not developed by the usual NICE guideline systematic review process because of the scale and complexity of the topic. Using the nominal group technique to vote on statements about the content of postnatal care contacts, the committee made recommendations through formal consensus because reaching consensus by committee discussion alone would be challenging. The statements were based on a review, including critical appraisal, of existing guidelines and systematic reviews. The committee based the recommendations on these and their knowledge and experience.
The committee agreed that at each postnatal contact, women's general health and wellbeing, including psychological and emotional health, should be assessed and women should be asked if they have any concerns. The committee also agreed the physical health areas that midwives should assess. In order to prevent serious outcomes, women should also be made aware of the signs and symptoms of potentially serious conditions so they can seek help. Women's physical health assessment is not in the remit of the health visitor but when there are concerns, either observed by the healthcare professional or expressed by the woman, all healthcare professionals, including health visitors, should refer or advise self-referral so that the woman can get appropriate assessment and care.
The committee acknowledged that some women may want to talk about their birth experience. In some cases, women might need additional support in coping with their experience.
No evidence was identified on the timing of the comprehensive routine postnatal check. Based on their knowledge and experience, the committee agreed this should ideally happen between 6 and 8 weeks after birth, as is current practice, to coincide with the Public Health England newborn and infant physical examination.
No evidence was identified about which tools are effective in the clinical postnatal review of women. A tool that has been tested and validated in an independent sample assessing postnatal physical and mental health problems could help identify those women who need additional care and support, so the committee made a recommendation for research on clinical tools to assess women's health.
References were made to NICE guidelines on different conditions that may affect women postnatally. A bacterial infection could be transmitted to the baby, so it is important to assess the baby if the mother has suspected or confirmed puerperal sepsis.
## How the recommendations might affect practice
By ensuring that women's physical and psychological health and wellbeing is comprehensively assessed, and any problems are managed appropriately, there may be an increase in referrals if problems are identified. The committee agreed that any referrals would prevent delays in diagnosing and treating problems, and improve care.
Return to recommendations
# Postpartum bleeding
Recommendations 1.2.13 and 1.2.14
## Why the committee made the recommendations
No relevant evidence was identified about how to assess early symptoms and signs of postpartum haemorrhage, so the committee used their knowledge and experience to make the recommendations. Discussing with women what to expect after birth helps women to distinguish between a normal amount of lochia (vaginal discharge containing blood, mucus and uterine tissue) and signs and symptoms of postpartum haemorrhage. Women should be advised to seek medical advice if they observe these signs or symptoms because postpartum haemorrhage can have severe consequences.
The committee agreed that although all women are at risk of secondary postpartum haemorrhage, some factors increase this risk and these should be taken into account when assessing the severity of blood loss. The risk factors for postpartum haemorrhage are listed in the NICE guideline on intrapartum care for healthy women and babies. The committee used their knowledge and experience to list other factors that might worsen the consequences of postpartum bleeding so that appropriate action can be taken.
## How the recommendations might affect practice
It is not routine practice to discuss what blood loss to expect postnatally, so the recommendations will involve a minor change to current practice but will potentially improve outcomes by early identification of secondary postpartum haemorrhage.
Return to recommendations
# Perineal health
Recommendations 1.2.15 to 1.2.22
## Why the committee made the recommendations
Perineal pain and its complications are often overlooked and falsely considered to be part of normal postnatal healing. However, early identification and management of perineal pain may prevent long-term consequences and improve the woman's overall experience of postnatal care. To help healthcare professionals identify women with perineal pain and to prompt appropriate care, healthcare professionals should ask women if they have any perineal concerns.
Practical advice about how to maintain good perineal hygiene can prevent infection or complications. In order to assess changes in the severity of perineal pain over time, a validated pain score might help to give a clearer view. Physical examination of the perineum could help determine the severity or cause of the pain, or whether further action is needed. In some cases, medication might be needed to alleviate the pain.
The committee emphasised that women with perineal wound breakdown should be urgently referred to appropriate maternity services for further management to prevent further complications and potential long-term adverse outcomes.
There was evidence that prolonged perineal pain and severity of pain is associated with depressive symptoms. There was no other relevant evidence about perineal pain, but the committee agreed, based on their knowledge and experience, that it can have negative long-term implications. To help healthcare professionals identify women with persistent or worsening perineal pain and to prompt appropriate care, they should be aware of the factors that can increase the risk of persistent postnatal perineal pain.
Because of the lack of evidence about what characteristics of perineal pain suggest the need for further evaluation, a recommendation for research on perineal pain was made.
## How the recommendations might affect practice
In current practice, some women only receive treatment for perineal complications when the situation has become serious. By ensuring that perineal pain is identified early and treated without delay, then further complications and long-term consequences can be avoided. There may be an increase in referrals to secondary care for women who are usually seen by their GP, but the recommendations should improve care and outcomes.
Return to recommendations
# Assessment and care of the baby
Recommendations 1.3.1 to 1.3.12
## Why the committee made the recommendations
Most of the recommendations in this section were not developed by the usual NICE guideline systematic review process because of the scale and complexity of the topic. Using the nominal group technique to vote on statements about the content of postnatal care contacts, the committee made recommendations through formal consensus because reaching consensus by committee discussion alone would be challenging. The statements were based on a review, including critical appraisal, of existing guidelines and systematic reviews. The committee based the recommendations on these, and their knowledge and experience.
The general wellbeing, feeding and development of the baby should be assessed at every postnatal contact so that any concerns can be identified early. Not passing meconium (the baby's first bowel movement) within the first 24 hours can be a sign of bowel obstruction, so it is important that healthcare professionals engaging with the family in the immediate postnatal period are aware of the need for advice from a doctor.
There was no reason for the committee to change the current recommended assessment criteria that healthcare professionals should use within 72 hours after the birth. The committee agreed that the same criteria could be used in the 6‑ to 8‑week assessment. The recommendation about weight and head circumference measurement is based on guidance from the UK-WHO (World Health Organization) growth charts.
The recommendations refer to other NICE guidelines for guidance on specific clinical situations, and relevant NHS screening programmes.
To help parents, healthcare professionals should also discuss and provide information about how to care for their baby. Established guidance exists on safer sleeping practices, and resources for these are available from, for example, UNICEF, Baby Sleep Information Source (Basis), and the Lullaby Trust.
Baby Check is a scoring system intended to help in the assessment of babies up to 6 months of age, taking into account the presence or absence of various symptoms and signs of illness. It gives an overall score to help in deciding whether the baby may need clinical assessment or care. Although the evidence base for the Baby Check was predominantly in relation to babies attending secondary care, there was evidence that in the community setting, it can identify babies who are likely to be well. Also, the studies included babies ranging from birth to 6 months and were not therefore specifically focused on those in the early weeks of life.
The Lullaby Trust has produced parent-friendly modified versions of the Baby Check scoring system, in the form of a mobile app and a downloadable booklet. Although the modifications are mostly related to the language used, the committee had some concerns because the modified versions have not been validated, and neither has the use of Baby Check by parents, as opposed to healthcare professionals. Finally, the committee noted that the Lullaby Trust's modified versions have adopted current practices regarding temperature measurement (armpit or ear), and this differs from the original Baby Check evaluations, which use rectal temperature.
Although Baby Check cannot therefore provide complete reassurance, the committee agreed that the Baby Check scoring system could be helpful to parents as a 'checklist' of symptoms and signs of possible illness when they are uncertain whether their baby might be unwell and deciding whether to seek advice from a healthcare professional. The committee agreed it would be best for parents to be given information about Baby Check in advance rather than when they are concerned about their baby's wellbeing.
## How the recommendations might affect practice
The recommendations largely reflect current practice. There may be an increase in the use of Baby Check scoring system by parents. It is not known if this would have an impact on parents seeking advice from healthcare professionals, but the impact would not be expected to be large.
Return to recommendations
# Bed sharing
Recommendations 1.3.13 and 1.3.14
## Why the committee made the recommendations
There was evidence of varying quality from multiple studies about the different risk factors associated with sudden unexpected death in infancy when bed sharing (up to 1 year of age). Based on the evidence and their knowledge and experience, the committee agreed the safe bed sharing practices that should be discussed with all parents and the circumstances in which bed sharing with a baby should be strongly advised against. The evidence also showed an association between bed sharing and breastfeeding although there is uncertainty about the causality. Preterm babies are outside the remit of this guideline and are therefore not mentioned in the recommendations; however, the committee were aware of evidence showing an increased risk of sudden unexpected death in infancy when bed sharing with a baby born preterm.
## How the recommendations might affect practice
In current practice, there is confusion and mixed messages from both healthcare professionals and within the community on the best practice for safe sleeping, including advice about never sharing a bed with a baby. These recommendations should lead to clear guidance, reduce variation in practice, and improve care for women and babies.
Return to recommendations
# Promoting emotional attachment
Recommendations 1.3.15 to 1.3.18
## Why the committee made the recommendations
There was limited evidence on how to promote attachment between the mother and baby, and it did not show any specific interventions to be effective, so the recommendations are based on the committee's knowledge and experience. The committee agreed to make the recommendations for parents, not just the mother, because discussing and recognising the issues related to developing emotional attachment are relevant for other parental caregivers as well.
The committee agreed that discussions about emotional attachment should begin antenatally and continue into the postnatal period. The committee highlighted that emotional attachment will usually happen naturally if the primary carer is able to spend quality time with their baby. The value of such quality time is not always recognised as important by the parent(s) when there are so many other demands on parents' time in the postnatal period.
The committee recognised that attachment can also be affected by the woman's wellbeing, recovery from birth and other demands that parenthood brings. Therefore, it is important to discuss these issues with the parents to support them in building a relationship with their baby. It was considered important for the woman's partner (if there is one) to understand the various challenging aspects that the mother might be experiencing in the postnatal period, which might affect bonding and emotional attachment.
Based on their knowledge and experience, the committee highlighted particular groups of parents who may be more vulnerable to difficulties in attachment and may need more support.
## How the recommendations might affect practice
There is variation in practice regarding what women are offered in support relating to emotional attachment. The recommendations should lead to clear guidance, reduce variation in practice and improve care for women.
Return to recommendations
# Symptoms and signs of illness in babies
Recommendations 1.4.1 to 1.4.10
## Why the committee made the recommendations
It is important to identify babies who are seriously ill early so that the condition can be managed and adverse outcomes can be avoided. In the committee's experience, parents' concern about 'something being not quite right' can sometimes be overlooked, but it can be an important sign of serious illness and should be taken seriously.
Baby Check is a scoring system intended to help in the assessment of babies up to 6 months of age, taking into account the presence or absence of various symptoms and signs of illness. It gives an overall score to help in deciding whether the baby may need clinical assessment or care. Based on the evidence in the secondary care setting, its sensitivity to identify those babies who are seriously ill varied. In the community setting, it was found to identify babies who are well suggesting that further assessment is not needed but the evidence regarding its accuracy in identifying seriously ill babies is lacking. Also, the studies in which it was being tested included babies ranging from birth to 6 months and were not therefore specifically focused on those in the early weeks of life as this guideline.
The Lullaby Trust has produced parent-friendly modified versions of the Baby Check scoring system, in the form of a mobile app and a downloadable booklet. Although the modifications are mostly related to the language used, the committee had some concerns because the modified versions have not been validated, and neither has the use of Baby Check by parents, as opposed to healthcare professionals. Finally, the committee noted that the Lullaby Trust's modified versions have adopted current practices regarding temperature measurement (armpit or ear), and this differs from the original Baby Check evaluations, which use rectal temperature.
For these reasons, the committee agreed that Baby Check should not be used in isolation to determine the need for further assessment or care but that it could be a helpful tool when used in addition to clinical judgement. Also, by focusing attention on important symptoms and signs, it could help during a remote assessment as a communication aid between healthcare professionals and parents.
The committee also noted that sometimes the presence of fever in young babies is not recognised as a serious concern. It is particularly important to note changes in the baby's wellbeing and behaviour.
There was evidence that single signs and symptoms are not necessarily useful predictors of serious illness on their own. However, based on various other NICE guidelines, there are some 'red flag' symptoms and signs that indicate a serious illness that needs immediate action.
## How the recommendations might affect practice
The recommendations should reinforce current good practice and improve care for babies. There may be an increase in the use of the Baby Check scoring system as a supplemental tool for healthcare professionals, particularly during remote appointments.
Return to recommendations
# General principles about babies' feeding
Recommendation 1.5.1
## Why the committee made the recommendation
Based on their knowledge and experience, the committee agreed that the choices parents make around feeding are not easy and sometimes their preferred choice might not be an option for them. Evidence among parents who bottle fed their babies showed that they sometimes felt judged by the healthcare professionals about their choices. Therefore, the committee agreed that as a general principle, discussions around feeding should be respectful and acknowledge the various consequences different feeding options may have.
## How the recommendation might affect practice
There is some variation in practice, so the recommendation aims to improve the consistency of support given to parents about feeding their baby.
Return to recommendations
# Giving information about breastfeeding
Recommendations 1.5.2 to 1.5.5
## Why the committee made the recommendations
Based on their knowledge and experience, the committee agreed that discussion and support around breastfeeding should start in the antenatal period so that women are equipped to make decisions about feeding and are prepared to start breastfeeding when the baby is born. The discussions and support should continue in the postnatal period so that any questions and concerns can be addressed and women feel they are being supported.
There was good evidence about women being motivated by the many benefits of breastfeeding, so it is important to share these with the women. It is established knowledge that breastfeeding has nutritional and health benefits for the baby (such as lower rates of infection) and some health benefits for the woman (such as lower risk of breast cancer). There was evidence that women felt they were able to soothe and comfort the baby by breastfeeding.
The committee agreed that it is important to explain that breastfeeding can have benefits even if done for a short period of time. For example, colostrum (the breast milk that is produced in the first few days) is known to have various nutritional and health benefits for the baby.
The committee also agreed that parents should receive information about partners' involvement in supporting breastfeeding. The evidence showed that some women and their families believed that bottle feeding was a way for the baby to bond with their partner or other family members. The committee agreed that partners and family members should be given information about alternative ways to comfort and bond with the baby.
Because breastfeeding women may be at risk of vitamin D deficiency, they should be informed about the NICE recommendation about taking vitamin D supplementation.
There was evidence that some women thought that other people felt that breastfeeding in public is inappropriate or insensitive to other people's feelings, which can be a barrier for breastfeeding in public places. The committee agreed the importance of reassuring women and their partners that under the 2010 Equality Act, women have the right to breastfeed in 'any public space'.
## How the recommendations might affect practice
The recommendations largely reflect current practice and should reinforce good practice across the country.
Return to recommendations
# Role of the healthcare professional supporting breastfeeding
Recommendations 1.5.6 to 1.5.8
## Why the committee made the recommendations
Feeding is an integral part of the postnatal period, so healthcare professionals should have the relevant knowledge to encourage breastfeeding and to support women to establish and continue breastfeeding. The BNF provides useful information on safe medicine use and prescribing for women who are breastfeeding. If needed, further advice is available from an NHS medicines information centre or other specialist sources.
The World Health Organization (WHO) recommends that breastfeeding is started early in order to facilitate establishment of breastfeeding, and the committee agreed that healthcare professionals caring for women and babies in the immediate postnatal period should encourage early skin-to-skin contact to help start breastfeeding when the baby and the mother feel ready.
The committee agreed that healthcare professionals should be sensitive to the individual preferences, experiences and values of the woman when supporting her with breastfeeding. There was evidence that after birth, women value having privacy in hospital, and a lack of privacy can be a barrier to breastfeeding and expressing breast milk. However, the committee noted that healthcare professionals also need to be able to carry out clinical observations of women easily, so recommended that these needs be balanced against each other.
The evidence also showed that varying experiences with breastfeeding can have an impact on the woman's emotional wellbeing, and women often need reassurance and encouragement to gain confidence.
## How the recommendations might affect practice
In the committee's experience, some healthcare professionals caring for women and babies during the postnatal period may not have adequate knowledge to support women with breastfeeding and might need more training. The recommendations should reinforce best clinical practice and lead to better consistency of care.
Return to recommendations
# Supporting women to breastfeed
Recommendations 1.5.9 to 1.5.12
## Why the committee made the recommendations
There was evidence that women value breastfeeding care that provides individualised support and continuity of carer, and feel that 'remote' support (such as online or telephone support) can be a helpful addition but should not replace face-to-face support.
The evidence also showed that partners often feel that they lack knowledge and understanding of breastfeeding, and want to know how they can best support breastfeeding mothers.
There was evidence that women find peer support valuable. Through peer support, women can share their experiences and gain information and social contacts, which can provide ongoing support.
There was no evidence that extra interventions increase breastfeeding rates so the committee agreed that breastfeeding support should be an integral part of standard postnatal care contacts.
There was some evidence that younger women may have additional barriers to breastfeeding, such as feeling alone in the maternity unit, the feeling of needing to 'carry on with life' and therefore choosing to formula feed, and lack of peer support. Evidence also suggested that additional support may be beneficial for improving the rate of breastfeeding among women from low income or socially disadvantaged backgrounds.
The evidence showed that women value support and practical information about breastfeeding, as well as information about the underlying physiology of breastfeeding. This will help them to recognise what is or is not normal, and when to seek help. The evidence also showed that some common features of breastfeeding, such as sore nipples, can discourage women if they do not know in advance what to expect.
There was no evidence about breastfeeding support for parents of twins or triplets, so the committee made a recommendation for research.
## How the recommendations might affect practice
There is significant variation in the provision of practical and professional breastfeeding support, so the recommendations will support best practice in some settings and improve practice in other settings. They will reduce variation in practice and improve care for women and babies. Providing continuity of carer may have an impact on how services are organised, but no significant resource impact is expected.
Return to recommendations
# Assessing breastfeeding
Recommendations 1.5.13 to 1.5.15
## Why the committee made the recommendations
Assessing breastfeeding is an important part of postnatal contacts. None of the clinical tools identified in the evidence review were useful in identifying women who would not be breastfeeding (or exclusively breastfeeding) at follow up, which was considered an indication of breastfeeding difficulties, so the committee did not recommend any tools. The committee used their knowledge and experience to make the recommendations, in line with the principles in the UNICEF Baby Friendly Initiative (BFI) breastfeeding assessment tool, including asking the parents about any concerns and about indications of successful breastfeeding.
In addition, observing a feed twice in the first week can help establish good breastfeeding practice. Additional observations or interventions may be needed if there are ongoing concerns.
## How the recommendations might affect practice
In current practice, observing a full feed in the first week might not always happen, so this may mean a change in practice and may have some impact on time needed at the postnatal contacts. The recommendations are based on the UNICEF BFI breastfeeding assessment tool, which is already widely used in practice. In places where it is not already used, the committee were aware that work is underway to reach that standard. The recommendations will improve and standardise practice.
Return to recommendations
# Formula feeding
Recommendations 1.5.16 to 1.5.20
## Why the committee made the recommendations
The committee recognised that babies can be formula fed in combination with breastmilk or they can be fed with formula milk only. There was good evidence about what information and support parents who formula feed find helpful, so the committee used the evidence together with their knowledge and experience to make the recommendations. Common themes in the evidence were the lack of impartial information about formula feeding, women feeling that they were not supported in their feeding choices, and the emotional impact that feeding choices can have on parents. The committee agreed that, as for women who breastfeed, women who formula feed should be supported regardless of their feeding choices. The recommendations reflect the key features of formula feeding support and the information that should be given to women and their families if they are formula feeding or are considering to formula feed and who need to formula feed because of a medical or other reason.
The evidence showed that women value face-to-face feeding support but also feel that additional information to support feeding can be helpful. The evidence showed that women who are formula feeding feel that they are not given the information or support they need, for example, about how to interpret and respond to the baby's behaviours and cues, and how to formula feed safely. Based on the committee's experience, it is important to give information about how to hold the baby and how feeding can be used as an opportunity to bond with the baby, and also advise parents against using a 'propped up' bottle during a feed because it can be harmful for the baby.
The evidence also showed that women were unaware of the impact introducing formula feeding could have on breastfeeding and felt unsupported by healthcare professionals when considering this. Therefore, the committee agreed it was important that women were supported to make an informed, guilt-free decision by providing balanced and evidence-based information.
## How the recommendations might affect practice
The committee noted that there is significant variation in practice in providing formula feeding support, so the recommendations will support best practice in some settings and improve practice in other settings. Overall, they will improve consistency.
Return to recommendations
# Lactation suppression
Recommendation 1.5.21
## Why the committee made the recommendation
No evidence was identified on the information and support that should be given to women about lactation suppression. The committee discussed when discussions about lactation suppression should happen and what should be discussed, and used their knowledge and experience to agree the recommendation. The committee agreed that discussions should be sensitive and individualised according to the woman's situation. Practical advice about how to ease the process of milk drying up can be helpful for women, and in some cases, medicine to suppress lactation might also be appropriate to make the process quicker, although for most this is not needed.
Donating breast milk to a local breast milk bank, depending on the local services, could be valuable to some women who cannot breastfeed their own baby.
## How the recommendation might affect practice
The recommendation largely reflects current practice and should reinforce best practice. To ensure that women understand the information they are given, and that information is being provided at the most appropriate time, some extra time from healthcare professionals may be needed.
Return to recommendations# Context
Approximately 700,000 women give birth in England and Wales each year. For women, their partners and their babies, this is a major life event that means considerable emotional and physical adjustment. It applies to all births but is perhaps most marked for those having their first child. Healthcare professionals have the responsibility to help families adjust to their new life, but at the same time they have to be able to spot and care for the families where complications arise.
Postnatal care has for long been regarded as a 'Cinderella service' where in comparison with some other European countries, provision is scanty and inadequate. This approach risks missing an opportunity to have a profoundly beneficial effect on the lives of the babies and their families, now and in the future. In a National Childbirth Trust (NCT) survey: left to your own devices – the postnatal care experiences of 1,260 first-time mothers, 1 in 8 women were highly critical of their postnatal care. Their feedback reflects fragmentation of care, poor planning and communication between healthcare professionals, and insufficient advice about emotional recovery. Furthermore, women continue to report receiving insufficient or inconsistent information on baby's feeding, particularly after giving birth to their first baby.
This guideline addresses the organisation and delivery of postnatal care, including the relationship between the different agencies that share the responsibility for postnatal care; assessment and health of women; assessment and health of babies; how to help parents form strong relationships with their babies; and babies' feeding. It specifically does not cover issues covered by other NICE guidelines, in particular problems of mental health, preterm birth or specialist care (care beyond routine postnatal care), but refers to other NICE guidelines, where appropriate.
This guideline covers the postnatal period up to 8 weeks after birth. However, the sections on babies' feeding and emotional attachment also address the antenatal period because discussion around these is essential already during pregnancy. The postnatal period of course does not end at 8 weeks. A time point of 8 weeks was agreed in order to focus the guideline on the most critical early weeks after birth. The remit for some of the topics in this guideline was to address the needs of families giving birth to twins and triplets in addition to single babies. The evidence specific to twins and triplets was lacking and the consensus was that healthcare professionals and families dealing with twins or triplet births should use the recommendations of the guideline within the constraints of the changed circumstances of having to care for more than 1 child.
The committee were aware of the higher postnatal mortality rates among women of black, Asian and minority ethnic origin and women living in deprived areas reported in the MBRRACE-UK report: saving lives, improving mothers' care (2020). Black women in particular had an over four‑fold increase in maternal mortality rates compared with white women. The MBRRACE-UK report: perinatal mortality surveillance report (2020) also highlights the higher neonatal mortality rates for babies of black and Asian ethnicity and babies born to mothers living in deprived areas. It is important that clinicians are aware of these inequalities in clinical practice.
This guideline was written with the hope that healthcare professionals can use it to provide consistent and high-quality care, while taking into consideration each family's individual situation and needs, in order to reduce morbidity and mortality and to support families in this new phase.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Parents and carers have the right to be involved in planning and making decisions about their baby's health and care, and to be given information and support to enable them to do this, as set out in the NHS Constitution and summarised in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nPlease note that the Royal College of Obstetricians and Gynaecologists has produced guidance on COVID-19 infection and pregnancy for all midwifery and obstetric services.\n\nThis guideline uses the term 'woman' or 'mother' and includes all people who have given birth, even if they may not identify as women or mothers. 'Woman' is generally used but in some instances, 'mother' is used when referring to her in relation to her baby.\n\nThis guideline uses the term 'partner' to refer to the woman's chosen supporter. This could be the baby's father, the woman's partner, a family member or friend, or anyone who the woman feels supported by or wishes to involve. The term 'parents' refers to those with the main responsibility for the care of a baby. This will often be the mother and the father, but many other family arrangements exist, including single parents.\n\n# Organisation and delivery of postnatal care\n\n## Principles of care\n\nWhen caring for a woman who has recently given birth, listen to her and be responsive to her needs and preferences. Also see the NICE guideline on patient experience in adult NHS services.\n\nBe aware that the 2020\xa0MBRRACE-UK reports on maternal and perinatal mortality showed that women and babies from some minority ethnic backgrounds and those who live in deprived areas have an increased risk of death and may need closer monitoring. The reports showed that:\n\ncompared with white women (8\xa0per\xa0100,000), the risk of maternal death during pregnancy and up to 6\xa0weeks after birth is:\n\n\n\ntimes higher in black women (34\xa0per\xa0100,000)\n\ntimes higher in mixed ethnicity women (25\xa0per\xa0100,000)\n\ntimes higher in Asian women (15\xa0per\xa0100,000; does not include Chinese women)\n\n\n\nthe neonatal mortality rate is around 50% higher in black and Asian babies compared with white babies (17\xa0compared with 25\xa0per\xa010,000)\n\nwomen living in the most deprived areas are more than 2.5\xa0times more likely to die compared with women living in the least deprived areas (6\xa0compared with 15\xa0per\xa0100,000)\n\nthe neonatal mortality rate increases according to the level of deprivation in the area the mother lives in, with almost twice as many babies dying in the most deprived areas compared with the least deprived areas (12\xa0compared with 22\xa0per\xa010,000).\n\nA woman may be supported by her partner in the postnatal period. Involve them according to the woman's wishes.\n\nWhen caring for a baby, remember that those with parental responsibility have the right be involved in the baby's care, if they choose.\n\nWhen giving information about postnatal care, use clear language and tailor the timing, content and delivery of information to the woman's needs and preferences. Information should support shared decision making and be:\n\nprovided face-to-face and supplemented by virtual discussions and written formats, for example, digital, printed, braille or Easy Read\n\noffered throughout the woman's care\n\nindividualised and sensitive\n\nsupportive and respectful\n\nevidence based and consistent\n\ntranslated by an appropriate interpreter to overcome language barriers.For more guidance on communication, providing information (including different formats and languages) and shared decision making, see the NICE guidelines on patient experience in adult NHS services and shared decision making, and the NHS Accessible Information Standard.\n\nCheck that the woman understands the information she has been given, and how it relates to her. Provide regular opportunities for her to ask questions, and set aside enough time to discuss any concerns.\n\nFollow the principles in the NICE guideline on pregnancy and complex social factors for women who may need additional support, for example:\n\nwomen who misuse substances\n\nrecent migrants, asylum seekers or refugees, or women who have difficulty reading or speaking English\n\nyoung women aged under\xa020\n\nwomen who experience domestic abuse.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on principles of care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: provision of information about the postnatal health of women.\n\nLoading. Please wait.\n\n## Communication between healthcare professionals at transfer of care\n\nEnsure that there is effective and prompt communication between healthcare professionals when women transfer between services, for example, from secondary to primary care, and from midwifery to health visitor care. This should include sharing relevant information about:\n\nthe pregnancy, birth, postnatal period and any complications\n\nthe plan of ongoing care, including any condition that needs long-term management\n\nproblems related to previous pregnancies that may be relevant to current care\n\nprevious or current mental health concerns\n\nfemale genital mutilation (mother or previous child)\n\nwho has parental responsibility for the baby, if known\n\nthe woman's next of kin\n\nsafeguarding issues (also see the NICE guideline on domestic violence and abuse and the NICE guideline on child abuse and neglect)\n\nconcerns about the woman's health and care, raised by her, her partner or a healthcare professional\n\nconcerns about the baby's health and care, raised by the parents or a healthcare professional\n\nthe baby's feeding.\n\nMidwifery services should ensure that:\n\nthe transfer of care from midwife to health visitor is clearly communicated between healthcare professionals and\n\nthe woman or the parents are informed about the transfer of care from midwife to health visitor.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on communication between healthcare professionals at transfer of care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: information transfer.\n\nLoading. Please wait.\n\n## Transfer to community care\n\nBefore transfer from the maternity unit to community care, or before the midwife leaves after a home birth:\n\nassess the woman's health (see recommendations 1.2.2 and\xa01.2.3)\n\nassess the woman's bladder function by measuring the volume of the first void after giving birth\n\nassess the baby's health (including physical inspection and observation)\n\nif the baby has not passed meconium, advise the parents that if the baby does not do so within 24\xa0hours of birth, they should seek advice from a healthcare professional (also see recommendation 1.3.12)\n\nmake sure there is a plan for feeding the baby, which should include observing at least 1\xa0effective feed.\n\nBefore transfer from the maternity unit to community care, discuss the timing of transfer to community care with the woman, and ask her about her needs, preferences and support available.\n\nWhen deciding on the timing of the transfer to community care, take into account the woman's preferences, the factors in recommendations 1.1.10 and 1.1.11 and any concerns, including any safeguarding issues (also see the NICE guideline on domestic violence and abuse).\n\nBefore transfer from the maternity unit to community care, or before the midwife leaves after a home birth, give women information about:\n\nthe postnatal period and what to expect\n\nthe importance of pelvic floor exercises (see the NICE guideline on pelvic floor dysfunction)\n\nwhat support is available (statutory and voluntary services)\n\nwho to contact if any concerns arise at different stages.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on transfer to community care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: length of postpartum stay.\n\nLoading. Please wait.\n\n## First midwife visit after transfer of care from the place of birth or after a home birth\n\nEnsure that the first postnatal visit by a midwife takes place within 36\xa0hours after transfer of care from the place of birth or after a home birth. The visit should be face-to-face and usually at the woman's home, depending on her circumstances and preferences.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on first midwife visit after transfer of care from the place of birth or after a home birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: timing of first postnatal contact by midwife.\n\nLoading. Please wait.\n\n## First health visitor visit\n\nConsider arranging the first postnatal health visitor home visit to take place between 7\xa0and 14\xa0days after transfer of care from midwifery care so that the timing of postnatal contacts is evenly spread out.\n\nIf a woman did not receive an antenatal health visitor visit, consider arranging an additional early postnatal health visitor visit.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on first health visitor visit\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: timing of first postnatal contact by health visitor.\n\nLoading. Please wait.\n\n# Postnatal care of the woman\n\n## Assessment and care of the woman\n\nAt each postnatal contact, ask the woman about her general health and whether she has any concerns, and assess her general wellbeing. Discuss topics that may be affecting her daily life, and provide information, reassurance and further care as appropriate. Topics to discuss may include:\n\nthe postnatal period and what to expect\n\nsymptoms and signs of potential postnatal mental health problems and how to seek help\n\nsymptoms and signs of potential postnatal physical problems and how to seek help\n\nthe importance of pelvic floor exercises, how to do them and when to seek help (see the NICE guideline on pelvic floor dysfunction)\n\nfatigue\n\nfactors such as nutrition and diet, physical activity, smoking, alcohol consumption and recreational drug use (also see the NICE guidelines on maternal and child nutrition, weight management before, during and after pregnancy, tobacco and the UK Chief Medical Officer's physical activity guidelines for women after birth)\n\ncontraception (see the Faculty of Sexual & Reproductive Healthcare (FSRH) guideline on contraception after pregnancy)\n\nsexual intercourse\n\nsafeguarding concerns, including domestic abuse (see the NICE guideline on domestic violence and abuse and the NICE guideline on child abuse and neglect).\n\nAt each postnatal contact, assess the woman's psychological and emotional wellbeing. Follow the recommendations on recognising mental health problems in pregnancy and the postnatal period and referral in the NICE guideline on antenatal and postnatal mental health. If there are concerns, arrange for further assessment and follow\xa0up.\n\nAt each postnatal contact by a midwife, assess the woman's physical health, including the following:\n\nfor all women:\n\n\n\nsymptoms and signs of infection\n\npain\n\nvaginal discharge and bleeding (see the section on postpartum bleeding)\n\nbladder function\n\nbowel function\n\nnipple and breast discomfort and symptoms of inflammation\n\nsymptoms and signs of thromboembolism\n\nsymptoms and signs of anaemia\n\nsymptoms and signs of pre‑eclampsia\n\n\n\nfor women who have had a vaginal birth:\n\n\n\nperineal healing (see the section on perineal health)\n\n\n\nfor women who have had a caesarean section (also see the NICE guideline on caesarean birth):\n\n\n\nwound healing\n\nsymptoms of wound infection.\n\n\n\nAt the first postnatal midwife contact, inform the woman that the following are symptoms or signs of potentially serious conditions, and she should seek medical advice without delay if any of these occur:\n\nsudden or very heavy vaginal bleeding, or persistent or increased vaginal bleeding, which could indicate retained placental tissue or endometritis\n\nabdominal, pelvic or perineal pain, fever, shivering, or vaginal discharge with an unpleasant smell, which could indicate infection\n\nleg swelling and tenderness, or shortness of breath, which could indicate venous thromboembolism\n\nchest pain, which could indicate venous thromboembolism or cardiac problems\n\npersistent or severe headache, which could indicate hypertension, pre‑eclampsia, postdural-puncture headache, migraine, intracranial pathology or infection\n\nworsening reddening and swelling of breasts persisting for more than 24\xa0hours despite self-management, which could indicate mastitis\n\nsymptoms or signs of potentially serious conditions that do not respond to treatment.\n\nAt each postnatal contact, give the woman the opportunity to talk about her birth experience, and provide information about relevant support and birth reflection services, if appropriate. See the section on traumatic birth, stillbirth and miscarriage in the NICE guideline on antenatal and postnatal mental health and the NICE guideline on post-traumatic stress disorder.\n\nAll healthcare professionals should ensure appropriate referral if there are concerns about the woman's health.\n\nAt 6\xa0to\xa08\xa0weeks after the birth, a GP should:\n\ncarry out an assessment including the points in recommendations 1.2.1 to 1.2.5 and taking into account the time since the birth\n\nrespond to any concerns, which may include referral to specialist services in either secondary care or other healthcare services such as physiotherapy.\n\nFor guidance on care for women with symptoms or signs of sepsis, see the NICE guideline on sepsis. If the woman has confirmed or suspected puerperal sepsis, assess the baby for symptoms or signs of infection.\n\nFor postnatal care of women who have had hypertension or pre‑eclampsia in pregnancy, see the NICE guideline on hypertension in pregnancy, in particular:\n\npostnatal investigation, monitoring and treatment:\n\n\n\nfor women with chronic hypertension\n\nfor women with gestational hypertension\n\nfor women with pre-eclampsia\n\n\n\nantihypertensive treatment during the postnatal period, including when breastfeeding\n\nadvice and follow-up at transfer to community care.\n\nFor postnatal care of women with pre-existing diabetes or who had gestational diabetes, see the recommendations on postnatal care in the NICE guideline on diabetes in pregnancy.\n\nFor guidance on assessing the risk and preventing venous thromboembolism in women who have given birth, see the NICE guideline on venous thromboembolism and the Royal College of Obstetricians and Gynaecologists' guideline on reducing the risk of venous thromboembolism during pregnancy and the puerperium.\n\nFor guidance on assessing and managing urinary incontinence and pelvic organ prolapse in women who have given birth, see:\n\nthe NICE guideline on urinary incontinence and pelvic organ prolapse in women\n\nthe NICE guideline on pelvic floor dysfunction.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on assessment and care of the woman\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0F: content of postnatal care contacts\n\nevidence review\xa0H: tools for the clinical review of women\n\nevidence review\xa0I: assessment of secondary postpartum haemorrhage\n\nevidence review\xa0E: timing of comprehensive assessment.\n\nLoading. Please wait.\n\n## Postpartum bleeding\n\nDiscuss with women what vaginal bleeding to expect after the birth (lochia), and advise women to seek medical advice if:\n\nthe vaginal bleeding is sudden or very heavy\n\nthe bleeding increases\n\nthey pass clots, placental tissue or membranes\n\nthey have symptoms of possible infection, such as abdominal, pelvic or perineal pain, fever, shivering, or vaginal bleeding or discharge has an unpleasant smell\n\nthey have concerns about vaginal bleeding after the birth.\n\nIf a women seeks medical advice about vaginal bleeding after the birth, assess the severity, and be aware of the risk factors for postpartum haemorrhage in the NICE guideline on intrapartum care for healthy women and babies. Also be aware of the following factors, which may worsen the consequences of secondary postpartum haemorrhage:\n\nanaemia\n\nweight of less than 50\xa0kg at the first appointment with the midwife during pregnancy (booking appointment).\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on postpartum bleeding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: assessment of secondary postpartum haemorrhage.\n\nLoading. Please wait.\n\n## Perineal health\n\nAt each postnatal contact, as part of assessing perineal wound healing, ask the woman if she has any concerns and ask about:\n\npain not resolving or worsening\n\nincreasing need for pain relief\n\ndischarge that has a strong or unpleasant smell\n\nswelling\n\nwound breakdown.\n\nAdvise the woman about the importance of good perineal hygiene, including daily showering of the perineum, frequent changing of sanitary pads, and hand washing before and after doing this.\n\nConsider using a validated pain scale to monitor perineal pain.\n\nIf the woman or the healthcare professional has concerns about perineal healing or if the woman asks for reassurance, offer or arrange an examination of the perineum by a midwife or a doctor.\n\nIf needed, discuss available pain relief options, taking into account if the woman is breastfeeding.\n\nIf the perineal wound breaks down or there are ongoing healing concerns, refer the woman urgently to specialist maternity services (to be seen the same day in the case of a perineal wound breakdown).\n\nBe aware that perineal pain that persists or gets worse within the first few weeks after the birth may be associated with symptoms of depression, long-term perineal pain, problems with daily functioning and psychosexual difficulties.\n\nBe aware of the following risk factors for persistent postnatal perineal pain:\n\nepisiotomy, or labial or perineal tear\n\nassisted vaginal birth\n\nwound infection or breakdown\n\nbirth experienced as traumatic.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on perineal health\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: perineal pain and evidence review\xa0H: tools for the clinical review of women.\n\nLoading. Please wait.\n\n# Postnatal care of the baby\n\n## Assessment and care of the baby\n\nAt each postnatal contact, ask parents if they have any concerns about their baby's general wellbeing, feeding or development. Review the history and assess the baby's health, including physical inspection and observation. If there are any concerns, take appropriate further action.\n\nBe aware that if the baby has not passed meconium within 24\xa0hours of birth, this may indicate a serious disorder and requires medical advice.\n\nCarry out a complete examination of the baby within 72\xa0hours of the birth and at 6\xa0to\xa08\xa0weeks after the birth (see the Public Health England newborn and infant physical examination [NIPE] screening programme). This should include checking the baby's:\n\nappearance, including colour, breathing, behaviour, activity and posture\n\nhead (including fontanelles), face, nose, mouth (including palate), ears, neck and general symmetry of head and facial features\n\neyes: opacities, red reflex and colour of sclera\n\nneck and clavicles, limbs, hands, feet and digits; assess proportions and symmetry\n\nheart: position, heart rate, rhythm and sounds, murmurs and femoral pulse volume\n\nlungs: respiratory effort, rate and lung sounds\n\nabdomen: assess shape and palpate to identify any organomegaly; check condition of umbilical cord\n\ngenitalia and anus: completeness and patency and undescended testes in boys\n\nspine: inspect and palpate bony structures and check integrity of the skin\n\nskin: colour and texture as well as any birthmarks or rashes\n\ncentral nervous system: tone, behaviour, movements and posture; check newborn reflexes only if concerned\n\nhips: symmetry of the limbs, Barlow and Ortolani's manoeuvres\n\ncry: assess sound.\n\nAt 6\xa0to\xa08\xa0weeks, assess the baby's social smiling and visual fixing and following.\n\nMeasure weight and head circumference of babies in the first week and around 8\xa0weeks, and at other times only if there are concerns. Plot the results on the growth chart.\n\nFor advice on identifying and managing jaundice, see the NICE guideline on jaundice in newborn babies under 28\xa0days.\n\nIf there are concerns about the baby's growth, see the NICE guideline on faltering growth.\n\nCarry out newborn blood spot screening in line with the NHS newborn blood spot screening programme.\n\nCarry out newborn hearing screening in line with the NHS newborn hearing screening programme.\n\nGive parents information about:\n\nhow to bathe their baby and care for their skin\n\ncare of the umbilical stump\n\nfeeding (see recommendations on planning and supporting babies' feeding)\n\nbonding and emotional attachment (see recommendations on promoting emotional attachment)\n\nhow to recognise if the baby is unwell, and how to seek help (see recommendations on symptoms and signs of illness in babies)\n\nestablished guidance on safer sleeping (including recommendations on bed sharing)\n\nmaintaining a smoke-free environment for the baby (see also the NICE guideline on tobacco)\n\nvitamin D supplements for babies in line with the NICE guideline on vitamin\xa0D supplement use\n\nimmunising the baby in line with Public Health England's routine childhood immunisations schedule.\n\nConsider giving parents information about the Baby Check scoring system and how it may help them to decide whether to seek advice from a healthcare professional if they think their baby might be unwell.\n\nAdvise parents to seek advice from a healthcare professional if they think their baby is unwell, and to contact emergency services (call\xa0999) if they think their baby is seriously ill.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on assessment and care of the baby\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: content of postnatal care contacts and evidence review\xa0L2: scoring systems for illness in babies.\n\nLoading. Please wait.\n\n## Bed sharing\n\nDiscuss with parents safer practices for bed sharing, including:\n\nmaking sure the baby sleeps on a firm, flat mattress, lying face up (rather than face down or on their side)\n\nnot sleeping on a sofa or chair with the baby\n\nnot having pillows or duvets near the baby\n\nnot having other children or pets in the bed when sharing a bed with a baby.\n\nStrongly advise parents not to share a bed with their baby if their baby was low birth weight or if either parent:\n\nhas had 2\xa0or more units of alcohol\n\nsmokes\n\nhas taken medicine that causes drowsiness\n\nhas used recreational drugs.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on bed sharing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: benefits and harms of bed sharing and evidence review\xa0N: co-sleeping risk factors.\n\nLoading. Please wait.\n\n## Promoting emotional attachment\n\nBefore and after the birth, discuss the importance of bonding and emotional attachment with parents, and the approaches that can help them to bond with their baby.\n\nEncourage parents to value the time they spend with their baby as a way of promoting emotional attachment, including:\n\nface-to-face interaction\n\nskin-to-skin contact\n\nresponding appropriately to the baby's cues.\n\nDiscuss with parents the potentially challenging aspects of the postnatal period that may affect bonding and emotional attachment, including:\n\nthe woman's physical and emotional recovery from birth\n\nexperience of a traumatic birth or birth complications\n\nfatigue and sleep deprivation\n\nfeeding concerns\n\ndemands of parenthood.\n\nRecognise that additional support in bonding and emotional attachment may be needed by some parents who, for example:\n\nhave been through the care system\n\nhave experienced adverse childhood events\n\nhave experienced a traumatic birth\n\nhave complex psychosocial needs.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on promoting emotional attachment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: emotional attachment.\n\nLoading. Please wait.\n\n# Symptoms and signs of illness in babies\n\nListen carefully to parents' concerns about their baby's health and treat their concerns as an important indicator of possible serious illness in their baby.\n\nHealthcare professionals should consider using the Baby Check scoring system:\n\nto supplement the clinical assessment of babies for possible illness, particularly as part of a remote assessment and\n\nas a communication aid in conversations with parents to help them describe the baby's condition.\n\nFollow the recommendations in the NICE guideline on neonatal infection on:\n\nassessing and managing the risk of early-onset neonatal infection after birth (within 72\xa0hours of the birth)\n\nrisk factors for and clinical indicators of possible late-onset neonatal infection (more than 72\xa0hours after the birth).\n\nBe aware that fever may not be present in young babies with a serious infection.\n\nIf the baby has a fever, follow the recommendations in the NICE guideline on fever in under\xa05s.\n\nIf there are concerns about the baby's growth, follow the recommendations in the NICE guideline on faltering growth.\n\nBe aware of the possible significance of a change in the baby's behaviour or signs, such as refusing feeds or a change in the level of responsiveness.\n\nBe aware that the presence or absence of individual symptoms or signs may be of limited value in identifying or ruling out serious illness in a young baby.\n\nRecognise the following as 'red flags' for serious illness in young babies:\n\nappearing ill to a healthcare professional\n\nappearing pale, ashen, mottled or blue (cyanosis)\n\nunresponsive or unrousable\n\nhaving a weak, abnormally high-pitched or continuous cry\n\nabnormal breathing pattern, such as:\n\n\n\ngrunting respirations\n\nincreased respiratory rate (over 60\xa0breaths/minute)\n\nchest indrawing\n\n\n\ntemperature of 38°C or over or under\xa036°C\n\nnon-blanching rash\n\nbulging fontanelle\n\nneck stiffness\n\nseizures\n\nfocal neurological signs\n\ndiarrhoea associated with dehydration\n\nfrequent forceful (projectile) vomiting\n\nbilious vomiting (green or yellow-green vomit).See the following sections in other NICE guidelines for more information:\n\nfever in under\xa05s: clinical assessment of children with fever\n\nneonatal infection: assessing and managing the risk of early-onset neonatal infection after birth and risk factors for and clinical indicators of possible late-onset neonatal infection\n\nsepsis: identifying people with suspected sepsis\n\nmeningitis (bacterial) and meningococcal septicaemia in under\xa016s: symptoms, signs and initial assessment\n\ngastroesophageal reflux disease (GORD) in children and young people: diagnosing and investigating GORD\n\ndiarrhoea and vomiting caused by gastroenteritis in under\xa05s: assessing dehydration and shock\n\nurinary tract infection in under\xa016s: diagnosis.\n\nIf a baby is thought to be seriously unwell based on a 'red flag' (see recommendation 1.4.9) or on an overall assessment of their condition, arrange an immediate assessment with an appropriate emergency service. If the baby's condition is immediately life-threatening, dial\xa0999.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on symptoms and signs of illness in babies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L1: signs and symptoms of serious illness in babies and evidence review\xa0L2: scoring systems for illness in babies.\n\nLoading. Please wait.\n\n# Planning and supporting babies' feeding\n\n## General principles about babies' feeding\n\nWhen discussing babies' feeding, follow the recommendations in the section on principles of care, and:\n\nacknowledge the parents' emotional, social, financial and environmental concerns about feeding options\n\nbe respectful of parents' choices.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on general principles about babies' feeding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0T: formula feeding information and support.\n\nLoading. Please wait.\n\n## Giving information about breastfeeding\n\nBefore and after the birth, discuss breastfeeding and provide information and breastfeeding support (see the section on supporting women to breastfeed). Topics to discuss may include (see also recommendation 1.5.12):\n\nnutritional benefits for the baby\n\nhealth benefits for both the baby and the woman\n\nhow it can have benefits even if only done for a short time\n\nhow it can soothe and comfort the baby.\n\nGive information about how the partner can support the woman to breastfeed, including:\n\nthe value of their involvement and support\n\nhow they can comfort and bond with the baby.\n\nInform women that vitamin\xa0D supplements are recommended for all breastfeeding women (see the NICE guideline on vitamin\xa0D).\n\nInform women and their partners that under the Equality Act\xa02010, women have the right to breastfeed in 'any public space'.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on giving information about breastfeeding\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0P: breastfeeding interventions\n\nevidence review\xa0Q: breastfeeding facilitators and barriers\n\nevidence review\xa0S: breastfeeding information and support.\n\nLoading. Please wait.\n\n## Role of the healthcare professional supporting breastfeeding\n\nHealthcare professionals caring for women and babies in the postnatal period should know about:\n\nbreast milk production\n\nsigns of good attachment at the breast\n\neffective milk transfer\n\nhow to encourage and support women with common breastfeeding problems\n\nappropriate resources for safe medicine use and prescribing for breastfeeding women.\n\nEncourage the woman to have early skin-to-skin contact with her baby so that breastfeeding can start when the baby and mother are ready.\n\nThose providing breastfeeding support should:\n\nbe respectful of women's personal space, cultural influences, preferences and previous experience of infant feeding\n\nbalance the woman's preference for privacy to breastfeed and express milk in hospital with the need to carry out routine observations\n\nobtain consent before offering physical assistance with breastfeeding\n\nrecognise the emotional impact of breastfeeding\n\ngive women the time, reassurance and encouragement they need to gain confidence in breastfeeding.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on the role of the healthcare professional supporting breastfeeding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0Q: breastfeeding facilitators and barriers and evidence review\xa0S: breastfeeding information and support.\n\nLoading. Please wait.\n\n## Supporting women to breastfeed\n\nGive breastfeeding care that is tailored to the woman's individual needs and provides:\n\nface-to-face support\n\nwritten, digital or telephone information to supplement (but not replace) face-to-face support\n\ncontinuity of carer\n\ninformation about what to do and who to contact if she needs additional support\n\ninformation for partners about breastfeeding and how best to support breastfeeding women, taking into account the woman's preferences about the partner's involvement\n\ninformation about opportunities for peer support.\n\nMake face-to-face breastfeeding support integral to the standard postnatal contacts for women who breastfeed. Continue this until breastfeeding is established and any problems have been addressed.\n\nBe aware that younger women and women from a low income or disadvantaged background may need more support and encouragement to start and continue breastfeeding, and that continuity of carer is particularly important for these women.\n\nProvide information, advice and reassurance about breastfeeding, so women (and their partners) know what to expect, and when and how to seek help. Topics to discuss include:\n\nhow milk is produced, how much is produced in the early stages, and the supply-and-demand nature of breastfeeding\n\nresponsive breastfeeding\n\nhow often babies typically need to feed and for how long, taking into account individual variation\n\nfeeding positions and how to help the baby attach to the breast\n\nsigns of effective feeding so the woman knows her baby is getting enough milk (it is not possible to overfeed a breastfed baby; see also recommendation 1.5.14)\n\nexpressing breast milk (by hand or with a breast pump) as part of breastfeeding and how it can be useful; safe storage and preparation of expressed breast milk; and the dangers of 'prop' feeding\n\nnormal breast changes during pregnancy and after the birth\n\npain when breastfeeding and when to seek help\n\nbreastfeeding complications (for example, mastitis or breast abscess) and when to seek help\n\nstrategies to manage fatigue when breastfeeding\n\nsupplementary feeding with formula milk that is sometimes, but not commonly, clinically indicated (also see the NICE guideline on faltering growth)\n\nhow breastfeeding can affect the woman's body image and identity\n\nthat the information given may change as the baby grows\n\nthe possibility of relactation after a gap in breastfeeding\n\nsafe medicine use when breastfeeding.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on supporting women to breastfeed\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0P: breastfeeding interventions\n\nevidence review\xa0Q: breastfeeding facilitators and barriers\n\nevidence review\xa0S: breastfeeding information and support.\n\nLoading. Please wait.\n\n## Assessing breastfeeding\n\nA practitioner with skills and competencies in breastfeeding support should assess breastfeeding to identify and address any concerns.\n\nAs part of the breastfeeding assessment:\n\nask about:\n\n\n\nany concerns the parents have about their baby's feeding\n\nhow often and how long the feeds are\n\nrhythmic sucking and audible swallowing\n\nif the baby is content after the feed\n\nif the baby is waking up for feeds\n\nthe baby's weight gain or weight loss\n\nthe number of wet and dirty nappies\n\nthe condition of the woman's breasts and nipples\n\n\n\nobserve a feed within the first 24\xa0hours after the birth, and at least 1\xa0other feed within the first week.\n\nIf there are ongoing concerns, consider:\n\nobserving additional feeds\n\nother actions, such as:\n\n\n\nadjusting positioning and attachment to the breast\n\ngiving expressed milk\n\nreferring to additional support such as a lactation consultation or peer support\n\nassessing for tongue‑tie.\n\n\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on assessing breastfeeding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: tools for predicting breastfeeding difficulties.\n\nLoading. Please wait.\n\n## Formula feeding\n\nBefore and after the birth, discuss formula feeding with parents who are considering or who need to formula feed, taking into account that babies may be partially formula fed alongside breastfeeding or expressed breast milk.\n\nInformation about formula feeding should include:\n\nthe differences between breast milk and formula milk\n\nthat first infant formula is the only formula milk that babies need in the first year of life, unless there are specific medical needs\n\nhow to sterilise feeding equipment and prepare formula feeds safely, including a practical demonstration if needed\n\nfor women who are trying to establish breastfeeding and considering supplementing with formula feeding, the possible effects on breastfeeding success, and how to maintain adequate milk supply while supplementing.\n\nFor parents who formula feed:\n\nhave a one-to-one discussion about safe formula feeding\n\nprovide face-to-face support\n\nprovide written, digital or telephone information to supplement (but not replace) face-to-face support.\n\nFace-to-face formula feeding support should include:\n\nadvice about responsive bottle feeding and help to recognise feeding cues\n\noffering to observe a feed\n\npositions for holding a baby for bottle feeding and the dangers of 'prop' feeding\n\nadvice about how to pace bottle feeding and how to recognise signs that a baby has had enough milk (because it is possible to overfeed a formula-fed baby), and advice about ways other than feeding that can comfort and soothe the baby\n\nhow to bond with the baby when bottle feeding, through skin-to-skin contact, eye contact and the potential benefit of minimising the number of people regularly feeding the baby.\n\nFor parents who are thinking about supplementing breastfeeding with formula or changing from breastfeeding to formula feeding, support them to make an informed decision.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on formula feeding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0T: formula feeding information and support.\n\nLoading. Please wait.\n\n## Lactation suppression\n\nDiscuss lactation suppression with women if breastfeeding is not started or is stopped, breastfeeding is contraindicated for the baby or the woman, or in the event of the death of a baby. Follow the recommendations in the section on principles of care. Topics to discuss include:\n\nhow the body produces milk, what happens when milk production stops, and how long it takes for milk production to stop\n\nself-help advice, such as:\n\n\n\navoiding stimulating the breast\n\nwearing a supportive bra\n\nusing ice packs\n\nover-the-counter pain relief\n\nsparingly expressing milk to ease engorgement\n\n\n\nwhen to seek help\n\nmedicines that can be prescribed to suppress lactation\n\nthe advantages and disadvantages of the different methods of lactation suppression\n\nthe possibility of becoming a breast milk donor (also see the section on screening and selecting donors in the NICE guideline on donor milk banks).\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on lactation suppression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: information for lactation suppression.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Bonding and emotional attachment\n\nBonding is the positive emotional and psychological connection that the parent develops with the baby.\n\nEmotional attachment refers to the relationship between the baby and parent, driven by innate behaviour and which ensures the baby's proximity to the parent and safety. Its development is a complex and dynamic process dependent on sensitive and emotionally attuned parent interactions supporting healthy infant psychological and social development and a secure attachment. Babies form attachments with a variety of caregivers but the first, and usually most significant of these, will be with the mother and/or father.\n\n## Continuity of carer\n\nBetter Births, a report by the National Maternity Review, defines continuity of carer as consistency in the midwifery team (between 4\xa0and 8\xa0individuals) that provides care for the woman and her baby throughout pregnancy, labour and the postnatal period. A named midwife coordinates the care and takes responsibility for ensuring the needs of the woman and her baby are met throughout the antenatal, intrapartum and postnatal periods.\n\nFor the purpose of this guideline, the definition of continuity of carer in the Better Births report has been adapted to include not just the midwifery team but any healthcare team involved in the care of the woman and her baby, including the health visitor team. It emphasises the importance of effective information transfer between the individuals within the team. Having continuity of carer means that a trusting relationship can be developed between the woman and the healthcare professional(s) who cares for her. For more information, see the NHS Implementing Better Births: continuity of carer.\n\n## Effective feed\n\nIn general, effective feeding includes the baby showing readiness to feed, rhythmic sucking, calmness during the feed and satisfactory weight gain. For a first feed at the breast or with a bottle, effective feeding is shown by the baby latching to the breast or drawing the teat into mouth when offered and showing some rhythmic sucking.\n\n## First infant formula\n\nFirst infant formula or 'first milk' is the type of formula milk that is suitable for a baby from birth to 12\xa0months.\n\n## Low birth weight\n\nA birth weight of less than 2,500\xa0grams regardless of gestational age.\n\n## Nominal group technique\n\nThis is a structured method that uses the opinions of individuals within a group to reach a consensus. It involves anonymous voting with an opportunity to provide comments. Options with low agreement are eliminated and options with high agreement are retained. Using the comments that individuals provide, options with medium agreement are revised and then considered in a second round. For more information, see supplement\xa01 on methods.\n\n## Parental responsibility\n\nSee the government definition of parental responsibility.\n\n## Parents\n\nParents are those with the main responsibility for the care of a baby. This will often be the mother and the father, but many other family arrangements exist, including single parents.\n\n## Partner\n\nPartner refers to the woman's chosen supporter. This could be the baby's father, the woman's partner, a family member or friend, or anyone who the woman feels supported by or wishes to involve.\n\n## Prop feeding\n\nWhen a baby's feeding bottle is propped against a pillow or other support, rather than the baby and the bottle being held when feeding.\n\n## Responsive feeding\n\nResponsive feeding means feeding in response to the baby's cues. It recognises that feeds are not just for nutrition, but also for love, comfort and reassurance between the baby and mother (or parent in case of bottle feeding). Responsive breastfeeding also involves a mother responding to her own desire to feed for her comfort or convenience. Responsive bottle feeding involves holding the baby close, pacing the feeds and avoiding forcing the baby to finish the feed by recognising signs that the baby has had enough milk, and to reduce the risk of overfeeding. For more information, see the UNICEF Baby Friendly Initiative (BFI) information sheet on responsive feeding.", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\n# Length of postpartum stay and first midwife visit after transfer of care\n\nHow does the length of postpartum stay and the timing of the first midwife visit after transfer of care affect unplanned or emergency health contacts for women and babies?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on timing of transfer to community care\xa0.\n\nFull details of the recommendation for research are in evidence review\xa0A: length of postpartum stay.\n\nLoading. Please wait.\n\nSee also the rationale section on first midwife visit after transfer of care from the place of birth or after a home birth\xa0.\n\nFull details of the recommendation for research are in evidence review\xa0C: timing of first postnatal contact by midwife.\n\nLoading. Please wait.\n\n# Timing of first health visitor visit\n\nWhat is the most effective timing of the first postnatal contact by a health visitor?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on first health visitor visit\xa0.\n\nFull details of the recommendation for research are in evidence review\xa0D: timing of first postnatal contact by health visitor.\n\nLoading. Please wait.\n\n# Clinical tools to assess women's health\n\nWhat tools for the clinical review of women (including pain scores) are effective during the first 8\xa0weeks after birth?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and care of the woman\xa0.\n\nFull details of the recommendation for research are in evidence review\xa0H: tools for the clinical review of women.\n\nLoading. Please wait.\n\n# Perineal pain\n\nWhat characteristics of perineal pain suggest the need for further evaluation?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on perineal health\xa0.\n\nFull details of the recommendation for research are in evidence review\xa0J: perineal pain.\n\nLoading. Please wait.\n\n# Breastfeeding support for parents with twins or triplets\n\nWhat support with breastfeeding do parents of twins or triplets find helpful?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on supporting women to breastfeed\xa0.\n\nFull details of the recommendation for research are in evidence review\xa0S: breastfeeding information and support.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Principles of care\n\nRecommendations 1.1.1 to 1.1.7\n\n## Why the committee made the recommendations\n\nThe committee agreed that one\xa0of the key principles of care in the postnatal period is to listen to women and be responsive to their needs, in line with the findings of the Ockenden report on maternity services at the Shrewsbury and Telford hospital NHS trust. The NICE guideline on patient experience in adult NHS services gives comprehensive guidance on individualised and person-centred care.\n\nThe committee also agreed that healthcare professionals should be aware of the disproportionate maternal and neonatal mortality rates among women and babies from black, Asian and minority ethnic backgrounds and those living in deprived areas, as highlighted by the 2020\xa0MBRRACE-UK reports on maternal and perinatal mortality. This increased risk of death indicates that closer monitoring and lower thresholds for further care or admission might be needed. Future research could help understand these disparities and what interventions could improve the outcomes.\n\nThe committee recognised that the home and family circumstances for women vary, and it is up to the woman who she may want to involve in her postnatal care. The committee also recognised the role of the baby's father or other parents (or whoever has parental responsibility) in the care of the baby.\n\nThere was evidence that information given in the postnatal period is often inconsistent, and this was supported by the committee's experience. There was some evidence that information may need to be repeated at different times by different healthcare professionals. The committee agreed that this is good practice given the number of healthcare professionals that new parents are likely to come into contact with. They discussed concerns about the wide range and varied quality of information available from healthcare professionals, the internet and social media.\n\nThe evidence showed that healthcare professionals are a trusted source of information, so the committee agreed that it is important for healthcare professionals to provide evidence-based and consistent information throughout the woman's care. It should also take into consideration the individual needs and preferences of the woman. The evidence suggested that it is helpful to deliver information in different formats, for example, face-to-face discussions and printed or digital materials. The NICE guideline on patient experience in adult NHS services gives more information. The committee discussed the importance of allowing sufficient time for discussions.\n\nThe NICE guideline on pregnancy and complex social factors provides guidance for the antenatal period for specific groups. The committee agreed that the principles of care that are not specific to the antenatal period can also be applied to the postnatal period for potentially vulnerable groups of women.\n\n## How the recommendations might affect practice\n\nThere is some variation in what information is provided, and the recommendations may result in a change in practice for some centres, involving more training for healthcare professionals, and more time in postnatal appointments. The recommendations are expected to have a positive effect on women's experience of the healthcare service by increasing their confidence in the information provided. This may result in parents being more likely to follow the advice given, which may enable them to react more appropriately to difficulties and thereby reduce morbidity and mortality.\n\nReturn to recommendations\n\n# Communication between healthcare professionals at transfer of care\n\nRecommendations 1.1.8 and 1.1.9\n\n## Why the committee made the recommendations\n\nThe evidence highlighted issues that should be communicated between healthcare professionals at transfer of care, including the woman's history in relation to her pregnancy and birth experience, and any mental health problems or safeguarding issues. Based on this evidence and their knowledge and experience, the committee agreed the information that should be passed on when women transfer between services, so that healthcare professionals do not miss relevant information and the woman does not always have to repeat the same information to different healthcare professionals. What is relevant and the level of detail needed may vary depending on whether the healthcare professional is a GP, midwife or a health visitor.\n\nThe committee also emphasised the importance of seamless transfer of care from midwifery to health visitor care so that there is continuous care provision.\n\n## How the recommendations might affect practice\n\nThere is variation in practice regarding what information, if any, is transferred between the different teams. The recommendation should lead to clearer guidance, improve relevant transfer of information and improve care for women and babies.\n\nReturn to recommendations\n\n# Transfer to community care\n\nRecommendations 1.1.10 to 1.1.13\n\n## Why the committee made the recommendations\n\nStudies looking at varying transfer timings showed that there was no consistent evidence about the best time to transfer the care of women and their babies to community care. Based on their knowledge and experience, the committee agreed that the timing should depend on the health and wellbeing of the woman and the baby. This also applies to the departure of the midwife in the case of a home birth. This will help to safely manage potential complications, prevent readmissions in the immediate postnatal period, and take into account any safeguarding concerns so that the woman and the baby are not discharged to an unsafe environment.\n\nAssessing the woman's bladder function to rule out urinary retention is important because undetected or unmanaged urinary retention can lead to serious long-term consequences such as urinary incontinence.\n\nNot passing meconium (the baby's first bowel movement) within the first 24\xa0hours can be a sign of bowel obstruction, so it is important that parents know to seek advice from a healthcare professional. This might be for example a midwife, a doctor or, if the baby is thought to be seriously unwell, the emergency services.\n\nObserving at least 1\xa0effective feed (regardless of the method of feeding) is important to establish feeding and lower the chance of feeding problems at home and the need for readmission.\n\nThe committee also agreed that in order to reassure women that they and their babies are being taken care of, they should be given information about what happens next, what support is available and who to contact in case of concerns. It is also important to highlight the importance of pelvic floor exercises soon after birth to prevent potentially long-term and serious conditions such as incontinence and pelvic organ prolapse.\n\nNo evidence on timing of transfer to home care was identified for twins or triplets, but the committee agreed that the same principles apply for multiple births as for singleton births.\n\nBecause of the lack of clear evidence, the committee made a recommendation for research on length of postpartum stay to assess how the length of the hospital stay after giving birth affects unplanned or emergency contacts with primary or secondary care.\n\n## How the recommendations might affect practice\n\nThere is wide variation in practice in how long women stay in hospital after giving birth. The committee noted that observing a feed before transfer is already current practice in settings that are UNICEF Baby Friendly Initiative (BFI)-accredited, but many providers in England do not have this accreditation. The recommendations should lead to more consistency. If potential problems are prevented or managed early, this could potentially lead to cost savings because of lower reattendance or readmission.\n\nReturn to recommendations\n\n# First midwife visit after transfer of care from the place of birth or after a home birth\n\nRecommendation 1.1.14\n\n## Why the committee made the recommendation\n\nThere was little evidence and the committee had low confidence in it, so the committee used their knowledge and experience to agree the timing of the first midwife visit. Having the first visit within 36\xa0hours after transfer of care would usually mean that the visit is not left too long, so that any health or support needs can be identified early.\n\nThe committee agreed that the first postnatal visit by the midwifery team should be by a midwife (and not, for example, by a maternity support worker), face-to-face and, depending on the woman's circumstances and preferences, in the home. This should enable a comprehensive assessment of the health and support needs of the woman and her baby.\n\nBecause of the lack of evidence, the committee made a recommendation for research on the first midwife visit after discharge to assess how the timing of the first midwife visit after the transfer of care affects unplanned or emergency contacts with primary or secondary care.\n\n## How the recommendation might affect practice\n\nThe recommendation should reduce variation in practice and improve care for women. The recommendation might affect practice because a midwife should attend the first postnatal visit, and in current practice this might be a maternity support worker or a student midwife instead. However, no significant resource implications are expected.\n\nReturn to recommendations\n\n# First health visitor visit\n\nRecommendations 1.1.15 and 1.1.16\n\n## Why the committee made the recommendations\n\nNo evidence was found about when the first postnatal health visitor visit should take place, so the committee used their knowledge and experience to agree the timing. The aim is to involve health visitors when they are most needed, and spread the visits evenly throughout the postnatal period.\n\nAccording to the Department of Health and Social Care's Healthy Child Programme, there should be 2\xa0health visitor visits in the postnatal period. The first visit is often very soon after transfer of care from midwifery care (which usually takes places 10\xa0to\xa014\xa0days after birth). This creates a gap of several weeks before the second health visitor visit at around 6\xa0to\xa08\xa0weeks. The first 2\xa0weeks after birth may be overwhelming for some families, with several visits from both the midwifery team and health visitors. Having the first postnatal health visitor visit 1\xa0to\xa02\xa0weeks after transfer of care from midwifery care will mean that the visits are more evenly spread out.\n\nAlthough the Healthy Child Programme includes an antenatal visit by the health visitor, the committee agreed that this does not always happen. If this is the case, an additional early postnatal visit by the health visitor to replace the missed antenatal visit could be considered to enable the health visitor to get to know the family and their circumstances early on.\n\nBecause of the lack of evidence, the committee made a recommendation for research on the most effective timing of the first postnatal visit by a health visitor.\n\n## How the recommendations might affect practice\n\nThere is variation in when the first postnatal health visitor visit takes place. However, 1\xa0of the key performance indicators of the Healthy Child Programme is that the first postnatal health visitor visit takes place between 10\xa0and 14\xa0days after birth, so the recommendation would mean a change in practice. The recommendation aims to reduce variation in practice and improve care for women and their babies. Some additional resources may be needed to organise an additional early postnatal visit by a health visitor in the exceptional circumstance when a mandated antenatal health visitor visit has not taken place; however, the resource impact of this is not considered to be large, and is likely outweighed by the potential benefits.\n\nReturn to recommendations\n\n# Assessment and care of the woman\n\nRecommendations 1.2.1 to 1.2.12\n\n## Why the committee made the recommendations\n\nThe recommendations were not developed by the usual NICE guideline systematic review process because of the scale and complexity of the topic. Using the nominal group technique to vote on statements about the content of postnatal care contacts, the committee made recommendations through formal consensus because reaching consensus by committee discussion alone would be challenging. The statements were based on a review, including critical appraisal, of existing guidelines and systematic reviews. The committee based the recommendations on these and their knowledge and experience.\n\nThe committee agreed that at each postnatal contact, women's general health and wellbeing, including psychological and emotional health, should be assessed and women should be asked if they have any concerns. The committee also agreed the physical health areas that midwives should assess. In order to prevent serious outcomes, women should also be made aware of the signs and symptoms of potentially serious conditions so they can seek help. Women's physical health assessment is not in the remit of the health visitor but when there are concerns, either observed by the healthcare professional or expressed by the woman, all healthcare professionals, including health visitors, should refer or advise self-referral so that the woman can get appropriate assessment and care.\n\nThe committee acknowledged that some women may want to talk about their birth experience. In some cases, women might need additional support in coping with their experience.\n\nNo evidence was identified on the timing of the comprehensive routine postnatal check. Based on their knowledge and experience, the committee agreed this should ideally happen between 6\xa0and 8\xa0weeks after birth, as is current practice, to coincide with the Public Health England newborn and infant physical examination.\n\nNo evidence was identified about which tools are effective in the clinical postnatal review of women. A tool that has been tested and validated in an independent sample assessing postnatal physical and mental health problems could help identify those women who need additional care and support, so the committee made a recommendation for research on clinical tools to assess women's health.\n\nReferences were made to NICE guidelines on different conditions that may affect women postnatally. A bacterial infection could be transmitted to the baby, so it is important to assess the baby if the mother has suspected or confirmed puerperal sepsis.\n\n## How the recommendations might affect practice\n\nBy ensuring that women's physical and psychological health and wellbeing is comprehensively assessed, and any problems are managed appropriately, there may be an increase in referrals if problems are identified. The committee agreed that any referrals would prevent delays in diagnosing and treating problems, and improve care.\n\nReturn to recommendations\n\n# Postpartum bleeding\n\nRecommendations 1.2.13 and 1.2.14\n\n## Why the committee made the recommendations\n\nNo relevant evidence was identified about how to assess early symptoms and signs of postpartum haemorrhage, so the committee used their knowledge and experience to make the recommendations. Discussing with women what to expect after birth helps women to distinguish between a normal amount of lochia (vaginal discharge containing blood, mucus and uterine tissue) and signs and symptoms of postpartum haemorrhage. Women should be advised to seek medical advice if they observe these signs or symptoms because postpartum haemorrhage can have severe consequences.\n\nThe committee agreed that although all women are at risk of secondary postpartum haemorrhage, some factors increase this risk and these should be taken into account when assessing the severity of blood loss. The risk factors for postpartum haemorrhage are listed in the NICE guideline on intrapartum care for healthy women and babies. The committee used their knowledge and experience to list other factors that might worsen the consequences of postpartum bleeding so that appropriate action can be taken.\n\n## How the recommendations might affect practice\n\nIt is not routine practice to discuss what blood loss to expect postnatally, so the recommendations will involve a minor change to current practice but will potentially improve outcomes by early identification of secondary postpartum haemorrhage.\n\nReturn to recommendations\n\n# Perineal health\n\nRecommendations 1.2.15 to 1.2.22\n\n## Why the committee made the recommendations\n\nPerineal pain and its complications are often overlooked and falsely considered to be part of normal postnatal healing. However, early identification and management of perineal pain may prevent long-term consequences and improve the woman's overall experience of postnatal care. To help healthcare professionals identify women with perineal pain and to prompt appropriate care, healthcare professionals should ask women if they have any perineal concerns.\n\nPractical advice about how to maintain good perineal hygiene can prevent infection or complications. In order to assess changes in the severity of perineal pain over time, a validated pain score might help to give a clearer view. Physical examination of the perineum could help determine the severity or cause of the pain, or whether further action is needed. In some cases, medication might be needed to alleviate the pain.\n\nThe committee emphasised that women with perineal wound breakdown should be urgently referred to appropriate maternity services for further management to prevent further complications and potential long-term adverse outcomes.\n\nThere was evidence that prolonged perineal pain and severity of pain is associated with depressive symptoms. There was no other relevant evidence about perineal pain, but the committee agreed, based on their knowledge and experience, that it can have negative long-term implications. To help healthcare professionals identify women with persistent or worsening perineal pain and to prompt appropriate care, they should be aware of the factors that can increase the risk of persistent postnatal perineal pain.\n\nBecause of the lack of evidence about what characteristics of perineal pain suggest the need for further evaluation, a recommendation for research on perineal pain was made.\n\n## How the recommendations might affect practice\n\nIn current practice, some women only receive treatment for perineal complications when the situation has become serious. By ensuring that perineal pain is identified early and treated without delay, then further complications and long-term consequences can be avoided. There may be an increase in referrals to secondary care for women who are usually seen by their GP, but the recommendations should improve care and outcomes.\n\nReturn to recommendations\n\n# Assessment and care of the baby\n\nRecommendations 1.3.1 to 1.3.12\n\n## Why the committee made the recommendations\n\nMost of the recommendations in this section were not developed by the usual NICE guideline systematic review process because of the scale and complexity of the topic. Using the nominal group technique to vote on statements about the content of postnatal care contacts, the committee made recommendations through formal consensus because reaching consensus by committee discussion alone would be challenging. The statements were based on a review, including critical appraisal, of existing guidelines and systematic reviews. The committee based the recommendations on these, and their knowledge and experience.\n\nThe general wellbeing, feeding and development of the baby should be assessed at every postnatal contact so that any concerns can be identified early. Not passing meconium (the baby's first bowel movement) within the first 24\xa0hours can be a sign of bowel obstruction, so it is important that healthcare professionals engaging with the family in the immediate postnatal period are aware of the need for advice from a doctor.\n\nThere was no reason for the committee to change the current recommended assessment criteria that healthcare professionals should use within 72\xa0hours after the birth. The committee agreed that the same criteria could be used in the 6‑ to 8‑week assessment. The recommendation about weight and head circumference measurement is based on guidance from the UK-WHO (World Health Organization) growth charts.\n\nThe recommendations refer to other NICE guidelines for guidance on specific clinical situations, and relevant NHS screening programmes.\n\nTo help parents, healthcare professionals should also discuss and provide information about how to care for their baby. Established guidance exists on safer sleeping practices, and resources for these are available from, for example, UNICEF, Baby Sleep Information Source (Basis), and the Lullaby Trust.\n\nBaby Check is a scoring system intended to help in the assessment of babies up to 6\xa0months of age, taking into account the presence or absence of various symptoms and signs of illness. It gives an overall score to help in deciding whether the baby may need clinical assessment or care. Although the evidence base for the Baby Check was predominantly in relation to babies attending secondary care, there was evidence that in the community setting, it can identify babies who are likely to be well. Also, the studies included babies ranging from birth to 6\xa0months and were not therefore specifically focused on those in the early weeks of life.\n\nThe Lullaby Trust has produced parent-friendly modified versions of the Baby Check scoring system, in the form of a mobile app and a downloadable booklet. Although the modifications are mostly related to the language used, the committee had some concerns because the modified versions have not been validated, and neither has the use of Baby Check by parents, as opposed to healthcare professionals. Finally, the committee noted that the Lullaby Trust's modified versions have adopted current practices regarding temperature measurement (armpit or ear), and this differs from the original Baby Check evaluations, which use rectal temperature.\n\nAlthough Baby Check cannot therefore provide complete reassurance, the committee agreed that the Baby Check scoring system could be helpful to parents as a 'checklist' of symptoms and signs of possible illness when they are uncertain whether their baby might be unwell and deciding whether to seek advice from a healthcare professional. The committee agreed it would be best for parents to be given information about Baby Check in advance rather than when they are concerned about their baby's wellbeing.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current practice. There may be an increase in the use of Baby Check scoring system by parents. It is not known if this would have an impact on parents seeking advice from healthcare professionals, but the impact would not be expected to be large.\n\nReturn to recommendations\n\n# Bed sharing\n\nRecommendations 1.3.13 and 1.3.14\n\n## Why the committee made the recommendations\n\nThere was evidence of varying quality from multiple studies about the different risk factors associated with sudden unexpected death in infancy when bed sharing (up to 1\xa0year of age). Based on the evidence and their knowledge and experience, the committee agreed the safe bed sharing practices that should be discussed with all parents and the circumstances in which bed sharing with a baby should be strongly advised against. The evidence also showed an association between bed sharing and breastfeeding although there is uncertainty about the causality. Preterm babies are outside the remit of this guideline and are therefore not mentioned in the recommendations; however, the committee were aware of evidence showing an increased risk of sudden unexpected death in infancy when bed sharing with a baby born preterm.\n\n## How the recommendations might affect practice\n\nIn current practice, there is confusion and mixed messages from both healthcare professionals and within the community on the best practice for safe sleeping, including advice about never sharing a bed with a baby. These recommendations should lead to clear guidance, reduce variation in practice, and improve care for women and babies.\n\nReturn to recommendations\n\n# Promoting emotional attachment\n\nRecommendations 1.3.15 to 1.3.18\n\n## Why the committee made the recommendations\n\nThere was limited evidence on how to promote attachment between the mother and baby, and it did not show any specific interventions to be effective, so the recommendations are based on the committee's knowledge and experience. The committee agreed to make the recommendations for parents, not just the mother, because discussing and recognising the issues related to developing emotional attachment are relevant for other parental caregivers as well.\n\nThe committee agreed that discussions about emotional attachment should begin antenatally and continue into the postnatal period. The committee highlighted that emotional attachment will usually happen naturally if the primary carer is able to spend quality time with their baby. The value of such quality time is not always recognised as important by the parent(s) when there are so many other demands on parents' time in the postnatal period.\n\nThe committee recognised that attachment can also be affected by the woman's wellbeing, recovery from birth and other demands that parenthood brings. Therefore, it is important to discuss these issues with the parents to support them in building a relationship with their baby. It was considered important for the woman's partner (if there is one) to understand the various challenging aspects that the mother might be experiencing in the postnatal period, which might affect bonding and emotional attachment.\n\nBased on their knowledge and experience, the committee highlighted particular groups of parents who may be more vulnerable to difficulties in attachment and may need more support.\n\n## How the recommendations might affect practice\n\nThere is variation in practice regarding what women are offered in support relating to emotional attachment. The recommendations should lead to clear guidance, reduce variation in practice and improve care for women.\n\nReturn to recommendations\n\n# Symptoms and signs of illness in babies\n\nRecommendations 1.4.1 to 1.4.10\n\n## Why the committee made the recommendations\n\nIt is important to identify babies who are seriously ill early so that the condition can be managed and adverse outcomes can be avoided. In the committee's experience, parents' concern about 'something being not quite right' can sometimes be overlooked, but it can be an important sign of serious illness and should be taken seriously.\n\nBaby Check is a scoring system intended to help in the assessment of babies up to 6\xa0months of age, taking into account the presence or absence of various symptoms and signs of illness. It gives an overall score to help in deciding whether the baby may need clinical assessment or care. Based on the evidence in the secondary care setting, its sensitivity to identify those babies who are seriously ill varied. In the community setting, it was found to identify babies who are well suggesting that further assessment is not needed but the evidence regarding its accuracy in identifying seriously ill babies is lacking. Also, the studies in which it was being tested included babies ranging from birth to 6\xa0months and were not therefore specifically focused on those in the early weeks of life as this guideline.\n\nThe Lullaby Trust has produced parent-friendly modified versions of the Baby Check scoring system, in the form of a mobile app and a downloadable booklet. Although the modifications are mostly related to the language used, the committee had some concerns because the modified versions have not been validated, and neither has the use of Baby Check by parents, as opposed to healthcare professionals. Finally, the committee noted that the Lullaby Trust's modified versions have adopted current practices regarding temperature measurement (armpit or ear), and this differs from the original Baby Check evaluations, which use rectal temperature.\n\nFor these reasons, the committee agreed that Baby Check should not be used in isolation to determine the need for further assessment or care but that it could be a helpful tool when used in addition to clinical judgement. Also, by focusing attention on important symptoms and signs, it could help during a remote assessment as a communication aid between healthcare professionals and parents.\n\nThe committee also noted that sometimes the presence of fever in young babies is not recognised as a serious concern. It is particularly important to note changes in the baby's wellbeing and behaviour.\n\nThere was evidence that single signs and symptoms are not necessarily useful predictors of serious illness on their own. However, based on various other NICE guidelines, there are some 'red flag' symptoms and signs that indicate a serious illness that needs immediate action.\n\n## How the recommendations might affect practice\n\nThe recommendations should reinforce current good practice and improve care for babies. There may be an increase in the use of the Baby Check scoring system as a supplemental tool for healthcare professionals, particularly during remote appointments.\n\nReturn to recommendations\n\n# General principles about babies' feeding\n\nRecommendation 1.5.1\n\n## Why the committee made the recommendation\n\nBased on their knowledge and experience, the committee agreed that the choices parents make around feeding are not easy and sometimes their preferred choice might not be an option for them. Evidence among parents who bottle fed their babies showed that they sometimes felt judged by the healthcare professionals about their choices. Therefore, the committee agreed that as a general principle, discussions around feeding should be respectful and acknowledge the various consequences different feeding options may have.\n\n## How the recommendation might affect practice\n\nThere is some variation in practice, so the recommendation aims to improve the consistency of support given to parents about feeding their baby.\n\nReturn to recommendations\n\n# Giving information about breastfeeding\n\nRecommendations 1.5.2 to 1.5.5\n\n## Why the committee made the recommendations\n\nBased on their knowledge and experience, the committee agreed that discussion and support around breastfeeding should start in the antenatal period so that women are equipped to make decisions about feeding and are prepared to start breastfeeding when the baby is born. The discussions and support should continue in the postnatal period so that any questions and concerns can be addressed and women feel they are being supported.\n\nThere was good evidence about women being motivated by the many benefits of breastfeeding, so it is important to share these with the women. It is established knowledge that breastfeeding has nutritional and health benefits for the baby (such as lower rates of infection) and some health benefits for the woman (such as lower risk of breast cancer). There was evidence that women felt they were able to soothe and comfort the baby by breastfeeding.\n\nThe committee agreed that it is important to explain that breastfeeding can have benefits even if done for a short period of time. For example, colostrum (the breast milk that is produced in the first few days) is known to have various nutritional and health benefits for the baby.\n\nThe committee also agreed that parents should receive information about partners' involvement in supporting breastfeeding. The evidence showed that some women and their families believed that bottle feeding was a way for the baby to bond with their partner or other family members. The committee agreed that partners and family members should be given information about alternative ways to comfort and bond with the baby.\n\nBecause breastfeeding women may be at risk of vitamin\xa0D deficiency, they should be informed about the NICE recommendation about taking vitamin\xa0D supplementation.\n\nThere was evidence that some women thought that other people felt that breastfeeding in public is inappropriate or insensitive to other people's feelings, which can be a barrier for breastfeeding in public places. The committee agreed the importance of reassuring women and their partners that under the 2010\xa0Equality Act, women have the right to breastfeed in 'any public space'.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current practice and should reinforce good practice across the country.\n\nReturn to recommendations\n\n# Role of the healthcare professional supporting breastfeeding\n\nRecommendations 1.5.6 to 1.5.8\n\n## Why the committee made the recommendations\n\nFeeding is an integral part of the postnatal period, so healthcare professionals should have the relevant knowledge to encourage breastfeeding and to support women to establish and continue breastfeeding. The BNF provides useful information on safe medicine use and prescribing for women who are breastfeeding. If needed, further advice is available from an NHS medicines information centre or other specialist sources.\n\nThe World Health Organization (WHO) recommends that breastfeeding is started early in order to facilitate establishment of breastfeeding, and the committee agreed that healthcare professionals caring for women and babies in the immediate postnatal period should encourage early skin-to-skin contact to help start breastfeeding when the baby and the mother feel ready.\n\nThe committee agreed that healthcare professionals should be sensitive to the individual preferences, experiences and values of the woman when supporting her with breastfeeding. There was evidence that after birth, women value having privacy in hospital, and a lack of privacy can be a barrier to breastfeeding and expressing breast milk. However, the committee noted that healthcare professionals also need to be able to carry out clinical observations of women easily, so recommended that these needs be balanced against each other.\n\nThe evidence also showed that varying experiences with breastfeeding can have an impact on the woman's emotional wellbeing, and women often need reassurance and encouragement to gain confidence.\n\n## How the recommendations might affect practice\n\nIn the committee's experience, some healthcare professionals caring for women and babies during the postnatal period may not have adequate knowledge to support women with breastfeeding and might need more training. The recommendations should reinforce best clinical practice and lead to better consistency of care.\n\nReturn to recommendations\n\n# Supporting women to breastfeed\n\nRecommendations 1.5.9 to 1.5.12\n\n## Why the committee made the recommendations\n\nThere was evidence that women value breastfeeding care that provides individualised support and continuity of carer, and feel that 'remote' support (such as online or telephone support) can be a helpful addition but should not replace face-to-face support.\n\nThe evidence also showed that partners often feel that they lack knowledge and understanding of breastfeeding, and want to know how they can best support breastfeeding mothers.\n\nThere was evidence that women find peer support valuable. Through peer support, women can share their experiences and gain information and social contacts, which can provide ongoing support.\n\nThere was no evidence that extra interventions increase breastfeeding rates so the committee agreed that breastfeeding support should be an integral part of standard postnatal care contacts.\n\nThere was some evidence that younger women may have additional barriers to breastfeeding, such as feeling alone in the maternity unit, the feeling of needing to 'carry on with life' and therefore choosing to formula feed, and lack of peer support. Evidence also suggested that additional support may be beneficial for improving the rate of breastfeeding among women from low income or socially disadvantaged backgrounds.\n\nThe evidence showed that women value support and practical information about breastfeeding, as well as information about the underlying physiology of breastfeeding. This will help them to recognise what is or is not normal, and when to seek help. The evidence also showed that some common features of breastfeeding, such as sore nipples, can discourage women if they do not know in advance what to expect.\n\nThere was no evidence about breastfeeding support for parents of twins or triplets, so the committee made a recommendation for research.\n\n## How the recommendations might affect practice\n\nThere is significant variation in the provision of practical and professional breastfeeding support, so the recommendations will support best practice in some settings and improve practice in other settings. They will reduce variation in practice and improve care for women and babies. Providing continuity of carer may have an impact on how services are organised, but no significant resource impact is expected.\n\nReturn to recommendations\n\n# Assessing breastfeeding\n\nRecommendations 1.5.13 to 1.5.15\n\n## Why the committee made the recommendations\n\nAssessing breastfeeding is an important part of postnatal contacts. None of the clinical tools identified in the evidence review were useful in identifying women who would not be breastfeeding (or exclusively breastfeeding) at follow\xa0up, which was considered an indication of breastfeeding difficulties, so the committee did not recommend any tools. The committee used their knowledge and experience to make the recommendations, in line with the principles in the UNICEF Baby Friendly Initiative (BFI) breastfeeding assessment tool, including asking the parents about any concerns and about indications of successful breastfeeding.\n\nIn addition, observing a feed twice in the first week can help establish good breastfeeding practice. Additional observations or interventions may be needed if there are ongoing concerns.\n\n## How the recommendations might affect practice\n\nIn current practice, observing a full feed in the first week might not always happen, so this may mean a change in practice and may have some impact on time needed at the postnatal contacts. The recommendations are based on the UNICEF BFI breastfeeding assessment tool, which is already widely used in practice. In places where it is not already used, the committee were aware that work is underway to reach that standard. The recommendations will improve and standardise practice.\n\nReturn to recommendations\n\n# Formula feeding\n\nRecommendations 1.5.16 to 1.5.20\n\n## Why the committee made the recommendations\n\nThe committee recognised that babies can be formula fed in combination with breastmilk or they can be fed with formula milk only. There was good evidence about what information and support parents who formula feed find helpful, so the committee used the evidence together with their knowledge and experience to make the recommendations. Common themes in the evidence were the lack of impartial information about formula feeding, women feeling that they were not supported in their feeding choices, and the emotional impact that feeding choices can have on parents. The committee agreed that, as for women who breastfeed, women who formula feed should be supported regardless of their feeding choices. The recommendations reflect the key features of formula feeding support and the information that should be given to women and their families if they are formula feeding or are considering to formula feed and who need to formula feed because of a medical or other reason.\n\nThe evidence showed that women value face-to-face feeding support but also feel that additional information to support feeding can be helpful. The evidence showed that women who are formula feeding feel that they are not given the information or support they need, for example, about how to interpret and respond to the baby's behaviours and cues, and how to formula feed safely. Based on the committee's experience, it is important to give information about how to hold the baby and how feeding can be used as an opportunity to bond with the baby, and also advise parents against using a 'propped up' bottle during a feed because it can be harmful for the baby.\n\nThe evidence also showed that women were unaware of the impact introducing formula feeding could have on breastfeeding and felt unsupported by healthcare professionals when considering this. Therefore, the committee agreed it was important that women were supported to make an informed, guilt-free decision by providing balanced and evidence-based information.\n\n## How the recommendations might affect practice\n\nThe committee noted that there is significant variation in practice in providing formula feeding support, so the recommendations will support best practice in some settings and improve practice in other settings. Overall, they will improve consistency.\n\nReturn to recommendations\n\n# Lactation suppression\n\nRecommendation 1.5.21\n\n## Why the committee made the recommendation\n\nNo evidence was identified on the information and support that should be given to women about lactation suppression. The committee discussed when discussions about lactation suppression should happen and what should be discussed, and used their knowledge and experience to agree the recommendation. The committee agreed that discussions should be sensitive and individualised according to the woman's situation. Practical advice about how to ease the process of milk drying up can be helpful for women, and in some cases, medicine to suppress lactation might also be appropriate to make the process quicker, although for most this is not needed.\n\nDonating breast milk to a local breast milk bank, depending on the local services, could be valuable to some women who cannot breastfeed their own baby.\n\n## How the recommendation might affect practice\n\nThe recommendation largely reflects current practice and should reinforce best practice. To ensure that women understand the information they are given, and that information is being provided at the most appropriate time, some extra time from healthcare professionals may be needed.\n\nReturn to recommendations", 'Context': "Approximately 700,000\xa0women give birth in England and Wales each year. For women, their partners and their babies, this is a major life event that means considerable emotional and physical adjustment. It applies to all births but is perhaps most marked for those having their first child. Healthcare professionals have the responsibility to help families adjust to their new life, but at the same time they have to be able to spot and care for the families where complications arise.\n\nPostnatal care has for long been regarded as a 'Cinderella service' where in comparison with some other European countries, provision is scanty and inadequate. This approach risks missing an opportunity to have a profoundly beneficial effect on the lives of the babies and their families, now and in the future. In a National Childbirth Trust (NCT) survey: left to your own devices – the postnatal care experiences of 1,260\xa0first-time mothers, 1\xa0in\xa08\xa0women were highly critical of their postnatal care. Their feedback reflects fragmentation of care, poor planning and communication between healthcare professionals, and insufficient advice about emotional recovery. Furthermore, women continue to report receiving insufficient or inconsistent information on baby's feeding, particularly after giving birth to their first baby.\n\nThis guideline addresses the organisation and delivery of postnatal care, including the relationship between the different agencies that share the responsibility for postnatal care; assessment and health of women; assessment and health of babies; how to help parents form strong relationships with their babies; and babies' feeding. It specifically does not cover issues covered by other NICE guidelines, in particular problems of mental health, preterm birth or specialist care (care beyond routine postnatal care), but refers to other NICE guidelines, where appropriate.\n\nThis guideline covers the postnatal period up to 8\xa0weeks after birth. However, the sections on babies' feeding and emotional attachment also address the antenatal period because discussion around these is essential already during pregnancy. The postnatal period of course does not end at 8\xa0weeks. A time point of 8\xa0weeks was agreed in order to focus the guideline on the most critical early weeks after birth. The remit for some of the topics in this guideline was to address the needs of families giving birth to twins and triplets in addition to single babies. The evidence specific to twins and triplets was lacking and the consensus was that healthcare professionals and families dealing with twins or triplet births should use the recommendations of the guideline within the constraints of the changed circumstances of having to care for more than 1\xa0child.\n\nThe committee were aware of the higher postnatal mortality rates among women of black, Asian and minority ethnic origin and women living in deprived areas reported in the MBRRACE-UK report: saving lives, improving mothers' care (2020). Black women in particular had an over four‑fold increase in maternal mortality rates compared with white women. The MBRRACE-UK report: perinatal mortality surveillance report (2020) also highlights the higher neonatal mortality rates for babies of black and Asian ethnicity and babies born to mothers living in deprived areas. It is important that clinicians are aware of these inequalities in clinical practice.\n\nThis guideline was written with the hope that healthcare professionals can use it to provide consistent and high-quality care, while taking into consideration each family's individual situation and needs, in order to reduce morbidity and mortality and to support families in this new phase."}
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https://www.nice.org.uk/guidance/ng194
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This guideline covers the routine postnatal care that women and their babies should receive in the first 8 weeks after the birth. It includes the organisation and delivery of postnatal care, identifying and managing common and serious health problems in women and their babies, how to help parents form strong relationships with their babies, and baby feeding. The recommendations on emotional attachment and baby feeding also cover the antenatal period.
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26467112e606d02eed8adaca291f4ba945ae5c09
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nice
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Neonatal infection: antibiotics for prevention and treatment
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Neonatal infection: antibiotics for prevention and treatment
This guideline covers preventing bacterial infection in healthy babies of up to and including 28 days corrected gestational age, treating pregnant women whose unborn baby is at risk of infection, and caring for babies of up to and including 28 days corrected gestational age with a suspected or confirmed bacterial infection. It aims to reduce delays in recognising and treating infection and prevent unnecessary use of antibiotics. The guideline does not cover viral infections.
# Recommendations
Parents and carers have the right to be involved in planning and making decisions about their baby's health and care, and to be given information and support to enable them to do this, as set out in the NHS Constitution and summarised in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Please note that the Royal College of Obstetricians and Gynaecologists has produced guidance on COVID-19 and pregnancy for all midwifery and obstetric services. The Royal College of Paediatrics and Child Health has published guidance on COVID-19 for neonatal services.
Throughout this guideline, unless otherwise specified, the term neonatal infection covers both early-onset and late-onset infections.
# Information and support
For guidance on communication (including different formats and languages), providing information, and shared decision making, see the NICE guidelines on patient experience in adult NHS services, babies, children and young people's experience of healthcare and shared decision making.
## Parents and carers of babies at increased risk of neonatal infection
If clinical concerns about possible neonatal infection arise at any point:
talk to the baby's parents and carers, explaining the reason for concern, and explain what neonatal infection is
discuss the options for management that may be best for their baby (for example, observation, investigations or antibiotic treatment)
do not delay treatment, but when possible give the baby's parents and carers time to think about the information they have been given and ask any questions they may have before making treatment decisions.
If giving antibiotics because of clinical concerns about possible early- or late-onset neonatal infection, discuss with parents and carers:
the reason for the treatment
the risks and benefits in relation to their baby's circumstances
the observations and investigations that might be needed to guide treatment (for example, to help decide when to stop treatment)
the preferred antibiotic regimen (including how it will be delivered) and likely duration of treatment
the impact, if any, on where the woman or her baby will be cared for.
To maintain communication with a woman in labour whose baby is at increased risk of early-onset neonatal infection:
involve the woman in any handover of care, either when additional expertise is brought in because of the risk of infection or during planned changes in staff
include an update in the handover about the presence of any infection.For more guidance, see the section on communication in the NICE guideline on intrapartum care.
For babies who are considered to be at increased risk of early-onset infection, inform their parents and GP about this verbally and in writing:
when the baby is discharged from the hospital or midwifery-led unit or
in the immediate postnatal period, if the baby was born at home.
Reassure parents and carers that babies who have or are at increased risk of neonatal infection can usually continue to breastfeed, and that every effort will be made to help with this. If a baby is temporarily unable to breastfeed, support the mother to express breast milk if she wishes to do so.
## When a woman is identified as having group B streptococcal colonisation, bacteriuria or infection during her current pregnancy:
advise the woman that if she becomes pregnant again:
that her new baby will be at increased risk of early-onset group B streptococcal infection
she should inform her maternity care team that she has had a positive group B streptococcal infection test in a previous pregnancy
her maternity care team will offer her antibiotics in labour
inform the woman's GP in writing that there is a risk of group B streptococcal infection in babies in future pregnancies.
## Parents and carers of babies treated for neonatal infection
Reassure parents and carers that they will be able to continue caring for and holding their baby according to their wishes, unless the baby is too ill to allow this. If the severity of the baby's illness means they need to change the way they care for the baby, discuss this with them.
Offer parents and carers contact details of organisations that provide parent support, befriending, counselling, information and advocacy.
If a baby has been treated for suspected or confirmed neonatal infection:
advise the parents and carers about potential long-term effects of the baby's illness and likely patterns of recovery, and reassure them if no problems are anticipated
take account of parents' and carers' concerns when providing information and planning follow-up.
When a baby who has had a group B streptococcal infection is discharged from hospital:
advise the woman that if she becomes pregnant again:
that her new baby will be at increased risk of early-onset group B streptococcal infection
she should inform her maternity care team that she has had a previous baby with a group B streptococcal infection
her maternity care team will offer her antibiotics in labour
inform the woman's GP in writing that there is a risk of:
group B streptococcal infection recurrence in the baby and
group B streptococcal infection in babies in future pregnancies.
## Parents and carers of all babies
Before any baby is transferred home from the hospital or midwifery-led unit (or in the immediate postnatal period in the case of babies born at home), advise parents and carers to seek urgent medical help (for example, from NHS 111, their GP, or an accident and emergency department) if they are concerned that their baby:
is showing abnormal behaviour (for example, inconsolable crying or listlessness), or
is unusually floppy, or
has an abnormal temperature unexplained by environmental factors (lower than 36°C or higher than 38°C), or
has abnormal breathing (rapid breathing, difficulty in breathing or grunting), or
has a change in skin colour (for example where the baby becomes very pale, blue/grey or dark yellow), or
has developed new difficulties with feeding.Give the advice both in person, and as written information and advice for them to take away.
## Post-discharge planning for babies who have not been given antibiotics
When there has been a clinical concern about neonatal infection in a baby, make a post-discharge management plan, taking into account factors such as:
the level of the initial clinical concern
the presence of risk factors
parents' and carers' concerns.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on information and support .
Full details of the evidence and the committee's discussion are in evidence review A: information and support.
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# Preventing early-onset neonatal infection before birth
## Intrapartum antibiotics
Offer antibiotics during labour to women who:
are in pre-term labour or
have group B streptococcal colonisation, bacteriuria or infection during the current pregnancy or
have had group B streptococcal colonisation, bacteriuria or infection in a previous pregnancy, and have not had a negative test for group B streptococcus by enrichment culture or PCR on a rectovaginal swab samples collected between 35 and 37 weeks' gestation or 3-5 weeks before the anticipated delivery date in the current pregnancy or
have had a previous baby with an invasive group B streptococcal infection or
have a clinical diagnosis of chorioamnionitis.
Use table 1 to decide which antibiotic to use when giving intrapartum antibiotics for neonatal infection.
Allergies
Women without chorioamnionitis
Women with chorioamnionitis
No penicillin allergy
Use Benzylpenicillin.
Use Benzylpenicillin plus gentamicin plus metronidazole.
Penicillin allergy that is not severe
Use Cephalosporin with activity against group B streptococcus (for example cefotaxime).
Use with caution.
In April 2021 this was an off-label use of cephalosporins. See NICE's information on prescribing medicines.
Use Cephalosporin with activity against group B streptococcus (for example cefotaxime) plus metronidazole.
Use with caution.
In April 2021 this was an off-label use of cephalosporins. See NICE's information on prescribing medicines.
Severe penicillin allergy
Consider:
Vancomycin or
An alternative antibiotic that would be expected to be active against group B streptococcus based on either sensitivity testing performed on the woman's isolate or on local antibiotic susceptibility surveillance data.
In April 2021 this was an off-label use of vancomycin. See NICE's information on prescribing medicines.
Consider:
Vancomycin plus gentamicin plus metronidazole or
An alternative antibiotic to vancomycin that would be expected to be active against group B streptococcus based on either sensitivity testing performed on the woman's isolate or on local antibiotic susceptibility surveillance data plus gentamicin plus metronidazole.
In April 2021 this was an off-label use of vancomycin. See NICE's information on prescribing medicines.
If using intravenous gentamicin during labour, use once-daily dosing.
Give the first dose of antibiotics as soon as possible after labour starts (or as soon as infection is suspected, in the case of chorioamnionitis), and continue until the birth of the baby.
Be aware that therapeutic drug monitoring may be needed when using gentamicin or vancomycin during labour.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on intrapartum antibiotics .
Full details of the evidence and the committee's discussion are in evidence review B: intrapartum antibiotics.
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## Women with prolonged prelabour rupture of membranes who have group B streptococcal colonisation, bacteriuria or infection
Offer an immediate birth (by induction of labour or caesarean birth) to women who are between 34 and 37 weeks' gestation who:
have prolonged prelabour rupture of membranes, and
have group B streptococcal colonisation, bacteriuria or infection at any time in their current pregnancy.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on women with prolonged prelabour rupture of membranes .
Full details of the evidence and the committee's discussion are in evidence review C: timing of delivery.
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# Risk factors for and clinical indicators of possible early-onset neonatal infection
## Before birth
For women in labour, identify and assess any risk factors for early-onset neonatal infection (see box 1). Throughout labour, monitor for any new risk factors.
For guidance on managing prelabour rupture of membranes at term, see the NICE guideline on intrapartum care.
## Assessing and managing the risk of early-onset neonatal infection after birth
If there are any risk factors for early-onset neonatal infection (see box 1), or if there are clinical indicators of possible early-onset neonatal infection (see box 2):
perform an immediate clinical assessment
review the maternal and neonatal history
carry out a physical examination of the baby, including an assessment of vital signs.
If group B streptococcus is first identified in the mother within 72 hours after the baby's birth:
ask those directly involved in the baby's care (for example, a parent, carer, or healthcare professional) whether they have any concerns in relation to the clinical indicators listed in box 2, and
identify any other risk factors present, and
look for clinical indicators of infection.Use this assessment to decide on clinical management (see recommendation 1.3.5).
Red flag risk factor:
Suspected or confirmed infection in another baby in the case of a multiple pregnancy.
Other risk factors:
Invasive group B streptococcal infection in a previous baby or maternal group B streptococcal colonisation, bacteriuria or infection in the current pregnancy.
Pre-term birth following spontaneous labour before 37 weeks' gestation.
Confirmed rupture of membranes for more than 18 hours before a pre-term birth.
Confirmed prelabour rupture of membranes at term for more than 24 hours before the onset of labour.
Intrapartum fever higher than 38°C if there is suspected or confirmed bacterial infection.
Clinical diagnosis of chorioamnionitis.
Red flag clinical indicators:
Apnoea (temporary stopping of breathing)
Seizures
Need for cardiopulmonary resuscitation
Need for mechanical ventilation
Signs of shock
Other clinical indicators:
Altered behaviour or responsiveness
Altered muscle tone (for example, floppiness)
Feeding difficulties (for example, feed refusal)
Feed intolerance, including vomiting, excessive gastric aspirates and abdominal distension
Abnormal heart rate (bradycardia or tachycardia)
Signs of respiratory distress (including grunting, recession, tachypnoea)
Hypoxia (for example, central cyanosis or reduced oxygen saturation level)
Persistent pulmonary hypertension of newborns
Jaundice within 24 hours of birth
Signs of neonatal encephalopathy
Temperature abnormality (lower than 36°C or higher than 38°C) unexplained by environmental factors
Unexplained excessive bleeding, thrombocytopenia, or abnormal coagulation
Altered glucose homeostasis (hypoglycaemia or hyperglycaemia)
Metabolic acidosis (base deficit of 10 mmol/litre or greater)
Use the following framework, based on the risk factors in box 1 and the clinical indicators in box 2, to make antibiotic management decisions as directed:
In babies with any red flag, or with 2 or more 'non-red-flag' risk factors or clinical indicators:
follow recommendations 1.4.1 to 1.4.8 on investigations before starting antibiotics, and
start antibiotic treatment according to recommendations 1.5.1 to 1.6.7, and
do not wait for the test results before starting antibiotics
in babies without red flags and only 1 risk factor or 1 clinical indicator, use clinical judgement to decide:
whether it is safe to withhold antibiotics, and
whether the baby's vital signs and clinical condition need to be monitored. If monitoring is needed, continue for at least 12 hours using a newborn early warning system
for babies without risk factors or clinical indicators of possible infection, continue routine postnatal care as covered in the NICE guideline on postnatal care.
# Kaiser Permanente neonatal sepsis calculator
The Kaiser Permanente neonatal sepsis calculator can be used as an alternative to the framework outlined in recommendation 1.3.5 for babies born after 34+0 weeks of pregnancy who are being cared for in a neonatal unit, transitional care or postnatal ward. It should only be used if it is part of a prospective audit, which should record:
total number of babies assessed using the calculator
number of babies correctly identified by the calculator who develop a culture-confirmed neonatal infection
number of babies incorrectly identified by the calculator who do not develop a culture-confirmed neonatal infection
number of babies missed by the calculator who develop a culture-confirmed neonatal infection.
If using the Kaiser Permanente neonatal sepsis calculator (see recommendation 1.3.6) to assess the risk of early-onset neonatal infection, use the classification given by the calculator to direct management decisions.
# Management for babies at increased risk of infection
In babies being monitored for possible early-onset neonatal infection:
consider starting antibiotic treatment (see recommendations 1.4.1 to 1.4.8 on investigations before starting antibiotics, and recommendations 1.5.1 to 1.5.9 on which antibiotics to use).
if no further concerns arise during observation reassure the family and, if the baby is to be discharged, give information and advice to the parents and carers (see recommendations 1.1.12 and 1.1.13).
If a baby needs antibiotic treatment, give this as soon as possible and always within 1 hour of the decision to treat.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on risk factors for and clinical indicators of possible early-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review D: maternal and neonatal risk factors.
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# Investigations before starting antibiotics in babies who may have early-onset infection
When starting antibiotic treatment in babies who may have early-onset neonatal infection (see recommendations on recognising risk factors and clinical indicators), perform a blood culture before giving the first dose.
Measure baseline C-reactive protein concentration when starting antibiotic treatment in babies who may have early-onset neonatal infection.
If it is safe to do so, perform a lumbar puncture to obtain a cerebrospinal fluid sample when:
there is a strong clinical suspicion of early-onset neonatal infection or
there are clinical symptoms or signs suggesting meningitis.
Do not routinely perform urine microscopy or culture as part of the investigations for early-onset neonatal infection.
Do not perform skin swab microscopy or culture as part of the investigations for early-onset neonatal infection if there are no clinical signs of a localised infection.
## Advice for site-specific infections
Be aware that, although minor conjunctivitis with encrusted eyelids is common and often benign, a purulent discharge may indicate a serious infection (for example, with chlamydia or gonococcus).
In babies with a purulent eye discharge take swab samples urgently for microbiological investigation, using methods that can detect chlamydia and gonococcus. Start systemic antibiotic treatment for possible gonococcal infection while waiting for the swab microbiology results.
In babies with clinical signs of umbilical infection, such as a purulent discharge or signs of periumbilical cellulitis (for example, redness, increased skin warmth or swelling):
perform a blood culture and
take a swab sample for microscopy and culture and
start antibiotic treatment with intravenous flucloxacillin and gentamicin (see recommendations 1.5.3 and 1.5.4).If the microbiology results show that the infection is not caused by a Gram-negative bacterium, stop the gentamicin.
# Antibiotics for suspected early-onset infection
Use intravenous benzylpenicillin with gentamicin as the first-choice antibiotic regimen for empirical treatment of suspected early-onset infection, unless microbiological surveillance data show local bacterial resistance patterns that indicate the need for a different antibiotic.
Give benzylpenicillin in a dosage of 25 mg/kg every 12 hours. Consider shortening the dose interval to every 8 hours, based on clinical judgement (for example, if the baby appears very ill).
Give gentamicin in a starting dose of 5 mg/kg (see recommendation 1.5.4).
When prescribing gentamicin, be aware that:
the summary of product characteristics recommends a dosage of 4 to 7 mg/kg/day administered in a single dose
the evidence reviewed for the guideline supports a starting dosage of 5 mg/kg every 36 hours administered in a single dose.In 2021, a dosage of 5 mg/kg every 36 hours is an off-label use of gentamicin. See NICE's information on prescribing medicines.
If a second dose of gentamicin is given (see recommendation 1.6.3) this should usually be 36 hours after the first dose. Use a shorter interval if clinical judgement suggests this is needed, for example if:
the baby appears very ill
the blood culture shows a Gram-negative infection.
Take account of blood gentamicin concentrations when deciding on subsequent gentamicin dosing regimen (see recommendations 1.15.1 to 1.15.8).
Record the times of:
gentamicin administration
sampling for therapeutic monitoring.
Regularly reassess the clinical condition and results of investigations in babies receiving antibiotics. Consider whether to change the antibiotic regimen, taking account of:
the baby's clinical condition (for example, if there is no improvement)
the results of microbiological investigations
expert microbiological advice, including local surveillance data.
If there is microbiological evidence of Gram-negative bacterial sepsis, add another antibiotic to the benzylpenicillin and gentamicin regimen that is active against Gram-negative bacteria (for example, cefotaxime). If Gram-negative infection is confirmed, stop benzylpenicillin.
# Duration of antibiotic treatment for early-onset neonatal infection
## Investigations during antibiotic treatment for early-onset neonatal infection
In babies given antibiotics because of risk factors for infection or clinical indicators of possible early-onset infection, measure the C-reactive protein concentration 18 to 24 hours after presentation.
Consider performing a lumbar puncture to obtain a cerebrospinal fluid sample in a baby who did not have a lumbar puncture at presentation who is receiving antibiotics, if it is thought safe to do so and if:
the baby has a positive blood culture (other than coagulase negative staphylococcus) or
the baby does not respond satisfactorily to antibiotic treatment, or
there is a strong clinical suspicion of infection or
there are clinical symptoms or signs suggesting meningitis.
## Decisions 36 hours after starting antibiotic treatment
In babies given antibiotics because of risk factors for early-onset infection or clinical indicators of possible infection, consider stopping the antibiotics at 36 hours if:
the blood culture is negative and
the initial clinical suspicion of infection was not strong and
the baby's clinical condition is reassuring, with no clinical indicators of possible infection and
the levels and trends of C-reactive protein concentration are reassuring.
Consider establishing hospital systems to provide blood culture results 36 hours after starting antibiotics, to allow timely stopping of treatment and discharge from hospital.
Healthcare professionals with specific experience in neonatal infection should be available every day to give clinical microbiology or paediatric infectious disease advice.
## Treatment duration for early-onset neonatal infection without meningitis
Give antibiotic treatment for 7 days for babies with a positive blood culture, and for babies with a negative blood culture if sepsis has been strongly suspected. Consider continuing antibiotic treatment for more than 7 days if:
the baby has not yet fully recovered or
this is advisable because of the pathogen identified on blood culture (seek expert microbiological advice if necessary).
If continuing antibiotics for longer than 36 hours despite negative blood cultures, review the baby at least once every 24 hours. Consider at each review whether it is appropriate to stop antibiotic treatment, taking account of:
the level of initial clinical suspicion of infection and
the baby's clinical progress and current condition and
the levels and trends of C-reactive protein concentration.
# Antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection
Do not use rifampicin-miconazole-impregnated catheters for newborn babies.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review F: intravascular catheters.
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# Risk factors for and clinical indicators of possible late-onset neonatal infection
When assessing or reviewing a baby:
Check for, the possible clinical indicators of late-onset neonatal infection shown in table 2.
take into account that prematurity, mechanical ventilation, history of surgery and presence of a central catheter are associated with greater risk of late-onset neonatal infection.
Think about infection in the other babies when one baby from a multiple birth has infection.
Seek early advice from a paediatrician when late-onset infection is suspected in non-inpatient settings.
Refer to the NICE guidelines on fever in under 5s and sepsis when assessing babies for late-onset neonatal infection who have been admitted to the hospital from home. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Category
Indicators
Behaviour
Parent or care-giver concern for change in behaviour
Appears ill to a healthcare professional
Does not wake, or if roused does not stay awake
Weak high-pitched or continuous cry
Respiratory
Raised respiratory rate: 60 breaths per minute or more
Grunting
Apnoea
Oxygen saturation of less than 90% in air or increased oxygen requirement over baseline
Circulation and hydration
Persistent tachycardia: heart rate 160 beats per minute or more
Persistent bradycardia: heart rate less than 100 beats per minute
Skin
Mottled or ashen appearance
Cyanosis of skin, lips or tongue
Non-blanching rash of skin
Other
Temperature 38°C or more unexplained by environmental factors
Temperature less than 36°C unexplained by environmental factors
Alterations in feeding pattern
Abdominal distension
Seizures
Bulging fontanelle
This table has been adapted from the high-risk criteria in table 3 of the NICE guideline on sepsis.
Timing of antibiotics for late-onset neonatal infection
If a baby needs antibiotic treatment, give this as soon as possible and always within 1 hour of the decision to treat.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on risk factors for and clinical indicators of possible late-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review E: risk factors for late-onset neonatal infection.
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# Investigations before starting antibiotics in babies who may have late-onset infection
When starting antibiotic treatment in babies who may have late-onset neonatal infection (see recognising risk factors and clinical indicators), perform a blood culture before giving the first dose.
Measure baseline C-reactive protein concentration when starting antibiotic treatment in babies who may have late-onset neonatal infection. Use this together with later readings to assess the likelihood of infection and response to treatment.
If it is safe to do so, perform a lumbar puncture to obtain a cerebrospinal fluid sample when:
there is a strong clinical suspicion of neonatal infection or
there are clinical symptoms or signs suggesting meningitis.
Do not routinely perform urine microscopy or culture as part of the investigations for late-onset neonatal infection for babies in neonatal units.
Perform urine microscopy and culture for babies outside of neonatal units in line with the NICE guideline on urinary tract infection in under 16s.
Do not perform skin swab microscopy or culture as part of the investigations for late-onset neonatal infection if there are no clinical signs of a localised infection.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on investigations for late-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review G: investigations before starting treatment.
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# Antibiotics for late-onset neonatal infection
## Choice of antibiotics
For babies with suspected late-onset neonatal infection who are already in a neonatal unit:
give a combination of narrow-spectrum antibiotics (such as intravenous flucloxacillin plus gentamicin) as first-line treatment
use local antibiotic susceptibility and resistance data (or national data if local data are inadequate) when deciding which antibiotics to use
give antibiotics that are effective against both Gram-negative and Gram-positive bacteria
if necrotising enterocolitis is suspected, also include an antibiotic that is active against anaerobic bacteria (such as metronidazole).
For babies with suspected late-onset neonatal infection or meningitis who have been admitted from home, treat according to recommendation 1.7.12 in the NICE guideline on sepsis.
When using gentamicin, see recommendations 1.15.1 to 1.15.8 on therapeutic drug monitoring for gentamicin.
# Duration of antibiotic treatment for late-onset neonatal infection
## Investigations during antibiotic treatment for late-onset neonatal infection
In babies given antibiotics because of risk factors for infection or clinical indicators of possible late-onset neonatal infection, measure the C‑reactive protein concentration 18 to 24 hours after starting antibiotics.
Consider performing a lumbar puncture to obtain a cerebrospinal fluid sample in a baby who did not have a lumbar puncture at presentation who is receiving antibiotics, if it is thought safe to do so and if:
the baby has a positive blood culture (other than coagulase negative staphylococcus) or
the baby does not respond satisfactorily to antibiotic treatment, or
there is a strong clinical suspicion of infection or
there are clinical symptoms or signs suggesting meningitis.
## Decisions 48 hours after starting antibiotic treatment
For babies given antibiotics because of suspected late-onset infection, consider stopping the antibiotics at 48 hours if:
the blood culture is negative and
the initial clinical suspicion of infection was not strong and
the baby's clinical condition is reassuring, with no clinical indicators of possible infection and
the levels and trends of C‑reactive protein concentration are reassuring.
Healthcare professionals with specific experience in neonatal infection should be available every day to give clinical microbiology or paediatric infectious disease advice.
## Treatment duration for late-onset neonatal infection without meningitis
Give antibiotic treatment for 7 days for babies with a positive blood culture. Consider continuing antibiotic treatment for more than 7 days if:
the baby has not yet fully recovered or
longer treatment is needed because of the pathogen identified on blood culture (for example, Gram-negative bacteria or Staphylococcus aureus; seek expert microbiological advice if necessary) or
longer treatment is needed because of the site of the infection (such as intra-abdominal co-pathology, necrotising enterocolitis, osteomyelitis or infection of a central venous catheter).
Use a shorter treatment duration than 7 days when the baby makes a prompt recovery, and either no pathogen is identified or the pathogen identified is a common commensal (for example, coagulase negative staphylococcus).
If continuing antibiotics for longer than 48 hours for suspected late‑onset neonatal infection despite negative blood culture, review the baby at least once every 24 hours. At each review, decide whether to stop antibiotics, taking account of:
the level of initial clinical suspicion of infection and
the baby's clinical progress and current condition and
the levels and trends of C-reactive protein.
For guidance on treatment duration for suspected or confirmed meningitis, refer to the section on meningitis (babies in neonatal units).
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on antibiotics for late-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review H: antibiotics.
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# Antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection
Give prophylactic oral nystatin to babies treated with antibiotics for suspected late-onset neonatal bacterial infection if they:
have a birthweight of up to 1,500 g or
were born at less than 30 weeks' gestation. If oral administration of nystatin is not possible, give intravenous fluconazole. In April 2021, this was an off-label use of fluconazole. See NICE's information on prescribing medicines and use clinical judgement to determine the dosage.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review I: antifungals.
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# Avoiding routine use of antibiotics in babies
Do not routinely give antibiotic treatment to babies without risk factors for infection or clinical indicators or laboratory evidence of possible infection.
# Early- and late-onset meningitis (babies in neonatal units)
If a baby is in a neonatal unit and meningitis is suspected but the causative pathogen is unknown (for example, because the cerebrospinal fluid Gram stain is uninformative), treat with intravenous amoxicillin and cefotaxime.
If a baby is in a neonatal unit and meningitis is shown (by either cerebrospinal fluid Gram stain or culture) to be caused by Gram-negative infection, stop amoxicillin and treat with cefotaxime alone.
If a baby is in a neonatal unit and meningitis is shown (by cerebrospinal fluid Gram stain) to be caused by a Gram-positive bacterium:
continue treatment with intravenous amoxicillin and cefotaxime while waiting for the cerebrospinal fluid culture result and
seek expert microbiological advice.
If the cerebrospinal fluid culture is positive for group B streptococcus, consider changing the antibiotic treatment to:
benzylpenicillin 50 mg/kg every 12 hours, normally for at least 14 days and
gentamicin, with:
a starting dosage of 5 mg/kg every 36 hours (see recommendation 1.5.3)
subsequent doses and intervals adjusted if necessary based on clinical judgement (see recommendation 1.5.5) and blood gentamicin concentrations (see recommendations 1.15.1 to 1.15.3)
treatment lasting for 5 days.
If the blood culture or cerebrospinal fluid culture is positive for listeria, consider stopping cefotaxime and treating with amoxicillin and gentamicin.
If the cerebrospinal fluid culture identifies a Gram-positive bacterium other than group B streptococcus or listeria, seek expert microbiological advice on management.
For a short explanation of why the committee amended the 2012 recommendations and how they might affect practice, see the rationale and impact section on early- and late-onset meningitis .
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## Discharge after antibiotic treatment
After antibiotic treatment, consider prompt discharge of the baby from hospital, with support for the parents and carers and a point of contact for advice.
# Therapeutic drug monitoring for babies receiving gentamicin
## Trough concentrations
If giving a second dose of gentamicin, measure the trough blood gentamicin concentration immediately before giving the second dose. Take the trough concentrations into account before giving the third dose of gentamicin.
Repeat the measurement of trough concentrations immediately before every subsequent third dose of gentamicin, or more frequently if necessary (for example, if there has been concern about previous trough concentrations or renal function).
Hospital services should make blood gentamicin concentrations available to healthcare professionals in time to inform the next dosage decision.
Adjust the gentamicin dose interval, aiming to achieve trough concentrations of less than 2 mg/litre. If the course of gentamicin lasts for more than 3 doses, aim for a trough concentration of less than 1 mg/litre.
Do not withhold a dose of gentamicin because of delays in getting a trough concentration measurement, unless there is evidence of impaired renal function (for example, an elevated serum urea or creatinine concentration, or anuria).
## Peak concentrations
Consider measuring peak blood gentamicin concentrations in selected babies, such as in those with:
-edema
macrosomia (birthweight more than 4.5 kg)
an unsatisfactory response to treatment
proven Gram-negative infection.
When measuring peak blood gentamicin concentrations, take the measurement 1 hour after starting gentamicin.
If a baby has a Gram-negative or staphylococcal infection, consider increasing the dose of gentamicin if the peak concentration is less than 8 mg/litre.
# Care setting
Using clinical judgement, consider completing a course of intravenous antibiotics outside of hospital (for example, at home or through visits to a midwifery-led unit) in babies who are well and for whom there are no ongoing concerns if there is adequate local support.
When deciding on the appropriate care setting for a baby, take into account the baby's clinical needs and the competencies needed to ensure safe and effective care (for example, the insertion and care of intravenous cannulas).
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.
## Early-onset neonatal infection
Neonatal infection less than 72 hours after birth.
## Late-onset neonatal infection
Neonatal infection 72 hours or more after birth.
## Peak blood gentamicin concentration
The level of gentamicin in the baby's bloodstream shortly after administration. The blood sample is usually taken about 1 hour after giving the drug. High peak concentrations of gentamicin are necessary to kill bacteria.
## Severe penicillin allergy
A history of allergy to penicillin with effects that are clearly likely to be allergic in nature such as anaphylaxis, respiratory distress, angioedema or urticaria.
## Therapeutic monitoring
A process of measuring the concentration of a drug in the bloodstream, to avoid excessive levels that might be associated with adverse effects or to ensure adequate levels for therapeutic effect.
## Trough blood gentamicin concentration
The level of gentamicin in the baby's bloodstream shortly before a further dose is given. High trough gentamicin concentrations may be associated with an increased risk of adverse effects.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Risk factors for and clinical indicators of early-onset infection
What is the accuracy of clinical prediction models for early-onset neonatal infection in the UK and what is their effectiveness in guiding management in the baby?
What is the risk of early-onset neonatal infection with maternal obesity and how does this change with increasing body mass index?
For a short explanation of why the committee made these recommendations for research, see the rationale on risk factors for and clinical indicators of possible early-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review D: maternal and neonatal risk factors.
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## Investigations for babies who may have early-onset infection
What is the clinical and cost effectiveness of laboratory investigations used individually or in combination to exclude early-onset neonatal infection in babies receiving antibiotics for suspected infection?
## Antibiotics for suspected early-onset neonatal infection
What is the optimal duration of treatment (course length) in babies who receive antibiotics for confirmed early-onset neonatal infection?
## Risk factors for and clinical indicators of late-onset infection
What is the accuracy of new or existing clinical prediction models for late-onset neonatal infection in the UK and what is their effectiveness in guiding management:
for babies already on a neonatal unit?
for babies admitted from home?
For a short explanation of why the committee made the recommendation for research, see the rationale on risk factors for and clinical indicators of possible late-onset infection .
Full details of the evidence and the committee's discussion are in evidence review E: risk factors for late onset.
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## Antibiotics for suspected late-onset neonatal infection
What is the optimal antibiotic treatment regimen for suspected late-onset neonatal infection?
For a short explanation of why the committee made the recommendation for research, see the rationale on antibiotics for late-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review H: antibiotics.
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## Impact of neonatal infection on the baby's family
What is the impact of neonatal infection on the health-related quality of life of the baby's family?
For a short explanation of why the committee made the recommendation for research, see the rationale on women with prolonged prelabour rupture of membranes .
Full details of the evidence and the committee's discussion are in evidence review C: timing of delivery.
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# Other recommendations for research
## Information and support
How does each step in the care pathway for prevention and treatment of early-onset neonatal infection impact on babies and their families?
What is the clinical and cost effectiveness of information and support offered to parents and carers of babies who have received antibiotics for suspected or proven early-onset neonatal infection?
## Intrapartum antibiotics
What is the clinical and cost effectiveness of intrapartum antibiotics for women with meconium-stained amniotic fluid?
For a short explanation of why the committee made the recommendation for research, see the rationale on intrapartum antibiotics .
Full details of the evidence and the committee's discussion are in evidence review B: intrapartum antibiotics.
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## Antibiotics for suspected early-onset infection
What is the incidence in England and Wales of resistance to commonly used antibiotics among bacteria that cause early-onset neonatal infection?
What is the optimal antibiotic dosage regimen for the treatment of early-onset neonatal infection?
What is the incidence and severity of adverse effects with antibiotics used to prevent or treat early-onset neonatal infection?
What are the core exposures and outcomes that should be used to evaluate clinical effectiveness of antibiotics to prevent or treat early- onset neonatal infection?
## Intravascular catheters for reducing the risk of late-onset neonatal infection
What is the effectiveness of antimicrobial-impregnated catheters other than those impregnated with rifampicin and miconazole for preventing late-onset catheter-related bloodstream infections in newborn babies?
What is the effectiveness of catheters impregnated with silver zeolite for preventing late-onset catheter-related bloodstream infections in newborn babies?
For a short explanation of why the committee made these recommendations for research, see rationale on antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review F: intravascular catheters.
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## Antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection
What is the optimum regimen (including treatment duration and dose) for using antifungals to prevent secondary fungal infection associated with antibiotic treatment for late-onset neonatal infection?
For a short explanation of why the committee made this recommendation for research, see the rationale on antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection .
Full details of the evidence and the committee's discussion are in evidence review I: antifungals.
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## Early and late-onset meningitis
What is the optimal antibiotic treatment regimen for early-onset neonatal meningitis?
## Care setting
What is the clinical and cost effectiveness of different models of care for the prevention and treatment of early-onset neonatal infection? # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Information and support
Recommendations 1.1.1 to 1.1.13
## Why the committee made the recommendations
The committee decided that some of the information and support recommendations in the previous version of the NICE guideline on neonatal infection for the families of babies with early-onset infection were also applicable to the families of babies who may develop late-onset infection.
The previous version of the guideline on early-onset infection recommended that parents and carers of babies with risk factors for early-onset infection should be given verbal and written information on the signs and symptoms of infection. This is particularly important when the baby already has risk factors that indicate they may develop infection. However, the committee noted that any baby can develop an infection, even if they are not identified as high risk at the time of discharge. The committee therefore thought it was important that all parents and carers should be given information about the signs and symptoms of neonatal infection before their baby is discharged from hospital.
The committee also wanted to ensure that the signs of infection listed in the recommendations were written in simple language that families could understand, rather than using clinical terminology. Therefore, examples of the most common breathing problems experienced by babies with neonatal infection were added to the recommendation on signs and symptoms.
The committee thought it was important that information was given in accessible formats, including different languages where appropriate to ensure that information was equally accessible to all. They noted these principles are outlined in the NICE guideline on patient experience in adult NHS services and so cross-referred to this guideline.
## How the recommendations might affect practice
These recommendations have been adapted from the existing guidelines for early-onset neonatal infection, reflecting standard practice. As such, they are not expected to have a substantial impact on practice. Expanding the recommendation on signs and symptoms so that advice is given to all parents and carers will mean that more families will be aware of the signs of infection and will know to seek medical help if their baby develops any of them.
Return to recommendations
# Intrapartum antibiotics
Recommendations 1.2.1 to 1.2.5
## Why the committee made the recommendations
No new evidence was identified since 2012, when the previous version of the guideline was published. The committee extended the 2012 recommendation on antibiotics for group B streptococcus to cover women who had colonisation in a previous pregnancy. This was because group B streptococcus colonisation in a previous pregnancy greatly increases the chance of being colonised in future pregnancies. The committee were concerned about a woman not receiving treatment because of a false negative test result, and so they decided to specify that a negative test should be from enrichment culture or PCR on rectovaginal swab samples. Although some tests may have higher false positive rates, all women with positive tests should be treated as if they have GBS so that no babies who are at higher risk of infection are missed.
For women in pre-term labour and women with a clinical diagnosis of chorioamnionitis, there was no evidence identified on the effects on intrapartum antibiotics on the number of neonatal infections. However, antibiotics did reduce the number of maternal infections in women in pre-term labour. The committee also agreed that pre-term labour and chorioamnionitis are important risk factors for neonatal infection, so intrapartum antibiotics are very likely to reduce the risk to the baby. Chorioamnionitis is a serious infection that needs to be treated with antibiotics to prevent harm to the mother. The committee thought that it was important to make recommendations for antibiotic treatment that would simultaneously treat infection in the mother and prevent early-onset group B streptococcal infection in the baby to make the best use of antibiotics.
The committee retained the recommendations on using benzylpenicillin as first-choice antibiotic from the 2012 guideline. Based on their knowledge and experience, gentamicin and metronidazole are also now recommended for women with chorioamnionitis, because chorioamnionitis can be caused by Gram positive or negative aerobic and anaerobic bacteria, so clinicians need to use broad-spectrum antibiotics that are effective against both. Once-daily dosing for gentamicin was recommended based on the knowledge and experience of the committee because 8 hourly dosing has additional monitoring requirements and would need additional nursing time for administration.
The committee also provided guidance on alternatives for women with a penicillin allergy, based on their knowledge and experience. The committee amended the 2012 recommendation on antibiotic alternatives for women who are allergic to penicillin. They changed the recommended antibiotic from clindamycin because there is evidence of resistance to group B streptococcus emerging with clindamycin, meaning that this antibiotic should no longer be used routinely. Based on their knowledge and experience, the committee recommended a cephalosporin with activity against group B streptococcus as an alternative for women with a penicillin allergy that was not severe, and vancomycin or an alternative antibiotic with activity against group B streptococcus in the case of severe penicillin allergy. The committee were aware of the possibility of allergic reaction to cephalosporins in women with a history of penicillin allergy. For women with a history of penicillin allergy that was not severe they thought that this risk was small and was outweighed by the benefits of using cephalosporins to treat chorioamnionitis and prevent neonatal infection. They noted that cephalosporins should be used with caution in these women. Cephalosporins were not recommended in the case of severe penicillin allergy because of an increased chance of a severe allergic reaction to cephalosporins. Severe penicillin allergy refers to a history of allergy to penicillin with effects that are clearly likely to be allergic in nature such as anaphylaxis, respiratory distress, angioedema or urticaria.
## How the recommendations might affect practice
Many of the recommendations remain the same as in the 2012 guideline. The recommendations on intrapartum antibiotics have been extended to cover women in pre-term labour without prelabour rupture of membranes, women with chorioamnionitis and women with group B streptococcus colonisation in a previous pregnancy. However, these changes reflect current practice, as many of these women already receive intrapartum antibiotics.
The committee expected that the recommendation on intrapartum antibiotics for chorioamnionitis would have the greatest impact on clinical practice. There is currently variation in which antibiotics are given to women with chorioamnionitis, with some units prescribing broad-spectrum antibiotics to treat infection in the mother and benzylpenicillin to prevent infection in the baby. Recommending a combination of narrow-spectrum antibiotics for women without an allergy to penicillin is likely to reduce the use of broad-spectrum antibiotics, which will improve antibiotic stewardship.
Return to recommendations
# Women with prolonged prelabour rupture of membranes who have group B streptococcal colonisation, bacteriuria or infection
Recommendation 1.2.6
## Why the committee made the recommendation
The evidence suggested that immediate delivery can result in a reduced risk of a baby developing neonatal infection when a mother is between 34 and 37 weeks' gestation and has prolonged prelabour rupture of membranes and a positive test result for group B streptococcus. The evidence did not indicate any significant harms to the baby from choosing immediate delivery over expectant management. Therefore, the committee decided that, given the potential serious consequences of a baby developing neonatal infection, a recommendation in favour of immediate delivery was important. This was further supported by the economic evidence, which showed not only a clinical benefit to immediate delivery but also lower associated costs in comparison to expectant management, which has increased antenatal costs and higher rates of infections.
The committee made a recommendation for research on examining the health-related quality of life impact on parents or carers when a baby has neonatal infection. This information was not available and would have improved how well the economic model truly reflected the costs and health consequences of neonatal infection.
## How the recommendation might affect practice
This recommendation could increase the number of women who are offered immediate delivery when they have both prolonged prelabour rupture of membranes and a positive test for group B streptococcus. This in turn could reduce the number of babies who need to be treated for neonatal infection and also reduce the number of mothers who need to be monitored throughout the expectant management period. The exact impact of these recommendations will vary between those hospitals where group B streptococcus screening and testing is more routinely performed and those where it is not. Recommendations on group B streptococcus screening were outside of the scope of this guideline. An economic model suggested that increasing the number of women offered immediate delivery would reduce costs overall.
Return to recommendation
# Risk factors for and clinical indicators of possible early-onset neonatal infection
Recommendations 1.3.1 to 1.3.9
## Why the committee made the recommendations
No evidence was found that related specifically to this topic, and the committee agreed that the recommendations from the previous version of this guideline still reflected current best practice so did not need to be changed. These recommendations apply to all women with risk factors, including those who decline antibiotics, or those who either do not receive antibiotics or receive their first dose of antibiotics shortly before birth because of precipitate birth. As such, any women with risk factors should be monitored throughout labour, and these factors should be taken into account when assessing the risk of infection in the baby.
The committee based their recommendations on evidence on the accuracy of clinical decision models for early-onset neonatal infection, as well as evidence on individual neonatal and maternal risk factors.
There was uncertainty about how well the Kaiser Permanente neonatal sepsis calculator identified true cases of early-onset infection, because the studies included very few cases of infection that were confirmed by blood culture. This was a problem for the framework outlined in the 2012 version of the guideline as well, but the committee believed that the framework is more conservative and would lead to more antibiotics being prescribed than the Kaiser Permanente calculator (both appropriately and inappropriately). Evidence on the Kaiser Permanente neonatal sepsis calculator suggests that it is good at correctly identifying babies without neonatal infection, so reducing the amount of antibiotics that are prescribed unnecessarily. However, given the very serious consequences of missing an infection, the committee preferred the conservative approach from the framework in the 2012 guideline, with some amendments as outlined. However, as the evidence does not clearly show one option to be better and some UK centres currently use the Kaiser Permanente calculator, they also recommended this as an alternative, but only in the context of a research or audit project. By using the Kaiser Permanente calculator as part of an audit, centres will be able to collect detailed data on the use of the tool within NHS practice, including the number of babies who correctly received treatment, those who received antibiotics unnecessarily, and any who were not recommended antibiotics but did have infection. This information will provide a more detailed understanding of the effectiveness and safety of the Kaiser Permanente calculator which can be used to inform decisions on its use in future updates of this guideline.
The committee decided to specify that the Kaiser Permanente calculator should only be used for babies who are being cared for in a neonatal unit (neonatal intensive care units, local neonatal units and special care units), transitional care or a postnatal ward. The committee highlighted how it would be more difficult to collect the information needed for the audit in other settings. They did not think the calculator should be recommended for use in the emergency department, as babies who are brought in from home are likely to already be showing signs of being unwell and therefore need more immediate treatment than babies who are being assessed for risk of infection in a neonatal unit. In these cases, waiting to consult the calculator could instead delay treatment. The committee also thought that the calculator was not appropriate for use in a midwife-led unit or freestanding midwifery unit as there is currently no evidence that has used the calculator in these settings.
As there was only limited new evidence, the framework for assessing and managing risk, involving red flag indicators and other indicators of infection, has been retained from the 2012 guideline. The committee selected the red flag indicators as those that, based on their clinical experience, are the most high risk factors that need immediate treatment. Non-red flag indicators are those that can have causes other than neonatal infection and therefore do not always signal the need for immediate treatment. Many of the clinical indicators matched those in the 2012 guideline, with the following changes.
Parenteral antibiotics are no longer a risk factor. Since the 2012 guideline, awareness of the risks of maternal sepsis has increased and there has been a focus on early treatment with antibiotics. This has led to more babies being prescribed antibiotics even when a maternal infection is not strongly suspected. This rise in antibiotic use can result in babies being unnecessarily exposed to the side effects associated with antibiotics, such as nephrotoxicity, as well as increasing a baby's length of stay in hospital. Increased antibiotic use is also associated with an increase in the development of antibiotic resistance.
Chorioamnionitis and intrapartum fever are now separate risk factors because intrapartum fever has other potential causes. This change means that women with chorioamnionitis and intrapartum fever will have 2 risk factors, so their babies will receive antibiotics.
Invasive group B streptococcal infection in a previous baby and maternal group B streptococcal colonisation, bacteriuria or infection in the current pregnancy have been combined into a single risk factor, because having a previous baby with invasive group B streptococcal infection increases the risk of future colonisation and infection, but does not confer additional risk if infection, bacteriuria or infection in the current pregnancy is already known about.
Mechanical ventilation, which was previously a red flag risk factor pre-term babies, and a non-red flag risk factor for term babies has been merged into one recommendation. The committee agreed that mechanical ventilation is a risk factor for infection regardless of prematurity, and so they decided to merge these into one red flag risk factor which did not refer to whether a baby was born pre-term or at term.
Confirmed prelabour rupture of membranes was removed from the table because the committee decided that it is now covered by other risk factors in the table (pre-term birth and confirmed rupture of membranes in a pre-term or term birth). Babies born to mothers with prelabour rupture of membranes will therefore still receive treatment when using the updated version of the framework.
To address the limited evidence, the committee recommended further research on the accuracy of the Kaiser Permanente neonatal sepsis calculator and other clinical prediction models.
No evidence was found that related specifically to this topic, and the committee agreed that the recommendations from the previous version of this guideline still reflected current best practice so did not need to be changed.
## How the recommendations might affect practice
Many neonatal units use the framework from the 2012 version of the NICE guideline. Removal of parenteral antibiotics as a risk factor is expected to reduce the number of babies given antibiotics unnecessarily.
Some centres use the Kaiser Permanente neonatal sepsis calculator as an alternative, and the recommendations may increase the number of centres who use this calculator in the context of a research or audit project. Current evidence suggests that this may reduce the number of babies who are unnecessarily given antibiotics, but there was substantial uncertainty about how well the calculator identified true cases of infection. If an increase in use of the Kaiser calculator resulted in more cases of infection being missed, this could increase costs associated with treating neonatal infections, as well as the very serious impact on the baby and their families.
Reducing the number of babies being given antibiotics may reduce costs for the NHS, both by reducing prescriptions and by reducing the amount of time babies and their mothers spend in hospital.
Return to recommendations
# Antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection
Recommendation 1.7.1
## Why the committee made the recommendation
There were only 2 studies looking at antimicrobial-impregnated catheters in newborn babies:
One study looked at rifampicin-miconazole-impregnated catheters. These provided no benefit over standard catheters. In addition, they are more expensive than standard catheters.
The other study looked at silver-zeolite-impregnated catheters. They showed some benefit compared with standard catheters, but the study was small and the committee had concerns about its quality. It was also conducted in Italy, and there are differences in clinical practice and infection rates between Italy and the UK.
The committee agreed they could not recommend antimicrobial-impregnated catheters based on the available evidence. The recommendation against the use of rifampicin-miconazole-impregnated catheters was made on the basis of the evidence that they provide no additional benefit over a standard catheter, and not because of any safety concerns over their use. There is a wider range of antimicrobials that can be used to impregnate catheters than have currently been investigated in newborn babies and uncertainty over which type of impregnated catheter is the most effective and whether monotherapy or the use of more than one antimicrobial would provide the most benefits. To address the shortage of evidence they made recommendations for further research.
## How the recommendation might affect practice
The recommendation will reduce the use of rifampicin-miconazole-impregnated catheters. However, antimicrobial-impregnated catheters are not commonly used for newborn babies, so this should have a limited impact.
Return to recommendations
# Risk factors for and clinical indicators of possible late-onset neonatal infection
Recommendations 1.8.1 and 1.8.4
## Why the committee made the recommendations
The committee did not feel that there was sufficient, high-quality evidence for any individual model to make a recommendation on clinical prediction models for late‑onset neonatal infection. Instead, they recommended a review of the individual risk factors that may predict a baby's risk of having or developing late-onset neonatal infection.
Although there was evidence on a number of tools aimed at predicting late-onset neonatal infection, the committee did not think that there was sufficient, high quality, evidence including external validation to recommend any of them for use in practice. Most of the evidence was not from recent studies, the models were not readily available as web-based tools or in other formats that could be easily used by clinicians and it was thought that implementing them would have needed considerable changes in clinical practice.
Given the limited evidence currently available for prognostic models for late‑onset infection, the committee decided that they should make a recommendation for research. The recommendation is designed to encourage the development of new models to identify babies at risk of late-onset neonatal infection as well as promoting the validation of these models and evaluation of their effects on practice. This should help to improve the understanding of the factors associated with late-onset neonatal infection so that committees can make recommendations on this area in future guideline updates.
With limited evidence on prognostic models, the committee agreed that it was instead important for clinicians to be aware of the clinical indicators and risk factors for late-onset neonatal infection. There was very limited evidence on maternal risk factors for late-onset infection and so the recommendations were based on the risk factors and signs and symptoms in the baby. The committee decided that the list of high‑risk criteria from the risk stratification tool in the NICE guideline on sepsis (section 1.4, table 3) covered the most important indicators that clinicians in both community and specialist settings should be aware of. They included the recommendation to seek early advice from a paediatrician to highlight the importance of early treatment if any of the main clinical indicators are present. Early specialist advice was thought to be particularly important when caring for babies in the community as they need to be taken to hospital and admitted before treatment can begin, while babies who are on a neonatal unit can be monitored and treated more quickly. It was agreed that in addition to clinical indicators, it was also important to highlight potential risk factors for infection. This will help to ensure that babies who are at greater risk for infection are closely monitored for the presence of any of the clinical indicators. The committee also recommended that clinicians should think about infection in the other babies when one baby from a multiple birth has infection. Evidence was not found on this, but the committee thought that it was in line with current best practice because of the risk that all the babies from the pregnancy will have the same risk of infection.
There was very limited evidence on the signs and symptoms of infection. The committee was aware of existing recommendations on clinical indicators of infection in the NICE guideline on sepsis and so it considered this information when deciding on recommendations. It was agreed that the high-risk indicators listed in the sepsis guideline were an accurate reflection of the committee's experience with babies who develop late-onset infection. Parental or carer concern over changes in behaviour was added to the list of high-risk criteria as this was highlighted as an important indicator of potential infection for babies in the community. Other potential clinical indicators were discussed, but the committee were concerned about the risk of over-treatment if too many clinical indicators were listed in the recommendation, especially if some of those indicators could have causes other than neonatal infection. The committee decided that the signs included in the recommendation were those that were most likely to indicate infection and therefore the most important to consider when assessing whether a baby may need treatment.
## How the recommendations might affect practice
The recommendations are consistent with current practice and therefore a large resource impact is not anticipated. The table of clinical indicators may increase awareness of when a baby is at greater risk of late-onset neonatal infection. This may increase the number of babies who receive early treatment in hospital and reduce the negative effects and costs associated with infection.
Clinicians working on a neonatal or paediatric ward are already likely to be aware of the risk factors that were identified in the evidence review. As such, the recommendations are helpful to reinforce the knowledge of these clinicians about the risk factors but may not have a substantial effect on current practice in a hospital setting.
Return to recommendations
# Investigations for late-onset neonatal infection
Recommendations 1.9.1 to 1.9.6
## Why the committee made the recommendations
Blood culture is the current 'gold standard' for identifying neonatal infection. However, babies with late-onset infection can still sometimes have a negative blood culture. It can also take hours or days to get the results of blood cultures. These inaccuracies and delays mean that many babies receive treatment before blood culture results are returned, because delaying treatment could lead to complications or death. Having another diagnostic test as an alternative or an addition to blood culture results could therefore reduce unnecessary antibiotic treatment. The committee reviewed the evidence for late-onset infection. Of the other diagnostic tests, only C-reactive protein has enough evidence to recommend it. It is not accurate enough to be used as an alternative to blood culture, but when used in combination it can improve the accuracy of the diagnosis. The committee discussed how a single C-reactive protein measurement is not sufficient to diagnose infection, as this can vary between babies. They therefore decided to recommend that a C‑reactive protein sample is taken when starting antibiotics. This will provide clinicians with a baseline against which to compare future C-reactive protein results, to indicate whether a baby is likely to have infection, whether they are responding to treatment and when to consider stopping antibiotics. Blood culture is still considered the gold standard test for diagnosing neonatal infection but using it in combination with C-reactive protein measurements will allow babies who do not need antibiotics to stop taking them sooner.
As the evidence for late-onset infection lined up with the evidence from the 2012 guideline for early-onset infection, the committee amended the 2012 recommendations to cover all neonatal infection.
There was limited evidence on lumbar puncture specifically for late-onset infection. However, lumbar puncture is the 'gold standard' test for identifying meningitis, and it was recommended in the 2012 guideline for babies with early-onset infection. The committee extended this recommendation to cover both early- and late-onset neonatal infection, as they felt that the benefits of identifying meningitis outweighed the risks of the procedure.
No evidence was identified that supported using urine culture or skin swabs in the neonatal unit. These tests were also not recommended in the 2012 guideline for babies with early-onset infection and so the committee decided to recommend against their use for babies in neonatal units. However, they also discussed how urine culture can be an important test for babies in a paediatric ward if a urinary tract infection is suspected, so included a recommendation which supported its use in babies who are being cared for outside of neonatal units. This is consistent with the recommendations from the NICE guideline on urinary tract infection in under 16s.
## How the recommendations might affect practice
The recommendations are not expected to have a major impact on practice as they reflect the procedures currently followed in most hospitals.
Return to recommendations
# Antibiotics for late-onset neonatal infection
Recommendations 1.10.1 to 1.11.7
## Why the committee made the recommendations
There is variation across the country in antibiotic resistance patterns and in which organisms are most likely to cause late-onset neonatal infection. Because of this, local data needs to be used when choosing antibiotics.
Babies in a neonatal unit are likely to have been exposed to different bacteria than babies at home, so the committee made separate recommendations for the 2 groups.
For babies in a neonatal unit, the committee did not believe there was enough evidence to recommend specific antibiotics, and so made a recommendation for research into the best antibiotic regimen to treat late-onset infection. However, the evidence available did show that combinations of narrower‑spectrum antibiotics are as effective as broader-spectrum antibiotics. The committee were aware that using broad-spectrum antibiotics in babies is associated with altered gut flora, increased risk of invasive fungal infection and the development of antibiotic resistance, and so a combination of narrow spectrum antibiotics was recommended as first-line treatment.
For babies who have been admitted from home, there was also limited evidence on which antibiotics to use. The NICE guideline on sepsis recommends treating community-acquired sepsis with ceftriaxone or cefotaxime depending on gestational age. The committee agreed that these antibiotics would be appropriate for late-onset neonatal infection in babies who have been admitted from home, and none of the evidence for this group contradicted it.
There was no evidence on duration of antibiotic treatment for late-onset infection. However, the 2012 guideline made recommendations on this for early-onset infection, and the committee adapted these so that they were applicable to late-onset infection. The duration of initial treatment is recommended to be 48 hours rather than 36 hours as recommended for early-onset infection. This is thought to reflect the different bacteria that cause late-onset infection, which grow more slowly and have a lower load in the bloodstream. This means that it can take longer for a blood culture to become positive for late-onset than early-onset infection and so treatment needs to continue for longer until a negative blood culture result can be confirmed. To help with treatment decisions, the 2012 version of the guideline recommended that healthcare professionals with experience in neonatal infection should be available to provide microbiological or paediatric infection disease advice. The committee decided that this recommendation is also important when making decisions about antibiotic treatment for late-onset infection.
No evidence on treatment duration was identified, and so the committee made recommendations based on their knowledge and experience. The committee recommended a treatment of 7 days for babies with a positive blood culture, consistent with the recommendation on early-onset neonatal infection from the 2012 version of the guideline. The committee recommended that a shorter treatment duration should be used when no pathogen is identified (the blood culture is negative) or the pathogen is a common commensal. In these situations, the committee noted that infection was likely to be less severe and could be safely treated with a shorter treatment duration, which would have the advantage of reducing exposure to antibiotics, which is consistent with the principles of good antibiotic stewardship. The committee also specified situations when a longer treatment duration should be used, such as when there is intra-abdominal co-pathology, necrotising enterocolitis, osteomyelitis or infection of a central venous catheter. There was no evidence for the specific situations where longer treatment would be required, but the committee based their decisions on their knowledge and experience.
## How the recommendations might affect practice
These recommendations will help to reduce the use of broad-spectrum antibiotics as first-line treatment for babies in neonatal units, which may help reduce antibiotic resistance. However, use of narrow-spectrum antibiotics is already standard practice in many units, and the costs of antibiotics are low, so there is expected to be very little impact on resource use, especially as most of the affected babies are already receiving intensive care and monitoring.
The recommendation for babies admitted from home may not have a substantial impact on practice, as it refers to an existing recommendation in the NICE sepsis guideline.
The recommendations on duration of treatment are consistent with current practice.
Return to recommendations
# Antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection
Recommendations 1.12.1 and 1.12.2
## Why the committee made the recommendations
Evidence from randomised controlled trials showed that both nystatin and fluconazole can reduce the risk of a baby developing an invasive fungal infection in comparison to placebo or no treatment. Evidence marginally favoured the use of nystatin over fluconazole for reducing the risk of fungal infection and based on the knowledge and experience of the committee, nystatin is better tolerated and there is a lower risk of fungi developing resistance to this antifungal than fluconazole. Economic evidence showed that nystatin was also likely to be the most cost-effective option, and so the committee recommended oral nystatin for antifungal prophylaxis when a baby is being given antibiotics for late-onset neonatal infection. The recommendation for antifungal prophylaxis was limited to babies below 1,500 g or 30 weeks' gestational age because the evidence was from babies in these population groups.
Although oral nystatin was the committee's first choice for antifungal prophylaxis, oral administration of antifungals may not be possible for all babies, particularly those who are very premature. The committee therefore specified that the use of intravenous fluconazole is appropriate when oral administration is not possible.
The committee made a recommendation for research for studies investigating the optimum regimen for giving antifungal prophylaxis when treating a baby with antibiotics for late-onset infection, because evidence was not available to support specific recommendations on the duration and dose of antifungal treatment that should be used.
## How the recommendations might affect practice
This recommendation may increase the number of babies who are given nystatin as antifungal prophylaxis when they are prescribed antibiotics for late-onset infection. This should decrease the number of babies who need to be treated for fungal infection which, although rare, can have serious consequences. Economic modelling showed that giving antifungal prophylaxis is likely to be cost saving because of a reduction in costs associated with treating invasive fungal infections and their consequences.
Return to recommendations
# Early- and late-onset meningitis (babies in neonatal units)
Recommendations 1.14.1 to 1.14.6
## Why the committee amended the recommendations
These recommendations were carried forward from the 2012 version of the guideline, but were expanded to cover both early- and late-onset neonatal meningitis for babies in neonatal units based on the knowledge and experience of the committee. Evidence relating to these recommendations was not reviewed for late-onset meningitis, but the committee agreed that the recommendations that were made in 2012 for early-onset infection would also apply to late-onset meningitis for babies treated in neonatal units.
Return to recommendations# Context
Neonatal bacterial infection is a significant cause of mortality and morbidity in newborn babies. Parent organisations and the scientific literature report that there can be unnecessary delays in recognising and treating sick babies. In addition, concern about the possibility of neonatal infection is common. This concern is an important influence on the care given to pregnant women and newborn babies. There is wide variation in how the risk of neonatal infection is managed in healthy babies. The approach taken by the NHS needs to:
prevent neonatal infection when possible
prioritise the treatment of sick babies
minimise the impact of management pathways on healthy women and babies
use antibiotics wisely to avoid the development of resistance to antibiotics.
These drivers have not always been addressed consistently in the NHS, and this guideline was commissioned to ensure they would be addressed in future.
Five key principles underpin the recommendations in this guideline:
Unless it is dangerous, families should be offered choice. The guideline includes recommendations to support families in making choices through provision of information and, when appropriate, reassurance.
Intrapartum antibiotic prophylaxis should be administered in a timely manner to all eligible women who choose it.
Babies with suspected neonatal infection should receive treatment as quickly as possible.
Antibiotic exposure should be minimised in babies who do not have a neonatal infection.
An integrated system of clinical care is needed to allow full implementation of the guideline recommendations.
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{'Recommendations': "Parents and carers have the right to be involved in planning and making decisions about their baby's health and care, and to be given information and support to enable them to do this, as set out in the NHS Constitution and summarised in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nPlease note that the Royal College of Obstetricians and Gynaecologists has produced guidance on COVID-19 and pregnancy for all midwifery and obstetric services. The Royal College of Paediatrics and Child Health has published guidance on COVID-19 for neonatal services.\n\nThroughout this guideline, unless otherwise specified, the term neonatal infection covers both early-onset and late-onset infections.\n\n# Information and support\n\nFor guidance on communication (including different formats and languages), providing information, and shared decision making, see the NICE guidelines on patient experience in adult NHS services, babies, children and young people's experience of healthcare and shared decision making.\xa0\n\n## Parents and carers of babies at increased risk of neonatal infection\n\nIf clinical concerns about possible neonatal infection arise at any point:\n\ntalk to the baby's parents and carers, explaining the reason for concern, and explain what neonatal infection is\n\ndiscuss the options for management that may be best for their baby (for example, observation, investigations or antibiotic treatment)\n\ndo not delay treatment, but when possible give the baby's parents and carers time to think about the information they have been given and ask any questions they may have before making treatment decisions. \n\nIf giving antibiotics because of clinical concerns about possible early- or late-onset neonatal infection, discuss with parents and carers:\n\nthe reason for the treatment\n\nthe risks and benefits in relation to their baby's circumstances\n\nthe observations and investigations that might be needed to guide treatment (for example, to help decide when to stop treatment)\n\nthe preferred antibiotic regimen (including how it will be delivered) and likely duration of treatment\n\nthe impact, if any, on where the woman or her baby will be cared for. \n\nTo maintain communication with a woman in labour whose baby is at increased risk of early-onset neonatal infection:\n\ninvolve the woman in any handover of care, either when additional expertise is brought in because of the risk of infection or during planned changes in staff\n\ninclude an update in the handover about the presence of any infection.For more guidance, see the section on communication in the NICE guideline on intrapartum care. \n\nFor babies who are considered to be at increased risk of early-onset infection, inform their parents and GP about this verbally and in writing:\n\nwhen the baby is discharged from the hospital or midwifery-led unit or\n\nin the immediate postnatal period, if the baby was born at home. \n\nReassure parents and carers that babies who have or are at increased risk of neonatal infection can usually continue to breastfeed, and that every effort will be made to help with this. If a baby is temporarily unable to breastfeed, support the mother to express breast milk if she wishes to do so. \n\n## When a woman is identified as having group\xa0B streptococcal colonisation, bacteriuria or infection during her current pregnancy:\n\nadvise the woman that if she becomes pregnant again:\n\n\n\nthat her new baby will be at increased risk of early-onset group\xa0B streptococcal infection\n\nshe should inform her maternity care team that she has had a positive group B streptococcal infection test in a previous pregnancy\n\nher maternity care team will offer her antibiotics in labour\n\n\n\ninform the woman's GP in writing that there is a risk of group\xa0B streptococcal infection in babies in future pregnancies. [2012, amended 2021]\n\n## Parents and carers of babies treated for neonatal infection\n\nReassure parents and carers that they will be able to continue caring for and holding their baby according to their wishes, unless the baby is too ill to allow this. If the severity of the baby's illness means they need to change the way they care for the baby, discuss this with them. \n\nOffer parents and carers contact details of organisations that provide parent support, befriending, counselling, information and advocacy. \n\nIf a baby has been treated for suspected or confirmed neonatal infection:\n\nadvise the parents and carers about potential long-term effects of the baby's illness and likely patterns of recovery, and reassure them if no problems are anticipated\n\ntake account of parents' and carers' concerns when providing information and planning follow-up. \n\nWhen a baby who has had a group\xa0B streptococcal infection is discharged from hospital:\n\nadvise the woman that if she becomes pregnant again:\n\n\n\nthat her new baby will be at increased risk of early-onset group\xa0B streptococcal infection\n\nshe should inform her maternity care team that she has had a previous baby with a group\xa0B streptococcal infection\n\nher maternity care team will offer her antibiotics in labour\n\n\n\ninform the woman's GP in writing that there is a risk of:\n\n\n\ngroup\xa0B streptococcal infection recurrence in the baby and\n\ngroup\xa0B streptococcal infection in babies in future pregnancies. \n\n\n\n## Parents and carers of all babies\n\nBefore any baby is transferred home from the hospital or midwifery-led unit (or in the immediate postnatal period in the case of babies born at home), advise parents and carers to seek urgent medical help (for example, from NHS 111, their GP, or an accident and emergency department) if they are concerned that their baby:\n\nis showing abnormal behaviour (for example, inconsolable crying or listlessness), or\n\nis unusually floppy, or\n\nhas an abnormal temperature unexplained by environmental factors (lower than 36°C or higher than 38°C), or\n\nhas abnormal breathing (rapid breathing, difficulty in breathing or grunting), or\n\nhas a change in skin colour (for example where the baby becomes very pale, blue/grey or dark yellow), or\n\nhas developed new difficulties with feeding.Give the advice both in person, and as written information and advice for them to take away. \n\n## Post-discharge planning for babies who have not been given antibiotics\n\nWhen there has been a clinical concern about neonatal infection in a baby, make a post-discharge management plan, taking into account factors such as:\n\nthe level of the initial clinical concern\n\nthe presence of risk factors\n\nparents' and carers' concerns. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information and support.\n\nLoading. Please wait.\n\n# Preventing early-onset neonatal infection before birth\n\n## Intrapartum antibiotics\n\nOffer antibiotics during labour to women who:\n\nare in pre-term labour or\n\nhave group\xa0B streptococcal colonisation, bacteriuria or infection during the current pregnancy or\n\nhave had group\xa0B streptococcal colonisation, bacteriuria or infection in a previous pregnancy, and have not had a negative test for group\xa0B streptococcus by enrichment culture or PCR on a rectovaginal swab samples collected between 35\xa0and 37\xa0weeks' gestation or 3-5\xa0weeks before the anticipated delivery date in the current pregnancy or\n\nhave had a previous baby with an invasive group\xa0B streptococcal infection or\n\nhave a clinical diagnosis of chorioamnionitis. \n\nUse table 1 to decide which antibiotic to use when giving intrapartum antibiotics for neonatal infection.\n\nAllergies\n\nWomen without chorioamnionitis\n\nWomen with chorioamnionitis\n\nNo penicillin allergy\n\nUse Benzylpenicillin.\n\nUse Benzylpenicillin plus gentamicin plus metronidazole.\n\nPenicillin allergy that is not severe\n\nUse Cephalosporin with activity against group\xa0B streptococcus (for example cefotaxime).\n\n\n\nUse with caution.\n\n\n\nIn April 2021 this was an off-label use of cephalosporins. See NICE's information on prescribing medicines.\n\nUse Cephalosporin with activity against group\xa0B streptococcus (for example cefotaxime) plus metronidazole.\n\n\n\nUse with caution.\n\n\n\nIn April 2021 this was an off-label use of cephalosporins. See NICE's information on prescribing medicines.\n\nSevere penicillin allergy\n\nConsider:\n\nVancomycin or\n\nAn alternative antibiotic that would be expected to be active against group\xa0B streptococcus based on either sensitivity testing performed on the woman's isolate or on local antibiotic susceptibility surveillance data.\n\n\n\nIn April 2021 this was an off-label use of vancomycin. See NICE's information on prescribing medicines.\n\nConsider:\n\nVancomycin plus gentamicin plus metronidazole or\n\nAn alternative antibiotic to vancomycin that would be expected to be active against group\xa0B streptococcus based on either sensitivity testing performed on the woman's isolate or on local antibiotic susceptibility surveillance data plus gentamicin plus metronidazole.\n\n\n\nIn April 2021 this was an off-label use of vancomycin. See NICE's information on prescribing medicines.\n\nIf using intravenous gentamicin during labour, use once-daily dosing. \n\nGive the first dose of antibiotics as soon as possible after labour starts (or as soon as infection is suspected, in the case of chorioamnionitis), and continue until the birth of the baby. \n\nBe aware that therapeutic drug monitoring may be needed when using gentamicin or vancomycin during labour. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on intrapartum antibiotics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: intrapartum antibiotics.\n\nLoading. Please wait.\n\n## Women with prolonged prelabour rupture of membranes who have group\xa0B streptococcal colonisation, bacteriuria or infection\n\nOffer an immediate birth (by induction of labour or caesarean birth) to women who are between 34\xa0and 37\xa0weeks' gestation who:\n\nhave prolonged prelabour rupture of membranes, and\n\nhave group\xa0B streptococcal colonisation, bacteriuria or infection at any time in their current pregnancy. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on women with prolonged prelabour rupture of membranes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: timing of delivery.\n\nLoading. Please wait.\n\n# Risk factors for and clinical indicators of possible early-onset neonatal infection\n\n## Before birth\n\nFor women in labour, identify and assess any risk factors for early-onset neonatal infection (see box 1). Throughout labour, monitor for any new risk factors. \n\nFor guidance on managing prelabour rupture of membranes at term, see the NICE guideline on intrapartum care. \n\n## Assessing and managing the risk of early-onset neonatal infection after birth\n\nIf there are any risk factors for early-onset neonatal infection (see box 1), or if there are clinical indicators of possible early-onset neonatal infection (see box 2):\n\nperform an immediate clinical assessment\n\nreview the maternal and neonatal history\n\ncarry out a physical examination of the baby, including an assessment of vital signs. \n\nIf group\xa0B streptococcus is first identified in the mother within 72\xa0hours after the baby's birth:\n\nask those directly involved in the baby's care (for example, a parent, carer, or healthcare professional) whether they have any concerns in relation to the clinical indicators listed in box 2, and\n\nidentify any other risk factors present, and\n\nlook for clinical indicators of infection.Use this assessment to decide on clinical management (see recommendation 1.3.5). \n\nRed flag risk factor:\n\nSuspected or confirmed infection in another baby in the case of a multiple pregnancy.\n\nOther risk factors:\n\nInvasive group\xa0B streptococcal infection in a previous baby or maternal group\xa0B streptococcal colonisation, bacteriuria or infection in the current pregnancy.\n\nPre-term birth following spontaneous labour before 37\xa0weeks' gestation.\n\nConfirmed rupture of membranes for more than 18\xa0hours before a pre-term birth.\n\nConfirmed prelabour rupture of membranes at term for more than 24\xa0hours before the onset of labour.\n\nIntrapartum fever higher than 38°C if there is suspected or confirmed bacterial infection.\n\nClinical diagnosis of chorioamnionitis.\n\nRed flag clinical indicators:\n\nApnoea (temporary stopping of breathing)\n\nSeizures\n\nNeed for cardiopulmonary resuscitation\n\nNeed for mechanical ventilation\n\nSigns of shock\n\nOther clinical indicators:\n\nAltered behaviour or responsiveness\n\nAltered muscle tone (for example, floppiness)\n\nFeeding difficulties (for example, feed refusal)\n\nFeed intolerance, including vomiting, excessive gastric aspirates and abdominal distension\n\nAbnormal heart rate (bradycardia or tachycardia)\n\nSigns of respiratory distress (including grunting, recession, tachypnoea)\n\nHypoxia (for example, central cyanosis or reduced oxygen saturation level)\n\nPersistent pulmonary hypertension of newborns\n\nJaundice within 24\xa0hours of birth\n\nSigns of neonatal encephalopathy\n\nTemperature abnormality (lower than 36°C or higher than 38°C) unexplained by environmental factors\n\nUnexplained excessive bleeding, thrombocytopenia, or abnormal coagulation\n\nAltered glucose homeostasis (hypoglycaemia or hyperglycaemia)\n\nMetabolic acidosis (base deficit of 10\xa0mmol/litre or greater)\n\nUse the following framework, based on the risk factors in box 1 and the clinical indicators in box 2, to make antibiotic management decisions as directed:\n\nIn babies with any red flag, or with 2 or more 'non-red-flag' risk factors or clinical indicators:\n\n\n\nfollow recommendations 1.4.1 to 1.4.8 on investigations before starting antibiotics, and\n\nstart antibiotic treatment according to recommendations 1.5.1 to 1.6.7, and\n\ndo not wait for the test results before starting antibiotics\n\n\n\nin babies without red flags and only 1 risk factor or 1 clinical indicator, use clinical judgement to decide:\n\n\n\nwhether it is safe to withhold antibiotics, and\n\nwhether the baby's vital signs and clinical condition need to be monitored. If monitoring is needed, continue for at least 12\xa0hours using a newborn early warning system\n\n\n\nfor babies without risk factors or clinical indicators of possible infection, continue routine postnatal care as covered in the NICE guideline on postnatal care. \n\n# Kaiser Permanente neonatal sepsis calculator\n\nThe Kaiser Permanente neonatal sepsis calculator can be used as an alternative to the framework outlined in recommendation 1.3.5 for babies born after 34+0\xa0weeks of pregnancy who are being cared for in a neonatal unit, transitional care or postnatal ward. It should only be used if it is part of a prospective audit, which should record:\n\ntotal number of babies assessed using the calculator\n\nnumber of babies correctly identified by the calculator who develop a culture-confirmed neonatal infection\n\nnumber of babies incorrectly identified by the calculator who do not develop a culture-confirmed neonatal infection\n\nnumber of babies missed by the calculator who develop a culture-confirmed neonatal infection. \n\nIf using the Kaiser Permanente neonatal sepsis calculator (see recommendation 1.3.6) to assess the risk of early-onset neonatal infection, use the classification given by the calculator to direct management decisions. \n\n# Management for babies at increased risk of infection\n\nIn babies being monitored for possible early-onset neonatal infection:\n\nconsider starting antibiotic treatment (see recommendations 1.4.1 to 1.4.8 on investigations before starting antibiotics, and recommendations 1.5.1 to 1.5.9 on which antibiotics to use).\n\nif no further concerns arise during observation reassure the family and, if the baby is to be discharged, give information and advice to the parents and carers (see recommendations 1.1.12 and 1.1.13). \n\nIf a baby needs antibiotic treatment, give this as soon as possible and always within 1\xa0hour of the decision to treat. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on risk factors for and clinical indicators of possible early-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: maternal and neonatal risk factors.\n\nLoading. Please wait.\n\n# Investigations before starting antibiotics in babies who may have early-onset infection\n\nWhen starting antibiotic treatment in babies who may have early-onset neonatal infection (see recommendations on recognising risk factors and clinical indicators), perform a blood culture before giving the first dose. \n\nMeasure baseline C-reactive protein concentration when starting antibiotic treatment in babies who may have early-onset neonatal infection. \n\nIf it is safe to do so, perform a lumbar puncture to obtain a cerebrospinal fluid sample when:\n\nthere is a strong clinical suspicion of early-onset neonatal infection or\n\nthere are clinical symptoms or signs suggesting meningitis. \n\nDo not routinely perform urine microscopy or culture as part of the investigations for early-onset neonatal infection. \n\nDo not perform skin swab microscopy or culture as part of the investigations for early-onset neonatal infection if there are no clinical signs of a localised infection. \n\n## Advice for site-specific infections\n\nBe aware that, although minor conjunctivitis with encrusted eyelids is common and often benign, a purulent discharge may indicate a serious infection (for example, with chlamydia or gonococcus). \n\nIn babies with a purulent eye discharge take swab samples urgently for microbiological investigation, using methods that can detect chlamydia and gonococcus. Start systemic antibiotic treatment for possible gonococcal infection while waiting for the swab microbiology results. \n\nIn babies with clinical signs of umbilical infection, such as a purulent discharge or signs of periumbilical cellulitis (for example, redness, increased skin warmth or swelling):\n\nperform a blood culture and\n\ntake a swab sample for microscopy and culture and\n\nstart antibiotic treatment with intravenous flucloxacillin and gentamicin (see recommendations 1.5.3 and 1.5.4).If the microbiology results show that the infection is not caused by a Gram-negative bacterium, stop the gentamicin. \n\n# Antibiotics for suspected early-onset infection\n\nUse intravenous benzylpenicillin with gentamicin as the first-choice antibiotic regimen for empirical treatment of suspected early-onset infection, unless microbiological surveillance data show local bacterial resistance patterns that indicate the need for a different antibiotic. \n\nGive benzylpenicillin in a dosage of 25\xa0mg/kg every 12\xa0hours. Consider shortening the dose interval to every 8\xa0hours, based on clinical judgement (for example, if the baby appears very ill). \n\nGive gentamicin in a starting dose of 5\xa0mg/kg (see recommendation 1.5.4). \n\nWhen prescribing gentamicin, be aware that:\n\nthe summary of product characteristics recommends a dosage of 4\xa0to\xa07\xa0mg/kg/day administered in a single dose\n\nthe evidence reviewed for the guideline supports a starting dosage of 5\xa0mg/kg every 36\xa0hours administered in a single dose.In 2021, a dosage of 5\xa0mg/kg every 36\xa0hours is an off-label use of gentamicin. See NICE's information on prescribing medicines. \n\nIf a second dose of gentamicin is given (see recommendation 1.6.3) this should usually be 36\xa0hours after the first dose. Use a shorter interval if clinical judgement suggests this is needed, for example if:\n\nthe baby appears very ill\n\nthe blood culture shows a Gram-negative infection. \n\nTake account of blood gentamicin concentrations when deciding on subsequent gentamicin dosing regimen (see recommendations 1.15.1 to 1.15.8). \n\nRecord the times of:\n\ngentamicin administration\n\nsampling for therapeutic monitoring. \n\nRegularly reassess the clinical condition and results of investigations in babies receiving antibiotics. Consider whether to change the antibiotic regimen, taking account of:\n\nthe baby's clinical condition (for example, if there is no improvement)\n\nthe results of microbiological investigations\n\nexpert microbiological advice, including local surveillance data. \n\nIf there is microbiological evidence of Gram-negative bacterial sepsis, add another antibiotic to the benzylpenicillin and gentamicin regimen that is active against Gram-negative bacteria (for example, cefotaxime). If Gram-negative infection is confirmed, stop benzylpenicillin. \n\n# Duration of antibiotic treatment for early-onset neonatal infection\n\n## Investigations during antibiotic treatment for early-onset neonatal infection\n\nIn babies given antibiotics because of risk factors for infection or clinical indicators of possible early-onset infection, measure the C-reactive protein concentration 18\xa0to 24\xa0hours after presentation. \n\nConsider performing a lumbar puncture to obtain a cerebrospinal fluid sample in a baby who did not have a lumbar puncture at presentation who is receiving antibiotics, if it is thought safe to do so and if:\n\nthe baby has a positive blood culture (other than coagulase negative staphylococcus) or\n\nthe baby does not respond satisfactorily to antibiotic treatment, or\n\nthere is a strong clinical suspicion of infection or\n\nthere are clinical symptoms or signs suggesting meningitis. [2012, amended 2021]\n\n## Decisions 36 hours after starting antibiotic treatment\n\nIn babies given antibiotics because of risk factors for early-onset infection or clinical indicators of possible infection, consider stopping the antibiotics at 36\xa0hours if:\n\nthe blood culture is negative and\n\nthe initial clinical suspicion of infection was not strong and\n\nthe baby's clinical condition is reassuring, with no clinical indicators of possible infection and\n\nthe levels and trends of C-reactive protein concentration are reassuring. \n\nConsider establishing hospital systems to provide blood culture results 36\xa0hours after starting antibiotics, to allow timely stopping of treatment and discharge from hospital. \n\nHealthcare professionals with specific experience in neonatal infection should be available every day to give clinical microbiology or paediatric infectious disease advice. \n\n## Treatment duration for early-onset neonatal infection without meningitis\n\nGive antibiotic treatment for 7 days for babies with a positive blood culture, and for babies with a negative blood culture if sepsis has been strongly suspected. Consider continuing antibiotic treatment for more than 7\xa0days if:\n\nthe baby has not yet fully recovered or\n\nthis is advisable because of the pathogen identified on blood culture (seek expert microbiological advice if necessary). \n\nIf continuing antibiotics for longer than 36\xa0hours despite negative blood cultures, review the baby at least once every 24\xa0hours. Consider at each review whether it is appropriate to stop antibiotic treatment, taking account of:\n\nthe level of initial clinical suspicion of infection and\n\nthe baby's clinical progress and current condition and\n\nthe levels and trends of C-reactive protein concentration. \n\n# Antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection\n\nDo not use rifampicin-miconazole-impregnated catheters for newborn babies. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: intravascular catheters.\n\nLoading. Please wait.\n\n# Risk factors for and clinical indicators of possible late-onset neonatal infection\n\nWhen assessing or reviewing a baby:\n\nCheck for, the possible clinical indicators of late-onset neonatal infection shown in table 2.\n\ntake into account that prematurity, mechanical ventilation, history of surgery and presence of a central catheter are associated with greater risk of late-onset neonatal infection.\n\nThink about infection in the other babies when one baby from a multiple birth has infection. \n\nSeek early advice from a paediatrician when late-onset infection is suspected in non-inpatient settings. \n\nRefer to the NICE guidelines on fever in under 5s and sepsis when assessing babies for late-onset neonatal infection who have been admitted to the hospital from home. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nCategory\n\nIndicators\n\nBehaviour\n\nParent or care-giver concern for change in behaviour\n\nAppears ill to a healthcare professional\n\nDoes not wake, or if roused does not stay awake\n\nWeak high-pitched or continuous cry\n\nRespiratory\n\nRaised respiratory rate: 60\xa0breaths per minute or more\n\nGrunting\n\nApnoea\n\nOxygen saturation of less than 90% in air or increased oxygen requirement over baseline\n\nCirculation and hydration\n\nPersistent tachycardia: heart rate 160\xa0beats per minute or more\n\nPersistent bradycardia: heart rate less than 100\xa0beats per minute\n\nSkin\n\nMottled or ashen appearance\n\nCyanosis of skin, lips or tongue\n\nNon-blanching rash of skin\n\nOther\n\nTemperature 38°C or more unexplained by environmental factors\n\nTemperature less than 36°C unexplained by environmental factors\n\nAlterations in feeding pattern\n\nAbdominal distension\n\nSeizures\n\nBulging fontanelle\n\nThis table has been adapted from the high-risk criteria in table 3 of the NICE guideline on sepsis.\n\nTiming of antibiotics for late-onset neonatal infection\n\nIf a baby needs antibiotic treatment, give this as soon as possible and always within 1 hour of the decision to treat. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on risk factors for and clinical indicators of possible late-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: risk factors for late-onset neonatal infection.\n\nLoading. Please wait.\n\n# Investigations before starting antibiotics in babies who may have late-onset infection\n\nWhen starting antibiotic treatment in babies who may have late-onset neonatal infection (see recognising risk factors and clinical indicators), perform a blood culture before giving the first dose. \n\nMeasure baseline C-reactive protein concentration when starting antibiotic treatment in babies who may have late-onset neonatal infection. Use this together with later readings to assess the likelihood of infection and response to treatment. \n\nIf it is safe to do so, perform a lumbar puncture to obtain a cerebrospinal fluid sample when:\n\nthere is a strong clinical suspicion of neonatal infection or\n\nthere are clinical symptoms or signs suggesting meningitis. \n\nDo not routinely perform urine microscopy or culture as part of the investigations for late-onset neonatal infection for babies in neonatal units. \n\nPerform urine microscopy and culture for babies outside of neonatal units in line with the NICE guideline on urinary tract infection in under 16s.\n\nDo not perform skin swab microscopy or culture as part of the investigations for late-onset neonatal infection if there are no clinical signs of a localised infection. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on investigations for late-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: investigations before starting treatment.\n\nLoading. Please wait.\n\n# Antibiotics for late-onset neonatal infection\n\n## Choice of antibiotics\n\nFor babies with suspected late-onset neonatal infection who are already in a neonatal unit:\n\ngive a combination of narrow-spectrum antibiotics (such as intravenous flucloxacillin plus gentamicin) as first-line treatment\n\nuse local antibiotic susceptibility and resistance data (or national data if local data are inadequate) when deciding which antibiotics to use\n\ngive antibiotics that are effective against both Gram-negative and Gram-positive bacteria\n\nif necrotising enterocolitis is suspected, also include an antibiotic that is active against anaerobic bacteria (such as metronidazole). \n\nFor babies with suspected late-onset neonatal infection or meningitis who have been admitted from home, treat according to recommendation 1.7.12 in the NICE guideline on sepsis. \n\nWhen using gentamicin, see recommendations 1.15.1 to 1.15.8 on therapeutic drug monitoring for gentamicin. \n\n# Duration of antibiotic treatment for late-onset neonatal infection\n\n## Investigations during antibiotic treatment for late-onset neonatal infection\n\nIn babies given antibiotics because of risk factors for infection or clinical indicators of possible late-onset neonatal infection, measure the C‑reactive protein concentration 18 to 24\xa0hours after starting antibiotics. \n\nConsider performing a lumbar puncture to obtain a cerebrospinal fluid sample in a baby who did not have a lumbar puncture at presentation who is receiving antibiotics, if it is thought safe to do so and if:\n\nthe baby has a positive blood culture (other than coagulase negative staphylococcus) or\n\nthe baby does not respond satisfactorily to antibiotic treatment, or\n\nthere is a strong clinical suspicion of infection or\n\nthere are clinical symptoms or signs suggesting meningitis. \n\n## Decisions 48 hours after starting antibiotic treatment\n\nFor babies given antibiotics because of suspected late-onset infection, consider stopping the antibiotics at 48\xa0hours if:\n\nthe blood culture is negative and\n\nthe initial clinical suspicion of infection was not strong and\n\nthe baby's clinical condition is reassuring, with no clinical indicators of possible infection and\n\nthe levels and trends of C‑reactive protein concentration are reassuring. \n\nHealthcare professionals with specific experience in neonatal infection should be available every day to give clinical microbiology or paediatric infectious disease advice. \n\n## Treatment duration for late-onset neonatal infection without meningitis\n\nGive antibiotic treatment for 7\xa0days for babies with a positive blood culture. Consider continuing antibiotic treatment for more than 7\xa0days if:\n\nthe baby has not yet fully recovered or\n\nlonger treatment is needed because of the pathogen identified on blood culture (for example, Gram-negative bacteria or Staphylococcus aureus; seek expert microbiological advice if necessary) or\n\nlonger treatment is needed because of the site of the infection (such as intra-abdominal co-pathology, necrotising enterocolitis, osteomyelitis or infection of a central venous catheter). \n\nUse a shorter treatment duration than 7\xa0days when the baby makes a prompt recovery, and either no pathogen is identified or the pathogen identified is a common commensal (for example, coagulase negative staphylococcus). \n\nIf continuing antibiotics for longer than 48\xa0hours for suspected late‑onset neonatal infection despite negative blood culture, review the baby at least once every 24\xa0hours. At each review, decide whether to stop antibiotics, taking account of:\n\nthe level of initial clinical suspicion of infection and\n\nthe baby's clinical progress and current condition and\n\nthe levels and trends of C-reactive protein. \n\nFor guidance on treatment duration for suspected or confirmed meningitis, refer to the section on meningitis (babies in neonatal units). \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on antibiotics for late-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: antibiotics.\n\nLoading. Please wait.\n\n# Antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection\n\nGive prophylactic oral nystatin to babies treated with antibiotics for suspected late-onset neonatal bacterial infection if they:\n\nhave a birthweight of up to 1,500\xa0g or\n\nwere born at less than 30\xa0weeks' gestation. If oral administration of nystatin is not possible, give intravenous fluconazole. In April 2021, this was an off-label use of fluconazole. See NICE's information on prescribing medicines and use clinical judgement to determine the dosage. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: antifungals.\n\nLoading. Please wait.\n\n# Avoiding routine use of antibiotics in babies\n\nDo not routinely give antibiotic treatment to babies without risk factors for infection or clinical indicators or laboratory evidence of possible infection. \n\n# Early- and late-onset meningitis (babies in neonatal units)\n\nIf a baby is in a neonatal unit and meningitis is suspected but the causative pathogen is unknown (for example, because the cerebrospinal fluid Gram stain is uninformative), treat with intravenous amoxicillin and cefotaxime. [2012, amended 2021]\n\nIf a baby is in a neonatal unit and meningitis is shown (by either cerebrospinal fluid Gram stain or culture) to be caused by Gram-negative infection, stop amoxicillin and treat with cefotaxime alone. [2012, amended 2021]\n\nIf a baby is in a neonatal unit and meningitis is shown (by cerebrospinal fluid Gram stain) to be caused by a Gram-positive bacterium:\n\ncontinue treatment with intravenous amoxicillin and cefotaxime while waiting for the cerebrospinal fluid culture result and\n\nseek expert microbiological advice. [2012, amended 2021]\n\nIf the cerebrospinal fluid culture is positive for group\xa0B streptococcus, consider changing the antibiotic treatment to:\n\nbenzylpenicillin 50\xa0mg/kg every 12\xa0hours, normally for at least 14\xa0days and\n\ngentamicin, with:\n\n\n\na starting dosage of 5\xa0mg/kg every 36\xa0hours (see recommendation 1.5.3)\n\nsubsequent doses and intervals adjusted if necessary based on clinical judgement (see recommendation 1.5.5) and blood gentamicin concentrations (see recommendations 1.15.1 to 1.15.3)\n\ntreatment lasting for 5\xa0days. [2012, amended 2021]\n\n\n\nIf the blood culture or cerebrospinal fluid culture is positive for listeria, consider stopping cefotaxime and treating with amoxicillin and gentamicin. [2012, amended 2021]\n\nIf the cerebrospinal fluid culture identifies a Gram-positive bacterium other than group\xa0B streptococcus or listeria, seek expert microbiological advice on management. [2012, amended 2021]\n\nFor a short explanation of why the committee amended the 2012 recommendations and how they might affect practice, see the rationale and impact section on early- and late-onset meningitis\xa0.\n\nLoading. Please wait.\n\n## Discharge after antibiotic treatment\n\nAfter antibiotic treatment, consider prompt discharge of the baby from hospital, with support for the parents and carers and a point of contact for advice. \n\n# Therapeutic drug monitoring for babies receiving gentamicin\n\n## Trough concentrations\n\nIf giving a second dose of gentamicin, measure the trough blood gentamicin concentration immediately before giving the second dose. Take the trough concentrations into account before giving the third dose of gentamicin. \n\nRepeat the measurement of trough concentrations immediately before every subsequent third dose of gentamicin, or more frequently if necessary (for example, if there has been concern about previous trough concentrations or renal function). \n\nHospital services should make blood gentamicin concentrations available to healthcare professionals in time to inform the next dosage decision. \n\nAdjust the gentamicin dose interval, aiming to achieve trough concentrations of less than 2\xa0mg/litre. If the course of gentamicin lasts for more than 3\xa0doses, aim for a trough concentration of less than 1\xa0mg/litre. \n\nDo not withhold a dose of gentamicin because of delays in getting a trough concentration measurement, unless there is evidence of impaired renal function (for example, an elevated serum urea or creatinine concentration, or anuria). \n\n## Peak concentrations\n\nConsider measuring peak blood gentamicin concentrations in selected babies, such as in those with:\n\noedema\n\nmacrosomia (birthweight more than 4.5\xa0kg)\n\nan unsatisfactory response to treatment\n\nproven Gram-negative infection. \n\nWhen measuring peak blood gentamicin concentrations, take the measurement 1\xa0hour after starting gentamicin. \n\nIf a baby has a Gram-negative or staphylococcal infection, consider increasing the dose of gentamicin if the peak concentration is less than 8\xa0mg/litre. \n\n# Care setting\n\nUsing clinical judgement, consider completing a course of intravenous antibiotics outside of hospital (for example, at home or through visits to a midwifery-led unit) in babies who are well and for whom there are no ongoing concerns if there is adequate local support. \n\nWhen deciding on the appropriate care setting for a baby, take into account the baby's clinical needs and the competencies needed to ensure safe and effective care (for example, the insertion and care of intravenous cannulas). \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Early-onset neonatal infection\n\nNeonatal infection less than 72\xa0hours after birth.\n\n## Late-onset neonatal infection\n\nNeonatal infection 72\xa0hours or more after birth.\n\n## Peak blood gentamicin concentration\n\nThe level of gentamicin in the baby's bloodstream shortly after administration. The blood sample is usually taken about 1 hour after giving the drug. High peak concentrations of gentamicin are necessary to kill bacteria.\n\n## Severe penicillin allergy\n\nA history of allergy to penicillin with effects that are clearly likely to be allergic in nature such as anaphylaxis, respiratory distress, angioedema or urticaria.\n\n## Therapeutic monitoring\n\nA process of measuring the concentration of a drug in the bloodstream, to avoid excessive levels that might be associated with adverse effects or to ensure adequate levels for therapeutic effect.\n\n## Trough blood gentamicin concentration\n\nThe level of gentamicin in the baby's bloodstream shortly before a further dose is given. High trough gentamicin concentrations may be associated with an increased risk of adverse effects.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Risk factors for and clinical indicators of early-onset infection\n\nWhat is the accuracy of clinical prediction models for early-onset neonatal infection in the UK and what is their effectiveness in guiding management in the baby? \n\nWhat is the risk of early-onset neonatal infection with maternal obesity and how does this change with increasing body mass index? \n\nFor a short explanation of why the committee made these recommendations for research, see the rationale on risk factors for and clinical indicators of possible early-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: maternal and neonatal risk factors.\n\nLoading. Please wait.\n\n## Investigations for babies who may have early-onset infection\n\nWhat is the clinical and cost effectiveness of laboratory investigations used individually or in combination to exclude early-onset neonatal infection in babies receiving antibiotics for suspected infection? \n\n## Antibiotics for suspected early-onset neonatal infection\n\nWhat is the optimal duration of treatment (course length) in babies who receive antibiotics for confirmed early-onset neonatal infection? \n\n## Risk factors for and clinical indicators of late-onset infection\n\nWhat is the accuracy of new or existing clinical prediction models for late-onset neonatal infection in the UK and what is their effectiveness in guiding management:\n\nfor babies already on a neonatal unit?\n\nfor babies admitted from home? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on risk factors for and clinical indicators of possible late-onset infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: risk factors for late onset.\n\nLoading. Please wait.\n\n## Antibiotics for suspected late-onset neonatal infection\n\nWhat is the optimal antibiotic treatment regimen for suspected late-onset neonatal infection? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on antibiotics for late-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: antibiotics.\n\nLoading. Please wait.\n\n## Impact of neonatal infection on the baby's family\n\nWhat is the impact of neonatal infection on the health-related quality of life of the baby's family? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on women with prolonged prelabour rupture of membranes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: timing of delivery.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Information and support\n\nHow does each step in the care pathway for prevention and treatment of early-onset neonatal infection impact on babies and their families? \n\nWhat is the clinical and cost effectiveness of information and support offered to parents and carers of babies who have received antibiotics for suspected or proven early-onset neonatal infection? \n\n## Intrapartum antibiotics\n\nWhat is the clinical and cost effectiveness of intrapartum antibiotics for women with meconium-stained amniotic fluid? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on intrapartum antibiotics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: intrapartum antibiotics.\n\nLoading. Please wait.\n\n## Antibiotics for suspected early-onset infection\n\nWhat is the incidence in England and Wales of resistance to commonly used antibiotics among bacteria that cause early-onset neonatal infection? \n\nWhat is the optimal antibiotic dosage regimen for the treatment of early-onset neonatal infection? \n\nWhat is the incidence and severity of adverse effects with antibiotics used to prevent or treat early-onset neonatal infection? \n\nWhat are the core exposures and outcomes that should be used to evaluate clinical effectiveness of antibiotics to prevent or treat early- onset neonatal infection? \n\n## Intravascular catheters for reducing the risk of late-onset neonatal infection\n\nWhat is the effectiveness of antimicrobial-impregnated catheters other than those impregnated with rifampicin and miconazole for preventing late-onset catheter-related bloodstream infections in newborn babies? \n\nWhat is the effectiveness of catheters impregnated with silver zeolite for preventing late-onset catheter-related bloodstream infections in newborn babies? \n\nFor a short explanation of why the committee made these recommendations for research, see rationale on antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: intravascular catheters.\n\nLoading. Please wait.\n\n## Antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection\n\nWhat is the optimum regimen (including treatment duration and dose) for using antifungals to prevent secondary fungal infection associated with antibiotic treatment for late-onset neonatal infection? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: antifungals.\n\nLoading. Please wait.\n\n## Early and late-onset meningitis\n\nWhat is the optimal antibiotic treatment regimen for early-onset neonatal meningitis? \n\n## Care setting\n\nWhat is the clinical and cost effectiveness of different models of care for the prevention and treatment of early-onset neonatal infection? ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Information and support\n\nRecommendations 1.1.1 to 1.1.13\n\n## Why the committee made the recommendations\n\nThe committee decided that some of the information and support recommendations in the previous version of the NICE guideline on neonatal infection for the families of babies with early-onset infection were also applicable to the families of babies who may develop late-onset infection.\n\nThe previous version of the guideline on early-onset infection recommended that parents and carers of babies with risk factors for early-onset infection should be given verbal and written information on the signs and symptoms of infection. This is particularly important when the baby already has risk factors that indicate they may develop infection. However, the committee noted that any baby can develop an infection, even if they are not identified as high risk at the time of discharge. The committee therefore thought it was important that all parents and carers should be given information about the signs and symptoms of neonatal infection before their baby is discharged from hospital.\n\nThe committee also wanted to ensure that the signs of infection listed in the recommendations were written in simple language that families could understand, rather than using clinical terminology. Therefore, examples of the most common breathing problems experienced by babies with neonatal infection were added to the recommendation on signs and symptoms.\n\nThe committee thought it was important that information was given in accessible formats, including different languages where appropriate to ensure that information was equally accessible to all. They noted these principles are outlined in the NICE guideline on patient experience in adult NHS services and so cross-referred to this guideline.\n\n## How the recommendations might affect practice\n\nThese recommendations have been adapted from the existing guidelines for early-onset neonatal infection, reflecting standard practice. As such, they are not expected to have a substantial impact on practice. Expanding the recommendation on signs and symptoms so that advice is given to all parents and carers will mean that more families will be aware of the signs of infection and will know to seek medical help if their baby develops any of them.\n\nReturn to recommendations\n\n# Intrapartum antibiotics\n\nRecommendations 1.2.1 to 1.2.5\n\n## Why the committee made the recommendations\n\nNo new evidence was identified since 2012, when the previous version of the guideline was published. The committee extended the 2012 recommendation on antibiotics for group\xa0B streptococcus to cover women who had colonisation in a previous pregnancy. This was because group\xa0B streptococcus colonisation in a previous pregnancy greatly increases the chance of being colonised in future pregnancies. The committee were concerned about a woman not receiving treatment because of a false negative test result, and so they decided to specify that a negative test should be from enrichment culture or PCR on rectovaginal swab samples. Although some tests may have higher false positive rates, all women with positive tests should be treated as if they have GBS so that no babies who are at higher risk of infection are missed.\n\nFor women in pre-term labour and women with a clinical diagnosis of chorioamnionitis, there was no evidence identified on the effects on intrapartum antibiotics on the number of neonatal infections. However, antibiotics did reduce the number of maternal infections in women in pre-term labour. The committee also agreed that pre-term labour and chorioamnionitis are important risk factors for neonatal infection, so intrapartum antibiotics are very likely to reduce the risk to the baby. Chorioamnionitis is a serious infection that needs to be treated with antibiotics to prevent harm to the mother. The committee thought that it was important to make recommendations for antibiotic treatment that would simultaneously treat infection in the mother and prevent early-onset group\xa0B streptococcal infection in the baby to make the best use of antibiotics.\n\nThe committee retained the recommendations on using benzylpenicillin as first-choice antibiotic from the 2012 guideline. Based on their knowledge and experience, gentamicin and metronidazole are also now recommended for women with chorioamnionitis, because chorioamnionitis can be caused by Gram positive or negative aerobic and anaerobic bacteria, so clinicians need to use broad-spectrum antibiotics that are effective against both. Once-daily dosing for gentamicin was recommended based on the knowledge and experience of the committee because 8 hourly dosing has additional monitoring requirements and would need additional nursing time for administration.\n\nThe committee also provided guidance on alternatives for women with a penicillin allergy, based on their knowledge and experience. The committee amended the 2012 recommendation on antibiotic alternatives for women who are allergic to penicillin. They changed the recommended antibiotic from clindamycin because there is evidence of resistance to group\xa0B streptococcus emerging with clindamycin, meaning that this antibiotic should no longer be used routinely. Based on their knowledge and experience, the committee recommended a cephalosporin with activity against group\xa0B streptococcus as an alternative for women with a penicillin allergy that was not severe, and vancomycin or an alternative antibiotic with activity against group\xa0B streptococcus in the case of severe penicillin allergy. The committee were aware of the possibility of allergic reaction to cephalosporins in women with a history of penicillin allergy. For women with a history of penicillin allergy that was not severe they thought that this risk was small and was outweighed by the benefits of using cephalosporins to treat chorioamnionitis and prevent neonatal infection. They noted that cephalosporins should be used with caution in these women. Cephalosporins were not recommended in the case of severe penicillin allergy because of an increased chance of a severe allergic reaction to cephalosporins. Severe penicillin allergy refers to a history of allergy to penicillin with effects that are clearly likely to be allergic in nature such as anaphylaxis, respiratory distress, angioedema or urticaria.\n\n## How the recommendations might affect practice\n\nMany of the recommendations remain the same as in the 2012 guideline. The recommendations on intrapartum antibiotics have been extended to cover women in pre-term labour without prelabour rupture of membranes, women with chorioamnionitis and women with group\xa0B streptococcus colonisation in a previous pregnancy. However, these changes reflect current practice, as many of these women already receive intrapartum antibiotics.\n\nThe committee expected that the recommendation on intrapartum antibiotics for chorioamnionitis would have the greatest impact on clinical practice. There is currently variation in which antibiotics are given to women with chorioamnionitis, with some units prescribing broad-spectrum antibiotics to treat infection in the mother and benzylpenicillin to prevent infection in the baby. Recommending a combination of narrow-spectrum antibiotics for women without an allergy to penicillin is likely to reduce the use of broad-spectrum antibiotics, which will improve antibiotic stewardship.\n\nReturn to recommendations\n\n# Women with prolonged prelabour rupture of membranes who have group\xa0B streptococcal colonisation, bacteriuria or infection\n\nRecommendation 1.2.6\n\n## Why the committee made the recommendation\n\nThe evidence suggested that immediate delivery can result in a reduced risk of a baby developing neonatal infection when a mother is between 34\xa0and 37\xa0weeks' gestation and has prolonged prelabour rupture of membranes and a positive test result for group\xa0B streptococcus. The evidence did not indicate any significant harms to the baby from choosing immediate delivery over expectant management. Therefore, the committee decided that, given the potential serious consequences of a baby developing neonatal infection, a recommendation in favour of immediate delivery was important. This was further supported by the economic evidence, which showed not only a clinical benefit to immediate delivery but also lower associated costs in comparison to expectant management, which has increased antenatal costs and higher rates of infections.\n\nThe committee made a recommendation for research on examining the health-related quality of life impact on parents or carers when a baby has neonatal infection. This information was not available and would have improved how well the economic model truly reflected the costs and health consequences of neonatal infection.\n\n## How the recommendation might affect practice\n\nThis recommendation could increase the number of women who are offered immediate delivery when they have both prolonged prelabour rupture of membranes and a positive test for group\xa0B streptococcus. This in turn could reduce the number of babies who need to be treated for neonatal infection and also reduce the number of mothers who need to be monitored throughout the expectant management period. The exact impact of these recommendations will vary between those hospitals where group\xa0B streptococcus screening and testing is more routinely performed and those where it is not. Recommendations on group\xa0B streptococcus screening were outside of the scope of this guideline. An economic model suggested that increasing the number of women offered immediate delivery would reduce costs overall.\n\nReturn to recommendation\n\n# Risk factors for and clinical indicators of possible early-onset neonatal infection\n\nRecommendations 1.3.1 to 1.3.9\n\n## Why the committee made the recommendations\n\nNo evidence was found that related specifically to this topic, and the committee agreed that the recommendations from the previous version of this guideline still reflected current best practice so did not need to be changed. These recommendations apply to all women with risk factors, including those who decline antibiotics, or those who either do not receive antibiotics or receive their first dose of antibiotics shortly before birth because of precipitate birth. As such, any women with risk factors should be monitored throughout labour, and these factors should be taken into account when assessing the risk of infection in the baby.\n\nThe committee based their recommendations on evidence on the accuracy of clinical decision models for early-onset neonatal infection, as well as evidence on individual neonatal and maternal risk factors.\n\nThere was uncertainty about how well the Kaiser Permanente neonatal sepsis calculator identified true cases of early-onset infection, because the studies included very few cases of infection that were confirmed by blood culture. This was a problem for the framework outlined in the 2012 version of the guideline as well, but the committee believed that the framework is more conservative and would lead to more antibiotics being prescribed than the Kaiser Permanente calculator (both appropriately and inappropriately). Evidence on the Kaiser Permanente neonatal sepsis calculator suggests that it is good at correctly identifying babies without neonatal infection, so reducing the amount of antibiotics that are prescribed unnecessarily. However, given the very serious consequences of missing an infection, the committee preferred the conservative approach from the framework in the 2012 guideline, with some amendments as outlined. However, as the evidence does not clearly show one option to be better and some UK centres currently use the Kaiser Permanente calculator, they also recommended this as an alternative, but only in the context of a research or audit project. By using the Kaiser Permanente calculator as part of an audit, centres will be able to collect detailed data on the use of the tool within NHS practice, including the number of babies who correctly received treatment, those who received antibiotics unnecessarily, and any who were not recommended antibiotics but did have infection. This information will provide a more detailed understanding of the effectiveness and safety of the Kaiser Permanente calculator which can be used to inform decisions on its use in future updates of this guideline.\n\nThe committee decided to specify that the Kaiser Permanente calculator should only be used for babies who are being cared for in a neonatal unit (neonatal intensive care units, local neonatal units and special care units), transitional care or a postnatal ward. The committee highlighted how it would be more difficult to collect the information needed for the audit in other settings. They did not think the calculator should be recommended for use in the emergency department, as babies who are brought in from home are likely to already be showing signs of being unwell and therefore need more immediate treatment than babies who are being assessed for risk of infection in a neonatal unit. In these cases, waiting to consult the calculator could instead delay treatment. The committee also thought that the calculator was not appropriate for use in a midwife-led unit or freestanding midwifery unit as there is currently no evidence that has used the calculator in these settings.\n\nAs there was only limited new evidence, the framework for assessing and managing risk, involving red flag indicators and other indicators of infection, has been retained from the 2012 guideline. The committee selected the red flag indicators as those that, based on their clinical experience, are the most high risk factors that need immediate treatment. Non-red flag indicators are those that can have causes other than neonatal infection and therefore do not always signal the need for immediate treatment. Many of the clinical indicators matched those in the 2012 guideline, with the following changes.\n\nParenteral antibiotics are no longer a risk factor. Since the 2012 guideline, awareness of the risks of maternal sepsis has increased and there has been a focus on early treatment with antibiotics. This has led to more babies being prescribed antibiotics even when a maternal infection is not strongly suspected. This rise in antibiotic use can result in babies being unnecessarily exposed to the side effects associated with antibiotics, such as nephrotoxicity, as well as increasing a baby's length of stay in hospital. Increased antibiotic use is also associated with an increase in the development of antibiotic resistance.\n\nChorioamnionitis and intrapartum fever are now separate risk factors because intrapartum fever has other potential causes. This change means that women with chorioamnionitis and intrapartum fever will have 2 risk factors, so their babies will receive antibiotics.\n\nInvasive group\xa0B streptococcal infection in a previous baby and maternal group\xa0B streptococcal colonisation, bacteriuria or infection in the current pregnancy have been combined into a single risk factor, because having a previous baby with invasive group\xa0B streptococcal infection increases the risk of future colonisation and infection, but does not confer additional risk if infection, bacteriuria or infection in the current pregnancy is already known about.\n\nMechanical ventilation, which was previously a red flag risk factor pre-term babies, and a non-red flag risk factor for term babies has been merged into one recommendation. The committee agreed that mechanical ventilation is a risk factor for infection regardless of prematurity, and so they decided to merge these into one red flag risk factor which did not refer to whether a baby was born pre-term or at term.\n\nConfirmed prelabour rupture of membranes was removed from the table because the committee decided that it is now covered by other risk factors in the table (pre-term birth and confirmed rupture of membranes in a pre-term or term birth). Babies born to mothers with prelabour rupture of membranes will therefore still receive treatment when using the updated version of the framework.\n\nTo address the limited evidence, the committee recommended further research on the accuracy of the Kaiser Permanente neonatal sepsis calculator and other clinical prediction models.\n\nNo evidence was found that related specifically to this topic, and the committee agreed that the recommendations from the previous version of this guideline still reflected current best practice so did not need to be changed.\n\n## How the recommendations might affect practice\n\nMany neonatal units use the framework from the 2012 version of the NICE guideline. Removal of parenteral antibiotics as a risk factor is expected to reduce the number of babies given antibiotics unnecessarily.\n\nSome centres use the Kaiser Permanente neonatal sepsis calculator as an alternative, and the recommendations may increase the number of centres who use this calculator in the context of a research or audit project. Current evidence suggests that this may reduce the number of babies who are unnecessarily given antibiotics, but there was substantial uncertainty about how well the calculator identified true cases of infection. If an increase in use of the Kaiser calculator resulted in more cases of infection being missed, this could increase costs associated with treating neonatal infections, as well as the very serious impact on the baby and their families.\n\nReducing the number of babies being given antibiotics may reduce costs for the NHS, both by reducing prescriptions and by reducing the amount of time babies and their mothers spend in hospital.\n\nReturn to recommendations\n\n# Antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection\n\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\n\nThere were only 2 studies looking at antimicrobial-impregnated catheters in newborn babies:\n\nOne study looked at rifampicin-miconazole-impregnated catheters. These provided no benefit over standard catheters. In addition, they are more expensive than standard catheters.\n\nThe other study looked at silver-zeolite-impregnated catheters. They showed some benefit compared with standard catheters, but the study was small and the committee had concerns about its quality. It was also conducted in Italy, and there are differences in clinical practice and infection rates between Italy and the UK.\n\nThe committee agreed they could not recommend antimicrobial-impregnated catheters based on the available evidence. The recommendation against the use of rifampicin-miconazole-impregnated catheters was made on the basis of the evidence that they provide no additional benefit over a standard catheter, and not because of any safety concerns over their use. There is a wider range of antimicrobials that can be used to impregnate catheters than have currently been investigated in newborn babies and uncertainty over which type of impregnated catheter is the most effective and whether monotherapy or the use of more than one antimicrobial would provide the most benefits. To address the shortage of evidence they made recommendations for further research.\n\n## How the recommendation might affect practice\n\nThe recommendation will reduce the use of rifampicin-miconazole-impregnated catheters. However, antimicrobial-impregnated catheters are not commonly used for newborn babies, so this should have a limited impact.\n\nReturn to recommendations\n\n# Risk factors for and clinical indicators of possible late-onset neonatal infection\n\nRecommendations 1.8.1 and 1.8.4\n\n## Why the committee made the recommendations\n\nThe committee did not feel that there was sufficient, high-quality evidence for any individual model to make a recommendation on clinical prediction models for late‑onset neonatal infection. Instead, they recommended a review of the individual risk factors that may predict a baby's risk of having or developing late-onset neonatal infection.\n\nAlthough there was evidence on a number of tools aimed at predicting late-onset neonatal infection, the committee did not think that there was sufficient, high quality, evidence including external validation to recommend any of them for use in practice. Most of the evidence was not from recent studies, the models were not readily available as web-based tools or in other formats that could be easily used by clinicians and it was thought that implementing them would have needed considerable changes in clinical practice.\n\nGiven the limited evidence currently available for prognostic models for late‑onset infection, the committee decided that they should make a recommendation for research. The recommendation is designed to encourage the development of new models to identify babies at risk of late-onset neonatal infection as well as promoting the validation of these models and evaluation of their effects on practice. This should help to improve the understanding of the factors associated with late-onset neonatal infection so that committees can make recommendations on this area in future guideline updates.\n\nWith limited evidence on prognostic models, the committee agreed that it was instead important for clinicians to be aware of the clinical indicators and risk factors for late-onset neonatal infection. There was very limited evidence on maternal risk factors for late-onset infection and so the recommendations were based on the risk factors and signs and symptoms in the baby. The committee decided that the list of high‑risk criteria from the risk stratification tool in the NICE guideline on sepsis (section 1.4, table 3) covered the most important indicators that clinicians in both community and specialist settings should be aware of. They included the recommendation to seek early advice from a paediatrician to highlight the importance of early treatment if any of the main clinical indicators are present. Early specialist advice was thought to be particularly important when caring for babies in the community as they need to be taken to hospital and admitted before treatment can begin, while babies who are on a neonatal unit can be monitored and treated more quickly. It was agreed that in addition to clinical indicators, it was also important to highlight potential risk factors for infection. This will help to ensure that babies who are at greater risk for infection are closely monitored for the presence of any of the clinical indicators. The committee also recommended that clinicians should think about infection in the other babies when one baby from a multiple birth has infection. Evidence was not found on this, but the committee thought that it was in line with current best practice because of the risk that all the babies from the pregnancy will have the same risk of infection.\n\nThere was very limited evidence on the signs and symptoms of infection. The committee was aware of existing recommendations on clinical indicators of infection in the NICE guideline on sepsis and so it considered this information when deciding on recommendations. It was agreed that the high-risk indicators listed in the sepsis guideline were an accurate reflection of the committee's experience with babies who develop late-onset infection. Parental or carer concern over changes in behaviour was added to the list of high-risk criteria as this was highlighted as an important indicator of potential infection for babies in the community. Other potential clinical indicators were discussed, but the committee were concerned about the risk of over-treatment if too many clinical indicators were listed in the recommendation, especially if some of those indicators could have causes other than neonatal infection. The committee decided that the signs included in the recommendation were those that were most likely to indicate infection and therefore the most important to consider when assessing whether a baby may need treatment.\n\n## How the recommendations might affect practice\n\nThe recommendations are consistent with current practice and therefore a large resource impact is not anticipated. The table of clinical indicators may increase awareness of when a baby is at greater risk of late-onset neonatal infection. This may increase the number of babies who receive early treatment in hospital and reduce the negative effects and costs associated with infection.\n\nClinicians working on a neonatal or paediatric ward are already likely to be aware of the risk factors that were identified in the evidence review. As such, the recommendations are helpful to reinforce the knowledge of these clinicians about the risk factors but may not have a substantial effect on current practice in a hospital setting.\n\nReturn to recommendations\n\n# Investigations for late-onset neonatal infection\n\nRecommendations 1.9.1 to 1.9.6\n\n## Why the committee made the recommendations\n\nBlood culture is the current 'gold standard' for identifying neonatal infection. However, babies with late-onset infection can still sometimes have a negative blood culture. It can also take hours or days to get the results of blood cultures. These inaccuracies and delays mean that many babies receive treatment before blood culture results are returned, because delaying treatment could lead to complications or death. Having another diagnostic test as an alternative or an addition to blood culture results could therefore reduce unnecessary antibiotic treatment. The committee reviewed the evidence for late-onset infection. Of the other diagnostic tests, only C-reactive protein has enough evidence to recommend it. It is not accurate enough to be used as an alternative to blood culture, but when used in combination it can improve the accuracy of the diagnosis. The committee discussed how a single C-reactive protein measurement is not sufficient to diagnose infection, as this can vary between babies. They therefore decided to recommend that a C‑reactive protein sample is taken when starting antibiotics. This will provide clinicians with a baseline against which to compare future C-reactive protein results, to indicate whether a baby is likely to have infection, whether they are responding to treatment and when to consider stopping antibiotics. Blood culture is still considered the gold standard test for diagnosing neonatal infection but using it in combination with C-reactive protein measurements will allow babies who do not need antibiotics to stop taking them sooner.\n\nAs the evidence for late-onset infection lined up with the evidence from the 2012 guideline for early-onset infection, the committee amended the 2012 recommendations to cover all neonatal infection.\n\nThere was limited evidence on lumbar puncture specifically for late-onset infection. However, lumbar puncture is the 'gold standard' test for identifying meningitis, and it was recommended in the 2012 guideline for babies with early-onset infection. The committee extended this recommendation to cover both early- and late-onset neonatal infection, as they felt that the benefits of identifying meningitis outweighed the risks of the procedure.\n\nNo evidence was identified that supported using urine culture or skin swabs in the neonatal unit. These tests were also not recommended in the 2012 guideline for babies with early-onset infection and so the committee decided to recommend against their use for babies in neonatal units. However, they also discussed how urine culture can be an important test for babies in a paediatric ward if a urinary tract infection is suspected, so included a recommendation which supported its use in babies who are being cared for outside of neonatal units. This is consistent with the recommendations from the NICE guideline on urinary tract infection in under 16s.\n\n## How the recommendations might affect practice\n\nThe recommendations are not expected to have a major impact on practice as they reflect the procedures currently followed in most hospitals.\n\nReturn to recommendations\n\n# Antibiotics for late-onset neonatal infection\n\nRecommendations 1.10.1 to 1.11.7\n\n## Why the committee made the recommendations\n\nThere is variation across the country in antibiotic resistance patterns and in which organisms are most likely to cause late-onset neonatal infection. Because of this, local data needs to be used when choosing antibiotics.\n\nBabies in a neonatal unit are likely to have been exposed to different bacteria than babies at home, so the committee made separate recommendations for the 2\xa0groups.\n\nFor babies in a neonatal unit, the committee did not believe there was enough evidence to recommend specific antibiotics, and so made a recommendation for research into the best antibiotic regimen to treat late-onset infection. However, the evidence available did show that combinations of narrower‑spectrum antibiotics are as effective as broader-spectrum antibiotics. The committee were aware that using broad-spectrum antibiotics in babies is associated with altered gut flora, increased risk of invasive fungal infection and the development of antibiotic resistance, and so a combination of narrow spectrum antibiotics was recommended as first-line treatment.\n\nFor babies who have been admitted from home, there was also limited evidence on which antibiotics to use. The NICE guideline on sepsis recommends treating community-acquired sepsis with ceftriaxone or cefotaxime depending on gestational age. The committee agreed that these antibiotics would be appropriate for late-onset neonatal infection in babies who have been admitted from home, and none of the evidence for this group contradicted it.\n\nThere was no evidence on duration of antibiotic treatment for late-onset infection. However, the 2012 guideline made recommendations on this for early-onset infection, and the committee adapted these so that they were applicable to late-onset infection. The duration of initial treatment is recommended to be 48 hours rather than 36 hours as recommended for early-onset infection. This is thought to reflect the different bacteria that cause late-onset infection, which grow more slowly and have a lower load in the bloodstream. This means that it can take longer for a blood culture to become positive for late-onset than early-onset infection and so treatment needs to continue for longer until a negative blood culture result can be confirmed. To help with treatment decisions, the 2012 version of the guideline recommended that healthcare professionals with experience in neonatal infection should be available to provide microbiological or paediatric infection disease advice. The committee decided that this recommendation is also important when making decisions about antibiotic treatment for late-onset infection.\n\nNo evidence on treatment duration was identified, and so the committee made recommendations based on their knowledge and experience. The committee recommended a treatment of 7 days for babies with a positive blood culture, consistent with the recommendation on early-onset neonatal infection from the 2012 version of the guideline. The committee recommended that a shorter treatment duration should be used when no pathogen is identified (the blood culture is negative) or the pathogen is a common commensal. In these situations, the committee noted that infection was likely to be less severe and could be safely treated with a shorter treatment duration, which would have the advantage of reducing exposure to antibiotics, which is consistent with the principles of good antibiotic stewardship. The committee also specified situations when a longer treatment duration should be used, such as when there is intra-abdominal co-pathology, necrotising enterocolitis, osteomyelitis or infection of a central venous catheter. There was no evidence for the specific situations where longer treatment would be required, but the committee based their decisions on their knowledge and experience.\n\n## How the recommendations might affect practice\n\nThese recommendations will help to reduce the use of broad-spectrum antibiotics as first-line treatment for babies in neonatal units, which may help reduce antibiotic resistance. However, use of narrow-spectrum antibiotics is already standard practice in many units, and the costs of antibiotics are low, so there is expected to be very little impact on resource use, especially as most of the affected babies are already receiving intensive care and monitoring.\n\nThe recommendation for babies admitted from home may not have a substantial impact on practice, as it refers to an existing recommendation in the NICE sepsis guideline.\n\nThe recommendations on duration of treatment are consistent with current practice.\n\nReturn to recommendations\n\n# Antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection\n\nRecommendations 1.12.1 and 1.12.2\n\n## Why the committee made the recommendations\n\nEvidence from randomised controlled trials showed that both nystatin and fluconazole can reduce the risk of a baby developing an invasive fungal infection in comparison to placebo or no treatment. Evidence marginally favoured the use of nystatin over fluconazole for reducing the risk of fungal infection and based on the knowledge and experience of the committee, nystatin is better tolerated and there is a lower risk of fungi developing resistance to this antifungal than fluconazole. Economic evidence showed that nystatin was also likely to be the most cost-effective option, and so the committee recommended oral nystatin for antifungal prophylaxis when a baby is being given antibiotics for late-onset neonatal infection. The recommendation for antifungal prophylaxis was limited to babies below 1,500\xa0g or 30\xa0weeks' gestational age because the evidence was from babies in these population groups.\n\nAlthough oral nystatin was the committee's first choice for antifungal prophylaxis, oral administration of antifungals may not be possible for all babies, particularly those who are very premature. The committee therefore specified that the use of intravenous fluconazole is appropriate when oral administration is not possible.\n\nThe committee made a recommendation for research for studies investigating the optimum regimen for giving antifungal prophylaxis when treating a baby with antibiotics for late-onset infection, because evidence was not available to support specific recommendations on the duration and dose of antifungal treatment that should be used.\n\n## How the recommendations might affect practice\n\nThis recommendation may increase the number of babies who are given nystatin as antifungal prophylaxis when they are prescribed antibiotics for late-onset infection. This should decrease the number of babies who need to be treated for fungal infection which, although rare, can have serious consequences. Economic modelling showed that giving antifungal prophylaxis is likely to be cost saving because of a reduction in costs associated with treating invasive fungal infections and their consequences.\n\nReturn to recommendations\n\n# Early- and late-onset meningitis (babies in neonatal units)\n\nRecommendations 1.14.1 to 1.14.6\n\n## Why the committee amended the recommendations\n\nThese recommendations were carried forward from the 2012 version of the guideline, but were expanded to cover both early- and late-onset neonatal meningitis for babies in neonatal units based on the knowledge and experience of the committee. Evidence relating to these recommendations was not reviewed for late-onset meningitis, but the committee agreed that the recommendations that were made in 2012 for early-onset infection would also apply to late-onset meningitis for babies treated in neonatal units.\n\nReturn to recommendations", 'Context': 'Neonatal bacterial infection is a significant cause of mortality and morbidity in newborn babies. Parent organisations and the scientific literature report that there can be unnecessary delays in recognising and treating sick babies. In addition, concern about the possibility of neonatal infection is common. This concern is an important influence on the care given to pregnant women and newborn babies. There is wide variation in how the risk of neonatal infection is managed in healthy babies. The approach taken by the NHS needs to:\n\nprevent neonatal infection when possible\n\nprioritise the treatment of sick babies\n\nminimise the impact of management pathways on healthy women and babies\n\nuse antibiotics wisely to avoid the development of resistance to antibiotics.\n\nThese drivers have not always been addressed consistently in the NHS, and this guideline was commissioned to ensure they would be addressed in future.\n\nFive key principles underpin the recommendations in this guideline:\n\nUnless it is dangerous, families should be offered choice. The guideline includes recommendations to support families in making choices through provision of information and, when appropriate, reassurance.\n\nIntrapartum antibiotic prophylaxis should be administered in a timely manner to all eligible women who choose it.\n\nBabies with suspected neonatal infection should receive treatment as quickly as possible.\n\nAntibiotic exposure should be minimised in babies who do not have a neonatal infection.\n\nAn integrated system of clinical care is needed to allow full implementation of the guideline recommendations.'}
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https://www.nice.org.uk/guidance/ng195
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This guideline covers preventing bacterial infection in healthy babies of up to and including 28 days corrected gestational age, treating pregnant women whose unborn baby is at risk of infection, and caring for babies of up to and including 28 days corrected gestational age with a suspected or confirmed bacterial infection. It aims to reduce delays in recognising and treating infection and prevent unnecessary use of antibiotics. The guideline does not cover viral infections.
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26985caf74b120b0ee29fa966cb748f0e7d7350d
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nice
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Chronic pain (primary and secondary) in over 16s: assessment of all chronic pain and management of chronic primary pain
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Chronic pain (primary and secondary) in over 16s: assessment of all chronic pain and management of chronic primary pain
This guideline covers assessing all chronic pain (chronic primary pain, chronic secondary pain, or both) and managing chronic primary pain in people aged 16 years and over. Chronic primary pain is pain with no clear underlying cause, or pain (or its impact) that is out of proportion to any observable injury or disease.
# Context
Chronic pain (sometimes known as long-term pain or persistent pain) is pain that lasts for more than 3 months. Pain can be secondary to (caused by) an underlying condition (for example, osteoarthritis, rheumatoid arthritis, ulcerative colitis, endometriosis). Chronic pain can also be primary. Chronic primary pain has no clear underlying condition or the pain (or its impact) appears to be out of proportion to any observable injury or disease. The decisions about the search for any injury or disease that may be causing the pain, and about whether the pain or its impact are out of proportion to any identified injury or disease, are matters for clinical judgement in discussion with the patient. The mechanisms underlying chronic primary pain are only partially understood and the definitions are fairly new. All forms of pain can cause distress and disability, but these features are particularly prominent in presentations of chronic primary pain. This guideline is consistent with the ICD-11 definition of chronic primary pain.
ICD-11 gives examples of chronic primary pain, including fibromyalgia (chronic widespread pain), complex regional pain syndrome, chronic primary headache and orofacial pain, chronic primary visceral pain and chronic primary musculoskeletal pain. These specific conditions were used as search terms for the evidence underpinning the recommendations in this guideline, along with more general terms that describe studies in chronic pain populations. Categorisations may change with time and advances in understanding of disease mechanisms.
Section 1.1 of this guideline covers assessment for people living with all types of chronic pain (chronic primary pain, chronic secondary pain, or both). The experience of pain is always influenced by social factors (including deprivation, isolation, lack of access to services), emotional factors (including anxiety, distress, previous trauma), expectations and beliefs, mental health (including depression and post-traumatic stress disorder) and biological factors. When assessing chronic primary pain and chronic secondary pain, these potential contributors to the presentation should be considered.
Section 1.2 of this guideline contains recommendations for managing chronic primary pain. Recommendations for managing chronic secondary pain can be found in the NICE guidelines for those conditions. Diagnostic categories may overlap and primary and secondary pain conditions may coexist. In these cases, management should be guided by both this guideline and the NICE guideline for the secondary pain condition.
In the UK the prevalence of chronic pain is uncertain, but appears common, affecting perhaps one‑third to one‑half of the population. It is not known what proportion of people with chronic pain either need or wish for treatment. The prevalence of chronic primary pain is unknown, but is estimated to be between 1% and 6% in England.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Assessing all types of chronic pain (chronic primary pain, chronic secondary pain, or both)
This section covers all types of chronic pain (pain that persists or recurs for more than 3 months). It includes chronic primary pain (in which no underlying condition adequately accounts for the pain or its impact) and chronic secondary pain (in which an underlying condition adequately accounts for the pain or its impact).
Chronic primary pain and chronic secondary pain can coexist.
These recommendations aim to inform a care and support plan by setting out a comprehensive person‑centred assessment of the causes and effects of pain and agreeing possible management strategies, including self‑management.
## Person-centred assessment
Offer a person-centred assessment to those presenting with chronic pain (chronic primary pain, chronic secondary pain, or both), to identify factors contributing to the pain and how the pain affects the person's life.
When assessing and managing any type of chronic pain (chronic primary pain, chronic secondary pain, or both) follow the recommendations in the NICE guidelines on patient experience in adult NHS services and shared decision making, particularly relating to:
knowing the patient as an individual
enabling patients to actively participate in their care, including:
communication
information
shared decision making.
Foster a collaborative and supportive relationship with the person with chronic pain.
## Thinking about possible causes for pain
Think about a diagnosis of chronic primary pain if there is no clear underlying (secondary) cause or the pain or its impact is out of proportion to any observable injury or disease, particularly when the pain is causing significant distress and disability.
Make decisions about the search for any injury or disease that may be causing the pain, and about whether the pain or its impact are out of proportion to any identified injury or disease, using clinical judgement in discussion with the person with chronic pain.
Recognise that an initial diagnosis of chronic primary pain may change with time. Re-evaluate the diagnosis if the presentation changes.
Recognise that chronic primary pain can coexist with chronic secondary pain.
## Talking about pain – how this affects life and how life affects pain
Ask the person to describe how chronic pain affects their life, and that of their family, carers and significant others, and how aspects of their life may affect their chronic pain. This might include:
lifestyle and day-to-day activities, including work and sleep disturbance
physical and psychological wellbeing
stressful life events, including previous or current physical or emotional trauma
current or past history of substance misuse
social interaction and relationships
difficulties with employment, housing, income and other social concerns.
Be sensitive to the person's socioeconomic, cultural and ethnic background, and faith group, and think about how these might influence their symptoms, understanding and choice of management.
Explore a person's strengths as well as the impact of pain on their life. This might include talking about:
their views on living well
the skills they have for managing their pain
what helps when their pain is difficult to control.
Ask the person about their understanding of their condition, and that of their family, carers and significant others. This might include:
their understanding of the causes of their pain
their expectations of what might happen in the future in relation to their pain
their understanding of the outcome of possible treatments.
When assessing chronic pain in people aged 16 to 25 years, take into account:
any age-related differences in presentation of symptoms
the impact of the pain on family interactions and dynamics
the impact of the pain on education and social and emotional development. See the NICE guideline on transition from children's to adult's services for young people using health or social care services.
Recognise that living with pain can be distressing and acknowledge this with the person with chronic pain.
## Providing advice and information
Provide advice and information relevant to the person's individual preferences, at all stages of care, to help them make decisions about managing their condition, including self-management.
Discuss with the person with chronic pain and their family or carers (as appropriate):
the likelihood that symptoms will fluctuate over time and that they may have flare-ups
the possibility that a reason for the pain (or flare-up) may not be identified
the possibility that the pain may not improve or may get worse and may need ongoing management
there can be improvements in quality of life even if the pain remains unchanged.
When communicating normal or negative test results, be sensitive to the risk of invalidating the person's experience of chronic pain.
## Developing a care and support plan
Discuss a care and support plan with the person with chronic pain. Explore in the discussions:
their priorities, abilities and goals
what they are already doing that is helpful
their preferred approach to treatment and balance of treatments for multiple conditions
any support needed for young adults (aged 16 to 25) to continue with their education or training, if this is appropriate.
Explain the evidence for possible benefits, risks and uncertainties of all management options when first developing the care and support plan and at all stages of care.
Use these discussions to inform and agree the care and support plan with the person with chronic pain and their family or carers (as appropriate).
Offer management options:
in line with section 1.2 of this guideline if the assessment suggests the person has chronic primary pain
in line with the NICE guideline for the underlying chronic pain condition if the underlying condition adequately accounts for the pain and its impact (see the NICE guidelines on headaches, low back pain and sciatica, rheumatoid arthritis, osteoarthritis, spondyloarthritis, endometriosis, neuropathic pain and irritable bowel syndrome).
When chronic primary pain and chronic secondary pain coexist, use clinical judgement to inform shared decision making about management options in section 1.2 of this guideline and in the NICE guideline for the chronic pain condition.
## Flare-ups
Offer a reassessment if a person presents with a change in symptoms such as a flare-up of chronic pain. Be aware that a cause for the flare-up may not be identified.
If a person has a flare-up of chronic pain:
review the care and support plan
consider investigating and managing any new symptoms
discuss what might have contributed to the flare-up (see recommendation 1.1.8 for influences on the experience of pain).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing chronic pain .
Full details of the evidence and the committee's discussion are in evidence review A: factors that may be barriers to successfully managing chronic pain (chronic primary pain and chronic secondary pain) and evidence review B: communication between healthcare professionals and people with chronic pain (chronic primary pain and chronic secondary pain).
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See also the rationale section on pain management programmes .
Full details of the evidence and the committee's discussion are in evidence review C: pain management programmes for chronic pain (chronic primary pain and chronic secondary pain).
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# Managing chronic primary pain
This section covers managing chronic primary pain (in which no underlying condition adequately accounts for the pain or its impact). Chronic primary pain and chronic secondary pain can coexist.
## Non-pharmacological management of chronic primary pain
Offer a supervised group exercise programme to people aged 16 years and over to manage chronic primary pain. Take people's specific needs, preferences and abilities into account.
Encourage people with chronic primary pain to remain physically active for longer-term general health benefits (also see NICE guidelines on physical activity and behaviour change: individual approaches).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on exercise programmes and physical activity for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review E: exercise for chronic primary pain.
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Consider acceptance and commitment therapy (ACT) or cognitive behavioural therapy (CBT) for pain for people aged 16 years and over with chronic primary pain, delivered by healthcare professionals with appropriate training.
Do not offer biofeedback to people aged 16 years and over to manage chronic primary pain.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological therapy for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review F: psychological therapy for chronic primary pain.
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Consider a single course of acupuncture or dry needling, within a traditional Chinese or Western acupuncture system, for people aged 16 years and over to manage chronic primary pain, but only if the course:
is delivered in a community setting and
is delivered by a band 7 (equivalent or lower) healthcare professional with appropriate training and
is made up of no more than 5 hours of healthcare professional time (the number and length of sessions can be adapted within these boundaries) or
is delivered by another healthcare professional with appropriate training and/or in another setting for equivalent or lower cost.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on acupuncture for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review G: acupuncture for chronic primary pain.
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Do not offer any of the following to people aged 16 years and over to manage chronic primary pain because there is no evidence of benefit:
TENS
ultrasound
interferential therapy.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on electrical physical modalities for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review H: electrical physical modalities for chronic primary pain.
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## Pharmacological management of chronic primary pain
For guidance on safe prescribing and managing withdrawal of antidepressants and dependence-forming medicines, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
Consider an antidepressant, either amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine or sertraline, for people aged 18 years and over to manage chronic primary pain, after a full discussion of the benefits and harms. In April 2021, this was an off-label use of these antidepressants. See NICE's information on prescribing medicines.
Seek specialist advice if pharmacological management with antidepressants is being considered for young people aged 16 to 17 years.
If an antidepressant is offered to manage chronic primary pain, explain that this is because these medicines may help with quality of life, pain, sleep and psychological distress, even in the absence of a diagnosis of depression.
Do not initiate any of the following medicines to manage chronic primary pain in people aged 16 years and over:
antiepileptic drugs including gabapentinoids, unless gabapentinoids are offered as part of a clinical trial for complex regional pain syndrome (see the recommendation for research on pharmacological interventions)
antipsychotic drugs
benzodiazepines
corticosteroid trigger point injections
ketamine
local anaesthetics (topical or intravenous), unless as part of a clinical trial for complex regional pain syndrome (see the recommendation for research on pharmacological interventions)
local anaesthetic/corticosteroid combination trigger point injections
non-steroidal anti-inflammatory drugs
-pioids
paracetamol.Pregabalin and gabapentin (gabapentinoids) are Class C controlled substances (under the Misuse of Drugs Act 1971) and scheduled under the Misuse of Drugs Regulations 2001 as Schedule 3. Evaluate patients carefully for a history of drug misuse before prescribing and observe patients for development of signs of misuse and dependence (MHRA Drug Safety Update April 2019).
If a person with chronic primary pain is already taking any of the medicines in recommendation 1.2.10, review the prescribing as part of shared decision making:
explain the lack of evidence for these medicines for chronic primary pain and
agree a shared plan for continuing safely if they report benefit at a safe dose and few harms or
explain the risks of continuing if they report little benefit or significant harm, and encourage and support them to reduce and stop the medicine if possible.
When making shared decisions about whether to stop antidepressants, opioids, gabapentinoids or benzodiazepines, discuss with the person any problems associated with withdrawal. For more information, see the section on making shared decisions about withdrawing medicines in NICE's guideline on medicines associated with dependence or withdrawal symptoms.
For recommendations on stopping or reducing antidepressants or dependence-forming medicines, see:
the section on medication review in NICE's guideline on medicines optimisation and
the section on reviewing medicines in NICE's guideline on medicines adherence and
the section on reviewing a dependence-forming medicine or antidepressant in NICE's guideline on medicines associated with dependence or withdrawal symptoms
For recommendations on reviewing treatments, see:
the section on medication review in NICE's guideline on medicines optimisation and
the section on reviewing medicines in NICE's guideline on medicines adherence and
the section on reviewing a dependence-forming medicine or antidepressant in NICE's guideline on medicines associated with dependence or withdrawal symptoms.
For recommendations on cannabis-based medicinal products, including recommendations for research, see the NICE guideline on cannabis-based medicinal products.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pharmacological management for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review J: pharmacological management for chronic primary pain.
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# Terms used in this guideline
## Chronic pain
Pain that persists or recurs for more than 3 months. This includes both chronic primary pain and chronic secondary pain, which can coexist. Other terms used include persistent pain and long-term pain.
## Chronic primary pain
Chronic primary pain has no clear underlying condition or the pain or its impact is out of proportion to any observable injury or disease. The mechanisms underlying chronic primary pain are only partially understood and the definitions are fairly new. All forms of pain can cause distress and disability, but these features are particularly prominent in presentations of chronic primary pain. This guideline is consistent with the ICD-11 definition of chronic primary pain.
Fibromyalgia (chronic widespread pain) is a type of chronic primary pain. ICD-11 also categorises complex regional pain syndrome, chronic primary headache and orofacial pain, chronic primary visceral pain and chronic primary musculoskeletal pain as types of chronic primary pain.
## Flare-up
A flare‑up is a sudden, temporary worsening of symptoms. Usually this refers to more intense pain on a day‑to‑day basis. It can also refer to a change in fatigue, stiffness, function or disease activity. Flare‑ups can be unpredictable and the time they last can vary.
## Pain management programme
This guideline defines a pain management programme as any intervention that has 2 or more components, including a physical and a psychological component, delivered by trained people, with some interaction/coordination between the 2 components.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Psychological therapy – mindfulness for chronic primary pain
What is the clinical and cost effectiveness of mindfulness therapy for managing chronic primary pain in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on psychological therapy for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review F: psychological therapy for chronic primary pain.
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## Psychological therapy – CBT for insomnia in chronic primary pain
What is the clinical and cost effectiveness of cognitive behavioural therapy (CBT) for insomnia or CBT for insomnia and pain for managing chronic primary pain in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on psychological therapy for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review F: psychological therapy for chronic primary pain.
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## Manual therapies for chronic primary pain
What is the clinical and cost effectiveness of manual therapy for managing chronic primary pain in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on manual therapy for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review I: manual therapy for chronic primary pain.
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## Repeat courses of acupuncture for chronic primary pain
What is the clinical and cost effectiveness of repeat courses of acupuncture or dry needling for managing chronic primary pain in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on acupuncture for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review G: acupuncture for chronic primary pain.
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## Pharmacological interventions – gabapentinoids and local anaesthetics for complex regional pain syndrome
What is the clinical and cost effectiveness of gabapentinoids or local anaesthetics for managing complex regional pain syndrome in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pharmacological management for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review J: pharmacological management for chronic primary pain.
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# Other recommendations for research
## Factors that may be barriers to successfully managing chronic pain, including chronic primary pain
What risk factors enable stratification of treatment for people aged 16 years and over with chronic pain?
For a short explanation of why the committee made the recommendation for research, see the rationale section on assessing chronic pain .
Full details of the evidence and the committee's discussion are in evidence review A: factors that may be barriers to successfully managing chronic pain (chronic primary pain and chronic secondary pain).
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## Social interventions for chronic pain, including chronic primary pain
What is the clinical and cost effectiveness of social interventions aimed at improving the quality of life of people aged 16 years and over with chronic pain?
For a short explanation of why the committee made the recommendation for research, see the rationale section on social interventions for chronic pain .
Full details of the evidence and the committee's discussion are in evidence review D: social interventions for chronic pain (chronic primary pain and chronic secondary pain).
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## Psychotherapy for chronic primary pain
What is the clinical and cost effectiveness of psychodynamic psychotherapy for managing chronic primary pain in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on psychological therapy for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review F: psychological therapy for chronic primary pain.
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## Relaxation therapy for chronic primary pain
What is the clinical and cost effectiveness of relaxation therapies for managing chronic primary pain in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on psychological therapy for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review F: psychological therapy for chronic primary pain.
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## Laser therapy for chronic primary pain
What is the clinical and cost effectiveness of laser therapy for managing chronic primary pain in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on electrical physical modalities for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review H: electrical physical modalities for chronic primary pain.
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## Transcranial magnetic stimulation for chronic primary pain
What is the clinical and cost effectiveness of transcranial magnetic stimulation for managing chronic primary pain in people aged 16 years and over?
For a short explanation of why the committee made the recommendation for research, see the rationale section on electrical physical modalities for chronic primary pain .
Full details of the evidence and the committee's discussion are in evidence review H: electrical physical modalities for chronic primary pain.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Assessing chronic pain (chronic primary pain and chronic secondary pain)
Recommendations 1.1.1 to 1.1.23
## Why the committee made the recommendations
There was not enough evidence to indicate whether any psychological, biological or social factors predict successful pain management. The committee acknowledged the importance of a comprehensive patient‑centred approach to assessment and management. They agreed that it is important for the healthcare professional to understand how pain is affecting a person's life and vice versa, taking into account the person's socioeconomic, cultural and ethnic background, and faith group. A care and support plan should be based on the effects of pain on day-to-day activities, as well as a person's preferences, abilities and goals, while acknowledging that it is not possible to predict what might happen in the future.
The committee agreed that it was important to acknowledge that pain can fluctuate over time and flare-ups are to be expected. Recommendations were formed by expert consensus to guide assessment of flare-ups of pain.
The committee agreed that the evidence on communication was in line with what was generally considered best practice. However, evidence demonstrated shortcomings in people's experience of consultations with healthcare professionals. The committee agreed that this area needs addressing. They emphasised the fundamental importance of good communication to the experience of care for people with chronic pain, especially when many or all treatments are ineffective for some people or not well tolerated by everyone. The committee reviewed the recommendations from the NICE guideline on patient experience in adult NHS services alongside the qualitative evidence to identify any areas needing specific recommendations for people with chronic pain. They agreed that the heterogeneous, complex and potentially distressing nature of the condition should be reflected in the recommendations. More specifically, a comprehensive assessment should elicit an understanding of the effects of the pain, and how this is viewed by the person and those around them. Understanding what is important to the person is the first step in developing a care and support plan. The committee agreed that it is important to explore a person's priorities, preferences, abilities and goals, because these can help inform the plan.
The committee highlighted the importance of being honest about the uncertainty of the prognosis, because the evidence suggested that this is valued by people with chronic pain. Evidence showed that discussions about self‑management often happen late in the care pathway, or not at all. The committee considered that all relevant management options should be considered at all stages of care, including the first contact. They made a recommendation to provide advice and information, relevant to the person's individual preferences, at all stages of care, to help them make decisions about managing their condition. Evidence showed that normal or negative test results can be communicated in a way that is perceived as being dismissive of pain. Therefore, the committee made a recommendation to promote sensitivity around communicating test results.
No evidence was identified for people aged 16 to 18 years. The committee agreed that the recommendations still apply, but they also agreed that there may be specific considerations for young adults (aged 16 to 25), including age-related differences in presentation of symptoms, family interactions and dynamics, and impact on their education and emotional development.
## How the recommendations might affect practice
The recommendations reflect best practice, but are currently implemented to varying degrees across NHS settings and will involve a change of practice for some providers. To fully implement these recommendations for people with chronic pain, longer consultations or additional follow up may be needed to discuss self-management and treatment options.
Return to recommendations
# Exercise programmes and physical activity for chronic primary pain
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendations
Evidence from many studies showed that exercise reduced pain (23 studies) and improved quality of life (22 studies) compared with usual care in people with chronic primary pain. Benefit was seen for both short‑ and long‑term follow up and was consistent across different types of exercise. Most of the evidence was for professionally led supervised group exercise and for women with fibromyalgia or people with chronic neck pain. As there was no evidence to suggest that effectiveness differed for types of chronic primary pain, it was agreed there was no reason this evidence could not apply for the whole review population. There was limited evidence comparing different types of exercise with each other although, from what was available, there was minimal difference between the types. The committee agreed the most appropriate type of exercise may depend on the type of pain. For these reasons, the committee did not specify what type of exercise should be used, and agreed it could be any of the types included in the studies reviewed (cardiovascular, mind–body, strength, or a combination of approaches).
An economic model comparing exercise (all types) with no exercise was developed for this guideline and showed that exercise was likely to be cost effective (both if using only the time horizon of the trials and also when extrapolating the quality of life gain beyond the trials). The analysis used studies in which exercise was predominantly group based. The committee considered the results to be robust, and agreed that the studies used in the model were representative of the whole evidence review. Exercise remained cost effective when the assumed benefits and costs were varied (sensitivity analysis).
There were no negative effects demonstrated except for more people discontinuing from exercise programmes. The committee agreed that people are more likely to continue with exercise if the programme offered suits their lifestyle and physical ability and addresses their individual health needs. They agreed that the choice of programme as well as the content should take into account people's abilities and preferences. This might include providing individual exercise advice for different members of a group.
The committee's experience was that many people with chronic primary pain find it difficult to be physically active. The committee agreed that it is important for these people to continue to be physically active after a formal exercise programme ends, but the type of physical activity should be sustainable for the person.
## How the recommendations might affect practice
The types of exercise programmes currently offered vary from place to place, often determined by the needs of the local population. In areas where supervised group exercise is currently not provided, implementing the recommendation will lead to increased resource use.
The committee discussed that if costs are incurred by engaging in physical activity after a formal exercise programme ends, this would be a personal cost for people with chronic primary pain, and would not fall to the NHS.
Return to recommendations
# Psychological therapy for chronic primary pain
Recommendations 1.2.3 and 1.2.4
## Why the committee made the recommendations
Most of the evidence showed that acceptance and commitment therapy (ACT) improved quality of life and sleep, and reduced pain and psychological distress. Although clinical evidence was from a fairly small number of studies, 1 economic evaluation also showed ACT to be cost effective. The committee agreed that ACT was likely to offer a good balance of benefits and costs and so recommended that it should be considered as a psychological therapy for chronic primary pain. There was not enough evidence to support a preference for ACT over cognitive behavioural therapy (CBT) or CBT over ACT.
Most of the evidence showed that CBT for pain improved quality of life for people with chronic primary pain. A consistent benefit was not demonstrated in other outcomes, but the committee considered that the evidence may have underestimated the benefits because the studies varied in terms of the level of training of the therapists and the way the therapy was delivered. There was no strong evidence of harm. Two economic evaluations also showed CBT to be cost effective. The committee agreed that the evidence was not of high quality so they decided to recommend that CBT (for pain) is considered, rather than making a stronger recommendation to offer CBT (for pain).
Although there was some benefit of CBT for insomnia (CBT-I), particularly for quality of life and sleep, the amount of evidence was smaller and did not include economic evidence, so was insufficient to justify a practice recommendation. The committee agreed to make a recommendation for research on CBT-I to inform future guidance.
Evidence for biofeedback was conflicting, with little evidence of benefit and some evidence of harm. For this reason, the committee decided that this should not be offered as a management option for people with chronic primary pain.
There was not enough evidence for relaxation therapy, mindfulness or psychotherapy for the committee to make recommendations, but what evidence there was suggested there may be some benefit. The committee decided to make recommendations for research on relaxation, mindfulness and psychotherapy to inform future guidance. For psychotherapy this was specifically for psychodynamic psychotherapy.
Limited evidence showed no clinically important effect of pain education in improving quality of life or psychological distress for people with chronic primary pain. But there was a possible benefit for pain and no evidence of harm. The committee noted that education should be part of good clinical practice and providing information to help increase a person's understanding about their condition should be encouraged. They agreed that providing information on pain was part of developing a care and support plan, covered by other recommendations in this guideline.
Limited evidence showed a benefit of sleep hygiene for improving quality of life, sleep and pain. The committee considered that sleep hygiene is a component of CBT-I and evidence showed that sleep hygiene was no more effective than CBT-I. Therefore the committee decided not to make a recommendation for sleep hygiene.
Evidence from a single study suggested that hypnosis may improve pain, but there was no benefit seen for quality of life or psychological distress for people with chronic primary pain. The committee agreed that hypnosis is not widely used to manage chronic primary pain in current clinical practice and the evidence did not indicate enough benefit to warrant further research.
## How the recommendations might affect practice
The resource impact will depend on the uptake of the recommendations. CBT is used in the NHS for chronic primary pain, although it is not standard practice everywhere. ACT is a relatively new intervention but is also used to varying degrees in practice. The costs of both interventions depend on the number and length of sessions, whether they are group or individual (or face to face or virtual/online), and who they are run by. Therefore costs can vary.
If used for chronic primary pain, biofeedback is usually used in physiotherapy as a method of monitoring progress, rather than as a treatment in itself. The recommendation is therefore unlikely to have a significant impact on current practice.
Return to recommendations
# Acupuncture for chronic primary pain
Recommendation 1.2.5
## Why the committee made the recommendation
Many studies (27 in total) showed that acupuncture reduced pain and improved quality of life in the short term (up to 3 months) compared with usual care or sham acupuncture. There was not enough evidence to determine longer-term benefits. The committee acknowledged the difficulty in blinding for sham procedures, but agreed that the benefit compared with a sham procedure indicated a specific treatment effect of acupuncture. There was a wide variation among the studies in the type and intensity of the intervention used, and the studies were from many different countries. The committee agreed that the type of acupuncture or dry needling should depend on the individual needs of the person with pain.
Two economic evaluations (1 in the UK) showed that acupuncture offered a good balance of benefits and costs for people with chronic neck pain. However, both studies had limitations; a notable limitation being that the costs of acupuncture seemed low. Threshold analysis based on these studies indicated the maximum number of hours of a band 6 and 7 healthcare professional's time that would make the intervention cost effective.
An original economic model was developed for this guideline, which compared acupuncture with no acupuncture. The model used data from studies with usual care comparisons, not comparisons with sham acupuncture, because the committee agreed that a usual care comparison in an economic model better reflects the real world benefit of the intervention. The model showed that acupuncture was likely to be cost effective. The committee considered the results to be robust, and agreed that the studies used in the model were representative of the whole evidence review. Acupuncture remained cost effective when the assumed benefits and costs were varied (sensitivity analysis).
Overall, the committee agreed that there was a large evidence base showing acupuncture to be clinically effective in the short term (3 months); the original economic modelling also showed it is likely to be cost effective. However, they were uncertain whether the beneficial effects would be sustained long term and were aware of the high resource impact of implementation. Taking these factors into account, the committee made a recommendation to consider acupuncture or dry needling for chronic primary pain, caveated by the factors likely to make the intervention cost effective. These were: only if delivered in the community, and with a maximum of 5 treatment hours (based on the average resource use in the trials in the model and on the threshold analysis), and from a band 7 (equivalent cost or lower) healthcare professional (based on the threshold analysis). It was agreed there may be different ways of delivering the service that enable acupuncture to be delivered for the same costs, which would equally be appropriate. The committee agreed that discontinuing before this total amount of course time would be an option if the person finds that the first few sessions are not effective.
No evidence was found to inform a recommendation for repeat courses of acupuncture. The committee agreed that further research would help to inform future practice (see the recommendation for research on repeat courses of acupuncture for chronic primary pain).
## How the recommendation might affect practice
There is variation in the availability and use of acupuncture for chronic primary pain, with a recent reduction in these services. The recommendation is expected to lead to increased use and need for acupuncture services and therefore to have a resource impact. This is due to the number of people with chronic primary pain, and acupuncture usually being an individual patient intervention and so staff intensive.
Return to recommendation
# Electrical physical modalities for chronic primary pain
Recommendation 1.2.6
## Why the committee made the recommendation
Limited evidence showed some benefit of electrical therapies for chronic primary pain, but sample sizes were small and benefit beyond 3 months was unclear.
The exception was laser therapy and transcranial magnetic stimulation (TMS), which both showed a benefit for patient-reported pain. Laser therapy also demonstrated improvements in quality of life in larger studies than for other electrical physical modalities.
The laser therapy used in the studies varied widely, particularly in terms of wavelength, power, and the time the laser was applied to each painful area. Evidence for TMS was from 7 studies, and although benefits were seen in pain reduction, there were no benefits in any other outcome.
Evidence at more than 3 months' follow up was limited for both laser therapy and TMS, and there was no evidence on cost effectiveness.
Taking into account the quality of the evidence, the limited long-term data and the lack of evidence on cost effectiveness, the committee decided not to make a practice recommendation for laser therapy or TMS. However, because the limited evidence was promising, they agreed to make recommendations for research on laser therapy for chronic primary pain and transcranial magnetic stimulation for chronic primary pain to inform future guidance.
Limited evidence for TENS showed no clinically important difference compared with sham TENS and usual care across several outcomes at less than 3 months, and no longer-term evidence was identified. There was no evidence for ultrasound or interferential therapy. The committee noted these technologies have been around for some time so it is unlikely that new research would be undertaken. These treatments are being used by some in the NHS without evidence of benefit, so the committee agreed that TENS, ultrasound and interferential therapy should not be offered for chronic primary pain. Resources should be re-allocated to areas with more evidence of clinical and cost effectiveness.
There was a very limited amount of evidence for PENS and transcranial direct current stimulation (TDCS), which suggested inconsistent benefits in some outcomes only. The committee agreed this was insufficient for a recommendation. As neither intervention is widely used in current practice for chronic primary pain, they did not think further research was warranted.
## How the recommendation might affect practice
TENS, ultrasound and interferential therapy are being used by some in the NHS without evidence of benefit. Resources should be re-allocated to areas with more evidence of clinical and cost effectiveness.
Return to recommendation
# Pain management programmes
## Why the committee did not make a recommendation
Most of the evidence for people with chronic primary pain (8 studies) showed no difference in quality of life with pain management programmes led by professionals compared with usual care or waiting list controls. There were no benefits observed in any other outcomes. The committee agreed that because of this evidence, and uncertainty about cost effectiveness, they were unable to make a recommendation for or against the use of pain management programmes for chronic primary pain. They agreed that management options should be tailored after a patient-centred assessment.
For mixed types of chronic pain, benefit was observed in quality of life from all 4 studies. However, limited benefits were observed for function, psychological distress and other outcomes. Where benefits were observed, they were only small. The committee noted that most of the evidence for quality of life was from people with chronic low back pain, with the exception of 1 small study in people with knee pain. Evidence for other outcomes was from a broader mix of types of chronic pain. The committee agreed that they could not determine the effectiveness of pain management programmes for all types of chronic pain from this evidence. They agreed to cross-refer to related NICE guidelines for pain management options.
The committee discussed that although it may be expected that combinations of single interventions within a pain management programme might result in aggregated benefits or at least equal benefits to those shown from the interventions delivered individually, this was not reflected in the evidence. The committee discussed possible reasons for this, which might include the possibility that interventions were delivered differently or to different intensity in programmes than when delivered individually. They may also be more tailored to individual preferences when delivered in isolation. The committee also considered that people who attend pain management programmes may have already tried single interventions and so might respond differently to others, even though they have the same diagnosis.
The committee discussed whether pain management programmes may be beneficial to some people with chronic pain and may also be cost effective, but agreed that the evidence did not allow conclusions to be drawn.
Differences in programme delivery methods, including intensity, duration, components, structure and staffing, and aims meant that the committee were not able to determine whether there was a particular content and characteristics of a programme that could be effective. The committee discussed making a research recommendation to help determine the elements that could make up an effective pain management programme for people with chronic pain, but agreed that there are too many contributing factors to effectively address this for all types of chronic pain.
# Manual therapy for chronic primary pain
Recommendation for research on manual therapy for chronic primary pain
## Why the committee made the recommendation
There was only a small amount of evidence available for each of the types of manual therapy from studies of small sample sizes. The committee considered the lack of evidence for the different types of manual therapy as well as the limitations of the evidence. The committee were concerned about the quality of the evidence and the variation in the type and intensity of the therapy. For example, vigorous soft tissue techniques might be very similar in practice to mobilisation. For some types of manual therapy, there was no evidence for outcomes beyond 3 months. The committee were not able to draw any definite conclusions from the evidence about the best type of manual therapy and so could not make recommendations for practice. However, the committee agreed that the benefits compared with usual care were promising and there was no evidence of harm. Therefore, they decided to make a research recommendation.
# Pharmacological management for chronic primary pain
Recommendations 1.2.7 to 1.2.15
## Why the committee made the recommendations
Evidence indicated that antidepressants (amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine and sertraline) improved quality of life, pain, sleep and psychological distress compared with placebo. But there were some limitations in the quality and amount of the evidence. Most of the evidence was for women with fibromyalgia. However, included evidence from other types of chronic primary pain was consistent with these findings. The committee agreed that there was no evidence demonstrating a different response to treatment in other chronic primary pain conditions, and therefore it was agreed there was no reason this recommendation could not apply to all chronic primary pain conditions.
The antidepressants were considered by class, but evidence was only available for certain drugs within each class. The committee agreed these should be stated in the recommendation. No evidence was identified that compared antidepressant classes with each other, and the committee agreed that although there were some inconsistencies in benefits observed between classes, they could not assume one class to be more or less effective than another. Duloxetine (the only SNRI with evidence for chronic primary pain) had a larger amount of long-term evidence of effectiveness. However, due to the lack of head-to-head comparisons between the antidepressant classes, the committee could not recommend duloxetine in preference to the other antidepressants for which there was evidence. The committee agreed to recommend considering any of the antidepressants for which there was evidence of benefit. The decision of which antidepressant to try should be based on a fully informed discussion with the person with chronic primary pain, taking into account the risks and benefits.
Although none of the antidepressants have marketing authorisations for chronic primary pain, there are no licensed alternatives for this indication and these medications are already used in practice for this purpose. The committee agreed that doses of SSRIs and SNRIs should be in line with BNF recommendations for depression. For amitriptyline, the evidence indicating benefit included very low doses of 5 mg per day. The committee therefore agreed it was appropriate to start amitriptyline at the lowest possible dose and titrate up to no more than 100 mg per day. Efficacy of antidepressants should be reviewed at 4 to 6 weeks. No evidence was identified for people aged 16 to 17 years. The committee agreed that if pharmacological management was being considered for people of this age, specialist advice should be sought.
The committee agreed that the risk of withdrawal symptoms should be considered when prescribing antidepressants and these should not be continued if they were not effective. They recommended that the recommendations in the NICE guideline on depression in adults should be followed if stopping or reducing antidepressants.
No evidence was identified on the effectiveness of cannabis-based products for chronic primary pain, and some evidence suggested that the treatment could cause adverse events in the short term. However, this was limited evidence from a small study. Although the committee agreed that more research would be useful to inform future practice, they decided this was adequately covered within the NICE guideline on cannabis-based medicinal products.
No evidence was identified on the effectiveness of opioids for chronic primary pain. Although there were limitations, evidence from non-randomised studies on the long-term use (more than 6 months) of opioids for chronic pain suggested an increased risk of dependence. Based on their experience, the committee agreed that even short-term use of opioids could be harmful for a chronic condition. The evidence of long‑term harm, along with lack of evidence on effectiveness of opioids, persuaded the committee to recommend against starting opioid treatment for people with chronic primary pain.
Limited evidence suggested a lack of benefit of benzodiazepines and non-steroidal anti-inflammatory drugs (NSAIDs) for chronic primary pain. Evidence suggested that psychological and physical functioning were poorer with benzodiazepines than with placebo. Although there was no evidence for long-term use, the committee noted the addictive properties of benzodiazepines and agreed to recommend against starting treatment with benzodiazepines for chronic primary pain.
Evidence suggested that short-term use of NSAIDs made no difference to people's quality of life, pain or psychological distress. A small amount of evidence suggested that NSAIDs reduced physical function, compared with placebo. In view of the risks of harm with NSAIDs (gastrointestinal bleeding) and the lack of evidence of short-term or long-term effectiveness, the committee decided to recommend against starting NSAIDs for chronic primary pain.
Evidence suggested a lack of benefit of gabapentinoids for chronic primary pain. No evidence was identified on the long-term safety of gabapentinoids, however the committee were aware of reports of harm and risk of misuse and dependence highlighted by the MHRA notification of the reclassification of gabapentinoids as a class C substance controlled under the Misuse of Drugs Act 1971 and scheduled under the Misuse of Drugs Regulations 2001 as Schedule 3. There was no evidence identified for any other antiepileptics for chronic primary pain. Because antiepileptics are associated with known harms, particularly gabapentinoids which carry a risk of substance misuse and dependence, the committee agreed that they could not recommend starting antiepileptics for chronic primary pain. They applied this recommendation across all types of chronic primary pain and all antiepileptics (although there was evidence for only some types) because of their knowledge of the harms associated with these drugs. They were aware that gabapentinoids are currently recommended for neuropathic pain and expert opinion within the committee suggested that complex regional pain syndrome (CRPS) is sometimes understood as a neuropathic pain disorder. Based on the expert opinion of some committee members they therefore decided to make a recommendation for research on the use of gabapentinoids for CRPS to inform future guidance.
Evidence for local anaesthetics was limited. A small amount of evidence for short-term use of topical local anaesthetics suggested that there is either no benefit or that their use could result in worse outcomes for pain than placebo. No evidence was identified for intravenous use. The committee therefore agreed to recommend against the use of topical or intravenous local anaesthetics for chronic primary pain. However, based on the expert opinion of some members of the committee, it was noted that local anaesthetics may be useful for people with CRPS, who are under-represented in randomised controlled trials. They therefore decided to make a recommendation for research on the use of local anaesthetics for CRPS to inform future guidance.
No evidence was identified for paracetamol, ketamine, antipsychotics, corticosteroids or anaesthetic/corticosteroid combinations (for the latter 2 evidence was only considered for trigger point injections). From their own experience, and from the summaries of product characteristics, the committee agreed that these medicines have possible harms. The committee agreed that not commenting on these medicines could result in their continued use in practice, which would be inappropriate given the lack of evidence and possible harms, so they recommended against starting any of these treatments for chronic primary pain.
The committee agreed that when recommendations had been made against the use of medicines, there should be guidance for people who are already taking these, including guidance for those who report benefit from these medicines (this includes pain medicines bought over the counter). They therefore included a recommendation based on expert opinion to explain the risks of continuing a medicine, to inform a decision about whether the risks outweighed the benefits and whether the medicine should be reduced or stopped, or continued safely. A recommendation was also made to highlight possible withdrawal symptoms after stopping some medicines.
## How the recommendations might affect practice
There is currently variation in the use of drugs to treat chronic primary pain. The recommendations are likely to have a resource impact in the short term because there may be increased resource use from helping people to stop treatments, particularly opioids and gabapentinoids. SNRI antidepressants are also slightly more expensive than other types of antidepressant such as tricyclics, but this does depend on dose. In the longer term, the recommendations should reduce the use of drugs for managing chronic primary pain, with a consequent reduction in harms and cost savings.
Return to recommendations
# Social interventions for chronic pain (chronic primary pain and chronic secondary pain)
Recommendation for research on social interventions for chronic pain, including chronic primary pain
## Why the committee made the recommendation
No evidence was identified. The committee noted that provision of social prescribing link workers is part of the NHS long term plan, and so there is already a move towards social interventions within the NHS. The committee were aware of evidence for social interventions in conditions other than chronic pain, but they agreed that this evidence could not be extrapolated as the issues faced by people with chronic pain are likely to be different from those populations. They could not make a recommendation for chronic pain without evidence on clinical and cost effectiveness. The committee decided to make a research recommendation to gather high-quality evidence on social interventions in the NHS, specifically for adults with chronic pain. This will hopefully inform future guidance.
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{'Context': 'Chronic pain (sometimes known as long-term pain or persistent pain) is pain that lasts for more than 3\xa0months. Pain can be secondary to (caused by) an underlying condition (for example, osteoarthritis, rheumatoid arthritis, ulcerative colitis, endometriosis). Chronic pain can also be primary. Chronic primary pain has no clear underlying condition or the pain (or its impact) appears to be out of proportion to any observable injury or disease. The decisions about the search for any injury or disease that may be causing the pain, and about whether the pain or its impact are out of proportion to any identified injury or disease, are matters for clinical judgement in discussion with the patient. The mechanisms underlying chronic primary pain are only partially understood and the definitions are fairly new. All forms of pain can cause distress and disability, but these features are particularly prominent in presentations of chronic primary pain. This guideline is consistent with the ICD-11 definition of chronic primary pain.\n\nICD-11 gives examples of chronic primary pain, including fibromyalgia (chronic widespread pain), complex regional pain syndrome, chronic primary headache and orofacial pain, chronic primary visceral pain and chronic primary musculoskeletal pain. These specific conditions were used as search terms for the evidence underpinning the recommendations in this guideline, along with more general terms that describe studies in chronic pain populations. Categorisations may change with time and advances in understanding of disease mechanisms.\n\nSection 1.1 of this guideline covers assessment for people living with all types of chronic pain (chronic primary pain, chronic secondary pain, or both). The experience of pain is always influenced by social factors (including deprivation, isolation, lack of access to services), emotional factors (including anxiety, distress, previous trauma), expectations and beliefs, mental health (including depression and post-traumatic stress disorder) and biological factors. When assessing chronic primary pain and chronic secondary pain, these potential contributors to the presentation should be considered.\n\nSection 1.2 of this guideline contains recommendations for managing chronic primary pain. Recommendations for managing chronic secondary pain can be found in the NICE guidelines for those conditions. Diagnostic categories may overlap and primary and secondary pain conditions may coexist. In these cases, management should be guided by both this guideline and the NICE guideline for the secondary pain condition.\n\nIn the UK the prevalence of chronic pain is uncertain, but appears common, affecting perhaps one‑third to one‑half of the population. It is not known what proportion of people with chronic pain either need or wish for treatment. The prevalence of chronic primary pain is unknown, but is estimated to be between 1% and 6% in England.', 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessing all types of chronic pain (chronic primary pain, chronic secondary pain, or both)\n\nThis section covers all types of chronic pain (pain that persists or recurs for more than 3\xa0months). It includes chronic primary pain (in which no underlying condition adequately accounts for the pain or its impact) and chronic secondary pain (in which an underlying condition adequately accounts for the pain or its impact).\n\nChronic primary pain and chronic secondary pain can coexist.\n\nThese recommendations aim to inform a care and support plan by setting out a comprehensive person‑centred assessment of the causes and effects of pain and agreeing possible management strategies, including self‑management.\n\n## Person-centred assessment\n\nOffer a person-centred assessment to those presenting with chronic pain (chronic primary pain, chronic secondary pain, or both), to identify factors contributing to the pain and how the pain affects the person's life.\n\nWhen assessing and managing any type of chronic pain (chronic primary pain, chronic secondary pain, or both) follow the recommendations in the NICE guidelines on patient experience in adult NHS services and shared decision making, particularly relating to:\n\nknowing the patient as an individual\n\nenabling patients to actively participate in their care, including:\n\n\n\ncommunication\n\ninformation\n\nshared decision making.\n\n\n\nFoster a collaborative and supportive relationship with the person with chronic pain.\n\n## Thinking about possible causes for pain\n\nThink about a diagnosis of chronic primary pain if there is no clear underlying (secondary) cause or the pain or its impact is out of proportion to any observable injury or disease, particularly when the pain is causing significant distress and disability.\n\nMake decisions about the search for any injury or disease that may be causing the pain, and about whether the pain or its impact are out of proportion to any identified injury or disease, using clinical judgement in discussion with the person with chronic pain.\n\nRecognise that an initial diagnosis of chronic primary pain may change with time. Re-evaluate the diagnosis if the presentation changes.\n\nRecognise that chronic primary pain can coexist with chronic secondary pain.\n\n## Talking about pain – how this affects life and how life affects pain\n\nAsk the person to describe how chronic pain affects their life, and that of their family, carers and significant others, and how aspects of their life may affect their chronic pain. This might include:\n\nlifestyle and day-to-day activities, including work and sleep disturbance\n\nphysical and psychological wellbeing\n\nstressful life events, including previous or current physical or emotional trauma\n\ncurrent or past history of substance misuse\n\nsocial interaction and relationships\n\ndifficulties with employment, housing, income and other social concerns.\n\nBe sensitive to the person's socioeconomic, cultural and ethnic background, and faith group, and think about how these might influence their symptoms, understanding and choice of management.\n\nExplore a person's strengths as well as the impact of pain on their life. This might include talking about:\n\ntheir views on living well\n\nthe skills they have for managing their pain\n\nwhat helps when their pain is difficult to control.\n\nAsk the person about their understanding of their condition, and that of their family, carers and significant others. This might include:\n\ntheir understanding of the causes of their pain\n\ntheir expectations of what might happen in the future in relation to their pain\n\ntheir understanding of the outcome of possible treatments.\n\nWhen assessing chronic pain in people aged 16 to 25\xa0years, take into account:\n\nany age-related differences in presentation of symptoms\n\nthe impact of the pain on family interactions and dynamics\n\nthe impact of the pain on education and social and emotional development. See the NICE guideline on transition from children's to adult's services for young people using health or social care services.\n\nRecognise that living with pain can be distressing and acknowledge this with the person with chronic pain.\n\n## Providing advice and information\n\nProvide advice and information relevant to the person's individual preferences, at all stages of care, to help them make decisions about managing their condition, including self-management.\n\nDiscuss with the person with chronic pain and their family or carers (as appropriate):\n\nthe likelihood that symptoms will fluctuate over time and that they may have flare-ups\n\nthe possibility that a reason for the pain (or flare-up) may not be identified\n\nthe possibility that the pain may not improve or may get worse and may need ongoing management\n\nthere can be improvements in quality of life even if the pain remains unchanged.\n\nWhen communicating normal or negative test results, be sensitive to the risk of invalidating the person's experience of chronic pain.\n\n## Developing a care and support plan\n\nDiscuss a care and support plan with the person with chronic pain. Explore in the discussions:\n\ntheir priorities, abilities and goals\n\nwhat they are already doing that is helpful\n\ntheir preferred approach to treatment and balance of treatments for multiple conditions\n\nany support needed for young adults (aged 16 to 25) to continue with their education or training, if this is appropriate.\n\nExplain the evidence for possible benefits, risks and uncertainties of all management options when first developing the care and support plan and at all stages of care.\n\nUse these discussions to inform and agree the care and support plan with the person with chronic pain and their family or carers (as appropriate).\n\nOffer management options:\n\nin line with section 1.2 of this guideline if the assessment suggests the person has chronic primary pain\n\nin line with the NICE guideline for the underlying chronic pain condition if the underlying condition adequately accounts for the pain and its impact (see the NICE guidelines on headaches, low back pain and sciatica, rheumatoid arthritis, osteoarthritis, spondyloarthritis, endometriosis, neuropathic pain and irritable bowel syndrome).\n\nWhen chronic primary pain and chronic secondary pain coexist, use clinical judgement to inform shared decision making about management options in section 1.2 of this guideline and in the NICE guideline for the chronic pain condition.\n\n## Flare-ups\n\nOffer a reassessment if a person presents with a change in symptoms such as a flare-up of chronic pain. Be aware that a cause for the flare-up may not be identified.\n\nIf a person has a flare-up of chronic pain:\n\nreview the care and support plan\n\nconsider investigating and managing any new symptoms\n\ndiscuss what might have contributed to the flare-up (see recommendation 1.1.8 for influences on the experience of pain).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing chronic pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: factors that may be barriers to successfully managing chronic pain (chronic primary pain and chronic secondary pain) and evidence review B: communication between healthcare professionals and people with chronic pain (chronic primary pain and chronic secondary pain).\n\nLoading. Please wait.\n\nSee also the rationale section on pain management programmes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: pain management programmes for chronic pain (chronic primary pain and chronic secondary pain).\n\nLoading. Please wait.\n\n# Managing chronic primary pain\n\nThis section covers managing chronic primary pain (in which no underlying condition adequately accounts for the pain or its impact). Chronic primary pain and chronic secondary pain can coexist.\n\n## Non-pharmacological management of chronic primary pain\n\nOffer a supervised group exercise programme to people aged 16\xa0years and over to manage chronic primary pain. Take people's specific needs, preferences and abilities into account.\n\nEncourage people with chronic primary pain to remain physically active for longer-term general health benefits (also see NICE guidelines on physical activity and behaviour change: individual approaches).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on exercise programmes and physical activity for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: exercise for chronic primary pain.\n\nLoading. Please wait.\n\nConsider acceptance and commitment therapy (ACT) or cognitive behavioural therapy (CBT) for pain for people aged 16\xa0years and over with chronic primary pain, delivered by healthcare professionals with appropriate training.\n\nDo not offer biofeedback to people aged 16\xa0years and over to manage chronic primary pain.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological therapy for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: psychological therapy for chronic primary pain.\n\nLoading. Please wait.\n\nConsider a single course of acupuncture or dry needling, within a traditional Chinese or Western acupuncture system, for people aged 16\xa0years and over to manage chronic primary pain, but only if the course:\n\nis delivered in a community setting and\n\nis delivered by a band\xa07 (equivalent or lower) healthcare professional with appropriate training and\n\nis made up of no more than 5\xa0hours of healthcare professional time (the number and length of sessions can be adapted within these boundaries) or\n\nis delivered by another healthcare professional with appropriate training and/or in another setting for equivalent or lower cost.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on acupuncture for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: acupuncture for chronic primary pain.\n\nLoading. Please wait.\n\nDo not offer any of the following to people aged 16\xa0years and over to manage chronic primary pain because there is no evidence of benefit:\n\nTENS\n\nultrasound\n\ninterferential therapy.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on electrical physical modalities for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: electrical physical modalities for chronic primary pain.\n\nLoading. Please wait.\n\n## Pharmacological management of chronic primary pain\n\nFor guidance on safe prescribing and managing withdrawal of antidepressants and dependence-forming medicines, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nConsider an antidepressant, either amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine or sertraline, for people aged 18\xa0years and over to manage chronic primary pain, after a full discussion of the benefits and harms. In April 2021, this was an off-label use of these antidepressants. See NICE's information on prescribing medicines.\n\nSeek specialist advice if pharmacological management with antidepressants is being considered for young people aged 16 to 17\xa0years.\n\nIf an antidepressant is offered to manage chronic primary pain, explain that this is because these medicines may help with quality of life, pain, sleep and psychological distress, even in the absence of a diagnosis of depression.\n\nDo not initiate any of the following medicines to manage chronic primary pain in people aged 16\xa0years and over:\n\nantiepileptic drugs including gabapentinoids, unless gabapentinoids are offered as part of a clinical trial for complex regional pain syndrome (see the recommendation for research on pharmacological interventions)\n\nantipsychotic drugs\n\nbenzodiazepines\n\ncorticosteroid trigger point injections\n\nketamine\n\nlocal anaesthetics (topical or intravenous), unless as part of a clinical trial for complex regional pain syndrome (see the recommendation for research on pharmacological interventions)\n\nlocal anaesthetic/corticosteroid combination trigger point injections\n\nnon-steroidal anti-inflammatory drugs\n\nopioids\n\nparacetamol.Pregabalin and gabapentin (gabapentinoids) are Class C controlled substances (under the Misuse of Drugs Act 1971) and scheduled under the Misuse of Drugs Regulations 2001 as Schedule 3. Evaluate patients carefully for a history of drug misuse before prescribing and observe patients for development of signs of misuse and dependence (MHRA Drug Safety Update April 2019).\n\nIf a person with chronic primary pain is already taking any of the medicines in recommendation 1.2.10, review the prescribing as part of shared decision making:\n\nexplain the lack of evidence for these medicines for chronic primary pain and\n\nagree a shared plan for continuing safely if they report benefit at a safe dose and few harms or\n\nexplain the risks of continuing if they report little benefit or significant harm, and encourage and support them to reduce and stop the medicine if possible.\n\nWhen making shared decisions about whether to stop antidepressants, opioids, gabapentinoids or benzodiazepines, discuss with the person any problems associated with withdrawal. For more information, see the section on making shared decisions about withdrawing medicines in NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor recommendations on stopping or reducing antidepressants or dependence-forming medicines, see:\n\nthe section on medication review in NICE's guideline on medicines optimisation and\n\nthe section on reviewing medicines in NICE's guideline on medicines adherence and\n\nthe section on reviewing a dependence-forming medicine or antidepressant in NICE's guideline on medicines associated with dependence or withdrawal symptoms\n\nFor recommendations on reviewing treatments, see:\n\nthe section on medication review in NICE's guideline on medicines optimisation and\n\nthe section on reviewing medicines in NICE's guideline on medicines adherence and\n\nthe section on reviewing a dependence-forming medicine or antidepressant in NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor recommendations on cannabis-based medicinal products, including recommendations for research, see the NICE guideline on cannabis-based medicinal products.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pharmacological management for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: pharmacological management for chronic primary pain.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Chronic pain\n\nPain that persists or recurs for more than 3\xa0months. This includes both chronic primary pain and chronic secondary pain, which can coexist. Other terms used include persistent pain and long-term pain.\n\n## Chronic primary pain\n\nChronic primary pain has no clear underlying condition or the pain or its impact is out of proportion to any observable injury or disease. The mechanisms underlying chronic primary pain are only partially understood and the definitions are fairly new. All forms of pain can cause distress and disability, but these features are particularly prominent in presentations of chronic primary pain. This guideline is consistent with the ICD-11 definition of chronic primary pain.\n\nFibromyalgia (chronic widespread pain) is a type of chronic primary pain. ICD-11 also categorises complex regional pain syndrome, chronic primary headache and orofacial pain, chronic primary visceral pain and chronic primary musculoskeletal pain as types of chronic primary pain.\n\n## Flare-up\n\nA flare‑up is a sudden, temporary worsening of symptoms. Usually this refers to more intense pain on a day‑to‑day basis. It can also refer to a change in fatigue, stiffness, function or disease activity. Flare‑ups can be unpredictable and the time they last can vary.\n\n## Pain management programme\n\nThis guideline defines a pain management programme as any intervention that has 2 or more components, including a physical and a psychological component, delivered by trained people, with some interaction/coordination between the 2 components.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Psychological therapy – mindfulness for chronic primary pain\n\nWhat is the clinical and cost effectiveness of mindfulness therapy for managing chronic primary pain in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on psychological therapy for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: psychological therapy for chronic primary pain.\n\nLoading. Please wait.\n\n## Psychological therapy – CBT for insomnia in chronic primary pain\n\nWhat is the clinical and cost effectiveness of cognitive behavioural therapy (CBT) for insomnia or CBT for insomnia and pain for managing chronic primary pain in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on psychological therapy for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: psychological therapy for chronic primary pain.\n\nLoading. Please wait.\n\n## Manual therapies for chronic primary pain\n\nWhat is the clinical and cost effectiveness of manual therapy for managing chronic primary pain in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on manual therapy for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: manual therapy for chronic primary pain.\n\nLoading. Please wait.\n\n## Repeat courses of acupuncture for chronic primary pain\n\nWhat is the clinical and cost effectiveness of repeat courses of acupuncture or dry needling for managing chronic primary pain in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on acupuncture for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: acupuncture for chronic primary pain.\n\nLoading. Please wait.\n\n## Pharmacological interventions – gabapentinoids and local anaesthetics for complex regional pain syndrome\n\nWhat is the clinical and cost effectiveness of gabapentinoids or local anaesthetics for managing complex regional pain syndrome in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pharmacological management for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: pharmacological management for chronic primary pain.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Factors that may be barriers to successfully managing chronic pain, including chronic primary pain\n\nWhat risk factors enable stratification of treatment for people aged 16\xa0years and over with chronic pain?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on assessing chronic pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: factors that may be barriers to successfully managing chronic pain (chronic primary pain and chronic secondary pain).\n\nLoading. Please wait.\n\n## Social interventions for chronic pain, including chronic primary pain\n\nWhat is the clinical and cost effectiveness of social interventions aimed at improving the quality of life of people aged 16\xa0years and over with chronic pain?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on social interventions for chronic pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: social interventions for chronic pain (chronic primary pain and chronic secondary pain).\n\nLoading. Please wait.\n\n## Psychotherapy for chronic primary pain\n\nWhat is the clinical and cost effectiveness of psychodynamic psychotherapy for managing chronic primary pain in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on psychological therapy for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: psychological therapy for chronic primary pain.\n\nLoading. Please wait.\n\n## Relaxation therapy for chronic primary pain\n\nWhat is the clinical and cost effectiveness of relaxation therapies for managing chronic primary pain in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on psychological therapy for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: psychological therapy for chronic primary pain.\n\nLoading. Please wait.\n\n## Laser therapy for chronic primary pain\n\nWhat is the clinical and cost effectiveness of laser therapy for managing chronic primary pain in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on electrical physical modalities for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: electrical physical modalities for chronic primary pain.\n\nLoading. Please wait.\n\n## Transcranial magnetic stimulation for chronic primary pain\n\nWhat is the clinical and cost effectiveness of transcranial magnetic stimulation for managing chronic primary pain in people aged 16\xa0years and over?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on electrical physical modalities for chronic primary pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: electrical physical modalities for chronic primary pain.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Assessing chronic pain (chronic primary pain and chronic secondary pain)\n\nRecommendations 1.1.1 to 1.1.23\n\n## Why the committee made the recommendations\n\nThere was not enough evidence to indicate whether any psychological, biological or social factors predict successful pain management. The committee acknowledged the importance of a comprehensive patient‑centred approach to assessment and management. They agreed that it is important for the healthcare professional to understand how pain is affecting a person's life and vice versa, taking into account the person's socioeconomic, cultural and ethnic background, and faith group. A care and support plan should be based on the effects of pain on day-to-day activities, as well as a person's preferences, abilities and goals, while acknowledging that it is not possible to predict what might happen in the future.\n\nThe committee agreed that it was important to acknowledge that pain can fluctuate over time and flare-ups are to be expected. Recommendations were formed by expert consensus to guide assessment of flare-ups of pain.\n\nThe committee agreed that the evidence on communication was in line with what was generally considered best practice. However, evidence demonstrated shortcomings in people's experience of consultations with healthcare professionals. The committee agreed that this area needs addressing. They emphasised the fundamental importance of good communication to the experience of care for people with chronic pain, especially when many or all treatments are ineffective for some people or not well tolerated by everyone. The committee reviewed the recommendations from the NICE guideline on patient experience in adult NHS services alongside the qualitative evidence to identify any areas needing specific recommendations for people with chronic pain. They agreed that the heterogeneous, complex and potentially distressing nature of the condition should be reflected in the recommendations. More specifically, a comprehensive assessment should elicit an understanding of the effects of the pain, and how this is viewed by the person and those around them. Understanding what is important to the person is the first step in developing a care and support plan. The committee agreed that it is important to explore a person's priorities, preferences, abilities and goals, because these can help inform the plan.\n\nThe committee highlighted the importance of being honest about the uncertainty of the prognosis, because the evidence suggested that this is valued by people with chronic pain. Evidence showed that discussions about self‑management often happen late in the care pathway, or not at all. The committee considered that all relevant management options should be considered at all stages of care, including the first contact. They made a recommendation to provide advice and information, relevant to the person's individual preferences, at all stages of care, to help them make decisions about managing their condition. Evidence showed that normal or negative test results can be communicated in a way that is perceived as being dismissive of pain. Therefore, the committee made a recommendation to promote sensitivity around communicating test results.\n\nNo evidence was identified for people aged 16 to 18\xa0years. The committee agreed that the recommendations still apply, but they also agreed that there may be specific considerations for young adults (aged 16\xa0to\xa025), including age-related differences in presentation of symptoms, family interactions and dynamics, and impact on their education and emotional development.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect best practice, but are currently implemented to varying degrees across NHS settings and will involve a change of practice for some providers. To fully implement these recommendations for people with chronic pain, longer consultations or additional follow up may be needed to discuss self-management and treatment options.\n\nReturn to recommendations\n\n# Exercise programmes and physical activity for chronic primary pain\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nEvidence from many studies showed that exercise reduced pain (23 studies) and improved quality of life (22\xa0studies) compared with usual care in people with chronic primary pain. Benefit was seen for both short‑ and long‑term follow up and was consistent across different types of exercise. Most of the evidence was for professionally led supervised group exercise and for women with fibromyalgia or people with chronic neck pain. As there was no evidence to suggest that effectiveness differed for types of chronic primary pain, it was agreed there was no reason this evidence could not apply for the whole review population. There was limited evidence comparing different types of exercise with each other although, from what was available, there was minimal difference between the types. The committee agreed the most appropriate type of exercise may depend on the type of pain. For these reasons, the committee did not specify what type of exercise should be used, and agreed it could be any of the types included in the studies reviewed (cardiovascular, mind–body, strength, or a combination of approaches).\n\nAn economic model comparing exercise (all types) with no exercise was developed for this guideline and showed that exercise was likely to be cost effective (both if using only the time horizon of the trials and also when extrapolating the quality of life gain beyond the trials). The analysis used studies in which exercise was predominantly group based. The committee considered the results to be robust, and agreed that the studies used in the model were representative of the whole evidence review. Exercise remained cost effective when the assumed benefits and costs were varied (sensitivity analysis).\n\nThere were no negative effects demonstrated except for more people discontinuing from exercise programmes. The committee agreed that people are more likely to continue with exercise if the programme offered suits their lifestyle and physical ability and addresses their individual health needs. They agreed that the choice of programme as well as the content should take into account people's abilities and preferences. This might include providing individual exercise advice for different members of a group.\n\nThe committee's experience was that many people with chronic primary pain find it difficult to be physically active. The committee agreed that it is important for these people to continue to be physically active after a formal exercise programme ends, but the type of physical activity should be sustainable for the person.\n\n## How the recommendations might affect practice\n\nThe types of exercise programmes currently offered vary from place to place, often determined by the needs of the local population. In areas where supervised group exercise is currently not provided, implementing the recommendation will lead to increased resource use.\n\nThe committee discussed that if costs are incurred by engaging in physical activity after a formal exercise programme ends, this would be a personal cost for people with chronic primary pain, and would not fall to the NHS.\n\nReturn to recommendations\n\n# Psychological therapy for chronic primary pain\n\nRecommendations 1.2.3 and 1.2.4\n\n## Why the committee made the recommendations\n\nMost of the evidence showed that acceptance and commitment therapy (ACT) improved quality of life and sleep, and reduced pain and psychological distress. Although clinical evidence was from a fairly small number of studies, 1 economic evaluation also showed ACT to be cost effective. The committee agreed that ACT was likely to offer a good balance of benefits and costs and so recommended that it should be considered as a psychological therapy for chronic primary pain. There was not enough evidence to support a preference for ACT over cognitive behavioural therapy (CBT) or CBT over ACT.\n\nMost of the evidence showed that CBT for pain improved quality of life for people with chronic primary pain. A consistent benefit was not demonstrated in other outcomes, but the committee considered that the evidence may have underestimated the benefits because the studies varied in terms of the level of training of the therapists and the way the therapy was delivered. There was no strong evidence of harm. Two economic evaluations also showed CBT to be cost effective. The committee agreed that the evidence was not of high quality so they decided to recommend that CBT (for pain) is considered, rather than making a stronger recommendation to offer CBT (for pain).\n\nAlthough there was some benefit of CBT for insomnia (CBT-I), particularly for quality of life and sleep, the amount of evidence was smaller and did not include economic evidence, so was insufficient to justify a practice recommendation. The committee agreed to make a recommendation for research on CBT-I to inform future guidance.\n\nEvidence for biofeedback was conflicting, with little evidence of benefit and some evidence of harm. For this reason, the committee decided that this should not be offered as a management option for people with chronic primary pain.\n\nThere was not enough evidence for relaxation therapy, mindfulness or psychotherapy for the committee to make recommendations, but what evidence there was suggested there may be some benefit. The committee decided to make recommendations for research on relaxation, mindfulness and psychotherapy to inform future guidance. For psychotherapy this was specifically for psychodynamic psychotherapy.\n\nLimited evidence showed no clinically important effect of pain education in improving quality of life or psychological distress for people with chronic primary pain. But there was a possible benefit for pain and no evidence of harm. The committee noted that education should be part of good clinical practice and providing information to help increase a person's understanding about their condition should be encouraged. They agreed that providing information on pain was part of developing a care and support plan, covered by other recommendations in this guideline.\n\nLimited evidence showed a benefit of sleep hygiene for improving quality of life, sleep and pain. The committee considered that sleep hygiene is a component of CBT-I and evidence showed that sleep hygiene was no more effective than CBT-I. Therefore the committee decided not to make a recommendation for sleep hygiene.\n\nEvidence from a single study suggested that hypnosis may improve pain, but there was no benefit seen for quality of life or psychological distress for people with chronic primary pain. The committee agreed that hypnosis is not widely used to manage chronic primary pain in current clinical practice and the evidence did not indicate enough benefit to warrant further research.\n\n## How the recommendations might affect practice\n\nThe resource impact will depend on the uptake of the recommendations. CBT is used in the NHS for chronic primary pain, although it is not standard practice everywhere. ACT is a relatively new intervention but is also used to varying degrees in practice. The costs of both interventions depend on the number and length of sessions, whether they are group or individual (or face to face or virtual/online), and who they are run by. Therefore costs can vary.\n\nIf used for chronic primary pain, biofeedback is usually used in physiotherapy as a method of monitoring progress, rather than as a treatment in itself. The recommendation is therefore unlikely to have a significant impact on current practice.\n\nReturn to recommendations\n\n# Acupuncture for chronic primary pain\n\nRecommendation 1.2.5\n\n## Why the committee made the recommendation\n\nMany studies (27 in total) showed that acupuncture reduced pain and improved quality of life in the short term (up to 3\xa0months) compared with usual care or sham acupuncture. There was not enough evidence to determine longer-term benefits. The committee acknowledged the difficulty in blinding for sham procedures, but agreed that the benefit compared with a sham procedure indicated a specific treatment effect of acupuncture. There was a wide variation among the studies in the type and intensity of the intervention used, and the studies were from many different countries. The committee agreed that the type of acupuncture or dry needling should depend on the individual needs of the person with pain.\n\nTwo economic evaluations (1 in the UK) showed that acupuncture offered a good balance of benefits and costs for people with chronic neck pain. However, both studies had limitations; a notable limitation being that the costs of acupuncture seemed low. Threshold analysis based on these studies indicated the maximum number of hours of a band 6 and 7 healthcare professional's time that would make the intervention cost effective.\n\nAn original economic model was developed for this guideline, which compared acupuncture with no acupuncture. The model used data from studies with usual care comparisons, not comparisons with sham acupuncture, because the committee agreed that a usual care comparison in an economic model better reflects the real world benefit of the intervention. The model showed that acupuncture was likely to be cost effective. The committee considered the results to be robust, and agreed that the studies used in the model were representative of the whole evidence review. Acupuncture remained cost effective when the assumed benefits and costs were varied (sensitivity analysis).\n\nOverall, the committee agreed that there was a large evidence base showing acupuncture to be clinically effective in the short term (3\xa0months); the original economic modelling also showed it is likely to be cost effective. However, they were uncertain whether the beneficial effects would be sustained long term and were aware of the high resource impact of implementation. Taking these factors into account, the committee made a recommendation to consider acupuncture or dry needling for chronic primary pain, caveated by the factors likely to make the intervention cost effective. These were: only if delivered in the community, and with a maximum of 5 treatment hours (based on the average resource use in the trials in the model and on the threshold analysis), and from a band 7 (equivalent cost or lower) healthcare professional (based on the threshold analysis). It was agreed there may be different ways of delivering the service that enable acupuncture to be delivered for the same costs, which would equally be appropriate. The committee agreed that discontinuing before this total amount of course time would be an option if the person finds that the first few sessions are not effective.\n\nNo evidence was found to inform a recommendation for repeat courses of acupuncture. The committee agreed that further research would help to inform future practice (see the recommendation for research on repeat courses of acupuncture for chronic primary pain).\n\n## How the recommendation might affect practice\n\nThere is variation in the availability and use of acupuncture for chronic primary pain, with a recent reduction in these services. The recommendation is expected to lead to increased use and need for acupuncture services and therefore to have a resource impact. This is due to the number of people with chronic primary pain, and acupuncture usually being an individual patient intervention and so staff intensive.\n\nReturn to recommendation\n\n# Electrical physical modalities for chronic primary pain\n\nRecommendation 1.2.6\n\n## Why the committee made the recommendation\n\nLimited evidence showed some benefit of electrical therapies for chronic primary pain, but sample sizes were small and benefit beyond 3\xa0months was unclear.\n\nThe exception was laser therapy and transcranial magnetic stimulation (TMS), which both showed a benefit for patient-reported pain. Laser therapy also demonstrated improvements in quality of life in larger studies than for other electrical physical modalities.\n\nThe laser therapy used in the studies varied widely, particularly in terms of wavelength, power, and the time the laser was applied to each painful area. Evidence for TMS was from 7 studies, and although benefits were seen in pain reduction, there were no benefits in any other outcome.\n\nEvidence at more than 3\xa0months' follow up was limited for both laser therapy and TMS, and there was no evidence on cost effectiveness.\n\nTaking into account the quality of the evidence, the limited long-term data and the lack of evidence on cost effectiveness, the committee decided not to make a practice recommendation for laser therapy or TMS. However, because the limited evidence was promising, they agreed to make recommendations for research on laser therapy for chronic primary pain and transcranial magnetic stimulation for chronic primary pain to inform future guidance.\n\nLimited evidence for TENS showed no clinically important difference compared with sham TENS and usual care across several outcomes at less than 3\xa0months, and no longer-term evidence was identified. There was no evidence for ultrasound or interferential therapy. The committee noted these technologies have been around for some time so it is unlikely that new research would be undertaken. These treatments are being used by some in the NHS without evidence of benefit, so the committee agreed that TENS, ultrasound and interferential therapy should not be offered for chronic primary pain. Resources should be re-allocated to areas with more evidence of clinical and cost effectiveness.\n\nThere was a very limited amount of evidence for PENS and transcranial direct current stimulation (TDCS), which suggested inconsistent benefits in some outcomes only. The committee agreed this was insufficient for a recommendation. As neither intervention is widely used in current practice for chronic primary pain, they did not think further research was warranted.\n\n## How the recommendation might affect practice\n\nTENS, ultrasound and interferential therapy are being used by some in the NHS without evidence of benefit. Resources should be re-allocated to areas with more evidence of clinical and cost effectiveness.\n\nReturn to recommendation\n\n# Pain management programmes\n\n## Why the committee did not make a recommendation\n\nMost of the evidence for people with chronic primary pain (8 studies) showed no difference in quality of life with pain management programmes led by professionals compared with usual care or waiting list controls. There were no benefits observed in any other outcomes. The committee agreed that because of this evidence, and uncertainty about cost effectiveness, they were unable to make a recommendation for or against the use of pain management programmes for chronic primary pain. They agreed that management options should be tailored after a patient-centred assessment.\n\nFor mixed types of chronic pain, benefit was observed in quality of life from all 4 studies. However, limited benefits were observed for function, psychological distress and other outcomes. Where benefits were observed, they were only small. The committee noted that most of the evidence for quality of life was from people with chronic low back pain, with the exception of 1 small study in people with knee pain. Evidence for other outcomes was from a broader mix of types of chronic pain. The committee agreed that they could not determine the effectiveness of pain management programmes for all types of chronic pain from this evidence. They agreed to cross-refer to related NICE guidelines for pain management options.\n\nThe committee discussed that although it may be expected that combinations of single interventions within a pain management programme might result in aggregated benefits or at least equal benefits to those shown from the interventions delivered individually, this was not reflected in the evidence. The committee discussed possible reasons for this, which might include the possibility that interventions were delivered differently or to different intensity in programmes than when delivered individually. They may also be more tailored to individual preferences when delivered in isolation. The committee also considered that people who attend pain management programmes may have already tried single interventions and so might respond differently to others, even though they have the same diagnosis.\n\nThe committee discussed whether pain management programmes may be beneficial to some people with chronic pain and may also be cost effective, but agreed that the evidence did not allow conclusions to be drawn.\n\nDifferences in programme delivery methods, including intensity, duration, components, structure and staffing, and aims meant that the committee were not able to determine whether there was a particular content and characteristics of a programme that could be effective. The committee discussed making a research recommendation to help determine the elements that could make up an effective pain management programme for people with chronic pain, but agreed that there are too many contributing factors to effectively address this for all types of chronic pain.\n\n# Manual therapy for chronic primary pain\n\nRecommendation for research on manual therapy for chronic primary pain\n\n## Why the committee made the recommendation\n\nThere was only a small amount of evidence available for each of the types of manual therapy from studies of small sample sizes. The committee considered the lack of evidence for the different types of manual therapy as well as the limitations of the evidence. The committee were concerned about the quality of the evidence and the variation in the type and intensity of the therapy. For example, vigorous soft tissue techniques might be very similar in practice to mobilisation. For some types of manual therapy, there was no evidence for outcomes beyond 3\xa0months. The committee were not able to draw any definite conclusions from the evidence about the best type of manual therapy and so could not make recommendations for practice. However, the committee agreed that the benefits compared with usual care were promising and there was no evidence of harm. Therefore, they decided to make a research recommendation.\n\n# Pharmacological management for chronic primary pain\n\nRecommendations 1.2.7 to 1.2.15\n\n## Why the committee made the recommendations\n\nEvidence indicated that antidepressants (amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine and sertraline) improved quality of life, pain, sleep and psychological distress compared with placebo. But there were some limitations in the quality and amount of the evidence. Most of the evidence was for women with fibromyalgia. However, included evidence from other types of chronic primary pain was consistent with these findings. The committee agreed that there was no evidence demonstrating a different response to treatment in other chronic primary pain conditions, and therefore it was agreed there was no reason this recommendation could not apply to all chronic primary pain conditions.\n\nThe antidepressants were considered by class, but evidence was only available for certain drugs within each class. The committee agreed these should be stated in the recommendation. No evidence was identified that compared antidepressant classes with each other, and the committee agreed that although there were some inconsistencies in benefits observed between classes, they could not assume one class to be more or less effective than another. Duloxetine (the only SNRI with evidence for chronic primary pain) had a larger amount of long-term evidence of effectiveness. However, due to the lack of head-to-head comparisons between the antidepressant classes, the committee could not recommend duloxetine in preference to the other antidepressants for which there was evidence. The committee agreed to recommend considering any of the antidepressants for which there was evidence of benefit. The decision of which antidepressant to try should be based on a fully informed discussion with the person with chronic primary pain, taking into account the risks and benefits.\n\nAlthough none of the antidepressants have marketing authorisations for chronic primary pain, there are no licensed alternatives for this indication and these medications are already used in practice for this purpose. The committee agreed that doses of SSRIs and SNRIs should be in line with BNF recommendations for depression. For amitriptyline, the evidence indicating benefit included very low doses of 5\xa0mg per day. The committee therefore agreed it was appropriate to start amitriptyline at the lowest possible dose and titrate up to no more than 100\xa0mg per day. Efficacy of antidepressants should be reviewed at 4 to 6\xa0weeks. No evidence was identified for people aged 16 to 17\xa0years. The committee agreed that if pharmacological management was being considered for people of this age, specialist advice should be sought.\n\nThe committee agreed that the risk of withdrawal symptoms should be considered when prescribing antidepressants and these should not be continued if they were not effective. They recommended that the recommendations in the NICE guideline on depression in adults should be followed if stopping or reducing antidepressants.\n\nNo evidence was identified on the effectiveness of cannabis-based products for chronic primary pain, and some evidence suggested that the treatment could cause adverse events in the short term. However, this was limited evidence from a small study. Although the committee agreed that more research would be useful to inform future practice, they decided this was adequately covered within the NICE guideline on cannabis-based medicinal products.\n\nNo evidence was identified on the effectiveness of opioids for chronic primary pain. Although there were limitations, evidence from non-randomised studies on the long-term use (more than 6\xa0months) of opioids for chronic pain suggested an increased risk of dependence. Based on their experience, the committee agreed that even short-term use of opioids could be harmful for a chronic condition. The evidence of long‑term harm, along with lack of evidence on effectiveness of opioids, persuaded the committee to recommend against starting opioid treatment for people with chronic primary pain.\n\nLimited evidence suggested a lack of benefit of benzodiazepines and non-steroidal anti-inflammatory drugs (NSAIDs) for chronic primary pain. Evidence suggested that psychological and physical functioning were poorer with benzodiazepines than with placebo. Although there was no evidence for long-term use, the committee noted the addictive properties of benzodiazepines and agreed to recommend against starting treatment with benzodiazepines for chronic primary pain.\n\nEvidence suggested that short-term use of NSAIDs made no difference to people's quality of life, pain or psychological distress. A small amount of evidence suggested that NSAIDs reduced physical function, compared with placebo. In view of the risks of harm with NSAIDs (gastrointestinal bleeding) and the lack of evidence of short-term or long-term effectiveness, the committee decided to recommend against starting NSAIDs for chronic primary pain.\n\nEvidence suggested a lack of benefit of gabapentinoids for chronic primary pain. No evidence was identified on the long-term safety of gabapentinoids, however the committee were aware of reports of harm and risk of misuse and dependence highlighted by the MHRA notification of the reclassification of gabapentinoids as a class C substance controlled under the Misuse of Drugs Act 1971 and scheduled under the Misuse of Drugs Regulations 2001 as Schedule 3. There was no evidence identified for any other antiepileptics for chronic primary pain. Because antiepileptics are associated with known harms, particularly gabapentinoids which carry a risk of substance misuse and dependence, the committee agreed that they could not recommend starting antiepileptics for chronic primary pain. They applied this recommendation across all types of chronic primary pain and all antiepileptics (although there was evidence for only some types) because of their knowledge of the harms associated with these drugs. They were aware that gabapentinoids are currently recommended for neuropathic pain and expert opinion within the committee suggested that complex regional pain syndrome (CRPS) is sometimes understood as a neuropathic pain disorder. Based on the expert opinion of some committee members they therefore decided to make a recommendation for research on the use of gabapentinoids for CRPS to inform future guidance.\n\nEvidence for local anaesthetics was limited. A small amount of evidence for short-term use of topical local anaesthetics suggested that there is either no benefit or that their use could result in worse outcomes for pain than placebo. No evidence was identified for intravenous use. The committee therefore agreed to recommend against the use of topical or intravenous local anaesthetics for chronic primary pain. However, based on the expert opinion of some members of the committee, it was noted that local anaesthetics may be useful for people with CRPS, who are under-represented in randomised controlled trials. They therefore decided to make a recommendation for research on the use of local anaesthetics for CRPS to inform future guidance.\n\nNo evidence was identified for paracetamol, ketamine, antipsychotics, corticosteroids or anaesthetic/corticosteroid combinations (for the latter 2 evidence was only considered for trigger point injections). From their own experience, and from the summaries of product characteristics, the committee agreed that these medicines have possible harms. The committee agreed that not commenting on these medicines could result in their continued use in practice, which would be inappropriate given the lack of evidence and possible harms, so they recommended against starting any of these treatments for chronic primary pain.\n\nThe committee agreed that when recommendations had been made against the use of medicines, there should be guidance for people who are already taking these, including guidance for those who report benefit from these medicines (this includes pain medicines bought over the counter). They therefore included a recommendation based on expert opinion to explain the risks of continuing a medicine, to inform a decision about whether the risks outweighed the benefits and whether the medicine should be reduced or stopped, or continued safely. A recommendation was also made to highlight possible withdrawal symptoms after stopping some medicines.\n\n## How the recommendations might affect practice\n\nThere is currently variation in the use of drugs to treat chronic primary pain. The recommendations are likely to have a resource impact in the short term because there may be increased resource use from helping people to stop treatments, particularly opioids and gabapentinoids. SNRI antidepressants are also slightly more expensive than other types of antidepressant such as tricyclics, but this does depend on dose. In the longer term, the recommendations should reduce the use of drugs for managing chronic primary pain, with a consequent reduction in harms and cost savings.\n\nReturn to recommendations\n\n# Social interventions for chronic pain (chronic primary pain and chronic secondary pain)\n\nRecommendation for research on social interventions for chronic pain, including chronic primary pain\n\n## Why the committee made the recommendation\n\nNo evidence was identified. The committee noted that provision of social prescribing link workers is part of the NHS long term plan, and so there is already a move towards social interventions within the NHS. The committee were aware of evidence for social interventions in conditions other than chronic pain, but they agreed that this evidence could not be extrapolated as the issues faced by people with chronic pain are likely to be different from those populations. They could not make a recommendation for chronic pain without evidence on clinical and cost effectiveness. The committee decided to make a research recommendation to gather high-quality evidence on social interventions in the NHS, specifically for adults with chronic pain. This will hopefully inform future guidance."}
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https://www.nice.org.uk/guidance/ng193
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This guideline covers assessing all chronic pain (chronic primary pain, chronic secondary pain, or both) and managing chronic primary pain in people aged 16 years and over. Chronic primary pain is pain with no clear underlying cause, or pain (or its impact) that is out of proportion to any observable injury or disease.
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cfcbfcc891180160d22b47067a9ba2cb51434440
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nice
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Transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids
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Transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids
Evidence-based recommendations on transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids in adults. This involves inserting a device through the cervix into the womb to destroy the fibroid using radiofrequency energy.
# Recommendations
Evidence on the safety of transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids raises no major safety concerns. However, evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids should:
Inform the clinical governance leads in their healthcare organisation.
Give patients clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
During the consent process clinicians should tell patients that the procedure may not fully relieve their symptoms and further procedures may be needed.
Further research should include comparative studies, preferably randomised controlled trials. It should report details of patient selection, disease-specific quality of life and long-term outcomes.# The condition, current treatments and procedure
# The condition
Uterine fibroids (also known as uterine leiomyomas or myomas) are benign tumours of the uterine wall. They can be asymptomatic or cause symptoms including menorrhagia, intermenstrual bleeding, pelvic pressure or pain, and urinary incontinence. They can be associated with fertility problems and miscarriage.
# Current treatments
Treatment depends on whether the fibroids cause symptoms, and if the person would like to become pregnant in the future. For symptomatic fibroids, treatment options include medications, interventional radiology and surgery. Interventional radiology treatments include uterine artery embolisation and MRI-guided focused ultrasound. Surgery includes hysterectomy, myomectomy, endometrial ablation techniques and myolysis.
# The procedure
Transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids is done using general or regional anaesthesia, or sedation. A radiofrequency ablation device with an ultrasound probe at the tip is inserted through the cervix into the endometrial cavity. The ultrasound probe is used to visualise and target the fibroid, which is then ablated with radiofrequency energy. The aim is to shrink the fibroid and reduce symptoms.
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{'Recommendations': "Evidence on the safety of transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids raises no major safety concerns. However, evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nDuring the consent process clinicians should tell patients that the procedure may not fully relieve their symptoms and further procedures may be needed.\n\nFurther research should include comparative studies, preferably randomised controlled trials. It should report details of patient selection, disease-specific quality of life and long-term outcomes.", 'The condition, current treatments and procedure': '# The condition\n\nUterine fibroids (also known as uterine leiomyomas or myomas) are benign tumours of the uterine wall. They can be asymptomatic or cause symptoms including menorrhagia, intermenstrual bleeding, pelvic pressure or pain, and urinary incontinence. They can be associated with fertility problems and miscarriage.\n\n# Current treatments\n\nTreatment depends on whether the fibroids cause symptoms, and if the person would like to become pregnant in the future. For symptomatic fibroids, treatment options include medications, interventional radiology and surgery. Interventional radiology treatments include uterine artery embolisation and MRI-guided focused ultrasound. Surgery includes hysterectomy, myomectomy, endometrial ablation techniques and myolysis.\n\n# The procedure\n\nTranscervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids is done using general or regional anaesthesia, or sedation. A radiofrequency ablation device with an ultrasound probe at the tip is inserted through the cervix into the endometrial cavity. The ultrasound probe is used to visualise and target the fibroid, which is then ablated with radiofrequency energy. The aim is to shrink the fibroid and reduce symptoms.'}
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https://www.nice.org.uk/guidance/ipg689
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Evidence-based recommendations on transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids in adults. This involves inserting a device through the cervix into the womb to destroy the fibroid using radiofrequency energy.
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1d30b4967bdba17e1e307e7f87d2ca486c650f0f
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nice
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Extracorporeal whole liver perfusion for acute liver failure
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Extracorporeal whole liver perfusion for acute liver failure
Evidence-based recommendations on extracorporeal whole liver perfusion for acute liver failure. This involves blood being diverted from a large vein, usually in the leg, to a whole liver (perfusion) outside the body (extracorporeal) and returned to the patient through another large vein, usually in the neck.
# Recommendations
Evidence on the safety of extracorporeal whole liver perfusion for acute liver failure shows serious, well-recognised complications. Evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Clinicians and centres doing this procedure must follow the relevant regulatory and legal requirements of the Human Tissue Authority and the procedure should only be done in accordance with the policies of the NHS Blood and Transplant (NHSBT) Organ Donation and Transplantation Liver Advisory Group. Details of any patient who has a liver transplant after extracorporeal whole liver perfusion for acute liver failure should be entered into the NHSBT UK transplant registry, and clinical outcomes should be reviewed locally.
Further research should report details of patient selection, the exact protocol followed, the type of liver used, and long-term immunological and microbiological surveillance. Outcomes should be reported in a way that allows the procedure to be compared with other current treatments.
The procedure should only be done in centres specialising in treating acute liver failure and liver transplantation by a multidisciplinary team experienced in managing this condition.# The condition, current treatments and procedure
# The condition
Acute liver failure is characterised by a rapid (typically in less than 4 weeks) decline in liver function. Causes include poisoning because of alcohol, pharmaceutical or recreational drugs, and viral infection. Less common causes are metabolic disease and acute fatty liver of pregnancy.
# Current treatments
Untreated, acute liver failure can have a high mortality. Current treatment options include medication (to reverse poisoning and to prevent complications caused by acute liver failure), temporary liver support therapies (such as haemodialysis or filtration, plasma exchange, and bioartificial liver support), hepatocyte transplantation and liver transplantation.
# The procedure
In this procedure a veno-venous circuit is usually used to perfuse the patient's blood through an extracorporeal whole liver. The aim is to provide metabolic support and prolong survival, to allow time for the patient's liver function to recover or to find a suitable donor liver for transplantation.
Blood is pumped from a catheter inserted into the femoral vein through an oxygenator and the hepatic artery and portal vein of an extracorporeal whole liver. The liver may be a human liver not suitable for transplantation or a xenogeneic liver (typically a pig liver). Effluent blood from the extracorporeal liver, which is maintained at a normal temperature with a normal pH and electrolytes, is returned to the patient through a subclavian or jugular venous cannula. The literature describes modifications to the technique, such as isolating the patient's immune system from the extracorporeal liver and using different sites for venous access.
Extracorporeal perfusion is continued for up to 5 days until either the patient has a liver transplant or their liver function recovers.
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{'Recommendations': 'Evidence on the safety of extracorporeal whole liver perfusion for acute liver failure shows serious, well-recognised complications. Evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians and centres doing this procedure must follow the relevant regulatory and legal requirements of the Human Tissue Authority and the procedure should only be done in accordance with the policies of the NHS Blood and Transplant (NHSBT) Organ Donation and Transplantation Liver Advisory Group. Details of any patient who has a liver transplant after extracorporeal whole liver perfusion for acute liver failure should be entered into the NHSBT UK transplant registry, and clinical outcomes should be reviewed locally.\n\nFurther research should report details of patient selection, the exact protocol followed, the type of liver used, and long-term immunological and microbiological surveillance. Outcomes should be reported in a way that allows the procedure to be compared with other current treatments.\n\nThe procedure should only be done in centres specialising in treating acute liver failure and liver transplantation by a multidisciplinary team experienced in managing this condition.', 'The condition, current treatments and procedure': "# The condition\n\nAcute liver failure is characterised by a rapid (typically in less than 4\xa0weeks) decline in liver function. Causes include poisoning because of alcohol, pharmaceutical or recreational drugs, and viral infection. Less common causes are metabolic disease and acute fatty liver of pregnancy.\n\n# Current treatments\n\nUntreated, acute liver failure can have a high mortality. Current treatment options include medication (to reverse poisoning and to prevent complications caused by acute liver failure), temporary liver support therapies (such as haemodialysis or filtration, plasma exchange, and bioartificial liver support), hepatocyte transplantation and liver transplantation.\n\n# The procedure\n\nIn this procedure a veno-venous circuit is usually used to perfuse the patient's blood through an extracorporeal whole liver. The aim is to provide metabolic support and prolong survival, to allow time for the patient's liver function to recover or to find a suitable donor liver for transplantation.\n\nBlood is pumped from a catheter inserted into the femoral vein through an oxygenator and the hepatic artery and portal vein of an extracorporeal whole liver. The liver may be a human liver not suitable for transplantation or a xenogeneic liver (typically a pig liver). Effluent blood from the extracorporeal liver, which is maintained at a normal temperature with a normal pH and electrolytes, is returned to the patient through a subclavian or jugular venous cannula. The literature describes modifications to the technique, such as isolating the patient's immune system from the extracorporeal liver and using different sites for venous access.\n\nExtracorporeal perfusion is continued for up to 5\xa0days until either the patient has a liver transplant or their liver function recovers."}
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https://www.nice.org.uk/guidance/ipg690
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Evidence-based recommendations on extracorporeal whole liver perfusion for acute liver failure. This involves blood being diverted from a large vein, usually in the leg, to a whole liver (perfusion) outside the body (extracorporeal) and returned to the patient through another large vein, usually in the neck.
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8306e514cf280f7f6ca6302785c398e7df4563e8
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nice
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Danis stent for acute oesophageal variceal bleeding
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Danis stent for acute oesophageal variceal bleeding
Evidence-based recommendations on Danis stent for acute oesophageal variceal bleeding.
# Recommendations
Evidence supports the case for adopting Danis stent for treating acute oesophageal variceal bleeding. Danis stent improves the short-term control of bleeding compared with a balloon tamponade and can be left in place for longer, allowing time for stabilisation.
Danis stent should be considered for people aged 16 and over with acute oesophageal variceal bleeding that does not respond to endoluminal therapy and whose oesophageal varices are being considered for definitive treatment. Also, Danis stent should be considered for people when definitive treatment is not appropriate and if they are likely to be offered palliative care.
Cost modelling shows that Danis stent is cost saving compared with balloon tamponade for acute oesophageal variceal bleeding being considered for definitive treatment. This is because having Danis stent results in a shorter stay in intensive care. To be cost saving, Danis stent needs to decrease intensive care stay by approximately 1 day or more compared with balloon tamponade. For more details, see the NICE resource impact report.
Why the committee made these recommendations
Danis stent puts pressure on enlarged veins (varices) in a person's food pipe (oesophagus) when they are bleeding uncontrollably. Enlarged veins can develop when a person has longstanding scarring liver disease (cirrhosis) that affects blood flow through the liver. This causes pressure in the blood vessel that drains blood from the gut into the liver and enlargement of these veins in the oesophagus can predispose to bleeding. Danis stent is designed to be used as a bridging treatment to control the bleeding until a decision on definitive treatment to manage the underlying pressure problem (such as a transjugular intrahepatic portosystemic shunt procedure, or band ligation) can be made. It can also be used for people when definitive treatment is not appropriate and if they are likely to be offered palliative care.
Studies show that Danis stent is better than the balloon tamponade device (a balloon inflation device that compresses the bleeding veins) in controlling bleeding in the short term. It can stay in place for up to 7 days. This is longer than the balloon tamponade, which needs to be removed after 24 hours. This allows more time to stabilise the person before their next treatment and also means that they do not usually need to stay in intensive care. Cost analysis concludes that Danis stent is cost saving compared with balloon tamponade because it reduces the number of days a person needs to stay in intensive care.# The technology
# Technology
Danis stent is a self-expanding and removable stent used to stop acute bleeding from oesophageal varices. The stent is a variable weave, made of nitinol with a silicone membrane. It is 135 mm long and 25 mm in diameter at the centre, increasing to 30 mm in diameter at the flared distal ends. During insertion, a balloon is inflated in the stomach to make sure the stent self-expands in an accurate position at the gastro-oesophageal junction, providing direct compression of oesophageal varices. The aim of Danis stent is to stabilise the bleeding, until the person can have definitive treatment to manage the underlying problem. Features of the stent include radiopaque markers for visibility, a security pressure valve and retrieval loops with gold markers. The company recommends that Danis stent stays in place for no longer than 7 days. A specially designed removal device, the Ella extractor, is needed to remove the stent unless a definitive treatment has been done, in which case the risk of re-bleed may be considered low and the stent may be removed with grasping forceps.
# Innovative aspects
The company states that Danis stent can be used without direct endoscopic imaging, which may allow for more rapid control of variceal bleeds in emergency situations compared with balloon tamponade. The delivery system has a security pressure valve that prevents the gastric balloon from being inflated in the oesophagus, which may help minimise the risk of oesophageal perforation. The stent can stay in place for up to a week (compared with balloon tamponade, which should not be left in place for more than 24 hours to 36 hours). This may allow more time to plan definitive therapy (such as transjugular intrahepatic portosystemic shunt insertion, usually done more than 72 hours after Danis stent insertion) or secondary band ligation. It may also keep the bleeding stable for longer, allowing liver function to improve. Danis stent keeps the oesophagus open, allowing oral nutrition to be maintained, which is an important element in recovery. Its variable weave stent body is designed to conform to oesophageal peristalsis, with the aim of preventing stent migration.
# Intended use
Danis stent is intended for use in acute refractory oesophageal variceal bleeding, after first-line therapy, such as variceal band ligation, has failed, to allow more time for a definitive procedure to be done. It is intended to be used as an alternative to balloon tamponade or early TIPS insertion (that is, done within 72 hours), in people aged 16 and over.
The technology is intended to be used in secondary or tertiary care by gastroenterologists, hepatologists, emergency care practitioners, paramedics or nurse practitioners. Comprehensive training is needed and is delivered by the company.
# Costs
The cost of Danis stent is £1,495 (excluding VAT) per stent. The cost of the Ella extractor is £695 (excluding VAT). For more details, see the website for Danis stent.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. See the committee papers for full details of the evidence.
# Clinical evidence
## The main clinical evidence comprises 9 studies
The evidence assessed by the EAC included 9 full-text peer-reviewed studies including 247 people. Two of the studies were comparative: a randomised controlled trial and a retrospective case‑controlled study. The remaining 7 studies were non-comparative case series. For full details of the clinical evidence, see section 3 of the assessment report in supporting documentation.
## The comparative evidence is relevant to the decision problem but has limitations
Both comparative studies compare the use of Danis stent with balloon tamponade. The studies report that using Danis stent improves control of bleeding at 5 days and 15 days. The randomised controlled trial (Escorsell et al. 2016) is the strongest evidence for Danis stent and reports a composite end point including control of bleeding and adverse events but it is underpowered for this result. The retrospective case-controlled study only included patients with acute-on-chronic liver failure and there were significant differences between the disease-severity scores of the patients in the control group compared with the interventional group. The EAC reported that both studies have a moderate risk of bias.
## The randomised controlled trial (Escorsell et al. 2016) is not reflective of the UK care pathway
The randomised controlled trial was done in Spain and differences in the care pathway limit the generalisability of the findings to the UK setting. Expert advisers stated that the definitive procedure, transjugular intrahepatic portosystemic shunt (TIPS), was delivered at an earlier stage after presentation in this trial than it would be in the UK.
## The EAC did a meta-analysis on the 7 non-comparative studies
The 7 non-comparative studies are low in quality. The studies have broadly similar populations and outcomes. Outcomes with low heterogeneity were included in the analysis. Immediate bleeding control was found to have been achieved in 88% of cases (95% confidence interval 0.38 to 0.9) based on the 7 case series, one of which (Wright et al. 2010) was done in the UK. Survival rate at 30 days was 68% from 3 studies.
# Cost evidence
## The company's comparison of the cost of Danis stent and balloon tamponade uses a cost-calculator model
The cost comparison has a 6‑week time horizon and is from an NHS and personal and social services perspective. The model estimates the cost associated with using Danis stent compared with balloon tamponade as bridging treatment for patients aged 16 or over with acute refractory oesophageal variceal bleeding in whom first-line therapy is unsuitable or has failed. The model captures the cost of the initial procedures, the likelihood of adverse events for both technologies and the cost and use of resources to remove the devices. The key model parameters are:
The proportion of patients that have either balloon tamponade or Danis stent as a bridging treatment and the proportion of patients that have either TIPS or band ligation as a definitive treatment.
Survival 6 weeks after treatment and relative risk of dying at 6 weeks with balloon tamponade compared with Danis stent.
Proportion of patients that have adverse events after treatment.For full details of the cost evidence, see section 4 of the assessment report in supporting documentation.
## The EAC's updates to the cost model change the direction of the cost case
The EAC updated 5 cost parameters, including the cost of:
removing Danis stent (company, £1,257.00; EAC, £1,452.00)
re-bleed (company, £3,287.00; EAC, £4,978.75)
definitive TIPS treatment (company, £3,928.00; EAC, £4,965.56)
definitive band ligation (company, £1,114.00; EAC, £4,983.67)
severe hepatic encephalopathy (company, £400.52; EAC £400.56).
With the updated cost parameters, the EAC's base case shows that Danis stent is cost incurring by £923.00 per person. The company also presented 3 scenario analyses, all of which the EAC considered relevant. Scenario 1 modelled the cost of using each technology by cumulating the costs of the resources needed. Scenarios 2 and 3 explored uncertainty in the assumed impact of the bridge treatment on the choice of definitive treatment including (scenario 3) and excluding (scenario 2) hepatic encephalopathy costs.
## Two additional scenario analyses include a second endoscopy for patients who have a balloon tamponade
Clinical experts highlighted that a second endoscopy at the time of balloon removal is needed for people that have balloon tamponade. The choice of definitive treatment is done on a case-by-case basis regardless of the bridging treatment used. Therefore scenarios 4 and 5 were done to include the cost of a second endoscopy:
Scenario 4 – an extension of scenario 2 but with the addition of a second endoscopy for people treated with balloon tamponade based on expert comments.
Scenario 5 – an extension of scenario 1 to explore the impact of reduced intensive care unit (ICU) bed days in the Danis stent group and a second endoscopy for people treated with balloon tamponade.
## Updates to resource parameters in the micro-costed model are based on expert advice and data about hospital admissions
Estimates about resource use in the care pathway were updated based on expert advice and were reported as scenarios 5A and 5B. The key parameters changed were the:
proportion of patients that had Danis stent inserted in a theatre setting (increased)
ICU length of stay in the Danis stent group (reduced) and in the balloon tamponade group (increased)
cost of the balloon tamponade procedure (increased).
Costs were modelled for the proportion of patients that needed transferring from a secondary care setting to a tertiary care setting (scenario 5B only).# Committee discussion
# The clinical care pathway is complex
The clinical experts explained that oesophageal variceal bleeding is an acute clinical emergency and clinical care is managed on a case-by-case basis. First-line treatment is an endoscopy followed by band ligation. However, in rare cases, balloon tamponade may be done to control the bleeding before an endoscopy. If first-line therapy fails, balloon tamponade or Danis stent is used as a bridging therapy to stabilise the patient before a definitive treatment can be done, such as transjugular intrahepatic portosystemic shunt (TIPS) insertion.
People who cannot have definitive treatment are given palliative care. Clinical experts explained that Danis stent can be used to control bleeding as a component of palliative care after all other lines of treatment have failed or if the patient cannot have definitive treatment with TIPS or transplant surgery. The committee concluded that the care pathway is complex, and that practice varies depending on the individual circumstances of each patient.
# Balloon tamponade is an appropriate comparator
The committee noted that TIPS was included as a comparator in the scope and that in the randomised controlled trial TIPS was done within 72 hours of presentation. The experts explained that when TIPS is done this early it could be considered a comparator to Danis stent. However, the experts explained that it usually takes between 5 days and 7 days to deliver TIPS in the UK and that Danis stent would be used before this timepoint. The committee concluded therefore that, in the UK NHS setting, balloon tamponade is the best comparator for Danis stent.
# The evidence shows that Danis stent improves short-term clinical outcomes
The comparative evidence reported that Danis stent improves control of bleeding for patients in the short term (15 days). The committee recognised there were some key limitations in the evidence. For example, the population included in the retrospective case-controlled comparator study (Maiwall et al. 2018) was limited to patients with acute-on-chronic liver failure, and the randomised controlled trial (Escorsell et al. 2016) was underpowered and was not done in the UK. The committee considered the randomised controlled trial to be the most robust evidence for Danis stent and recognised the difficulties in doing controlled studies and generating evidence in this patient population. While the committee acknowledged the limitations in the studies it concluded that on balance the evidence shows that Danis stent improves short-term clinical outcomes.
# The evidence does not reflect the potential use of Danis stent in the UK care pathway
The randomised controlled trial (Escorsell et al. 2016) was done in Spain and the clinical experts advised that TIPS was more accessible in this trial than it would be in the UK. They explained that TIPS procedures are arranged and done in regional tertiary centres in the UK and that this procedure may only be suitable for people with less severe liver disease (Child–Pugh score A). In contrast, the experts explained that in the randomised controlled trial patients with more severe liver disease (Child–Pugh score B or C) were given a TIPS procedure, and were given it at an earlier timepoint than in the UK. The committee concluded that the protocol used in the randomised controlled trial does not accurately reflect UK practice.
# Side effects and adverse events
## Adverse events are unlikely if users are well trained in using Danis stent
Stent migration is reported to happen in 20% of cases. Clinical experts explained that, in their experience, this figure is likely to be an overestimation and that stent migration happens rarely if operators are fully trained in using the device. They advised that there is a small risk of lung aspiration with the procedure and that the patient's condition should initially be managed in an intensive care setting after stent insertion. The risk of oesophageal perforation is higher in patients who have had balloon tamponade first. The committee concluded from the evidence and expert advice that using Danis stent does not increase the risk of an adverse event.
# Outcome measures
## The evidence is limited to a 6-week follow-up time but this is acceptable
The evidence is limited to a follow-up time of 6 weeks or less. The committee recognised that some patients who have definitive treatment will live beyond 6 weeks, however it noted that the clinical evidence did not report a significant difference in mortality at 6 weeks between the Danis stent group and the balloon tamponade group. The committee also understood that people with oesophageal variceal bleeding have other comorbidities that are likely to affect survival beyond 6 weeks. So it concluded that the time horizon to definitive treatment was appropriate for the cost modelling.
# NHS considerations
## The evidence does not capture all the system benefits of using Danis stent
Danis stent can be left in place for up to 7 days compared with a balloon tamponade, which needs to be removed after 24 hours. The clinical experts commented that, in secondary or tertiary care settings, this additional time allows healthcare professionals the time to stabilise and monitor patients and arrive at a carefully considered clinical decision about the next stage of treatment. They highlighted that, when patients need to be transferred to a tertiary care centre for definitive treatment, using Danis stent can increase patient safety during the transfer. The committee recognised that there are limitations in the evidence and accepted expert advice about the additional patient and system benefits.
# Training
## Danis stent users need training and regular reskilling
Healthcare professionals are trained to use Danis stent. Clinical experts stated that training is straightforward for healthcare professionals with experience of endoscopic procedures and it is also possible to gain the necessary skills even without this experience. They described how maintaining clinical competence in a large team is challenging because of the limited number of patients needing this procedure each year, which necessitates regular reskilling. The committee considered that a lack of clinical confidence in using Danis stent during a medical emergency situation might serve as a barrier for adoption and suggested that the company should make sure centres that use the device have access to training and reskilling support.
# Other patient benefits or issues
## Danis stent has benefits for people for whom further treatment may not be suitable
The clinical experts advised that, for a small proportion of the patient cohort, estimated at between 5% and 6%, further definitive treatment may not be appropriate. The clinical experts advised that Danis stent can be used if all previous lines of therapy have failed, and in patients for whom either transplant surgery or a TIPS procedure is not suitable. After the stent is inserted, patients can be extubated, moved off a high dependency ward and managed in a more comfortable and less intensive environment where interaction with family and friends is more possible. The clinical experts explained that when used in this way Danis stent can stay in place for at least 7 days and even longer. This scenario was not included in the cost modelling, however the committee recognised that data collection is unrealistic in this population. It concluded that, in the proportion of people for whom definitive therapy is not appropriate, using Danis stent may offer substantial patient benefits in alleviating suffering and allowing compassionate care.
# Cost-modelling overview
## The base-case assumptions are not reflective of UK practice
The EAC base-case cost model used clinical parameters based on the randomised controlled trial (Escorsell et al. 2016) and case series data. The committee received the following expert advice:
definitive treatment is decided on a case-by-case basis in the NHS and is not affected by the choice of bridging treatment
a second endoscopy is needed in the balloon tamponade group, which was not included in the base-case model
use of multiple healthcare resource group costs could result in an overestimation of procedure costs
the incidence of hepatic encephalopathy should not differ between arms.The committee concluded that the assumptions used in the base case did not accurately reflect the cost of using Danis stent in the UK.
## Scenarios based on expert advice to estimate resource use in the care pathway are acceptable
The EAC developed scenarios 5A and 5B based on clinical advice so that the cost model better reflected UK practice. Scenario 5A reported that using Danis stent was cost saving by £2,423. Scenario 5B included the cost of transferring a proportion of people from secondary to tertiary care, although this cost had little effect on the results. This scenario reported Danis stent to be cost saving by £2,426. The main cost drivers of these scenarios were the risk of re-bleeding, the procedure costs and the estimated length of intensive care unit (ICU) stay. The committee recognised that there were uncertainties in the parameters because they were primarily based on expert advice, but concluded that scenarios 5A and 5B were the most appropriate models for estimating the cost of Danis stent in the NHS.
## Danis stent is cost saving and length of ICU stay is the main cost driver
The committee noted that the estimated difference in length of ICU stay had the greatest effect on the direction of the cost case results. Clinical experts estimated that length of ICU stay for the Danis stent group is 3.6 days, and 6 days for the balloon tamponade group. The EAC did a threshold analysis for this parameter and reported that Danis stent would be cost neutral or cost saving when the balloon tamponade group had an increased length of ICU stay of 0.6 days or more compared with the Danis stent group. The committee accepted the expert clinical advice that the clinical effectiveness of Danis stent is likely to affect the length of ICU stay and concluded that in all probability, Danis stent will reduce time in ICU by more than approximately 1 day (that is, more that 0.6 days) in UK clinical practice. The committee concluded that Danis stent is very likely to be cost saving compared with balloon tamponade in people being considered for definitive treatment for oesophageal varices.
## Further data collection is welcome to address uncertainties in the cost case
The committee recognised that there are uncertainties in the cost case because of the limited information available about resource use. The committee noted that a planned multicentre UK randomised controlled trial was not completed because of difficulties with recruitment. It recognised that generating evidence is challenging in this small and heterogenous population and accepted that expert advice was an appropriate alternative to definitive UK evidence. Further data collection is welcomed by the committee to inform more accurate assessments of the cost savings associated with using Danis stent in the future.
|
{'Recommendations': "Evidence supports the case for adopting Danis stent for treating acute oesophageal variceal bleeding. Danis stent improves the short-term control of bleeding compared with a balloon tamponade and can be left in place for longer, allowing time for stabilisation.\n\nDanis stent should be considered for people aged\xa016 and over with acute oesophageal variceal bleeding that does not respond to endoluminal therapy and whose oesophageal varices are being considered for definitive treatment. Also, Danis stent should be considered for people when definitive treatment is not appropriate and if they are likely to be offered palliative care.\n\nCost modelling shows that Danis stent is cost saving compared with balloon tamponade for acute oesophageal variceal bleeding being considered for definitive treatment. This is because having Danis stent results in a shorter stay in intensive care. To be cost saving, Danis stent needs to decrease intensive care stay by approximately 1\xa0day or more compared with balloon tamponade. For more details, see the NICE resource impact report.\n\nWhy the committee made these recommendations\n\nDanis stent puts pressure on enlarged veins (varices) in a person's food pipe (oesophagus) when they are bleeding uncontrollably. Enlarged veins can develop when a person has longstanding scarring liver disease (cirrhosis) that affects blood flow through the liver. This causes pressure in the blood vessel that drains blood from the gut into the liver and enlargement of these veins in the oesophagus can predispose to bleeding. Danis stent is designed to be used as a bridging treatment to control the bleeding until a decision on definitive treatment to manage the underlying pressure problem (such as a transjugular intrahepatic portosystemic shunt [TIPS] procedure, or band ligation) can be made. It can also be used for people when definitive treatment is not appropriate and if they are likely to be offered palliative care.\n\nStudies show that Danis stent is better than the balloon tamponade device (a balloon inflation device that compresses the bleeding veins) in controlling bleeding in the short term. It can stay in place for up to 7\xa0days. This is longer than the balloon tamponade, which needs to be removed after 24\xa0hours. This allows more time to stabilise the person before their next treatment and also means that they do not usually need to stay in intensive care. Cost analysis concludes that Danis stent is cost saving compared with balloon tamponade because it reduces the number of days a person needs to stay in intensive care.", 'The technology': '# Technology\n\nDanis stent is a self-expanding and removable stent used to stop acute bleeding from oesophageal varices. The stent is a variable weave, made of nitinol with a silicone membrane. It is 135\xa0mm long and 25\xa0mm in diameter at the centre, increasing to 30\xa0mm in diameter at the flared distal ends. During insertion, a balloon is inflated in the stomach to make sure the stent self-expands in an accurate position at the gastro-oesophageal junction, providing direct compression of oesophageal varices. The aim of Danis stent is to stabilise the bleeding, until the person can have definitive treatment to manage the underlying problem. Features of the stent include radiopaque markers for visibility, a security pressure valve and retrieval loops with gold markers. The company recommends that Danis stent stays in place for no longer than 7\xa0days. A specially designed removal device, the Ella extractor, is needed to remove the stent unless a definitive treatment has been done, in which case the risk of re-bleed may be considered low and the stent may be removed with grasping forceps.\n\n# Innovative aspects\n\nThe company states that Danis stent can be used without direct endoscopic imaging, which may allow for more rapid control of variceal bleeds in emergency situations compared with balloon tamponade. The delivery system has a security pressure valve that prevents the gastric balloon from being inflated in the oesophagus, which may help minimise the risk of oesophageal perforation. The stent can stay in place for up to a week (compared with balloon tamponade, which should not be left in place for more than 24\xa0hours to 36\xa0hours). This may allow more time to plan definitive therapy (such as transjugular intrahepatic portosystemic shunt [TIPS] insertion, usually done more than 72\xa0hours after Danis stent insertion) or secondary band ligation. It may also keep the bleeding stable for longer, allowing liver function to improve. Danis stent keeps the oesophagus open, allowing oral nutrition to be maintained, which is an important element in recovery. Its variable weave stent body is designed to conform to oesophageal peristalsis, with the aim of preventing stent migration.\n\n# Intended use\n\nDanis stent is intended for use in acute refractory oesophageal variceal bleeding, after first-line therapy, such as variceal band ligation, has failed, to allow more time for a definitive procedure to be done. It is intended to be used as an alternative to balloon tamponade or early TIPS insertion (that is, done within 72\xa0hours), in people aged\xa016 and over.\n\nThe technology is intended to be used in secondary or tertiary care by gastroenterologists, hepatologists, emergency care practitioners, paramedics or nurse practitioners. Comprehensive training is needed and is delivered by the company.\n\n# Costs\n\nThe cost of Danis stent is £1,495 (excluding VAT) per stent. The cost of the Ella extractor is £695 (excluding VAT). For more details, see the website for Danis stent.', 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. See the committee papers for full details of the evidence.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 9 studies\n\nThe evidence assessed by the EAC included 9\xa0full-text peer-reviewed studies including 247\xa0people. Two of the studies were comparative: a randomised controlled trial and a retrospective case‑controlled\xa0study. The remaining 7\xa0studies were non-comparative case series. For full details of the clinical evidence, see section\xa03 of the assessment report in supporting documentation.\n\n## The comparative evidence is relevant to the decision problem but has limitations\n\nBoth comparative studies compare the use of Danis stent with balloon tamponade. The studies report that using Danis stent improves control of bleeding at 5\xa0days and 15\xa0days. The randomised controlled trial (Escorsell et al. 2016) is the strongest evidence for Danis stent and reports a composite end point including control of bleeding and adverse events but it is underpowered for this result. The retrospective case-controlled study only included patients with acute-on-chronic liver failure and there were significant differences between the disease-severity scores of the patients in the control group compared with the interventional group. The EAC reported that both studies have a moderate risk of bias.\n\n## The randomised controlled trial (Escorsell et al. 2016) is not reflective of the UK care pathway\n\nThe randomised controlled trial was done in Spain and differences in the care pathway limit the generalisability of the findings to the UK setting. Expert advisers stated that the definitive procedure, transjugular intrahepatic portosystemic shunt (TIPS), was delivered at an earlier stage after presentation in this trial than it would be in the UK.\n\n## The EAC did a meta-analysis on the 7 non-comparative studies\n\nThe 7\xa0non-comparative studies are low in quality. The studies have broadly similar populations and outcomes. Outcomes with low heterogeneity were included in the analysis. Immediate bleeding control was found to have been achieved in 88% of cases (95% confidence interval\xa00.38 to\xa00.9) based on the 7\xa0case series, one of which (Wright et al. 2010) was done in the UK. Survival rate at 30\xa0days was 68% from 3\xa0studies.\n\n# Cost evidence\n\n## The company's comparison of the cost of Danis stent and balloon tamponade uses a cost-calculator model\n\nThe cost comparison has a 6‑week time horizon and is from an NHS and personal and social services perspective. The model estimates the cost associated with using Danis stent compared with balloon tamponade as bridging treatment for patients aged\xa016 or over with acute refractory oesophageal variceal bleeding in whom first-line therapy is unsuitable or has failed. The model captures the cost of the initial procedures, the likelihood of adverse events for both technologies and the cost and use of resources to remove the devices. The key model parameters are:\n\nThe proportion of patients that have either balloon tamponade or Danis stent as a bridging treatment and the proportion of patients that have either TIPS or band ligation as a definitive treatment.\n\nSurvival 6\xa0weeks after treatment and relative risk of dying at 6\xa0weeks with balloon tamponade compared with Danis stent.\n\nProportion of patients that have adverse events after treatment.For full details of the cost evidence, see section\xa04 of the assessment report in supporting documentation.\n\n## The EAC's updates to the cost model change the direction of the cost case\n\nThe EAC updated 5\xa0cost parameters, including the cost of:\n\nremoving Danis stent (company, £1,257.00; EAC, £1,452.00)\n\nre-bleed (company, £3,287.00; EAC, £4,978.75)\n\ndefinitive TIPS treatment (company, £3,928.00; EAC, £4,965.56)\n\ndefinitive band ligation (company, £1,114.00; EAC, £4,983.67)\n\nsevere hepatic encephalopathy (company, £400.52; EAC £400.56).\n\nWith the updated cost parameters, the EAC's base case shows that Danis stent is cost incurring by £923.00 per person. The company also presented 3\xa0scenario analyses, all of which the EAC considered relevant. Scenario\xa01 modelled the cost of using each technology by cumulating the costs of the resources needed. Scenarios\xa02 and\xa03 explored uncertainty in the assumed impact of the bridge treatment on the choice of definitive treatment including (scenario\xa03) and excluding (scenario\xa02) hepatic encephalopathy costs.\n\n## Two additional scenario analyses include a second endoscopy for patients who have a balloon tamponade\n\nClinical experts highlighted that a second endoscopy at the time of balloon removal is needed for people that have balloon tamponade. The choice of definitive treatment is done on a case-by-case basis regardless of the bridging treatment used. Therefore scenarios\xa04 and\xa05 were done to include the cost of a second endoscopy:\n\nScenario\xa04 – an extension of scenario\xa02 but with the addition of a second endoscopy for people treated with balloon tamponade based on expert comments.\n\nScenario\xa05 – an extension of scenario\xa01 to explore the impact of reduced intensive care unit (ICU) bed days in the Danis stent group and a second endoscopy for people treated with balloon tamponade.\n\n## Updates to resource parameters in the micro-costed model are based on expert advice and data about hospital admissions\n\nEstimates about resource use in the care pathway were updated based on expert advice and were reported as scenarios\xa05A and 5B. The key parameters changed were the:\n\nproportion of patients that had Danis stent inserted in a theatre setting (increased)\n\nICU length of stay in the Danis stent group (reduced) and in the balloon tamponade group (increased)\n\ncost of the balloon tamponade procedure (increased).\n\nCosts were modelled for the proportion of patients that needed transferring from a secondary care setting to a tertiary care setting (scenario\xa05B only).", 'Committee discussion': "# The clinical care pathway is complex\n\nThe clinical experts explained that oesophageal variceal bleeding is an acute clinical emergency and clinical care is managed on a case-by-case basis. First-line treatment is an endoscopy followed by band ligation. However, in rare cases, balloon tamponade may be done to control the bleeding before an endoscopy. If first-line therapy fails, balloon tamponade or Danis stent is used as a bridging therapy to stabilise the patient before a definitive treatment can be done, such as transjugular intrahepatic portosystemic shunt (TIPS) insertion.\n\nPeople who cannot have definitive treatment are given palliative care. Clinical experts explained that Danis stent can be used to control bleeding as a component of palliative care after all other lines of treatment have failed or if the patient cannot have definitive treatment with TIPS or transplant surgery. The committee concluded that the care pathway is complex, and that practice varies depending on the individual circumstances of each patient.\n\n# Balloon tamponade is an appropriate comparator\n\nThe committee noted that TIPS was included as a comparator in the scope and that in the randomised controlled trial TIPS was done within 72\xa0hours of presentation. The experts explained that when TIPS is done this early it could be considered a comparator to Danis stent. However, the experts explained that it usually takes between 5\xa0days and 7\xa0days to deliver TIPS in the UK and that Danis stent would be used before this timepoint. The committee concluded therefore that, in the UK NHS setting, balloon tamponade is the best comparator for Danis stent.\n\n# The evidence shows that Danis stent improves short-term clinical outcomes\n\nThe comparative evidence reported that Danis stent improves control of bleeding for patients in the short term (15\xa0days). The committee recognised there were some key limitations in the evidence. For example, the population included in the retrospective case-controlled comparator study (Maiwall et al. 2018) was limited to patients with acute-on-chronic liver failure, and the randomised controlled trial (Escorsell et al. 2016) was underpowered and was not done in the UK. The committee considered the randomised controlled trial to be the most robust evidence for Danis stent and recognised the difficulties in doing controlled studies and generating evidence in this patient population. While the committee acknowledged the limitations in the studies it concluded that on balance the evidence shows that Danis stent improves short-term clinical outcomes.\n\n# The evidence does not reflect the potential use of Danis stent in the UK care pathway\n\nThe randomised controlled trial (Escorsell et al. 2016) was done in Spain and the clinical experts advised that TIPS was more accessible in this trial than it would be in the UK. They explained that TIPS procedures are arranged and done in regional tertiary centres in the UK and that this procedure may only be suitable for people with less severe liver disease (Child–Pugh score\xa0A). In contrast, the experts explained that in the randomised controlled trial patients with more severe liver disease (Child–Pugh score\xa0B or\xa0C) were given a TIPS procedure, and were given it at an earlier timepoint than in the UK. The committee concluded that the protocol used in the randomised controlled trial does not accurately reflect UK practice.\n\n# Side effects and adverse events\n\n## Adverse events are unlikely if users are well trained in using Danis stent\n\nStent migration is reported to happen in 20% of cases. Clinical experts explained that, in their experience, this figure is likely to be an overestimation and that stent migration happens rarely if operators are fully trained in using the device. They advised that there is a small risk of lung aspiration with the procedure and that the patient's condition should initially be managed in an intensive care setting after stent insertion. The risk of oesophageal perforation is higher in patients who have had balloon tamponade first. The committee concluded from the evidence and expert advice that using Danis stent does not increase the risk of an adverse event.\n\n# Outcome measures\n\n## The evidence is limited to a 6-week follow-up time but this is acceptable\n\nThe evidence is limited to a follow-up time of 6\xa0weeks or less. The committee recognised that some patients who have definitive treatment will live beyond 6\xa0weeks, however it noted that the clinical evidence did not report a significant difference in mortality at 6\xa0weeks between the Danis stent group and the balloon tamponade group. The committee also understood that people with oesophageal variceal bleeding have other comorbidities that are likely to affect survival beyond 6\xa0weeks. So it concluded that the time horizon to definitive treatment was appropriate for the cost modelling.\n\n# NHS considerations\n\n## The evidence does not capture all the system benefits of using Danis stent\n\nDanis stent can be left in place for up to 7\xa0days compared with a balloon tamponade, which needs to be removed after 24\xa0hours. The clinical experts commented that, in secondary or tertiary care settings, this additional time allows healthcare professionals the time to stabilise and monitor patients and arrive at a carefully considered clinical decision about the next stage of treatment. They highlighted that, when patients need to be transferred to a tertiary care centre for definitive treatment, using Danis stent can increase patient safety during the transfer. The committee recognised that there are limitations in the evidence and accepted expert advice about the additional patient and system benefits.\n\n# Training\n\n## Danis stent users need training and regular reskilling\n\nHealthcare professionals are trained to use Danis stent. Clinical experts stated that training is straightforward for healthcare professionals with experience of endoscopic procedures and it is also possible to gain the necessary skills even without this experience. They described how maintaining clinical competence in a large team is challenging because of the limited number of patients needing this procedure each year, which necessitates regular reskilling. The committee considered that a lack of clinical confidence in using Danis stent during a medical emergency situation might serve as a barrier for adoption and suggested that the company should make sure centres that use the device have access to training and reskilling support.\n\n# Other patient benefits or issues\n\n## Danis stent has benefits for people for whom further treatment may not be suitable\n\nThe clinical experts advised that, for a small proportion of the patient cohort, estimated at between 5% and 6%, further definitive treatment may not be appropriate. The clinical experts advised that Danis stent can be used if all previous lines of therapy have failed, and in patients for whom either transplant surgery or a TIPS procedure is not suitable. After the stent is inserted, patients can be extubated, moved off a high dependency ward and managed in a more comfortable and less intensive environment where interaction with family and friends is more possible. The clinical experts explained that when used in this way Danis stent can stay in place for at least 7\xa0days and even longer. This scenario was not included in the cost modelling, however the committee recognised that data collection is unrealistic in this population. It concluded that, in the proportion of people for whom definitive therapy is not appropriate, using Danis stent may offer substantial patient benefits in alleviating suffering and allowing compassionate care.\n\n# Cost-modelling overview\n\n## The base-case assumptions are not reflective of UK practice\n\nThe EAC base-case cost model used clinical parameters based on the randomised controlled trial (Escorsell et al. 2016) and case series data. The committee received the following expert advice:\n\ndefinitive treatment is decided on a case-by-case basis in the NHS and is not affected by the choice of bridging treatment\n\na second endoscopy is needed in the balloon tamponade group, which was not included in the base-case model\n\nuse of multiple healthcare resource group costs could result in an overestimation of procedure costs\n\nthe incidence of hepatic encephalopathy should not differ between arms.The committee concluded that the assumptions used in the base case did not accurately reflect the cost of using Danis stent in the UK.\n\n## Scenarios based on expert advice to estimate resource use in the care pathway are acceptable\n\nThe EAC developed scenarios\xa05A and 5B based on clinical advice so that the cost model better reflected UK practice. Scenario\xa05A reported that using Danis stent was cost saving by £2,423. Scenario\xa05B included the cost of transferring a proportion of people from secondary to tertiary care, although this cost had little effect on the results. This scenario reported Danis stent to be cost saving by £2,426. The main cost drivers of these scenarios were the risk of re-bleeding, the procedure costs and the estimated length of intensive care unit (ICU) stay. The committee recognised that there were uncertainties in the parameters because they were primarily based on expert advice, but concluded that scenarios\xa05A and 5B were the most appropriate models for estimating the cost of Danis stent in the NHS.\n\n## Danis stent is cost saving and length of ICU stay is the main cost driver\n\nThe committee noted that the estimated difference in length of ICU stay had the greatest effect on the direction of the cost case results. Clinical experts estimated that length of ICU stay for the Danis stent group is 3.6\xa0days, and 6\xa0days for the balloon tamponade group. The EAC did a threshold analysis for this parameter and reported that Danis stent would be cost neutral or cost saving when the balloon tamponade group had an increased length of ICU stay of 0.6\xa0days or more compared with the Danis stent group. The committee accepted the expert clinical advice that the clinical effectiveness of Danis stent is likely to affect the length of ICU stay and concluded that in all probability, Danis stent will reduce time in ICU by more than approximately 1\xa0day (that is, more that 0.6\xa0days) in UK clinical practice. The committee concluded that Danis stent is very likely to be cost saving compared with balloon tamponade in people being considered for definitive treatment for oesophageal varices.\n\n## Further data collection is welcome to address uncertainties in the cost case\n\nThe committee recognised that there are uncertainties in the cost case because of the limited information available about resource use. The committee noted that a planned multicentre UK randomised controlled trial was not completed because of difficulties with recruitment. It recognised that generating evidence is challenging in this small and heterogenous population and accepted that expert advice was an appropriate alternative to definitive UK evidence. Further data collection is welcomed by the committee to inform more accurate assessments of the cost savings associated with using Danis stent in the future."}
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https://www.nice.org.uk/guidance/mtg57
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Evidence-based recommendations on Danis stent for acute oesophageal variceal bleeding.
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66c2a22593aee789a2726e95d0eabb38050f0628
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nice
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Ribociclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy
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Ribociclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy
Evidence-based recommendations on ribociclib (Kisqali) for treating hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer in adults who have had previous endocrine therapy.
# Recommendations
Ribociclib plus fulvestrant is recommended as an option for treating hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer in adults who have had previous endocrine therapy only if:
exemestane plus everolimus is the most appropriate alternative to a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor, and
the company provides ribociclib according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for ribociclib plus fulvestrant for hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer in people who have had previous endocrine (hormone) therapy.
The new evidence includes data from patients in clinical trials and from patients having treatment in the NHS, while this treatment was available in the Cancer Drugs Fund in England. It suggests that, compared with fulvestrant alone, people taking ribociclib plus fulvestrant have longer before their disease progresses and live longer.
Ribociclib is a CDK 4/6 inhibitor. Another treatment option is exemestane plus everolimus, which is a hormone therapy. There are no trials directly comparing ribociclib plus fulvestrant against exemestane plus everolimus. But an indirect comparison suggests that ribociclib plus fulvestrant may be the more effective option for people who have already had hormone therapy.
There are uncertainties about the economic modelling. But the base-case results and most of the exploratory analyses suggest that ribociclib plus fulvestrant is a cost-effective alternative to exemestane plus everolimus. So, ribociclib plus fulvestrant is recommended only if exemestane plus everolimus is the most appropriate alternative to a CDK 4/6 inhibitor.# Information about ribociclib
# Marketing authorisation indication
Ribociclib (Kisqali, Novartis) is indicated for 'the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.' NICE guidance recommends ribociclib with an aromatase inhibitor as initial endocrine-based therapy. The current appraisal covers only the combination of ribociclib with fulvestrant in people who have already had endocrine therapy.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for ribociclib is £2,950.00 for a 63‑tablet pack of 200 mg tablets (excluding VAT; British national formulary online, accessed January 2021). The company has a commercial arrangement (simple discount patient access scheme). This makes ribociclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. The list price for fulvestrant is £522.41 per 2 × 250 mg/5 ml solution for injection. Fulvestrant is available to the NHS at contract prices negotiated through the Commercial Medicines Unit. These prices are lower than the list prices but are commercial in confidence.# Committee discussion
The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
# Experience of people with advanced breast cancer
## Advanced breast cancer affects all aspects of a person's life
Advanced breast cancer is an incurable condition. It can affect all aspects of life (physical, psychological, social and financial). Treatments that extend survival while improving quality of life are important to patients because they provide valuable extra time with families and friends.
# Treatment pathway
## Ribociclib would be a welcome treatment option for people who have already had endocrine therapy
First-line treatment for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer is usually a cyclin-dependent kinase 4 or 6 (CDK 4/6) inhibitor (abemaciclib, palbociclib or ribociclib) with an aromatase inhibitor (letrozole or anastrozole). If symptoms are severe or the disease is progressing rapidly, then chemotherapy may also be needed first line. Tamoxifen can also be offered to some people in line with NICE's guideline on advanced breast cancer. NICE guidance recommends everolimus plus exemestane at second line in postmenopausal women without symptomatic visceral disease that has recurred or progressed after a non-steroidal aromatase inhibitor. The patient and clinical experts explained that some people need second-line CDK 4/6 inhibitors. This includes people whose disease is progressing slowly. The experts also highlighted that during the COVID-19 pandemic, some people will have been started on endocrine therapy alone. They explained that the various CDK 4/6 inhibitors have a similar mode of action but have different side effect profiles. They are effective at increasing progression-free survival in clinical practice and are generally less toxic than the combination of exemestane and everolimus, or chemotherapy. The clinical expert explained that everolimus is associated with mouth ulcers and people report feeling ill while taking it. Therefore, patients would welcome the availability of CDK 4/6 inhibitors at second line in preference to everolimus and exemestane, and to delay the need for chemotherapy. Having a choice of CDK 4/6 inhibitors would also be welcome to allow switching if needed because of side effects. The committee concluded that a well-tolerated treatment that extends progression-free survival and delays the need for chemotherapy would be welcomed by people who have already had endocrine therapy.
# Clinical evidence
## Sub-population B from MONALEESA-3 is relevant to NHS clinical practice
MONALEESA‑3 is a multicentre, double-blind, randomised placebo-controlled trial comparing ribociclib plus fulvestrant against placebo plus fulvestrant in 726 postmenopausal women with hormone receptor-positive, HER2‑negative advanced breast cancer. The company submitted results for a subgroup of patients who had had previous endocrine therapy (n=346; referred to as sub-population B). The committee noted that MONALEESA‑3 was not designed to have statistical power to detect treatment effects within subgroups and that this is a concern. However, it agreed that sub-population B is relevant to this appraisal and to NHS clinical practice.
## Ribociclib plus fulvestrant improves progression-free survival and overall survival compared with fulvestrant alone
The primary outcome measure of MONALEESA‑3 is investigator-assessed progression-free survival. During the appraisal for TA593, the committee was presented with a data cut from November 2017. This showed a clear progression-free survival benefit, but the results for overall survival were not statistically significant. Ribociclib was therefore recommended for use in the Cancer Drugs Fund while data was collected in MONALEESA‑3. For the current appraisal, the company presented the latest data cut from June 2019. It noted that data collection for MONALEESA‑3 has stopped, because it has met a pre-specified significance level for overall survival in the full population. After 46 months of follow up of patients who had had previous endocrine therapy (sub-population‑B), ribociclib plus fulvestrant increased median progression-free survival compared with placebo plus fulvestrant from 9.1 months to 14.6 months (hazard ratio 0.57; 95% confidence interval 0.43 to 0.74). Median overall survival increased from 32.5 months to 40.2 months (HR 0.73; 95% CI 0.53 to 1.00). The committee noted that the upper boundary of the confidence interval for overall survival included 1, and so could not be considered statistically significant. It agreed that any significance tests should be interpreted with caution because the study was not powered for this subgroup. But it noted that the confidence intervals have narrowed since the November 2017 data cut, which suggests less uncertainty in the overall survival benefit. The committee concluded that ribociclib plus fulvestrant improves progression-free survival and overall survival, compared with placebo plus fulvestrant. However, it noted that the most relevant comparator is exemestane plus everolimus but this was not the comparator in the trial.
## Ribociclib plus fulvestrant gives a numerical but not statistically significant benefit in overall survival
There is no trial directly comparing ribociclib plus fulvestrant against exemestane plus everolimus. So the company did network meta-analyses (NMAs) for sub-population B using overall-survival data from 4 trials and progression-free survival data from 5 trials. It connected the network to exemestane plus everolimus using data from the BOLERO-2 study. This is a phase 3 randomised controlled trial comparing exemestane plus everolimus with exemestane alone in 724 postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer refractory to a nonsteroidal aromatase inhibitor. The company used a Bucher NMA for overall survival. This showed a numerical (but generally, not statistically significant) benefit in overall survival for ribociclib plus fulvestrant compared with the comparators (fulvestrant only, exemestane plus everolimus and exemestane only).
## Ribociclib plus fulvestrant provides a numerical but not statistically significant benefit in progression-free survival
For progression-free survival, the ERG expressed concerns that the assumption of proportional hazards in BOLERO‑2 appeared to have been violated. To address this, the company did a Bayesian NMA with hazards characterised by fractional polynomials (FP) to provide time-varying hazard ratios. The ERG noted that the company used data for fulvestrant 500 mg from MONALEESA‑3 as the source of the informed priors. The ERG considered this approach to be inappropriate because it could lead to confirmation bias. It noted that the results of all the company's NMAs (Bucher and FP) suggest a numerical (but not statistically significant) benefit in progression-free survival for ribociclib plus fulvestrant over the comparators (fulvestrant only, exemestane plus everolimus and exemestane only). The ERG was therefore reasonably confident that there is a progression-free survival benefit for ribociclib plus fulvestrant compared with the comparators, but quantifying the exact level of this benefit is uncertain. The ERG noted that while the FP reduced the uncertainty related to proportional hazards, it increased the uncertainty overall. This is because it resulted in broader credible intervals and had used an informed prior from MONALEESA‑3. Given the uncertainty, the ERG preferred to use the most conservative estimate in its base case, which uses results from the Bucher NMA. The committee agreed that the results from all the NMAs (Bucher and FP) for progression-free survival are highly uncertain. But it noted that the different NMAs had similar effects on the cost-effectiveness estimates. The committee concluded that the results of the NMAs suggest that ribociclib plus fulvestrant has a numerical (although not statistically significant) benefit in progression-free survival compared with fulvestrant only, exemestane plus everolimus and exemestane only.
# Company's economic model
## The partitioned survival model is preferred for decision making
The company submitted a semi-Markov state-transition model for the cost effectiveness of ribociclib plus fulvestrant compared with fulvestrant 500 mg and exemestane plus everolimus. It used data from MONALEESA‑3 and the Bucher NMA to estimate progression-free survival. It used post-progression survival as a proxy for overall survival. The company assumed that post-progression survival was equal for all treatments. Overall-survival data became available in the latest June 2019 data cut for MONALEESA‑3 and, in response to technical engagement, the company submitted a new partitioned survival model. This has 3 health states (progression-free survival, post-progression survival and death), a 28‑day model cycle, and a 40‑year time horizon. All patients enter the model in the progression-free health state and start treatment. During each model cycle, patients in the progression-free health state can be on-treatment or off-treatment depending on if they experience unacceptable side effects. The proportion of patients who are progression-free and on-treatment is estimated using the time to stopping treatment. The proportion of patients in the post-progression health state is calculated as the difference between overall survival and progression-free survival per cycle. The ERG considered the structure of the company's model to be appropriate, capturing all relevant health states and clinically plausible transitions between health states. The committee agreed that it was preferable to use the model which best allows the use of actual survival data. Therefore, it concluded that the company's partitioned survival model is more appropriate for decision making.
# Modelling overall survival
## The overall-survival extrapolation is uncertain
The company fitted parametric survival distributions to the individual patient data from sub-population B of MONALEESA‑3 to estimate overall survival for ribociclib plus fulvestrant and placebo plus fulvestrant. The company selected the Weibull-R distribution (R referring to a jointly fitted model) to extrapolate overall-survival data. It considered that the Weibull had the best statistical fit, excellent visual fit to the Kaplan–Meier data, projected overall survival consistent with clinical experts' expectations and met the proportional hazards assumptions. To produce the overall-survival curve for exemestane plus everolimus, the company applied the hazard ratio from the Bucher NMA to the Weibull-R distribution for overall survival for ribociclib plus fulvestrant. The ERG considered the Gompertz-R curve provided a better extrapolation, because it gave more plausible predictions according to its clinical expert (at least 90% of patients on fulvestrant or exemestane plus everolimus would die by 5 years and at least 95% would die by 10 years). It also provided a better visual fit to the Kaplan–Meier data in the fulvestrant-only arm. The ERG noted that there is heavy censoring at the end of the Kaplan–Meier overall-survival curve for sub-population B of MONALEESA‑3 from 34 months onward, so data beyond this point may be unreliable. The clinical expert at the appraisal meeting explained that it is possible for patients on ribociclib plus fulvestrant to survive for 10 years and some patients who were in the MONALEESA‑3 trial are still alive 8 to 9 years later. The committee noted that the Weibull distribution estimated a 10‑year survival of 5%, compared with 0% for the Gompertz distribution. It concluded that the most appropriate extrapolation of overall survival is uncertain but agreed that it is likely to lie between the Weibull curve and the Gompertz curve.
# Modelling of time to stopping treatment
## Time to stopping everolimus is likely to be between clinical opinion and the ERG's model using BOLERO-2 data
In its original model, the company assumed that everolimus is taken until the disease progresses. However, many people stop everolimus because of its toxicity. In response to technical engagement, the company used the ERG's clinical expert opinion to model time to stopping everolimus. In the company's updated model, 20% of patients stop everolimus at month 6, and 70% of patients who continue on everolimus will reduce their dose at month 6 from 10 mg daily to 5 mg daily. The ERG agreed that this is an acceptable and more realistic approach. However, it explained an alternative approach using summary data from BOLERO‑2 to estimate the hazard ratios for stopping exemestane plus everolimus. The clinical expert considered the model based on clinical opinion to be more plausible. They explained that in clinical practice, and as seen in BOLERO‑2, about 20% of patients cannot tolerate the side effects of everolimus and stop taking it within the first 2 to 3 months. Many patients who continue treatment do so at a reduced dose (such as 5 mg). They noted that some patients experience later toxicities and then stop treatment. They explained that patients taking a reduced dose still have some benefit in terms of progression-free survival compared with those who stop completely. The Cancer Drugs Fund expert considered the ERG's model using BOLERO‑2 data provides a smoother curve and is more plausible. The ERG highlighted that their extrapolation based on BOLERO‑2 does not take into account the large proportion of patients stopping treatment early on, because it uses a summary statistic. The committee agreed that the time to stopping everolimus is likely to be between clinical opinion and the ERG's model using BOLERO‑2 data.
# The company's and ERG's base-case analyses
## The committee took into account the results of the different base cases and scenarios in its decision making
The company's revised base case used:
a partitioned survival model (see section 3.7)
estimates from the second order fractional polynomial network meta-analysis for progression-free survival (see section 3.6)
the Weibull curve to extrapolate overall survival (see section 3.8)
the ERG's clinical expert opinion to model time to stopping everolimus (see section 3.9)
an additional proposed discount for ribociclib, valid for this indication only (commercial access arrangement).The ERG's analyses used the Bucher NMA for progression-free survival, and the Gompertz curve to extrapolate overall survival. The ERG provided 2 base cases using different approaches to stopping everolimus, using clinical expert opinion in its main base case and data from BOLERO‑2 in its alternative base case. The committee agreed with using the partitioned survival model but noted uncertainty in which was the best assumption for estimating progression-free survival (the FP NMA or the Bucher NMA), extrapolating overall survival (Weibull or Gompertz) and modelling time to stopping everolimus (clinical opinion or BOLERO‑2 data). The committee noted that the Bucher NMA that the ERG had chosen for its base-case analyses provided a conservative estimate and that the ERG consider the true estimate to lie between its 2 base cases, which differed in the approach used for modelling time to stopping everolimus. The committee agreed that the true incremental cost-effectiveness ratio (ICER) is likely to be between the company's and ERG's base-case ICER. It therefore concluded that it would take into account the results of the different base-case analyses and scenarios in its decision making.
# Cost-effectiveness estimates
## The most plausible ICERs for ribociclib plus fulvestrant are within the range normally considered to be a cost-effective use of NHS resources
The committee considered the cost effectiveness of ribociclib plus fulvestrant in people who could have exemestane plus everolimus. It recognised that there is uncertainty about the most appropriate NMA to use for estimating progression-free survival (see section 3.6), the most appropriate parametric curve to extrapolate overall survival (see section 3.8) and the assumptions to use to model time to stopping everolimus (see section 3.9). It agreed that the most plausible assumptions lie between the base cases that the company and ERG have presented (see section 3.10). It noted that the company's revised base case, the ERG's main base case and most of the exploratory analyses resulted in ICERs that were within the range NICE normally considers to be a cost-effective use of NHS resources. These ICERs are presented as commercial in confidence to maintain the confidentiality of the patient access scheme for ribociclib and everolimus and the commercial arrangement for fulvestrant. Therefore, they cannot be reported here. The committee concluded that it could recommend ribociclib with fulvestrant as an option for treating hormone receptor-positive, HER2‑negative, locally advanced or metastatic breast cancer in people who have had previous endocrine therapy only if exemestane plus everolimus is the most appropriate alternative to a CDK 4/6 inhibitor.
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{'Recommendations': 'Ribociclib plus fulvestrant is recommended as an option for treating hormone receptor-positive, human epidermal growth factor receptor\xa02 (HER2)-negative, locally advanced or metastatic breast cancer in adults who have had previous endocrine therapy only if:\n\nexemestane plus everolimus is the most appropriate alternative to a cyclin-dependent kinase\xa04 and\xa06 (CDK\xa04/6) inhibitor, and\n\nthe company provides ribociclib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for ribociclib plus fulvestrant for hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer in people who have had previous endocrine (hormone) therapy.\n\nThe new evidence includes data from patients in clinical trials and from patients having treatment in the NHS, while this treatment was available in the Cancer Drugs Fund in England. It suggests that, compared with fulvestrant alone, people taking ribociclib plus fulvestrant have longer before their disease progresses and live longer.\n\nRibociclib is a CDK\xa04/6 inhibitor. Another treatment option is exemestane plus everolimus, which is a hormone therapy. There are no trials directly comparing ribociclib plus fulvestrant against exemestane plus everolimus. But an indirect comparison suggests that ribociclib plus fulvestrant may be the more effective option for people who have already had hormone therapy.\n\nThere are uncertainties about the economic modelling. But the base-case results and most of the exploratory analyses suggest that ribociclib plus fulvestrant is a cost-effective alternative to exemestane plus everolimus. So, ribociclib plus fulvestrant is recommended only if exemestane plus everolimus is the most appropriate alternative to a CDK\xa04/6 inhibitor.', 'Information about ribociclib': "# Marketing authorisation indication\n\nRibociclib (Kisqali, Novartis) is indicated for 'the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor\xa02 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.' NICE guidance recommends ribociclib with an aromatase inhibitor as initial endocrine-based therapy. The current appraisal covers only the combination of ribociclib with fulvestrant in people who have already had endocrine therapy.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for ribociclib is £2,950.00 for a 63‑tablet pack of 200\xa0mg tablets (excluding VAT; British national formulary online, accessed January 2021). The company has a commercial arrangement (simple discount patient access scheme). This makes ribociclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. The list price for fulvestrant is £522.41 per 2\xa0×\xa0250\xa0mg/5\xa0ml solution for injection. Fulvestrant is available to the NHS at contract prices negotiated through the Commercial Medicines Unit. These prices are lower than the list prices but are commercial in confidence.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Experience of people with advanced breast cancer\n\n## Advanced breast cancer affects all aspects of a person's life\n\nAdvanced breast cancer is an incurable condition. It can affect all aspects of life (physical, psychological, social and financial). Treatments that extend survival while improving quality of life are important to patients because they provide valuable extra time with families and friends.\n\n# Treatment pathway\n\n## Ribociclib would be a welcome treatment option for people who have already had endocrine therapy\n\nFirst-line treatment for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer is usually a cyclin-dependent kinase\xa04 or\xa06 (CDK\xa04/6) inhibitor (abemaciclib, palbociclib or ribociclib) with an aromatase inhibitor (letrozole or anastrozole). If symptoms are severe or the disease is progressing rapidly, then chemotherapy may also be needed first line. Tamoxifen can also be offered to some people in line with NICE's guideline on advanced breast cancer. NICE guidance recommends everolimus plus exemestane at second line in postmenopausal women without symptomatic visceral disease that has recurred or progressed after a non-steroidal aromatase inhibitor. The patient and clinical experts explained that some people need second-line CDK\xa04/6 inhibitors. This includes people whose disease is progressing slowly. The experts also highlighted that during the COVID-19 pandemic, some people will have been started on endocrine therapy alone. They explained that the various CDK\xa04/6 inhibitors have a similar mode of action but have different side effect profiles. They are effective at increasing progression-free survival in clinical practice and are generally less toxic than the combination of exemestane and everolimus, or chemotherapy. The clinical expert explained that everolimus is associated with mouth ulcers and people report feeling ill while taking it. Therefore, patients would welcome the availability of CDK\xa04/6 inhibitors at second line in preference to everolimus and exemestane, and to delay the need for chemotherapy. Having a choice of CDK\xa04/6 inhibitors would also be welcome to allow switching if needed because of side effects. The committee concluded that a well-tolerated treatment that extends progression-free survival and delays the need for chemotherapy would be welcomed by people who have already had endocrine therapy.\n\n# Clinical evidence\n\n## Sub-population\xa0B from MONALEESA-3 is relevant to NHS clinical practice\n\nMONALEESA‑3 is a multicentre, double-blind, randomised placebo-controlled trial comparing ribociclib plus fulvestrant against placebo plus fulvestrant in 726\xa0postmenopausal women with hormone receptor-positive, HER2‑negative advanced breast cancer. The company submitted results for a subgroup of patients who had had previous endocrine therapy (n=346; referred to as sub-population\xa0B). The committee noted that MONALEESA‑3 was not designed to have statistical power to detect treatment effects within subgroups and that this is a concern. However, it agreed that sub-population\xa0B is relevant to this appraisal and to NHS clinical practice.\n\n## Ribociclib plus fulvestrant improves progression-free survival and overall survival compared with fulvestrant alone\n\nThe primary outcome measure of MONALEESA‑3 is investigator-assessed progression-free survival. During the appraisal for TA593, the committee was presented with a data cut from November\xa02017. This showed a clear progression-free survival benefit, but the results for overall survival were not statistically significant. Ribociclib was therefore recommended for use in the Cancer Drugs Fund while data was collected in MONALEESA‑3. For the current appraisal, the company presented the latest data cut from June\xa02019. It noted that data collection for MONALEESA‑3 has stopped, because it has met a pre-specified significance level for overall survival in the full population. After 46\xa0months of follow up of patients who had had previous endocrine therapy (sub-population‑B), ribociclib plus fulvestrant increased median progression-free survival compared with placebo plus fulvestrant from 9.1\xa0months to 14.6\xa0months (hazard ratio [HR]\xa00.57; 95% confidence interval [CI] 0.43\xa0to\xa00.74). Median overall survival increased from 32.5\xa0months to 40.2\xa0months (HR\xa00.73; 95% CI 0.53\xa0to\xa01.00). The committee noted that the upper boundary of the confidence interval for overall survival included\xa01, and so could not be considered statistically significant. It agreed that any significance tests should be interpreted with caution because the study was not powered for this subgroup. But it noted that the confidence intervals have narrowed since the November\xa02017 data cut, which suggests less uncertainty in the overall survival benefit. The committee concluded that ribociclib plus fulvestrant improves progression-free survival and overall survival, compared with placebo plus fulvestrant. However, it noted that the most relevant comparator is exemestane plus everolimus but this was not the comparator in the trial.\n\n## Ribociclib plus fulvestrant gives a numerical but not statistically significant benefit in overall survival\n\nThere is no trial directly comparing ribociclib plus fulvestrant against exemestane plus everolimus. So the company did network meta-analyses (NMAs) for sub-population\xa0B using overall-survival data from 4\xa0trials and progression-free survival data from 5\xa0trials. It connected the network to exemestane plus everolimus using data from the BOLERO-2 study. This is a phase\xa03 randomised controlled trial comparing exemestane plus everolimus with exemestane alone in 724\xa0postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer refractory to a nonsteroidal aromatase inhibitor. The company used a Bucher NMA for overall survival. This showed a numerical (but generally, not statistically significant) benefit in overall survival for ribociclib plus fulvestrant compared with the comparators (fulvestrant only, exemestane plus everolimus and exemestane only).\n\n## Ribociclib plus fulvestrant provides a numerical but not statistically significant benefit in progression-free survival\n\nFor progression-free survival, the ERG expressed concerns that the assumption of proportional hazards in BOLERO‑2 appeared to have been violated. To address this, the company did a Bayesian NMA with hazards characterised by fractional polynomials (FP) to provide time-varying hazard ratios. The ERG noted that the company used data for fulvestrant 500\xa0mg from MONALEESA‑3 as the source of the informed priors. The ERG considered this approach to be inappropriate because it could lead to confirmation bias. It noted that the results of all the company's NMAs (Bucher and FP) suggest a numerical (but not statistically significant) benefit in progression-free survival for ribociclib plus fulvestrant over the comparators (fulvestrant only, exemestane plus everolimus and exemestane only). The ERG was therefore reasonably confident that there is a progression-free survival benefit for ribociclib plus fulvestrant compared with the comparators, but quantifying the exact level of this benefit is uncertain. The ERG noted that while the FP reduced the uncertainty related to proportional hazards, it increased the uncertainty overall. This is because it resulted in broader credible intervals and had used an informed prior from MONALEESA‑3. Given the uncertainty, the ERG preferred to use the most conservative estimate in its base case, which uses results from the Bucher NMA. The committee agreed that the results from all the NMAs (Bucher and FP) for progression-free survival are highly uncertain. But it noted that the different NMAs had similar effects on the cost-effectiveness estimates. The committee concluded that the results of the NMAs suggest that ribociclib plus fulvestrant has a numerical (although not statistically significant) benefit in progression-free survival compared with fulvestrant only, exemestane plus everolimus and exemestane only.\n\n# Company's economic model\n\n## The partitioned survival model is preferred for decision making\n\nThe company submitted a semi-Markov state-transition model for the cost effectiveness of ribociclib plus fulvestrant compared with fulvestrant 500\xa0mg and exemestane plus everolimus. It used data from MONALEESA‑3 and the Bucher NMA to estimate progression-free survival. It used post-progression survival as a proxy for overall survival. The company assumed that post-progression survival was equal for all treatments. Overall-survival data became available in the latest June 2019 data cut for MONALEESA‑3 and, in response to technical engagement, the company submitted a new partitioned survival model. This has 3\xa0health states (progression-free survival, post-progression survival and death), a 28‑day model cycle, and a 40‑year time horizon. All patients enter the model in the progression-free health state and start treatment. During each model cycle, patients in the progression-free health state can be on-treatment or off-treatment depending on if they experience unacceptable side effects. The proportion of patients who are progression-free and on-treatment is estimated using the time to stopping treatment. The proportion of patients in the post-progression health state is calculated as the difference between overall survival and progression-free survival per cycle. The ERG considered the structure of the company's model to be appropriate, capturing all relevant health states and clinically plausible transitions between health states. The committee agreed that it was preferable to use the model which best allows the use of actual survival data. Therefore, it concluded that the company's partitioned survival model is more appropriate for decision making.\n\n# Modelling overall survival\n\n## The overall-survival extrapolation is uncertain\n\nThe company fitted parametric survival distributions to the individual patient data from sub-population\xa0B of MONALEESA‑3 to estimate overall survival for ribociclib plus fulvestrant and placebo plus fulvestrant. The company selected the Weibull-R distribution (R referring to a jointly fitted model) to extrapolate overall-survival data. It considered that the Weibull had the best statistical fit, excellent visual fit to the Kaplan–Meier data, projected overall survival consistent with clinical experts' expectations and met the proportional hazards assumptions. To produce the overall-survival curve for exemestane plus everolimus, the company applied the hazard ratio from the Bucher NMA to the Weibull-R distribution for overall survival for ribociclib plus fulvestrant. The ERG considered the Gompertz-R curve provided a better extrapolation, because it gave more plausible predictions according to its clinical expert (at least 90% of patients on fulvestrant or exemestane plus everolimus would die by 5\xa0years and at least 95% would die by 10\xa0years). It also provided a better visual fit to the Kaplan–Meier data in the fulvestrant-only arm. The ERG noted that there is heavy censoring at the end of the Kaplan–Meier overall-survival curve for sub-population\xa0B of MONALEESA‑3 from 34\xa0months onward, so data beyond this point may be unreliable. The clinical expert at the appraisal meeting explained that it is possible for patients on ribociclib plus fulvestrant to survive for 10\xa0years and some patients who were in the MONALEESA‑3 trial are still alive 8\xa0to 9\xa0years later. The committee noted that the Weibull distribution estimated a 10‑year survival of 5%, compared with 0% for the Gompertz distribution. It concluded that the most appropriate extrapolation of overall survival is uncertain but agreed that it is likely to lie between the Weibull curve and the Gompertz curve.\n\n# Modelling of time to stopping treatment\n\n## Time to stopping everolimus is likely to be between clinical opinion and the ERG's model using BOLERO-2 data\n\nIn its original model, the company assumed that everolimus is taken until the disease progresses. However, many people stop everolimus because of its toxicity. In response to technical engagement, the company used the ERG's clinical expert opinion to model time to stopping everolimus. In the company's updated model, 20% of patients stop everolimus at month\xa06, and 70% of patients who continue on everolimus will reduce their dose at month\xa06 from 10\xa0mg daily to 5\xa0mg daily. The ERG agreed that this is an acceptable and more realistic approach. However, it explained an alternative approach using summary data from BOLERO‑2 to estimate the hazard ratios for stopping exemestane plus everolimus. The clinical expert considered the model based on clinical opinion to be more plausible. They explained that in clinical practice, and as seen in BOLERO‑2, about 20% of patients cannot tolerate the side effects of everolimus and stop taking it within the first 2\xa0to 3\xa0months. Many patients who continue treatment do so at a reduced dose (such as 5\xa0mg). They noted that some patients experience later toxicities and then stop treatment. They explained that patients taking a reduced dose still have some benefit in terms of progression-free survival compared with those who stop completely. The Cancer Drugs Fund expert considered the ERG's model using BOLERO‑2 data provides a smoother curve and is more plausible. The ERG highlighted that their extrapolation based on BOLERO‑2 does not take into account the large proportion of patients stopping treatment early on, because it uses a summary statistic. The committee agreed that the time to stopping everolimus is likely to be between clinical opinion and the ERG's model using BOLERO‑2 data.\n\n# The company's and ERG's base-case analyses\n\n## The committee took into account the results of the different base cases and scenarios in its decision making\n\nThe company's revised base case used:\n\na partitioned survival model (see section\xa03.7)\n\nestimates from the second order fractional polynomial network meta-analysis for progression-free survival (see section\xa03.6)\n\nthe Weibull curve to extrapolate overall survival (see section\xa03.8)\n\nthe ERG's clinical expert opinion to model time to stopping everolimus (see section\xa03.9)\n\nan additional proposed discount for ribociclib, valid for this indication only (commercial access arrangement).The ERG's analyses used the Bucher NMA for progression-free survival, and the Gompertz curve to extrapolate overall survival. The ERG provided 2\xa0base cases using different approaches to stopping everolimus, using clinical expert opinion in its main base case and data from BOLERO‑2 in its alternative base case. The committee agreed with using the partitioned survival model but noted uncertainty in which was the best assumption for estimating progression-free survival (the FP NMA or the Bucher NMA), extrapolating overall survival (Weibull or Gompertz) and modelling time to stopping everolimus (clinical opinion or BOLERO‑2 data). The committee noted that the Bucher NMA that the ERG had chosen for its base-case analyses provided a conservative estimate and that the ERG consider the true estimate to lie between its 2\xa0base cases, which differed in the approach used for modelling time to stopping everolimus. The committee agreed that the true incremental cost-effectiveness ratio (ICER) is likely to be between the company's and ERG's base-case ICER. It therefore concluded that it would take into account the results of the different base-case analyses and scenarios in its decision making.\n\n# Cost-effectiveness estimates\n\n## The most plausible ICERs for ribociclib plus fulvestrant are within the range normally considered to be a cost-effective use of NHS resources\n\nThe committee considered the cost effectiveness of ribociclib plus fulvestrant in people who could have exemestane plus everolimus. It recognised that there is uncertainty about the most appropriate NMA to use for estimating progression-free survival (see section\xa03.6), the most appropriate parametric curve to extrapolate overall survival (see section\xa03.8) and the assumptions to use to model time to stopping everolimus (see section\xa03.9). It agreed that the most plausible assumptions lie between the base cases that the company and ERG have presented (see section\xa03.10). It noted that the company's revised base case, the ERG's main base case and most of the exploratory analyses resulted in ICERs that were within the range NICE normally considers to be a cost-effective use of NHS resources. These ICERs are presented as commercial in confidence to maintain the confidentiality of the patient access scheme for ribociclib and everolimus and the commercial arrangement for fulvestrant. Therefore, they cannot be reported here. The committee concluded that it could recommend ribociclib with fulvestrant as an option for treating hormone receptor-positive, HER2‑negative, locally advanced or metastatic breast cancer in people who have had previous endocrine therapy only if exemestane plus everolimus is the most appropriate alternative to a CDK\xa04/6 inhibitor."}
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https://www.nice.org.uk/guidance/ta687
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Evidence-based recommendations on ribociclib (Kisqali) for treating hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer in adults who have had previous endocrine therapy.
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8aad5a6a88650582a9357befe963ff403ed60f0c
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nice
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Selective internal radiation therapies for treating hepatocellular carcinoma
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Selective internal radiation therapies for treating hepatocellular carcinoma
Evidence-based recommendations on selective internal radiation therapies SIR-Spheres (Sirtex), TheraSphere (BTG) and QuiremSphere (Quirem Medical) for treating hepatocellular carcinoma in adults.
# Recommendations
The selective internal radiation therapy (SIRT) SIR‑Spheres is recommended as an option for treating unresectable advanced hepatocellular carcinoma (HCC) in adults, only if:
used for people with Child–Pugh grade A liver impairment when conventional transarterial therapies are inappropriate, and
the company provides SIR‑Spheres according to the commercial arrangement.
The SIRT TheraSphere is recommended as an option for treating unresectable advanced HCC in adults, only if:
used for people with Child–Pugh grade A liver impairment when conventional transarterial therapies are inappropriate, and
the company provides TheraSphere according to the commercial arrangement.
The SIRT QuiremSpheres is not recommended for treating unresectable advanced HCC in adults.
These recommendations are not intended to affect treatment with SIR‑Spheres, TheraSphere and QuiremSpheres that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment for HCC depends on the stage of the disease and liver function. Treatment options include surgery, ablation, transarterial therapies, chemotherapy (such as sorafenib) and best supportive care. Treatment does not cure the disease for most people.
SIRTs are small radioactive beads that are injected into the liver's blood supply to treat liver cancer. QuiremSpheres, SIR-Spheres and TheraSphere are the 3 SIRTs considered in this appraisal. The clinical trial data for these SIRTs compared with other treatment options are limited. But, compared with sorafenib, SIRTs may have fewer and more manageable adverse effects, which can improve quality of life.
There is not enough evidence to consider SIRTs a cost-effective use of NHS resources for people with early and intermediate HCC.
For people with advanced HCC, QuiremSpheres is less clinically effective than sorafenib and costs more, so it is not recommended. SIR-Spheres and TheraSphere are slightly less clinically effective than sorafenib but cost less. The cost savings mean that SIR‑Spheres and TheraSphere can be recommended as options for people with Child–Pugh grade A liver impairment when conventional transarterial therapies are inappropriate.# Information about QuiremSpheres, SIR-Spheres and TheraSphere
# CE mark for QuiremSpheres
QuiremSpheres (Quirem Medical, manufacturer; Terumo Europe, distributor) received its CE mark in April 2015. It is classified as an Active Implantable Medical Device by Council Directive 90/385/EEC. It is indicated for treating unresectable liver tumours.
# Dosage in the CE mark for QuiremSpheres
QuiremSpheres is given through a catheter to the hepatic artery. The product is supplied as a customised, patient-specific dose. The maximum range of the emitted beta particles in tissue is 8.7 mm with a mean of 2.5 mm. Also, holmium‑166 emits primary gamma photons (81 kilo electronvolt, KeV). The half-life is 26.8 hours, which means more than 90% of the radiation is given in the first 4 days after the procedure. At the moment of treatment, the activity per microsphere is 200 to 400 Becquerel (Bq). The number of particles implanted depends on the targeted liver volume and ranges, on average, from 10 to 30 million.
# Price for QuiremSpheres
The company has stated that the acquisition cost of QuiremSpheres is £9,896 for a single treatment. The company has a commercial arrangement, which would have applied if the technology had been recommended.
# CE mark for SIR-Spheres
SIR-Spheres (Sirtex) received its CE mark as an Active Implantable Medical Device in October 2002. It is indicated for treating advanced inoperable liver tumours.
# Dosage in the CE mark for SIR-Spheres
SIR-Spheres is given through a catheter to the hepatic artery. It is supplied at 3 GBq yttrium‑90 per vial in 5 ml water for injection in a shielded shipping vial. Each vial contains 40 to 80 million microspheres, ranging from 20 to 60 micrometres in diameter (median diameter 32.5 micrometres). The maximum range of beta emission in tissue is 11 mm with a mean of 2.5 mm. The average number of particles implanted is 30 million to 60 million.
# Price for SIR-Spheres
The company has stated that the acquisition cost of SIR‑Spheres is £8,000 for a single treatment. The company has a commercial arrangement. This makes SIR‑Spheres available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.
# CE mark for TheraSphere
TheraSphere (BTG) received its CE mark as an Active Implantable Medical Device in September 2014. It is indicated for treating hepatic neoplasia.
# Dosage in the CE mark for TheraSphere
TheraSphere is given through a catheter to the hepatic artery. It is supplied in 6 dose sizes: 3 GBq, 5 GBq, 7 GBq, 10 GBq, 15 GBq or 20 GBq in 0.6 ml pyrogen‑free water supplied in a 1 ml vial, inside an acrylic shield. Custom dose sizes are also available in increments of 0.5 GBq between 3 GBq and 20 GBq. A single treatment with TheraSphere contains 1.2 million to 8 million microspheres. The recommended dose to the liver is 80 Gy to 150 Gy.
# Price for TheraSphere
The company has stated that the acquisition cost of TheraSphere is £8,000 for a single treatment. The company has a commercial arrangement. This makes TheraSphere available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Potential new treatment option
## People with hepatocellular carcinoma would welcome a new treatment option
Hepatocellular carcinoma (HCC) is the most common form of liver cancer in England. Treatment depends on the location and stage of the cancer, and how well the liver is functioning. Treatment options include surgery or ablation in early-stage disease, transarterial therapies in intermediate‑stage disease, and chemotherapy or systemic therapy in advanced-stage disease, as well as best supportive care. Treatment does not cure the disease for many people. The clinical experts explained that selective internal radiation therapy (SIRT) has also been used for HCC in England through compassionate schemes. Patient experts explained that HCC can have a substantial impact on quality of life. People with HCC and their carers live with uncertainty and hopelessness. Often people with HCC also live with stigma and isolation because of underlying causes of disease, such as alcohol. Clinical experts highlighted that people with advanced HCC have a poor prognosis with median life expectancy of less than 12 months. The committee concluded that people with HCC would welcome a new treatment option.
## People with HCC and portal vein thrombosis are a relevant subgroup
The clinical experts explained that portal vein involvement, such as portal vein thrombosis (PVT), is a common comorbidity that might negatively affect prognosis. PVT happens when a blood clot narrows the vein that takes blood to the liver from the intestines. The committee understood that people with PVT were included in the NICE scope for this appraisal. It concluded that evidence for people with HCC and PVT should be considered.
## This appraisal assesses 3 SIRTs for treating HCC
QuiremSpheres, SIR-Spheres and TheraSphere are SIRTs. These are small radioactive beads that are injected into the liver's blood supply to treat liver cancer. The 3 SIRTs are medical devices with CE marks for their indications. QuiremSpheres is indicated for treating unresectable liver tumours, SIR‑Spheres for treating advanced inoperable liver tumours and TheraSphere for treating hepatic neoplasia. The committee was aware that the scope for the appraisal was narrower than the CE marks, because it only included unresectable HCC, when SIRTs are most likely to be used. The committee agreed that the 3 SIRTs should be compared with each other and with available treatments to assess their cost effectiveness for treating HCC.
## SIRTs are already used in the NHS for other cancers, but not for HCC
The clinical experts and NHS England explained that SIRTs are available in some specialist centres across England for other cancers (such as metastatic colorectal cancer). The committee understood that SIRTs are currently not commissioned for HCC in the NHS but that the infrastructure and knowledge for using SIRTs exists in some specialist centres.
# Clinical management
## Stage of cancer and liver function characterise the disease and people with HCC are a heterogenous population
There are different causes of HCC, including cirrhosis, alcohol, fatty liver disease and hepatitis. Therefore, people with HCC are a heterogenous population and their disease is characterised by both stage of cancer and liver function. Treatment choice is multifaceted because both the cancer and liver function affect treatment outcomes. Clinical experts advised that in England clinicians use the Barcelona Clinic Liver Cancer (BCLC) staging system and the Child–Pugh score to inform treatment decisions.
BCLC staging looks at the number and size of tumours in the liver. There are 5 stages: very early stage (BCLC 0), early stage (BCLC A), intermediate stage (BCLC B), advanced stage (BCLC C) and terminal stage (BCLC D). The committee agreed that stages A, B and C align with the scope for this appraisal.
The Child–Pugh score assesses liver function. It has 5 components: serum albumin levels, bilirubin levels, time for blood to clot, presence of ascites (fluid in the peritoneal cavity) and presence of hepatic encephalopathy. There are 3 classes: class A (the liver is working normally), class B (mild to moderate liver damage), class C (severe liver damage). People with BCLC A to C can have either good liver function (Child–Pugh A) or mild to moderate liver damage (Child–Pugh B).
More recently an alternative measure, the albumin-bilirubin (ALBI) grade, was developed to look at liver function. The committee was aware that in previous NICE guidance for HCC, the Child–Pugh score was used as a criterion for treatment, and that ALBI was not available at that time. The clinical experts advised that ALBI is less frequently used for this purpose, and that Child–Pugh score is expected to be the measure of choice for the foreseeable future.
## Treatment of HCC differs between the 3 BCLC stages and is influenced by Child–Pugh score
Treatment options include ablation and transplant in early disease, and conventional transarterial therapies (CTT) such as transarterial chemoembolisation (TACE) or transarterial embolisation (TAE) in intermediate disease. In advanced disease, treatment options are chemotherapy or systemic therapy with sorafenib, lenvatinib or regorafenib. For some people the aim of treatment might be to reduce the tumour size ('downstaging') to potentially allow subsequent transplantation, surgical resection or tumour ablation that could cure the disease. The committee understood that people with HCC have different treatment options depending on the stage of their disease as assessed by BCLC and Child–Pugh score.
## There are 3 distinct subgroups relevant to this appraisal
The committee concluded that there are 3 subgroups relevant for this appraisal:
People for whom liver transplant is appropriate, including people with BCLC A and Child‑Pugh A or B.
People for whom CTT is appropriate, including people with BCLC B and Child–Pugh A or B.
People for whom CTT is inappropriate, including people with BCLC C and Child–Pugh A or B.
## In people with early disease, ablation and transplant are standard care in current NHS practice in England
Treatment options for early disease (BCLC A) are ablation and transplant. However, 1 clinical expert explained that transplants might not be available for people with good liver function (Child‑Pugh A). The committee concluded that both ablation and transplant are standard care for people with early disease in clinical practice in England.
## In people with intermediate disease, CTTs are standard care in current NHS practice in England
Treatments for intermediate disease (BCLC B) are CTTs, including transarterial chemoembolisation (TACE), drug-eluting bead transarterial chemoembolisation (DEB-TACE) and transarterial embolisation (TAE). The committee accepted that all CTTs available in the NHS in England are appropriate comparators for people with intermediate disease.
## In people with advanced disease, sorafenib is standard care in current NHS practice in England
The systemic therapies sorafenib and lenvatinib are both recommended for advanced HCC (BCLC C) in people with Child–Pugh grade A liver impairment (NICE technology appraisal guidance on sorafenib for treating advanced hepatocellular carcinoma and lenvatinib for untreated advanced hepatocellular carcinoma). Regorafenib is only recommended after treatment with sorafenib (NICE technology appraisal guidance on regorafenib for previously treated advanced hepatocellular carcinoma). The committee understood that sorafenib is standard care in clinical practice in England because there are subsequent treatments available after progression with sorafenib. The clinical expert confirmed that lenvatinib is now rarely used. The committee concluded that sorafenib is the most appropriate comparator for SIRTs in people with advanced disease and with Child–Pugh grade A liver impairment.
# Clinical evidence
## The systematic review included non-RCT evidence when not enough RCT evidence was identified
The assessment group (AG) did a systematic review of the clinical evidence on SIRTs and comparators. Randomised controlled trials (RCTs) were eligible for inclusion in the review. The AG had identified all the RCTs that were also identified by the companies in their submissions. The committee was aware of non-RCT evidence and noted that typically the risk of bias in non-RCT evidence is higher than in RCT evidence. It agreed with the AG's approach to only include non-RCT evidence in the review when there was not enough RCT evidence. The committee understood that some studies might include a mixed population containing all 3 subgroups of interest. It agreed to exclude studies from the network meta-analyses if they did not provide separate results for the 3 subgroups (see section 3.7). The committee used the AG's analysis for its decision making. This was because it included evidence for all 3 SIRTs and so was more comprehensive than the companies' submissions.
## There is not enough evidence to assess the clinical effectiveness of QuiremSpheres in the 3 subgroups relevant to this appraisal
The clinical evidence for QuiremSpheres came from 1 retrospective case series including 9 people that showed a 56% response rate. A mixed population was included, and results were only presented for the whole study population. The committee concluded that the single, small retrospective study did not provide enough data to assess the clinical effectiveness of QuiremSpheres in any of the 3 subgroups relevant to this appraisal (see section 3.7).
## There is limited randomised clinical evidence for TheraSphere compared with TACE when transplant is appropriate
Two small RCTs (PREMIERE and Kulik et al. 2014) for TheraSphere were identified that included people for whom transplant was appropriate (see section 3.7). The committee was also aware of 10 non-RCT studies, including 7 prospective comparative studies, that included people from the 3 subgroups relevant to this appraisal. The PREMIERE study was done in the US and included 45 people for whom transplant was appropriate. It compared TheraSphere with TACE as an alternative to prepare for transplant. The AG advised that PREMIERE had a high risk of bias because of concerns with randomisation and potential deviations from the intended interventions. Also, the baseline characteristics were different in the 2 arms so people in the TACE arm had better prognosis than people in the TheraSphere arm. Overall survival of people who had a transplant was numerically, but not statistically, significantly longer in the TheraSphere arm. The median overall survival for TheraSphere was 18.6 months (95% confidence interval 7.4 to 32.5) compared with 17.7 months (95% CI 7.4 to 32.5) for TACE. The committee concluded that there was limited evidence, with a high risk of bias, to establish whether TheraSphere was better or worse than TACE when transplant is appropriate.
## There is limited evidence for TheraSphere compared with TheraSphere plus sorafenib when transplant is appropriate
The study by Kulik et al. (2014) was done in the US and included 20 people for whom transplant was appropriate. It compared TheraSphere with TheraSphere plus sorafenib. The AG had some concerns with the randomisation process, treatments received and measurement of outcomes. The baseline characteristics were different in the 2 arms so people in the TheraSphere plus sorafenib arm had a better prognosis. There was no evidence of a difference in overall survival between the 2 arms (3 deaths in the TheraSphere arm, 2 deaths in the combination arm). The committee was aware that TheraSphere plus sorafenib was not included in sorafenib's marketing authorisation or TheraSphere's CE mark. The committee concluded that there was limited evidence, with high risk of bias, to establish whether TheraSphere is better or worse than TheraSphere with sorafenib when transplant is appropriate.
## Non-randomised evidence comparing TheraSphere with non-SIRT treatments is not robust enough for decision making
Of the 7 prospective comparative non-RCTs, only 4 reported overall survival or progression-free survival. Of these, 2 compared TheraSphere with TACE or DEB-TACE across the 3 subgroups. The AG suggested that both studies had high risk of bias and differences in baseline characteristics such as age, tumour size and number of tumours. The committee concluded that results from these studies might be unreliable for decision making. Another study compared TheraSphere with TheraSphere plus sorafenib, in people for whom CTT is inappropriate. The remaining prospective study was done in people for whom CTT is inappropriate. This compared TheraSphere in people with PVT with TheraSphere in people without PVT and best supportive care. The AG advised that this study had a high risk of bias, and that the people in the treatment arms had very different baseline characteristics. The committee recognised that the large volume of non-randomised evidence might be useful for tentative conclusions, but it remained aware of the limitations of non-RCT studies. Therefore, it agreed that they should not be used for decision making. Also, there was not enough evidence to establish whether TheraSphere is better or worse than other treatments in people for whom CTT is appropriate and in people for whom CTT is inappropriate.
## There are insufficient data to establish the clinical effectiveness of SIR-Spheres compared with non-SIRT treatments when transplant is appropriate
The AG identified 1 RCT comparing SIR-Spheres with TACE (SIR-TACE) that included people for whom transplant was appropriate. SIR-TACE was done in Germany and Spain, and included 28 people with early, intermediate and late-stage disease. Only overall results for the mixed population were available. The AG assessed that the study had a high risk of bias because of the randomisation process, missing outcome data and measurement of the outcome. The committee concluded that there are insufficient data to establish whether SIR‑Spheres are better than TACE when transplant is appropriate.
## It is unclear whether SIR-Spheres is better than DEB-TACE or TACE when CTT is appropriate
The AG identified 2 RCTs that compared SIR‑Spheres with TACE (SIR‑TACE) or DEB‑TACE (Pitton et al. 2015) that included people for whom CTT is appropriate in their trial populations. SIR-TACE is described in section 3.16. Pitton et al. (2015) was done in Germany and included 24 people with intermediate-stage disease (BCLC B). Overall survival and progression-free survival were longer in the DEB‑TACE arm compared with the SIR-Spheres arm, but this was not statistically significant (788 days compared with 592 days and 216 days compared with 180 days, respectively). Because of this and the small sample size, the committee concluded that it could not establish whether SIR‑Spheres was better than TACE or DEB‑TACE when CTT is appropriate.
## People in SARAH had poorer prognosis than people seen in clinical practice in England
The AG identified 2 RCTs comparing SIR-Spheres with sorafenib (SARAH and SIRveNIB) in people for whom CTT was inappropriate. SARAH was done in France between 2011 and 2015 and included a heterogeneous population of people with HCC. This included, for example, people with advanced HCC, people with HCC who had previous treatment with 2 treatments of TACE, and people with Child–Pugh A or B liver impairment. There was no difference in overall survival or progression-free survival between the treatment arms. The median overall survival was 8.0 months (95% CI 6.7 to 9.9) for SIR‑Spheres and 9.9 months (95% CI 8.7 to 11.4) for sorafenib. The hazard ratios (HRs) were 1.15 (95% CI 0.94 to 1.41) for the intention‑to‑treat (ITT) population and 0.99 (95% CI 0.79 to 1.24) for the per-protocol population. The median progression-free survival was 4.1 months (95% CI 3.8 to 4.6) for SIR‑Spheres and 3.7 months (95% CI 3.3 to 5.4) for sorafenib. The HR was 1.03 (95% CI 0.85 to 1.25) for the ITT population. More adverse events were reported with sorafenib than SIR‑Spheres. A post-hoc analysis of SARAH focused on people with ALBI grade 1 and low tumour burden (25% or less tumour burden). Again, there was no statistically significant difference in overall or progression‑free survival between the treatment arms. The median overall survival was 21.9 months (95% CI 15.2 to 2.5) for SIR‑Spheres and 17.0 months (95% CI 11.6 to 20.8) for sorafenib. The HR was 0.73 (95% CI 0.44 to 1.21). The median progression-free survival HR was 0.65 (95% CI 0.41 to 1.02). The clinical experts advised that the SARAH trial had more people with a high tumour burden, PVT and impaired liver function than people seen in clinical practice in England. The committee concluded that people in the SARAH trial had poorer prognosis than people seen in clinical practice in England.
## The results from SIRveNIB may not be fully generalisable to the NHS
SIRveNIB was done in the Asia-Pacific region between 2010 and 2018. The clinical experts explained that results from SIRveNIB might not be generalisable to the NHS in England. This was because in the Asia-Pacific region HCC is often caused by hepatitis B and C, whereas in the UK fatty liver disease and alcohol are the most common causes. There was no difference in overall survival or progression-free survival between the treatment arms. The median overall survival was 8.8 months for SIR‑Spheres and 10.0 months for sorafenib. The HRs were 1.12 (95% CI 0.9 to 1.4) for the ITT population and 0.86 (95% CI 0.7 to 1.1) for the per-protocol population. The median progression‑free survival was 5.8 months for SIR-Spheres and 5.1 months for sorafenib. The HRs were 0.89 (95% CI 0.7 to 1.1) for the ITT population and 0.73 (95% CI 0.6 to 0.9) for the per-protocol population. More adverse events were reported with sorafenib than SIR‑Spheres. The committee concluded that results from SIRveNIB may not be fully generalisable to people seen in the NHS.
## The evidence from SARAH and SIRveNIB is preferable to non-RCT evidence for decision making when CTT is inappropriate
The committee considered including non-RCT evidence identified by the AG. The AG assessed the 3 non-RCT studies as having a high risk of bias. So, the committee concluded that the RCT evidence from SARAH and SIRveNIB was preferable for decision making in people for whom CTT was inappropriate.
## There is no evidence to compare the 3 SIRTs' effectiveness when transplant or CTT is appropriate
The clinical evidence for comparative effectiveness of the 3 SIRTs came from 6 retrospective studies that reported overall survival or progression‑free survival. Of these, 5 compared SIR-Spheres with TheraSphere and 1 small study of 30 people compared all 3 SIRTs. The AG advised that most of these studies had a high risk of bias because of selection and performance bias. None of the studies included people for whom transplant was appropriate. The study comparing all 3 SIRTs may have included people for whom CTTs were appropriate but there were no results presented for this subgroup. The committee concluded that there was no evidence identified for people when transplant or CTT was appropriate.
## There is not enough direct evidence to compare the 3 SIRTs' effectiveness when CTT is inappropriate, so a mixed treatment comparison is considered
The AG identified 5 retrospective studies that included people for whom CTT is inappropriate (see section 3.21). The study comparing all 3 SIRTs also included people for whom CTTs were appropriate, but no results for subgroups were presented. The committee was aware that the populations were different across these studies and acknowledged that this meant results were difficult to compare. The committee was also aware that the baseline characteristics were different in most studies, and that this might affect prognosis and outcomes between the arms. In 2 studies that compared TheraSphere with SIR‑Spheres, there was no difference in overall survival. In van der Gucht et al. (2017; n=77), the median overall survival was 7.0 months for TheraSphere (95% CI 1.6 to 12.4) compared with 7.7 months for SIR‑Spheres (95% CI 7.2 to 8.2). In Bhangoo et al. (2015; n=17) the median overall survival for TheraSphere was 8.4 months (95% CI 1.3 to 21.1) compared with 7.8 months for SIR‑Spheres (95% CI 2.3 to 12.5). In 2 studies (Biederman et al. 2015 and Biederman et al. 2016) that compared TheraSphere with SIR‑Spheres in people with PVT, overall survival was better in the TheraSphere arm than the SIR‑Spheres arm. The committee concluded that there was not enough direct evidence to establish the relative effectiveness of the 3 SIRTs in people with HCC, and so decided to consider mixed treatment comparisons for decision making.
## There was not enough robust evidence to establish the clinical effectiveness of SIRTs compared with non-SIRT treatments for people with PVT
The clinical expert explained that people with PVT (see section 3.2) have poorer prognosis and limited treatment options. Often the only available treatment is sorafenib because people with PVT do not tolerate TACE. Therefore, the committee agreed that people with PVT might benefit more than others from treatment with SIRTs. It considered the evidence that included people with PVT (see section 3.15 and section 3.22). There was no new evidence presented specifically for this subgroup at consultation. The committee concluded there was not enough robust evidence to establish the clinical effectiveness of SIRTs compared with non-SIRT treatments for people with PVT.
## There is not enough robust data to establish whether SIRTs are better or worse than sorafenib or TACE in people with large tumours
After consultation, the committee considered the evidence for people with 1 or more large tumours (5 cm or larger) with or without PVT. This was because this subgroup might benefit more than others from treatment with SIRTs. The committee understood that in the UK this group currently has sorafenib or TACE. Clinical evidence showed that TACE is not very effective and there are substantial adverse events with sorafenib. The committee saw data from 1 study in this group. This study, DOSISPHERE-01, compared TheraSphere personalised dosimetry with TheraSphere standard dosimetry. Personalised dosimetry improved the response rate and overall survival compared with standard dosimetry (overall survival for personalised dosimetry 26.6 months, 95% CI 11.7 months to not reached; compared with standard dosimetry 10.7 months, 95% CI 6.0 months to 16.8 months; p=0.0096). The committee understood that people in the 2 arms of the study might not be similar and therefore the results may have selection bias. Also, there were no data comparing SIRTs with sorafenib or TACE in this group. The committee acknowledged that personalised dosimetry could improve the effectiveness of SIRTs. It concluded that there were not enough robust data to establish whether SIRTs are better or worse than sorafenib or TACE in people with 1 or more large tumours.
## People who are unable to tolerate sorafenib might benefit from treatment with SIRTs but there is no comparative evidence
Clinical expert comments provided during consultation advised that people who are unable to tolerate sorafenib do not have alternative treatment options. This means they have best supportive care. The committee understood that there is some clinical experience in England of this group having treatment with SIRTs, with promising outcomes. It also acknowledged that this group is not included in the RCTs because of their characteristics (for example, older age and comorbidities). Despite the lack of evidence, the committee concluded that people who are unable to tolerate sorafenib might benefit from treatment with SIRTs.
## Most of the RCT evidence is in people with advanced disease with Child–Pugh A grade liver impairment, which is the relevant subgroup
The committee recalled that current treatments for advanced HCC are only recommended for people with Child–Pugh grade A liver impairment (see section 3.10). People with Child–Pugh grade B liver impairment have best supportive care. It noted that there was no best supportive care arm in the RCTs (SARAH and SIRveNIB), which compared SIR-Spheres with sorafenib only. The committee acknowledged that most people in the trials had Child–Pugh grade A liver impairment (83% in SARAH and 90% in SIRveNIB). Therefore, it concluded that the trial results were acceptable for decision making in people with Child–Pugh grade A liver impairment. However, it could not establish whether SIRTs were effective in people with Child–Pugh grade B liver impairment, because of the lack of evidence comparing SIRTs with the relevant comparator for that group. Therefore, in people with advanced HCC, the subgroup with Child–Pugh A liver impairment was appropriate for decision making.
## SIRTs have fewer and less severe side effects than other treatment options
The clinical and patient experts stated that there were fewer and less severe side effects with SIRTs than with other treatments. Also, side effects from SIRTs have a shorter duration, whereas side effects from chemotherapies such as sorafenib can continue for the whole treatment course. After the second committee meeting, the committee invited companies and stakeholders to submit additional data on adverse event severity and duration. The committee considered adverse event data from SARAH for SIR‑Spheres and non-RCT studies for TheraSphere. The data included adverse event rates and durations for all severity grades. They showed that SIRTs and sorafenib have different adverse event profiles. The committee was aware that data on event duration were averaged across all severity grades and both study arms in SARAH. The committee concluded that SIRTs were likely to have fewer and less severe side effects than sorafenib, and that this benefit may be important to patients. The committee agreed that this should be captured in the cost‑effectiveness analysis and taken into account during decision making.
# Mixed treatment comparisons
## Data are not robust enough to provide a meaningful comparison between treatment options when transplant is appropriate
The AG considered the feasibility of a mixed treatment comparison to estimate comparative effectiveness between available treatment options for people when transplant is appropriate. There are 2 RCTs that could be included in this analysis. Both were done in the US and compared TheraSphere with TACE (n=45) or with a combination of TheraSphere and sorafenib (n=20). Also, the committee recalled that ablation or transplant was the most relevant comparator for people for whom transplant is appropriate (see section 3.8). Because of limited data, results from the mixed treatment comparison would be very uncertain. The committee concluded that a mixed treatment comparison in this population would not help decision making for the subgroup for whom transplant is appropriate.
## Estimates comparing effectiveness for treatment options in people for whom CTT is appropriate are very uncertain, and are not suitable for decision making
After consultation on the assessment report, the AG did a mixed treatment comparison in people for whom CTT was appropriate. There were 6 RCTs that could be included in this analysis: 5 compared different CTTs with each other and 1 compared SIR-Spheres with DEB‑TACE (n=24). The AG also included 1 retrospective study that compared SIR-Spheres with TheraSphere (n=77). From this study, only a subgroup of 35 people with early or intermediate HCC could be included in the analysis. The study had a high risk of bias because its 2 treatment groups were not similar at baseline (people with small tumour volumes were preferentially treated with TheraSphere). The committee agreed that there was little evidence to link SIR-Spheres and TheraSphere to the network of treatments. Results from the mixed treatment comparison for overall survival and progression-free survival were uncertain, with wide credible intervals that included a HR of 1 (no statistical difference between treatment options). The committee concluded that the results from the mixed treatment comparison in this population were uncertain. Also, there was not enough evidence in this population to compare SIR‑Spheres with TheraSphere, or compare the SIRTs with TACE, DEB‑TACE and TAE.
## The comparative effectiveness estimates of the 3 SIRTs in people for whom CTT is inappropriate are uncertain
The AG did a mixed treatment comparison to estimate comparative effectiveness between available treatment options in people when CTT was inappropriate. There were 3 RCTs included in this analysis. Of these, 1 RCT compared lenvatinib with sorafenib and 2 compared sorafenib with SIR-Spheres. To include TheraSphere in the network, 2 retrospective studies comparing TheraSphere with SIR‑Spheres were included in sensitivity analyses. There were no data for QuiremSpheres to be included in the analysis. In the main analysis, when CTT is inappropriate and people have Child–Pugh grade A liver impairment, there was no evidence of a difference between SIR‑Spheres and sorafenib. In the ITT population for SIR‑Spheres compared with sorafenib, the hazard ratio was 1.13 (95% CI 0.96 to 1.32). A value of less than 1 indicates better overall survival. The committee recalled the AG's assessment that the retrospective studies had a high risk of bias and uncertain results (see section 3.15). The committee agreed that retrospective studies should not be included in the analysis because of the risk of bias. It concluded that the comparative effectiveness results based on RCT evidence from SIR‑Spheres could be used in a cost-effectiveness analysis. The committee also concluded that, because its preferred network meta‑analysis only had evidence for 1 SIRT (SIR-Spheres), the comparative effectiveness of the 3 SIRTs compared with each other was uncertain.
# Cost-effectiveness evidence
## The AG's model is used for decision making
Two companies included economic analyses in their evidence submissions. For SIR-Spheres, the company submitted a cost‑minimisation analysis for people for whom CTT was appropriate, and a cost–utility analysis for people for whom CTT was inappropriate. The base case of the cost–utility analysis was people with ALBI grade 1 and low tumour burden, a subpopulation from the SARAH trial. The ITT and per-protocol populations of the SARAH trial were included as scenario analyses. For TheraSphere, the company submitted 2 cost–utility analyses, 1 for people for whom CTT was appropriate and 1 for people for whom CTT was inappropriate. The committee acknowledged the submission of the companies' models. It noted that the AG model used a similar structure (see section 3.32) as the companies' cost–utility analyses. Also, the AG used inputs from the companies' models, such as costs and treatment frequency. The committee concluded that there was not enough evidence to support an economic analysis in people for whom CTT was appropriate (see section 3.29). When CTT was inappropriate, the AG model was the most suitable for decision making because it included all 3 SIRTs as specified in the NICE scope (see section 3.3).
## The structure of the AG model for people for whom CTT is inappropriate is acceptable for decision making
The AG did a cost–utility analysis for people with unresectable intermediate (BCLC stage B) or advanced (BCLC stage C) HCC, when CTT was inappropriate, with or without macroscopic vascular invasion but without extrahepatic disease. The model consisted of a decision tree and partitioned survival model with 3 health states. The decision tree represented the outcome of the work-up procedure that happens before SIRT. The partitioned survival model was like that used by the companies. The interventions were SIR-Spheres, TheraSphere and QuiremSpheres, which were assumed to have equal effectiveness in the base case (see section 3.33). The comparators were initially sorafenib and lenvatinib. Because sorafenib and lenvatinib are recommended only for people with Child–Pugh grade A liver impairment, the base-case analysis was restricted to this population. The committee concluded that the model structure was acceptable for decision making.
## Cost-effectiveness results assuming all SIRTs are equally effective have been considered, but this is uncertain for QuiremSpheres
The AG's economic analysis assumed that the 3 SIRTs were equally effective. Most data used in the model, such as clinical effectiveness and adverse event data, were from the SARAH trial for SIR-Spheres. There was very little evidence for QuiremSpheres to inform the model (see section 3.12), and the evidence for TheraSphere was less certain than the evidence for SIR-Spheres (see section 3.15). The committee noted that there was not enough evidence to establish whether the 3 SIRTs had different effectiveness (see section 3.22 and section 3.29). The committee considered whether it was appropriate to assume the 3 SIRTs were equally effective. It noted that the technologies used different beads to give treatment, and QuiremSpheres used a different isotope to the other SIRTs. It agreed that these differences might result in different effectiveness and adverse event profiles, to an unknown extent. In the absence of better evidence, the committee concluded that it would consider the cost effectiveness of the 3 SIRTs by assuming they were equally effective, generalising the SIR‑Spheres data to the other 2 SIRTs. It also concluded that by doing so, the cost-effectiveness estimates for QuiremSpheres would be more uncertain than those for TheraSphere and substantially more uncertain than for SIR-Spheres. It took this uncertainty into consideration in its decision making.
## Sorafenib is the only relevant comparator for assessing the cost effectiveness of SIRTs in people for whom CTT is inappropriate
In line with the NICE scope, the AG initially included sorafenib and lenvatinib as comparators in the model. The AG used the hazard ratio from the mixed treatment comparison to include lenvatinib in the model and assumed proportional hazards over time. Therefore, it chose the Weibull function to model overall survival and progression‑free survival, even though the Weibull was not the best-fitting function. After consultation on the AG report, sorafenib was considered to be the only relevant comparator (see section 3.10). The generalised gamma was used to fit overall survival and progression‑free survival in the revised base case, because the proportional hazards assumption was no longer needed. The committee also recalled that the trial evidence could be generalised to people with Child–Pugh A liver impairment, who can have sorafenib in current practice, but not to people with Child–Pugh B liver impairment, who have best supportive care (see section 3.26). It concluded that sorafenib was the only appropriate comparator, and that the best-fitting function (generalised gamma) should be used to estimate overall survival and progression-free survival.
## There are not enough robust data for the ALBI grade 1 and low tumour burden subgroup for decision making
The AG presented scenario analyses that restricted the population to people with ALBI grade 1 and low tumour burden. The clinical experts explained that ALBI grade could be a more objective measure than Child–Pugh score for liver impairment and that people with ALBI grade 1 have good liver function. However, this measure is not routinely used in the NHS, and the Child–Pugh score is expected to be the standard assessment method for liver impairment for the foreseeable future (see section 3.5). The committee was aware that clinical outcomes for the ALBI grade 1, low tumour burden subgroup came from a post-hoc analysis of the SARAH trial (n=85, section 3.18). It agreed that this analysis was not robust because the subgroup was not prespecified and the numbers were small. It was not presented with additional evidence after consultation. It concluded that it had not seen sufficiently robust data in this subgroup, but agreed that more evidence may be useful for decision making.
## Usually, only 1 lobe is treated at a time in people with bilobar disease
HCC can be unilobar (tumour in 1 lobe of the liver) or bilobar (tumours in both lobes of the liver). The clinical experts explained that people with bilobar disease have a higher risk of liver impairment, and therefore usually only 1 lobe is treated at a time. The same lobe might be treated twice to reduce the size of the tumour. The committee concluded that it is not appropriate for a model to assume that both lobes are treated simultaneously in bilobar disease.
## Downstaging of HCC might benefit some people with advanced HCC, but the proportion of people and subsequent outcomes are uncertain
The clinical experts explained that downstaging might be a treatment aim for some people who have SIRT, because they then might be able to have a liver transplant, surgical resection or tumour ablation. For some people downstaging might have a large impact on quality of life. This is because of the potential for curative treatment. Both clinical experience and limited trial evidence (for example SARAH) show that downstaging is rare in advanced HCC. The committee understood that people whose tumour downstages have different subsequent treatments, and few might have a liver transplant, surgical resection or tumour ablation. It was unclear whether people who have a liver transplant after downstaging of their tumour have similar outcomes to those who have a liver transplant without the need for downstaging. The committee reconsidered downstaging after consultation and during its third meeting. It concluded that downstaging may be an option for a small proportion of people with advanced HCC. However, the proportion of people who have tumours that downstage, and the subsequent outcomes, are uncertain. Therefore, downstaging was not included in the base-case model.
## SIRTs may have fewer and less severe adverse events than sorafenib and these have not been captured in the economic modelling
Both the SARAH and SIRveNIB trials collected data on health-related quality of life. SARAH used the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC‑QLQ‑C30) questionnaire. The company mapped this onto the EQ‑5D scale using the Longworth et al. algorithm. The AG used these estimates in its model. The committee noted that utility values were similar between SIRTs and sorafenib for the following disease states: progression-free survival, progressive disease and after transplant. There were only small differences in utilities between progression-free survival and progressive disease. The clinical experts explained that people who had sorafenib for a long time may have a long-lasting negative effect on their quality of life. SIRTs are given in 1 procedure, meaning there is a shorter duration of effect on health-related quality of life. The committee was concerned that the potential important differences in long-term quality of life might not be captured in clinical trial results because quality-of-life data are collected at fixed time points (3, 6, 9 and 12 months after randomisation). It noted that in SARAH, EORTC‑QLQ‑C30 values in the SIR-Spheres arm were relatively constant over the 12 months from randomisation. Values for people in the sorafenib arm worsened for 6 months then stayed relatively stable . This decline was not seen in the mapped EQ-5D values. The committee acknowledged that this might be because the EORTC‑QLQ‑C30 scale is more sensitive than the EQ-5D to adverse events associated with sorafenib (fatigue, diarrhoea and skin reactions). The committee was also aware that the mapping algorithm did not include data from people with HCC, meaning that differences important to people with HCC might not accurately translate across to the EQ-5D. The committee recalled its conclusion that SIRTs have fewer and less severe adverse events than sorafenib (see section 3.27). It concluded that some aspects of health-related quality of life might not be captured in the utility values.
## Adverse event disutility values should be included in the model to capture differences in quality of life between SIRTs and sorafenib
The clinical experts advised that the side-effect profiles of SIRTs and sorafenib were different and should result in improved health-related quality of life for SIRTs compared with sorafenib. The committee understood that some people stop taking sorafenib because of intolerable adverse events. After consultation and additional analysis by the AG, the committee considered analyses applying disutility values for adverse events of grade 3 and above, and for adverse events of any grade. Various assumptions were included about the effect of less severe (grade 1 and 2) events. SARAH provided data on adverse event rates and pooled event duration (see section 3.27). The disutility values were informed by previous NICE technology appraisals. The committee understood that these values came from primary studies of variable quality, including vignette studies which are less robust. In these additional analyses, the smallest incremental quality-adjusted life year (QALY) gain from adverse events for SIRTs compared with sorafenib resulted in no additional total QALYs, when assuming that health-state utility values adequately captured all adverse effects. The biggest gain was 0.120 QALYs, when applying event-specific disutility values for events regardless of their severity (grades 1 and above). The committee agreed that there is some QALY gain with SIRTs resulting from the fewer and less severe adverse events. However, it also agreed that it was inappropriate to assume grade 1 and 2 events have the same effect on quality of life as grade 3 and 4 events. It also noted that typically, only grade 3 or 4 events are included in cost-effectiveness analyses. Therefore, it agreed that a gain of 0.120 QALYs would be too optimistic. It agreed that an intermediate adverse event QALY gain would be appropriate. The committee concluded that an adverse event-related QALY gain of 0.047 for SIRTs compared with sorafenib might be plausible and should be included in the base-case analysis. It also concluded that there was high uncertainty associated with this estimate and that the uncertainty was highest for QuiremSpheres because of its limited data.
# Cost-effectiveness results
## SIR-Spheres and TheraSphere are a cost-effective use of NHS resources for HCC
The committee agreed that its preferred approach to modelling included:
identical procedure-related administration costs for all SIRTs
individual participant data from SARAH for duration of sorafenib
for regorafenib assuming the same mean time on treatment as for sorafenib and no savings from dose interruptions and adjustments an additional SIRT QALY gain of 0.047 to account for differences in adverse events compared with sorafenib.The economic analysis included the committee's preferred assumptions and confidential patient access schemes for QuiremSpheres, SIR‑Spheres, TheraSphere, regorafenib and sorafenib. It assumed that the 3 SIRTs had the same effectiveness. It showed that all SIRTs were less effective than sorafenib despite the additional SIRT QALY gains to account for differences in adverse events, giving 0.029 fewer QALYs overall. QuiremSpheres was more costly than sorafenib. SIR‑Spheres and TheraSphere were less costly than sorafenib and provided fewer QALYs. Because of confidential discounts for interventions, comparator and follow-on therapies, exact cost-effectiveness results cannot be reported here. The AG also presented extensive scenario analyses during the first committee meeting and after consultation. This included:
alternative functions to model overall survival and progression‑free survival (see section 3.34)
alternative costs and utility values
ALBI grade 1 and low tumour burden subpopulation (see section 3.35)
retrospective studies with high risk of bias (see section 3.15)
downstaging (see section 3.37).Alternative functions, costs and utility values did not have a great effect on the incremental cost-effectiveness ratios (ICERs). The committee agreed that scenarios that restricted the population to people with ALBI grade 1 and low tumour burden were not taken into account because the ALBI score is not routinely used in NHS practice in England (see section 3.35). It also agreed that retrospective studies should not be included because of high risk of bias and uncertainty of the data (see section 3.15). Additionally, downstaging should not be included in the committee's preferred base case because the proportion of people who have tumours that downstage, and subsequent outcomes, are uncertain (see section 3.37). The committee concluded that in the probabilistic base-case analysis, QuiremSpheres was less effective and more costly than sorafenib. This meant sorafenib dominated QuiremSpheres (that is, it was more effective and less costly). SIR-Spheres and TheraSphere were less effective and less costly than sorafenib. The cost savings were sufficient to offset the QALY loss at a £30,000 saved per QALY lost level. The committee also recalled that the model assumed that SIRTs were equally effective, and that this was a highly uncertain assumption for QuiremSpheres because of its very limited evidence base compared with SIR-Spheres and TheraSphere (see section 3.33). The committee also recalled that personalised dosimetry could improve the effectiveness of SIRTs, which may increase their QALYs (see section 3.24). It considered that this would not meaningfully affect the cost-effectiveness estimate for QuiremSpheres or offset the uncertainty in its evidence base. Because of its higher costs compared with sorafenib and its limited clinical evidence, the committee considered QuiremSpheres not to be a cost‑effective use of NHS resources for treating HCC. Because of the cost savings per QALYs lost, the committee considered that both SIR-Spheres and TheraSphere are cost-effective use of NHS resources.
# End of life
## The end of life criteria are not met
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.
When transplant or CTT is appropriate, people have a life expectancy of more than 24 months. This means that the life-expectancy criterion (that is, the treatment is indicated for patients with a short life expectancy, normally less than 24 months) was not met for these subgroups.
When CTT is inappropriate, in advanced disease, people have a poor prognosis with a life expectancy of less than 24 months. Therefore, the short life-expectancy criterion was met for this subgroup.
In all plausible scenarios, there was no increase in the modelled undiscounted life expectancy with SIRTs compared with sorafenib. The committee concluded that the life-extending criterion (that is, there is sufficient evidence that the treatment could extend life, normally by a mean value of at least an additional 3 months, compared with current NHS treatment) was not met.Because both parts of the criteria were not met, the committee concluded that the end‑of‑life criteria were not met.
# Innovation
## No evidence was identified showing additional benefits of SIRT, above those captured in the cost-effectiveness analysis
The companies considered SIRTs to be innovative because they offer a more personalised treatment option. The patient experts stated that SIRTs would be a substantial change in treating HCC because they could offer a chance for subsequent curative treatment for people who would not otherwise have this option. The committee concluded it had not seen evidence of any additional benefits that were not captured in the measurement of QALYs in its preferred model.
# Conclusion
## SIR-Spheres and TheraSphere, but not QuiremSpheres, are recommended for treating HCC
In the committee's preferred analysis, SIRTs were less effective than sorafenib with an incremental quality-adjusted life years loss of 0.029 QALYs. In clinical trials, SIR‑Spheres did not improve survival compared with sorafenib. There was very limited clinical evidence to compare the effectiveness of QuiremSpheres and TheraSphere with sorafenib and for all the SIRT technologies. The committee also considered that there were limited data for QuiremSpheres and TheraSphere, and the effectiveness estimates and resulting ICERs were more uncertain than those of SIR‑Spheres. However, the committee considered that the adverse event profiles of SIRTs and sorafenib are different and people with HCC would welcome new treatment options (see section 3.1). Taking this into account, the committee concluded that QuiremSpheres was less effective and more costly than sorafenib and was not considered a cost‑effective use of NHS resources. QuiremSpheres was not recommended for HCC. SIR‑Spheres and TheraSphere were less costly than sorafenib and the estimated cost savings outweigh the loss of QALYs after taking into account the uncertainty associated with the clinical effectiveness. Therefore, the committee considered SIR‑Spheres and TheraSphere to be a cost‑effective use of NHS resources, and recommended both as options for treating advanced HCC for people with Child–Pugh grade A liver impairment for whom CTT is inappropriate.
|
{'Recommendations': "The selective internal radiation therapy (SIRT) SIR‑Spheres is recommended as an option for treating unresectable advanced hepatocellular carcinoma (HCC) in adults, only if:\n\nused for people with Child–Pugh grade\xa0A liver impairment when conventional transarterial therapies are inappropriate, and\n\nthe company provides SIR‑Spheres according to the commercial arrangement.\n\nThe SIRT TheraSphere is recommended as an option for treating unresectable advanced HCC in adults, only if:\n\nused for people with Child–Pugh grade\xa0A liver impairment when conventional transarterial therapies are inappropriate, and\n\nthe company provides TheraSphere according to the commercial arrangement.\n\nThe SIRT QuiremSpheres is not recommended for treating unresectable advanced HCC in adults.\n\nThese recommendations are not intended to affect treatment with SIR‑Spheres, TheraSphere and QuiremSpheres that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for HCC depends on the stage of the disease and liver function. Treatment options include surgery, ablation, transarterial therapies, chemotherapy (such as sorafenib) and best supportive care. Treatment does not cure the disease for most people.\n\nSIRTs are small radioactive beads that are injected into the liver's blood supply to treat liver cancer. QuiremSpheres, SIR-Spheres and TheraSphere are the 3\xa0SIRTs considered in this appraisal. The clinical trial data for these SIRTs compared with other treatment options are limited. But, compared with sorafenib, SIRTs may have fewer and more manageable adverse effects, which can improve quality of life.\n\nThere is not enough evidence to consider SIRTs a cost-effective use of NHS resources for people with early and intermediate HCC.\n\nFor people with advanced HCC, QuiremSpheres is less clinically effective than sorafenib and costs more, so it is not recommended. SIR-Spheres and TheraSphere are slightly less clinically effective than sorafenib but cost less. The cost savings mean that SIR‑Spheres and TheraSphere can be recommended as options for people with Child–Pugh grade\xa0A liver impairment when conventional transarterial therapies are inappropriate.", 'Information about QuiremSpheres, SIR-Spheres and TheraSphere': "# CE mark for QuiremSpheres\n\nQuiremSpheres (Quirem Medical, manufacturer; Terumo Europe, distributor) received its CE mark in April\xa02015. It is classified as an Active Implantable Medical Device by Council Directive 90/385/EEC. It is indicated for treating unresectable liver tumours.\n\n# Dosage in the CE mark for QuiremSpheres\n\nQuiremSpheres is given through a catheter to the hepatic artery. The product is supplied as a customised, patient-specific dose. The maximum range of the emitted beta particles in tissue is 8.7\xa0mm with a mean of 2.5\xa0mm. Also, holmium‑166 emits primary gamma photons (81\xa0kilo\xa0electronvolt, KeV). The half-life is 26.8\xa0hours, which means more than 90% of the radiation is given in the first 4\xa0days after the procedure. At the moment of treatment, the activity per microsphere is 200\xa0to 400\xa0Becquerel (Bq). The number of particles implanted depends on the targeted liver volume and ranges, on average, from 10\xa0to 30\xa0million.\n\n# Price for QuiremSpheres\n\nThe company has stated that the acquisition cost of QuiremSpheres is £9,896 for a single treatment. The company has a commercial arrangement, which would have applied if the technology had been recommended.\n\n# CE mark for SIR-Spheres\n\nSIR-Spheres (Sirtex) received its CE mark as an Active Implantable Medical Device in October\xa02002. It is indicated for treating advanced inoperable liver tumours.\n\n# Dosage in the CE mark for SIR-Spheres\n\nSIR-Spheres is given through a catheter to the hepatic artery. It is supplied at 3\xa0GBq yttrium‑90\xa0per vial in 5\xa0ml water for injection in a shielded shipping vial. Each vial contains 40\xa0to 80\xa0million microspheres, ranging from 20\xa0to 60\xa0micrometres in diameter (median diameter 32.5\xa0micrometres). The maximum range of beta emission in tissue is 11\xa0mm with a mean of 2.5\xa0mm. The average number of particles implanted is 30\xa0million to 60\xa0million.\n\n# Price for SIR-Spheres\n\nThe company has stated that the acquisition cost of SIR‑Spheres is £8,000 for a single treatment. The company has a commercial arrangement. This makes SIR‑Spheres available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\n# CE mark for TheraSphere\n\nTheraSphere (BTG) received its CE mark as an Active Implantable Medical Device in September\xa02014. It is indicated for treating hepatic neoplasia.\n\n# Dosage in the CE mark for TheraSphere\n\nTheraSphere is given through a catheter to the hepatic artery. It is supplied in 6\xa0dose sizes: 3\xa0GBq, 5\xa0GBq, 7\xa0GBq, 10\xa0GBq, 15\xa0GBq or 20\xa0GBq in 0.6\xa0ml pyrogen‑free water supplied in a 1\xa0ml vial, inside an acrylic shield. Custom dose sizes are also available in increments of 0.5\xa0GBq between 3\xa0GBq and 20\xa0GBq. A single treatment with TheraSphere contains 1.2\xa0million to 8\xa0million microspheres. The recommended dose to the liver is 80\xa0Gy to 150\xa0Gy.\n\n# Price for TheraSphere\n\nThe company has stated that the acquisition cost of TheraSphere is £8,000 for a single treatment. The company has a commercial arrangement. This makes TheraSphere available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Potential new treatment option\n\n## People with hepatocellular carcinoma would welcome a new treatment option\n\nHepatocellular carcinoma (HCC) is the most common form of liver cancer in England. Treatment depends on the location and stage of the cancer, and how well the liver is functioning. Treatment options include surgery or ablation in early-stage disease, transarterial therapies in intermediate‑stage disease, and chemotherapy or systemic therapy in advanced-stage disease, as well as best supportive care. Treatment does not cure the disease for many people. The clinical experts explained that selective internal radiation therapy (SIRT) has also been used for HCC in England through compassionate schemes. Patient experts explained that HCC can have a substantial impact on quality of life. People with HCC and their carers live with uncertainty and hopelessness. Often people with HCC also live with stigma and isolation because of underlying causes of disease, such as alcohol. Clinical experts highlighted that people with advanced HCC have a poor prognosis with median life expectancy of less than 12\xa0months. The committee concluded that people with HCC would welcome a new treatment option.\n\n## People with HCC and portal vein thrombosis are a relevant subgroup\n\nThe clinical experts explained that portal vein involvement, such as portal vein thrombosis (PVT), is a common comorbidity that might negatively affect prognosis. PVT happens when a blood clot narrows the vein that takes blood to the liver from the intestines. The committee understood that people with PVT were included in the NICE scope for this appraisal. It concluded that evidence for people with HCC and PVT should be considered.\n\n## This appraisal assesses 3\xa0SIRTs for treating HCC\n\nQuiremSpheres, SIR-Spheres and TheraSphere are SIRTs. These are small radioactive beads that are injected into the liver's blood supply to treat liver cancer. The 3\xa0SIRTs are medical devices with CE marks for their indications. QuiremSpheres is indicated for treating unresectable liver tumours, SIR‑Spheres for treating advanced inoperable liver tumours and TheraSphere for treating hepatic neoplasia. The committee was aware that the scope for the appraisal was narrower than the CE marks, because it only included unresectable HCC, when SIRTs are most likely to be used. The committee agreed that the 3\xa0SIRTs should be compared with each other and with available treatments to assess their cost\xa0effectiveness for treating HCC.\n\n## SIRTs are already used in the NHS for other cancers, but not for HCC\n\nThe clinical experts and NHS England explained that SIRTs are available in some specialist centres across England for other cancers (such as metastatic colorectal cancer). The committee understood that SIRTs are currently not commissioned for HCC in the NHS but that the infrastructure and knowledge for using SIRTs exists in some specialist centres.\n\n# Clinical management\n\n## Stage of cancer and liver function characterise the disease and people with HCC are a heterogenous population\n\nThere are different causes of HCC, including cirrhosis, alcohol, fatty liver disease and hepatitis. Therefore, people with HCC are a heterogenous population and their disease is characterised by both stage of cancer and liver function. Treatment choice is multifaceted because both the cancer and liver function affect treatment outcomes. Clinical experts advised that in England clinicians use the Barcelona Clinic Liver Cancer (BCLC) staging system and the Child–Pugh score to inform treatment decisions.\n\nBCLC staging looks at the number and size of tumours in the liver. There are 5\xa0stages: very early stage (BCLC\xa00), early stage (BCLC\xa0A), intermediate stage (BCLC\xa0B), advanced stage (BCLC\xa0C) and terminal stage (BCLC\xa0D). The committee agreed that stages\xa0A, B and C align with the scope for this appraisal.\n\nThe Child–Pugh score assesses liver function. It has 5\xa0components: serum albumin levels, bilirubin levels, time for blood to clot, presence of ascites (fluid in the peritoneal cavity) and presence of hepatic encephalopathy. There are 3\xa0classes: class\xa0A (the liver is working normally), class\xa0B (mild to moderate liver damage), class\xa0C (severe liver damage). People with BCLC\xa0A to\xa0C can have either good liver function (Child–Pugh\xa0A) or mild to moderate liver damage (Child–Pugh\xa0B).\n\nMore recently an alternative measure, the albumin-bilirubin (ALBI) grade, was developed to look at liver function. The committee was aware that in previous NICE guidance for HCC, the Child–Pugh score was used as a criterion for treatment, and that ALBI was not available at that time. The clinical experts advised that ALBI is less frequently used for this purpose, and that Child–Pugh score is expected to be the measure of choice for the foreseeable future.\n\n## Treatment of HCC differs between the 3\xa0BCLC stages and is influenced by Child–Pugh score\n\nTreatment options include ablation and transplant in early disease, and conventional transarterial therapies (CTT) such as transarterial chemoembolisation (TACE) or transarterial embolisation (TAE) in intermediate disease. In advanced disease, treatment options are chemotherapy or systemic therapy with sorafenib, lenvatinib or regorafenib. For some people the aim of treatment might be to reduce the tumour size ('downstaging') to potentially allow subsequent transplantation, surgical resection or tumour ablation that could cure the disease. The committee understood that people with HCC have different treatment options depending on the stage of their disease as assessed by BCLC and Child–Pugh score.\n\n## There are 3\xa0distinct subgroups relevant to this appraisal\n\nThe committee concluded that there are 3\xa0subgroups relevant for this appraisal:\n\nPeople for whom liver transplant is appropriate, including people with BCLC\xa0A and Child‑Pugh\xa0A or\xa0B.\n\nPeople for whom CTT is appropriate, including people with BCLC\xa0B and Child–Pugh\xa0A or\xa0B.\n\nPeople for whom CTT is inappropriate, including people with BCLC\xa0C and Child–Pugh\xa0A or B.\n\n## In people with early disease, ablation and transplant are standard care in current NHS practice in England\n\nTreatment options for early disease (BCLC\xa0A) are ablation and transplant. However, 1\xa0clinical expert explained that transplants might not be available for people with good liver function (Child‑Pugh\xa0A). The committee concluded that both ablation and transplant are standard care for people with early disease in clinical practice in England.\n\n## In people with intermediate disease, CTTs are standard care in current NHS practice in England\n\nTreatments for intermediate disease (BCLC\xa0B) are CTTs, including transarterial chemoembolisation (TACE), drug-eluting bead transarterial chemoembolisation (DEB-TACE) and transarterial embolisation (TAE). The committee accepted that all CTTs available in the NHS in England are appropriate comparators for people with intermediate disease.\n\n## In people with advanced disease, sorafenib is standard care in current NHS practice in England\n\nThe systemic therapies sorafenib and lenvatinib are both recommended for advanced HCC (BCLC\xa0C) in people with Child–Pugh grade\xa0A liver impairment (NICE technology appraisal guidance on sorafenib for treating advanced hepatocellular carcinoma and lenvatinib for untreated advanced hepatocellular carcinoma). Regorafenib is only recommended after treatment with sorafenib (NICE technology appraisal guidance on regorafenib for previously treated advanced hepatocellular carcinoma). The committee understood that sorafenib is standard care in clinical practice in England because there are subsequent treatments available after progression with sorafenib. The clinical expert confirmed that lenvatinib is now rarely used. The committee concluded that sorafenib is the most appropriate comparator for SIRTs in people with advanced disease and with Child–Pugh grade\xa0A liver impairment.\n\n# Clinical evidence\n\n## The systematic review included non-RCT evidence when not enough RCT evidence was identified\n\nThe assessment group (AG) did a systematic review of the clinical evidence on SIRTs and comparators. Randomised controlled trials (RCTs) were eligible for inclusion in the review. The AG had identified all the RCTs that were also identified by the companies in their submissions. The committee was aware of non-RCT evidence and noted that typically the risk of bias in non-RCT evidence is higher than in RCT evidence. It agreed with the AG's approach to only include non-RCT evidence in the review when there was not enough RCT evidence. The committee understood that some studies might include a mixed population containing all 3\xa0subgroups of interest. It agreed to exclude studies from the network meta-analyses if they did not provide separate results for the 3\xa0subgroups (see section\xa03.7). The committee used the AG's analysis for its decision\xa0making. This was because it included evidence for all 3\xa0SIRTs and so was more comprehensive than the companies' submissions.\n\n## There is not enough evidence to assess the clinical effectiveness of QuiremSpheres in the 3\xa0subgroups relevant to this appraisal\n\nThe clinical evidence for QuiremSpheres came from 1\xa0retrospective case series including 9\xa0people that showed a 56% response rate. A mixed population was included, and results were only presented for the whole study population. The committee concluded that the single, small retrospective study did not provide enough data to assess the clinical effectiveness of QuiremSpheres in any of the 3\xa0subgroups relevant to this appraisal (see section\xa03.7).\n\n## There is limited randomised clinical evidence for TheraSphere compared with TACE when transplant is appropriate\n\nTwo small RCTs (PREMIERE and Kulik et al. 2014) for TheraSphere were identified that included people for whom transplant was appropriate (see section\xa03.7). The committee was also aware of 10\xa0non-RCT studies, including 7\xa0prospective comparative studies, that included people from the 3\xa0subgroups relevant to this appraisal. The PREMIERE study was done in the US and included 45\xa0people for whom transplant was appropriate. It compared TheraSphere with TACE as an alternative to prepare for transplant. The AG advised that PREMIERE had a high risk of bias because of concerns with randomisation and potential deviations from the intended interventions. Also, the baseline characteristics were different in the 2\xa0arms so people in the TACE arm had better prognosis than people in the TheraSphere arm. Overall survival of people who had a transplant was numerically, but not statistically, significantly longer in the TheraSphere arm. The median overall survival for TheraSphere was 18.6\xa0months (95%\xa0confidence interval [CI]\xa07.4 to\xa032.5) compared with 17.7\xa0months (95%\xa0CI\xa07.4 to\xa032.5) for TACE. The committee concluded that there was limited evidence, with a high risk of bias, to establish whether TheraSphere was better or worse than TACE when transplant is appropriate.\n\n## There is limited evidence for TheraSphere compared with TheraSphere plus sorafenib when transplant is appropriate\n\nThe study by Kulik et al. (2014) was done in the US and included 20\xa0people for whom transplant was appropriate. It compared TheraSphere with TheraSphere plus sorafenib. The AG had some concerns with the randomisation process, treatments received and measurement of outcomes. The baseline characteristics were different in the 2\xa0arms so people in the TheraSphere plus sorafenib arm had a better prognosis. There was no evidence of a difference in overall survival between the 2\xa0arms (3\xa0deaths in the TheraSphere arm, 2\xa0deaths in the combination arm). The committee was aware that TheraSphere plus sorafenib was not included in sorafenib's marketing authorisation or TheraSphere's CE mark. The committee concluded that there was limited evidence, with high risk of bias, to establish whether TheraSphere is better or worse than TheraSphere with sorafenib when transplant is appropriate.\n\n## Non-randomised evidence comparing TheraSphere with non-SIRT treatments is not robust enough for decision making\n\nOf the 7\xa0prospective comparative non-RCTs, only 4\xa0reported overall survival or progression-free survival. Of these, 2\xa0compared TheraSphere with TACE or DEB-TACE across the 3\xa0subgroups. The AG suggested that both studies had high risk of bias and differences in baseline characteristics such as age, tumour size and number of tumours. The committee concluded that results from these studies might be unreliable for decision making. Another study compared TheraSphere with TheraSphere plus sorafenib, in people for whom CTT is inappropriate. The remaining prospective study was done in people for whom CTT is inappropriate. This compared TheraSphere in people with PVT with TheraSphere in people without PVT and best supportive care. The AG advised that this study had a high risk of bias, and that the people in the treatment arms had very different baseline characteristics. The committee recognised that the large volume of non-randomised evidence might be useful for tentative conclusions, but it remained aware of the limitations of non-RCT studies. Therefore, it agreed that they should not be used for decision making. Also, there was not enough evidence to establish whether TheraSphere is better or worse than other treatments in people for whom CTT is appropriate and in people for whom CTT is inappropriate.\n\n## There are insufficient data to establish the clinical effectiveness of SIR-Spheres compared with non-SIRT treatments when transplant is appropriate\n\nThe AG identified 1\xa0RCT comparing SIR-Spheres with TACE (SIR-TACE) that included people for whom transplant was appropriate. SIR-TACE was done in Germany and Spain, and included 28\xa0people with early, intermediate and late-stage disease. Only overall results for the mixed population were available. The AG assessed that the study had a high risk of bias because of the randomisation process, missing outcome data and measurement of the outcome. The committee concluded that there are insufficient data to establish whether SIR‑Spheres are better than TACE when transplant is appropriate.\n\n## It is unclear whether SIR-Spheres is better than DEB-TACE or TACE when CTT is appropriate\n\nThe AG identified 2\xa0RCTs that compared SIR‑Spheres with TACE (SIR‑TACE) or DEB‑TACE (Pitton et al. 2015) that included people for whom CTT is appropriate in their trial populations. SIR-TACE is described in section 3.16. Pitton et al. (2015) was done in Germany and included 24\xa0people with intermediate-stage disease (BCLC\xa0B). Overall survival and progression-free survival were longer in the DEB‑TACE arm compared with the SIR-Spheres arm, but this was not statistically significant (788\xa0days compared with 592\xa0days and 216\xa0days compared with 180\xa0days, respectively). Because of this and the small sample size, the committee concluded that it could not establish whether SIR‑Spheres was better than TACE or DEB‑TACE when CTT is appropriate.\n\n## People in SARAH had poorer prognosis than people seen in clinical practice in England\n\nThe AG identified 2\xa0RCTs comparing SIR-Spheres with sorafenib (SARAH and SIRveNIB) in people for whom CTT was inappropriate. SARAH was done in France between 2011 and 2015 and included a heterogeneous population of people with HCC. This included, for example, people with advanced HCC, people with HCC who had previous treatment with 2\xa0treatments of TACE, and people with Child–Pugh\xa0A or\xa0B liver impairment. There was no difference in overall survival or progression-free survival between the treatment arms. The median overall survival was 8.0\xa0months (95%\xa0CI\xa06.7 to\xa09.9) for SIR‑Spheres and 9.9\xa0months (95%\xa0CI\xa08.7 to\xa011.4) for sorafenib. The hazard ratios (HRs) were 1.15\xa0(95%\xa0CI\xa00.94 to\xa01.41) for the intention‑to‑treat (ITT) population and 0.99\xa0(95%\xa0CI\xa00.79 to\xa01.24) for the per-protocol population. The median progression-free survival was 4.1\xa0months (95%\xa0CI\xa03.8 to 4.6) for SIR‑Spheres and 3.7\xa0months (95%\xa0CI\xa03.3 to 5.4) for sorafenib. The HR was 1.03 (95%\xa0CI\xa00.85 to 1.25) for the ITT population. More adverse events were reported with sorafenib than SIR‑Spheres. A post-hoc analysis of SARAH focused on people with ALBI grade\xa01 and low tumour burden (25% or less tumour burden). Again, there was no statistically significant difference in overall or progression‑free survival between the treatment arms. The median overall survival was 21.9\xa0months (95%\xa0CI\xa015.2 to\xa02.5) for SIR‑Spheres and 17.0\xa0months (95%\xa0CI\xa011.6\xa0to\xa020.8) for sorafenib. The HR was 0.73 (95%\xa0CI\xa00.44\xa0to\xa01.21). The median progression-free survival HR was 0.65\xa0(95%\xa0CI\xa00.41 to 1.02). The clinical experts advised that the SARAH trial had more people with a high tumour burden, PVT and impaired liver function than people seen in clinical practice in England. The committee concluded that people in the SARAH trial had poorer prognosis than people seen in clinical practice in England.\n\n## The results from SIRveNIB may not be fully generalisable to the NHS\n\nSIRveNIB was done in the Asia-Pacific region between 2010 and 2018. The clinical experts explained that results from SIRveNIB might not be generalisable to the NHS in England. This was because in the Asia-Pacific region HCC is often caused by hepatitis\xa0B and\xa0C, whereas in the UK fatty liver disease and alcohol are the most common causes. There was no difference in overall survival or progression-free survival between the treatment arms. The median overall survival was 8.8\xa0months for SIR‑Spheres and 10.0\xa0months for sorafenib. The HRs were 1.12\xa0(95%\xa0CI\xa00.9 to\xa01.4) for the ITT population and 0.86 (95%\xa0CI\xa00.7\xa0to\xa01.1) for the per-protocol population. The median progression‑free survival was 5.8\xa0months for SIR-Spheres and 5.1\xa0months for sorafenib. The HRs were 0.89 (95%\xa0CI\xa00.7 to\xa01.1) for the ITT population and 0.73 (95%\xa0CI\xa00.6 to\xa00.9) for the per-protocol population. More adverse events were reported with sorafenib than SIR‑Spheres. The committee concluded that results from SIRveNIB may not be fully generalisable to people seen in the NHS.\n\n## The evidence from SARAH and SIRveNIB is preferable to non-RCT evidence for decision making when CTT is inappropriate\n\nThe committee considered including non-RCT evidence identified by the AG. The AG assessed the 3\xa0non-RCT studies as having a high risk of bias. So, the committee concluded that the RCT evidence from SARAH and SIRveNIB was preferable for decision making in people for whom CTT was inappropriate.\n\n## There is no evidence to compare the 3\xa0SIRTs' effectiveness when transplant or CTT is appropriate\n\nThe clinical evidence for comparative effectiveness of the 3\xa0SIRTs came from 6\xa0retrospective studies that reported overall survival or progression‑free survival. Of these, 5\xa0compared SIR-Spheres with TheraSphere and 1\xa0small study of 30\xa0people compared all 3\xa0SIRTs. The AG advised that most of these studies had a high risk of bias because of selection and performance bias. None of the studies included people for whom transplant was appropriate. The study comparing all 3\xa0SIRTs may have included people for whom CTTs were appropriate but there were no results presented for this subgroup. The committee concluded that there was no evidence identified for people when transplant or CTT was appropriate.\n\n## There is not enough direct evidence to compare the 3\xa0SIRTs' effectiveness when CTT is inappropriate, so a mixed treatment comparison is considered\n\nThe AG identified 5\xa0retrospective studies that included people for whom CTT is inappropriate (see section\xa03.21). The study comparing all 3\xa0SIRTs also included people for whom CTTs were appropriate, but no results for subgroups were presented. The committee was aware that the populations were different across these studies and acknowledged that this meant results were difficult to compare. The committee was also aware that the baseline characteristics were different in most studies, and that this might affect prognosis and outcomes between the arms. In 2\xa0studies that compared TheraSphere with SIR‑Spheres, there was no difference in overall survival. In van der Gucht et al. (2017; n=77), the median overall survival was 7.0\xa0months for TheraSphere (95%\xa0CI\xa01.6 to\xa012.4) compared with 7.7\xa0months for SIR‑Spheres (95%\xa0CI\xa07.2 to\xa08.2). In Bhangoo et al. (2015; n=17) the median overall survival for TheraSphere was 8.4\xa0months (95%\xa0CI\xa01.3 to\xa021.1) compared with 7.8\xa0months for SIR‑Spheres (95%\xa0CI\xa02.3 to\xa012.5). In 2\xa0studies (Biederman et al. 2015 and Biederman et al. 2016) that compared TheraSphere with SIR‑Spheres in people with PVT, overall survival was better in the TheraSphere arm than the SIR‑Spheres arm. The committee concluded that there was not enough direct evidence to establish the relative effectiveness of the 3\xa0SIRTs in people with HCC, and so decided to consider mixed treatment comparisons for decision making.\n\n## There was not enough robust evidence to establish the clinical effectiveness of SIRTs compared with non-SIRT treatments for people with PVT\n\nThe clinical expert explained that people with PVT (see section\xa03.2) have poorer prognosis and limited treatment options. Often the only available treatment is sorafenib because people with PVT do not tolerate TACE. Therefore, the committee agreed that people with PVT might benefit more than others from treatment with SIRTs. It considered the evidence that included people with PVT (see section\xa03.15 and section\xa03.22). There was no new evidence presented specifically for this subgroup at consultation. The committee concluded there was not enough robust evidence to establish the clinical effectiveness of SIRTs compared with non-SIRT treatments for people with PVT.\n\n## There is not enough robust data to establish whether SIRTs are better or worse than sorafenib or TACE in people with large tumours\n\nAfter consultation, the committee considered the evidence for people with 1\xa0or more large tumours (5\xa0cm or larger) with or without PVT. This was because this subgroup might benefit more than others from treatment with SIRTs. The committee understood that in the UK this group currently has sorafenib or TACE. Clinical evidence showed that TACE is not very effective and there are substantial adverse events with sorafenib. The committee saw data from 1\xa0study in this group. This study, DOSISPHERE-01, compared TheraSphere personalised dosimetry with TheraSphere standard dosimetry. Personalised dosimetry improved the response rate and overall survival compared with standard dosimetry (overall survival for personalised dosimetry 26.6\xa0months, 95%\xa0CI\xa011.7\xa0months to not reached; compared with standard dosimetry 10.7\xa0months, 95%\xa0CI\xa06.0\xa0months to 16.8\xa0months; p=0.0096). The committee understood that people in the 2\xa0arms of the study might not be similar and therefore the results may have selection bias. Also, there were no data comparing SIRTs with sorafenib or TACE in this group. The committee acknowledged that personalised dosimetry could improve the effectiveness of SIRTs. It concluded that there were not enough robust data to establish whether SIRTs are better or worse than sorafenib or TACE in people with 1\xa0or more large tumours.\n\n## People who are unable to tolerate sorafenib might benefit from treatment with SIRTs but there is no comparative evidence\n\nClinical expert comments provided during consultation advised that people who are unable to tolerate sorafenib do not have alternative treatment options. This means they have best supportive care. The committee understood that there is some clinical experience in England of this group having treatment with SIRTs, with promising outcomes. It also acknowledged that this group is not included in the RCTs because of their characteristics (for example, older age and comorbidities). Despite the lack of evidence, the committee concluded that people who are unable to tolerate sorafenib might benefit from treatment with SIRTs.\n\n## Most of the RCT evidence is in people with advanced disease with Child–Pugh A\xa0grade liver impairment, which is the relevant subgroup\n\nThe committee recalled that current treatments for advanced HCC are only recommended for people with Child–Pugh grade\xa0A liver impairment (see section\xa03.10). People with Child–Pugh grade\xa0B liver impairment have best supportive care. It noted that there was no best supportive care arm in the RCTs (SARAH and SIRveNIB), which compared SIR-Spheres with sorafenib only. The committee acknowledged that most people in the trials had Child–Pugh grade\xa0A liver impairment (83% in SARAH and 90% in SIRveNIB). Therefore, it concluded that the trial results were acceptable for decision making in people with Child–Pugh grade\xa0A liver impairment. However, it could not establish whether SIRTs were effective in people with Child–Pugh grade\xa0B liver impairment, because of the lack of evidence comparing SIRTs with the relevant comparator for that group. Therefore, in people with advanced HCC, the subgroup with Child–Pugh\xa0A liver impairment was appropriate for decision making.\n\n## SIRTs have fewer and less severe side effects than other treatment options\n\nThe clinical and patient experts stated that there were fewer and less severe side effects with SIRTs than with other treatments. Also, side effects from SIRTs have a shorter duration, whereas side effects from chemotherapies such as sorafenib can continue for the whole treatment course. After the second committee meeting, the committee invited companies and stakeholders to submit additional data on adverse event severity and duration. The committee considered adverse event data from SARAH for SIR‑Spheres and non-RCT studies for TheraSphere. The data included adverse event rates and durations for all severity grades. They showed that SIRTs and sorafenib have different adverse event profiles. The committee was aware that data on event duration were averaged across all severity grades and both study arms in SARAH. The committee concluded that SIRTs were likely to have fewer and less severe side effects than sorafenib, and that this benefit may be important to patients. The committee agreed that this should be captured in the cost‑effectiveness analysis and taken into account during decision making.\n\n# Mixed treatment comparisons\n\n## Data are not robust enough to provide a meaningful comparison between treatment options when transplant is appropriate\n\nThe AG considered the feasibility of a mixed treatment comparison to estimate comparative effectiveness between available treatment options for people when transplant is appropriate. There are 2\xa0RCTs that could be included in this analysis. Both were done in the US and compared TheraSphere with TACE (n=45) or with a combination of TheraSphere and sorafenib (n=20). Also, the committee recalled that ablation or transplant was the most relevant comparator for people for whom transplant is appropriate (see section\xa03.8). Because of limited data, results from the mixed treatment comparison would be very uncertain. The committee concluded that a mixed treatment comparison in this population would not help decision making for the subgroup for whom transplant is appropriate.\n\n## Estimates comparing effectiveness for treatment options in people for whom CTT is appropriate are very uncertain, and are not suitable for decision making\n\nAfter consultation on the assessment report, the AG did a mixed treatment comparison in people for whom CTT was appropriate. There were 6\xa0RCTs that could be included in this analysis: 5\xa0compared different CTTs with each other and 1\xa0compared SIR-Spheres with DEB‑TACE (n=24). The AG also included 1\xa0retrospective study that compared SIR-Spheres with TheraSphere (n=77). From this study, only a subgroup of 35\xa0people with early or intermediate HCC could be included in the analysis. The study had a high risk of bias because its 2\xa0treatment groups were not similar at baseline (people with small tumour volumes were preferentially treated with TheraSphere). The committee agreed that there was little evidence to link SIR-Spheres and TheraSphere to the network of treatments. Results from the mixed treatment comparison for overall survival and progression-free survival were uncertain, with wide credible intervals that included a HR of 1 (no statistical difference between treatment options). The committee concluded that the results from the mixed treatment comparison in this population were uncertain. Also, there was not enough evidence in this population to compare SIR‑Spheres with TheraSphere, or compare the SIRTs with TACE, DEB‑TACE and TAE.\n\n## The comparative effectiveness estimates of the 3\xa0SIRTs in people for whom CTT is inappropriate are uncertain\n\nThe AG did a mixed treatment comparison to estimate comparative effectiveness between available treatment options in people when CTT was inappropriate. There were 3\xa0RCTs included in this analysis. Of these, 1\xa0RCT compared lenvatinib with sorafenib and 2\xa0compared sorafenib with SIR-Spheres. To include TheraSphere in the network, 2\xa0retrospective studies comparing TheraSphere with SIR‑Spheres were included in sensitivity analyses. There were no data for QuiremSpheres to be included in the analysis. In the main analysis, when CTT is inappropriate and people have Child–Pugh grade\xa0A liver impairment, there was no evidence of a difference between SIR‑Spheres and sorafenib. In the ITT population for SIR‑Spheres compared with sorafenib, the hazard ratio was 1.13\xa0(95%\xa0CI\xa00.96 to\xa01.32). A value of less than 1 indicates better overall survival. The committee recalled the AG's assessment that the retrospective studies had a high risk of bias and uncertain results (see section\xa03.15). The committee agreed that retrospective studies should not be included in the analysis because of the risk of bias. It concluded that the comparative effectiveness results based on RCT evidence from SIR‑Spheres could be used in a cost-effectiveness analysis. The committee also concluded that, because its preferred network meta‑analysis only had evidence for 1\xa0SIRT (SIR-Spheres), the comparative effectiveness of the 3\xa0SIRTs compared with each other was uncertain.\n\n# Cost-effectiveness evidence\n\n## The AG's model is used for decision making\n\nTwo\xa0companies included economic analyses in their evidence submissions. For SIR-Spheres, the company submitted a cost‑minimisation analysis for people for whom CTT was appropriate, and a cost–utility analysis for people for whom CTT was inappropriate. The base case of the cost–utility analysis was people with ALBI grade\xa01 and low tumour burden, a subpopulation from the SARAH trial. The ITT and per-protocol populations of the SARAH trial were included as scenario analyses. For TheraSphere, the company submitted 2\xa0cost–utility analyses, 1\xa0for people for whom CTT was appropriate and 1\xa0for people for whom CTT was inappropriate. The committee acknowledged the submission of the companies' models. It noted that the AG model used a similar structure (see section\xa03.32) as the companies' cost–utility analyses. Also, the AG used inputs from the companies' models, such as costs and treatment frequency. The committee concluded that there was not enough evidence to support an economic analysis in people for whom CTT was appropriate (see section\xa03.29). When CTT was inappropriate, the AG model was the most suitable for decision making because it included all 3\xa0SIRTs as specified in the NICE scope (see section\xa03.3).\n\n## The structure of the AG model for people for whom CTT is inappropriate is acceptable for decision making\n\nThe AG did a cost–utility analysis for people with unresectable intermediate (BCLC stage\xa0B) or advanced (BCLC stage\xa0C) HCC, when CTT was inappropriate, with or without macroscopic vascular invasion but without extrahepatic disease. The model consisted of a decision tree and partitioned survival model with 3\xa0health states. The decision tree represented the outcome of the work-up procedure that happens before SIRT. The partitioned survival model was like that used by the companies. The interventions were SIR-Spheres, TheraSphere and QuiremSpheres, which were assumed to have equal effectiveness in the base case (see section\xa03.33). The comparators were initially sorafenib and lenvatinib. Because sorafenib and lenvatinib are recommended only for people with Child–Pugh grade\xa0A liver impairment, the base-case analysis was restricted to this population. The committee concluded that the model structure was acceptable for decision making.\n\n## Cost-effectiveness results assuming all SIRTs are equally effective have been considered, but this is uncertain for QuiremSpheres\n\nThe AG's economic analysis assumed that the 3\xa0SIRTs were equally effective. Most data used in the model, such as clinical effectiveness and adverse event data, were from the SARAH trial for SIR-Spheres. There was very little evidence for QuiremSpheres to inform the model (see section\xa03.12), and the evidence for TheraSphere was less certain than the evidence for SIR-Spheres (see section\xa03.15). The committee noted that there was not enough evidence to establish whether the 3\xa0SIRTs had different effectiveness (see section\xa03.22 and section\xa03.29). The committee considered whether it was appropriate to assume the 3\xa0SIRTs were equally effective. It noted that the technologies used different beads to give treatment, and QuiremSpheres used a different isotope to the other SIRTs. It agreed that these differences might result in different effectiveness and adverse event profiles, to an unknown extent. In the absence of better evidence, the committee concluded that it would consider the cost effectiveness of the 3\xa0SIRTs by assuming they were equally effective, generalising the SIR‑Spheres data to the other 2\xa0SIRTs. It also concluded that by doing so, the cost-effectiveness estimates for QuiremSpheres would be more uncertain than those for TheraSphere and substantially more uncertain than for SIR-Spheres. It took this uncertainty into consideration in its decision making.\n\n## Sorafenib is the only relevant comparator for assessing the cost effectiveness of SIRTs in people for whom CTT is inappropriate\n\nIn line with the NICE scope, the AG initially included sorafenib and lenvatinib as comparators in the model. The AG used the hazard ratio from the mixed treatment comparison to include lenvatinib in the model and assumed proportional hazards over time. Therefore, it chose the Weibull function to model overall survival and progression‑free survival, even though the Weibull was not the best-fitting function. After consultation on the AG report, sorafenib was considered to be the only relevant comparator (see section\xa03.10). The generalised gamma was used to fit overall survival and progression‑free survival in the revised base case, because the proportional hazards assumption was no longer needed. The committee also recalled that the trial evidence could be generalised to people with Child–Pugh\xa0A liver impairment, who can have sorafenib in current practice, but not to people with Child–Pugh\xa0B liver impairment, who have best supportive care (see section\xa03.26). It concluded that sorafenib was the only appropriate comparator, and that the best-fitting function (generalised gamma) should be used to estimate overall survival and progression-free survival.\n\n## There are not enough robust data for the ALBI grade\xa01 and low tumour burden subgroup for decision making\n\nThe AG presented scenario analyses that restricted the population to people with ALBI grade\xa01 and low tumour burden. The clinical experts explained that ALBI grade could be a more objective measure than Child–Pugh score for liver impairment and that people with ALBI grade\xa01 have good liver function. However, this measure is not routinely used in the NHS, and the Child–Pugh score is expected to be the standard assessment method for liver impairment for the foreseeable future (see section\xa03.5). The committee was aware that clinical outcomes for the ALBI\xa0grade\xa01, low tumour burden subgroup came from a post-hoc analysis of the SARAH trial (n=85, section\xa03.18). It agreed that this analysis was not robust because the subgroup was not prespecified and the numbers were small. It was not presented with additional evidence after consultation. It concluded that it had not seen sufficiently robust data in this subgroup, but agreed that more evidence may be useful for decision making.\n\n## Usually, only 1\xa0lobe is treated at a time in people with bilobar disease\n\nHCC can be unilobar (tumour in 1\xa0lobe of the liver) or bilobar (tumours in both lobes of the liver). The clinical experts explained that people with bilobar disease have a higher risk of liver impairment, and therefore usually only 1\xa0lobe is treated at a time. The same lobe might be treated twice to reduce the size of the tumour. The committee concluded that it is not appropriate for a model to assume that both lobes are treated simultaneously in bilobar disease.\n\n## Downstaging of HCC might benefit some people with advanced HCC, but the proportion of people and subsequent outcomes are uncertain\n\nThe clinical experts explained that downstaging might be a treatment aim for some people who have SIRT, because they then might be able to have a liver transplant, surgical resection or tumour ablation. For some people downstaging might have a large impact on quality of life. This is because of the potential for curative treatment. Both clinical experience and limited trial evidence (for example SARAH) show that downstaging is rare in advanced HCC. The committee understood that people whose tumour downstages have different subsequent treatments, and few might have a liver transplant, surgical resection or tumour ablation. It was unclear whether people who have a liver transplant after downstaging of their tumour have similar outcomes to those who have a liver transplant without the need for downstaging. The committee reconsidered downstaging after consultation and during its third meeting. It concluded that downstaging may be an option for a small proportion of people with advanced HCC. However, the proportion of people who have tumours that downstage, and the subsequent outcomes, are uncertain. Therefore, downstaging was not included in the base-case model.\n\n## SIRTs may have fewer and less severe adverse events than sorafenib and these have not been captured in the economic modelling\n\nBoth the SARAH and SIRveNIB trials collected data on health-related quality of life. SARAH used the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core\xa030 (EORTC‑QLQ‑C30) questionnaire. The company mapped this onto the EQ‑5D scale using the Longworth et al. algorithm. The AG used these estimates in its model. The committee noted that utility values were similar between SIRTs and sorafenib for the following disease states: progression-free survival, progressive disease and after transplant. There were only small differences in utilities between progression-free survival and progressive disease. The clinical experts explained that people who had sorafenib for a long time may have a long-lasting negative effect on their quality of life. SIRTs are given in 1\xa0procedure, meaning there is a shorter duration of effect on health-related quality of life. The committee was concerned that the potential important differences in long-term quality of life might not be captured in clinical trial results because quality-of-life data are collected at fixed time points (3, 6, 9\xa0and 12\xa0months after randomisation). It noted that in SARAH, EORTC‑QLQ‑C30 values in the SIR-Spheres arm were relatively constant over the 12\xa0months from randomisation. Values for people in the sorafenib arm worsened for 6\xa0months then stayed relatively stable . This decline was not seen in the mapped EQ-5D values. The committee acknowledged that this might be because the EORTC‑QLQ‑C30 scale is more sensitive than the EQ-5D to adverse events associated with sorafenib (fatigue, diarrhoea and skin reactions). The committee was also aware that the mapping algorithm did not include data from people with HCC, meaning that differences important to people with HCC might not accurately translate across to the EQ-5D. The committee recalled its conclusion that SIRTs have fewer and less severe adverse events than sorafenib (see section\xa03.27). It concluded that some aspects of health-related quality of life might not be captured in the utility values.\n\n## Adverse event disutility values should be included in the model to capture differences in quality of life between SIRTs and sorafenib\n\nThe clinical experts advised that the side-effect profiles of SIRTs and sorafenib were different and should result in improved health-related quality of life for SIRTs compared with sorafenib. The committee understood that some people stop taking sorafenib because of intolerable adverse events. After consultation and additional analysis by the AG, the committee considered analyses applying disutility values for adverse events of grade\xa03 and above, and for adverse events of any grade. Various assumptions were included about the effect of less severe (grade\xa01 and\xa02) events. SARAH provided data on adverse event rates and pooled event duration (see section\xa03.27). The disutility values were informed by previous NICE technology appraisals. The committee understood that these values came from primary studies of variable quality, including vignette studies which are less robust. In these additional analyses, the smallest incremental quality-adjusted life year (QALY) gain from adverse events for SIRTs compared with sorafenib resulted in no additional total QALYs, when assuming that health-state utility values adequately captured all adverse effects. The biggest gain was 0.120\xa0QALYs, when applying event-specific disutility values for events regardless of their severity (grades\xa01 and above). The committee agreed that there is some QALY gain with SIRTs resulting from the fewer and less severe adverse events. However, it also agreed that it was inappropriate to assume grade\xa01 and\xa02 events have the same effect on quality of life as grade\xa03\xa0and 4\xa0events. It also noted that typically, only grade\xa03\xa0or 4\xa0events are included in cost-effectiveness analyses. Therefore, it agreed that a gain of 0.120\xa0QALYs would be too optimistic. It agreed that an intermediate adverse event QALY gain would be appropriate. The committee concluded that an adverse event-related QALY gain of 0.047 for SIRTs compared with sorafenib might be plausible and should be included in the base-case analysis. It also concluded that there was high uncertainty associated with this estimate and that the uncertainty was highest for QuiremSpheres because of its limited data.\n\n# Cost-effectiveness results\n\n## SIR-Spheres and TheraSphere are a cost-effective use of NHS resources for HCC\n\nThe committee agreed that its preferred approach to modelling included:\n\nidentical procedure-related administration costs for all SIRTs\n\nindividual participant data from SARAH for duration of sorafenib\n\nfor regorafenib assuming the same mean time on treatment as for sorafenib and no savings from dose interruptions and adjustments an additional SIRT QALY gain of 0.047 to account for differences in adverse events compared with sorafenib.The economic analysis included the committee's preferred assumptions and confidential patient access schemes for QuiremSpheres, SIR‑Spheres, TheraSphere, regorafenib and sorafenib. It assumed that the 3\xa0SIRTs had the same effectiveness. It showed that all SIRTs were less effective than sorafenib despite the additional SIRT QALY gains to account for differences in adverse events, giving 0.029 fewer QALYs overall. QuiremSpheres was more costly than sorafenib. SIR‑Spheres and TheraSphere were less costly than sorafenib and provided fewer QALYs. Because of confidential discounts for interventions, comparator and follow-on therapies, exact cost-effectiveness results cannot be reported here. The AG also presented extensive scenario analyses during the first committee meeting and after consultation. This included:\n\nalternative functions to model overall survival and progression‑free\xa0survival (see section\xa03.34)\n\nalternative costs and utility values\n\nALBI grade\xa01 and low tumour burden subpopulation (see section\xa03.35)\n\nretrospective studies with high risk of bias (see section\xa03.15)\n\ndownstaging (see section\xa03.37).Alternative functions, costs and utility values did not have a great effect on the incremental cost-effectiveness ratios (ICERs). The committee agreed that scenarios that restricted the population to people with ALBI grade\xa01 and low tumour burden were not taken into account because the ALBI\xa0score is not routinely used in NHS practice in England (see section\xa03.35). It also agreed that retrospective studies should not be included because of high risk of bias and uncertainty of the data (see section\xa03.15). Additionally, downstaging should not be included in the committee's preferred base case because the proportion of people who have tumours that downstage, and subsequent outcomes, are uncertain (see section\xa03.37). The committee concluded that in the probabilistic base-case analysis, QuiremSpheres was less effective and more costly than sorafenib. This meant sorafenib dominated QuiremSpheres (that is, it was more effective and less costly). SIR-Spheres and TheraSphere were less effective and less costly than sorafenib. The cost savings were sufficient to offset the QALY loss at a £30,000 saved per QALY lost level. The committee also recalled that the model assumed that SIRTs were equally effective, and that this was a highly uncertain assumption for QuiremSpheres because of its very limited evidence base compared with SIR-Spheres and TheraSphere (see section\xa03.33). The committee also recalled that personalised dosimetry could improve the effectiveness of SIRTs, which may increase their QALYs (see section\xa03.24). It considered that this would not meaningfully affect the cost-effectiveness estimate for QuiremSpheres or offset the uncertainty in its evidence base. Because of its higher costs compared with sorafenib and its limited clinical evidence, the committee considered QuiremSpheres not to be a cost‑effective use of NHS resources for treating HCC. Because of the cost savings per QALYs lost, the committee considered that both SIR-Spheres and TheraSphere are cost-effective use of NHS resources.\n\n# End of life\n\n## The end of life criteria are not met\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.\n\nWhen transplant or CTT is appropriate, people have a life expectancy of more than 24\xa0months. This means that the life-expectancy criterion (that is, the treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months) was not met for these subgroups.\n\nWhen CTT is inappropriate, in advanced disease, people have a poor prognosis with a life expectancy of less than 24\xa0months. Therefore, the short life-expectancy criterion was met for this subgroup.\n\nIn all plausible scenarios, there was no increase in the modelled undiscounted life expectancy with SIRTs compared with sorafenib. The committee concluded that the life-extending criterion (that is, there is sufficient evidence that the treatment could extend life, normally by a mean value of at least an additional 3\xa0months, compared with current NHS treatment) was not met.Because both parts of the criteria were not met, the committee concluded that the end‑of‑life criteria were not met.\n\n# Innovation\n\n## No evidence was identified showing additional benefits of SIRT, above those captured in the cost-effectiveness analysis\n\nThe companies considered SIRTs to be innovative because they offer a more personalised treatment option. The patient experts stated that SIRTs would be a substantial change in treating HCC because they could offer a chance for subsequent curative treatment for people who would not otherwise have this option. The committee concluded it had not seen evidence of any additional benefits that were not captured in the measurement of QALYs in its preferred model.\n\n# Conclusion\n\n## SIR-Spheres and TheraSphere, but not QuiremSpheres, are recommended for treating HCC\n\nIn the committee's preferred analysis, SIRTs were less effective than sorafenib with an incremental quality-adjusted life years loss of 0.029\xa0QALYs. In clinical trials, SIR‑Spheres did not improve survival compared with sorafenib. There was very limited clinical evidence to compare the effectiveness of QuiremSpheres and TheraSphere with sorafenib and for all the SIRT technologies. The committee also considered that there were limited data for QuiremSpheres and TheraSphere, and the effectiveness estimates and resulting ICERs were more uncertain than those of SIR‑Spheres. However, the committee considered that the adverse event profiles of SIRTs and sorafenib are different and people with HCC would welcome new treatment options (see section\xa03.1). Taking this into account, the committee concluded that QuiremSpheres was less effective and more costly than sorafenib and was not considered a cost‑effective use of NHS resources. QuiremSpheres was not recommended for HCC. SIR‑Spheres and TheraSphere were less costly than sorafenib and the estimated cost savings outweigh the loss of QALYs after taking into account the uncertainty associated with the clinical effectiveness. Therefore, the committee considered SIR‑Spheres and TheraSphere to be a cost‑effective use of NHS resources, and recommended both as options for treating advanced HCC for people with Child–Pugh grade\xa0A liver impairment for whom CTT is inappropriate."}
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https://www.nice.org.uk/guidance/ta688
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Evidence-based recommendations on selective internal radiation therapies SIR-Spheres (Sirtex), TheraSphere (BTG) and QuiremSphere (Quirem Medical) for treating hepatocellular carcinoma in adults.
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4d9ad201c4a058400f1d8a1dbfbea51e4f6a3ebe
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nice
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Anakinra for treating Still's disease
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Anakinra for treating Still's disease
Evidence-based recommendations on anakinra (Kineret) for treating adult‑onset Still’s disease and systemic juvenile idiopathic arthritis in people 8 months and older.
# Recommendations
Anakinra is recommended as an option for treating Still's disease with moderate to high disease activity, or continued disease activity after non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids. It is only recommended for:
adult-onset Still's disease that has responded inadequately to 2 or more conventional disease‑modifying antirheumatic drugs (DMARDs)
systemic juvenile idiopathic arthritis in people 8 months and older with a body weight of 10 kg or more that has not responded to at least 1 conventional DMARD.
This recommendation is not intended to affect treatment with anakinra that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. In the case of children and young people, this decision should be made jointly by the clinician, the child or young person, and their parents or carers.
Why the committee made these recommendations
Still's disease is a rare systemic autoinflammatory condition. People who are 16 years and under at diagnosis are considered to have systemic juvenile idiopathic arthritis, even in adulthood. People who are over 16 years at diagnosis are considered to have adult-onset Still's disease. Treatment options for Still's disease include NSAIDs, corticosteroids, non-biological DMARDs and biological DMARDs such as tocilizumab and anakinra.
Clinical evidence about the efficacy of anakinra after treatment with NSAIDs and corticosteroids is highly uncertain. But it is reasonable to assume that it is as effective as tocilizumab. Cost-effectiveness estimates for anakinra are also uncertain because of issues with the company's economic model and the lack of robust clinical evidence to support it. However, a comparison of the costs of anakinra and tocilizumab shows that they have similar weekly costs for:
adult-onset Still's disease that has responded inadequately to 2 or more conventional DMARDs
systemic juvenile idiopathic arthritis that has not responded to at least 1 conventional DMARD.
Anakinra is therefore recommended for use in the NHS in these circumstances.# Information about anakinra
# Marketing authorisation indication
Anakinra (Kineret, Sobi) is 'indicated in adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg or above for the treatment of Still's disease, including Systemic Juvenile Idiopathic Arthritis (sJIA) and Adult-Onset Still's Disease (AOSD), with active systemic features of moderate to high disease activity, or in patients with continued disease activity after treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids'. It can be given alone or with other anti-inflammatory drugs and disease‑modifying antirheumatic drugs.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The cost for 7 prefilled injections (each containing 100 mg anakinra per 0.67 ml) is £183.61 (excluding VAT; BNF online, accessed December 2020). The average cost of 1 year of treatment is £9,580.00.# Committee discussion
The appraisal committee considered evidence submitted by Sobi, a review of this submission by the evidence review group (ERG), NICE's technical report and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage. It agreed that canakinumab is not routinely used in the NHS for treating either systemic juvenile idiopathic arthritis (JIA) or adult-onset Still's disease (AOSD), so is not a relevant comparator for anakinra.
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 25), and took these into account in its decision making. It discussed issues 1, 3, 4, 5, 6, and 7, which were outstanding after the technical engagement stage.
# Clinical need
## Still's disease substantially affects health-related quality of life
The patient and clinical experts explained that there is a considerable unmet need for people with systemic JIA and AOSD. The patient experts described that Still's disease is a highly debilitating condition affecting many aspects of life, including normal activities of everyday living, education and work opportunities, and personal relationships. A patient expert, who was diagnosed with Still's disease before biological disease‑modifying antirheumatic drugs (DMARDs) were available, described their experience of having multiple joint replacement surgeries from an early age. The committee heard that treatment with corticosteroids and conventional DMARDs such as methotrexate is associated with adverse reactions. These can affect quality of life, including important life decisions such as whether to have children (methotrexate is contraindicated in pregnancy). The committee concluded that Still's disease is a debilitating condition that substantially affects both physical and psychological aspects of health-related quality of life.
# Clinical management
## Clinicians and patients would prefer earlier access to biological DMARDs such as anakinra
The clinical experts explained that the NHS England clinical commissioning policy on anakinra and tocilizumab for AOSD and its policy statement on biologic therapies for the treatment of juvenile idiopathic arthritis do not reflect how clinicians would like to treat systemic JIA and AOSD. They provide funding for anakinra for people with:
AOSD when the condition has not responded to 2 or more conventional DMARDs
systemic JIA when the condition has not responded to tocilizumab, in line with NICE's technology appraisal guidance on tocilizumab.This guidance recommends using tocilizumab to treat systemic JIA that has responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids and methotrexate. The clinical experts explained that greater flexibility to use biological DMARDs such as anakinra earlier in the treatment pathway would enable better outcomes for people with the condition. This is because it would result in quicker disease control that would better prevent progressive joint and systemic damage. One clinical expert suggested that the need to use conventional DMARDs before biological DMARDs can cause substantial delays in controlling Still's disease, and can lead to prolonged corticosteroid use. The company highlighted that the marketing authorisation allows anakinra to be used earlier in the pathway than the NHS England commissioning policies do. The committee heard that, by following the NHS England commissioning policies, people can wait up to 6 months before their condition is controlled because of the requirement to try multiple treatments before anakinra. The patient experts explained that using anakinra earlier in the pathway could dramatically improve quality of life through improved disease control and better long-term outcomes (such as avoiding or delaying joint damage). The clinical experts further explained that there are different phenotypes in systemic JIA and AOSD. Some people present with mainly systemic disease, some with evidence of macrophage activation syndrome and some with a strong arthritic component. This complexity means that some symptoms might respond more to 1 specific biological DMARD than another. The committee concluded that clinicians would welcome the option to choose when and how to use biological DMARDs with NSAIDs, corticosteroids and conventional DMARDs according to disease phenotype. The aim would be to achieve more rapid disease control and improve outcomes.
## Anakinra's use for macrophage activation syndrome is not within the remit of this appraisal
Using anakinra for macrophage activation syndrome falls outside of its marketing authorisation. The committee noted that the NHS England clinical commissioning policy for systemic JIA provides funding for anakinra for macrophage activation syndrome. The committee understood that the relevant part of the commissioning policy for macrophage activation syndrome in systemic JIA would continue to stand regardless of the outcome of this appraisal. NICE can only appraise a technology within its marketing authorisation, so the committee concluded that using anakinra in macrophage activation syndrome is not within the remit of this appraisal.
# Clinical evidence
## The clinical evidence for anakinra after conventional DMARDs is limited
The company's clinical-effectiveness evidence included:
for systemic JIA: 2 randomised controlled trials comparing anakinra with placebo and 1 non‑randomised registry study comparing it with tocilizumab
for AOSD: 1 open-label randomised controlled trial comparing anakinra with conventional DMARDs.The clinical trials were either open label or had a short, blinded phase followed by short open-label extensions. The placebo-controlled trials had very small patient numbers, which the committee heard was because of the rarity of Still's disease. The ERG noted that the results from these trials showed a good response in disease activity measures with anakinra. However, they were highly uncertain, mainly because of the small patient numbers. The trial limitations were acknowledged by the study authors and the company. The clinical experts explained that, because of the rarity of Still's disease, the low quantity and quality of the data are to be expected, and are unlikely to improve. The committee concluded that the evidence to support the clinical efficacy of anakinra after conventional DMARDs was limited because of the small patient numbers in the trials.
## It is reasonable to assume that anakinra and tocilizumab have similar efficacy
The company submission stated that there was no direct trial evidence comparing anakinra with tocilizumab, but that a network meta-analysis (NMA) of clinical trials for systemic JIA included an indirect comparison between the 2 drugs. It explained that this suggested the treatments are similarly effective, and associated with the same adverse event profiles and stopping rates in the third-line setting (that is, after conventional DMARDs). The company did not include the results of the NMA in its economic model. This was because it considered that methodological differences between the included trials meant the results were not robust. The clinical experts explained that anakinra and tocilizumab are both biological DMARDs that target cytokines involved in the inflammation pathway. However, they noted that the drugs have slightly different mechanisms of action, and that anakinra targets interleukin‑1 while tocilizumab targets interleukin‑6. The clinical experts agreed that this difference does have implications for the way in which the drugs are used in clinical practice. This is because of the different phenotypes in systemic JIA and AOSD (see section 3.2). Anakinra will often be preferred for presentations in which systemic features prevail, and tocilizumab will often be preferred when there are mainly arthritic joint features. The clinical experts added that, in many cases, it may be necessary to swap back and forth between these drugs to achieve disease control. The committee noted that the clinical experts considered anakinra and tocilizumab to be broadly equivalent in terms of efficacy and adverse reactions. The ERG also considered that it was reasonable to assume similar efficacy between the drugs based on the available evidence. The committee concluded that it was appropriate to consider that anakinra and tocilizumab are clinically equivalent.
## There is no robust evidence to support using anakinra earlier in the treatment pathway
The clinical trials in the company submission (see section 3.4) only included people who had had treatment with NSAIDs, corticosteroids and conventional DMARDs. The trials were therefore aligned to current NHS practice (as set out in the NHS England commissioning policies). They were not aligned to the full breadth of the marketing authorisation, which was the company's preferred position for anakinra (that is, before conventional DMARDs). The company submitted supplementary evidence at technical engagement in support of using anakinra before conventional DMARDs. The anaSTILLs randomised placebo-controlled trial of anakinra met its primary endpoint but was stopped because of issues with recruitment. The company described how the results of this study showed the benefit of administering anakinra before conventional DMARDs. The committee noted the trial only included 6 people on anakinra and 5 people on placebo. It was aware that the other non‑randomised studies submitted by the company support the emerging clinical view that interleukin‑1 plays a particularly important role in early Still's disease. It was also aware that treatment with anakinra earlier in the pathway may lead to improved outcomes (see section 3.2). This is particularly so for systemic features of the condition, and is referred to as the 'window of opportunity' hypothesis. The committee acknowledged the biological plausibility of the 'window of opportunity' hypothesis but concluded that there was no robust clinical evidence to support it.
# Economic model
## Treatment discontinuation rates in the company's model are not clinically plausible
In the company's model, changing from 1 treatment to another in the pathway was set at a fixed probability per weekly cycle for disease not in remission. The committee heard that the same probabilities were also used in NICE's technology appraisal guidance on tocilizumab. The company presented several scenario analyses in which the rate was increased or decreased by 20% after 6 or 12 months, either for all treatments or just for biological DMARDs. The ERG explained that the fixed probability for changing from 1 treatment to another meant it was possible for a proportion of patients to remain on the same treatment for the whole time horizon of the model, without their disease going into remission. Based on its clinical expert advice, the ERG considered this to be clinically implausible. For example, it would mean that, of people having their first biological DMARD whose disease was not yet in remission, over 55% would still be on this treatment after 1 year and about 33% would still be on it after 2 years. The clinical experts explained that it is possible that someone might remain on a biological treatment for an extended period without their condition going into remission. This would be because of other treatment benefits, such as improved symptom control and quality of life. The company accepted that a limitation of its model was that it did not account for the full range of clinically plausible health states experienced by people with systemic JIA and AOSD. The ERG noted that, other than remission, the benefits of remaining on a treatment were not captured in the model. In response to consultation, the company clarified that continued treatment for symptom control is associated with higher utility through avoiding 'unresolved' disease (either indefinitely or for a certain period of time). The committee concluded that the way in which treatment discontinuation rates were modelled was not clinically plausible.
## Disease remission rates in the company's model are not clinically plausible
The company model assumed that the probability of reaching disease remission with conventional DMARDs for people with chronic disease was 0%. It also presented a scenario analysis in which the probability was the same for people with chronic disease as monocyclic disease: a weekly remission probability of 12.56%. The ERG explained that, based on its own clinical expert advice, it is clinically implausible that nobody with chronic disease would reach remission with conventional DMARDs. The ERG explained that the remission rates for people with monocyclic disease had been taken from the Nordström et al. (2012) study. It highlighted that, in 20% of people in the conventional DMARDs arm of this study, their condition was in remission at 12 months. This suggests that conventional DMARDS are effective for some people. The clinical experts agreed that this was the case, and that there is good disease control with conventional DMARDs in some people, who then do not need biological DMARDs. However, they differed in their experience of the occurrence of remission in people with chronic disease having conventional DMARDs. One clinical expert estimated that remission would occur in less than 5% of people, assuming no prolonged corticosteroid use. Another considered that it would occur in 25% to 30% of people. The committee agreed that the second estimate seemed more plausible. It concluded that the remission rates for conventional DMARDs used in the company's model were unreliable.
## The ERG's assumptions on the way tocilizumab is administered are appropriate
Tocilizumab can be administered intravenously or subcutaneously. The company model assumed that 50% of people would have it by intravenous injection, and 50% by subcutaneous injection. The ERG's clinical advisers considered this to be unlikely and that, for systemic JIA, about 20% of people would have it subcutaneously and about 80% intravenously. For AOSD, clinical advice to the ERG was that everyone having tocilizumab would have it subcutaneously. The clinical experts explained that there are no available data on the proportions, but that the ERG's assumptions were broadly correct. The NHS England representative noted that subcutaneous injections can be administered either at home or in a community setting, rather than in hospital. This can be preferable in certain situations, and patient choice is important. People are increasingly choosing to have tocilizumab by subcutaneous rather than intravenous injection. The committee concluded that the ERG's assumptions on the way tocilizumab is administered were appropriate.
## The company's economic model is unsuitable for decision making
The ERG explained that, as well as the issues about the highly uncertain evidence base that informed it, there were structural flaws in the model leading to implausible situations. These included:
Treatment switching in the model was set at a fixed probability per weekly cycle for people whose disease was not in remission (see section 3.7). This made it possible for people to remain on a treatment that led to remission for the whole of the model time horizon.
The model allowed people to start a treatment, for their condition to go into remission and relapse, and then for them to return to the same treatment before their condition went into remission again. This was a perpetual loop for the whole model time horizon. In addition, the patient pathway loops in the model meant that, over time, people in specific health states became increasingly heterogeneous. The extent to which health state transition probabilities reflected the transition probabilities for the health state population decreased over time.
It was assumed that 50% of people prescribed a biological DMARD would remain on that treatment during remission. However, when these people's condition relapsed, it was assumed that they would return to treatment with the same biological DMARD that they were taking before relapse. It was assumed that people would have the same probability of remission as they had before the relapse.The ERG explained that, based on clinical advice, it considered these situations to be clinically implausible. The committee also questioned the validity of the model results. These showed a cost saving of about £25,000 over the model time horizon when anakinra was used about 6 months earlier in the treatment pathway compared with after conventional DMARDs. This cost saving could not be fully explained by the clinical experts. The committee acknowledged the structural flaws in the model and the lack of validity in the model results. It concluded that the company's economic model was not suitable for decision making.
# Cost-minimisation analysis
## A cost-minimisation analysis is sufficient for decision making
Because of its concerns over the lack of clinical evidence and structural flaws in the model, the ERG provided a cost-minimisation analysis. It based this analysis on the assumption of equal efficacy between anakinra and tocilizumab in treating systemic JIA and AOSD. The committee considered that this was reasonable based on the clinical experts' opinions, and because there was no evidence of a difference in treatment effect (see section 3.5). The committee concluded that a cost-minimisation analysis was sufficient for decision making.
# Cost-minimisation results
## Anakinra has a similar weekly cost compared with tocilizumab
The ERG's cost-minimisation analysis considered the third-line treatment setting for anakinra (that is after conventional DMARDs) in both systemic JIA and AOSD. The analysis assumed that anakinra and tocilizumab had:
equal efficacy
the same side effect profiles
the same treatment discontinuation rates.The analysis included the costs of the different methods of administration (see section 3.9) and monitoring costs. Tocilizumab has a confidential commercial arrangement, which was included in the analyses, but means that the exact results cannot be reported here. The committee concluded that the results suggest that anakinra has a similar weekly cost to tocilizumab for both systemic JIA and AOSD.
# Other factors
## There are no equality or social value judgement issues
The committee noted that no equality or social value judgement issues were identified.
# Conclusion
## Anakinra is recommended for routine commissioning
The committee acknowledged the need for biological treatment options for people with Still's disease. It considered that the company's economic model was not suitable for decision making. However, it concluded that the cost-minimisation analysis suggested that anakinra has similar weekly costs compared with tocilizumab. Therefore, anakinra is recommended as an option for:
systemic JIA when the disease has not responded to at least 1 conventional DMARD, and
AOSD when the disease has responded inadequately to 2 or more conventional DMARDs.
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{'Recommendations': "Anakinra is recommended as an option for treating Still's disease with moderate to high disease activity, or continued disease activity after non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids. It is only recommended for:\n\nadult-onset Still's disease that has responded inadequately to 2\xa0or more conventional disease‑modifying antirheumatic drugs (DMARDs)\n\nsystemic juvenile idiopathic arthritis in people 8\xa0months and older with a body weight of 10\xa0kg or more that has not responded to at least 1\xa0conventional DMARD.\n\nThis recommendation is not intended to affect treatment with anakinra that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. In the case of children and young people, this decision should be made jointly by the clinician, the child or young person, and their parents or carers.\n\nWhy the committee made these recommendations\n\nStill's disease is a rare systemic autoinflammatory condition. People who are 16\xa0years and under at diagnosis are considered to have systemic juvenile idiopathic arthritis, even in adulthood. People who are over\xa016 years at diagnosis are considered to have adult-onset Still's disease. Treatment options for Still's disease include NSAIDs, corticosteroids, non-biological DMARDs and biological DMARDs such as tocilizumab and anakinra.\n\nClinical evidence about the efficacy of anakinra after treatment with NSAIDs and corticosteroids is highly uncertain. But it is reasonable to assume that it is as effective as tocilizumab. Cost-effectiveness estimates for anakinra are also uncertain because of issues with the company's economic model and the lack of robust clinical evidence to support it. However, a comparison of the costs of anakinra and tocilizumab shows that they have similar weekly costs for:\n\nadult-onset Still's disease that has responded inadequately to 2\xa0or more conventional DMARDs\n\nsystemic juvenile idiopathic arthritis that has not responded to at least 1\xa0conventional DMARD.\n\nAnakinra is therefore recommended for use in the NHS in these circumstances.", 'Information about anakinra': "# Marketing authorisation indication\n\nAnakinra (Kineret, Sobi) is 'indicated in adults, adolescents, children and infants aged 8\xa0months and older with a body weight of 10\xa0kg or above for the treatment of Still's disease, including Systemic Juvenile Idiopathic Arthritis (sJIA) and Adult-Onset Still's Disease (AOSD), with active systemic features of moderate to high disease activity, or in patients with continued disease activity after treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids'. It can be given alone or with other anti-inflammatory drugs and disease‑modifying antirheumatic drugs.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe cost for 7\xa0prefilled injections (each containing 100\xa0mg anakinra per 0.67\xa0ml) is £183.61 (excluding VAT; BNF online, accessed December 2020). The average cost of 1\xa0year of treatment is £9,580.00.", 'Committee discussion': "The appraisal committee considered evidence submitted by Sobi, a review of this submission by the evidence review group (ERG), NICE's technical report and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage. It agreed that canakinumab is not routinely used in the NHS for treating either systemic juvenile idiopathic arthritis (JIA) or adult-onset Still's disease (AOSD), so is not a relevant comparator for anakinra.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa025), and took these into account in its decision making. It discussed issues\xa01, 3,\xa04,\xa05, 6, and\xa07, which were outstanding after the technical engagement stage.\n\n# Clinical need\n\n## Still's disease substantially affects health-related quality of life\n\nThe patient and clinical experts explained that there is a considerable unmet need for people with systemic JIA and AOSD. The patient experts described that Still's disease is a highly debilitating condition affecting many aspects of life, including normal activities of everyday living, education and work opportunities, and personal relationships. A patient expert, who was diagnosed with Still's disease before biological disease‑modifying antirheumatic drugs (DMARDs) were available, described their experience of having multiple joint replacement surgeries from an early age. The committee heard that treatment with corticosteroids and conventional DMARDs such as methotrexate is associated with adverse reactions. These can affect quality of life, including important life decisions such as whether to have children (methotrexate is contraindicated in pregnancy). The committee concluded that Still's disease is a debilitating condition that substantially affects both physical and psychological aspects of health-related quality of life.\n\n# Clinical management\n\n## Clinicians and patients would prefer earlier access to biological DMARDs such as anakinra\n\nThe clinical experts explained that the NHS England clinical commissioning policy on anakinra and tocilizumab for AOSD and its policy statement on biologic therapies for the treatment of juvenile idiopathic arthritis do not reflect how clinicians would like to treat systemic JIA and AOSD. They provide funding for anakinra for people with:\n\nAOSD when the condition has not responded to 2\xa0or more conventional DMARDs\n\nsystemic JIA when the condition has not responded to tocilizumab, in line with NICE's technology appraisal guidance on tocilizumab.This guidance recommends using tocilizumab to treat systemic JIA that has responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids and methotrexate. The clinical experts explained that greater flexibility to use biological DMARDs such as anakinra earlier in the treatment pathway would enable better outcomes for people with the condition. This is because it would result in quicker disease control that would better prevent progressive joint and systemic damage. One clinical expert suggested that the need to use conventional DMARDs before biological DMARDs can cause substantial delays in controlling Still's disease, and can lead to prolonged corticosteroid use. The company highlighted that the marketing authorisation allows anakinra to be used earlier in the pathway than the NHS England commissioning policies do. The committee heard that, by following the NHS England commissioning policies, people can wait up to 6\xa0months before their condition is controlled because of the requirement to try multiple treatments before anakinra. The patient experts explained that using anakinra earlier in the pathway could dramatically improve quality of life through improved disease control and better long-term outcomes (such as avoiding or delaying joint damage). The clinical experts further explained that there are different phenotypes in systemic JIA and AOSD. Some people present with mainly systemic disease, some with evidence of macrophage activation syndrome and some with a strong arthritic component. This complexity means that some symptoms might respond more to 1\xa0specific biological DMARD than another. The committee concluded that clinicians would welcome the option to choose when and how to use biological DMARDs with NSAIDs, corticosteroids and conventional DMARDs according to disease phenotype. The aim would be to achieve more rapid disease control and improve outcomes.\n\n## Anakinra's use for macrophage activation syndrome is not within the remit of this appraisal\n\nUsing anakinra for macrophage activation syndrome falls outside of its marketing authorisation. The committee noted that the NHS England clinical commissioning policy for systemic JIA provides funding for anakinra for macrophage activation syndrome. The committee understood that the relevant part of the commissioning policy for macrophage activation syndrome in systemic JIA would continue to stand regardless of the outcome of this appraisal. NICE can only appraise a technology within its marketing authorisation, so the committee concluded that using anakinra in macrophage activation syndrome is not within the remit of this appraisal.\n\n# Clinical evidence\n\n## The clinical evidence for anakinra after conventional DMARDs is limited\n\nThe company's clinical-effectiveness evidence included:\n\nfor systemic JIA: 2\xa0randomised controlled trials comparing anakinra with placebo and 1\xa0non‑randomised registry study comparing it with tocilizumab\n\nfor AOSD: 1\xa0open-label randomised controlled trial comparing anakinra with conventional DMARDs.The clinical trials were either open label or had a short, blinded phase followed by short open-label extensions. The placebo-controlled trials had very small patient numbers, which the committee heard was because of the rarity of Still's disease. The ERG noted that the results from these trials showed a good response in disease activity measures with anakinra. However, they were highly uncertain, mainly because of the small patient numbers. The trial limitations were acknowledged by the study authors and the company. The clinical experts explained that, because of the rarity of Still's disease, the low quantity and quality of the data are to be expected, and are unlikely to improve. The committee concluded that the evidence to support the clinical efficacy of anakinra after conventional DMARDs was limited because of the small patient numbers in the trials.\n\n## It is reasonable to assume that anakinra and tocilizumab have similar efficacy\n\nThe company submission stated that there was no direct trial evidence comparing anakinra with tocilizumab, but that a network meta-analysis (NMA) of clinical trials for systemic JIA included an indirect comparison between the 2\xa0drugs. It explained that this suggested the treatments are similarly effective, and associated with the same adverse event profiles and stopping rates in the third-line setting (that is, after conventional DMARDs). The company did not include the results of the NMA in its economic model. This was because it considered that methodological differences between the included trials meant the results were not robust. The clinical experts explained that anakinra and tocilizumab are both biological DMARDs that target cytokines involved in the inflammation pathway. However, they noted that the drugs have slightly different mechanisms of action, and that anakinra targets interleukin‑1 while tocilizumab targets interleukin‑6. The clinical experts agreed that this difference does have implications for the way in which the drugs are used in clinical practice. This is because of the different phenotypes in systemic JIA and AOSD (see section\xa03.2). Anakinra will often be preferred for presentations in which systemic features prevail, and tocilizumab will often be preferred when there are mainly arthritic joint features. The clinical experts added that, in many cases, it may be necessary to swap back and forth between these drugs to achieve disease control. The committee noted that the clinical experts considered anakinra and tocilizumab to be broadly equivalent in terms of efficacy and adverse reactions. The ERG also considered that it was reasonable to assume similar efficacy between the drugs based on the available evidence. The committee concluded that it was appropriate to consider that anakinra and tocilizumab are clinically equivalent.\n\n## There is no robust evidence to support using anakinra earlier in the treatment pathway\n\nThe clinical trials in the company submission (see section\xa03.4) only included people who had had treatment with NSAIDs, corticosteroids and conventional DMARDs. The trials were therefore aligned to current NHS practice (as set out in the NHS England commissioning policies). They were not aligned to the full breadth of the marketing authorisation, which was the company's preferred position for anakinra (that is, before conventional DMARDs). The company submitted supplementary evidence at technical engagement in support of using anakinra before conventional DMARDs. The anaSTILLs randomised placebo-controlled trial of anakinra met its primary endpoint but was stopped because of issues with recruitment. The company described how the results of this study showed the benefit of administering anakinra before conventional DMARDs. The committee noted the trial only included 6\xa0people on anakinra and 5\xa0people on placebo. It was aware that the other non‑randomised studies submitted by the company support the emerging clinical view that interleukin‑1 plays a particularly important role in early Still's disease. It was also aware that treatment with anakinra earlier in the pathway may lead to improved outcomes (see section\xa03.2). This is particularly so for systemic features of the condition, and is referred to as the 'window of opportunity' hypothesis. The committee acknowledged the biological plausibility of the 'window of opportunity' hypothesis but concluded that there was no robust clinical evidence to support it.\n\n# Economic model\n\n## Treatment discontinuation rates in the company's model are not clinically plausible\n\nIn the company's model, changing from 1\xa0treatment to another in the pathway was set at a fixed probability per weekly cycle for disease not in remission. The committee heard that the same probabilities were also used in NICE's technology appraisal guidance on tocilizumab. The company presented several scenario analyses in which the rate was increased or decreased by 20% after 6\xa0or 12\xa0months, either for all treatments or just for biological DMARDs. The ERG explained that the fixed probability for changing from 1\xa0treatment to another meant it was possible for a proportion of patients to remain on the same treatment for the whole time horizon of the model, without their disease going into remission. Based on its clinical expert advice, the ERG considered this to be clinically implausible. For example, it would mean that, of people having their first biological DMARD whose disease was not yet in remission, over 55% would still be on this treatment after 1\xa0year and about 33% would still be on it after 2\xa0years. The clinical experts explained that it is possible that someone might remain on a biological treatment for an extended period without their condition going into remission. This would be because of other treatment benefits, such as improved symptom control and quality of life. The company accepted that a limitation of its model was that it did not account for the full range of clinically plausible health states experienced by people with systemic JIA and AOSD. The ERG noted that, other than remission, the benefits of remaining on a treatment were not captured in the model. In response to consultation, the company clarified that continued treatment for symptom control is associated with higher utility through avoiding 'unresolved' disease (either indefinitely or for a certain period of time). The committee concluded that the way in which treatment discontinuation rates were modelled was not clinically plausible.\n\n## Disease remission rates in the company's model are not clinically plausible\n\nThe company model assumed that the probability of reaching disease remission with conventional DMARDs for people with chronic disease was 0%. It also presented a scenario analysis in which the probability was the same for people with chronic disease as monocyclic disease: a weekly remission probability of 12.56%. The ERG explained that, based on its own clinical expert advice, it is clinically implausible that nobody with chronic disease would reach remission with conventional DMARDs. The ERG explained that the remission rates for people with monocyclic disease had been taken from the Nordström et al. (2012) study. It highlighted that, in 20% of people in the conventional DMARDs arm of this study, their condition was in remission at 12\xa0months. This suggests that conventional DMARDS are effective for some people. The clinical experts agreed that this was the case, and that there is good disease control with conventional DMARDs in some people, who then do not need biological DMARDs. However, they differed in their experience of the occurrence of remission in people with chronic disease having conventional DMARDs. One clinical expert estimated that remission would occur in less than 5% of people, assuming no prolonged corticosteroid use. Another considered that it would occur in 25% to 30% of people. The committee agreed that the second estimate seemed more plausible. It concluded that the remission rates for conventional DMARDs used in the company's model were unreliable.\n\n## The ERG's assumptions on the way tocilizumab is administered are appropriate\n\nTocilizumab can be administered intravenously or subcutaneously. The company model assumed that 50% of people would have it by intravenous injection, and 50% by subcutaneous injection. The ERG's clinical advisers considered this to be unlikely and that, for systemic JIA, about 20% of people would have it subcutaneously and about 80% intravenously. For AOSD, clinical advice to the ERG was that everyone having tocilizumab would have it subcutaneously. The clinical experts explained that there are no available data on the proportions, but that the ERG's assumptions were broadly correct. The NHS England representative noted that subcutaneous injections can be administered either at home or in a community setting, rather than in hospital. This can be preferable in certain situations, and patient choice is important. People are increasingly choosing to have tocilizumab by subcutaneous rather than intravenous injection. The committee concluded that the ERG's assumptions on the way tocilizumab is administered were appropriate.\n\n## The company's economic model is unsuitable for decision making\n\nThe ERG explained that, as well as the issues about the highly uncertain evidence base that informed it, there were structural flaws in the model leading to implausible situations. These included:\n\nTreatment switching in the model was set at a fixed probability per weekly cycle for people whose disease was not in remission (see section\xa03.7). This made it possible for people to remain on a treatment that led to remission for the whole of the model time horizon.\n\nThe model allowed people to start a treatment, for their condition to go into remission and relapse, and then for them to return to the same treatment before their condition went into remission again. This was a perpetual loop for the whole model time horizon. In addition, the patient pathway loops in the model meant that, over time, people in specific health states became increasingly heterogeneous. The extent to which health state transition probabilities reflected the transition probabilities for the health state population decreased over time.\n\nIt was assumed that 50% of people prescribed a biological DMARD would remain on that treatment during remission. However, when these people's condition relapsed, it was assumed that they would return to treatment with the same biological DMARD that they were taking before relapse. It was assumed that people would have the same probability of remission as they had before the relapse.The ERG explained that, based on clinical advice, it considered these situations to be clinically implausible. The committee also questioned the validity of the model results. These showed a cost saving of about £25,000 over the model time horizon when anakinra was used about 6\xa0months earlier in the treatment pathway compared with after conventional DMARDs. This cost saving could not be fully explained by the clinical experts. The committee acknowledged the structural flaws in the model and the lack of validity in the model results. It concluded that the company's economic model was not suitable for decision making.\n\n# Cost-minimisation analysis\n\n## A cost-minimisation analysis is sufficient for decision making\n\nBecause of its concerns over the lack of clinical evidence and structural flaws in the model, the ERG provided a cost-minimisation analysis. It based this analysis on the assumption of equal efficacy between anakinra and tocilizumab in treating systemic JIA and AOSD. The committee considered that this was reasonable based on the clinical experts' opinions, and because there was no evidence of a difference in treatment effect (see section\xa03.5). The committee concluded that a cost-minimisation analysis was sufficient for decision making.\n\n# Cost-minimisation results\n\n## Anakinra has a similar weekly cost compared with tocilizumab\n\nThe ERG's cost-minimisation analysis considered the third-line treatment setting for anakinra (that is after conventional DMARDs) in both systemic JIA and AOSD. The analysis assumed that anakinra and tocilizumab had:\n\nequal efficacy\n\nthe same side effect profiles\n\nthe same treatment discontinuation rates.The analysis included the costs of the different methods of administration (see section\xa03.9) and monitoring costs. Tocilizumab has a confidential commercial arrangement, which was included in the analyses, but means that the exact results cannot be reported here. The committee concluded that the results suggest that anakinra has a similar weekly cost to tocilizumab for both systemic JIA and AOSD.\n\n# Other factors\n\n## There are no equality or social value judgement issues\n\nThe committee noted that no equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Anakinra is recommended for routine commissioning\n\nThe committee acknowledged the need for biological treatment options for people with Still's disease. It considered that the company's economic model was not suitable for decision making. However, it concluded that the cost-minimisation analysis suggested that anakinra has similar weekly costs compared with tocilizumab. Therefore, anakinra is recommended as an option for:\n\nsystemic JIA when the disease has not responded to at least 1\xa0conventional DMARD, and\n\nAOSD when the disease has responded inadequately to 2\xa0or more conventional DMARDs."}
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https://www.nice.org.uk/guidance/ta685
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Evidence-based recommendations on anakinra (Kineret) for treating adult‑onset Still’s disease and systemic juvenile idiopathic arthritis in people 8 months and older.
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9d263d4f1ae8318f792a55524e754d3d6a9bfa92
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nice
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Cannabis-based medicinal products
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Cannabis-based medicinal products
This guideline covers prescribing of cannabis-based medicinal products for people with intractable nausea and vomiting, chronic pain, spasticity and severe treatment-resistant epilepsy.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Intractable nausea and vomiting
Consider nabilone as an add-on treatment for adults (18 years and over) with chemotherapy-induced nausea and vomiting which persists with optimised conventional antiemetics.
When considering nabilone for adults with chemotherapy-induced nausea and vomiting, take into account potential adverse drug interactions, for example, with central nervous system depressants and other centrally active drugs.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intractable nausea and vomiting .
Full details of the evidence and the committee's discussion are in evidence review A: intractable nausea and vomiting.
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# Chronic pain
Do not offer the following to manage chronic pain in adults:
nabilone
dronabinol
THC (delta-9-tetrahydrocannabinol)
a combination of cannabidiol (CBD) with THC.
Do not offer CBD to manage chronic pain in adults unless as part of a clinical trial.
Adults who started cannabis-based medicinal products to manage chronic pain in the NHS before this guidance was published (November 2019) should be able to continue treatment until they and their NHS clinician think it appropriate to stop.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on chronic pain .
Full details of the evidence and the committee's discussion are in evidence review B: chronic pain.
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# Spasticity
Offer a 4-week trial of THC:CBD spray to treat moderate to severe spasticity in adults with multiple sclerosis, if:
-ther pharmacological treatments for spasticity are not effective (see the recommendations on spasticity in NICE's guideline on multiple sclerosis in adults)
the company provides THC:CBD spray according to its pay-for-responders scheme (it funds the first 3 x10-ml vials if there is agreement for continued funding for people with at least a 20% reduction in spasticity-related symptoms on a 0 to 10 patient-reported numeric rating scale after 4 weeks).After the 4-week trial, continue THC:CBD spray if the person has had at least a 20% reduction in spasticity-related symptoms on a 0 to 10 patient-reported numeric rating scale.
Treatment with THC:CBD spray should be initiated and supervised by a physician with specialist expertise in treating spasticity due to multiple sclerosis, in line with its marketing authorisation.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on spasticity .
Full details of the evidence and the committee's discussion are in evidence review C: spasticity.
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# Severe treatment-resistant epilepsy
NICE has made recommendations for research on the use of cannabis-based medicinal products for severe treatment-resistant epilepsy.
NICE has published technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Lennox-Gastaut syndrome and Dravet syndrome.
For a short explanation of why the committee made the recommendation for research on CBD, and THC in combination with CBD for severe treatment-resistant epilepsy, see the rationale section on severe treatment-resistant epilepsy .
Full details of the evidence and the committee's discussion are in evidence review D: epilepsy.
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# Prescribing
## Who should prescribe?
Initial prescription of cannabis-based medicinal products (excluding nabilone, THC:CBD spray and medicines not classed as controlled drugs such as cannabidiol) must be made by a specialist medical practitioner (a doctor included in the register of specialist medical practitioners , see section 34D of the Medical Act 1983). They should also have a special interest in the condition being treated (see the GMC's information for doctors on cannabis-based products for medicinal use). For children and young people under the care of paediatric services, the initiating prescriber should also be a tertiary paediatric specialist in the condition being treated.
## Shared care
After the initial prescription, subsequent prescriptions of cannabis-based medicinal products may be issued by another prescriber as part of a shared care agreement under the direction of the initiating specialist prescriber, if:
shared care is appropriate and in the person's best interest
the person's clinical condition is stable
the other prescriber is confident to make a fully informed prescribing decision about cannabis-based medicinal products.For more information about shared care, see NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care.
Efficacy and safety of cannabis-based medicinal products should be monitored and evaluated, and doses should be adjusted by the initiating specialist prescriber as part of the shared care agreement.
A shared care agreement for a person prescribed a cannabis-based medicinal product should include:
the responsibilities of all parties
the nature and frequency of monitoring and how this will be recorded
when treatment might be stopped, for example, if it is not effective
how suspected or known adverse reactions will be managed
how communication will be managed between the initiating specialist prescriber, the other prescriber, the patient, family and/or carers
how the treatment will be funded
how care will be maintained when the patient, initiating specialist prescriber or other prescriber moves location (including transition to adult services).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prescribing: who should prescribe and shared care .
Full details of the evidence and the committee's discussion are in evidence review E: prescribing cannabis-based medicinal products.
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## Factors to think about when prescribing
When prescribing and monitoring cannabis-based medicinal products, take into account:
current and past use of cannabis (including any over-the-counter and online products)
history of substance misuse including the illicit use of cannabis
potential for dependence, diversion and misuse (in particular with THC)
mental health and medical history, in particular, liver impairment, renal impairment, cardiovascular disease
potential for interaction with other medicines, for example, central nervous system depressants and other centrally active drugs, antiepileptics and hormonal contraceptives
pregnancy and breastfeeding (breastfeeding is a contraindication for Sativex and nabilone; there is limited evidence on the safety of cannabis-based medicinal products during pregnancy and breastfeeding).
When prescribing cannabis-based medicinal products for babies, children and young people, pay particular attention to the:
potential impact on psychological, emotional and cognitive development
potential impact of sedation
potential impact on structural and functional brain development.NICE has produced a guideline on babies, children and young people's experience of healthcare.
When prescribing cannabis-based medicinal products, advise people to stop any non-prescribed cannabis, including over-the-counter, online and illicit products.
Prescribers should record details of treatment, clinical outcomes and adverse effects for people prescribed cannabis-based medicinal products, using local or national registers if available.
For more information on safe prescribing and use of cannabis-based medicinal products, see the recommendations in the NICE guideline on controlled drugs.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prescribing: factors to think about when prescribing .
Full details of the evidence and the committee's discussion are in evidence review E: prescribing cannabis-based medicinal products.
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## Supporting shared decision making
Before prescribing cannabis-based medicinal products, discuss with people:
the potential benefits and harms, including any risk of dependence or interaction with other medicines
the licensing status of the medicines
how long they might take the medicine
how long it will take to work
what it has been prescribed for and how to take it
how it may affect their ability to drive (see the advice from the Department of Transport on drug driving and medicine)
the need to seek advice before travelling abroad about the legality of cannabis-based medicinal products in other countries (see the UK Government's advice on travelling with medicine containing a controlled drug).
the importance of not allowing others to use the prescribed medicine.
When discussing cannabis-based medicinal products with patients and their families and carers, follow the NICE guideline on shared decision making.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prescribing: supporting shared decision making .
Full details of the evidence and the committee's discussion are in evidence review E: prescribing cannabis-based medicinal products.
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# Terms used in this guideline
## Cannabis-based medicinal products
In this guideline cannabis-based medicinal products include:
cannabis-based products for medicinal use as set out by the UK Government in the 2018 Regulations
the licensed products delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex) and nabilone
plant-derived cannabinoids such as pure cannabidiol (CBD)
synthetic compounds which are identical in structure to naturally occurring cannabinoids such as delta-9-tetrahydrocannabinol (THC), for example, dronabinol.
## Optimised conventional antiemetics
These are treatments that are commonly used in practice at an optimum tolerated dose to manage nausea and vomiting.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Fibromyalgia or persistent treatment-resistant neuropathic pain in adults
For adults with fibromyalgia or persistent treatment-resistant neuropathic pain, what is the clinical and cost effectiveness of cannabidiol (CBD), containing no, or traces of, delta-9-tetrahydrocannabinol (THC), as an add-on to standard treatment?
For a short explanation of why the committee made the recommendation for research, see the rationale section on chronic pain .
Full details of the evidence and the committee's discussion are in evidence review B: chronic pain.
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## Chronic pain in children and young people
For children and young people with intractable cancer-related pain and pain associated with specific diseases (such as epidermolysis bullosa), what is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on to standard treatment to improve symptoms compared with treatment with standard care?
For a short explanation of why the committee made the recommendation for research, see the rationale section on chronic pain .
Full details of the evidence and the committee's discussion are in evidence review B: chronic pain.
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## CBD for severe treatment-resistant epilepsy
What is the clinical and cost effectiveness of CBD in epileptic disorders in children, young people and adults?
For a short explanation of why the committee made the recommendation for research, see the rationale section on severe treatment-resistant epilepsy .
Full details of the evidence and the committee's discussion are in evidence review D: epilepsy.
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## THC in combination with CBD for severe treatment-resistant epilepsy
Does the addition of THC to CBD have an effect on seizure frequency, brain structure and neuropsychological performance when compared with both CBD alone and placebo in epileptic disorders in children, young people and adults?
For a short explanation of why the committee made the recommendation for research, see the rationale section on severe treatment-resistant epilepsy .
Full details of the evidence and the committee's discussion are in evidence review D: epilepsy.
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## Spasticity
What is the clinical and cost effectiveness of cannabis-based medicinal products other than THC: CBD spray for children, young people and adults with spasticity? In particular, what is the impact of spasticity on improvements in quality of life?
For a short explanation of why the committee made the recommendation for research, see the rationale section on spasticity .
Full details of the evidence and the committee's discussion are in evidence review C: spasticity.
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# Other recommendations for research
## Chemotherapy-induced intractable nausea and vomiting in adults
What is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment for adults with chemotherapy-induced nausea and vomiting which persists with optimised conventional antiemetics?
## Chemotherapy-induced intractable nausea and vomiting in babies, children and young people
What is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment in babies, children and young people with chemotherapy-induced nausea or vomiting which persists with optimised conventional antiemetics?
## Intractable nausea and vomiting not caused by chemotherapy in adults
What is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment for adults with persistent nausea or vomiting not caused by chemotherapy which hasn't fully responded to optimised conventional antiemetics?
## Intractable nausea and vomiting not caused by chemotherapy in babies, children and young people
What is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment for babies, children and young people with persistent nausea or vomiting not caused by chemotherapy which hasn't fully responded to optimised conventional antiemetics?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Intractable nausea and vomiting
Recommendations 1.1.1. and 1.1.2
## Why the committee made the recommendations
Intractable nausea or vomiting can be defined as persistent nausea or vomiting that does not respond fully to optimised conventional antiemetics. Although there are different causes of intractable or persistent nausea and vomiting, evidence was only identified for the use of delta-9-tetrahydrocannabinol (THC), nabilone and dronabinol in people with chemotherapy-induced and radiotherapy-induced nausea and vomiting.
Limited evidence showed that nabilone, which is licensed in the UK for adults, resulted in complete or partial reduction in chemotherapy-induced nausea and vomiting. However, most of the studies were old, of low quality and used outdated antiemetic regimens that do not reflect current practice. Nabilone was also associated with more adverse events (drowsiness, dizziness and dry mouth), particularly in children. The committee noted that although use of cannabis-based medicinal products for intractable chemotherapy-induced nausea and vomiting would be short term, there was a lack of evidence on longer term adverse events, such as dependence and the development of psychological disorders. They identified this as a concern, particularly when considering repeated use. The committee also noted the limited evidence for children and young people. Based on these findings they were unable to make recommendations specifically for this group.
The committee agreed that nabilone may play a role in treating intractable chemotherapy-induced nausea and vomiting in people who have not had a full response to optimised conventional antiemetics. Based on the limited evidence, the committee only recommended that nabilone could be considered as an add-on treatment in adults with intractable chemotherapy-induced nausea and vomiting which persists despite the use of optimised conventional antiemetics.
The committee were aware that people may be taking other medication when using nabilone and were concerned about potential adverse drug interactions. They recommended that adverse drug interactions should be carefully considered when prescribing nabilone. The committee highlighted concerns for the use of nabilone with central nervous system depressants and other centrally active drugs. They recommended that healthcare professionals should think about these when considering nabilone and refer to the summary of product characteristics for further information on dosing, patient monitoring, contraindications and adverse events.
Evidence for the use of other cannabis-based medicinal products was limited and the committee were unable to make any practice recommendations. However, they made a recommendation for research to inform future guidance.
Nabilone is not currently licensed in the UK for children and young people under 18 years because its safety and efficacy has not been established. Therefore, the committee made another recommendation for research on the effectiveness of cannabis-based medicinal products in babies, children and young people with intractable nausea and vomiting.
Only 1 study was identified which included people with radiotherapy-induced nausea and vomiting. The committee noted that there are other causes of intractable nausea and vomiting but were unable to make further recommendations due to lack of evidence. Therefore, the committee made an additional recommendation for research.
## How the recommendations might affect practice
The committee highlighted that the use of nabilone is uncommon in current practice and it is not used as first-line treatment for chemotherapy-induced nausea and vomiting. The recommendations could result in an increase in use of nabilone as an add-on treatment for adults with chemotherapy-induced nausea and vomiting, but the current level of use is uncertain.
Return to recommendations
# Chronic pain
Recommendations 1.2.1 to 1.2.3
## Why the committee made the recommendations
Some evidence showed that CBD reduced chronic pain, but the treatment effect was modest (an average improvement of about 0.4 on a scale ranging from 0 to 10). The evidence did not show a reduction in opioid use in people prescribed medicinal cannabis. Because the number of people who might benefit is large and the cost potentially high, an economic model was developed to compare benefits with the potential costs. The model used data from the trials in the base-case analysis but also assumed a larger potential benefit from cannabis-based medicinal products in various sensitivity analyses. In all cases, the potential benefits offered were small compared with the high and ongoing costs, and the products were not an effective use of NHS resources. The evidence included CBD in combination with THC, THC alone, dronabinol and nabilone so the committee named these products in the recommendation. The committee also agreed that the recommendation should follow the evidence and specify adults.
There was no evidence for the use of CBD alone (either as a pure product or containing traces of THC). Therefore, the committee recommended that CBD should not be offered unless as part of a clinical trial. People who have fibromyalgia or persistent treatment-resistant neuropathic pain are often taking high doses of medicines for pain relief over long periods. These can cause nausea, drowsiness, mood disturbance and fatigue. The committee noted that this is a significant population of people with chronic pain (around 15%). They therefore made a recommendation for research for CBD in adults with fibromyalgia or treatment-resistant neuropathic pain.
There was no evidence for intractable cancer-related pain or pain associated with painful childhood diseases. The committee agreed that cannabis-based medicinal products could potentially offer additional benefits for this group, for example, by allowing them to receive their care in an outpatient rather than an inpatient setting or by reducing the overall opioid use. They agreed to make a recommendation for research to explore the clinical and cost effectiveness.
## How the recommendations might affect practice
Prescriptions of cannabis-based medicinal products for chronic pain are currently rare. GPs refer people with chronic pain to specialist pain services where clinicians on the Specialist Register with expertise in this area decide whether cannabis-based medicinal products should be prescribed. The new recommendation might reduce the number of these prescriptions.
Return to recommendations
# Spasticity
Recommendations 1.3.1 and 1.3.2
## Why the committee made the recommendations
The committee agreed that the evidence showed benefits of THC:CBD spray (licensed product in UK: Sativex) for treating spasticity in people with multiple sclerosis. There were reductions in some measures of patient-reported spasticity and no difference in adverse events in the treatment or placebo groups, although much of the evidence was assessed as low quality. The committee agreed that the longer-term benefits of THC:CBD spray are likely to outweigh any potential harms, although it was not clear how benefits related to improvements in quality of life.
The committee considered the evidence from 2 published economic evaluations but noted that they had contradictory conclusions about the cost effectiveness of THC:CBD spray and were subject to potentially serious limitations. So they considered results from a new economic model developed specifically for the cannabis guideline. The model included data from all relevant trials, longer-term registry data and data on adverse events. In reflection of the trial evidence, the model predicted that the average person would receive a quality of life (QALY) gain equivalent to around 30 days perfect health with THC:CBD spray added to standard care. The acquisition costs of the treatment are offset by predicted savings in management costs. The model estimates that THC:CBD spray would offer sufficient QALY gains if reduction in spasticity led to a halving of management costs and the acquisition cost of THC:CBD spray was also reduced (in addition to the existing pay-for-responders scheme). The committee agreed that under these conditions THC:CBD spray could be recommended to treat moderate to severe spasticity in adults with multiple sclerosis if other pharmacological treatments had not been effective.
The committee agreed that the evidence for the effectiveness and safety of other cannabis-based medicinal products was much more limited. There is also currently no evidence on the cost effectiveness of products other than THC:CBD spray and in other clinical indications (for example, motor neurone disease and spinal cord injury).
The committee acknowledged that women are more likely to receive a diagnosis of multiple sclerosis than men. However, they considered this would not cause an inequality in relation to treatment.
Because there is limited evidence from trials on how reductions in spasticity affect quality of life and no evidence was found for conditions such as cerebral palsy, the committee agreed to make a recommendation for research to inform future guidance.
## How the recommendations might affect practice
These recommendations are a change to NICE's previous guidance on treating spasticity in adults with multiple sclerosis, which did not support the use of THC:CBD spray. They are therefore expected to lead to THC:CBD spray being used as an add-on treatment for adults with treatment-resistant spasticity due to multiple sclerosis, with concomitant reductions in the need for supportive care.
Return to recommendations
# Severe treatment-resistant epilepsy
Recommendation for research on CBD, and THC in combination with CBD
## Why the committee made the recommendations for research
The only cannabis-based medicinal product available for the treatment of epilepsy is epidyolex, which is licensed specifically for Dravet and Lennox-Gastaut syndromes. All other cannabis-based medicinal products are unlicensed for epilepsy. The committee were aware from cases highlighted by stakeholders that individual patients have reported having fewer seizures with these medicines when other treatments have not fully controlled the seizures. But current research is limited and of low quality, making it difficult to assess just how effective these medicines are for people with epilepsy. Published randomised controlled trials have focused on the use of pure CBD in people with Dravet and Lennox-Gastaut syndromes. People with these epilepsy syndromes also report a very high rate of adverse events. Open-label studies (clinical trials in which the treatment and placebo groups are not disguised) of cannabis-based medicinal products in other types of epilepsy have also shown a very high level of adverse events (in up to 98% of people), but it was not possible to determine how many of these were due to the cannabis-based products.
The committee discussed the limited evidence and agreed that it did not warrant a practice recommendation. However, they also agreed that they should not make a recommendation against the use of cannabis-based medicinal products as this would restrict further research in this area and would prevent people who are currently apparently benefiting from continuing with their treatment. Specialists, people with epilepsy and their carers should continue to make treatment decisions in the best interests of each person with epilepsy, in line with the GMC's guidance for doctors. However, people seeking treatment for severe epilepsy should be made aware that currently there is no clear evidence of the safety and effectiveness of cannabis-based medicinal products.
The committee agreed that more evidence is needed on the effectiveness of cannabis-based medicinal products in severe treatment-resistant epilepsy and made a recommendation for research to inform future practice. They discussed that some individual funding requests are denied because of lack of evidence of effectiveness. More research across different types of epilepsy may address this evidence gap.
The committee discussed the constituents of cannabis-based medicinal products. They were aware that it is difficult to extract pure CBD without other cannabinoids being present in trace amounts and this varies depending on extraction methods. Some medicines contain either purified 'pure' CBD alone (with trace amounts of other cannabinoids) or CBD combined with higher than trace amounts of THC. Most studies of cannabis-based medicinal products for severe epilepsy have evaluated 'pure' CBD, but the committee agreed it is important to know whether adding medicinal amounts of THC to CBD offers benefits or affects the type of adverse events observed. They decided to make a recommendation for research on how the constituents of a cannabis-based medicinal product influence its effectiveness.
Return to recommendation for research
# Prescribing: who should prescribe and shared care
Recommendations 1.5.1 to 1.5.4
## Why the committee made the recommendations
Based on current legislation, the complexity of the conditions, and the licensed (nabilone and Sativex) and unlicensed status of these medicines, the committee agreed that the initial prescription of unlicensed cannabis-based medicinal products must be made by a specialist medical practitioner (a doctor included in the register of specialist medical practitioners ). They should also have a special interest in the condition being treated. The committee also agreed that THC:CBD spray should be initiated by a physician with special expertise in treating spasticity due to multiple sclerosis. Although there are no legal requirements for nabilone to be prescribed by a specialist prescriber.
There was limited evidence on who should prescribe and monitor cannabis-based medicinal products. Studies were conducted in Australia and Canada, and 1 study included participants from 8 different European countries. These countries have different healthcare systems, funding streams and legislation, which raised questions about their applicability to the prescribing of cannabis-based medicinal products in England. It was also not clear whether all products could be considered cannabis-based products for medicinal use as defined in the 2018 Regulations.
Guidance from the British Paediatric Neurology Association, based on current UK legislation and policy, advises that for children with intractable epilepsy, cannabis-based products should only be prescribed by a consultant paediatric neurologist. The committee agreed that for children and young people the initiating specialist prescriber for cannabis-based medicinal products should be a tertiary paediatric specialist with a special interest in the condition being treated (for example, for a child or young person with epilepsy, this would be a tertiary paediatric epilepsy specialist).
The committee noted that NICE's guideline on controlled drugs recommends that no more than a 30-day supply of a controlled drug is prescribed at any one time. Once their condition is stable, people taking cannabis-based medicinal products are likely to need repeat prescriptions. They will also need close monitoring of effectiveness and adverse effects, and dose adjustments. The committee agreed that there are potential burdens for patients associated with limiting prescribing and monitoring to tertiary care. They were aware of electronic prescription systems that could help patients to access prescriptions locally, but knew that these services vary by location. The committee discussed whether shared care would be appropriate and in the patient's best interest. They agreed that a shared care agreement could be considered, which could involve other healthcare professionals such as GPs and non-medical prescribers if they were confident to take on the responsibility of prescribing. The committee endorsed and agreed to reference NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care.
The committee agreed that after the initial assessment and prescription by a specialist, allowing other prescribers to prescribe cannabis-based products under specialist direction would improve access for patients.
The specialist initiating treatment should also be involved in monitoring, evaluation and dose adjustment. This should be part of a shared care plan with a clear division of responsibilities between the initiating specialist prescriber and the prescriber acting under their direction.
The committee noted that a shared care agreement should detail the responsibilities of all parties, including the patient and their family and/or carers. The committee highlighted that the agreement should include details of how communication between parties would be managed, how funding would be obtained and the frequency and nature of monitoring.
Because some patients may need long-term treatment, the agreement should ensure continuity of care by setting out what should happen when the patient, other prescriber or specialist moves location. This should include handover of responsibilities to other specialists or prescribers.
## How the recommendations might affect practice
Currently, prescribing and monitoring cannabis-based medicinal products takes place in tertiary care. The recommendations focus on shared care after the initial prescription with the involvement of other healthcare professionals such as non-medical prescribers and GPs. This will allow a more holistic approach to care. Moving away from tertiary care may be cost saving for the NHS.
Return to recommendations
# Prescribing: factors to think about when prescribing
Recommendations 1.5.5 to 1.5.9
## Why the committee made the recommendations
The committee agreed a number of factors that should be considered before prescribing cannabis-based medicinal products, based on study data, summaries of product characteristics and committee experience. They highlighted these in a recommendation along with some of the contraindications from the studies of the effectiveness and safety of cannabis-based medicinal products for nausea and vomiting, chronic pain, epilepsy and spasticity.
The committee also discussed whether there were any particular considerations when prescribing cannabis-based medicinal products for babies, children and young people. They discussed the limited evidence about the effects in this group and were mindful about the potential effects on cognitive function. The committee agreed that when considering the balance of benefits and harms, it would be prudent to take into account the potential impact of treatment on brain and cognitive development, and the effect of sedation.
The committee discussed the importance of collecting data on the treatment, clinical outcomes and adverse events experienced by people prescribed cannabis-based medicinal products, to inform future guidance and use. They noted the ambition to develop a UK register outlined in NHS England and NHS Improvement's barriers to accessing cannabis-based products for medicinal use on NHS prescription, and supported this.
Many people use non-prescribed, over-the-counter or over-the-internet, cannabis-based food supplements. The committee agreed that when someone is prescribed cannabis-based medicinal products they should be advised to stop using any non-prescribed cannabis products. This will reduce the risk of any drug interactions and reduce the potential for people taking a higher dose of cannabis than prescribed.
## How the recommendations might affect practice
These recommendations will help to guide prescribers on some of the important issues to consider when prescribing cannabis-based medicinal products. This may result in more prescriptions for cannabis-based medicinal products, which may increase costs to the NHS. However, if symptoms are reduced with the use of cannabis-based medicinal products this may ultimately reduce the cost of other treatment for these patients, either through primary care or urgent care services.
Return to recommendations
# Prescribing: supporting shared decision making
Recommendations 1.5.10 and 1.5.11
## Why the committee made the recommendations
Limited evidence was identified on the support prescribers and people may need when making decisions on cannabis-based medicinal products. Some evidence identified the need for training and further education for prescribers, while international guidelines described the overarching support that people seeking cannabis-based medicinal products may need.
The committee agreed that the key theme was the need for prescribers to discuss the risks, benefits and alternatives to cannabis-based medicinal products with people seeking treatment. The committee noted that with the change in legislation people may require licensed or unlicensed medicines, which would also be a key area for discussion. This recommendation should encourage shared decision making and allow people to make informed decisions about their care.
The committee also recommended that prescribers follow the NICE guideline on patient experience in adult NHS services. This has specific recommendations on shared decision making and details the support prescribers can provide when discussing treatment options.
## How the recommendations might affect practice
The recommendations promote shared decision making and allow people to make informed decisions about their care. The committee noted that there may be situations in which a multidisciplinary team may help to reach a decision on treatment, such as the care of babies, children or young people. A multidisciplinary team may also need to be involved when decisions need to be made that are in the patient's best interest. This may not be feasible in all specialist care settings because staffing and structure of care provision varies.
Return to recommendations# Context
Cannabis-based medicinal products have been suggested for a variety of medical conditions. In line with prescribing for all medicines, the potential for harm must be weighed up against the potential for benefit for individual patients.
At the time of developing this guideline, delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex), nabilone and cannabidiol (Epidyolex) were the only cannabis-based medicines licensed for use in the UK. Delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex) has been licensed by the MHRA as a treatment for spasticity in adults with multiple sclerosis and is listed under Schedule 4 of the Misuse of Drugs Regulations 2001 ('2001 Regulations'). Nabilone has been licensed by the MHRA as a control of chemotherapy-induced nausea and vomiting in adults and is listed under Schedule 2 of the 2001 Regulations. Cannabidiol (Epidyolex) has been licensed by the MHRA as an add-on treatment for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, in conjunction with clobazam, for people aged 2 years and over and is listed under Schedule 2 of the 2001 Regulations. Dronabinol is listed under Schedule 2 controlled drugs but does not have a marketing authorisation from the MHRA in the UK.
Until September 2018, in cases of exceptional and unmet clinical need, legislation allowed the prescribing of cannabis-based medicinal products through the granting of an individual licence. As Schedule 1 controlled drugs, prescribing was controlled through the licensing process operated by the Home Office.
In November 2018, the UK Government set out the following requirements for the prescription of a cannabis-based product:
'A preparation or other product, other than one to which paragraph 5 of part 1 of schedule 4 applies, which:
is or contains cannabis, cannabis resin, cannabinol or a cannabinol derivative (not being dronabinol or its stereoisomers)
is produced for medicinal use in humans; and
is a medicinal product, or
a substance or preparation for use as an ingredient of, or in the production of an ingredient of, a medicinal product.'
Cannabis-based products for medicinal use related only to cannabis and cannabis preparations (such as extracts from cannabis as well as cannabinoids isolated from cannabis). It does not include synthetic versions of naturally occurring cannabinoids (for example, dronabinol) or any non-natural cannabinoids obtained by chemical synthesis (nabilone).
In this guideline, cannabis-based medicinal products include:
cannabis-based products for medicinal use as set out by the UK Government in the 2018 Regulations
the licensed products delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex) and nabilone
plant-derived cannabinoids such as pure cannabidiol (CBD)
synthetic compounds which are identical in structure to naturally occurring cannabinoids such as delta-9-tetrahydrocannabinol (THC), for example, dronabinol.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Intractable nausea and vomiting\n\nConsider nabilone as an add-on treatment for adults (18 years and over) with chemotherapy-induced nausea and vomiting which persists with optimised conventional antiemetics.\n\nWhen considering nabilone for adults with chemotherapy-induced nausea and vomiting, take into account potential adverse drug interactions, for example, with central nervous system depressants and other centrally active drugs.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intractable nausea and vomiting\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: intractable nausea and vomiting.\n\nLoading. Please wait.\n\n# Chronic pain\n\nDo not offer the following to manage chronic pain in adults:\n\nnabilone\n\ndronabinol\n\nTHC (delta-9-tetrahydrocannabinol)\n\na combination of cannabidiol (CBD) with THC.\n\nDo not offer CBD to manage chronic pain in adults unless as part of a clinical trial.\n\nAdults who started cannabis-based medicinal products to manage chronic pain in the NHS before this guidance was published (November 2019) should be able to continue treatment until they and their NHS clinician think it appropriate to stop.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on chronic pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: chronic pain.\n\nLoading. Please wait.\n\n# Spasticity\n\nOffer a 4-week trial of THC:CBD spray to treat moderate to severe spasticity in adults with multiple sclerosis, if:\n\nother pharmacological treatments for spasticity are not effective (see the recommendations on spasticity in NICE's guideline on multiple sclerosis in adults)\n\nthe company provides THC:CBD spray according to its pay-for-responders scheme (it funds the first 3 x10-ml vials if there is agreement for continued funding for people with at least a 20% reduction in spasticity-related symptoms on a 0 to 10 patient-reported numeric rating scale after 4\xa0weeks).After the 4-week trial, continue THC:CBD spray if the person has had at least a 20% reduction in spasticity-related symptoms on a 0 to 10 patient-reported numeric rating scale.\n\nTreatment with THC:CBD spray should be initiated and supervised by a physician with specialist expertise in treating spasticity due to multiple sclerosis, in line with its marketing authorisation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on spasticity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: spasticity.\n\nLoading. Please wait.\n\n# Severe treatment-resistant epilepsy\n\nNICE has made recommendations for research on the use of cannabis-based medicinal products for severe treatment-resistant epilepsy.\n\nNICE has published technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Lennox-Gastaut syndrome and Dravet syndrome.\n\nFor a short explanation of why the committee made the recommendation for research on CBD, and THC in combination with CBD for severe treatment-resistant epilepsy, see the rationale section on severe treatment-resistant epilepsy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: epilepsy.\n\nLoading. Please wait.\n\n# Prescribing\n\n## Who should prescribe?\n\nInitial prescription of cannabis-based medicinal products (excluding nabilone, THC:CBD spray [Sativex] and medicines not classed as controlled drugs such as cannabidiol) must be made by a specialist medical practitioner (a doctor included in the register of specialist medical practitioners [the Specialist Register], see section 34D of the Medical Act 1983). They should also have a special interest in the condition being treated (see the GMC's information for doctors on cannabis-based products for medicinal use). For children and young people under the care of paediatric services, the initiating prescriber should also be a tertiary paediatric specialist in the condition being treated.\n\n## Shared care\n\nAfter the initial prescription, subsequent prescriptions of cannabis-based medicinal products may be issued by another prescriber as part of a shared care agreement under the direction of the initiating specialist prescriber, if:\n\nshared care is appropriate and in the person's best interest\n\nthe person's clinical condition is stable\n\nthe other prescriber is confident to make a fully informed prescribing decision about cannabis-based medicinal products.For more information about shared care, see NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care.\n\nEfficacy and safety of cannabis-based medicinal products should be monitored and evaluated, and doses should be adjusted by the initiating specialist prescriber as part of the shared care agreement.\n\nA shared care agreement for a person prescribed a cannabis-based medicinal product should include:\n\nthe responsibilities of all parties [the initiating specialist prescriber, the other prescriber(s), the patient, family and/or carers]\n\nthe nature and frequency of monitoring and how this will be recorded\n\nwhen treatment might be stopped, for example, if it is not effective\n\nhow suspected or known adverse reactions will be managed\n\nhow communication will be managed between the initiating specialist prescriber, the other prescriber, the patient, family and/or carers\n\nhow the treatment will be funded\n\nhow care will be maintained when the patient, initiating specialist prescriber or other prescriber moves location (including transition to adult services).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prescribing: who should prescribe and shared care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: prescribing cannabis-based medicinal products.\n\nLoading. Please wait.\n\n## Factors to think about when prescribing\n\nWhen prescribing and monitoring cannabis-based medicinal products, take into account:\n\ncurrent and past use of cannabis (including any over-the-counter and online products)\n\nhistory of substance misuse including the illicit use of cannabis\n\npotential for dependence, diversion and misuse (in particular with THC)\n\nmental health and medical history, in particular, liver impairment, renal impairment, cardiovascular disease\n\npotential for interaction with other medicines, for example, central nervous system depressants and other centrally active drugs, antiepileptics and hormonal contraceptives\n\npregnancy and breastfeeding (breastfeeding is a contraindication for Sativex and nabilone; there is limited evidence on the safety of cannabis-based medicinal products during pregnancy and breastfeeding).\n\nWhen prescribing cannabis-based medicinal products for babies, children and young people, pay particular attention to the:\n\npotential impact on psychological, emotional and cognitive development\n\npotential impact of sedation\n\npotential impact on structural and functional brain development.NICE has produced a guideline on babies, children and young people's experience of healthcare.\n\nWhen prescribing cannabis-based medicinal products, advise people to stop any non-prescribed cannabis, including over-the-counter, online and illicit products.\n\nPrescribers should record details of treatment, clinical outcomes and adverse effects for people prescribed cannabis-based medicinal products, using local or national registers if available.\n\nFor more information on safe prescribing and use of cannabis-based medicinal products, see the recommendations in the NICE guideline on controlled drugs.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prescribing: factors to think about when prescribing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: prescribing cannabis-based medicinal products.\n\nLoading. Please wait.\n\n## Supporting shared decision making\n\nBefore prescribing cannabis-based medicinal products, discuss with people:\n\nthe potential benefits and harms, including any risk of dependence or interaction with other medicines\n\nthe licensing status of the medicines\n\nhow long they might take the medicine\n\nhow long it will take to work\n\nwhat it has been prescribed for and how to take it\n\nhow it may affect their ability to drive (see the advice from the Department of Transport on drug driving and medicine)\n\nthe need to seek advice before travelling abroad about the legality of cannabis-based medicinal products in other countries (see the UK Government's advice on travelling with medicine containing a controlled drug).\n\nthe importance of not allowing others to use the prescribed medicine.\n\nWhen discussing cannabis-based medicinal products with patients and their families and carers, follow the NICE guideline on shared decision making.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prescribing: supporting shared decision making\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: prescribing cannabis-based medicinal products.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Cannabis-based medicinal products\n\nIn this guideline cannabis-based medicinal products include:\n\ncannabis-based products for medicinal use as set out by the UK Government in the 2018 Regulations\n\nthe licensed products delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex) and nabilone\n\nplant-derived cannabinoids such as pure cannabidiol (CBD)\n\nsynthetic compounds which are identical in structure to naturally occurring cannabinoids such as delta-9-tetrahydrocannabinol (THC), for example, dronabinol.\n\n## Optimised conventional antiemetics\n\nThese are treatments that are commonly used in practice at an optimum tolerated dose to manage nausea and vomiting.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Fibromyalgia or persistent treatment-resistant neuropathic pain in adults\n\nFor adults with fibromyalgia or persistent treatment-resistant neuropathic pain, what is the clinical and cost effectiveness of cannabidiol (CBD), containing no, or traces of, delta-9-tetrahydrocannabinol (THC), as an add-on to standard treatment?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on chronic pain\xa0.\n\nFull details of the evidence and the committee's discussion are in\xa0evidence review B: chronic pain.\n\nLoading. Please wait.\n\n## Chronic pain in children and young people\n\nFor children and young people with intractable cancer-related pain and pain associated with specific diseases (such as epidermolysis bullosa), what is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on to standard treatment to improve symptoms compared with treatment with standard care?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on chronic pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: chronic pain.\n\nLoading. Please wait.\n\n## CBD for severe treatment-resistant epilepsy\n\nWhat is the clinical and cost effectiveness of CBD in epileptic disorders in children, young people and adults?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on severe treatment-resistant epilepsy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: epilepsy.\n\nLoading. Please wait.\n\n## THC in combination with CBD for severe treatment-resistant epilepsy\n\nDoes the addition of THC to CBD have an effect on seizure frequency, brain structure and neuropsychological performance when compared with both CBD alone and placebo in epileptic disorders in children, young people and adults?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on severe treatment-resistant epilepsy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: epilepsy.\n\nLoading. Please wait.\n\n## Spasticity\n\nWhat is the clinical and cost effectiveness of cannabis-based medicinal products other than THC: CBD spray for children, young people and adults with spasticity? In particular, what is the impact of spasticity on improvements in quality of life?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on spasticity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: spasticity.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Chemotherapy-induced intractable nausea and vomiting in adults\n\nWhat is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment for adults with chemotherapy-induced nausea and vomiting which persists with optimised conventional antiemetics?\n\n## Chemotherapy-induced intractable nausea and vomiting in babies, children and young people\n\nWhat is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment in babies, children and young people with chemotherapy-induced nausea or vomiting which persists with optimised conventional antiemetics?\n\n## Intractable nausea and vomiting not caused by chemotherapy in adults\n\nWhat is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment for adults with persistent nausea or vomiting not caused by chemotherapy which hasn't fully responded to optimised conventional antiemetics?\n\n## Intractable nausea and vomiting not caused by chemotherapy in babies, children and young people\n\nWhat is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment for babies, children and young people with persistent nausea or vomiting not caused by chemotherapy which hasn't fully responded to optimised conventional antiemetics?", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Intractable nausea and vomiting\n\nRecommendations 1.1.1. and 1.1.2\n\n## Why the committee made the recommendations\n\nIntractable nausea or vomiting can be defined as persistent nausea or vomiting that does not respond fully to optimised conventional antiemetics. Although there are different causes of intractable or persistent nausea and vomiting, evidence was only identified for the use of delta-9-tetrahydrocannabinol (THC), nabilone and dronabinol in people with chemotherapy-induced and radiotherapy-induced nausea and vomiting.\n\nLimited evidence showed that nabilone, which is licensed in the UK for adults, resulted in complete or partial reduction in chemotherapy-induced nausea and vomiting. However, most of the studies were old, of low quality and used outdated antiemetic regimens that do not reflect current practice. Nabilone was also associated with more adverse events (drowsiness, dizziness and dry mouth), particularly in children. The committee noted that although use of cannabis-based medicinal products for intractable chemotherapy-induced nausea and vomiting would be short term, there was a lack of evidence on longer term adverse events, such as dependence and the development of psychological disorders. They identified this as a concern, particularly when considering repeated use. The committee also noted the limited evidence for children and young people. Based on these findings they were unable to make recommendations specifically for this group.\n\nThe committee agreed that nabilone may play a role in treating intractable chemotherapy-induced nausea and vomiting in people who have not had a full response to optimised conventional antiemetics. Based on the limited evidence, the committee only recommended that nabilone could be considered as an add-on treatment in adults with intractable chemotherapy-induced nausea and vomiting which persists despite the use of optimised conventional antiemetics.\n\nThe committee were aware that people may be taking other medication when using nabilone and were concerned about potential adverse drug interactions. They recommended that adverse drug interactions should be carefully considered when prescribing nabilone. The committee highlighted concerns for the use of nabilone with central nervous system depressants and other centrally active drugs. They recommended that healthcare professionals should think about these when considering nabilone and refer to the summary of product characteristics for further information on dosing, patient monitoring, contraindications and adverse events.\n\nEvidence for the use of other cannabis-based medicinal products was limited and the committee were unable to make any practice recommendations. However, they made a recommendation for research to inform future guidance.\n\nNabilone is not currently licensed in the UK for children and young people under 18\xa0years because its safety and efficacy has not been established. Therefore, the committee made another recommendation for research on the effectiveness of cannabis-based medicinal products in babies, children and young people with intractable nausea and vomiting.\n\nOnly 1 study was identified which included people with radiotherapy-induced nausea and vomiting. The committee noted that there are other causes of intractable nausea and vomiting but were unable to make further recommendations due to lack of evidence. Therefore, the committee made an additional recommendation for research.\n\n## How the recommendations might affect practice\n\nThe committee highlighted that the use of nabilone is uncommon in current practice and it is not used as first-line treatment for chemotherapy-induced nausea and vomiting. The recommendations could result in an increase in use of nabilone as an add-on treatment for adults with chemotherapy-induced nausea and vomiting, but the current level of use is uncertain.\n\nReturn to recommendations\n\n# Chronic pain\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nSome evidence showed that CBD reduced chronic pain, but the treatment effect was modest (an average improvement of about 0.4 on a scale ranging from 0 to 10). The evidence did not show a reduction in opioid use in people prescribed medicinal cannabis. Because the number of people who might benefit is large and the cost potentially high, an economic model was developed to compare benefits with the potential costs. The model used data from the trials in the base-case analysis but also assumed a larger potential benefit from cannabis-based medicinal products in various sensitivity analyses. In all cases, the potential benefits offered were small compared with the high and ongoing costs, and the products were not an effective use of NHS resources. The evidence included CBD in combination with THC, THC alone, dronabinol and nabilone so the committee named these products in the recommendation. The committee also agreed that the recommendation should follow the evidence and specify adults.\n\nThere was no evidence for the use of CBD alone (either as a pure product or containing traces of THC). Therefore, the committee recommended that CBD should not be offered unless as part of a clinical trial. People who have fibromyalgia or persistent treatment-resistant neuropathic pain are often taking high doses of medicines for pain relief over long periods. These can cause nausea, drowsiness, mood disturbance and fatigue. The committee noted that this is a significant population of people with chronic pain (around 15%). They therefore made a recommendation for research for CBD in adults with fibromyalgia or treatment-resistant neuropathic pain.\n\nThere was no evidence for intractable cancer-related pain or pain associated with painful childhood diseases. The committee agreed that cannabis-based medicinal products could potentially offer additional benefits for this group, for example, by allowing them to receive their care in an outpatient rather than an inpatient setting or by reducing the overall opioid use. They agreed to make a recommendation for research to explore the clinical and cost effectiveness.\n\n## How the recommendations might affect practice\n\nPrescriptions of cannabis-based medicinal products for chronic pain are currently rare. GPs refer people with chronic pain to specialist pain services where clinicians on the Specialist Register with expertise in this area decide whether cannabis-based medicinal products should be prescribed. The new recommendation might reduce the number of these prescriptions.\n\nReturn to recommendations\n\n# Spasticity\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nThe committee agreed that the evidence showed benefits of THC:CBD spray (licensed product in UK: Sativex) for treating spasticity in people with multiple sclerosis. There were reductions in some measures of patient-reported spasticity and no difference in adverse events in the treatment or placebo groups, although much of the evidence was assessed as low quality. The committee agreed that the longer-term benefits of THC:CBD spray are likely to outweigh any potential harms, although it was not clear how benefits related to improvements in quality of life.\n\nThe committee considered the evidence from 2 published economic evaluations but noted that they had contradictory conclusions about the cost effectiveness of THC:CBD spray and were subject to potentially serious limitations. So they considered results from a new economic model developed specifically for the cannabis guideline. The model included data from all relevant trials, longer-term registry data and data on adverse events. In reflection of the trial evidence, the model predicted that the average person would receive a quality of life (QALY) gain equivalent to around 30\xa0days perfect health with THC:CBD spray added to standard care. The acquisition costs of the treatment are offset by predicted savings in management costs. The model estimates that THC:CBD spray would offer sufficient QALY gains if reduction in spasticity led to a halving of management costs and the acquisition cost of THC:CBD spray was also reduced (in addition to the existing pay-for-responders scheme). The committee agreed that under these conditions THC:CBD spray could be recommended to treat moderate to severe spasticity in adults with multiple sclerosis if other pharmacological treatments had not been effective.\n\nThe committee agreed that the evidence for the effectiveness and safety of other cannabis-based medicinal products was much more limited. There is also currently no evidence on the cost effectiveness of products other than THC:CBD spray and in other clinical indications (for example, motor neurone disease and spinal cord injury).\n\nThe committee acknowledged that women are more likely to receive a diagnosis of multiple sclerosis than men. However, they considered this would not cause an inequality in relation to treatment.\n\nBecause there is limited evidence from trials on how reductions in spasticity affect quality of life and no evidence was found for conditions such as cerebral palsy, the committee agreed to make a recommendation for research to inform future guidance.\n\n## How the recommendations might affect practice\n\nThese recommendations are a change to NICE's previous guidance on treating spasticity in adults with multiple sclerosis, which did not support the use of THC:CBD spray. They are therefore expected to lead to THC:CBD spray being used as an add-on treatment for adults with treatment-resistant spasticity due to multiple sclerosis, with concomitant reductions in the need for supportive care.\n\nReturn to recommendations\n\n# Severe treatment-resistant epilepsy\n\nRecommendation for research on CBD, and THC in combination with CBD\n\n## Why the committee made the recommendations for research\n\nThe only cannabis-based medicinal product available for the treatment of epilepsy is epidyolex, which is licensed specifically for Dravet and Lennox-Gastaut syndromes. All other cannabis-based medicinal products are unlicensed for epilepsy. The committee were aware from cases highlighted by stakeholders that individual patients have reported having fewer seizures with these medicines when other treatments have not fully controlled the seizures. But current research is limited and of low quality, making it difficult to assess just how effective these medicines are for people with epilepsy. Published randomised controlled trials have focused on the use of pure CBD in people with Dravet and Lennox-Gastaut syndromes. People with these epilepsy syndromes also report a very high rate of adverse events. Open-label studies (clinical trials in which the treatment and placebo groups are not disguised) of cannabis-based medicinal products in other types of epilepsy have also shown a very high level of adverse events (in up to 98% of people), but it was not possible to determine how many of these were due to the cannabis-based products.\n\nThe committee discussed the limited evidence and agreed that it did not warrant a practice recommendation. However, they also agreed that they should not make a recommendation against the use of cannabis-based medicinal products as this would restrict further research in this area and would prevent people who are currently apparently benefiting from continuing with their treatment. Specialists, people with epilepsy and their carers should continue to make treatment decisions in the best interests of each person with epilepsy, in line with the GMC's guidance for doctors. However, people seeking treatment for severe epilepsy should be made aware that currently there is no clear evidence of the safety and effectiveness of cannabis-based medicinal products.\n\nThe committee agreed that more evidence is needed on the effectiveness of cannabis-based medicinal products in severe treatment-resistant epilepsy and made a recommendation for research to inform future practice. They discussed that some individual funding requests are denied because of lack of evidence of effectiveness. More research across different types of epilepsy may address this evidence gap.\n\nThe committee discussed the constituents of cannabis-based medicinal products. They were aware that it is difficult to extract pure CBD without other cannabinoids being present in trace amounts and this varies depending on extraction methods. Some medicines contain either purified 'pure' CBD alone (with trace amounts of other cannabinoids) or CBD combined with higher than trace amounts of THC. Most studies of cannabis-based medicinal products for severe epilepsy have evaluated 'pure' CBD, but the committee agreed it is important to know whether adding medicinal amounts of THC to CBD offers benefits or affects the type of adverse events observed. They decided to make a recommendation for research on how the constituents of a cannabis-based medicinal product influence its effectiveness.\n\nReturn to recommendation for research\n\n# Prescribing: who should prescribe and shared care\n\nRecommendations 1.5.1 to 1.5.4\n\n## Why the committee made the recommendations\n\nBased on current legislation, the complexity of the conditions, and the licensed (nabilone and Sativex) and unlicensed status of these medicines, the committee agreed that the initial prescription of unlicensed cannabis-based medicinal products must be made by a specialist medical practitioner (a doctor included in the register of specialist medical practitioners [the Specialist Register]). They should also have a special interest in the condition being treated. The committee also agreed that THC:CBD spray should be initiated by a physician with special expertise in treating spasticity due to multiple sclerosis. Although there are no legal requirements for nabilone to be prescribed by a specialist prescriber.\n\nThere was limited evidence on who should prescribe and monitor cannabis-based medicinal products. Studies were conducted in Australia and Canada, and 1 study included participants from 8 different European countries. These countries have different healthcare systems, funding streams and legislation, which raised questions about their applicability to the prescribing of cannabis-based medicinal products in England. It was also not clear whether all products could be considered cannabis-based products for medicinal use as defined in the 2018 Regulations.\n\nGuidance from the British Paediatric Neurology Association, based on current UK legislation and policy, advises that for children with intractable epilepsy, cannabis-based products should only be prescribed by a consultant paediatric neurologist. The committee agreed that for children and young people the initiating specialist prescriber for cannabis-based medicinal products should be a tertiary paediatric specialist with a special interest in the condition being treated (for example, for a child or young person with epilepsy, this would be a tertiary paediatric epilepsy specialist).\n\nThe committee noted that NICE's guideline on controlled drugs recommends that no more than a 30-day supply of a controlled drug is prescribed at any one time. Once their condition is stable, people taking cannabis-based medicinal products are likely to need repeat prescriptions. They will also need close monitoring of effectiveness and adverse effects, and dose adjustments. The committee agreed that there are potential burdens for patients associated with limiting prescribing and monitoring to tertiary care. They were aware of electronic prescription systems that could help patients to access prescriptions locally, but knew that these services vary by location. The committee discussed whether shared care would be appropriate and in the patient's best interest. They agreed that a shared care agreement could be considered, which could involve other healthcare professionals such as GPs and non-medical prescribers if they were confident to take on the responsibility of prescribing. The committee endorsed and agreed to reference NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care.\n\nThe committee agreed that after the initial assessment and prescription by a specialist, allowing other prescribers to prescribe cannabis-based products under specialist direction would improve access for patients.\n\nThe specialist initiating treatment should also be involved in monitoring, evaluation and dose adjustment. This should be part of a shared care plan with a clear division of responsibilities between the initiating specialist prescriber and the prescriber acting under their direction.\n\nThe committee noted that a shared care agreement should detail the responsibilities of all parties, including the patient and their family and/or carers. The committee highlighted that the agreement should include details of how communication between parties would be managed, how funding would be obtained and the frequency and nature of monitoring.\n\nBecause some patients may need long-term treatment, the agreement should ensure continuity of care by setting out what should happen when the patient, other prescriber or specialist moves location. This should include handover of responsibilities to other specialists or prescribers.\n\n## How the recommendations might affect practice\n\nCurrently, prescribing and monitoring cannabis-based medicinal products takes place in tertiary care. The recommendations focus on shared care after the initial prescription with the involvement of other healthcare professionals such as non-medical prescribers and GPs. This will allow a more holistic approach to care. Moving away from tertiary care may be cost saving for the NHS.\n\nReturn to recommendations\n\n# Prescribing: factors to think about when prescribing\n\nRecommendations 1.5.5 to 1.5.9\n\n## Why the committee made the recommendations\n\nThe committee agreed a number of factors that should be considered before prescribing cannabis-based medicinal products, based on study data, summaries of product characteristics and committee experience. They highlighted these in a recommendation along with some of the contraindications from the studies of the effectiveness and safety of cannabis-based medicinal products for nausea and vomiting, chronic pain, epilepsy and spasticity.\n\nThe committee also discussed whether there were any particular considerations when prescribing cannabis-based medicinal products for babies, children and young people. They discussed the limited evidence about the effects in this group and were mindful about the potential effects on cognitive function. The committee agreed that when considering the balance of benefits and harms, it would be prudent to take into account the potential impact of treatment on brain and cognitive development, and the effect of sedation.\n\nThe committee discussed the importance of collecting data on the treatment, clinical outcomes and adverse events experienced by people prescribed cannabis-based medicinal products, to inform future guidance and use. They noted the ambition to develop a UK register outlined in NHS England and NHS Improvement's barriers to accessing cannabis-based products for medicinal use on NHS prescription, and supported this.\n\nMany people use non-prescribed, over-the-counter or over-the-internet, cannabis-based food supplements. The committee agreed that when someone is prescribed cannabis-based medicinal products they should be advised to stop using any non-prescribed cannabis products. This will reduce the risk of any drug interactions and reduce the potential for people taking a higher dose of cannabis than prescribed.\n\n## How the recommendations might affect practice\n\nThese recommendations will help to guide prescribers on some of the important issues to consider when prescribing cannabis-based medicinal products. This may result in more prescriptions for cannabis-based medicinal products, which may increase costs to the NHS. However, if symptoms are reduced with the use of cannabis-based medicinal products this may ultimately reduce the cost of other treatment for these patients, either through primary care or urgent care services.\n\nReturn to recommendations\n\n# Prescribing: supporting shared decision making\n\nRecommendations 1.5.10 and 1.5.11\n\n## Why the committee made the recommendations\n\nLimited evidence was identified on the support prescribers and people may need when making decisions on cannabis-based medicinal products. Some evidence identified the need for training and further education for prescribers, while international guidelines described the overarching support that people seeking cannabis-based medicinal products may need.\n\nThe committee agreed that the key theme was the need for prescribers to discuss the risks, benefits and alternatives to cannabis-based medicinal products with people seeking treatment. The committee noted that with the change in legislation people may require licensed or unlicensed medicines, which would also be a key area for discussion. This recommendation should encourage shared decision making and allow people to make informed decisions about their care.\n\nThe committee also recommended that prescribers follow the NICE guideline on patient experience in adult NHS services. This has specific recommendations on shared decision making and details the support prescribers can provide when discussing treatment options.\n\n## How the recommendations might affect practice\n\nThe recommendations promote shared decision making and allow people to make informed decisions about their care. The committee noted that there may be situations in which a multidisciplinary team may help to reach a decision on treatment, such as the care of babies, children or young people. A multidisciplinary team may also need to be involved when decisions need to be made that are in the patient's best interest. This may not be feasible in all specialist care settings because staffing and structure of care provision varies.\n\nReturn to recommendations", 'Context': "Cannabis-based medicinal products have been suggested for a variety of medical conditions. In line with prescribing for all medicines, the potential for harm must be weighed up against the potential for benefit for individual patients.\n\nAt the time of developing this guideline, delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex), nabilone and cannabidiol (Epidyolex) were the only cannabis-based medicines licensed for use in the UK. Delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex) has been licensed by the MHRA as a treatment for spasticity in adults with multiple sclerosis and is listed under Schedule 4 of the Misuse of Drugs Regulations 2001 ('2001 Regulations'). Nabilone has been licensed by the MHRA as a control of chemotherapy-induced nausea and vomiting in adults and is listed under Schedule 2 of the 2001 Regulations. Cannabidiol (Epidyolex) has been licensed by the MHRA as an add-on treatment for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, in conjunction with clobazam, for people aged 2 years and over and is listed under Schedule 2 of the 2001 Regulations. Dronabinol is listed under Schedule 2 controlled drugs but does not have a marketing authorisation from the MHRA in the UK.\n\nUntil September 2018, in cases of exceptional and unmet clinical need, legislation allowed the prescribing of cannabis-based medicinal products through the granting of an individual licence. As Schedule 1 controlled drugs, prescribing was controlled through the licensing process operated by the Home Office.\n\nIn November 2018, the UK Government set out the following requirements for the prescription of a cannabis-based product:\n\n'A preparation or other product, other than one to which paragraph 5 of part 1 of schedule 4 applies, which:\n\nis or contains cannabis, cannabis resin, cannabinol or a cannabinol derivative (not being dronabinol or its stereoisomers)\n\nis produced for medicinal use in humans; and\n\nis a medicinal product, or\n\na substance or preparation for use as an ingredient of, or in the production of an ingredient of, a medicinal product.'\n\nCannabis-based products for medicinal use related only to cannabis and cannabis preparations (such as extracts from cannabis as well as cannabinoids isolated from cannabis). It does not include synthetic versions of naturally occurring cannabinoids (for example, dronabinol) or any non-natural cannabinoids obtained by chemical synthesis (nabilone).\n\nIn this guideline, cannabis-based medicinal products include:\n\ncannabis-based products for medicinal use as set out by the UK Government in the 2018 Regulations\n\nthe licensed products delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex) and nabilone\n\nplant-derived cannabinoids such as pure cannabidiol (CBD)\n\nsynthetic compounds which are identical in structure to naturally occurring cannabinoids such as delta-9-tetrahydrocannabinol (THC), for example, dronabinol."}
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https://www.nice.org.uk/guidance/ng144
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This guideline covers prescribing of cannabis-based medicinal products for people with intractable nausea and vomiting, chronic pain, spasticity and severe treatment-resistant epilepsy.
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d2bc6c03552e82fac32d32a677c2c479842673dd
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nice
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Asthma: diagnosis, monitoring and chronic asthma management
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Asthma: diagnosis, monitoring and chronic asthma management
This guideline covers diagnosing, monitoring and managing asthma in adults, young people and children. It aims to improve the accuracy of diagnosis, help people to control their asthma and reduce the risk of asthma attacks. It does not cover managing severe asthma or acute asthma attacks.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Initial clinical assessment
See also algorithm A for initial clinical assessment in adults, young people and children with suspected asthma.
## Clinical history
Take a structured clinical history in people with suspected asthma. Specifically, check for:
wheeze, cough or breathlessness, and any daily or seasonal variation in these symptoms
any triggers that make symptoms worse
a personal or family history of atopic disorders.
Do not use symptoms alone without an objective test to diagnose asthma.
Do not use a history of atopic disorders alone to diagnose asthma.
## Physical examination
Examine people with suspected asthma to identify expiratory polyphonic wheeze and signs of other causes of respiratory symptoms, but be aware that even if examination results are normal the person may still have asthma.
## Initial treatment and objective tests for acute symptoms at presentation
Treat people immediately if they are acutely unwell at presentation, and perform objective tests for asthma (for example, fractional exhaled nitric oxide , spirometry and peak flow variability) if the equipment is available and testing will not compromise treatment of the acute episode.
If objective tests for asthma cannot be done immediately for people who are acutely unwell at presentation, carry them out when acute symptoms have been controlled, and advise people to contact their healthcare professional immediately if they become unwell while waiting to have objective tests.
Be aware that the results of spirometry and FeNO tests may be affected in people who have been treated empirically with inhaled corticosteroids.
## Testing for asthma
Do not offer the following as diagnostic tests for asthma:
skin prick tests to aeroallergens
serum total and specific IgE
peripheral blood eosinophil count
exercise challenge (to adults aged 17 and over).
Use skin prick tests to aeroallergens or specific IgE tests to identify triggers after a formal diagnosis of asthma has been made.
## Occupational asthma
Check for possible occupational asthma by asking employed people with suspected new-onset asthma, or established asthma that is poorly controlled:
Are symptoms better on days away from work?
Are symptoms better when on holiday (time away from work longer than usual breaks at weekends or between shifts)? Make sure all answers are recorded for later review.
Refer people with suspected occupational asthma to an occupational asthma specialist.
# Diagnosing asthma in young children
For children under 5 with suspected asthma, treat symptoms based on observation and clinical judgement, and review the child on a regular basis (see the section on pharmacological treatment pathway for children under 5). If they still have symptoms when they reach 5 years, carry out objective tests (see the section on objective tests for diagnosing asthma in adults, young people and children aged 5 and over and algorithm B).
If a child is unable to perform objective tests when they are aged 5:
continue to treat based on observation and clinical judgement
try doing the tests again every 6 to 12 months until satisfactory results are obtained
consider referral for specialist assessment if the child repeatedly cannot perform objective tests and is not responding to treatment.
# Objective tests for diagnosing asthma in adults, young people and children aged 5 and over
See also table 1 for a summary of objective test threshold levels.
## Diagnostic hubs
Those responsible for planning diagnostic service support to primary care (for example, clinical commissioning groups) should consider establishing asthma diagnostic hubs to achieve economies of scale and improve the practicality of implementing the recommendations in this guideline.
## Airway inflammation measures
Offer a FeNO test to adults (aged 17 and over) if a diagnosis of asthma is being considered. Regard a FeNO level of 40 parts per billion (ppb) or more as a positive test.
Consider a FeNO test in children and young people (aged 5 to 16) if there is diagnostic uncertainty after initial assessment and they have either:
normal spirometry or
-bstructive spirometry with a negative bronchodilator reversibility (BDR) test.Regard a FeNO level of 35 ppb or more as a positive test. Note: apply the principles in recommendation 1.2.2 for young children unable to do the FeNO test adequately.
Be aware that a person's current smoking status can lower FeNO levels both acutely and cumulatively. However, a high level remains useful in supporting a diagnosis of asthma.
## Lung function tests
Offer spirometry to adults, young people and children aged 5 and over if a diagnosis of asthma is being considered. Regard a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio of less than 70% (or below the lower limit of normal if this value is available) as a positive test for obstructive airway disease (obstructive spirometry).
Offer a BDR test to adults (aged 17 and over) with obstructive spirometry (FEV1/FVC ratio less than 70%). Regard an improvement in FEV1 of 12% or more, together with an increase in volume of 200 ml or more, as a positive test.
Consider a BDR test in children and young people (aged 5 to 16) with obstructive spirometry (FEV1/FVC ratio less than 70%). Regard an improvement in FEV1 of 12% or more as a positive test.
Monitor peak flow variability for 2 to 4 weeks in adults (aged 17 and over) if there is diagnostic uncertainty after initial assessment and a FeNO test and they have either:
normal spirometry or
-bstructive spirometry, reversible airways obstruction (positive BDR) but a FeNO level of 39 ppb or less. Regard a value of more than 20% variability as a positive test.
Consider monitoring peak flow variability for 2 to 4 weeks in adults (aged 17 and over) if there is diagnostic uncertainty after initial assessment and they have:
-bstructive spirometry and
irreversible airways obstruction (negative BDR) and
a FeNO level between 25 ppb and 39 ppb.Regard a value of more than 20% variability as a positive test.
Monitor peak flow variability for 2 to 4 weeks in children and young people (aged 5 to 16) if there is diagnostic uncertainty after initial assessment and a FeNO test and they have either:
normal spirometry or
-bstructive spirometry, irreversible airways obstruction (negative BDR) and a FeNO level of 35 ppb or more.Regard a value of more than 20% variability as a positive test.
## Airway hyperreactivity measures
In November 2017, the use of histamine and methacholine described in recommendations 1.3.11 and 1.3.12 was off label. See NICE's information on prescribing medicines.
Offer a direct bronchial challenge test with histamine or methacholine to adults (aged 17 and over) if there is diagnostic uncertainty after a normal spirometry and either a:
FeNO level of 40 ppb or more and no variability in peak flow readings or
FeNO level of 39 ppb or less with variability in peak flow readings.Regard a PC20 value of 8 mg/ml or less as a positive test.
Consider a direct bronchial challenge test with histamine or methacholine in adults (aged 17 and over) with:
-bstructive spirometry without bronchodilator reversibility and
a FeNO level between 25 ppb and 39 ppb and
no variability in peak flow readings (less than 20% variability over 2 to 4 weeks). Regard a PC20 value of 8 mg/ml or less as a positive test.
If a direct bronchial challenge test with histamine or methacholine is unavailable, suspect asthma and review the diagnosis after treatment, or refer to a centre with access to a histamine or methacholine challenge test.
## Diagnosis in children and young people aged 5 to 16
See also algorithm B for objective tests in young people and children aged 5 to 16.
Diagnose asthma in children and young people (aged 5 to 16) if they have symptoms suggestive of asthma and:
a FeNO level of 35 ppb or more and positive peak flow variability or
-bstructive spirometry and positive bronchodilator reversibility.
Suspect asthma in children and young people (aged 5 to 16) if they have symptoms suggestive of asthma and:
a FeNO level of 35 ppb or more with normal spirometry and negative peak flow variability or
a FeNO level of 35 ppb or more with obstructive spirometry but negative bronchodilator reversibility and no variability in peak flow readings or
normal spirometry, a FeNO level of 34 ppb or less and positive peak flow variability.Do not rule out other diagnoses if symptom control continues to remain poor after treatment. Review the diagnosis after 6 weeks by repeating any abnormal tests and reviewing symptoms.
Refer children and young people (aged 5 to 16) for specialist assessment if they have obstructive spirometry, negative bronchodilator reversibility and a FeNO level of 34 ppb or less.
Consider alternative diagnoses and referral for specialist assessment in children and young people (aged 5 to 16) if they have symptoms suggestive of asthma but normal spirometry, a FeNO level of 34 ppb or less and negative peak flow variability.
## Diagnosis in adults aged 17 and over
See also algorithm C for objective tests in adults aged 17 and over.
Diagnose asthma in adults (aged 17 and over) if they have symptoms suggestive of asthma and:
a FeNO level of 40 ppb or more with either positive bronchodilator reversibility or positive peak flow variability or bronchial hyperreactivity or
a FeNO level between 25 ppb and 39 ppb and a positive bronchial challenge test or
positive bronchodilator reversibility and positive peak flow variability irrespective of FeNO level.
Suspect asthma in adults (aged 17 and over) with symptoms suggestive of asthma, obstructive spirometry and:
negative bronchodilator reversibility, and either a FeNO level of 40 ppb or more, or a FeNO level between 25 ppb and 39 ppb and positive peak flow variability or
positive bronchodilator reversibility, a FeNO level between 25 ppb and 39 ppb and negative peak flow variability.Do not rule out other diagnoses if symptom control continues to remain poor after treatment. Review the diagnosis after 6 to 10 weeks by repeating spirometry and objective measures of asthma control and reviewing symptoms.
Consider alternative diagnoses, or referral for a second opinion, in adults (aged 17 and over) with symptoms suggestive of asthma and:
a FeNO level below 40 ppb, normal spirometry and positive peak flow variability or
a FeNO level of 40 ppb or more but normal spirometry, negative peak flow variability, and negative bronchial challenge test or
-bstructive spirometry with bronchodilator reversibility, but a FeNO level below 25 ppb, and negative peak flow variability or
positive peak flow variability but normal spirometry, a FeNO level below 40 ppb, and a negative bronchial challenge test or
-bstructive spirometry with negative bronchodilator reversibility, a FeNO level below 25 ppb, and negative peak flow variability (if measured).
## Diagnosis in people who are unable to perform an objective test
For young children who cannot perform objective tests, see the section on diagnosing asthma in young children.
If an adult, young person or child with symptoms suggestive of asthma cannot perform a particular test, try to perform at least 2 other objective tests. Diagnose suspected asthma based on symptoms and any positive objective test results.
## Good clinical practice in asthma diagnosis
Record the basis for a diagnosis of asthma in a single entry in the person's medical records, alongside the coded diagnostic entry.
# Diagnostic summary
The following algorithms have been produced that summarise clinical assessment and objective testing for asthma. Table 1 summarises the objective test threshold levels.
Test
Population
Positive result
Fractional exhaled nitric oxide (FeNO)
Adults
ppb or more
FeNO
Children and young people
ppb or more
Obstructive spirometry
Adults, young people and children
Forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio less than 70% (or below the lower limit of normal if this value is available)
Bronchodilator reversibility (BDR) test
Adults
Improvement in FEV1 of 12% or more and increase in volume of 200 ml or more
BDR test
Children and young people
Improvement in FEV1 of 12% or more
Peak flow variability
Adults, young people and children
Variability over 20%
Direct bronchial challenge test with histamine or methacholine
Adults
Provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of 8 mg/ml or less
Direct bronchial challenge test with histamine or methacholine
Children and young people
n/a
## Algorithms
A full-size downloadable PDF version of algorithm A is available in tools and resources.
A full-size downloadable PDF version of algorithm B is available in tools and resources.
A full-size downloadable PDF version of algorithm C is available in tools and resources.
# Principles of pharmacological treatment
Take into account the possible reasons for uncontrolled asthma, before starting or adjusting medicines for asthma in adults, young people and children. These may include:
alternative diagnoses
lack of adherence
suboptimal inhaler technique
smoking (active or passive)
-ccupational exposures
psychosocial factors
seasonal or environmental factors.
After starting or adjusting medicines for asthma, review the response to treatment in 4 to 8 weeks (see the section on monitoring asthma control).
If inhaled corticosteroid (ICS) maintenance therapy is needed, offer regular daily ICS rather than intermittent or 'when required' ICS therapy.
Adjust maintenance therapy ICS doses over time, aiming for the lowest dose required for effective asthma control.
Ensure that a person with asthma can use their inhaler device:
at any asthma review, either routine or unscheduled
whenever a new type of device is supplied.
# Pharmacological treatment pathway for adults (aged 17 and over)
This section is for people with newly diagnosed asthma or asthma that is uncontrolled on their current treatment. Where the recommendations represent a change from traditional clinical practice, people whose asthma is well controlled on their current treatment should not have their treatment changed purely to follow this guidance.
Offer a short-acting beta2 agonist (SABA) as reliever therapy to adults (aged 17 and over) with newly diagnosed asthma.
For adults (aged 17 and over) with asthma who have infrequent, short-lived wheeze and normal lung function, consider treatment with SABA reliever therapy alone.
Offer a low dose of an ICS as the first-line maintenance therapy to adults (aged 17 and over) with:
symptoms at presentation that clearly indicate the need for maintenance therapy (for example, asthma-related symptoms 3 times a week or more, or causing waking at night) or
asthma that is uncontrolled with a SABA alone.
If asthma is uncontrolled in adults (aged 17 and over) on a low dose of ICS as maintenance therapy, offer a leukotriene receptor antagonist (LTRA) in addition to the ICS and review the response to treatment in 4 to 8 weeks.
If asthma is uncontrolled in adults (aged 17 and over) on a low dose of ICS and an LTRA as maintenance therapy, offer a long-acting beta2 agonist (LABA) in combination with the ICS, and review LTRA treatment as follows:
discuss with the person whether or not to continue LTRA treatment
take into account the degree of response to LTRA treatment.
If asthma is uncontrolled in adults (aged 17 and over) on a low dose of ICS and a LABA, with or without an LTRA, as maintenance therapy, offer to change the person's ICS and LABA maintenance therapy to a MART regimen with a low maintenance ICS dose.
If asthma is uncontrolled in adults (aged 17 and over) on a MART regimen with a low maintenance ICS dose, with or without an LTRA, consider increasing the ICS to a moderate maintenance dose (either continuing on a MART regimen or changing to a fixed dose of an ICS and a LABA, with a SABA as a reliever therapy).
If asthma is uncontrolled in adults (aged 17 and over) on a moderate maintenance ICS dose with a LABA (either as MART or a fixed-dose regimen), with or without an LTRA, consider:
increasing the ICS to a high maintenance dose (this should only be offered as part of a fixed-dose regimen, with a SABA used as a reliever therapy) or
a trial of an additional drug (for example, a long-acting muscarinic receptor antagonist or theophylline) or
seeking advice from a healthcare professional with expertise in asthma.
# Pharmacological treatment pathway for children and young people aged 5 to 16
This section is for children and young people with newly diagnosed asthma or asthma that is uncontrolled on their current treatment. Where the recommendations represent a change from traditional clinical practice, children and young people whose asthma is well controlled on their current treatment should not have their treatment changed purely to follow guidance.
In November 2017, the use of some medicines was off label:
Not all LTRAs and LABAs had a UK marketing authorisation for children and young people aged under 18 for the use described in recommendations 1.7.4 and 1.7.5.
The use of MART described in recommendations 1.7.6, 1.7.7 and 1.7.8 was off label in children and young people (aged under 12).
See NICE's information on prescribing medicines.
Offer a SABA as reliever therapy to children and young people (aged 5 to 16) with newly diagnosed asthma.
For children and young people (aged 5 to 16) with asthma who have infrequent, short-lived wheeze and normal lung function, consider treatment with SABA reliever therapy alone.
Offer a paediatric low dose of an ICS as the first-line maintenance therapy to children and young people (aged 5 to 16) with:
symptoms at presentation that clearly indicate the need for maintenance therapy (for example, asthma-related symptoms 3 times a week or more, or causing waking at night) or
asthma that is uncontrolled with a SABA alone.
If asthma is uncontrolled in children and young people (aged 5 to 16) on a paediatric low dose of ICS as maintenance therapy, consider an LTRA in addition to the ICS and review the response to treatment in 4 to 8 weeks.
If asthma is uncontrolled in children and young people (aged 5 to 16) on a paediatric low dose of ICS and an LTRA as maintenance therapy, consider stopping the LTRA and starting a LABA in combination with the ICS.
If asthma is uncontrolled in children and young people (aged 5 to 16) on a paediatric low dose of ICS and a LABA as maintenance therapy, consider changing their ICS and LABA maintenance therapy to a MART regimen with a paediatric low maintenance ICS dose. Ensure that the child or young person is able to understand and comply with the MART regimen.
If asthma is uncontrolled in children and young people (aged 5 to 16) on a MART regimen with a paediatric low maintenance ICS dose, consider increasing the ICS to a paediatric moderate maintenance dose (either continuing on a MART regimen or changing to a fixed dose of an ICS and a LABA, with a SABA as a reliever therapy).
If asthma is uncontrolled in children and young people (aged 5 to 16) on a paediatric moderate maintenance ICS dose with LABA (either as MART or a fixed-dose regimen), consider seeking advice from a healthcare professional with expertise in asthma and consider either:
increasing the ICS dose to paediatric high maintenance dose (only as part of a fixed-dose regimen, with a SABA used as a reliever therapy) or
a trial of an additional drug (for example, theophylline).
# Pharmacological treatment pathway for children under 5
It can be difficult to confirm asthma diagnosis in young children, therefore these recommendations apply to children with suspected or confirmed asthma. Asthma diagnosis should be confirmed when the child is able to undergo objective tests (see the section on diagnosing asthma in young children).
This section is for children under 5 with newly suspected or confirmed asthma, or with asthma symptoms that are uncontrolled on their current treatment. Where the recommendations represent a change from traditional clinical practice, children whose asthma is well controlled on their current treatment should not have their treatment changed purely to follow this guidance.
Offer a SABA as reliever therapy to children under 5 with suspected asthma. This should be used for symptom relief alongside all maintenance therapy.
Consider an 8‑week trial of a paediatric moderate dose of an ICS in children under 5 with:
symptoms at presentation that clearly indicate the need for maintenance therapy (for example, asthma-related symptoms 3 times a week or more, or causing waking at night) or
suspected asthma that is uncontrolled with a SABA alone.
After 8 weeks, stop ICS treatment and continue to monitor the child's symptoms:
if symptoms did not resolve during the trial period, review whether an alternative diagnosis is likely
if symptoms resolved then reoccurred within 4 weeks of stopping ICS treatment, restart the ICS at a paediatric low dose as first-line maintenance therapy
if symptoms resolved but reoccurred beyond 4 weeks after stopping ICS treatment, repeat the 8‑week trial of a paediatric moderate dose of ICS.
If suspected asthma is uncontrolled in children under 5 on a paediatric low dose of ICS as maintenance therapy, consider an LTRA in addition to the ICS. In November 2017, not all LTRAs had a UK marketing authorisation for this use in children aged under 5. See NICE's information on prescribing medicines.
If suspected asthma is uncontrolled in children under 5 on a paediatric low dose of ICS and an LTRA as maintenance therapy, stop the LTRA and refer the child to a healthcare professional with expertise in asthma for further investigation and management.
# Adherence
For guidance on managing non-adherence to medicines in people with asthma, see the NICE guideline on medicines adherence.
# Self-management
For adults, young people and children aged 5 and over with a diagnosis of asthma (and their families or carers if appropriate):
Offer an asthma self-management programme, comprising a written personalised action plan and education.
Explain that pollution can trigger or exacerbate asthma, and include in the personalised action plan approaches for minimising exposure to indoor and outdoor air pollution.For more guidance on how to minimise exposure and the effect of air pollution on health, see:
the recommendations on vulnerable groups in the NICE guideline on air pollution: outdoor air quality and health and
the recommendations on people with asthma, other respiratory conditions or cardiovascular conditions in the NICE guideline on indoor air quality at home.
Within a self-management programme, offer an increased dose of ICS for 7 days to adults (aged 17 and over) who are using an ICS in a single inhaler, when asthma control deteriorates. Clearly outline in the person's asthma action plan how and when to do this, and what to do if symptoms do not improve. When increasing ICS treatment:
consider quadrupling the regular ICS dose
do not exceed the maximum licensed daily dose.
For children and young people aged 5 to 16 with a diagnosis of asthma, include advice in their self-management programme on contacting a healthcare professional for a review if their asthma control deteriorates (see the section on monitoring asthma control).
For children and young people aged 5 to 16 with deteriorating asthma who have not been taking their ICS consistently, explain that restarting regular use may help them to regain control of their asthma. The evidence for increasing ICS doses to self-manage deteriorating asthma control is limited.
Consider an asthma self-management programme, comprising a written personalised action plan (including approaches to minimising exposure to indoor and outdoor air pollution) and education, for the families or carers of children under 5 with suspected or confirmed asthma.
For a short explanation of why the committee made the 2020 recommendations on self-management and removed the 2017 recommendation on increasing ICS treatment within a self-management programme in children and young people and how this might affect practice, see the rationale and impact section on self-management .
Full details of the evidence and the committee's discussion are in evidence review A: increasing ICS treatment within supported self-management for children and young people.
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# Decreasing maintenance therapy
Consider decreasing maintenance therapy when a person's asthma has been controlled with their current maintenance therapy for at least 3 months.
Discuss with the person (or their family or carer if appropriate) the potential risks and benefits of decreasing maintenance therapy.
When reducing maintenance therapy:
Stop or reduce dose of medicines in an order that takes into account the clinical effectiveness when introduced, side effects and the person's preference.
Only consider stopping ICS treatment completely for people who are using low dose ICS alone as maintenance therapy and are symptom free.
Agree with the person (or their family or carer if appropriate) how the effects of decreasing maintenance therapy will be monitored and reviewed, including self-monitoring and a follow‑up with a healthcare professional.
Review and update the person's asthma action plan when decreasing maintenance therapy.
# Risk stratification
Consider using risk stratification to identify people with asthma who are at increased risk of poor outcomes, and use this information to optimise their care. Base risk stratification on factors such as non-adherence to asthma medicines, psychosocial problems and repeated episodes of unscheduled care for asthma.
# Monitoring asthma control
Monitor asthma control at every review. If control is suboptimal:
confirm the person's adherence to prescribed treatment in line with the recommendations on assessing adherence in the NICE guideline on medicines adherence
review the person's inhaler technique
review if treatment needs to be changed
ask about occupational asthma (see recommendation on checking for possible occupational asthma) and/or other triggers, if relevant.
Consider using a validated questionnaire (for example, the Asthma Control Questionnaire or Asthma Control Test) to monitor asthma control in adults (aged 17 and over).
Monitor asthma control at each review in adults, young people and children aged 5 and over using either spirometry or peak flow variability testing.
Do not routinely use FeNO to monitor asthma control.
Consider FeNO measurement as an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids. (This recommendation is from NICE's diagnostics guidance on measuring fractional exhaled nitric oxide concentration in asthma.)
Do not use challenge testing to monitor asthma control.
Observe and give advice on the person's inhaler technique:
at every consultation relating to an asthma attack, in all care settings
when there is deterioration in asthma control
when the inhaler device is changed
at every annual review
if the person asks for it to be checked.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary.
## Expiratory polyphonic wheeze
A wheeze is a continuous, whistling sound produced in the airways during breathing. It is caused by narrowing or obstruction in the airways. An expiratory polyphonic wheeze has multiple pitches and tones heard over different areas of the lung when the person breathes out.
## ICS doses
ICS doses and their pharmacological strengths vary across different formulations. In general, people with asthma should use the smallest doses of ICS that provide optimal control for their asthma, in order to reduce the risk of side effects.
For adults aged 17 and over:
less than or equal to 400 micrograms budesonide or equivalent would be considered a low dose
more than 400 micrograms to 800 micrograms budesonide or equivalent would be considered a moderate dose
more than 800 micrograms budesonide or equivalent would be considered a high dose.
For children and young people aged 16 and under:
less than or equal to 200 micrograms budesonide or equivalent would be considered a paediatric low dose
more than 200 micrograms to 400 micrograms budesonide or equivalent would be considered a paediatric moderate dose
more than 400 micrograms budesonide or equivalent would be considered a paediatric high dose.
## MART
Maintenance and reliever therapy (MART) is a form of combined ICS and LABA treatment in which a single inhaler, containing both ICS and a fast-acting LABA, is used for both daily maintenance therapy and the relief of symptoms as required. MART is only available for ICS and LABA combinations in which the LABA has a fast-acting component (for example, formoterol).
## Objective test to diagnose asthma
Tests carried out to help determine whether a person has asthma, the results of which are not based on the person's symptoms, for example, tests to measure lung function or evidence of inflammation. There is no single objective test to diagnose asthma.
## Risk stratification
Risk stratification is a process of categorising a population by their relative likelihood of experiencing certain outcomes. In the context of this guideline, risk stratification involves categorising people with asthma by their relative likelihood of experiencing negative clinical outcomes (for example, severe exacerbations or hospitalisations). Factors including non-adherence to asthma medicines, psychosocial problems and repeated episodes of unscheduled care can be used to guide risk stratification. Once the population is stratified, the delivery of care for the population can be targeted with the aim of improving the care of the strata with the highest risk.
## Suspected asthma
Suspected asthma describes a potential diagnosis of asthma based on symptoms and response to treatment that has not yet been confirmed with objective tests.
## Uncontrolled asthma
Uncontrolled asthma describes asthma that has an impact on a person's lifestyle or restricts their normal activities. Symptoms such as coughing, wheezing, shortness of breath and chest tightness associated with uncontrolled asthma can significantly decrease a person's quality of life and may lead to a medical emergency. Questionnaires are available that can be quantify this.
This guideline uses the following pragmatic thresholds to define uncontrolled asthma:
-r more days a week with symptoms or
-r more days a week with required use of a SABA for symptomatic relief or
-r more nights a week with awakening due to asthma.# Putting this guideline into practice
NICE is recommending objective testing with spirometry and FeNO for most people with suspected asthma. This is a significant enhancement to current practice, which will take the NHS some time to implement, with additional infrastructure and training needed in primary care. New models of care, being developed locally, could offer the opportunity to implement these recommendations. This may involve establishing diagnostic hubs to make testing efficient and affordable. They will be able to draw on the positive experience of NICE's primary care pilot sites, which trialled the use of FeNO.
The investment and training required to implement the new guidance will take time. In the meantime, primary care services should implement what they can of the new guidelines, using currently available approaches to diagnosis until the infrastructure for objective testing is in place.
NICE has produced tools and resources to help you put this guideline into practice.
Adoption support resource
Resource impact report
Resource impact templates# Recommendations for research
The 2017 guideline committees made the following recommendations for research on diagnosing and monitoring asthma and for managing chronic asthma (marked ). The committee's full set of research recommendations is detailed in the 2017 full guideline on asthma: diagnosis and monitoring and the 2017 full guideline on chronic asthma management.
As part of the 2020 update, the guideline committee made 1 new research recommendation on managing asthma within a self-management programme for children and young people (marked ).
# Diagnosing and monitoring asthma
## Diagnosing asthma in children and young people aged 5 to 16
What is the acceptability and diagnostic accuracy of objective tests that could be used to comprise a diagnostic pathway for asthma in children and young people aged 5 to 16 (for example, exercise challenge, direct bronchial challenge with histamine or methacholine, indirect bronchial challenge with mannitol and peripheral blood eosinophil count)?
## Diagnosing asthma in adults (aged 17 and over)
What is the clinical and cost effectiveness of using an indirect bronchial challenge test with mannitol to diagnose asthma in adults (aged 17 and over)?
## Monitoring adherence to treatment
What is the clinical and cost effectiveness of using electronic alert systems designed to monitor and improve adherence with regular inhaled maintenance therapy in people with asthma?
## Monitoring inhaler technique
What is the current frequency and the current method being used to check the inhaler technique of people with asthma? What is the optimal frequency and the best method of checking inhaler technique to improve clinical outcomes for people with asthma?
## Monitoring asthma control using tele-healthcare
What is the long-term (more than 12 months) clinical and cost effectiveness of using tele-healthcare as a means to monitor asthma control in adults, young people and children? Methods of tele-healthcare can include telephone interview (with healthcare professional involvement) and internet or smartphone-based monitoring support (no healthcare professional involvement).
# Managing chronic asthma
## Increasing the dose of ICS within a personalised self-management programme for children and young people
For children and young people with asthma that is managed in primary care, is there an advantage to increasing the inhaled corticosteroid (ICS) dose when asthma control has deteriorated compared with using the usual dose in a self-management programme?
For a short explanation of why the committee made the recommendation for research, see the rationale on increasing the dose of ICS within a personalised self-management programme for children and young people .
Full details of the research recommendation are in evidence review A: increasing ICS treatment within supported self-management for children and young people.
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## Starting asthma treatment
In adults, young people and children with asthma who have not been treated previously, is it more clinically and cost effective to start treatment with a reliever alone (a short-acting beta2 agonist ) or with a reliever (a SABA) and maintenance therapy (such as ICS)? Are there specific prognostic features that indicate that one of these treatment options may be more appropriate for some groups?
## Second-line maintenance therapy in children and young people (under 16)
Is maintenance therapy more effective with a paediatric low dose of ICS plus a leukotriene receptor antagonist (LTRA) or with a paediatric low dose of ICS plus a long-acting beta2 agonist (LABA) in the treatment of asthma in children and young people (under 16) who have uncontrolled asthma on a paediatric low dose of ICS alone?
## Additional maintenance therapy for asthma uncontrolled on a moderate dose of ICS plus LABA with or without LTRA
What is the clinical and cost effectiveness of offering additional maintenance therapy to adults, young people and children with asthma that is uncontrolled on a moderate dose of ICS plus LABA with or without LTRA?
## Decreasing pharmacological treatment
In adults, young people and children with well-controlled asthma, what are the objective measurements and prognostic factors that indicate that a decrease in regular maintenance treatment is appropriate?
## Improving adherence to asthma medication
What are the most clinically and cost-effective strategies to improve medicines adherence in adults, young people and children with asthma who are non-adherent to prescribed medicines? # Rationale and impact
This section briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Self-management
Recommendations 1.10.3 and 1.10.4
## Why the committee changed the recommendations
The evidence for children and young people found that increasing the dose of inhaled corticosteroid (ICS) when asthma control deteriorates did not result in any benefits or harms compared to the usual dose in terms of reducing subsequent asthma exacerbations. It was limited to only 1 study with a small number of participants who had a personalised action plan. The committee also looked at studies in adults, but agreed that the evidence was not applicable because of the high average age of participants.
The 2017 guideline recommended that quadrupling the dose of ICS could be considered within a self-management programme for children and young people whose asthma is deteriorating. The 2020 update committee agreed that this 2017 recommendation was based on limited evidence, mostly in adults, and that the new evidence identified in this update did not support this. However, it also agreed that there wasn't any significant evidence to suggest that increasing the dose of ICS is harmful compared to the usual dose. Based on their experience, the committee agreed that increasing the dose of ICS within the licensed limit would not adversely affect child growth. This was supported by the evidence, which showed that increasing the ICS dose in the short term did not result in a statistically significant decrease in child growth, even though the doses used in the study exceeded the licensed limit. Therefore, the committee decided to remove the 2017 recommendation rather than replacing it with a recommendation that prohibits increasing the dose of ICS.
The committee discussed the importance of a personalised action plan to guide children and young people if their asthma worsens and to reassure them that they are in control of their treatment. Children and young people who find that increasing their dose of ICS is helpful when their asthma control worsens should be able to continue to do this as an agreed strategy in their action plan. However, based on their experience the committee members agreed that it is important to review the child or young person's self-management plan if their asthma control is deteriorating. Reviews involve checking current medicines and inhaler technique, discussing any factors that may be triggering symptoms, discussing adherence and education needs, and reviewing their action plan. They should be carried out as needed, in addition to annual review. The committee also stressed the importance of continuing regular ICS maintenance therapy, or restarting it if the child or young person has stopped taking it, to prevent deterioration.
The committee discussed the importance of an individualised approach for children and young people, because they have varied and changing support needs at different ages. Studies have shown that most child asthma deaths involve children who have frequent but mild symptoms that are not responding to management in their personalised action plan. This recommendation should help to ensure that these children and young people receive the support that they need if they start to have problems with their asthma control.
The committee agreed that further research is needed to give clearer guidance on increasing the dose of ICS in children and young people within a self-management programme and made a research recommendation on increasing the dose of ICS within a personalised self-management programme for children and young people to promote further research and inform future practice.
## How the recommendations might affect practice
The recommendations will lead to an increase in the review of self-management programmes for children and young people and reduce the variation in current practice for this. The increase in resources needed for this is likely to be offset by a reduction in the cost of treating asthma exacerbations.
Return to recommendations# Context
Asthma is a chronic inflammatory respiratory disease. It can affect people of any age, but often starts in childhood. Asthma is a variable disease which can change throughout a person's life, throughout the year and from day to day. It is characterised by attacks (also known as exacerbations) of breathlessness and wheezing, with the severity and frequency of attacks varying from person to person. The attacks are associated with variable airflow obstruction and inflammation within the lungs, which if left untreated can be life-threatening, however with the appropriate treatment can be reversible.
In 2018, the Global Asthma report estimated that asthma affects 339 million people worldwide. It is the most common chronic condition to affect children, and in the UK approximately 5.4 million people (1.1 million children and 4.3 million adults) currently get treatment for asthma (Asthma UK).
The causes of asthma are not well understood. A number of risk factors are associated with the condition, often in combination. These influences can be genetic (the condition clusters in families) and/or environmental (such as inhalation of allergens or chemical irritants). Occupational causes of asthma in adults are often under-recognised.
There is currently no gold standard test available to diagnose asthma; diagnosis is principally based on a thorough history taken by an experienced clinician. Studies of adults diagnosed with asthma suggest that up to 30% do not have clear evidence of asthma. Some may have had asthma in the past, but it is likely that many have been given an incorrect diagnosis. Conversely, other studies suggest that asthma may be underdiagnosed in some cases.
The diagnosis recommendations will improve patient outcomes and will be cost effective to the NHS in the long-term; NICE's cost impact assessment projects a saving of approximately £12 million per year in England, before implementation costs.
Initial clinical assessment should include questions about symptoms (wheezing, cough, breathing and chest problems) and any personal or family history of allergies, atopic disorders or asthma. Various tests can be used to support a diagnosis, but there is no single test that can definitively diagnose asthma.
A number of methods and assessments are available to determine the likelihood of asthma. These include measuring airflow obstruction (spirometry and peak flow) and assessment of reversibility with bronchodilators, with both methods being widely used in current clinical practice. However, normal results do not exclude asthma and abnormal results do not always mean it is asthma, because they could be indicators of other respiratory diseases or spurious readings.
Testing for airway inflammation is increasingly used as a diagnostic strategy in clinical practice. This includes measuring fractional exhaled nitric oxide (FeNO).
Other diagnostic strategies include blood or skin prick tests to detect allergic reactions to environmental influences, exercise tests to detect evidence of bronchoconstriction, and measures of airway hyperreactivity such as histamine/methacholine or mannitol challenge tests. However, it is debatable which test or measure, or combination of them, is the most effective to accurately diagnose asthma.
It is recognised that asthma control is suboptimal in many people with asthma. This has an impact on their quality of life, their use of healthcare services and the associated costs. Asthma control can be monitored by measuring airway obstruction or inflammation and by using validated questionnaires, but the most effective monitoring strategy is unclear.
The severity of asthma varies; some people have severe asthma that limits normal activities, whereas others are able to lead a relatively normal life. The illness fluctuates during the year and over time, so the level of treatment needs to be tailored to the person's current level of asthma severity. Many people with asthma, particularly children, seem to have fewer symptoms over time, and an important part of management is decreasing treatment if asthma is well controlled.
There is no cure for asthma, so management focuses on reducing exposure to known triggers if possible, relief of symptoms if there is airway narrowing, and reduction in airway inflammation by regular preventive treatment. Adherence to regular treatment reduces the risk of significant asthma attacks in most people with asthma. The focus of asthma management in recent years has been on supporting people with asthma and their healthcare professional to devise a personalised treatment plan that is effective and relatively easy to implement.
The guideline covers children under 5, children and young people aged 5 to 16, and adults aged 17 and over with suspected or diagnosed asthma. The guideline applies to all primary, secondary and community care settings in which NHS-funded care is provided for people with asthma.
The sections on diagnosing and monitoring asthma (sections 1.1 to 1.4 and 1.13) aim to provide clear advice on effectively diagnosing people presenting with new symptoms of suspected asthma and monitoring to ensure optimum asthma control. It is not intended to be used to re‑diagnose people who already have an asthma diagnosis.
The sections on managing chronic asthma (sections 1.5 to 1.12) aim to provide clear advice for healthcare professionals and people with asthma to develop a personalised action plan. The plan should support self-management of asthma, and ensure that the person is receiving the best possible treatment for their current level of illness. It focuses on the pharmacological management of chronic asthma, in particular the treatment pathway for people with uncontrolled asthma. It also covers adherence to treatment, risk stratification and self-management.
The guideline does not cover severe, difficult-to-control asthma or the management of acute asthma attacks.
In 2018, new evidence was identified by the NICE surveillance team on increasing the dose of inhaled corticosteroids within a self-management programme in children and young people with asthma. Topic experts, including those who helped to develop the 2017 guideline, agreed that the new evidence could have an impact on the recommendations. This evidence was reviewed and the recommendations in this area updated.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Initial clinical assessment\n\nSee also algorithm\xa0A for initial clinical assessment in adults, young people and children with suspected asthma.\n\n## Clinical history\n\nTake a structured clinical history in people with suspected asthma. Specifically, check for:\n\nwheeze, cough or breathlessness, and any daily or seasonal variation in these symptoms\n\nany triggers that make symptoms worse\n\na personal or family history of atopic disorders. \n\nDo not use symptoms alone without an objective test to diagnose asthma. \n\nDo not use a history of atopic disorders alone to diagnose asthma. \n\n## Physical examination\n\nExamine people with suspected asthma to identify expiratory polyphonic wheeze and signs of other causes of respiratory symptoms, but be aware that even if examination results are normal the person may still have asthma. \n\n## Initial treatment and objective tests for acute symptoms at presentation\n\nTreat people immediately if they are acutely unwell at presentation, and perform objective tests for asthma (for example, fractional exhaled nitric oxide [FeNO], spirometry and peak flow variability) if the equipment is available and testing will not compromise treatment of the acute episode. \n\nIf objective tests for asthma cannot be done immediately for people who are acutely unwell at presentation, carry them out when acute symptoms have been controlled, and advise people to contact their healthcare professional immediately if they become unwell while waiting to have objective tests. \n\nBe aware that the results of spirometry and FeNO tests may be affected in people who have been treated empirically with inhaled corticosteroids. \n\n## Testing for asthma\n\nDo not offer the following as diagnostic tests for asthma:\n\nskin prick tests to aeroallergens\n\nserum total and specific IgE\n\nperipheral blood eosinophil count\n\nexercise challenge (to adults aged 17\xa0and over). \n\nUse skin prick tests to aeroallergens or specific IgE tests to identify triggers after a formal diagnosis of asthma has been made. \n\n## Occupational asthma\n\nCheck for possible occupational asthma by asking employed people with suspected new-onset asthma, or established asthma that is poorly controlled:\n\nAre symptoms better on days away from work?\n\nAre symptoms better when on holiday (time away from work longer than usual breaks at weekends or between shifts)? Make sure all answers are recorded for later review. \n\nRefer people with suspected occupational asthma to an occupational asthma specialist. \n\n# Diagnosing asthma in young children\n\nFor children under\xa05 with suspected asthma, treat symptoms based on observation and clinical judgement, and review the child on a regular basis (see the section on pharmacological treatment pathway for children under\xa05). If they still have symptoms when they reach 5\xa0years, carry out objective tests (see the section on objective tests for diagnosing asthma in adults, young people and children aged 5\xa0and over and algorithm\xa0B). \n\nIf a child is unable to perform objective tests when they are aged\xa05:\n\ncontinue to treat based on observation and clinical judgement\n\ntry doing the tests again every 6\xa0to 12\xa0months until satisfactory results are obtained\n\nconsider referral for specialist assessment if the child repeatedly cannot perform objective tests and is not responding to treatment. \n\n# Objective tests for diagnosing asthma in adults, young people and children aged 5\xa0and over\n\nSee also table\xa01 for a summary of objective test threshold levels.\n\n## Diagnostic hubs\n\nThose responsible for planning diagnostic service support to primary care (for example, clinical commissioning groups) should consider establishing asthma diagnostic hubs to achieve economies of scale and improve the practicality of implementing the recommendations in this guideline. \n\n## Airway inflammation measures\n\nOffer a FeNO test to adults (aged 17\xa0and over) if a diagnosis of asthma is being considered. Regard a FeNO level of 40\xa0parts per billion (ppb) or more as a positive test. \n\nConsider a FeNO test in children and young people (aged 5\xa0to\xa016) if there is diagnostic uncertainty after initial assessment and they have either:\n\nnormal spirometry or\n\nobstructive spirometry with a negative bronchodilator reversibility (BDR) test.Regard a FeNO level of 35\xa0ppb or more as a positive test. Note: apply the principles in recommendation\xa01.2.2 for young children unable to do the FeNO test adequately. \n\nBe aware that a person's current smoking status can lower FeNO levels both acutely and cumulatively. However, a high level remains useful in supporting a diagnosis of asthma. \n\n## Lung function tests\n\nOffer spirometry to adults, young people and children aged 5\xa0and over if a diagnosis of asthma is being considered. Regard a forced expiratory volume in 1\xa0second/forced vital capacity (FEV1/FVC) ratio of less than 70% (or below the lower limit of normal if this value is available) as a positive test for obstructive airway disease (obstructive spirometry). \n\nOffer a BDR test to adults (aged 17\xa0and over) with obstructive spirometry (FEV1/FVC ratio less than 70%). Regard an improvement in FEV1 of 12% or more, together with an increase in volume of 200\xa0ml or more, as a positive test. \n\nConsider a BDR test in children and young people (aged 5\xa0to\xa016) with obstructive spirometry (FEV1/FVC ratio less than 70%). Regard an improvement in FEV1 of 12% or more as a positive test. \n\nMonitor peak flow variability for 2\xa0to 4\xa0weeks in adults (aged 17\xa0and over) if there is diagnostic uncertainty after initial assessment and a FeNO test and they have either:\n\nnormal spirometry or\n\nobstructive spirometry, reversible airways obstruction (positive BDR) but a FeNO level of 39\xa0ppb or less. Regard a value of more than 20% variability as a positive test. \n\nConsider monitoring peak flow variability for 2\xa0to 4\xa0weeks in adults (aged 17\xa0and over) if there is diagnostic uncertainty after initial assessment and they have:\n\nobstructive spirometry and\n\nirreversible airways obstruction (negative BDR) and\n\na FeNO level between 25\xa0ppb and 39\xa0ppb.Regard a value of more than 20% variability as a positive test. \n\nMonitor peak flow variability for 2\xa0to 4\xa0weeks in children and young people (aged 5\xa0to\xa016) if there is diagnostic uncertainty after initial assessment and a FeNO test and they have either:\n\nnormal spirometry or\n\nobstructive spirometry, irreversible airways obstruction (negative BDR) and a FeNO level of 35\xa0ppb or more.Regard a value of more than 20% variability as a positive test. \n\n## Airway hyperreactivity measures\n\nIn November 2017, the use of histamine and methacholine described in recommendations 1.3.11 and 1.3.12 was off label. See NICE's information on prescribing medicines.\n\nOffer a direct bronchial challenge test with histamine or methacholine to adults (aged 17\xa0and over) if there is diagnostic uncertainty after a normal spirometry and either a:\n\nFeNO level of 40\xa0ppb or more and no variability in peak flow readings or\n\nFeNO level of 39\xa0ppb or less with variability in peak flow readings.Regard a PC20 value of 8\xa0mg/ml or less as a positive test. \n\nConsider a direct bronchial challenge test with histamine or methacholine in adults (aged 17\xa0and over) with:\n\nobstructive spirometry without bronchodilator reversibility and\n\na FeNO level between 25\xa0ppb and 39\xa0ppb and\n\nno variability in peak flow readings (less than 20% variability over 2\xa0to 4\xa0weeks). Regard a PC20 value of 8\xa0mg/ml or less as a positive test. \n\nIf a direct bronchial challenge test with histamine or methacholine is unavailable, suspect asthma and review the diagnosis after treatment, or refer to a centre with access to a histamine or methacholine challenge test. \n\n## Diagnosis in children and young people aged 5\xa0to\xa016\n\nSee also algorithm\xa0B for objective tests in young people and children aged 5\xa0to\xa016.\n\nDiagnose asthma in children and young people (aged 5\xa0to\xa016) if they have symptoms suggestive of asthma and:\n\na FeNO level of 35\xa0ppb or more and positive peak flow variability or\n\nobstructive spirometry and positive bronchodilator reversibility. \n\nSuspect asthma in children and young people (aged 5\xa0to\xa016) if they have symptoms suggestive of asthma and:\n\na FeNO level of 35\xa0ppb or more with normal spirometry and negative peak flow variability or\n\na FeNO level of 35\xa0ppb or more with obstructive spirometry but negative bronchodilator reversibility and no variability in peak flow readings or\n\nnormal spirometry, a FeNO level of 34\xa0ppb or less and positive peak flow variability.Do not rule out other diagnoses if symptom control continues to remain poor after treatment. Review the diagnosis after 6\xa0weeks by repeating any abnormal tests and reviewing symptoms. \n\nRefer children and young people (aged 5\xa0to\xa016) for specialist assessment if they have obstructive spirometry, negative bronchodilator reversibility and a FeNO level of 34\xa0ppb or less. \n\nConsider alternative diagnoses and referral for specialist assessment in children and young people (aged 5\xa0to\xa016) if they have symptoms suggestive of asthma but normal spirometry, a FeNO level of 34\xa0ppb or less and negative peak flow variability. \n\n## Diagnosis in adults aged 17\xa0and over\n\nSee also algorithm\xa0C for objective tests in adults aged 17\xa0and over.\n\nDiagnose asthma in adults (aged 17\xa0and over) if they have symptoms suggestive of asthma and:\n\na FeNO level of 40\xa0ppb or more with either positive bronchodilator reversibility or positive peak flow variability or bronchial hyperreactivity or\n\na FeNO level between 25\xa0ppb and 39\xa0ppb and a positive bronchial challenge test or\n\npositive bronchodilator reversibility and positive peak flow variability irrespective of FeNO level. \n\nSuspect asthma in adults (aged 17\xa0and over) with symptoms suggestive of asthma, obstructive spirometry and:\n\nnegative bronchodilator reversibility, and either a FeNO level of 40\xa0ppb or more, or a FeNO level between 25\xa0ppb and 39\xa0ppb and positive peak flow variability or\n\npositive bronchodilator reversibility, a FeNO level between 25\xa0ppb and 39\xa0ppb and negative peak flow variability.Do not rule out other diagnoses if symptom control continues to remain poor after treatment. Review the diagnosis after 6\xa0to\xa010\xa0weeks by repeating spirometry and objective measures of asthma control and reviewing symptoms. \n\nConsider alternative diagnoses, or referral for a second opinion, in adults (aged 17\xa0and over) with symptoms suggestive of asthma and:\n\na FeNO level below 40\xa0ppb, normal spirometry and positive peak flow variability or\n\na FeNO level of 40\xa0ppb or more but normal spirometry, negative peak flow variability, and negative bronchial challenge test or\n\nobstructive spirometry with bronchodilator reversibility, but a FeNO level below 25\xa0ppb, and negative peak flow variability or\n\npositive peak flow variability but normal spirometry, a FeNO level below 40\xa0ppb, and a negative bronchial challenge test or\n\nobstructive spirometry with negative bronchodilator reversibility, a FeNO level below 25\xa0ppb, and negative peak flow variability (if measured). \n\n## Diagnosis in people who are unable to perform an objective test\n\nFor young children who cannot perform objective tests, see the section on diagnosing asthma in young children.\n\nIf an adult, young person or child with symptoms suggestive of asthma cannot perform a particular test, try to perform at least 2\xa0other objective tests. Diagnose suspected asthma based on symptoms and any positive objective test results. \n\n## Good clinical practice in asthma diagnosis\n\nRecord the basis for a diagnosis of asthma in a single entry in the person's medical records, alongside the coded diagnostic entry. \n\n# Diagnostic summary\n\nThe following algorithms have been produced that summarise clinical assessment and objective testing for asthma. Table\xa01 summarises the objective test threshold levels.\n\nTest\n\nPopulation\n\nPositive result\n\nFractional exhaled nitric oxide (FeNO)\n\nAdults\n\nppb or more\n\nFeNO\n\nChildren and young people\n\nppb or more\n\nObstructive spirometry\n\nAdults, young people and children\n\nForced expiratory volume in 1\xa0second/forced vital capacity (FEV1/FVC) ratio less than 70% (or below the lower limit of normal if this value is available)\n\nBronchodilator reversibility (BDR) test\n\nAdults\n\nImprovement in FEV1 of 12% or more and increase in volume of 200\xa0ml or more\n\nBDR test\n\nChildren and young people\n\nImprovement in FEV1 of 12% or more\n\nPeak flow variability\n\nAdults, young people and children\n\nVariability over 20%\n\nDirect bronchial challenge test with histamine or methacholine\n\nAdults\n\nProvocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of 8\xa0mg/ml or less\n\nDirect bronchial challenge test with histamine or methacholine\n\nChildren and young people\n\nn/a\n\n## Algorithms\n\nA full-size downloadable PDF version of algorithm\xa0A is available in tools and resources.\n\nA full-size downloadable PDF version of algorithm\xa0B is available in tools and resources.\n\nA full-size downloadable PDF version of algorithm\xa0C is available in tools and resources.\n\n# Principles of pharmacological treatment\n\nTake into account the possible reasons for uncontrolled asthma, before starting or adjusting medicines for asthma in adults, young people and children. These may include:\n\nalternative diagnoses\n\nlack of adherence\n\nsuboptimal inhaler technique\n\nsmoking (active or passive)\n\noccupational exposures\n\npsychosocial factors\n\nseasonal or environmental factors. \n\nAfter starting or adjusting medicines for asthma, review the response to treatment in 4\xa0to\xa08\xa0weeks (see the section on monitoring asthma control). \n\nIf inhaled corticosteroid (ICS) maintenance therapy is needed, offer regular daily ICS rather than intermittent or 'when required' ICS therapy. \n\nAdjust maintenance therapy ICS doses over time, aiming for the lowest dose required for effective asthma control. \n\nEnsure that a person with asthma can use their inhaler device:\n\nat any asthma review, either routine or unscheduled\n\nwhenever a new type of device is supplied. \n\n# Pharmacological treatment pathway for adults (aged 17\xa0and over)\n\nThis section is for people with newly diagnosed asthma or asthma that is uncontrolled on their current treatment. Where the recommendations represent a change from traditional clinical practice, people whose asthma is well controlled on their current treatment should not have their treatment changed purely to follow this guidance.\n\nOffer a short-acting beta2 agonist (SABA) as reliever therapy to adults (aged 17\xa0and over) with newly diagnosed asthma. \n\nFor adults (aged 17\xa0and over) with asthma who have infrequent, short-lived wheeze and normal lung function, consider treatment with SABA reliever therapy alone. \n\nOffer a low dose of an ICS as the first-line maintenance therapy to adults (aged 17\xa0and over) with:\n\nsymptoms at presentation that clearly indicate the need for maintenance therapy (for example, asthma-related symptoms 3\xa0times a week or more, or causing waking at night) or\n\nasthma that is uncontrolled with a SABA alone. \n\nIf asthma is uncontrolled in adults (aged 17\xa0and over) on a low dose of ICS as maintenance therapy, offer a leukotriene receptor antagonist (LTRA) in addition to the ICS and review the response to treatment in 4\xa0to\xa08\xa0weeks. \n\nIf asthma is uncontrolled in adults (aged 17\xa0and over) on a low dose of ICS and an LTRA as maintenance therapy, offer a long-acting beta2 agonist (LABA) in combination with the ICS, and review LTRA treatment as follows:\n\ndiscuss with the person whether or not to continue LTRA treatment\n\ntake into account the degree of response to LTRA treatment. \n\nIf asthma is uncontrolled in adults (aged 17\xa0and over) on a low dose of ICS and a LABA, with or without an LTRA, as maintenance therapy, offer to change the person's ICS and LABA maintenance therapy to a MART regimen with a low maintenance ICS dose. \n\nIf asthma is uncontrolled in adults (aged 17\xa0and over) on a MART regimen with a low maintenance ICS dose, with or without an LTRA, consider increasing the ICS to a moderate maintenance dose (either continuing on a MART regimen or changing to a fixed dose of an ICS and a LABA, with a SABA as a reliever therapy). \n\nIf asthma is uncontrolled in adults (aged 17\xa0and over) on a moderate maintenance ICS dose with a LABA (either as MART or a fixed-dose regimen), with or without an LTRA, consider:\n\nincreasing the ICS to a high maintenance dose (this should only be offered as part of a fixed-dose regimen, with a SABA used as a reliever therapy) or\n\na trial of an additional drug (for example, a long-acting muscarinic receptor antagonist or theophylline) or\n\nseeking advice from a healthcare professional with expertise in asthma. \n\n# Pharmacological treatment pathway for children and young people aged 5\xa0to\xa016\n\nThis section is for children and young people with newly diagnosed asthma or asthma that is uncontrolled on their current treatment. Where the recommendations represent a change from traditional clinical practice, children and young people whose asthma is well controlled on their current treatment should not have their treatment changed purely to follow guidance.\n\nIn November 2017, the use of some medicines was off label:\n\nNot all LTRAs and LABAs had a UK marketing authorisation for children and young people aged under\xa018 for the use described in recommendations 1.7.4 and 1.7.5.\n\nThe use of MART described in recommendations 1.7.6, 1.7.7 and 1.7.8 was off label in children and young people (aged under\xa012).\n\nSee NICE's information on prescribing medicines.\n\nOffer a SABA as reliever therapy to children and young people (aged 5\xa0to\xa016) with newly diagnosed asthma. \n\nFor children and young people (aged 5\xa0to\xa016) with asthma who have infrequent, short-lived wheeze and normal lung function, consider treatment with SABA reliever therapy alone. \n\nOffer a paediatric low dose of an ICS as the first-line maintenance therapy to children and young people (aged 5\xa0to\xa016) with:\n\nsymptoms at presentation that clearly indicate the need for maintenance therapy (for example, asthma-related symptoms 3\xa0times a week or more, or causing waking at night) or\n\nasthma that is uncontrolled with a SABA alone. \n\nIf asthma is uncontrolled in children and young people (aged 5\xa0to\xa016) on a paediatric low dose of ICS as maintenance therapy, consider an LTRA in addition to the ICS and review the response to treatment in 4\xa0to\xa08\xa0weeks. \n\nIf asthma is uncontrolled in children and young people (aged 5\xa0to\xa016) on a paediatric low dose of ICS and an LTRA as maintenance therapy, consider stopping the LTRA and starting a LABA in combination with the ICS. \n\nIf asthma is uncontrolled in children and young people (aged 5\xa0to\xa016) on a paediatric low dose of ICS and a LABA as maintenance therapy, consider changing their ICS and LABA maintenance therapy to a MART regimen with a paediatric low maintenance ICS dose. Ensure that the child or young person is able to understand and comply with the MART regimen. \n\nIf asthma is uncontrolled in children and young people (aged 5\xa0to\xa016) on a MART regimen with a paediatric low maintenance ICS dose, consider increasing the ICS to a paediatric moderate maintenance dose (either continuing on a MART regimen or changing to a fixed dose of an ICS and a LABA, with a SABA as a reliever therapy). \n\nIf asthma is uncontrolled in children and young people (aged 5\xa0to\xa016) on a paediatric moderate maintenance ICS dose with LABA (either as MART or a fixed-dose regimen), consider seeking advice from a healthcare professional with expertise in asthma and consider either:\n\nincreasing the ICS dose to paediatric high maintenance dose (only as part of a fixed-dose regimen, with a SABA used as a reliever therapy) or\n\na trial of an additional drug (for example, theophylline). \n\n# Pharmacological treatment pathway for children under 5\n\nIt can be difficult to confirm asthma diagnosis in young children, therefore these recommendations apply to children with suspected or confirmed asthma. Asthma diagnosis should be confirmed when the child is able to undergo objective tests (see the section on diagnosing asthma in young children).\n\nThis section is for children under\xa05 with newly suspected or confirmed asthma, or with asthma symptoms that are uncontrolled on their current treatment. Where the recommendations represent a change from traditional clinical practice, children whose asthma is well controlled on their current treatment should not have their treatment changed purely to follow this guidance.\n\nOffer a SABA as reliever therapy to children under\xa05 with suspected asthma. This should be used for symptom relief alongside all maintenance therapy. \n\nConsider an 8‑week trial of a paediatric moderate dose of an ICS in children under\xa05 with:\n\nsymptoms at presentation that clearly indicate the need for maintenance therapy (for example, asthma-related symptoms 3\xa0times a week or more, or causing waking at night) or\n\nsuspected asthma that is uncontrolled with a SABA alone. \n\nAfter 8\xa0weeks, stop ICS treatment and continue to monitor the child's symptoms:\n\nif symptoms did not resolve during the trial period, review whether an alternative diagnosis is likely\n\nif symptoms resolved then reoccurred within 4\xa0weeks of stopping ICS treatment, restart the ICS at a paediatric low dose as first-line maintenance therapy\n\nif symptoms resolved but reoccurred beyond 4\xa0weeks after stopping ICS treatment, repeat the 8‑week trial of a paediatric moderate dose of ICS. \n\nIf suspected asthma is uncontrolled in children under\xa05 on a paediatric low dose of ICS as maintenance therapy, consider an LTRA in addition to the ICS. In November 2017, not all LTRAs had a UK marketing authorisation for this use in children aged under\xa05. See NICE's information on prescribing medicines.\n\nIf suspected asthma is uncontrolled in children under\xa05 on a paediatric low dose of ICS and an LTRA as maintenance therapy, stop the LTRA and refer the child to a healthcare professional with expertise in asthma for further investigation and management. \n\n# Adherence\n\nFor guidance on managing non-adherence to medicines in people with asthma, see the NICE guideline on medicines adherence. \n\n# Self-management\n\nFor adults, young people and children aged 5\xa0and over with a diagnosis of asthma (and their families or carers if appropriate):\n\nOffer an asthma self-management programme, comprising a written personalised action plan and education.\n\nExplain that pollution can trigger or exacerbate asthma, and include in the personalised action plan approaches for minimising exposure to indoor and outdoor air pollution.For more guidance on how to minimise exposure and the effect of air pollution on health, see:\n\nthe recommendations on vulnerable groups in the NICE guideline on air pollution: outdoor air quality and health\xa0and\n\nthe recommendations on people with asthma, other respiratory conditions or cardiovascular conditions in the NICE guideline on indoor air quality at home. [2017, amended 2021]\n\nWithin a self-management programme, offer an increased dose of ICS for 7\xa0days to adults (aged 17\xa0and over) who are using an ICS in a single inhaler, when asthma control deteriorates. Clearly outline in the person's asthma action plan how and when to do this, and what to do if symptoms do not improve. When increasing ICS treatment:\n\nconsider quadrupling the regular ICS dose\n\ndo not exceed the maximum licensed daily dose. \n\nFor children and young people aged 5\xa0to\xa016 with a diagnosis of asthma, include advice in their self-management programme on contacting a healthcare professional for a review if their asthma control deteriorates (see the section on monitoring asthma control). \n\nFor children and young people aged 5\xa0to\xa016 with deteriorating asthma who have not been taking their ICS consistently, explain that restarting regular use may help them to regain control of their asthma. The evidence for increasing ICS doses to self-manage deteriorating asthma control is limited. \n\nConsider an asthma self-management programme, comprising a written personalised action plan (including approaches to minimising exposure to indoor and outdoor air pollution) and education, for the families or carers of children under 5 with suspected or confirmed asthma. [2017, amended 2021]\n\nFor a short explanation of why the committee made the 2020 recommendations on self-management and removed the 2017 recommendation on increasing ICS treatment within a self-management programme in children and young people and how this might affect practice, see the rationale and impact section on self-management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: increasing ICS treatment within supported self-management for children and young people.\n\nLoading. Please wait.\n\n# Decreasing maintenance therapy\n\nConsider decreasing maintenance therapy when a person's asthma has been controlled with their current maintenance therapy for at least 3\xa0months. \n\nDiscuss with the person (or their family or carer if appropriate) the potential risks and benefits of decreasing maintenance therapy. \n\nWhen reducing maintenance therapy:\n\nStop or reduce dose of medicines in an order that takes into account the clinical effectiveness when introduced, side effects and the person's preference.\n\nOnly consider stopping ICS treatment completely for people who are using low dose ICS alone as maintenance therapy and are symptom free. \n\nAgree with the person (or their family or carer if appropriate) how the effects of decreasing maintenance therapy will be monitored and reviewed, including self-monitoring and a follow‑up with a healthcare professional. \n\nReview and update the person's asthma action plan when decreasing maintenance therapy. \n\n# Risk stratification\n\nConsider using risk stratification to identify people with asthma who are at increased risk of poor outcomes, and use this information to optimise their care. Base risk stratification on factors such as non-adherence to asthma medicines, psychosocial problems and repeated episodes of unscheduled care for asthma. \n\n# Monitoring asthma control\n\nMonitor asthma control at every review. If control is suboptimal:\n\nconfirm the person's adherence to prescribed treatment in line with the recommendations on assessing adherence in the NICE guideline on medicines adherence\n\nreview the person's inhaler technique\n\nreview if treatment needs to be changed\n\nask about occupational asthma (see recommendation on checking for possible occupational asthma) and/or other triggers, if relevant. \n\nConsider using a validated questionnaire (for example, the Asthma Control Questionnaire or Asthma Control Test) to monitor asthma control in adults (aged 17\xa0and over). \n\nMonitor asthma control at each review in adults, young people and children aged 5\xa0and over using either spirometry or peak flow variability testing. \n\nDo not routinely use FeNO to monitor asthma control. \n\nConsider FeNO measurement as an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids. (This recommendation is from NICE's diagnostics guidance on measuring fractional exhaled nitric oxide concentration in asthma.) \n\nDo not use challenge testing to monitor asthma control. \n\nObserve and give advice on the person's inhaler technique:\n\nat every consultation relating to an asthma attack, in all care settings\n\nwhen there is deterioration in asthma control\n\nwhen the inhaler device is changed\n\nat every annual review\n\nif the person asks for it to be checked. \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary.\n\n## Expiratory polyphonic wheeze\n\nA wheeze is a continuous, whistling sound produced in the airways during breathing. It is caused by narrowing or obstruction in the airways. An expiratory polyphonic wheeze has multiple pitches and tones heard over different areas of the lung when the person breathes out.\n\n## ICS doses\n\nICS doses and their pharmacological strengths vary across different formulations. In general, people with asthma should use the smallest doses of ICS that provide optimal control for their asthma, in order to reduce the risk of side effects.\n\nFor adults aged 17\xa0and over:\n\nless than or equal to 400\xa0micrograms budesonide or equivalent would be considered a low dose\n\nmore than 400\xa0micrograms to 800\xa0micrograms budesonide or equivalent would be considered a moderate dose\n\nmore than 800\xa0micrograms budesonide or equivalent would be considered a high dose.\n\nFor children and young people aged 16\xa0and under:\n\nless than or equal to 200\xa0micrograms budesonide or equivalent would be considered a paediatric low dose\n\nmore than 200\xa0micrograms to 400 micrograms budesonide or equivalent would be considered a paediatric moderate dose\n\nmore than 400\xa0micrograms budesonide or equivalent would be considered a paediatric high dose.\n\n## MART\n\nMaintenance and reliever therapy (MART) is a form of combined ICS and LABA treatment in which a single inhaler, containing both ICS and a fast-acting LABA, is used for both daily maintenance therapy and the relief of symptoms as required. MART is only available for ICS and LABA combinations in which the LABA has a fast-acting component (for example, formoterol).\n\n## Objective test to diagnose asthma\n\nTests carried out to help determine whether a person has asthma, the results of which are not based on the person's symptoms, for example, tests to measure lung function or evidence of inflammation. There is no single objective test to diagnose asthma.\n\n## Risk stratification\n\nRisk stratification is a process of categorising a population by their relative likelihood of experiencing certain outcomes. In the context of this guideline, risk stratification involves categorising people with asthma by their relative likelihood of experiencing negative clinical outcomes (for example, severe exacerbations or hospitalisations). Factors including non-adherence to asthma medicines, psychosocial problems and repeated episodes of unscheduled care can be used to guide risk stratification. Once the population is stratified, the delivery of care for the population can be targeted with the aim of improving the care of the strata with the highest risk.\n\n## Suspected asthma\n\nSuspected asthma describes a potential diagnosis of asthma based on symptoms and response to treatment that has not yet been confirmed with objective tests.\n\n## Uncontrolled asthma\n\nUncontrolled asthma describes asthma that has an impact on a person's lifestyle or restricts their normal activities. Symptoms such as coughing, wheezing, shortness of breath and chest tightness associated with uncontrolled asthma can significantly decrease a person's quality of life and may lead to a medical emergency. Questionnaires are available that can be quantify this.\n\nThis guideline uses the following pragmatic thresholds to define uncontrolled asthma:\n\nor more days a week with symptoms or\n\nor more days a week with required use of a SABA for symptomatic relief or\n\nor more nights a week with awakening due to asthma.", 'Putting this guideline into practice': "NICE is recommending objective testing with spirometry and FeNO for most people with suspected asthma. This is a significant enhancement to current practice, which will take the NHS some time to implement, with additional infrastructure and training needed in primary care. New models of care, being developed locally, could offer the opportunity to implement these recommendations. This may involve establishing diagnostic hubs to make testing efficient and affordable. They will be able to draw on the positive experience of NICE's primary care pilot sites, which trialled the use of FeNO.\n\nThe investment and training required to implement the new guidance will take time. In the meantime, primary care services should implement what they can of the new guidelines, using currently available approaches to diagnosis until the infrastructure for objective testing is in place.\n\nNICE has produced tools and resources to help you put this guideline into practice.\n\nAdoption support resource\n\nResource impact report\n\nResource impact templates", 'Recommendations for research': "The 2017 guideline committees made the following recommendations for research on diagnosing and monitoring asthma and for managing chronic asthma (marked ). The committee's full set of research recommendations is detailed in the 2017 full guideline on asthma: diagnosis and monitoring and the 2017 full guideline on chronic asthma management.\n\nAs part of the 2020 update, the guideline committee made 1 new research recommendation on managing asthma within a self-management programme for children and young people (marked ).\n\n# Diagnosing and monitoring asthma\n\n## Diagnosing asthma in children and young people aged 5\xa0to\xa016\n\nWhat is the acceptability and diagnostic accuracy of objective tests that could be used to comprise a diagnostic pathway for asthma in children and young people aged 5\xa0to\xa016 (for example, exercise challenge, direct bronchial challenge with histamine or methacholine, indirect bronchial challenge with mannitol and peripheral blood eosinophil count)? \n\n## Diagnosing asthma in adults (aged 17\xa0and over)\n\nWhat is the clinical and cost effectiveness of using an indirect bronchial challenge test with mannitol to diagnose asthma in adults (aged 17\xa0and over)? \n\n## Monitoring adherence to treatment\n\nWhat is the clinical and cost effectiveness of using electronic alert systems designed to monitor and improve adherence with regular inhaled maintenance therapy in people with asthma? \n\n## Monitoring inhaler technique\n\nWhat is the current frequency and the current method being used to check the inhaler technique of people with asthma? What is the optimal frequency and the best method of checking inhaler technique to improve clinical outcomes for people with asthma? \n\n## Monitoring asthma control using tele-healthcare\n\nWhat is the long-term (more than 12\xa0months) clinical and cost effectiveness of using tele-healthcare as a means to monitor asthma control in adults, young people and children? Methods of tele-healthcare can include telephone interview (with healthcare professional involvement) and internet or smartphone-based monitoring support (no healthcare professional involvement). \n\n# Managing chronic asthma\n\n## Increasing the dose of ICS within a personalised self-management programme for children and young people\n\nFor children and young people with asthma that is managed in primary care, is there an advantage to increasing the inhaled corticosteroid (ICS) dose when asthma control has deteriorated compared with using the usual dose in a self-management programme? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on increasing the dose of ICS within a personalised self-management programme for children and young people\xa0.\n\nFull details of the research recommendation are in evidence review\xa0A: increasing ICS treatment within supported self-management for children and young people.\n\nLoading. Please wait.\n\n## Starting asthma treatment\n\nIn adults, young people and children with asthma who have not been treated previously, is it more clinically and cost effective to start treatment with a reliever alone (a short-acting beta2 agonist [SABA]) or with a reliever (a SABA) and maintenance therapy (such as ICS)? Are there specific prognostic features that indicate that one of these treatment options may be more appropriate for some groups? \n\n## Second-line maintenance therapy in children and young people (under\xa016)\n\nIs maintenance therapy more effective with a paediatric low dose of ICS plus a leukotriene receptor antagonist (LTRA) or with a paediatric low dose of ICS plus a long-acting beta2 agonist (LABA) in the treatment of asthma in children and young people (under\xa016) who have uncontrolled asthma on a paediatric low dose of ICS alone? \n\n## Additional maintenance therapy for asthma uncontrolled on a moderate dose of ICS plus LABA with or without LTRA\n\nWhat is the clinical and cost effectiveness of offering additional maintenance therapy to adults, young people and children with asthma that is uncontrolled on a moderate dose of ICS plus LABA with or without LTRA? \n\n## Decreasing pharmacological treatment\n\nIn adults, young people and children with well-controlled asthma, what are the objective measurements and prognostic factors that indicate that a decrease in regular maintenance treatment is appropriate? \n\n## Improving adherence to asthma medication\n\nWhat are the most clinically and cost-effective strategies to improve medicines adherence in adults, young people and children with asthma who are non-adherent to prescribed medicines? ", 'Rationale and impact': "This section briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Self-management\n\nRecommendations 1.10.3 and 1.10.4\n\n## Why the committee changed the recommendations\n\nThe evidence for children and young people found that increasing the dose of inhaled corticosteroid (ICS) when asthma control deteriorates did not result in any benefits or harms compared to the usual dose in terms of reducing subsequent asthma exacerbations. It was limited to only 1\xa0study with a small number of participants who had a personalised action plan. The committee also looked at studies in adults, but agreed that the evidence was not applicable because of the high average age of participants.\n\nThe 2017 guideline recommended that quadrupling the dose of ICS could be considered within a self-management programme for children and young people whose asthma is deteriorating. The 2020 update committee agreed that this 2017 recommendation was based on limited evidence, mostly in adults, and that the new evidence identified in this update did not support this. However, it also agreed that there wasn't any significant evidence to suggest that increasing the dose of ICS is harmful compared to the usual dose. Based on their experience, the committee agreed that increasing the dose of ICS within the licensed limit would not adversely affect child growth. This was supported by the evidence, which showed that increasing the ICS dose in the short term did not result in a statistically significant decrease in child growth, even though the doses used in the study exceeded the licensed limit. Therefore, the committee decided to remove the 2017 recommendation rather than replacing it with a recommendation that prohibits increasing the dose of ICS.\n\nThe committee discussed the importance of a personalised action plan to guide children and young people if their asthma worsens and to reassure them that they are in control of their treatment. Children and young people who find that increasing their dose of ICS is helpful when their asthma control worsens should be able to continue to do this as an agreed strategy in their action plan. However, based on their experience the committee members agreed that it is important to review the child or young person's self-management plan if their asthma control is deteriorating. Reviews involve checking current medicines and inhaler technique, discussing any factors that may be triggering symptoms, discussing adherence and education needs, and reviewing their action plan. They should be carried out as needed, in addition to annual review. The committee also stressed the importance of continuing regular ICS maintenance therapy, or restarting it if the child or young person has stopped taking it, to prevent deterioration.\n\nThe committee discussed the importance of an individualised approach for children and young people, because they have varied and changing support needs at different ages. Studies have shown that most child asthma deaths involve children who have frequent but mild symptoms that are not responding to management in their personalised action plan. This recommendation should help to ensure that these children and young people receive the support that they need if they start to have problems with their asthma control.\n\nThe committee agreed that further research is needed to give clearer guidance on increasing the dose of ICS in children and young people within a self-management programme and made a research recommendation on increasing the dose of ICS within a personalised self-management programme for children and young people to promote further research and inform future practice.\n\n## How the recommendations might affect practice\n\nThe recommendations will lead to an increase in the review of self-management programmes for children and young people and reduce the variation in current practice for this. The increase in resources needed for this is likely to be offset by a reduction in the cost of treating asthma exacerbations.\n\nReturn to recommendations", 'Context': "Asthma is a chronic inflammatory respiratory disease. It can affect people of any age, but often starts in childhood. Asthma is a variable disease which can change throughout a person's life, throughout the year and from day to day. It is characterised by attacks (also known as exacerbations) of breathlessness and wheezing, with the severity and frequency of attacks varying from person to person. The attacks are associated with variable airflow obstruction and inflammation within the lungs, which if left untreated can be life-threatening, however with the appropriate treatment can be reversible.\n\nIn 2018, the Global Asthma report estimated that asthma affects 339\xa0million people worldwide. It is the most common chronic condition to affect children, and in the UK approximately 5.4\xa0million people (1.1\xa0million children and 4.3\xa0million adults) currently get treatment for asthma (Asthma UK).\n\nThe causes of asthma are not well understood. A number of risk factors are associated with the condition, often in combination. These influences can be genetic (the condition clusters in families) and/or environmental (such as inhalation of allergens or chemical irritants). Occupational causes of asthma in adults are often under-recognised.\n\nThere is currently no gold standard test available to diagnose asthma; diagnosis is principally based on a thorough history taken by an experienced clinician. Studies of adults diagnosed with asthma suggest that up to 30% do not have clear evidence of asthma. Some may have had asthma in the past, but it is likely that many have been given an incorrect diagnosis. Conversely, other studies suggest that asthma may be underdiagnosed in some cases.\n\nThe diagnosis recommendations will improve patient outcomes and will be cost effective to the NHS in the long-term; NICE's cost impact assessment projects a saving of approximately £12\xa0million per year in England, before implementation costs.\n\nInitial clinical assessment should include questions about symptoms (wheezing, cough, breathing and chest problems) and any personal or family history of allergies, atopic disorders or asthma. Various tests can be used to support a diagnosis, but there is no single test that can definitively diagnose asthma.\n\nA number of methods and assessments are available to determine the likelihood of asthma. These include measuring airflow obstruction (spirometry and peak flow) and assessment of reversibility with bronchodilators, with both methods being widely used in current clinical practice. However, normal results do not exclude asthma and abnormal results do not always mean it is asthma, because they could be indicators of other respiratory diseases or spurious readings.\n\nTesting for airway inflammation is increasingly used as a diagnostic strategy in clinical practice. This includes measuring fractional exhaled nitric oxide (FeNO).\n\nOther diagnostic strategies include blood or skin prick tests to detect allergic reactions to environmental influences, exercise tests to detect evidence of bronchoconstriction, and measures of airway hyperreactivity such as histamine/methacholine or mannitol challenge tests. However, it is debatable which test or measure, or combination of them, is the most effective to accurately diagnose asthma.\n\nIt is recognised that asthma control is suboptimal in many people with asthma. This has an impact on their quality of life, their use of healthcare services and the associated costs. Asthma control can be monitored by measuring airway obstruction or inflammation and by using validated questionnaires, but the most effective monitoring strategy is unclear.\n\nThe severity of asthma varies; some people have severe asthma that limits normal activities, whereas others are able to lead a relatively normal life. The illness fluctuates during the year and over time, so the level of treatment needs to be tailored to the person's current level of asthma severity. Many people with asthma, particularly children, seem to have fewer symptoms over time, and an important part of management is decreasing treatment if asthma is well controlled.\n\nThere is no cure for asthma, so management focuses on reducing exposure to known triggers if possible, relief of symptoms if there is airway narrowing, and reduction in airway inflammation by regular preventive treatment. Adherence to regular treatment reduces the risk of significant asthma attacks in most people with asthma. The focus of asthma management in recent years has been on supporting people with asthma and their healthcare professional to devise a personalised treatment plan that is effective and relatively easy to implement.\n\nThe guideline covers children under\xa05, children and young people aged 5\xa0to\xa016, and adults aged 17\xa0and over with suspected or diagnosed asthma. The guideline applies to all primary, secondary and community care settings in which NHS-funded care is provided for people with asthma.\n\nThe sections on diagnosing and monitoring asthma (sections\xa01.1 to 1.4 and 1.13) aim to provide clear advice on effectively diagnosing people presenting with new symptoms of suspected asthma and monitoring to ensure optimum asthma control. It is not intended to be used to re‑diagnose people who already have an asthma diagnosis.\n\nThe sections on managing chronic asthma (sections\xa01.5 to 1.12) aim to provide clear advice for healthcare professionals and people with asthma to develop a personalised action plan. The plan should support self-management of asthma, and ensure that the person is receiving the best possible treatment for their current level of illness. It focuses on the pharmacological management of chronic asthma, in particular the treatment pathway for people with uncontrolled asthma. It also covers adherence to treatment, risk stratification and self-management.\n\nThe guideline does not cover severe, difficult-to-control asthma or the management of acute asthma attacks.\n\nIn 2018, new evidence was identified by the NICE surveillance team on increasing the dose of inhaled corticosteroids within a self-management programme in children and young people with asthma. Topic experts, including those who helped to develop the 2017 guideline, agreed that the new evidence could have an impact on the recommendations. This evidence was reviewed and the recommendations in this area updated."}
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https://www.nice.org.uk/guidance/ng80
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This guideline covers diagnosing, monitoring and managing asthma in adults, young people and children. It aims to improve the accuracy of diagnosis, help people to control their asthma and reduce the risk of asthma attacks. It does not cover managing severe asthma or acute asthma attacks.
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6002f79e661767f259813ce276dbb48eabc5ca92
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nice
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QAngio XA 3D QFR and CAAS vFFR imaging software for assessing coronary stenosis during invasive coronary angiography
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QAngio XA 3D QFR and CAAS vFFR imaging software for assessing coronary stenosis during invasive coronary angiography
Evidence-based recommendations on QAngio XA 3D QFR and CAAS vFFR imaging software for assessing coronary stenosis during invasive coronary angiography.
# Recommendations
There is not enough evidence to recommend using QAngio XA 3D quantitative flow ratio (QAngio QFR) and CAAS vessel fractional flow reserve (CAAS vFFR) during invasive coronary angiography to assess coronary stenosis in stable angina. QAngio QFR's diagnostic accuracy is considered acceptable for assessing coronary stenosis during invasive coronary angiography, but its clinical effectiveness is uncertain. CAAS vFFR's diagnostic accuracy and clinical effectiveness is uncertain. Further research is recommended in both diagnostic-only catheter labs and interventional catheter labs.
Further research is recommended (see section 5) on:
people's experiences of QAngio QFR and CAAS vFFR compared with the reference standard of FFR or instantaneous wave‑free ratio (iFR)
test failure rates of QAngio QFR and CAAS vFFR in clinical practice and how these affect whether revascularisation is done
the clinical benefit of using QAngio QFR and CAAS vFFR
the diagnostic accuracy of CAAS vFFR.
Why the committee made these recommendations
FFR or iFR can be used with invasive coronary angiography to assess coronary stenosis. However, they can have unpleasant side effects and increase the risk of adverse events, such as damage to the artery.
CAAS vFFR and QAngio QFR use X‑ray images taken during an invasive coronary angiography to construct a 3D image of the artery. This image is used to estimate the effect of coronary stenosis on blood flow through the artery without the side effects and risk of adverse events of FFR or iFR.
Published evidence shows that the diagnostic accuracy of QAngio QFR is similar to FFR, but the diagnostic accuracy of CAAS vFFR is very uncertain. Whether QAngio QFR or CAAS vFFR affect clinical outcomes and improve quality of life is also uncertain. Also, in clinical practice the quality of the images varies depending on if they are done in a diagnostic‑only centre or one that offers interventional procedures. Poor image quality might mean the tests fail.
The cost‑effectiveness estimates for CAAS vFFR and QAngio QFR are uncertain but suggest that they are more cost effective than invasive coronary angiography alone. The estimates suggest that, compared with FFR and iFR, CAAS vFFR is less cost effective and QAngio QFR is slightly cheaper but less clinically effective.
There are multiple tests in use that assess coronary stenosis and it is not clear what clinical benefits QAngio QFR and CAAS vFFR offer over these. Therefore, QAngio QFR and CAAS vFFR are not recommended for use in the NHS, and further research is recommended.# The diagnostic tests
# Clinical need and practice
Angina is chest pain caused by insufficient blood supply to the heart (myocardial ischaemia). Stable angina is brought on by physical activity or emotional stress and goes away with rest. It is the key symptom of coronary artery disease, which is one of the main causes of morbidity and mortality in economically developed countries.
Options for managing stable angina include lifestyle advice, drug treatment and revascularisation using percutaneous (stent placement during percutaneous coronary intervention) or surgical techniques (such as coronary artery bypass surgery). Choosing the appropriate management option relies on correctly detecting and characterising coronary stenosis. Therefore, the diagnostic pathway for stable angina:
confirms a diagnosis of stable angina
defines the severity of coronary stenosis, which provides prognostic information and identifies people who are likely to benefit from myocardial revascularisation, in addition to optimal medical therapy.
The NICE guideline on assessment and diagnosis of chest pain of recent onset recommends diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone. It recommends offering 64‑slice (or above) CT coronary angiography as the first-line diagnostic test when:
clinical assessment indicates typical or atypical angina or
clinical assessment indicates non-anginal chest pain but 12-lead resting ECG has been done and indicates ST-T changes or Q waves.
For people in whom 64-slice (or above) CT coronary angiography has shown coronary artery disease of uncertain functional significance, or is non-diagnostic, the guideline recommends offering non-invasive functional imaging for myocardial ischaemia. This could be:
myocardial perfusion scintigraphy with single-photon emission CT (MPS with SPECT) or
stress echocardiography or
first-pass contrast-enhanced magnetic resonance (MR) perfusion or
MR imaging for stress-induced wall motion abnormalities.
If the results of non-invasive functional imaging are inconclusive, invasive coronary angiography is recommended. Invasive coronary angiography shows whether the arteries are blocked or narrowed, and the degree of stenosis. It is usually used as a third-line investigation for stable angina or during the initial stages of percutaneous coronary intervention. However, it is difficult to differentiate between functionally significant and non-significant (not substantially affecting blood supply) coronary stenosis using visual assessment of invasive coronary angiograms.
If it is necessary to more accurately understand the functional significance of a stenosis, fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) measurements can be done during invasive coronary angiography. These invasive techniques use a pressure wire with or without a vasodilator drug, such as adenosine, and can only be done in interventional catheter laboratories.
QAngio XA 3D quantitative flow ratio (QAngio QFR) and CAAS vessel FFR (CAAS vFFR) are analytical software that can be used during invasive coronary angiography to assess the functional significance of coronary stenosis. By avoiding unnecessary invasive measurement of FFR or iFR, these technologies could help avoid the risks associated with passing the pressure wire to the coronary arteries, and with adenosine infusion.
# The interventions
Both tests included in the assessment are CE marked and available to the NHS.
## CAAS vFFR
The CAAS vFFR software (Pie Medical Imaging) works by building a 3D reconstruction of a coronary artery as well as assessing the pressure drop across the stenosis and calculating a vFFR value. Therefore, it gives both anatomical and functional assessments of the stenosis. It uses 2 standard X-ray angiograms, and is compatible with most X-ray systems (that is, it is vendor independent). The company claims that the total analysis time is about 2 minutes per coronary artery. Thresholds for interpretation of vFFR are not provided in the instructions for use document.
## QAngio XA 3D QFR
The QAngio software (Medis Medical Imaging) uses X-ray angiographic images taken during invasive coronary angiography. Two images are needed, which have to be taken with at least 25 degrees difference in viewing angle and with a frame speed of at least 12.5 frames per second. High image quality is crucial for appropriate results. The QAngio software creates a 3D anatomical model of a coronary artery from these 2 images, and then estimates QFR from the 3D vessel anatomy and flow velocity. The company claims that the total analysis time is about 4 to 5 minutes per coronary artery. The analysis time may decrease with routine use of the software. The QFR represents an assessment of the pressure drop over the artery, with a value of 1 representing a normally functioning artery with no pressure drop. A 20% or more drop in blood pressure (QFR value of 0.80 or less) is usually considered a significant obstruction, where revascularisation should be considered.
The QAngio software offers 2 different flow models to calculate QFR:
fixed-flow QFR (fQFR), using fixed-flow velocity and
contrast QFR (cQFR), using contrast frame count in an angiogram without hyperaemia.Fixed-flow QFR is faster to compute, but may be less accurate than contrast QFR.
# The comparator
The comparator is clinical decision making based on the visual interpretation of the images from invasive coronary angiography, alongside clinical judgement. The reference standard for assessing diagnostic accuracy is FFR or iFR.# Evidence
The diagnostics advisory committee considered evidence on QAngio XA 3D quantitative flow ratio (QAngio QFR) and CAAS vessel fractional flow reserve (CAAS vFFR) for assessing coronary stenosis during invasive coronary angiography from several sources. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
The external assessment group (EAG) identified 41 unique studies that met the selection criteria for inclusion in the review. Of the included studies, 39 evaluated QAngio QFR, 3 evaluated CAAS vFFR and only 1 study directly compared QAngio QFR with CAAS vFFR. There were 2 studies that did not report diagnostic accuracy data but included other eligible outcomes. Seventeen of the studies were conference abstracts only, 15 of which were included in the diagnostic accuracy review.
Fifteen of the studies were done in multiple centres. Most studies were done in Asia, including 33 with sites in Japan, 5 in China, 4 in South Korea and 1 site in Singapore. A total of 22 studies had sites in Europe, 3 of which were in the UK. Two of the studies had sites in the US and 2 separate single studies had sites in Brazil and Australia.
Of the 22 QAngio QFR studies, 11 were at low risk of bias. The main source of bias was related to patient selection. The EAG also noted concerns that a high number of studies had been done retrospectively (offline use of QAngio QFR) rather than as part of invasive coronary angiography and before FFR.
Of the CAAS vFFR studies, all did CAAS vFFR analyses retrospectively (offline), and 2 were done at a single centre. Only the ILUMIEN I study had a full text manuscript. This study was considered at high risk of selection bias because of the large percentage of lesions excluded.
## Diagnostic test accuracy
Of the 4 studies reporting the diagnostic accuracy of CAAS vFFR only 1 (ILUMIEN I) reported a 2 x 2 table of diagnostic accuracy, and only 1 presented a Bland–Altman plot (FAST; Masdjedi et al. 2019) from which data were extracted to calculate diagnostic accuracy. Two of the studies were conference abstracts and only reported sensitivity and specificity without confidence intervals (Jin et al. 2019 and FAST EXTEND). One of these studies used an acquisition speed of 7.5 frames per second rather than the 12.5 frames per second recommended in the instructions for use (Jin et al. 2019). There was notable heterogeneity across this small number of studies. The FAST EXTEND study was used in the base-case cost-effectiveness analysis. The ILUMIEN I and Jin et al. (2019) studies were not included in the base-case cost-effectiveness analysis. Instead, they were included in separate scenario analyses to test the sensitivity of the cost-effectiveness results.
The EAG noted that the meta-analyses of the CAAS vFFR studies should be interpreted with caution because imputation of data (replacing missing data with substituted values) was needed. This was for 2 studies on the prevalence of FFR results below and above the cut-off for revascularisation decisions (0.80 or less), and because of the high heterogeneity across studies. The results of these bivariate meta-analyses are summarised in table 1.
Analysis
Sensitivity
% confidence intervals
Specificity
% confidence intervals
Using FAST
(Masdjedi et al. 2019)
to 83.22
to 88.89
Using FAST EXTEND
to 95.11
to 86.95
Only 1 study, reported as a conference abstract, directly compared CAAS vFFR with QAngio QFR. It concluded that diagnostic performance of CAAS vFFR was poorer than for QAngio QFR, with area under the curves of 0.719 (95% confidence interval 0.621 to 0.804) for CAAS vFFR and 0.886 (95% CI 0.807 to 0.940) for contrast QFR (cQFR).
The EAG did a meta-analysis of the included studies, focusing on the diagnostic accuracy of QAngio QFR to detect lesions or vessels needing intervention (defined as having an FFR of 0.80 or less). Two approaches were used. The primary analysis consisted of a meta-analysis of reported diagnostic accuracy data. The secondary analysis used a data extraction approach in which FFR and QAngio QFR values from published plots were extracted and used to calculate diagnostic accuracy. This second approach allowed for a wider range of analyses.
The EAG identified 26 studies with sufficient diagnostic accuracy data to be included in the primary meta-analysis. Both univariate and bivariate meta-analyses of sensitivity and specificity were done and compared. These were divided into 3 modes of QAngio QFR: fixed-flow QFR (fQFR), contrast QFR (cQFR) and studies in which the type of QAngio QFR was not specified. Most studies included in the primary analysis used FFR as the reference standard, using a cut-off of 0.80, although 1 study used instantaneous wave‑free ratio (iFR) as the reference standard. The EAG noted that there was no conclusive evidence of a significant difference between cQFR and fQFR.
In the univariate meta-analysis for the random-effect analysis, QAngio QFR at a cut-off of 0.80 had good diagnostic accuracy to predict FFR (also at a cut-off of 0.80). cQFR had a sensitivity of 85% (95% CI 78% to 90%) and specificity of 91% (95% CI 85% to 95%); fQFR had a sensitivity of 82% (95% CI 68% to 91%) and specificity of 89% (95% CI 77% to 95%). Studies that did not specify the mode of QAngio QFR had a sensitivity of 84% (95% CI 78% to 89%) and specificity of 89% (95% CI 87% to 91%).
Summary positive predictive values were 77% (95% CI 69% to 83%) for fQFR, 85% (95% CI 80% to 89%) for cQFR and 80% (95% CI 76% to 84%) for non-specified QAngio QFR (see figure 27 in the appendix of the diagnostics assessment report). Summary negative predictive values were 92% (95% CI 89% to 94%) for fQFR, 91% (95% CI 85% to 94%) for cQFR and 91% (95% CI 87% to 93%) for non-specified QAngio QFR.
The results of the bivariate meta-analysis were almost identical to the univariate analyses, with no conclusive evidence of a significant difference between fQFR and cQFR. The results of this analysis are summarised in table 2.
Mode
Sensitivity
% confidence intervals
Specificity
% confidence intervals
cQFR
to 89.48
to 95.24
fQFR
to 90.66
to 95.38
Non-specified QFR
to 88.68
to 90.61
cQFR or
non-specified QFR
to 87.85
to 92.45
Abbreviations: QFR, quantitative flow ratio; cQFR, contrast QFR; fQFR, fixed-flow QFR.
The mean difference between QAngio QFR and FFR was almost exactly zero for all 3 modes of QAngio QFR testing. For fQFR the mean difference was 0 (95% CI -0.05 to 0.06), for cQFR the mean difference was -0.01 (95% CI -0.06 to 0.04) and for non-specified QAngio QFR the mean difference was 0.01 (95% CI -0.03 to 0.05). FFR and QAngio QFR were highly correlated in all studies, with correlation coefficients of 0.78 (95% CI 0.72 to 0.82) for fQFR, 0.78 (95% CI 0.70 to 0.85) for cQFR and 0.79 (95% CI 0.73 to 0.83) for non-specified QAngio QFR.
The secondary analysis allowed for a wider range of analyses, such as considering different QAngio QFR and FFR cut-offs, and the effect of using a grey zone, in which people with intermediate QAngio QFR values go on to have confirmatory FFR.
A bivariate meta-analysis of diagnostic accuracy using data extracted from figures gave summary estimates for sensitivity and specificity of 84.6% (95% CI 80.7% to 87.8%) and 87.2% (95% CI 83.4% to 90.3%), respectively. This was similar to the results from the primary analysis when cQFR and non-specified QFR were combined.
QFR, as measured by QAngio, was highly correlated with FFR (r=0.80). In 50% of people, QFR and FFR differed by no more than 0.04. In 95% of people, values differed by no more than 0.14.
In the grey-zone analysis:
If QAngio QFR is more than 0.84: continue without stenting or bypass and defer FFR (test negative).
If QAngio QFR is 0.78 or less: proceed directly to stenting or bypass without FFR (test positive).
If QAngio QFR is between 0.78 and 0.84: do an FFR and proceed based on that result (at 0.80 cut-off).
This strategy increased diagnostic accuracy compared with using QAngio QFR alone. The sensitivity was 93.1% (95% CI 90.1% to 94.9%) and the specificity was 92.1% (95% CI 88.3% to 94.5%). A total of 20.1% of people were in the grey zone and would have confirmatory FFR. However, only 30.4% of people with QAngio QFR results in the grey zone had results that differed from their FFR.
The EAG identified 5 studies included in the meta-analysis that also reported 2 x 2 table data on the diagnostic accuracy of using 2D or 3D invasive coronary angiography alone. These studies used 50% diameter stenosis as the cut-off and FFR of 0.80 or less as the reference standard. Given the small number of studies, and because 2D and 3D invasive coronary angiography may have very different performance, no bivariate meta-analysis of these data was done. However, the results of the individual studies showed that the diagnostic accuracy of invasive coronary angiography was inferior to QAngio QFR.
To inform the economic analysis, the EAG did an additional pragmatic search for studies that compared 2D invasive coronary angiography with FFR assessment. Data extracted from these studies showed that compared with QAngio QFR, the correlation of 2D invasive coronary angiography with FFR was much weaker (correlation coefficient -0.432). A bivariate meta-analysis of these extracted data produced summary sensitivity and specificity estimates of 62.6% (95% CI 51.5% to 72.5%) and 61.6% (95% CI 53.1% to 69.4%), respectively.
## Other intermediate outcomes
The most reported (15 studies) causes of exclusion were issues with image acquisition and quality (for example, lack of at least 2 projections with a 25 degree angle in between, or poor image quality). The second most reported reason for exclusion was anatomical features of arteries (for example, excessive overlapping or foreshortening, ostial lesions, severe tortuosity).
Exclusion rates for QAngio QFR were higher overall in retrospective studies (median 28%, range 6% to 92%) compared with prospective studies (median 17%, range 7% to 52%). This may be partly explained by the fact that invasive coronary angiography images in retrospective studies were less likely to have been collected following manufacturer instructions.
There were only 2 retrospective CAAS vFFR studies that reported exclusion rates, and these were both high at 63% and 65%. In both studies most exclusions were because of angiographic image processing issues such as lack of suitable projections or poor image quality (rather than directly because of CAAS vFFR).
There were 8 studies that reported outcomes data on reproducibility of QAngio QFR readings between 2 different analysts (inter-observer variability). QAngio QFR was found to have a moderate to high level of inter-observer reliability. In 2 studies, CAAS vFFR was also found to have a high level of inter-observer reliability.
There were 8 retrospective studies that reported outcomes data on intra-observer reproducibility of QAngio QFR readings. The time gap between initial and repeated measurements was reported in 4 studies and ranged from 3 days to 2 weeks. Most studies reported a high level of intra-observer reliability for QAngio QFR. One study evaluated both QAngio QFR and CAAS vFFR and found high levels of repeatability and no statistically significant changes between repeated tests.
There were 6 studies of QAngio QFR that reported the time needed to complete QFR analysis. Time to QFR data acquisition ranged from an average of 2 minutes and 7 seconds to 10 minutes (standard deviation 3 minutes). One study of 268 patients reported that time to image acquisition significantly decreased with the number of invasive coronary angiographies analysed, from 5 minutes and 59 seconds to 2 minutes and 7 seconds between the first and last 50 patients.
There were 3 cohort studies that reported mortality or major clinical outcomes in eligible patients with QAngio QFR measurements. All found that a clinically significant QAngio QFR predicted a higher incidence of long-term major cardiovascular adverse events. No data were reported for CAAS vFFR.
Five studies included in the diagnostic accuracy review retrospectively derived a grey-zone strategy based on their diagnostic accuracy results to model a potential reduction in adenosine and FFR use. These results are summarised in table 3.
Study
Grey zone
Diagnostic accuracy of grey-zone strategy (QFR compared with FFR)
Percentage of adenosine or FFR procedures avoided
FAVOR II Europe-Japan Westra (2018)
to 0.86
Sensitivity and specificity more than 95%
Kanno (2019) (A) (conference abstract)
to 0.84
Positive predictive value and negative predictive value more than 90%
Mejia-Renteria (2019)
to 0.84
More than 95% agreement
Smit (2019)
to 0.86
Sensitivity: 95%, specificity: 92.5%
WIFI II
to 0.87
Sensitivity and specificity more than 90%
WIFI II
to 0.90
Sensitivity and specificity more than 95%
Abbreviations: FFR, fractional flow reserve; QFR, quantitative flow ratio.
Because of the lack of published data on QAngio QFR's clinical effectiveness, the EAG did a simulation study to investigate its possible effect on coronary outcomes compared with FFR.
The sample population was taken from data extracted from published Bland–Altman figures. Only cQFR or non-specified QAngio QFR data were used, for 3,193 people, each with an FFR measurement and its associated QAngio QFR measurement. To predict coronary outcomes, the results of the recent IRIS-FFR registry report were used. This represented 5,846 people who either had revascularisation (stent or bypass surgery) or continued with current management without surgery based on their measured FFR result. The IRIS‑FFR study used major adverse cardiovascular events as its primary outcome.
Three strategies for deciding whether to revascularise were investigated:
FFR only: do FFR for all and revascularise if FFR is 0.80 or less.
QAngio QFR only: do QAngio QFR for all and revascularise if QAngio QFR is 0.80 or less, without measuring FFR.
Grey zone: do QAngio QFR for all and:
revascularise if QAngio QFR is 0.78 or less
defer if QAngio QFR is more than 0.84
if QAngio QFR is between 0.78 and 0.84, do FFR and revascularise if FFR is 0.80 or less.
If using the FFR only strategy 40.2% of people would have revascularisation. Using the QAngio QFR only strategy 42.0% would have revascularisation, and using the grey-zone strategy 43.2% would have revascularisation. Using QAngio QFR therefore moderately increased the revascularisation rate, and using it with a grey zone increased it further.
These simulations suggest that using FFR may prevent slightly more major adverse cardiovascular events, at around 1 event per 1,000 people, but the overlap in simulated distributions means it is highly uncertain whether the difference is genuine. By contrast, the simulation suggests that QAngio QFR increases the number of revascularisations done, without substantially improving the number of major adverse cardiovascular events prevented. Overall these simulations suggested that there was little conclusive clinical difference between using QAngio QFR and FFR to make revascularisation decisions.
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG did a search to identify studies investigating the cost effectiveness of using QAngio QFR and CAAS vFFR imaging software to assess the functional significance of coronary stenosis during invasive coronary angiography. No studies were found so a review of published cost-effectiveness studies evaluating invasive coronary angiography (alone or with FFR) in managing coronary artery disease was done. The EAG identified 21 relevant studies and of these, 2 models (Walker et al. 2011 and Genders et al. 2015) were good examples of alternative ways to evaluate diagnostic strategies in patients with suspected stable angina.
For the economic analysis, the following 5 diagnostic strategies were considered:
invasive coronary angiography alone (strategy 1)
invasive coronary angiography followed by confirmatory FFR or instantaneous wave‑free ratio (iFR; reference standard, strategy 2)
invasive coronary angiography with QAngio QFR (strategy 3)
invasive coronary angiography with QAngio QFR, followed by confirmatory FFR or iFR if QFR is inconclusive (strategy 4)
invasive coronary angiography with CAAS vFFR (strategy 5).
## Economic model
The EAG developed a de novo economic model. It was designed to estimate the cost effectiveness of using QAngio QFR and CAAS vFFR during invasive coronary angiography to assess the functional significance of coronary stenosis in people with stable angina whose angiograms showed intermediate stenosis. The model had 2 parts, a diagnostic model and a prognostic model. The diagnostic model was used to link the diagnostic accuracy of QAngio QFR and CAAS vFFR to short-term costs and consequences relating to decisions about revascularisation. The prognostic model took the diagnostic outcomes and modelled the risk of longer-term events, such as myocardial infarction, sudden cardiac death and the need for urgent or unplanned revascularisation.
The population consisted of people with stable coronary artery disease whose invasive coronary angiograms showed intermediate stenosis. The age and sex distribution of the population was derived from the IRIS-FFR registry (mean age of 64 years and 72% men).
The prevalence of functionally significant stenosis in the population was based on studies that reported values of FFR and cQFR or non-specified QFR. It was assumed that the population in these QAngio QFR studies reflected the UK population. This suggested a prior likelihood of functionally significant stenosis of 40.2%, based on the proportion of people in the studies who had an FFR measurement of 0.80 or less.
The proportion of positive or negative test results when using the QAngio QFR, CAAS vFFR or invasive coronary angiography (strategies 3, 5 and 1) was based on the estimated accuracy of the 3 tests. The diagnostic accuracy estimates for these 3 tests are shown in table 4.
Test
Strategy
Analysis
Sensitivity
Specificity
Source
QAngio QFR
Base case
Bivariate meta-analysis for combined cQFR and non-specified QFR mode
QAngio QFR
Scenario
Bivariate meta-analysis for cQFR mode
QAngio QFR
Scenario
Bivariate meta-analysis for fQFR mode
CAAS vFFR
Base case
FAST EXTEND (2019)
CAAS vFFR
Scenario
ILUMIEN I (2019)
CAAS vFFR
Scenario
Jin et al. (2019)
ICA
Base case
Bivariate meta-analysis of 6 studies
ICA
Scenario
Danad et al. (2017) per vessel analysis
Abbreviations: ICA, invasive coronary angiography; QFR, quantitative flow ratio; cQFR, contrast QFR; fQFR, fixed-flow QFR; vFFR, vessel fractional flow reserve.
The diagnostic accuracy of QAngio QFR in strategy 4 was based on the joint distribution of QFR and FFR measurements in the extracted individual-level patient data. The probabilities of QAngio QFR test results being positive (QFR less than 0.78), negative (QFR more than 0.84) or inconclusive (QFR of 0.78 to 0.84) are shown in table 5.
QAngio QFR test result
Probability
Functionally significant stenosis (FFR 0.80 or less)
Non-significant stenosis (FFR 0.80 or more)
Positive
QFR less than 0.78
Inconclusive (grey zone)
QFR 0.78 or more to 0.84 or less
Negative
QFR more than 0.84
Abbreviations: FFR, fractional flow reserve; QFR, quantitative flow ratio.
The rates of FFR and iFR procedural complications applied in the base-case analysis are summarised in table 6.
Serious procedural complication
Rate
Source
Coronary dissection
IRIS-FFR registry
Venous occlusion
IRIS-FFR registry
Ventricular arrhythmia
IRIS-FFR registry
Conduction disturbance needing treatment
IRIS-FFR registry
Bronchospasm
IRIS-FFR registry
Thrombus formation
IRIS-FFR registry
Death
Fearon et al. (2003)
The rate of procedural deaths associated with revascularisation was sourced from UK audit data, which gives a 0.99% death risk for non-emergency coronary artery bypass graft and 0.17% for percutaneous coronary intervention. The mortality rate associated with revascularisation was estimated as a weighted average of the mortality rates for percutaneous coronary intervention and coronary artery bypass graft. This was relative to the proportion of percutaneous coronary interventions and coronary artery bypass graft procedures. In the base case, 87% of revascularisation procedures were assumed to be percutaneous coronary intervention, and 13% were assumed to be coronary artery bypass graft.
The reported 1‑year and long-term (up to 3 years) cumulative incidence of major adverse cardiovascular events in the IRIS‑FFR registry for deferred lesions was used in the model to estimate the baseline risk of major adverse cardiovascular events for the first year and subsequent years. The baseline risk of major adverse cardiovascular events used in the model for people in the group with the highest FFR values (0.91 or more) was 0.64% in the first year and 0.32% per year in subsequent years. The hazard ratios were 1.06 (95% CI 0.99 to 1.13), 1.09 (95% CI 1.05 to 1.14), 1.07 (95% CI 1.06 to 1.09) per 0.01 decrease in FFR for cardiac death, myocardial infarction, and unplanned or urgent revascularisation, respectively.
The treatment effect of revascularisation on major adverse cardiovascular events in people with stable coronary artery disease is highly uncertain. The ISCHEMIA trial, a randomised, parallel, open-label clinical trial comparing revascularisation with optimal medical therapy, did not find evidence that revascularisation reduced the risk of major adverse cardiovascular events. Therefore, in the base-case analysis, the diagnostic tests did not benefit major adverse cardiovascular events outcomes. Scenario analyses were done to explore the effect of this assumption.
By identifying the appropriateness for revascularisation, the tests can have health benefits through greater symptom relief and, therefore, higher health-related quality of life (HRQoL). Because the base-case analysis assumed that there was no treatment effect of revascularisation on major adverse cardiovascular events, the improvement in symptom relief was the only benefit. The HRQoL effects of revascularisation were based on the FAME trials. Both were randomised, parallel, open-label clinical trials. FAME I compared invasive coronary angiography with FFR for guiding percutaneous coronary interventions in patients with multivessel coronary artery disease. FAME II compared clinical outcomes, safety and cost effectiveness of FFR-guided percutaneous coronary intervention with optimal medical treatment alone in patients with stable coronary artery disease. These trials showed that HRQoL improved significantly from baseline after percutaneous coronary intervention.
In the diagnostic model a one-off procedural disutility was applied for people having invasive FFR or iFR and for those who had revascularisation. In the prognostic model, a one-off utility decrement was also applied for people who had a non-fatal myocardial infarction or needed an unplanned revascularisation. A separate utility decrement was applied to the post-myocardial infarction health state, to reflect a decrease in HRQoL for those with a history of myocardial infarction.
The base-case analysis made an assumption that the quality-adjusted life year (QALY) loss applied for FFR or iFR was representative of both types of pressure wire procedures. The QALY loss estimates associated with each procedure in the diagnostic model are summarised in table 7.
Procedure
Mean QALY loss (95% confidence interval)
Source
ICA
Assumed to cancel across strategies
FFR/iFR
(0.0051 to 0.0062)
Assumed the same as for PCI (in the absence of any other source)
PCI
(0.0051 to 0.0062)
Bagust et al. (2006)
CABG
(0.031 to 0.035)
Bagust et al. (2006)
Abbreviations: ICA, invasive coronary angiography; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; QALY, quality-adjusted life year.
The base-case cost of QAngio QFR with a throughput of 200 people per year was £430.61 per person tested. This was based on the purchase of vouchers for 100 people, which covered the cost of the software licence and the training and certification of up to 4 QAngio QFR users, in addition to a staff cost per person tested of £7.76. An update to the QAngio QFR price structure was submitted during consultation. Using the base-case throughput of 200 people per year, the new voucher price reduced the cost to £362.94 per person tested. An alternative annual licence option reduced this further to £223.50 per person tested. The base-case cost of CAAS vFFR with a throughput of 200 people per year was £172.18 per person tested. This included staff training and annual maintenance and was based on the purchase of a perpetual licence, which allows analysis of as many people as needed per year. The model did not consider a cost for invasive coronary angiography because all people who entered the diagnostic model had this test.
The unit cost for FFR and iFR was estimated as the difference between the activity weighted average of the healthcare resource group codes for complex and standard cardiac catheterisation (£436.80).
The following assumptions were applied in the base-case analysis:
A diagnostic threshold of 0.80 was used to define functionally significant stenosis for QAngio QFR and FFR.
A grey-zone boundary of 0.78 to 0.84 for QAngio QFR was used as suggested by the manufacturer of QAngio QFR.
The baseline risk of major adverse cardiovascular events in the absence of revascularisation depends on disease severity as measured by FFR, while the distribution of FFR values differs by diagnostic strategy.
There is no treatment effect of revascularisation on risk of major adverse cardiovascular events, based on the findings of the ISCHEMIA trial.
Costs of QAngio QFR and CAAS vFFR were based on an average annual throughput of 200 people.
The base case assumed all diagnostic procedures took place in an interventional setting. The diagnostic-only setting was considered in scenario analyses.
HRQoL benefits of revascularisation and optimal medical therapy observed at 1 year for the true positive and false negative health states applied for a lifetime duration.
Procedural disutility associated with FFR was equivalent to that of percutaneous coronary intervention.
The deterministic and probabilistic cost-effectiveness results for the base-case analysis, expressed in terms of net health benefit at a maximum acceptable incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, are shown in tables 8 and 9, respectively. The incremental net health benefit was calculated for each strategy compared with invasive coronary angiography alone. The results were consistent for both the deterministic and probabilistic analysis.
Strategy
Identification
Total QALYs
Total costs
NHB
INHB
NHB rank
ICA alone
ICA with FFR
ICA with QAngio QFR
ICA with QAngio QFR and confirmatory FFR (grey zone)
ICA with CAAS vFFR
NHB and INHB are measured at a maximum acceptable ICER of £20,000 per QALY gained. Incremental NHB is relative to ICA alone. Abbreviations: ICA, invasive coronary angiography; FFR, fractional flow reserve; QFR, quantitative flow ratio; vFFR, vessel FFR; QALY, quality-adjusted life year; NHB, net health benefit; INHB, incremental NHB.
Strategy
Identification
Total QALYs
Total costs
NHB
INHB
NHB rank
Probability cost effective at £20,000 per QALY gained
ICA alone
ICA with FFR
ICA with QAngio QFR
ICA with QAngio QFR and confirmatory FFR (grey zone)
ICA with CAAS vFFR
NHB and INHB are measured at a maximum acceptable ICER of £20,000 per QALY gained. Incremental NHB is relative to ICA alone. Abbreviations: ICA, invasive coronary angiography; FFR, fractional flow reserve; QFR, quantitative flow ratio; vFFR, vessel FFR; QALY, quality-adjusted life year; NHB, net health benefit; INHB, incremental NHB.
Strategy 2 (invasive coronary angiography with FFR) had the highest net health benefit and the highest probability of being cost effective, although the differences between all the strategies were small. Strategy 1 (invasive coronary angiography alone) was the cheapest and had the lowest QALY gain, while strategy 5 (invasive coronary angiography with vFFR) was the most expensive and had the highest QALY gain.
Results from the scenario analyses showed that the base-case results were generally robust when alterations were made to the sources of data used in the model and when different assumptions were made. However, sometimes these alterations resulted in significant changes to the net health benefit rankings of the different strategies.
In the base case, the diagnostic accuracy estimates for vFFR were based on the FAST EXTEND study (sensitivity 97.0% and specificity 74.0%), the largest study of vFFR (330 patients). Using accuracy estimates from ILUMIEN I reduced the cost effectiveness of vFFR, but estimates from Jin et al. (2019) increased it. This resulted in vFFR being the second most cost-effective strategy. This highlighted the substantial uncertainty surrounding the cost effectiveness of vFFR in strategy 5.
When QAngio QFR was considered to have the same diagnostic accuracy as FFR (that is, 100% sensitivity and specificity), the total QALYs and costs for strategy 3 increased by 0.017 QALYs and £6 per person from the base-case scenario. In this scenario strategy 3 became cost effective with the highest net health benefit, largely because of greater total QALYs gained for strategy 3 compared with strategy 2. This difference was mainly because of the procedural disutility associated with FFR or iFR.
When the procedural disutility of FFR was more than that used in the base case, the net health benefit of strategies 2 and 4 were affected most. The total QALYs for both strategies were reduced, resulting in strategy 2 becoming the second least cost effective and strategy 3 the most cost effective. An FFR disutility of 0.014 QALYs resulted in an equal net health benefit for strategies 2 and 3. This procedural disutility was 2.5 times greater than that associated with percutaneous coronary intervention, but less than half the disutility associated with coronary artery bypass graft.
In terms of how duration of HRQoL affected cost effectiveness, the benefits need to last for at least 7 years to offset the disutility associated with FFR or iFR in the base case for strategy 2 to remain more cost effective than strategy 3.
The benefits of revascularisation, in terms of improved HRQoL, suggested that the sensitivity of test results was a more important driver of cost effectiveness than specificity. This was because true positive test results translated into higher QALY gains than mismanagement of false negative test results.
In a diagnostic-only setting, the large additional costs of repeating diagnostic catheterisation at a subsequent appointment in an interventional centre for strategies involving measuring FFR or iFR (strategies 2 and 4) meant that strategies without this testing component were more cost effective. Strategy 3 (QAngio QFR alone) became the strategy with the highest net benefit, followed by strategy 5 (CAAS vFFR alone).# Committee discussion
# Clinical need
## FFR and iFR are not frequently used so QAngio QFR and CAAS vFFR may help with decision making during invasive coronary angiography
Clinical experts explained that in general, physiological testing using fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) is available but not frequently used in the UK. People typically have an invasive coronary angiography after a previous functional test (see section 2.4). Sometimes decisions about revascularisation are based on the images from the invasive coronary angiography, results of the previous tests and patient history. If the revascularisation decision is still uncertain after invasive coronary angiography, people may be referred for FFR or iFR. Using QAngio XA 3D quantitative flow ratio (QAngio QFR) and CAAS vessel FFR (CAAS vFFR) during invasive coronary angiography may provide more information to help with decision making. It could also mean that in some cases clinical decisions could be made without needing FFR.
## Less invasive tests may benefit patients and carers by reducing anxiety, unpleasant side effects and risk of complications
A patient expert explained the potential benefits of testing using QAngio QFR or CAAS vFFR. These included reduced anxiety, discomfort and distress than more invasive testing, which may be needed if a definitive treatment decision cannot be made during the initial invasive coronary angiography. Using an invasive test like FFR with a pressure wire means using an adenosine infusion. The committee noted that around 30% of people may experience chest pain and shortness of breath from this. These side effects usually pass quickly but can be distressing. Around 3% of people may experience discomfort from the pressure wire itself and there is a small risk of rupture of the blood vessel. By avoiding adenosine infusion and a pressure wire, QAngio QFR and CAAS vFFR could reduce unpleasant side effects and risk of complications.
# Clinical effectiveness
## The diagnostic accuracy evidence for CAAS vFFR is highly uncertain
The committee noted that there were only 3 studies using CAAS vFFR that matched the inclusion criteria for review in the diagnostics assessment report. These included 500 patients. The external assessment group (EAG) explained that there was notable heterogeneity across this small number of studies and that the meta-analyses of the CAAS vFFR studies should be interpreted with caution. Where reported, there was a high exclusion rate because of angiographic image processing issues. In 2 of the studies, the technology was not used in the way it was intended (ILUMIEN I and Jin et al. 2019). The committee concluded that the diagnostic accuracy of CAAS vFFR was highly uncertain and recommended further research (see research recommendation 5.4).
## The diagnostic accuracy of QAngio QFR appears to be similar to FFR
The committee noted that 39 studies using QAngio QFR matched the inclusion criteria for the review in the diagnostics assessment report. These included 5,440 patients. These studies showed that QAngio QFR had good diagnostic accuracy to predict the FFR result. The clinical experts explained that there was good agreement between QFR and FFR values particularly at the extremes of measurement. While there was some disagreement between QFR and FFR results within the grey zone, (in the range of 0.78 to 0.84), the clinical experts noted that there is likely to be a limited clinical effect of not identifying someone with an FFR of between 0.76 and 0.80, that is, a false negative result. A more significant effect could occur for people with an FFR result of less than 0.76 who have a negative result on QAngio QFR (0.80 or higher). The EAG noted that modelling suggested around 3% of people with an FFR result of less than 0.76 would be misdiagnosed if using QFR for functional imaging. Clinical experts also explained that with FFR values close to the 0.80 cut-off, it is unclear whether there is any added benefit of revascularisation compared to optimal medical therapy. The committee concluded that there was good agreement between QAngio QFR and FFR values. Although there was some uncertainty around the grey zone, this was not a particular concern.
## Technical failure rates in diagnostic-only centres may be higher because of lower quality angiography images
In the UK, invasive coronary angiography is usually done in diagnostic-only catheter laboratories or in interventional catheter laboratories that can also do percutaneous coronary intervention in the same procedure. Clinical experts explained that the quality of angiography images from diagnostic-only centres was generally lower than those from interventional centres. This is because in the diagnostic centre, invasive coronary angiography is done so the information can be used to guide decisions about what further testing and treatment might be needed. In the interventional centre, invasive coronary angiography is often done to help plan percutaneous coronary intervention. Clinical experts noted that QAngio QFR and CAAS vFFR need high-quality angiography images so in diagnostic centres the tests may have a high technical failure rate. The committee concluded that because all the data considered were from interventional centres, it was not certain what the technical failure rate would be in diagnostic-only centres.
## It is unclear how clinical history and symptoms affect clinical decisions based on QAngio QFR or CAAS vFFR results
The NICE guideline on assessment and diagnosis of chest pain of recent onset recommends invasive coronary angiography as a third-line test. People who have invasive coronary angiography should have already had a previous assessment such as 64-slice coronary angiography and non-invasive functional imaging tests, but this may vary between centres. Some people may also have HeartFlow FFRCT which is recommended in the NICE medical technologies guidance on HeartFlow FFRCT for estimating FFR from coronary CT angiography. The clinical experts explained that these previous assessments can rule out the need for interventional treatment. Therefore, it is likely that people who do go on to have invasive coronary angiography have more severe disease than the people in the diagnostic accuracy studies. While the previous functional assessments may be used to guide further testing decisions such as whether to do an FFR, the QAngio QFR and CAAS vFFR results would be used to guide high-level treatment decisions with substantial consequences. Therefore, clinicians need to be confident that making a decision based on the results of these tests would lead to improved outcomes for patients. The committee commented that the diagnostic accuracy studies did not incorporate clinical history and the effect that symptoms had on decision making based on the QAngio QFR result. Therefore, it is unclear how this additional information combined with a QAngio QFR or CAAS vFFR result affects clinical decision making about revascularisation.
## QAngio QFR may slightly increase revascularisation rates compared with FFR but this is uncertain
The EAG did a simulation study analysis to investigate the possible effect of using QAngio QFR compared with invasive coronary angiography and FFR on coronary outcomes such as revascularisation rates and major adverse cardiovascular events. QAngio QFR (with or without a grey zone) led to slightly more revascularisations compared with FFR (40.2% revascularisations using FFR compared with 42.0% for QAngio QFR and 43.2% using the grey-zone strategy). Both methods prevented broadly the same number of major adverse cardiovascular events (FFR may prevent more major adverse cardiovascular events but only for 1 in 1,000 people). However, the committee noted that the simulation study made numerous assumptions, so its results were uncertain.
## Clinical outcome data from large endpoint studies for QAngio QFR and CAAS vFFR are needed
The clinical experts noted the lack of prospective outcome data when a QAngio QFR or CAAS vFFR-based approach was used to guide revascularisation decisions after invasive coronary angiography. The clinical experts explained that there was a need for clinical outcome data from large endpoint studies comparing these imaging software with FFR or invasive coronary angiography‑guided treatment. There are already multiple tests in the care pathway, and it was unclear how QAngio QFR or CAAS vFFR could offer additional clinical benefit. There are currently 2 ongoing clinical trials of QAngio QFR. The FAVOR III Europe-Japan study will compare QFR with standard FFR-guided percutaneous coronary intervention, and the FAVOR III China study will compare QFR with angiography‑alone guided percutaneous coronary intervention. These trials will be completed in December 2023 and February 2023, respectively. There is 1 ongoing trial of CAAS vFFR. The LIPSIA STRATEGY trial will compare vFFR with FFR for the assessment of intermediate coronary stenosis and is due to be completed in November 2026. The committee concluded that data from trials like these are essential to be confident that revascularisation decisions based on QAngio QFR or CAAS vFFR results would improve patient outcomes (see research recommendation 5.3).
# Cost effectiveness
## The disutility associated with FFR or iFR used in the model may not be appropriate
In the model the procedural disutility for FFR was assumed to be the same as for percutaneous coronary intervention. This was because no data were available on the disutility of FFR. The clinical experts explained that this assumption may not accurately reflect the actual side effects or people's experiences of the procedure. The EAG also looked at different scenario analyses where the disutility of FFR was increased. The committee commented that a disutility equivalent to percutaneous coronary intervention was likely too high. This affected the cost effectiveness of FFR more than might be expected in clinical practice. It noted further that there were important differences between FFR and iFR that were considered the same in the model. Because iFR does not need a hyperaemic agent such as adenosine, it avoids the associated unpleasant side effects. This disutility was a key driver of the cost-effectiveness results, but because of a lack of evidence it was uncertain what disutility should be used. The committee recommended further research into the disutility associated with FFR (see research recommendation 5.1).
## Test costs may not be accurate because test failure rates are not adequately captured in the model
Test failure rates were high in the studies, especially the retrospective ones, because the invasive coronary angiography images were not good enough to run QAngio QFR and CAAS vFFR. The committee noted that in clinical practice some images may not be of a sufficient quality for the software programs to produce a result. Therefore, the cost per test may have been underestimated because test failure rates were not factored into the model. Only people who had a QAngio QFR or CAAS vFFR result were included. The EAG did a scenario analysis in which patient throughput was varied, which affected the cost per test. However, the committee noted that this may not have explored a wide enough range to sufficiently capture this effect. It suggested that failure rates in routine clinical practice would be reduced over time as the operator gained experience in using the system. However, the clinical experts explained that this may be dependent on the setting, with sub-optimal angiography images more likely in diagnostic-only centres (see section 4.5). The committee concluded that further research on QAngio QFR and CAAS vFFR failure rates in clinical practice would be beneficial (see research recommendation 5.2).
## QAngio QFR and CAAS vFFR are more cost effective than invasive coronary angiography alone, but the results are uncertain
In the base case QAngio QFR was within the range NICE considers cost effective compared with invasive coronary angiography alone in both the deterministic and probabilistic analyses. However, the clinical experts commented that the strategy of invasive coronary angiography alone was not representative of clinical practice, where the results of previous tests and people's preferences would also influence a treatment decision (see section 4.6). The committee noted that similar results were seen for CAAS vFFR but concluded that there was greater uncertainty in this result because of the lack of diagnostic accuracy evidence.
## More data are needed because the clinical utility and cost effectiveness of QAngio QFR and CAAS vFFR are uncertain
Compared with the reference standard of FFR or iFR, QAngio QFR (with and without a grey zone) and CAAS vFFR were less cost effective (generated less quality-adjusted life years but were slightly cheaper) in the base-case analysis. However, the committee noted that a review of the accuracy of FFR or iFR was not done by the EAG and they were assumed in the model to be 100% accurate. It also noted that the difference between the new technologies and the reference standard was small at 0.007 QALYs or £140 per person for QAngio QFR and 0.011 QALYs or £220 per person for CAAS vFFR. Following an update to the price structure of QAngio QFR by the company during consultation, QAngio QFR using an annual licence became slightly cheaper but remained less clinically effective than the reference standard of FFR or iFR. However, given the small difference in costs and outcomes, the committee reiterated the need for clinical outcome data from studies that directly compare QAngio QFR and CAAS vFFR with FFR or iFR (see research recommendation 5.3). These data would give clinicians confidence in their decision making based on the results of the tests. The committee concluded that given the uncertainty in clinical utility the cost-effectiveness results were also uncertain.
## The potential role of QAngio QFR and CAAS vFFR in a diagnostic-only setting is unclear
In a scenario analysis in which the tests were done in a diagnostic-only setting, QAngio QFR and CAAS vFFR became the most cost effective options in the fully incremental analyses. This was because of the additional cost of onward referral for the reference standard tests. However, clinical experts explained that fewer people are having invasive coronary angiography because it is recommended as a third-line test in the NICE guideline on assessment and diagnosis of chest pain of recent onset (see section 4.6). The appropriate use of CT coronary angiography and functional testing has resulted in a fall in the number of people having invasive coronary angiography in diagnostic-only centres. Having an angiographic procedure in an interventional centre means that invasive coronary angiography, FFR or iFR and percutaneous coronary intervention can be done in a single visit, if appropriate. This reduces the need for multiple hospital visits, which has the potential to reduce people's anxiety. A clinical expert explained that according to 2017 to 2018 data from the National Institute of Cardiovascular Outcomes Research, around 35,000 invasive coronary angiography procedures were done in diagnostic-only settings, compared with around 205,000 in interventional centres. The committee concluded that the future role of QAngio QFR and CAAS vFFR in a diagnostic-only setting is unclear because diagnostic-only catheter laboratories are likely to decline in number.
## QAngio QFR and CAAS vFFR are not recommended for routine use
The committee noted that QAngio QFR and CAAS vFFR were more cost effective than invasive coronary angiography alone. QAngio QFR using the proposed annual licence was slightly cheaper but less clinically effective than FFR or iFR. However, the incremental difference in terms of costs and QALYs between the tests was small. For CAAS vFFR, the committee recalled that the diagnostic accuracy data was highly uncertain so it could not be recommended for routine use. The committee noted further that there were no clinical outcome studies for QAngio QFR or CAAS vFFR, which meant that the EAG had to make assumptions about treatment decisions and clinical outcomes, which led to uncertainty in the results. The clinical experts commented that these tests may be used to guide high-level clinical decisions about treatment, so clinicians need to be confident when making decisions based on the tests' results. The committee considered that clinical utility is uncertain and more data are needed. There were concerns around the results of the simulation study that showed that QAngio QFR could lead to an increase in revascularisations (see section 4.7). The committee also recalled the trend in clinical practice of moving away from diagnostic-only settings to interventional centres (see section 4.13) and considered that there was too much uncertainty to consider QAngio QFR and CAAS vFFR in this scenario. The committee concluded that because of the uncertainty in diagnostic accuracy and clinical evidence, CAAS vFFR was not recommended. Despite having good diagnostic accuracy evidence, QAngio QFR should not be recommended for use until further data showing that it improves patient outcomes are available.# Recommendations for further research
A patient experience study is recommended to better understand the general effect on patients of having an invasive coronary angiography and the range and severity of side effects and complications from QAngio XA 3D quantitative flow ratio (QAngio QFR), CAAS vessel fractional flow reserve (CAAS vFFR), FFR and instantaneous wave-free ratio.
Further research is recommended on test failure rates of QAngio QFR and CAAS vFFR and how these affect clinical decision making for revascularisation in clinical practice.
Outcome studies are needed to understand the clinical benefit of using QAngio QFR and CAAS vFFR (see section 4.8). These include rates of major adverse cardiovascular events, mortality and EQ-5D data to assess the effect on quality of life.
More diagnostic accuracy studies are needed for CAAS vFFR against an appropriate reference standard.
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{'Recommendations': "There is not enough evidence to recommend using QAngio XA 3D quantitative flow ratio (QAngio QFR) and CAAS vessel fractional flow reserve (CAAS vFFR) during invasive coronary angiography to assess coronary stenosis in stable angina. QAngio QFR's diagnostic accuracy is considered acceptable for assessing coronary stenosis during invasive coronary angiography, but its clinical effectiveness is uncertain. CAAS vFFR's diagnostic accuracy and clinical effectiveness is uncertain. Further research is recommended in both diagnostic-only catheter labs and interventional catheter labs.\n\nFurther research is recommended (see section 5) on:\n\npeople's experiences of QAngio QFR and CAAS vFFR compared with the reference standard of FFR or instantaneous wave‑free ratio (iFR)\n\ntest failure rates of QAngio QFR and CAAS vFFR in clinical practice and how these affect whether revascularisation is done\n\nthe clinical benefit of using QAngio QFR and CAAS vFFR\n\nthe diagnostic accuracy of CAAS vFFR.\n\nWhy the committee made these recommendations\n\nFFR or iFR can be used with invasive coronary angiography to assess coronary stenosis. However, they can have unpleasant side effects and increase the risk of adverse events, such as damage to the artery.\n\nCAAS vFFR and QAngio QFR use X‑ray images taken during an invasive coronary angiography to construct a 3D image of the artery. This image is used to estimate the effect of coronary stenosis on blood flow through the artery without the side effects and risk of adverse events of FFR or iFR.\n\nPublished evidence shows that the diagnostic accuracy of QAngio QFR is similar to FFR, but the diagnostic accuracy of CAAS vFFR is very uncertain. Whether QAngio QFR or CAAS vFFR affect clinical outcomes and improve quality of life is also uncertain. Also, in clinical practice the quality of the images varies depending on if they are done in a diagnostic‑only centre or one that offers interventional procedures. Poor image quality might mean the tests fail.\n\nThe cost‑effectiveness estimates for CAAS vFFR and QAngio QFR are uncertain but suggest that they are more cost effective than invasive coronary angiography alone. The estimates suggest that, compared with FFR and iFR, CAAS vFFR is less cost effective and QAngio QFR is slightly cheaper but less clinically effective.\n\nThere are multiple tests in use that assess coronary stenosis and it is not clear what clinical benefits QAngio QFR and CAAS vFFR offer over these. Therefore, QAngio QFR and CAAS vFFR are not recommended for use in the NHS, and further research is recommended.", 'The diagnostic tests': '# Clinical need and practice\n\nAngina is chest pain caused by insufficient blood supply to the heart (myocardial ischaemia). Stable angina is brought on by physical activity or emotional stress and goes away with rest. It is the key symptom of coronary artery disease, which is one of the main causes of morbidity and mortality in economically developed countries.\n\nOptions for managing stable angina include lifestyle advice, drug treatment and revascularisation using percutaneous (stent placement during percutaneous coronary intervention) or surgical techniques (such as coronary artery bypass surgery). Choosing the appropriate management option relies on correctly detecting and characterising coronary stenosis. Therefore, the diagnostic pathway for stable angina:\n\nconfirms a diagnosis of stable angina\n\ndefines the severity of coronary stenosis, which provides prognostic information and identifies people who are likely to benefit from myocardial revascularisation, in addition to optimal medical therapy.\n\nThe NICE guideline on assessment and diagnosis of chest pain of recent onset recommends diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone. It recommends offering 64‑slice (or above) CT coronary angiography as the first-line diagnostic test when:\n\nclinical assessment indicates typical or atypical angina or\n\nclinical assessment indicates non-anginal chest pain but 12-lead resting ECG has been done and indicates ST-T changes or Q waves.\n\nFor people in whom 64-slice (or above) CT coronary angiography has shown coronary artery disease of uncertain functional significance, or is non-diagnostic, the guideline recommends offering non-invasive functional imaging for myocardial ischaemia. This could be:\n\nmyocardial perfusion scintigraphy with single-photon emission CT (MPS with SPECT) or\n\nstress echocardiography or\n\nfirst-pass contrast-enhanced magnetic resonance (MR) perfusion or\n\nMR imaging for stress-induced wall motion abnormalities.\n\nIf the results of non-invasive functional imaging are inconclusive, invasive coronary angiography is recommended. Invasive coronary angiography shows whether the arteries are blocked or narrowed, and the degree of stenosis. It is usually used as a third-line investigation for stable angina or during the initial stages of percutaneous coronary intervention. However, it is difficult to differentiate between functionally significant and non-significant (not substantially affecting blood supply) coronary stenosis using visual assessment of invasive coronary angiograms.\n\nIf it is necessary to more accurately understand the functional significance of a stenosis, fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) measurements can be done during invasive coronary angiography. These invasive techniques use a pressure wire with or without a vasodilator drug, such as adenosine, and can only be done in interventional catheter laboratories.\n\nQAngio XA 3D quantitative flow ratio (QAngio QFR) and CAAS vessel FFR (CAAS vFFR) are analytical software that can be used during invasive coronary angiography to assess the functional significance of coronary stenosis. By avoiding unnecessary invasive measurement of FFR or iFR, these technologies could help avoid the risks associated with passing the pressure wire to the coronary arteries, and with adenosine infusion.\n\n# The interventions\n\nBoth tests included in the assessment are CE marked and available to the NHS.\n\n## CAAS vFFR\n\nThe CAAS vFFR software (Pie Medical Imaging) works by building a 3D reconstruction of a coronary artery as well as assessing the pressure drop across the stenosis and calculating a vFFR value. Therefore, it gives both anatomical and functional assessments of the stenosis. It uses 2 standard X-ray angiograms, and is compatible with most X-ray systems (that is, it is vendor independent). The company claims that the total analysis time is about 2\xa0minutes per coronary artery. Thresholds for interpretation of vFFR are not provided in the instructions for use document.\n\n## QAngio XA 3D QFR\n\nThe QAngio software (Medis Medical Imaging) uses X-ray angiographic images taken during invasive coronary angiography. Two images are needed, which have to be taken with at least 25\xa0degrees difference in viewing angle and with a frame speed of at least 12.5\xa0frames per second. High image quality is crucial for appropriate results. The QAngio software creates a 3D anatomical model of a coronary artery from these 2\xa0images, and then estimates QFR from the 3D vessel anatomy and flow velocity. The company claims that the total analysis time is about 4 to 5\xa0minutes per coronary artery. The analysis time may decrease with routine use of the software. The QFR represents an assessment of the pressure drop over the artery, with a value of 1 representing a normally functioning artery with no pressure drop. A 20% or more drop in blood pressure (QFR value of 0.80 or less) is usually considered a significant obstruction, where revascularisation should be considered.\n\nThe QAngio software offers 2 different flow models to calculate QFR:\n\nfixed-flow QFR (fQFR), using fixed-flow velocity and\n\ncontrast QFR (cQFR), using contrast frame count in an angiogram without hyperaemia.Fixed-flow QFR is faster to compute, but may be less accurate than contrast QFR.\n\n# The comparator\n\nThe comparator is clinical decision making based on the visual interpretation of the images from invasive coronary angiography, alongside clinical judgement. The reference standard for assessing diagnostic accuracy is FFR or iFR.', 'Evidence': "The diagnostics advisory committee considered evidence on QAngio XA 3D quantitative flow ratio (QAngio QFR) and CAAS vessel fractional flow reserve (CAAS vFFR) for assessing coronary stenosis during invasive coronary angiography from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) identified 41 unique studies that met the selection criteria for inclusion in the review. Of the included studies, 39 evaluated QAngio QFR, 3 evaluated CAAS vFFR and only 1\xa0study directly compared QAngio QFR with CAAS vFFR. There were 2\xa0studies that did not report diagnostic accuracy data but included other eligible outcomes. Seventeen of the studies were conference abstracts only, 15 of which were included in the diagnostic accuracy review.\n\nFifteen of the studies were done in multiple centres. Most studies were done in Asia, including 33 with sites in Japan, 5 in China, 4 in South Korea and 1 site in Singapore. A total of 22\xa0studies had sites in Europe, 3 of which were in the UK. Two of the studies had sites in the US and 2 separate single studies had sites in Brazil and Australia.\n\nOf the 22 QAngio QFR studies, 11 were at low risk of bias. The main source of bias was related to patient selection. The EAG also noted concerns that a high number of studies had been done retrospectively (offline use of QAngio QFR) rather than as part of invasive coronary angiography and before FFR.\n\nOf the CAAS vFFR studies, all did CAAS vFFR analyses retrospectively (offline), and 2 were done at a single centre. Only the ILUMIEN I study had a full text manuscript. This study was considered at high risk of selection bias because of the large percentage of lesions excluded.\n\n## Diagnostic test accuracy\n\nOf the 4\xa0studies reporting the diagnostic accuracy of CAAS vFFR only 1 (ILUMIEN I) reported a 2 x 2 table of diagnostic accuracy, and only 1 presented a Bland–Altman plot (FAST; Masdjedi et al. 2019) from which data were extracted to calculate diagnostic accuracy. Two of the studies were conference abstracts and only reported sensitivity and specificity without confidence intervals (Jin et al. 2019 and FAST EXTEND). One of these studies used an acquisition speed of 7.5\xa0frames per second rather than the 12.5\xa0frames per second recommended in the instructions for use (Jin et al. 2019). There was notable heterogeneity across this small number of studies. The FAST EXTEND study was used in the base-case cost-effectiveness analysis. The ILUMIEN I and Jin et al. (2019) studies were not included in the base-case cost-effectiveness analysis. Instead, they were included in separate scenario analyses to test the sensitivity of the cost-effectiveness results.\n\nThe EAG noted that the meta-analyses of the CAAS vFFR studies should be interpreted with caution because imputation of data (replacing missing data with substituted values) was needed. This was for 2\xa0studies on the prevalence of FFR results below and above the cut-off for revascularisation decisions (0.80 or less), and because of the high heterogeneity across studies. The results of these bivariate meta-analyses are summarised in table 1.\n\nAnalysis\n\nSensitivity\n\n% confidence intervals\n\nSpecificity\n\n% confidence intervals\n\nUsing FAST\n\n(Masdjedi et al. 2019)\n\n\n\nto 83.22\n\n\n\nto 88.89\n\nUsing FAST EXTEND\n\n\n\nto 95.11\n\n\n\nto 86.95\n\nOnly 1\xa0study, reported as a conference abstract, directly compared CAAS vFFR with QAngio QFR. It concluded that diagnostic performance of CAAS vFFR was poorer than for QAngio QFR, with area under the curves of 0.719 (95% confidence interval [CI] 0.621 to 0.804) for CAAS vFFR and 0.886 (95% CI 0.807 to 0.940) for contrast QFR (cQFR).\n\nThe EAG did a meta-analysis of the included studies, focusing on the diagnostic accuracy of QAngio QFR to detect lesions or vessels needing intervention (defined as having an FFR of 0.80 or less). Two approaches were used. The primary analysis consisted of a meta-analysis of reported diagnostic accuracy data. The secondary analysis used a data extraction approach in which FFR and QAngio QFR values from published plots were extracted and used to calculate diagnostic accuracy. This second approach allowed for a wider range of analyses.\n\nThe EAG identified 26\xa0studies with sufficient diagnostic accuracy data to be included in the primary meta-analysis. Both univariate and bivariate meta-analyses of sensitivity and specificity were done and compared. These were divided into 3\xa0modes of QAngio QFR: fixed-flow QFR (fQFR), contrast QFR (cQFR) and studies in which the type of QAngio QFR was not specified. Most studies included in the primary analysis used FFR as the reference standard, using a cut-off of 0.80, although 1\xa0study used instantaneous wave‑free ratio (iFR) as the reference standard. The EAG noted that there was no conclusive evidence of a significant difference between cQFR and fQFR.\n\nIn the univariate meta-analysis for the random-effect analysis, QAngio QFR at a cut-off of 0.80 had good diagnostic accuracy to predict FFR (also at a cut-off of 0.80). cQFR had a sensitivity of 85% (95% CI 78% to 90%) and specificity of 91% (95% CI 85% to 95%); fQFR had a sensitivity of 82% (95% CI 68% to 91%) and specificity of 89% (95% CI 77% to 95%). Studies that did not specify the mode of QAngio QFR had a sensitivity of 84% (95% CI 78% to 89%) and specificity of 89% (95% CI 87% to 91%).\n\nSummary positive predictive values were 77% (95% CI 69% to 83%) for fQFR, 85% (95% CI 80% to 89%) for cQFR and 80% (95% CI 76% to 84%) for non-specified QAngio QFR (see figure\xa027 in the appendix of the diagnostics assessment report). Summary negative predictive values were 92% (95% CI 89% to 94%) for fQFR, 91% (95% CI 85% to 94%) for cQFR and 91% (95% CI 87% to 93%) for non-specified QAngio QFR.\n\nThe results of the bivariate meta-analysis were almost identical to the univariate analyses, with no conclusive evidence of a significant difference between fQFR and cQFR. The results of this analysis are summarised in table 2.\n\nMode\n\nSensitivity\n\n% confidence intervals\n\nSpecificity\n\n% confidence intervals\n\ncQFR\n\n\n\nto 89.48\n\n\n\nto 95.24\n\nfQFR\n\n\n\nto 90.66\n\n\n\nto 95.38\n\nNon-specified QFR\n\n\n\nto 88.68\n\n\n\nto 90.61\n\ncQFR or\n\nnon-specified QFR\n\n\n\nto 87.85\n\n\n\nto 92.45\n\nAbbreviations: QFR, quantitative flow ratio; cQFR, contrast QFR; fQFR, fixed-flow QFR.\n\nThe mean difference between QAngio QFR and FFR was almost exactly zero for all 3 modes of QAngio QFR testing. For fQFR the mean difference was 0 (95% CI -0.05 to 0.06), for cQFR the mean difference was -0.01 (95% CI -0.06 to 0.04) and for non-specified QAngio QFR the mean difference was 0.01 (95% CI -0.03 to 0.05). FFR and QAngio QFR were highly correlated in all studies, with correlation coefficients of 0.78 (95% CI 0.72 to 0.82) for fQFR, 0.78 (95% CI 0.70 to 0.85) for cQFR and 0.79 (95% CI 0.73 to 0.83) for non-specified QAngio QFR.\n\nThe secondary analysis allowed for a wider range of analyses, such as considering different QAngio QFR and FFR cut-offs, and the effect of using a grey zone, in which people with intermediate QAngio QFR values go on to have confirmatory FFR.\n\nA bivariate meta-analysis of diagnostic accuracy using data extracted from figures gave summary estimates for sensitivity and specificity of 84.6% (95% CI 80.7% to 87.8%) and 87.2% (95% CI 83.4% to 90.3%), respectively. This was similar to the results from the primary analysis when cQFR and non-specified QFR were combined.\n\nQFR, as measured by QAngio, was highly correlated with FFR (r=0.80). In 50% of people, QFR and FFR differed by no more than 0.04. In 95% of people, values differed by no more than 0.14.\n\nIn the grey-zone analysis:\n\nIf QAngio QFR is more than 0.84: continue without stenting or bypass and defer FFR (test negative).\n\nIf QAngio QFR is 0.78 or less: proceed directly to stenting or bypass without FFR (test positive).\n\nIf QAngio QFR is between 0.78 and 0.84: do an FFR and proceed based on that result (at 0.80 cut-off).\n\nThis strategy increased diagnostic accuracy compared with using QAngio QFR alone. The sensitivity was 93.1% (95% CI 90.1% to 94.9%) and the specificity was 92.1% (95% CI 88.3% to 94.5%). A total of 20.1% of people were in the grey zone and would have confirmatory FFR. However, only 30.4% of people with QAngio QFR results in the grey zone had results that differed from their FFR.\n\nThe EAG identified 5\xa0studies included in the meta-analysis that also reported 2 x 2 table data on the diagnostic accuracy of using 2D or 3D invasive coronary angiography alone. These studies used 50% diameter stenosis as the cut-off and FFR of 0.80 or less as the reference standard. Given the small number of studies, and because 2D and 3D invasive coronary angiography may have very different performance, no bivariate meta-analysis of these data was done. However, the results of the individual studies showed that the diagnostic accuracy of invasive coronary angiography was inferior to QAngio QFR.\n\nTo inform the economic analysis, the EAG did an additional pragmatic search for studies that compared 2D invasive coronary angiography with FFR assessment. Data extracted from these studies showed that compared with QAngio QFR, the correlation of 2D invasive coronary angiography with FFR was much weaker (correlation coefficient -0.432). A bivariate meta-analysis of these extracted data produced summary sensitivity and specificity estimates of 62.6% (95% CI 51.5% to 72.5%) and 61.6% (95% CI 53.1% to 69.4%), respectively.\n\n## Other intermediate outcomes\n\nThe most reported (15\xa0studies) causes of exclusion were issues with image acquisition and quality (for example, lack of at least 2\xa0projections with a 25\xa0degree angle in between, or poor image quality). The second most reported reason for exclusion was anatomical features of arteries (for example, excessive overlapping or foreshortening, ostial lesions, severe tortuosity).\n\nExclusion rates for QAngio QFR were higher overall in retrospective studies (median 28%, range 6% to 92%) compared with prospective studies (median 17%, range 7% to 52%). This may be partly explained by the fact that invasive coronary angiography images in retrospective studies were less likely to have been collected following manufacturer instructions.\n\nThere were only 2 retrospective CAAS vFFR studies that reported exclusion rates, and these were both high at 63% and 65%. In both studies most exclusions were because of angiographic image processing issues such as lack of suitable projections or poor image quality (rather than directly because of CAAS vFFR).\n\nThere were 8\xa0studies that reported outcomes data on reproducibility of QAngio QFR readings between 2 different analysts (inter-observer variability). QAngio QFR was found to have a moderate to high level of inter-observer reliability. In 2\xa0studies, CAAS vFFR was also found to have a high level of inter-observer reliability.\n\nThere were 8 retrospective studies that reported outcomes data on intra-observer reproducibility of QAngio QFR readings. The time gap between initial and repeated measurements was reported in 4\xa0studies and ranged from 3\xa0days to 2\xa0weeks. Most studies reported a high level of intra-observer reliability for QAngio QFR. One study evaluated both QAngio QFR and CAAS vFFR and found high levels of repeatability and no statistically significant changes between repeated tests.\n\nThere were 6\xa0studies of QAngio QFR that reported the time needed to complete QFR analysis. Time to QFR data acquisition ranged from an average of 2\xa0minutes and 7\xa0seconds to 10\xa0minutes (standard deviation 3\xa0minutes). One study of 268\xa0patients reported that time to image acquisition significantly decreased with the number of invasive coronary angiographies analysed, from 5\xa0minutes and 59\xa0seconds to 2\xa0minutes and 7\xa0seconds between the first and last 50\xa0patients.\n\nThere were 3 cohort studies that reported mortality or major clinical outcomes in eligible patients with QAngio QFR measurements. All found that a clinically significant QAngio QFR predicted a higher incidence of long-term major cardiovascular adverse events. No data were reported for CAAS vFFR.\n\nFive studies included in the diagnostic accuracy review retrospectively derived a grey-zone strategy based on their diagnostic accuracy results to model a potential reduction in adenosine and FFR use. These results are summarised in table 3.\n\nStudy\n\nGrey zone\n\nDiagnostic accuracy of grey-zone strategy (QFR compared with FFR)\n\nPercentage of adenosine or FFR procedures avoided\n\nFAVOR II Europe-Japan Westra (2018)\n\nto 0.86\n\nSensitivity and specificity more than 95%\n\n%\n\nKanno (2019) (A) (conference abstract)\n\nto 0.84\n\nPositive predictive value and negative predictive value more than 90%\n\n%\n\nMejia-Renteria (2019)\n\nto 0.84\n\nMore than 95% agreement\n\n%\n\nSmit (2019)\n\nto 0.86\n\nSensitivity: 95%, specificity: 92.5%\n\n%\n\nWIFI II\n\nto 0.87\n\nSensitivity and specificity more than 90%\n\n%\n\nWIFI II\n\nto 0.90\n\nSensitivity and specificity more than 95%\n\n%\n\nAbbreviations: FFR, fractional flow reserve; QFR, quantitative flow ratio.\n\nBecause of the lack of published data on QAngio QFR's clinical effectiveness, the EAG did a simulation study to investigate its possible effect on coronary outcomes compared with FFR.\n\nThe sample population was taken from data extracted from published Bland–Altman figures. Only cQFR or non-specified QAngio QFR data were used, for 3,193\xa0people, each with an FFR measurement and its associated QAngio QFR measurement. To predict coronary outcomes, the results of the recent IRIS-FFR registry report were used. This represented 5,846\xa0people who either had revascularisation (stent or bypass surgery) or continued with current management without surgery based on their measured FFR result. The IRIS‑FFR study used major adverse cardiovascular events as its primary outcome.\n\nThree strategies for deciding whether to revascularise were investigated:\n\nFFR only: do FFR for all and revascularise if FFR is 0.80 or less.\n\nQAngio QFR only: do QAngio QFR for all and revascularise if QAngio QFR is 0.80 or less, without measuring FFR.\n\nGrey zone: do QAngio QFR for all and:\n\n\n\nrevascularise if QAngio QFR is 0.78 or less\n\ndefer if QAngio QFR is more than 0.84\n\nif QAngio QFR is between 0.78 and 0.84, do FFR and revascularise if FFR is 0.80 or less.\n\n\n\nIf using the FFR only strategy 40.2% of people would have revascularisation. Using the QAngio QFR only strategy 42.0% would have revascularisation, and using the grey-zone strategy 43.2% would have revascularisation. Using QAngio QFR therefore moderately increased the revascularisation rate, and using it with a grey zone increased it further.\n\nThese simulations suggest that using FFR may prevent slightly more major adverse cardiovascular events, at around 1\xa0event per 1,000\xa0people, but the overlap in simulated distributions means it is highly uncertain whether the difference is genuine. By contrast, the simulation suggests that QAngio QFR increases the number of revascularisations done, without substantially improving the number of major adverse cardiovascular events prevented. Overall these simulations suggested that there was little conclusive clinical difference between using QAngio QFR and FFR to make revascularisation decisions.\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG did a search to identify studies investigating the cost effectiveness of using QAngio QFR and CAAS vFFR imaging software to assess the functional significance of coronary stenosis during invasive coronary angiography. No studies were found so a review of published cost-effectiveness studies evaluating invasive coronary angiography (alone or with FFR) in managing coronary artery disease was done. The EAG identified 21 relevant studies and of these, 2\xa0models (Walker et al. 2011 and Genders et al. 2015) were good examples of alternative ways to evaluate diagnostic strategies in patients with suspected stable angina.\n\nFor the economic analysis, the following 5 diagnostic strategies were considered:\n\ninvasive coronary angiography alone (strategy\xa01)\n\ninvasive coronary angiography followed by confirmatory FFR or instantaneous wave‑free ratio (iFR; reference standard, strategy\xa02)\n\ninvasive coronary angiography with QAngio QFR (strategy\xa03)\n\ninvasive coronary angiography with QAngio QFR, followed by confirmatory FFR or iFR if QFR is inconclusive (strategy\xa04)\n\ninvasive coronary angiography with CAAS vFFR (strategy\xa05).\n\n## Economic model\n\nThe EAG developed a de novo economic model. It was designed to estimate the cost effectiveness of using QAngio QFR and CAAS vFFR during invasive coronary angiography to assess the functional significance of coronary stenosis in people with stable angina whose angiograms showed intermediate stenosis. The model had 2\xa0parts, a diagnostic model and a prognostic model. The diagnostic model was used to link the diagnostic accuracy of QAngio QFR and CAAS vFFR to short-term costs and consequences relating to decisions about revascularisation. The prognostic model took the diagnostic outcomes and modelled the risk of longer-term events, such as myocardial infarction, sudden cardiac death and the need for urgent or unplanned revascularisation.\n\nThe population consisted of people with stable coronary artery disease whose invasive coronary angiograms showed intermediate stenosis. The age and sex distribution of the population was derived from the IRIS-FFR registry (mean age of 64\xa0years and 72% men).\n\nThe prevalence of functionally significant stenosis in the population was based on studies that reported values of FFR and cQFR or non-specified QFR. It was assumed that the population in these QAngio QFR studies reflected the UK population. This suggested a prior likelihood of functionally significant stenosis of 40.2%, based on the proportion of people in the studies who had an FFR measurement of 0.80 or less.\n\nThe proportion of positive or negative test results when using the QAngio QFR, CAAS vFFR or invasive coronary angiography (strategies 3, 5 and 1) was based on the estimated accuracy of the 3 tests. The diagnostic accuracy estimates for these 3 tests are shown in table 4.\n\nTest\n\nStrategy\n\nAnalysis\n\nSensitivity\n\nSpecificity\n\nSource\n\nQAngio QFR\n\n\n\nBase case\n\n%\n\n%\n\nBivariate meta-analysis for combined cQFR and non-specified QFR mode\n\nQAngio QFR\n\n\n\nScenario\n\n%\n\n%\n\nBivariate meta-analysis for cQFR mode\n\nQAngio QFR\n\n\n\nScenario\n\n%\n\n%\n\nBivariate meta-analysis for fQFR mode\n\nCAAS vFFR\n\n\n\nBase case\n\n%\n\n%\n\nFAST EXTEND (2019)\n\nCAAS vFFR\n\n\n\nScenario\n\n%\n\n%\n\nILUMIEN I (2019)\n\nCAAS vFFR\n\n\n\nScenario\n\n%\n\n%\n\nJin et al. (2019)\n\nICA\n\n\n\nBase case\n\n%\n\n%\n\nBivariate meta-analysis of 6 studies\n\nICA\n\n\n\nScenario\n\n%\n\n%\n\nDanad et al. (2017) per vessel analysis\n\nAbbreviations: ICA, invasive coronary angiography; QFR, quantitative flow ratio; cQFR, contrast QFR; fQFR, fixed-flow QFR; vFFR, vessel fractional flow reserve.\n\nThe diagnostic accuracy of QAngio QFR in strategy 4 was based on the joint distribution of QFR and FFR measurements in the extracted individual-level patient data. The probabilities of QAngio QFR test results being positive (QFR less than 0.78), negative (QFR more than 0.84) or inconclusive (QFR of 0.78 to 0.84) are shown in table 5.\n\nQAngio QFR test result\n\nProbability\n\nFunctionally significant stenosis (FFR 0.80 or less)\n\nNon-significant stenosis (FFR 0.80 or more)\n\nPositive\n\nQFR less than 0.78\n\n\n\n\n\nInconclusive (grey zone)\n\nQFR 0.78 or more to 0.84 or less\n\n\n\n\n\nNegative\n\nQFR more than 0.84\n\n\n\n\n\nAbbreviations: FFR, fractional flow reserve; QFR, quantitative flow ratio.\n\nThe rates of FFR and iFR procedural complications applied in the base-case analysis are summarised in table 6.\n\nSerious procedural complication\n\nRate\n\nSource\n\nCoronary dissection\n\n%\n\nIRIS-FFR registry\n\nVenous occlusion\n\n%\n\nIRIS-FFR registry\n\nVentricular arrhythmia\n\n%\n\nIRIS-FFR registry\n\nConduction disturbance needing treatment\n\n%\n\nIRIS-FFR registry\n\nBronchospasm\n\n%\n\nIRIS-FFR registry\n\nThrombus formation\n\n%\n\nIRIS-FFR registry\n\nDeath\n\n%\n\nFearon et al. (2003)\n\nThe rate of procedural deaths associated with revascularisation was sourced from UK audit data, which gives a 0.99% death risk for non-emergency coronary artery bypass graft and 0.17% for percutaneous coronary intervention. The mortality rate associated with revascularisation was estimated as a weighted average of the mortality rates for percutaneous coronary intervention and coronary artery bypass graft. This was relative to the proportion of percutaneous coronary interventions and coronary artery bypass graft procedures. In the base case, 87% of revascularisation procedures were assumed to be percutaneous coronary intervention, and 13% were assumed to be coronary artery bypass graft.\n\nThe reported 1‑year and long-term (up to 3\xa0years) cumulative incidence of major adverse cardiovascular events in the IRIS‑FFR registry for deferred lesions was used in the model to estimate the baseline risk of major adverse cardiovascular events for the first year and subsequent years. The baseline risk of major adverse cardiovascular events used in the model for people in the group with the highest FFR values (0.91 or more) was 0.64% in the first year and 0.32% per year in subsequent years. The hazard ratios were 1.06 (95% CI 0.99 to 1.13), 1.09 (95% CI 1.05 to 1.14), 1.07 (95% CI 1.06 to 1.09) per 0.01 decrease in FFR for cardiac death, myocardial infarction, and unplanned or urgent revascularisation, respectively.\n\nThe treatment effect of revascularisation on major adverse cardiovascular events in people with stable coronary artery disease is highly uncertain. The ISCHEMIA trial, a randomised, parallel, open-label clinical trial comparing revascularisation with optimal medical therapy, did not find evidence that revascularisation reduced the risk of major adverse cardiovascular events. Therefore, in the base-case analysis, the diagnostic tests did not benefit major adverse cardiovascular events outcomes. Scenario analyses were done to explore the effect of this assumption.\n\nBy identifying the appropriateness for revascularisation, the tests can have health benefits through greater symptom relief and, therefore, higher health-related quality of life (HRQoL). Because the base-case analysis assumed that there was no treatment effect of revascularisation on major adverse cardiovascular events, the improvement in symptom relief was the only benefit. The HRQoL effects of revascularisation were based on the FAME trials. Both were randomised, parallel, open-label clinical trials. FAME I compared invasive coronary angiography with FFR for guiding percutaneous coronary interventions in patients with multivessel coronary artery disease. FAME II compared clinical outcomes, safety and cost effectiveness of FFR-guided percutaneous coronary intervention with optimal medical treatment alone in patients with stable coronary artery disease. These trials showed that HRQoL improved significantly from baseline after percutaneous coronary intervention.\n\nIn the diagnostic model a one-off procedural disutility was applied for people having invasive FFR or iFR and for those who had revascularisation. In the prognostic model, a one-off utility decrement was also applied for people who had a non-fatal myocardial infarction or needed an unplanned revascularisation. A separate utility decrement was applied to the post-myocardial infarction health state, to reflect a decrease in HRQoL for those with a history of myocardial infarction.\n\nThe base-case analysis made an assumption that the quality-adjusted life year (QALY) loss applied for FFR or iFR was representative of both types of pressure wire procedures. The QALY loss estimates associated with each procedure in the diagnostic model are summarised in table 7.\n\nProcedure\n\nMean QALY loss (95% confidence interval)\n\nSource\n\nICA\n\n\n\nAssumed to cancel across strategies\n\nFFR/iFR\n\n(0.0051 to 0.0062)\n\nAssumed the same as for PCI (in the absence of any other source)\n\nPCI\n\n(0.0051 to 0.0062)\n\nBagust et al. (2006)\n\nCABG\n\n(0.031 to 0.035)\n\nBagust et al. (2006)\n\nAbbreviations: ICA, invasive coronary angiography; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; QALY, quality-adjusted life year.\n\nThe base-case cost of QAngio QFR with a throughput of 200\xa0people per year was £430.61 per person tested. This was based on the purchase of vouchers for 100\xa0people, which covered the cost of the software licence and the training and certification of up to 4 QAngio QFR users, in addition to a staff cost per person tested of £7.76. An update to the QAngio QFR price structure was submitted during consultation. Using the base-case throughput of 200\xa0people per year, the new voucher price reduced the cost to £362.94 per person tested. An alternative annual licence option reduced this further to £223.50 per person tested. The base-case cost of CAAS vFFR with a throughput of 200\xa0people per year was £172.18 per person tested. This included staff training and annual maintenance and was based on the purchase of a perpetual licence, which allows analysis of as many people as needed per year. The model did not consider a cost for invasive coronary angiography because all people who entered the diagnostic model had this test.\n\nThe unit cost for FFR and iFR was estimated as the difference between the activity weighted average of the healthcare resource group codes for complex and standard cardiac catheterisation (£436.80).\n\nThe following assumptions were applied in the base-case analysis:\n\nA diagnostic threshold of 0.80 was used to define functionally significant stenosis for QAngio QFR and FFR.\n\nA grey-zone boundary of 0.78 to 0.84 for QAngio QFR was used as suggested by the manufacturer of QAngio QFR.\n\nThe baseline risk of major adverse cardiovascular events in the absence of revascularisation depends on disease severity as measured by FFR, while the distribution of FFR values differs by diagnostic strategy.\n\nThere is no treatment effect of revascularisation on risk of major adverse cardiovascular events, based on the findings of the ISCHEMIA trial.\n\nCosts of QAngio QFR and CAAS vFFR were based on an average annual throughput of 200\xa0people.\n\nThe base case assumed all diagnostic procedures took place in an interventional setting. The diagnostic-only setting was considered in scenario analyses.\n\nHRQoL benefits of revascularisation and optimal medical therapy observed at 1\xa0year for the true positive and false negative health states applied for a lifetime duration.\n\nProcedural disutility associated with FFR was equivalent to that of percutaneous coronary intervention.\n\nThe deterministic and probabilistic cost-effectiveness results for the base-case analysis, expressed in terms of net health benefit at a maximum acceptable incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, are shown in tables 8 and 9, respectively. The incremental net health benefit was calculated for each strategy compared with invasive coronary angiography alone. The results were consistent for both the deterministic and probabilistic analysis.\n\nStrategy\n\nIdentification\n\nTotal QALYs\n\nTotal costs\n\nNHB\n\nINHB\n\nNHB rank\n\n\n\nICA alone\n\n\n\n£4,697\n\n\n\n–\n\n\n\n\n\nICA with FFR\n\n\n\n£4,825\n\n\n\n\n\n\n\n\n\nICA with QAngio QFR\n\n\n\n£4,812\n\n\n\n\n\n\n\n\n\nICA with QAngio QFR and confirmatory FFR (grey zone)\n\n\n\n£5,019\n\n\n\n\n\n\n\n\n\nICA with CAAS vFFR\n\n\n\n£5,118\n\n\n\n\n\n\n\nNHB and INHB are measured at a maximum acceptable ICER of £20,000 per QALY gained. Incremental NHB is relative to ICA alone. Abbreviations: ICA, invasive coronary angiography; FFR, fractional flow reserve; QFR, quantitative flow ratio; vFFR, vessel FFR; QALY, quality-adjusted life year; NHB, net health benefit; INHB, incremental NHB.\n\nStrategy\n\nIdentification\n\nTotal QALYs\n\nTotal costs\n\nNHB\n\nINHB\n\nNHB rank\n\nProbability cost effective at £20,000 per QALY gained\n\n\n\nICA alone\n\n\n\n£4,696\n\n\n\n–\n\n\n\n\n\n\n\nICA with FFR\n\n\n\n£4,825\n\n\n\n\n\n\n\n\n\n\n\nICA with QAngio QFR\n\n\n\n£4,813\n\n\n\n\n\n\n\n\n\n\n\nICA with QAngio QFR and confirmatory FFR (grey zone)\n\n\n\n£5,020\n\n\n\n\n\n\n\n\n\n\n\nICA with CAAS vFFR\n\n\n\n£5,119\n\n\n\n\n\n\n\n\n\nNHB and INHB are measured at a maximum acceptable ICER of £20,000 per QALY gained. Incremental NHB is relative to ICA alone. Abbreviations: ICA, invasive coronary angiography; FFR, fractional flow reserve; QFR, quantitative flow ratio; vFFR, vessel FFR; QALY, quality-adjusted life year; NHB, net health benefit; INHB, incremental NHB.\n\nStrategy 2 (invasive coronary angiography with FFR) had the highest net health benefit and the highest probability of being cost effective, although the differences between all the strategies were small. Strategy 1 (invasive coronary angiography alone) was the cheapest and had the lowest QALY gain, while strategy 5 (invasive coronary angiography with vFFR) was the most expensive and had the highest QALY gain.\n\nResults from the scenario analyses showed that the base-case results were generally robust when alterations were made to the sources of data used in the model and when different assumptions were made. However, sometimes these alterations resulted in significant changes to the net health benefit rankings of the different strategies.\n\nIn the base case, the diagnostic accuracy estimates for vFFR were based on the FAST EXTEND study (sensitivity 97.0% and specificity 74.0%), the largest study of vFFR (330\xa0patients). Using accuracy estimates from ILUMIEN I reduced the cost effectiveness of vFFR, but estimates from Jin et al. (2019) increased it. This resulted in vFFR being the second most cost-effective strategy. This highlighted the substantial uncertainty surrounding the cost effectiveness of vFFR in strategy 5.\n\nWhen QAngio QFR was considered to have the same diagnostic accuracy as FFR (that is, 100% sensitivity and specificity), the total QALYs and costs for strategy 3 increased by 0.017 QALYs and £6 per person from the base-case scenario. In this scenario strategy 3 became cost effective with the highest net health benefit, largely because of greater total QALYs gained for strategy 3 compared with strategy 2. This difference was mainly because of the procedural disutility associated with FFR or iFR.\n\nWhen the procedural disutility of FFR was more than that used in the base case, the net health benefit of strategies 2 and 4 were affected most. The total QALYs for both strategies were reduced, resulting in strategy 2 becoming the second least cost effective and strategy 3 the most cost effective. An FFR disutility of 0.014 QALYs resulted in an equal net health benefit for strategies 2 and 3. This procedural disutility was 2.5\xa0times greater than that associated with percutaneous coronary intervention, but less than half the disutility associated with coronary artery bypass graft.\n\nIn terms of how duration of HRQoL affected cost effectiveness, the benefits need to last for at least 7\xa0years to offset the disutility associated with FFR or iFR in the base case for strategy\xa02 to remain more cost effective than strategy\xa03.\n\nThe benefits of revascularisation, in terms of improved HRQoL, suggested that the sensitivity of test results was a more important driver of cost effectiveness than specificity. This was because true positive test results translated into higher QALY gains than mismanagement of false negative test results.\n\nIn a diagnostic-only setting, the large additional costs of repeating diagnostic catheterisation at a subsequent appointment in an interventional centre for strategies involving measuring FFR or iFR (strategies 2 and 4) meant that strategies without this testing component were more cost effective. Strategy 3 (QAngio QFR alone) became the strategy with the highest net benefit, followed by strategy 5 (CAAS vFFR alone).", 'Committee discussion': "# Clinical need\n\n## FFR and iFR are not frequently used so QAngio QFR and CAAS vFFR may help with decision making during invasive coronary angiography\n\nClinical experts explained that in general, physiological testing using fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) is available but not frequently used in the UK. People typically have an invasive coronary angiography after a previous functional test (see section 2.4). Sometimes decisions about revascularisation are based on the images from the invasive coronary angiography, results of the previous tests and patient history. If the revascularisation decision is still uncertain after invasive coronary angiography, people may be referred for FFR or iFR. Using QAngio XA 3D quantitative flow ratio (QAngio QFR) and CAAS vessel FFR (CAAS vFFR) during invasive coronary angiography may provide more information to help with decision making. It could also mean that in some cases clinical decisions could be made without needing FFR.\n\n## Less invasive tests may benefit patients and carers by reducing anxiety, unpleasant side effects and risk of complications\n\nA patient expert explained the potential benefits of testing using QAngio QFR or CAAS vFFR. These included reduced anxiety, discomfort and distress than more invasive testing, which may be needed if a definitive treatment decision cannot be made during the initial invasive coronary angiography. Using an invasive test like FFR with a pressure wire means using an adenosine infusion. The committee noted that around 30% of people may experience chest pain and shortness of breath from this. These side effects usually pass quickly but can be distressing. Around 3% of people may experience discomfort from the pressure wire itself and there is a small risk of rupture of the blood vessel. By avoiding adenosine infusion and a pressure wire, QAngio QFR and CAAS vFFR could reduce unpleasant side effects and risk of complications.\n\n# Clinical effectiveness\n\n## The diagnostic accuracy evidence for CAAS vFFR is highly uncertain\n\nThe committee noted that there were only 3 studies using CAAS vFFR that matched the inclusion criteria for review in the diagnostics assessment report. These included 500\xa0patients. The external assessment group (EAG) explained that there was notable heterogeneity across this small number of studies and that the meta-analyses of the CAAS vFFR studies should be interpreted with caution. Where reported, there was a high exclusion rate because of angiographic image processing issues. In 2 of the studies, the technology was not used in the way it was intended (ILUMIEN I and Jin et al. 2019). The committee concluded that the diagnostic accuracy of CAAS vFFR was highly uncertain and recommended further research (see research recommendation 5.4).\n\n## The diagnostic accuracy of QAngio QFR appears to be similar to FFR\n\nThe committee noted that 39\xa0studies using QAngio QFR matched the inclusion criteria for the review in the diagnostics assessment report. These included 5,440\xa0patients. These studies showed that QAngio QFR had good diagnostic accuracy to predict the FFR result. The clinical experts explained that there was good agreement between QFR and FFR values particularly at the extremes of measurement. While there was some disagreement between QFR and FFR results within the grey zone, (in the range of 0.78 to 0.84), the clinical experts noted that there is likely to be a limited clinical effect of not identifying someone with an FFR of between 0.76 and 0.80, that is, a false negative result. A more significant effect could occur for people with an FFR result of less than 0.76 who have a negative result on QAngio QFR (0.80 or higher). The EAG noted that modelling suggested around 3% of people with an FFR result of less than 0.76 would be misdiagnosed if using QFR for functional imaging. Clinical experts also explained that with FFR values close to the 0.80 cut-off, it is unclear whether there is any added benefit of revascularisation compared to optimal medical therapy. The committee concluded that there was good agreement between QAngio QFR and FFR values. Although there was some uncertainty around the grey zone, this was not a particular concern.\n\n## Technical failure rates in diagnostic-only centres may be higher because of lower quality angiography images\n\nIn the UK, invasive coronary angiography is usually done in diagnostic-only catheter laboratories or in interventional catheter laboratories that can also do percutaneous coronary intervention in the same procedure. Clinical experts explained that the quality of angiography images from diagnostic-only centres was generally lower than those from interventional centres. This is because in the diagnostic centre, invasive coronary angiography is done so the information can be used to guide decisions about what further testing and treatment might be needed. In the interventional centre, invasive coronary angiography is often done to help plan percutaneous coronary intervention. Clinical experts noted that QAngio QFR and CAAS vFFR need high-quality angiography images so in diagnostic centres the tests may have a high technical failure rate. The committee concluded that because all the data considered were from interventional centres, it was not certain what the technical failure rate would be in diagnostic-only centres.\n\n## It is unclear how clinical history and symptoms affect clinical decisions based on QAngio QFR or CAAS vFFR results\n\nThe NICE guideline on assessment and diagnosis of chest pain of recent onset recommends invasive coronary angiography as a third-line test. People who have invasive coronary angiography should have already had a previous assessment such as 64-slice coronary angiography and non-invasive functional imaging tests, but this may vary between centres. Some people may also have HeartFlow FFRCT which is recommended in the NICE medical technologies guidance on HeartFlow FFRCT for estimating FFR from coronary CT angiography. The clinical experts explained that these previous assessments can rule out the need for interventional treatment. Therefore, it is likely that people who do go on to have invasive coronary angiography have more severe disease than the people in the diagnostic accuracy studies. While the previous functional assessments may be used to guide further testing decisions such as whether to do an FFR, the QAngio QFR and CAAS vFFR results would be used to guide high-level treatment decisions with substantial consequences. Therefore, clinicians need to be confident that making a decision based on the results of these tests would lead to improved outcomes for patients. The committee commented that the diagnostic accuracy studies did not incorporate clinical history and the effect that symptoms had on decision making based on the QAngio QFR result. Therefore, it is unclear how this additional information combined with a QAngio QFR or CAAS vFFR result affects clinical decision making about revascularisation.\n\n## QAngio QFR may slightly increase revascularisation rates compared with FFR but this is uncertain\n\nThe EAG did a simulation study analysis to investigate the possible effect of using QAngio QFR compared with invasive coronary angiography and FFR on coronary outcomes such as revascularisation rates and major adverse cardiovascular events. QAngio QFR (with or without a grey zone) led to slightly more revascularisations compared with FFR (40.2% revascularisations using FFR compared with 42.0% for QAngio QFR and 43.2% using the grey-zone strategy). Both methods prevented broadly the same number of major adverse cardiovascular events (FFR may prevent more major adverse cardiovascular events but only for 1 in 1,000 people). However, the committee noted that the simulation study made numerous assumptions, so its results were uncertain.\n\n## Clinical outcome data from large endpoint studies for QAngio QFR and CAAS vFFR are needed\n\nThe clinical experts noted the lack of prospective outcome data when a QAngio QFR or CAAS vFFR-based approach was used to guide revascularisation decisions after invasive coronary angiography. The clinical experts explained that there was a need for clinical outcome data from large endpoint studies comparing these imaging software with FFR or invasive coronary angiography‑guided treatment. There are already multiple tests in the care pathway, and it was unclear how QAngio QFR or CAAS vFFR could offer additional clinical benefit. There are currently 2 ongoing clinical trials of QAngio QFR. The FAVOR III Europe-Japan study will compare QFR with standard FFR-guided percutaneous coronary intervention, and the FAVOR III China study will compare QFR with angiography‑alone guided percutaneous coronary intervention. These trials will be completed in December 2023 and February 2023, respectively. There is 1 ongoing trial of CAAS vFFR. The LIPSIA STRATEGY trial will compare vFFR with FFR for the assessment of intermediate coronary stenosis and is due to be completed in November 2026. The committee concluded that data from trials like these are essential to be confident that revascularisation decisions based on QAngio QFR or CAAS vFFR results would improve patient outcomes (see research recommendation 5.3).\n\n# Cost effectiveness\n\n## The disutility associated with FFR or iFR used in the model may not be appropriate\n\nIn the model the procedural disutility for FFR was assumed to be the same as for percutaneous coronary intervention. This was because no data were available on the disutility of FFR. The clinical experts explained that this assumption may not accurately reflect the actual side effects or people's experiences of the procedure. The EAG also looked at different scenario analyses where the disutility of FFR was increased. The committee commented that a disutility equivalent to percutaneous coronary intervention was likely too high. This affected the cost effectiveness of FFR more than might be expected in clinical practice. It noted further that there were important differences between FFR and iFR that were considered the same in the model. Because iFR does not need a hyperaemic agent such as adenosine, it avoids the associated unpleasant side effects. This disutility was a key driver of the cost-effectiveness results, but because of a lack of evidence it was uncertain what disutility should be used. The committee recommended further research into the disutility associated with FFR (see research recommendation 5.1).\n\n## Test costs may not be accurate because test failure rates are not adequately captured in the model\n\nTest failure rates were high in the studies, especially the retrospective ones, because the invasive coronary angiography images were not good enough to run QAngio QFR and CAAS vFFR. The committee noted that in clinical practice some images may not be of a sufficient quality for the software programs to produce a result. Therefore, the cost per test may have been underestimated because test failure rates were not factored into the model. Only people who had a QAngio QFR or CAAS vFFR result were included. The EAG did a scenario analysis in which patient throughput was varied, which affected the cost per test. However, the committee noted that this may not have explored a wide enough range to sufficiently capture this effect. It suggested that failure rates in routine clinical practice would be reduced over time as the operator gained experience in using the system. However, the clinical experts explained that this may be dependent on the setting, with sub-optimal angiography images more likely in diagnostic-only centres (see section 4.5). The committee concluded that further research on QAngio QFR and CAAS vFFR failure rates in clinical practice would be beneficial (see research recommendation 5.2).\n\n## QAngio QFR and CAAS vFFR are more cost effective than invasive coronary angiography alone, but the results are uncertain\n\nIn the base case QAngio QFR was within the range NICE considers cost effective compared with invasive coronary angiography alone in both the deterministic and probabilistic analyses. However, the clinical experts commented that the strategy of invasive coronary angiography alone was not representative of clinical practice, where the results of previous tests and people's preferences would also influence a treatment decision (see section 4.6). The committee noted that similar results were seen for CAAS vFFR but concluded that there was greater uncertainty in this result because of the lack of diagnostic accuracy evidence.\n\n## More data are needed because the clinical utility and cost effectiveness of QAngio QFR and CAAS vFFR are uncertain\n\nCompared with the reference standard of FFR or iFR, QAngio QFR (with and without a grey zone) and CAAS vFFR were less cost effective (generated less quality-adjusted life years [QALYs] but were slightly cheaper) in the base-case analysis. However, the committee noted that a review of the accuracy of FFR or iFR was not done by the EAG and they were assumed in the model to be 100% accurate. It also noted that the difference between the new technologies and the reference standard was small at 0.007 QALYs or £140 per person for QAngio QFR and 0.011 QALYs or £220 per person for CAAS vFFR. Following an update to the price structure of QAngio QFR by the company during consultation, QAngio QFR using an annual licence became slightly cheaper but remained less clinically effective than the reference standard of FFR or iFR. However, given the small difference in costs and outcomes, the committee reiterated the need for clinical outcome data from studies that directly compare QAngio QFR and CAAS vFFR with FFR or iFR (see research recommendation 5.3). These data would give clinicians confidence in their decision making based on the results of the tests. The committee concluded that given the uncertainty in clinical utility the cost-effectiveness results were also uncertain.\n\n## The potential role of QAngio QFR and CAAS vFFR in a diagnostic-only setting is unclear\n\nIn a scenario analysis in which the tests were done in a diagnostic-only setting, QAngio QFR and CAAS vFFR became the most cost effective options in the fully incremental analyses. This was because of the additional cost of onward referral for the reference standard tests. However, clinical experts explained that fewer people are having invasive coronary angiography because it is recommended as a third-line test in the NICE guideline on assessment and diagnosis of chest pain of recent onset (see section 4.6). The appropriate use of CT coronary angiography and functional testing has resulted in a fall in the number of people having invasive coronary angiography in diagnostic-only centres. Having an angiographic procedure in an interventional centre means that invasive coronary angiography, FFR or iFR and percutaneous coronary intervention can be done in a single visit, if appropriate. This reduces the need for multiple hospital visits, which has the potential to reduce people's anxiety. A clinical expert explained that according to 2017 to 2018 data from the National Institute of Cardiovascular Outcomes Research, around 35,000\xa0invasive coronary angiography procedures were done in diagnostic-only settings, compared with around 205,000 in interventional centres. The committee concluded that the future role of QAngio QFR and CAAS vFFR in a diagnostic-only setting is unclear because diagnostic-only catheter laboratories are likely to decline in number.\n\n## QAngio QFR and CAAS vFFR are not recommended for routine use\n\nThe committee noted that QAngio QFR and CAAS vFFR were more cost effective than invasive coronary angiography alone. QAngio QFR using the proposed annual licence was slightly cheaper but less clinically effective than FFR or iFR. However, the incremental difference in terms of costs and QALYs between the tests was small. For CAAS vFFR, the committee recalled that the diagnostic accuracy data was highly uncertain so it could not be recommended for routine use. The committee noted further that there were no clinical outcome studies for QAngio QFR or CAAS vFFR, which meant that the EAG had to make assumptions about treatment decisions and clinical outcomes, which led to uncertainty in the results. The clinical experts commented that these tests may be used to guide high-level clinical decisions about treatment, so clinicians need to be confident when making decisions based on the tests' results. The committee considered that clinical utility is uncertain and more data are needed. There were concerns around the results of the simulation study that showed that QAngio QFR could lead to an increase in revascularisations (see section 4.7). The committee also recalled the trend in clinical practice of moving away from diagnostic-only settings to interventional centres (see section 4.13) and considered that there was too much uncertainty to consider QAngio QFR and CAAS vFFR in this scenario. The committee concluded that because of the uncertainty in diagnostic accuracy and clinical evidence, CAAS vFFR was not recommended. Despite having good diagnostic accuracy evidence, QAngio QFR should not be recommended for use until further data showing that it improves patient outcomes are available.", 'Recommendations for further research': 'A patient experience study is recommended to better understand the general effect on patients of having an invasive coronary angiography and the range and severity of side effects and complications from QAngio XA 3D quantitative flow ratio (QAngio QFR), CAAS vessel fractional flow reserve (CAAS vFFR), FFR and instantaneous wave-free ratio.\n\nFurther research is recommended on test failure rates of QAngio QFR and CAAS vFFR and how these affect clinical decision making for revascularisation in clinical practice.\n\nOutcome studies are needed to understand the clinical benefit of using QAngio QFR and CAAS vFFR (see section 4.8). These include rates of major adverse cardiovascular events, mortality and EQ-5D data to assess the effect on quality of life.\n\nMore diagnostic accuracy studies are needed for CAAS vFFR against an appropriate reference standard.'}
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https://www.nice.org.uk/guidance/dg43
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Evidence-based recommendations on QAngio XA 3D QFR and CAAS vFFR imaging software for assessing coronary stenosis during invasive coronary angiography.
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454fcadaa58532bd9ac7470f0a08c6ea12cf8513
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nice
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Nivolumab for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease
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Nivolumab for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease
Evidence-based recommendations on nivolumab (Opdivo) for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease in adults.
# Recommendations
Nivolumab is recommended, within its marketing authorisation, as an option for the adjuvant treatment of completely resected melanoma in adults with lymph node involvement or metastatic disease. It is recommended only if the company provides nivolumab according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for nivolumab for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease (NICE technology appraisal guidance 558).
Until recently, standard care for people with completely resected melanoma was routine surveillance. Adjuvant immunotherapies such as dabrafenib with trametinib or pembrolizumab alone are now available for some people.
Clinical evidence shows that adjuvant nivolumab increases how long people live without the cancer coming back compared with adjuvant ipilimumab (an immunotherapy that is not used in the NHS). There are no trials directly comparing nivolumab with standard care in the NHS. But an indirect comparison suggests that people taking nivolumab are likely to live longer before the cancer comes back than with routine surveillance. There are still not enough data from the Cancer Drugs Fund and the trial to be certain by how much nivolumab increases the length of time people live.
Because of the uncertainty the cost-effectiveness estimates vary. However, the most likely estimates are within what NICE considers a cost-effective use of NHS resources. Therefore, nivolumab is recommended.# Information about nivolumab
# Marketing authorisation indication
Nivolumab (Opdivo, Bristol-Myers Squibb) is indicated as monotherapy for 'the adjuvant treatment of adult patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £439 per 40 mg/4 ml concentrate for solution for infusion vial; £1,097 per 100 mg/10 ml concentrate for solution for infusion vial; and £2,633 per 240 mg/24 ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed October 2020).
The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bristol-Myers Squibb, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that an issue was resolved during the technical engagement stage and agreed that the new flat 4‑weekly dose of nivolumab is suitable for decision making.
# Clinical pathway
## Effective adjuvant treatment options for people with completely resected stage 3 and 4 melanoma are needed
Melanoma often affects people at a younger age than some other cancers. It has a substantial effect on people and their families and carers. Tumour and associated lymph node resection are standard treatment for most people with stage 3 melanoma, and some people with stage 4 melanoma. Until recently standard care for people with completely resected melanoma was routine surveillance. In 2018, NICE's technology appraisal guidance on dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma recommended it for use. In the previous appraisal of nivolumab, NICE recommended it for use within the Cancer Drugs Fund for the adjuvant treatment of completely resected melanoma in adults with lymph node involvement or metastatic disease (stage 3 and stage 4 melanoma; NICE technology appraisal guidance 558). Pembrolizumab is also currently recommended for use in NICE's technology appraisal guidance on pembrolizumab for adjuvant treatment of resected melanoma with high risk of recurrence. It is recommended for the adjuvant treatment of stage 3 melanoma with lymph node involvement in adults who have had complete resection. The aim of adjuvant treatment is to remove any residual microscopic disease after resection to reduce the risk of relapse and progression to metastatic disease, which is currently considered incurable. The clinical expert explained that treatments that can be given very early (in the adjuvant setting) seem to show a clear benefit and hopefully will reduce the number of people returning with metastatic disease. The committee agreed that effective adjuvant treatments for people with completely resected stage 3 and 4 melanoma are needed.
# Clinical evidence
## Nivolumab improves recurrence-free survival compared with ipilimumab however survival data are still immature
CheckMate 238 is an ongoing multinational randomised double-blind trial. It compared adjuvant nivolumab with adjuvant ipilimumab in 906 patients (aged 18 years or over) who have had complete resection of stage 3B, 3C, or 4 melanoma. The median age was 56 years for patients who had nivolumab. Approximately half of the people with known BRAF status who had adjuvant nivolumab had disease without mutations in the BRAF gene (197/384) and 18% had stage 4 disease (82/453). In the original appraisal for nivolumab, patients in CheckMate 238 had been followed for a minimum of 24 months. A statistically significant improvement in recurrence-free survival was seen with nivolumab compared with ipilimumab (hazard ratio 0.66, 95% confidence interval 0.54 to 0.81). Overall survival data were immature. Since the original appraisal, patients in CheckMate 238 have now been followed for a minimum of 48 months. A statistically significant improvement in recurrence-free survival was seen with nivolumab compared with ipilimumab (HR 0.71, 95% CI 0.60 to 0.86). Overall survival data were still immature (HR 0.87; 95% CI 0.66 to 1.14). Through the Cancer Drugs Fund, systemic anti-cancer therapy data were collected from people having adjuvant nivolumab for resected stage 3 and 4 melanoma. Between 30 November 2018 and 29 October 2019, 284 people had adjuvant nivolumab. The median age was 63 years. Most people (78%) had disease without mutations in the BRAF gene and 35% had stage 4 disease. Compared with CheckMate 238, the patients were older, fewer had mutations in the BRAF gene and more had stage 4 disease. At the end of the data collection period, 72% of patients were still having treatment. The estimate of median overall survival was not available. The committee understood that because nivolumab is an adjuvant treatment, collection of survival data could take some time and considered it was positive that overall survival data were still immature for nivolumab. The clinical experts explained that if a treatment has a clinically meaningful difference in recurrence-free survival then it was likely that this would be reflected in overall survival. In practice, many patients who had started treatment with nivolumab had done so 18 months ago. A few patients' disease had relapsed early, within a year, but most were still disease free. The committee concluded that nivolumab improves recurrence-free survival compared with ipilimumab. However, it is not known if nivolumab increases the length of time people live, or by how much, because the survival data are still immature.
## Although the data on subsequent treatments are still immature, the data from CheckMate 238 reflect clinical practice
The committee noted that a number of therapies are currently available if the cancer comes back after adjuvant nivolumab (see NICE's Pathway on melanoma). These include immunotherapy (nivolumab with ipilimumab, nivolumab monotherapy, pembrolizumab monotherapy and ipilimumab monotherapy), and targeted therapy for people with disease with mutations in the BRAF gene (encorafenib with binimetinib, trametinib with dabrafenib, dabrafenib monotherapy, and vemurafenib monotherapy). Further data on subsequent treatments collected from Checkmate 238 were marked academic in confidence by the company so cannot be included here. The evidence from the Cancer Drugs Fund after use of adjuvant nivolumab is limited, and to date only 14% of people have had subsequent treatments. Most people had nivolumab with ipilimumab (34%), ipilimumab (29%), trametinib with dabrafenib (22%) and encorafenib with binimetinib (15%). However, because the data are immature, they are based on disease that relapsed early, so may not be representative of all completely resected stage 3 and 4 melanoma. The clinical experts stated that the fact that the data are immature is positive, because it suggests that the number of people whose disease comes back after adjuvant nivolumab is low. The clinical experts explained that the choice of subsequent treatment will depend on many factors. They agreed that most people who can tolerate a combination therapy would be offered nivolumab with ipilimumab after both routine surveillance and adjuvant nivolumab. People who cannot tolerate a combination therapy may be offered monotherapy (the choice of immunotherapy is likely to depend on whether adjuvant nivolumab was given, and, if it was, on the time since the last dose). People with disease with mutations in the BRAF gene may choose targeted therapies because they are less toxic and can be taken orally (immunotherapy is delivered by intravenous infusion). Clinicians agreed that the subsequent treatments in CheckMate 238 are consistent with what would be expected to be used in the clinical practice. Because the trial data are more mature there is a greater degree of certainty with these data than with the data from the Cancer Drugs Fund. Clinical experts explained that the subsequent treatments given in the nivolumab arm reflect what is currently used in clinical practice. The committee concluded that subsequent treatment data are still immature but that data from the nivolumab arm of CheckMate 238 reflect clinical practice.
# Indirect comparison of nivolumab with routine surveillance
## Despite changes to the classification of the disease, the patients in the trials are similar to patients in the NHS
No trial directly compared nivolumab with routine surveillance in the adjuvant setting. The company did an indirect comparison using individual patient data for recurrence-free survival and overall survival from the CheckMate 238 and CA184‑029 trials. CA184‑029 is a multinational randomised double-blind trial. It compared ipilimumab with placebo in 951 patients (aged 18 years or over) with high-risk stage 3 cutaneous melanoma who had had complete regional lymph node dissection. CA184‑029 trial did not include any patients with stage 4 disease, while CheckMate 238 does not include patients with stage 3A disease. However, the new American Joint Committee on Cancer (AJCC) 8th edition criteria mean that some patients with stage 3B disease in CheckMate 238 could now be classed as having stage 3A disease. The clinical experts noted that CA184‑029, CheckMate 238 and KEYNOTE 054 (an ongoing trial of adjuvant pembrolizumab compared with placebo in patients with resected high-risk stage 3 melanoma) show similar results across all disease stages. They stated that in practice, people with all these stages of disease would be treated the same way. The committee concluded that the difference in the staging of disease in the trials was not too much of a concern because the patients in the trials were similar to those seen in the NHS.
## Censoring of overall survival is preferred in the indirect treatment comparison
Patients in CheckMate 238 had ipilimumab up to 1 year, while patients had ipilimumab up to 3 years in CA184‑029. Therefore, patients from CA184‑029 who had treatment with ipilimumab beyond 1 year were excluded (censored) in the analysis of recurrence-free survival in the original appraisal for nivolumab. This is because the longer duration of ipilimumab treatment in CA184‑029 could result in a more optimistic indirect comparison for nivolumab. In this appraisal, the company's fitted parametric curves with censoring suggested that nivolumab is likely to improve recurrence-free survival compared with routine surveillance. The results of the indirect comparisons were marked academic in confidence by the company so cannot be included here. The company used the censored analysis for recurrence-free survival, but not for overall survival. It explained that censoring excluded patients with the best prognosis introduced large informative censoring (excluding patients because of reasons related to the trial results in biased estimates). Therefore, the company did not consider that censoring was suitable for overall survival. The company also considered that the number of censored patients was too large. The ERG agreed that censoring was likely to bias the indirect comparison against nivolumab. However, it noted that 25% of patients in CA184‑029 had ipilimumab for more than 1 year (and 13% of patients had ipilimumab for 3 years). The ERG preferred the censored analysis (reflecting the ipilimumab regimen in CheckMate 238) of overall survival. The committee considered the difference in ipilimumab treatment duration of the 2 trials to be a limitation of the indirect comparison. It agreed that the censored analysis is likely to be biased towards routine surveillance and viewed it as a conservative scenario. In response to the appraisal consultation document, the company reiterated that it did not consider that censoring is needed but included analyses both with and without censoring of ipilimumab. The committee continued to prefer the censored analysis and concluded that, although conservative, for consistency with recurrence-free survival, the censored overall survival analysis is preferred.
# The company's economic models
## The partitioned survival model is preferred
Because of immature survival data, 2 models, a partitioned survival model and a state transition model, were considered in the original appraisal for nivolumab. During this appraisal, an indirect comparison was done for both recurrence-free survival and overall survival. However, only the partitioned survival model used the overall survival data. The state transition model based post-recurrence survival on weighted subsequent treatment-specific survival data obtained from published sources. This meant that it included a number of assumptions to estimate post-recurrence survival. The ERG noted that the estimates of life years for recurrence-free survival from the state transition model were different to the partitioned survival model. This was despite both using the same CheckMate 238 data, which suggested that the state transition model lacked face validity. The ERG therefore considered only the partitioned survival model for its preferred base case. The company agreed that there are limitations to estimating post-recurrence survival from the literature. However, they explained that the state transition model offers an alternative approach that is not based on the immature overall survival data from CheckMate 238. They stated that both models should be explored because they were both considered in the original appraisal for nivolumab. The committee noted that both models had their strengths and limitations. Because the main uncertainty was the modelling of overall survival (see section 3.2, section 3.5 and section 3.7), and only the partitioned survival model allowed exploration of assumptions around the CheckMate 238 overall survival data extrapolation, the committee concluded that the partitioned survival model was preferred.
# Survival modelling in the partitioned survival model
## Overall survival is highly uncertain therefore assuming the same hazard of death at 3 to 5 years is appropriate for decision making
In the original appraisal for nivolumab, overall survival in the placebo group in CA184‑029 was not considered to reflect that of routine surveillance because of advances in subsequent treatments since the trial started. In response to the appraisal consultation document, the company provided new analyses using a partitioned survival model only. It extrapolated the overall survival data from the indirect comparison for 10 years and used the American Joint Committee on Cancer data for long-term survival (the same as the extrapolation of recurrence-free survival). The company did not consider that the ERG's scenarios (which the committee had preferred and that assumed the same hazard of death for routine surveillance and adjuvant nivolumab after 2 years) were clinically plausible. Patients having routine surveillance were predicted to have lower risk of death than those having ipilimumab after 2 years (contradicting the data in CA184‑029). In the company's response to consultation, it presented several analyses suggesting that assuming the same hazard at 2 years is not appropriate (analyses are marked as academic in confidence and therefore cannot be presented here). It considered that the minimum time point should be 4 years (the minimum follow up in CheckMate 238) and presented a range of scenarios assuming the same hazard of death at 3 to 10 years. The ERG agreed with the company, that based on the new analyses, assuming equal hazard of death at 2 years is too conservative. It considered the company's minimum time point of 3 years, with exploratory analyses up to 5 years (which covers the most recent data cut for CheckMate 238) to be a plausible range. The ERG noted that the timepoint that limits the uncertainty the most is 3 years. The clinical expert considered that the effect of nivolumab on overall survival is likely to last after the 4 years of the minimal follow up in CheckMate 238. The committee concluded that because of the uncertainty around overall survival, the ERG's preferred range of 3 to 5 years is appropriate for decision making. However, it noted that the lower bound of the range may be too conservative.
## Subsequent treatments, after equal hazard of death is assumed in the model, are based on treatments in the nivolumab arm in CheckMate 238
In the ERG's 2 scenarios which assumed the same hazard at 2 years and were considered at the first committee meeting, one approach assumed the same treatments for routine surveillance and adjuvant nivolumab, based on the subsequent treatments in the nivolumab arm in CheckMate 238. The other approach assumed that nivolumab (for simplification to represent immunotherapy treatment) would be the subsequent treatment for all people having routine surveillance. In both approaches, nivolumab subsequent treatments were based on treatments in the nivolumab arm in CheckMate 238. Subsequent treatments for routine therapy were based on the ipilimumab arm in CheckMate 238 before the same hazard was assumed. The company considered that assuming nivolumab as a subsequent treatment for all people on routine surveillance is incorrect. It based subsequent treatments on CheckMate 238 and after the equal hazard of death is assumed, subsequent treatments for both nivolumab and routine surveillance are based on the nivolumab arm in CheckMate 238, so the same cost and benefits are applied to both arms. After consultation on the appraisal document, the ERG agreed with the company's choice of subsequent treatment based on the committee's preference (see section 3.3). However, it did state that in clinical practice, using immunotherapies for patients whose disease has relapsed during routine surveillance is likely to be higher than for patients whose disease has relapsed on nivolumab. This was explored in 2 illustrative scenarios. The committee concluded that the company's approach after the equal hazard of death is assumed, using the subsequent treatments used in the nivolumab arm from CheckMate 238 for both nivolumab and routine surveillance is appropriate.
# Cost-effectiveness results
## The cost-effectiveness estimates are uncertain and vary based on the assumptions around the same hazard of death and censoring of the indirect comparison
The committee considered the revised cost-effectiveness estimates submitted by the company. These included the confidential patient access schemes for nivolumab and ipilimumab but did not include the patient access schemes for subsequent treatments. The company presented a range of incremental cost-effectiveness ratios (ICERs) which explored different assumptions around: equal hazards of death for the nivolumab and routine surveillance arms ranging from 3 years to 10 years (see section 3.7); and uncensored and censored ipilimumab arm indirect comparison (see section 3.5). All the scenarios in the company's model used the subsequent treatments for nivolumab and routine surveillance, after the same hazard of death is assumed, and are based on treatments given in the nivolumab arm in CheckMate 238 (see section 3.8). The company's base case (uncensored indirect comparison and assuming the same hazard of death at 10 years) resulted in an ICER of £14,301 per quality-adjusted life year (QALY) gained. The ICER that was considered the most conservative in the range presented by the company was the censored indirect comparison, assuming the same hazard of death at 3 years, which resulted in an ICER of £29,011 per QALY gained. The ERG's most plausible ICER was the company's highest ICER (£29,011 per QALY gained). The committee agreed that there was uncertainty around the hazard of death (see section 3.7) but concluded that the highest plausible ICER, which could be considered the most conservative, was £29,011 per QALY gained, noting this did not include the discounts for subsequent treatments used in the model.
## The most likely estimate is within the range NICE considers a cost-effective use of NHS resources
When the committee took into account all the confidential patient access schemes for subsequent treatments and the committee's preferences of the censoring of overall survival (see section 3.5) and the same hazard of death for routine surveillance and adjuvant nivolumab after 3 to 5 years (see section 3.7), then most of the resulting ICERs were less than £30,000 per QALY gained. The committee noted that both the censoring (see section 3.5) and the lower bound of the same hazard range at 3 years (see section 3.7) are conservative scenarios. Therefore, the committee concluded that the most likely ICER is within the range NICE considers a cost-effective use of NHS resources.
# Conclusion
## Nivolumab is recommended for routine use
The committee concluded that the most plausible estimates are within the range NICE considers a cost-effective use of NHS resources. Therefore, nivolumab is recommended for the adjuvant treatment of completely resected melanoma in adults with lymph node involvement or metastatic disease.
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{'Recommendations': 'Nivolumab is recommended, within its marketing authorisation, as an option for the adjuvant treatment of completely resected melanoma in adults with lymph node involvement or metastatic disease. It is recommended only if the company provides nivolumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for nivolumab for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease (NICE technology appraisal guidance 558).\n\nUntil recently, standard care for people with completely resected melanoma was routine surveillance. Adjuvant immunotherapies such as dabrafenib with trametinib or pembrolizumab alone are now available for some people.\n\nClinical evidence shows that adjuvant nivolumab increases how long people live without the cancer coming back compared with adjuvant ipilimumab (an immunotherapy that is not used in the NHS). There are no trials directly comparing nivolumab with standard care in the NHS. But an indirect comparison suggests that people taking nivolumab are likely to live longer before the cancer comes back than with routine surveillance. There are still not enough data from the Cancer Drugs Fund and the trial to be certain by how much nivolumab increases the length of time people live.\n\nBecause of the uncertainty the cost-effectiveness estimates vary. However, the most likely estimates are within what NICE considers a cost-effective use of NHS resources. Therefore, nivolumab is recommended.', 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol-Myers Squibb) is indicated as monotherapy for 'the adjuvant treatment of adult patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £439 per 40\xa0mg/4\xa0ml concentrate for solution for infusion vial; £1,097 per 100\xa0mg/10\xa0ml concentrate for solution for infusion vial; and £2,633 per 240\xa0mg/24\xa0ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed October 2020).\n\nThe company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol-Myers Squibb, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that an issue was resolved during the technical engagement stage and agreed that the new flat 4‑weekly dose of nivolumab is suitable for decision making.\n\n# Clinical pathway\n\n## Effective adjuvant treatment options for people with completely resected stage\xa03 and\xa04 melanoma are needed\n\nMelanoma often affects people at a younger age than some other cancers. It has a substantial effect on people and their families and carers. Tumour and associated lymph node resection are standard treatment for most people with stage\xa03 melanoma, and some people with stage\xa04 melanoma. Until recently standard care for people with completely resected melanoma was routine surveillance. In 2018, NICE's technology appraisal guidance on dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma recommended it for use. In the previous appraisal of nivolumab, NICE recommended it for use within the Cancer Drugs Fund for the adjuvant treatment of completely resected melanoma in adults with lymph node involvement or metastatic disease (stage\xa03 and stage\xa04 melanoma; NICE technology appraisal guidance 558). Pembrolizumab is also currently recommended for use in NICE's technology appraisal guidance on pembrolizumab for adjuvant treatment of resected melanoma with high risk of recurrence. It is recommended for the adjuvant treatment of stage\xa03 melanoma with lymph node involvement in adults who have had complete resection. The aim of adjuvant treatment is to remove any residual microscopic disease after resection to reduce the risk of relapse and progression to metastatic disease, which is currently considered incurable. The clinical expert explained that treatments that can be given very early (in the adjuvant setting) seem to show a clear benefit and hopefully will reduce the number of people returning with metastatic disease. The committee agreed that effective adjuvant treatments for people with completely resected stage\xa03 and\xa04 melanoma are needed.\n\n# Clinical evidence\n\n## Nivolumab improves recurrence-free survival compared with ipilimumab however survival data are still immature\n\nCheckMate\xa0238 is an ongoing multinational randomised double-blind trial. It compared adjuvant nivolumab with adjuvant ipilimumab in 906\xa0patients (aged 18\xa0years or over) who have had complete resection of stage\xa03B, 3C,\xa0or\xa04 melanoma. The median age was 56\xa0years for patients who had nivolumab. Approximately half of the people with known BRAF status who had adjuvant nivolumab had disease without mutations in the BRAF gene (197/384) and 18% had stage\xa04 disease (82/453). In the original appraisal for nivolumab, patients in CheckMate\xa0238 had been followed for a minimum of 24\xa0months. A statistically significant improvement in recurrence-free survival was seen with nivolumab compared with ipilimumab (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54\xa0to\xa00.81). Overall survival data were immature. Since the original appraisal, patients in CheckMate\xa0238 have now been followed for a minimum of 48\xa0months. A statistically significant improvement in recurrence-free survival was seen with nivolumab compared with ipilimumab (HR\xa00.71, 95%\xa0CI 0.60\xa0to\xa00.86). Overall survival data were still immature (HR\xa00.87; 95%\xa0CI 0.66\xa0to\xa01.14). Through the Cancer Drugs Fund, systemic anti-cancer therapy data were collected from people having adjuvant nivolumab for resected stage\xa03 and\xa04 melanoma. Between 30\xa0November\xa02018 and 29\xa0October\xa02019, 284\xa0people had adjuvant nivolumab. The median age was 63\xa0years. Most people (78%) had disease without mutations in the BRAF gene and 35% had stage\xa04 disease. Compared with CheckMate\xa0238, the patients were older, fewer had mutations in the BRAF gene and more had stage\xa04 disease. At the end of the data collection period, 72% of patients were still having treatment. The estimate of median overall survival was not available. The committee understood that because nivolumab is an adjuvant treatment, collection of survival data could take some time and considered it was positive that overall survival data were still immature for nivolumab. The clinical experts explained that if a treatment has a clinically meaningful difference in recurrence-free survival then it was likely that this would be reflected in overall survival. In practice, many patients who had started treatment with nivolumab had done so 18\xa0months ago. A few patients' disease had relapsed early, within a year, but most were still disease free. The committee concluded that nivolumab improves recurrence-free survival compared with ipilimumab. However, it is not known if nivolumab increases the length of time people live, or by how much, because the survival data are still immature.\n\n## Although the data on subsequent treatments are still immature, the data from CheckMate\xa0238 reflect clinical practice\n\nThe committee noted that a number of therapies are currently available if the cancer comes back after adjuvant nivolumab (see NICE's Pathway on melanoma). These include immunotherapy (nivolumab with ipilimumab, nivolumab monotherapy, pembrolizumab monotherapy and ipilimumab monotherapy), and targeted therapy for people with disease with mutations in the BRAF gene (encorafenib with binimetinib, trametinib with dabrafenib, dabrafenib monotherapy, and vemurafenib monotherapy). Further data on subsequent treatments collected from Checkmate\xa0238 were marked academic in confidence by the company so cannot be included here. The evidence from the Cancer Drugs Fund after use of adjuvant nivolumab is limited, and to date only 14% of people have had subsequent treatments. Most people had nivolumab with ipilimumab (34%), ipilimumab (29%), trametinib with dabrafenib (22%) and encorafenib with binimetinib (15%). However, because the data are immature, they are based on disease that relapsed early, so may not be representative of all completely resected stage\xa03 and\xa04 melanoma. The clinical experts stated that the fact that the data are immature is positive, because it suggests that the number of people whose disease comes back after adjuvant nivolumab is low. The clinical experts explained that the choice of subsequent treatment will depend on many factors. They agreed that most people who can tolerate a combination therapy would be offered nivolumab with ipilimumab after both routine surveillance and adjuvant nivolumab. People who cannot tolerate a combination therapy may be offered monotherapy (the choice of immunotherapy is likely to depend on whether adjuvant nivolumab was given, and, if it was, on the time since the last dose). People with disease with mutations in the BRAF gene may choose targeted therapies because they are less toxic and can be taken orally (immunotherapy is delivered by intravenous infusion). Clinicians agreed that the subsequent treatments in CheckMate\xa0238 are consistent with what would be expected to be used in the clinical practice. Because the trial data are more mature there is a greater degree of certainty with these data than with the data from the Cancer Drugs Fund. Clinical experts explained that the subsequent treatments given in the nivolumab arm reflect what is currently used in clinical practice. The committee concluded that subsequent treatment data are still immature but that data from the nivolumab arm of CheckMate\xa0238 reflect clinical practice.\n\n# Indirect comparison of nivolumab with routine surveillance\n\n## Despite changes to the classification of the disease, the patients in the trials are similar to patients in the NHS\n\nNo trial directly compared nivolumab with routine surveillance in the adjuvant setting. The company did an indirect comparison using individual patient data for recurrence-free survival and overall survival from the CheckMate\xa0238 and CA184‑029 trials. CA184‑029 is a multinational randomised double-blind trial. It compared ipilimumab with placebo in 951\xa0patients (aged 18\xa0years or over) with high-risk stage\xa03 cutaneous melanoma who had had complete regional lymph node dissection. CA184‑029 trial did not include any patients with stage\xa04 disease, while CheckMate\xa0238 does not include patients with stage\xa03A disease. However, the new American Joint Committee on Cancer (AJCC) 8th edition criteria mean that some patients with stage\xa03B disease in CheckMate\xa0238 could now be classed as having stage\xa03A disease. The clinical experts noted that CA184‑029, CheckMate\xa0238 and KEYNOTE\xa0054 (an ongoing trial of adjuvant pembrolizumab compared with placebo in patients with resected high-risk stage\xa03 melanoma) show similar results across all disease stages. They stated that in practice, people with all these stages of disease would be treated the same way. The committee concluded that the difference in the staging of disease in the trials was not too much of a concern because the patients in the trials were similar to those seen in the NHS.\n\n## Censoring of overall survival is preferred in the indirect treatment comparison\n\nPatients in CheckMate\xa0238 had ipilimumab up to 1\xa0year, while patients had ipilimumab up to 3\xa0years in CA184‑029. Therefore, patients from CA184‑029 who had treatment with ipilimumab beyond 1\xa0year were excluded (censored) in the analysis of recurrence-free survival in the original appraisal for nivolumab. This is because the longer duration of ipilimumab treatment in CA184‑029 could result in a more optimistic indirect comparison for nivolumab. In this appraisal, the company's fitted parametric curves with censoring suggested that nivolumab is likely to improve recurrence-free survival compared with routine surveillance. The results of the indirect comparisons were marked academic in confidence by the company so cannot be included here. The company used the censored analysis for recurrence-free survival, but not for overall survival. It explained that censoring excluded patients with the best prognosis introduced large informative censoring (excluding patients because of reasons related to the trial results in biased estimates). Therefore, the company did not consider that censoring was suitable for overall survival. The company also considered that the number of censored patients was too large. The ERG agreed that censoring was likely to bias the indirect comparison against nivolumab. However, it noted that 25% of patients in CA184‑029 had ipilimumab for more than 1\xa0year (and 13% of patients had ipilimumab for 3\xa0years). The ERG preferred the censored analysis (reflecting the ipilimumab regimen in CheckMate\xa0238) of overall survival. The committee considered the difference in ipilimumab treatment duration of the 2\xa0trials to be a limitation of the indirect comparison. It agreed that the censored analysis is likely to be biased towards routine surveillance and viewed it as a conservative scenario. In response to the appraisal consultation document, the company reiterated that it did not consider that censoring is needed but included analyses both with and without censoring of ipilimumab. The committee continued to prefer the censored analysis and concluded that, although conservative, for consistency with recurrence-free survival, the censored overall survival analysis is preferred.\n\n# The company's economic models\n\n## The partitioned survival model is preferred\n\nBecause of immature survival data, 2\xa0models, a partitioned survival model and a state transition model, were considered in the original appraisal for nivolumab. During this appraisal, an indirect comparison was done for both recurrence-free survival and overall survival. However, only the partitioned survival model used the overall survival data. The state transition model based post-recurrence survival on weighted subsequent treatment-specific survival data obtained from published sources. This meant that it included a number of assumptions to estimate post-recurrence survival. The ERG noted that the estimates of life years for recurrence-free survival from the state transition model were different to the partitioned survival model. This was despite both using the same CheckMate\xa0238 data, which suggested that the state transition model lacked face validity. The ERG therefore considered only the partitioned survival model for its preferred base case. The company agreed that there are limitations to estimating post-recurrence survival from the literature. However, they explained that the state transition model offers an alternative approach that is not based on the immature overall survival data from CheckMate\xa0238. They stated that both models should be explored because they were both considered in the original appraisal for nivolumab. The committee noted that both models had their strengths and limitations. Because the main uncertainty was the modelling of overall survival (see section\xa03.2, section\xa03.5 and section\xa03.7), and only the partitioned survival model allowed exploration of assumptions around the CheckMate\xa0238 overall survival data extrapolation, the committee concluded that the partitioned survival model was preferred.\n\n# Survival modelling in the partitioned survival model\n\n## Overall survival is highly uncertain therefore assuming the same hazard of death at 3 to 5\xa0years is appropriate for decision making\n\nIn the original appraisal for nivolumab, overall survival in the placebo group in CA184‑029 was not considered to reflect that of routine surveillance because of advances in subsequent treatments since the trial started. In response to the appraisal consultation document, the company provided new analyses using a partitioned survival model only. It extrapolated the overall survival data from the indirect comparison for 10\xa0years and used the American Joint Committee on Cancer data for long-term survival (the same as the extrapolation of recurrence-free survival). The company did not consider that the ERG's scenarios (which the committee had preferred and that assumed the same hazard of death for routine surveillance and adjuvant nivolumab after 2\xa0years) were clinically plausible. Patients having routine surveillance were predicted to have lower risk of death than those having ipilimumab after 2\xa0years (contradicting the data in CA184‑029). In the company's response to consultation, it presented several analyses suggesting that assuming the same hazard at 2\xa0years is not appropriate (analyses are marked as academic in confidence and therefore cannot be presented here). It considered that the minimum time point should be 4\xa0years (the minimum follow up in CheckMate\xa0238) and presented a range of scenarios assuming the same hazard of death at 3 to 10\xa0years. The ERG agreed with the company, that based on the new analyses, assuming equal hazard of death at 2\xa0years is too conservative. It considered the company's minimum time point of 3\xa0years, with exploratory analyses up to 5\xa0years (which covers the most recent data cut for CheckMate\xa0238) to be a plausible range. The ERG noted that the timepoint that limits the uncertainty the most is 3\xa0years. The clinical expert considered that the effect of nivolumab on overall survival is likely to last after the 4\xa0years of the minimal follow up in CheckMate\xa0238. The committee concluded that because of the uncertainty around overall survival, the ERG's preferred range of 3 to 5\xa0years is appropriate for decision making. However, it noted that the lower bound of the range may be too conservative.\n\n## Subsequent treatments, after equal hazard of death is assumed in the model, are based on treatments in the nivolumab arm in CheckMate\xa0238\n\nIn the ERG's 2\xa0scenarios which assumed the same hazard at 2\xa0years and were considered at the first committee meeting, one approach assumed the same treatments for routine surveillance and adjuvant nivolumab, based on the subsequent treatments in the nivolumab arm in CheckMate\xa0238. The other approach assumed that nivolumab (for simplification to represent immunotherapy treatment) would be the subsequent treatment for all people having routine surveillance. In both approaches, nivolumab subsequent treatments were based on treatments in the nivolumab arm in CheckMate\xa0238. Subsequent treatments for routine therapy were based on the ipilimumab arm in CheckMate\xa0238 before the same hazard was assumed. The company considered that assuming nivolumab as a subsequent treatment for all people on routine surveillance is incorrect. It based subsequent treatments on CheckMate\xa0238 and after the equal hazard of death is assumed, subsequent treatments for both nivolumab and routine surveillance are based on the nivolumab arm in CheckMate\xa0238, so the same cost and benefits are applied to both arms. After consultation on the appraisal document, the ERG agreed with the company's choice of subsequent treatment based on the committee's preference (see section\xa03.3). However, it did state that in clinical practice, using immunotherapies for patients whose disease has relapsed during routine surveillance is likely to be higher than for patients whose disease has relapsed on nivolumab. This was explored in 2\xa0illustrative scenarios. The committee concluded that the company's approach after the equal hazard of death is assumed, using the subsequent treatments used in the nivolumab arm from CheckMate\xa0238 for both nivolumab and routine surveillance is appropriate.\n\n# Cost-effectiveness results\n\n## The cost-effectiveness estimates are uncertain and vary based on the assumptions around the same hazard of death and censoring of the indirect comparison\n\nThe committee considered the revised cost-effectiveness estimates submitted by the company. These included the confidential patient access schemes for nivolumab and ipilimumab but did not include the patient access schemes for subsequent treatments. The company presented a range of incremental cost-effectiveness ratios (ICERs) which explored different assumptions around: equal hazards of death for the nivolumab and routine surveillance arms ranging from 3\xa0years to 10\xa0years (see section\xa03.7); and uncensored and censored ipilimumab arm indirect comparison (see section\xa03.5). All the scenarios in the company's model used the subsequent treatments for nivolumab and routine surveillance, after the same hazard of death is assumed, and are based on treatments given in the nivolumab arm in CheckMate\xa0238 (see section\xa03.8). The company's base case (uncensored indirect comparison and assuming the same hazard of death at 10\xa0years) resulted in an ICER of £14,301 per quality-adjusted life year (QALY) gained. The ICER that was considered the most conservative in the range presented by the company was the censored indirect comparison, assuming the same hazard of death at 3\xa0years, which resulted in an ICER of £29,011 per QALY gained. The ERG's most plausible ICER was the company's highest ICER (£29,011 per QALY gained). The committee agreed that there was uncertainty around the hazard of death (see section\xa03.7) but concluded that the highest plausible ICER, which could be considered the most conservative, was £29,011 per QALY gained, noting this did not include the discounts for subsequent treatments used in the model.\n\n## The most likely estimate is within the range NICE considers a cost-effective use of NHS resources\n\nWhen the committee took into account all the confidential patient access schemes for subsequent treatments and the committee's preferences of the censoring of overall survival (see section\xa03.5) and the same hazard of death for routine surveillance and adjuvant nivolumab after 3 to 5\xa0years (see section\xa03.7), then most of the resulting ICERs were less than £30,000 per QALY gained. The committee noted that both the censoring (see section\xa03.5) and the lower bound of the same hazard range at 3\xa0years (see section\xa03.7) are conservative scenarios. Therefore, the committee concluded that the most likely ICER is within the range NICE considers a cost-effective use of NHS resources.\n\n# Conclusion\n\n## Nivolumab is recommended for routine use\n\nThe committee concluded that the most plausible estimates are within the range NICE considers a cost-effective use of NHS resources. Therefore, nivolumab is recommended for the adjuvant treatment of completely resected melanoma in adults with lymph node involvement or metastatic disease."}
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https://www.nice.org.uk/guidance/ta684
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Evidence-based recommendations on nivolumab (Opdivo) for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease in adults.
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8078b565e4c5e1b998e9c986ca69b4b86a795f3c
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nice
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Erenumab for preventing migraine
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Erenumab for preventing migraine
Evidence-based recommendations on erenumab (Aimovig) for preventing migraine in adults.
# Recommendations
Erenumab is recommended as an option for preventing migraine in adults, only if:
they have 4 or more migraine days a month
at least 3 preventive drug treatments have failed
the 140 mg dose of erenumab is used and
the company provides it according to the commercial arrangement.
Stop erenumab after 12 weeks of treatment if:
in episodic migraine (less than 15 headache days a month) the frequency does not reduce by at least 50%
in chronic migraine (15 headache days a month or more with at least 8 of those having features of migraine) the frequency does not reduce by at least 30%.
These recommendations are not intended to affect treatment with erenumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatments for preventing chronic or episodic migraine include beta-blockers, antidepressants and antiepileptic drugs. If chronic migraine does not respond to at least 3 preventive drug treatments, botulinum toxin type A or best supportive care (treatment for the migraine symptoms) is offered. If episodic migraine does not respond to at least 3 preventive drug treatments, best supportive care is offered.
For people whose migraine has not responded to at least 3 preventive treatments, the clinical trial evidence shows that erenumab 140 mg works better than best supportive care for preventing chronic or episodic migraine. There is no direct evidence comparing erenumab with botulinum toxin type A in chronic migraine, but an indirect comparison suggests that erenumab has some benefit. It is plausible that erenumab may work better than botulinum toxin type A.
The cost-effectiveness estimates are within what NICE usually considers an acceptable use of NHS resources. So erenumab is recommended for preventing migraine in adults who have at least 4 migraine days per month.# Information about erenumab
# Marketing authorisation indication
Erenumab (Aimovig, Novartis) is indicated for 'prophylaxis of migraine in adults who have at least 4 migraine days per month'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of erenumab is £386.50 per 70 mg or 140 mg injection (excluding VAT, BNF online, accessed November 2020). The company has a commercial arrangement. This makes erenumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# The condition and current treatment
## Migraine significantly affects health-related quality of life
The patient experts described the effect of migraine on their quality of life and how it affects their ability to work and take part in social activities. People with migraine can often miss out on family time and find it difficult to plan future activities. The severity and frequency of the condition can fluctuate over time and can be poorly understood in the workplace. The patient experts explained that symptoms can start in the days leading up to a migraine and that recovery can take a few days, so people with chronic migraine may have few symptom-free days. Chronic migraine is defined as 15 or more headache days a month, with at least 8 of those having features of migraine. Episodic migraine is defined as less than 15 headache days a month. The burden on quality of life can be similar to that of chronic migraine. The committee concluded that migraine, particularly chronic migraine, is a debilitating condition that substantially affects health-related quality of life and employment and is associated with an increase in the prevalence of psychiatric illness.
## Well-tolerated treatments are needed
The committee understood that current oral treatment options for preventing migraine include drugs that are used to treat other conditions, such as beta-blockers, antidepressants and antiepileptic drugs. The patient experts explained that these treatments can have significant side effects, can be poorly tolerated and may not work for some people. The committee was aware that NICE's technology appraisal guidance on botulinum toxin type A for the prevention of headaches in adults with chronic migraine recommends botulinum toxin type A for people with chronic migraine whose condition has not responded to at least 3 previous oral preventive drug treatments and is appropriately managed for medication overuse. Clinical experts stated that although botulinum toxin type A is recommended by NICE, there are lengthy waiting lists and it is not always available in some areas of the country. The committee concluded that effective, well-tolerated treatment options are needed.
# Current clinical management
## At least 3 oral preventive treatments are tried before more specialist treatment is considered
The clinical experts explained that the aim of treatment is to reduce the frequency, severity or duration of migraine and improve quality of life. In chronic migraine, a 30% reduction in migraine frequency is considered a clinically meaningful response to treatment. In episodic migraine, a 50% reduction is considered a clinically meaningful response. If the response is lower than this (an insufficient or partial clinical response), or the person is not able to have an adequate dosage for long enough or has adverse events, treatment is stopped and another oral preventive treatment is tried. The clinical experts explained that it is important for people to try a range of oral preventive treatments before considering more specialist treatment, such as botulinum toxin type A (for chronic migraine) or erenumab. The committee therefore concluded that a clinically meaningful response was a 30% reduction (for chronic migraine) or a 50% reduction (for episodic migraine) in migraine frequency. An insufficient response to at least 3 oral preventive treatments represents usual NHS practice before more specialist treatment is considered.
# Clinical evidence
## The most relevant comparators are best supportive care for episodic migraine and botulinum toxin type A for chronic migraine
The company's submission focused on people with migraine for whom at least 3 previous preventive treatments had failed (defined as insufficient or partial response, insufficient dosage or adverse events). This was because the company considered this group to reflect people most in need of treatment options and for whom erenumab would likely be used in practice. The company presented evidence for erenumab's clinical effectiveness compared with placebo for episodic migraine and compared with placebo and botulinum toxin type A for chronic migraine. The company considered that placebo was representative of best supportive care, because it comprised acute treatments that people would have for their migraine symptoms when preventive treatments had not worked. The clinical experts agreed that erenumab would likely be offered to people with migraine for whom at least 3 previous preventive treatments had failed. The committee suggested that some people may be able to have a fourth oral preventive treatment, given that it was important to try a range of oral preventive treatments before more specialist treatment is considered (see section 3.3). After consultation, clinical experts explained that most people will have either botulinum toxin type A or best supportive care. Only some people may have a fourth oral preventive treatment and this is unlikely to have a clinically meaningful benefit. The committee therefore did not consider that a fourth oral preventive treatment would be a relevant comparator. It concluded that best supportive care was the most appropriate comparator in episodic migraine. For people with chronic migraine who have tried 3 oral preventive treatments that have not worked, the committee recalled comments from patient and clinical experts that these people are most in need of effective therapy. They would be offered botulinum toxin type A at this point in the treatment pathway. The committee concluded that botulinum toxin type A or best supportive care were the relevant comparators in chronic migraine. But it considered that most people would have botulinum toxin type A rather than best supportive care after trying 3 oral preventive treatments.
## The evidence may not fully reflect the people who may be eligible for erenumab in clinical practice
The evidence was from 4 randomised controlled trials that compared 2 different dosages of erenumab (70 mg and 140 mg) with placebo: study 295 in chronic migraine, and STRIVE, ARISE and LIBERTY in episodic migraine. The committee noted that the company's evidence was for a subgroup of people for whom at least 3 previous treatments had failed (see section 3.3). However, people whose migraine had no therapeutic response (defined as no reduction in headache frequency, duration or severity) to a number of previous preventive treatment categories (more than 3 in study 295, more than 2 in STRIVE and ARISE) were excluded from the trials. In LIBERTY, people for whom more than 4 previous treatments had failed were excluded. The committee was concerned that the people excluded from the trials were likely to represent the people most in need of treatment and were therefore the most clinically important subgroup. The committee concluded that the evidence may not fully reflect the people who may be eligible for erenumab in clinical practice and it would take this into account.
## Erenumab 140 mg is clinically effective for chronic migraine compared with best supportive care but less so at 70 mg
Study 295 compared erenumab's effectiveness with placebo in 667 people with chronic migraine. The company presented the results of a post-hoc subgroup analysis of erenumab's effectiveness in people for whom at least 3 previous preventive treatments had failed, defined as insufficient or partial response, insufficient dosage or adverse events. The trial excluded people whose condition had no therapeutic response to more than 3 treatment categories. Results showed that erenumab 140 mg reduced the number of monthly migraine days from baseline to week 12 by 4.1 days more on average than placebo (95% confidence interval -5.8 to -2.3). The 70 mg dosage reduced monthly migraine days by 2.5 days more on average than placebo (95% CI -4.3 to -0.8). The proportion of people with at least a 50% reduction in monthly migraine days was 38.5% for the 140 mg dosage, 34.8% for the 70 mg dosage, and 15.3% for placebo. The results were statistically significant. The committee recognised that erenumab 140 mg also improved other outcomes compared with placebo, including the severity of migraine pain and the number of headache days each month. It noted that erenumab 140 mg reduced monthly migraine days compared with placebo more than the 70 mg dosage compared with placebo. The committee also noted that in this population at least a 30% reduction in migraine frequency was considered a clinically meaningful response (see section 3.3). Therefore, the clinical evidence did not fully reflect the most relevant outcomes. It concluded that erenumab 140 mg was clinically effective in chronic migraine when compared with best supportive care, but less so at the 70 mg dosage.
## Erenumab 140 mg may be clinically effective for episodic migraine compared with best supportive care but erenumab 70 mg is not
STRIVE, ARISE and LIBERTY compared erenumab with placebo in 1,778 people with episodic migraine. A post-hoc subgroup analysis was done to show erenumab's effectiveness in people for whom at least 3 previous treatments had failed. In STRIVE and ARISE this was defined as insufficient or partial response, insufficient dosage or adverse events (excluding people whose condition had no therapeutic response to more than 2 treatment categories). In LIBERTY, this was defined as insufficient, partial or no response, insufficient dosage or adverse events (excluding people for whom more than 4 treatments had failed). The proportion of people with at least a 50% reduction in monthly migraine days was greater for erenumab than for placebo (results are academic in confidence and cannot be reported here). Erenumab was also more effective than placebo in reducing the number of monthly migraine days from baseline to week 12. The results were statistically significant for the 140 mg dose in STRIVE but not in LIBERTY (ARISE only studied the 70 mg dose). But the committee noted that in STRIVE, monthly migraine days increased in the placebo group. This was not seen in the full trial population or in the subgroup in the other trials, suggesting that this could be a chance effect in a small subgroup and therefore increased uncertainty in the effect shown. The committee also noted that none of the results for the 70 mg dosage were statistically significant. The committee concluded that erenumab 140 mg may be clinically effective for episodic migraine when compared with best supportive care but there was no evidence that the 70 mg dosage was clinically effective.
## High-frequency episodic migraine is not a distinct subgroup
At consultation, the company updated its submission to focus on chronic migraine and high-frequency episodic migraine only. The company defined high-frequency episodic migraine as between 10 and 14 monthly headache days. The committee was aware that the clinical-effectiveness data for the 140 mg dose of erenumab in people for whom at least 3 previous treatments had failed came from the STRIVE and LIBERTY trials. In STRIVE at week 24, people who had erenumab 140 mg had a statistically significant reduction in monthly migraine days compared with placebo. In LIBERTY, people who had erenumab 140 mg had a numerically greater reduction in monthly migraine days from baseline to week 12 compared with placebo. The exact results for this subgroup are academic in confidence and cannot be reported. The ERG noted that high-frequency episodic migraine was defined in the company's trials as between 8 and 14 monthly migraine days and the results may not give adequate effectiveness data for a population with high-frequency episodic migraine, defined as 10 to 14 monthly headache days. The committee was concerned by the small numbers of people included in the subgroup (17 people in the erenumab arm of STRIVE and 76 people in the erenumab arm of LIBERTY). It also noted that this was a subgroup derived from a post-hoc subgroup analysis of the population with episodic migraine (see section 3.7). At the second appraisal committee meeting, the clinical experts explained that there is no internationally recognised classification of high-frequency episodic migraine and that it is not a clearly defined clinical subgroup. Clinical experts noted that the definition of high-frequency episodic migraine is arbitrary and that a person's quality of life is negatively affected irrespective of which type of migraine they have. The nature of the condition means that some people's migraine can be episodic one month or chronic the next according to the definitions. The committee considered that the clinical-effectiveness results for the high-frequency episodic migraine group were highly uncertain. It concluded that high-frequency episodic migraine is not a distinct subgroup and agreed not to consider it further.
## The long-term comparative effectiveness of erenumab is unknown
The duration of the blinded phase in the trials was just 3 months for study 295 (chronic migraine), ARISE and LIBERTY (episodic migraine), and 6 months for STRIVE (episodic migraine). The company provided supporting data for erenumab's long-term effectiveness from 2 open-label extension studies: a phase 2 trial in episodic migraine and an extension to study 295 in chronic migraine. The results showed that, in people who completed the trials, the improvement in monthly migraine days at 12 weeks was maintained while on treatment for up to 64 weeks for episodic migraine, and for up to 52 weeks for chronic migraine. The committee noted that 87% of people in STRIVE and 74% of people in study 295 completed the follow-up period. The committee was aware that there was no evidence that comparative efficacy was maintained beyond the blinded phase of the trials. It also noted that the efficacy of erenumab in the open-label extension studies was from the full trial populations, with 13% to 26% of people discontinuing from the studies. The committee further noted that the results of the open-label extension phase 2 trial (of 70 mg erenumab) in episodic migraine were better than the intention-to-treat results from STRIVE and ARISE. It recalled that, in the evidence the company submitted for the subgroup of people for whom at least 3 previous treatments had failed, the benefit of the 70 mg dose was not statistically significantly different to placebo (see section 3.7). The benefit for the 140 mg dose of erenumab for episodic migraine was statistically significant in STRIVE compared with placebo, but not in LIBERTY. After the second meeting, the company presented additional clinical data on the long-term effectiveness of erenumab for episodic migraine from an open-label trial following a randomised controlled trial. The mean change in monthly migraine days in the open-label trial, from baseline to month 57, was -5.8 days (standard error 0.3). At this time 76.5% of the participants' mean monthly migraine days had reduced by 50% or more. The ERG had concerns about the additional clinical data. In particular, the population in the study was different to the company's proposed population for erenumab, which is people whose condition has not responded to at least 3 oral preventive treatments (see section 3.2 and section 3.3). The open-label study did not specify prior treatment failure and most people (56%) included had not had treatment before. Prior treatment had failed in 36%, but the number of prior treatments was not specified, and included discontinuations because of lack of efficacy, adverse events, or both. Therefore, the committee agreed that the additional clinical data from the open-label study were not directly applicable to the population being considered in the appraisal. The committee concluded that it was unclear whether erenumab works in the long term because there was no evidence that comparative efficacy was maintained in people whose condition had not responded to at least 3 oral preventive treatments.
## Treatment with a second anti-CGRP drug could not be assessed
The committee was aware the scope did not include other medicines in the anti-calcitonin gene-related peptide (CGRP) class as potential comparators. Therefore erenumab was not formally compared with them. It noted that there was insufficient clinical evidence to support any difference in efficacy between the different anti-CGRP drugs. Because the drugs target the same pathway it is plausible that their effectiveness is similar. The committee also noted that treatment preferences are not outlined in the British Association for the Study of Headache (BASH) guidelines. BASH and the Association of British Neurologists explained that, although there is some evidence for using another anti-CGRP drug after the failure of the first, treatment preferences are not outlined in BASH's guidelines because there is no overall evidence to favour the use of 1 particular anti-CGRP drug over any of the others. Therefore the committee considered it reasonable that the least expensive drug would be used unless an alternative was more suitable for the person. The committee concluded that treatment with another anti-CGRP drug, after failure of a previous anti-CGRP drug, could not be assessed.
## The clinical evidence for having erenumab after botulinum toxin type A or when botulinum toxin type A is contraindicated is uncertain
After a previous version of the final appraisal document was released, an appeal was brought against the decision by BASH and the Association of British Neurologists. One of the appeal points was upheld by the appeal panel. This was that the committee unreasonably failed to consider the cost effectiveness of erenumab compared with best supportive care in those whose chronic migraine had failed to benefit from the comparator drug. Before the appeal, the company had not provided any evidence on the efficacy of erenumab after the use of botulinum toxin type A. It had also not provided any evidence for an alternative treatment sequence when erenumab is used beyond the fourth line of treatment and when botulinum toxin type A is contraindicated. After the appeal, the company presented evidence from study 295 on erenumab's treatment effect in 2 post-hoc subgroups:
people with chronic migraine for whom at least 4 previous treatments, including botulinum toxin type A, had failed
people with chronic migraine for whom 3 or more previous preventive treatments had failed, and who had not previously had botulinum toxin type A.The latter subgroup was used as a proxy for those for whom botulinum toxin type A was contraindicated. In both these subgroups, erenumab reduced monthly migraine days more on average than placebo. Also, a higher percentage of each population had a 30% reduction in monthly migraine days on erenumab compared with placebo (the values cannot be shown here, because they are considered confidential by the company). The ERG questioned the validity of not having botulinum toxin type A treatment as a proxy for botulinum toxin type A being contraindicated, because there are other reasons for not having botulinum toxin type A. The ERG also noted that these post-hoc subgroups were very small, so a meaningful analysis of them may not have been possible. The company and BASH provided some observational data on the use of erenumab in English centres, which supported the study 295 data because a 30% or more reduction in monthly migraine days was seen for some people at week 12. The committee concluded that because of the small subgroups, and the post-hoc analysis of these, there was uncertainty around the clinical evidence. It took this into account in decision making.
# Indirect treatment comparison
## The indirect treatment comparison does not show a statistically significant treatment effect for erenumab over botulinum toxin type A
There was no direct evidence comparing erenumab with botulinum toxin type A in chronic migraine. So the company did an indirect comparison using data from study 295 for erenumab and PREEMPT1 and PREEMPT2, which compared botulinum toxin type A with placebo. It indirectly compared the proportion of people on:
erenumab with at least a 50% reduction in monthly migraine days at 12 weeks
botulinum toxin type A with at least a 50% reduction in monthly headache days at 24 weeks.The comparison was in the subgroup for whom at least 3 previous treatments had failed (as defined in section 3.3). The difference in outcomes and time points reflected the difference in primary outcomes and timing of assessments between the trials. The resulting odds ratio favoured erenumab. But the result was not statistically significant either for the subgroup of people for whom at least 3 previous treatments had failed, or for the full trial populations (presented as supporting data; results are academic in confidence and cannot be reported here). Because the results were not statistically significant (that is, the confidence interval included an odds ratio of 1), erenumab could be more effective or less effective than botulinum toxin type A. The committee noted that the confidence interval around the odds ratio favouring erenumab was wide, which meant that there was a high degree of uncertainty associated with it. The committee considered that the company's methods for the indirect treatment comparison were appropriate but noted the differences between the trials for erenumab and botulinum toxin type A. The company used placebo as the common comparator, but it was administered differently in the trials: as a single subcutaneous injection every 4 weeks in the erenumab trial and as intramuscular injections into 31 to 39 different sites on the head and neck in the botulinum toxin type A trials. Given these differences, the committee did not think these should be considered the same, and this could have affected the substantially different placebo responses recorded in the trials. There was a difference in monthly migraine days with erenumab and monthly headache days with botulinum toxin type A. Given that these were separately reported as clinically distinct outcomes the committee did not think that these should be considered as the same. Also, the baseline characteristics of people in the PREEMPT trials in the subgroup of people for whom 3 previous treatments had failed were not available to the company and so it was uncertain whether the populations were similar. The committee also considered that the long-term variability in symptom frequency and severity associated with chronic migraine was not adequately captured by the short duration of the indirect treatment comparison. The committee was concerned about the analysis, given the lack of statistically significant results and the wide confidence intervals. It concluded that, based on the indirect treatment comparison alone, it was uncertain whether erenumab is more clinically effective than botulinum toxin type A for chronic migraine.
# Adverse events
## Erenumab is generally well tolerated in the populations studied
The rates of serious adverse events in the 4 trials were low, and most of the adverse events were of low to moderate severity. The company considered that erenumab has a safety and tolerability profile comparable with placebo. The committee was aware however that the adverse event data were for the full trial populations and may be different in people for whom 3 previous treatments had failed (including because of intolerability). However, this would be a much smaller group of people and it would be unlikely that firm conclusions could be drawn. But the committee was also aware that the trials excluded people over 65, anyone with a significant comorbidity (for example, cardiovascular disease), and women who could become pregnant, and that no conclusions could be drawn for these groups either. The committee concluded that the adverse events in the trials with erenumab were generally not severe and were comparable with placebo, and erenumab was generally well tolerated in the studied populations. The company noted that the safety profiles for erenumab 140 mg and 70 mg were similar. It provided evidence from UK neurologists, who considered that they would likely start people with difficult-to-treat migraine on the 140 mg dose, rather than the 70 mg dose. The committee recognised that sometimes it would be more appropriate for a person to have treatment with the lower dose.
# The company's economic model
## The company's updated economic model is appropriate
The company modelled the assessment period of 12 weeks (24 weeks for botulinum toxin type A) as a decision tree, and the post-assessment period as a Markov model that included 3 states: on treatment, off treatment and death. The company updated its economic model and modelling assumptions after consultation and after the second committee meeting to include:
a lifetime time horizon
-nly the 140 mg dose of erenumab.The committee concluded that the company's updated model using a lifetime time horizon was appropriate. It concluded that the 140 mg dose of erenumab was clinically effective in chronic migraine but less so at the 70 mg dose, based on the clinical-effectiveness results (see section 3.6 and section 3.7). It also concluded that it was acceptable to consider only the 140 mg dose in the cost-effectiveness model.
# Comparison with botulinum toxin type A
## The indirect treatment comparison results are uncertain, so erenumab and botulinum toxin type A may have similar effectiveness
The company's base case (up to and including the third committee meeting) used the odds ratio from the indirect treatment comparison to inform the relative effectiveness of erenumab compared with botulinum toxin type A. The committee was aware that the results of the indirect treatment comparison were highly uncertain (see section 3.12). It noted that the relative benefit of erenumab in the company's base case was unchanged over the lifetime time horizon in the model and considered this unlikely (see section 3.17). The committee also noted the additional uncertainty in the indirect treatment comparison, which was not captured in the confidence intervals. This arose from differences in the study populations' baseline characteristics, outcome measures (that is, monthly migraine days for erenumab and monthly headache days for botulinum toxin type A) and treatment assessment times (see section 3.12). At consultation and after the second appraisal committee meeting, the company presented scenarios with the odds ratio for the comparison with botulinum toxin type A set to 1 (similar efficacy) or using a midpoint between 1 and the odds ratio of the indirect comparison. The committee agreed with the ERG that the midpoint odds ratio scenario was not methodologically justified because it was an arbitrary figure and not supported by evidence. It did not consider this scenario further. The committee noted consultation comments that long-term real-world evidence on botulinum toxin type A from the NHS in England was available. This was for the relevant population (people for whom at least 3 previous treatments had failed) and showed that adherence, efficacy and safety is sustained or improved over a 5‑year period. It also noted the clinical experts' consultation comments that it was plausible that botulinum toxin type A and erenumab could be considered to have equal efficacy. However, given the long-term and promising real-world data for botulinum toxin type A, the committee considered that the relative effectiveness of erenumab compared with botulinum toxin type A was not certain in the long term. Also, it recalled its concerns and the uncertainty with the indirect treatment comparison (see section 3.12). Because of the uncertainty in the results of the indirect treatment comparison, at the time of the third committee meeting the committee considered it appropriate to also consider cost-effectiveness analyses in which erenumab and botulinum toxin type A were assumed to have similar effectiveness (that is, using an odds ratio of 1).
## Including a treatment effect for erenumab compared with botulinum toxin type A is acceptable
In the company's indirect treatment comparison, to determine the relative efficacy of erenumab 140 mg compared with botulinum toxin type A, there was some uncertainty about whether erenumab may be more effective. The difference in monthly migraine days, which was not statistically significant, favoured erenumab over botulinum toxin type A. The company used these indirect treatment comparison estimates in a scenario analysis for the fourth appraisal committee meeting (the odds ratio used was considered confidential by the company so cannot be shown here). This was in line with the modelling done in NICE's technology appraisal guidance on galcanezumab for preventing migraine. In this, a treatment effect for galcanezumab compared with botulinum toxin type A was used in the final decision-making model (instead of assuming equivalence). The committee recalled that according to clinical opinion, anti-CGRP drugs are more effective than botulinum toxin type A. Also, the committee was aware that in NICE's technology appraisal guidance on fremanezumab for preventing migraine and on galcanezumab, the companies provided indirect treatment comparison point estimates that favoured the anti-CGRP drug over botulinum toxin type A. However, this was associated with uncertainty. The committee was aware that the commercial arrangement for erenumab had been improved. The company provided threshold analysis showing that even a marginal benefit of erenumab over botulinum toxin type A reduced the cost-effectiveness estimates for erenumab for chronic migraine. The committee was aware that, for galcanezumab in the same population, it was able to accept the indirect treatment comparison results. This was because they showed a positive effect for galcanezumab compared with botulinum toxin type A in terms of monthly migraine days. The evidence for erenumab was similar, so the committee agreed that this treatment effect should be taken into account in its decision making.
# Modelling long-term treatment effectiveness
## While people stay on treatment, it is reasonable to assume that the treatment effect does not wane over time
The company's model assumed that the treatment effect stayed constant while people were on treatment. The committee was aware, however, that in other chronic conditions the effects of monoclonal antibodies can wane over time. It noted that the company had provided a scenario during clarification that incorporated a treatment waning effect. In this, health state costs and utilities for erenumab and botulinum toxin type A were linearly reduced over 10 years until they were in line with best supportive care. The ERG had also modelled this and another scenario whereby treatment effect waned over a 5‑year period. At consultation, the company provided an additional treatment waning scenario whereby treatment waning started at 5 years and waned over a 10‑year period. The committee was not presented with any evidence to suggest that erenumab would follow this type of waning pattern. After the second meeting, the company commented that in the ERG's 5‑ and 10‑year waning scenarios, health state costs and health state utilities were reduced for people whose migraine responded to treatment. However, treatment was not stopped as efficacy waned; therefore, treatment costs continued to accrue over the long term. The company considered these as extreme scenarios because treatment should be stopped if people no longer have a clinically meaningful benefit (see section 3.19). The company therefore submitted an alternative scenario that used an additional discontinuation rate instead of a waning assumption, along with longer-term clinical data from an open-label extension study in episodic migraine. The committee agreed that treatment waning effect and treatment discontinuation are 2 separate issues, and adjusting the discontinuation probabilities does not reflect the uncertainty of potential waning (see section 3.18). The long-term clinical data from the extension study showed that low numbers of people withdrew from erenumab treatment because of a lack of efficacy. The committee was aware of conflicting clinical expert opinion as to whether treatment resistance could occur with erenumab. At the second committee meeting the clinical expert suggested that erenumab's mechanism of action as a CGRP inhibitor meant that it may not be associated with a treatment waning effect. However, the committee also noted that a clinical expert at consultation thought that development of treatment resistance was possible. The committee noted that in the erenumab clinical trials, the number of people who developed neutralising antibodies to erenumab was low (approximately 0% to 3%). To date there is no evidence of the impact of anti-erenumab antibody development on efficacy and safety. The committee understood that if a person did develop anti-erenumab antibodies, waning is unlikely to be linear over time because efficacy would be lost quickly. Based on the evidence available, the committee considered that it was reasonable to assume that the treatment effect does not wane over time.
## The company's additional treatment discontinuation scenario is not appropriate
After the second meeting, the company submitted another scenario analysis that used an additional discontinuation rate as an alternative to treatment waning (see section 3.17). In this scenario, an annual discontinuation rate of 10% because of loss of efficacy was applied in addition to the 2.38% all-cause discontinuation rate already in the company's base case. This additional discontinuation rate was applied to both the erenumab and botulinum toxin type A treatment arms in the model. The ERG agreed that loss of efficacy may result in treatment discontinuation, but the company's scenario did not reflect the gradual loss of effectiveness that would likely occur before treatment was stopped. This was because people were taken off treatment without any loss of effectiveness in this company scenario. The committee considered that the longer-term data for erenumab submitted by the company after the second meeting (see section 3.9) did not support this level of treatment discontinuation because of loss of efficacy. The data showed that only 5.6% of people taking the 140 mg dose of erenumab stopped treatment, and none of them because of loss of efficacy. Approximately half of these people had asked to stop treatment, but the reasons for stopping were unknown. The committee concluded that the company's additional treatment discontinuation scenario was not appropriate.
## Applying a negative stopping rule is appropriate
The company's model assumed that treatment would be stopped for people who did not respond to erenumab at 3 months (a negative stopping rule). The clinical experts had noted that applying a rule using a 50% reduction in monthly migraine days would accurately reflect the efficacy of episodic migraine treatments in clinical practice. Similarly, a 30% reduction in monthly migraine days would be appropriate for chronic migraine (see section 3.3). The committee considered the 30% threshold for the chronic migraine group to be appropriate and consistent with NICE's technology appraisal guidance on botulinum toxin type A and BASH's guidelines. The committee concluded that it was appropriate to include a negative stopping rule at 3 months in the economic model if there was no response to treatment. No response was defined as less than a 30% reduction (for chronic migraine) or 50% reduction (for episodic migraine) in monthly migraine days at the 12‑week assessment.
## The company's positive stopping rule scenarios are not appropriate
The clinical experts explained that in practice, if migraine responds to treatment, some people may try a treatment break. The committee also noted the clinical experts' written comments that some people may stay on treatment indefinitely. The committee recalled that the company's base-case modelling reflected a constant treatment effect over a lifetime time horizon. At consultation the company presented 2 positive stopping scenarios, which assumed that people staying on treatment would be reassessed after 64.5 weeks. After that, 20% of people would stop treatment, while the remainder would resume treatment and be reassessed at 76.5‑week intervals. In the first scenario, people who stop treatment would continue to benefit from erenumab for the lifetime time horizon of the model without incurring the costs. The committee was aware that there was no evidence to show the duration of treatment benefit (see section 3.17), or maintenance of constant benefit, once treatment had been stopped. The patient expert explained that once erenumab treatment was stopped the benefit was maintained for only a short time before the migraine returned. In the second scenario, people who stop treatment would return to monthly migraine days based on the placebo arm of the trial. The committee did not consider this scenario appropriate either because erenumab would need to be restarted for these people and the company's model did not allow this once the positive stopping rule was applied. The committee therefore concluded that the positive stopping scenarios were not appropriate for consideration.
## It is acceptable to account for a loss of the placebo effect when migraine responds to best supportive care
In the company's modelling at the time of the third appraisal committee meeting, the treatment effect for people whose migraine responded to best supportive care was maintained for the lifetime time horizon of the model. In the model, everyone who stopped treatment (regardless of the treatment they had) maintained the same improvement in monthly migraine days as for people whose migraine did not respond (rather than continuing with any on-treatment improvement). For the fourth appraisal committee meeting, the company did a scenario analysis in which people whose migraine responded to best supportive care reverted to baseline monthly migraine days at the end of year 1 (a sudden and full loss of placebo effect). Everyone stopping treatment was assumed to return to baseline monthly migraine days. The company considered this to be a slightly more conservative approach than that taken in NICE's technology appraisal guidance on galcanezumab and fremanezumab. When applying this assumption, the cost-effectiveness estimates for erenumab compared with best supportive care improved. The committee accepted this approach and used it for decision making.
# Utilities
## Utility values used in the model are highly uncertain
The company collected quality-of-life data in study 295 (chronic migraine), STRIVE and ARISE (episodic migraine) using the Migraine-Specific Quality of Life Questionnaire (MSQ) and in LIBERTY (episodic migraine) using the EQ‑5D‑5L. The utility values used in the model were generated from mapping MSQ results to EQ‑5D‑3L using the Gillard et al. 2012 algorithm. The company explained that the EQ‑5D‑5L data collected in LIBERTY were not sensitive to changes in quality of life with migraine because the questionnaire was given on appointment days, and asked people about their quality of life on that day. If a person was having a migraine that day, they would likely rearrange their appointment. So the company considered that the EQ‑5D‑5L data were collected when the person did not have migraine, and were therefore not appropriate to use in the model. It considered the MSQ to be more appropriate because it had a 4‑week recall period. The clinical experts explained that in clinical practice they use the HIT‑6 and MIDAS tools, not the MSQ, to measure quality of life, so it was not known whether MSQ was the best available measure of quality of life. The committee agreed that the rationale for using MSQ instead of direct EQ‑5D‑5L data was plausible. However, the committee considered that the actual utility values generated from mapping the MSQ data to EQ‑5D‑3L may be underestimates, given that they were low (average values ranged from 0.466 to 0.784 across the different health states). However, it recognised that the baseline values for people with chronic migraine represented people having on average about 15 migraine days a month. Given the before and after effects of migraine described by the patient experts (see section 3.1) the low utility value of 0.466 could accurately represent quality of life. The committee was also aware that the MSQ data had been mapped to EQ‑5D‑3L in NICE's technology appraisal guidance on botulinum toxin type A and that the utility values used were broadly similar. The committee understood that the MSQ data were based on the full trial population, and not just on those for whom at least 3 previous treatments had failed. Also, there were separate mapping algorithms for chronic and episodic migraine but because of small patient numbers these had been applied at the individual patient level based on the number of migraine or headache days at baseline, which created more uncertainty. The committee noted that the utility data were a key driver of the cost-effectiveness estimates. It was concerned about the reliability of the values given the uncertainty of using data from a broader population and mapping this to EQ‑5D‑3L. On balance, the committee concluded that the utility values used in the model may be reasonable but were uncertain.
## Applying a mode of administration utility decrement to botulinum toxin type A is not appropriate
The company provided scenario analyses which incorporated a utility decrement associated with the mode of administration of botulinum toxin type A. The company suggested that treatment with botulinum toxin type A leads to an increased burden on people compared with treatment with erenumab because of the number of injections needed in the head and neck. At consultation clinical experts noted that erenumab could have a reduced burden on people compared with botulinum toxin type A. However, other comments received during consultation suggested that long-term real-world evidence showed an improvement in quality of life with botulinum toxin type A compared with best supportive care. The company's scenario used a vignette-based time-trade-off utility valuation study, done in the UK, to derive mode of administration decrements for migraine prophylaxis treatments relative to erenumab. The decrements were applied additively to each monthly migraine day-specific utility value throughout the model. The committee noted that when the utility decrement scenario was applied the total quality-adjusted life years (QALYs) for botulinum toxin type A were lower than for best supportive care. It considered that this scenario was not clinically plausible. The committee concluded that applying a mode of administration utility decrement to botulinum toxin type A was not appropriate.
## It is acceptable to use differential utilities in the modelling
The company's original modelling used equal utilities for a health state, regardless of treatment received. The committee recognised that there was some evidence of a treatment effect for erenumab beyond a decrease in monthly migraine days. NICE asked the company for any evidence it had to support the use of differential utilities, capturing treatment benefit beyond a decrease in monthly migraine days, which it had not provided before. The company initially submitted analyses based on a regression model, but the ERG had major concerns about the company's approach. It noted that the regression model was flawed and should not be used. This was because the estimated differential utility (using a 'treatment' covariate where baseline observations were categorised as best supportive care) partly included the placebo effect. In response, the company amended its approach to address the ERG's concerns. It used separate regression models, including one where baseline quality-of-life data were included with monthly migraine days as the only covariate. Post-baseline quality-of-life data were included in a second regression model with monthly migraine days and treatment as covariates. In this way, separate regression models were used to generate 'off-treatment' utility values and 'on-treatment' utility values, with values differing between erenumab 140 mg and placebo for a given frequency of monthly migraine days. The ERG thought that the company's updated regression models had been implemented correctly and the company's face validity checks were reasonable. However, the ERG preferred the approach to implementation of differential utility values by intervention and model state taken by the company in its initial differential utility analyses. The ERG carried out some scenario analyses with alternative approaches. It found that the exact approach to implement a differential treatment utility was unlikely to be a main driver of the cost effectiveness of erenumab 140 mg. In NICE's technology appraisal guidance on galcanezumab, the committee accepted the use of differential utilities for a health state depending on the treatment used. The committee was satisfied that it had seen enough evidence to support the use of differential utilities for erenumab. It considered that, regardless of the exact implementation approach taken, it was acceptable to use differential utilities in the modelling.
## It is appropriate to adjust health state utilities for age in the model
NICE's guide to the methods of technology appraisal states that adjustments to utility values, for example for age or comorbidities, may sometimes be needed. When extrapolating health-related quality-of-life data over long time horizons, it is often considered appropriate to adjust for age. This reflects the natural decline in health-related quality of life over time, and ensures utilities do not exceed general population values at a given age. For the fourth appraisal committee meeting, the company did a scenario analysis to use age-adjusted utilities in its modelling. It used a common methodology with utility values weighted based on age decrements for the UK general population (Ara and Brazier 2010). The committee noted that this adjustment did not have a large effect on the cost-effectiveness estimates and considered it appropriate to include in its decision making.
# Costs
## All relevant costs for using erenumab in practice are captured in the model
The clinical experts explained that erenumab would initially be used in a secondary care specialist headache clinic. The committee recognised the advantages of a self-injectable treatment. But given the need for starting and stopping rules to ensure erenumab was used appropriately, treatment would need to be started by doctors experienced in treating migraine. The committee considered that for erenumab to be available for the most refractory cases of migraine, and to meet the monitoring requirements, additional resources would likely be needed, and that the cost of setting up these additional services should be accounted for in the model. To inform its assumptions about resource use involving healthcare professionals, the company had used results from a National Health and Wellness Survey involving people across Europe (including the UK), which aimed to characterise migraine burden from the patients' perspective. However, the company assumed that the results, which were grouped into categories based on the number of headache days per month, approximated resource use per migraine day. Consultation comments from clinical experts noted that erenumab treatment would be started in a specialist headache clinic, but the person would be trained to self-administer treatment at home. Consultation comments suggested that self-administration is important because it gives people a sense of control. Further comments from clinical experts suggested that using erenumab in practice is unlikely to affect referrals to specialist services because this was not the case when botulinum toxin type A became available. Also, these people are already being seen in specialist clinics. At consultation the company updated its economic model to include the appropriate triptan injection price, which the committee accepted. After the appeal, the company incorporated an anti-CGRP administration cost (a 30‑minute appointment with a nurse in hospital) in its modelling. This was applied for 10% of patients having erenumab. This was in line with the modelling in previous appraisals of anti-CGRP drugs for migraine. The committee was satisfied that all relevant costs were captured in the modelling.
# Cost-effectiveness estimates
## The company's updated cost-effectiveness analyses are appropriate for decision making
At consultation the updated company's base case included populations with chronic migraine and high-frequency episodic migraine only. The committee recalled that the high-frequency episodic migraine population was not a distinct group (see section 3.8) and therefore agreed that it should not consider the cost-effectiveness analyses for this population further. After the appeal, the company provided updated cost-effectiveness analyses for chronic and episodic migraine, and included the following assumptions and scenarios:
a revised commercial arrangement (confidential simple discount only)
evidence for erenumab compared with botulinum toxin type A and best supportive care (chronic migraine) or best supportive care only (episodic migraine; see section 3.4)
differential utilities for erenumab 140 mg compared with placebo (see section 3.24)
a negative stopping rule (see section 3.19)
a scenario including administration costs for 10% of people having erenumab (see section 3.26)
a scenario including age-adjusted utilities (see section 3.25)
a scenario with loss of placebo effect after 1 year for people whose migraine responded to best supportive care (see section 3.21)
a scenario with a greater treatment effect for erenumab than for botulinum toxin type A (instead of assuming equivalence) from the indirect treatment comparison (see section 3.16).All of the company's incremental cost-effectiveness ratios (ICERs) presented at the fourth committee meeting included a confidential commercial arrangement. The ICERs were considered confidential by the company and cannot be reported here. Most of the ICERs were around £20,000 per QALY gained, with many below that. The committee noted that the ERG was able to reproduce the company's cost-effectiveness estimates, for both the chronic migraine and episodic migraine populations. The committee concluded that the company's updated cost-effectiveness analyses were appropriate for decision making.
## Erenumab is cost effective for chronic migraine and for episodic migraine after 3 preventive treatments have failed
The committee recalled that:
It had concluded that high-frequency episodic migraine was not a distinct group and that it should not consider the cost-effectiveness analysis for this population further (see section 3.8).
The treatment effect does not wane over time (see section 3.17).
It was not appropriate to include an additional discontinuation rate along with the company's original 2.38% rate for all-cause discontinuation every 12 weeks (see section 3.18).
It was appropriate to include a treatment effect favouring erenumab over botulinum toxin type A in chronic migraine, because evidence supporting this from an indirect treatment comparison was provided. Also, threshold analysis showed that even a marginal treatment effect made erenumab much more cost effective than when erenumab and botulinum toxin type A were assumed to have equal effectiveness (see section 3.16).
It was appropriate to use differential utilities in the analysis. This was because of the evidence supporting a treatment benefit for erenumab compared with placebo beyond a reduction in monthly migraine days. It was also because of the company's revised regression modelling with off-treatment and on-treatment utilities, with values differing for erenumab 140 mg and placebo for a given frequency of monthly migraine days (see section 3.24).
The model should use a standard method of adjusting utilities for age over a long time horizon (see section 3.25).
Administration costs for erenumab should be applied for 10% of people having it (see section 3.26).
The modelling should account for a loss of the placebo effect in people whose migraine responded to best supportive care (see section 3.21).The committee was aware that the ICERs were highly sensitive to the assumption about the effectiveness of erenumab compared with botulinum toxin type A. It preferred a fully incremental analysis, that is, a combined single analysis in which best supportive care is compared with botulinum toxin type A, which in turn is then compared with erenumab. The committee took its preferences into account after the fourth meeting, including the updated confidential commercial arrangement for erenumab and the confidential Commercial Medicines Unit price for botulinum toxin type A. It agreed that most of the plausible cost-effectiveness estimates were below £20,000 per QALY gained. The committee concluded that erenumab was cost effective for chronic migraine and for episodic migraine after 3 preventive treatments have failed.
# Other factors
## No adjustments are needed for equality
No equalities issues were identified by the company. The clinical and patient submissions highlighted that migraine can be classed as a disability under the Equality Act 2010. Because migraine is most common in people of working age and affects more women than men, women may be further disadvantaged in the workplace. It was also noted that there may be unequal access to specialist headache clinics and botulinum toxin type A. The committee considered these issues and noted that unequal access was not associated with a protected characteristic. So, it concluded that no specific adjustments were needed to NICE's methods in this case.
## All relevant aspects of erenumab are captured in the economic modelling
Erenumab was considered innovative when first discussed by the committee. In its original submission, the company explained that erenumab was a first-in-class therapy and therefore a step change in the management of migraine. But now, 2 other anti-CGRP drugs have been recommended for use in the NHS to treat migraine. The committee accepted the use of differential utilities (capturing erenumab's benefit beyond a reduction in monthly migraine days), and a treatment benefit of erenumab compared with botulinum toxin type A for chronic migraine after at least 3 previous treatments have failed. So it considered that all relevant aspects of erenumab were captured in the economic modelling.
# Conclusion
## Erenumab is recommended for chronic migraine after 3 or more preventive treatments have failed
The committee considered the evidence that erenumab was clinically effective (at 140 mg) in chronic migraine when compared with best supportive care and when response was measured as a 50% or greater reduction in monthly migraine days (see section 3.6). However, it considered that a 30% reduction in monthly migraine days was more clinically relevant (see section 3.3), and treatment should be stopped if this is not achieved. It considered that there was a high degree of uncertainty about whether erenumab was more clinically effective than botulinum toxin type A (see section 3.12). But after the company provided further evidence from an indirect treatment comparison, it agreed that it was appropriate to assume a treatment benefit of erenumab over botulinum toxin type A (see section 3.16). The committee considered the substantial effect of this assumption on the ICER, which was within the range usually considered a cost-effective use of NHS resources. Therefore, it recommended erenumab for preventing chronic migraine in adults after at least 3 preventive treatments have failed. This includes people with chronic migraine when botulinum toxin type A treatment has failed or is contraindicated. The committee was aware that numbers in these groups would reduce over time because of the introduction of anti-CGRP drugs. Erenumab should be stopped if migraine frequency does not reduce by at least 30% after 12 weeks of treatment.
## Erenumab is recommended for episodic migraine after 3 or more preventive treatments have failed
In episodic migraine, the committee had concluded that the evidence showed that erenumab 140 mg may be clinically effective when compared with best supportive care, that is, when response was measured as a 50% or greater reduction in monthly migraine days (see section 3.7). Treatment should be stopped if this is not achieved. It considered that the evidence to support the effectiveness of erenumab in high-frequency episodic migraine was uncertain and did not consider it further because it is not a distinct subgroup (see section 3.8). The company presented updated analyses for erenumab for preventing episodic migraine for the fourth committee meeting. The clinical evidence supported a treatment benefit, and cost-effectiveness results were within what NICE usually considers an acceptable use of NHS resources. Therefore, the committee recommended erenumab for use in the NHS for preventing episodic migraine in adults after at least 3 preventive treatments have failed. Erenumab should be stopped if migraine frequency does not reduce by at least 50% after 12 weeks of treatment.
|
{'Recommendations': 'Erenumab is recommended as an option for preventing migraine in adults, only if:\n\nthey have 4\xa0or more migraine days a month\n\nat least 3\xa0preventive drug treatments have failed\n\nthe 140\xa0mg dose of erenumab is used and\n\nthe company provides it according to the commercial arrangement.\n\nStop erenumab after 12\xa0weeks of treatment if:\n\nin episodic migraine (less than 15\xa0headache days a month) the frequency does not reduce by at least 50%\n\nin chronic migraine (15\xa0headache days a month or more with at least\xa08 of those having features of migraine) the frequency does not reduce by at least 30%.\n\nThese recommendations are not intended to affect treatment with erenumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatments for preventing chronic or episodic migraine include beta-blockers, antidepressants and antiepileptic drugs. If chronic migraine does not respond to at least 3\xa0preventive drug treatments, botulinum toxin type\xa0A or best supportive care (treatment for the migraine symptoms) is offered. If episodic migraine does not respond to at least 3\xa0preventive drug treatments, best supportive care is offered.\n\nFor people whose migraine has not responded to at least 3\xa0preventive treatments, the clinical trial evidence shows that erenumab 140\xa0mg works better than best supportive care for preventing chronic or episodic migraine. There is no direct evidence comparing erenumab with botulinum toxin type\xa0A in chronic migraine, but an indirect comparison suggests that erenumab has some benefit. It is plausible that erenumab may work better than botulinum toxin type\xa0A.\n\nThe cost-effectiveness estimates are within what NICE usually considers an acceptable use of NHS resources. So erenumab is recommended for preventing migraine in adults who have at least 4\xa0migraine days per month.', 'Information about erenumab': "# Marketing authorisation indication\n\nErenumab (Aimovig, Novartis) is indicated for 'prophylaxis of migraine in adults who have at least 4\xa0migraine days per month'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of erenumab is £386.50 per 70\xa0mg or 140\xa0mg injection (excluding VAT, BNF online, accessed November\xa02020). The company has a commercial arrangement. This makes erenumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# The condition and current treatment\n\n## Migraine significantly affects health-related quality of life\n\nThe patient experts described the effect of migraine on their quality of life and how it affects their ability to work and take part in social activities. People with migraine can often miss out on family time and find it difficult to plan future activities. The severity and frequency of the condition can fluctuate over time and can be poorly understood in the workplace. The patient experts explained that symptoms can start in the days leading up to a migraine and that recovery can take a few days, so people with chronic migraine may have few symptom-free days. Chronic migraine is defined as\xa015 or more headache days a month, with at least 8\xa0of those having features of migraine. Episodic migraine is defined as less than 15\xa0headache days a month. The burden on quality of life can be similar to that of chronic migraine. The committee concluded that migraine, particularly chronic migraine, is a debilitating condition that substantially affects health-related quality of life and employment and is associated with an increase in the prevalence of psychiatric illness.\n\n## Well-tolerated treatments are needed\n\nThe committee understood that current oral treatment options for preventing migraine include drugs that are used to treat other conditions, such as beta-blockers, antidepressants and antiepileptic drugs. The patient experts explained that these treatments can have significant side effects, can be poorly tolerated and may not work for some people. The committee was aware that NICE's technology appraisal guidance on botulinum toxin type\xa0A for the prevention of headaches in adults with chronic migraine recommends botulinum toxin type\xa0A for people with chronic migraine whose condition has not responded to at least 3\xa0previous oral preventive drug treatments and is appropriately managed for medication overuse. Clinical experts stated that although botulinum toxin type\xa0A is recommended by NICE, there are lengthy waiting lists and it is not always available in some areas of the country. The committee concluded that effective, well-tolerated treatment options are needed.\n\n# Current clinical management\n\n## At least 3\xa0oral preventive treatments are tried before more specialist treatment is considered\n\nThe clinical experts explained that the aim of treatment is to reduce the frequency, severity or duration of migraine and improve quality of life. In chronic migraine, a 30% reduction in migraine frequency is considered a clinically meaningful response to treatment. In episodic migraine, a 50% reduction is considered a clinically meaningful response. If the response is lower than this (an insufficient or partial clinical response), or the person is not able to have an adequate dosage for long enough or has adverse events, treatment is stopped and another oral preventive treatment is tried. The clinical experts explained that it is important for people to try a range of oral preventive treatments before considering more specialist treatment, such as botulinum toxin type\xa0A (for chronic migraine) or erenumab. The committee therefore concluded that a clinically meaningful response was a 30% reduction (for chronic migraine) or a 50% reduction (for episodic migraine) in migraine frequency. An insufficient response to at least 3\xa0oral preventive treatments represents usual NHS practice before more specialist treatment is considered.\n\n# Clinical evidence\n\n## The most relevant comparators are best supportive care for episodic migraine and botulinum toxin type\xa0A for chronic migraine\n\nThe company's submission focused on people with migraine for whom at least 3\xa0previous preventive treatments had failed (defined as insufficient or partial response, insufficient dosage or adverse events). This was because the company considered this group to reflect people most in need of treatment options and for whom erenumab would likely be used in practice. The company presented evidence for erenumab's clinical effectiveness compared with placebo for episodic migraine and compared with placebo and botulinum toxin type\xa0A for chronic migraine. The company considered that placebo was representative of best supportive care, because it comprised acute treatments that people would have for their migraine symptoms when preventive treatments had not worked. The clinical experts agreed that erenumab would likely be offered to people with migraine for whom at least 3\xa0previous preventive treatments had failed. The committee suggested that some people may be able to have a fourth oral preventive treatment, given that it was important to try a range of oral preventive treatments before more specialist treatment is considered (see section\xa03.3). After consultation, clinical experts explained that most people will have either botulinum toxin type\xa0A or best supportive care. Only some people may have a fourth oral preventive treatment and this is unlikely to have a clinically meaningful benefit. The committee therefore did not consider that a fourth oral preventive treatment would be a relevant comparator. It concluded that best supportive care was the most appropriate comparator in episodic migraine. For people with chronic migraine who have tried 3\xa0oral preventive treatments that have not worked, the committee recalled comments from patient and clinical experts that these people are most in need of effective therapy. They would be offered botulinum toxin type\xa0A at this point in the treatment pathway. The committee concluded that botulinum toxin type\xa0A or best supportive care were the relevant comparators in chronic migraine. But it considered that most people would have botulinum toxin type\xa0A rather than best supportive care after trying 3\xa0oral preventive treatments.\n\n## The evidence may not fully reflect the people who may be eligible for erenumab in clinical practice\n\nThe evidence was from 4\xa0randomised controlled trials that compared 2\xa0different dosages of erenumab (70\xa0mg and 140\xa0mg) with placebo: study\xa0295 in chronic migraine, and STRIVE, ARISE and LIBERTY in episodic migraine. The committee noted that the company's evidence was for a subgroup of people for whom at least 3\xa0previous treatments had failed (see section\xa03.3). However, people whose migraine had no therapeutic response (defined as no reduction in headache frequency, duration or severity) to a number of previous preventive treatment categories (more than\xa03 in study\xa0295, more than\xa02 in STRIVE and ARISE) were excluded from the trials. In LIBERTY, people for whom more than\xa04 previous treatments had failed were excluded. The committee was concerned that the people excluded from the trials were likely to represent the people most in need of treatment and were therefore the most clinically important subgroup. The committee concluded that the evidence may not fully reflect the people who may be eligible for erenumab in clinical practice and it would take this into account.\n\n## Erenumab 140\xa0mg is clinically effective for chronic migraine compared with best supportive care but less so at 70\xa0mg\n\nStudy\xa0295 compared erenumab's effectiveness with placebo in 667\xa0people with chronic migraine. The company presented the results of a post-hoc subgroup analysis of erenumab's effectiveness in people for whom at least 3\xa0previous preventive treatments had failed, defined as insufficient or partial response, insufficient dosage or adverse events. The trial excluded people whose condition had no therapeutic response to more than 3\xa0treatment categories. Results showed that erenumab 140\xa0mg reduced the number of monthly migraine days from baseline to week\xa012 by 4.1\xa0days more on average than placebo (95%\xa0confidence interval [CI] -5.8 to -2.3). The 70\xa0mg dosage reduced monthly migraine days by 2.5\xa0days more on average than placebo (95%\xa0CI -4.3 to -0.8). The proportion of people with at least a 50% reduction in monthly migraine days was 38.5% for the 140\xa0mg dosage, 34.8% for the 70\xa0mg dosage, and 15.3% for placebo. The results were statistically significant. The committee recognised that erenumab 140\xa0mg also improved other outcomes compared with placebo, including the severity of migraine pain and the number of headache days each month. It noted that erenumab 140\xa0mg reduced monthly migraine days compared with placebo more than the 70\xa0mg dosage compared with placebo. The committee also noted that in this population at least a 30% reduction in migraine frequency was considered a clinically meaningful response (see section\xa03.3). Therefore, the clinical evidence did not fully reflect the most relevant outcomes. It concluded that erenumab 140\xa0mg was clinically effective in chronic migraine when compared with best supportive care, but less so at the 70\xa0mg dosage.\n\n## Erenumab 140\xa0mg may be clinically effective for episodic migraine compared with best supportive care but erenumab 70\xa0mg is not\n\nSTRIVE, ARISE and LIBERTY compared erenumab with placebo in 1,778\xa0people with episodic migraine. A post-hoc subgroup analysis was done to show erenumab's effectiveness in people for whom at least 3\xa0previous treatments had failed. In STRIVE and ARISE this was defined as insufficient or partial response, insufficient dosage or adverse events (excluding people whose condition had no therapeutic response to more than 2\xa0treatment categories). In LIBERTY, this was defined as insufficient, partial or no response, insufficient dosage or adverse events (excluding people for whom more than 4\xa0treatments had failed). The proportion of people with at least a 50% reduction in monthly migraine days was greater for erenumab than for placebo (results are academic in confidence and cannot be reported here). Erenumab was also more effective than placebo in reducing the number of monthly migraine days from baseline to week\xa012. The results were statistically significant for the 140\xa0mg dose in STRIVE but not in LIBERTY (ARISE only studied the 70\xa0mg dose). But the committee noted that in STRIVE, monthly migraine days increased in the placebo group. This was not seen in the full trial population or in the subgroup in the other trials, suggesting that this could be a chance effect in a small subgroup and therefore increased uncertainty in the effect shown. The committee also noted that none of the results for the 70\xa0mg dosage were statistically significant. The committee concluded that erenumab 140\xa0mg may be clinically effective for episodic migraine when compared with best supportive care but there was no evidence that the 70\xa0mg dosage was clinically effective.\n\n## High-frequency episodic migraine is not a distinct subgroup\n\nAt consultation, the company updated its submission to focus on chronic migraine and high-frequency episodic migraine only. The company defined high-frequency episodic migraine as between\xa010 and 14\xa0monthly headache days. The committee was aware that the clinical-effectiveness data for the 140\xa0mg dose of erenumab in people for whom at least 3\xa0previous treatments had failed came from the STRIVE and LIBERTY trials. In STRIVE at week\xa024, people who had erenumab 140\xa0mg had a statistically significant reduction in monthly migraine days compared with placebo. In LIBERTY, people who had erenumab 140\xa0mg had a numerically greater reduction in monthly migraine days from baseline to week\xa012 compared with placebo. The exact results for this subgroup are academic in confidence and cannot be reported. The ERG noted that high-frequency episodic migraine was defined in the company's trials as between\xa08 and 14\xa0monthly migraine days and the results may not give adequate effectiveness data for a population with high-frequency episodic migraine, defined as 10\xa0to 14\xa0monthly headache days. The committee was concerned by the small numbers of people included in the subgroup (17\xa0people in the erenumab arm of STRIVE and 76\xa0people in the erenumab arm of LIBERTY). It also noted that this was a subgroup derived from a post-hoc subgroup analysis of the population with episodic migraine (see section\xa03.7). At the second appraisal committee meeting, the clinical experts explained that there is no internationally recognised classification of high-frequency episodic migraine and that it is not a clearly defined clinical subgroup. Clinical experts noted that the definition of high-frequency episodic migraine is arbitrary and that a person's quality of life is negatively affected irrespective of which type of migraine they have. The nature of the condition means that some people's migraine can be episodic one month or chronic the next according to the definitions. The committee considered that the clinical-effectiveness results for the high-frequency episodic migraine group were highly uncertain. It concluded that high-frequency episodic migraine is not a distinct subgroup and agreed not to consider it further.\n\n## The long-term comparative effectiveness of erenumab is unknown\n\nThe duration of the blinded phase in the trials was just 3\xa0months for study\xa0295 (chronic migraine), ARISE and LIBERTY (episodic migraine), and 6\xa0months for STRIVE (episodic migraine). The company provided supporting data for erenumab's long-term effectiveness from 2\xa0open-label extension studies: a phase\xa02 trial in episodic migraine and an extension to study\xa0295 in chronic migraine. The results showed that, in people who completed the trials, the improvement in monthly migraine days at 12\xa0weeks was maintained while on treatment for up to 64\xa0weeks for episodic migraine, and for up to 52\xa0weeks for chronic migraine. The committee noted that 87% of people in STRIVE and 74% of people in study\xa0295 completed the follow-up period. The committee was aware that there was no evidence that comparative efficacy was maintained beyond the blinded phase of the trials. It also noted that the efficacy of erenumab in the open-label extension studies was from the full trial populations, with 13% to 26% of people discontinuing from the studies. The committee further noted that the results of the open-label extension phase\xa02 trial (of 70\xa0mg erenumab) in episodic migraine were better than the intention-to-treat results from STRIVE and ARISE. It recalled that, in the evidence the company submitted for the subgroup of people for whom at least 3\xa0previous treatments had failed, the benefit of the 70\xa0mg dose was not statistically significantly different to placebo (see section\xa03.7). The benefit for the 140\xa0mg dose of erenumab for episodic migraine was statistically significant in STRIVE compared with placebo, but not in LIBERTY. After the second meeting, the company presented additional clinical data on the long-term effectiveness of erenumab for episodic migraine from an open-label trial following a randomised controlled trial. The mean change in monthly migraine days in the open-label trial, from baseline to month\xa057, was -5.8\xa0days (standard error 0.3). At this time 76.5% of the participants' mean monthly migraine days had reduced by 50% or more. The ERG had concerns about the additional clinical data. In particular, the population in the study was different to the company's proposed population for erenumab, which is people whose condition has not responded to at least 3\xa0oral preventive treatments (see section\xa03.2 and section 3.3). The open-label study did not specify prior treatment failure and most people (56%) included had not had treatment before. Prior treatment had failed in 36%, but the number of prior treatments was not specified, and included discontinuations because of lack of efficacy, adverse events, or both. Therefore, the committee agreed that the additional clinical data from the open-label study were not directly applicable to the population being considered in the appraisal. The committee concluded that it was unclear whether erenumab works in the long term because there was no evidence that comparative efficacy was maintained in people whose condition had not responded to at least 3\xa0oral preventive treatments.\n\n## Treatment with a second anti-CGRP drug could not be assessed\n\nThe committee was aware the scope did not include other medicines in the anti-calcitonin gene-related peptide (CGRP) class as potential comparators. Therefore erenumab was not formally compared with them. It noted that there was insufficient clinical evidence to support any difference in efficacy between the different anti-CGRP drugs. Because the drugs target the same pathway it is plausible that their effectiveness is similar. The committee also noted that treatment preferences are not outlined in the British Association for the Study of Headache (BASH) guidelines. BASH and the Association of British Neurologists explained that, although there is some evidence for using another anti-CGRP drug after the failure of the first, treatment preferences are not outlined in BASH's guidelines because there is no overall evidence to favour the use of 1\xa0particular anti-CGRP drug over any of the others. Therefore the committee considered it reasonable that the least expensive drug would be used unless an alternative was more suitable for the person. The committee concluded that treatment with another anti-CGRP drug, after failure of a previous anti-CGRP drug, could not be assessed.\n\n## The clinical evidence for having erenumab after botulinum toxin type\xa0A or when botulinum toxin type\xa0A is contraindicated is uncertain\n\nAfter a previous version of the final appraisal document was released, an appeal was brought against the decision by BASH and the Association of British Neurologists. One of the appeal points was upheld by the appeal panel. This was that the committee unreasonably failed to consider the cost effectiveness of erenumab compared with best supportive care in those whose chronic migraine had failed to benefit from the comparator drug. Before the appeal, the company had not provided any evidence on the efficacy of erenumab after the use of botulinum toxin type\xa0A. It had also not provided any evidence for an alternative treatment sequence when erenumab is used beyond the fourth line of treatment and when botulinum toxin type\xa0A is contraindicated. After the appeal, the company presented evidence from study\xa0295 on erenumab's treatment effect in 2\xa0post-hoc subgroups:\n\npeople with chronic migraine for whom at least 4\xa0previous treatments, including botulinum toxin type\xa0A, had failed\n\npeople with chronic migraine for whom 3\xa0or more previous preventive treatments had failed, and who had not previously had botulinum toxin type\xa0A.The latter subgroup was used as a proxy for those for whom botulinum toxin type\xa0A was contraindicated. In both these subgroups, erenumab reduced monthly migraine days more on average than placebo. Also, a higher percentage of each population had a 30% reduction in monthly migraine days on erenumab compared with placebo (the values cannot be shown here, because they are considered confidential by the company). The ERG questioned the validity of not having botulinum toxin type\xa0A treatment as a proxy for botulinum toxin type\xa0A being contraindicated, because there are other reasons for not having botulinum toxin type\xa0A. The ERG also noted that these post-hoc subgroups were very small, so a meaningful analysis of them may not have been possible. The company and BASH provided some observational data on the use of erenumab in English centres, which supported the study\xa0295 data because a 30% or more reduction in monthly migraine days was seen for some people at week\xa012. The committee concluded that because of the small subgroups, and the post-hoc analysis of these, there was uncertainty around the clinical evidence. It took this into account in decision making.\n\n# Indirect treatment comparison\n\n## The indirect treatment comparison does not show a statistically significant treatment effect for erenumab over botulinum toxin type\xa0A\n\nThere was no direct evidence comparing erenumab with botulinum toxin type\xa0A in chronic migraine. So the company did an indirect comparison using data from study\xa0295 for erenumab and PREEMPT1 and PREEMPT2, which compared botulinum toxin type\xa0A with placebo. It indirectly compared the proportion of people on:\n\nerenumab with at least a 50% reduction in monthly migraine days at 12\xa0weeks\n\nbotulinum toxin type\xa0A with at least a 50% reduction in monthly headache days at 24\xa0weeks.The comparison was in the subgroup for whom at least 3\xa0previous treatments had failed (as defined in section\xa03.3). The difference in outcomes and time points reflected the difference in primary outcomes and timing of assessments between the trials. The resulting odds ratio favoured erenumab. But the result was not statistically significant either for the subgroup of people for whom at least 3\xa0previous treatments had failed, or for the full trial populations (presented as supporting data; results are academic in confidence and cannot be reported here). Because the results were not statistically significant (that is, the confidence interval included an odds ratio of\xa01), erenumab could be more effective or less effective than botulinum toxin type\xa0A. The committee noted that the confidence interval around the odds ratio favouring erenumab was wide, which meant that there was a high degree of uncertainty associated with it. The committee considered that the company's methods for the indirect treatment comparison were appropriate but noted the differences between the trials for erenumab and botulinum toxin type\xa0A. The company used placebo as the common comparator, but it was administered differently in the trials: as a single subcutaneous injection every 4\xa0weeks in the erenumab trial and as intramuscular injections into\xa031 to 39\xa0different sites on the head and neck in the botulinum toxin type\xa0A trials. Given these differences, the committee did not think these should be considered the same, and this could have affected the substantially different placebo responses recorded in the trials. There was a difference in monthly migraine days with erenumab and monthly headache days with botulinum toxin type\xa0A. Given that these were separately reported as clinically distinct outcomes the committee did not think that these should be considered as the same. Also, the baseline characteristics of people in the PREEMPT trials in the subgroup of people for whom 3\xa0previous treatments had failed were not available to the company and so it was uncertain whether the populations were similar. The committee also considered that the long-term variability in symptom frequency and severity associated with chronic migraine was not adequately captured by the short duration of the indirect treatment comparison. The committee was concerned about the analysis, given the lack of statistically significant results and the wide confidence intervals. It concluded that, based on the indirect treatment comparison alone, it was uncertain whether erenumab is more clinically effective than botulinum toxin type\xa0A for chronic migraine.\n\n# Adverse events\n\n## Erenumab is generally well tolerated in the populations studied\n\nThe rates of serious adverse events in the 4\xa0trials were low, and most of the adverse events were of low to moderate severity. The company considered that erenumab has a safety and tolerability profile comparable with placebo. The committee was aware however that the adverse event data were for the full trial populations and may be different in people for whom 3\xa0previous treatments had failed (including because of intolerability). However, this would be a much smaller group of people and it would be unlikely that firm conclusions could be drawn. But the committee was also aware that the trials excluded people over\xa065, anyone with a significant comorbidity (for example, cardiovascular disease), and women who could become pregnant, and that no conclusions could be drawn for these groups either. The committee concluded that the adverse events in the trials with erenumab were generally not severe and were comparable with placebo, and erenumab was generally well tolerated in the studied populations. The company noted that the safety profiles for erenumab 140\xa0mg and 70\xa0mg were similar. It provided evidence from UK neurologists, who considered that they would likely start people with difficult-to-treat migraine on the 140\xa0mg dose, rather than the 70\xa0mg dose. The committee recognised that sometimes it would be more appropriate for a person to have treatment with the lower dose.\n\n# The company's economic model\n\n## The company's updated economic model is appropriate\n\nThe company modelled the assessment period of 12\xa0weeks (24\xa0weeks for botulinum toxin type\xa0A) as a decision tree, and the post-assessment period as a Markov model that included 3\xa0states: on treatment, off treatment and death. The company updated its economic model and modelling assumptions after consultation and after the second committee meeting to include:\n\na lifetime time horizon\n\nonly the 140\xa0mg dose of erenumab.The committee concluded that the company's updated model using a lifetime time horizon was appropriate. It concluded that the 140\xa0mg dose of erenumab was clinically effective in chronic migraine but less so at the 70\xa0mg dose, based on the clinical-effectiveness results (see section\xa03.6 and section 3.7). It also concluded that it was acceptable to consider only the 140\xa0mg dose in the cost-effectiveness model.\n\n# Comparison with botulinum toxin type\xa0A\n\n## The indirect treatment comparison results are uncertain, so erenumab and botulinum toxin type\xa0A may have similar effectiveness\n\nThe company's base case (up to and including the third committee meeting) used the odds ratio from the indirect treatment comparison to inform the relative effectiveness of erenumab compared with botulinum toxin type\xa0A. The committee was aware that the results of the indirect treatment comparison were highly uncertain (see section\xa03.12). It noted that the relative benefit of erenumab in the company's base case was unchanged over the lifetime time horizon in the model and considered this unlikely (see section\xa03.17). The committee also noted the additional uncertainty in the indirect treatment comparison, which was not captured in the confidence intervals. This arose from differences in the study populations' baseline characteristics, outcome measures (that is, monthly migraine days for erenumab and monthly headache days for botulinum toxin type\xa0A) and treatment assessment times (see section\xa03.12). At consultation and after the second appraisal committee meeting, the company presented scenarios with the odds ratio for the comparison with botulinum toxin type\xa0A set to\xa01 (similar efficacy) or using a midpoint between\xa01 and the odds ratio of the indirect comparison. The committee agreed with the ERG that the midpoint odds ratio scenario was not methodologically justified because it was an arbitrary figure and not supported by evidence. It did not consider this scenario further. The committee noted consultation comments that long-term real-world evidence on botulinum toxin type\xa0A from the NHS in England was available. This was for the relevant population (people for whom at least 3\xa0previous treatments had failed) and showed that adherence, efficacy and safety is sustained or improved over a 5‑year period. It also noted the clinical experts' consultation comments that it was plausible that botulinum toxin type\xa0A and erenumab could be considered to have equal efficacy. However, given the long-term and promising real-world data for botulinum toxin type\xa0A, the committee considered that the relative effectiveness of erenumab compared with botulinum toxin type\xa0A was not certain in the long term. Also, it recalled its concerns and the uncertainty with the indirect treatment comparison (see section\xa03.12). Because of the uncertainty in the results of the indirect treatment comparison, at the time of the third committee meeting the committee considered it appropriate to also consider cost-effectiveness analyses in which erenumab and botulinum toxin type\xa0A were assumed to have similar effectiveness (that is, using an odds ratio of\xa01).\n\n## Including a treatment effect for erenumab compared with botulinum toxin type\xa0A is acceptable\n\nIn the company's indirect treatment comparison, to determine the relative efficacy of erenumab 140\xa0mg compared with botulinum toxin type\xa0A, there was some uncertainty about whether erenumab may be more effective. The difference in monthly migraine days, which was not statistically significant, favoured erenumab over botulinum toxin type\xa0A. The company used these indirect treatment comparison estimates in a scenario analysis for the fourth appraisal committee meeting (the odds ratio used was considered confidential by the company so cannot be shown here). This was in line with the modelling done in NICE's technology appraisal guidance on galcanezumab for preventing migraine. In this, a treatment effect for galcanezumab compared with botulinum toxin type\xa0A was used in the final decision-making model (instead of assuming equivalence). The committee recalled that according to clinical opinion, anti-CGRP drugs are more effective than botulinum toxin type\xa0A. Also, the committee was aware that in NICE's technology appraisal guidance on fremanezumab for preventing migraine and on galcanezumab, the companies provided indirect treatment comparison point estimates that favoured the anti-CGRP drug over botulinum toxin type\xa0A. However, this was associated with uncertainty. The committee was aware that the commercial arrangement for erenumab had been improved. The company provided threshold analysis showing that even a marginal benefit of erenumab over botulinum toxin type\xa0A reduced the cost-effectiveness estimates for erenumab for chronic migraine. The committee was aware that, for galcanezumab in the same population, it was able to accept the indirect treatment comparison results. This was because they showed a positive effect for galcanezumab compared with botulinum toxin type\xa0A in terms of monthly migraine days. The evidence for erenumab was similar, so the committee agreed that this treatment effect should be taken into account in its decision making.\n\n# Modelling long-term treatment effectiveness\n\n## While people stay on treatment, it is reasonable to assume that the treatment effect does not wane over time\n\nThe company's model assumed that the treatment effect stayed constant while people were on treatment. The committee was aware, however, that in other chronic conditions the effects of monoclonal antibodies can wane over time. It noted that the company had provided a scenario during clarification that incorporated a treatment waning effect. In this, health state costs and utilities for erenumab and botulinum toxin type\xa0A were linearly reduced over 10\xa0years until they were in line with best supportive care. The ERG had also modelled this and another scenario whereby treatment effect waned over a 5‑year period. At consultation, the company provided an additional treatment waning scenario whereby treatment waning started at 5\xa0years and waned over a 10‑year period. The committee was not presented with any evidence to suggest that erenumab would follow this type of waning pattern. After the second meeting, the company commented that in the ERG's 5‑ and 10‑year waning scenarios, health state costs and health state utilities were reduced for people whose migraine responded to treatment. However, treatment was not stopped as efficacy waned; therefore, treatment costs continued to accrue over the long term. The company considered these as extreme scenarios because treatment should be stopped if people no longer have a clinically meaningful benefit (see section\xa03.19). The company therefore submitted an alternative scenario that used an additional discontinuation rate instead of a waning assumption, along with longer-term clinical data from an open-label extension study in episodic migraine. The committee agreed that treatment waning effect and treatment discontinuation are 2\xa0separate issues, and adjusting the discontinuation probabilities does not reflect the uncertainty of potential waning (see section\xa03.18). The long-term clinical data from the extension study showed that low numbers of people withdrew from erenumab treatment because of a lack of efficacy. The committee was aware of conflicting clinical expert opinion as to whether treatment resistance could occur with erenumab. At the second committee meeting the clinical expert suggested that erenumab's mechanism of action as a CGRP inhibitor meant that it may not be associated with a treatment waning effect. However, the committee also noted that a clinical expert at consultation thought that development of treatment resistance was possible. The committee noted that in the erenumab clinical trials, the number of people who developed neutralising antibodies to erenumab was low (approximately 0% to 3%). To date there is no evidence of the impact of anti-erenumab antibody development on efficacy and safety. The committee understood that if a person did develop anti-erenumab antibodies, waning is unlikely to be linear over time because efficacy would be lost quickly. Based on the evidence available, the committee considered that it was reasonable to assume that the treatment effect does not wane over time.\n\n## The company's additional treatment discontinuation scenario is not appropriate\n\nAfter the second meeting, the company submitted another scenario analysis that used an additional discontinuation rate as an alternative to treatment waning (see section\xa03.17). In this scenario, an annual discontinuation rate of 10% because of loss of efficacy was applied in addition to the 2.38% all-cause discontinuation rate already in the company's base case. This additional discontinuation rate was applied to both the erenumab and botulinum toxin type\xa0A treatment arms in the model. The ERG agreed that loss of efficacy may result in treatment discontinuation, but the company's scenario did not reflect the gradual loss of effectiveness that would likely occur before treatment was stopped. This was because people were taken off treatment without any loss of effectiveness in this company scenario. The committee considered that the longer-term data for erenumab submitted by the company after the second meeting (see section\xa03.9) did not support this level of treatment discontinuation because of loss of efficacy. The data showed that only 5.6% of people taking the 140\xa0mg dose of erenumab stopped treatment, and none of them because of loss of efficacy. Approximately half of these people had asked to stop treatment, but the reasons for stopping were unknown. The committee concluded that the company's additional treatment discontinuation scenario was not appropriate.\n\n## Applying a negative stopping rule is appropriate\n\nThe company's model assumed that treatment would be stopped for people who did not respond to erenumab at 3\xa0months (a negative stopping rule). The clinical experts had noted that applying a rule using a 50% reduction in monthly migraine days would accurately reflect the efficacy of episodic migraine treatments in clinical practice. Similarly, a 30% reduction in monthly migraine days would be appropriate for chronic migraine (see section\xa03.3). The committee considered the 30% threshold for the chronic migraine group to be appropriate and consistent with NICE's technology appraisal guidance on botulinum toxin type\xa0A and BASH's guidelines. The committee concluded that it was appropriate to include a negative stopping rule at 3\xa0months in the economic model if there was no response to treatment. No response was defined as less than a 30% reduction (for chronic migraine) or 50% reduction (for episodic migraine) in monthly migraine days at the 12‑week assessment.\n\n## The company's positive stopping rule scenarios are not appropriate\n\nThe clinical experts explained that in practice, if migraine responds to treatment, some people may try a treatment break. The committee also noted the clinical experts' written comments that some people may stay on treatment indefinitely. The committee recalled that the company's base-case modelling reflected a constant treatment effect over a lifetime time horizon. At consultation the company presented 2\xa0positive stopping scenarios, which assumed that people staying on treatment would be reassessed after 64.5\xa0weeks. After that, 20% of people would stop treatment, while the remainder would resume treatment and be reassessed at 76.5‑week intervals. In the first scenario, people who stop treatment would continue to benefit from erenumab for the lifetime time horizon of the model without incurring the costs. The committee was aware that there was no evidence to show the duration of treatment benefit (see section\xa03.17), or maintenance of constant benefit, once treatment had been stopped. The patient expert explained that once erenumab treatment was stopped the benefit was maintained for only a short time before the migraine returned. In the second scenario, people who stop treatment would return to monthly migraine days based on the placebo arm of the trial. The committee did not consider this scenario appropriate either because erenumab would need to be restarted for these people and the company's model did not allow this once the positive stopping rule was applied. The committee therefore concluded that the positive stopping scenarios were not appropriate for consideration.\n\n## It is acceptable to account for a loss of the placebo effect when migraine responds to best supportive care\n\nIn the company's modelling at the time of the third appraisal committee meeting, the treatment effect for people whose migraine responded to best supportive care was maintained for the lifetime time horizon of the model. In the model, everyone who stopped treatment (regardless of the treatment they had) maintained the same improvement in monthly migraine days as for people whose migraine did not respond (rather than continuing with any on-treatment improvement). For the fourth appraisal committee meeting, the company did a scenario analysis in which people whose migraine responded to best supportive care reverted to baseline monthly migraine days at the end of year\xa01 (a sudden and full loss of placebo effect). Everyone stopping treatment was assumed to return to baseline monthly migraine days. The company considered this to be a slightly more conservative approach than that taken in NICE's technology appraisal guidance on galcanezumab and fremanezumab. When applying this assumption, the cost-effectiveness estimates for erenumab compared with best supportive care improved. The committee accepted this approach and used it for decision making.\n\n# Utilities\n\n## Utility values used in the model are highly uncertain\n\nThe company collected quality-of-life data in study\xa0295 (chronic migraine), STRIVE and ARISE (episodic migraine) using the Migraine-Specific Quality of Life Questionnaire (MSQ) and in LIBERTY (episodic migraine) using the EQ‑5D‑5L. The utility values used in the model were generated from mapping MSQ results to EQ‑5D‑3L using the Gillard et al. 2012 algorithm. The company explained that the EQ‑5D‑5L data collected in LIBERTY were not sensitive to changes in quality of life with migraine because the questionnaire was given on appointment days, and asked people about their quality of life on that day. If a person was having a migraine that day, they would likely rearrange their appointment. So the company considered that the EQ‑5D‑5L data were collected when the person did not have migraine, and were therefore not appropriate to use in the model. It considered the MSQ to be more appropriate because it had a 4‑week recall period. The clinical experts explained that in clinical practice they use the HIT‑6 and MIDAS tools, not the MSQ, to measure quality of life, so it was not known whether MSQ was the best available measure of quality of life. The committee agreed that the rationale for using MSQ instead of direct EQ‑5D‑5L data was plausible. However, the committee considered that the actual utility values generated from mapping the MSQ data to EQ‑5D‑3L may be underestimates, given that they were low (average values ranged from 0.466 to 0.784 across the different health states). However, it recognised that the baseline values for people with chronic migraine represented people having on average about 15\xa0migraine days a month. Given the before and after effects of migraine described by the patient experts (see section\xa03.1) the low utility value of 0.466 could accurately represent quality of life. The committee was also aware that the MSQ data had been mapped to EQ‑5D‑3L in NICE's technology appraisal guidance on botulinum toxin type\xa0A and that the utility values used were broadly similar. The committee understood that the MSQ data were based on the full trial population, and not just on those for whom at least 3\xa0previous treatments had failed. Also, there were separate mapping algorithms for chronic and episodic migraine but because of small patient numbers these had been applied at the individual patient level based on the number of migraine or headache days at baseline, which created more uncertainty. The committee noted that the utility data were a key driver of the cost-effectiveness estimates. It was concerned about the reliability of the values given the uncertainty of using data from a broader population and mapping this to EQ‑5D‑3L. On balance, the committee concluded that the utility values used in the model may be reasonable but were uncertain.\n\n## Applying a mode of administration utility decrement to botulinum toxin type\xa0A is not appropriate\n\nThe company provided scenario analyses which incorporated a utility decrement associated with the mode of administration of botulinum toxin type\xa0A. The company suggested that treatment with botulinum toxin type\xa0A leads to an increased burden on people compared with treatment with erenumab because of the number of injections needed in the head and neck. At consultation clinical experts noted that erenumab could have a reduced burden on people compared with botulinum toxin type\xa0A. However, other comments received during consultation suggested that long-term real-world evidence showed an improvement in quality of life with botulinum toxin type\xa0A compared with best supportive care. The company's scenario used a vignette-based time-trade-off utility valuation study, done in the UK, to derive mode of administration decrements for migraine prophylaxis treatments relative to erenumab. The decrements were applied additively to each monthly migraine day-specific utility value throughout the model. The committee noted that when the utility decrement scenario was applied the total quality-adjusted life years (QALYs) for botulinum toxin type\xa0A were lower than for best supportive care. It considered that this scenario was not clinically plausible. The committee concluded that applying a mode of administration utility decrement to botulinum toxin type\xa0A was not appropriate.\n\n## It is acceptable to use differential utilities in the modelling\n\nThe company's original modelling used equal utilities for a health state, regardless of treatment received. The committee recognised that there was some evidence of a treatment effect for erenumab beyond a decrease in monthly migraine days. NICE asked the company for any evidence it had to support the use of differential utilities, capturing treatment benefit beyond a decrease in monthly migraine days, which it had not provided before. The company initially submitted analyses based on a regression model, but the ERG had major concerns about the company's approach. It noted that the regression model was flawed and should not be used. This was because the estimated differential utility (using a 'treatment' covariate where baseline observations were categorised as best supportive care) partly included the placebo effect. In response, the company amended its approach to address the ERG's concerns. It used separate regression models, including one where baseline quality-of-life data were included with monthly migraine days as the only covariate. Post-baseline quality-of-life data were included in a second regression model with monthly migraine days and treatment as covariates. In this way, separate regression models were used to generate 'off-treatment' utility values and 'on-treatment' utility values, with values differing between erenumab 140\xa0mg and placebo for a given frequency of monthly migraine days. The ERG thought that the company's updated regression models had been implemented correctly and the company's face validity checks were reasonable. However, the ERG preferred the approach to implementation of differential utility values by intervention and model state taken by the company in its initial differential utility analyses. The ERG carried out some scenario analyses with alternative approaches. It found that the exact approach to implement a differential treatment utility was unlikely to be a main driver of the cost effectiveness of erenumab 140\xa0mg. In NICE's technology appraisal guidance on galcanezumab, the committee accepted the use of differential utilities for a health state depending on the treatment used. The committee was satisfied that it had seen enough evidence to support the use of differential utilities for erenumab. It considered that, regardless of the exact implementation approach taken, it was acceptable to use differential utilities in the modelling.\n\n## It is appropriate to adjust health state utilities for age in the model\n\nNICE's guide to the methods of technology appraisal states that adjustments to utility values, for example for age or comorbidities, may sometimes be needed. When extrapolating health-related quality-of-life data over long time horizons, it is often considered appropriate to adjust for age. This reflects the natural decline in health-related quality of life over time, and ensures utilities do not exceed general population values at a given age. For the fourth appraisal committee meeting, the company did a scenario analysis to use age-adjusted utilities in its modelling. It used a common methodology with utility values weighted based on age decrements for the UK general population (Ara and Brazier 2010). The committee noted that this adjustment did not have a large effect on the cost-effectiveness estimates and considered it appropriate to include in its decision making.\n\n# Costs\n\n## All relevant costs for using erenumab in practice are captured in the model\n\nThe clinical experts explained that erenumab would initially be used in a secondary care specialist headache clinic. The committee recognised the advantages of a self-injectable treatment. But given the need for starting and stopping rules to ensure erenumab was used appropriately, treatment would need to be started by doctors experienced in treating migraine. The committee considered that for erenumab to be available for the most refractory cases of migraine, and to meet the monitoring requirements, additional resources would likely be needed, and that the cost of setting up these additional services should be accounted for in the model. To inform its assumptions about resource use involving healthcare professionals, the company had used results from a National Health and Wellness Survey involving people across Europe (including the UK), which aimed to characterise migraine burden from the patients' perspective. However, the company assumed that the results, which were grouped into categories based on the number of headache days per month, approximated resource use per migraine day. Consultation comments from clinical experts noted that erenumab treatment would be started in a specialist headache clinic, but the person would be trained to self-administer treatment at home. Consultation comments suggested that self-administration is important because it gives people a sense of control. Further comments from clinical experts suggested that using erenumab in practice is unlikely to affect referrals to specialist services because this was not the case when botulinum toxin type\xa0A became available. Also, these people are already being seen in specialist clinics. At consultation the company updated its economic model to include the appropriate triptan injection price, which the committee accepted. After the appeal, the company incorporated an anti-CGRP administration cost (a 30‑minute appointment with a nurse in hospital) in its modelling. This was applied for 10% of patients having erenumab. This was in line with the modelling in previous appraisals of anti-CGRP drugs for migraine. The committee was satisfied that all relevant costs were captured in the modelling.\n\n# Cost-effectiveness estimates\n\n## The company's updated cost-effectiveness analyses are appropriate for decision making\n\nAt consultation the updated company's base case included populations with chronic migraine and high-frequency episodic migraine only. The committee recalled that the high-frequency episodic migraine population was not a distinct group (see section\xa03.8) and therefore agreed that it should not consider the cost-effectiveness analyses for this population further. After the appeal, the company provided updated cost-effectiveness analyses for chronic and episodic migraine, and included the following assumptions and scenarios:\n\na revised commercial arrangement (confidential simple discount only)\n\nevidence for erenumab compared with botulinum toxin type\xa0A and best supportive care (chronic migraine) or best supportive care only (episodic migraine; see section\xa03.4)\n\ndifferential utilities for erenumab 140\xa0mg compared with placebo (see section\xa03.24)\n\na negative stopping rule (see section\xa03.19)\n\na scenario including administration costs for 10% of people having erenumab (see section\xa03.26)\n\na scenario including age-adjusted utilities (see section\xa03.25)\n\na scenario with loss of placebo effect after 1\xa0year for people whose migraine responded to best supportive care (see section\xa03.21)\n\na scenario with a greater treatment effect for erenumab than for botulinum toxin type\xa0A (instead of assuming equivalence) from the indirect treatment comparison (see section\xa03.16).All of the company's incremental cost-effectiveness ratios (ICERs) presented at the fourth committee meeting included a confidential commercial arrangement. The ICERs were considered confidential by the company and cannot be reported here. Most of the ICERs were around £20,000 per QALY gained, with many below that. The committee noted that the ERG was able to reproduce the company's cost-effectiveness estimates, for both the chronic migraine and episodic migraine populations. The committee concluded that the company's updated cost-effectiveness analyses were appropriate for decision making.\n\n## Erenumab is cost effective for chronic migraine and for episodic migraine after 3\xa0preventive treatments have failed\n\nThe committee recalled that:\n\nIt had concluded that high-frequency episodic migraine was not a distinct group and that it should not consider the cost-effectiveness analysis for this population further (see section\xa03.8).\n\nThe treatment effect does not wane over time (see section\xa03.17).\n\nIt was not appropriate to include an additional discontinuation rate along with the company's original 2.38% rate for all-cause discontinuation every 12\xa0weeks (see section\xa03.18).\n\nIt was appropriate to include a treatment effect favouring erenumab over botulinum toxin type\xa0A in chronic migraine, because evidence supporting this from an indirect treatment comparison was provided. Also, threshold analysis showed that even a marginal treatment effect made erenumab much more cost effective than when erenumab and botulinum toxin type\xa0A were assumed to have equal effectiveness (see section\xa03.16).\n\nIt was appropriate to use differential utilities in the analysis. This was because of the evidence supporting a treatment benefit for erenumab compared with placebo beyond a reduction in monthly migraine days. It was also because of the company's revised regression modelling with off-treatment and on-treatment utilities, with values differing for erenumab 140\xa0mg and placebo for a given frequency of monthly migraine days (see section\xa03.24).\n\nThe model should use a standard method of adjusting utilities for age over a long time horizon (see section\xa03.25).\n\nAdministration costs for erenumab should be applied for 10% of people having it (see section\xa03.26).\n\nThe modelling should account for a loss of the placebo effect in people whose migraine responded to best supportive care (see section\xa03.21).The committee was aware that the ICERs were highly sensitive to the assumption about the effectiveness of erenumab compared with botulinum toxin type\xa0A. It preferred a fully incremental analysis, that is, a combined single analysis in which best supportive care is compared with botulinum toxin type\xa0A, which in turn is then compared with erenumab. The committee took its preferences into account after the fourth meeting, including the updated confidential commercial arrangement for erenumab and the confidential Commercial Medicines Unit price for botulinum toxin type\xa0A. It agreed that most of the plausible cost-effectiveness estimates were below £20,000 per QALY gained. The committee concluded that erenumab was cost effective for chronic migraine and for episodic migraine after 3\xa0preventive treatments have failed.\n\n# Other factors\n\n## No adjustments are needed for equality\n\nNo equalities issues were identified by the company. The clinical and patient submissions highlighted that migraine can be classed as a disability under the Equality Act 2010. Because migraine is most common in people of working age and affects more women than men, women may be further disadvantaged in the workplace. It was also noted that there may be unequal access to specialist headache clinics and botulinum toxin type\xa0A. The committee considered these issues and noted that unequal access was not associated with a protected characteristic. So, it concluded that no specific adjustments were needed to NICE's methods in this case.\n\n## All relevant aspects of erenumab are captured in the economic modelling\n\nErenumab was considered innovative when first discussed by the committee. In its original submission, the company explained that erenumab was a first-in-class therapy and therefore a step change in the management of migraine. But now, 2\xa0other anti-CGRP drugs have been recommended for use in the NHS to treat migraine. The committee accepted the use of differential utilities (capturing erenumab's benefit beyond a reduction in monthly migraine days), and a treatment benefit of erenumab compared with botulinum toxin type\xa0A for chronic migraine after at least 3\xa0previous treatments have failed. So it considered that all relevant aspects of erenumab were captured in the economic modelling.\n\n# Conclusion\n\n## Erenumab is recommended for chronic migraine after 3\xa0or more preventive treatments have failed\n\nThe committee considered the evidence that erenumab was clinically effective (at 140\xa0mg) in chronic migraine when compared with best supportive care and when response was measured as a 50% or greater reduction in monthly migraine days (see section\xa03.6). However, it considered that a 30% reduction in monthly migraine days was more clinically relevant (see section\xa03.3), and treatment should be stopped if this is not achieved. It considered that there was a high degree of uncertainty about whether erenumab was more clinically effective than botulinum toxin type\xa0A (see section\xa03.12). But after the company provided further evidence from an indirect treatment comparison, it agreed that it was appropriate to assume a treatment benefit of erenumab over botulinum toxin type\xa0A (see section\xa03.16). The committee considered the substantial effect of this assumption on the ICER, which was within the range usually considered a cost-effective use of NHS resources. Therefore, it recommended erenumab for preventing chronic migraine in adults after at least 3\xa0preventive treatments have failed. This includes people with chronic migraine when botulinum toxin type\xa0A treatment has failed or is contraindicated. The committee was aware that numbers in these groups would reduce over time because of the introduction of anti-CGRP drugs. Erenumab should be stopped if migraine frequency does not reduce by at least 30% after 12\xa0weeks of treatment.\n\n## Erenumab is recommended for episodic migraine after 3\xa0or more preventive treatments have failed\n\nIn episodic migraine, the committee had concluded that the evidence showed that erenumab 140\xa0mg may be clinically effective when compared with best supportive care, that is, when response was measured as a 50% or greater reduction in monthly migraine days (see section\xa03.7). Treatment should be stopped if this is not achieved. It considered that the evidence to support the effectiveness of erenumab in high-frequency episodic migraine was uncertain and did not consider it further because it is not a distinct subgroup (see section\xa03.8). The company presented updated analyses for erenumab for preventing episodic migraine for the fourth committee meeting. The clinical evidence supported a treatment benefit, and cost-effectiveness results were within what NICE usually considers an acceptable use of NHS resources. Therefore, the committee recommended erenumab for use in the NHS for preventing episodic migraine in adults after at least 3\xa0preventive treatments have failed. Erenumab should be stopped if migraine frequency does not reduce by at least 50% after 12\xa0weeks of treatment."}
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https://www.nice.org.uk/guidance/ta682
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Evidence-based recommendations on erenumab (Aimovig) for preventing migraine in adults.
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Pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous non-small-cell lung cancer
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Pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous non-small-cell lung cancer
Evidence-based recommendations on pembrolizumab (Keytruda) with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous non-small-cell lung cancer (NSCLC) in adults whose tumours have no epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive mutations.
# Recommendations
Pembrolizumab with pemetrexed and platinum chemotherapy is recommended as an option for untreated, metastatic, non-squamous non-small-cell lung cancer (NSCLC) in adults whose tumours have no epidermal growth factor receptor (EGFR)‑positive or anaplastic lymphoma kinase (ALK)‑positive mutations. This is only if:
it is stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses and
the company provides pembrolizumab according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for pembrolizumab with pemetrexed and platinum chemotherapy (pembrolizumab combination) for untreated, metastatic, non‑squamous NSCLC (NICE technology appraisal guidance 557).
Standard care for tumours that have no EGFR‑positive or ALK‑positive mutations depends on PD‑L1 status. If tumours are PD‑L1 negative, or PD‑L1 positive with a tumour proportion score below 50%, pemetrexed with carboplatin or cisplatin (pemetrexed platinum chemotherapy) may be offered. If tumours are PD‑L1 positive with a score of at least 50%, pembrolizumab monotherapy is offered. Pembrolizumab combination would be offered whether or not tumours are PD‑L1 positive, and regardless of tumour proportion score.
Clinical evidence collected while pembrolizumab combination was in the Cancer Drugs Fund shows that people having pembrolizumab combination for up to 2 years are likely to live longer than those who have pemetrexed platinum chemotherapy. There are no clinical trials directly comparing pembrolizumab combination with pembrolizumab monotherapy. But an indirect comparison suggests that for people with PD‑L1 positive tumours with a tumour proportion score of at least 50%, there is no difference in how long people having pembrolizumab combination live compared with pembrolizumab monotherapy.
Pembrolizumab combination meets NICE's criteria to be considered a life-extending end of life treatment compared with pemetrexed platinum chemotherapy but does not meet the criteria when compared with pembrolizumab monotherapy.
The cost-effectiveness estimates for pembrolizumab combination are within what NICE considers to be an acceptable use of NHS resources, if it is stopped at 2 years. So, it is recommended.# Information about pembrolizumab with pemetrexed and platinum chemotherapy
# Marketing authorisation indication
Pembrolizumab (Keytruda, Merck Sharp & Dohme) with pemetrexed and platinum chemotherapy has a marketing authorisation for the first-line treatment of metastatic non-squamous non-small-cell lung carcinoma (NSCLC) in adults whose tumours have no epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive tumour mutations.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
Pembrolizumab solution for infusion costs £2,630.00 per 100‑mg vial (excluding VAT; BNF online, accessed October 2020).The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck Sharp & Dohme, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the KEYNOTE‑189 study for people with untreated, metastatic, non-squamous non-small-cell lung cancer (NSCLC).
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage. It agreed that the model time horizon for the cost effectiveness should increase to 25 years (issue 5, page 8 of technical report). Also, that a 2‑year stopping rule for pembrolizumab was appropriate.
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, page 8), and took these into account in its decision making. The committee discussed the following issues, which were outstanding after the technical engagement stage:
The choice of parametric models to predict overall survival.
The choice of parametric models to predict time on treatment.
The continued duration of treatment benefit if pembrolizumab with pemetrexed and platinum chemotherapy (pembrolizumab combination) is stopped at 2 years.
The choice of utility values.
# Clinical management
## Pemetrexed with carboplatin or cisplatin and pembrolizumab monotherapy are the most relevant comparators
In the original appraisal pemetrexed with carboplatin or cisplatin chemotherapy and pembrolizumab monotherapy were considered appropriate comparators. Chemotherapy using docetaxel, gemcitabine, paclitaxel or vinorelbine as monotherapy is rarely used in NHS clinical practice for treating non-squamous metastatic NSCLC. NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC recommends pembrolizumab monotherapy only for people whose tumours express at least a 50% PD‑L1 tumour proportion score. Since the original appraisal was published, NICE has recommended atezolizumab combination for metastatic non-squamous NSCLC for people whose tumours express less than a 50% PD‑L1 tumour proportion score. In line with NICE's guide to the methods of technology appraisal, the original scope was not changed for this Cancer Drugs Fund review. Therefore, atezolizumab was not considered as a comparator because it was recommended after the original guidance was published. The committee concluded that the appropriate comparators are:
pemetrexed with carboplatin or cisplatin (referred to as pemetrexed platinum chemotherapy), with or without pemetrexed maintenance therapy
pembrolizumab monotherapy for people whose tumours express at least a 50% PD‑L1 tumour proportion score (referred to as the high PD‑L1 subgroup).
# Clinical effectiveness
## For the intention-to-treat population pembrolizumab combination is more clinically effective than pemetrexed platinum chemotherapy
There were additional data from KEYNOTE‑189, which was a randomised controlled phase 3 trial. The trial included 616 people with untreated advanced or metastatic non-squamous NSCLC regardless of PD‑L1 tumour proportion score who were randomised to pembrolizumab combination or pemetrexed platinum chemotherapy. Two thirds of the trial population had tumours with a PD‑L1 tumour proportion score of at least 50% while the rest had tumours with a PD‑L1 tumour proportion score below 50%. The results showed that pembrolizumab combination was associated with a statistically significant improvement in overall survival compared with pemetrexed platinum chemotherapy (hazard ratio 0.56, 95% confidence interval 0.46 to 0.69). The committee concluded that for the intention-to-treat (ITT) population, that is, people with untreated advanced or metastatic non-squamous NSCLC regardless of PD‑L1 tumour proportion score, pembrolizumab combination was clinically effective compared with pemetrexed platinum chemotherapy.
## For the high PD-L1 subgroup overall survival is similar for pembrolizumab combination and pembrolizumab monotherapy
Pembrolizumab monotherapy is standard care in clinical practice in the NHS for people with untreated NSCLC and at least a 50% PD‑L1 tumour proportion score (see section 3.1). The company presented updated results for this subgroup from an indirect treatment comparison based on data from:
KEYNOTE‑189 (see section 3.2)
KEYNOTE‑021 Cohort G, a trial including 267 people comparing pembrolizumab combination with platinum‑based chemotherapy
KEYNOTE‑042, a trial including 1,274 people with PD‑L1 positive tumours comparing pembrolizumab monotherapy with platinum-based chemotherapy
KEYNOTE‑024, a trial including 305 people with high PD‑L1 tumour proportion score comparing pembrolizumab monotherapy with platinum-based chemotherapy.Although the point estimate suggested better overall survival for pembrolizumab combination compared with pembrolizumab monotherapy, the 95% credible interval showed that this was not statistically significant. The exact results were academic in confidence so cannot be reported here. The committee concluded that overall survival was similar for people with at least a 50% PD‑L1 tumour proportion score who had pembrolizumab combination compared with pembrolizumab monotherapy.
# Overall survival and time on treatment
## The 5-year survival rate for pembrolizumab combination is between that estimated by the company and the ERG
The company used a log-logistic distribution to extrapolate overall survival for both pemetrexed platinum chemotherapy and pembrolizumab combination in the model for the ITT population. This is because for the comparator arm this distribution gave the most clinically plausible estimates for overall survival at 5 years and had the best statistical fit. The ERG used a generalised gamma distribution for both arms because this distribution fitted the pembrolizumab combination arm better. Both the log-logistic and the generalised gamma distributions gave clinically plausible 5‑year survival estimates for the comparator arm of between 5% and 11%. The clinical experts explained that people who have immunotherapy such as pembrolizumab second line have a 5‑year survival rate of approximately 13%. They reasoned that people who have pembrolizumab combination earlier in the pathway will benefit from this treatment, so the 5‑year survival rate is likely to be greater than 13%. They agreed that the overall survival in the pembrolizumab combination arm could be somewhere between what was predicted in the generalised gamma and log-logistic extrapolation (the estimates are confidential and cannot be reported here). The committee concluded that the ERG's overall survival estimates for the ITT population were pessimistic but the company's estimates were too optimistic.
## Retreatment with pembrolizumab combination might affect the overall survival seen in the trial but is not NHS clinical practice
Some people in the pembrolizumab combination arm of KEYNOTE‑189 were still having treatment after 2 years. It was not clear, however, how many people were still having combination therapy and how many were having pemetrexed platinum chemotherapy only. The Cancer Drugs Fund clinical lead explained that people could have pembrolizumab for up to 35 cycles, which could extend beyond 2 years. The company confirmed that some people did have further treatment with pembrolizumab alone or in combination with other therapies. From the data presented by the company it was unclear how many people this was. Retreatment with pembrolizumab is not NHS clinical practice. The committee noted that the overall survival curves for the pembrolizumab combination arm included the effect of retreatment. Therefore, the potential survival benefits in the trial might not be seen in NHS practice. The clinical experts explained that retreatment with pembrolizumab or similar drugs could improve survival prospects in this population, especially if they had a good response to initial treatment. The committee noted that retreatment with pembrolizumab could affect the overall survival outcome for the pembrolizumab combination arm. Also, it was aware that the costs of retreatment were not included in the model. The committee concluded that results from the trial might not be generalisable because retreatment with pembrolizumab is not NHS clinical practice.
## Overall survival estimates for the high PD-L1 subgroup are uncertain
To estimate overall survival for the comparison with pembrolizumab monotherapy in the high PD‑L1 subgroup the company used the same approach as for the ITT population (see section 3.4). Therefore, the committee could not establish whether the company's approach was the most appropriate approach, because no alternatives were provided by the company and ERG. The committee recalled that results from the indirect treatment comparison showed no statistically significant difference in the overall survival estimates for pembrolizumab combination compared with monotherapy (see section 3.3). It concluded that the overall survival estimates for the high PD‑L1 subgroup were uncertain.
## Generalised gamma distribution is appropriate for extrapolating time on treatment
The company extrapolated time on treatment in the model using the exponential distribution, which assumes a proportional hazard for both arms (that is, at every timepoint the difference between the time on treatment curves for the 2 treatment arms is the same). The company did not provide evidence to support this assumption. The ERG explained that the proportional hazards assumption might not hold because:
the cumulative hazard plot showed a clear change in gradient of the pembrolizumab combination curve at just over 100 weeks
pembrolizumab combination and pemetrexed platinum chemotherapy have different mechanisms of action.The ERG preferred the generalised gamma distribution which does not require the proportional hazards assumption and had a better statistical fit. The ERG noted that the choice of distribution had a minimal effect on the cost-effectiveness estimates. The committee concluded that the generalised gamma distribution was the most appropriate for extrapolating time on treatment.
## Gradually decreasing treatment effect from 3 years after treatment is started until 5 years is appropriate
In the company's base-case model the relative treatment effect of pembrolizumab combination remained constant for 5 years from the start of treatment. At 5 years the hazard in the pembrolizumab combination arm dropped to match the hazard in the comparator arm. The clinical experts explained that this was implausible and did not reflect their clinical experience with pembrolizumab and other similar drugs. The committee agreed that, although it was biologically plausible for the treatment effect to continue after stopping pembrolizumab, its course and duration was uncertain. The committee concluded that the ERG's approach of a gradually decreasing treatment effect from 3 years after treatment started until 5 years, at which point the treatment effect matches that of pemetrexed platinum chemotherapy, was appropriate for decision making.
# Health-related quality of life
## The approach taken in the original appraisal to estimate utility values is still preferred
The company did not present new data on health-related quality of life. In the original appraisal the committee preferred to combine the time-to-death approach with progression-based utility values. From the 2 approaches presented by the ERG the committee chose to calculate utilities using progression status with a quality-of-life decrement associated with time to death of less than 360 days applied for people who are likely to live less than 360 days. This was included in the committee's preferred assumptions in the original appraisal. The committee concluded that its preference from the original appraisal had not changed.
# End of life
## Pembrolizumab combination meets NICE's end of life criteria when compared with pemetrexed platinum chemotherapy
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The updated KEYNOTE‑189 data showed that life expectancy for the ITT population, that is, regardless of PD‑L1 tumour proportion score, was less than 24 months and that pembrolizumab combination extended life by at least 3 months. Therefore, the committee concluded that pembrolizumab combination met the end of life criteria and could be considered a life-extending treatment at the end of life when compared with pemetrexed platinum chemotherapy.
## Pembrolizumab combination does not meet NICE's end of life criteria when compared with pembrolizumab monotherapy
Standard care for people with at least a 50% PD‑L1 tumour proportion score is pembrolizumab monotherapy (see section 3.1). The clinical expert explained that many people who have pembrolizumab monotherapy die within 2 years, but some people can live longer. Results from KEYNOTE‑024 showed that median overall survival with pembrolizumab monotherapy was 30.0 months (95% confidence interval 18.3 months to not reached). The committee noted that the company's indirect treatment comparison showed no statistically significant difference in overall survival between pembrolizumab combination and pembrolizumab monotherapy in people with at least a 50% PD‑L1 tumour proportion score (see section 3.3). Therefore, the additional 3‑month survival gain for pembrolizumab combination therapy compared with pembrolizumab monotherapy was uncertain. The committee concluded that pembrolizumab combination did not meet the end of life criteria when compared with pembrolizumab monotherapy for people with a high PD‑L1 tumour proportion score.
# Cost effectiveness
## Pembrolizumab combination is considered cost effective compared with pemetrexed platinum chemotherapy
For the ITT population the most plausible incremental cost-effectiveness ratios (ICERs) were within the range NICE considers a cost-effective use of NHS resources. The committee agreed that its preferred approach to modelling would:
include an overall survival extrapolation for pembrolizumab combination between that of the log-logistic and generalised gamma distributions (see section 3.4)
extrapolate time on treatment using the generalised gamma distribution (see section 3.7)
include a gradual decrease of treatment effect from 3 years after the start of treatment until 5 years, when it matches pemetrexed platinum chemotherapy (see section 3.8)
calculate utility values using progression status with a quality-of-life decrement associated with time to death of less than 360 days applied for people who are likely to live less than 360 days (see section 3.9)
include costs of retreatment with pembrolizumab combination (see section 3.5)
include dose intensities and costs from the updated results
include a 2‑year stopping rule.Using the committee's preferred assumptions the range of plausible ICERs for pembrolizumab combination compared with pemetrexed platinum chemotherapy was below £50,000 per quality‑adjusted life year (QALY) gained. Because of confidential discounts for pembrolizumab, pemetrexed maintenance and subsequent therapies, the exact ICERs cannot be reported here. Because the end of life criteria are met for the ITT population, the committee concluded that the cost-effectiveness estimates for pembrolizumab combination compared with pemetrexed platinum chemotherapy are within the range NICE normally considers a cost-effective use of NHS resources.
## For the high PD-L1 subgroup the most plausible ICERs are within the range NICE considers cost effective
Using the committee's preferred assumptions for the ITT population (see section 3.12) the ICER for pembrolizumab combination compared with pembrolizumab monotherapy was between £20,000 and £30,000 per QALY gained. Because of confidential discounts for pembrolizumab and follow-on therapies, the exact ICERs cannot be reported here. The committee concluded that the cost-effectiveness estimates for pembrolizumab combination compared with pembrolizumab monotherapy for people with at least a 50% PD‑L1 tumour proportion score are within the range NICE normally considers a cost-effective use of NHS resources.
# Other factors
No equality or social value judgement issues were identified.
# Conclusion
## Pembrolizumab combination is recommended with a 2-year stopping rule
Pembrolizumab combination is more clinically effective than pemetrexed platinum chemotherapy. There is no statistically significant difference in the clinical effectiveness of pembrolizumab combination compared with monotherapy. The most plausible estimates of cost effectiveness for pembrolizumab combination compared with either comparator were within what NICE considers a cost-effective use of NHS resources. Therefore, pembrolizumab combination is recommended as an option for untreated, metastatic, non-squamous NSCLC with a 2‑year stopping rule.
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{'Recommendations': "Pembrolizumab with pemetrexed and platinum chemotherapy is recommended as an option for untreated, metastatic, non-squamous non-small-cell lung cancer (NSCLC) in adults whose tumours have no epidermal growth factor receptor (EGFR)‑positive or anaplastic lymphoma kinase (ALK)‑positive mutations. This is only if:\n\nit is stopped at 2\xa0years of uninterrupted treatment, or earlier if the disease progresses and\n\nthe company provides pembrolizumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for pembrolizumab with pemetrexed and platinum chemotherapy (pembrolizumab combination) for untreated, metastatic, non‑squamous NSCLC (NICE technology appraisal guidance 557).\n\nStandard care for tumours that have no EGFR‑positive or ALK‑positive mutations depends on PD‑L1 status. If tumours are PD‑L1 negative, or PD‑L1 positive with a tumour proportion score below 50%, pemetrexed with carboplatin or cisplatin (pemetrexed platinum chemotherapy) may be offered. If tumours are PD‑L1 positive with a score of at least 50%, pembrolizumab monotherapy is offered. Pembrolizumab combination would be offered whether or not tumours are PD‑L1 positive, and regardless of tumour proportion score.\n\nClinical evidence collected while pembrolizumab combination was in the Cancer Drugs Fund shows that people having pembrolizumab combination for up to 2\xa0years are likely to live longer than those who have pemetrexed platinum chemotherapy. There are no clinical trials directly comparing pembrolizumab combination with pembrolizumab monotherapy. But an indirect comparison suggests that for people with PD‑L1 positive tumours with a tumour proportion score of at least 50%, there is no difference in how long people having pembrolizumab combination live compared with pembrolizumab monotherapy.\n\nPembrolizumab combination meets NICE's criteria to be considered a life-extending end of life treatment compared with pemetrexed platinum chemotherapy but does not meet the criteria when compared with pembrolizumab monotherapy.\n\nThe cost-effectiveness estimates for pembrolizumab combination are within what NICE considers to be an acceptable use of NHS resources, if it is stopped at 2\xa0years. So, it is recommended.", 'Information about pembrolizumab with pemetrexed and platinum chemotherapy': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp & Dohme) with pemetrexed and platinum chemotherapy has a marketing authorisation for the first-line treatment of metastatic non-squamous non-small-cell lung carcinoma (NSCLC) in adults whose tumours have no epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive tumour mutations.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nPembrolizumab solution for infusion costs £2,630.00 per 100‑mg vial (excluding VAT; BNF online, accessed October 2020).The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck Sharp & Dohme, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the KEYNOTE‑189 study for people with untreated, metastatic, non-squamous non-small-cell lung cancer (NSCLC).\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage. It agreed that the model time horizon for the cost effectiveness should increase to 25\xa0years (issue\xa05, page\xa08 of technical report). Also, that a 2‑year stopping rule for pembrolizumab was appropriate.\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, page\xa08), and took these into account in its decision making. The committee discussed the following issues, which were outstanding after the technical engagement stage:\n\nThe choice of parametric models to predict overall survival.\n\nThe choice of parametric models to predict time on treatment.\n\nThe continued duration of treatment benefit if pembrolizumab with pemetrexed and platinum chemotherapy (pembrolizumab combination) is stopped at 2\xa0years.\n\nThe choice of utility values.\n\n# Clinical management\n\n## Pemetrexed with carboplatin or cisplatin and pembrolizumab monotherapy are the most relevant comparators\n\nIn the original appraisal pemetrexed with carboplatin or cisplatin chemotherapy and pembrolizumab monotherapy were considered appropriate comparators. Chemotherapy using docetaxel, gemcitabine, paclitaxel or vinorelbine as monotherapy is rarely used in NHS clinical practice for treating non-squamous metastatic NSCLC. NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC recommends pembrolizumab monotherapy only for people whose tumours express at least a 50%\xa0PD‑L1 tumour proportion score. Since the original appraisal was published, NICE has recommended atezolizumab combination for metastatic non-squamous NSCLC for people whose tumours express less than a 50%\xa0PD‑L1 tumour proportion score. In line with NICE's guide to the methods of technology appraisal, the original scope was not changed for this Cancer Drugs Fund review. Therefore, atezolizumab was not considered as a comparator because it was recommended after the original guidance was published. The committee concluded that the appropriate comparators are:\n\npemetrexed with carboplatin or cisplatin (referred to as pemetrexed platinum chemotherapy), with or without pemetrexed maintenance therapy\n\npembrolizumab monotherapy for people whose tumours express at least a 50%\xa0PD‑L1 tumour proportion score (referred to as the high PD‑L1 subgroup).\n\n# Clinical effectiveness\n\n## For the intention-to-treat population pembrolizumab combination is more clinically effective than pemetrexed platinum chemotherapy\n\nThere were additional data from KEYNOTE‑189, which was a randomised controlled phase\xa03\xa0trial. The trial included 616\xa0people with untreated advanced or metastatic non-squamous NSCLC regardless of PD‑L1 tumour proportion score who were randomised to pembrolizumab combination or pemetrexed platinum chemotherapy. Two thirds of the trial population had tumours with a PD‑L1 tumour proportion score of at least 50% while the rest had tumours with a PD‑L1 tumour proportion score below 50%. The results showed that pembrolizumab combination was associated with a statistically significant improvement in overall survival compared with pemetrexed platinum chemotherapy (hazard ratio 0.56, 95%\xa0confidence interval 0.46 to 0.69). The committee concluded that for the intention-to-treat (ITT) population, that is, people with untreated advanced or metastatic non-squamous NSCLC regardless of PD‑L1 tumour proportion score, pembrolizumab combination was clinically effective compared with pemetrexed platinum chemotherapy.\n\n## For the high PD-L1 subgroup overall survival is similar for pembrolizumab combination and pembrolizumab monotherapy\n\nPembrolizumab monotherapy is standard care in clinical practice in the NHS for people with untreated NSCLC and at least a 50%\xa0PD‑L1 tumour proportion score (see section\xa03.1). The company presented updated results for this subgroup from an indirect treatment comparison based on data from:\n\nKEYNOTE‑189 (see section\xa03.2)\n\nKEYNOTE‑021 Cohort\xa0G, a trial including 267\xa0people comparing pembrolizumab combination with platinum‑based chemotherapy\n\nKEYNOTE‑042, a trial including 1,274\xa0people with PD‑L1 positive tumours comparing pembrolizumab monotherapy with platinum-based chemotherapy\n\nKEYNOTE‑024, a trial including 305\xa0people with high PD‑L1 tumour proportion score comparing pembrolizumab monotherapy with platinum-based chemotherapy.Although the point estimate suggested better overall survival for pembrolizumab combination compared with pembrolizumab monotherapy, the 95% credible interval showed that this was not statistically significant. The exact results were academic in confidence so cannot be reported here. The committee concluded that overall survival was similar for people with at least a 50%\xa0PD‑L1 tumour proportion score who had pembrolizumab combination compared with pembrolizumab monotherapy.\n\n# Overall survival and time on treatment\n\n## The 5-year survival rate for pembrolizumab combination is between that estimated by the company and the ERG\n\nThe company used a log-logistic distribution to extrapolate overall survival for both pemetrexed platinum chemotherapy and pembrolizumab combination in the model for the ITT population. This is because for the comparator arm this distribution gave the most clinically plausible estimates for overall survival at 5\xa0years and had the best statistical fit. The ERG used a generalised gamma distribution for both arms because this distribution fitted the pembrolizumab combination arm better. Both the log-logistic and the generalised gamma distributions gave clinically plausible 5‑year survival estimates for the comparator arm of between 5% and 11%. The clinical experts explained that people who have immunotherapy such as pembrolizumab second line have a 5‑year survival rate of approximately 13%. They reasoned that people who have pembrolizumab combination earlier in the pathway will benefit from this treatment, so the 5‑year survival rate is likely to be greater than 13%. They agreed that the overall survival in the pembrolizumab combination arm could be somewhere between what was predicted in the generalised gamma and log-logistic extrapolation (the estimates are confidential and cannot be reported here). The committee concluded that the ERG's overall survival estimates for the ITT population were pessimistic but the company's estimates were too optimistic.\n\n## Retreatment with pembrolizumab combination might affect the overall survival seen in the trial but is not NHS clinical practice\n\nSome people in the pembrolizumab combination arm of KEYNOTE‑189 were still having treatment after 2\xa0years. It was not clear, however, how many people were still having combination therapy and how many were having pemetrexed platinum chemotherapy only. The Cancer Drugs Fund clinical lead explained that people could have pembrolizumab for up to 35\xa0cycles, which could extend beyond 2\xa0years. The company confirmed that some people did have further treatment with pembrolizumab alone or in combination with other therapies. From the data presented by the company it was unclear how many people this was. Retreatment with pembrolizumab is not NHS clinical practice. The committee noted that the overall survival curves for the pembrolizumab combination arm included the effect of retreatment. Therefore, the potential survival benefits in the trial might not be seen in NHS practice. The clinical experts explained that retreatment with pembrolizumab or similar drugs could improve survival prospects in this population, especially if they had a good response to initial treatment. The committee noted that retreatment with pembrolizumab could affect the overall survival outcome for the pembrolizumab combination arm. Also, it was aware that the costs of retreatment were not included in the model. The committee concluded that results from the trial might not be generalisable because retreatment with pembrolizumab is not NHS clinical practice.\n\n## Overall survival estimates for the high PD-L1 subgroup are uncertain\n\nTo estimate overall survival for the comparison with pembrolizumab monotherapy in the high PD‑L1 subgroup the company used the same approach as for the ITT population (see section 3.4). Therefore, the committee could not establish whether the company's approach was the most appropriate approach, because no alternatives were provided by the company and ERG. The committee recalled that results from the indirect treatment comparison showed no statistically significant difference in the overall survival estimates for pembrolizumab combination compared with monotherapy (see section 3.3). It concluded that the overall survival estimates for the high PD‑L1 subgroup were uncertain.\n\n## Generalised gamma distribution is appropriate for extrapolating time on treatment\n\nThe company extrapolated time on treatment in the model using the exponential distribution, which assumes a proportional hazard for both arms (that is, at every timepoint the difference between the time on treatment curves for the 2\xa0treatment arms is the same). The company did not provide evidence to support this assumption. The ERG explained that the proportional hazards assumption might not hold because:\n\nthe cumulative hazard plot showed a clear change in gradient of the pembrolizumab combination curve at just over 100\xa0weeks\n\npembrolizumab combination and pemetrexed platinum chemotherapy have different mechanisms of action.The ERG preferred the generalised gamma distribution which does not require the proportional hazards assumption and had a better statistical fit. The ERG noted that the choice of distribution had a minimal effect on the cost-effectiveness estimates. The committee concluded that the generalised gamma distribution was the most appropriate for extrapolating time on treatment.\n\n## Gradually decreasing treatment effect from 3\xa0years after treatment is started until 5\xa0years is appropriate\n\nIn the company's base-case model the relative treatment effect of pembrolizumab combination remained constant for 5\xa0years from the start of treatment. At 5\xa0years the hazard in the pembrolizumab combination arm dropped to match the hazard in the comparator arm. The clinical experts explained that this was implausible and did not reflect their clinical experience with pembrolizumab and other similar drugs. The committee agreed that, although it was biologically plausible for the treatment effect to continue after stopping pembrolizumab, its course and duration was uncertain. The committee concluded that the ERG's approach of a gradually decreasing treatment effect from 3\xa0years after treatment started until 5\xa0years, at which point the treatment effect matches that of pemetrexed platinum chemotherapy, was appropriate for decision making.\n\n# Health-related quality of life\n\n## The approach taken in the original appraisal to estimate utility values is still preferred\n\nThe company did not present new data on health-related quality of life. In the original appraisal the committee preferred to combine the time-to-death approach with progression-based utility values. From the 2\xa0approaches presented by the ERG the committee chose to calculate utilities using progression status with a quality-of-life decrement associated with time to death of less than 360\xa0days applied for people who are likely to live less than 360\xa0days. This was included in the committee's preferred assumptions in the original appraisal. The committee concluded that its preference from the original appraisal had not changed.\n\n# End of life\n\n## Pembrolizumab combination meets NICE's end of life criteria when compared with pemetrexed platinum chemotherapy\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The updated KEYNOTE‑189 data showed that life expectancy for the ITT population, that is, regardless of PD‑L1 tumour proportion score, was less than 24\xa0months and that pembrolizumab combination extended life by at least 3\xa0months. Therefore, the committee concluded that pembrolizumab combination met the end of life criteria and could be considered a life-extending treatment at the end of life when compared with pemetrexed platinum chemotherapy.\n\n## Pembrolizumab combination does not meet NICE's end of life criteria when compared with pembrolizumab monotherapy\n\nStandard care for people with at least a 50% PD‑L1 tumour proportion score is pembrolizumab monotherapy (see section\xa03.1). The clinical expert explained that many people who have pembrolizumab monotherapy die within 2\xa0years, but some people can live longer. Results from KEYNOTE‑024 showed that median overall survival with pembrolizumab monotherapy was 30.0\xa0months (95%\xa0confidence interval 18.3\xa0months to not reached). The committee noted that the company's indirect treatment comparison showed no statistically significant difference in overall survival between pembrolizumab combination and pembrolizumab monotherapy in people with at least a 50% PD‑L1 tumour proportion score (see section\xa03.3). Therefore, the additional 3‑month survival gain for pembrolizumab combination therapy compared with pembrolizumab monotherapy was uncertain. The committee concluded that pembrolizumab combination did not meet the end of life criteria when compared with pembrolizumab monotherapy for people with a high PD‑L1 tumour proportion score.\n\n# Cost effectiveness\n\n## Pembrolizumab combination is considered cost effective compared with pemetrexed platinum chemotherapy\n\nFor the ITT population the most plausible incremental cost-effectiveness ratios (ICERs) were within the range NICE considers a cost-effective use of NHS resources. The committee agreed that its preferred approach to modelling would:\n\ninclude an overall survival extrapolation for pembrolizumab combination between that of the log-logistic and generalised gamma distributions (see section\xa03.4)\n\nextrapolate time on treatment using the generalised gamma distribution (see section\xa03.7)\n\ninclude a gradual decrease of treatment effect from 3\xa0years after the start of treatment until 5\xa0years, when it matches pemetrexed platinum chemotherapy (see section\xa03.8)\n\ncalculate utility values using progression status with a quality-of-life decrement associated with time to death of less than 360\xa0days applied for people who are likely to live less than 360\xa0days (see section\xa03.9)\n\ninclude costs of retreatment with pembrolizumab combination (see section\xa03.5)\n\ninclude dose intensities and costs from the updated results\n\ninclude a 2‑year stopping rule.Using the committee's preferred assumptions the range of plausible ICERs for pembrolizumab combination compared with pemetrexed platinum chemotherapy was below £50,000 per quality‑adjusted life year (QALY) gained. Because of confidential discounts for pembrolizumab, pemetrexed maintenance and subsequent therapies, the exact ICERs cannot be reported here. Because the end of life criteria are met for the ITT population, the committee concluded that the cost-effectiveness estimates for pembrolizumab combination compared with pemetrexed platinum chemotherapy are within the range NICE normally considers a cost-effective use of NHS resources.\n\n## For the high PD-L1 subgroup the most plausible ICERs are within the range NICE considers cost effective\n\nUsing the committee's preferred assumptions for the ITT population (see section 3.12) the ICER for pembrolizumab combination compared with pembrolizumab monotherapy was between £20,000 and £30,000 per QALY gained. Because of confidential discounts for pembrolizumab and follow-on therapies, the exact ICERs cannot be reported here. The committee concluded that the cost-effectiveness estimates for pembrolizumab combination compared with pembrolizumab monotherapy for people with at least a 50%\xa0PD‑L1 tumour proportion score are within the range NICE normally considers a cost-effective use of NHS resources.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Pembrolizumab combination is recommended with a 2-year stopping rule\n\nPembrolizumab combination is more clinically effective than pemetrexed platinum chemotherapy. There is no statistically significant difference in the clinical effectiveness of pembrolizumab combination compared with monotherapy. The most plausible estimates of cost effectiveness for pembrolizumab combination compared with either comparator were within what NICE considers a cost-effective use of NHS resources. Therefore, pembrolizumab combination is recommended as an option for untreated, metastatic, non-squamous NSCLC with a 2‑year stopping rule."}
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https://www.nice.org.uk/guidance/ta683
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Evidence-based recommendations on pembrolizumab (Keytruda) with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous non-small-cell lung cancer (NSCLC) in adults whose tumours have no epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive mutations.
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c842cf1cc64db6e22937cd0cf695f8e43d70b39a
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nice
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Alpha-Stim AID for anxiety disorders
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Alpha-Stim AID for anxiety disorders
Evidence-based recommendations on Alpha‑Stim AID for managing anxiety disorders.
# Recommendations
Alpha‑Stim AID shows promise for managing anxiety disorders. However, there is not enough good-quality evidence to support the case for routine adoption.
Research is recommended to address uncertainties about Alpha‑Stim AID's:
short- and long-term efficacy
position in the care pathway for managing anxiety disorders and
resource impact.This research should include:
a study to better understand how Alpha‑Stim AID affects brain function in people with anxiety disorders
a randomised controlled trial comparing Alpha‑Stim AID with individual cognitive behavioural therapy (CBT), medication or both.Find out details of the research recommended in section 4.11.
Why the committee made these recommendations
Treatment for anxiety disorders usually includes CBT, medication or both. Alpha‑Stim AID uses an electric current intended to generate calming brain waves, which may relieve anxiety symptoms.
Clinical trial evidence shows that Alpha‑Stim AID can relieve anxiety symptoms in people with anxiety disorders. But it is not clear how this happens and how much benefit people get. Also, the evidence is of low quality. How long any benefit lasts is unclear because most of the trials lasted for only 5 or 6 weeks. There is also no evidence comparing Alpha‑Stim AID with individual CBT or medication.
The effect of adopting Alpha‑Stim AID on costs and resources is unclear because its clinical effectiveness and its position in the care pathway are uncertain. Alpha‑Stim AID is not recommended for routine adoption and further research is needed.# The technology
# Technology
Alpha‑Stim AID is an electrotherapy device that uses a variable electric microcurrent to stimulate alpha wave activity. The current has a pulse repetition rate of 0.5 hertz, with a pattern of bipolar asymmetric rectangular waves which repeat at 10‑second intervals.
Alpha‑Stim AID is compact, about the size of a mobile phone, and delivers an electric current through a pair of small clips attached to the ear lobes. The clips have removable soft pads that are moistened to ensure electricity conduction. The strength of the current can be adjusted. Alpha‑Stim AID is recommended to be used for between 20 and 60 minutes every day, every other day or as needed to treat symptoms of anxiety. Alpha‑Stim AID is battery powered and portable. The company has 7 previous versions of the Alpha‑Stim AID device and states that all versions are based on the same mechanism of action.
# Innovative aspects
Alpha‑Stim AID differs from other anxiety disorder treatments because it uses a patented electrical wave pattern that is transmitted to the brain to stimulate the production of alpha waves.
# Intended use
Alpha‑Stim AID is intended to be used to treat anxiety, insomnia and depression. This guidance focuses on the use of Alpha‑Stim AID for treating anxiety disorders. The device can be self-administered at home, or by a healthcare professional in a hospital or clinic. Alpha‑Stim AID may affect the functioning of implanted cardiac pacemakers and defibrillators. The instructions for use note that people should not operate potentially dangerous machinery or vehicles during treatment, and sometimes for several hours after treatment. The safety of cranial electrotherapy has not been established during pregnancy. The device has a 5‑year warranty.
# Relevant pathway
NICE's guideline on generalised anxiety disorder and panic disorder in adults: management provides principles of care for people with generalised anxiety disorder. It recommends a stepped‑care model to organise service provision and to help people with generalised anxiety disorder, their families, carers and practitioners choose the most effective intervention.
Improving Access to Psychological Therapies (IAPT) services provide evidence-based psychological therapies to people with anxiety disorders and depression. A clinical expert noted that IAPT teams are the standard structure of service provision for people with anxiety and depression in most regions of England. IAPT teams deliver the NICE-recommended stepped-care model for generalised anxiety disorder.
NICE's guideline on social anxiety disorder: recognition, assessment and treatment provides treatment principles for adults with social anxiety disorder. It recommends the use of individual cognitive behavioural therapy (CBT). If a person wants to have drug treatment, a selective serotonin reuptake inhibitor (escitalopram or sertraline) should be offered. For adults who decline CBT and drug treatment, short-term psychodynamic psychotherapy, that has been specifically developed to treat social anxiety disorder, should be considered.
# Costs
The cost of Alpha‑Stim AID is £450 (excluding VAT) per device. The device can be reused by multiple people. A per-person treatment cost of £70 is used in the cost modelling, which is based on a treatment time of 10 weeks and includes £40 to cover other costs such as staff time, postage and consumables.For more details, see the Alpha-Stim website for Alpha-Stim AID for anxiety disorders.# Evidence
# Clinical evidence
## The clinical evidence comprises 6 studies, of which 3 are randomised controlled trials
Six studies provided evidence relevant to the decision problem in the scope, including 2 published randomised controlled trials, 1 unpublished randomised controlled trial and 3 non-comparative observational studies. The studies included between 12 and 197 people. Only 1 study used the current model of the device, the others used older models. One study was done in the UK.
## Evidence shows that using Alpha‑Stim AID relieves anxiety symptoms
The 3 randomised controlled trials showed a statistically significant improvement in patient-reported anxiety scores with Alpha‑Stim AID compared with drugs alone, a sham device or no treatment in people with anxiety disorders. The benefit of Alpha‑Stim AID in relieving anxiety symptoms was also reported consistently in the observational studies.
## There is no evidence of the long-term effect of Alpha‑Stim AID
The studies were of short duration (usually 5 to 6 weeks) with only 1 observational study reporting longer‑term outcomes at 24 weeks.
## The published evidence on the effect of Alpha‑Stim AID on quality of life is limited
Only 2 of the studies reported improvements in quality of life (Morriss et al. 2019, Lu and Hu 2014) using health questionnaire (EQ‑5D‑5L and WHOQOL BREF) scores. An improvement in quality of life was also reported with Alpha‑Stim AID in a patient survey run by NICE's Public Involvement Programme. For details, see the assessment report overview in the supporting documents for this guidance.
## Alpha‑Stim AID is considered a safe device
Adverse events reported with Alpha‑Stim AID in 2 studies included mild headache, dizziness, nausea and feeling strange. Similar symptoms were reported by people who used Alpha‑Stim AID in the patient survey that was done as part of this assessment. Additional symptoms reported in this survey included ear discomfort and worsening of anxiety symptoms. All reported adverse events were mild. The instructions for use note that prolonged electrotherapy stimulation treatment at currents higher than necessary may cause dizziness or nausea that can last for hours to days. The clinical experts did not identify any specific safety concerns with Alpha‑Stim AID.
## Additional evidence on the mechanism of action of Alpha‑Stim AID for treating anxiety disorders is uncertain
In response to consultation comments about the mechanism of action of Alpha‑Stim AID, the external assessment centre (EAC) reviewed additional studies that were highlighted by the consultees. It concluded that 2 published studies (Kennerly 2004; Lande and Gragnani 2018), and 1 PhD thesis (Kennerly 2006) which reported electroencephalogram (EEG) parameters of brain activities after using the Alpha‑Stim AID device, were potentially relevant. The EAC noted, however, that none of these studies examined the association between changes in brain wave activity and changes in anxiety symptoms. The EAC also reviewed a conference abstract and an unpublished single case report, which reported an increase in brain alpha waves and a reduction in perceived anxiety symptoms after using the Alpha‑Stim AID device. But the EAC emphasised that these results should be treated with caution because of the small sample size and uncertainties around study details and the generalisability of the results.
## Further investigation of Alpha‑Stim AID's mechanism of action is needed
Three clinical experts, including 1 expert with extensive expertise in interpreting EEG recordings, also reviewed the additional evidence and agreed with the EAC's conclusions. The expert with EEG expertise considered that further investigation, preferably in studies that include a sham control, is justified to improve the understanding of Alpha‑Stim AID's mechanism of action.
# Cost evidence
## One UK study is included in the economic modelling
The company identified 1 UK study (Morriss et al. 2019). This reported the cost impact of Alpha‑Stim AID as a treatment option for people with anxiety disorders who were waiting for individual cognitive behavioural therapy (CBT) delivered by Improving Access to Psychological Therapies (IAPT) services. No additional economic analyses were identified by the EAC.
## The company's IAPT model shows cost savings in treating anxiety disorders
The company developed a decision tree model with a time horizon of 6 months. The model compared the cost of using Alpha‑Stim AID as an option for people waiting for individual CBT in IAPT services with that of individual CBT alone. The results showed that Alpha‑Stim AID was cost saving by £817.68 per person.
## The EAC changes the company's IAPT model to reflect the evidence and expert opinion
The EAC agreed with many of the assumptions in the company's IAPT model but found some limitations. In the UK observational study, a significant proportion of people who were offered Alpha‑Stim AID chose not to use it and preferred to wait for individual CBT (Morriss et al. 2019). The EAC therefore revised the model to reflect the reduced uptake of Alpha‑Stim AID. The EAC also modified the structure of the model to better reflect the current care pathway as outlined by clinical experts. The EAC's base case included drug treatment as an option at the start of the pathway and for people whose anxiety symptoms did not respond to Alpha‑Stim AID or individual CBT. The EAC excluded the second course of individual CBT for people whose anxiety symptoms did not respond to an initial course of treatment.
## The EAC's updated analysis suggests that cost saving is influenced by response rate and assumptions about the treatment pathway
The EAC's base case showed that using Alpha‑Stim AID saved £80.79 per person compared with individual CBT. This was based on a 47.2% response rate with Alpha‑Stim AID (Morriss et al. 2019) and a 54.2% response rate with individual CBT (Gyani et al. 2013). The reported response rate for Alpha‑Stim AID included everyone who used it in the Morriss et al. study. However, many people may also have had individual CBT alongside or after Alpha‑Stim AID. The reported response rates for treatment combinations were more uncertain and varied. For instance, the response rate was 65.0% in people using Alpha‑Stim AID alone and 13.0% in people having Alpha‑Stim AID followed by individual CBT (Morriss et al. 2019). The EAC explored the effect of different response rates and treatment regimens. For details, see the addendum to the EAC's assessment report in the supporting documents for this guidance.
## Additional analysis suggests cost savings but uncertainties remain
In response to committee, clinical expert and consultation comments, the EAC revised the IAPT cost model to more closely reflect the current IAPT pathway. Results from this model suggested that introducing Alpha‑Stim AID to the current pathway could be cost saving and result in fewer people being discharged from IAPT to primary care for further treatment. However, because of the limited data available and uncertainties in the modelling, the EAC concluded that the cost impact of using Alpha‑Stim AID in the current IAPT care pathway remained uncertain.
## A primary care cost model shows that using Alpha‑Stim AID could have additional savings but does not reflect clinical practice
During consultation, the company submitted a new model, which included Alpha‑Stim AID in primary care as a first-line treatment for anxiety. The model was based on an unpublished study in the NHS and the results showed a cost saving of £285.00 per person when Alpha‑Stim AID was included in the care pathway. However, the EAC considered that the proposed model did not reflect clinical practice because it did not capture medication use, possible variations in treatment options and repeat visits to a GP or nurse.# Committee discussion
# Clinical-effectiveness overview
## A better understanding of how Alpha‑Stim AID works in people with anxiety disorders is needed
The committee considered that Alpha‑Stim AID's mode of action was uncertain although the clinical experts explained the physiological role of alpha brain waves in mediating feelings of calmness. The clinical experts and the external assessment centre (EAC) reviewed the evidence submitted at consultation. They concluded that there was no robust evidence showing the effect of regular use of Alpha‑Stim AID on the brain waves of people with anxiety disorders. The committee considered that a clear understanding of the therapeutic effect of this technology is important. It proposed that further evidence is generated to investigate any acute or longer-term changes in brain activity after using Alpha‑Stim AID in people with anxiety disorders. Potential studies could involve using a sham device as a control and recording brain activity, for example by electroencephalography or functional imaging.
## Alpha‑Stim AID is a promising treatment option for managing anxiety disorders, but the evidence is weak
The randomised controlled trial evidence showed short-term relief of anxiety symptoms with Alpha‑Stim AID in people with anxiety disorders. However, the committee noted that the quality of the evidence was low because of a high risk of bias. The committee was concerned about the possibility of a significant placebo effect with Alpha‑Stim AID. But it also acknowledged that reducing anxiety symptoms was the most important outcome regardless of how this was achieved. The committee concluded that a well-planned and well-conducted trial is needed to be certain about Alpha‑Stim AID's clinical benefit.
## Evidence on the long-term benefit of using Alpha‑Stim AID is needed
The evidence consisted of relatively short-term studies, mostly with follow-up periods of 6 to 12 weeks. In 1 study follow up was 24 weeks. The clinical experts advised that anxiety disorders are long-term conditions and many people have relapses in symptoms. No convincing evidence was available on the longer-term benefits of Alpha‑Stim AID and the committee concluded that further research was needed to explore this.
## More evidence is needed to assess the effect of Alpha‑Stim AID compared with other options in the care pathway
The clinical experts explained that there are several different treatments offered to people with anxiety disorders in the NHS. The committee considered that Morriss et al. (2019) provided information about the use of Alpha‑Stim AID in people waiting for individual cognitive behavioural therapy (CBT). But aside from this, there is a lack of evidence to support the use of Alpha‑Stim AID at specific points in the pathway. Also, there is uncertainty about how the clinical effect of Alpha‑Stim AID compares with other treatments. The committee noted, for example, that there was no evidence for the effect of Alpha‑Stim AID compared with medication in people with anxiety disorders. It recognised that Alpha‑Stim AID may not replace other options in the treatment pathway, but it could be an additional option (see section 4.7 and section 4.8). The committee proposed that further evidence would be helpful to understand Alpha‑Stim AID's benefit compared with established treatments for anxiety disorders, such as individual CBT or medication, or both.
# Side effects and adverse events
## Alpha‑Stim AID is a low-risk device with no serious side effects
The evidence suggested that adverse events with Alpha‑Stim AID were mild. The clinical experts explained that people may have vertigo or dizziness when Alpha‑Stim AID is first used, particularly at a high electric current, but these symptoms tend to lessen when the current is reduced. Data from the patient survey confirmed that the device is generally well tolerated. The committee concluded that people using Alpha‑Stim AID have a low risk of side effects. Also, the device might be a treatment option for some people for whom conventional treatments are unsuitable or who would prefer to avoid them.
# NHS considerations overview
## Training and ongoing support is important for people using Alpha‑Stim AID at home
The clinical experts advised that training on the correct use of Alpha‑Stim AID is important and this is offered to people before treatment starts. This involves explaining technical issues such as ensuring correct connections and setting appropriate currents. The patient expert also noted that people may need ongoing support while using Alpha‑Stim AID at home. The committee concluded that providing information and support was essential to ensure that the technology is used correctly.
## The position of Alpha‑Stim AID in the treatment pathway is not clear
The clinical experts explained that because of the number of people with anxiety disorders there is huge pressure on individual CBT services. They also explained that individual CBT is not suitable for everyone and some people may have to wait a long time to have it. So, easy access to self-administered treatment such as Alpha‑Stim AID that can be used at home is a potentially attractive option for people waiting for individual CBT. The committee also considered that a range of different options for anxiety disorders was needed in the NHS so that treatment can be tailored to the person's needs. The clinical experts explained that Alpha‑Stim AID can be offered early in the care pathway (see section 4.8) and it may help people engage better with subsequent individual CBT if it is still needed. The clinical experts also suggested that Alpha‑Stim AID may particularly benefit people who want to avoid taking medication or when medication is unsuitable for them. The committee understood the importance of choice in treating anxiety in primary care and that this technology could be used to complement existing treatments for anxiety disorders. It concluded that Alpha‑Stim AID has the potential to be a useful addition to the care pathway if evidence showing its clinical benefits is generated (see sections 4.2 to 4.4).
## There is potential for Alpha‑Stim AID to be used in primary care to help people manage anxiety disorders
The clinical experts explained about the potential role of Alpha‑Stim AID in primary care, where there is an unmet clinical need for people with anxiety disorders. The committee noted that the EAC has reviewed the results of a study exploring the use of Alpha‑Stim AID as a first‑line treatment for anxiety in primary care. A clinical expert who is a GP described the use of Alpha‑Stim AID within social prescribing in his practice. Initial results suggested that uptake of Alpha‑Stim AID and feedback from people using it was good. The clinical experts advised that people who do not want to have medication or psychological therapy often prefer to use Alpha‑Stim AID. The committee concluded that Alpha‑Stim AID may fit better in primary care where a range of treatment options is needed and this should be explored in further studies.
# Cost modelling overview
## The EAC's updated IAPT model is acceptable but uncertainties remain
The committee considered that the Improving Access to Psychological Therapies (IAPT) model reflects current care but there was limited data available to populate the uptake and response rates in this complex pathway. The primary care model reflected an alternative position for the technology in the care pathway, but the committee again noted that limited data was available to populate the model. So, it was difficult to draw firm conclusions from either model about the cost benefits of using Alpha‑Stim AID. The committee concluded that further clinical efficacy evidence was needed to accurately assess whether using Alpha‑Stim AID alone or as an add-on treatment would lead to cost savings compared with standard care.
## Further information about resource use would be valuable
In the EAC's base-case analysis for the IAPT model, the main drivers in the cost model were the uptake rate and response rates for the different treatments. The clinical experts explained that the uptake rates were likely to vary across services and people's preferences. They considered that the uptake rate of 22% used in the EAC's model did not reflect the much higher rates found in their own clinical practice. The clinical experts also commented that people may stop treatment early with Alpha‑Stim AID if their symptoms improved and this may have confounded the calculated response rates. The committee concluded that more robust data was needed to understand the potential resource impact of using Alpha‑Stim AID in the NHS.
# Further research
## Further good-quality research is needed to address uncertainties about the clinical efficacy of Alpha‑Stim AID
The committee noted the mostly positive patient experience described in the response to the patient survey and in patients' consultation comments. It considered that Alpha‑Stim AID shows significant promise for managing anxiety disorders, but further studies are needed to address uncertainties about its clinical efficacy. A fundamental understanding of the effect of Alpha‑Stim AID on brain function in people with anxiety disorders would be helpful. For example, from a study using electroencephalography or functional imaging in treatment and sham groups. The committee considered that a well-conducted randomised controlled trial should be done to evaluate the short- and long-term effects of Alpha‑Stim AID compared with established treatment options such as medication and individual CBT. Such a study should include an assessment of patient-reported outcome measures and resource use to inform a future assessment of the cost consequence of using Alpha‑Stim AID in the NHS.
## Collecting real-world data is encouraged
The committee considered that collecting real‑world data on the use of Alpha‑Stim AID would be helpful to understand issues in different clinical scenarios, such as:
people's treatment preferences
the uptake of the device and
the response rates and treatment completion rates.
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{'Recommendations': "Alpha‑Stim\xa0AID shows promise for managing anxiety disorders. However, there is not enough good-quality evidence to support the case for routine adoption.\n\nResearch is recommended to address uncertainties about Alpha‑Stim\xa0AID's:\n\nshort- and long-term efficacy\n\nposition in the care pathway for managing anxiety disorders and\n\nresource impact.This research should include:\n\na study to better understand how Alpha‑Stim\xa0AID affects brain function in people with anxiety disorders\n\na randomised controlled trial comparing Alpha‑Stim\xa0AID with individual cognitive behavioural therapy (CBT), medication or both.Find out details of the research recommended in section\xa04.11.\n\nWhy the committee made these recommendations\n\nTreatment for anxiety disorders usually includes CBT, medication or both. Alpha‑Stim\xa0AID uses an electric current intended to generate calming brain waves, which may relieve anxiety symptoms.\n\nClinical trial evidence shows that Alpha‑Stim\xa0AID can relieve anxiety symptoms in people with anxiety disorders. But it is not clear how this happens and how much benefit people get. Also, the evidence is of low quality. How long any benefit lasts is unclear because most of the trials lasted for only 5\xa0or 6\xa0weeks. There is also no evidence comparing Alpha‑Stim\xa0AID with individual CBT or medication.\n\nThe effect of adopting Alpha‑Stim\xa0AID on costs and resources is unclear because its clinical effectiveness and its position in the care pathway are uncertain. Alpha‑Stim\xa0AID is not recommended for routine adoption and further research is needed.", 'The technology': "# Technology\n\nAlpha‑Stim\xa0AID is an electrotherapy device that uses a variable electric microcurrent to stimulate alpha wave activity. The current has a pulse repetition rate of 0.5\xa0hertz, with a pattern of bipolar asymmetric rectangular waves which repeat at 10‑second intervals.\n\nAlpha‑Stim\xa0AID is compact, about the size of a mobile phone, and delivers an electric current through a pair of small clips attached to the ear lobes. The clips have removable soft pads that are moistened to ensure electricity conduction. The strength of the current can be adjusted. Alpha‑Stim\xa0AID is recommended to be used for between 20\xa0and 60\xa0minutes every day, every other day or as needed to treat symptoms of anxiety. Alpha‑Stim\xa0AID is battery powered and portable. The company has 7\xa0previous versions of the Alpha‑Stim AID device and states that all versions are based on the same mechanism of action.\n\n# Innovative aspects\n\nAlpha‑Stim\xa0AID differs from other anxiety disorder treatments because it uses a patented electrical wave pattern that is transmitted to the brain to stimulate the production of alpha waves.\n\n# Intended use\n\nAlpha‑Stim\xa0AID is intended to be used to treat anxiety, insomnia and depression. This guidance focuses on the use of Alpha‑Stim\xa0AID for treating anxiety disorders. The device can be self-administered at home, or by a healthcare professional in a hospital or clinic. Alpha‑Stim\xa0AID may affect the functioning of implanted cardiac pacemakers and defibrillators. The instructions for use note that people should not operate potentially dangerous machinery or vehicles during treatment, and sometimes for several hours after treatment. The safety of cranial electrotherapy has not been established during pregnancy. The device has a 5‑year warranty.\n\n# Relevant pathway\n\nNICE's guideline on generalised anxiety disorder and panic disorder in adults: management provides principles of care for people with generalised anxiety disorder. It recommends a stepped‑care model to organise service provision and to help people with generalised anxiety disorder, their families, carers and practitioners choose the most effective intervention.\n\nImproving Access to Psychological Therapies (IAPT) services provide evidence-based psychological therapies to people with anxiety disorders and depression. A clinical expert noted that IAPT teams are the standard structure of service provision for people with anxiety and depression in most regions of England. IAPT teams deliver the NICE-recommended stepped-care model for generalised anxiety disorder.\n\nNICE's guideline on social anxiety disorder: recognition, assessment and treatment provides treatment principles for adults with social anxiety disorder. It recommends the use of individual cognitive behavioural therapy (CBT). If a person wants to have drug treatment, a selective serotonin reuptake inhibitor (escitalopram or sertraline) should be offered. For adults who decline CBT and drug treatment, short-term psychodynamic psychotherapy, that has been specifically developed to treat social anxiety disorder, should be considered.\n\n# Costs\n\nThe cost of Alpha‑Stim\xa0AID is £450 (excluding VAT) per device. The device can be reused by multiple people. A per-person treatment cost of £70 is used in the cost modelling, which is based on a treatment time of 10\xa0weeks and includes £40 to cover other costs such as staff time, postage and consumables.For more details, see the Alpha-Stim website for Alpha-Stim AID for anxiety disorders.", 'Evidence': "# Clinical evidence\n\n## The clinical evidence comprises 6\xa0studies, of which 3\xa0are randomised controlled trials\n\nSix\xa0studies provided evidence relevant to the decision problem in the scope, including 2\xa0published randomised controlled trials, 1\xa0unpublished randomised controlled trial and 3\xa0non-comparative observational studies. The studies included between 12\xa0and 197\xa0people. Only 1\xa0study used the current model of the device, the others used older models. One\xa0study was done in the UK.\n\n## Evidence shows that using Alpha‑Stim\xa0AID relieves anxiety symptoms\n\nThe 3\xa0randomised controlled trials showed a statistically significant improvement in patient-reported anxiety scores with Alpha‑Stim\xa0AID compared with drugs alone, a sham device or no treatment in people with anxiety disorders. The benefit of Alpha‑Stim\xa0AID in relieving anxiety symptoms was also reported consistently in the observational studies.\n\n## There is no evidence of the long-term effect of Alpha‑Stim\xa0AID\n\nThe studies were of short duration (usually 5\xa0to 6\xa0weeks) with only 1\xa0observational study reporting longer‑term outcomes at 24\xa0weeks.\n\n## The published evidence on the effect of Alpha‑Stim\xa0AID on quality of life is limited\n\nOnly 2\xa0of the studies reported improvements in quality of life (Morriss et al. 2019, Lu and Hu 2014) using health questionnaire (EQ‑5D‑5L and WHOQOL\xa0BREF) scores. An improvement in quality of life was also reported with Alpha‑Stim\xa0AID in a patient survey run by NICE's Public Involvement Programme. For details, see the assessment report overview in the supporting documents for this guidance.\n\n## Alpha‑Stim\xa0AID is considered a safe device\n\nAdverse events reported with Alpha‑Stim\xa0AID in 2\xa0studies included mild headache, dizziness, nausea and feeling strange. Similar symptoms were reported by people who used Alpha‑Stim\xa0AID in the patient survey that was done as part of this assessment. Additional symptoms reported in this survey included ear discomfort and worsening of anxiety symptoms. All reported adverse events were mild. The instructions for use note that prolonged electrotherapy stimulation treatment at currents higher than necessary may cause dizziness or nausea that can last for hours to days. The clinical experts did not identify any specific safety concerns with Alpha‑Stim\xa0AID.\n\n## Additional evidence on the mechanism of action of Alpha‑Stim\xa0AID for treating anxiety disorders is uncertain\n\nIn response to consultation comments about the mechanism of action of Alpha‑Stim\xa0AID, the external assessment centre (EAC) reviewed additional studies that were highlighted by the consultees. It concluded that 2\xa0published studies (Kennerly 2004; Lande and Gragnani 2018), and 1\xa0PhD thesis (Kennerly 2006) which reported electroencephalogram (EEG) parameters of brain activities after using the Alpha‑Stim\xa0AID device, were potentially relevant. The EAC noted, however, that none of these studies examined the association between changes in brain wave activity and changes in anxiety symptoms. The EAC also reviewed a conference abstract and an unpublished single case report, which reported an increase in brain alpha waves and a reduction in perceived anxiety symptoms after using the Alpha‑Stim\xa0AID device. But the EAC emphasised that these results should be treated with caution because of the small sample size and uncertainties around study details and the generalisability of the results.\n\n## Further investigation of Alpha‑Stim\xa0AID's mechanism of action is needed\n\nThree\xa0clinical experts, including 1\xa0expert with extensive expertise in interpreting EEG recordings, also reviewed the additional evidence and agreed with the EAC's conclusions. The expert with EEG expertise considered that further investigation, preferably in studies that include a sham control, is justified to improve the understanding of Alpha‑Stim\xa0AID's mechanism of action.\n\n# Cost evidence\n\n## One\xa0UK study is included in the economic modelling\n\nThe company identified 1\xa0UK study (Morriss et al. 2019). This reported the cost impact of Alpha‑Stim\xa0AID as a treatment option for people with anxiety disorders who were waiting for individual cognitive behavioural therapy (CBT) delivered by Improving Access to Psychological Therapies (IAPT) services. No additional economic analyses were identified by the EAC.\n\n## The company's IAPT model shows cost savings in treating anxiety disorders\n\nThe company developed a decision tree model with a time horizon of 6\xa0months. The model compared the cost of using Alpha‑Stim\xa0AID as an option for people waiting for individual CBT in IAPT services with that of individual CBT alone. The results showed that Alpha‑Stim\xa0AID was cost saving by £817.68 per person.\n\n## The EAC changes the company's IAPT model to reflect the evidence and expert opinion\n\nThe EAC agreed with many of the assumptions in the company's IAPT model but found some limitations. In the UK observational study, a significant proportion of people who were offered Alpha‑Stim\xa0AID chose not to use it and preferred to wait for individual CBT (Morriss et al. 2019). The EAC therefore revised the model to reflect the reduced uptake of Alpha‑Stim\xa0AID. The EAC also modified the structure of the model to better reflect the current care pathway as outlined by clinical experts. The EAC's base case included drug treatment as an option at the start of the pathway and for people whose anxiety symptoms did not respond to Alpha‑Stim\xa0AID or individual CBT. The EAC excluded the second course of individual CBT for people whose anxiety symptoms did not respond to an initial course of treatment.\n\n## The EAC's updated analysis suggests that cost saving is influenced by response rate and assumptions about the treatment pathway\n\nThe EAC's base case showed that using Alpha‑Stim\xa0AID saved £80.79 per person compared with individual CBT. This was based on a 47.2% response rate with Alpha‑Stim\xa0AID (Morriss et al. 2019) and a 54.2% response rate with individual CBT (Gyani et al. 2013). The reported response rate for Alpha‑Stim\xa0AID included everyone who used it in the Morriss et al. study. However, many people may also have had individual CBT alongside or after Alpha‑Stim\xa0AID. The reported response rates for treatment combinations were more uncertain and varied. For instance, the response rate was 65.0% in people using Alpha‑Stim\xa0AID alone and 13.0% in people having Alpha‑Stim\xa0AID followed by individual CBT (Morriss et al. 2019). The EAC explored the effect of different response rates and treatment regimens. For details, see the addendum to the EAC's assessment report in the supporting documents for this guidance.\n\n## Additional analysis suggests cost savings but uncertainties remain\n\nIn response to committee, clinical expert and consultation comments, the EAC revised the IAPT cost model to more closely reflect the current IAPT pathway. Results from this model suggested that introducing Alpha‑Stim\xa0AID to the current pathway could be cost saving and result in fewer people being discharged from IAPT to primary care for further treatment. However, because of the limited data available and uncertainties in the modelling, the EAC concluded that the cost impact of using Alpha‑Stim\xa0AID in the current IAPT care pathway remained uncertain.\n\n## A primary care cost model shows that using Alpha‑Stim\xa0AID could have additional savings but does not reflect clinical practice\n\nDuring consultation, the company submitted a new model, which included Alpha‑Stim\xa0AID in primary care as a first-line treatment for anxiety. The model was based on an unpublished study in the NHS and the results showed a cost saving of £285.00 per person when Alpha‑Stim\xa0AID was included in the care pathway. However, the EAC considered that the proposed model did not reflect clinical practice because it did not capture medication use, possible variations in treatment options and repeat visits to a GP or nurse.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## A better understanding of how Alpha‑Stim\xa0AID works in people with anxiety disorders is needed\n\nThe committee considered that Alpha‑Stim\xa0AID's mode of action was uncertain although the clinical experts explained the physiological role of alpha brain waves in mediating feelings of calmness. The clinical experts and the external assessment centre (EAC) reviewed the evidence submitted at consultation. They concluded that there was no robust evidence showing the effect of regular use of Alpha‑Stim\xa0AID on the brain waves of people with anxiety disorders. The committee considered that a clear understanding of the therapeutic effect of this technology is important. It proposed that further evidence is generated to investigate any acute or longer-term changes in brain activity after using Alpha‑Stim\xa0AID in people with anxiety disorders. Potential studies could involve using a sham device as a control and recording brain activity, for example by electroencephalography or functional imaging.\n\n## Alpha‑Stim\xa0AID is a promising treatment option for managing anxiety disorders, but the evidence is weak\n\nThe randomised controlled trial evidence showed short-term relief of anxiety symptoms with Alpha‑Stim\xa0AID in people with anxiety disorders. However, the committee noted that the quality of the evidence was low because of a high risk of bias. The committee was concerned about the possibility of a significant placebo effect with Alpha‑Stim\xa0AID. But it also acknowledged that reducing anxiety symptoms was the most important outcome regardless of how this was achieved. The committee concluded that a well-planned and well-conducted trial is needed to be certain about Alpha‑Stim\xa0AID's clinical benefit.\n\n## Evidence on the long-term benefit of using Alpha‑Stim\xa0AID is needed\n\nThe evidence consisted of relatively short-term studies, mostly with follow-up periods of 6\xa0to 12\xa0weeks. In 1\xa0study follow up was 24\xa0weeks. The clinical experts advised that anxiety disorders are long-term conditions and many people have relapses in symptoms. No convincing evidence was available on the longer-term benefits of Alpha‑Stim\xa0AID and the committee concluded that further research was needed to explore this.\n\n## More evidence is needed to assess the effect of Alpha‑Stim\xa0AID compared with other options in the care pathway\n\nThe clinical experts explained that there are several different treatments offered to people with anxiety disorders in the NHS. The committee considered that Morriss et al. (2019) provided information about the use of Alpha‑Stim\xa0AID in people waiting for individual cognitive behavioural therapy (CBT). But aside from this, there is a lack of evidence to support the use of Alpha‑Stim\xa0AID at specific points in the pathway. Also, there is uncertainty about how the clinical effect of Alpha‑Stim\xa0AID compares with other treatments. The committee noted, for example, that there was no evidence for the effect of Alpha‑Stim\xa0AID compared with medication in people with anxiety disorders. It recognised that Alpha‑Stim\xa0AID may not replace other options in the treatment pathway, but it could be an additional option (see section 4.7 and section 4.8). The committee proposed that further evidence would be helpful to understand Alpha‑Stim\xa0AID's benefit compared with established treatments for anxiety disorders, such as individual CBT or medication, or both.\n\n# Side effects and adverse events\n\n## Alpha‑Stim\xa0AID is a low-risk device with no serious side effects\n\nThe evidence suggested that adverse events with Alpha‑Stim\xa0AID were mild. The clinical experts explained that people may have vertigo or dizziness when Alpha‑Stim\xa0AID is first used, particularly at a high electric current, but these symptoms tend to lessen when the current is reduced. Data from the patient survey confirmed that the device is generally well tolerated. The committee concluded that people using Alpha‑Stim\xa0AID have a low risk of side effects. Also, the device might be a treatment option for some people for whom conventional treatments are unsuitable or who would prefer to avoid them.\n\n# NHS considerations overview\n\n## Training and ongoing support is important for people using Alpha‑Stim\xa0AID at home\n\nThe clinical experts advised that training on the correct use of Alpha‑Stim\xa0AID is important and this is offered to people before treatment starts. This involves explaining technical issues such as ensuring correct connections and setting appropriate currents. The patient expert also noted that people may need ongoing support while using Alpha‑Stim\xa0AID at home. The committee concluded that providing information and support was essential to ensure that the technology is used correctly.\n\n## The position of Alpha‑Stim\xa0AID in the treatment pathway is not clear\n\nThe clinical experts explained that because of the number of people with anxiety disorders there is huge pressure on individual CBT services. They also explained that individual CBT is not suitable for everyone and some people may have to wait a long time to have it. So, easy access to self-administered treatment such as Alpha‑Stim\xa0AID that can be used at home is a potentially attractive option for people waiting for individual CBT. The committee also considered that a range of different options for anxiety disorders was needed in the NHS so that treatment can be tailored to the person's needs. The clinical experts explained that Alpha‑Stim\xa0AID can be offered early in the care pathway (see section 4.8) and it may help people engage better with subsequent individual CBT if it is still needed. The clinical experts also suggested that Alpha‑Stim\xa0AID may particularly benefit people who want to avoid taking medication or when medication is unsuitable for them. The committee understood the importance of choice in treating anxiety in primary care and that this technology could be used to complement existing treatments for anxiety disorders. It concluded that Alpha‑Stim\xa0AID has the potential to be a useful addition to the care pathway if evidence showing its clinical benefits is generated (see sections 4.2 to 4.4).\n\n## There is potential for Alpha‑Stim\xa0AID to be used in primary care to help people manage anxiety disorders\n\nThe clinical experts explained about the potential role of Alpha‑Stim\xa0AID in primary care, where there is an unmet clinical need for people with anxiety disorders. The committee noted that the EAC has reviewed the results of a study exploring the use of Alpha‑Stim\xa0AID as a first‑line treatment for anxiety in primary care. A clinical expert who is a GP described the use of Alpha‑Stim\xa0AID within social prescribing in his practice. Initial results suggested that uptake of Alpha‑Stim\xa0AID and feedback from people using it was good. The clinical experts advised that people who do not want to have medication or psychological therapy often prefer to use Alpha‑Stim\xa0AID. The committee concluded that Alpha‑Stim\xa0AID may fit better in primary care where a range of treatment options is needed and this should be explored in further studies.\n\n# Cost modelling overview\n\n## The EAC's updated IAPT model is acceptable but uncertainties remain\n\nThe committee considered that the Improving Access to Psychological Therapies (IAPT) model reflects current care but there was limited data available to populate the uptake and response rates in this complex pathway. The primary care model reflected an alternative position for the technology in the care pathway, but the committee again noted that limited data was available to populate the model. So, it was difficult to draw firm conclusions from either model about the cost benefits of using Alpha‑Stim\xa0AID. The committee concluded that further clinical efficacy evidence was needed to accurately assess whether using Alpha‑Stim\xa0AID alone or as an add-on treatment would lead to cost savings compared with standard care.\n\n## Further information about resource use would be valuable\n\nIn the EAC's base-case analysis for the IAPT model, the main drivers in the cost model were the uptake rate and response rates for the different treatments. The clinical experts explained that the uptake rates were likely to vary across services and people's preferences. They considered that the uptake rate of 22% used in the EAC's model did not reflect the much higher rates found in their own clinical practice. The clinical experts also commented that people may stop treatment early with Alpha‑Stim\xa0AID if their symptoms improved and this may have confounded the calculated response rates. The committee concluded that more robust data was needed to understand the potential resource impact of using Alpha‑Stim\xa0AID in the NHS.\n\n# Further research\n\n## Further good-quality research is needed to address uncertainties about the clinical efficacy of Alpha‑Stim\xa0AID\n\nThe committee noted the mostly positive patient experience described in the response to the patient survey and in patients' consultation comments. It considered that Alpha‑Stim\xa0AID shows significant promise for managing anxiety disorders, but further studies are needed to address uncertainties about its clinical efficacy. A fundamental understanding of the effect of Alpha‑Stim\xa0AID on brain function in people with anxiety disorders would be helpful. For example, from a study using electroencephalography or functional imaging in treatment and sham groups. The committee considered that a well-conducted randomised controlled trial should be done to evaluate the short- and long-term effects of Alpha‑Stim\xa0AID compared with established treatment options such as medication and individual CBT. Such a study should include an assessment of patient-reported outcome measures and resource use to inform a future assessment of the cost consequence of using Alpha‑Stim\xa0AID in the NHS.\n\n## Collecting real-world data is encouraged\n\nThe committee considered that collecting real‑world data on the use of Alpha‑Stim\xa0AID would be helpful to understand issues in different clinical scenarios, such as:\n\npeople's treatment preferences\n\nthe uptake of the device and\n\nthe response rates and treatment completion rates."}
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https://www.nice.org.uk/guidance/mtg56
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Evidence-based recommendations on Alpha‑Stim AID for managing anxiety disorders.
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c71aabb6e3702de7f507f4f1110d9209847745a8
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nice
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Free-functioning gracilis transfer to restore upper limb function in brachial plexus injury
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Free-functioning gracilis transfer to restore upper limb function in brachial plexus injury
Evidence-based recommendations on free-functioning gracilis transfer to restore upper limb function in brachial plexus injury in adults. This involves a piece of hamstring muscle and its nerve and blood supply (free-functioning gracilis) being taken from the inner thigh, transferred to the arm and joined to the damaged nerve.
# Recommendations
Evidence on the safety of free-functioning gracilis transfer to restore upper limb function in brachial plexus injury shows well-recognised complications. Evidence on its efficacy is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE website.
This procedure should only be done in a specialist brachial plexus unit by a multidisciplinary team including specialised physiotherapists, with input from microvascular surgeons.# The condition, current treatments and procedure
# The condition
The brachial plexus is a network of nerves that carries signals from the spinal cord to the shoulder, arm and hand. These nerves can be damaged by being stretched, compressed or torn from the spinal cord. The most severe brachial plexus injuries are often a result of road traffic accidents. Severe nerve damage can lead to paralysis of an upper limb, with a loss of function and sensation, and severe pain.
# Current treatments
Treatment depends on the type and severity of the injury, and the length of time since the injury. Injuries of the upper brachial plexus roots affect the muscles around the shoulder. Injuries of the lower roots affect the hand. Many injuries affect both upper and lower roots. Current treatments include medicines to treat pain and conservative care (such as physiotherapy). For some people, surgical procedures are needed to restore function. These include direct suture, nerve grafts, nerve transfer, tendon transfer and free-functioning muscle transfer.
# The procedure
This procedure aims to restore the function of the upper limb after brachial plexus injury, improving the patient's ability to carry out daily activities.
The procedure is done under general anaesthesia, with the patient in a supine position. A functioning gracilis muscle, with its own nerve and blood supply, is dissected from the inner thigh. The gracilis muscle is then transferred and joined to the prepared recipient site of the upper limb. The gracilis muscle's nerve is connected to a functioning nerve in the arm. The transfer is usually to 1 muscle group but transfer to different sites, such as the biceps or the finger flexors, may be needed depending on the nerve injury. The aim is usually to reconstruct a single function, such as elbow flexion.
After the procedure, the patient needs to wear a cast or splint for about 6 weeks to immobilise the elbow and protect the transferred gracilis muscle. Long-term physiotherapy is needed after the procedure so that the patient can learn to control the transferred muscle.
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{'Recommendations': 'Evidence on the safety of free-functioning gracilis transfer to restore upper limb function in brachial plexus injury shows well-recognised complications. Evidence on its efficacy is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE website.\n\nThis procedure should only be done in a specialist brachial plexus unit by a multidisciplinary team including specialised physiotherapists, with input from microvascular surgeons.', 'The condition, current treatments and procedure': "# The condition\n\nThe brachial plexus is a network of nerves that carries signals from the spinal cord to the shoulder, arm and hand. These nerves can be damaged by being stretched, compressed or torn from the spinal cord. The most severe brachial plexus injuries are often a result of road traffic accidents. Severe nerve damage can lead to paralysis of an upper limb, with a loss of function and sensation, and severe pain.\n\n# Current treatments\n\nTreatment depends on the type and severity of the injury, and the length of time since the injury. Injuries of the upper brachial plexus roots affect the muscles around the shoulder. Injuries of the lower roots affect the hand. Many injuries affect both upper and lower roots. Current treatments include medicines to treat pain and conservative care (such as physiotherapy). For some people, surgical procedures are needed to restore function. These include direct suture, nerve grafts, nerve transfer, tendon transfer and free-functioning muscle transfer.\n\n# The procedure\n\nThis procedure aims to restore the function of the upper limb after brachial plexus injury, improving the patient's ability to carry out daily activities.\n\nThe procedure is done under general anaesthesia, with the patient in a supine position. A functioning gracilis muscle, with its own nerve and blood supply, is dissected from the inner thigh. The gracilis muscle is then transferred and joined to the prepared recipient site of the upper limb. The gracilis muscle's nerve is connected to a functioning nerve in the arm. The transfer is usually to 1\xa0muscle group but transfer to different sites, such as the biceps or the finger flexors, may be needed depending on the nerve injury. The aim is usually to reconstruct a single function, such as elbow flexion.\n\nAfter the procedure, the patient needs to wear a cast or splint for about 6\xa0weeks to immobilise the elbow and protect the transferred gracilis muscle. Long-term physiotherapy is needed after the procedure so that the patient can learn to control the transferred muscle."}
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https://www.nice.org.uk/guidance/ipg687
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Evidence-based recommendations on free-functioning gracilis transfer to restore upper limb function in brachial plexus injury in adults. This involves a piece of hamstring muscle and its nerve and blood supply (free-functioning gracilis) being taken from the inner thigh, transferred to the arm and joined to the damaged nerve.
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553bf2e6fe8f8a9bb6d6736314b9a8eba48655db
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nice
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Cytoreduction surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis
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Cytoreduction surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis
Evidence-based recommendations on cytoreduction surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis. This involves surgically removing visible cancer and bathing the abdominal cavity with heated chemotherapy fluid to reach any remaining cancer cells.
# Recommendations
Evidence on the safety of cytoreduction surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis shows frequent and serious but well-recognised complications. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE website.
Clinicians wishing to do cytoreduction surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
Patient selection should be done by an experienced multidisciplinary team.
The procedure should only be done in highly specialised centres by clinicians with specialist expertise and specific training in cytoreduction surgery and hyperthermic intraoperative peritoneal chemotherapy.
NICE encourages further research in the form of randomised controlled trials. These should clearly describe the patient selection criteria, the types of cancer being treated and the chemotherapy regimens used. Outcomes should include survival, reduction in tumour burden and quality of life.
NICE may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Peritoneal carcinomatosis is an advanced form of cancer resulting from the regional spread of gastrointestinal, gynaecological and other malignancies. It is associated with short survival and poor quality of life. It may lead to bowel obstruction, ascites and pain.
# Current treatments
Current standard management includes treating complications such as bowel obstruction using systemic chemotherapy (alone or with surgery), closed peritoneal instillation of chemotherapy or surgery alone.
# The procedure
Cytoreduction surgery is done to remove all macroscopic tumours within the abdominal cavity. Hyperthermic intraoperative peritoneal chemotherapy is then used to distribute a chemotherapeutic drug uniformly to all surfaces within the abdominal cavity and to increase drug penetration. This is done to treat any remaining microscopic traces of the cancer. The aim is to reduce symptoms, extend survival and improve quality of life.
Using general anaesthesia, a laparotomy is done and all macroscopic tumour is removed, with resection of involved organs and stripping of the tumour from the surface of some organs and peritoneum. The surgery is extensive and complex. It is followed by perfusion of the abdominal cavity with a heated (between 40 and 48°degrees Celsius) chemotherapy solution for 30 to 120 minutes, with the abdomen open or closed. The fluid is drained from the abdominal cavity before closure. A further course of systemic or early postoperative intraperitoneal chemotherapy may be administered.
|
{'Recommendations': "Evidence on the safety of cytoreduction surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis shows frequent and serious but well-recognised complications. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE website.\n\nClinicians wishing to do cytoreduction surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by an experienced multidisciplinary team.\n\nThe procedure should only be done in highly specialised centres by clinicians with specialist expertise and specific training in cytoreduction surgery and hyperthermic intraoperative peritoneal chemotherapy.\n\nNICE encourages further research in the form of randomised controlled trials. These should clearly describe the patient selection criteria, the types of cancer being treated and the chemotherapy regimens used. Outcomes should include survival, reduction in tumour burden and quality of life.\n\nNICE may update the guidance on publication of further evidence.", 'The condition, current treatments and procedure': '# The condition\n\nPeritoneal carcinomatosis is an advanced form of cancer resulting from the regional spread of gastrointestinal, gynaecological and other malignancies. It is associated with short survival and poor quality of life. It may lead to bowel obstruction, ascites and pain.\n\n# Current treatments\n\nCurrent standard management includes treating complications such as bowel obstruction using systemic chemotherapy (alone or with surgery), closed peritoneal instillation of chemotherapy or surgery alone.\n\n# The procedure\n\nCytoreduction surgery is done to remove all macroscopic tumours within the abdominal cavity. Hyperthermic intraoperative peritoneal chemotherapy is then used to distribute a chemotherapeutic drug uniformly to all surfaces within the abdominal cavity and to increase drug penetration. This is done to treat any remaining microscopic traces of the cancer. The aim is to reduce symptoms, extend survival and improve quality of life.\n\nUsing general anaesthesia, a laparotomy is done and all macroscopic tumour is removed, with resection of involved organs and stripping of the tumour from the surface of some organs and peritoneum. The surgery is extensive and complex. It is followed by perfusion of the abdominal cavity with a heated (between 40\xa0and 48°degrees Celsius) chemotherapy solution for 30\xa0to 120\xa0minutes, with the abdomen open or closed. The fluid is drained from the abdominal cavity before closure. A further course of systemic or early postoperative intraperitoneal chemotherapy may be administered.'}
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https://www.nice.org.uk/guidance/ipg688
|
Evidence-based recommendations on cytoreduction surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis. This involves surgically removing visible cancer and bathing the abdominal cavity with heated chemotherapy fluid to reach any remaining cancer cells.
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aa38501d1445e486c290b2b66e3466c7de82b056
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nice
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Lenalidomide maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma
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Lenalidomide maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma
Evidence-based recommendations on lenalidomide (Revlimid) for maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma in adults.
# Recommendations
Lenalidomide is recommended as maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma in adults, only if:
the dosage schedule is 10 mg per day on days 1 to 21 of a 28‑day cycle and
the company provides lenalidomide according to the commercial arrangement.
This recommendation is not intended to affect treatment with lenalidomide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There is currently no maintenance treatment for newly diagnosed multiple myeloma in people who have had an autologous stem cell transplant. The condition is usually monitored until it gets worse.
Clinical trial results show that, compared with monitoring alone, lenalidomide increases how long people live and extends the time before the condition gets worse.
The most likely cost-effectiveness estimates for lenalidomide compared with monitoring alone are within the range NICE normally considers an acceptable use of NHS resources. Therefore, lenalidomide is recommended.# Information about lenalidomide
# Marketing authorisation indication
Lenalidomide (Revlimid, Celgene) is indicated for 'the maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics. This technology appraisal guidance makes recommendations outside of the marketing authorisation for lenalidomide. The dosage schedule recommended by NICE is 10 mg per day on days 1 to 21 of a 28‑day cycle.
# Price
The list price for lenalidomide is £3,780 per pack of 21 capsules, each containing 10 mg of the active ingredient (excluding VAT; BNF online, November 2020). The company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Celgene, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway
## Most people with newly diagnosed multiple myeloma would have lenalidomide maintenance treatment after an autologous stem cell transplant
After a first autologous stem cell transplant, newly diagnosed multiple myeloma is usually monitored until the first relapse, and not actively treated. Lenalidomide is the only treatment option licensed as a maintenance therapy to replace monitoring for this indication. Lenalidomide would be used to try to lengthen the time until first relapse. The clinical experts advised that most people with newly diagnosed multiple myeloma who have had a first transplant would have lenalidomide maintenance treatment if it was recommended, and that only a small proportion would have no active treatment. The committee was aware that lenalidomide (plus dexamethasone) is currently available in the NHS for treating multiple myeloma later in the treatment pathway. The clinical experts explained that if people had lenalidomide maintenance treatment they would not then have lenalidomide again later in the treatment pathway. However, the clinical and patient experts emphasised that the benefits of lenalidomide maintenance treatment would likely outweigh the benefits of using it later in the pathway. This is because, with each line of new therapy, a substantial proportion of people stop having treatment because they become too ill or have complications. Therefore, the most effective treatments should be given as early in the treatment pathway as possible. Also, the first remission is often the 'best' remission because it is when people with the condition are at their fittest. Clinical experts also explained that it is also when people have the highest quality of life before the negative effects of the disease and its treatments have accumulated. Therefore, extending the first remission maximises the chances of people maintaining a higher quality of life for the longest possible period. The patient experts also explained that lenalidomide is a well-tolerated treatment and that, during the ongoing coronavirus pandemic, it is particularly convenient. This is because it is taken orally and does not need a hospital visit. The committee concluded that, if lenalidomide maintenance treatment was to be recommended, most people with newly diagnosed multiple myeloma who have had an autologous stem cell transplant would have it.
# Licensed dose
## The dosing schedule that would be used in clinical practice differs from the marketing authorisation
The lenalidomide marketing authorisation recommends a dosage of 10 mg once daily on days 1 to 28 of repeated 28‑day cycles. The committee was aware that recommendations are normally made within the marketing authorisation of the drug under appraisal (see section 3.15). However, the dosage in the company's submission is 10 mg once daily on days 1 to 21 of repeated 28‑day cycles. This reflects the dosing schedule used in the Myeloma XI randomised controlled trial, which was the main source of clinical evidence in the company's submission. The company stated its understanding that 21 days of dosing followed by a 7‑day treatment-free period would be used in the NHS. This is because this is the schedule used in the Myeloma XI trial and for all other lenalidomide indications so is what healthcare professionals are familiar with. The company highlighted that there may be safety and tolerability benefits associated with having a treatment-free week incorporated into the 28‑day cycle. It explained that the risk of an unplanned and prolonged treatment break would be lower with the 21‑day schedule that incorporates a treatment-free week compared with the continuous 28‑day schedule and this might mean people would continue to have lenalidomide treatment for longer overall. It claimed that using a lenalidomide dosage that is tolerated for as long as possible would fit with the aim of maintenance treatment, which is to avoid relapse for as long as possible. The company clarified that the only reason the licence specifies a 28‑day dosing schedule is because the marketing authorisation was based on the CALGB 100104 and IFM 2005‑02 trials, both of which used a 28‑day dosing schedule. The clinical experts explained that because of the known toxicity profile of lenalidomide, they would have major concerns about prescribing lenalidomide for 28 days without a short treatment‑free period incorporated into the treatment cycle. They agreed with the company that 21 days of treatment per 28‑day cycle would result in fewer and shorter unplanned treatment breaks, maximising the tolerability of lenalidomide, and making sure the treatment could be given for as long as possible. The clinical experts clarified that the 28‑day continuous schedule was likely to result in more dose reductions or increases to the cycle length (for example the same number of capsules but over at least 35 days instead of 28 days). The patient and clinical experts, the ERG, and other stakeholders all showed unanimous support for, and agreement with, all of the company's views on the dosing schedule, while the Cancer Drugs Fund clinical lead for NHS England confirmed that only the 21‑day dosing schedule would be commissioned in the NHS. The committee concluded that a 21‑day dosing schedule would likely be used in clinical practice, but it noted this dose is outside the terms of the marketing authorisation for lenalidomide.
# Clinical evidence
## Lenalidomide is an effective maintenance treatment for people who have had an autologous stem cell transplant
The main clinical evidence for lenalidomide maintenance treatment came from Myeloma XI, a phase 3 open-label randomised trial based in 110 NHS centres in the UK. A total of 1,971 people with newly diagnosed multiple myeloma were enrolled and stratified by their eligibility for an autologous stem cell transplant (only people eligible for a transplant are relevant for the population in this appraisal). The trial had an adaptive design in which ongoing trial results were used to inform changes in the protocol. Also, there were multiple levels of randomisation in the trial. The company's submission focused on a smaller cohort of 1,032 people from Myeloma XI. These people had had a first transplant and been randomised to have maintenance with lenalidomide 10 mg daily on days 1 to 21 of each 28‑day cycle, or to have monitoring of their disease with no lenalidomide treatment. The company considered this cohort to be directly relevant to this appraisal (when Myeloma XI is mentioned from this point, it is referring to this cohort of interest unless otherwise specified). The primary outcomes were progression-free survival and overall survival, both of which were longer with lenalidomide maintenance treatment than with monitoring. The clinical experts advised that the trial was representative of NHS practice, and that the results were generalisable to the population in this appraisal. Based on the results from Myeloma XI, the committee concluded that lenalidomide is an effective maintenance treatment for newly diagnosed multiple myeloma in people who have had an autologous stem cell transplant.
## The company presented evidence from all trials that met the inclusion criteria for its systematic literature review
The company originally identified 4 trials of lenalidomide maintenance treatment in its systematic literature review: Myeloma XI, CALGB 100104, GIMEMA and IFM 2005‑02. It then applied a subsequent set of criteria to exclude CALGB 100104, GIMEMA, and IFM 2005‑02, leaving only Myeloma XI as a source of clinical-effectiveness evidence in its original submission. The company argued that Myeloma XI was the only trial that reflected the decision problem and UK clinical practice. However, it used both CALGB 100104 and Myeloma XI data to estimate survival in its cost‑effectiveness model. The ERG was of the view that the company's approach was inconsistent. The ERG was also concerned that the subsequent set of criteria used to exclude trials was arbitrary and not prespecified. It considered that IFM 2005‑02 should have been excluded based on the company's original systematic literature review criteria, but that CALGB 100104 and GIMEMA should have been included. The committee agreed that the company's approach was inconsistent and would have preferred the company to present all trials meeting the original systematic literature review criteria. The committee also acknowledged that the cohort of interest from Myeloma XI was likely to provide the most generalisable source of clinical-effectiveness evidence to NHS practice. However, because the marketing authorisation is based on trials with 28‑days of dosing, the committee stated that it needed to see evidence on the clinical effectiveness from CALGB 100104 because it used this dosage. In response to consultation, the company presented detailed methods and results from CALGB 100104 and GIMEMA. At its second meeting, the committee concluded it was satisfied that the company had presented all relevant evidence for lenalidomide maintenance treatment.
## The safety profile of lenalidomide as a maintenance treatment compared with monitoring alone is likely to be acceptable
The company explained that there were no data on adverse events available from Myeloma XI for the monitoring arm of the cohort of interest. The ERG stated that this was an area of uncertainty because between-arm comparisons of adverse event rates were needed to understand the comparative safety profile of lenalidomide maintenance treatment. The company provided adverse-events data from both the lenalidomide and monitoring arms of CALGB 100104. The ERG thought that it was useful as supplementary information but that it was not directly generalisable to the population in the NHS. The clinical experts considered that the rates of adverse events in the lenalidomide arm of Myeloma XI for the cohort of interest were similar to those seen in clinical practice for other indications. A patient expert explained that results from a survey done by Myeloma UK showed that most people having lenalidomide maintenance treatment found it easy to take and tolerated it well. The committee concluded that there was some uncertainty about the risk of adverse events, but the safety profile of lenalidomide as a maintenance treatment compared with monitoring alone is likely to be acceptable.
# The company's economic model
## The company's model structure does not allow assumptions about subsequent treatments to be explored
The company chose a partitioned survival model comprising 3 health states (pre-progression, progressive disease and death). It explained that it had previously considered a more complex model structure such as a multistate model. However, there were not enough data to estimate transition probabilities for this approach, so it chose a partitioned survival model instead. The ERG stated that the simple structure of the company's model did not allow uncertainty in the model to be fully explored. It was particularly concerned about the effect of subsequent treatments. This was because survival in the company's model was based on Myeloma XI and CALGB 100104, and the treatments given at second line and beyond in these trials are not generalisable to current NHS practice. The treatment of myeloma has changed since Myeloma XI was started, which means that, despite it being a UK trial, the treatments used do not reflect current NHS practice. Also, CALGB 100104 has limited generalisability to the UK because it was based in the US. The ERG highlighted that the company's partitioned survival model structure did not allow alternative assumptions about subsequent treatments to be explored. This meant that the modelled survival may not have been representative of what would be seen in the NHS. The committee concluded that the company's model structure had limitations. It also concluded that there was likely to be uncertainty around the cost-effectiveness estimate because assumptions about the effects of subsequent therapies on survival could not be fully explored.
## The rank-preserving structural-failure time method is appropriate to adjust for treatment switching in the CALGB 100104 trial
In the CALGB 100104 trial, people were offered the option to switch from placebo to lenalidomide if their disease had not yet progressed. In the committee's first meeting, the company explained that it used the rank-preserving structural-failure time method to adjust for treatment switching in CALGB 100104 and that it did not explore any alternative approaches. The committee recognised that different treatment switching adjustment methods were available and was disappointed the company did not provide any justification for using its chosen method. In response to consultation, the company explored several alternative methods, including the inverse probability of censoring weights and 2‑stage methods. After assessing the key assumptions and limitations associated with each approach, the company concluded that the rank-preserving structural-failure time method remained the most appropriate. The ERG was generally satisfied with the company's rationale. The committee was concerned that some people in CALGB 100104 could have multiple lines of lenalidomide, which is not an option in current NHS practice. The company clarified that it had not adjusted for this in its survival analysis. However, clinical experts explained that lenalidomide is not given more than once in the pathway. This is because it is now acknowledged that it is not likely to be effective if the disease has previously stopped responding to treatment. Therefore, even if it were given multiple times, this is unlikely to positively bias estimates of overall survival in the lenalidomide arm of the CALGB 100104 trial. The committee concluded that the company's use of the rank-preserving structural-failure time method to adjust for treatment switching in the CALGB 100104 trial had some limitations, but was appropriate.
## Survival extrapolations should use Myeloma XI as the main evidence source but supplemented with CALGB 100104 data adjusted to reflect Myeloma XI
Survival models were needed to predict survival beyond the end of the clinical trials for lenalidomide maintenance treatment. The company and ERG had different preferred approaches to using trial data to extrapolate survival:
The company preferred to use data from both Myeloma XI and CALGB 100104 because CALGB 100104 provided longer-term data. It also mentioned that, despite heterogeneity between the trials, the survival results were very similar.
The ERG preferred to use Myeloma XI data only, because of key differences between the 2 trials, such as dosing, baseline characteristics and subsequent treatments.In its original base case, the company fitted survival curves to Myeloma XI data and used CALGB 100104 data to help with curve selection. However, in response to technical engagement, it pooled data from Myeloma XI and CALGB 100104, and fitted curves to the pooled data. It confirmed that it used a simple method for pooling the individual patient data from the trials. This did not involve adjusting CALGB 100104 data to reflect Myeloma XI, for example by adjusting for differences in trial design or population. The ERG noted that it was unable to validate the company's methods for pooling data because not enough detail was provided. The committee was disappointed that the company's approach could not be scrutinised and validated based on the information provided and considered that the differences between the trials meant a simple pooling approach may have been inappropriate. In particular, the 28‑day dosing regimen in CALGB 100104 meant survival in the model was based on a dosage that the company, ERG, and patient and clinical experts explained would not be given in NHS practice. The committee recognised that CALGB 100104 had a longer median follow up (91 months) than Myeloma XI (31 months), so provided information about longer-term survival. At its first meeting, the committee concluded that it would prefer to see a survival analysis that used Myeloma XI as the main source of evidence. CALGB 100104 could be used to help extrapolation, with data adjusted to reflect the Myeloma XI population as far as possible and based on the underlying survival of patients in Myeloma XI. In response to consultation, the company presented survival analyses based on Myeloma XI data up to 60 months, followed by adjusted CALGB 100104 data, using propensity score weighting to adjust CALGB 100104 to better reflect Myeloma XI in its base case. The ERG was satisfied that propensity score weighting was an appropriate method and that the company's analysis was generally well conducted. However, it also highlighted that an important limitation of the propensity score weighting approach is that it cannot adjust for the difference in doses between the 2 trials. The committee concluded that the company had appropriately used the committee's preferred approach to extrapolate survival in its updated analyses (that is, Myeloma XI used as the main source of evidence, with CALGB 100104 used to inform longer-term extrapolation). It further concluded that, despite important limitations associated with the propensity score weighting approach, the company had appropriately adjusted CALGB 100104 data to better reflect Myeloma XI.
## The company's method for selecting overall-survival curves based on adjusted CALGB 100104 data has limitations
In response to technical engagement, the company updated its base case to use a joint Weibull model to extrapolate survival based on pooled Myeloma XI and unadjusted CALGB 100104 data. The ERG preferred to use a joint log-logistic model and to extrapolate Myeloma XI data only. In its first meeting, the committee concluded that survival extrapolations should use Myeloma XI as the main source of evidence but could be supplemented with adjusted CALGB 100104 data for longer‑term survival (see section 3.8). Therefore, in response to consultation, the company revised its base case to use Myeloma XI data in the short term (up to 60 months), followed by adjusted CALGB 100104 data thereafter. However, the committee noted that when choosing the best fitting curve to extrapolate survival, the company had based its choice on adjusted CALGB 100104 data only, rather than all of the data in the model (that is, Myeloma XI data to 60 months followed by adjusted CALGB 100104 data for the remainder of the model time horizon). The company also reported that it selected the joint gamma distribution because it was the best fit to the adjusted CALGB 100104 data, yet it had used the joint generalised gamma in its model. The ERG highlighted several limitations with the company's approach. It would have preferred the company to have used the combined Myeloma XI and adjusted CALGB 100104 data as a basis for curve selection, rather than adjusted CALGB 100104 data alone. It also suggested that the company could have explored a piecewise approach with 2 different distributions for the initial Myeloma XI period (to 60 months) and adjusted CALGB period (after 60 months). Furthermore, the ERG questioned why the company had used the generalised gamma distribution instead of the gamma in its base case, as the company had not provided any supporting information or rationale for its selection. In its own analysis, the ERG chose the joint log‑logistic model for overall survival. After examining the company's and ERG's overall-survival curves, the clinical experts explained that the joint log‑logistic was likely the best representation of long-term survival in clinical practice. The committee concluded that the company's method for selecting overall‑survival curves based on CALGB 100104 data (adjusted to reflect Myeloma XI) has limitations and that it would have preferred the company to have explored a piecewise approach. It also concluded that the log‑logistic curve is the most appropriate choice for extrapolating overall survival.
# Waning of treatment effect
## Treatment waning should be included in the model, and 10 years may be a conservative estimate of when the treatment effect starts to wane
Treatment waning refers to whether or not the relative treatment effect between lenalidomide and monitoring of the condition is likely to reduce over time after people stop taking lenalidomide. Not including treatment waning in the model implies that the relative treatment effect stays the same and lenalidomide remains more effective than monitoring for the entire modelled time horizon, even if people are no longer on treatment. Based on its survival curves, the company took the view that there was no evidence of a treatment-waning effect with lenalidomide and did not include waning in its original base case. The ERG did not include a treatment-waning effect in its base case but explained that there were no long-term data to rule out the possibility that the relative treatment effect decreases over time. The ERG therefore did a scenario analysis that looked at different treatment-waning scenarios. It found the cost‑effectiveness estimate to be sensitive to assumptions about how long the treatment effect lasts for. At the committee's first meeting, the clinical experts advised that they would not expect lenalidomide to have a continued effect after people had stopped taking it. Based on this, the committee had agreed that the treatment effect of lenalidomide therapy may wane over time and that this should have been included in the company's model. In response to consultation, the company reiterated that there was no evidence of a treatment-waning effect and so did not include it in its base case. Instead, it did a scenario analysis in which it assumed lenalidomide loses efficacy at 10 years, which it stated was a conservative assumption aligned with available evidence from the CALGB 100104 follow-up period. At the committee's second meeting, the clinical experts suggested that people can stay on lenalidomide for a long time so the lasting treatment effect in the trials may happen because people are still on treatment, rather than because of a lasting treatment effect after people stop taking lenalidomide. They further explained that if people stop treatment, they are unlikely to progress immediately, so there is likely to be some lasting effect that will eventually disappear. The committee considered that it is unclear when the treatment effect of lenalidomide maintenance may start to wane, but that it is likely to be between 10 to 25 years. It concluded that treatment effect waning should be included in the model, and that 10 years may be a conservative estimate of when the treatment effect starts to wane.
# Costs of subsequent treatments
## Costs of subsequent treatments in the model are hypothetical and highly uncertain
The company's model included the costs of second- and third-line treatments given after maintenance treatment. The committee was aware that the subsequent therapies used in Myeloma XI are no longer generalisable to NHS practice. The clinical experts explained that most people who have had a first autologous stem cell transplant will go on to have a treatment recommended in the Cancer Drugs Fund at a later line of therapy. However, the NICE Cancer Drugs Fund position statement specifies that companies should not include treatments recommended for use in the Cancer Drugs Fund as treatment-sequence products in their economic modelling. This is because they do not yet reflect routine NHS practice. The committee acknowledged that this made it difficult to develop assumptions about subsequent therapies in the model, and that any assumptions were hypothetical and highly uncertain. In its first meeting, the committee had therefore concluded that modelled subsequent treatments should reflect as closely as possible treatments that are currently given in NHS practice, and what would be given in the absence of Cancer Drugs Fund treatments. In response to consultation, the committee and the ERG had provided several exploratory scenarios, which the committee went on to discuss (see section 3.12 and section 3.13).
## Most people whose condition was monitored after their first transplant would have lenalidomide plus dexamethasone after relapse if treatments in the Cancer Drugs Fund are not available
At the committee's first meeting, the Cancer Drugs Fund clinical lead estimated that, if treatments recommended for use in the Cancer Drugs Fund were not available, about half of people whose condition was monitored after their first transplant would then have lenalidomide plus dexamethasone after their first relapse. The clinical experts agreed with this estimate. In its original base case, the company estimated this figure to be 15%. In response to consultation, the company revised its subsequent treatment assumptions, but did not substantially adjust the proportion of people in the observation arm having lenalidomide second line. The company explained that its revised scenarios were based on the subsequent therapies given in Myeloma XI and CALGB 100104 and were therefore aligned with the efficacy data used in the model. However, the committee thought that the numbers of people having lenalidomide plus dexamethasone after their first relapse remained too low in the company's revised assumptions. At the second meeting, the Cancer Drugs Fund clinical lead highlighted that even more people than usual are currently having lenalidomide plus dexamethasone after their first relapse. This is because the alternative treatment in the Cancer Drugs Fund (daratumumab with bortezomib and dexamethasone) is administered in hospital, and people have been reluctant to attend hospital during the ongoing coronavirus pandemic. The committee concluded that at least half of people whose condition was monitored after their first transplant would likely have lenalidomide plus dexamethasone after their first relapse if treatments in the Cancer Drugs Fund were not available, and that this should be reflected in the model.
## The number of people having a second autologous stem cell transplant is decreasing as alternative treatment options become available
The committee discussed whether a second autologous stem cell transplant may be an option for some people after a first relapse following their first transplant. The company explained that second transplants would be highly unlikely in clinical practice, while the ERG stated that they are a relevant option. The clinical experts estimated that about 5% to 10% of people get a second transplant, although 1 expert thought this number could be as high as 20%. The clinical and patient experts agreed that the availability of effective treatments in the Cancer Drugs Fund has led to decreasing rates of second transplants. They thought that these rates would decrease more if lenalidomide maintenance treatment was recommended. The committee concluded that about 5% to 10% of people currently get a second autologous stem cell transplant and that this should be reflected in the model, but these numbers are likely to fall in the future as alternative treatment options become available.
# Dose adjustments and drug wastage
## Both the company's and ERG's approaches to estimating relative dose intensity have limitations
Relative dose intensity is the percentage of the prescribed dose of lenalidomide that people take. Assumptions about the relative dose intensity could affect the cost-effectiveness estimate because it shows how much of the total cost of a prescribed drug is incurred (with a lower relative dose intensity meaning lower accrued drug costs). The company used individual patient data from Myeloma XI to estimate the relative dose intensity for lenalidomide maintenance treatment to be 86% to 87% depending on whether people were prescribed 5 mg or 10 mg in the trial. The ERG's opinion was that the company's relative dose-intensity estimate was too low, so the cost-effectiveness estimate was optimistic. It noted that the company's relative dose-intensity estimate from Myeloma XI was lower than in TOURMALINE‑MM1 (TMM1). This trial was identified by the ERG and was in people with relapsed or refractory multiple myeloma, so was not directly relevant to the appraisal. The ERG explained that TMM1 had used a higher lenalidomide dose of 25 mg daily on days 1 to 21 of each 28‑day cycle. It argued that the lower relative dose-intensity estimate from Myeloma XI compared with TMM1 was counterintuitive because people taking a higher dose would be expected to have more safety and tolerability issues, so would be less likely to maintain the target dose. The ERG used the relative dose intensity of 94.9% from TMM1 in its original base case. The ERG also considered that the company did not provide enough clear information to allow for its relative dose-intensity calculation to be validated. The committee was aware of the higher relative dose-intensity estimate from TMM1 compared with Myeloma XI. However, it decided that Myeloma XI was a better source of information because it was directly relevant to the decision problem and was based in the UK. Conversely, TMM1 included people with relapsed and refractory multiple myeloma and was international. The committee was satisfied with the company's decision to use Myeloma XI to estimate relative dose intensity, but considered that the company should have provided the full methods it used to determine this so that the ERG could validate it. In response to consultation, the company provided more detailed methods and explained that it based its calculations on prescribing data from Myeloma XI, accounting for reductions in dose and changes to the dosing frequency or treatment cycle length that were allowed in the trial. The ERG had outstanding concerns about the company's methods because it could still not interpret or recalculate the company's estimates. It considered the relative dose intensity value used in the company's model to be too low based on conversations with clinical experts. At consultation, the ERG provided an alternative estimate of 92% based on a simplified approach in which it calculated the average dose using the number of 5 mg and 10 mg treatment cycles in Myeloma XI. The ERG clarified that this method cannot account for changes to cycle length or other types of dose adjustment. The committee concluded that there were limitations associated with both the company's and ERG's approaches and the relative dose intensity remained uncertain. There was further uncertainty with this value because there may be patient-specific dose reductions in NHS practice, such as extending the length of the treatment cycle, which may be given to extend the maintenance phase (see section 3.2). However, in light of the uncertainty, it was reasonable to assume a value somewhere in between the company's and the ERG's estimates.
# Cost-effectiveness estimate
## Maintenance therapy with lenalidomide is likely to be a cost-effective use of NHS resources when given on days 1 to 21 of each 28-day cycle
The committee went on to discuss the company and ERG base cases, and agreed that the scenario that best reflected its preferences incorporated the following assumptions:
survival estimates in the economic model based on Myeloma XI data to 60 months, followed by propensity-score weighted CALGB 100104 data thereafter (see section 3.8)
log-logistic distribution to extrapolate overall survival (see section 3.9)
waning of the treatment effect of lenalidomide applied at between 10 and 25 years (see section 3.10)
% to 10% of people having a second autologous stem cell transplant (see section 3.13)
% of people in the observation arm having lenalidomide plus dexamethasone after first relapse (see section 3.12)
relative dose-intensity value falling between the company's and ERG's estimates (see section 3.14).The committee was presented with 2 different dosing schedules for these scenarios; the schedule of once daily lenalidomide on days 1 to 21 of repeated 28‑day cycles (which the committee had concluded best reflected the dose used in NHS practice) or once daily lenalidomide continuously on days 1 to 28 of repeated 28‑day cycles (which was the dose as recommended in the marketing authorisation, see section 2.2). The committee was aware that NICE's guide to the methods of technology appraisal states that the committee 'does not normally make recommendations regarding the use of a drug outside the terms of its marketing authorisation'. The committee first considered incremental cost-effectiveness ratios (ICERs) for lenalidomide as per the licensed schedule of 28 days of dosing per 28‑day cycle. However, the committee noted that the ICER for this scenario only adjusted the cost of treatment up from 21 to 28 days, while the effectiveness, time-on-treatment, relative dose intensity, medical resource use and adverse events were all the same as the scenario using 21 days of dosing. Furthermore, the committee considered that 28 days of dosing was highly unlikely to be used in NHS practice. The committee noted that NICE's guide to the methods of technology appraisal also states that evidence relating to using the technology under appraisal outside the terms of its marketing authorisation may inform deliberations. The committee therefore agreed that it was appropriate to consider the lower costs of lenalidomide administration that would arise when using 21 day rather than 28 day dosing in NHS practice. When taking this into account, the ICERs were within a range normally considered to be a cost-effective use of NHS resources (below £30,000 per quality-adjusted life year gained). Because of confidential discounts for treatments used in the model, ICERs are confidential so cannot be reported here.
## There is no evidence to suggest any additional benefits not adequately captured by the QALY and no equalities issues
The committee was aware that there is currently no active maintenance treatment for newly diagnosed multiple myeloma in adults who have had an autologous stem cell transplant in the UK, which represents a gap in NHS practice. However, it saw no evidence to suggest any additional benefits not adequately captured by the QALY. No equality or social value judgement issues were identified.
|
{'Recommendations': 'Lenalidomide is recommended as maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma in adults, only if:\n\nthe dosage schedule is 10\xa0mg per day on days 1\xa0to\xa021 of a 28‑day cycle and\n\nthe company provides lenalidomide according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with lenalidomide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere is currently no maintenance treatment for newly diagnosed multiple myeloma in people who have had an autologous stem cell transplant. The condition is usually monitored until it gets worse.\n\nClinical trial results show that, compared with monitoring alone, lenalidomide increases how long people live and extends the time before the condition gets worse.\n\nThe most likely cost-effectiveness estimates for lenalidomide compared with monitoring alone are within the range NICE normally considers an acceptable use of NHS resources. Therefore, lenalidomide is recommended.', 'Information about lenalidomide': "# Marketing authorisation indication\n\nLenalidomide (Revlimid, Celgene) is indicated for 'the maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics. This technology appraisal guidance makes recommendations outside of the marketing authorisation for lenalidomide. The dosage schedule recommended by NICE is 10\xa0mg per day on days 1\xa0to\xa021 of a 28‑day cycle.\n\n# Price\n\nThe list price for lenalidomide is £3,780 per pack of 21\xa0capsules, each containing 10\xa0mg of the active ingredient (excluding VAT; BNF online, November 2020). The company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Celgene, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Most people with newly diagnosed multiple myeloma would have lenalidomide maintenance treatment after an autologous stem cell transplant\n\nAfter a first autologous stem cell transplant, newly diagnosed multiple myeloma is usually monitored until the first relapse, and not actively treated. Lenalidomide is the only treatment option licensed as a maintenance therapy to replace monitoring for this indication. Lenalidomide would be used to try to lengthen the time until first relapse. The clinical experts advised that most people with newly diagnosed multiple myeloma who have had a first transplant would have lenalidomide maintenance treatment if it was recommended, and that only a small proportion would have no active treatment. The committee was aware that lenalidomide (plus dexamethasone) is currently available in the NHS for treating multiple myeloma later in the treatment pathway. The clinical experts explained that if people had lenalidomide maintenance treatment they would not then have lenalidomide again later in the treatment pathway. However, the clinical and patient experts emphasised that the benefits of lenalidomide maintenance treatment would likely outweigh the benefits of using it later in the pathway. This is because, with each line of new therapy, a substantial proportion of people stop having treatment because they become too ill or have complications. Therefore, the most effective treatments should be given as early in the treatment pathway as possible. Also, the first remission is often the 'best' remission because it is when people with the condition are at their fittest. Clinical experts also explained that it is also when people have the highest quality of life before the negative effects of the disease and its treatments have accumulated. Therefore, extending the first remission maximises the chances of people maintaining a higher quality of life for the longest possible period. The patient experts also explained that lenalidomide is a well-tolerated treatment and that, during the ongoing coronavirus pandemic, it is particularly convenient. This is because it is taken orally and does not need a hospital visit. The committee concluded that, if lenalidomide maintenance treatment was to be recommended, most people with newly diagnosed multiple myeloma who have had an autologous stem cell transplant would have it.\n\n# Licensed dose\n\n## The dosing schedule that would be used in clinical practice differs from the marketing authorisation\n\nThe lenalidomide marketing authorisation recommends a dosage of 10\xa0mg once daily on days\xa01\xa0to\xa028 of repeated 28‑day cycles. The committee was aware that recommendations are normally made within the marketing authorisation of the drug under appraisal (see section\xa03.15). However, the dosage in the company's submission is 10\xa0mg once daily on days\xa01\xa0to\xa021 of repeated 28‑day cycles. This reflects the dosing schedule used in the Myeloma\xa0XI randomised controlled trial, which was the main source of clinical evidence in the company's submission. The company stated its understanding that 21\xa0days of dosing followed by a 7‑day treatment-free period would be used in the NHS. This is because this is the schedule used in the Myeloma\xa0XI trial and for all other lenalidomide indications so is what healthcare professionals are familiar with. The company highlighted that there may be safety and tolerability benefits associated with having a treatment-free week incorporated into the 28‑day cycle. It explained that the risk of an unplanned and prolonged treatment break would be lower with the 21‑day schedule that incorporates a treatment-free week compared with the continuous 28‑day schedule and this might mean people would continue to have lenalidomide treatment for longer overall. It claimed that using a lenalidomide dosage that is tolerated for as long as possible would fit with the aim of maintenance treatment, which is to avoid relapse for as long as possible. The company clarified that the only reason the licence specifies a 28‑day dosing schedule is because the marketing authorisation was based on the CALGB\xa0100104 and IFM\xa02005‑02 trials, both of which used a 28‑day dosing schedule. The clinical experts explained that because of the known toxicity profile of lenalidomide, they would have major concerns about prescribing lenalidomide for 28\xa0days without a short treatment‑free period incorporated into the treatment cycle. They agreed with the company that 21\xa0days of treatment per 28‑day cycle would result in fewer and shorter unplanned treatment breaks, maximising the tolerability of lenalidomide, and making sure the treatment could be given for as long as possible. The clinical experts clarified that the 28‑day continuous schedule was likely to result in more dose reductions or increases to the cycle length (for example the same number of capsules but over at least 35\xa0days instead of 28\xa0days). The patient and clinical experts, the ERG, and other stakeholders all showed unanimous support for, and agreement with, all of the company's views on the dosing schedule, while the Cancer Drugs Fund clinical lead for NHS England confirmed that only the 21‑day dosing schedule would be commissioned in the NHS. The committee concluded that a 21‑day dosing schedule would likely be used in clinical practice, but it noted this dose is outside the terms of the marketing authorisation for lenalidomide.\n\n# Clinical evidence\n\n## Lenalidomide is an effective maintenance treatment for people who have had an autologous stem cell transplant\n\nThe main clinical evidence for lenalidomide maintenance treatment came from Myeloma\xa0XI, a phase\xa03 open-label randomised trial based in 110\xa0NHS centres in the UK. A total of 1,971\xa0people with newly diagnosed multiple myeloma were enrolled and stratified by their eligibility for an autologous stem cell transplant (only people eligible for a transplant are relevant for the population in this appraisal). The trial had an adaptive design in which ongoing trial results were used to inform changes in the protocol. Also, there were multiple levels of randomisation in the trial. The company's submission focused on a smaller cohort of 1,032\xa0people from Myeloma\xa0XI. These people had had a first transplant and been randomised to have maintenance with lenalidomide 10\xa0mg daily on days\xa01\xa0to\xa021 of each 28‑day cycle, or to have monitoring of their disease with no lenalidomide treatment. The company considered this cohort to be directly relevant to this appraisal (when Myeloma\xa0XI is mentioned from this point, it is referring to this cohort of interest unless otherwise specified). The primary outcomes were progression-free survival and overall survival, both of which were longer with lenalidomide maintenance treatment than with monitoring. The clinical experts advised that the trial was representative of NHS practice, and that the results were generalisable to the population in this appraisal. Based on the results from Myeloma\xa0XI, the committee concluded that lenalidomide is an effective maintenance treatment for newly diagnosed multiple myeloma in people who have had an autologous stem cell transplant.\n\n## The company presented evidence from all trials that met the inclusion criteria for its systematic literature review\n\nThe company originally identified 4\xa0trials of lenalidomide maintenance treatment in its systematic literature review: Myeloma\xa0XI, CALGB\xa0100104, GIMEMA and IFM\xa02005‑02. It then applied a subsequent set of criteria to exclude CALGB\xa0100104, GIMEMA, and IFM\xa02005‑02, leaving only Myeloma\xa0XI as a source of clinical-effectiveness evidence in its original submission. The company argued that Myeloma\xa0XI was the only trial that reflected the decision problem and UK clinical practice. However, it used both CALGB\xa0100104 and Myeloma\xa0XI data to estimate survival in its cost‑effectiveness model. The ERG was of the view that the company's approach was inconsistent. The ERG was also concerned that the subsequent set of criteria used to exclude trials was arbitrary and not prespecified. It considered that IFM\xa02005‑02 should have been excluded based on the company's original systematic literature review criteria, but that CALGB\xa0100104 and GIMEMA should have been included. The committee agreed that the company's approach was inconsistent and would have preferred the company to present all trials meeting the original systematic literature review criteria. The committee also acknowledged that the cohort of interest from Myeloma\xa0XI was likely to provide the most generalisable source of clinical-effectiveness evidence to NHS practice. However, because the marketing authorisation is based on trials with 28‑days of dosing, the committee stated that it needed to see evidence on the clinical effectiveness from CALGB\xa0100104 because it used this dosage. In response to consultation, the company presented detailed methods and results from CALGB\xa0100104 and GIMEMA. At its second meeting, the committee concluded it was satisfied that the company had presented all relevant evidence for lenalidomide maintenance treatment.\n\n## The safety profile of lenalidomide as a maintenance treatment compared with monitoring alone is likely to be acceptable\n\nThe company explained that there were no data on adverse events available from Myeloma\xa0XI for the monitoring arm of the cohort of interest. The ERG stated that this was an area of uncertainty because between-arm comparisons of adverse event rates were needed to understand the comparative safety profile of lenalidomide maintenance treatment. The company provided adverse-events data from both the lenalidomide and monitoring arms of CALGB\xa0100104. The ERG thought that it was useful as supplementary information but that it was not directly generalisable to the population in the NHS. The clinical experts considered that the rates of adverse events in the lenalidomide arm of Myeloma\xa0XI for the cohort of interest were similar to those seen in clinical practice for other indications. A patient expert explained that results from a survey done by Myeloma\xa0UK showed that most people having lenalidomide maintenance treatment found it easy to take and tolerated it well. The committee concluded that there was some uncertainty about the risk of adverse events, but the safety profile of lenalidomide as a maintenance treatment compared with monitoring alone is likely to be acceptable.\n\n# The company's economic model\n\n## The company's model structure does not allow assumptions about subsequent treatments to be explored\n\nThe company chose a partitioned survival model comprising 3\xa0health states (pre-progression, progressive disease and death). It explained that it had previously considered a more complex model structure such as a multistate model. However, there were not enough data to estimate transition probabilities for this approach, so it chose a partitioned survival model instead. The ERG stated that the simple structure of the company's model did not allow uncertainty in the model to be fully explored. It was particularly concerned about the effect of subsequent treatments. This was because survival in the company's model was based on Myeloma\xa0XI and CALGB\xa0100104, and the treatments given at second line and beyond in these trials are not generalisable to current NHS practice. The treatment of myeloma has changed since Myeloma\xa0XI was started, which means that, despite it being a UK trial, the treatments used do not reflect current NHS practice. Also, CALGB\xa0100104 has limited generalisability to the UK because it was based in the US. The ERG highlighted that the company's partitioned survival model structure did not allow alternative assumptions about subsequent treatments to be explored. This meant that the modelled survival may not have been representative of what would be seen in the NHS. The committee concluded that the company's model structure had limitations. It also concluded that there was likely to be uncertainty around the cost-effectiveness estimate because assumptions about the effects of subsequent therapies on survival could not be fully explored.\n\n## The rank-preserving structural-failure time method is appropriate to adjust for treatment switching in the CALGB\xa0100104 trial\n\nIn the CALGB\xa0100104 trial, people were offered the option to switch from placebo to lenalidomide if their disease had not yet progressed. In the committee's first meeting, the company explained that it used the rank-preserving structural-failure time method to adjust for treatment switching in CALGB\xa0100104 and that it did not explore any alternative approaches. The committee recognised that different treatment switching adjustment methods were available and was disappointed the company did not provide any justification for using its chosen method. In response to consultation, the company explored several alternative methods, including the inverse probability of censoring weights and 2‑stage methods. After assessing the key assumptions and limitations associated with each approach, the company concluded that the rank-preserving structural-failure time method remained the most appropriate. The ERG was generally satisfied with the company's rationale. The committee was concerned that some people in CALGB\xa0100104 could have multiple lines of lenalidomide, which is not an option in current NHS practice. The company clarified that it had not adjusted for this in its survival analysis. However, clinical experts explained that lenalidomide is not given more than once in the pathway. This is because it is now acknowledged that it is not likely to be effective if the disease has previously stopped responding to treatment. Therefore, even if it were given multiple times, this is unlikely to positively bias estimates of overall survival in the lenalidomide arm of the CALGB\xa0100104 trial. The committee concluded that the company's use of the rank-preserving structural-failure time method to adjust for treatment switching in the CALGB\xa0100104 trial had some limitations, but was appropriate.\n\n## Survival extrapolations should use Myeloma\xa0XI as the main evidence source but supplemented with CALGB\xa0100104 data adjusted to reflect Myeloma\xa0XI\n\nSurvival models were needed to predict survival beyond the end of the clinical trials for lenalidomide maintenance treatment. The company and ERG had different preferred approaches to using trial data to extrapolate survival:\n\nThe company preferred to use data from both Myeloma\xa0XI and CALGB\xa0100104 because CALGB\xa0100104 provided longer-term data. It also mentioned that, despite heterogeneity between the trials, the survival results were very similar.\n\nThe ERG preferred to use Myeloma\xa0XI data only, because of key differences between the 2\xa0trials, such as dosing, baseline characteristics and subsequent treatments.In its original base case, the company fitted survival curves to Myeloma\xa0XI data and used CALGB\xa0100104 data to help with curve selection. However, in response to technical engagement, it pooled data from Myeloma\xa0XI and CALGB\xa0100104, and fitted curves to the pooled data. It confirmed that it used a simple method for pooling the individual patient data from the trials. This did not involve adjusting CALGB\xa0100104 data to reflect Myeloma\xa0XI, for example by adjusting for differences in trial design or population. The ERG noted that it was unable to validate the company's methods for pooling data because not enough detail was provided. The committee was disappointed that the company's approach could not be scrutinised and validated based on the information provided and considered that the differences between the trials meant a simple pooling approach may have been inappropriate. In particular, the 28‑day dosing regimen in CALGB\xa0100104 meant survival in the model was based on a dosage that the company, ERG, and patient and clinical experts explained would not be given in NHS practice. The committee recognised that CALGB\xa0100104 had a longer median follow up (91\xa0months) than Myeloma\xa0XI (31\xa0months), so provided information about longer-term survival. At its first meeting, the committee concluded that it would prefer to see a survival analysis that used Myeloma\xa0XI as the main source of evidence. CALGB\xa0100104 could be used to help extrapolation, with data adjusted to reflect the Myeloma\xa0XI population as far as possible and based on the underlying survival of patients in Myeloma\xa0XI. In response to consultation, the company presented survival analyses based on Myeloma\xa0XI data up to 60\xa0months, followed by adjusted CALGB\xa0100104 data, using propensity score weighting to adjust CALGB\xa0100104 to better reflect Myeloma\xa0XI in its base case. The ERG was satisfied that propensity score weighting was an appropriate method and that the company's analysis was generally well conducted. However, it also highlighted that an important limitation of the propensity score weighting approach is that it cannot adjust for the difference in doses between the 2\xa0trials. The committee concluded that the company had appropriately used the committee's preferred approach to extrapolate survival in its updated analyses (that is, Myeloma\xa0XI used as the main source of evidence, with CALGB\xa0100104 used to inform longer-term extrapolation). It further concluded that, despite important limitations associated with the propensity score weighting approach, the company had appropriately adjusted CALGB\xa0100104 data to better reflect Myeloma\xa0XI.\n\n## The company's method for selecting overall-survival curves based on adjusted CALGB\xa0100104 data has limitations\n\nIn response to technical engagement, the company updated its base case to use a joint Weibull model to extrapolate survival based on pooled Myeloma\xa0XI and unadjusted CALGB\xa0100104 data. The ERG preferred to use a joint log-logistic model and to extrapolate Myeloma\xa0XI data only. In its first meeting, the committee concluded that survival extrapolations should use Myeloma\xa0XI as the main source of evidence but could be supplemented with adjusted CALGB\xa0100104 data for longer‑term survival (see section\xa03.8). Therefore, in response to consultation, the company revised its base case to use Myeloma\xa0XI data in the short term (up to 60\xa0months), followed by adjusted CALGB\xa0100104 data thereafter. However, the committee noted that when choosing the best fitting curve to extrapolate survival, the company had based its choice on adjusted CALGB\xa0100104 data only, rather than all of the data in the model (that is, Myeloma\xa0XI data to 60\xa0months followed by adjusted CALGB\xa0100104 data for the remainder of the model time horizon). The company also reported that it selected the joint gamma distribution because it was the best fit to the adjusted CALGB\xa0100104 data, yet it had used the joint generalised gamma in its model. The ERG highlighted several limitations with the company's approach. It would have preferred the company to have used the combined Myeloma\xa0XI and adjusted CALGB\xa0100104 data as a basis for curve selection, rather than adjusted CALGB\xa0100104 data alone. It also suggested that the company could have explored a piecewise approach with 2\xa0different distributions for the initial Myeloma\xa0XI period (to 60\xa0months) and adjusted CALGB period (after 60\xa0months). Furthermore, the ERG questioned why the company had used the generalised gamma distribution instead of the gamma in its base case, as the company had not provided any supporting information or rationale for its selection. In its own analysis, the ERG chose the joint log‑logistic model for overall survival. After examining the company's and ERG's overall-survival curves, the clinical experts explained that the joint log‑logistic was likely the best representation of long-term survival in clinical practice. The committee concluded that the company's method for selecting overall‑survival curves based on CALGB\xa0100104 data (adjusted to reflect Myeloma\xa0XI) has limitations and that it would have preferred the company to have explored a piecewise approach. It also concluded that the log‑logistic curve is the most appropriate choice for extrapolating overall survival.\n\n# Waning of treatment effect\n\n## Treatment waning should be included in the model, and 10\xa0years may be a conservative estimate of when the treatment effect starts to wane\n\nTreatment waning refers to whether or not the relative treatment effect between lenalidomide and monitoring of the condition is likely to reduce over time after people stop taking lenalidomide. Not including treatment waning in the model implies that the relative treatment effect stays the same and lenalidomide remains more effective than monitoring for the entire modelled time horizon, even if people are no longer on treatment. Based on its survival curves, the company took the view that there was no evidence of a treatment-waning effect with lenalidomide and did not include waning in its original base case. The ERG did not include a treatment-waning effect in its base case but explained that there were no long-term data to rule out the possibility that the relative treatment effect decreases over time. The ERG therefore did a scenario analysis that looked at different treatment-waning scenarios. It found the cost‑effectiveness estimate to be sensitive to assumptions about how long the treatment effect lasts for. At the committee's first meeting, the clinical experts advised that they would not expect lenalidomide to have a continued effect after people had stopped taking it. Based on this, the committee had agreed that the treatment effect of lenalidomide therapy may wane over time and that this should have been included in the company's model. In response to consultation, the company reiterated that there was no evidence of a treatment-waning effect and so did not include it in its base case. Instead, it did a scenario analysis in which it assumed lenalidomide loses efficacy at 10\xa0years, which it stated was a conservative assumption aligned with available evidence from the CALGB\xa0100104 follow-up period. At the committee's second meeting, the clinical experts suggested that people can stay on lenalidomide for a long time so the lasting treatment effect in the trials may happen because people are still on treatment, rather than because of a lasting treatment effect after people stop taking lenalidomide. They further explained that if people stop treatment, they are unlikely to progress immediately, so there is likely to be some lasting effect that will eventually disappear. The committee considered that it is unclear when the treatment effect of lenalidomide maintenance may start to wane, but that it is likely to be between 10\xa0to 25\xa0years. It concluded that treatment effect waning should be included in the model, and that 10\xa0years may be a conservative estimate of when the treatment effect starts to wane.\n\n# Costs of subsequent treatments\n\n## Costs of subsequent treatments in the model are hypothetical and highly uncertain\n\nThe company's model included the costs of second- and third-line treatments given after maintenance treatment. The committee was aware that the subsequent therapies used in Myeloma\xa0XI are no longer generalisable to NHS practice. The clinical experts explained that most people who have had a first autologous stem cell transplant will go on to have a treatment recommended in the Cancer Drugs Fund at a later line of therapy. However, the NICE Cancer Drugs Fund position statement specifies that companies should not include treatments recommended for use in the Cancer Drugs Fund as treatment-sequence products in their economic modelling. This is because they do not yet reflect routine NHS practice. The committee acknowledged that this made it difficult to develop assumptions about subsequent therapies in the model, and that any assumptions were hypothetical and highly uncertain. In its first meeting, the committee had therefore concluded that modelled subsequent treatments should reflect as closely as possible treatments that are currently given in NHS practice, and what would be given in the absence of Cancer Drugs Fund treatments. In response to consultation, the committee and the ERG had provided several exploratory scenarios, which the committee went on to discuss (see section\xa03.12 and\xa0section 3.13).\n\n## Most people whose condition was monitored after their first transplant would have lenalidomide plus dexamethasone after relapse if treatments in the Cancer Drugs Fund are not available\n\nAt the committee's first meeting, the Cancer Drugs Fund clinical lead estimated that, if treatments recommended for use in the Cancer Drugs Fund were not available, about half of people whose condition was monitored after their first transplant would then have lenalidomide plus dexamethasone after their first relapse. The clinical experts agreed with this estimate. In its original base case, the company estimated this figure to be 15%. In response to consultation, the company revised its subsequent treatment assumptions, but did not substantially adjust the proportion of people in the observation arm having lenalidomide second line. The company explained that its revised scenarios were based on the subsequent therapies given in Myeloma\xa0XI and CALGB\xa0100104 and were therefore aligned with the efficacy data used in the model. However, the committee thought that the numbers of people having lenalidomide plus dexamethasone after their first relapse remained too low in the company's revised assumptions. At the second meeting, the Cancer Drugs Fund clinical lead highlighted that even more people than usual are currently having lenalidomide plus dexamethasone after their first relapse. This is because the alternative treatment in the Cancer Drugs Fund (daratumumab with bortezomib and dexamethasone) is administered in hospital, and people have been reluctant to attend hospital during the ongoing coronavirus pandemic. The committee concluded that at least half of people whose condition was monitored after their first transplant would likely have lenalidomide plus dexamethasone after their first relapse if treatments in the Cancer Drugs Fund were not available, and that this should be reflected in the model.\n\n## The number of people having a second autologous stem cell transplant is decreasing as alternative treatment options become available\n\nThe committee discussed whether a second autologous stem cell transplant may be an option for some people after a first relapse following their first transplant. The company explained that second transplants would be highly unlikely in clinical practice, while the ERG stated that they are a relevant option. The clinical experts estimated that about 5% to 10% of people get a second transplant, although 1\xa0expert thought this number could be as high as 20%. The clinical and patient experts agreed that the availability of effective treatments in the Cancer Drugs Fund has led to decreasing rates of second transplants. They thought that these rates would decrease more if lenalidomide maintenance treatment was recommended. The committee concluded that about 5% to 10% of people currently get a second autologous stem cell transplant and that this should be reflected in the model, but these numbers are likely to fall in the future as alternative treatment options become available.\n\n# Dose adjustments and drug wastage\n\n## Both the company's and ERG's approaches to estimating relative dose intensity have limitations\n\nRelative dose intensity is the percentage of the prescribed dose of lenalidomide that people take. Assumptions about the relative dose intensity could affect the cost-effectiveness estimate because it shows how much of the total cost of a prescribed drug is incurred (with a lower relative dose intensity meaning lower accrued drug costs). The company used individual patient data from Myeloma\xa0XI to estimate the relative dose intensity for lenalidomide maintenance treatment to be 86% to 87% depending on whether people were prescribed 5\xa0mg or 10\xa0mg in the trial. The ERG's opinion was that the company's relative dose-intensity estimate was too low, so the cost-effectiveness estimate was optimistic. It noted that the company's relative dose-intensity estimate from Myeloma\xa0XI was lower than in TOURMALINE‑MM1 (TMM1). This trial was identified by the ERG and was in people with relapsed or refractory multiple myeloma, so was not directly relevant to the appraisal. The ERG explained that TMM1 had used a higher lenalidomide dose of 25\xa0mg daily on days\xa01\xa0to\xa021 of each 28‑day cycle. It argued that the lower relative dose-intensity estimate from Myeloma\xa0XI compared with TMM1 was counterintuitive because people taking a higher dose would be expected to have more safety and tolerability issues, so would be less likely to maintain the target dose. The ERG used the relative dose intensity of 94.9% from TMM1 in its original base case. The ERG also considered that the company did not provide enough clear information to allow for its relative dose-intensity calculation to be validated. The committee was aware of the higher relative dose-intensity estimate from TMM1 compared with Myeloma\xa0XI. However, it decided that Myeloma\xa0XI was a better source of information because it was directly relevant to the decision problem and was based in the UK. Conversely, TMM1 included people with relapsed and refractory multiple myeloma and was international. The committee was satisfied with the company's decision to use Myeloma\xa0XI to estimate relative dose intensity, but considered that the company should have provided the full methods it used to determine this so that the ERG could validate it. In response to consultation, the company provided more detailed methods and explained that it based its calculations on prescribing data from Myeloma\xa0XI, accounting for reductions in dose and changes to the dosing frequency or treatment cycle length that were allowed in the trial. The ERG had outstanding concerns about the company's methods because it could still not interpret or recalculate the company's estimates. It considered the relative dose intensity value used in the company's model to be too low based on conversations with clinical experts. At consultation, the ERG provided an alternative estimate of 92% based on a simplified approach in which it calculated the average dose using the number of 5\xa0mg and 10\xa0mg treatment cycles in Myeloma\xa0XI. The ERG clarified that this method cannot account for changes to cycle length or other types of dose adjustment. The committee concluded that there were limitations associated with both the company's and ERG's approaches and the relative dose intensity remained uncertain. There was further uncertainty with this value because there may be patient-specific dose reductions in NHS practice, such as extending the length of the treatment cycle, which may be given to extend the maintenance phase (see section\xa03.2). However, in light of the uncertainty, it was reasonable to assume a value somewhere in between the company's and the ERG's estimates.\n\n# Cost-effectiveness estimate\n\n## Maintenance therapy with lenalidomide is likely to be a cost-effective use of NHS resources when given on days\xa01\xa0to\xa021 of each 28-day cycle\n\nThe committee went on to discuss the company and ERG base cases, and agreed that the scenario that best reflected its preferences incorporated the following assumptions:\n\nsurvival estimates in the economic model based on Myeloma\xa0XI data to 60\xa0months, followed by propensity-score weighted CALGB\xa0100104 data thereafter (see section\xa03.8)\n\nlog-logistic distribution to extrapolate overall survival (see section\xa03.9)\n\nwaning of the treatment effect of lenalidomide applied at between 10\xa0and 25\xa0years (see section\xa03.10)\n\n%\xa0to 10%\xa0of people having a second autologous stem cell transplant (see section\xa03.13)\n\n% of people in the observation arm having lenalidomide plus dexamethasone after first relapse (see section\xa03.12)\n\nrelative dose-intensity value falling between the company's and ERG's estimates (see section\xa03.14).The committee was presented with 2 different dosing schedules for these scenarios; the schedule of once daily lenalidomide on days\xa01\xa0to\xa021 of repeated 28‑day cycles (which the committee had concluded best reflected the dose used in NHS practice) or once daily lenalidomide continuously on days\xa01\xa0to\xa028 of repeated 28‑day cycles (which was the dose as recommended in the marketing authorisation, see section 2.2). The committee was aware that NICE's guide to the methods of technology appraisal states that the committee 'does not normally make recommendations regarding the use of a drug outside the terms of its marketing authorisation'. The committee first considered incremental cost-effectiveness ratios (ICERs) for lenalidomide as per the licensed schedule of 28\xa0days of dosing per 28‑day cycle. However, the committee noted that the ICER for this scenario only adjusted the cost of treatment up from 21\xa0to\xa028\xa0days, while the effectiveness, time-on-treatment, relative dose intensity, medical resource use and adverse events were all the same as the scenario using 21\xa0days of dosing. Furthermore, the committee considered that 28\xa0days of dosing was highly unlikely to be used in NHS practice. The committee noted that NICE's guide to the methods of technology appraisal also states that evidence relating to using the technology under appraisal outside the terms of its marketing authorisation may inform deliberations. The committee therefore agreed that it was appropriate to consider the lower costs of lenalidomide administration that would arise when using 21\xa0day rather than 28\xa0day dosing in NHS practice. When taking this into account, the ICERs were within a range normally considered to be a cost-effective use of NHS resources (below £30,000 per quality-adjusted life year [QALY] gained). Because of confidential discounts for treatments used in the model, ICERs are confidential so cannot be reported here.\n\n## There is no evidence to suggest any additional benefits not adequately captured by the QALY and no equalities issues\n\nThe committee was aware that there is currently no active maintenance treatment for newly diagnosed multiple myeloma in adults who have had an autologous stem cell transplant in the UK, which represents a gap in NHS practice. However, it saw no evidence to suggest any additional benefits not adequately captured by the QALY. No equality or social value judgement issues were identified."}
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https://www.nice.org.uk/guidance/ta680
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Evidence-based recommendations on lenalidomide (Revlimid) for maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma in adults.
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ae522afbb9601e666983afaa7893dc0b9b4f872a
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nice
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Baricitinib for treating moderate to severe atopic dermatitis
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Baricitinib for treating moderate to severe atopic dermatitis
Evidence-based recommendations on baricitinib for treating moderate to severe atopic dermatitis in adults.
# Recommendations
Baricitinib is recommended as an option for treating moderate to severe atopic dermatitis in adults, only if:
the disease has not responded to at least 1 systemic immunosuppressant, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or these are not suitable, and
the company provides it according to the commercial arrangement.
Assess response from 8 weeks and stop baricitinib if there has not been an adequate response at 16 weeks, defined as a reduction of at least:
% in the Eczema Area and Severity Index score (EASI 50) from when treatment started and
points in the Dermatology Life Quality Index (DLQI) from when treatment started.
When using the EASI, take into account skin colour and how this could affect the EASI score, and make appropriate clinical adjustments.
When using the DLQI, take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI, and make any appropriate adjustments.
These recommendations are not intended to affect treatment with baricitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with moderate to severe atopic dermatitis that has not responded to at least 1 systemic immunosuppressant are usually offered either dupilumab or best supportive care. Dupilumab does not always work, and some people stop taking it because of side effects. Baricitinib is an alternative to dupilumab and best supportive care. It is likely to be offered alongside topical corticosteroids.
Clinical trial results show that baricitinib reduces the severity and symptoms of atopic dermatitis compared with placebo. Baricitinib has not been directly compared with dupilumab. The results of an indirect comparison suggest that baricitinib is less effective than dupilumab.
The most likely cost-effectiveness estimates for baricitinib are within what NICE considers an acceptable use of NHS resources. Therefore, baricitinib is recommended as an option for moderate to severe atopic dermatitis when at least 1 systemic immunosuppressant has not worked or is not suitable.# Information about baricitinib
# Marketing authorisation indication
Baricitinib (Olumiant, Eli Lilly) is 'indicated for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
A 28‑pack of 4‑mg tablets costs £805.56 (excluding VAT, BNF online, accessed December 2020). The company has a commercial arrangement. This makes baricitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The drug acquisition cost for best supportive care should be removed from the model, to avoid duplication with the costs for concomitant medications.
Baricitinib should be assumed to have no benefit over best supportive care in reducing flare frequency in the model.
The costs of bathing products should be removed from the model.
There would be 9 doses of dupilumab given during induction.
There should be 4 annual full blood tests assumed for baricitinib in the model.
The company's 'secondary' censoring rule better reflected clinical practice. Under secondary censoring, the disease was considered to have not responded after people stopped treatment or started systemic rescue therapies.
The appraisal committee recognised that there were remaining areas of uncertainty (see technical report pages 2 to 17), and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:
the positioning of baricitinib in the treatment pathway (issue 1, see technical report, page 2)
whether systemic immunosuppressant therapy is a relevant comparator for baricitinib (issue 2, see technical report, page 2)
whether a 50% reduction in Eczema Area and Severity Index score (EASI 50) plus an improvement in the Dermatology Life Quality Index (DLQI) of at least 4, or a 75% reduction in EASI score (EASI 75), is more appropriate to define an adequate response to baricitinib (issue 4, see technical report, page 5)
when response to baricitinib would be assessed in clinical practice (issue 5, see technical report, page 5)
whether baricitinib and dupilumab are likely to be used in a sequence, and how cost-effectiveness analyses for treatment sequences should be considered in decision making (issue 6, see technical report, page 6)
what proportion of patients having best supportive care would lose the quality‑of‑life benefit over time in clinical practice (issue 7, see technical report, page 7)
whether the stopping rate between week 16 and week 52 in the model should be based on loss of response, or stopping treatment for any reason (issue 8, see technical report, page 9)
whether it was appropriate to assume that a proportion of patients having baricitinib or dupilumab lose the quality-of-life benefit from treatment over time (issue 9, see technical report, page 12)
which utility values were most appropriate for decision making (issue 10, see technical report, page 2)
whether it was appropriate to include the data from people of Japanese family origin in the baricitinib clinical trials, given that this may not be generalisable to the UK population (issue 11, see technical report, page 14)
whether the results of the indirect treatment comparison were suitable for decision making (issue 12, see technical report, page 16).
# Experience of people with atopic dermatitis
## Atopic dermatitis affects all aspects of a person's life
The clinical experts explained that atopic dermatitis is a chronic, recurrently flaring, generalised skin condition starting in childhood and continuing into adulthood for most people. People with severe atopic dermatitis may need hospitalisation for treatment. Feedback from patient and professional organisations highlighted that the condition is debilitating and isolating, affecting all aspects of life (physical, psychological, social and financial). They emphasised that, if the condition is severe, it is associated with intolerable itch that disrupts sleep, and there is a higher risk of depression and suicide. The committee noted that having treatments that improve the condition and are associated with few or manageable adverse effects is important to people with atopic dermatitis.
# Clinical management
## People with moderate to severe atopic dermatitis would welcome a new oral treatment option with a different mechanism of action
Although clinicians individualise therapy for patients, a typical treatment pathway involves emollients and topical corticosteroids (first‑line), topical calcineurin inhibitors (second‑line), phototherapy (third‑line) and systemic immunosuppressant therapies (fourth‑line). Fourth-line treatments include ciclosporin (the only systemic immunosuppressant with a marketing authorisation for atopic dermatitis), methotrexate, azathioprine and mycophenolate mofetil. The committee heard that patients often have difficulty adhering to topical corticosteroids, and would welcome a new treatment option that reduces topical corticosteroid use. Clinical experts also explained that systemic immunosuppressants need frequent blood monitoring tests and may have serious adverse effects. Also, ciclosporin is only used for short periods because of toxicity concerns. If a systemic immunosuppressant is no longer effective, it will be stopped and another immunosuppressant may be offered. Dupilumab is recommended as an option if the atopic dermatitis has not responded to at least 1 other systemic therapy (fifth‑line). However, atopic dermatitis does not always respond to dupilumab, and some people must stop treatment because of adverse effects. For people whose disease has not responded to all available systemic therapies, the only remaining treatment option is best supportive care. This may include education, psychological support, emollients, topical corticosteroids, bandages and hospitalisation. Exacerbations (flares) in atopic dermatitis are managed using short‑term high‑potency topical corticosteroids, oral corticosteroids and systemic therapy. The committee concluded that patients and clinicians would welcome a well‑tolerated oral treatment with a different mechanism of action, that could potentially reduce topical corticosteroid use.
# Positioning in the treatment pathway, comparators and sequencing
## Baricitinib would be used after at least 1 systemic immunosuppressant
The marketing authorisation for baricitinib is 'for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy'. The company positioned baricitinib as a fifth‑line treatment, after at least 1 systemic immunosuppressant, as an alternative to dupilumab and best supportive care. Clinical experts agreed that they would prefer to offer baricitinib as an alternative to systemic immunosuppressants, because it needs less monitoring. However, they acknowledged that in clinical practice people are likely to have had at least 1 systemic immunosuppressant before having baricitinib. The committee concluded that it would appraise baricitinib for moderate to severe atopic dermatitis after at least 1 systemic immunosuppressant, in the same position as dupilumab.
## Dupilumab and best supportive care are the most appropriate comparators for baricitinib
The company suggested that systemic immunosuppressants are not a relevant comparator in people who have had at least 1 systemic immunosuppressant. For these people, the only remaining treatment options are dupilumab or best supportive care. The clinical experts agreed that in clinical practice some patients have a second systemic immunosuppressant before dupilumab, but most patients have dupilumab after only 1 systemic immunosuppressant. At technical engagement, the company attempted an indirect treatment comparison of baricitinib with ciclosporin, in the absence of direct evidence. However, the ERG and company agreed that the results of the indirect comparison were not reliable because of difficulties in matching the patient populations and outcomes between trials. The committee concluded that systemic immunosuppressants were a relevant comparator for baricitinib in some people, but that dupilumab and best supportive care were the most appropriate comparators. This was because most patients have dupilumab at the point in the treatment pathway where the company had positioned baricitinib, and there was a lack of data to compare baricitinib with systemic immunosuppressants.
## Baricitinib and dupilumab are likely to be used in a sequence, but the reliability of sequencing analyses is uncertain
The company did not consider the sequence of baricitinib followed by dupilumab, or dupilumab followed by baricitinib. This was because the company positioned baricitinib as an alternative to dupilumab (see section 3.3), and there was a lack of data on the effectiveness of baricitinib in a sequence with dupilumab. The ERG considered it likely that in clinical practice baricitinib and dupilumab will be used in a sequence. The clinical experts explained that because dupilumab is likely to be more effective than baricitinib (see section 3.11), it would usually be used first in a sequence. However, treatment decisions are individualised, and there would likely be no 'standard' sequence of dupilumab and baricitinib. The committee understood that atopic dermatitis is a lifelong disease, and that most patients would need to stop treatment with dupilumab eventually. The committee considered that cost-effectiveness analyses for sequences of baricitinib and dupilumab should be taken into account in decision making. But, it acknowledged the uncertainty because of the lack of clinical data on sequential effectiveness.
# Clinical evidence
## The JAIN (BREEZE-AD4) and JAIY (BREEZE-AD7) trials provide the key clinical evidence for baricitinib
The evidence for baricitinib came from 5 trials: 2 on baricitinib monotherapy (JAHL and JAHM ), 2 on baricitinib plus background topical corticosteroids (JAIN and JAIY ), and a long-term extension study (JAHN ) for patients completing JAHL, JAHM or JAIY. The clinical experts explained that baricitinib is likely to be offered alongside topical corticosteroids. The committee therefore agreed to focus on the evidence of baricitinib 'combination therapy' with topical corticosteroids from JAIN and JAIY. Both were randomised double‑blind trials including patients who had moderate to severe atopic dermatitis for at least 12 months. Moderate to severe atopic dermatitis was defined as an EASI score of 16 or more, an Investigator's Global Assessment (IGA) score of 3 or more, and body surface area involvement of 10% or more. The disease must have responded inadequately to topical corticosteroids. In JAIN, ciclosporin had to be contraindicated or not tolerated, or the disease uncontrolled on ciclosporin. The trials compared 3 doses of baricitinib (1 mg, 2 mg, or 4 mg once daily) with placebo. However, the committee agreed that it would focus only on the 4 mg dose because it was the licensed dose relevant for most patients. The primary end points were assessed at 16 weeks after the 'induction' period:
JAIN: at least a 75% reduction in the EASI score from when treatment started (EASI 75)
JAIY: a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the IGA, and at least a 2‑point improvement from baseline.Patients in JAIN had an additional 36 weeks of treatment, followed by a long-term extension study. The committee understood that data from the JAIN extension study were not available at the time of the submission. The committee concluded that the JAIN and JAIY trials provided the key clinical evidence for baricitinib.
## Baricitinib with topical corticosteroids is more clinically effective than placebo
In the analysis of the trial data using secondary censoring, patients having baricitinib plus topical corticosteroids in JAIN and JAIY were statistically significantly more likely to achieve EASI 50, EASI 75, and have an IGA score of 0 or 1 at week 16 than patients having placebo. Baricitinib also produced statistically significant reductions in itch and skin pain at week 16, as well as quality-of-life improvements based on the DLQI and EQ-5D. The committee noted that the data showed a peak response to baricitinib at, or before, week 12 for many outcomes. However, by week 24 in JAIN baricitinib was no longer statistically significantly more effective than placebo for EASI 75 or an IGA score of 0 or 1. The committee concluded that baricitinib was more clinically effective than placebo at week 16, but that this appeared to wane over time.
## The data from JAIN and the JAIN-like subgroup of patients from JAIY represents who would have baricitinib in the NHS
The company's base case was based on a pooled population of patients from JAIN and a subgroup of patients from JAIY for whom ciclosporin was contraindicated or not tolerated, or whose disease was uncontrolled on ciclosporin (the 'JAIN‑like' subgroup). The ERG noted that the mean EASI score for these patients was within the published definition of severe atopic dermatitis (21.1 to 50), and that they therefore represented more severe disease. The clinical experts agreed that the patients in JAIN and JAIY had severe disease, but considered that they were representative of patients who would likely have baricitinib in the NHS. The committee concluded that the pooled JAIN plus JAIN‑like subgroup from JAIY generally reflected people who would have baricitinib in NHS clinical practice.
## A composite end point of EASI 50 plus an improvement in the DLQI of at least 4 is most relevant for decision making
In its original model, the company defined a clinical benefit using the composite end point of EASI 50 plus an improvement in the DLQI of at least 4. This was for consistency with NICE's technology appraisal guidance on dupilumab for treating moderate to severe atopic dermatitis (from now, TA534). At technical engagement, the company updated its model to define a clinical benefit using EASI 75. This was because the composite end point was not associated with a quality-of-life improvement in the baricitinib clinical trials. The company noted a move towards using EASI 75 in clinical practice, and that an EASI 75 response correlated better with a quality-of-life improvement in the baricitinib clinical trials. In addition, EASI 75 at week 16 was the primary end point in JAIN, and a key secondary end point in JAIY. The committee heard from clinical experts that the composite end point was widely used in clinical practice. Also, the EASI without the DLQI would fail to capture important patient‑reported quality‑of‑life improvements, such as reduced itching. The committee recognised that the composite end point of EASI 50 plus an improvement in the DLQI of at least 4 was widely used in clinical practice, included patient-reported quality of life, and was consistent for comparing baricitinib with dupilumab. Therefore, it concluded that this is the most relevant end point for decision making and should be used to define response.
# Indirect treatment comparison
## The company's indirect treatment comparison with dupilumab is acceptable for decision making
There was no direct evidence comparing baricitinib with dupilumab for atopic dermatitis, so the company did an indirect treatment comparison. For baricitinib, the company pooled the data from JAIN plus the JAIN‑like subgroup from JAIY. For dupilumab, the company pooled the data from the CAFÉ trial and a subgroup of patients from the CHRONOS trial for whom ciclosporin was contraindicated or not tolerated, or whose disease was uncontrolled on ciclosporin (the 'CAFÉ‑like' subgroup). The ERG noted several differences between the baricitinib and dupilumab trials included in the indirect comparison, which may reduce the reliability of the results:
There was a higher proportion of people of Asian family origin in JAIN and JAIY compared with CAFÉ and CHRONOS.
Baseline EASI scores were higher in CAFÉ and CHRONOS, indicating patients had more severe atopic dermatitis.
Unlike CAFÉ and CHRONOS, patients in JAIN and JAIY had a 2‑week washout period when they could not use topical treatments for their atopic dermatitis. Patients in CAFÉ and CHRONOS may therefore have experienced fewer flares immediately after entering the trial than those in JAIN or JAIY.
Data from patients who had rescue therapy or stopped study treatment in CAFÉ and CHRONOS were used, whereas data from JAIN and JAIY were subject to secondary censoring. This potentially favours dupilumab, because patients having systemic rescue treatment would not have been censored as having atopic dermatitis that did not respond to treatment.The clinical experts agreed that the differences in the washout period and censoring rules between the trials likely favoured dupilumab. The committee concluded that, despite its limitations, the company's indirect treatment comparison with dupilumab was acceptable for decision making.
## The results of the indirect treatment comparison suggest that baricitinib is less effective than dupilumab
The proportion of patients achieving EASI 50 plus an improvement in the DLQI of at least 4 compared with placebo was statistically significantly greater for patients having dupilumab compared with patients having baricitinib. At technical engagement the company updated the indirect comparison using EASI 75, to reflect that they had changed the definition of response in the model (see section 3.9). The direction of the results was similar to the indirect comparison using the composite end point. The committee recalled its earlier conclusion that baricitinib was more clinically effective than placebo, but concluded that baricitinib is likely to be less effective than dupilumab.
# Adverse events
## Patients on baricitinib generally experience few serious adverse events
The committee noted that the rates of serious adverse events were generally low in the baricitinib and placebo groups of the trial populations across all studies. Although the proportion of baricitinib patients in JAIN who experienced 1 or more treatment-emergent adverse event was higher than placebo, the committee concluded that patients were likely to tolerate baricitinib.
# Company's economic model
## The structure of the company's model is similar to that in TA534, and appropriate for decision making
The company originally submitted a Markov model with 4 health states: induction, maintenance, non-response, and death. Patients entered the model in the 'induction' state, during which they could not stop treatment. At week 16, people in the baricitinib or dupilumab arms whose disease had not responded to treatment switched to best supportive care. People whose disease had responded to treatment moved into the 'maintenance' state, where they continued to have baricitinib or dupilumab until their disease stopped responding (up to week 52) or they stopped treatment for any reason (from year 2 onwards). At this point patients switched to best supportive care. People having best supportive care entered the 'non-response' state if their disease had either not responded at week 16 or stopped responding by week 52, or they stopped treatment for any reason from year 2 onwards. Patients in the 'non-response' state could not transition back into previous states. Patients could move into the 'death' state at any time. The committee noted that the company's model was generally similar to that of TA534. It concluded that, despite some uncertainties around how the loss of quality-of-life benefit of treatment over time was modelled (see section 3.17 and section 3.18), the structure of the company's model was appropriate for decision making.
# Assumptions in the economic model
## The stopping rate from week 16 to week 52 should be based on stopping treatment for any reason
The company assumed that 6.1% of people having dupilumab plus topical corticosteroids as maintenance therapy stop treatment in the first year and then have best supportive care. This reflected the proportion of people in CHRONOS whose condition responded to treatment at 16 weeks (EASI 50 plus an improvement in the DLQI of at least 4), but was no longer responding to treatment at 52 weeks. For people having baricitinib plus topical corticosteroids, the company based the stopping rate in the first year on the 52‑week data from JAIN. The company's assumption reflected the proportion of people in JAIN whose condition responded to treatment at 16 weeks, but was no longer responding to treatment at 52 weeks. The ERG disagreed with deriving stopping rates in the first year from loss of response at 52 weeks, conditional on response at 16 weeks. This was because stopping treatment depends not only on loss of efficacy but also other factors such as adverse events. The ERG preferred to base the stopping rates on the all-cause stopping rate in JAIN (and CHRONOS, for dupilumab) for people whose condition responded to treatment at 16 weeks, but who withdrew from the trial by 52 weeks. The committee concluded that, on balance, the ERG's approach was more appropriate.
## Treatment response to baricitinib should be assessed by 16 weeks, with an earlier assessment likely to improve baricitinib's cost effectiveness
The committee understood from the summary of product characteristics for baricitinib that 'consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit after 8 weeks of treatment'. The committee was aware that a 16‑week 'induction' phase was implemented in the clinical trials (see section 3.6) and in the company's economic model, which was consistent with TA534. However, the results from JAIN showed a peak response at 12 weeks or earlier across many outcomes. In clinical practice, response to baricitinib may be assessed earlier than 16 weeks (although this scenario was not modelled by the company or the ERG), which would likely improve the cost effectiveness of baricitinib. This was because response rates would be similar, but patients whose disease did not respond would accrue fewer treatment costs. The committee concluded that response to baricitinib should be assessed from 8 weeks, and baricitinib stopped if the atopic dermatitis does not respond adequately by 16 weeks.
# Utility values in the economic model
## The utility values from TA534 are preferable when response is defined as EASI 50 plus an improvement in the DLQI of at least 4
The company's original model, when response was defined using EASI 50 plus an improvement in the DLQI of at least 4, used 2 utility values. A utility value of 0.78 was assigned to people in the 'maintenance' state, and a utility value of 0.5979 was assigned to people in the 'induction' and 'non-response' states. These were derived from the pooled data from JAIN plus the JAIN‑like subgroup from JAIY, and were the same regardless of treatment arm in the model (baricitinib, dupilumab or best supportive care). The ERG had several concerns with the company's utilities. The pooled data from JAIN plus the JAIN‑like subgroup from JAIY showed that patients whose disease responded to treatment based on the composite end point had a lower utility gain from baseline (0.1821) than those whose disease had not responded to treatment (0.2042). However, the company only applied the utility increase for people whose disease responded to treatment in the model, and assigned the baseline utility to those whose disease did not respond. The ERG found this approach to be flawed, and likely confounded by regression to the mean effects. It also questioned why the company had also not included the data from the 'JAIN‑like' subgroups from JAHL and JAHM when deriving the utilities. In addition, the ERG considered that using only 2 utility values was overly simplistic and failed to capture magnitude of response. It preferred to use the utility values from TA534, which were treatment-specific and had previously been accepted by the committee. The committee considered which utility values were more appropriate for the composite end point. It noted the flaws in the company's original approach, and acknowledged the ERG's concern that the 'maintenance' health state was not associated with a utility gain. However, it heard from clinical experts that patients achieving EASI 50 plus an improvement in the DLQI of at least 4 were likely to have an improvement in quality of life, even if this had not been shown in the pivotal trials. The committee also understood that the EQ‑5D often fails to capture quality-of-life improvements for people with skin conditions. The committee concluded that, given the flaws with the company's utility values, the utility values from TA534 were preferable.
# Modelling of best supportive care
## The loss of quality-of-life benefit on best supportive care over time is likely to be between the base cases of the company and ERG
At technical engagement, the company used the same approach as the ERG by removing best supportive care discontinuation. 'Discontinuing' best supportive care meant that patients moved permanently into the 'non-response' state, with a lower utility value and higher costs than the 'maintenance' state (see section 3.13). The ERG's approach was consistent with the 52‑week placebo arm data from CHRONOS. This data suggested that people having best supportive care fluctuated between periods of good and bad disease control, and that for every patient losing disease control, another had an improvement. In both the company's and ERG's base cases, costs were therefore a weighted average of people whose disease responded to treatment and those whose disease did not respond. However, the company considered that quality of life for patients having best supportive care would return to baseline over time, despite costs not increasing. The company thought it implausible that the effectiveness of best supportive care would be maintained after the trial, when there is decreased treatment adherence. Therefore, it explored the 2 committee‑preferred sensitivity analyses from TA534 in its updated base cases. These modelled 2 trajectories of the proportion of patients losing the quality‑of‑life benefit of best supportive care over time, based on the data from CHRONOS. The ERG considered that the company's revised approach was methodologically flawed, because it separated utilities from costs within the model. It was also based on a selective analysis of the clinical trials, in that the placebo arm data were disregarded as being unrealistic, while the data from the baricitinib and dupilumab arms were treated as generalisable to clinical practice. The clinical experts explained that patients are monitored closely in clinical trials, and that only a minority of patients having best supportive care would retain long‑term disease control. The committee acknowledged that the ERG's approach represented different patients moving in and out of disease control over time. Even so, the committee considered that it overestimated the quality of life of patients having best supportive care, because it was implausible that there would be no loss of quality-of-life benefit over time on average. However, the committee also found that the company's 2 quality‑of‑life waning approaches underestimated the likely quality of life of patients having best supportive care. The committee concluded that the proportion of patients having best supportive care losing the quality‑of‑life benefit over time was likely to be somewhere between the base cases of the company and ERG.
# Quality-of-life waning for baricitinib and dupilumab
## Applying quality-of-life waning assumptions for baricitinib and dupilumab has minimal impact on the ICERs
At technical engagement, the company also applied the committee-preferred quality-of-life waning assumptions for dupilumab from TA534, for consistency with that appraisal. The company assumed that the following proportion of patients would lose the quality-of-life benefit from treatment over time: year 2: 2%, year 3: 5%, year 4: 7%, year 5 and beyond: 8%. The company applied the same assumptions for both baricitinib and dupilumab. The ERG had similar criticisms of the company's approach as described in section 3.17, in that it separated costs from utilities in the model. The committee concluded that the degree of quality‑of‑life waning for patients having baricitinib or dupilumab was uncertain, but noted that it had minimal impact on the incremental cost‑effectiveness ratios (ICERs).
# Cost-effectiveness results
## Baricitinib is cost effective compared with dupilumab based on the pairwise ICERs for the committee's preferred scenarios
The committee initially focused on the pairwise ICERs for baricitinib compared with dupilumab. The company and ERG's deterministic base cases included the confidential patient access scheme discounts for both baricitinib and dupilumab. These showed that baricitinib resulted in cost savings and a quality-adjusted life year (QALY) loss compared with dupilumab, producing ICERs that reflected savings per QALY lost. In situations when an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The ERG's base case included the committee's preferred assumptions:
using EASI 50 plus an improvement in the DLQI of at least 4 to define response (see section 3.9)
using the utility values from TA534 (see section 3.16)
stopping rates from week 16 to week 52 based on stopping treatment for any reason, rather than only loss of response (see section 3.14).The ERG's base case assumed no loss of quality-of-life benefit over time on average for patients having best supportive care. The committee recalled that there was considerable uncertainty about this assumption (see section 3.17). However, the committee noted that in the ERG's base case both with and without quality-of-life waning on best supportive care, the ICERs for baricitinib compared with dupilumab were within what NICE considers an acceptable use of NHS resources. Because of a confidential commercial arrangement for dupilumab, the cost-effectiveness results cannot be reported here.
## Baricitinib is likely to be cost effective compared with best supportive care based on the pairwise ICERs
The committee considered the pairwise ICERs for baricitinib compared with best supportive care. The company's and ERG's base cases showed that baricitinib resulted in greater costs and a QALY gain. As such, the standard decision rule of accepting ICERs below a given threshold was applied. The company's deterministic base case showed that baricitinib was associated with ICERs of £27,037 and £28,396 per QALY gained compared with best supportive care, for the best supportive care quality-of-life waning scenarios 1 and 2 respectively (see section 3.17). In the ERG's base case (with no quality-of-life waning on best supportive care) the ICER was £70,825 per QALY gained. However, with quality-of-life waning on best supportive care only this decreased to £26,987 per QALY gained. The committee concluded that there was uncertainty related to the ICER compared with best supportive care, depending on the quality-of-life waning assumptions. But, it was likely to be at the upper end of what NICE normally considers an acceptable use of NHS resources. The committee concluded that baricitinib is likely to be cost effective compared with best supportive care.
## Although uncertain, incremental analyses support the cost effectiveness of baricitinib when used before or after dupilumab
The committee also considered incremental analyses that included sequences of baricitinib and dupilumab. In the ERG's base case both with and without quality-of-life waning on best supportive care, baricitinib followed by dupilumab had a similar incremental net monetary benefit (when the benefit is expressed in monetary terms, minus the costs) to dupilumab followed by best supportive care, at both thresholds of £20,000 and £30,000 per QALY gained. The same applied for the sequence of dupilumab followed by baricitinib. The committee understood that in the sequencing analyses the efficacy of baricitinib and dupilumab was assumed to be unaffected by their position in the sequence. It recalled its uncertainty around treatment sequences (see section 3.5), but concluded that the analyses supported the cost effectiveness of baricitinib when used before or after dupilumab.
# Other factors
## EASI and DLQI may not be appropriate for all people with atopic dermatitis
The committee noted potential equality issues, namely that:
the EASI might underestimate the severity of atopic dermatitis in people with dark skin
the DLQI may not account for anxiety and depression.The committee concluded that, when using the EASI, healthcare professionals should take into account skin colour and how this could affect the EASI score. Also, it concluded that when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or difficulties in communication that could affect a person's response to the DLQI.
## It is not possible to establish the efficacy of baricitinib in patients with dark skin
The ERG noted that no subgroup data were reported for patients with dark skin in the baricitinib clinical trials, and so it was not possible to establish the efficacy of baricitinib in this population. Feedback from clinical experts highlighted that the pattern of atopic dermatitis is different in people of African family origin, but that interleukin‑4 and interleukin‑13 cytokines predominate in most populations. The committee understood that there is insufficient evidence to determine the efficacy of baricitinib in patients with dark skin. Therefore, it could not account for potential differences during decision making.
## Baricitinib is not a 'step change' in the same way as dupilumab
The company considered baricitinib to be an innovative treatment. It has a novel, targeted mechanism of action, and is an oral treatment not associated with the adverse events experienced by patients having dupilumab. The committee considered that baricitinib was not a 'step change' in the same way as dupilumab. However, having a new oral treatment option would be appreciated by some patients. The committee heard and concluded that there were no additional gains in health-related quality of life associated with baricitinib over those already included in the QALY calculations.
# Conclusion
## Baricitinib is recommended in people when at least 1 systemic immunosuppressant has not worked or is not suitable
The committee noted that there was considerable uncertainty around the loss of quality-of-life benefit over time for patients having best supportive care, which had a large impact on the ICERs. However, in the scenarios with the committee's preferred assumptions and quality-of-life waning on best supportive care, the pairwise ICERs suggested that baricitinib was cost effective compared with both dupilumab and best supportive care. Incremental analyses supported the cost effectiveness of baricitinib when used before or after dupilumab, despite uncertainty. Also, the summary of product characteristics states that response to baricitinib may be assessed from 8 weeks rather than the 16 weeks used in the model. This would likely improve the cost effectiveness of baricitinib. The committee concluded that baricitinib is a cost-effective use of NHS resources and could be recommended as an option for people with moderate to severe atopic dermatitis when at least 1 systemic immunosuppressant has not worked or is not suitable. Given the QALY losses for baricitinib compared with dupilumab, treatment choice should be a decision made between the doctor and the patient.
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{'Recommendations': 'Baricitinib is recommended as an option for treating moderate to severe atopic dermatitis in adults, only if:\n\nthe disease has not responded to at least 1\xa0systemic immunosuppressant, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or these are not suitable, and\n\nthe company provides it according to the commercial arrangement.\n\nAssess response from 8\xa0weeks and stop baricitinib if there has not been an adequate response at 16\xa0weeks, defined as a reduction of at least:\n\n% in the Eczema Area and Severity Index score (EASI\xa050) from when treatment started and\n\npoints in the Dermatology Life Quality Index (DLQI) from when treatment started.\n\nWhen using the EASI, take into account skin colour and how this could affect the EASI score, and make appropriate clinical adjustments.\n\nWhen using the DLQI, take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI, and make any appropriate adjustments.\n\nThese recommendations are not intended to affect treatment with baricitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with moderate to severe atopic dermatitis that has not responded to at least 1\xa0systemic immunosuppressant are usually offered either dupilumab or best supportive care. Dupilumab does not always work, and some people stop taking it because of side effects. Baricitinib is an alternative to dupilumab and best supportive care. It is likely to be offered alongside topical corticosteroids.\n\nClinical trial results show that baricitinib reduces the severity and symptoms of atopic dermatitis compared with placebo. Baricitinib has not been directly compared with dupilumab. The results of an indirect comparison suggest that baricitinib is less effective than dupilumab.\n\nThe most likely cost-effectiveness estimates for baricitinib are within what NICE considers an acceptable use of NHS resources. Therefore, baricitinib is recommended as an option for moderate to severe atopic dermatitis when at least 1\xa0systemic immunosuppressant has not worked or is not suitable.', 'Information about baricitinib': "# Marketing authorisation indication\n\nBaricitinib (Olumiant, Eli Lilly) is 'indicated for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nA 28‑pack of 4‑mg tablets costs £805.56 (excluding VAT, BNF online, accessed December 2020). The company has a commercial arrangement. This makes baricitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe drug acquisition cost for best supportive care should be removed from the model, to avoid duplication with the costs for concomitant medications.\n\nBaricitinib should be assumed to have no benefit over best supportive care in reducing flare frequency in the model.\n\nThe costs of bathing products should be removed from the model.\n\nThere would be 9\xa0doses of dupilumab given during induction.\n\nThere should be 4\xa0annual full blood tests assumed for baricitinib in the model.\n\nThe company's 'secondary' censoring rule better reflected clinical practice. Under secondary censoring, the disease was considered to have not responded after people stopped treatment or started systemic rescue therapies.\n\nThe appraisal committee recognised that there were remaining areas of uncertainty (see technical report pages\xa02 to\xa017), and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:\n\nthe positioning of baricitinib in the treatment pathway (issue\xa01, see technical report, page\xa02)\n\nwhether systemic immunosuppressant therapy is a relevant comparator for baricitinib (issue\xa02, see technical report, page\xa02)\n\nwhether a 50% reduction in Eczema Area and Severity Index score (EASI\xa050) plus an improvement in the Dermatology Life Quality Index (DLQI) of at least\xa04, or a 75% reduction in EASI score (EASI\xa075), is more appropriate to define an adequate response to baricitinib (issue\xa04, see technical report, page\xa05)\n\nwhen response to baricitinib would be assessed in clinical practice (issue\xa05, see technical report, page\xa05)\n\nwhether baricitinib and dupilumab are likely to be used in a sequence, and how cost-effectiveness analyses for treatment sequences should be considered in decision making (issue\xa06, see technical report, page\xa06)\n\nwhat proportion of patients having best supportive care would lose the quality‑of‑life benefit over time in clinical practice (issue\xa07, see technical report, page\xa07)\n\nwhether the stopping rate between week\xa016 and week\xa052 in the model should be based on loss of response, or stopping treatment for any reason (issue\xa08, see technical report, page\xa09)\n\nwhether it was appropriate to assume that a proportion of patients having baricitinib or dupilumab lose the quality-of-life benefit from treatment over time (issue\xa09, see technical report, page\xa012)\n\nwhich utility values were most appropriate for decision making (issue\xa010, see technical report, page\xa02)\n\nwhether it was appropriate to include the data from people of Japanese family origin in the baricitinib clinical trials, given that this may not be generalisable to the UK population (issue\xa011, see technical report, page\xa014)\n\nwhether the results of the indirect treatment comparison were suitable for decision making (issue\xa012, see technical report, page\xa016).\n\n# Experience of people with atopic dermatitis\n\n## Atopic dermatitis affects all aspects of a person's life\n\nThe clinical experts explained that atopic dermatitis is a chronic, recurrently flaring, generalised skin condition starting in childhood and continuing into adulthood for most people. People with severe atopic dermatitis may need hospitalisation for treatment. Feedback from patient and professional organisations highlighted that the condition is debilitating and isolating, affecting all aspects of life (physical, psychological, social and financial). They emphasised that, if the condition is severe, it is associated with intolerable itch that disrupts sleep, and there is a higher risk of depression and suicide. The committee noted that having treatments that improve the condition and are associated with few or manageable adverse effects is important to people with atopic dermatitis.\n\n# Clinical management\n\n## People with moderate to severe atopic dermatitis would welcome a new oral treatment option with a different mechanism of action\n\nAlthough clinicians individualise therapy for patients, a typical treatment pathway involves emollients and topical corticosteroids (first‑line), topical calcineurin inhibitors (second‑line), phototherapy (third‑line) and systemic immunosuppressant therapies (fourth‑line). Fourth-line treatments include ciclosporin (the only systemic immunosuppressant with a marketing authorisation for atopic dermatitis), methotrexate, azathioprine and mycophenolate mofetil. The committee heard that patients often have difficulty adhering to topical corticosteroids, and would welcome a new treatment option that reduces topical corticosteroid use. Clinical experts also explained that systemic immunosuppressants need frequent blood monitoring tests and may have serious adverse effects. Also, ciclosporin is only used for short periods because of toxicity concerns. If a systemic immunosuppressant is no longer effective, it will be stopped and another immunosuppressant may be offered. Dupilumab is recommended as an option if the atopic dermatitis has not responded to at least 1 other systemic therapy (fifth‑line). However, atopic dermatitis does not always respond to dupilumab, and some people must stop treatment because of adverse effects. For people whose disease has not responded to all available systemic therapies, the only remaining treatment option is best supportive care. This may include education, psychological support, emollients, topical corticosteroids, bandages and hospitalisation. Exacerbations (flares) in atopic dermatitis are managed using short‑term high‑potency topical corticosteroids, oral corticosteroids and systemic therapy. The committee concluded that patients and clinicians would welcome a well‑tolerated oral treatment with a different mechanism of action, that could potentially reduce topical corticosteroid use.\n\n# Positioning in the treatment pathway, comparators and sequencing\n\n## Baricitinib would be used after at least 1 systemic immunosuppressant\n\nThe marketing authorisation for baricitinib is 'for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy'. The company positioned baricitinib as a fifth‑line treatment, after at least 1 systemic immunosuppressant, as an alternative to dupilumab and best supportive care. Clinical experts agreed that they would prefer to offer baricitinib as an alternative to systemic immunosuppressants, because it needs less monitoring. However, they acknowledged that in clinical practice people are likely to have had at least 1 systemic immunosuppressant before having baricitinib. The committee concluded that it would appraise baricitinib for moderate to severe atopic dermatitis after at least 1 systemic immunosuppressant, in the same position as dupilumab.\n\n## Dupilumab and best supportive care are the most appropriate comparators for baricitinib\n\nThe company suggested that systemic immunosuppressants are not a relevant comparator in people who have had at least 1 systemic immunosuppressant. For these people, the only remaining treatment options are dupilumab or best supportive care. The clinical experts agreed that in clinical practice some patients have a second systemic immunosuppressant before dupilumab, but most patients have dupilumab after only 1 systemic immunosuppressant. At technical engagement, the company attempted an indirect treatment comparison of baricitinib with ciclosporin, in the absence of direct evidence. However, the ERG and company agreed that the results of the indirect comparison were not reliable because of difficulties in matching the patient populations and outcomes between trials. The committee concluded that systemic immunosuppressants were a relevant comparator for baricitinib in some people, but that dupilumab and best supportive care were the most appropriate comparators. This was because most patients have dupilumab at the point in the treatment pathway where the company had positioned baricitinib, and there was a lack of data to compare baricitinib with systemic immunosuppressants.\n\n## Baricitinib and dupilumab are likely to be used in a sequence, but the reliability of sequencing analyses is uncertain\n\nThe company did not consider the sequence of baricitinib followed by dupilumab, or dupilumab followed by baricitinib. This was because the company positioned baricitinib as an alternative to dupilumab (see section\xa03.3), and there was a lack of data on the effectiveness of baricitinib in a sequence with dupilumab. The ERG considered it likely that in clinical practice baricitinib and dupilumab will be used in a sequence. The clinical experts explained that because dupilumab is likely to be more effective than baricitinib (see section\xa03.11), it would usually be used first in a sequence. However, treatment decisions are individualised, and there would likely be no 'standard' sequence of dupilumab and baricitinib. The committee understood that atopic dermatitis is a lifelong disease, and that most patients would need to stop treatment with dupilumab eventually. The committee considered that cost-effectiveness analyses for sequences of baricitinib and dupilumab should be taken into account in decision making. But, it acknowledged the uncertainty because of the lack of clinical data on sequential effectiveness.\n\n# Clinical evidence\n\n## The JAIN (BREEZE-AD4) and JAIY (BREEZE-AD7) trials provide the key clinical evidence for baricitinib\n\nThe evidence for baricitinib came from 5 trials: 2 on baricitinib monotherapy (JAHL [BREEZE-AD1] and JAHM [BREEZE-AD2]), 2 on baricitinib plus background topical corticosteroids (JAIN [BREEZE-AD4] and JAIY [BREEZE-AD7]), and a long-term extension study (JAHN [BREEZE-AD3]) for patients completing JAHL, JAHM or JAIY. The clinical experts explained that baricitinib is likely to be offered alongside topical corticosteroids. The committee therefore agreed to focus on the evidence of baricitinib 'combination therapy' with topical corticosteroids from JAIN and JAIY. Both were randomised double‑blind trials including patients who had moderate to severe atopic dermatitis for at least 12\xa0months. Moderate to severe atopic dermatitis was defined as an EASI score of 16 or more, an Investigator's Global Assessment (IGA) score of 3 or more, and body surface area involvement of 10% or more. The disease must have responded inadequately to topical corticosteroids. In JAIN, ciclosporin had to be contraindicated or not tolerated, or the disease uncontrolled on ciclosporin. The trials compared 3\xa0doses of baricitinib (1\xa0mg, 2\xa0mg, or 4\xa0mg once daily) with placebo. However, the committee agreed that it would focus only on the 4\xa0mg dose because it was the licensed dose relevant for most patients. The primary end points were assessed at 16\xa0weeks after the 'induction' period:\n\nJAIN: at least a 75% reduction in the EASI score from when treatment started (EASI\xa075)\n\nJAIY: a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the IGA, and at least a 2‑point improvement from baseline.Patients in JAIN had an additional 36\xa0weeks of treatment, followed by a long-term extension study. The committee understood that data from the JAIN extension study were not available at the time of the submission. The committee concluded that the JAIN and JAIY trials provided the key clinical evidence for baricitinib.\n\n## Baricitinib with topical corticosteroids is more clinically effective than placebo\n\nIn the analysis of the trial data using secondary censoring, patients having baricitinib plus topical corticosteroids in JAIN and JAIY were statistically significantly more likely to achieve EASI\xa050, EASI\xa075, and have an IGA score of 0 or 1 at week\xa016 than patients having placebo. Baricitinib also produced statistically significant reductions in itch and skin pain at week\xa016, as well as quality-of-life improvements based on the DLQI and EQ-5D. The committee noted that the data showed a peak response to baricitinib at, or before, week\xa012 for many outcomes. However, by week\xa024 in JAIN baricitinib was no longer statistically significantly more effective than placebo for EASI\xa075 or an IGA score of 0 or 1. The committee concluded that baricitinib was more clinically effective than placebo at week\xa016, but that this appeared to wane over time.\n\n## The data from JAIN and the JAIN-like subgroup of patients from JAIY represents who would have baricitinib in the NHS\n\nThe company's base case was based on a pooled population of patients from JAIN and a subgroup of patients from JAIY for whom ciclosporin was contraindicated or not tolerated, or whose disease was uncontrolled on ciclosporin (the 'JAIN‑like' subgroup). The ERG noted that the mean EASI score for these patients was within the published definition of severe atopic dermatitis (21.1 to 50), and that they therefore represented more severe disease. The clinical experts agreed that the patients in JAIN and JAIY had severe disease, but considered that they were representative of patients who would likely have baricitinib in the NHS. The committee concluded that the pooled JAIN plus JAIN‑like subgroup from JAIY generally reflected people who would have baricitinib in NHS clinical practice.\n\n## A composite end point of EASI 50 plus an improvement in the DLQI of at least 4 is most relevant for decision making\n\nIn its original model, the company defined a clinical benefit using the composite end point of EASI\xa050 plus an improvement in the DLQI of at least 4. This was for consistency with NICE's technology appraisal guidance on dupilumab for treating moderate to severe atopic dermatitis (from now, TA534). At technical engagement, the company updated its model to define a clinical benefit using EASI\xa075. This was because the composite end point was not associated with a quality-of-life improvement in the baricitinib clinical trials. The company noted a move towards using EASI\xa075 in clinical practice, and that an EASI\xa075 response correlated better with a quality-of-life improvement in the baricitinib clinical trials. In addition, EASI\xa075 at week\xa016 was the primary end point in JAIN, and a key secondary end point in JAIY. The committee heard from clinical experts that the composite end point was widely used in clinical practice. Also, the EASI without the DLQI would fail to capture important patient‑reported quality‑of‑life improvements, such as reduced itching. The committee recognised that the composite end point of EASI\xa050 plus an improvement in the DLQI of at least 4 was widely used in clinical practice, included patient-reported quality of life, and was consistent for comparing baricitinib with dupilumab. Therefore, it concluded that this is the most relevant end point for decision making and should be used to define response.\n\n# Indirect treatment comparison\n\n## The company's indirect treatment comparison with dupilumab is acceptable for decision making\n\nThere was no direct evidence comparing baricitinib with dupilumab for atopic dermatitis, so the company did an indirect treatment comparison. For baricitinib, the company pooled the data from JAIN plus the JAIN‑like subgroup from JAIY. For dupilumab, the company pooled the data from the CAFÉ trial and a subgroup of patients from the CHRONOS trial for whom ciclosporin was contraindicated or not tolerated, or whose disease was uncontrolled on ciclosporin (the 'CAFÉ‑like' subgroup). The ERG noted several differences between the baricitinib and dupilumab trials included in the indirect comparison, which may reduce the reliability of the results:\n\nThere was a higher proportion of people of Asian family origin in JAIN and JAIY compared with CAFÉ and CHRONOS.\n\nBaseline EASI scores were higher in CAFÉ and CHRONOS, indicating patients had more severe atopic dermatitis.\n\nUnlike CAFÉ and CHRONOS, patients in JAIN and JAIY had a 2‑week washout period when they could not use topical treatments for their atopic dermatitis. Patients in CAFÉ and CHRONOS may therefore have experienced fewer flares immediately after entering the trial than those in JAIN or JAIY.\n\nData from patients who had rescue therapy or stopped study treatment in CAFÉ and CHRONOS were used, whereas data from JAIN and JAIY were subject to secondary censoring. This potentially favours dupilumab, because patients having systemic rescue treatment would not have been censored as having atopic dermatitis that did not respond to treatment.The clinical experts agreed that the differences in the washout period and censoring rules between the trials likely favoured dupilumab. The committee concluded that, despite its limitations, the company's indirect treatment comparison with dupilumab was acceptable for decision making.\n\n## The results of the indirect treatment comparison suggest that baricitinib is less effective than dupilumab\n\nThe proportion of patients achieving EASI\xa050 plus an improvement in the DLQI of at least 4 compared with placebo was statistically significantly greater for patients having dupilumab compared with patients having baricitinib. At technical engagement the company updated the indirect comparison using EASI\xa075, to reflect that they had changed the definition of response in the model (see section\xa03.9). The direction of the results was similar to the indirect comparison using the composite end point. The committee recalled its earlier conclusion that baricitinib was more clinically effective than placebo, but concluded that baricitinib is likely to be less effective than dupilumab.\n\n# Adverse events\n\n## Patients on baricitinib generally experience few serious adverse events\n\nThe committee noted that the rates of serious adverse events were generally low in the baricitinib and placebo groups of the trial populations across all studies. Although the proportion of baricitinib patients in JAIN who experienced 1 or more treatment-emergent adverse event was higher than placebo, the committee concluded that patients were likely to tolerate baricitinib.\n\n# Company's economic model\n\n## The structure of the company's model is similar to that in TA534, and appropriate for decision making\n\nThe company originally submitted a Markov model with 4 health states: induction, maintenance, non-response, and death. Patients entered the model in the 'induction' state, during which they could not stop treatment. At week\xa016, people in the baricitinib or dupilumab arms whose disease had not responded to treatment switched to best supportive care. People whose disease had responded to treatment moved into the 'maintenance' state, where they continued to have baricitinib or dupilumab until their disease stopped responding (up to week\xa052) or they stopped treatment for any reason (from year\xa02 onwards). At this point patients switched to best supportive care. People having best supportive care entered the 'non-response' state if their disease had either not responded at week\xa016 or stopped responding by week\xa052, or they stopped treatment for any reason from year 2 onwards. Patients in the 'non-response' state could not transition back into previous states. Patients could move into the 'death' state at any time. The committee noted that the company's model was generally similar to that of TA534. It concluded that, despite some uncertainties around how the loss of quality-of-life benefit of treatment over time was modelled (see section\xa03.17 and section\xa03.18), the structure of the company's model was appropriate for decision making.\n\n# Assumptions in the economic model\n\n## The stopping rate from week 16 to week 52 should be based on stopping treatment for any reason\n\nThe company assumed that 6.1% of people having dupilumab plus topical corticosteroids as maintenance therapy stop treatment in the first year and then have best supportive care. This reflected the proportion of people in CHRONOS whose condition responded to treatment at 16\xa0weeks (EASI\xa050 plus an improvement in the DLQI of at least\xa04), but was no longer responding to treatment at 52\xa0weeks. For people having baricitinib plus topical corticosteroids, the company based the stopping rate in the first year on the 52‑week data from JAIN. The company's assumption reflected the proportion of people in JAIN whose condition responded to treatment at 16\xa0weeks, but was no longer responding to treatment at 52\xa0weeks. The ERG disagreed with deriving stopping rates in the first year from loss of response at 52\xa0weeks, conditional on response at 16\xa0weeks. This was because stopping treatment depends not only on loss of efficacy but also other factors such as adverse events. The ERG preferred to base the stopping rates on the all-cause stopping rate in JAIN (and CHRONOS, for dupilumab) for people whose condition responded to treatment at 16\xa0weeks, but who withdrew from the trial by 52\xa0weeks. The committee concluded that, on balance, the ERG's approach was more appropriate.\n\n## Treatment response to baricitinib should be assessed by 16 weeks, with an earlier assessment likely to improve baricitinib's cost effectiveness\n\nThe committee understood from the summary of product characteristics for baricitinib that 'consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit after 8\xa0weeks of treatment'. The committee was aware that a 16‑week 'induction' phase was implemented in the clinical trials (see section\xa03.6) and in the company's economic model, which was consistent with TA534. However, the results from JAIN showed a peak response at 12\xa0weeks or earlier across many outcomes. In clinical practice, response to baricitinib may be assessed earlier than 16\xa0weeks (although this scenario was not modelled by the company or the ERG), which would likely improve the cost effectiveness of baricitinib. This was because response rates would be similar, but patients whose disease did not respond would accrue fewer treatment costs. The committee concluded that response to baricitinib should be assessed from 8\xa0weeks, and baricitinib stopped if the atopic dermatitis does not respond adequately by 16\xa0weeks.\n\n# Utility values in the economic model\n\n## The utility values from TA534 are preferable when response is defined as EASI 50 plus an improvement in the DLQI of at least 4\n\nThe company's original model, when response was defined using EASI\xa050 plus an improvement in the DLQI of at least\xa04, used 2\xa0utility values. A utility value of 0.78 was assigned to people in the 'maintenance' state, and a utility value of 0.5979 was assigned to people in the 'induction' and 'non-response' states. These were derived from the pooled data from JAIN plus the JAIN‑like subgroup from JAIY, and were the same regardless of treatment arm in the model (baricitinib, dupilumab or best supportive care). The ERG had several concerns with the company's utilities. The pooled data from JAIN plus the JAIN‑like subgroup from JAIY showed that patients whose disease responded to treatment based on the composite end point had a lower utility gain from baseline (0.1821) than those whose disease had not responded to treatment (0.2042). However, the company only applied the utility increase for people whose disease responded to treatment in the model, and assigned the baseline utility to those whose disease did not respond. The ERG found this approach to be flawed, and likely confounded by regression to the mean effects. It also questioned why the company had also not included the data from the 'JAIN‑like' subgroups from JAHL and JAHM when deriving the utilities. In addition, the ERG considered that using only 2\xa0utility values was overly simplistic and failed to capture magnitude of response. It preferred to use the utility values from TA534, which were treatment-specific and had previously been accepted by the committee. The committee considered which utility values were more appropriate for the composite end point. It noted the flaws in the company's original approach, and acknowledged the ERG's concern that the 'maintenance' health state was not associated with a utility gain. However, it heard from clinical experts that patients achieving EASI\xa050 plus an improvement in the DLQI of at least 4 were likely to have an improvement in quality of life, even if this had not been shown in the pivotal trials. The committee also understood that the EQ‑5D often fails to capture quality-of-life improvements for people with skin conditions. The committee concluded that, given the flaws with the company's utility values, the utility values from TA534 were preferable.\n\n# Modelling of best supportive care\n\n## The loss of quality-of-life benefit on best supportive care over time is likely to be between the base cases of the company and ERG\n\nAt technical engagement, the company used the same approach as the ERG by removing best supportive care discontinuation. 'Discontinuing' best supportive care meant that patients moved permanently into the 'non-response' state, with a lower utility value and higher costs than the 'maintenance' state (see section\xa03.13). The ERG's approach was consistent with the 52‑week placebo arm data from CHRONOS. This data suggested that people having best supportive care fluctuated between periods of good and bad disease control, and that for every patient losing disease control, another had an improvement. In both the company's and ERG's base cases, costs were therefore a weighted average of people whose disease responded to treatment and those whose disease did not respond. However, the company considered that quality of life for patients having best supportive care would return to baseline over time, despite costs not increasing. The company thought it implausible that the effectiveness of best supportive care would be maintained after the trial, when there is decreased treatment adherence. Therefore, it explored the 2 committee‑preferred sensitivity analyses from TA534 in its updated base cases. These modelled 2 trajectories of the proportion of patients losing the quality‑of‑life benefit of best supportive care over time, based on the data from CHRONOS. The ERG considered that the company's revised approach was methodologically flawed, because it separated utilities from costs within the model. It was also based on a selective analysis of the clinical trials, in that the placebo arm data were disregarded as being unrealistic, while the data from the baricitinib and dupilumab arms were treated as generalisable to clinical practice. The clinical experts explained that patients are monitored closely in clinical trials, and that only a minority of patients having best supportive care would retain long‑term disease control. The committee acknowledged that the ERG's approach represented different patients moving in and out of disease control over time. Even so, the committee considered that it overestimated the quality of life of patients having best supportive care, because it was implausible that there would be no loss of quality-of-life benefit over time on average. However, the committee also found that the company's 2\xa0quality‑of‑life waning approaches underestimated the likely quality of life of patients having best supportive care. The committee concluded that the proportion of patients having best supportive care losing the quality‑of‑life benefit over time was likely to be somewhere between the base cases of the company and ERG.\n\n# Quality-of-life waning for baricitinib and dupilumab\n\n## Applying quality-of-life waning assumptions for baricitinib and dupilumab has minimal impact on the ICERs\n\nAt technical engagement, the company also applied the committee-preferred quality-of-life waning assumptions for dupilumab from TA534, for consistency with that appraisal. The company assumed that the following proportion of patients would lose the quality-of-life benefit from treatment over time: year\xa02: 2%, year\xa03: 5%, year\xa04: 7%, year\xa05 and beyond: 8%. The company applied the same assumptions for both baricitinib and dupilumab. The ERG had similar criticisms of the company's approach as described in section\xa03.17, in that it separated costs from utilities in the model. The committee concluded that the degree of quality‑of‑life waning for patients having baricitinib or dupilumab was uncertain, but noted that it had minimal impact on the incremental cost‑effectiveness ratios (ICERs).\n\n# Cost-effectiveness results\n\n## Baricitinib is cost effective compared with dupilumab based on the pairwise ICERs for the committee's preferred scenarios\n\nThe committee initially focused on the pairwise ICERs for baricitinib compared with dupilumab. The company and ERG's deterministic base cases included the confidential patient access scheme discounts for both baricitinib and dupilumab. These showed that baricitinib resulted in cost savings and a quality-adjusted life year (QALY) loss compared with dupilumab, producing ICERs that reflected savings per QALY lost. In situations when an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The ERG's base case included the committee's preferred assumptions:\n\nusing EASI\xa050 plus an improvement in the DLQI of at least 4 to define response (see section\xa03.9)\n\nusing the utility values from TA534 (see section\xa03.16)\n\nstopping rates from week\xa016 to week\xa052 based on stopping treatment for any reason, rather than only loss of response (see section\xa03.14).The ERG's base case assumed no loss of quality-of-life benefit over time on average for patients having best supportive care. The committee recalled that there was considerable uncertainty about this assumption (see section\xa03.17). However, the committee noted that in the ERG's base case both with and without quality-of-life waning on best supportive care, the ICERs for baricitinib compared with dupilumab were within what NICE considers an acceptable use of NHS resources. Because of a confidential commercial arrangement for dupilumab, the cost-effectiveness results cannot be reported here.\n\n## Baricitinib is likely to be cost effective compared with best supportive care based on the pairwise ICERs\n\nThe committee considered the pairwise ICERs for baricitinib compared with best supportive care. The company's and ERG's base cases showed that baricitinib resulted in greater costs and a QALY gain. As such, the standard decision rule of accepting ICERs below a given threshold was applied. The company's deterministic base case showed that baricitinib was associated with ICERs of £27,037 and £28,396 per QALY gained compared with best supportive care, for the best supportive care quality-of-life waning scenarios 1 and 2 respectively (see section\xa03.17). In the ERG's base case (with no quality-of-life waning on best supportive care) the ICER was £70,825 per QALY gained. However, with quality-of-life waning on best supportive care only this decreased to £26,987 per QALY gained. The committee concluded that there was uncertainty related to the ICER compared with best supportive care, depending on the quality-of-life waning assumptions. But, it was likely to be at the upper end of what NICE normally considers an acceptable use of NHS resources. The committee concluded that baricitinib is likely to be cost effective compared with best supportive care.\n\n## Although uncertain, incremental analyses support the cost effectiveness of baricitinib when used before or after dupilumab\n\nThe committee also considered incremental analyses that included sequences of baricitinib and dupilumab. In the ERG's base case both with and without quality-of-life waning on best supportive care, baricitinib followed by dupilumab had a similar incremental net monetary benefit (when the benefit is expressed in monetary terms, minus the costs) to dupilumab followed by best supportive care, at both thresholds of £20,000 and £30,000 per QALY gained. The same applied for the sequence of dupilumab followed by baricitinib. The committee understood that in the sequencing analyses the efficacy of baricitinib and dupilumab was assumed to be unaffected by their position in the sequence. It recalled its uncertainty around treatment sequences (see section\xa03.5), but concluded that the analyses supported the cost effectiveness of baricitinib when used before or after dupilumab.\n\n# Other factors\n\n## EASI and DLQI may not be appropriate for all people with atopic dermatitis\n\nThe committee noted potential equality issues, namely that:\n\nthe EASI might underestimate the severity of atopic dermatitis in people with dark skin\n\nthe DLQI may not account for anxiety and depression.The committee concluded that, when using the EASI, healthcare professionals should take into account skin colour and how this could affect the EASI score. Also, it concluded that when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or difficulties in communication that could affect a person's response to the DLQI.\n\n## It is not possible to establish the efficacy of baricitinib in patients with dark skin\n\nThe ERG noted that no subgroup data were reported for patients with dark skin in the baricitinib clinical trials, and so it was not possible to establish the efficacy of baricitinib in this population. Feedback from clinical experts highlighted that the pattern of atopic dermatitis is different in people of African family origin, but that interleukin‑4 and interleukin‑13 cytokines predominate in most populations. The committee understood that there is insufficient evidence to determine the efficacy of baricitinib in patients with dark skin. Therefore, it could not account for potential differences during decision making.\n\n## Baricitinib is not a 'step change' in the same way as dupilumab\n\nThe company considered baricitinib to be an innovative treatment. It has a novel, targeted mechanism of action, and is an oral treatment not associated with the adverse events experienced by patients having dupilumab. The committee considered that baricitinib was not a 'step change' in the same way as dupilumab. However, having a new oral treatment option would be appreciated by some patients. The committee heard and concluded that there were no additional gains in health-related quality of life associated with baricitinib over those already included in the QALY calculations.\n\n# Conclusion\n\n## Baricitinib is recommended in people when at least 1 systemic immunosuppressant has not worked or is not suitable\n\nThe committee noted that there was considerable uncertainty around the loss of quality-of-life benefit over time for patients having best supportive care, which had a large impact on the ICERs. However, in the scenarios with the committee's preferred assumptions and quality-of-life waning on best supportive care, the pairwise ICERs suggested that baricitinib was cost effective compared with both dupilumab and best supportive care. Incremental analyses supported the cost effectiveness of baricitinib when used before or after dupilumab, despite uncertainty. Also, the summary of product characteristics states that response to baricitinib may be assessed from 8\xa0weeks rather than the 16\xa0weeks used in the model. This would likely improve the cost effectiveness of baricitinib. The committee concluded that baricitinib is a cost-effective use of NHS resources and could be recommended as an option for people with moderate to severe atopic dermatitis when at least 1 systemic immunosuppressant has not worked or is not suitable. Given the QALY losses for baricitinib compared with dupilumab, treatment choice should be a decision made between the doctor and the patient."}
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https://www.nice.org.uk/guidance/ta681
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Evidence-based recommendations on baricitinib for treating moderate to severe atopic dermatitis in adults.
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Secondary bacterial infection of eczema and other common skin conditions: antimicrobial prescribing
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Secondary bacterial infection of eczema and other common skin conditions: antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for secondary bacterial infection of eczema and covers infection of other common skin conditions. It aims to optimise antibiotic use and reduce antibiotic resistance. The recommendations are for adults, young people and children aged 72 hours and over. They do not cover diagnosis.
# Recommendations
# Managing secondary bacterial infections of eczema
## Treatment
In people with symptoms or signs of cellulitis, follow the NICE guideline on cellulitis and erysipelas: antimicrobial prescribing.
Manage underlying eczema and flares with treatments such as emollients and topical corticosteroids, whether antibiotics are offered or not (see the NICE guideline on atopic eczema in under 12s and also see NICE's technology appraisal guidance on alitretinoin for the treatment of severe chronic hand eczema, dupilumab for treating moderate to severe atopic dermatitis, tacrolimus and pimecrolimus for atopic eczema and frequency of application of topical corticosteroids for atopic eczema).
Be aware that:
the symptoms and signs of secondary bacterial infection of eczema can include: weeping, pustules, crusts, no response to treatment, rapidly worsening eczema, fever and malaise
not all eczema flares are caused by a bacterial infection, so will not respond to antibiotics, even if weeping and crusts are present
eczema is often colonised with bacteria but may not be clinically infected
eczema can also be infected with herpes simplex virus (eczema herpeticum).For managing eczema and eczema herpeticum in children under 12, see the NICE guideline on atopic eczema in under 12s.
Do not routinely take a skin swab for microbiological testing in people with secondary bacterial infection of eczema at the initial presentation.
In people who are not systemically unwell, do not routinely offer either a topical or oral antibiotic for secondary bacterial infection of eczema. Take into account:
the evidence, which suggests a limited benefit with antibiotics in addition to topical corticosteroids compared with topical corticosteroids alone
the risk of antimicrobial resistance with repeated courses of antibiotics
the extent and severity of symptoms or signs
the risk of developing complications, which is higher in people with underlying conditions such as immunosuppression.
If an antibiotic is offered to people who are not systemically unwell with a secondary bacterial infection of eczema (see the recommendations on choice of antibiotic), when choosing between a topical or oral antibiotic, take into account:
their preferences (and those of their parents and carers as appropriate) for topical or oral administration
the extent and severity of symptoms or signs (a topical antibiotic may be more appropriate if the infection is localised and not severe; an oral antibiotic may be more appropriate if the infection is widespread or severe)
possible adverse effects
previous use of topical antibiotics because antimicrobial resistance can develop rapidly with extended or repeated use.
In people who are systemically unwell, offer an oral antibiotic for secondary bacterial infection of eczema (see the recommendations on choice of antibiotic).
For a short explanation of why the committee made these recommendations, see the rationale section on treatment .
For more details, see the evidence review.
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## Advice
If an antibiotic is not given, advise the person (and their parents and carers as appropriate):
about the reasons why an antibiotic is unlikely to provide any benefit
to seek medical help if symptoms worsen rapidly or significantly at any time.
If an antibiotic is given, advise the person (and their parents and carers as appropriate):
about possible adverse effects
about the risk of developing antimicrobial resistance with extended or repeated use
that they should continue treatments such as emollients and topical corticosteroids
that it can take time for secondary bacterial infection of eczema to resolve, and full resolution is not expected until after the antibiotic course is completed
to seek medical help if symptoms worsen rapidly or significantly at any time.
For a short explanation of why the committee made these recommendations, see the rationale section on advice .
For more details, see the evidence review.
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## Reassessment
Reassess people with secondary bacterial infection of eczema if:
they become systemically unwell or have pain that is out of proportion to the infection
their symptoms worsen rapidly or significantly at any time
their symptoms have not improved after completing a course of antibiotics.
When reassessing people with secondary bacterial infection of eczema, take account of:
-ther possible diagnoses, such as eczema herpeticum
any symptoms or signs suggesting a more serious illness or condition, such as cellulitis, necrotising fasciitis or sepsis
previous antibiotic use, which may have caused resistant bacteria.
For people with secondary bacterial infection of eczema that is worsening or has not improved as expected, consider sending a skin swab for microbiological testing.
For people with secondary bacterial infection of eczema that recurs frequently:
send a skin swab for microbiological testing and
consider taking a nasal swab and starting treatment for decolonisation.
If a skin swab has been sent for microbiological testing:
review the choice of antibiotic when results are available and
change the antibiotic according to results if symptoms are not improving, using a narrow‑spectrum antibiotic if possible.
For a short explanation of why the committee made these recommendations, see the rationale section on reassessment .
For more details, see the evidence review.
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## Referral and seeking specialist advice
Refer people with secondary bacterial infection of eczema to hospital if they have any symptoms or signs suggesting a more serious illness or condition, such as necrotising fasciitis or sepsis.
Consider referral or seeking specialist advice for people with secondary bacterial infection of eczema if they:
have spreading infection that is not responding to oral antibiotics
are systemically unwell
are at high risk of complications
have infections that recur frequently.
For a short explanation of why the committee made these recommendations, see the rationale section on referral and seeking specialist advice .
For more details, see the evidence review.
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# Choice of antibiotic
When prescribing an antibiotic for secondary bacterial infection of eczema, take account of local antimicrobial resistance data when available and follow:
table 1 for adults aged 18 years and over
table 2 for children and young people under 18 years (for children under 1 month, antibiotic choice is based on specialist advice).
Treatment
Antibiotic, dosage and course length
For secondary bacterial infection of eczema in people who are not systemically unwell
Do not routinely offer either a topical or oral antibiotic
First-choice topical
if a topical antibiotic is appropriate (see recommendations 1.1.5 and 1.1.6)
Fusidic acid 2%:
Apply three times a day for 5 to 7 days
For localised infections only. Extended or recurrent use may increase the risk of developing antimicrobial resistance.
First-choice oral
if an oral antibiotic is appropriate (see recommendations 1.1.5 to 1.1.7)
Flucloxacillin:
mg four times a day for 5 to 7 days
Alternative oral antibiotic for penicillin allergy or if flucloxacillin is unsuitable (for people who are not pregnant)
Clarithromycin:
mg twice a day for 5 to 7 days
The dosage can be increased to 500 mg twice a day for severe infections.
Alternative oral antibiotic for penicillin allergy in pregnancy
Erythromycin:
mg to 500 mg four times a day for 5 to 7 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
If meticillin-resistant
Staphylococcus aureus
is suspected or confirmed
Consult a microbiologist
See the BNF for appropriate use and dosing of the antibiotics recommended in specific populations, for example, people with hepatic or renal impairment, and in pregnancy and breastfeeding.
Treatment
Antibiotic, dosage and course length
For secondary bacterial infection of eczema in people who are not systemically unwell
Do not routinely offer either a topical or oral antibiotic
First-choice topical if a topical antibiotic is appropriate (see recommendations 1.1.5 and 1.1.6)
Fusidic acid 2%:
Apply three times a day for 5 to 7 days
For localised infections only. Extended or recurrent use may increase the risk of developing antimicrobial resistance.
First-choice oral if an oral antibiotic is appropriate (see recommendations 1.1.5 to 1.1.7)
Flucloxacillin (oral solution or capsules):
month to 1 year: 62.5 mg to 125 mg four times a day for 5 to 7 days
years to 9 years: 125 mg to 250 mg four times a day for 5 to 7 days
years to 17 years: 250 mg to 500 mg four times a day for 5 to 7 days
Alternative oral antibiotic for penicillin allergy or if flucloxacillin is unsuitable (for people who are not pregnant)
Clarithromycin:
month to 11 years:
under 8 kg: 7.5 mg/kg twice a day for 5 to 7 days
kg to 11 kg: 62.5 mg twice a day for 5 to 7 days
kg to 19 kg: 125 mg twice a day for 5 to 7 days
kg to 29 kg: 187.5 mg twice a day for 5 to 7 days
kg to 40 kg: 250 mg twice a day for 5 to 7 days
years to 17 years:
mg twice a day for 5 to 7 days. The dosage can be increased to 500 mg twice a day for severe infections
Alternative oral antibiotic for penicillin allergy in pregnancy
Erythromycin:
years to 17 years: 250 mg to 500 mg four times a day for 5 to 7 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
If meticillin-resistant
Staphylococcus aureus
is suspected or confirmed
Consult a local microbiologist
See the BNF for Children for appropriate use and dosing of the antibiotics recommended in specific populations, for example, people with hepatic or renal impairment, and in pregnancy and breastfeeding.
The age bands for children apply to children of average size. In practice, they will be used alongside other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.
For advice on helping children to swallow medicines, see Medicines for Children's leaflet on helping your child to swallow tablets.
For a short explanation of why the committee made these recommendations, see the rationale section on choice of antibiotic .
For more details, see the summary of the evidence.
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# Managing secondary bacterial infections of psoriasis, chicken pox, shingles and scabies
## Treatment
Be aware that no evidence was found on the use of antibiotics in managing secondary bacterial infections of other common skin conditions such as psoriasis, chicken pox, shingles and scabies. Seek specialist advice, if needed.
For a short explanation of why the committee made this recommendation, see the rationale section on treatment .
For more details, see the evidence review.
Loading. Please wait.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Antibiotics (oral route) compared with topical treatments (antiseptics or antibiotics) or placebo for infected psoriasis, chicken pox, shingles or scabies
What is the clinical effectiveness and safety of oral antibiotics compared with topical treatments (antiseptics or antibiotics) or placebo for treating infected psoriasis, chicken pox, shingles or scabies in adults, young people and children?
For a short explanation of why the committee made this recommendation for research, see the rationale section on treatment .
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# Antiseptic bath emollient compared with non-antiseptic bath emollient for infected eczema
What is the clinical effectiveness and safety of antiseptic bath emollient compared with non-antiseptic bath emollient for treating infected eczema in adults, young people and children?
For a short explanation of why the committee made this recommendation for research, see the rationale section on treatment .
Loading. Please wait.# Rationales
The recommendations in this guideline are based on the evidence identified and the experience of the committee.
# Treatment
## Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.7
The committee agreed, based on their experience, that it is important to optimally manage underlying eczema in people who present with a suspected secondary bacterial infection, for example, with emollients and topical corticosteroids. They also agreed that it is important to optimally manage flares in all people with stepped topical corticosteroids; for managing eczema in children under 12, there are recommendations on the use of stepped corticosteroids in the NICE guideline on atopic eczema in under 12s. The committee also noted that information on optimally managing atopic eczema in all people (aged over 1 month) was available in NICE's clinical knowledge summary on atopic eczema.
The committee agreed with the symptoms and signs of secondary bacterial infection of eczema in the NICE guideline on atopic eczema in under 12s. The committee recognised that, in practice, it can be difficult to tell the difference between a non-infected flare of eczema and eczema that has become infected. There may be no bacterial infection even if there are classic signs of infection such as weeping and crusts. A more useful indicator of infection may be that a person feels systemically unwell with fever or malaise. However, without definitive diagnostic criteria, diagnosing secondary bacterial infection of eczema will be based on history taking and the person's (or parent's or carer's) knowledge of their own condition. The committee also discussed that healthcare professionals should be aware that redness, one of the signs of infection, may be less visible on darker skin tones.
The committee agreed that skin swabs for microbiological testing should not routinely be taken at the initial presentation of a suspected secondary bacterial infection of eczema. The skin of people with eczema is often heavily colonised with Staphylococcus aureus (S. aureus) bacteria, and bacterial growth from a skin swab is likely regardless of infection status. Taking skin swabs from everyone with a suspected infection could lead to inappropriate antibiotic prescribing. If the eczema is clinically infected, the most likely causative organisms are S. aureus or Streptococcus pyogenes (S. pyogenes), so empirical treatment with topical fusidic acid or oral flucloxacillin would be effective.
The evidence suggested that using topical or oral antibiotics in addition to topical corticosteroids offered little benefit over using topical corticosteroids alone in people with a suspected secondary bacterial infection of eczema. The committee agreed that the evidence is limited because there are no definitive criteria for diagnosing a secondary bacterial infection. The committee went on to discuss that the available evidence was in children (or it was unclear whether the population included adults); they noted that the results from the evidence in children could be extrapolated to adults because the response to treatment would be sufficiently similar across different age groups. The committee also notes that trials have often excluded people with a severe infection or at high risk of complications from an infection.
Because a severe secondary bacterial infection of eczema could lead to a more serious illness or condition, such as cellulitis, the committee agreed that people who are systemically unwell, for example, with fever or malaise, should be offered an oral antibiotic. If the symptoms or signs of infection suggest cellulitis, the committee agreed that it should be managed with antibiotics as outlined in the NICE guideline on cellulitis and erysipelas: antimicrobial prescribing.
However, for people who are not systemically unwell, the committee agreed that an antibiotic is not routinely needed. This was based on evidence from a UK trial in children with clinically infected eczema. In this trial, a 7‑day course of topical fusidic acid or oral flucloxacillin had no benefit in terms of clinical effectiveness, quality of life or microbiological outcomes over standard treatment with topical corticosteroids.
Another trial in children, young people and adults with clinically infected eczema showed that topical fusidic acid plus a topical corticosteroid was not more effective than placebo plus a topical corticosteroid for clinical and biological response. The committee agreed, based on their experience, that this reinforced the importance of topical corticosteroid use during a flare. People should continue to use topical corticosteroids if their eczema is infected, matching the potency of the corticosteroid to the severity of eczema. This aligns with recommendations in the NICE guideline on atopic eczema in under 12s and in NICE's clinical knowledge summary on atopic eczema.
The committee agreed that if, after considering a person's history and clinical presentation, an antibiotic is clinically needed for infected eczema, a short course of a topical or oral antibiotic may be appropriate. The choice of a topical or oral antibiotic would be an individual clinical decision taking into account the extent and severity of symptoms or signs, and the risk of developing complications. Local antimicrobial resistance data, patient preference, administration practicalities (particularly to large areas), possible adverse effects and previous use would also need to be taken into account.
Antimicrobial resistance can develop rapidly with topical antibiotics. The committee agreed that repeated doses or extended use of the same topical antibiotic should be avoided. Evidence from a 2016 UK trial showed that there was more resistance to fusidic acid (after a 7‑day course) in S. aureus skin isolates than with oral flucloxacillin treatment. But there were no statistically significant differences in the trial in clinical effectiveness, adverse events, other antibiotic resistance outcomes or healthcare use between the topical and oral treatment. However, in a Danish trial from 2007 comparing topical fusidic acid plus a topical corticosteroid with placebo, there was no statistically significant difference between the groups in the number of S. aureus isolates resistant to fusidic acid after 14 days of treatment.
After discussing the evidence for antiseptics, the committee agreed that there was insufficient evidence on whether an antiseptic bath emollient was more effective than a standard bath emollient in children with infected eczema. Therefore, the committee made no recommendations on using antiseptic bath emollients, and made a recommendation for research.
The only evidence found for bleach baths (half a cup of 6% bleach in a bath, final concentration 0.005%; bathing for 5 to 10 minutes twice weekly) was a small trial of intranasal mupirocin (for decolonisation) plus a bleach bath compared with placebo in children and young people with secondary bacterial infection of eczema. This combination was more effective than placebo in children with infected eczema for several clinical-effectiveness outcomes. However, the committee agreed that this trial did not provide evidence that bleach baths alone are effective.
Return to the recommendations
# Advice
## Why the committee made the recommendations
Recommendations 1.1.8 and 1.1.9
A severe bacterial infection of eczema could lead to a more serious illness or condition, such as cellulitis. So, the committee agreed that people should be advised to seek medical help if their symptoms worsen rapidly or significantly at any time. This is particularly important if they did not have antibiotics initially, or their symptoms have not improved after completing a course of antibiotics.
However, people should also be advised that it can take time for infected eczema to resolve, and that there may not be full symptom resolution until after they have finished the course of antibiotics.
Return to the recommendations
# Reassessment
## Why the committee made the recommendations
Recommendations 1.1.10 to 1.1.14
Based on experience, the committee agreed when people with secondary bacterial infection of eczema should be reassessed. If symptoms of the infection worsen rapidly or significantly at any time, or do not start to improve after completing a course of antibiotics, this may indicate that the person has a more serious illness needing referral, or a resistant infection (possibly because of previous antibiotic use).
The committee agreed that people need to be reassessed if they are systemically unwell or have severe pain that is out of proportion to the infection (this can be a symptom of necrotising fasciitis, which is a rare but serious bacterial infection). The committee discussed that, at reassessment, it is important to consider other possible diagnoses, including viral (rather than bacterial) infection; for example, eczema herpeticum.
The committee agreed that it would be appropriate to send a skin swab for microbiological testing if the infection recurs frequently, and to consider doing this if the symptoms or signs of the infection are worsening or have not improved as expected. This will guide future antibiotic choice if the person has a resistant infection. A nasal swab should also be considered if nasal carriage of S. aureus is suspected. A nasal or skin (or both) decolonisation regimen should be considered, based on clinical judgement and microbiological test results, to remove the bacteria causing recurring infection. The committee agreed that decolonisation is supported by the small trial of intranasal mupirocin plus a bleach bath in children with infected eczema. The committee recognised that family decolonisation may sometimes be appropriate, but did not make a recommendation because this decision should be based on specialist advice.
The committee agreed on good practice for antimicrobial stewardship when reviewing the results of microbiological tests.
Return to the recommendations
# Referral and seeking specialist advice
## Why the committee made the recommendations
Recommendations 1.1.15 and 1.1.16
Based on their experience, the committee agreed that people with secondary bacterial infection of eczema who may have a more serious illness or condition need referral for further assessment and treatment in hospital.
Return to the recommendations
# Choice of antibiotic
## Why the committee made the recommendations
Recommendation 1.2.1
Most of the evidence for topical antibiotics was for fusidic acid. The committee agreed that this was more effective than topical neomycin sulfate for microbiological outcomes in 1 trial. Topical mupirocin was more effective than oral cefalexin for some microbiological outcomes (but not others) in 1 trial. However, there was no evidence comparing topical mupirocin with topical fusidic acid.
Based on committee experience, current practice and limited evidence, the committee agreed that the first-choice topical antibiotic in adults, young people and children with secondary bacterial infection of eczema is fusidic acid 2% (either as a cream or an ointment). A topical rather than an oral antibiotic is more appropriate if the person is not systemically unwell, and the infection is localised and not severe. The committee discussed that, in the absence of strong evidence, fusidic acid 2% was the most appropriate first-choice topical antibiotic because topical mupirocin should be reserved for treating meticillin-resistant S. aureus (MRSA) colonisation.
Based on their experience and limited evidence, the committee agreed that fusidic acid resistance rates are higher than for some other antibiotics, so previous use should be considered to avoid extended or repeated use. National antimicrobial resistance data from Public Health England's voluntary surveillance reports on Staphylococcus aureus showed fusidic acid resistance rates of 13% for meticillin-susceptible S. aureus bloodstream infections and of 25% for MRSA bloodstream infections. However, the committee discussed that resistance rates in blood isolates may not be a good indicator of resistance rates in skin isolates. These can vary greatly from person to person based on their history of antibiotic use and between localities.
The committee did not recommend an alternative topical antibiotic for secondary bacterial infection of eczema. This was because, if fusidic acid is unsuitable or ineffective, an oral antibiotic is preferred.
Based on their experience and knowledge of current practice, the committee agreed that the first-choice oral antibiotic in adults, young people and children with secondary bacterial infection of eczema is flucloxacillin. An oral rather than a topical antibiotic is more appropriate if the person is systemically unwell, or if the infection is widespread or severe. Flucloxacillin is a relatively narrow‑spectrum penicillin that is effective against S. aureus and S. pyogenes. The committee recognised that some children cannot tolerate flucloxacillin solution. However, they were aware of many useful resources that are available (for example, Medicines for Children's leaflet on helping your child to swallow tablets) to teach children how to swallow tablets or capsules. For children who are unable to swallow capsules, 1 of the alternative oral antibiotics is suitable.
The alternative oral antibiotic in adults, young people and children with penicillin allergy or if flucloxacillin is unsuitable, is clarithromycin. In pregnancy, erythromycin was recommended if there is true penicillin allergy. The committee agreed that these antibiotics are effective against the common pathogens that cause secondary bacterial infection of eczema.
The committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
The committee noted that, in their experience, MRSA infection in secondary bacterial infection of eczema is rare and that appropriate antibiotic choice may depend on local antimicrobial resistance rates. Therefore, they agreed that, if MRSA is suspected or confirmed, a local microbiologist should be consulted.
No evidence was identified for course length. Therefore, the recommendations were based on committee experience of current practice. The committee also agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and adverse effects. Based on their experience that lower doses (250 mg four times a day) of flucloxacillin are not clinically effective because of poor oral bioavailability, the committee agreed that the higher dose for flucloxacillin of 500 mg four times a day is appropriate for treating secondary bacterial infection of eczema in adults. They agreed that dose ranges are appropriate for children because the appropriate dose may vary depending on the severity of the infection and the age and weight of the child.
From their experience, the committee agreed that 5 to 7 days of treatment, based on clinical assessment, would be sufficient for treating secondary bacterial infection of eczema if an antibiotic was needed. The committee noted that this was a shorter duration than the previous recommendation in the NICE guideline on atopic eczema in under 12s, which says to use fusidic acid 2% for 1 to 2 weeks. They also discussed that the shorter duration had been recommended to provide effective treatment for the infection while reducing the risk of resistance occurring.
Return to the recommendations
# Treatment
## Why the committee made the recommendations
Recommendation 1.3.1
For this guideline, the committee considered the management of secondary bacterial infections in people with common skin conditions other than eczema, namely psoriasis, chicken pox, shingles and scabies. However, no evidence was found in these conditions. The committee agreed that it was not appropriate to extrapolate evidence from people with infected eczema to those with infected psoriasis, chicken pox, shingles or scabies. Therefore, no recommendations on the secondary bacterial infection of these other skin conditions were made, and the committee agreed that specialist advice should be sought where needed. The committee agreed that more research was needed on the optimum treatment of infected psoriasis, chicken pox, shingles and scabies, so made a recommendation for research.
Return to the recommendations# Context
Breaks in the skin caused by common skin conditions are particularly susceptible to infection. This is because bacteria that live on the skin may infiltrate the damaged area. The most common bacterial pathogens are Staphylococcus aureus (S. aureus) or Streptococcus pyogenes (S. pyogenes). The most commonly infected skin conditions are eczema, psoriasis, chicken pox, shingles and scabies.# Summary of the evidence
This is a summary of the evidence. For full details, see the evidence review.
All evidence identified included people with secondary bacterial infection of eczema. All the evidence either was in children, or the population was not reported, so it is unclear whether any studies included an adult population. The evidence for the efficacy, safety and resistance of antimicrobials is based on 1 systematic review and meta-analysis of randomised controlled trials (RCTs; George et al. 2019) and 2 RCTs (Larsen et al. 2007 and Francis et al. 2016). The evidence for choice of antibiotics is based on 1 RCT (Pratap et al. 2013). The evidence for route of administration of antibiotics is based on 2 RCTs (Francis et al. 2016 and Rist et al. 2002).
# Antimicrobials
## Efficacy of oral antibiotics
Evidence was from 1 systematic review of RCTs.
There were no statistically significant differences in clinical effectiveness, quality of life or microbiological outcomes for oral flucloxacillin compared with placebo in children with infected eczema. Both groups had corticosteroids and were encouraged to use emollients.
Some differences were seen in the presence of clinically apparent infection (definition unclear) at the end of treatment for oral cefadroxil compared with placebo in children with infected eczema (it was unclear whether topical corticosteroids were used in either group). However, there were no statistically significant differences in other clinical-effectiveness outcomes.
There were no differences in adverse events or withdrawals caused by adverse events for oral antibiotics (flucloxacillin or cefadroxil) compared with placebo in children with infected eczema.
## Efficacy of topical antibiotics
Evidence for efficacy of topical antibiotics was from 1 systematic review of RCTs.
Some statistically significant differences were seen for the following comparison in children with infected eczema:
topical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) reduced quality of life (using the Children's Dermatology Life Quality Index) compared with placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) at the end of treatment
topical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) was less effective at reducing the extent and severity of eczema (when measured with the Eczema Area and Severity Index) than placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) at the end of treatment.
There were no statistically significant differences in other quality of life, clinical-effectiveness or microbiological outcomes for the same comparison.
There were no statistically significant differences in clinical outcome for topical gentamicin plus a topical corticosteroid (betamethasone valerate) compared with a topical corticosteroid (betamethasone valerate) alone in children with infected eczema.
There were no statistically significant differences in microbiological outcomes for a topical antibiotic (fusidic acid or gentamicin) plus a topical corticosteroid (clobetasone butyrate, hydrocortisone or betamethasone valerate) compared with a topical corticosteroid (clobetasone butyrate, hydrocortisone or betamethasone valerate) alone in people (age not reported) with infected eczema.
There were no differences in adverse events for topical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) compared with a topical corticosteroid (clobetasone butyrate or hydrocortisone) alone in children with infected eczema.
## Efficacy of an antibiotic and corticosteroid combination compared with placebo alone
Evidence for efficacy of an antibiotic and corticosteroid combination compared with placebo alone was from 1 RCT.
Topical fusidic acid plus a topical corticosteroid (betamethasone valerate) was statistically significantly more effective than placebo for several 'responders' (people with a marked improvement or complete clearance of their eczema) and for several people with a successful biological response (baseline pathogen eradication or no visible target lesions) in children aged over 6 years, young people and adults. It was also statistically significantly more effective in terms of total severity score at end of treatment. There were no statistically significant differences in microbiological outcomes for the same comparison.
There were no differences in the number of people reporting adverse events for topical fusidic acid plus a topical corticosteroid (betamethasone valerate) compared with placebo in children with infected eczema. However, statistically significantly fewer people reported adverse drug reactions with topical fusidic acid plus a topical corticosteroid than with placebo.
## Efficacy of topical antiseptics
Evidence was from 1 systematic review of RCTs.
The study did not report any data (no event rates), so no conclusions could be made about the differences in clinical effectiveness for triclosan and benzalkonium chloride emollient in bath water compared with non-antimicrobial emollient in bath water in children with infected eczema.
## Efficacy of intranasal antibiotic with a bleach bath
Evidence was from 1 systematic review of RCTs.
Intranasal mupirocin (for decolonisation) plus a bleach bath was statistically significantly more effective than placebo in children with infected eczema for:
reducing the extent and severity of eczema (when measured with the Eczema Area and Severity Index) at 1 and 3 months after the start of treatment
the number of children with a reduced Investigators Global Assessment score at 3 months after the start of treatment.
There were no statistically significant differences in microbiological outcomes, withdrawals due to adverse events or minor adverse events for the same comparison.
## Antibiotic resistance
In 1 systematic review, there were no statistically significant differences in antibiotic resistance outcomes for topical fusidic acid plus a topical corticosteroid (betamethasone) compared with placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) in children aged over 6 years, young people and adults.
One systematic review found that topical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) in children aged over 8 years was associated with the presence of more Staphylococcus aureus (S. aureus) skin isolates resistant to fusidic acid than placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) at 2‑week follow up, but not at 3‑month follow up. There was no difference for S. aureus nose or mouth skin isolates at 2‑week or 3‑month follow up.
One systematic review found that topical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) was not statistically significantly different to placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) in children aged over 8 years for the presence of S. aureus nose, mouth or skin isolates resistant to oral flucloxacillin or oral erythromycin at 2‑week or 3‑month follow up.
In 1 systematic review, there were no statistically significant differences between oral flucloxacillin and placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) in children for the presence of S. aureus nose, mouth or skin isolates resistant to oral flucloxacillin, oral erythromycin or topical fusidic acid at 2‑week or 3‑month follow up.
In 1 RCT, treatment with topical fusidic acid was associated with more resistance to fusidic acid in S. aureus skin isolates taken 2 weeks after treatment than treatment with oral flucloxacillin in children with infected eczema.
No antibiotic resistance outcomes were reported for other comparisons.
# Choice of antibiotics
## Oral antibiotics
No evidence was identified for choice of oral antibiotic.
## Topical antibiotics
In 1 RCT, topical fusidic acid plus a topical corticosteroid (halometasone) was statistically significantly more effective than neomycin sulfate plus a topical corticosteroid (betamethasone) in reducing the number of people with a positive bacterial culture at day 10 or end of treatment (20 or 30 days) in adults with infected eczema. There were no statistically significant differences in clinical effectiveness or adverse events for the same comparison.
# Course length
No evidence was identified for course length.
# Route of administration
## Oral antibiotic compared with topical antibiotic
In 1 RCT, there were no statistically significant differences between topical fusidic acid and oral flucloxacillin (both groups had topical corticosteroids) in clinical-effectiveness outcomes, adverse events or healthcare use in children with infected eczema.
In 1 RCT, topical mupirocin was statistically significantly more effective than oral cefalexin at eradicating or improving S. aureus isolates in children aged over 8 years, young people and adults with infected eczema. Patient preference for treatment indicated that more people preferred topical treatment. There were no statistically significant differences in other microbiological outcomes, all clinical-effectiveness outcomes and adverse events for the same comparison.# Other considerations
# Medicines safety
As with all antibiotics, extended or recurrent use of topical fusidic acid may increase the risk of developing antimicrobial resistance. See the BNF for more information.
About 10% of the general population claim to have a penicillin allergy. This is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
Cholestatic jaundice and hepatitis can occur with flucloxacillin up to 2 months after stopping treatment, with risk factors being increasing age and use for more than 14 days (BNF information on flucloxacillin).
Macrolides should be used with caution in people with a predisposition to QT‑interval prolongation (BNF information on erythromycin).
See the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines.
# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).
# Resource implications
Recommended antibiotics are available as generic formulations. See the NHS Drug Tariff for costs.
See the evidence review for more information.
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{'Recommendations': "# Managing secondary bacterial infections of eczema\n\n## Treatment\n\nIn people with symptoms or signs of cellulitis, follow the NICE guideline on cellulitis and erysipelas: antimicrobial prescribing.\n\nManage underlying eczema and flares with treatments such as emollients and topical corticosteroids, whether antibiotics are offered or not (see the NICE guideline on atopic eczema in under\xa012s and also see NICE's technology appraisal guidance on alitretinoin for the treatment of severe chronic hand eczema, dupilumab for treating moderate to severe atopic dermatitis, tacrolimus and pimecrolimus for atopic eczema and frequency of application of topical corticosteroids for atopic eczema).\n\nBe aware that:\n\nthe symptoms and signs of secondary bacterial infection of eczema can include: weeping, pustules, crusts, no response to treatment, rapidly worsening eczema, fever and malaise\n\nnot all eczema flares are caused by a bacterial infection, so will not respond to antibiotics, even if weeping and crusts are present\n\neczema is often colonised with bacteria but may not be clinically infected\n\neczema can also be infected with herpes simplex virus (eczema herpeticum).For managing eczema and eczema herpeticum in children under\xa012, see the NICE guideline on atopic eczema in under\xa012s.\n\nDo not routinely take a skin swab for microbiological testing in people with secondary bacterial infection of eczema at the initial presentation.\n\nIn people who are not systemically unwell, do not routinely offer either a topical or oral antibiotic for secondary bacterial infection of eczema. Take into account:\n\nthe evidence, which suggests a limited benefit with antibiotics in addition to topical corticosteroids compared with topical corticosteroids alone\n\nthe risk of antimicrobial resistance with repeated courses of antibiotics\n\nthe extent and severity of symptoms or signs\n\nthe risk of developing complications, which is higher in people with underlying conditions such as immunosuppression.\n\nIf an antibiotic is offered to people who are not systemically unwell with a secondary bacterial infection of eczema (see the recommendations on choice of antibiotic), when choosing between a topical or oral antibiotic, take into account:\n\ntheir preferences (and those of their parents and carers as appropriate) for topical or oral administration\n\nthe extent and severity of symptoms or signs (a topical antibiotic may be more appropriate if the infection is localised and not severe; an oral antibiotic may be more appropriate if the infection is widespread or severe)\n\npossible adverse effects\n\nprevious use of topical antibiotics because antimicrobial resistance can develop rapidly with extended or repeated use.\n\nIn people who are systemically unwell, offer an oral antibiotic for secondary bacterial infection of eczema (see the recommendations on choice of antibiotic).\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on treatment\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Advice\n\nIf an antibiotic is not given, advise the person (and their parents and carers as appropriate):\n\nabout the reasons why an antibiotic is unlikely to provide any benefit\n\nto seek medical help if symptoms worsen rapidly or significantly at any time.\n\nIf an antibiotic is given, advise the person (and their parents and carers as appropriate):\n\nabout possible adverse effects\n\nabout the risk of developing antimicrobial resistance with extended or repeated use\n\nthat they should continue treatments such as emollients and topical corticosteroids\n\nthat it can take time for secondary bacterial infection of eczema to resolve, and full resolution is not expected until after the antibiotic course is completed\n\nto seek medical help if symptoms worsen rapidly or significantly at any time.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on advice\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Reassessment\n\nReassess people with secondary bacterial infection of eczema if:\n\nthey become systemically unwell or have pain that is out of proportion to the infection\n\ntheir symptoms worsen rapidly or significantly at any time\n\ntheir symptoms have not improved after completing a course of antibiotics.\n\nWhen reassessing people with secondary bacterial infection of eczema, take account of:\n\nother possible diagnoses, such as eczema herpeticum\n\nany symptoms or signs suggesting a more serious illness or condition, such as cellulitis, necrotising fasciitis or sepsis\n\nprevious antibiotic use, which may have caused resistant bacteria.\n\nFor people with secondary bacterial infection of eczema that is worsening or has not improved as expected, consider sending a skin swab for microbiological testing.\n\nFor people with secondary bacterial infection of eczema that recurs frequently:\n\nsend a skin swab for microbiological testing and\n\nconsider taking a nasal swab and starting treatment for decolonisation.\n\nIf a skin swab has been sent for microbiological testing:\n\nreview the choice of antibiotic when results are available and\n\nchange the antibiotic according to results if symptoms are not improving, using a narrow‑spectrum antibiotic if possible.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on reassessment\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Referral and seeking specialist advice\n\nRefer people with secondary bacterial infection of eczema to hospital if they have any symptoms or signs suggesting a more serious illness or condition, such as necrotising fasciitis or sepsis.\n\nConsider referral or seeking specialist advice for people with secondary bacterial infection of eczema if they:\n\nhave spreading infection that is not responding to oral antibiotics\n\nare systemically unwell\n\nare at high risk of complications\n\nhave infections that recur frequently.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on referral and seeking specialist advice\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic for secondary bacterial infection of eczema, take account of local antimicrobial resistance data when available and follow:\n\ntable\xa01 for adults aged 18\xa0years and over\n\ntable\xa02 for children and young people under 18\xa0years (for children under 1\xa0month, antibiotic choice is based on specialist advice).\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFor secondary bacterial infection of eczema in people who are not systemically unwell\n\nDo not routinely offer either a topical or oral antibiotic\n\nFirst-choice topical\n if a topical antibiotic is appropriate (see recommendations 1.1.5 and 1.1.6)\n\nFusidic acid\xa02%:\n\nApply three\xa0times a day for 5\xa0to 7\xa0days\n\nFor localised infections only. Extended or recurrent use may increase the risk of developing antimicrobial resistance.\n\nFirst-choice oral\n if an oral antibiotic is appropriate (see recommendations 1.1.5 to 1.1.7)\n\nFlucloxacillin:\n\nmg four\xa0times a day for 5\xa0to 7\xa0days\n\nAlternative oral antibiotic for penicillin allergy or if flucloxacillin is unsuitable (for people who are not pregnant)\n\nClarithromycin:\n\nmg twice a day for 5\xa0to 7\xa0days\n\nThe dosage can be increased to 500\xa0mg twice a day for severe infections.\n\nAlternative oral antibiotic for penicillin allergy in pregnancy\n\nErythromycin:\n\nmg to 500\xa0mg four\xa0times a day for 5\xa0to 7\xa0days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nIf meticillin-resistant \n \n Staphylococcus aureus\n \n is suspected or confirmed\n\nConsult a microbiologist\n\nSee the BNF for appropriate use and dosing of the antibiotics recommended in specific populations, for example, people with hepatic or renal impairment, and in pregnancy and breastfeeding.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFor secondary bacterial infection of eczema in people who are not systemically unwell\n\nDo not routinely offer either a topical or oral antibiotic\n\nFirst-choice topical if a topical antibiotic is appropriate (see recommendations 1.1.5 and 1.1.6)\n\nFusidic acid 2%:\n\nApply three\xa0times a day for 5\xa0to 7\xa0days\n\nFor localised infections only. Extended or recurrent use may increase the risk of developing antimicrobial resistance.\n\nFirst-choice oral if an oral antibiotic is appropriate (see recommendations 1.1.5 to 1.1.7)\n\nFlucloxacillin (oral solution or capsules):\n\nmonth to 1\xa0year: 62.5\xa0mg to 125\xa0mg four\xa0times a day for 5\xa0to 7\xa0days\n\nyears to 9\xa0years: 125\xa0mg to 250\xa0mg four\xa0times a day for 5\xa0to 7\xa0days\n\nyears to 17\xa0years: 250\xa0mg to 500\xa0mg four\xa0times a day for 5\xa0to 7\xa0days\n\nAlternative oral antibiotic for penicillin allergy or if flucloxacillin is unsuitable (for people who are not pregnant)\n\nClarithromycin:\n\nmonth to 11\xa0years:\n\nunder 8\xa0kg: 7.5\xa0mg/kg twice a day for 5\xa0to 7\xa0days\n\nkg to 11\xa0kg: 62.5\xa0mg twice a day for 5\xa0to 7\xa0days\n\nkg to 19\xa0kg: 125\xa0mg twice a day for 5\xa0to 7\xa0days\n\nkg to 29\xa0kg: 187.5\xa0mg twice a day for 5\xa0to 7\xa0days\n\nkg to 40\xa0kg: 250\xa0mg twice a day for 5\xa0to 7\xa0days\n\nyears to 17\xa0years:\n\nmg twice a day for 5\xa0to 7\xa0days. The dosage can be increased to 500\xa0mg twice a day for severe infections\n\nAlternative oral antibiotic for penicillin allergy in pregnancy\n\nErythromycin:\n\nyears to 17\xa0years: 250\xa0mg to 500\xa0mg four\xa0times a day for 5\xa0to 7\xa0days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nIf meticillin-resistant \n \n Staphylococcus aureus\n \n is suspected or confirmed\n\nConsult a local microbiologist\n\nSee the BNF for Children for appropriate use and dosing of the antibiotics recommended in specific populations, for example, people with hepatic or renal impairment, and in pregnancy and breastfeeding.\n\nThe age bands for children apply to children of average size. In practice, they will be used alongside other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.\n\nFor advice on helping children to swallow medicines, see Medicines for Children's leaflet on helping your child to swallow tablets.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on choice of antibiotic\xa0.\n\nFor more details, see the summary of the evidence.\n\nLoading. Please wait.\n\n# Managing secondary bacterial infections of psoriasis, chicken pox, shingles and scabies\n\n## Treatment\n\nBe aware that no evidence was found on the use of antibiotics in managing secondary bacterial infections of other common skin conditions such as psoriasis, chicken pox, shingles and scabies. Seek specialist advice, if needed.\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on treatment\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Antibiotics (oral route) compared with topical treatments (antiseptics or antibiotics) or placebo for infected psoriasis, chicken pox, shingles or scabies\n\nWhat is the clinical effectiveness and safety of oral antibiotics compared with topical treatments (antiseptics or antibiotics) or placebo for treating infected psoriasis, chicken pox, shingles or scabies in adults, young people and children?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on treatment\xa0.\n\nLoading. Please wait.\n\n# Antiseptic bath emollient compared with non-antiseptic bath emollient for infected eczema\n\nWhat is the clinical effectiveness and safety of antiseptic bath emollient compared with non-antiseptic bath emollient for treating infected eczema in adults, young people and children?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on treatment\xa0.\n\nLoading. Please wait.', 'Rationales': "The recommendations in this guideline are based on the evidence identified and the experience of the committee.\n\n# Treatment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.1 to 1.1.7\n\nThe committee agreed, based on their experience, that it is important to optimally manage underlying eczema in people who present with a suspected secondary bacterial infection, for example, with emollients and topical corticosteroids. They also agreed that it is important to optimally manage flares in all people with stepped topical corticosteroids; for managing eczema in children under\xa012, there are recommendations on the use of stepped corticosteroids in the NICE guideline on atopic eczema in under 12s. The committee also noted that information on optimally managing atopic eczema in all people (aged over 1\xa0month) was available in NICE's clinical knowledge summary on atopic eczema.\n\nThe committee agreed with the symptoms and signs of secondary bacterial infection of eczema in the NICE guideline on atopic eczema in under 12s. The committee recognised that, in practice, it can be difficult to tell the difference between a non-infected flare of eczema and eczema that has become infected. There may be no bacterial infection even if there are classic signs of infection such as weeping and crusts. A more useful indicator of infection may be that a person feels systemically unwell with fever or malaise. However, without definitive diagnostic criteria, diagnosing secondary bacterial infection of eczema will be based on history taking and the person's (or parent's or carer's) knowledge of their own condition. The committee also discussed that healthcare professionals should be aware that redness, one of the signs of infection, may be less visible on darker skin tones.\n\nThe committee agreed that skin swabs for microbiological testing should not routinely be taken at the initial presentation of a suspected secondary bacterial infection of eczema. The skin of people with eczema is often heavily colonised with Staphylococcus aureus (S.\xa0aureus) bacteria, and bacterial growth from a skin swab is likely regardless of infection status. Taking skin swabs from everyone with a suspected infection could lead to inappropriate antibiotic prescribing. If the eczema is clinically infected, the most likely causative organisms are S.\xa0aureus or Streptococcus pyogenes (S.\xa0pyogenes), so empirical treatment with topical fusidic acid or oral flucloxacillin would be effective.\n\nThe evidence suggested that using topical or oral antibiotics in addition to topical corticosteroids offered little benefit over using topical corticosteroids alone in people with a suspected secondary bacterial infection of eczema. The committee agreed that the evidence is limited because there are no definitive criteria for diagnosing a secondary bacterial infection. The committee went on to discuss that the available evidence was in children (or it was unclear whether the population included adults); they noted that the results from the evidence in children could be extrapolated to adults because the response to treatment would be sufficiently similar across different age groups. The committee also notes that trials have often excluded people with a severe infection or at high risk of complications from an infection.\n\nBecause a severe secondary bacterial infection of eczema could lead to a more serious illness or condition, such as cellulitis, the committee agreed that people who are systemically unwell, for example, with fever or malaise, should be offered an oral antibiotic. If the symptoms or signs of infection suggest cellulitis, the committee agreed that it should be managed with antibiotics as outlined in the NICE guideline on cellulitis and erysipelas: antimicrobial prescribing.\n\nHowever, for people who are not systemically unwell, the committee agreed that an antibiotic is not routinely needed. This was based on evidence from a UK trial in children with clinically infected eczema. In this trial, a 7‑day course of topical fusidic acid or oral flucloxacillin had no benefit in terms of clinical effectiveness, quality of life or microbiological outcomes over standard treatment with topical corticosteroids.\n\nAnother trial in children, young people and adults with clinically infected eczema showed that topical fusidic acid plus a topical corticosteroid was not more effective than placebo plus a topical corticosteroid for clinical and biological response. The committee agreed, based on their experience, that this reinforced the importance of topical corticosteroid use during a flare. People should continue to use topical corticosteroids if their eczema is infected, matching the potency of the corticosteroid to the severity of eczema. This aligns with recommendations in the NICE guideline on atopic eczema in under\xa012s and in NICE's clinical knowledge summary on atopic eczema.\n\nThe committee agreed that if, after considering a person's history and clinical presentation, an antibiotic is clinically needed for infected eczema, a short course of a topical or oral antibiotic may be appropriate. The choice of a topical or oral antibiotic would be an individual clinical decision taking into account the extent and severity of symptoms or signs, and the risk of developing complications. Local antimicrobial resistance data, patient preference, administration practicalities (particularly to large areas), possible adverse effects and previous use would also need to be taken into account.\n\nAntimicrobial resistance can develop rapidly with topical antibiotics. The committee agreed that repeated doses or extended use of the same topical antibiotic should be avoided. Evidence from a 2016 UK trial showed that there was more resistance to fusidic acid (after a 7‑day course) in S.\xa0aureus skin isolates than with oral flucloxacillin treatment. But there were no statistically significant differences in the trial in clinical effectiveness, adverse events, other antibiotic resistance outcomes or healthcare use between the topical and oral treatment. However, in a Danish trial from 2007 comparing topical fusidic acid plus a topical corticosteroid with placebo, there was no statistically significant difference between the groups in the number of S.\xa0aureus isolates resistant to fusidic acid after 14\xa0days of treatment.\n\nAfter discussing the evidence for antiseptics, the committee agreed that there was insufficient evidence on whether an antiseptic bath emollient was more effective than a standard bath emollient in children with infected eczema. Therefore, the committee made no recommendations on using antiseptic bath emollients, and made a recommendation for research.\n\nThe only evidence found for bleach baths (half a cup of 6% bleach in a bath, final concentration 0.005%; bathing for 5\xa0to 10\xa0minutes twice weekly) was a small trial of intranasal mupirocin (for decolonisation) plus a bleach bath compared with placebo in children and young people with secondary bacterial infection of eczema. This combination was more effective than placebo in children with infected eczema for several clinical-effectiveness outcomes. However, the committee agreed that this trial did not provide evidence that bleach baths alone are effective.\n\nReturn to the recommendations\n\n# Advice\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.8 and 1.1.9\n\nA severe bacterial infection of eczema could lead to a more serious illness or condition, such as cellulitis. So, the committee agreed that people should be advised to seek medical help if their symptoms worsen rapidly or significantly at any time. This is particularly important if they did not have antibiotics initially, or their symptoms have not improved after completing a course of antibiotics.\n\nHowever, people should also be advised that it can take time for infected eczema to resolve, and that there may not be full symptom resolution until after they have finished the course of antibiotics.\n\nReturn to the recommendations\n\n# Reassessment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.10 to 1.1.14\n\nBased on experience, the committee agreed when people with secondary bacterial infection of eczema should be reassessed. If symptoms of the infection worsen rapidly or significantly at any time, or do not start to improve after completing a course of antibiotics, this may indicate that the person has a more serious illness needing referral, or a resistant infection (possibly because of previous antibiotic use).\n\nThe committee agreed that people need to be reassessed if they are systemically unwell or have severe pain that is out of proportion to the infection (this can be a symptom of necrotising fasciitis, which is a rare but serious bacterial infection). The committee discussed that, at reassessment, it is important to consider other possible diagnoses, including viral (rather than bacterial) infection; for example, eczema herpeticum.\n\nThe committee agreed that it would be appropriate to send a skin swab for microbiological testing if the infection recurs frequently, and to consider doing this if the symptoms or signs of the infection are worsening or have not improved as expected. This will guide future antibiotic choice if the person has a resistant infection. A nasal swab should also be considered if nasal carriage of S.\xa0aureus is suspected. A nasal or skin (or both) decolonisation regimen should be considered, based on clinical judgement and microbiological test results, to remove the bacteria causing recurring infection. The committee agreed that decolonisation is supported by the small trial of intranasal mupirocin plus a bleach bath in children with infected eczema. The committee recognised that family decolonisation may sometimes be appropriate, but did not make a recommendation because this decision should be based on specialist advice.\n\nThe committee agreed on good practice for antimicrobial stewardship when reviewing the results of microbiological tests.\n\nReturn to the recommendations\n\n# Referral and seeking specialist advice\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.15 and 1.1.16\n\nBased on their experience, the committee agreed that people with secondary bacterial infection of eczema who may have a more serious illness or condition need referral for further assessment and treatment in hospital.\n\nReturn to the recommendations\n\n# Choice of antibiotic\n\n## Why the committee made the recommendations\n\nRecommendation 1.2.1\n\nMost of the evidence for topical antibiotics was for fusidic acid. The committee agreed that this was more effective than topical neomycin sulfate for microbiological outcomes in 1\xa0trial. Topical mupirocin was more effective than oral cefalexin for some microbiological outcomes (but not others) in 1\xa0trial. However, there was no evidence comparing topical mupirocin with topical fusidic acid.\n\nBased on committee experience, current practice and limited evidence, the committee agreed that the first-choice topical antibiotic in adults, young people and children with secondary bacterial infection of eczema is fusidic acid 2% (either as a cream or an ointment). A topical rather than an oral antibiotic is more appropriate if the person is not systemically unwell, and the infection is localised and not severe. The committee discussed that, in the absence of strong evidence, fusidic acid 2% was the most appropriate first-choice topical antibiotic because topical mupirocin should be reserved for treating meticillin-resistant S.\xa0aureus (MRSA) colonisation.\n\nBased on their experience and limited evidence, the committee agreed that fusidic acid resistance rates are higher than for some other antibiotics, so previous use should be considered to avoid extended or repeated use. National antimicrobial resistance data from Public Health England's voluntary surveillance reports on Staphylococcus aureus showed fusidic acid resistance rates of 13% for meticillin-susceptible S.\xa0aureus bloodstream infections and of 25% for MRSA bloodstream infections. However, the committee discussed that resistance rates in blood isolates may not be a good indicator of resistance rates in skin isolates. These can vary greatly from person to person based on their history of antibiotic use and between localities.\n\nThe committee did not recommend an alternative topical antibiotic for secondary bacterial infection of eczema. This was because, if fusidic acid is unsuitable or ineffective, an oral antibiotic is preferred.\n\nBased on their experience and knowledge of current practice, the committee agreed that the first-choice oral antibiotic in adults, young people and children with secondary bacterial infection of eczema is flucloxacillin. An oral rather than a topical antibiotic is more appropriate if the person is systemically unwell, or if the infection is widespread or severe. Flucloxacillin is a relatively narrow‑spectrum penicillin that is effective against S.\xa0aureus and S.\xa0pyogenes. The committee recognised that some children cannot tolerate flucloxacillin solution. However, they were aware of many useful resources that are available (for example, Medicines for Children's leaflet on helping your child to swallow tablets) to teach children how to swallow tablets or capsules. For children who are unable to swallow capsules, 1\xa0of the alternative oral antibiotics is suitable.\n\nThe alternative oral antibiotic in adults, young people and children with penicillin allergy or if flucloxacillin is unsuitable, is clarithromycin. In pregnancy, erythromycin was recommended if there is true penicillin allergy. The committee agreed that these antibiotics are effective against the common pathogens that cause secondary bacterial infection of eczema.\n\nThe committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.\n\nThe committee noted that, in their experience, MRSA infection in secondary bacterial infection of eczema is rare and that appropriate antibiotic choice may depend on local antimicrobial resistance rates. Therefore, they agreed that, if MRSA is suspected or confirmed, a local microbiologist should be consulted.\n\nNo evidence was identified for course length. Therefore, the recommendations were based on committee experience of current practice. The committee also agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and adverse effects. Based on their experience that lower doses (250\xa0mg four times a day) of flucloxacillin are not clinically effective because of poor oral bioavailability, the committee agreed that the higher dose for flucloxacillin of 500\xa0mg four times a day is appropriate for treating secondary bacterial infection of eczema in adults. They agreed that dose ranges are appropriate for children because the appropriate dose may vary depending on the severity of the infection and the age and weight of the child.\n\nFrom their experience, the committee agreed that 5\xa0to 7\xa0days of treatment, based on clinical assessment, would be sufficient for treating secondary bacterial infection of eczema if an antibiotic was needed. The committee noted that this was a shorter duration than the previous recommendation in the NICE guideline on atopic eczema in under 12s, which says to use fusidic acid 2% for 1\xa0to 2\xa0weeks. They also discussed that the shorter duration had been recommended to provide effective treatment for the infection while reducing the risk of resistance occurring.\n\nReturn to the recommendations\n\n# Treatment\n\n## Why the committee made the recommendations\n\nRecommendation 1.3.1\n\nFor this guideline, the committee considered the management of secondary bacterial infections in people with common skin conditions other than eczema, namely psoriasis, chicken pox, shingles and scabies. However, no evidence was found in these conditions. The committee agreed that it was not appropriate to extrapolate evidence from people with infected eczema to those with infected psoriasis, chicken pox, shingles or scabies. Therefore, no recommendations on the secondary bacterial infection of these other skin conditions were made, and the committee agreed that specialist advice should be sought where needed. The committee agreed that more research was needed on the optimum treatment of infected psoriasis, chicken pox, shingles and scabies, so made a recommendation for research.\n\nReturn to the recommendations", 'Context': 'Breaks in the skin caused by common skin conditions are particularly susceptible to infection. This is because bacteria that live on the skin may infiltrate the damaged area. The most common bacterial pathogens are Staphylococcus aureus (S.\xa0aureus) or Streptococcus pyogenes (S.\xa0pyogenes). The most commonly infected skin conditions are eczema, psoriasis, chicken pox, shingles and scabies.', 'Summary of the evidence': "This is a summary of the evidence. For full details, see the evidence review.\n\nAll evidence identified included people with secondary bacterial infection of eczema. All the evidence either was in children, or the population was not reported, so it is unclear whether any studies included an adult population. The evidence for the efficacy, safety and resistance of antimicrobials is based on 1\xa0systematic review and meta-analysis of randomised controlled trials (RCTs; George et al. 2019) and 2\xa0RCTs (Larsen et al. 2007 and Francis et al. 2016). The evidence for choice of antibiotics is based on 1\xa0RCT (Pratap et al. 2013). The evidence for route of administration of antibiotics is based on 2\xa0RCTs (Francis et al. 2016 and Rist et al. 2002).\n\n# Antimicrobials\n\n## Efficacy of oral antibiotics\n\nEvidence was from 1\xa0systematic review of RCTs.\n\nThere were no statistically significant differences in clinical effectiveness, quality of life or microbiological outcomes for oral flucloxacillin compared with placebo in children with infected eczema. Both groups had corticosteroids and were encouraged to use emollients.\n\nSome differences were seen in the presence of clinically apparent infection (definition unclear) at the end of treatment for oral cefadroxil compared with placebo in children with infected eczema (it was unclear whether topical corticosteroids were used in either group). However, there were no statistically significant differences in other clinical-effectiveness outcomes.\n\nThere were no differences in adverse events or withdrawals caused by adverse events for oral antibiotics (flucloxacillin or cefadroxil) compared with placebo in children with infected eczema.\n\n## Efficacy of topical antibiotics\n\nEvidence for efficacy of topical antibiotics was from 1\xa0systematic review of RCTs.\n\nSome statistically significant differences were seen for the following comparison in children with infected eczema:\n\ntopical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) reduced quality of life (using the Children's Dermatology Life Quality Index) compared with placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) at the end of treatment\n\ntopical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) was less effective at reducing the extent and severity of eczema (when measured with the Eczema Area and Severity Index) than placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) at the end of treatment.\n\nThere were no statistically significant differences in other quality of life, clinical-effectiveness or microbiological outcomes for the same comparison.\n\nThere were no statistically significant differences in clinical outcome for topical gentamicin plus a topical corticosteroid (betamethasone valerate) compared with a topical corticosteroid (betamethasone valerate) alone in children with infected eczema.\n\nThere were no statistically significant differences in microbiological outcomes for a topical antibiotic (fusidic acid or gentamicin) plus a topical corticosteroid (clobetasone butyrate, hydrocortisone or betamethasone valerate) compared with a topical corticosteroid (clobetasone butyrate, hydrocortisone or betamethasone valerate) alone in people (age not reported) with infected eczema.\n\nThere were no differences in adverse events for topical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) compared with a topical corticosteroid (clobetasone butyrate or hydrocortisone) alone in children with infected eczema.\n\n## Efficacy of an antibiotic and corticosteroid combination compared with placebo alone\n\nEvidence for efficacy of an antibiotic and corticosteroid combination compared with placebo alone was from 1\xa0RCT.\n\nTopical fusidic acid plus a topical corticosteroid (betamethasone valerate) was statistically significantly more effective than placebo for several 'responders' (people with a marked improvement or complete clearance of their eczema) and for several people with a successful biological response (baseline pathogen eradication or no visible target lesions) in children aged over 6\xa0years, young people and adults. It was also statistically significantly more effective in terms of total severity score at end of treatment. There were no statistically significant differences in microbiological outcomes for the same comparison.\n\nThere were no differences in the number of people reporting adverse events for topical fusidic acid plus a topical corticosteroid (betamethasone valerate) compared with placebo in children with infected eczema. However, statistically significantly fewer people reported adverse drug reactions with topical fusidic acid plus a topical corticosteroid than with placebo.\n\n## Efficacy of topical antiseptics\n\nEvidence was from 1\xa0systematic review of RCTs.\n\nThe study did not report any data (no event rates), so no conclusions could be made about the differences in clinical effectiveness for triclosan and benzalkonium chloride emollient in bath water compared with non-antimicrobial emollient in bath water in children with infected eczema.\n\n## Efficacy of intranasal antibiotic with a bleach bath\n\nEvidence was from 1\xa0systematic review of RCTs.\n\nIntranasal mupirocin (for decolonisation) plus a bleach bath was statistically significantly more effective than placebo in children with infected eczema for:\n\nreducing the extent and severity of eczema (when measured with the Eczema Area and Severity Index) at 1\xa0and 3\xa0months after the start of treatment\n\nthe number of children with a reduced Investigators Global Assessment score at 3\xa0months after the start of treatment.\n\nThere were no statistically significant differences in microbiological outcomes, withdrawals due to adverse events or minor adverse events for the same comparison.\n\n## Antibiotic resistance\n\nIn 1\xa0systematic review, there were no statistically significant differences in antibiotic resistance outcomes for topical fusidic acid plus a topical corticosteroid (betamethasone) compared with placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) in children aged over 6\xa0years, young people and adults.\n\nOne systematic review found that topical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) in children aged over 8\xa0years was associated with the presence of more Staphylococcus aureus (S.\xa0aureus) skin isolates resistant to fusidic acid than placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) at 2‑week follow up, but not at 3‑month follow up. There was no difference for S.\xa0aureus nose or mouth skin isolates at 2‑week or 3‑month follow up.\n\nOne systematic review found that topical fusidic acid plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) was not statistically significantly different to placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) in children aged over 8\xa0years for the presence of S.\xa0aureus nose, mouth or skin isolates resistant to oral flucloxacillin or oral erythromycin at 2‑week or 3‑month follow up.\n\nIn 1\xa0systematic review, there were no statistically significant differences between oral flucloxacillin and placebo plus a topical corticosteroid (clobetasone butyrate or hydrocortisone) in children for the presence of S.\xa0aureus nose, mouth or skin isolates resistant to oral flucloxacillin, oral erythromycin or topical fusidic acid at 2‑week or 3‑month follow up.\n\nIn 1\xa0RCT, treatment with topical fusidic acid was associated with more resistance to fusidic acid in S.\xa0aureus skin isolates taken 2\xa0weeks after treatment than treatment with oral flucloxacillin in children with infected eczema.\n\nNo antibiotic resistance outcomes were reported for other comparisons.\n\n# Choice of antibiotics\n\n## Oral antibiotics\n\nNo evidence was identified for choice of oral antibiotic.\n\n## Topical antibiotics\n\nIn 1\xa0RCT, topical fusidic acid plus a topical corticosteroid (halometasone) was statistically significantly more effective than neomycin sulfate plus a topical corticosteroid (betamethasone) in reducing the number of people with a positive bacterial culture at day\xa010 or end of treatment (20\xa0or 30\xa0days) in adults with infected eczema. There were no statistically significant differences in clinical effectiveness or adverse events for the same comparison.\n\n# Course length\n\nNo evidence was identified for course length.\n\n# Route of administration\n\n## Oral antibiotic compared with topical antibiotic\n\nIn 1\xa0RCT, there were no statistically significant differences between topical fusidic acid and oral flucloxacillin (both groups had topical corticosteroids) in clinical-effectiveness outcomes, adverse events or healthcare use in children with infected eczema.\n\nIn 1\xa0RCT, topical mupirocin was statistically significantly more effective than oral cefalexin at eradicating or improving S.\xa0aureus isolates in children aged over 8\xa0years, young people and adults with infected eczema. Patient preference for treatment indicated that more people preferred topical treatment. There were no statistically significant differences in other microbiological outcomes, all clinical-effectiveness outcomes and adverse events for the same comparison.", 'Other considerations': '# Medicines safety\n\nAs with all antibiotics, extended or recurrent use of topical fusidic acid may increase the risk of developing antimicrobial resistance. See the BNF for more information.\n\nAbout 10% of the general population claim to have a penicillin allergy. This is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nCholestatic jaundice and hepatitis can occur with flucloxacillin up to 2\xa0months after stopping treatment, with risk factors being increasing age and use for more than 14\xa0days (BNF information on flucloxacillin).\n\nMacrolides should be used with caution in people with a predisposition to QT‑interval prolongation (BNF information on erythromycin).\n\nSee the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines.\n\n# Medicines adherence\n\nMedicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).\n\n# Resource implications\n\nRecommended antibiotics are available as generic formulations. See the NHS Drug Tariff for costs.\n\nSee the evidence review for more information.'}
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https://www.nice.org.uk/guidance/ng190
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This guideline sets out an antimicrobial prescribing strategy for secondary bacterial infection of eczema and covers infection of other common skin conditions. It aims to optimise antibiotic use and reduce antibiotic resistance. The recommendations are for adults, young people and children aged 72 hours and over. They do not cover diagnosis.
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9038f7335776752761615682b2ab65275355e679
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nice
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Safeguarding adults in care homes
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Safeguarding adults in care homes
This guideline covers keeping adults in care homes safe from abuse and neglect. It includes potential indicators of abuse and neglect by individuals or organisations, and covers the safeguarding process from when a concern is first identified through to section 42 safeguarding enquiries. There are recommendations on policy, training, and care home culture, to improve care home staff awareness of safeguarding and ensure people can report concerns when needed.
# Context
According to the Care Quality Commission's state of care report for 2019/20, there are over 10,800 residential care homes and 4,200 nursing homes in the UK. These provide support to around 410,000 older people (as estimated by the 2017 Competition and Markets Authority care homes market study), and to many younger adults with disabilities, mental health issues or complex support needs. In addition to long‑term residents, residential and nursing homes provide services for people who stay for shorter periods, including as day visitors. This is sometimes referred to as respite care or short break services. Many of these long- and short‑term residents have high care and support needs, and this means they are at an increased risk of abuse and neglect.
The quality of care in many care homes is good, but this is not always the case. The Care Quality Commission's report 2019/20 rated homes as follows:
inadequate: 2% of nursing homes and 1% of care homes
requiring improvement: 21% of nursing homes and 14% of care homes
good: 72% of nursing homes and 81% of care homes
-utstanding: 5% of nursing homes and 4% of care homes.
All adult safeguarding, including safeguarding in care homes, should be underpinned by the Care Act 2014, the Care Act 2014 statutory guidance, and the Making Safeguarding Personal framework.
Despite the legal framework and the associated statutory guidance, safeguarding procedures and practice vary at the local level. In particular, care homes often struggle to understand:
the difference between safeguarding issues and poor practice
when and how to make safeguarding referrals to the local authority.
The Safeguarding Adults 2019 Annual Report reported that care homes (including homes with and without nursing) accounted for 34% of all safeguarding enquiries conducted under section 42 of the Care Act 2014.
This guideline makes action-orientated recommendations to improve safeguarding for residents of care homes. It covers all adult residents of care homes, including people who stay at care homes for shorter periods (for example day visitors).
The guideline is based on:
the best available evidence on effectiveness (including cost effectiveness)
evidence on the views and experiences of care home residents, their families and carers, and practitioners involved in care and support for residents.
The guideline is also informed by existing adult safeguarding guidance from across these different sectors, including:
Association of Directors of Adult Social Services, Local Government Association (2019) Making decisions on the duty to carry out Safeguarding Adults enquiries.
Association of Directors of Adult Social Services, Social Care Institute for Excellence, National Health Service London, Metropolitan Police (2019) London multi-agency adult safeguarding policy and procedures.
Association of Directors of Adult Social Services North East (2011) Safeguarding threshold guidance.
Department of Health, Social Services and Public Safety (2009) Adult abuse: recognising adult abuse and what to do about it! Guidance for staff.
Royal College of Nursing (2018) Adult safeguarding: roles and competencies for healthcare staff.
Skills for Care (2017) What do I need to know about safeguarding adults?
Social Care Institute for Excellence (2018) Adult safeguarding practice questions.
Social Care Institute for Excellence (2015) At a glance 69: Safeguarding adults: Types and indicators of abuse.
Social Care Wales (2019) The social care manager: practice guidance for social care managers registered with Social Care Wales.
Volunteer Now (2010) Safeguarding vulnerable adults: a shared responsibility.
This guideline can be used together with the Making Safeguarding Personal resources published by the Local Government Association and ADASS, including understanding what constitutes a safeguarding concern and how to support effective outcomes.
The core legal duty for adult safeguarding is found in section 42 of the Care Act 2014.
The Care Act 2014 statutory guidance states that:
'Effective safeguarding is about seeking to promote an adult's rights to security, liberty and family life, as well as about protecting their physical safety and taking action to prevent the occurrence or reoccurrence of abuse or neglect. Any restriction on the individual's rights or freedom of action that is involved in the exercise of the function is kept to the minimum necessary.'
The local authority is the lead agency for adult safeguarding and should be notified whenever abuse or neglect is suspected. They will decide whether a safeguarding enquiry is necessary, and if so who will conduct it. The decision to conduct an enquiry depends on the criteria set out in the Care Act, and not on whether a person is eligible for or receiving services funded by the local authority.
Any actions taken in relation to a safeguarding concern should be based on the 6 principles set out in the Care Act statutory guidance. These principles should be known and understood by everyone working in care homes and should be part of their everyday practice:
. Empowerment: People being supported and encouraged to make their own decisions and informed consent.
. Prevention: It is better to take action before harm occurs.
. Proportionality: The least intrusive response appropriate to the risk presented.
. Protection: Support and representation for those in greatest need.
. Partnerships: Local solutions through services working with their communities. Communities have a part to play in preventing, detecting and reporting neglect and abuse.
. Accountability: Accountability and transparency in delivering safeguarding.
As well as the 6 principles, this guideline also recognises the importance of the wellbeing principle within the Care Act, and the safeguarding approaches based on the Making Safeguarding Personal framework. These both emphasise that people who have experienced or are at risk of abuse or neglect should be meaningfully involved in safeguarding whenever possible. Outcomes should be meaningful to the person, rather than simply following a process.
This approach is also endorsed by the Care Act statutory guidance, which states that:
'… safeguarding means protecting an adult's right to live in safety, free from abuse and neglect. It is about people and organisations working together to prevent and stop both the risks and experience of abuse or neglect, while at the same time making sure that the adult's wellbeing is promoted including, where appropriate, having regard to their views, wishes, feelings and beliefs in deciding on any action. This must recognise that adults sometimes have complex interpersonal relationships and may be ambivalent, unclear or unrealistic about their personal circumstances.'
The guideline complements statutory duties and good practice as set out in relevant legislation and guidance. The recommendations cross-refer to legislation and other guidance where appropriate. In particular, the guideline takes account of the Care Act 2014 and the Care Act 2014 statutory guidance, the Mental Health Acts 1983 and 2007, and the Health and Social Care Act 2008. It is also underpinned by the Human Rights Act 1998, notably Article 3 (No one shall be subjected to torture or to inhuman or degrading treatment or punishment), Article 5 (Right to liberty and security) and Article 8 (Right to respect for private and family life).
Also, because many people who use care homes may lack the capacity to make certain decisions, this guidance is also informed by the Mental Capacity Act 2005 and the Mental Capacity (Amendment) Act 2019. When a care home resident lacks capacity, this guideline should be used in line with the NICE guideline on decision making and mental capacity and relevant local guidance on this issue.
NICE guidelines provide recommendations on what works. This may include details on who should carry out interventions and where. NICE guidelines do not routinely describe how services are funded or commissioned, unless this has been formally requested by the Department of Health and Social Care.
The Care Quality Commission encourages health and social care providers to use NICE guidance to improve the quality of care they provide. Evidence of use and compliance with NICE guidance will help services achieve a Good or Outstanding rating.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Policy and procedure
## Care home safeguarding policy and procedure
Care homes and care home providers must have a safeguarding policy and procedure in place, to meet the requirements of the Care Act 2014 and the Care Act 2014 statutory guidance and to follow local safeguarding arrangements (overseen by the local Safeguarding Adults Board). Providers that operate across more than one area must ensure that each care home follows the local safeguarding arrangements in their area.
Care home and care home provider safeguarding policies should:
be clearly written and in line with Accessible Information Standard requirements to meet the communication support needs of individual residents
be easy to find, so that all residents, staff, visitors and service providers can request and read it when they need to
include clear and transparent arrangements for identifying, responding to and managing safeguarding concerns, and involve residents (and their families and carers) in designing and reviewing these arrangements
explain how to respond to safeguarding concerns, and how to report suspected abuse or neglect
be based on the principle of collaborative working, because safeguarding is everyone's responsibility.
Care homes and care home providers should have systems in place to track and monitor incidents, accidents, disciplinary action, complaints and safeguarding concerns, to identify patterns of potential harm.
Care homes should have systems in place for preserving evidence from reported safeguarding concerns, including care records, as these may be required in future, for example for local authority enquiries or police investigations.
Care homes should have a procedure for recording and sharing information (in line with data protection laws) about safeguarding concerns.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home safeguarding policy and procedure .
Full details of the evidence and the committee's discussion are in:
evidence review B: barriers and facilitators to identifying abuse and neglect
evidence review D: responding to and managing safeguarding concerns
evidence review C: tools to support recognition and reporting of safeguarding concerns.
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## Care home whistleblowing policy and procedure
Care homes and care home providers should have a whistleblowing policy and procedure, and make sure that staff and volunteers are aware of these.
Care home providers should have a clear procedure setting out how staff and volunteers can report a whistleblowing concern. This process must specify who people can contact, and how (for example a senior contact within a care home group, and the local authority or the Care Quality Commission). For more information, see the Care Quality Commission guidance on whistleblowing.
Care home providers should consider using an external whistleblowing service. If they do, they should make sure that staff know how to contact the service.
Care homes and care home providers must ensure that whistleblowers are not victimised and do not face negative consequences for reporting or disclosing a safeguarding concern. Be aware that whistleblowers are protected by law.
Be aware that care home staff and volunteers may be afraid of the repercussions of whistleblowing, and this can prevent them from identifying and reporting abuse and neglect.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home whistleblowing policy and procedure .
Full details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review C: tools to support recognition and reporting of safeguarding concerns.
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## Care home and care home provider roles and responsibilities
Care homes should:
have a safeguarding lead and
make sure everyone knows who this is, what they do, how to contact them, and who to speak to if they are unavailable.
Care homes and care home providers should make it clear who is accountable for different aspects of safeguarding within the home, in addition to the roles and responsibilities of the safeguarding lead.
Safeguarding responsibilities should be included in the job description of all care home staff, including at board level.
Care homes and care home providers should ensure that all staff understand how to meet their safeguarding responsibilities in their day‑to‑day work within the care home (see the recommendations on induction and training for more information).
Care homes should maintain and regularly audit care records (in addition to external checks, such as audits or Care Quality Commission inspections) and ensure that they are complete and available, in case they are needed if a safeguarding concern is raised.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home and care home provider roles and responsibilities .
Full details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review F: barriers and facilitators to effective strategic partnership working.
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## Local authorities, clinical commissioning groups, and other commissioners
Local authorities and other commissioners should ensure that all care homes they work with are fulfilling their statutory and contractual safeguarding responsibilities.
Commissioners should contribute to improving safeguarding practice in the care homes they work with, by:
sharing key messages from Safeguarding Adults Reviews and
helping care homes to learn from their own experience of managing safeguarding concerns.
Commissioners should:
ensure that care homes are maintaining records about safeguarding
make record-keeping responsibilities clear as part of contract management.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on local authorities, clinical commissioning groups, and other commissioners .
Full details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review F: barriers and facilitators to effective strategic partnership working.
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## Safeguarding Adults Boards
Safeguarding Adults Boards should be assured that local authorities and clinical commissioning groups have clear lines of communication in place with safeguarding leads in care homes.
Safeguarding Adults Boards should include specific objectives about safeguarding in care homes as part of their strategic planning.
Safeguarding Adults Boards should cover issues relevant to safeguarding in care homes as part of their annual report.
Safeguarding Adults Boards should share recommendations and key learning from Safeguarding Adults Reviews with key stakeholders (including care home providers, staff, residents and their families and carers).
Safeguarding Adults Boards should be assured that partner organisations are working together to support residents during safeguarding enquiries.
Safeguarding Adults Boards should ensure that their escalation procedures for resolving safeguarding disputes are applicable to care homes.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on Safeguarding Adults Boards .
Full details of the evidence and the committee's discussion are in evidence review E: support and information needs and evidence review F: barriers and facilitators to effective strategic partnership working.
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# Induction and training in care homes
All directly employed staff working in care homes should:
read and understand the safeguarding policy and procedure during their induction
complete mandatory training on safeguarding as soon as possible, and no later than 6 weeks after they start.
Care home managers must ensure that agency staff working at the home have completed the necessary safeguarding training for their role, and that they understand the local safeguarding policy and procedure.
Care home managers should assess staff safeguarding knowledge annually, and run refresher training if needed.
Safeguarding Adults Boards, their subgroups and partnership members should work with partner organisations to:
ensure that mandatory safeguarding training includes elements of multi-agency working
ensure that mandatory training reflects the safeguarding responsibilities of each member of staff (so staff with more responsibilities receive more comprehensive training)
encourage care home providers to arrange opportunities for staff and residents to learn together from recent Safeguarding Adults Reviews and other experiences of safeguarding.
Care homes should give staff protected time for induction and mandatory safeguarding training. They should ensure that staff have enough time to read and understand the induction and training materials and improve their knowledge and confidence about safeguarding.
Care home managers should:
assess staff understanding of safeguarding after induction and mandatory safeguarding training, to identify areas for improvement
request feedback on induction and training
help staff to understand the indicators of abuse and neglect, so they can identify safeguarding concerns more accurately
help staff increase their confidence in managing safeguarding concerns.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction and training in care homes .
Full details of the evidence and the committee's discussion are in:
evidence review B: barriers and facilitators to identifying abuse and neglect
evidence review H: the effectiveness and acceptability of safeguarding training
evidence review I: embedding organisational learning about safeguarding.
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## What mandatory training should cover
At a minimum, mandatory safeguarding training should include:
safeguarding and legal principles under the Care Act 2014
the 6 core principles of safeguarding and the Making Safeguarding Personal framework
specific responsibilities and accountabilities for safeguarding in the care home
how to recognise different forms of abuse and neglect, including organisational abuse and neglect
how to understand the differences between poor practice and abuse and neglect
the care homes whistleblowing policy and procedure, including what support and information is available in this situation
how to act on and report suspected abuse or neglect
how to deal with and preserve evidence
how to raise safeguarding concerns within the care home and how the care home should respond
how to escalate concerns (for example, to appropriate helplines or the local authority) if staff feel that the response taken was not appropriate or effective, or if the concern relates to the actions of the care home manager
confidentiality and data protection
the importance of being open and honest when things go wrong (the duty of candour)
duties under the Public Interest Disclosure Act 1998
-ther training that is needed, based on the staff member's role and their specific safeguarding responsibilities.
Mandatory safeguarding training should include reflective learning at the individual, team and organisational level, and include opportunities for problem-solving.
Mandatory safeguarding training should include an explanation of safeguarding concepts and terminology, including translations of specific terminology if needed (to ensure that training is accessible to all staff).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on what mandatory training should cover .
Full details of the evidence and the committee's discussion are in:
evidence review B: barriers and facilitators to identifying abuse and neglect
evidence review H: the effectiveness and acceptability of safeguarding training
evidence review I: embedding organisational learning about safeguarding.
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## Further training
Further training could cover:
how to ask about abuse and neglect in a sensitive and non-judgemental manner
how frequently to assess and ask about abuse and neglect
the wide range of situations and circumstances in which abuse and neglect can potentially occur
less obvious indicators of abuse and neglect, and more complex safeguarding concerns (for example organisational abuse and neglect)
risk assessments and their relationship to safeguarding
the skills needed to support a resident through a safeguarding enquiry.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on further training .
Full details of the evidence and the committee's discussion are in evidence review E: support and information needs and evidence review H: the effectiveness and acceptability of safeguarding training.
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## How to conduct training
Provide mandatory safeguarding training face-to-face whenever possible. This can be delivered either in person or remotely. It should be live and interactive, and e-learning should only be used when face-to-face training is not possible.
Include case studies and reflective practice in training and learning at the team and organisational level (for example, at team meetings and handovers).
Use case studies and examples to teach staff how safeguarding relates to personalised care and the human rights of residents.
Incorporate recommendations and other learning from Safeguarding Adults Reviews into training as quickly as possible after they are available.
Training should be directly applicable to the responsibilities and daily practices of the person being trained, and to the care and support needs of the residents they are working with.
Tailor training to reflect the safeguarding responsibilities of each member of staff, so staff with more responsibilities receive more comprehensive training.
If using e-learning, be aware of the limitations (for example, the lack of opportunity for discussion and asking questions, and the difficulty in ensuring that people have understood the training).
If using e-learning, care home managers should assess staff literacy levels and IT skills to ensure the training is appropriate. If staff cannot use it, find an alternative e-learning programme or another way to conduct training.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on how to conduct training .
Full details of the evidence and the committee's discussion are in evidence review H: the effectiveness and acceptability of safeguarding training.
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## Evaluating training
Care home managers and safeguarding leads should ensure that staff are learning from training and using it to improve their practice. This could be done by:
checking that training is completed, and that this is done within an agreed timeframe
follow-up conversations with staff
periodic checks that staff are adhering to safeguarding procedures.
Care home managers should evaluate changes in understanding and confidence before and after training. Assess this:
immediately after the training
annually
in regular long-term evaluations (for example, as part of supervision sessions).
Line managers should encourage staff to complete and apply learning from their training, for example during staff appraisals. This could include recognising and acknowledging new skills and competences, and changes in attitudes and behaviours.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on evaluating training .
Full details of the evidence and the committee's discussion are in evidence review H: the effectiveness and acceptability of safeguarding training and evidence review I: embedding organisational learning about safeguarding.
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# Care home culture, learning and management
## Management skills and competence
Registered managers and providers of regulated care must comply with all safeguarding requirements in regulations 12 and 13 of the Health and Social Care Act 2008 (regulated activities) Regulations 2014.
Care home managers and safeguarding leads should lead by example in maintaining up-to-date knowledge on safeguarding.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management skills and competence .
Full details of the evidence and the committee's discussion are in evidence review I: embedding organisational learning about safeguarding.
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## Line management and supervision
Be aware that staff may be reluctant to challenge poor practice or raise concerns about potential abuse or neglect, particularly if they feel isolated or unsupported.
Care home managers and supervisors should promote reflective supervision to help staff understand how to identify and respond to potential abuse and neglect in care homes. Consider making this independent of line management.
Line managers should provide feedback (through supervision and appraisals) acknowledging how staff have learned from their experience of identifying, reporting and managing safeguarding concerns.
Care home managers should encourage staff to discuss care home culture, learning and management in relation to safeguarding (e.g. in exit interviews) when leaving employment with the care home.
Be aware of the potential for under-reporting of safeguarding concerns by staff who may be afraid of losing their job (for example staff who have their housing or work permit linked specifically to their current role).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on line management and supervision .
Full details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review I: embedding organisational learning about safeguarding.
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## Care home culture
Care home providers (including trustees and company directors) and managers should:
promote a culture in which safeguarding is openly discussed and abuse and neglect can be readily reported
ensure that support is readily available for people raising concerns, for example, by appointing safeguarding champions.
Staff should be encouraged to watch out for changes in the mood and behaviour of residents, because this might indicate abuse or neglect (see indicators of individual abuse and neglect).
Staff should record and share relevant and important information about changes in mood or behaviour or other issues of concern in a timely manner (for example, at every shift handover or transfer of care). In cases of possible abuse or neglect, see the recommendations on immediate actions to take if you consider or suspect abuse or neglect.
Care home managers should make sure there are regular opportunities (for example in team meetings or one-to-one supervision) for all staff to:
share best practice in safeguarding, including learning from Safeguarding Adults Reviews
challenge poor practice or discuss uncertainty around practice
discuss the differences between poor practice (which is not necessarily a safeguarding issue) and abuse or neglect (which are safeguarding issues).Care home managers should make particular efforts to involve staff who work alone or who get very little direct oversight (for example night staff).
Care home managers should ask for feedback about safeguarding from residents (and their families, friends and carers) and other people working in care homes. They should:
ask them about their experience of safeguarding concerns and how these have been identified, reported, managed and resolved
respond to feedback and tell people about any changes made in response to their comments.This could be done using surveys, meetings and where appropriate, other community engagement (such as open days and visits).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home culture .
Full details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review I: embedding organisational learning about safeguarding.
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## Multi-agency working and shared learning with other organisations
Care homes, local authorities, clinical commissioning groups and other local agencies should work together to establish local strategic partnership arrangements that cover safeguarding adults in care homes, and that specifically include:
information sharing and communication protocols
roles, responsibilities and accountability for safeguarding within each organisation
procedures for raising and managing a safeguarding concern, the decision-making process and the procedure for enquiries
definitions of good practice and poor practice
the indicators of abuse and neglect that should result in safeguarding action (based on the indicators in sections 1.4 and 1.12 of this guideline).
Local health, social care and other practitioners working with care homes should use a multi-agency approach to safeguarding, bringing together a wide range of skills and expertise to keep residents safe.
Care home managers and providers should be aware that some staff may be apprehensive about external oversight, and may need time to build relationships with external agencies before effective multi-agency working and shared learning can take place.
Care home managers and providers should participate in local Safeguarding Adults Board arrangements for sharing experiences about managing safeguarding concerns in care homes.
Care home managers and providers should share relevant information from Safeguarding Adults Board meeting minutes and reports with their staff.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on multi-agency working and shared learning with other organisations .
Full details of the evidence and the committee's discussion are in:
evidence review D: responding to and managing safeguarding concerns
evidence review F: barriers and facilitators to effective strategic
evidence review I: embedding organisational learning about safeguarding.
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## Record-keeping
Care home managers should ensure that actions taken to safeguard residents are recorded, and shared with other staff as necessary.
Care home managers should ensure that all safeguarding records are focused on the wellbeing of the individual resident. Records should be clear and easily accessible for purposes such as performance management, audits, court proceedings, Care Quality Commission inspections, or learning and development.
Care home managers should regularly review safeguarding records for accuracy, quality and appropriateness.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on record-keeping .
Full details of the evidence and the committee's discussion are in evidence review I: embedding organisational learning about safeguarding.
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# Indicators of individual abuse and neglect
This section describes indicators that should alert people to the possibility of abuse or neglect of individuals within a care home. This section (and the sections on immediate actions to take if you consider or suspect abuse or neglect) applies to anyone in contact with care home residents. This includes staff, volunteers, visiting health and social care practitioners, other residents, family and friends, and any other visitors to the care home. Local authorities may wish to adapt and incorporate these indicators as part of their referral guidance or criteria.
The terms 'consider' and 'suspect' are used to define the extent to which an indicator suggests abuse or neglect, with 'suspect' indicating a stronger likelihood of abuse or neglect.
To 'consider' abuse or neglect means that this is one possible explanation for the indicator.
To 'suspect' abuse or neglect means a serious level of concern about the possibility of abuse or neglect.
None of the indicators are proof of abuse or neglect on their own. Instead, they are signs that the pathway set out between sections 1.4 and 1.11 of this guideline should be followed. See the indicators of individual abuse and neglect visual summary for a summarised view of this pathway.
This process is in line with the Department of Health and Social Care statutory guidance on adult safeguarding.
Some behavioural and emotional indicators of abuse and neglect may be due to past trauma, including non-recent incidents such as adverse childhood experiences, or past experience of domestic violence or modern slavery.
Some indicators of abuse and neglect can be similar to signs of distress or behaviours arising from other causes. In particular, there can be similarities with behaviours that may be associated with dementia, autism, learning disability or acute mental distress. However, the possibility of abuse or neglect should always be considered as a cause of behavioural and emotional indicators, even if they are seemingly explained by something else. This is particularly important for residents who do not communicate using speech.
Physical, sexual, psychological and financial abuse may be perpetrated by volunteers, visitors, and family members and carers, as well as by care home staff. When it is perpetrated by someone who is personally connected to the resident, this is considered to be domestic abuse. In some cases, this can be a continuation of past relationships of domestic violence or abuse.
Health and social care practitioners should provide information to residents and their families and carers, covering what abuse and neglect look like and how to recognise warning signs.
When responding to all indicators of abuse and neglect:
follow the principles of the Making Safeguarding Personal framework
ensure that any actions are guided by the wishes and feelings of the resident
for guidance on mental capacity, see the NICE guideline on decision making and mental capacity.
If a resident is in immediate danger or if there is a risk to other residents (for example if the alleged abuser is a person in a position of trust):
follow immediate actions to take if you suspect abuse or neglect and
report suspected abuse or neglect (see recommendation 1.6.13) as soon as is practical.
If a resident does not want any safeguarding actions to be taken, but you suspect abuse or neglect:
you should still follow the recommendations in this guideline from immediate actions to take if you suspect abuse or neglect onwards
a safeguarding referral must still be made.
If there are multiple indicators, and at least one is a 'suspect' indicator, you should suspect abuse or neglect (see immediate actions to take if you suspect abuse or neglect).
If you are not sure if an indicator is a 'consider' or a 'suspect' indicator, speak to your safeguarding lead and/or seek further advice from the local authority about whether to make a safeguarding referral (see also recommendation 1.7.3 for guidance on what safeguarding leads should do if they suspect abuse or neglect).
## Neglect
Consider neglect when residents:
are not supported to present themselves the way they would like (for example haircuts, makeup, fingernails and oral hygiene and care)
are given someone else's clothes to wear
-ccasionally have poor personal hygiene or are wearing dirty clothes
are wearing clothing that is unsuitable for the temperature or the environment
have lost or gained weight unintentionally
do not have access to food and drink in line with their dietary needs
have repeated urinary tract infections
are not getting care to protect their skin integrity, potentially leading to pressure ulcers (see the NICE guideline on pressure ulcers, and the quick guide on preventing pressure ulcers in care homes)
do not have opportunities to spend time with other people, either virtually or in person
uncharacteristically refuse or are reluctant to engage in social interaction
do not have opportunities to do activities that are meaningful to them
do not have access to medical and dental care
are occasionally denied access to communication and independence aids (such as hearing aids) contrary to their care and support plan
have not received prescribed medication, or medication has been administered incorrectly (for example, the wrong dose, timing, method, or type of medication)
do not have access to outdoor space, fresh air and sunlight
are not given first aid when needed.
Suspect neglect when residents:
do not have an agreed care and support plan
are not receiving the care in their agreed care and support plan
have deteriorating physical or mental health or mental capacity, and there is a lack of response to this from staff
live in a dirty, unhygienic or smelly environment
repeatedly have poor personal hygiene or are wearing soiled or dirty clothes
are malnourished
are frequently and uncharacteristically not engaging with other people, or in activities that are meaningful for them
have only inconsistent or reluctant contact with external health and social care organisations
have restricted access to food or drink, if this is not part of their agreed care and support plan
are not kept safe from everyday hazards or dangerous situations
repeatedly do not receive prescribed medication, or medication has been repeatedly administered incorrectly (for example the dose, timing, method, or type of medication)
are denied communication or independence aids (such as hearing aids, glasses or dentures), contrary to their care and support plan.
Be aware that some indicators of neglect may result from self-neglect. When deciding how to respond to self-neglect:
think about why the resident may be refusing support
think about whether the resident has capacity to understand the possible impact of their self-neglect on themselves and others (see the NICE guideline on decision making and mental capacity)
if the resident is refusing support, ask them why, and ask if they would like a different kind of support
make an assessment based on the risks and needs specific to the resident, in line with the Care Act 2014 statutory guidance.
## Physical abuse
Consider physical abuse when residents:
have unexplained marks or injuries (for example, minor bruising, cuts, abrasions or reddened skin)
tell you or show signs that they are in pain, and the cause is unexplained (for example, the pain is not caused by a pre-existing medical condition).
Suspect physical abuse when residents:
have multiple or repeated marks or injuries (for example, bruising, cuts, lesions, loss of hair in clumps, bald patches, burns and scalds)
have injuries that are very unlikely to be accidental (for example, grip marks, cigarette burns or strangulation marks)
are being restrained without authorisation (either by direct restraint or by being confined to a particular area)
flinch when approached, or change their behaviour (for example, acting subdued) in the presence of a particular person
have fractures that cannot be explained
have their activity limited by misuse of medication, or covert administration when not medically authorised.
Act immediately to safeguard residents and contact the police if you witness an assault or are told that a resident has been assaulted (see making sure people are safe).
Be aware that injuries can be caused by other residents.
## Sexual abuse
Be aware that residents have the right to engage in sexual activity if they have the mental capacity to consent. For more information, see:
the Care Quality Commission guidance on relationships and sexuality in adult social care services
the NICE guideline on decision making and mental capacity.
Consider sexual abuse when residents:
are spoken to or referred to using sexualised language
experience any instances of sexualised behaviour or teasing
show unexplained changes in their behaviour, such as:
resisting being touched
becoming aggressive or withdrawn
having trouble sleeping
using sexualised language
showing highly sexualised behaviours
show changes in their relationships (for example, being afraid of or avoiding particular residents, family members or members of staff).
Suspect sexual abuse if a resident has an intimate relationship with a member of staff.
Suspect sexual abuse when residents who lack capacity to consent to intimate or sexual relationships:
report being inappropriately touched or experience unwanted sexualised behaviours
have unexplainable physical symptoms that may be associated with sexual activity, such as itching, bleeding or bruising to the genitals, anal area or inner thighs
have unexplained bodily fluids on their underwear, clothing or bedding
are involved in a sexual act with another person, including their husband, wife, partner or another resident
have a sexually transmitted infection
become pregnant.
## Psychological abuse
Consider psychological abuse when residents:
are addressed rudely or inappropriately on any occasion (verbally or non-verbally)
are prevented from speaking freely
are deliberately and systematically isolated by other residents and/or staff
have information about their own care systematically withheld from them by the care home
are not involved in planning their own care, or when changes are made to their care without discussion or agreement
are denied a choice on any occasion (for example, around activities of daily living or freedom of movement)
are denied unsupervised access to others
show significant and otherwise unexplainable changes in their behaviour, including:
becoming withdrawn
avoiding or being afraid of particular individuals
being too eager to do anything they are asked
compulsive behaviour
not being able to do things they used to be able to do
not being able to concentrate or focus.
Suspect psychological abuse when residents:
are repeatedly addressed rudely or inappropriately (verbally or non-verbally)
are shouted at or verbally threatened
are repeatedly humiliated, belittled, or have their opinions or beliefs undermined
are getting married or entering a civil partnership, if you are concerned that they have not consented or lack capacity to consent to this.
are denied access to independent advocacy
are repeatedly denied choices (for example, around their activities of daily living or freedom of movement).
## Financial and material abuse
Be aware that not having systems to take care of residents' money and possessions is a form of organisational abuse and can lead to financial abuse.
Consider financial and material abuse when residents:
do not have their money or possessions appropriately recorded by the care home
lose money or possessions
do not have access to their money, or to possessions that they want or need
are not routinely involved in decisions about how their money is spent (for example if they do not get a personal allowance), or how their possessions are used
appear to have bought things they do not need or invested money in things where they may lack capacity to make informed decisions
find the person managing their financial affairs to be evasive or uncooperative
family or others show unusual interest in their assets
have unusual difficulty with their finances, and are uncharacteristically protective of money and things they own.
Suspect financial and material abuse when residents:
have their money spent or their possessions or property used by other people, in a way that does not appear to benefit the resident (for example, their personal allowance being used to fund staff gifts, or misuse of loyalty card points)
have treasured personal items constantly go missing
get married or enter a civil partnership, if they are likely to lack capacity to consent to this
change a will under duress or coercion
sign a lasting power of attorney when they do not have the mental capacity to make this decision
personal financial information is not kept confidential.
## Discriminatory abuse
Consider discriminatory abuse when residents:
are denied choices about the care and support that they receive
are receiving care and support that does not take account of their personal or cultural needs, or other needs associated with protected characteristics under the Equality Act 2010
show any of the indicators of psychological abuse in recommendation 1.4.18, if these are associated with protected characteristics.
Suspect discriminatory abuse when residents:
are not treated equitably and do not have equal access to available services
experience humiliation, violence or threatening behaviour related to protected characteristics
are not provided with the support they need, for example, relating to their religious or cultural beliefs
are denied access to independent advocacy
show any of the indicators of psychological abuse in recommendation 1.4.19, if these are associated with protected characteristics.
# Immediate actions to take if you consider abuse or neglect
If you 'consider' abuse or neglect:
Seek medical attention for the resident at risk if needed.
Record what you have found.
Seek advice from a safeguarding lead (unless they are implicated in the alleged abuse or neglect).
Check whether other indicators have previously been recorded.
Discuss the welfare of the resident at risk with a manager or supervisor and:
if you work in the care home, address the problem yourself
if you cannot address the problem yourself or you do not work in the care home, ask the manager or supervisor to address the problem.
Monitor to see if the problem persists or is repeated, and to check for any other indicators. Think whether new information gives cause for your level of concern to rise from 'consider' to 'suspect'.
After taking these steps, decide whether there is now a serious concern about the possibility of abuse or neglect. If there is, and if you 'suspect' abuse and neglect, see immediate actions to take if you suspect abuse or neglect.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indicators of individual abuse and neglect and immediate actions to take if you consider abuse and neglect .
Full details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.
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# Immediate actions to take if you suspect abuse or neglect
## Making sure people are safe
If you suspect abuse or neglect, you must act on it. Do not assume that someone else will.
If you suspect abuse or neglect, make sure that no one is in immediate danger. If there is immediate danger, call 999 and stay with the resident at risk until help arrives.
If a crime is suspected but the situation is not an emergency, encourage and support the resident to report the matter to the police. If they cannot or do not wish to report a suspected crime (for example, because they have been coerced or lack capacity), report the situation to the police yourself.
Depending on the risks the resident is facing, and who the alleged abuser is, think about who should be immediately notified. For example:
the care home manager
a healthcare professional or the NHS 111 service if there is a serious medical issue
the police or other emergency services if the resident is in immediate danger or you suspect a crime.
For a short explanation of why the committee made these recommendations, see the rationale and impact section on making sure people are safe .
Full details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.
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## Gathering information
As soon as the resident is safe, start gathering information about the suspected abuse or neglect. Write down:
what happened
when it happened
where it happened
who was involved (the resident at risk, any other person who has told you about the abuse or neglect, and the alleged abuser).
When talking to the resident (or any other person who has told you about the abuse or neglect):
give them the chance to speak freely about what has happened
use simple and open questions, and ask in a non-leading way
write down what they tell you, in their own words
if the resident does not communicate with speech, help them explain what has happened as far as possible, and report the situation to the safeguarding lead (see recommendation 1.7.1 for safeguarding lead responsibilities in this situation).
Explain the safeguarding process to the resident (or to any other person who has told you about the abuse or neglect) and discuss the next steps.
Provide emotional support to the resident (or to any other person who has told you about the abuse or neglect).
Do not contact the alleged abuser about the incident yourself, unless this is essential (for example, if a manager needs to immediately suspend a member of staff).
Do not investigate the situation yourself, because this could cause problems for police or other investigations and enquiries. Preserve any physical evidence as far as possible (for example, ask the resident to not wash or bathe), and gather information as specified in recommendations 1.6.5 and 1.6.6.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on gathering information .
Full details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.
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## Confidentiality and discussing suspected abuse and neglect
If someone discloses abuse or neglect, tell them that you have a responsibility to report your concerns. Tell them who you will report to, why, and when.
If someone discloses abuse or neglect, do not agree to keep secrets or make promises you cannot keep.
## Reporting suspected abuse and neglect
If you suspect abuse or neglect, tell a senior member of staff and the safeguarding lead as soon as is practical (unless the alleged abuser is the only senior member of staff or the safeguarding lead). If you do not feel confident reporting within your organisation, contact:
the local authority or
a whistleblowing helpline, if you are a member of staff or a volunteer (for more information, see the Care Quality Commission guidance on whistleblowing).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on confidentiality, and discussing and reporting suspected abuse and neglect .
Full details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.
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# Responding to reports of abuse or neglect
## Care home safeguarding leads
When abuse or neglect is reported, the safeguarding lead should treat it as a safeguarding concern and:
ask the resident at risk what they would like to happen next
ensure that they have access to communication support
explain that you have a responsibility to report your concerns to the local authority, and tell them who you will report to, why, and when.
When a safeguarding concern has been reported, the safeguarding lead should look at the broader context rather than assessing the concern in isolation. Take into account:
if any other people (including children) are at risk as well as the resident you are concerned about
if there have been repeat allegations
if there could be a criminal offence
if there is a current or past power imbalance in the relationship between the resident and alleged abuser.
If the safeguarding lead suspects abuse or neglect, they should make a safeguarding referral to the local authority, in line with the Care Act 2014 and Care Act 2014 statutory guidance.
If the safeguarding lead is not sure whether to make a safeguarding referral to the local authority (because they are not sure whether they suspect abuse or neglect), they should discuss it with the local authority first.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home safeguarding leads .
Full details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.
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## Local authorities
Local authorities should ensure that there is a process for care homes to discuss safeguarding concerns with social workers or other qualified safeguarding practitioners without formally making a safeguarding referral.
Local authorities should consider providing a single point of contact for care homes, local agencies and practitioners, so they can seek expert advice on safeguarding in care homes (for example, to help decide whether a referral should be made).
Local authorities should be aware that safeguarding referrals may come from a care home's openness and awareness of the safeguarding policy, as well as being possible signs of poor care.
Local authorities and other organisations involved in assessing safeguarding referrals should use professional judgement, supported by the recommendations on indicators of individual abuse and neglect. They should not be limited in their view of what abuse or neglect is, and should always consider the circumstances of the individual case.
When a safeguarding referral is made, the local authority should decide as quickly as possible whether this meets the legal criteria for a section 42 safeguarding enquiry (as defined in the Care Act). As soon as this is done, they should tell the resident and the care home safeguarding lead what they have decided.
If a section 42 safeguarding enquiry is not needed, the local authority should:
discuss what other support is needed with the care home and the resident
provide advice and support to help improve outcomes for the resident (for example, by reviewing the care and support plan and risk management procedures).
If a section 42 safeguarding enquiry is needed, the local authority should decide who needs to be informed or consulted, depending on the individual context. This might include:
the resident
their family and carers
anyone holding lasting power of attorney for the resident
the care home and care home provider
advocacy organisations
voluntary organisations
the police
the organisation commissioning care
the Office of the Public Guardian, if the safeguarding concern relates to lasting power of attorney
the Department for Work and Pensions, if the safeguarding concern relates to an appointee for the resident's benefits
specialist helplines or online support, for advice and information
GPs or other healthcare professionals
the Care Quality Commission or other regulators
banks (for financial abuse).
The local authority should set up an initial planning discussion about the safeguarding enquiry with relevant people, and (if appropriate) involve staff from the care home or care home provider.
The local authority should appoint an enquiry lead to coordinate the work of the enquiry and act as a main point of contact.
For more information about conducting a section 42 safeguarding enquiry see Making Safeguarding Personal.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on local authorities .
Full details of the evidence and the committee's discussion are in:
evidence review C: tools to support recognition and reporting of safeguarding concerns
evidence review E: support and information needs
evidence review G: multi-agency working at the operational level in the context of safeguarding.
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# Working with and supporting the resident at risk during a safeguarding enquiry
At the start of the safeguarding enquiry, the enquiry lead should ask the resident at risk what they would like the enquiry to achieve and how they would like to be involved.
The enquiry lead should ensure that the resident at risk has the chance to review and revise their desired outcomes throughout the process (if needed using speech and language therapy, non-instructed advocacy or other communication and decision-making aids).
Involve the resident at risk (and their family or an appropriate advocate) throughout the enquiry process, in line with their wishes and mental capacity, unless there are exceptional circumstances that justify their exclusion.
For more guidance about supporting decision making for residents who may lack capacity, see the NICE guideline on decision making and mental capacity.
Make reasonable adjustments to enable residents to fully participate in the safeguarding enquiry, in line with the Equality Act 2010.
Safeguarding Adults Boards should be assured that local authorities have auditing processes in place to monitor how residents and their advocates are included in safeguarding enquiries.
## Sharing information
The enquiry lead should ask the resident at risk:
if they would like to be kept up to date during the enquiry
how much detail they want
what format they would prefer this in
who they would like to contact them.
If the police are involved in a safeguarding enquiry, the enquiry lead should hold early discussions with the case officer on the rules of communication and information recording.
When safeguarding enquiries finish, the enquiry lead should provide feedback for the resident (and their family and advocates) that:
summarises the enquiry, and includes the relevant outcomes and recommendations
gives them the information needed to decide whether they wish to take any further action (for example, informing the Care Quality Commission or making a complaint to the Local Government and Social Care Ombudsman).
## Working with advocates
For guidance on finding out how residents want to be supported in decision making, see recommendation 1.2.1 in the NICE guideline on decision making and mental capacity.
All organisations involved with safeguarding adults in care homes should:
understand the role of advocacy in relation to safeguarding, and that the advocate is the only person who acts solely according to instructions from the resident
think about the resident's needs and know when to refer people for advocacy
involve an independent advocate for the resident, when this is required by the Care Act 2014 and Care Act 2014 statutory guidance or the Mental Capacity Act 2005
ensure that anyone supporting the resident as an informal or independent advocate has been identified in line with the resident's statutory rights to advocacy under the Care Act and the Mental Capacity Act.
Care homes should tell residents:
how advocates can help them with safeguarding enquiries
that they may have a legal right to an advocate, and what the criteria for this are.
Practitioners involved in managing safeguarding concerns should build effective working relationships with advocates and other people supporting the resident.
Local authorities and commissioners should monitor:
whether care homes are telling residents about advocacy and the criteria for accessing this and
how advocates are involved in the management of safeguarding concerns.
## Support during a safeguarding enquiry
Ask the resident at risk who they would like to support them through the enquiry (in addition to any legal rights to advocacy).
Provide practical and emotional support to the resident at risk:
while the enquiry is taking place
when the enquiry has finished, to help deliver the outcomes the person wishes to achieve
as needed after the enquiry (for example, by updating the care and support plan or protection plan, conducting risk assessments, or through future reviews).
Consider referring the resident for other specialist support (such as psychological support) after the enquiry.
Provide information and support to informal advocates chosen by the resident at risk (for example, family and friends).
Everyone involved with a safeguarding enquiry should remember that the resident is entitled to and may benefit from support (regardless of their mental capacity).
Ensure that the same level of support is offered to residents who self-fund their care and to residents whose care is publicly funded.
Be aware that when the alleged abuser is another resident, they may also need support (including advocacy). Manage the risks between residents while any enquiry takes place and work with relevant commissioners.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on working with and supporting the resident at risk during a safeguarding enquiry .
Full details of the evidence and the committee's discussion are in evidence review D: responding to and managing safeguarding concerns and evidence review E: support and information needs.
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# How care home providers and managers should support care home staff during an enquiry
## Supporting staff who are subject to a safeguarding enquiry
Care home providers and managers should:
be aware of how safeguarding allegations can affect the way other staff and residents view a person subject to a safeguarding enquiry
take steps to protect the person from victimisation or discriminatory behaviour.
When a member of staff is subject to a safeguarding enquiry, care home providers and managers should:
tell them about any available Employee Assistance Programme
tell them about professional counselling and occupational health services (if available)
nominate someone to keep in touch with them throughout the enquiry (if they are suspended from work).
Staff who are subject to a safeguarding enquiry should be able to request that the nominated person be replaced, if they think there is a conflict of interest.
The nominated person should not be directly involved with the enquiry.
If the police are involved, care home providers and managers should tell them who the nominated person is.
For members of staff who return to work after being suspended, care home providers and managers should:
arrange a return-to-work meeting when the enquiry is finished, to give them a chance to discuss and resolve any problems
agree a programme of guidance and support with them.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting care home staff who are subject to a safeguarding enquiry .
Full details of the evidence and the committee's discussion are in evidence review E: support and information needs.
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## Supporting care home staff
Unless they are subject to the safeguarding enquiry themselves, care home managers should:
find out from the local authority what they can share with staff at each stage of the enquiry
communicate as much as possible with all staff about the enquiry, and be open to answering questions.
During safeguarding enquiries, care home managers should:
acknowledge that enquiries are stressful and that morale may be low
think of ways to support staff (such as one-to-one supervision and team meetings)
provide extra support to cover absences as part of the enquiry, and to help staff continue providing consistent and high-quality care.
If a care home manager is subject to a safeguarding enquiry, the care home or care home provider should put an acting manager in their place.
If staff are concerned about working with a resident who has made allegations, care home managers should:
provide support, additional training and supervision to address these concerns
ensure that the resident is not victimised by staff.
Care home managers should direct staff to sources of external support or advice if needed.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting care home staff .
Full details of the evidence and the committee's discussion are in evidence review E: support and information needs.
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# How local authorities should support care homes during an enquiry
Local authorities should ensure that there is a single point of contact to keep the care home informed about the progress of the safeguarding enquiry.
Local authorities should be aware of the reputational impact on the care home's business (for example, on recruitment, resourcing and financial losses), and ensure that their actions are timely and proportionate.
Local authorities should be aware that care home staff may be anxious about their job security because of a safeguarding enquiry.
Local authorities should offer:
positive feedback to care homes when they handle safeguarding concerns well
practical support to care home staff, to help with safeguarding enquiries.
Local authorities should share the outcomes of safeguarding enquiries with commissioners, so that they can incorporate the findings into their own decisions (for example, whether to lift a placement embargo).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on how local authorities should support care homes during an enquiry .
Full details of the evidence and the committee's discussion are in evidence review E: support and information needs.
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# Meetings during a safeguarding enquiry
Only exclude people from a safeguarding meeting if this is in accordance with the safeguarding policy. If people have to be excluded from a meeting, explain why and give them a chance to share their views in another way.
If the care home manager and the care home provider safeguarding leads are not at a safeguarding meeting, the chair of the meeting should ensure they are informed of the outcome and the reasons behind it.
Keep the resident at risk informed about the outcome of the meetings. If the outcome is not what the resident was expecting, the chair of the meeting should take particular care to explain the reasons behind it.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on meetings during a safeguarding enquiry .
Full details of the evidence and the committee's discussion are in evidence review D: responding to and managing safeguarding concerns and evidence review G: multi-agency working at the operational level in the context of safeguarding.
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# Indicators of organisational abuse and neglect
This section describes indicators that should alert people to the possibility of organisational abuse or neglect within a care home, and immediate actions that should be taken. It does not go into detail about the process for raising a concern, making a referral or conducting an enquiry. This process will vary depending on the nature of the allegations, and the local arrangements in place for responding to such allegations.
This section is for anyone in contact with care home residents, including staff, volunteers, visiting health and social care practitioners, other residents, family and friends, and any other visitors to the care home.
Local authorities and others involved in care home quality assurance may wish to adapt and incorporate these indicators into notification and safeguarding referral guidance or quality assurance frameworks.
There is no one size fits all approach for managing and responding to organisational abuse. This is because of the huge range of actions and inactions that may contribute to organisational abuse, at all managerial and financial levels within organisations. Organisational abuse can also be caused by a single act of neglect or omission. However, commissioners should be alert to any allegations of organisational abuse within care homes, as part of their responsibility for monitoring standards of care against contractual requirements.
Organisational abuse (also known as institutional abuse) is distinct from other forms of abuse or neglect, because it is not directly caused by individual action or inaction. Instead, it is a cumulative consequence of how services are managed, led and funded. Some aspects of organisational abuse may be hidden (closed cultures), and staff may act differently when visitors are there (disguised compliance). Organisational abuse can affect one person or many residents. Therefore, it is important to consider each unique case, and the impact on individual residents as well as the whole care home.
The terms 'consider' and 'suspect' are used to define the extent to which an indicator suggests abuse or neglect, with 'suspect' indicating a stronger likelihood of abuse or neglect.
To 'consider' abuse or neglect means that this is one possible explanation for the indicator. See actions to take if you consider organisational abuse or neglect.
To 'suspect' abuse or neglect means a serious level of concern about the possibility of abuse or neglect. See actions to take if you suspect organisational abuse or neglect.
None of the indicators are proof of abuse or neglect on their own. Instead, they are signs that the recommendations on actions to take if you consider or suspect organisational abuse should be followed. See the indicators of organisational abuse and neglect visual summary for a summarised view of this pathway.
## When to consider abuse or neglect
Consider organisational abuse when:
safeguarding leadership or governance arrangements are unclear (for example, there is no registered manager or delegated safeguarding lead)
managers rarely or never observe their staff at work, or are rarely or never available to speak to residents (or their families and carers), staff, or other professionals
managers are overly controlling, constantly interfere when staff are working, and stop staff from trying to improve resident safety or care
the care home does not have policies and procedures covering:
safeguarding
whistleblowing
complaints
the care home has policies and procedures covering safeguarding, whistleblowing and complaints, but does not use them
the care home policy and procedure on safeguarding is inconsistent with the Care Act 2014 or this guideline
residents, visitors, staff and other people working in care homes do not have access to policies and procedures covering safeguarding, whistleblowing and complaints
the care homes enforces blanket procedures and decisions, regardless of residents individual needs, wishes and circumstances and which generally conflict with safeguarding policies and procedures
the care home does not explain the concepts of safeguarding, abuse and neglect to residents
residents are not involved in how the care home is run.
Consider organisational abuse when care homes:
do not meet contractual safeguarding requirements
do not meet national regulations, including the fundamental standards of quality and safety monitored by the Care Quality Commission
fail to improve or respond to actions or recommendations arising from inspections or audits by professionals, commissioners and regulators (for example clinical commissioning groups, local authorities, the Care Quality Commission and Healthwatch)
fail to sustain improvements
do not monitor the quality of their care using the Care Quality Commission's key lines of enquiry and prompts to ensure that the service is safe, effective, caring, responsive and well led.
Consider organisational abuse when:
safeguarding issues are not always reported
no audits or actions are taken after a disclosure
there is no clear safeguarding policy or information about how to raise a safeguarding concern
serious incidents are not reported (for example, unexplained deaths, serious fires, or infectious disease outbreaks)
there is a lack of safeguarding concerns recorded or referrals made
the care home has poor or outdated records
there are inconsistent patterns of safeguarding concerns logged (for example, if all concerns originate from 1 member of staff, then other staff may not be taking enough responsibility for safeguarding)
safeguarding concerns have been reported via complaints procedures rather than through safeguarding procedures
the care home does not comply with Mental Capacity Act requirements on deprivation of liberty and liberty protection safeguards (when enacted).
Consider organisational abuse when:
the care home does not have clear, safe recruitment processes (including reference checks and enhanced Disclosure and Barring Service checks)
staff are not properly supervised and supported, or there is no documentation that this is happening
there is no evidence that safeguarding training or induction is taking place
there are high rates of staff absence
staff work excessive hours without enough breaks
staff are working under poor conditions
there is high staff turnover and high dependency on contract or temporary staff.
Consider organisational abuse when:
there is evidence of poor medicines management (for example, excessive use of 'as needed' medicines)
restrictive practice is used:
residents are prevented from moving around the home freely or independently
staff teams have inflexible and non-negotiable routines that do not take account of what individual residents want or need
staff do not help residents live as independently as they can
meaningful and structured activities for residents are not available or accessible
behaviours of concern are mismanaged (for example, overuse of restrictive practices, including misuse of medication)
care and support plans are changed suddenly, without discussion with residents or others involved with their care
residents do not receive person-centred care, for example care is focused on completing tasks and ignores individual circumstances and preferences (including cultural preferences)
staff routinely make assumptions about residents or their needs, and miss hidden needs or disabilities
staff do not respond to requests from residents, or interfere with residents' preferences and choices
residents are reluctant to ask for changes or to make complaints
certain residents routinely receive preferential treatment over others
there are general inconsistencies in the standard of service provision.
Consider organisational abuse when:
residents miss appointments or are not referred to other professionals or services (such as GPs or dentists)
people who require independent advocacy are denied access to it.
Consider organisational abuse when:
there are not enough staff on each shift to meet the needs of residents
there are problems with care home equipment:
it does not meet the needs of residents
it is poorly maintained
there is not enough equipment for all residents
the care home admits or accepts referrals for residents that staff do not have the skills to care for
there is a lack of investment in the services the care home provides, compared with the fees it charges
resources (such as one-to-one support) for residents with assessed needs are not provided, despite funding being allocated for this
residents' money is not adequately protected (for example, they do not have personal allowances).
Consider organisational abuse when:
the care home is dirty or smelly, or is not compliant with basic infection control (for more information about infection control see the NICE quick guide on helping to prevent infection)
call bells have been removed or deactivated, or are routinely overused
there is a lack of engagement with visitors, or places in the care home that visitors are not allowed to see
the care home discourages visitors without justification
there is a lack of engagement with the organisation the care home is part of.
## Actions to take if you consider abuse or neglect
For indicators starting with 'consider'
raise the matter with the care home manager, in writing if possible
if the care home manager is believed to be part of the problem, go to the group manager, regional manager, owner or board of trustees
if the care home manager is the sole owner, follow the actions to take if you suspect abuse or neglect
explain the impact on residents, or the likely impact if the situation continues
ask for a response within a specified period of time (for example 2 weeks)
if the manager agrees to make changes, make sure these happen
after taking these steps, if the situation does not improve, raise your level of concern to 'suspect'.
## When to suspect organisational abuse or neglect
Suspect organisational abuse when:
incidents of abuse or neglect are not reported, or there is evidence of incidents being deliberately not reported
there is evidence of redacted, falsified, missing or incomplete records
there have been multiple hospital admissions of residents, resulting in safeguarding enquiries
there are repeated cases of residents not having access to nursing, medical or dental care
there is frequent, unexplained deterioration in residents' health and wellbeing
residents' money is being misused by the care home (for example, to purchase gifts for staff or other residents without permission)
there is a sudden increase in safeguarding concerns in which abuse or neglect has been identified
residents are repeatedly evicted or threatened with eviction after making complaints
repeated instances of residents, families and carers feeling victimised if they raise safeguarding concerns
the care home fails to improve or respond to actions or recommendations in local inspections or audit frameworks from clinical commissioning groups or the local authority, or reviews and inspections by the Care Quality Commission or Healthwatch, and deteriorates over time.
## Actions to take if you suspect abuse or neglect
If you 'suspect' abuse or neglect:
Contact your local authority and tell them that you want to make an adult safeguarding referral.
When local authorities receive adult safeguarding referrals:
they should gather information, under section 4 of the Care Act
they must decide if there is reasonable cause to suspect that an adult with care and support needs is experiencing abuse or neglect and is unable to protect themselves from harm
if this criteria is met, they must conduct a section 42 enquiry.
If many residents of a care home are affected, local authorities may conduct a large-scale enquiry, following their own local procedures.
If you are not satisfied with the response from your local authority, you can make a complaint to the Local Government and Social Care Ombudsman and give feedback to the Care Quality Commission.
When organisational abuse or neglect is identified, plan what individual or collective support is needed for residents, staff, and other people who might be affected.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indicators of organisational abuse and neglect .
Full details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.
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# How care homes should learn from safeguarding concerns, referrals and enquiries
Care home managers and managers from local agencies should help their organisations to identify key lessons from the outcome of any safeguarding concern, referral, enquiry, or Safeguarding Adults Review.
Care home managers should incorporate learning from safeguarding concerns, referrals and enquiries into the care home culture at all levels:
individual staff, for example through changes to support, supervision, retraining, and performance management)
care home, for example through:
-bservations of practice, discussion and watching people work across the home
changing practices, procedures, policy and learning, and group training (including training from other health and social care practitioners)
care home provider, for example through policy changes).In addition, see the recommendations on care home culture, learning and management.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on how care homes should learn from safeguarding concerns, referrals and enquiries .
Full details of the evidence and the committee's discussion are in evidence review I: embedding organisational learning about safeguarding.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.
## Care homes
Residential care homes (with or without nursing care) that are registered with and regulated by the Care Quality Commission.
## Care home providers
Companies that own and operate one or more care homes that are regulated by the Care Quality Commission.
## Commissioners
Local authorities, clinical commissioning groups and other public sector commissioners who oversee contracts for care and support services provided by care homes that pay for care home residents who are eligible for public funding. The term 'commissioner' does not apply to individuals who pay privately for their care.
## e-learning
Induction, training and assessment that people undertake on a computer or mobile device, without interacting with other people.
## Enquiry lead
Sometimes referred to as the lead enquiry officer or enquiry officer. This person is appointed by the local authority when a safeguarding enquiry begins. They may be a local authority social worker or a designated member of staff from the care home or care home provider. They are responsible for coordinating responses to the enquiry, coordinating decision making and acting as the main point of contact. They make sure that enquiry actions are undertaken in accordance with Care Act duties, related statutory guidance and the recommendations in this guideline.
## Face-to-face learning
Induction, training and assessment that is undertaken one-to-one, or in groups led by either in-house staff experts, managers or external trainers. It may take place with participants all in the same room, or using video or telephone conferencing. It may include online materials, but participants are able to ask questions, discuss, reflect on current practice and use case studies and examples. This type of training looks at how safeguarding relates to the particular role of the person being trained, and to the personalised care and support needs of residents.
## Multi-agency
Organisations working together in the context of safeguarding adults in care homes. Relevant organisations include:
local authorities and health and social care services
the police and other organisations in the criminal justice system
education and learning services
advocacy services
local voluntary and community groups.
National organisations or complaints services can also be included (such as the Local Government and Social Care Ombudsman).
## Reflective practice and reflective supervision
Opportunities for staff to:
reflect on previous practice
talk about why they made the decisions they made, and why they acted or behaved in particular ways
talk about their emotional responses to their actions and the actions of others
engage in continuous learning.
Reflective practice and supervision may also provide insight into personal values and beliefs, and help staff understand how these influence action and decision making within the care home.
## Registered managers
Care homes registered with the Care Quality Commission must have a registered manager, in line with the Health and Social Care Act 2008. The registered manager is responsible for leading and running the care home and making sure that standards are upheld. Note that other managers may also work within care homes and have responsibilities for staff supervision, line management, or other aspects of running the home. However, the registered manager is the person accountable to the Care Quality Commission for the standards of care and safeguarding within the home.
## Residents
Adults aged 18 and over who live in and receive care and support in care homes, or who use care homes to access care and support from time to time (for example respite care, including day care).
## Resident at risk
The resident at the centre of a safeguarding concern, when:
abuse or neglect is considered or suspected or
a safeguarding referral has been made to a local authority or
a section 42 safeguarding enquiry is taking place.
## Safeguarding adults reviews
Must be arranged by Safeguarding Adults Boards if:
there is reasonable cause for concern that partner agencies could have worked more effectively to protect an adult and
when serious abuse or neglect is known or suspected and
if certain conditions are met, in line with section 44 of the Care Act 2014 and related statutory guidance.
## Safeguarding champions
Safeguarding champions are staff already working within the care home, with good knowledge of safeguarding policy and procedure, who help ensure that procedures are followed and are available for discussion. They also ensure reflective learning about best practice in preventing abuse and neglect. Champions may also offer practical and emotional support to those worried about the impact of raising concerns. They are not a replacement or alternative to the safeguarding lead.
## Safeguarding concern
For the purposes of this guideline, a safeguarding concern is defined as a consideration, suspicion or indication of abuse or neglect of a resident, or residents within a care home. Anybody who works in, lives in or visits the home may have a safeguarding concern, either because of something they have seen or because of something they were told. All safeguarding concerns should be responded to in line with this guideline. Note that this definition relates to concerns in care home settings. For a more general definition, see the Local Government Association and ADASS definition in their report on understanding what constitutes a safeguarding concern.
## Safeguarding enquiry
If the local authority agrees that the safeguarding referral falls within the duty set out within section 42 of the Care Act 2014 and related statutory guidance, they must undertake an enquiry into the suspected abuse or neglect. Note that this definition relates to enquiries about abuse and neglect in care homes. For a more general definition, see the Local Government Association and ADASS definition in their report on understanding what constitutes a safeguarding concern.
## Safeguarding lead
This may be the care home registered manager or someone with delegated responsibility for safeguarding within the care home. It is a statutory requirement for care homes to have a designated safeguarding lead. Safeguarding leads should have had training in safeguarding, and should have the relevant skills and competencies to ensure the safety and protection of residents, in line with Care Quality Commission guidance.
## Safeguarding referral
As outlined in this guideline, if abuse or neglect is suspected this must be reported to the local authority. This is called making a safeguarding referral.
## Service providers
Other organisations providing services within care homes or contracted by care homes to provide services. These include health and social care services (for example, GP services, clinical psychology and occupational therapy), and other services such as cleaning, catering, gardening, transport, education, learning or activities.
## Staff
Anyone paid to work in a care home and involved either directly or indirectly in the care and support of residents. This includes care workers, nurses, managers, administrative staff, cleaners, caterers, gardeners or anyone else who the care home employs directly or via agencies or contractors, on a casual, part-time, full-time, temporary or permanent basis.
## Contract or temporary staff
Staff who are not employed on a permanent contract with the care home, who may be supplied by an employment agency on a short-term basis, or who might be employed on a zero hours contract or on a casual labour basis.# Recommendations for research
The guideline committee has made the following key recommendations for research.
# Indicators of self-neglect
What are the indicators of self-neglect among care home residents, and what should the responses be?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on indicators of individual abuse and neglect and immediate actions to take if you consider abuse or neglect .
Full details of the evidence and the committee's discussion are in evidence review A: indicators of abuse and neglect.
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# Local authority or provider-led enquiries
What is the effectiveness and cost effectiveness of local authority versus provider-led safeguarding enquiries?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on meetings during a safeguarding enquiry .
Full details of the evidence and the committee's discussion are in evidence review D: responding to and managing safeguarding concerns.
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# Person-centred and outcome-focused enquiries
To what extent are safeguarding enquiries in care homes person-centred and outcomes-focused, and what improvements could be made?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on working with and supporting the resident at risk during a safeguarding enquiry .
Full details of the evidence and the committee's discussion are in evidence review D: responding to and managing safeguarding concerns.
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# E-learning safeguarding training
What is the effectiveness, cost effectiveness and acceptability of e-learning safeguarding training compared with face-to-face?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on how to conduct training .
Full details of the evidence and the committee's discussion are in evidence review H: the effectiveness and acceptability of safeguarding training.
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# Embedding learning from Safeguarding Adults Reviews
What are the barriers and facilitators in care homes to embedding learning from Safeguarding Adults Reviews?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on how care homes should learn from safeguarding concerns, referrals and enquiries .
Full details of the evidence and the committee's discussion are in evidence review I: embedding organisational learning about safeguarding.
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# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Care home safeguarding policy and procedure
Recommendations 1.1.1 to 1.1.5
## Why the committee made the recommendations
These recommendations are based on:
qualitative themes from research evidence
the committee's own expertise and experience
health and social care guidance
the Care Act 2014 and Care Act 2014 statutory guidance.
Overall, the committee's confidence in the research evidence was low. The main issues with the evidence were that the included studies provided only limited data and reported research conducted in a range of settings, making it difficult to determine whether each finding was directly relevant to care home contexts. There were also concerns regarding the methods used in some of the included studies, for example their recruitment processes and how they considered the wider research context.
The committee also reviewed existing non-NICE UK health and social care guidance. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations, alongside their own expertise and experience. The guidance highlighted some of the challenges faced by individuals and organisations when there is no clear safeguarding procedure. This has implications for:
the safety and wellbeing of residents, because abuse or neglect may go unreported
the wellbeing of staff, because they can feel anxious and unsupported when they do not know what to do about safeguarding concerns.
The committee were keen to highlight the obligations of individuals (including visitors) and organisations, to ensure that everyone knows what to do when a safeguarding concern arises. The committee made a recommendation on ensuring that the safeguarding policy is accessible, easy to find and understand because safeguarding is everyone's responsibility, and people with little experience of safeguarding (such as visitors) may need to read it.
While having policies and procedures in place is important, care homes and care home providers can have problems ensuring that staff follow these. The committee believed it was important to have systems in place to make sure policies and procedures are followed. They made recommendations on how these systems should be used to record and share information.
## How the recommendations might affect practice
Care homes should already have a safeguarding policy and procedure, and the recommendations reflect statutory requirements. However, some care homes may need to change their policy and procedure so that they fully comply with these recommendations. This may involve extra work for care home managers. Care homes may need to update their systems to ensure that safeguarding concerns (and patterns of concerns) can be monitored. Care home staff may also need training to improve their understanding of safeguarding policy and procedure, and to show them how to preserve evidence from reported safeguarding concerns.
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# Care home whistleblowing policy and procedure
Recommendations 1.1.6 to 1.1.10
## Why the committee made the recommendations
The committee used qualitative themes from research evidence on identifying abuse and neglect to make the recommendations. There were several issues with this evidence. The main concern was relevance, as it was not always clear whether the data reported came from research conducted in a care home setting. There were also concerns regarding the methods used in some of the studies, for example in relation to their recruitment and data analysis processes.
The committee also reviewed existing non-NICE UK health and social care guidance, and legislation and care law about whistleblowing. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations. The guidance highlighted the challenges associated with whistleblowing and the impact whistleblowing can have on care homes, staff and volunteers. The committee felt that this was an important area, and built on the evidence using their own expertise. Good whistleblowing policies are important and help support a culture in which staff feel able to report concerns.
Based on their own knowledge, the committee decided to emphasise the legal protections for whistleblowers. This is because whistleblowers are vulnerable to victimisation.
## How the recommendations might affect practice
Care homes may need to revise and update their whistleblowing policy and procedure. They may also need to do more to promote more positive attitudes about whistleblowing among staff, and to encourage an open culture to help staff feel more confident raising concerns. In turn, this should help reduce the under-reporting of safeguarding concerns. There may be a cost for care homes who choose to provide external whistleblowing services, which is why the committee only ask care homes to consider using this service.
Return to recommendations
# Care home and care home provider roles and responsibilities
Recommendations 1.1.11 to 1.1.15
## Why the committee made the recommendations
Qualitative themes were identified from the research evidence, covering the challenges associated with governance, roles and responsibilities, and lines of communication. There were a number of issues that limited how the committee could use the findings. The main issues were the adequacy of the data and the relevance of the evidence, as it was not always clear whether data had been collected in a care home setting.
In addition, there were concerns about methods used in some of the studies, for example in relation to data analysis processes and how the researchers took account of ethical issues.
The evidence did, however, highlight the uncertainties and misunderstandings surrounding the roles, responsibilities and accountabilities for safeguarding within care homes and care home providers. The committee agreed that this is a crucial area and they built on the evidence with their own expertise.
## How the recommendations might affect practice
Care homes will need to ensure they implement relevant, up-to-date policies and procedures. This should only require minor changes to current practice because it is already a statutory requirement.
Return to recommendations
# Local authorities, clinical commissioning groups, and other commissioners
Recommendations 1.1.16 to 1.1.18
## Why the committee made the recommendations
The committee agreed that it is important to reiterate the responsibilities of local authorities, clinical commissioning groups and other public sector commissioners, because they can use contract monitoring and other statutory monitoring processes to ensure that care homes are meeting their safeguarding responsibilities.
The committee also wanted to emphasise the important role of commissioners in working with care homes. Commissioners can help care homes implement lessons from Safeguarding Adults Reviews and ensure that good safeguarding records are maintained.
## How the recommendations might affect practice
Local authorities, clinical commissioning groups and other commissioners should already be monitoring safeguarding in care homes as part of contract management, so this should not represent a significant change in practice. Commissioners may need to do more to promote good communication and working relationships with care homes, but this could be achieved without additional resources.
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# Safeguarding Adults Boards
Recommendations 1.1.19 to 1.1.24
## Why the committee made the recommendations
The committee made the recommendations based on a limited amount of qualitative evidence on the roles and responsibilities of Safeguarding Adults Boards. There were a number of concerns with this evidence, around:
the methods used, for example in relation to data analysis and sampling strategies
the relevance of the themes in the evidence, as some of the studies were conducted in care settings other than care homes
adequacy, as the themes were based on relatively limited data.
The evidence highlighted the challenges associated with partnership working, and the difficulties in communicating with care homes. The evidence also indicated that there may sometimes be confusion around:
lines of communication about safeguarding and safeguarding concerns
who is responsible for each part of the process
how and when care homes should be working with the local Safeguarding Adults Board.
## How the recommendations might affect practice
There is wide variation in the way Safeguarding Adults Boards operate and communicate. The recommendations should lead to greater consistency. Safeguarding Adults Boards should not need additional resources, but some will need to change the way they work. If they are not already doing so, they will need to promote a positive culture and encourage greater collaboration between their members and partner organisations, especially care homes.
Return to recommendations
# Induction and training in care homes
Recommendations 1.2.1 to 1.2.8
## Why the committee made the recommendations
Quantitative and qualitative data were available on training in the care sector, but the committee's confidence in this evidence was low. For the quantitative data, this was mostly because of the use of non-randomised trials and imprecision in effect estimates. For qualitative findings there was a shortage of evidence, with only limited data from a small number of studies. In addition, there were issues with the relevance of the qualitative data, because some studies may have been conducted outside of care homes, and some findings may not have been specifically related to safeguarding.
As a result of the limitations of the evidence, the committee also used their own expertise, and their knowledge of statutory guidance requirements, to make a recommendation. They believed this is important because good-quality training can have a big impact on safeguarding practice and the safety and wellbeing of care home residents.
The evidence highlighted the need for basic training for all staff employed by or contracted to work within the care home, to make sure they have a good understanding of what safeguarding is, how it is everyone's responsibility and how it might relate to their job within the care home.
Mandatory training is required to fulfil section 14.225 of the Care and support statutory guidance 2020, and each organisation is responsible for ensuring that staff receive effective training. This includes ensuring that agency staff have the necessary training. The committee discussed whether it is possible to specify how soon new staff should have mandatory safeguarding training. Although there was no evidence on this the committee agreed it would be helpful to specify that this should take place within 6 weeks of starting work. This is in line with standards that already exist, such as Adult Safeguarding: Roles and competencies for Health Care Staff 2018, but there is still inconsistent practice in this area. Evidence suggested that improvements in safeguarding practice were not always maintained in the longer-term, and the committee agreed that it was important to run refresher training if needed.
## How the recommendation might affect practice
Care Quality Commission standards cover basic safeguarding training for all staff (CQC: Regulation 13 - Safeguarding service users from abuse and improper treatment and CQC: Safeguarding Adults - Roles and responsibilities in health and care services) so this is not a new requirement and is unlikely to lead to significant resource implications. However, the content of training may vary across care homes, and some care homes may need to adapt their training programmes to make sure that safeguarding forms part of all new employee inductions within 6 weeks of starting work. Training programmes may also need to be adapted so that staff have protected time to ensure they fully understand the actions they need to take if they ever have a safeguarding concern.
There may also be minor resource implications associated with improved safeguarding practice. For example, if staff have a better understanding of abuse and neglect, they may raise more concerns and there may be an increase in safeguarding referrals and enquiries.
Return to recommendations
# What mandatory training should cover
Recommendations 1.2.7 to 1.2.9
## Why the committee made the recommendations
The strength of the evidence was limited, but the committee made recommendations in areas where the evidence aligned with their own experience and expertise.
The committee had low confidence in the quantitative outcomes, because of concerns about bias (as most studies were not randomised) and imprecision in effect estimates. They were also concerned about the short follow-up periods the studies used.
There were also issues with the qualitative evidence. This was mainly due to the relevance of the data, because it was not always clear whether findings related specifically to safeguarding. There were also concerns regarding the adequacy of data, as most of the themes in the evidence were based on limited data.
The evidence suggested that in some care homes, training only covers a basic understanding of adult protection policies and procedures, which staff may not then know how to apply in their daily work. To address this and ensure that staff have a more thorough understanding of safeguarding, the committee specified the different areas that need to be covered in training programmes for all staff.
## How the recommendations might affect practice
Care homes may need to change their safeguarding training programmes to make sure they cover the areas included in this guideline. They may need to make training programmes applicable to the daily practice and responsibilities of staff and particularly to safeguarding in the care home environment. Care homes will need to make sure that specific safeguarding concepts and terminology is clearly understood by all staff, regardless of literacy levels or language skills, and this may require some additional resources.
Return to recommendations
# Further training
Recommendation 1.2.10
## Why the committee made the recommendations
There was quantitative and qualitative evidence available, but the committee had limited confidence in this.
The quantitative evidence had issues with bias (as most studies were not randomised) and imprecision in effect estimates. In addition, the studies only used short-term follow-up periods.
There were issues with the relevance of the qualitative data, as it was not always clear whether findings related specifically to safeguarding. There were also concerns regarding adequacy, as most themes were based on limited data.
Because of the limitations with the evidence, the committee also used their expertise when making recommendations on further training.
Evidence on training suggested that improvements in safeguarding practice were not always maintained in the longer-term, and that there should be opportunities for further and more advanced learning. As a result, the committee agreed that it is important to emphasise that training should not be a one-off event. Their recommendations included advice about further training that may be beneficial for some staff. More detailed information on safeguarding training and the competencies that different staff need is covered in Adult Safeguarding: Roles and competencies for Health Care Staff 2018. Because of this, the committee did not make recommendations about who should have further training or when this should happen.
## How the recommendations might affect practice
Ensuring that care home staff can regularly take part in safeguarding training may lead to an increase in resource use, particularly if care homes choose to use external organisations to deliver these programmes. However, increased costs will be justified given the improvements in safeguarding practice that are likely to occur.
There may be an increase in the number of requests for training. There may also be cost implications if practitioners need training of their own in order to conduct training for staff. In addition, some staff posts may need to be backfilled while training takes place. However, any additional costs may be justified by the improvements in staff knowledge, competence and confidence, which will provide better quality of care for residents.
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# How to conduct training
Recommendations 1.2.11 to 1.2.18
## Why the committee made the recommendations
There was only limited evidence that focused specifically on safeguarding training in the care sector. There was no evidence comparing the effectiveness of different modes of training (for example e-learning programmes compared with group sessions). The committee provided anecdotal evidence of concerns about the efficacy of e-learning, in particular when there is no opportunity for discussion and human interaction. They agreed that further research is needed to evaluate the most effective modes of training, and to clarify whether e-learning training can meet best practice standards. To address this, the committee made a research recommendation to look at the effectiveness, cost effectiveness and acceptability of e-learning safeguarding training, compared with face-to-face training.
There was some limited economic evidence on training. This evidence did not demonstrate any differences in costs or effectiveness between 2 different programmes. An economic analysis showed that face-to-face training could be cost-effective relative to e-learning, under certain assumptions. Other evidence that was available highlighted the positive outcomes achieved with some training methods (such as case studies and examples), and the challenges associated with other types of training (such as e-learning). The committee supported this evidence with their own expertise.
The recommendations should help care home managers identify the most appropriate training methods for their staff, which will improve care home practice.
## How the recommendations might affect practice
There is some variation across the UK in the way care homes conduct training, although the contracts that providers have with local authorities will tend to encourage best practice and standardisation.
There may be an increase in the number of requests for training. There may also be cost implications if practitioners need training of their own in order to conduct training for staff, or if external organisations are used to deliver training. However, any additional costs will be justified by the improvements in staff knowledge, competence and confidence, which will provide better quality of care for care home residents.
Return to recommendations
# Evaluating training
Recommendations 1.2.19 to 1.2.21
## Why the committee made the recommendations
Although there was some quantitative evidence on the effectiveness of safeguarding training, there were concerns with this evidence. The main concerns were around bias (as most studies were not randomised) and imprecision in effect estimates. There were also concerns regarding the short-term follow-up periods used by the studies.
The qualitative evidence also had problems. There was a lack of detail regarding study methodology, making quality assessment difficult. The committee had concerns about the adequacy of the findings, which were based on 'thin' data. And it was unclear whether the data related specifically to safeguarding.
Because of the shortage of good-quality evidence, the committee made recommendations partly based on their own expertise and experience.
Despite the limitations of the evidence, the qualitative data indicated that training can improve staff safeguarding skills. This was also reflected in the qualitative evidence, which indicated that practitioners recognised the value of safeguarding training. However, this evidence also suggested that managers may be unwilling to implement learning from training programmes or make changes to care home procedures, which may negate any benefits associated with training. To address this, the committee made a recommendation on how managers should encourage staff to complete training.
The evidence on training only included short-term measurements of effectiveness. To address this potential issue, the committee made a recommendation on assessing how well training is working and whether it is being used to improve practice. For example, care home managers could assess this through follow-up conversations with staff, and by evaluating changes immediately after training and at further longer-term follow-up.
## How the recommendations might affect practice
Care home managers may need to re-assess how they engage with safeguarding training. They will need to find ways to identify positive changes from training, and implement these across the care home. This may mean that managers have to place greater emphasis on reflective practice and shared learning among staff. The structure of staff supervision sessions may need to be changed, to ensure that positive learning is acknowledged and reinforced.
Return to recommendations
# Management skills and competence
Recommendations 1.3.1 to 1.3.2
## Why the committee made the recommendations
Some qualitative evidence was available, but the committee had limited confidence in it. This was mostly due to issues with:
the study methods, such as the processes used to analyse the data
the relevance of the data, as it was not clear whether data was specific to safeguarding (rather than more general quality of care) or whether data had been generated in care settings other than care homes
the adequacy of the data, which was considered to be limited (and did not include any quotations).
As a result, the committee drew on their own expertise to supplement the evidence and make recommendations.
The evidence indicated that care home managers can play a key role in influencing the attitudes of their staff and colleagues towards training. Some staff may also need more support to benefit from training. Staff may not benefit from training if managers are unable or unwilling to allow staff to implement what they have learned within the care home and share their experience with other members of staff.
## How the recommendations might affect practice
Managers will need to make sure their safeguarding knowledge is up to date. This has been a legal requirement for some time so should not represent a change in practice.
There is variation in how much care home managers do to encourage other staff to learn more about safeguarding. The recommendations will help standardise practice, and ensure that managers promote safeguarding training and learning in care homes.
Return to recommendations
# Line management and supervision
Recommendations 1.3.3 to 1.3.7
## Why the committee made the recommendations
There was a good amount of qualitative evidence on identifying abuse and neglect in care homes, and the barriers and facilitators to this. In particular, the evidence looked at the concept of whistleblowing and the reasons why care home staff may be reluctant to report concerns (for example, fear of losing their job).
There were some problems with this evidence. There were issues with the methods used by some studies, such as their recruitment strategies and data analysis processes. Some of the included research was not conducted in care home settings, so there were concerns about how relevant it was. And some of the studies provided limited data, which led to issues with the overall adequacy of the data.
The committee therefore drew on their own experiences when drafting recommendations, with the aim of helping managers to increase staff confidence in identifying and raising safeguarding concerns.
## How the recommendations might affect practice
Reflective supervision is already a key feature of broader social work, but the extent to which it takes place in care homes is extremely varied. These recommendations will help standardise the use of reflective supervision. Care home managers may need to do more to support staff who are reluctant to raise concerns.
Return to recommendations
# Care home culture
Recommendations 1.3.8 to 1.3.12
## Why the committee made the recommendations
There was a good amount of qualitative evidence on the barriers and facilitators to identifying abuse and neglect in care homes. There were concerns with:
the appropriateness of some methods used by the studies, such as recruitment strategies and data analysis processes
the relevance of the data, because some of the research was not conducted in care home settings
the adequacy of the data, because some of the included studies provided limited data.
This research did not specifically evaluate the impact that care home culture can have on staff willingness to report safeguarding concerns. However, the committee agreed that the culture of a particular care home (and the role played by managers in shaping this) is a key factor in enabling and encouraging care home staff to report safeguarding concerns.
The committee suggested 'safeguarding champions' as a way to provide more informal support for people worried about the impact of raising concerns. This is in addition to the formal and mandatory role of a safeguarding lead.
The evidence also included data on how to reduce the risk or incidence of abuse and neglect by learning from past safeguarding issues in the care home. The committee agreed that this should be encouraged at all levels, to help create a care home culture where safeguarding is central and transparency is established. The committee also wanted care homes to reflect on and learn from Safeguarding Adults Reviews.
The committee recommended that care homes should ask for feedback from residents and families to find out what they thought about the way that safeguarding issues were addressed and managed in the home. It is important that this is used routinely to help improve safeguarding practices.
Staff are encouraged to watch out for changes in the mood and behaviour of residents, because many indicators of abuse and neglect are quite subtle physical or emotional changes or traits.
## How the recommendations might affect practice
Some care homes have a positive, open culture, in which staff and others are supported to reflect on, identify and report safeguarding concerns. For care homes where this is not the case, care home managers and care home providers will need to make major changes in leadership style. Additional resources should not be needed for care homes to appoint safeguarding champions, because the champions are expected to be existing staff members.
Creating a culture in which everyone can learn from safeguarding concerns should not represent a significant change. However, it will bring care homes in line with best practice, particularly in terms of supervision and continuing professional development.
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# Multi-agency working and shared learning with other organisations
Recommendations 1.3.13 to 1.3.17
## Why the committee made the recommendations
Qualitative evidence indicated that multi-agency working and learning can help to improve safeguarding practice. There were issues with this evidence (mainly with the methods used for recruitment and data analysis processes, and the limited adequacy and relevance of the data), but it did align well with the committee's own experience.
The recommendation covering staff apprehensions about external oversight was made because the committee are aware that staff can feel criticised and undermined by people delivering training (especially people from external agencies). The effectiveness of training and learning with other organisations is likely to be improved if positive relationships are established.
The committee made a recommendation on sharing information from Safeguarding Adults Boards with care home staff because they thought it could improve accountability, and help staff understand the responsibilities of other practitioners and organisations in relation to safeguarding.
## How the recommendations might affect practice
In some care homes, staff already have the opportunity to share good practice and challenge poor practice. However, it is not uncommon for staff to work in a climate of suspicion and defensiveness. These recommendations encourage openness about lessons learned across agencies, and emphasise the factors that might help care homes to make their culture more positive.
Managers will need to give staff time for these discussions to take place, and will need time themselves to promote the reflective and transparent approach to safeguarding.
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# Record-keeping
Recommendations 1.3.18 to 1.3.20
## Why the committee made the recommendations
Qualitative evidence suggested that recording actions or preventative measures and sharing these with colleagues can help staff to safeguard residents more effectively. Although there were concerns about this evidence (mainly regarding the adequacy and relevance of the data), the committee also drew on their own expertise to make the recommendations. In their experience, the way that safeguarding records are used and reviewed can play a key role in embedding learning and improving safeguarding practice.
## How the recommendations might affect practice
Standards of documentation and record-keeping within care homes vary widely, so these recommendations are expected to help standardise practice.
Return to recommendations
# Indicators of individual abuse and neglect and immediate actions to take if you consider abuse or neglect
Recommendations 1.4.1 to 1.4.24 and 1.5.1
## Why the committee made the recommendations
There was no research evidence about the indicators that should alert people to abuse and neglect in care homes. Instead, the committee based these recommendations on a review of existing non-NICE UK health and social care guidance (see the context and evidence review C for details of the guidance). There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to make recommendations, alongside their own expertise and experience.
Most of the indicators are adapted from the guidance the committee reviewed, and others were added by the committee based on their knowledge and expertise.
The aim of these recommendations is to help people better understand when a safeguarding referral should be made and when a referral should not be made. The committee felt that some indicators are more serious or urgent than others. This is because, in their experience, those indicators represented a higher likelihood of abuse and neglect. To reflect this, the indicators are split into 2 categories ('consider' and 'suspect'), with different actions based on the likelihood of abuse or neglect. The 'suspect' indicators need to be reported to a safeguarding lead and referred to the local authority.
Some of the indicators of neglect may also be indicators of self-neglect. The guidance the committee reviewed made little mention of this. Based on this lack of coverage the committee felt it was important to make a research recommendation on self-neglect in care homes. They also included a consensus-based recommendation on self-neglect as they agreed that this issue is especially important, because self-neglect in care homes raises questions about the balance between individual choice and the home's duty of care. It also affects the safety, health and wellbeing of other residents, staff and visitors, and can lead to false allegations of abuse and neglect against staff and care homes.
Medication misuse can be a sign of neglect or physical abuse, so the committee included slightly different indicators in both sections.
The committee agreed that indicators of sexual abuse are particularly important because residents may feel embarrassed and ashamed, and therefore reluctant to tell someone and because care homes need to uphold the rights of residents to engage in sexual activity in line with their mental capacity to consent. Care home staff need to be able to recognise these indicators and act upon them.
All types of abuse involve some level of psychological abuse, and psychological abuse may be a sign that other forms of abuse are also happening. Psychological abuse affects the safety, health and wellbeing of other residents, staff and visitors.
Recommendations on financial and material abuse are needed because, while staff are often experienced at recognising other types of abuse, they may find it more difficult to recognise certain types of financial and material abuse.
Discriminatory abuse is important to highlight because it may be difficult to recognise, and may also involve other types of abuse or neglect. It affects the safety, health and wellbeing of residents, because their care may not meet their needs.
## How the recommendations might affect practice
The recommendations are based on existing non-NICE UK guidance, so staff should be familiar with the indicators in this guideline. Some, such as being denied freedom of movement, are also enshrined in law (for example the Human Rights Act, Article 5: right to liberty and security).
Care homes may need to do more to help their staff understand these indicators. But doing so will help care homes manage safeguarding issues more proactively, and deal with early warning signs of potential neglect.
Acting early may improve the quality and safety of care and support for residents. The recommendations may also help to reduce the number of section 42 enquiries involving the care home, local authority and others.
Return to recommendations
# Making sure people are safe
Recommendations 1.6.1 to 1.6.4
## Why the committee made the recommendations
No directly relevant research evidence was identified on what to do if abuse or neglect is suspected. Instead, the committee used existing non-NICE UK health and social care guidance on recognising and reporting abuse and neglect in care homes. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work and used it to inform recommendations on:
ensuring that no one is in immediate danger
thinking about who needs to be informed or consulted
keeping the person at risk involved in the safeguarding process.
The existing guidance did not cover all the areas that the committee thought were important, so they also used their own knowledge and expertise when agreeing the recommendations.
Return to recommendations
# Gathering information
Recommendations 1.6.5 to 1.6.10
## Why the committee made the recommendations
There was no research evidence identified in this area. Instead, the committee used existing non-NICE UK health and social care guidance about information gathering when abuse or neglect is suspected. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations, alongside their own expertise and experience. The guidance highlighted the importance of writing down carefully what the person discloses using their own words, but not interviewing them, and encouraging the resident to preserve any physical evidence if a crime may have been committed.
## How the recommendations might affect practice
Inconsistent or poor-quality records could impact on future enquiries. To ensure staff understand how to gather and record information correctly, care homes and care home providers may need to provide extra training.
Return to recommendations
# Confidentiality, and discussing and reporting suspected abuse and neglect
Recommendations 1.6.11 to 1.6.13
## Why the committee made the recommendations
There was no research evidence identified on confidentiality and suspected abuse and neglect. Instead, the committee used existing non-NICE UK health and social care guidance on recognising and reporting abuse and neglect in care homes. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations.
When the existing guidance did not cover all the areas the committee thought were important they also used their own expertise and experience to make the recommendations.
The committee used their experience and expertise to make the recommendation on reporting suspected abuse and neglect, and who to contact if the problems are with the management of the care home. The committee felt it was important to be clear that if you suspect abuse and neglect you must tell someone in a responsible and accountable position about this.
## How the recommendations might affect practice
There may be uncertainty within care homes around confidentiality, and when to share information. Care homes may need to provide staff with training on the importance of sharing information and the potential risks of not doing this correctly. There may be an impact on staff time and resources. But this would be outweighed by the benefits of making staff aware of who to share concerns with, which should increase the speed of responses to safeguarding.
Return to recommendations
# Care home safeguarding leads
Recommendations 1.7.1 to 1.7.4
## Why the committee made the recommendations
There was no research evidence identified on safeguarding leads. Instead, the committee reviewed existing non-NICE UK sector guidance on recognising and reporting abuse and neglect in care homes. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations, alongside their own expertise and experience.
The committee emphasised the importance of asking the resident at risk what they would like to happen next, to ensure that the response to safeguarding was in line with the principles of Making Safeguarding Personal. They also agreed that care homes should build good relationships with local authorities, seeking advice if needed, in order to better judge when referrals should be made.
## How the recommendations might affect practice
Care homes will have to check that their safeguarding leads have the relevant skills and competencies to assess and act on concerns. If they do not, training may be needed. Care homes may also have to change the way they work with the local authority, to ensure they have a good relationship and can seek advice and support when needed. The implications for care home resources should not be significant, and some of the ways of working suggested may already be in place in some or most care homes.
Return to recommendations
# Local authorities
Recommendations 1.7.5 to 1.7.14
## Why the committee made the recommendations
The committee used evidence from a number of sources to make recommendations specifically for local authorities. These included qualitative themes from research evidence on progressing safeguarding concerns and information needs, and existing non-NICE UK health and social care guidance on recognising and reporting abuse and neglect in care homes.
The committee had low confidence in the qualitative evidence about this issue. The main limitations were:
relevance – in some studies it was not always clear whether research findings related specifically to care homes
limited data.
There were also methodological concerns regarding some of the studies, for example in relation to recruitment strategies and data analysis processes.
The committee also reviewed existing health and social care guidance. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations. The committee also used their own expertise and experience to make recommendations. In addition, they linked the recommendations to Care Act statutory requirements for local authorities. The committee emphasised what care homes find most important when they make a safeguarding referral to a local authority, and at the beginning of a section 42 enquiry.
The evidence highlighted the value that care homes place on local authorities as a key source of support and transparent advice. To reflect this, the recommendations emphasise how local authorities should work with other organisations and support care homes to promote best practice.
Local authorities also use guidance on section 42 enquiries from the Association of Directors of Adult Social Services and the Local Government Association. This guideline aims to complement these other sources of guidance, rather than duplicate them.
## How the recommendations might affect practice
Existing relationships between care homes and local authorities may vary. Depending on how well local authorities already work with other organisations, they may need to do more to develop good ongoing relationships about safeguarding with care homes and to promote multi-agency working. More resources may be needed for a multi-agency approach to safeguarding, but it should improve the quality and safety of care and support.
Return to recommendations
# Working with and supporting the resident at risk during a safeguarding enquiry
Recommendations 1.8.1 to 1.8.21
## Why the committee made the recommendations
The committee used qualitative themes from research evidence on responding to and managing safeguarding concerns in care homes, and support and information needs for everyone involved in safeguarding concerns in care homes.
The evidence showed that residents benefit when they are involved and kept informed throughout the safeguarding process. The evidence also emphasised the value that residents place on support from family, friends or advocates in helping them achieve their desired outcomes. However, the committee had some concerns about the quality of the data, which had some methodological limitations as well as questionable relevance (it was not always clear whether findings related specifically to care home settings).
The committee therefore also used the Making Safeguarding Personal framework and the Care Act 2014. These sources highlight the importance of involving people fully as possible in decisions and giving them the information and support they need to participate.
The evidence matched the committee's experience of practice. They agreed that involving people in decision making will help them achieve the outcomes they want, and make it more likely that they will receive safe and effective care after the enquiry ends. Although the committee were able to draw on their own knowledge and experience, they felt that the gap in the evidence indicated that a research recommendation was needed about the views of care home residents in relation to their experiences of safeguarding enquiries. Getting the views of residents will ensure that their needs are understood and that subsequent care can be person-centred and outcomes-focused.
The committee recognised that there should be a clear difference and understanding of the roles of the practitioners and independent advocate involved in safeguarding. Although the practitioner might be acting in the best interest of the person, they may be operating within the constraints of their role. It is only the independent advocate who acts according to instruction from the person.
Residents will often need emotional and practical support while an enquiry is taking place. In addition, they may need this support to continue afterwards, and their needs should be reassessed after the enquiry.
## How the recommendations might affect practice
Organisations may need to do more to involve people at risk and their independent advocates in safeguarding enquiries. Implementing the recommendations may involve minor changes to existing practice.
The recommendations could also lead to greater demand for support (for example, speech and language therapists) from people at risk. This may have cost implications, but access to support is a statutory right under the Care Act 2014 and is part of the Making Safeguarding Personal framework.
There is variation in how support is currently provided. Some organisations will need to review how they provide support. This may have resource implications for care homes, who will be responsible for ensuring that support is available in the short and long term and that it is tailored to each person's needs.
Return to recommendations
# Supporting care home staff who are subject to a safeguarding enquiry
Recommendations 1.9.1 to 1.9.6
## Why the committee made the recommendations
A small amount of qualitative evidence provided findings relating to the information and support that care home staff need during safeguarding enquiries. However, there were concerns with the adequacy of this data, limitations arising from the data analysis processes used in the studies, and issues with selection bias.
Despite the limitations of the evidence, the committee recognised that this is a crucial issue, in particular for staff who are subject to a safeguarding enquiry. The committee used their own expertise to support the evidence and make recommendations.
The recommendations should reduce the potential psychological and emotional distress on affected staff. They should also encourage staff to report safeguarding problems in the future, as it would be clear to them that everyone would receive support regardless of their involvement.
## How the recommendations might affect practice
Some care home providers already fund access to employee assistance programmes, so would not significantly need to change practice. There could be cost implications for care home providers that do not have employee assistance programmes, unless alternative programmes or funding are available for staff already. The committee did not believe that holding return-to-work meetings would be a substantial change in practice. These meetings already commonly occur, so they may just need more emphasis on guidance and support for the affected member of staff.
Care homes do not currently nominate people to provide support to staff accused of abuse or neglect. However, as this can be an existing member of staff, the committee were confident that there would be no significant resource impact.
Return to recommendations
# Supporting care home staff
Recommendations 1.9.7 to 1.9.11
## Why the committee made the recommendations
There was a small amount of qualitative evidence relating to the information and support needs of care home staff during a safeguarding enquiry. There were concerns around the adequacy of the data, issues with the methods used to analyse the data, and problems with how the study authors addressed potential bias. Despite these limitations, the committee agreed on the importance of support for care home staff, and built on the evidence with their own expertise. These recommendations are important because:
managers have a key role in helping staff obtain support and advice
care homes need to have a more honest and open culture when it comes to potential safeguarding issues
quality of care can be undermined when staff are treated negatively for raising safeguarding concerns, or when staff are afraid to work with residents who have raised or been involved in safeguarding concerns.
## How the recommendations might affect practice
During a safeguarding enquiry, care home managers will need to allocate time to hold discussions with staff and direct them to external information and advice. Managers will also need time to provide one-on-one support to anxious staff, and to make changes to policies, processes and training in response to the outcome of safeguarding enquiries.
In many care homes, managers already do all of this. However, in care homes where this is not the case, managers will need to spend more time supporting staff and learning from safeguarding enquiries.
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# How local authorities should support care homes during an enquiry
Recommendations 1.10.1 to 1.10.5
## Why the committee made the recommendations
There was a small amount of qualitative evidence about the impact of safeguarding enquiries on care homes and the support that care homes, managers and staff need. There were concerns regarding the adequacy and relevance of the data, as it was not clear whether all of the findings were from a care home context. The committee built on this evidence with their own expertise.
The committee made these recommendations because the business impact of safeguarding enquiries is often overlooked, but can be detrimental to care homes. There can be a financial impact, as well as problems with staff recruitment and retention. The recommendations should help reduce these risks. In addition, improved information sharing and trust between care homes and local authorities will help to reduce the stress of the enquiry process.
## How the recommendations might affect practice
Local authorities will need to identify a single point of contact for care homes, which in some cases will be a change in practice. Local authorities may also need to learn more about the reputational risks to care homes and effects on staff morale when they are involved in safeguarding enquiries. Finally, local authorities will need to offer feedback and practical support to care homes.
Return to recommendations
# Meetings during a safeguarding enquiry
Recommendations 1.11.1 to 1.11.3
## Why the committee made the recommendations
There was a small amount of qualitative evidence on effective multi-agency working, and on responding to and managing safeguarding concerns. This evidence had various problems:
issues with the methods used in the studies, such as the way they addressed bias and ethical issues, and their recruitment strategies
the adequacy of the findings, as the studies provided only limited data
the relevance of the evidence, as the studies presented findings from domiciliary settings and it was not always clear when findings related specifically to the care home context.
However, the committee recognised the importance of these issues and were able to build on this evidence using their own expertise.
The evidence suggested that some people felt excluded from important safeguarding meetings. While this is sometimes justifiable, the committee wanted to reduce suspicion about possible bias and increase transparency and collaboration by ensuring that people are always given an explanation and a chance to contribute in another way.
Safeguarding meetings should be opportunities for different organisations to share information and discuss the needs of adults at risk. Because of the multiple organisations involved and the complexity of the process, communication is important, so the committee made recommendations to ensure that everyone involved is kept informed about the process.
No evidence was identified on the management of safeguarding concerns. Because of the lack of evidence, and the potential variation in practice across the country, the committee made a research recommendation on the effectiveness and cost effectiveness of the different approaches to investigating safeguarding concerns.
## How the recommendations might affect practice
There is currently wide variation in what is communicated during safeguarding enquiries and how clear the outcomes are. These recommendations should lead to greater consistency and higher standards, by ensuring that everyone affected by the safeguarding enquiry is kept informed.
The recommendations do not require specific additional resources, but the chairs of meetings may need to take greater care in their documentation and communication.
Return to recommendations
# Indicators of organisational abuse and neglect
Recommendations 1.12.1 to 1.12.12
## Why the committee made the recommendations
No research evidence was identified about the indicators that should alert people to organisational abuse and neglect in care homes. Instead, the committee based these recommendations on a review of non-NICE UK health and social care guidance, (see evidence review C for details of this guidance). There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to make recommendations, alongside their own expertise and experience.
Most of the indicators are based on a synthesis of findings from the review of health and social care guidance documents, and others were agreed by the committee based on their experience.
The aim of these recommendations is to help people better understand when a safeguarding referral should be made and when a referral should not be made. The committee felt that some indicators would warrant more urgent or more significant action than others. This is because, in their experience, those indicators represented a higher likelihood of organisational abuse and neglect. To reflect this, the indicators are split into 2 categories ('consider' and 'suspect'), with different actions based on the likelihood of abuse or neglect. The committee particularly wanted to emphasise the key role of local authorities in relation to organisational abuse or neglect. This is true for their proactive role (monitoring care standards locally), and in their responsibility for starting and running section 42 enquiries (including large-scale enquiries when needed).
A wide range of people are involved in enquiries into organisational abuse and neglect. The committee agreed, based on their own expertise and experience, that local authorities needed to plan ahead for the support that these people might need (this would be especially important for large-scale enquiries). This is so that the support is in place at the right time during the enquiry.
Organisational abuse is distinct from other types of abuse or neglect because it is generally not directly caused by individual action or inaction. Instead, it is more likely to be a cumulative consequence of how services are managed, led and funded. Abuse and neglect are more likely to happen when staff are poorly trained, poorly supervised, unsupported by management, and when the care home has a culture that does not promote openness and good communication. Therefore, the committee made recommendations focusing on these issues.
Organisational abuse and neglect both involve some level of psychological or medical and physical abuse, and may be a sign that other types of abuse and neglect are also happening.
## How the recommendations might affect practice
The recommendations are based on a review of existing guidance, so staff should be familiar with the indicators referred to in this guideline.
Care homes may need to do more to help staff, residents and visitors understand these indicators. However, doing so will help care homes manage safeguarding issues more proactively, and deal with early warning signs of potential organisational abuse and neglect. Acting early may help to reduce the number of section 42 enquiries involving the care home. The recommendations may also improve the safety and quality of care and support for care home staff, residents and visitors.
Care homes may also need to change their recruitment processes, to ensure that applicants are suitable and have been properly vetted.
Staff may also need more training and support, to ensure that they understand their duty of care and to improve their confidence in identifying and reporting potential organisational abuse and neglect.
Identifying organisational abuse and neglect is likely to have other benefits for the care home, in reducing staff turnover and staff absences. This should in turn improve the safety, health and wellbeing of care home residents.
Return to recommendations
# How care homes should learn from safeguarding concerns, referrals and enquiries
Recommendations 1.13.1 to 1.13.2
## Why the committee made the recommendations
Although evidence on implementing learning in care homes was available, this did not focus specifically on using findings from past safeguarding referrals and enquiries in the care home. However, the committee agreed that these findings can be a key source of learning material for care home providers, and they regularly use information from Safeguarding Adults Reviews in their own work. As a result, they felt that it was important to make specific recommendations on this, to ensure that this learning is more widely promoted. The recommendations are for care home managers and local agencies, to ensure that organisations can implement this at the local level.
Given the limited evidence about the use of Safeguarding Adults Reviews, the committee made a research recommendation to identify how the findings from these reviews affect practice in care homes. This includes:
staff experiences in using findings from these reviews
the views of Safeguarding Adults Boards and commissioners on how care homes have learned from Safeguarding Adults Reviews
the barriers and facilitators to embedding learning from Safeguarding Adults Reviews in care homes.
The committee agreed that this research is important to identify how care homes understand Safeguarding Adults Reviews and what they learn from them. If the research allows care homes to better utilise these reviews to improve practice, the safety and wellbeing of care home residents will improve.
## How the recommendations might affect practice
Managers may need to dedicate time specifically to collating data and sharing findings with staff. However, this is unlikely to take a significant amount of time, as there should already be systems in place to record and share this information.
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{'Context': "According to the Care Quality Commission's state of care report for 2019/20, there are over 10,800 residential care homes and 4,200 nursing homes in the UK. These provide support to around 410,000 older people (as estimated by the 2017 Competition and Markets Authority care homes market study), and to many younger adults with disabilities, mental health issues or complex support needs. In addition to long‑term residents, residential and nursing homes provide services for people who stay for shorter periods, including as day visitors. This is sometimes referred to as respite care or short break services. Many of these long- and short‑term residents have high care and support needs, and this means they are at an increased risk of abuse and neglect.\n\nThe quality of care in many care homes is good, but this is not always the case. The Care Quality Commission's report 2019/20 rated homes as follows:\n\ninadequate: 2% of nursing homes and 1% of care homes\n\nrequiring improvement: 21% of nursing homes and 14% of care homes\n\ngood: 72% of nursing homes and 81% of care homes\n\noutstanding: 5% of nursing homes and 4% of care homes.\n\nAll adult safeguarding, including safeguarding in care homes, should be underpinned by the Care Act 2014, the Care Act 2014 statutory guidance, and the Making Safeguarding Personal framework.\n\nDespite the legal framework and the associated statutory guidance, safeguarding procedures and practice vary at the local level. In particular, care homes often struggle to understand:\n\nthe difference between safeguarding issues and poor practice\n\nwhen and how to make safeguarding referrals to the local authority.\n\nThe Safeguarding Adults 2019 Annual Report reported that care homes (including homes with and without nursing) accounted for 34% of all safeguarding enquiries conducted under section 42 of the Care Act 2014.\n\nThis guideline makes action-orientated recommendations to improve safeguarding for residents of care homes. It covers all adult residents of care homes, including people who stay at care homes for shorter periods (for example day visitors).\n\nThe guideline is based on:\n\nthe best available evidence on effectiveness (including cost effectiveness)\n\nevidence on the views and experiences of care home residents, their families and carers, and practitioners involved in care and support for residents.\n\nThe guideline is also informed by existing adult safeguarding guidance from across these different sectors, including:\n\nAssociation of Directors of Adult Social Services, Local Government Association (2019) Making decisions on the duty to carry out Safeguarding Adults enquiries.\n\nAssociation of Directors of Adult Social Services, Social Care Institute for Excellence, National Health Service London, Metropolitan Police (2019) London multi-agency adult safeguarding policy and procedures.\n\nAssociation of Directors of Adult Social Services North East (2011) Safeguarding threshold guidance.\n\nDepartment of Health, Social Services and Public Safety (2009) Adult abuse: recognising adult abuse and what to do about it! Guidance for staff.\n\nRoyal College of Nursing (2018) Adult safeguarding: roles and competencies for healthcare staff.\n\nSkills for Care (2017) What do I need to know about safeguarding adults?\n\nSocial Care Institute for Excellence (2018) Adult safeguarding practice questions.\n\nSocial Care Institute for Excellence (2015) At a glance 69: Safeguarding adults: Types and indicators of abuse.\n\nSocial Care Wales (2019) The social care manager: practice guidance for social care managers registered with Social Care Wales.\n\nVolunteer Now (2010) Safeguarding vulnerable adults: a shared responsibility.\n\nThis guideline can be used together with the Making Safeguarding Personal resources published by the Local Government Association and ADASS, including understanding what constitutes a safeguarding concern and how to support effective outcomes.\n\nThe core legal duty for adult safeguarding is found in section 42 of the Care Act 2014.\n\nThe Care Act 2014 statutory guidance states that:\n\n'Effective safeguarding is about seeking to promote an adult's rights to security, liberty and family life, as well as about protecting their physical safety and taking action to prevent the occurrence or reoccurrence of abuse or neglect. Any restriction on the individual's rights or freedom of action that is involved in the exercise of the function is kept to the minimum necessary.'\n\nThe local authority is the lead agency for adult safeguarding and should be notified whenever abuse or neglect is suspected. They will decide whether a safeguarding enquiry is necessary, and if so who will conduct it. The decision to conduct an enquiry depends on the criteria set out in the Care Act, and not on whether a person is eligible for or receiving services funded by the local authority.\n\nAny actions taken in relation to a safeguarding concern should be based on the 6 principles set out in the Care Act statutory guidance. These principles should be known and understood by everyone working in care homes and should be part of their everyday practice:\n\n. Empowerment: People being supported and encouraged to make their own decisions and informed consent.\n\n. Prevention: It is better to take action before harm occurs.\n\n. Proportionality: The least intrusive response appropriate to the risk presented.\n\n. Protection: Support and representation for those in greatest need.\n\n. Partnerships: Local solutions through services working with their communities. Communities have a part to play in preventing, detecting and reporting neglect and abuse.\n\n. Accountability: Accountability and transparency in delivering safeguarding.\n\nAs well as the 6 principles, this guideline also recognises the importance of the wellbeing principle within the Care Act, and the safeguarding approaches based on the Making Safeguarding Personal framework. These both emphasise that people who have experienced or are at risk of abuse or neglect should be meaningfully involved in safeguarding whenever possible. Outcomes should be meaningful to the person, rather than simply following a process.\n\nThis approach is also endorsed by the Care Act statutory guidance, which states that:\n\n'… safeguarding means protecting an adult's right to live in safety, free from abuse and neglect. It is about people and organisations working together to prevent and stop both the risks and experience of abuse or neglect, while at the same time making sure that the adult's wellbeing is promoted including, where appropriate, having regard to their views, wishes, feelings and beliefs in deciding on any action. This must recognise that adults sometimes have complex interpersonal relationships and may be ambivalent, unclear or unrealistic about their personal circumstances.'\n\nThe guideline complements statutory duties and good practice as set out in relevant legislation and guidance. The recommendations cross-refer to legislation and other guidance where appropriate. In particular, the guideline takes account of the Care Act 2014 and the Care Act 2014 statutory guidance, the Mental Health Acts 1983 and 2007, and the Health and Social Care Act 2008. It is also underpinned by the Human Rights Act 1998, notably Article 3 (No one shall be subjected to torture or to inhuman or degrading treatment or punishment), Article 5 (Right to liberty and security) and Article 8 (Right to respect for private and family life).\n\nAlso, because many people who use care homes may lack the capacity to make certain decisions, this guidance is also informed by the Mental Capacity Act 2005 and the Mental Capacity (Amendment) Act 2019. When a care home resident lacks capacity, this guideline should be used in line with the NICE guideline on decision making and mental capacity and relevant local guidance on this issue.\n\nNICE guidelines provide recommendations on what works. This may include details on who should carry out interventions and where. NICE guidelines do not routinely describe how services are funded or commissioned, unless this has been formally requested by the Department of Health and Social Care.\n\nThe Care Quality Commission encourages health and social care providers to use NICE guidance to improve the quality of care they provide. Evidence of use and compliance with NICE guidance will help services achieve a Good or Outstanding rating.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Policy and procedure\n\n## Care home safeguarding policy and procedure\n\nCare homes and care home providers must have a safeguarding policy and procedure in place, to meet the requirements of the Care Act 2014 and the Care Act 2014 statutory guidance and to follow local safeguarding arrangements (overseen by the local Safeguarding Adults Board). Providers that operate across more than one area must ensure that each care home follows the local safeguarding arrangements in their area.\n\nCare home and care home provider safeguarding policies should:\n\nbe clearly written and in line with Accessible Information Standard requirements to meet the communication support needs of individual residents\n\nbe easy to find, so that all residents, staff, visitors and service providers can request and read it when they need to\n\ninclude clear and transparent arrangements for identifying, responding to and managing safeguarding concerns, and involve residents (and their families and carers) in designing and reviewing these arrangements\n\nexplain how to respond to safeguarding concerns, and how to report suspected abuse or neglect\n\nbe based on the principle of collaborative working, because safeguarding is everyone's responsibility.\n\nCare homes and care home providers should have systems in place to track and monitor incidents, accidents, disciplinary action, complaints and safeguarding concerns, to identify patterns of potential harm.\n\nCare homes should have systems in place for preserving evidence from reported safeguarding concerns, including care records, as these may be required in future, for example for local authority enquiries or police investigations.\n\nCare homes should have a procedure for recording and sharing information (in line with data protection laws) about safeguarding concerns.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home safeguarding policy and procedure\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B: barriers and facilitators to identifying abuse and neglect\n\nevidence review D: responding to and managing safeguarding concerns\n\nevidence review C: tools to support recognition and reporting of safeguarding concerns.\n\nLoading. Please wait.\n\n## Care home whistleblowing policy and procedure\n\nCare homes and care home providers should have a whistleblowing policy and procedure, and make sure that staff and volunteers are aware of these.\n\nCare home providers should have a clear procedure setting out how staff and volunteers can report a whistleblowing concern. This process must specify who people can contact, and how (for example a senior contact within a care home group, and the local authority or the Care Quality Commission). For more information, see the Care Quality Commission guidance on whistleblowing.\n\nCare home providers should consider using an external whistleblowing service. If they do, they should make sure that staff know how to contact the service.\n\nCare homes and care home providers must ensure that whistleblowers are not victimised and do not face negative consequences for reporting or disclosing a safeguarding concern. Be aware that whistleblowers are protected by law.\n\nBe aware that care home staff and volunteers may be afraid of the repercussions of whistleblowing, and this can prevent them from identifying and reporting abuse and neglect.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home whistleblowing policy and procedure\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review C: tools to support recognition and reporting of safeguarding concerns.\n\nLoading. Please wait.\n\n## Care home and care home provider roles and responsibilities\n\nCare homes should:\n\nhave a safeguarding lead\xa0and\n\nmake sure everyone knows who this is, what they do, how to contact them, and who to speak to if they are unavailable.\n\nCare homes and care home providers should make it clear who is accountable for different aspects of safeguarding within the home, in addition to the roles and responsibilities of the safeguarding lead.\n\nSafeguarding responsibilities should be included in the job description of all care home staff, including at board level.\n\nCare homes and care home providers should ensure that all staff understand how to meet their safeguarding responsibilities in their day‑to‑day work within the care home (see the recommendations on induction and training for more information).\n\nCare homes should maintain and regularly audit care records (in addition to external checks, such as audits or Care Quality Commission inspections) and ensure that they are complete and available, in case they are needed if a safeguarding concern is raised.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home and care home provider roles and responsibilities\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review F: barriers and facilitators to effective strategic partnership working.\n\nLoading. Please wait.\n\n## Local authorities, clinical commissioning groups, and other commissioners\n\nLocal authorities and other commissioners should ensure that all care homes they work with are fulfilling their statutory and contractual safeguarding responsibilities.\n\nCommissioners should contribute to improving safeguarding practice in the care homes they work with, by:\n\nsharing key messages from Safeguarding Adults Reviews\xa0and\n\nhelping care homes to learn from their own experience of managing safeguarding concerns.\n\nCommissioners should:\n\nensure that care homes are maintaining records about safeguarding\n\nmake record-keeping responsibilities clear as part of contract management.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on local authorities, clinical commissioning groups, and other commissioners\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review F: barriers and facilitators to effective strategic partnership working.\n\nLoading. Please wait.\n\n## Safeguarding Adults Boards\n\nSafeguarding Adults Boards should be assured that local authorities and clinical commissioning groups have clear lines of communication in place with safeguarding leads in care homes.\n\nSafeguarding Adults Boards should include specific objectives about safeguarding in care homes as part of their strategic planning.\n\nSafeguarding Adults Boards should cover issues relevant to safeguarding in care homes as part of their annual report.\n\nSafeguarding Adults Boards should share recommendations and key learning from Safeguarding Adults Reviews with key stakeholders (including care home providers, staff, residents and their families and carers).\n\nSafeguarding Adults Boards should be assured that partner organisations are working together to support residents during safeguarding enquiries.\n\nSafeguarding Adults Boards should ensure that their escalation procedures for resolving safeguarding disputes are applicable to care homes.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on Safeguarding Adults Boards\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: support and information needs and evidence review F: barriers and facilitators to effective strategic partnership working.\n\nLoading. Please wait.\n\n# Induction and training in care homes\n\nAll directly employed staff working in care homes should:\n\nread and understand the safeguarding policy and procedure during their induction\n\ncomplete mandatory training on safeguarding as soon as possible, and no later than 6\xa0weeks after they start.\n\nCare home managers must ensure that agency staff working at the home have completed the necessary safeguarding training for their role, and that they understand the local safeguarding policy and procedure.\n\nCare home managers should assess staff safeguarding knowledge annually, and run refresher training if needed.\n\nSafeguarding Adults Boards, their subgroups and partnership members should work with partner organisations to:\n\nensure that mandatory safeguarding training includes elements of multi-agency working\n\nensure that mandatory training reflects the safeguarding responsibilities of each member of staff (so staff with more responsibilities receive more comprehensive training)\n\nencourage care home providers to arrange opportunities for staff and residents to learn together from recent Safeguarding Adults Reviews and other experiences of safeguarding.\n\nCare homes should give staff protected time for induction and mandatory safeguarding training. They should ensure that staff have enough time to read and understand the induction and training materials and improve their knowledge and confidence about safeguarding.\n\nCare home managers should:\n\nassess staff understanding of safeguarding after induction and mandatory safeguarding training, to identify areas for improvement\n\nrequest feedback on induction and training\n\nhelp staff to understand the indicators of abuse and neglect, so they can identify safeguarding concerns more accurately\n\nhelp staff increase their confidence in managing safeguarding concerns.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction and training in care homes\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B: barriers and facilitators to identifying abuse and neglect\n\nevidence review H: the effectiveness and acceptability of safeguarding training\n\nevidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n## What mandatory training should cover\n\nAt a minimum, mandatory safeguarding training should include:\n\nsafeguarding and legal principles under the Care Act 2014\n\nthe 6 core principles of safeguarding and the Making Safeguarding Personal framework\n\nspecific responsibilities and accountabilities for safeguarding in the care home\n\nhow to recognise different forms of abuse and neglect, including organisational abuse and neglect\n\nhow to understand the differences between poor practice and abuse and neglect\n\nthe care homes whistleblowing policy and procedure, including what support and information is available in this situation\n\nhow to act on and report suspected abuse or neglect\n\nhow to deal with and preserve evidence\n\nhow to raise safeguarding concerns within the care home and how the care home should respond\n\nhow to escalate concerns (for example, to appropriate helplines or the local authority) if staff feel that the response taken was not appropriate or effective, or if the concern relates to the actions of the care home manager\n\nconfidentiality and data protection\n\nthe importance of being open and honest when things go wrong (the duty of candour)\n\nduties under the Public Interest Disclosure Act 1998\n\nother training that is needed, based on the staff member's role and their specific safeguarding responsibilities.\n\nMandatory safeguarding training should include reflective learning at the individual, team and organisational level, and include opportunities for problem-solving.\n\nMandatory safeguarding training should include an explanation of safeguarding concepts and terminology, including translations of specific terminology if needed (to ensure that training is accessible to all staff).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on what mandatory training should cover\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B: barriers and facilitators to identifying abuse and neglect\n\nevidence review H: the effectiveness and acceptability of safeguarding training\n\nevidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n## Further training\n\nFurther training could cover:\n\nhow to ask about abuse and neglect in a sensitive and non-judgemental manner\n\nhow frequently to assess and ask about abuse and neglect\n\nthe wide range of situations and circumstances in which abuse and neglect can potentially occur\n\nless obvious indicators of abuse and neglect, and more complex safeguarding concerns (for example organisational abuse and neglect)\n\nrisk assessments and their relationship to safeguarding\n\nthe skills needed to support a resident through a safeguarding enquiry.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on further training\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: support and information needs and evidence review H: the effectiveness and acceptability of safeguarding training.\n\nLoading. Please wait.\n\n## How to conduct training\n\nProvide mandatory safeguarding training face-to-face whenever possible. This can be delivered either in person or remotely. It should be live and interactive, and e-learning should only be used when face-to-face training is not possible.\n\nInclude case studies and reflective practice in training and learning at the team and organisational level (for example, at team meetings and handovers).\n\nUse case studies and examples to teach staff how safeguarding relates to personalised care and the human rights of residents.\n\nIncorporate recommendations and other learning from Safeguarding Adults Reviews into training as quickly as possible after they are available.\n\nTraining should be directly applicable to the responsibilities and daily practices of the person being trained, and to the care and support needs of the residents they are working with.\n\nTailor training to reflect the safeguarding responsibilities of each member of staff, so staff with more responsibilities receive more comprehensive training.\n\nIf using e-learning, be aware of the limitations (for example, the lack of opportunity for discussion and asking questions, and the difficulty in ensuring that people have understood the training).\n\nIf using e-learning, care home managers should assess staff literacy levels and IT skills to ensure the training is appropriate. If staff cannot use it, find an alternative e-learning programme or another way to conduct training.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on how to conduct training\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: the effectiveness and acceptability of safeguarding training.\n\nLoading. Please wait.\n\n## Evaluating training\n\nCare home managers and safeguarding leads should ensure that staff are learning from training and using it to improve their practice. This could be done by:\n\nchecking that training is completed, and that this is done within an agreed timeframe\n\nfollow-up conversations with staff\n\nperiodic checks that staff are adhering to safeguarding procedures.\n\nCare home managers should evaluate changes in understanding and confidence before and after training. Assess this:\n\nimmediately after the training\n\nannually\n\nin regular long-term evaluations (for example, as part of supervision sessions).\n\nLine managers should encourage staff to complete and apply learning from their training, for example during staff appraisals. This could include recognising and acknowledging new skills and competences, and changes in attitudes and behaviours.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on evaluating training\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: the effectiveness and acceptability of safeguarding training and evidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n# Care home culture, learning and management\n\n## Management skills and competence\n\nRegistered managers and providers of regulated care must comply with all safeguarding requirements in regulations 12 and 13 of the Health and Social Care Act 2008 (regulated activities) Regulations 2014.\n\nCare home managers and safeguarding leads should lead by example in maintaining up-to-date knowledge on safeguarding.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management skills and competence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n## Line management and supervision\n\nBe aware that staff may be reluctant to challenge poor practice or raise concerns about potential abuse or neglect, particularly if they feel isolated or unsupported.\n\nCare home managers and supervisors should promote reflective supervision to help staff understand how to identify and respond to potential abuse and neglect in care homes. Consider making this independent of line management.\n\nLine managers should provide feedback (through supervision and appraisals) acknowledging how staff have learned from their experience of identifying, reporting and managing safeguarding concerns.\n\nCare home managers should encourage staff to discuss care home culture, learning and management in relation to safeguarding (e.g. in exit interviews) when leaving employment with the care home.\n\nBe aware of the potential for under-reporting of safeguarding concerns by staff who may be afraid of losing their job (for example staff who have their housing or work permit linked specifically to their current role).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on line management and supervision\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n## Care home culture\n\nCare home providers (including trustees and company directors) and managers should:\n\npromote a culture in which safeguarding is openly discussed and abuse and neglect can be readily reported\n\nensure that support is readily available for people raising concerns, for example, by appointing safeguarding champions.\n\nStaff should be encouraged to watch out for changes in the mood and behaviour of residents, because this might indicate abuse or neglect (see indicators of individual abuse and neglect).\n\nStaff should record and share relevant and important information about changes in mood or behaviour or other issues of concern in a timely manner (for example, at every shift handover or transfer of care). In cases of possible abuse or neglect, see the recommendations on immediate actions to take if you consider or suspect abuse or neglect.\n\nCare home managers should make sure there are regular opportunities (for example in team meetings or one-to-one supervision) for all staff to:\n\nshare best practice in safeguarding, including learning from Safeguarding Adults Reviews\n\nchallenge poor practice or discuss uncertainty around practice\n\ndiscuss the differences between poor practice (which is not necessarily a safeguarding issue) and abuse or neglect (which are safeguarding issues).Care home managers should make particular efforts to involve staff who work alone or who get very little direct oversight (for example night staff).\n\nCare home managers should ask for feedback about safeguarding from residents (and their families, friends and carers) and other people working in care homes. They should:\n\nask them about their experience of safeguarding concerns and how these have been identified, reported, managed and resolved\n\nrespond to feedback and tell people about any changes made in response to their comments.This could be done using surveys, meetings and where appropriate, other community engagement (such as open days and visits).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home culture\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators to identifying abuse and neglect and evidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n## Multi-agency working and shared learning with other organisations\n\nCare homes, local authorities, clinical commissioning groups and other local agencies should work together to establish local strategic partnership arrangements that cover safeguarding adults in care homes, and that specifically include:\n\ninformation sharing and communication protocols\n\nroles, responsibilities and accountability for safeguarding within each organisation\n\nprocedures for raising and managing a safeguarding concern, the decision-making process and the procedure for enquiries\n\ndefinitions of good practice and poor practice\n\nthe indicators of abuse and neglect that should result in safeguarding action (based on the indicators in sections 1.4 and 1.12 of this guideline).\n\nLocal health, social care and other practitioners working with care homes should use a multi-agency approach to safeguarding, bringing together a wide range of skills and expertise to keep residents safe.\n\nCare home managers and providers should be aware that some staff may be apprehensive about external oversight, and may need time to build relationships with external agencies before effective multi-agency working and shared learning can take place.\n\nCare home managers and providers should participate in local Safeguarding Adults Board arrangements for sharing experiences about managing safeguarding concerns in care homes.\n\nCare home managers and providers should share relevant information from Safeguarding Adults Board meeting minutes and reports with their staff.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on multi-agency working and shared learning with other organisations\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: responding to and managing safeguarding concerns\n\nevidence review F: barriers and facilitators to effective strategic\n\nevidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n## Record-keeping\n\nCare home managers should ensure that actions taken to safeguard residents are recorded, and shared with other staff as necessary.\n\nCare home managers should ensure that all safeguarding records are focused on the wellbeing of the individual resident. Records should be clear and easily accessible for purposes such as performance management, audits, court proceedings, Care Quality Commission inspections, or learning and development.\n\nCare home managers should regularly review safeguarding records for accuracy, quality and appropriateness.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on record-keeping\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n# Indicators of individual abuse and neglect\n\nThis section describes indicators that should alert people to the possibility of abuse or neglect of individuals within a care home. This section (and the sections on immediate actions to take if you consider or suspect abuse or neglect) applies to anyone in contact with care home residents. This includes staff, volunteers, visiting health and social care practitioners, other residents, family and friends, and any other visitors to the care home. Local authorities may wish to adapt and incorporate these indicators as part of their referral guidance or criteria.\n\nThe terms 'consider' and 'suspect' are used to define the extent to which an indicator suggests abuse or neglect, with 'suspect' indicating a stronger likelihood of abuse or neglect.\n\nTo 'consider' abuse or neglect means that this is one possible explanation for the indicator.\n\nTo 'suspect' abuse or neglect means a serious level of concern about the possibility of abuse or neglect.\n\nNone of the indicators are proof of abuse or neglect on their own. Instead, they are signs that the pathway set out between sections 1.4 and 1.11 of this guideline should be followed. See the indicators of individual abuse and neglect visual summary for a summarised view of this pathway.\n\nThis process is in line with the Department of Health and Social Care statutory guidance on adult safeguarding.\n\nSome behavioural and emotional indicators of abuse and neglect may be due to past trauma, including non-recent incidents such as adverse childhood experiences, or past experience of domestic violence or modern slavery.\n\nSome indicators of abuse and neglect can be similar to signs of distress or behaviours arising from other causes. In particular, there can be similarities with behaviours that may be associated with dementia, autism, learning disability or acute mental distress. However, the possibility of abuse or neglect should always be considered as a cause of behavioural and emotional indicators, even if they are seemingly explained by something else. This is particularly important for residents who do not communicate using speech.\n\nPhysical, sexual, psychological and financial abuse may be perpetrated by volunteers, visitors, and family members and carers, as well as by care home staff. When it is perpetrated by someone who is personally connected to the resident, this is considered to be domestic abuse. In some cases, this can be a continuation of past relationships of domestic violence or abuse.\n\nHealth and social care practitioners should provide information to residents and their families and carers, covering what abuse and neglect look like and how to recognise warning signs.\n\nWhen responding to all indicators of abuse and neglect:\n\nfollow the principles of the Making Safeguarding Personal framework\n\nensure that any actions are guided by the wishes and feelings of the resident\n\nfor guidance on mental capacity, see the NICE guideline on decision making and mental capacity.\n\nIf a resident is in immediate danger or if there is a risk to other residents (for example if the alleged abuser is a person in a position of trust):\n\nfollow immediate actions to take if you suspect abuse or neglect\xa0and\n\nreport suspected abuse or neglect (see recommendation 1.6.13) as soon as is practical.\n\nIf a resident does not want any safeguarding actions to be taken, but you suspect abuse or neglect:\n\nyou should still follow the recommendations in this guideline from immediate actions to take if you suspect abuse or neglect onwards\n\na safeguarding referral must still be made.\n\nIf there are multiple indicators, and at least one is a 'suspect' indicator, you should suspect abuse or neglect (see immediate actions to take if you suspect abuse or neglect).\n\nIf you are not sure if an indicator is a 'consider' or a 'suspect' indicator, speak to your safeguarding lead and/or seek further advice from the local authority about whether to make a safeguarding referral (see also recommendation 1.7.3 for guidance on what safeguarding leads should do if they suspect abuse or neglect).\n\n## Neglect\n\nConsider neglect when residents:\n\nare not supported to present themselves the way they would like (for example haircuts, makeup, fingernails and oral hygiene and care)\n\nare given someone else's clothes to wear\n\noccasionally have poor personal hygiene or are wearing dirty clothes\n\nare wearing clothing that is unsuitable for the temperature or the environment\n\nhave lost or gained weight unintentionally\n\ndo not have access to food and drink in line with their dietary needs\n\nhave repeated urinary tract infections\n\nare not getting care to protect their skin integrity, potentially leading to pressure ulcers (see the NICE guideline on pressure ulcers, and the quick guide on preventing pressure ulcers in care homes)\n\ndo not have opportunities to spend time with other people, either virtually or in person\n\nuncharacteristically refuse or are reluctant to engage in social interaction\n\ndo not have opportunities to do activities that are meaningful to them\n\ndo not have access to medical and dental care\n\nare occasionally denied access to communication and independence aids (such as hearing aids) contrary to their care and support plan\n\nhave not received prescribed medication, or medication has been administered incorrectly (for example, the wrong dose, timing, method, or type of medication)\n\ndo not have access to outdoor space, fresh air and sunlight\n\nare not given first aid when needed.\n\nSuspect neglect when residents:\n\ndo not have an agreed care and support plan\n\nare not receiving the care in their agreed care and support plan\n\nhave deteriorating physical or mental health or mental capacity, and there is a lack of response to this from staff\n\nlive in a dirty, unhygienic or smelly environment\n\nrepeatedly have poor personal hygiene or are wearing soiled or dirty clothes\n\nare malnourished\n\nare frequently and uncharacteristically not engaging with other people, or in activities that are meaningful for them\n\nhave only inconsistent or reluctant contact with external health and social care organisations\n\nhave restricted access to food or drink, if this is not part of their agreed care and support plan\n\nare not kept safe from everyday hazards or dangerous situations\n\nrepeatedly do not receive prescribed medication, or medication has been repeatedly administered incorrectly (for example the dose, timing, method, or type of medication)\n\nare denied communication or independence aids (such as hearing aids, glasses or dentures), contrary to their care and support plan.\n\nBe aware that some indicators of neglect may result from self-neglect. When deciding how to respond to self-neglect:\n\nthink about why the resident may be refusing support\n\nthink about whether the resident has capacity to understand the possible impact of their self-neglect on themselves and others (see the NICE guideline on decision making and mental capacity)\n\nif the resident is refusing support, ask them why, and ask if they would like a different kind of support\n\nmake an assessment based on the risks and needs specific to the resident, in line with the Care Act 2014 statutory guidance.\n\n## Physical abuse\n\nConsider physical abuse when residents:\n\nhave unexplained marks or injuries (for example, minor bruising, cuts, abrasions or reddened skin)\n\ntell you or show signs that they are in pain, and the cause is unexplained (for example, the pain is not caused by a pre-existing medical condition).\n\nSuspect physical abuse when residents:\n\nhave multiple or repeated marks or injuries (for example, bruising, cuts, lesions, loss of hair in clumps, bald patches, burns and scalds)\n\nhave injuries that are very unlikely to be accidental (for example, grip marks, cigarette burns or strangulation marks)\n\nare being restrained without authorisation (either by direct restraint or by being confined to a particular area)\n\nflinch when approached, or change their behaviour (for example, acting subdued) in the presence of a particular person\n\nhave fractures that cannot be explained\n\nhave their activity limited by misuse of medication, or covert administration when not medically authorised.\n\nAct immediately to safeguard residents and contact the police if you witness an assault or are told that a resident has been assaulted (see making sure people are safe).\n\nBe aware that injuries can be caused by other residents.\n\n## Sexual abuse\n\nBe aware that residents have the right to engage in sexual activity if they have the mental capacity to consent. For more information, see:\n\nthe Care Quality Commission guidance on relationships and sexuality in adult social care services\n\nthe NICE guideline on decision making and mental capacity.\n\nConsider sexual abuse when residents:\n\nare spoken to or referred to using sexualised language\n\nexperience any instances of sexualised behaviour or teasing\n\nshow unexplained changes in their behaviour, such as:\n\n\n\nresisting being touched\n\nbecoming aggressive or withdrawn\n\nhaving trouble sleeping\n\nusing sexualised language\n\nshowing highly sexualised behaviours\n\n\n\nshow changes in their relationships (for example, being afraid of or avoiding particular residents, family members or members of staff).\n\nSuspect sexual abuse if a resident has an intimate relationship with a member of staff.\n\nSuspect sexual abuse when residents who lack capacity to consent to intimate or sexual relationships:\n\nreport being inappropriately touched or experience unwanted sexualised behaviours\n\nhave unexplainable physical symptoms that may be associated with sexual activity, such as itching, bleeding or bruising to the genitals, anal area or inner thighs\n\nhave unexplained bodily fluids on their underwear, clothing or bedding\n\nare involved in a sexual act with another person, including their husband, wife, partner or another resident\n\nhave a sexually transmitted infection\n\nbecome pregnant.\n\n## Psychological abuse\n\nConsider psychological abuse when residents:\n\nare addressed rudely or inappropriately on any occasion (verbally or non-verbally)\n\nare prevented from speaking freely\n\nare deliberately and systematically isolated by other residents and/or staff\n\nhave information about their own care systematically withheld from them by the care home\n\nare not involved in planning their own care, or when changes are made to their care without discussion or agreement\n\nare denied a choice on any occasion (for example, around activities of daily living or freedom of movement)\n\nare denied unsupervised access to others\n\nshow significant and otherwise unexplainable changes in their behaviour, including:\n\n\n\nbecoming withdrawn\n\navoiding or being afraid of particular individuals\n\nbeing too eager to do anything they are asked\n\ncompulsive behaviour\n\nnot being able to do things they used to be able to do\n\nnot being able to concentrate or focus.\n\n\n\nSuspect psychological abuse when residents:\n\nare repeatedly addressed rudely or inappropriately (verbally or non-verbally)\n\nare shouted at or verbally threatened\n\nare repeatedly humiliated, belittled, or have their opinions or beliefs undermined\n\nare getting married or entering a civil partnership, if you are concerned that they have not consented or lack capacity to consent to this.\n\nare denied access to independent advocacy\n\nare repeatedly denied choices (for example, around their activities of daily living or freedom of movement).\n\n## Financial and material abuse\n\nBe aware that not having systems to take care of residents' money and possessions is a form of organisational abuse and can lead to financial abuse.\n\nConsider financial and material abuse when residents:\n\ndo not have their money or possessions appropriately recorded by the care home\n\nlose money or possessions\n\ndo not have access to their money, or to possessions that they want or need\n\nare not routinely involved in decisions about how their money is spent (for example if they do not get a personal allowance), or how their possessions are used\n\nappear to have bought things they do not need or invested money in things where they may lack capacity to make informed decisions\n\nfind the person managing their financial affairs to be evasive or uncooperative\n\nfamily or others show unusual interest in their assets\n\nhave unusual difficulty with their finances, and are uncharacteristically protective of money and things they own.\n\nSuspect financial and material abuse when residents:\n\nhave their money spent or their possessions or property used by other people, in a way that does not appear to benefit the resident (for example, their personal allowance being used to fund staff gifts, or misuse of loyalty card points)\n\nhave treasured personal items constantly go missing\n\nget married or enter a civil partnership, if they are likely to lack capacity to consent to this\n\nchange a will under duress or coercion\n\nsign a lasting power of attorney when they do not have the mental capacity to make this decision\n\npersonal financial information is not kept confidential.\n\n## Discriminatory abuse\n\nConsider discriminatory abuse when residents:\n\nare denied choices about the care and support that they receive\n\nare receiving care and support that does not take account of their personal or cultural needs, or other needs associated with protected characteristics under the Equality Act 2010\n\nshow any of the indicators of psychological abuse in recommendation 1.4.18, if these are associated with protected characteristics.\n\nSuspect discriminatory abuse when residents:\n\nare not treated equitably and do not have equal access to available services\n\nexperience humiliation, violence or threatening behaviour related to protected characteristics\n\nare not provided with the support they need, for example, relating to their religious or cultural beliefs\n\nare denied access to independent advocacy\n\nshow any of the indicators of psychological abuse in recommendation 1.4.19, if these are associated with protected characteristics.\n\n# Immediate actions to take if you consider abuse or neglect\n\nIf you 'consider' abuse or neglect:\n\nSeek medical attention for the resident at risk if needed.\n\nRecord what you have found.\n\nSeek advice from a safeguarding lead (unless they are implicated in the alleged abuse or neglect).\n\nCheck whether other indicators have previously been recorded.\n\nDiscuss the welfare of the resident at risk with a manager or supervisor and:\n\n\n\nif you work in the care home, address the problem yourself\n\nif you cannot address the problem yourself or you do not work in the care home, ask the manager or supervisor to address the problem.\n\n\n\nMonitor to see if the problem persists or is repeated, and to check for any other indicators. Think whether new information gives cause for your level of concern to rise from 'consider' to 'suspect'.\n\nAfter taking these steps, decide whether there is now a serious concern about the possibility of abuse or neglect. If there is, and if you 'suspect' abuse and neglect, see immediate actions to take if you suspect abuse or neglect.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indicators of individual abuse and neglect and immediate actions to take if you consider abuse and neglect\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.\n\nLoading. Please wait.\n\n# Immediate actions to take if you suspect abuse or neglect\n\n## Making sure people are safe\n\nIf you suspect abuse or neglect, you must act on it. Do not assume that someone else will.\n\nIf you suspect abuse or neglect, make sure that no one is in immediate danger. If there is immediate danger, call 999 and stay with the resident at risk until help arrives.\n\nIf a crime is suspected but the situation is not an emergency, encourage and support the resident to report the matter to the police. If they cannot or do not wish to report a suspected crime (for example, because they have been coerced or lack capacity), report the situation to the police yourself.\n\nDepending on the risks the resident is facing, and who the alleged abuser is, think about who should be immediately notified. For example:\n\nthe care home manager\n\na healthcare professional or the NHS 111 service if there is a serious medical issue\n\nthe police or other emergency services if the resident is in immediate danger or you suspect a crime.\n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on making sure people are safe\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.\n\nLoading. Please wait.\n\n## Gathering information\n\nAs soon as the resident is safe, start gathering information about the suspected abuse or neglect. Write down:\n\nwhat happened\n\nwhen it happened\n\nwhere it happened\n\nwho was involved (the resident at risk, any other person who has told you about the abuse or neglect, and the alleged abuser).\n\nWhen talking to the resident (or any other person who has told you about the abuse or neglect):\n\ngive them the chance to speak freely about what has happened\n\nuse simple and open questions, and ask in a non-leading way\n\nwrite down what they tell you, in their own words\n\nif the resident does not communicate with speech, help them explain what has happened as far as possible, and report the situation to the safeguarding lead (see recommendation 1.7.1 for safeguarding lead responsibilities in this situation).\n\nExplain the safeguarding process to the resident (or to any other person who has told you about the abuse or neglect) and discuss the next steps.\n\nProvide emotional support to the resident (or to any other person who has told you about the abuse or neglect).\n\nDo not contact the alleged abuser about the incident yourself, unless this is essential (for example, if a manager needs to immediately suspend a member of staff).\n\nDo not investigate the situation yourself, because this could cause problems for police or other investigations and enquiries. Preserve any physical evidence as far as possible (for example, ask the resident to not wash or bathe), and gather information as specified in recommendations 1.6.5 and 1.6.6.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on gathering information\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.\n\nLoading. Please wait.\n\n## Confidentiality and discussing suspected abuse and neglect\n\nIf someone discloses abuse or neglect, tell them that you have a responsibility to report your concerns. Tell them who you will report to, why, and when.\n\nIf someone discloses abuse or neglect, do not agree to keep secrets or make promises you cannot keep.\n\n## Reporting suspected abuse and neglect\n\nIf you suspect abuse or neglect, tell a senior member of staff and the safeguarding lead as soon as is practical (unless the alleged abuser is the only senior member of staff or the safeguarding lead). If you do not feel confident reporting within your organisation, contact:\n\nthe local authority\xa0or\n\na whistleblowing helpline, if you are a member of staff or a volunteer (for more information, see the Care Quality Commission guidance on whistleblowing).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on confidentiality, and discussing and reporting suspected abuse and neglect\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.\n\nLoading. Please wait.\n\n# Responding to reports of abuse or neglect\n\n## Care home safeguarding leads\n\nWhen abuse or neglect is reported, the safeguarding lead should treat it as a safeguarding concern and:\n\nask the resident at risk what they would like to happen next\n\nensure that they have access to communication support\n\nexplain that you have a responsibility to report your concerns to the local authority, and tell them who you will report to, why, and when.\n\nWhen a safeguarding concern has been reported, the safeguarding lead should look at the broader context rather than assessing the concern in isolation. Take into account:\n\nif any other people (including children) are at risk as well as the resident you are concerned about\n\nif there have been repeat allegations\n\nif there could be a criminal offence\n\nif there is a current or past power imbalance in the relationship between the resident and alleged abuser.\n\nIf the safeguarding lead suspects abuse or neglect, they should make a safeguarding referral to the local authority, in line with the Care Act 2014 and Care Act 2014 statutory guidance.\n\nIf the safeguarding lead is not sure whether to make a safeguarding referral to the local authority (because they are not sure whether they suspect abuse or neglect), they should discuss it with the local authority first.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care home safeguarding leads\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.\n\nLoading. Please wait.\n\n## Local authorities\n\nLocal authorities should ensure that there is a process for care homes to discuss safeguarding concerns with social workers or other qualified safeguarding practitioners without formally making a safeguarding referral.\n\nLocal authorities should consider providing a single point of contact for care homes, local agencies and practitioners, so they can seek expert advice on safeguarding in care homes (for example, to help decide whether a referral should be made).\n\nLocal authorities should be aware that safeguarding referrals may come from a care home's openness and awareness of the safeguarding policy, as well as being possible signs of poor care.\n\nLocal authorities and other organisations involved in assessing safeguarding referrals should use professional judgement, supported by the recommendations on indicators of individual abuse and neglect. They should not be limited in their view of what abuse or neglect is, and should always consider the circumstances of the individual case.\n\nWhen a safeguarding referral is made, the local authority should decide as quickly as possible whether this meets the legal criteria for a section 42 safeguarding enquiry (as defined in the Care Act). As soon as this is done, they should tell the resident and the care home safeguarding lead what they have decided.\n\nIf a section 42 safeguarding enquiry is not needed, the local authority should:\n\ndiscuss what other support is needed with the care home and the resident\n\nprovide advice and support to help improve outcomes for the resident (for example, by reviewing the care and support plan and risk management procedures).\n\nIf a section 42 safeguarding enquiry is needed, the local authority should decide who needs to be informed or consulted, depending on the individual context. This might include:\n\nthe resident\n\ntheir family and carers\n\nanyone holding lasting power of attorney for the resident\n\nthe care home and care home provider\n\nadvocacy organisations\n\nvoluntary organisations\n\nthe police\n\nthe organisation commissioning care\n\nthe Office of the Public Guardian, if the safeguarding concern relates to lasting power of attorney\n\nthe Department for Work and Pensions, if the safeguarding concern relates to an appointee for the resident's benefits\n\nspecialist helplines or online support, for advice and information\n\nGPs or other healthcare professionals\n\nthe Care Quality Commission or other regulators\n\nbanks (for financial abuse).\n\nThe local authority should set up an initial planning discussion about the safeguarding enquiry with relevant people, and (if appropriate) involve staff from the care home or care home provider.\n\nThe local authority should appoint an enquiry lead to coordinate the work of the enquiry and act as a main point of contact.\n\nFor more information about conducting a section 42 safeguarding enquiry see Making Safeguarding Personal.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on local authorities\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C: tools to support recognition and reporting of safeguarding concerns\n\nevidence review E: support and information needs\n\nevidence review G: multi-agency working at the operational level in the context of safeguarding.\n\nLoading. Please wait.\n\n# Working with and supporting the resident at risk during a safeguarding enquiry\n\nAt the start of the safeguarding enquiry, the enquiry lead should ask the resident at risk what they would like the enquiry to achieve and how they would like to be involved.\n\nThe enquiry lead should ensure that the resident at risk has the chance to review and revise their desired outcomes throughout the process (if needed using speech and language therapy, non-instructed advocacy or other communication and decision-making aids).\n\nInvolve the resident at risk (and their family or an appropriate advocate) throughout the enquiry process, in line with their wishes and mental capacity, unless there are exceptional circumstances that justify their exclusion.\n\nFor more guidance about supporting decision making for residents who may lack capacity, see the NICE guideline on decision making and mental capacity.\n\nMake reasonable adjustments to enable residents to fully participate in the safeguarding enquiry, in line with the Equality Act 2010.\n\nSafeguarding Adults Boards should be assured that local authorities have auditing processes in place to monitor how residents and their advocates are included in safeguarding enquiries.\n\n## Sharing information\n\nThe enquiry lead should ask the resident at risk:\n\nif they would like to be kept up to date during the enquiry\n\nhow much detail they want\n\nwhat format they would prefer this in\n\nwho they would like to contact them.\n\nIf the police are involved in a safeguarding enquiry, the enquiry lead should hold early discussions with the case officer on the rules of communication and information recording.\n\nWhen safeguarding enquiries finish, the enquiry lead should provide feedback for the resident (and their family and advocates) that:\n\nsummarises the enquiry, and includes the relevant outcomes and recommendations\n\ngives them the information needed to decide whether they wish to take any further action (for example, informing the Care Quality Commission or making a complaint to the Local Government and Social Care Ombudsman).\n\n## Working with advocates\n\nFor guidance on finding out how residents want to be supported in decision making, see recommendation 1.2.1 in the NICE guideline on decision making and mental capacity.\n\nAll organisations involved with safeguarding adults in care homes should:\n\nunderstand the role of advocacy in relation to safeguarding, and that the advocate is the only person who acts solely according to instructions from the resident\n\nthink about the resident's needs and know when to refer people for advocacy\n\ninvolve an independent advocate for the resident, when this is required by the Care Act 2014 and Care Act 2014 statutory guidance or the Mental Capacity Act 2005\n\nensure that anyone supporting the resident as an informal or independent advocate has been identified in line with the resident's statutory rights to advocacy under the Care Act and the Mental Capacity Act.\n\nCare homes should tell residents:\n\nhow advocates can help them with safeguarding enquiries\n\nthat they may have a legal right to an advocate, and what the criteria for this are.\n\nPractitioners involved in managing safeguarding concerns should build effective working relationships with advocates and other people supporting the resident.\n\nLocal authorities and commissioners should monitor:\n\nwhether care homes are telling residents about advocacy and the criteria for accessing this and\n\nhow advocates are involved in the management of safeguarding concerns.\n\n## Support during a safeguarding enquiry\n\nAsk the resident at risk who they would like to support them through the enquiry (in addition to any legal rights to advocacy).\n\nProvide practical and emotional support to the resident at risk:\n\nwhile the enquiry is taking place\n\nwhen the enquiry has finished, to help deliver the outcomes the person wishes to achieve\n\nas needed after the enquiry (for example, by updating the care and support plan or protection plan, conducting risk assessments, or through future reviews).\n\nConsider referring the resident for other specialist support (such as psychological support) after the enquiry.\n\nProvide information and support to informal advocates chosen by the resident at risk (for example, family and friends).\n\nEveryone involved with a safeguarding enquiry should remember that the resident is entitled to and may benefit from support (regardless of their mental capacity).\n\nEnsure that the same level of support is offered to residents who self-fund their care and to residents whose care is publicly funded.\n\nBe aware that when the alleged abuser is another resident, they may also need support (including advocacy). Manage the risks between residents while any enquiry takes place and work with relevant commissioners.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on working with and supporting the resident at risk during a safeguarding enquiry\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: responding to and managing safeguarding concerns and evidence review E: support and information needs.\n\nLoading. Please wait.\n\n# How care home providers and managers should support care home staff during an enquiry\n\n## Supporting staff who are subject to a safeguarding enquiry\n\nCare home providers and managers should:\n\nbe aware of how safeguarding allegations can affect the way other staff and residents view a person subject to a safeguarding enquiry\n\ntake steps to protect the person from victimisation or discriminatory behaviour.\n\nWhen a member of staff is subject to a safeguarding enquiry, care home providers and managers should:\n\ntell them about any available Employee Assistance Programme\n\ntell them about professional counselling and occupational health services (if available)\n\nnominate someone to keep in touch with them throughout the enquiry (if they are suspended from work).\n\nStaff who are subject to a safeguarding enquiry should be able to request that the nominated person be replaced, if they think there is a conflict of interest.\n\nThe nominated person should not be directly involved with the enquiry.\n\nIf the police are involved, care home providers and managers should tell them who the nominated person is.\n\nFor members of staff who return to work after being suspended, care home providers and managers should:\n\narrange a return-to-work meeting when the enquiry is finished, to give them a chance to discuss and resolve any problems\n\nagree a programme of guidance and support with them.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting care home staff who are subject to a safeguarding enquiry\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: support and information needs.\n\nLoading. Please wait.\n\n## Supporting care home staff\n\nUnless they are subject to the safeguarding enquiry themselves, care home managers should:\n\nfind out from the local authority what they can share with staff at each stage of the enquiry\n\ncommunicate as much as possible with all staff about the enquiry, and be open to answering questions.\n\nDuring safeguarding enquiries, care home managers should:\n\nacknowledge that enquiries are stressful and that morale may be low\n\nthink of ways to support staff (such as one-to-one supervision and team meetings)\n\nprovide extra support to cover absences as part of the enquiry, and to help staff continue providing consistent and high-quality care.\n\nIf a care home manager is subject to a safeguarding enquiry, the care home or care home provider should put an acting manager in their place.\n\nIf staff are concerned about working with a resident who has made allegations, care home managers should:\n\nprovide support, additional training and supervision to address these concerns\n\nensure that the resident is not victimised by staff.\n\nCare home managers should direct staff to sources of external support or advice if needed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting care home staff\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: support and information needs.\n\nLoading. Please wait.\n\n# How local authorities should support care homes during an enquiry\n\nLocal authorities should ensure that there is a single point of contact to keep the care home informed about the progress of the safeguarding enquiry.\n\nLocal authorities should be aware of the reputational impact on the care home's business (for example, on recruitment, resourcing and financial losses), and ensure that their actions are timely and proportionate.\n\nLocal authorities should be aware that care home staff may be anxious about their job security because of a safeguarding enquiry.\n\nLocal authorities should offer:\n\npositive feedback to care homes when they handle safeguarding concerns well\n\npractical support to care home staff, to help with safeguarding enquiries.\n\nLocal authorities should share the outcomes of safeguarding enquiries with commissioners, so that they can incorporate the findings into their own decisions (for example, whether to lift a placement embargo).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on how local authorities should support care homes during an enquiry\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: support and information needs.\n\nLoading. Please wait.\n\n# Meetings during a safeguarding enquiry\n\nOnly exclude people from a safeguarding meeting if this is in accordance with the safeguarding policy. If people have to be excluded from a meeting, explain why and give them a chance to share their views in another way.\n\nIf the care home manager and the care home provider safeguarding leads are not at a safeguarding meeting, the chair of the meeting should ensure they are informed of the outcome and the reasons behind it.\n\nKeep the resident at risk informed about the outcome of the meetings. If the outcome is not what the resident was expecting, the chair of the meeting should take particular care to explain the reasons behind it.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on meetings during a safeguarding enquiry\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: responding to and managing safeguarding concerns and evidence review G: multi-agency working at the operational level in the context of safeguarding.\n\nLoading. Please wait.\n\n# Indicators of organisational abuse and neglect\n\nThis section describes indicators that should alert people to the possibility of organisational abuse or neglect within a care home, and immediate actions that should be taken. It does not go into detail about the process for raising a concern, making a referral or conducting an enquiry. This process will vary depending on the nature of the allegations, and the local arrangements in place for responding to such allegations.\n\nThis section is for anyone in contact with care home residents, including staff, volunteers, visiting health and social care practitioners, other residents, family and friends, and any other visitors to the care home.\n\nLocal authorities and others involved in care home quality assurance may wish to adapt and incorporate these indicators into notification and safeguarding referral guidance or quality assurance frameworks.\n\nThere is no one size fits all approach for managing and responding to organisational abuse. This is because of the huge range of actions and inactions that may contribute to organisational abuse, at all managerial and financial levels within organisations. Organisational abuse can also be caused by a single act of neglect or omission. However, commissioners should be alert to any allegations of organisational abuse within care homes, as part of their responsibility for monitoring standards of care against contractual requirements.\n\nOrganisational abuse (also known as institutional abuse) is distinct from other forms of abuse or neglect, because it is not directly caused by individual action or inaction. Instead, it is a cumulative consequence of how services are managed, led and funded. Some aspects of organisational abuse may be hidden (closed cultures), and staff may act differently when visitors are there (disguised compliance). Organisational abuse can affect one person or many residents. Therefore, it is important to consider each unique case, and the impact on individual residents as well as the whole care home.\n\nThe terms 'consider' and 'suspect' are used to define the extent to which an indicator suggests abuse or neglect, with 'suspect' indicating a stronger likelihood of abuse or neglect.\n\nTo 'consider' abuse or neglect means that this is one possible explanation for the indicator. See actions to take if you consider organisational abuse or neglect.\n\nTo 'suspect' abuse or neglect means a serious level of concern about the possibility of abuse or neglect. See actions to take if you suspect organisational abuse or neglect.\n\nNone of the indicators are proof of abuse or neglect on their own. Instead, they are signs that the recommendations on actions to take if you consider or suspect organisational abuse should be followed. See the indicators of organisational abuse and neglect visual summary for a summarised view of this pathway.\n\n## When to consider abuse or neglect\n\nConsider organisational abuse when:\n\nsafeguarding leadership or governance arrangements are unclear (for example, there is no registered manager or delegated safeguarding lead)\n\nmanagers rarely or never observe their staff at work, or are rarely or never available to speak to residents (or their families and carers), staff, or other professionals\n\nmanagers are overly controlling, constantly interfere when staff are working, and stop staff from trying to improve resident safety or care\n\nthe care home does not have policies and procedures covering:\n\n\n\nsafeguarding\n\nwhistleblowing\n\ncomplaints\n\n\n\nthe care home has policies and procedures covering safeguarding, whistleblowing and complaints, but does not use them\n\nthe care home policy and procedure on safeguarding is inconsistent with the Care Act 2014 or this guideline\n\nresidents, visitors, staff and other people working in care homes do not have access to policies and procedures covering safeguarding, whistleblowing and complaints\n\nthe care homes enforces blanket procedures and decisions, regardless of residents individual needs, wishes and circumstances and which generally conflict with safeguarding policies and procedures\n\nthe care home does not explain the concepts of safeguarding, abuse and neglect to residents\n\nresidents are not involved in how the care home is run.\n\nConsider organisational abuse when care homes:\n\ndo not meet contractual safeguarding requirements\n\ndo not meet national regulations, including the fundamental standards of quality and safety monitored by the Care Quality Commission\n\nfail to improve or respond to actions or recommendations arising from inspections or audits by professionals, commissioners and regulators (for example clinical commissioning groups, local authorities, the Care Quality Commission and Healthwatch)\n\nfail to sustain improvements\n\ndo not monitor the quality of their care using the Care Quality Commission's key lines of enquiry and prompts to ensure that the service is safe, effective, caring, responsive and well led.\n\nConsider organisational abuse when:\n\nsafeguarding issues are not always reported\n\nno audits or actions are taken after a disclosure\n\nthere is no clear safeguarding policy or information about how to raise a safeguarding concern\n\nserious incidents are not reported (for example, unexplained deaths, serious fires, or infectious disease outbreaks)\n\nthere is a lack of safeguarding concerns recorded or referrals made\n\nthe care home has poor or outdated records\n\nthere are inconsistent patterns of safeguarding concerns logged (for example, if all concerns originate from 1 member of staff, then other staff may not be taking enough responsibility for safeguarding)\n\nsafeguarding concerns have been reported via complaints procedures rather than through safeguarding procedures\n\nthe care home does not comply with Mental Capacity Act requirements on deprivation of liberty and liberty protection safeguards (when enacted).\n\nConsider organisational abuse when:\n\nthe care home does not have clear, safe recruitment processes (including reference checks and enhanced Disclosure and Barring Service checks)\n\nstaff are not properly supervised and supported, or there is no documentation that this is happening\n\nthere is no evidence that safeguarding training or induction is taking place\n\nthere are high rates of staff absence\n\nstaff work excessive hours without enough breaks\n\nstaff are working under poor conditions\n\nthere is high staff turnover and high dependency on contract or temporary staff.\n\nConsider organisational abuse when:\n\nthere is evidence of poor medicines management (for example, excessive use of 'as needed' medicines)\n\nrestrictive practice is used:\n\n\n\nresidents are prevented from moving around the home freely or independently\n\nstaff teams have inflexible and non-negotiable routines that do not take account of what individual residents want or need\n\nstaff do not help residents live as independently as they can\n\n\n\nmeaningful and structured activities for residents are not available or accessible\n\nbehaviours of concern are mismanaged (for example, overuse of restrictive practices, including misuse of medication)\n\ncare and support plans are changed suddenly, without discussion with residents or others involved with their care\n\nresidents do not receive person-centred care, for example care is focused on completing tasks and ignores individual circumstances and preferences (including cultural preferences)\n\nstaff routinely make assumptions about residents or their needs, and miss hidden needs or disabilities\n\nstaff do not respond to requests from residents, or interfere with residents' preferences and choices\n\nresidents are reluctant to ask for changes or to make complaints\n\ncertain residents routinely receive preferential treatment over others\n\nthere are general inconsistencies in the standard of service provision.\n\nConsider organisational abuse when:\n\nresidents miss appointments or are not referred to other professionals or services (such as GPs or dentists)\n\npeople who require independent advocacy are denied access to it.\n\nConsider organisational abuse when:\n\nthere are not enough staff on each shift to meet the needs of residents\n\nthere are problems with care home equipment:\n\n\n\nit does not meet the needs of residents\n\nit is poorly maintained\n\nthere is not enough equipment for all residents\n\n\n\nthe care home admits or accepts referrals for residents that staff do not have the skills to care for\n\nthere is a lack of investment in the services the care home provides, compared with the fees it charges\n\nresources (such as one-to-one support) for residents with assessed needs are not provided, despite funding being allocated for this\n\nresidents' money is not adequately protected (for example, they do not have personal allowances).\n\nConsider organisational abuse when:\n\nthe care home is dirty or smelly, or is not compliant with basic infection control (for more information about infection control see the NICE quick guide on helping to prevent infection)\n\ncall bells have been removed or deactivated, or are routinely overused\n\nthere is a lack of engagement with visitors, or places in the care home that visitors are not allowed to see\n\nthe care home discourages visitors without justification\n\nthere is a lack of engagement with the organisation the care home is part of.\n\n## Actions to take if you consider abuse or neglect\n\nFor indicators starting with 'consider'\n\nraise the matter with the care home manager, in writing if possible\n\n\n\nif the care home manager is believed to be part of the problem, go to the group manager, regional manager, owner or board of trustees\n\nif the care home manager is the sole owner, follow the actions to take if you suspect abuse or neglect\n\n\n\nexplain the impact on residents, or the likely impact if the situation continues\n\nask for a response within a specified period of time (for example 2\xa0weeks)\n\nif the manager agrees to make changes, make sure these happen\n\nafter taking these steps, if the situation does not improve, raise your level of concern to 'suspect'.\n\n## When to suspect organisational abuse or neglect\n\nSuspect organisational abuse when:\n\nincidents of abuse or neglect are not reported, or there is evidence of incidents being deliberately not reported\n\nthere is evidence of redacted, falsified, missing or incomplete records\n\nthere have been multiple hospital admissions of residents, resulting in safeguarding enquiries\n\nthere are repeated cases of residents not having access to nursing, medical or dental care\n\nthere is frequent, unexplained deterioration in residents' health and wellbeing\n\nresidents' money is being misused by the care home (for example, to purchase gifts for staff or other residents without permission)\n\nthere is a sudden increase in safeguarding concerns in which abuse or neglect has been identified\n\nresidents are repeatedly evicted or threatened with eviction after making complaints\n\nrepeated instances of residents, families and carers feeling victimised if they raise safeguarding concerns\n\nthe care home fails to improve or respond to actions or recommendations in local inspections or audit frameworks from clinical commissioning groups or the local authority, or reviews and inspections by the Care Quality Commission or Healthwatch, and deteriorates over time.\n\n## Actions to take if you suspect abuse or neglect\n\nIf you 'suspect' abuse or neglect:\n\nContact your local authority and tell them that you want to make an adult safeguarding referral.\n\nWhen local authorities receive adult safeguarding referrals:\n\n\n\nthey should gather information, under section 4 of the Care Act\n\nthey must decide if there is reasonable cause to suspect that an adult with care and support needs is experiencing abuse or neglect and is unable to protect themselves from harm\n\nif this criteria is met, they must conduct a section 42 enquiry.\n\n\n\nIf many residents of a care home are affected, local authorities may conduct a large-scale enquiry, following their own local procedures.\n\nIf you are not satisfied with the response from your local authority, you can make a complaint to the Local Government and Social Care Ombudsman and give feedback to the Care Quality Commission.\n\nWhen organisational abuse or neglect is identified, plan what individual or collective support is needed for residents, staff, and other people who might be affected.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indicators of organisational abuse and neglect\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: tools to support recognition and reporting of safeguarding concerns.\n\nLoading. Please wait.\n\n# How care homes should learn from safeguarding concerns, referrals and enquiries\n\nCare home managers and managers from local agencies should help their organisations to identify key lessons from the outcome of any safeguarding concern, referral, enquiry, or Safeguarding Adults Review.\n\nCare home managers should incorporate learning from safeguarding concerns, referrals and enquiries into the care home culture at all levels:\n\nindividual staff, for example through changes to support, supervision, retraining, and performance management)\n\ncare home, for example through:\n\n\n\nobservations of practice, discussion and watching people work across the home\n\nchanging practices, procedures, policy and learning, and group training (including training from other health and social care practitioners)\n\n\n\ncare home provider, for example through policy changes).In addition, see the recommendations on care home culture, learning and management.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on how care homes should learn from safeguarding concerns, referrals and enquiries\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Care homes\n\nResidential care homes (with or without nursing care) that are registered with and regulated by the Care Quality Commission.\n\n## Care home providers\n\nCompanies that own and operate one or more care homes that are regulated by the Care Quality Commission.\n\n## Commissioners\n\nLocal authorities, clinical commissioning groups and other public sector commissioners who oversee contracts for care and support services provided by care homes that pay for care home residents who are eligible for public funding. The term 'commissioner' does not apply to individuals who pay privately for their care.\n\n## e-learning\n\nInduction, training and assessment that people undertake on a computer or mobile device, without interacting with other people.\n\n## Enquiry lead\n\nSometimes referred to as the lead enquiry officer or enquiry officer. This person is appointed by the local authority when a safeguarding enquiry begins. They may be a local authority social worker or a designated member of staff from the care home or care home provider. They are responsible for coordinating responses to the enquiry, coordinating decision making and acting as the main point of contact. They make sure that enquiry actions are undertaken in accordance with Care Act duties, related statutory guidance and the recommendations in this guideline.\n\n## Face-to-face learning\n\nInduction, training and assessment that is undertaken one-to-one, or in groups led by either in-house staff experts, managers or external trainers. It may take place with participants all in the same room, or using video or telephone conferencing. It may include online materials, but participants are able to ask questions, discuss, reflect on current practice and use case studies and examples. This type of training looks at how safeguarding relates to the particular role of the person being trained, and to the personalised care and support needs of residents.\n\n## Multi-agency\n\nOrganisations working together in the context of safeguarding adults in care homes. Relevant organisations include:\n\nlocal authorities and health and social care services\n\nthe police and other organisations in the criminal justice system\n\neducation and learning services\n\nadvocacy services\n\nlocal voluntary and community groups.\n\nNational organisations or complaints services can also be included (such as the Local Government and Social Care Ombudsman).\n\n## Reflective practice and reflective supervision\n\nOpportunities for staff to:\n\nreflect on previous practice\n\ntalk about why they made the decisions they made, and why they acted or behaved in particular ways\n\ntalk about their emotional responses to their actions and the actions of others\n\nengage in continuous learning.\n\nReflective practice and supervision may also provide insight into personal values and beliefs, and help staff understand how these influence action and decision making within the care home.\n\n## Registered managers\n\nCare homes registered with the Care Quality Commission must have a registered manager, in line with the Health and Social Care Act 2008. The registered manager is responsible for leading and running the care home and making sure that standards are upheld. Note that other managers may also work within care homes and have responsibilities for staff supervision, line management, or other aspects of running the home. However, the registered manager is the person accountable to the Care Quality Commission for the standards of care and safeguarding within the home.\n\n## Residents\n\nAdults aged 18 and over who live in and receive care and support in care homes, or who use care homes to access care and support from time to time (for example respite care, including day care).\n\n## Resident at risk\n\nThe resident at the centre of a safeguarding concern, when:\n\nabuse or neglect is considered or suspected or\n\na safeguarding referral has been made to a local authority or\n\na section 42 safeguarding enquiry is taking place.\n\n## Safeguarding adults reviews\n\nMust be arranged by Safeguarding Adults Boards if:\n\nthere is reasonable cause for concern that partner agencies could have worked more effectively to protect an adult and\n\nwhen serious abuse or neglect is known or suspected and\n\nif certain conditions are met, in line with section 44 of the Care Act 2014 and related statutory guidance.\n\n## Safeguarding champions\n\nSafeguarding champions are staff already working within the care home, with good knowledge of safeguarding policy and procedure, who help ensure that procedures are followed and are available for discussion. They also ensure reflective learning about best practice in preventing abuse and neglect. Champions may also offer practical and emotional support to those worried about the impact of raising concerns. They are not a replacement or alternative to the safeguarding lead.\n\n## Safeguarding concern\n\nFor the purposes of this guideline, a safeguarding concern is defined as a consideration, suspicion or indication of abuse or neglect of a resident, or residents within a care home. Anybody who works in, lives in or visits the home may have a safeguarding concern, either because of something they have seen or because of something they were told. All safeguarding concerns should be responded to in line with this guideline. Note that this definition relates to concerns in care home settings. For a more general definition, see the Local Government Association and ADASS definition in their report on understanding what constitutes a safeguarding concern.\n\n## Safeguarding enquiry\n\nIf the local authority agrees that the safeguarding referral falls within the duty set out within section 42 of the Care Act 2014 and related statutory guidance, they must undertake an enquiry into the suspected abuse or neglect. Note that this definition relates to enquiries about abuse and neglect in care homes. For a more general definition, see the Local Government Association and ADASS definition in their report on understanding what constitutes a safeguarding concern.\n\n## Safeguarding lead\n\nThis may be the care home registered manager or someone with delegated responsibility for safeguarding within the care home. It is a statutory requirement for care homes to have a designated safeguarding lead. Safeguarding leads should have had training in safeguarding, and should have the relevant skills and competencies to ensure the safety and protection of residents, in line with Care Quality Commission guidance.\n\n## Safeguarding referral\n\nAs outlined in this guideline, if abuse or neglect is suspected this must be reported to the local authority. This is called making a safeguarding referral.\n\n## Service providers\n\nOther organisations providing services within care homes or contracted by care homes to provide services. These include health and social care services (for example, GP services, clinical psychology and occupational therapy), and other services such as cleaning, catering, gardening, transport, education, learning or activities.\n\n## Staff\n\nAnyone paid to work in a care home and involved either directly or indirectly in the care and support of residents. This includes care workers, nurses, managers, administrative staff, cleaners, caterers, gardeners or anyone else who the care home employs directly or via agencies or contractors, on a casual, part-time, full-time, temporary or permanent basis.\n\n## Contract or temporary staff\n\nStaff who are not employed on a permanent contract with the care home, who may be supplied by an employment agency on a short-term basis, or who might be employed on a zero hours contract or on a casual labour basis.", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\n# Indicators of self-neglect\n\nWhat are the indicators of self-neglect among care home residents, and what should the responses be?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on indicators of individual abuse and neglect and immediate actions to take if you consider abuse or neglect\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: indicators of abuse and neglect.\n\nLoading. Please wait.\n\n# Local authority or provider-led enquiries\n\nWhat is the effectiveness and cost effectiveness of local authority versus provider-led safeguarding enquiries?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on meetings during a safeguarding enquiry\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: responding to and managing safeguarding concerns.\n\nLoading. Please wait.\n\n\n\n# Person-centred and outcome-focused enquiries\n\nTo what extent are safeguarding enquiries in care homes person-centred and outcomes-focused, and what improvements could be made?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on working with and supporting the resident at risk during a safeguarding enquiry\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: responding to and managing safeguarding concerns.\n\nLoading. Please wait.\n\n\n\n# E-learning safeguarding training\n\nWhat is the effectiveness, cost effectiveness and acceptability of e-learning safeguarding training compared with face-to-face?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on how to conduct training\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: the effectiveness and acceptability of safeguarding training.\n\nLoading. Please wait.\n\n\n\n# Embedding learning from Safeguarding Adults Reviews\n\nWhat are the barriers and facilitators in care homes to embedding learning from Safeguarding Adults Reviews?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on how care homes should learn from safeguarding concerns, referrals and enquiries\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: embedding organisational learning about safeguarding.\n\nLoading. Please wait.\n\n", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Care home safeguarding policy and procedure\n\nRecommendations 1.1.1 to 1.1.5\n\n## Why the committee made the recommendations\n\nThese recommendations are based on:\n\nqualitative themes from research evidence\n\nthe committee's own expertise and experience\n\nhealth and social care guidance\n\nthe Care Act 2014 and Care Act 2014 statutory guidance.\n\nOverall, the committee's confidence in the research evidence was low. The main issues with the evidence were that the included studies provided only limited data and reported research conducted in a range of settings, making it difficult to determine whether each finding was directly relevant to care home contexts. There were also concerns regarding the methods used in some of the included studies, for example their recruitment processes and how they considered the wider research context.\n\nThe committee also reviewed existing non-NICE UK health and social care guidance. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations, alongside their own expertise and experience. The guidance highlighted some of the challenges faced by individuals and organisations when there is no clear safeguarding procedure. This has implications for:\n\nthe safety and wellbeing of residents, because abuse or neglect may go unreported\n\nthe wellbeing of staff, because they can feel anxious and unsupported when they do not know what to do about safeguarding concerns.\n\nThe committee were keen to highlight the obligations of individuals (including visitors) and organisations, to ensure that everyone knows what to do when a safeguarding concern arises. The committee made a recommendation on ensuring that the safeguarding policy is accessible, easy to find and understand because safeguarding is everyone's responsibility, and people with little experience of safeguarding (such as visitors) may need to read it.\n\nWhile having policies and procedures in place is important, care homes and care home providers can have problems ensuring that staff follow these. The committee believed it was important to have systems in place to make sure policies and procedures are followed. They made recommendations on how these systems should be used to record and share information.\n\n## How the recommendations might affect practice\n\nCare homes should already have a safeguarding policy and procedure, and the recommendations reflect statutory requirements. However, some care homes may need to change their policy and procedure so that they fully comply with these recommendations. This may involve extra work for care home managers. Care homes may need to update their systems to ensure that safeguarding concerns (and patterns of concerns) can be monitored. Care home staff may also need training to improve their understanding of safeguarding policy and procedure, and to show them how to preserve evidence from reported safeguarding concerns.\n\nReturn to recommendations\n\n# Care home whistleblowing policy and procedure\n\nRecommendations 1.1.6 to 1.1.10\n\n## Why the committee made the recommendations\n\nThe committee used qualitative themes from research evidence on identifying abuse and neglect to make the recommendations. There were several issues with this evidence. The main concern was relevance, as it was not always clear whether the data reported came from research conducted in a care home setting. There were also concerns regarding the methods used in some of the studies, for example in relation to their recruitment and data analysis processes.\n\nThe committee also reviewed existing non-NICE UK health and social care guidance, and legislation and care law about whistleblowing. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations. The guidance highlighted the challenges associated with whistleblowing and the impact whistleblowing can have on care homes, staff and volunteers. The committee felt that this was an important area, and built on the evidence using their own expertise. Good whistleblowing policies are important and help support a culture in which staff feel able to report concerns.\n\nBased on their own knowledge, the committee decided to emphasise the legal protections for whistleblowers. This is because whistleblowers are vulnerable to victimisation.\n\n## How the recommendations might affect practice\n\nCare homes may need to revise and update their whistleblowing policy and procedure. They may also need to do more to promote more positive attitudes about whistleblowing among staff, and to encourage an open culture to help staff feel more confident raising concerns. In turn, this should help reduce the under-reporting of safeguarding concerns. There may be a cost for care homes who choose to provide external whistleblowing services, which is why the committee only ask care homes to consider using this service.\n\nReturn to recommendations\n\n# Care home and care home provider roles and responsibilities\n\nRecommendations 1.1.11 to 1.1.15\n\n## Why the committee made the recommendations\n\nQualitative themes were identified from the research evidence, covering the challenges associated with governance, roles and responsibilities, and lines of communication. There were a number of issues that limited how the committee could use the findings. The main issues were the adequacy of the data and the relevance of the evidence, as it was not always clear whether data had been collected in a care home setting.\n\nIn addition, there were concerns about methods used in some of the studies, for example in relation to data analysis processes and how the researchers took account of ethical issues.\n\nThe evidence did, however, highlight the uncertainties and misunderstandings surrounding the roles, responsibilities and accountabilities for safeguarding within care homes and care home providers. The committee agreed that this is a crucial area and they built on the evidence with their own expertise.\n\n## How the recommendations might affect practice\n\nCare homes will need to ensure they implement relevant, up-to-date policies and procedures. This should only require minor changes to current practice because it is already a statutory requirement.\n\nReturn to recommendations\n\n# Local authorities, clinical commissioning groups, and other commissioners\n\nRecommendations 1.1.16 to 1.1.18\n\n## Why the committee made the recommendations\n\nThe committee agreed that it is important to reiterate the responsibilities of local authorities, clinical commissioning groups and other public sector commissioners, because they can use contract monitoring and other statutory monitoring processes to ensure that care homes are meeting their safeguarding responsibilities.\n\nThe committee also wanted to emphasise the important role of commissioners in working with care homes. Commissioners can help care homes implement lessons from Safeguarding Adults Reviews and ensure that good safeguarding records are maintained.\n\n## How the recommendations might affect practice\n\nLocal authorities, clinical commissioning groups and other commissioners should already be monitoring safeguarding in care homes as part of contract management, so this should not represent a significant change in practice. Commissioners may need to do more to promote good communication and working relationships with care homes, but this could be achieved without additional resources.\n\nReturn to recommendations\n\n# Safeguarding Adults Boards\n\nRecommendations 1.1.19 to 1.1.24\n\n## Why the committee made the recommendations\n\nThe committee made the recommendations based on a limited amount of qualitative evidence on the roles and responsibilities of Safeguarding Adults Boards. There were a number of concerns with this evidence, around:\n\nthe methods used, for example in relation to data analysis and sampling strategies\n\nthe relevance of the themes in the evidence, as some of the studies were conducted in care settings other than care homes\n\nadequacy, as the themes were based on relatively limited data.\n\nThe evidence highlighted the challenges associated with partnership working, and the difficulties in communicating with care homes. The evidence also indicated that there may sometimes be confusion around:\n\nlines of communication about safeguarding and safeguarding concerns\n\nwho is responsible for each part of the process\n\nhow and when care homes should be working with the local Safeguarding Adults Board.\n\n## How the recommendations might affect practice\n\nThere is wide variation in the way Safeguarding Adults Boards operate and communicate. The recommendations should lead to greater consistency. Safeguarding Adults Boards should not need additional resources, but some will need to change the way they work. If they are not already doing so, they will need to promote a positive culture and encourage greater collaboration between their members and partner organisations, especially care homes.\n\nReturn to recommendations\n\n# Induction and training in care homes\n\nRecommendations 1.2.1 to 1.2.8\n\n## Why the committee made the recommendations\n\nQuantitative and qualitative data were available on training in the care sector, but the committee's confidence in this evidence was low. For the quantitative data, this was mostly because of the use of non-randomised trials and imprecision in effect estimates. For qualitative findings there was a shortage of evidence, with only limited data from a small number of studies. In addition, there were issues with the relevance of the qualitative data, because some studies may have been conducted outside of care homes, and some findings may not have been specifically related to safeguarding.\n\nAs a result of the limitations of the evidence, the committee also used their own expertise, and their knowledge of statutory guidance requirements, to make a recommendation. They believed this is important because good-quality training can have a big impact on safeguarding practice and the safety and wellbeing of care home residents.\n\nThe evidence highlighted the need for basic training for all staff employed by or contracted to work within the care home, to make sure they have a good understanding of what safeguarding is, how it is everyone's responsibility and how it might relate to their job within the care home.\n\nMandatory training is required to fulfil section 14.225 of the Care and support statutory guidance 2020, and each organisation is responsible for ensuring that staff receive effective training. This includes ensuring that agency staff have the necessary training. The committee discussed whether it is possible to specify how soon new staff should have mandatory safeguarding training. Although there was no evidence on this the committee agreed it would be helpful to specify that this should take place within 6\xa0weeks of starting work. This is in line with standards that already exist, such as Adult Safeguarding: Roles and competencies for Health Care Staff 2018, but there is still inconsistent practice in this area. Evidence suggested that improvements in safeguarding practice were not always maintained in the longer-term, and the committee agreed that it was important to run refresher training if needed.\n\n## How the recommendation might affect practice\n\nCare Quality Commission standards cover basic safeguarding training for all staff (CQC: Regulation 13 - Safeguarding service users from abuse and improper treatment and CQC: Safeguarding Adults - Roles and responsibilities in health and care services) so this is not a new requirement and is unlikely to lead to significant resource implications. However, the content of training may vary across care homes, and some care homes may need to adapt their training programmes to make sure that safeguarding forms part of all new employee inductions within 6\xa0weeks of starting work. Training programmes may also need to be adapted so that staff have protected time to ensure they fully understand the actions they need to take if they ever have a safeguarding concern.\n\nThere may also be minor resource implications associated with improved safeguarding practice. For example, if staff have a better understanding of abuse and neglect, they may raise more concerns and there may be an increase in safeguarding referrals and enquiries.\n\nReturn to recommendations\n\n# What mandatory training should cover\n\nRecommendations 1.2.7 to 1.2.9\n\n## Why the committee made the recommendations\n\nThe strength of the evidence was limited, but the committee made recommendations in areas where the evidence aligned with their own experience and expertise.\n\nThe committee had low confidence in the quantitative outcomes, because of concerns about bias (as most studies were not randomised) and imprecision in effect estimates. They were also concerned about the short follow-up periods the studies used.\n\nThere were also issues with the qualitative evidence. This was mainly due to the relevance of the data, because it was not always clear whether findings related specifically to safeguarding. There were also concerns regarding the adequacy of data, as most of the themes in the evidence were based on limited data.\n\nThe evidence suggested that in some care homes, training only covers a basic understanding of adult protection policies and procedures, which staff may not then know how to apply in their daily work. To address this and ensure that staff have a more thorough understanding of safeguarding, the committee specified the different areas that need to be covered in training programmes for all staff.\n\n## How the recommendations might affect practice\n\nCare homes may need to change their safeguarding training programmes to make sure they cover the areas included in this guideline. They may need to make training programmes applicable to the daily practice and responsibilities of staff and particularly to safeguarding in the care home environment. Care homes will need to make sure that specific safeguarding concepts and terminology is clearly understood by all staff, regardless of literacy levels or language skills, and this may require some additional resources.\n\nReturn to recommendations\n\n# Further training\n\nRecommendation 1.2.10\n\n## Why the committee made the recommendations\n\nThere was quantitative and qualitative evidence available, but the committee had limited confidence in this.\n\nThe quantitative evidence had issues with bias (as most studies were not randomised) and imprecision in effect estimates. In addition, the studies only used short-term follow-up periods.\n\nThere were issues with the relevance of the qualitative data, as it was not always clear whether findings related specifically to safeguarding. There were also concerns regarding adequacy, as most themes were based on limited data.\n\nBecause of the limitations with the evidence, the committee also used their expertise when making recommendations on further training.\n\nEvidence on training suggested that improvements in safeguarding practice were not always maintained in the longer-term, and that there should be opportunities for further and more advanced learning. As a result, the committee agreed that it is important to emphasise that training should not be a one-off event. Their recommendations included advice about further training that may be beneficial for some staff. More detailed information on safeguarding training and the competencies that different staff need is covered in Adult Safeguarding: Roles and competencies for Health Care Staff 2018. Because of this, the committee did not make recommendations about who should have further training or when this should happen.\n\n## How the recommendations might affect practice\n\nEnsuring that care home staff can regularly take part in safeguarding training may lead to an increase in resource use, particularly if care homes choose to use external organisations to deliver these programmes. However, increased costs will be justified given the improvements in safeguarding practice that are likely to occur.\n\nThere may be an increase in the number of requests for training. There may also be cost implications if practitioners need training of their own in order to conduct training for staff. In addition, some staff posts may need to be backfilled while training takes place. However, any additional costs may be justified by the improvements in staff knowledge, competence and confidence, which will provide better quality of care for residents.\n\nReturn to recommendations\n\n# How to conduct training\n\nRecommendations 1.2.11 to 1.2.18\n\n## Why the committee made the recommendations\n\nThere was only limited evidence that focused specifically on safeguarding training in the care sector. There was no evidence comparing the effectiveness of different modes of training (for example e-learning programmes compared with group sessions). The committee provided anecdotal evidence of concerns about the efficacy of e-learning, in particular when there is no opportunity for discussion and human interaction. They agreed that further research is needed to evaluate the most effective modes of training, and to clarify whether e-learning training can meet best practice standards. To address this, the committee made a research recommendation to look at the effectiveness, cost effectiveness and acceptability of e-learning safeguarding training, compared with face-to-face training.\n\nThere was some limited economic evidence on training. This evidence did not demonstrate any differences in costs or effectiveness between 2 different programmes. An economic analysis showed that face-to-face training could be cost-effective relative to e-learning, under certain assumptions. Other evidence that was available highlighted the positive outcomes achieved with some training methods (such as case studies and examples), and the challenges associated with other types of training (such as e-learning). The committee supported this evidence with their own expertise.\n\nThe recommendations should help care home managers identify the most appropriate training methods for their staff, which will improve care home practice.\n\n## How the recommendations might affect practice\n\nThere is some variation across the UK in the way care homes conduct training, although the contracts that providers have with local authorities will tend to encourage best practice and standardisation.\n\nThere may be an increase in the number of requests for training. There may also be cost implications if practitioners need training of their own in order to conduct training for staff, or if external organisations are used to deliver training. However, any additional costs will be justified by the improvements in staff knowledge, competence and confidence, which will provide better quality of care for care home residents.\n\nReturn to recommendations\n\n# Evaluating training\n\nRecommendations 1.2.19 to 1.2.21\n\n## Why the committee made the recommendations\n\nAlthough there was some quantitative evidence on the effectiveness of safeguarding training, there were concerns with this evidence. The main concerns were around bias (as most studies were not randomised) and imprecision in effect estimates. There were also concerns regarding the short-term follow-up periods used by the studies.\n\nThe qualitative evidence also had problems. There was a lack of detail regarding study methodology, making quality assessment difficult. The committee had concerns about the adequacy of the findings, which were based on 'thin' data. And it was unclear whether the data related specifically to safeguarding.\n\nBecause of the shortage of good-quality evidence, the committee made recommendations partly based on their own expertise and experience.\n\nDespite the limitations of the evidence, the qualitative data indicated that training can improve staff safeguarding skills. This was also reflected in the qualitative evidence, which indicated that practitioners recognised the value of safeguarding training. However, this evidence also suggested that managers may be unwilling to implement learning from training programmes or make changes to care home procedures, which may negate any benefits associated with training. To address this, the committee made a recommendation on how managers should encourage staff to complete training.\n\nThe evidence on training only included short-term measurements of effectiveness. To address this potential issue, the committee made a recommendation on assessing how well training is working and whether it is being used to improve practice. For example, care home managers could assess this through follow-up conversations with staff, and by evaluating changes immediately after training and at further longer-term follow-up.\n\n## How the recommendations might affect practice\n\nCare home managers may need to re-assess how they engage with safeguarding training. They will need to find ways to identify positive changes from training, and implement these across the care home. This may mean that managers have to place greater emphasis on reflective practice and shared learning among staff. The structure of staff supervision sessions may need to be changed, to ensure that positive learning is acknowledged and reinforced.\n\nReturn to recommendations\n\n# Management skills and competence\n\nRecommendations 1.3.1 to 1.3.2\n\n## Why the committee made the recommendations\n\nSome qualitative evidence was available, but the committee had limited confidence in it. This was mostly due to issues with:\n\nthe study methods, such as the processes used to analyse the data\n\nthe relevance of the data, as it was not clear whether data was specific to safeguarding (rather than more general quality of care) or whether data had been generated in care settings other than care homes\n\nthe adequacy of the data, which was considered to be limited (and did not include any quotations).\n\nAs a result, the committee drew on their own expertise to supplement the evidence and make recommendations.\n\nThe evidence indicated that care home managers can play a key role in influencing the attitudes of their staff and colleagues towards training. Some staff may also need more support to benefit from training. Staff may not benefit from training if managers are unable or unwilling to allow staff to implement what they have learned within the care home and share their experience with other members of staff.\n\n## How the recommendations might affect practice\n\nManagers will need to make sure their safeguarding knowledge is up to date. This has been a legal requirement for some time so should not represent a change in practice.\n\nThere is variation in how much care home managers do to encourage other staff to learn more about safeguarding. The recommendations will help standardise practice, and ensure that managers promote safeguarding training and learning in care homes.\n\nReturn to recommendations\n\n# Line management and supervision\n\nRecommendations 1.3.3 to 1.3.7\n\n## Why the committee made the recommendations\n\nThere was a good amount of qualitative evidence on identifying abuse and neglect in care homes, and the barriers and facilitators to this. In particular, the evidence looked at the concept of whistleblowing and the reasons why care home staff may be reluctant to report concerns (for example, fear of losing their job).\n\nThere were some problems with this evidence. There were issues with the methods used by some studies, such as their recruitment strategies and data analysis processes. Some of the included research was not conducted in care home settings, so there were concerns about how relevant it was. And some of the studies provided limited data, which led to issues with the overall adequacy of the data.\n\nThe committee therefore drew on their own experiences when drafting recommendations, with the aim of helping managers to increase staff confidence in identifying and raising safeguarding concerns.\n\n## How the recommendations might affect practice\n\nReflective supervision is already a key feature of broader social work, but the extent to which it takes place in care homes is extremely varied. These recommendations will help standardise the use of reflective supervision. Care home managers may need to do more to support staff who are reluctant to raise concerns.\n\nReturn to recommendations\n\n# Care home culture\n\nRecommendations 1.3.8 to 1.3.12\n\n## Why the committee made the recommendations\n\nThere was a good amount of qualitative evidence on the barriers and facilitators to identifying abuse and neglect in care homes. There were concerns with:\n\nthe appropriateness of some methods used by the studies, such as recruitment strategies and data analysis processes\n\nthe relevance of the data, because some of the research was not conducted in care home settings\n\nthe adequacy of the data, because some of the included studies provided limited data.\n\nThis research did not specifically evaluate the impact that care home culture can have on staff willingness to report safeguarding concerns. However, the committee agreed that the culture of a particular care home (and the role played by managers in shaping this) is a key factor in enabling and encouraging care home staff to report safeguarding concerns.\n\nThe committee suggested 'safeguarding champions' as a way to provide more informal support for people worried about the impact of raising concerns. This is in addition to the formal and mandatory role of a safeguarding lead.\n\nThe evidence also included data on how to reduce the risk or incidence of abuse and neglect by learning from past safeguarding issues in the care home. The committee agreed that this should be encouraged at all levels, to help create a care home culture where safeguarding is central and transparency is established. The committee also wanted care homes to reflect on and learn from Safeguarding Adults Reviews.\n\nThe committee recommended that care homes should ask for feedback from residents and families to find out what they thought about the way that safeguarding issues were addressed and managed in the home. It is important that this is used routinely to help improve safeguarding practices.\n\nStaff are encouraged to watch out for changes in the mood and behaviour of residents, because many indicators of abuse and neglect are quite subtle physical or emotional changes or traits.\n\n## How the recommendations might affect practice\n\nSome care homes have a positive, open culture, in which staff and others are supported to reflect on, identify and report safeguarding concerns. For care homes where this is not the case, care home managers and care home providers will need to make major changes in leadership style. Additional resources should not be needed for care homes to appoint safeguarding champions, because the champions are expected to be existing staff members.\n\nCreating a culture in which everyone can learn from safeguarding concerns should not represent a significant change. However, it will bring care homes in line with best practice, particularly in terms of supervision and continuing professional development.\n\nReturn to recommendations\n\n# Multi-agency working and shared learning with other organisations\n\nRecommendations 1.3.13 to 1.3.17\n\n## Why the committee made the recommendations\n\nQualitative evidence indicated that multi-agency working and learning can help to improve safeguarding practice. There were issues with this evidence (mainly with the methods used for recruitment and data analysis processes, and the limited adequacy and relevance of the data), but it did align well with the committee's own experience.\n\nThe recommendation covering staff apprehensions about external oversight was made because the committee are aware that staff can feel criticised and undermined by people delivering training (especially people from external agencies). The effectiveness of training and learning with other organisations is likely to be improved if positive relationships are established.\n\nThe committee made a recommendation on sharing information from Safeguarding Adults Boards with care home staff because they thought it could improve accountability, and help staff understand the responsibilities of other practitioners and organisations in relation to safeguarding.\n\n## How the recommendations might affect practice\n\nIn some care homes, staff already have the opportunity to share good practice and challenge poor practice. However, it is not uncommon for staff to work in a climate of suspicion and defensiveness. These recommendations encourage openness about lessons learned across agencies, and emphasise the factors that might help care homes to make their culture more positive.\n\nManagers will need to give staff time for these discussions to take place, and will need time themselves to promote the reflective and transparent approach to safeguarding.\n\nReturn to recommendations\n\n# Record-keeping\n\nRecommendations 1.3.18 to 1.3.20\n\n## Why the committee made the recommendations\n\nQualitative evidence suggested that recording actions or preventative measures and sharing these with colleagues can help staff to safeguard residents more effectively. Although there were concerns about this evidence (mainly regarding the adequacy and relevance of the data), the committee also drew on their own expertise to make the recommendations. In their experience, the way that safeguarding records are used and reviewed can play a key role in embedding learning and improving safeguarding practice.\n\n## How the recommendations might affect practice\n\nStandards of documentation and record-keeping within care homes vary widely, so these recommendations are expected to help standardise practice.\n\nReturn to recommendations\n\n# Indicators of individual abuse and neglect and immediate actions to take if you consider abuse or neglect\n\nRecommendations 1.4.1 to 1.4.24 and 1.5.1\n\n## Why the committee made the recommendations\n\nThere was no research evidence about the indicators that should alert people to abuse and neglect in care homes. Instead, the committee based these recommendations on a review of existing non-NICE UK health and social care guidance (see the context and evidence review C for details of the guidance). There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to make recommendations, alongside their own expertise and experience.\n\nMost of the indicators are adapted from the guidance the committee reviewed, and others were added by the committee based on their knowledge and expertise.\n\nThe aim of these recommendations is to help people better understand when a safeguarding referral should be made and when a referral should not be made. The committee felt that some indicators are more serious or urgent than others. This is because, in their experience, those indicators represented a higher likelihood of abuse and neglect. To reflect this, the indicators are split into 2 categories ('consider' and 'suspect'), with different actions based on the likelihood of abuse or neglect. The 'suspect' indicators need to be reported to a safeguarding lead and referred to the local authority.\n\nSome of the indicators of neglect may also be indicators of self-neglect. The guidance the committee reviewed made little mention of this. Based on this lack of coverage the committee felt it was important to make a research recommendation on self-neglect in care homes. They also included a consensus-based recommendation on self-neglect as they agreed that this issue is especially important, because self-neglect in care homes raises questions about the balance between individual choice and the home's duty of care. It also affects the safety, health and wellbeing of other residents, staff and visitors, and can lead to false allegations of abuse and neglect against staff and care homes.\n\nMedication misuse can be a sign of neglect or physical abuse, so the committee included slightly different indicators in both sections.\n\nThe committee agreed that indicators of sexual abuse are particularly important because residents may feel embarrassed and ashamed, and therefore reluctant to tell someone and because care homes need to uphold the rights of residents to engage in sexual activity in line with their mental capacity to consent. Care home staff need to be able to recognise these indicators and act upon them.\n\nAll types of abuse involve some level of psychological abuse, and psychological abuse may be a sign that other forms of abuse are also happening. Psychological abuse affects the safety, health and wellbeing of other residents, staff and visitors.\n\nRecommendations on financial and material abuse are needed because, while staff are often experienced at recognising other types of abuse, they may find it more difficult to recognise certain types of financial and material abuse.\n\nDiscriminatory abuse is important to highlight because it may be difficult to recognise, and may also involve other types of abuse or neglect. It affects the safety, health and wellbeing of residents, because their care may not meet their needs.\n\n## How the recommendations might affect practice\n\nThe recommendations are based on existing non-NICE UK guidance, so staff should be familiar with the indicators in this guideline. Some, such as being denied freedom of movement, are also enshrined in law (for example the Human Rights Act, Article 5: right to liberty and security).\n\nCare homes may need to do more to help their staff understand these indicators. But doing so will help care homes manage safeguarding issues more proactively, and deal with early warning signs of potential neglect.\n\nActing early may improve the quality and safety of care and support for residents. The recommendations may also help to reduce the number of section 42 enquiries involving the care home, local authority and others.\n\nReturn to recommendations\n\n# Making sure people are safe\n\nRecommendations 1.6.1 to 1.6.4\n\n## Why the committee made the recommendations\n\nNo directly relevant research evidence was identified on what to do if abuse or neglect is suspected. Instead, the committee used existing non-NICE UK health and social care guidance on recognising and reporting abuse and neglect in care homes. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work and used it to inform recommendations on:\n\nensuring that no one is in immediate danger\n\nthinking about who needs to be informed or consulted\n\nkeeping the person at risk involved in the safeguarding process.\n\nThe existing guidance did not cover all the areas that the committee thought were important, so they also used their own knowledge and expertise when agreeing the recommendations.\n\nReturn to recommendations\n\n# Gathering information\n\nRecommendations 1.6.5 to 1.6.10\n\n## Why the committee made the recommendations\n\nThere was no research evidence identified in this area. Instead, the committee used existing non-NICE UK health and social care guidance about information gathering when abuse or neglect is suspected. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations, alongside their own expertise and experience. The guidance highlighted the importance of writing down carefully what the person discloses using their own words, but not interviewing them, and encouraging the resident to preserve any physical evidence if a crime may have been committed.\n\n## How the recommendations might affect practice\n\nInconsistent or poor-quality records could impact on future enquiries. To ensure staff understand how to gather and record information correctly, care homes and care home providers may need to provide extra training.\n\nReturn to recommendations\n\n# Confidentiality, and discussing and reporting suspected abuse and neglect\n\nRecommendations 1.6.11 to 1.6.13\n\n## Why the committee made the recommendations\n\nThere was no research evidence identified on confidentiality and suspected abuse and neglect. Instead, the committee used existing non-NICE UK health and social care guidance on recognising and reporting abuse and neglect in care homes. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations.\n\nWhen the existing guidance did not cover all the areas the committee thought were important they also used their own expertise and experience to make the recommendations.\n\nThe committee used their experience and expertise to make the recommendation on reporting suspected abuse and neglect, and who to contact if the problems are with the management of the care home. The committee felt it was important to be clear that if you suspect abuse and neglect you must tell someone in a responsible and accountable position about this.\n\n## How the recommendations might affect practice\n\nThere may be uncertainty within care homes around confidentiality, and when to share information. Care homes may need to provide staff with training on the importance of sharing information and the potential risks of not doing this correctly. There may be an impact on staff time and resources. But this would be outweighed by the benefits of making staff aware of who to share concerns with, which should increase the speed of responses to safeguarding.\n\nReturn to recommendations\n\n# Care home safeguarding leads\n\nRecommendations 1.7.1 to 1.7.4\n\n## Why the committee made the recommendations\n\nThere was no research evidence identified on safeguarding leads. Instead, the committee reviewed existing non-NICE UK sector guidance on recognising and reporting abuse and neglect in care homes. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations, alongside their own expertise and experience.\n\nThe committee emphasised the importance of asking the resident at risk what they would like to happen next, to ensure that the response to safeguarding was in line with the principles of Making Safeguarding Personal. They also agreed that care homes should build good relationships with local authorities, seeking advice if needed, in order to better judge when referrals should be made.\n\n## How the recommendations might affect practice\n\nCare homes will have to check that their safeguarding leads have the relevant skills and competencies to assess and act on concerns. If they do not, training may be needed. Care homes may also have to change the way they work with the local authority, to ensure they have a good relationship and can seek advice and support when needed. The implications for care home resources should not be significant, and some of the ways of working suggested may already be in place in some or most care homes.\n\nReturn to recommendations\n\n# Local authorities\n\nRecommendations 1.7.5 to 1.7.14\n\n## Why the committee made the recommendations\n\nThe committee used evidence from a number of sources to make recommendations specifically for local authorities. These included qualitative themes from research evidence on progressing safeguarding concerns and information needs, and existing non-NICE UK health and social care guidance on recognising and reporting abuse and neglect in care homes.\n\nThe committee had low confidence in the qualitative evidence about this issue. The main limitations were:\n\nrelevance – in some studies it was not always clear whether research findings related specifically to care homes\n\nlimited data.\n\nThere were also methodological concerns regarding some of the studies, for example in relation to recruitment strategies and data analysis processes.\n\nThe committee also reviewed existing health and social care guidance. There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to inform the recommendations. The committee also used their own expertise and experience to make recommendations. In addition, they linked the recommendations to Care Act statutory requirements for local authorities. The committee emphasised what care homes find most important when they make a safeguarding referral to a local authority, and at the beginning of a section 42 enquiry.\n\nThe evidence highlighted the value that care homes place on local authorities as a key source of support and transparent advice. To reflect this, the recommendations emphasise how local authorities should work with other organisations and support care homes to promote best practice.\n\nLocal authorities also use guidance on section 42 enquiries from the Association of Directors of Adult Social Services and the Local Government Association. This guideline aims to complement these other sources of guidance, rather than duplicate them.\n\n## How the recommendations might affect practice\n\nExisting relationships between care homes and local authorities may vary. Depending on how well local authorities already work with other organisations, they may need to do more to develop good ongoing relationships about safeguarding with care homes and to promote multi-agency working. More resources may be needed for a multi-agency approach to safeguarding, but it should improve the quality and safety of care and support.\n\nReturn to recommendations\n\n# Working with and supporting the resident at risk during a safeguarding enquiry\n\nRecommendations 1.8.1 to 1.8.21\n\n## Why the committee made the recommendations\n\nThe committee used qualitative themes from research evidence on responding to and managing safeguarding concerns in care homes, and support and information needs for everyone involved in safeguarding concerns in care homes.\n\nThe evidence showed that residents benefit when they are involved and kept informed throughout the safeguarding process. The evidence also emphasised the value that residents place on support from family, friends or advocates in helping them achieve their desired outcomes. However, the committee had some concerns about the quality of the data, which had some methodological limitations as well as questionable relevance (it was not always clear whether findings related specifically to care home settings).\n\nThe committee therefore also used the Making Safeguarding Personal framework and the Care Act 2014. These sources highlight the importance of involving people fully as possible in decisions and giving them the information and support they need to participate.\n\nThe evidence matched the committee's experience of practice. They agreed that involving people in decision making will help them achieve the outcomes they want, and make it more likely that they will receive safe and effective care after the enquiry ends. Although the committee were able to draw on their own knowledge and experience, they felt that the gap in the evidence indicated that a research recommendation was needed about the views of care home residents in relation to their experiences of safeguarding enquiries. Getting the views of residents will ensure that their needs are understood and that subsequent care can be person-centred and outcomes-focused.\n\nThe committee recognised that there should be a clear difference and understanding of the roles of the practitioners and independent advocate involved in safeguarding. Although the practitioner might be acting in the best interest of the person, they may be operating within the constraints of their role. It is only the independent advocate who acts according to instruction from the person.\n\nResidents will often need emotional and practical support while an enquiry is taking place. In addition, they may need this support to continue afterwards, and their needs should be reassessed after the enquiry.\n\n## How the recommendations might affect practice\n\nOrganisations may need to do more to involve people at risk and their independent advocates in safeguarding enquiries. Implementing the recommendations may involve minor changes to existing practice.\n\nThe recommendations could also lead to greater demand for support (for example, speech and language therapists) from people at risk. This may have cost implications, but access to support is a statutory right under the Care Act 2014 and is part of the Making Safeguarding Personal framework.\n\nThere is variation in how support is currently provided. Some organisations will need to review how they provide support. This may have resource implications for care homes, who will be responsible for ensuring that support is available in the short and long term and that it is tailored to each person's needs.\n\nReturn to recommendations\n\n# Supporting care home staff who are subject to a safeguarding enquiry\n\nRecommendations 1.9.1 to 1.9.6\n\n## Why the committee made the recommendations\n\nA small amount of qualitative evidence provided findings relating to the information and support that care home staff need during safeguarding enquiries. However, there were concerns with the adequacy of this data, limitations arising from the data analysis processes used in the studies, and issues with selection bias.\n\nDespite the limitations of the evidence, the committee recognised that this is a crucial issue, in particular for staff who are subject to a safeguarding enquiry. The committee used their own expertise to support the evidence and make recommendations.\n\nThe recommendations should reduce the potential psychological and emotional distress on affected staff. They should also encourage staff to report safeguarding problems in the future, as it would be clear to them that everyone would receive support regardless of their involvement.\n\n## How the recommendations might affect practice\n\nSome care home providers already fund access to employee assistance programmes, so would not significantly need to change practice. There could be cost implications for care home providers that do not have employee assistance programmes, unless alternative programmes or funding are available for staff already. The committee did not believe that holding return-to-work meetings would be a substantial change in practice. These meetings already commonly occur, so they may just need more emphasis on guidance and support for the affected member of staff.\n\nCare homes do not currently nominate people to provide support to staff accused of abuse or neglect. However, as this can be an existing member of staff, the committee were confident that there would be no significant resource impact.\n\nReturn to recommendations\n\n# Supporting care home staff\n\nRecommendations 1.9.7 to 1.9.11\n\n## Why the committee made the recommendations\n\nThere was a small amount of qualitative evidence relating to the information and support needs of care home staff during a safeguarding enquiry. There were concerns around the adequacy of the data, issues with the methods used to analyse the data, and problems with how the study authors addressed potential bias. Despite these limitations, the committee agreed on the importance of support for care home staff, and built on the evidence with their own expertise. These recommendations are important because:\n\nmanagers have a key role in helping staff obtain support and advice\n\ncare homes need to have a more honest and open culture when it comes to potential safeguarding issues\n\nquality of care can be undermined when staff are treated negatively for raising safeguarding concerns, or when staff are afraid to work with residents who have raised or been involved in safeguarding concerns.\n\n## How the recommendations might affect practice\n\nDuring a safeguarding enquiry, care home managers will need to allocate time to hold discussions with staff and direct them to external information and advice. Managers will also need time to provide one-on-one support to anxious staff, and to make changes to policies, processes and training in response to the outcome of safeguarding enquiries.\n\nIn many care homes, managers already do all of this. However, in care homes where this is not the case, managers will need to spend more time supporting staff and learning from safeguarding enquiries.\n\nReturn to recommendations\n\n# How local authorities should support care homes during an enquiry\n\nRecommendations 1.10.1 to 1.10.5\n\n## Why the committee made the recommendations\n\nThere was a small amount of qualitative evidence about the impact of safeguarding enquiries on care homes and the support that care homes, managers and staff need. There were concerns regarding the adequacy and relevance of the data, as it was not clear whether all of the findings were from a care home context. The committee built on this evidence with their own expertise.\n\nThe committee made these recommendations because the business impact of safeguarding enquiries is often overlooked, but can be detrimental to care homes. There can be a financial impact, as well as problems with staff recruitment and retention. The recommendations should help reduce these risks. In addition, improved information sharing and trust between care homes and local authorities will help to reduce the stress of the enquiry process.\n\n## How the recommendations might affect practice\n\nLocal authorities will need to identify a single point of contact for care homes, which in some cases will be a change in practice. Local authorities may also need to learn more about the reputational risks to care homes and effects on staff morale when they are involved in safeguarding enquiries. Finally, local authorities will need to offer feedback and practical support to care homes.\n\nReturn to recommendations\n\n# Meetings during a safeguarding enquiry\n\nRecommendations 1.11.1 to 1.11.3\n\n## Why the committee made the recommendations\n\nThere was a small amount of qualitative evidence on effective multi-agency working, and on responding to and managing safeguarding concerns. This evidence had various problems:\n\nissues with the methods used in the studies, such as the way they addressed bias and ethical issues, and their recruitment strategies\n\nthe adequacy of the findings, as the studies provided only limited data\n\nthe relevance of the evidence, as the studies presented findings from domiciliary settings and it was not always clear when findings related specifically to the care home context.\n\nHowever, the committee recognised the importance of these issues and were able to build on this evidence using their own expertise.\n\nThe evidence suggested that some people felt excluded from important safeguarding meetings. While this is sometimes justifiable, the committee wanted to reduce suspicion about possible bias and increase transparency and collaboration by ensuring that people are always given an explanation and a chance to contribute in another way.\n\nSafeguarding meetings should be opportunities for different organisations to share information and discuss the needs of adults at risk. Because of the multiple organisations involved and the complexity of the process, communication is important, so the committee made recommendations to ensure that everyone involved is kept informed about the process.\n\nNo evidence was identified on the management of safeguarding concerns. Because of the lack of evidence, and the potential variation in practice across the country, the committee made a research recommendation on the effectiveness and cost effectiveness of the different approaches to investigating safeguarding concerns.\n\n## How the recommendations might affect practice\n\nThere is currently wide variation in what is communicated during safeguarding enquiries and how clear the outcomes are. These recommendations should lead to greater consistency and higher standards, by ensuring that everyone affected by the safeguarding enquiry is kept informed.\n\nThe recommendations do not require specific additional resources, but the chairs of meetings may need to take greater care in their documentation and communication.\n\nReturn to recommendations\n\n# Indicators of organisational abuse and neglect\n\nRecommendations 1.12.1 to 1.12.12\n\n## Why the committee made the recommendations\n\nNo research evidence was identified about the indicators that should alert people to organisational abuse and neglect in care homes. Instead, the committee based these recommendations on a review of non-NICE UK health and social care guidance, (see evidence review C for details of this guidance). There were uncertainties around the methods used to develop much of this guidance. However, the committee found the guidance to be highly relevant as a source of evidence to support their work, and used it to make recommendations, alongside their own expertise and experience.\n\nMost of the indicators are based on a synthesis of findings from the review of health and social care guidance documents, and others were agreed by the committee based on their experience.\n\nThe aim of these recommendations is to help people better understand when a safeguarding referral should be made and when a referral should not be made. The committee felt that some indicators would warrant more urgent or more significant action than others. This is because, in their experience, those indicators represented a higher likelihood of organisational abuse and neglect. To reflect this, the indicators are split into 2 categories ('consider' and 'suspect'), with different actions based on the likelihood of abuse or neglect. The committee particularly wanted to emphasise the key role of local authorities in relation to organisational abuse or neglect. This is true for their proactive role (monitoring care standards locally), and in their responsibility for starting and running section 42 enquiries (including large-scale enquiries when needed).\n\nA wide range of people are involved in enquiries into organisational abuse and neglect. The committee agreed, based on their own expertise and experience, that local authorities needed to plan ahead for the support that these people might need (this would be especially important for large-scale enquiries). This is so that the support is in place at the right time during the enquiry.\n\nOrganisational abuse is distinct from other types of abuse or neglect because it is generally not directly caused by individual action or inaction. Instead, it is more likely to be a cumulative consequence of how services are managed, led and funded. Abuse and neglect are more likely to happen when staff are poorly trained, poorly supervised, unsupported by management, and when the care home has a culture that does not promote openness and good communication. Therefore, the committee made recommendations focusing on these issues.\n\nOrganisational abuse and neglect both involve some level of psychological or medical and physical abuse, and may be a sign that other types of abuse and neglect are also happening.\n\n## How the recommendations might affect practice\n\nThe recommendations are based on a review of existing guidance, so staff should be familiar with the indicators referred to in this guideline.\n\nCare homes may need to do more to help staff, residents and visitors understand these indicators. However, doing so will help care homes manage safeguarding issues more proactively, and deal with early warning signs of potential organisational abuse and neglect. Acting early may help to reduce the number of section 42 enquiries involving the care home. The recommendations may also improve the safety and quality of care and support for care home staff, residents and visitors.\n\nCare homes may also need to change their recruitment processes, to ensure that applicants are suitable and have been properly vetted.\n\nStaff may also need more training and support, to ensure that they understand their duty of care and to improve their confidence in identifying and reporting potential organisational abuse and neglect.\n\nIdentifying organisational abuse and neglect is likely to have other benefits for the care home, in reducing staff turnover and staff absences. This should in turn improve the safety, health and wellbeing of care home residents.\n\nReturn to recommendations\n\n# How care homes should learn from safeguarding concerns, referrals and enquiries\n\nRecommendations 1.13.1 to 1.13.2\n\n## Why the committee made the recommendations\n\nAlthough evidence on implementing learning in care homes was available, this did not focus specifically on using findings from past safeguarding referrals and enquiries in the care home. However, the committee agreed that these findings can be a key source of learning material for care home providers, and they regularly use information from Safeguarding Adults Reviews in their own work. As a result, they felt that it was important to make specific recommendations on this, to ensure that this learning is more widely promoted. The recommendations are for care home managers and local agencies, to ensure that organisations can implement this at the local level.\n\nGiven the limited evidence about the use of Safeguarding Adults Reviews, the committee made a research recommendation to identify how the findings from these reviews affect practice in care homes. This includes:\n\nstaff experiences in using findings from these reviews\n\nthe views of Safeguarding Adults Boards and commissioners on how care homes have learned from Safeguarding Adults Reviews\n\nthe barriers and facilitators to embedding learning from Safeguarding Adults Reviews in care homes.\n\nThe committee agreed that this research is important to identify how care homes understand Safeguarding Adults Reviews and what they learn from them. If the research allows care homes to better utilise these reviews to improve practice, the safety and wellbeing of care home residents will improve.\n\n## How the recommendations might affect practice\n\nManagers may need to dedicate time specifically to collating data and sharing findings with staff. However, this is unlikely to take a significant amount of time, as there should already be systems in place to record and share this information.\n\nReturn to recommendations"}
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https://www.nice.org.uk/guidance/ng189
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This guideline covers keeping adults in care homes safe from abuse and neglect. It includes potential indicators of abuse and neglect by individuals or organisations, and covers the safeguarding process from when a concern is first identified through to section 42 safeguarding enquiries. There are recommendations on policy, training, and care home culture, to improve care home staff awareness of safeguarding and ensure people can report concerns when needed.
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4e5fc399e33cbba7307786af51ffbc4a2dc0b4f2
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nice
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Filgotinib for treating moderate to severe rheumatoid arthritis
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Filgotinib for treating moderate to severe rheumatoid arthritis
Evidence-based recommendations on filgotinib (Jyseleca) for moderate to severe rheumatoid arthritis in adults.
# Recommendations
Filgotinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with 2 or more conventional disease-modifying antirheumatic drugs (DMARDs), only if:
disease is moderate or severe (a disease activity score of 3.2 or more) and
the company provides filgotinib according to the commercial arrangement.
Filgotinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to or who cannot have other DMARDs, including at least 1 biological DMARD, only if:
disease is severe (a DAS28 of more than 5.1) and
they cannot have rituximab and
the company provides filgotinib according to the commercial arrangement.
Filgotinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to rituximab and at least 1 biological DMARD, only if:
disease is severe (a DAS28 of more than 5.1) and
the company provides filgotinib according to the commercial arrangement.
Filgotinib can be used as monotherapy when methotrexate is contraindicated or if people cannot tolerate it, when the criteria in sections 1.1, 1.2 or 1.3 are met.
Choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If more than 1 treatment is suitable, start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary from person to person because of differences in how the drugs are taken and treatment schedules.
Continue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months after starting therapy. If this initial response is not maintained, stop treatment.
When using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with filgotinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with severe rheumatoid arthritis have a number of advanced treatment options (biological and targeted synthetic DMARDs) available to them if their disease has not responded well enough to 2 or more conventional DMARDs. These advanced treatment options are currently not available for people with moderate rheumatoid arthritis.
Clinical trials show that filgotinib with methotrexate or other conventional DMARDs is more effective than adalimumab with methotrexate or methotrexate alone for treating moderate to severe rheumatoid arthritis that has not responded well enough to 2 or more conventional DMARDs. It is also more effective than conventional DMARDs alone for treating moderate to severe active rheumatoid arthritis that has not responded well enough to 1 or more biological DMARDs.
There are no trials comparing filgotinib with the full range of biological and targeted synthetic DMARDs in severe disease. However, an indirect comparison shows that filgotinib with conventional DMARDs (including methotrexate) works as well as the biological and targeted synthetic DMARDs recommended by NICE.
The most likely cost-effectiveness estimates show that filgotinib with methotrexate is an acceptable use of NHS resources for some people with moderate and severe rheumatoid arthritis (see sections 1.1 to 1.3).
The cost effectiveness of filgotinib monotherapy is more uncertain but is still likely to be within what NICE considers an acceptable use of NHS resources, therefore it is recommended.# Information about filgotinib
# Marketing authorisation indication
Filgotinib (Jyseleca, Galapagos Biotech Ltd) is 'indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to 1 or more disease-modifying antirheumatic drugs (DMARDs). Filgotinib may be used as monotherapy or in combination with methotrexate'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for filgotinib is £863.10 per bottle of 30-day pack (company submission). The average cost for each patient per year is estimated at £10,508.00 based on the list price. The company has a commercial arrangement. This makes filgotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Gilead, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved or partially resolved during the technical engagement stage:
Using direct head-to-head trial data from the overall moderate population to model the efficacy of filgotinib in people with moderate rheumatoid arthritis.
Modelling the efficacy of best supportive care based on the placebo plus methotrexate arm of the FINCH1 trial.
Using the company's approach to utility values, that is, estimating pain scores from the Health Assessment Questionnaire Disability Index (HAQ-DI).However, the committee discussed these issues further. Also, after technical engagement, there were a number of outstanding uncertainties in the analyses. The committee considered these in its decision making.
# Treatments for rheumatoid arthritis
## Additional treatment options for rheumatoid arthritis are important, especially for moderate disease
The patient expert explained that rheumatoid arthritis is a lifetime condition that has a large effect on mental and physical health and emotional wellbeing, causing fear, anxiety, stress, pain and fatigue. It can severely reduce quality of life and affect ability to work, everyday activities and relationships with children and other family members. The clinical expert stated that conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are inadequate for many people with active rheumatoid arthritis. Although a range of biological and targeted synthetic DMARDs are available for severe rheumatoid arthritis (see section 3.2), none of these treatments are currently available for people with moderate disease activity. Patient experts explained that currently people with moderate disease activity that has not responded adequately to conventional DMARDs have no effective treatment options. They feel that their disease needs to get worse before they can be offered effective treatments. They explained that progression in rheumatoid arthritis is relentless if not adequately treated. The clinical expert also added that for a significant proportion of people with severe disease who are eligible for treatment with biological DMARDs, their disease responds inadequately to these treatments, or they cannot tolerate the treatment. Both the clinical and patient experts said it would be helpful to have new treatments for various points in the treatment pathway. Clinical and patient experts also said that an oral drug taken daily may be preferable, especially for patients who are needle phobic or who have a significant hand disability. The committee concluded that a range of treatment options was important in rheumatoid arthritis and that filgotinib would be a welcome additional option, especially for moderate disease.
## There is NICE technology appraisal guidance for different points in the severe rheumatoid arthritis treatment pathway
Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease, between 3.2 and 5.1 indicates moderate disease, between 2.6 and 3.2 indicates mild disease, and 2.6 or less indicates disease remission. NICE technology appraisal guidance recommends the following biological and targeted synthetic DMARDs, all with methotrexate, for severe active rheumatoid arthritis that has responded inadequately to:
intensive treatment with a combination of conventional DMARDs (that is, responded inadequately to 2 or more conventional DMARDs): adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, abatacept, tofacitinib, baricitinib, sarilumab and tocilizumab
at least 1 TNF-alpha inhibitor: rituximab
at least 1 biological DMARD and rituximab is contraindicated or not tolerated: adalimumab, etanercept, infliximab, abatacept, certolizumab pegol, golimumab, tofacitinib, baricitinib, sarilumab and tocilizumab
at least 1 biological DMARD and to rituximab: sarilumab and tocilizumab.Of these, adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are tumour necrosis factor (TNF)-alpha inhibitors. Tofacitinib and baricitinib are Janus kinase (JAK) inhibitors and sarilumab and tocilizumab are interleukin‑6 (IL‑6) inhibitors. For people who cannot take methotrexate because it is contraindicated or because they cannot tolerate it, adalimumab, baricitinib, certolizumab pegol, etanercept, tofacitinib, sarilumab and tocilizumab can be used alone. Treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price per dose). It should only be continued if there is a moderate response using European League Against Rheumatism (EULAR) criteria at 6 months, and should be stopped if at least a moderate EULAR response is not maintained.
## In moderate disease, the most appropriate position for filgotinib is after an inadequate disease response to 2 or more conventional DMARDs
Filgotinib's marketing authorisation covers its use in people with moderate rheumatoid arthritis whose disease has responded inadequately to 1 or more conventional DMARDs. However, the company's submission covers filgotinib's use in moderate rheumatoid arthritis for people whose disease has responded inadequately to 2 or more conventional DMARDs. The committee agreed with the company's positioning of filgotinib in moderate disease. It noted such positioning is aligned with the use of biologic and targeted synthetic DMARDs in severe disease. The clinical expert explained that people whose disease has an inadequate response to 2 or more conventional DMARDs are usually offered continued treatment with the same conventional DMARDs. Corticosteroids can be used to manage disease flares. The committee concluded that the appropriate position for filgotinib in moderate disease is after inadequate response to 2 or more conventional DMARDs. It also agreed that the relevant comparator for this population is best supportive care, consisting of previously used conventional DMARDs with optional corticosteroids.
## In severe disease, filgotinib could be used at all 4 different points in the treatment pathway, with multiple comparators at each point
Filgotinib's marketing authorisation and the company's submission cover its use at all 4 points in the severe disease treatment pathway for which other biologic and targeted synthetic DMARDs are recommended (see section 3.2). The committee agreed with this positioning. It noted that the marketing authorisation includes the use of filgotinib alone or with methotrexate. The committee agreed that all treatments listed in section 3.2, all used with methotrexate, are relevant comparators for filgotinib with methotrexate, when used at the same position in the treatment pathway. For people who cannot have methotrexate, relevant comparators for filgotinib monotherapy are adalimumab, baricitinib, certolizumab pegol, etanercept, tofacitinib, sarilumab and tocilizumab, depending on the position in the treatment pathway.
# Clinical effectiveness
## The clinical trials are acceptable for decision making but do not include all relevant comparators for severe disease
The company's clinical evidence came from 2 randomised controlled trials in people with moderate to severe rheumatoid arthritis:
FINCH1 enrolled patients with inadequate disease response to methotrexate. A total of 24% of patients had moderate disease, and 76% had severe disease. Filgotinib was used with methotrexate and the comparators were adalimumab with methotrexate or placebo with methotrexate.
FINCH2 enrolled people with inadequate disease response to at least 1 biological DMARD. A total of 21% of patients had moderate disease and 79% had severe disease. Filgotinib was used with conventional DMARDs and the comparator was placebo with conventional DMARDs.The committee concluded that the trials were relevant and acceptable for decision making but did not include all relevant comparators for severe disease (see section 3.2).
## For moderate to severe disease that has responded inadequately to conventional DMARDs, filgotinib with methotrexate is more clinically effective than adalimumab with methotrexate or placebo with methotrexate
In FINCH1, filgotinib with methotrexate showed a statistically significant improvement in the primary end point, American College of Rheumatology responses (ACR20) at 12 weeks, compared with adalimumab with methotrexate or placebo with methotrexate (76.6% compared with 70.5% and 49.9%, respectively, p<0.05 for both comparisons). Filgotinib also showed improvement in key secondary endpoints at both 12 and 24 weeks, including ACR50, ACR70 or EULAR responses. The committee concluded that filgotinib with methotrexate was more clinically effective than adalimumab with methotrexate or placebo with methotrexate in people with moderate to severe disease that has responded inadequately to conventional DMARDs.
## For moderate to severe disease that has responded inadequately to biological DMARDs, filgotinib with conventional DMARDs is more clinically effective than placebo with conventional DMARDs
In FINCH2, filgotinib with conventional DMARDs showed a statistically significant improvement in the primary outcome, ACR20 at 12 weeks, compared with placebo with conventional DMARDs (66.0% compared with 31.1%, p<0.05). Filgotinib also showed improvement in key secondary endpoints at both 12 and 24 weeks, including ACR50, ACR70 or EULAR responses. The committee concluded that filgotinib with conventional DMARDs was more clinically effective than placebo with conventional DMARDs in people with moderate to severe disease that has responded inadequately to biological DMARDs.
## The clinical efficacy of filgotinib monotherapy is uncertain
FINCH1 and FINCH2 trials included filgotinib only with methotrexate or with conventional DMARDs, respectively. Therefore, no clinical efficacy data are available for filgotinib monotherapy in people with moderate to severe disease that has responded inadequately to conventional or biological DMARDs. The clinical expert explained that in the FINCH2 trial, which enrolled people who had not previously had methotrexate (that is, methotrexate-naive population), filgotinib monotherapy showed improved clinical outcomes compared with placebo. The committee noted that all biological and targeted synthetic DMARDs are recommended with methotrexate, unless methotrexate is contraindicated. This is because combination therapy is thought to be more clinically effective than monotherapy. The committee concluded that the clinical efficacy of filgotinib monotherapy is uncertain because there is no clinical trial data in the target population.
# Direct and indirect comparisons
## Network meta-analyses show that filgotinib with conventional DMARDs works as well as other biological and targeted synthetic DMARDs
A direct comparison was only possible with adalimumab and placebo, informed by FINCH1 and FINCH2 trials. To compare with other biological and targeted synthetic DMARDs, the company did 2 network meta-analyses for:
people whose disease responded inadequately to 1 or more conventional DMARDs,
people whose disease responded inadequately to 1 or more biological DMARDs.The results showed that for both populations, filgotinib gave similar EULAR response rates to other biological and targeted synthetic DMARDs. Filgotinib also gave better EULAR response rates than conventional DMARDs alone (the exact rates are confidential and cannot be reported here). However, the committee noted several limitations of the network meta-analyses:
They contained a mixed population of people with moderate and severe rheumatoid arthritis. Separate network meta-analyses for people with moderate and severe disease were not possible because most trials did not report efficacy results by disease severity.
They relied on EULAR responses mapped from ACR responses. This was because most trials did not report EULAR responses.
They assumed that the same treatment effect applied regardless of the position in the treatment pathway. This does not reflect clinical practice because treatments used later in the treatment pathway are likely to have a lower response rate.
The company assumed equal efficacy of filgotinib monotherapy and combination therapy (with methotrexate or conventional DMARDs). This was because no clinical trial data exists to inform efficacy of filgotinib monotherapy in the target population (see section 3.8).
They excluded potentially relevant studies. The ERG explained that the company excluded studies published before 1999, and studies for monotherapies.The committee agreed that for severe disease, there was limited direct trial evidence. Therefore, it accepted the network meta-analyses for decision making, bearing in mind their limitations. It agreed that using data from the moderate to severe population was appropriate to inform efficacy estimates for the severe population, because this was aligned with populations in other studies included in the network meta-analysis. The committee accepted that, in the absence of data, the efficacy of filgotinib combination therapy may be used as a proxy for the efficacy of filgotinib monotherapy, but noted this approach has limitations and could overestimate the efficacy of filgotinib monotherapy.
## Direct head-to-head trial data is most appropriate to model efficacy of filgotinib and best supportive care in moderate rheumatoid arthritis
Although the network meta-analysis was used for decision making for people with severe disease (see section 3.8), the technical team noted that for moderate disease it may be more appropriate to use FINCH1 trial data because:
the trial included all relevant comparators (with placebo plus methotrexate arm of the trial used as a proxy for best supportive care, see section 3.13)
this avoids limitations associated with company network meta-analysis (see section 3.8)
using direct head-to-head evidence is in line with NICE's guide to the methods of technology appraisal.In response to technical engagement, the company used direct head-to-head trial data to inform the efficacy of filgotinib and best supportive care in the moderate population. The committee agreed with this approach, noting that the FINCH1 trial data were more appropriate for decision making for moderate disease than the network meta-analyses.
## Data from the overall moderate population of FINCH1 trial is appropriate for decision making
The ERG explained that the FINCH1 trial enrolled people who had had 1 or more conventional DMARDs, and that about half the patients with moderate disease had only had 1 previous conventional DMARD. Therefore, FINCH1 data may not be generalisable to the target population (that is, after 2 or more previous conventional DMARDs). In response to technical engagement, the company provided pairwise comparisons of clinical efficacy data for patients with moderate disease who had had 1 previous conventional DMARD compared with those who had had 2 or more previous conventional DMARDs. The company highlighted that these are exploratory post hoc analyses based on small patient numbers, and FINCH1 was not powered for such a comparison. However, the number of previous conventional DMARDs did not appear to have any notable effect on clinical efficacy estimates. The company also provided exploratory cost-effectiveness analyses for the population who had had 2 or more previous DMARDs. The committee considered all evidence provided by the company and concluded that using the overall moderate population from FINCH1 is more appropriate for decision making. It noted that this is preferred to using small post hoc subgroup data.
## EULAR data from the FINCH1 trial should be used when modelling the efficacy of filgotinib and best supportive care in the moderate population
The revised company submission used direct head-to-head trial data to model the efficacy of filgotinib (see section 3.10). The FINCH1 trial collected EULAR response data. However, the company mapped the EULAR responses from ACR responses. The ERG explained this approach was aligned with the approach taken for the severe population, but noted it preferred to use the EULAR responses from FINCH1 directly in the model. This is because using direct data gives more precise estimates of clinical efficacy than using mapped values. The committee agreed with the ERG that EULAR response should be used directly in the model, instead of the mapped values.
# Modelling best supportive care in the moderate population
## Using the placebo plus methotrexate arm of the FINCH1 trial to model the efficacy of best supportive care has limitations but is acceptable
The revised company base case modelled the efficacy of best supportive care based on the response rates seen in the placebo plus methotrexate arm of the FINCH1 trial. The clinical expert explained that best supportive care is not expected to give a EULAR response in clinical practice. However, the committee noted that a considerable response rate was seen in the placebo plus methotrexate arm of the FINCH1 trial, as well as in other clinical trials in rheumatoid arthritis. It noted that this response could have been caused by several factors, including a placebo effect, disease resolving naturally over time, regression to the mean, response bias and variation in symptoms. Some of these factors might have also contributed to the response to filgotinib in the FINCH1 trial. Therefore, the committee agreed it would not be appropriate to assume full clinical efficacy for filgotinib while assuming no response to best supportive care. It agreed with revised company analyses, which used FINCH1 response rates for both filgotinib with methotrexate and placebo plus methotrexate (a proxy for best supportive care). However, it acknowledged that these analyses had limitations because they did not fully reflect what is expected to happen in clinical practice.
# Comparators and treatment sequences for severe disease
## The comparators and treatment sequences modelled by the company are sufficient for decision making
Rheumatoid arthritis is a heterogenous disease and treatment choices are influenced by many factors (see section 3.1). Because of the large number of possible treatment sequences, it was not practical to model them all. However, the clinical expert confirmed that the company model included the most relevant comparators and treatment sequences that are used in NHS clinical practice. One exception to that, noted by both clinical and patient experts, was that further advanced therapies would be used instead of best supportive care in clinical practice. The committee acknowledged this as a limitation but noted that this approach was aligned with previous NICE technology appraisals. It also noted that this is likely to have a limited effect on the cost-effectiveness estimates in severe disease, but could be important to consider for the moderate population in the treatment sequence upon progression to severe disease (see section 3.16).
# Modelling progression from moderate to severe rheumatoid arthritis
## The rate of progression from moderate to severe disease is uncertain but the company approach to model this is acceptable for decision making
In the revised company base case, the company used patients' mean baseline DAS28 and expected DAS28 trajectory, to estimate patients' progression from moderate to severe disease. Using this approach, the modelled progression rate with best supportive care was 11% at 2 years and 39% at 5 years. The clinical expert mentioned 1 study that reported 5% progression rate at 1 year. Another study (ERAN database) reported that 19% of people with moderate disease activity 1 year after diagnosis had severe disease activity at a 2‑year visit. The committee noted this estimate may be uncertain because of small patient numbers in the registry and single assessment of disease activity at both timepoints (so results could be subject to temporary fluctuation in disease activity, including flares). It also noted no data were available to inform long-term progression rates. The clinical expert highlighted that although published data on the progression rates are lacking, the rates modelled by the company seem reasonable. The committee discussed that some patients could start treatment for severe disease when they have a flare that temporarily increases their disease activity to a severe level. This could mean that the initiation of severe treatment sequences in NHS clinical practice is higher than modelled by the company. The patient and clinical experts explained that a single flare would usually trigger a change of treatment (start of severe treatment sequence) only for patients with their usual disease activity in the higher end of the moderate disease activity range (that is, close to the severe disease activity level). However, such a change after a single flare was unlikely for patients with disease activity in the lower end of disease activity range. The committee agreed the rate of progression in NHS clinical practice is uncertain but noted that higher progression rates would result in lower incremental cost-effectiveness ratios (ICERs) for filgotinib compared with best supportive care. This was because with higher progression rates, quality-adjusted life years (QALYs) and costs are increasing in both treatment arms, but to a higher degree in the best supportive care arm. The committee concluded that although the rates of progression from moderate to severe disease in NHS clinical practice is uncertain, the company approach to model this is reasonable. It also noted that if the true rates of progression are higher than those estimated in the model, the cost-effectiveness estimates for filgotinib would improve.
## Alternative treatment sequences after progression from moderate to severe disease are plausible
The committee recalled that rheumatoid arthritis is a heterogenous disease and it was not practical to model all possible treatment sequences (see section 3.1 and section 3.14). The clinical expert explained that generally, they would follow the standard treatment sequence for severe disease once patients' disease progresses to severe disease activity. This would generally be:
for people who can have methotrexate: a TNF-alpha inhibitor, followed by rituximab and then by an IL‑6 inhibitor (all given with methotrexate)
for people who cannot have methotrexate: a TNF-alpha inhibitor, followed by an IL‑6 inhibitor (most frequently), abatacept, or rituximab (only in some trusts), and then a drug with an alternative mode of action (all given as monotherapy or with an alternative conventional DMARD).The clinical expert explained that there was no evidence to suggest treatment for severe disease would change if filgotinib was used for moderate disease, except the lower likelihood of considering another JAK inhibitor. However, the committee recalled that an alternative treatment sequence was considered plausible in NICE's technology appraisal guidance on upadacitinib for previously treated moderate active rheumatoid arthritis. This is because JAK inhibitors (such as filgotinib) and IL‑6 inhibitors are targeting a similar signalling pathway. Using a drug with a distinct mechanism of action, such as abatacept, instead of an IL‑6 inhibitor could be preferred in people who have already had filgotinib for the moderate disease. However, the committee agreed this is uncertain and may depend on clinician and patient preferences. Clinical experts explained that filgotinib could be used after progression to severe disease, if it was not used for the moderate disease. However, the committee agreed not to consider this treatment sequence further because there is uncertainty about how filgotinib would be used in NHS practice. The committee concluded that a range of treatment sequences for severe disease are plausible and agreed to consider them all (see table 1). It also agreed that there is even higher uncertainly about treatment sequences after progression when methotrexate is not suitable, and considered this in its decision making.
Scenario
Treatment arm
First-line treatment for severe disease
Second-line treatment for severe disease
Third-line treatment for severe disease
Base case
Filgotinib
Adalimumab
Rituximab
Tocilizumab
Base case
Best supportive care
Adalimumab
Rituximab
Tocilizumab
Evidence review group scenario
Filgotinib
Etanercept
Rituximab
Tocilizumab
Evidence review group scenario
Best supportive care
Etanercept
Rituximab
Tocilizumab
Scenario 1
Filgotinib
Adalimumab
Rituximab
Sarilumab
Scenario 1
Best supportive care
Adalimumab
Rituximab
Sarilumab
Scenario 2
Filgotinib
Adalimumab
Rituximab
Abatacept (subcutaneous)
Scenario 2
Best supportive care
Adalimumab
Rituximab
Tocilizumab (or sarilumab)
Scenario 3
Filgotinib
Adalimumab
Rituximab
Tocilizumab (or sarilumab)
Scenario 3
Best supportive care
Adalimumab
Rituximab
Baricitinib
# Utility values
## The company's mapping algorithm to link HAQ and pain scores is appropriate for decision making
In the company's base case, health-related quality-of-life data was mapped from patients' long-term HAQ-DI score trajectory using a published mapping algorithm. In addition to HAQ-DI, the algorithm used patients' current age, sex, and visual analogue scale pain scores to determine a utility value at any point in the model. In the company's base case, the visual analogue scale pain scores were mapped from HAQ-DI as per NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed. The ERG explained their initial concerns about the mapping algorithm, which seemed to provide distinct utility values rather than those based on EQ‑5D data collected in the trial. However, in response to technical engagement, the company provided corrected validation of their mapping algorithm, using individual patient data. The ERG was satisfied that the QALY outputs are fairly similar using the 2 methods. Therefore, it agreed with the company's approach and followed it in the revised ERG base case. The committee noted this approach is consistent with a number of previous appraisals. It concluded that the company's approach may have limitations but is appropriate for decision making.
# Cost-effectiveness results
## Because of uncertainty in the cost-effectiveness estimates, an acceptable ICER is around £20,000 per QALY gained
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.The committee concluded that the cost-effectiveness results for moderate disease were uncertain because:
the response rates in the placebo arms of the trials did not reflect clinical practice. It is unlikely that a EULAR response would be seen after an inadequate response with 2 conventional DMARDs (see section 1.1)
the long-term rate of progression from moderate to severe disease is uncertain (see section 3.15)
there is uncertainty about the most appropriate treatment sequence for people whose disease progresses from moderate to severe disease state (see section 3.16).Because of this uncertainty, the committee agreed that an acceptable ICER would be around £20,000 per QALY gained.
## In moderate disease, filgotinib with methotrexate is cost effective after 2 or more conventional DMARDs
The committee noted that the revised company analyses applied the following committee preferences:
FINCH1 trial data (whole moderate population) were used to model the efficacy of both filgotinib and best supportive care (see section 3.10, section 3.11 and section 3.13).
The modelled rate of progression was uncertain but was judged to be reasonable by the clinical expert (see section 3.15).
A range of alternative treatment sequences were explored (see section 3.16).
The mapping algorithm from NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed was used to estimate utility values (see section 3.17). However, it noted that company analyses were based on EULAR responses mapped from ACR responses, instead of directly using EULAR responses from FINCH1 (see section 3.12). Therefore, the committee preferred to use the ERG analyses, which used trial-based EULAR responses. The ERG analyses also applied confidential discounts for treatments used after progression from moderate to severe disease. Because of these confidential discounts, exact ICERs are confidential and cannot be reported here. The committee noted that all analyses with alternative treatment sequences produced ICERs around £20,000 per QALY gained for filgotinib with methotrexate compared with best supportive care. The only exception was a treatment sequence assuming filgotinib use in the comparator arms for patients who did not have it for moderate disease. But the committee recalled that it had agreed this sequence was less relevant to decision making (see section 3.16). The committee also recalled that although the exact rate of progression from moderate to disease severity in NHS clinical practice is uncertain, a higher rate of progression would improve cost-effectiveness estimates for filgotinib. The committee concluded that it could recommend filgotinib with methotrexate as a cost-effective use of NHS resources for people with moderate rheumatoid arthritis whose disease had responded inadequately to 2 or more conventional DMARDs.
## In severe disease, filgotinib with methotrexate is cost effective after 2 or more conventional DMARDs
The ERG did analyses for people with severe rheumatoid arthritis whose disease had responded inadequately to 2 or more conventional DMARDs, applying confidential discounts for filgotinib, comparators and subsequent treatment options. Filgotinib with methotrexate provided a higher net health benefit (that is, was more cost effective) than alternative therapies used with methotrexate. Therefore, the committee concluded that it could recommend filgotinib with methotrexate as a cost‑effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to 2 or more conventional DMARDs.
## In severe disease, filgotinib with methotrexate is not cost effective after 1 or more biological DMARDs if rituximab is a treatment option
The ERG did analyses for people with severe disease whose disease had responded inadequately to 1 or more biological DMARDs, applying confidential discounts for filgotinib, rituximab and subsequent treatments. Filgotinib with methotrexate was dominated by rituximab with methotrexate (that is, filgotinib with methotrexate was more costly and less effective than rituximab with methotrexate). Therefore, the committee concluded that it could not recommend filgotinib with methotrexate as a cost‑effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to 1 or more biological DMARDs if rituximab is a treatment option.
## In severe disease, filgotinib with methotrexate is cost effective after 1 or more biological DMARDs, if rituximab is not a treatment option
The ERG did analyses for people with severe disease whose disease had responded inadequately to 1 or more biological DMARDs and rituximab is not a treatment option, applying confidential discounts for filgotinib, comparators and subsequent treatment options. Filgotinib with methotrexate provided a higher net health benefit (that is, was more cost effective) than alternative therapies used with methotrexate. Therefore, the committee concluded that it could recommend filgotinib with methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to 1 or more biological DMARDs, if rituximab is not a treatment option.
## In severe disease, filgotinib with methotrexate is cost effective after 1 or more biological DMARDs and rituximab
The ERG did analyses for people with severe disease whose disease had responded inadequately to 1 or more biological DMARDs and rituximab, applying confidential discounts for filgotinib, comparators and subsequent treatment options. Filgotinib with methotrexate provided a higher net health benefit (that is, was more cost effective) than alternative therapies used with methotrexate. Therefore, the committee concluded that it could recommend filgotinib with methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to 1 or more biological DMARDs and rituximab.
## The cost effectiveness of filgotinib monotherapy is more uncertain but it is likely to represent a good use of NHS resources if methotrexate is not suitable
The committee noted that cost-effectiveness estimates for filgotinib monotherapy were uncertain because filgotinib monotherapy has not been studied in its target population (see section 3.8). The committee also recalled that the company model assumed equal effectiveness of filgotinib monotherapy and combination therapy, which has limitations (see section 3.9). Also, for moderate disease, it recalled there was higher uncertainty related to treatment sequences after progression from moderate to severe disease (see section 3.16). However, the committee concluded that despite these limitations, filgotinib is likely to represent a good use of NHS resources for people for whom methotrexate is not suitable and so it recommended filgotinib monotherapy in the same positions as combination therapy. It also noted that this population is much smaller than the population of patients who can have methotrexate. It agreed that the small number of people who could not tolerate methotrexate should not be treated differently from other people with moderate to severe disease, as far as possible.
# Other factors
## Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure
A potential equality issue was raised in NICE's technology appraisal guidance on upadacitinib for treating severe rheumatoid arthritis, about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee agreed that this equality issue was also important to consider for this appraisal. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.
## Healthcare professionals should choose the most appropriate treatment after discussing the options with the person having treatment
The committee recalled that having a range of treatment options was important in rheumatoid arthritis (see section 3.1). It also recalled that a range of biological and targeted synthetic DMARDs are already available for severe rheumatoid arthritis (see section 3.2). It noted that a number of NICE technology appraisals are currently in development for moderate rheumatoid arthritis (NICE's ongoing technology appraisal on upadacitinib for previously treated moderate active rheumatoid arthritis and NICE's ongoing technology appraisal on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for moderate rheumatoid arthritis after conventional DMARDs only have failed). The committee concluded that healthcare professionals should choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If more than 1 treatment is suitable, they should start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary from person to person because of differences in how the drugs are taken and treatment schedules.
## The benefits of filgotinib were adequately captured in the cost-effectiveness analysis
Filgotinib is taken orally, which is valued by patients. The committee noted that for severe rheumatoid arthritis, other oral treatments with a similar mechanism of action are already available. But no biological or targeted synthetic DMARDs are currently available for people with moderate disease. The committee agreed that filgotinib is an important treatment option for these people. It concluded that all the benefits of filgotinib were adequately captured in the model.
|
{'Recommendations': 'Filgotinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with 2\xa0or more conventional disease-modifying antirheumatic drugs (DMARDs), only if:\n\ndisease is moderate or severe (a disease activity score [DAS28] of 3.2\xa0or more) and\n\nthe company provides filgotinib according to the commercial arrangement.\n\nFilgotinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to or who cannot have other DMARDs, including at least 1\xa0biological DMARD, only if:\n\ndisease is severe (a DAS28 of more than 5.1) and\n\nthey cannot have rituximab and\n\nthe company provides filgotinib according to the commercial arrangement.\n\nFilgotinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to rituximab and at least 1\xa0biological DMARD, only if:\n\ndisease is severe (a DAS28 of more than 5.1) and\n\nthe company provides filgotinib according to the commercial arrangement.\n\nFilgotinib can be used as monotherapy when methotrexate is contraindicated or if people cannot tolerate it, when the criteria in sections\xa01.1, 1.2 or\xa01.3 are met.\n\nChoose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If more than 1\xa0treatment is suitable, start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary from person to person because of differences in how the drugs are taken and treatment schedules.\n\nContinue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6\xa0months after starting therapy. If this initial response is not maintained, stop treatment.\n\nWhen using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with filgotinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with severe rheumatoid arthritis have a number of advanced treatment options (biological and targeted synthetic DMARDs) available to them if their disease has not responded well enough to 2\xa0or more conventional DMARDs. These advanced treatment options are currently not available for people with moderate rheumatoid arthritis.\n\nClinical trials show that filgotinib with methotrexate or other conventional DMARDs is more effective than adalimumab with methotrexate or methotrexate alone for treating moderate to severe rheumatoid arthritis that has not responded well enough to 2\xa0or more conventional DMARDs. It is also more effective than conventional DMARDs alone for treating moderate to severe active rheumatoid arthritis that has not responded well enough to 1\xa0or more biological DMARDs.\n\nThere are no trials comparing filgotinib with the full range of biological and targeted synthetic DMARDs in severe disease. However, an indirect comparison shows that filgotinib with conventional DMARDs (including methotrexate) works as well as the biological and targeted synthetic DMARDs recommended by NICE.\n\nThe most likely cost-effectiveness estimates show that filgotinib with methotrexate is an acceptable use of NHS resources for some people with moderate and severe rheumatoid arthritis (see sections\xa01.1 to\xa01.3).\n\nThe cost effectiveness of filgotinib monotherapy is more uncertain but is still likely to be within what NICE considers an acceptable use of NHS resources, therefore it is recommended.', 'Information about filgotinib': "# Marketing authorisation indication\n\nFilgotinib (Jyseleca, Galapagos Biotech Ltd) is 'indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to 1\xa0or more disease-modifying antirheumatic drugs (DMARDs). Filgotinib may be used as monotherapy or in combination with methotrexate'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for filgotinib is £863.10 per bottle of 30-day pack (company submission). The average cost for each patient per year is estimated at £10,508.00 based on the list price. The company has a commercial arrangement. This makes filgotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Gilead, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved or partially resolved during the technical engagement stage:\n\nUsing direct head-to-head trial data from the overall moderate population to model the efficacy of filgotinib in people with moderate rheumatoid arthritis.\n\nModelling the efficacy of best supportive care based on the placebo plus methotrexate arm of the FINCH1 trial.\n\nUsing the company's approach to utility values, that is, estimating pain scores from the Health Assessment Questionnaire Disability Index (HAQ-DI).However, the committee discussed these issues further. Also, after technical engagement, there were a number of outstanding uncertainties in the analyses. The committee considered these in its decision making.\n\n# Treatments for rheumatoid arthritis\n\n## Additional treatment options for rheumatoid arthritis are important, especially for moderate disease\n\nThe patient expert explained that rheumatoid arthritis is a lifetime condition that has a large effect on mental and physical health and emotional wellbeing, causing fear, anxiety, stress, pain and fatigue. It can severely reduce quality of life and affect ability to work, everyday activities and relationships with children and other family members. The clinical expert stated that conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are inadequate for many people with active rheumatoid arthritis. Although a range of biological and targeted synthetic DMARDs are available for severe rheumatoid arthritis (see section\xa03.2), none of these treatments are currently available for people with moderate disease activity. Patient experts explained that currently people with moderate disease activity that has not responded adequately to conventional DMARDs have no effective treatment options. They feel that their disease needs to get worse before they can be offered effective treatments. They explained that progression in rheumatoid arthritis is relentless if not adequately treated. The clinical expert also added that for a significant proportion of people with severe disease who are eligible for treatment with biological DMARDs, their disease responds inadequately to these treatments, or they cannot tolerate the treatment. Both the clinical and patient experts said it would be helpful to have new treatments for various points in the treatment pathway. Clinical and patient experts also said that an oral drug taken daily may be preferable, especially for patients who are needle phobic or who have a significant hand disability. The committee concluded that a range of treatment options was important in rheumatoid arthritis and that filgotinib would be a welcome additional option, especially for moderate disease.\n\n## There is NICE technology appraisal guidance for different points in the severe rheumatoid arthritis treatment pathway\n\nDisease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease, between 3.2 and 5.1 indicates moderate disease, between 2.6 and 3.2 indicates mild disease, and 2.6 or less indicates disease remission. NICE technology appraisal guidance recommends the following biological and targeted synthetic DMARDs, all with methotrexate, for severe active rheumatoid arthritis that has responded inadequately to:\n\nintensive treatment with a combination of conventional DMARDs (that is, responded inadequately to 2\xa0or more conventional DMARDs): adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, abatacept, tofacitinib, baricitinib, sarilumab and tocilizumab\n\nat least 1\xa0TNF-alpha inhibitor: rituximab\n\nat least 1\xa0biological DMARD and rituximab is contraindicated or not tolerated: adalimumab, etanercept, infliximab, abatacept, certolizumab pegol, golimumab, tofacitinib, baricitinib, sarilumab and tocilizumab\n\nat least 1\xa0biological DMARD and to rituximab: sarilumab and tocilizumab.Of these, adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are tumour necrosis factor (TNF)-alpha inhibitors. Tofacitinib and baricitinib are Janus kinase (JAK) inhibitors and sarilumab and tocilizumab are interleukin‑6 (IL‑6) inhibitors. For people who cannot take methotrexate because it is contraindicated or because they cannot tolerate it, adalimumab, baricitinib, certolizumab pegol, etanercept, tofacitinib, sarilumab and tocilizumab can be used alone. Treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price per dose). It should only be continued if there is a moderate response using European League Against Rheumatism (EULAR) criteria at 6\xa0months, and should be stopped if at least a moderate EULAR response is not maintained.\n\n## In moderate disease, the most appropriate position for filgotinib is after an inadequate disease response to 2\xa0or more conventional DMARDs\n\nFilgotinib's marketing authorisation covers its use in people with moderate rheumatoid arthritis whose disease has responded inadequately to 1\xa0or more conventional DMARDs. However, the company's submission covers filgotinib's use in moderate rheumatoid arthritis for people whose disease has responded inadequately to 2\xa0or more conventional DMARDs. The committee agreed with the company's positioning of filgotinib in moderate disease. It noted such positioning is aligned with the use of biologic and targeted synthetic DMARDs in severe disease. The clinical expert explained that people whose disease has an inadequate response to 2\xa0or more conventional DMARDs are usually offered continued treatment with the same conventional DMARDs. Corticosteroids can be used to manage disease flares. The committee concluded that the appropriate position for filgotinib in moderate disease is after inadequate response to 2\xa0or more conventional DMARDs. It also agreed that the relevant comparator for this population is best supportive care, consisting of previously used conventional DMARDs with optional corticosteroids.\n\n## In severe disease, filgotinib could be used at all 4\xa0different points in the treatment pathway, with multiple comparators at each point\n\nFilgotinib's marketing authorisation and the company's submission cover its use at all 4\xa0points in the severe disease treatment pathway for which other biologic and targeted synthetic DMARDs are recommended (see section\xa03.2). The committee agreed with this positioning. It noted that the marketing authorisation includes the use of filgotinib alone or with methotrexate. The committee agreed that all treatments listed in section\xa03.2, all used with methotrexate, are relevant comparators for filgotinib with methotrexate, when used at the same position in the treatment pathway. For people who cannot have methotrexate, relevant comparators for filgotinib monotherapy are adalimumab, baricitinib, certolizumab pegol, etanercept, tofacitinib, sarilumab and tocilizumab, depending on the position in the treatment pathway.\n\n# Clinical effectiveness\n\n## The clinical trials are acceptable for decision making but do not include all relevant comparators for severe disease\n\nThe company's clinical evidence came from 2\xa0randomised controlled trials in people with moderate to severe rheumatoid arthritis:\n\nFINCH1 enrolled patients with inadequate disease response to methotrexate. A total of 24% of patients had moderate disease, and 76% had severe disease. Filgotinib was used with methotrexate and the comparators were adalimumab with methotrexate or placebo with methotrexate.\n\nFINCH2 enrolled people with inadequate disease response to at least 1\xa0biological DMARD. A total of 21% of patients had moderate disease and 79% had severe disease. Filgotinib was used with conventional DMARDs and the comparator was placebo with conventional DMARDs.The committee concluded that the trials were relevant and acceptable for decision making but did not include all relevant comparators for severe disease (see section\xa03.2).\n\n## For moderate to severe disease that has responded inadequately to conventional DMARDs, filgotinib with methotrexate is more clinically effective than adalimumab with methotrexate or placebo with methotrexate\n\nIn FINCH1, filgotinib with methotrexate showed a statistically significant improvement in the primary end point, American College of Rheumatology responses (ACR20) at 12\xa0weeks, compared with adalimumab with methotrexate or placebo with methotrexate (76.6% compared with 70.5% and 49.9%, respectively, p<0.05 for both comparisons). Filgotinib also showed improvement in key secondary endpoints at both 12\xa0and 24\xa0weeks, including ACR50, ACR70 or EULAR responses. The committee concluded that filgotinib with methotrexate was more clinically effective than adalimumab with methotrexate or placebo with methotrexate in people with moderate to severe disease that has responded inadequately to conventional DMARDs.\n\n## For moderate to severe disease that has responded inadequately to biological DMARDs, filgotinib with conventional DMARDs is more clinically effective than placebo with conventional DMARDs\n\nIn FINCH2, filgotinib with conventional DMARDs showed a statistically significant improvement in the primary outcome, ACR20 at 12\xa0weeks, compared with placebo with conventional DMARDs (66.0% compared with 31.1%, p<0.05). Filgotinib also showed improvement in key secondary endpoints at both 12\xa0and 24\xa0weeks, including ACR50, ACR70 or EULAR responses. The committee concluded that filgotinib with conventional DMARDs was more clinically effective than placebo with conventional DMARDs in people with moderate to severe disease that has responded inadequately to biological DMARDs.\n\n## The clinical efficacy of filgotinib monotherapy is uncertain\n\nFINCH1 and FINCH2 trials included filgotinib only with methotrexate or with conventional DMARDs, respectively. Therefore, no clinical efficacy data are available for filgotinib monotherapy in people with moderate to severe disease that has responded inadequately to conventional or biological DMARDs. The clinical expert explained that in the FINCH2 trial, which enrolled people who had not previously had methotrexate (that is, methotrexate-naive population), filgotinib monotherapy showed improved clinical outcomes compared with placebo. The committee noted that all biological and targeted synthetic DMARDs are recommended with methotrexate, unless methotrexate is contraindicated. This is because combination therapy is thought to be more clinically effective than monotherapy. The committee concluded that the clinical efficacy of filgotinib monotherapy is uncertain because there is no clinical trial data in the target population.\n\n# Direct and indirect comparisons\n\n## Network meta-analyses show that filgotinib with conventional DMARDs works as well as other biological and targeted synthetic DMARDs\n\nA direct comparison was only possible with adalimumab and placebo, informed by FINCH1 and FINCH2 trials. To compare with other biological and targeted synthetic DMARDs, the company did 2\xa0network meta-analyses for:\n\npeople whose disease responded inadequately to 1\xa0or more conventional DMARDs,\n\npeople whose disease responded inadequately to 1\xa0or more biological DMARDs.The results showed that for both populations, filgotinib gave similar EULAR response rates to other biological and targeted synthetic DMARDs. Filgotinib also gave better EULAR response rates than conventional DMARDs alone (the exact rates are confidential and cannot be reported here). However, the committee noted several limitations of the network meta-analyses:\n\nThey contained a mixed population of people with moderate and severe rheumatoid arthritis. Separate network meta-analyses for people with moderate and severe disease were not possible because most trials did not report efficacy results by disease severity.\n\nThey relied on EULAR responses mapped from ACR responses. This was because most trials did not report EULAR responses.\n\nThey assumed that the same treatment effect applied regardless of the position in the treatment pathway. This does not reflect clinical practice because treatments used later in the treatment pathway are likely to have a lower response rate.\n\nThe company assumed equal efficacy of filgotinib monotherapy and combination therapy (with methotrexate or conventional DMARDs). This was because no clinical trial data exists to inform efficacy of filgotinib monotherapy in the target population (see section\xa03.8).\n\nThey excluded potentially relevant studies. The ERG explained that the company excluded studies published before 1999, and studies for monotherapies.The committee agreed that for severe disease, there was limited direct trial evidence. Therefore, it accepted the network meta-analyses for decision making, bearing in mind their limitations. It agreed that using data from the moderate to severe population was appropriate to inform efficacy estimates for the severe population, because this was aligned with populations in other studies included in the network meta-analysis. The committee accepted that, in the absence of data, the efficacy of filgotinib combination therapy may be used as a proxy for the efficacy of filgotinib monotherapy, but noted this approach has limitations and could overestimate the efficacy of filgotinib monotherapy.\n\n## Direct head-to-head trial data is most appropriate to model efficacy of filgotinib and best supportive care in moderate rheumatoid arthritis\n\nAlthough the network meta-analysis was used for decision making for people with severe disease (see section\xa03.8), the technical team noted that for moderate disease it may be more appropriate to use FINCH1 trial data because:\n\nthe trial included all relevant comparators (with placebo plus methotrexate arm of the trial used as a proxy for best supportive care, see section\xa03.13)\n\nthis avoids limitations associated with company network meta-analysis (see section\xa03.8)\n\nusing direct head-to-head evidence is in line with NICE's guide to the methods of technology appraisal.In response to technical engagement, the company used direct head-to-head trial data to inform the efficacy of filgotinib and best supportive care in the moderate population. The committee agreed with this approach, noting that the FINCH1 trial data were more appropriate for decision making for moderate disease than the network meta-analyses.\n\n## Data from the overall moderate population of FINCH1 trial is appropriate for decision making\n\nThe ERG explained that the FINCH1 trial enrolled people who had had 1\xa0or more conventional DMARDs, and that about half the patients with moderate disease had only had 1\xa0previous conventional DMARD. Therefore, FINCH1 data may not be generalisable to the target population (that is, after 2\xa0or more previous conventional DMARDs). In response to technical engagement, the company provided pairwise comparisons of clinical efficacy data for patients with moderate disease who had had 1\xa0previous conventional DMARD compared with those who had had 2\xa0or more previous conventional DMARDs. The company highlighted that these are exploratory post hoc analyses based on small patient numbers, and FINCH1 was not powered for such a comparison. However, the number of previous conventional DMARDs did not appear to have any notable effect on clinical efficacy estimates. The company also provided exploratory cost-effectiveness analyses for the population who had had 2\xa0or more previous DMARDs. The committee considered all evidence provided by the company and concluded that using the overall moderate population from FINCH1 is more appropriate for decision making. It noted that this is preferred to using small post hoc subgroup data.\n\n## EULAR data from the FINCH1 trial should be used when modelling the efficacy of filgotinib and best supportive care in the moderate population\n\nThe revised company submission used direct head-to-head trial data to model the efficacy of filgotinib (see section\xa03.10). The FINCH1 trial collected EULAR response data. However, the company mapped the EULAR responses from ACR responses. The ERG explained this approach was aligned with the approach taken for the severe population, but noted it preferred to use the EULAR responses from FINCH1 directly in the model. This is because using direct data gives more precise estimates of clinical efficacy than using mapped values. The committee agreed with the ERG that EULAR response should be used directly in the model, instead of the mapped values.\n\n# Modelling best supportive care in the moderate population\n\n## Using the placebo plus methotrexate arm of the FINCH1 trial to model the efficacy of best supportive care has limitations but is acceptable\n\nThe revised company base case modelled the efficacy of best supportive care based on the response rates seen in the placebo plus methotrexate arm of the FINCH1 trial. The clinical expert explained that best supportive care is not expected to give a EULAR response in clinical practice. However, the committee noted that a considerable response rate was seen in the placebo plus methotrexate arm of the FINCH1 trial, as well as in other clinical trials in rheumatoid arthritis. It noted that this response could have been caused by several factors, including a placebo effect, disease resolving naturally over time, regression to the mean, response bias and variation in symptoms. Some of these factors might have also contributed to the response to filgotinib in the FINCH1 trial. Therefore, the committee agreed it would not be appropriate to assume full clinical efficacy for filgotinib while assuming no response to best supportive care. It agreed with revised company analyses, which used FINCH1 response rates for both filgotinib with methotrexate and placebo plus methotrexate (a proxy for best supportive care). However, it acknowledged that these analyses had limitations because they did not fully reflect what is expected to happen in clinical practice.\n\n# Comparators and treatment sequences for severe disease\n\n## The comparators and treatment sequences modelled by the company are sufficient for decision making\n\nRheumatoid arthritis is a heterogenous disease and treatment choices are influenced by many factors (see section\xa03.1). Because of the large number of possible treatment sequences, it was not practical to model them all. However, the clinical expert confirmed that the company model included the most relevant comparators and treatment sequences that are used in NHS clinical practice. One exception to that, noted by both clinical and patient experts, was that further advanced therapies would be used instead of best supportive care in clinical practice. The committee acknowledged this as a limitation but noted that this approach was aligned with previous NICE technology appraisals. It also noted that this is likely to have a limited effect on the cost-effectiveness estimates in severe disease, but could be important to consider for the moderate population in the treatment sequence upon progression to severe disease (see section\xa03.16).\n\n# Modelling progression from moderate to severe rheumatoid arthritis\n\n## The rate of progression from moderate to severe disease is uncertain but the company approach to model this is acceptable for decision making\n\nIn the revised company base case, the company used patients' mean baseline DAS28 and expected DAS28 trajectory, to estimate patients' progression from moderate to severe disease. Using this approach, the modelled progression rate with best supportive care was 11% at 2\xa0years and 39% at 5\xa0years. The clinical expert mentioned 1\xa0study that reported 5% progression rate at 1\xa0year. Another study (ERAN database) reported that 19% of people with moderate disease activity 1\xa0year after diagnosis had severe disease activity at a 2‑year visit. The committee noted this estimate may be uncertain because of small patient numbers in the registry and single assessment of disease activity at both timepoints (so results could be subject to temporary fluctuation in disease activity, including flares). It also noted no data were available to inform long-term progression rates. The clinical expert highlighted that although published data on the progression rates are lacking, the rates modelled by the company seem reasonable. The committee discussed that some patients could start treatment for severe disease when they have a flare that temporarily increases their disease activity to a severe level. This could mean that the initiation of severe treatment sequences in NHS clinical practice is higher than modelled by the company. The patient and clinical experts explained that a single flare would usually trigger a change of treatment (start of severe treatment sequence) only for patients with their usual disease activity in the higher end of the moderate disease activity range (that is, close to the severe disease activity level). However, such a change after a single flare was unlikely for patients with disease activity in the lower end of disease activity range. The committee agreed the rate of progression in NHS clinical practice is uncertain but noted that higher progression rates would result in lower incremental cost-effectiveness ratios (ICERs) for filgotinib compared with best supportive care. This was because with higher progression rates, quality-adjusted life years (QALYs) and costs are increasing in both treatment arms, but to a higher degree in the best supportive care arm. The committee concluded that although the rates of progression from moderate to severe disease in NHS clinical practice is uncertain, the company approach to model this is reasonable. It also noted that if the true rates of progression are higher than those estimated in the model, the cost-effectiveness estimates for filgotinib would improve.\n\n## Alternative treatment sequences after progression from moderate to severe disease are plausible\n\nThe committee recalled that rheumatoid arthritis is a heterogenous disease and it was not practical to model all possible treatment sequences (see section\xa03.1 and section\xa03.14). The clinical expert explained that generally, they would follow the standard treatment sequence for severe disease once patients' disease progresses to severe disease activity. This would generally be:\n\nfor people who can have methotrexate: a TNF-alpha inhibitor, followed by rituximab and then by an IL‑6 inhibitor (all given with methotrexate)\n\nfor people who cannot have methotrexate: a TNF-alpha inhibitor, followed by an IL‑6 inhibitor (most frequently), abatacept, or rituximab (only in some trusts), and then a drug with an alternative mode of action (all given as monotherapy or with an alternative conventional DMARD).The clinical expert explained that there was no evidence to suggest treatment for severe disease would change if filgotinib was used for moderate disease, except the lower likelihood of considering another JAK inhibitor. However, the committee recalled that an alternative treatment sequence was considered plausible in NICE's technology appraisal guidance on upadacitinib for previously treated moderate active rheumatoid arthritis. This is because JAK inhibitors (such as filgotinib) and IL‑6 inhibitors are targeting a similar signalling pathway. Using a drug with a distinct mechanism of action, such as abatacept, instead of an IL‑6 inhibitor could be preferred in people who have already had filgotinib for the moderate disease. However, the committee agreed this is uncertain and may depend on clinician and patient preferences. Clinical experts explained that filgotinib could be used after progression to severe disease, if it was not used for the moderate disease. However, the committee agreed not to consider this treatment sequence further because there is uncertainty about how filgotinib would be used in NHS practice. The committee concluded that a range of treatment sequences for severe disease are plausible and agreed to consider them all (see table\xa01). It also agreed that there is even higher uncertainly about treatment sequences after progression when methotrexate is not suitable, and considered this in its decision making.\n\nScenario\n\nTreatment arm\n\nFirst-line treatment for severe disease\n\nSecond-line treatment for severe disease\n\nThird-line treatment for severe disease\n\nBase case\n\nFilgotinib\n\nAdalimumab\n\nRituximab\n\nTocilizumab\n\nBase case\n\nBest supportive care\n\nAdalimumab\n\nRituximab\n\nTocilizumab\n\nEvidence review group scenario\n\nFilgotinib\n\nEtanercept\n\nRituximab\n\nTocilizumab\n\nEvidence review group scenario\n\nBest supportive care\n\nEtanercept\n\nRituximab\n\nTocilizumab\n\nScenario 1\n\nFilgotinib\n\nAdalimumab\n\nRituximab\n\nSarilumab\n\nScenario 1\n\nBest supportive care\n\nAdalimumab\n\nRituximab\n\nSarilumab\n\nScenario 2\n\nFilgotinib\n\nAdalimumab\n\nRituximab\n\nAbatacept (subcutaneous)\n\nScenario 2\n\nBest supportive care\n\nAdalimumab\n\nRituximab\n\nTocilizumab (or sarilumab)\n\nScenario 3\n\nFilgotinib\n\nAdalimumab\n\nRituximab\n\nTocilizumab (or sarilumab)\n\nScenario 3\n\nBest supportive care\n\nAdalimumab\n\nRituximab\n\nBaricitinib\n\n# Utility values\n\n## The company's mapping algorithm to link HAQ and pain scores is appropriate for decision making\n\nIn the company's base case, health-related quality-of-life data was mapped from patients' long-term HAQ-DI score trajectory using a published mapping algorithm. In addition to HAQ-DI, the algorithm used patients' current age, sex, and visual analogue scale pain scores to determine a utility value at any point in the model. In the company's base case, the visual analogue scale pain scores were mapped from HAQ-DI as per NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed. The ERG explained their initial concerns about the mapping algorithm, which seemed to provide distinct utility values rather than those based on EQ‑5D data collected in the trial. However, in response to technical engagement, the company provided corrected validation of their mapping algorithm, using individual patient data. The ERG was satisfied that the QALY outputs are fairly similar using the 2\xa0methods. Therefore, it agreed with the company's approach and followed it in the revised ERG base case. The committee noted this approach is consistent with a number of previous appraisals. It concluded that the company's approach may have limitations but is appropriate for decision making.\n\n# Cost-effectiveness results\n\n## Because of uncertainty in the cost-effectiveness estimates, an acceptable ICER is around £20,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.The committee concluded that the cost-effectiveness results for moderate disease were uncertain because:\n\nthe response rates in the placebo arms of the trials did not reflect clinical practice. It is unlikely that a EULAR response would be seen after an inadequate response with 2\xa0conventional DMARDs (see section\xa01.1)\n\nthe long-term rate of progression from moderate to severe disease is uncertain (see section\xa03.15)\n\nthere is uncertainty about the most appropriate treatment sequence for people whose disease progresses from moderate to severe disease state (see section\xa03.16).Because of this uncertainty, the committee agreed that an acceptable ICER would be around £20,000 per QALY gained.\n\n## In moderate disease, filgotinib with methotrexate is cost effective after 2\xa0or more conventional DMARDs\n\nThe committee noted that the revised company analyses applied the following committee preferences:\n\nFINCH1 trial data (whole moderate population) were used to model the efficacy of both filgotinib and best supportive care (see section\xa03.10, section\xa03.11 and section\xa03.13).\n\nThe modelled rate of progression was uncertain but was judged to be reasonable by the clinical expert (see section\xa03.15).\n\nA range of alternative treatment sequences were explored (see section\xa03.16).\n\nThe mapping algorithm from NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed was used to estimate utility values (see section\xa03.17). However, it noted that company analyses were based on EULAR responses mapped from ACR responses, instead of directly using EULAR responses from FINCH1 (see section\xa03.12). Therefore, the committee preferred to use the ERG analyses, which used trial-based EULAR responses. The ERG analyses also applied confidential discounts for treatments used after progression from moderate to severe disease. Because of these confidential discounts, exact ICERs are confidential and cannot be reported here. The committee noted that all analyses with alternative treatment sequences produced ICERs around £20,000 per QALY gained for filgotinib with methotrexate compared with best supportive care. The only exception was a treatment sequence assuming filgotinib use in the comparator arms for patients who did not have it for moderate disease. But the committee recalled that it had agreed this sequence was less relevant to decision making (see section\xa03.16). The committee also recalled that although the exact rate of progression from moderate to disease severity in NHS clinical practice is uncertain, a higher rate of progression would improve cost-effectiveness estimates for filgotinib. The committee concluded that it could recommend filgotinib with methotrexate as a cost-effective use of NHS resources for people with moderate rheumatoid arthritis whose disease had responded inadequately to 2\xa0or more conventional DMARDs.\n\n## In severe disease, filgotinib with methotrexate is cost effective after 2\xa0or more conventional DMARDs\n\nThe ERG did analyses for people with severe rheumatoid arthritis whose disease had responded inadequately to 2\xa0or more conventional DMARDs, applying confidential discounts for filgotinib, comparators and subsequent treatment options. Filgotinib with methotrexate provided a higher net health benefit (that is, was more cost effective) than alternative therapies used with methotrexate. Therefore, the committee concluded that it could recommend filgotinib with methotrexate as a cost‑effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to 2\xa0or more conventional DMARDs.\n\n## In severe disease, filgotinib with methotrexate is not cost effective after 1\xa0or more biological DMARDs if rituximab is a treatment option\n\nThe ERG did analyses for people with severe disease whose disease had responded inadequately to 1\xa0or more biological DMARDs, applying confidential discounts for filgotinib, rituximab and subsequent treatments. Filgotinib with methotrexate was dominated by rituximab with methotrexate (that is, filgotinib with methotrexate was more costly and less effective than rituximab with methotrexate). Therefore, the committee concluded that it could not recommend filgotinib with methotrexate as a cost‑effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to 1\xa0or more biological DMARDs if rituximab is a treatment option.\n\n## In severe disease, filgotinib with methotrexate is cost effective after 1\xa0or more biological DMARDs, if rituximab is not a treatment option\n\nThe ERG did analyses for people with severe disease whose disease had responded inadequately to 1\xa0or more biological DMARDs and rituximab is not a treatment option, applying confidential discounts for filgotinib, comparators and subsequent treatment options. Filgotinib with methotrexate provided a higher net health benefit (that is, was more cost effective) than alternative therapies used with methotrexate. Therefore, the committee concluded that it could recommend filgotinib with methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to 1\xa0or more biological DMARDs, if rituximab is not a treatment option.\n\n## In severe disease, filgotinib with methotrexate is cost effective after 1\xa0or more biological DMARDs and rituximab\n\nThe ERG did analyses for people with severe disease whose disease had responded inadequately to 1\xa0or more biological DMARDs and rituximab, applying confidential discounts for filgotinib, comparators and subsequent treatment options. Filgotinib with methotrexate provided a higher net health benefit (that is, was more cost effective) than alternative therapies used with methotrexate. Therefore, the committee concluded that it could recommend filgotinib with methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to 1\xa0or more biological DMARDs and rituximab.\n\n## The cost effectiveness of filgotinib monotherapy is more uncertain but it is likely to represent a good use of NHS resources if methotrexate is not suitable\n\nThe committee noted that cost-effectiveness estimates for filgotinib monotherapy were uncertain because filgotinib monotherapy has not been studied in its target population (see section\xa03.8). The committee also recalled that the company model assumed equal effectiveness of filgotinib monotherapy and combination therapy, which has limitations (see section\xa03.9). Also, for moderate disease, it recalled there was higher uncertainty related to treatment sequences after progression from moderate to severe disease (see section\xa03.16). However, the committee concluded that despite these limitations, filgotinib is likely to represent a good use of NHS resources for people for whom methotrexate is not suitable and so it recommended filgotinib monotherapy in the same positions as combination therapy. It also noted that this population is much smaller than the population of patients who can have methotrexate. It agreed that the small number of people who could not tolerate methotrexate should not be treated differently from other people with moderate to severe disease, as far as possible.\n\n# Other factors\n\n## Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure\n\nA potential equality issue was raised in NICE's technology appraisal guidance on upadacitinib for treating severe rheumatoid arthritis, about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee agreed that this equality issue was also important to consider for this appraisal. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.\n\n## Healthcare professionals should choose the most appropriate treatment after discussing the options with the person having treatment\n\nThe committee recalled that having a range of treatment options was important in rheumatoid arthritis (see section\xa03.1). It also recalled that a range of biological and targeted synthetic DMARDs are already available for severe rheumatoid arthritis (see section\xa03.2). It noted that a number of NICE technology appraisals are currently in development for moderate rheumatoid arthritis (NICE's ongoing technology appraisal on upadacitinib for previously treated moderate active rheumatoid arthritis and NICE's ongoing technology appraisal on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for moderate rheumatoid arthritis after conventional DMARDs only have failed). The committee concluded that healthcare professionals should choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If more than 1\xa0treatment is suitable, they should start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary from person to person because of differences in how the drugs are taken and treatment schedules.\n\n## The benefits of filgotinib were adequately captured in the cost-effectiveness analysis\n\nFilgotinib is taken orally, which is valued by patients. The committee noted that for severe rheumatoid arthritis, other oral treatments with a similar mechanism of action are already available. But no biological or targeted synthetic DMARDs are currently available for people with moderate disease. The committee agreed that filgotinib is an important treatment option for these people. It concluded that all the benefits of filgotinib were adequately captured in the model."}
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https://www.nice.org.uk/guidance/ta676
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Evidence-based recommendations on filgotinib (Jyseleca) for moderate to severe rheumatoid arthritis in adults.
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a3837d3fc1c5dde266fae2ffd54aeecae3c0120f
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nice
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Autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory mantle cell lymphoma
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Autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory mantle cell lymphoma
Evidence-based recommendations on autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory mantle cell lymphoma in adults who have previously had a Bruton’s tyrosine kinase (BTK) inhibitor.
# Recommendations
Treatment with autologous anti-CD19-transduced CD3+ cells is recommended for use within the Cancer Drugs Fund as an option for relapsed or refractory mantle cell lymphoma in adults who have previously had a Bruton's tyrosine kinase (BTK) inhibitor. It is only recommended if the conditions in the managed access agreement for autologous anti‑CD19‑transduced CD3+ cells treatment are followed.
This recommendation is not intended to affect either treatment in preparation for or treatment with autologous anti-CD19-transduced CD3+ cells that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There is no standard treatment for relapsed or refractory mantle cell lymphoma after a BTK inhibitor. Rituximab, bendamustine and cytarabine (R‑BAC) is the most common treatment option. Autologous anti‑CD19-transduced CD3+ cells are a chimeric antigen receptor (CAR) T‑cell therapy. The therapy uses the patient's own T cells, which have been modified to attach to and kill cancer cells.
Evidence from a study of autologous anti-CD19-transduced CD3+ cells, which does not compare the therapy with anything else, suggests that people having it may live for longer and have more time before their disease relapses. However, the evidence is not certain because of the:
short follow up
small number of patients
uncertainty around how long people actually live
lack of evidence comparing autologous anti-CD19-transduced CD3+ cells directly with the most common alternative treatment.
There is also not enough evidence to tell if people having treatment with autologous anti-CD19-transduced CD3+ cells can be cured.
Autologous anti-CD19-transduced CD3+ cells meet NICE's criteria to be considered a life-extending treatment at the end of life. This is because people having it are likely to live for less than 24 months, and this treatment could extend their life by at least 3 months. The most likely cost‑effectiveness estimates for autologous anti‑CD19‑transduced CD3+ cells compared with the most common alternative treatment are not known because the final survival data for autologous anti‑CD19‑transduced CD3+ cells are not yet available. However, early estimates suggest it could be cost effective, and collecting further data on progression-free survival, overall survival and age when treatment starts will reduce the uncertainty in the evidence. Therefore, autologous anti-CD19-transduced CD3+ cells are recommended for use as an option within the Cancer Drugs Fund.# Information about autologous anti-CD19-transduced CD3+ cells
# Marketing authorisation indication
Autologous anti-CD19-transduced CD3+ cells (Tecartus, Kite) are indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma after 2 or more lines of systemic therapy including a Bruton's tyrosine kinase (BTK) inhibitor.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The price was submitted as commercial in confidence. The company has a commercial arrangement. This makes treatment with autologous anti‑CD19‑transduced CD3+ cells available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Kite, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
Rituximab, bendamustine and cytarabine (R‑BAC) is the most recognised form of standard care in clinical practice in the UK.
Using data from McCulloch et al. (2020) to inform the progression-free and overall survival of people treated with standard care is more appropriate than using uncertain estimates from an indirect treatment comparison of autologous anti‑CD19‑transduced CD3+ cells with standard care.The committee discussed the following issues (issues 1, 4, 5, 7 and 8), which were outstanding after the technical engagement stage.
# The condition
## There is an unmet clinical need for more effective treatment options
Mantle cell lymphoma is a subtype of non-Hodgkin lymphoma and can have debilitating symptoms. Rates of relapse after initial treatment are high, and it has a huge effect on quality of life. Mantle cell lymphoma is considered incurable with current treatment. Outcomes for people with refractory or relapsed disease are poor. Treatment options after relapse with a Bruton's tyrosine kinase (BTK) inhibitor are not well established and normally associated with lower responses and rapid disease progression. The patient experts explained that the disease always has the potential to relapse and that the side effects of existing treatments significantly reduce quality of life. A new treatment that offers the possibility of a cure would provide hope and be valued by patients. They highlighted that, although treatment with autologous anti‑CD19‑transduced CD3+ cells can have serious and even life-threatening side effects, people would be happy to accept this risk for a potential cure. Chimeric antigen receptor (CAR) T‑cell therapies such as autologous anti‑CD19‑transduced CD3+ cells cells are advanced, personalised cancer immunotherapies that collect and modify patients' own immune cells to treat the cancer. Treatment with CAR T‑cell therapies can be intense, requiring several weeks' stay in hospital, but can enable recovery within a few months. The committee concluded that there is an unmet need in this population and that patients and healthcare professionals would welcome potential new treatments. This could include CAR T‑cell therapies that improve the chance of survival and offer potential for a cure.
# Treatment pathway
## Autologous anti-CD19-transduced CD3+ cells are a new treatment option when there has been no response to, or relapse after, first- and second-line treatments
First-line treatment of mantle cell lymphoma may include rituximab chemotherapy, and stem cell transplant for fitter patients. Ibrutinib (a BTK inhibitor) is the most likely treatment to be used second line. Treatment options for later relapse are not well established. They may include more rituximab chemotherapy such as R‑BAC and rituximab plus bendamustine. Treatment with autologous anti-CD19-transduced CD3+ cells is proposed as a third-line treatment option for people whose disease has relapsed after ibrutinib. The committee concluded that there is no uniformly accepted standard care and limited treatment options for relapsed or refractory mantle cell lymphoma when there is disease progression after first- and second-line treatments including a BTK inhibitor.
# Clinical evidence
## Autologous anti-CD19-transduced CD3+ cells are clinically effective but survival data are immature
The clinical-effectiveness evidence for autologous anti‑CD19‑transduced CD3+ cells came from ZUMA‑2, an ongoing, phase 3, multicentre, open‑label, single-arm study. The company presented results from the study for a modified intention-to-treat group (68 patients who had treatment with autologous anti‑CD19‑transduced CD3+ cells), which were used in the economic analysis. The primary outcome measure was overall response rate, defined as complete response or partial response (based on the International Working Group response criteria for malignant lymphoma). Results show a promising overall response rate for patients having treatment with autologous anti‑CD19‑transduced CD3+ cells (exact results are confidential and cannot be reported here) and an extension to life for patients who have a complete response to autologous anti‑CD19‑transduced CD3+ cells compared with patients who have a partial response. At the latest data cut in December 2019, the median follow up in ZUMA‑2 was short and the survival data were immature. The committee noted the apparent plateau in the Kaplan–Meier curves for overall and progression-free survival. But the ERG explained that from month 12 onwards, the Kaplan–Meier plots were heavily influenced by censoring of data (that is, people who did not have an event during follow up whose survival is unknown beyond the point at which they were censored) so very few patients remained at risk of mortality or disease progression. Therefore, the estimates of survival beyond 12 months were highly uncertain. The committee concluded that treatment with autologous anti‑CD19‑transduced CD3+ cells is clinically effective, but the benefit cannot be quantified because of the immature survival data and lack of trial data compared with standard care.
## Longer-term survival data from the main trial may provide evidence of a cure, but the data are immature
The company considered that results from ZUMA‑2 supported the assumption of long-term survivors based on plateaus in the Kaplan–Meier curves. It also highlighted precedent from previous appraisals of CAR T‑cell therapies in relapsed or refractory B‑cell acute lymphoblastic leukaemia and relapsed or refractory diffuse large B‑cell lymphoma (DLBCL). The ERG noted that plateaus in the Kaplan–Meier curves are not robust evidence of long-term survival after treatment with autologous anti-CD19-transduced CD3+ cells because of data censoring and the trial's short follow up. The clinical experts noted that 3 years of follow up is needed to provide reliable evidence of a cure, and clinical consensus is that relapsed or refractory mantle cell lymphoma is generally incurable. They also noted that stem cell transplants are known to cure only a small proportion of patients but estimated that potentially 30% of people with a complete response to treatment with autologous anti-CD19-transduced CD3+ cells may go on to be cured. However, although there is some evidence of a potential cure with CAR T‑cell therapy in relapsed or refractory DLBCL, there is considerable uncertainty over whether this applies also to relapsed or refractory mantle cell lymphoma. This is because of differences in the disease biology, therapy regimens and patterns of relapse. The company reiterated through the technical engagement process that ZUMA‑2 remains the only source of direct evidence demonstrating that a proportion of patients will have long-term survival after treatment with autologous anti-CD19-transduced CD3+ cells. The committee concluded that long-term survival data from ZUMA‑2 were consistent with the possibility of a cure, but the data are too immature to establish this.
## The results of the main trial are generalisable to the people for whom autologous anti-CD19-transduced CD3+ cells would be an option in the NHS
The committee was concerned about how generalisable the results of the ZUMA‑2 study were to the NHS, given that it did not include any patients from the UK. It noted that the population in the trial included people who had had a median of 3 prior therapies, all with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (which means that their activities are relatively unrestricted by their disease) and a mean age of 63. Forty-three per cent of the trial population had also had a stem cell transplant. The committee noted that trials generally include highly selected populations. The ERG considered that the ZUMA‑2 population is likely to be younger and in better health than people with relapsed or refractory mantle cell lymphoma in the NHS who have had 2 prior lines of therapy including ibrutinib. The clinical experts said that before having treatment with autologous anti-CD19-transduced CD3+ cells people would need to have a good performance status to tolerate the treatment's toxicity. The clinical experts and NHS England's clinical lead for the Cancer Drugs Fund noted that, although patients in the NHS are likely to be older and less fit than the trial population, people matching the trial population can be selected through careful deliberations by specialist multidisciplinary CAR T‑cell treatment centres. The company also said that a mean age of 63 is reasonably reflective of people who would be selected to have treatment with autologous anti-CD19-transduced CD3+ cells. With ibrutinib established as second-line standard care in the NHS, people in the NHS with relapsed or refractory mantle cell lymphoma will have had fewer treatments before treatment with autologous anti‑CD19‑transduced CD3+ cells than people in the trial. The committee concluded that the results from ZUMA‑2 were generalisable to patients in the NHS.
# Cost effectiveness
## The company's model is acceptable for decision-making
The company presented cost-effectiveness analyses comparing treatment with autologous anti‑CD19‑transduced CD3+ cells with standard care, which was assumed to be R‑BAC. It used a partitioned survival model with 3 health states (progression-free, progressed disease and death). Progression-free and overall-survival estimates were modelled independently, with the proportion of progressed patients at each cycle calculated as the difference between the values for the overall-survival and progression-free survival curves. The company modelled the cost effectiveness of treatment with autologous anti-CD19-transduced CD3+ cells using data from ZUMA‑2, and the cost effectiveness of R‑BAC from a study by McCulloch et al. (2020). The committee concluded that the model was appropriate for decision-making.
## The company updated its model and cost-effectiveness analyses after technical engagement
The committee noted that after technical engagement, the company updated its economic model to align with all but one of the ERG's suggested amendments. The revised base case incorporated an updated commercial arrangement and used data from McCulloch et al. (2020) to inform the health outcomes and costs of standard care. The only suggested amendment not incorporated into the revised company base case was the increased mortality risk for patients who have long-term survival, which the company disputed. The committee therefore focused on the modelled outcomes for long-term survivors.
## People having autologous anti-CD19-transduced CD3+ cells are likely to be at a higher risk of mortality than the general population
The company's model assumed that people who have had treatment with autologous anti‑CD19‑transduced CD3+ cells and survive beyond the ZUMA‑2 trial follow up have a 9% higher probability of death than the general population. This was based on data from a French cohort of people with DLBCL reported in Maurer et al. (2014), which was used in NICE's technology appraisal guidance on axicabtagene ciloleucel for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma. The ERG considered that the excess mortality risk with DLBCL is not generalisable to people with relapsed or refractory mantle cell lymphoma. It also considered that the excess mortality risk compared with the general population is likely to be higher than predicted by the company. The ERG suggested that it was more appropriate to base the mortality adjustment on data from people with mantle cell lymphoma than with DLBCL. It suggested using data from Eskelund et al. (2016), which reports up to 15 years of follow up (median 11.4 years) of 160 newly diagnosed patients with mantle cell lymphoma after first-line treatment with chemotherapy then autologous stem cell transplant. The ERG said it was possible that excess mortality for people who had treatment with autologous anti-CD19-transduced CD3+ cells was similar to people with mantle cell lymphoma who had a sustained complete response, regardless of whether this was through a stem cell transplant or CAR T‑cell therapy. The ERG derived hazard ratios from the overall-survival curves from Eskelund et al. comparing the age and sex-matched general population with people who have mantle cell lymphoma in complete remission. For at least 1 year the hazard ratio was 4.37 and for at least 5 years it was 2.36. The lower and higher hazard ratios were used as the lower and upper mortality range of the excess mortality adjustment and used for the incremental cost-effectiveness ratio (ICER) range in the ERG's base-case analysis. The company acknowledged the significant uncertainty associated with the excess mortality adjustment, which was also acknowledged in NICE's technology appraisal guidance on axicabtagene ciloleucel. But it noted that the committee for that appraisal accepted the assumption that long-term survivors are at a 9% greater risk of death than the age and sex-matched general population. The company highlighted that the data from Eskelund et al. are based on people who had an autologous stem cell transplant and so do not necessarily reflect what would happen with treatment with autologous anti-CD19-transduced CD3+ cells. The company also considered that the ERG's method for deriving estimates for long-term excess mortality had limitations and was associated with significant uncertainty. The clinical experts agreed that the risk of death is expected to be higher in a heavily pre-treated population with relapsed or refractory mantle cell lymphoma than for people with DLBCL treated first-line. However, the clinical experts explained that an autologous stem cell transplant is not considered a curative treatment in mantle cell lymphoma, and patients are expected to relapse, which might not be the case with treatment with autologous anti-CD19-transduced CD3+ cells if it is proved to be curative. Also, patients in the Eskelund et al. study had not been treated with ibrutinib, which is known to increase survival. They noted that the higher overall mortality compared with the general population reported in Eskelund et al. is in the context of the current consensus that people with relapsed or refractory lymphoma cannot be cured. But the committee accepted that autologous anti‑CD19‑transduced CD3+ cells are a novel treatment that represents a step-change in the treatment pathway for the disease. The committee concluded that there is significant uncertainty in the excess mortality risk for long-term survivors, but considered that people having treatment with autologous anti‑CD19‑transduced CD3+ cells are likely to have higher mortality risks than the general population, even if they are cured, and this may be higher than estimated for DLBCL.
## Patients' age when they start treatment has a significant effect on cost-effectiveness estimates
The ERG highlighted that the cost-effectiveness analysis is very sensitive to the age of the patient population when treatment starts, and depends on the extent to which the age of patients in the NHS differs from that in the ZUMA‑2 trial. This impact is driven mostly by the general population mortality risk used to inform the mortality risk of long-term survivors in the company's base case (see section 3.7). The ERG also highlighted the considerable difference in age between the ZUMA‑2 population (median age 65) and of people with mantle cell lymphoma at diagnosis in the UK (median age 72.9) and noted that the mean age of the ZUMA‑2 population (63.2) was used in economic analysis. A clinical expert noted that the ZUMA‑2 trial population's mean age of 63 is around 8 to 10 years younger than the NHS population with refractory or relapsed mantle cell lymphoma. The company argued that CAR T‑cell therapies are generally only suitable for fitter patients, and that people offered treatment with autologous anti-CD19-transduced CD3+ cells would undergo the same rigorous selection criteria as currently available CAR T‑cell treatments. NHS England's clinical lead for the Cancer Drugs Fund agreed and noted that patient selection by multidisciplinary teams at CAR T‑cell therapy centres would be rigorous. The ERG agreed with the company, based on evidence from the Cancer Drug Fund, that the median age of people with relapsed or refractory DLBCL treated with CAR T‑cell therapies is 57. But it noted that it was not clear if there would be the same difference in age between real-world and trial data for people with relapsed or refractory mantle cell lymphoma. Illustrative scenario analyses by the ERG showed that even small variations in mean baseline age have a significant impact on the cost-effectiveness estimates. The committee concluded that the age of the patients when treatment starts is a significant area of uncertainty in the cost-effectiveness estimates.
## It is not clear if long-term survivors have the same health-related quality of life as people in the general population of the same age and sex
The company's model assumed that people who had treatment with autologous anti‑CD19‑transduced CD3+ cells whose disease has not progressed after 5 years of treatment have the same health-related quality of life as the general population. The ERG considered that data from ZUMA‑2 is not enough to support this assumption. It noted that, if long-term survivors are more at risk of mortality than the general population, their health-related quality of life would be lower. The ERG incorporated the company's assumption in its base-case analysis but explored other lower quality-of-life estimates for people who were progression-free for 5 years. It provided illustrative scenario analyses in which the health-related quality of life of long-term survivors was reduced by 10% to 20%. This resulted in higher cost-effectiveness estimates. The clinical experts noted that long-term survivors will have a slightly higher mortality risk and worse health-related quality of life because of the risks associated with CAR T‑cell treatments and the effect of prior therapies. The committee concluded that it was not clear if long-term survivors would have the same health-related quality of life as people in the general population of the same age and sex.
# End of life
## Autologous anti-CD19-transduced CD3+ cells meet both criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that autologous anti‑CD19‑transduced CD3+ cells met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24 months). The company based expected survival without treatment with autologous anti-CD19-transduced CD3+ cells on:
standard care survival estimated from the matching-adjusted indirect comparison done before technical engagement
reported survival after ibrutinib treatment (mean 3.6 months to 12.5 months)
standard care survival estimates from economic modelling.All 3 support the assertion that people with relapsed or refractory disease having third-line treatment have a life expectancy of less than 24 months. Extension to life with treatment with autologous anti‑CD19‑transduced CD3+ cells was based on survival estimates from matching-adjusted indirect comparison modelling from the ZUMA‑2 trial data (for which median survival was not reached) and from the company economic model (exact results are confidential and cannot be reported here). The ERG considered that the assumptions also hold for the ERG base case and that the short life-expectancy criterion was met. The committee concluded that treatment with autologous anti-CD19-transduced CD3+ cells meets both criteria to be considered a life-extending treatment at the end of life.
# Cost-effectiveness results
## The company proposes autologous anti-CD19-transduced CD3+ cells for the Cancer Drugs Fund
The company submitted a proposal for autologous anti-CD19-transduced CD3+ cells to be considered for the Cancer Drugs Fund rather than routine commissioning, and proposed an accompanying confidential commercial arrangement. The committee considered the ICERs based on this commercial arrangement in its decision-making. The committee understood that it was not considering autologous anti-CD19-transduced CD3+ cells for routine use, and discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum).
## There is a range of possible cost-effectiveness estimates
In the company's revised base case after technical engagement the deterministic ICER was £46,898 per quality-adjusted life year (QALY) gained for treatment with autologous anti‑CD19‑transduced CD3+ cells compared with standard care. This included a mortality adjustment of 1.09 and the confidential commercial arrangement for autologous anti‑CD19‑transduced CD3+ cells. The ERG's base-case analysis accounted for the lower and upper mortality range of the excess mortality adjustment (2.36 to 4.37) and produced ICERs ranging from £58,223 to £72,920 per QALY gained. Based on the available evidence, the committee concluded that the ICER (with the discount agreed in the commercial arrangement) ranged between £46,898 and £72,920 per QALY gained, but it favoured the lower ERG adjustment of mortality which gave an ICER of £58,223 per QALY gained. The committee recalled the uncertainty around the age of the patient population when treatment starts (see section 3.9) and the health-related quality of life of long-term survivors (see section 3.10) and noted that the ICER range could be wider.
# Cancer Drugs Fund
## Further data collection could address uncertainties in the clinical and cost‑effectiveness evidence
The committee recalled that it had concluded that autologous anti‑CD19‑transduced CD3+ cells met the criteria to be considered a life-extending treatment at the end of life (see section 3.11) and that the company had proposed autologous anti-CD19-transduced CD3+ cells for use in the Cancer Drugs Fund (see section 3.12). The committee recognised that treatment with autologous anti-CD19-transduced CD3+ cells is innovative and therefore considered if the clinical uncertainty over its use could be addressed by collecting more data. More data from ZUMA‑2 are expected, with additional years of follow up planned. The committee agreed that:
More data on progression-free, post-progression and overall survival up to 5 years will help clarify if treatment with autologous anti‑CD19‑transduced CD3+ cells improves long-term survival.
Using autologous anti-CD19-transduced CD3+ cells in the NHS allows data to be collected using the Systemic Anti‑Cancer Therapy (SACT) dataset to get more accurate costs and benefits for its use in clinical practice, as well as the median age of the patients who would be offered treatment with autologous anti-CD19-transduced CD3+ cells.
## Autologous anti-CD19-transduced CD3+ cells meet the criteria to be included in the Cancer Drugs Fund
Data from ZUMA‑2 showed that people having treatment with autologous anti-CD19-transduced CD3+ cells have good response rates, overall survival and progression-free survival. The committee noted that the company's revised base-case ICER for autologous anti-CD19-transduced CD3+ cells compared with standard care was below £50,000 per QALY gained. The ERG'S base-case range of ICERs was over £50,000 per QALY gained. The committee acknowledged that the ICERs for autologous anti-CD19-transduced CD3+ cells compared with standard care were not certain, but concluded that the treatment had the plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced. The committee recognised that more data on long-term survival and post-progression survival for treatment with autologous anti‑CD19‑transduced CD3+ cells would allow for a more robust cost-effectiveness estimate. It agreed that the treatment met the criteria to be considered for inclusion in the Cancer Drugs Fund for treating relapsed or refractory mantle cell lymphoma.
|
{'Recommendations ': "Treatment with autologous anti-CD19-transduced CD3+ cells is recommended for use within the Cancer Drugs Fund as an option for relapsed or refractory mantle cell lymphoma in adults who have previously had a Bruton's tyrosine kinase (BTK) inhibitor. It is only recommended if the conditions in the managed access agreement for autologous anti‑CD19‑transduced CD3+ cells treatment are followed.\n\nThis recommendation is not intended to affect either treatment in preparation for or treatment with autologous anti-CD19-transduced CD3+ cells that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere is no standard treatment for relapsed or refractory mantle cell lymphoma after a BTK inhibitor. Rituximab, bendamustine and cytarabine (R‑BAC) is the most common treatment option. Autologous anti‑CD19-transduced CD3+ cells are a chimeric antigen receptor (CAR) T‑cell therapy. The therapy uses the patient's own T\xa0cells, which have been modified to attach to and kill cancer cells.\n\nEvidence from a study of autologous anti-CD19-transduced CD3+ cells, which does not compare the therapy with anything else, suggests that people having it may live for longer and have more time before their disease relapses. However, the evidence is not certain because of the:\n\nshort follow up\n\nsmall number of patients\n\nuncertainty around how long people actually live\n\nlack of evidence comparing autologous anti-CD19-transduced CD3+ cells directly with the most common alternative treatment.\n\nThere is also not enough evidence to tell if people having treatment with autologous anti-CD19-transduced CD3+ cells can be cured.\n\nAutologous anti-CD19-transduced CD3+ cells meet NICE's criteria to be considered a life-extending treatment at the end of life. This is because people having it are likely to live for less than 24\xa0months, and this treatment could extend their life by at least 3\xa0months. The most likely cost‑effectiveness estimates for autologous anti‑CD19‑transduced CD3+ cells compared with the most common alternative treatment are not known because the final survival data for autologous anti‑CD19‑transduced CD3+ cells are not yet available. However, early estimates suggest it could be cost effective, and collecting further data on progression-free survival, overall survival and age when treatment starts will reduce the uncertainty in the evidence. Therefore, autologous anti-CD19-transduced CD3+ cells are recommended for use as an option within the Cancer Drugs Fund.", 'Information about autologous anti-CD19-transduced CD3+ cells': "# Marketing authorisation indication\n\nAutologous anti-CD19-transduced CD3+ cells (Tecartus, Kite) are indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma after 2 or more lines of systemic therapy including a Bruton's tyrosine kinase (BTK) inhibitor.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe price was submitted as commercial in confidence. The company has a commercial arrangement. This makes treatment with autologous anti‑CD19‑transduced CD3+ cells available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Kite, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nRituximab, bendamustine and cytarabine (R‑BAC) is the most recognised form of standard care in clinical practice in the UK.\n\nUsing data from McCulloch et al. (2020) to inform the progression-free and overall survival of people treated with standard care is more appropriate than using uncertain estimates from an indirect treatment comparison of autologous anti‑CD19‑transduced CD3+ cells with standard care.The committee discussed the following issues (issues 1, 4, 5, 7 and 8), which were outstanding after the technical engagement stage.\n\n# The condition\n\n## There is an unmet clinical need for more effective treatment options\n\nMantle cell lymphoma is a subtype of non-Hodgkin lymphoma and can have debilitating symptoms. Rates of relapse after initial treatment are high, and it has a huge effect on quality of life. Mantle cell lymphoma is considered incurable with current treatment. Outcomes for people with refractory or relapsed disease are poor. Treatment options after relapse with a Bruton's tyrosine kinase (BTK) inhibitor are not well established and normally associated with lower responses and rapid disease progression. The patient experts explained that the disease always has the potential to relapse and that the side effects of existing treatments significantly reduce quality of life. A new treatment that offers the possibility of a cure would provide hope and be valued by patients. They highlighted that, although treatment with autologous anti‑CD19‑transduced CD3+ cells can have serious and even life-threatening side effects, people would be happy to accept this risk for a potential cure. Chimeric antigen receptor (CAR) T‑cell therapies such as autologous anti‑CD19‑transduced CD3+ cells cells are advanced, personalised cancer immunotherapies that collect and modify patients' own immune cells to treat the cancer. Treatment with CAR T‑cell therapies can be intense, requiring several weeks' stay in hospital, but can enable recovery within a few months. The committee concluded that there is an unmet need in this population and that patients and healthcare professionals would welcome potential new treatments. This could include CAR T‑cell therapies that improve the chance of survival and offer potential for a cure.\n\n# Treatment pathway\n\n## Autologous anti-CD19-transduced CD3+ cells are a new treatment option when there has been no response to, or relapse after, first- and second-line treatments\n\nFirst-line treatment of mantle cell lymphoma may include rituximab chemotherapy, and stem cell transplant for fitter patients. Ibrutinib (a BTK inhibitor) is the most likely treatment to be used second line. Treatment options for later relapse are not well established. They may include more rituximab chemotherapy such as R‑BAC and rituximab plus bendamustine. Treatment with autologous anti-CD19-transduced CD3+ cells is proposed as a third-line treatment option for people whose disease has relapsed after ibrutinib. The committee concluded that there is no uniformly accepted standard care and limited treatment options for relapsed or refractory mantle cell lymphoma when there is disease progression after first- and second-line treatments including a BTK inhibitor.\n\n# Clinical evidence\n\n## Autologous anti-CD19-transduced CD3+ cells are clinically effective but survival data are immature\n\nThe clinical-effectiveness evidence for autologous anti‑CD19‑transduced CD3+ cells came from ZUMA‑2, an ongoing, phase 3, multicentre, open‑label, single-arm study. The company presented results from the study for a modified intention-to-treat group (68\xa0patients who had treatment with autologous anti‑CD19‑transduced CD3+ cells), which were used in the economic analysis. The primary outcome measure was overall response rate, defined as complete response or partial response (based on the International Working Group response criteria for malignant lymphoma). Results show a promising overall response rate for patients having treatment with autologous anti‑CD19‑transduced CD3+ cells (exact results are confidential and cannot be reported here) and an extension to life for patients who have a complete response to autologous anti‑CD19‑transduced CD3+ cells compared with patients who have a partial response. At the latest data cut in December 2019, the median follow up in ZUMA‑2 was short and the survival data were immature. The committee noted the apparent plateau in the Kaplan–Meier curves for overall and progression-free survival. But the ERG explained that from month\xa012 onwards, the Kaplan–Meier plots were heavily influenced by censoring of data (that is, people who did not have an event during follow up whose survival is unknown beyond the point at which they were censored) so very few patients remained at risk of mortality or disease progression. Therefore, the estimates of survival beyond 12 months were highly uncertain. The committee concluded that treatment with autologous anti‑CD19‑transduced CD3+ cells is clinically effective, but the benefit cannot be quantified because of the immature survival data and lack of trial data compared with standard care.\n\n## Longer-term survival data from the main trial may provide evidence of a cure, but the data are immature\n\nThe company considered that results from ZUMA‑2 supported the assumption of long-term survivors based on plateaus in the Kaplan–Meier curves. It also highlighted precedent from previous appraisals of CAR T‑cell therapies in relapsed or refractory B‑cell acute lymphoblastic leukaemia and relapsed or refractory diffuse large B‑cell lymphoma (DLBCL). The ERG noted that plateaus in the Kaplan–Meier curves are not robust evidence of long-term survival after treatment with autologous anti-CD19-transduced CD3+ cells because of data censoring and the trial's short follow up. The clinical experts noted that 3\xa0years of follow up is needed to provide reliable evidence of a cure, and clinical consensus is that relapsed or refractory mantle cell lymphoma is generally incurable. They also noted that stem cell transplants are known to cure only a small proportion of patients but estimated that potentially 30% of people with a complete response to treatment with autologous anti-CD19-transduced CD3+ cells may go on to be cured. However, although there is some evidence of a potential cure with CAR T‑cell therapy in relapsed or refractory DLBCL, there is considerable uncertainty over whether this applies also to relapsed or refractory mantle cell lymphoma. This is because of differences in the disease biology, therapy regimens and patterns of relapse. The company reiterated through the technical engagement process that ZUMA‑2 remains the only source of direct evidence demonstrating that a proportion of patients will have long-term survival after treatment with autologous anti-CD19-transduced CD3+ cells. The committee concluded that long-term survival data from ZUMA‑2 were consistent with the possibility of a cure, but the data are too immature to establish this.\n\n## The results of the main trial are generalisable to the people for whom autologous anti-CD19-transduced CD3+ cells would be an option in the NHS\n\nThe committee was concerned about how generalisable the results of the ZUMA‑2 study were to the NHS, given that it did not include any patients from the UK. It noted that the population in the trial included people who had had a median of 3 prior therapies, all with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (which means that their activities are relatively unrestricted by their disease) and a mean age of 63. Forty-three per cent of the trial population had also had a stem cell transplant. The committee noted that trials generally include highly selected populations. The ERG considered that the ZUMA‑2 population is likely to be younger and in better health than people with relapsed or refractory mantle cell lymphoma in the NHS who have had 2 prior lines of therapy including ibrutinib. The clinical experts said that before having treatment with autologous anti-CD19-transduced CD3+ cells people would need to have a good performance status to tolerate the treatment's toxicity. The clinical experts and NHS England's clinical lead for the Cancer Drugs Fund noted that, although patients in the NHS are likely to be older and less fit than the trial population, people matching the trial population can be selected through careful deliberations by specialist multidisciplinary CAR T‑cell treatment centres. The company also said that a mean age of 63 is reasonably reflective of people who would be selected to have treatment with autologous anti-CD19-transduced CD3+ cells. With ibrutinib established as second-line standard care in the NHS, people in the NHS with relapsed or refractory mantle cell lymphoma will have had fewer treatments before treatment with autologous anti‑CD19‑transduced CD3+ cells than people in the trial. The committee concluded that the results from ZUMA‑2 were generalisable to patients in the NHS.\n\n# Cost effectiveness\n\n## The company's model is acceptable for decision-making\n\nThe company presented cost-effectiveness analyses comparing treatment with autologous anti‑CD19‑transduced CD3+ cells with standard care, which was assumed to be R‑BAC. It used a partitioned survival model with 3 health states (progression-free, progressed disease and death). Progression-free and overall-survival estimates were modelled independently, with the proportion of progressed patients at each cycle calculated as the difference between the values for the overall-survival and progression-free survival curves. The company modelled the cost effectiveness of treatment with autologous anti-CD19-transduced CD3+ cells using data from ZUMA‑2, and the cost effectiveness of R‑BAC from a study by McCulloch et al. (2020). The committee concluded that the model was appropriate for decision-making.\n\n## The company updated its model and cost-effectiveness analyses after technical engagement\n\nThe committee noted that after technical engagement, the company updated its economic model to align with all but one of the ERG's suggested amendments. The revised base case incorporated an updated commercial arrangement and used data from McCulloch et al. (2020) to inform the health outcomes and costs of standard care. The only suggested amendment not incorporated into the revised company base case was the increased mortality risk for patients who have long-term survival, which the company disputed. The committee therefore focused on the modelled outcomes for long-term survivors.\n\n## People having autologous anti-CD19-transduced CD3+ cells are likely to be at a higher risk of mortality than the general population\n\nThe company's model assumed that people who have had treatment with autologous anti‑CD19‑transduced CD3+ cells and survive beyond the ZUMA‑2 trial follow up have a 9% higher probability of death than the general population. This was based on data from a French cohort of people with DLBCL reported in Maurer et al. (2014), which was used in NICE's technology appraisal guidance on axicabtagene ciloleucel for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma. The ERG considered that the excess mortality risk with DLBCL is not generalisable to people with relapsed or refractory mantle cell lymphoma. It also considered that the excess mortality risk compared with the general population is likely to be higher than predicted by the company. The ERG suggested that it was more appropriate to base the mortality adjustment on data from people with mantle cell lymphoma than with DLBCL. It suggested using data from Eskelund et al. (2016), which reports up to 15\xa0years of follow up (median 11.4\xa0years) of 160 newly diagnosed patients with mantle cell lymphoma after first-line treatment with chemotherapy then autologous stem cell transplant. The ERG said it was possible that excess mortality for people who had treatment with autologous anti-CD19-transduced CD3+ cells was similar to people with mantle cell lymphoma who had a sustained complete response, regardless of whether this was through a stem cell transplant or CAR T‑cell therapy. The ERG derived hazard ratios from the overall-survival curves from Eskelund et al. comparing the age and sex-matched general population with people who have mantle cell lymphoma in complete remission. For at least 1\xa0year the hazard ratio was 4.37 and for at least 5\xa0years it was 2.36. The lower and higher hazard ratios were used as the lower and upper mortality range of the excess mortality adjustment and used for the incremental cost-effectiveness ratio (ICER) range in the ERG's base-case analysis. The company acknowledged the significant uncertainty associated with the excess mortality adjustment, which was also acknowledged in NICE's technology appraisal guidance on axicabtagene ciloleucel. But it noted that the committee for that appraisal accepted the assumption that long-term survivors are at a 9% greater risk of death than the age and sex-matched general population. The company highlighted that the data from Eskelund et al. are based on people who had an autologous stem cell transplant and so do not necessarily reflect what would happen with treatment with autologous anti-CD19-transduced CD3+ cells. The company also considered that the ERG's method for deriving estimates for long-term excess mortality had limitations and was associated with significant uncertainty. The clinical experts agreed that the risk of death is expected to be higher in a heavily pre-treated population with relapsed or refractory mantle cell lymphoma than for people with DLBCL treated first-line. However, the clinical experts explained that an autologous stem cell transplant is not considered a curative treatment in mantle cell lymphoma, and patients are expected to relapse, which might not be the case with treatment with autologous anti-CD19-transduced CD3+ cells if it is proved to be curative. Also, patients in the Eskelund et al. study had not been treated with ibrutinib, which is known to increase survival. They noted that the higher overall mortality compared with the general population reported in Eskelund et al. is in the context of the current consensus that people with relapsed or refractory lymphoma cannot be cured. But the committee accepted that autologous anti‑CD19‑transduced CD3+ cells are a novel treatment that represents a step-change in the treatment pathway for the disease. The committee concluded that there is significant uncertainty in the excess mortality risk for long-term survivors, but considered that people having treatment with autologous anti‑CD19‑transduced CD3+ cells are likely to have higher mortality risks than the general population, even if they are cured, and this may be higher than estimated for DLBCL.\n\n## Patients' age when they start treatment has a significant effect on cost-effectiveness estimates\n\nThe ERG highlighted that the cost-effectiveness analysis is very sensitive to the age of the patient population when treatment starts, and depends on the extent to which the age of patients in the NHS differs from that in the ZUMA‑2 trial. This impact is driven mostly by the general population mortality risk used to inform the mortality risk of long-term survivors in the company's base case (see section 3.7). The ERG also highlighted the considerable difference in age between the ZUMA‑2 population (median age 65) and of people with mantle cell lymphoma at diagnosis in the UK (median age 72.9) and noted that the mean age of the ZUMA‑2 population (63.2) was used in economic analysis. A clinical expert noted that the ZUMA‑2 trial population's mean age of 63 is around 8 to 10\xa0years younger than the NHS population with refractory or relapsed mantle cell lymphoma. The company argued that CAR T‑cell therapies are generally only suitable for fitter patients, and that people offered treatment with autologous anti-CD19-transduced CD3+ cells would undergo the same rigorous selection criteria as currently available CAR T‑cell treatments. NHS England's clinical lead for the Cancer Drugs Fund agreed and noted that patient selection by multidisciplinary teams at CAR T‑cell therapy centres would be rigorous. The ERG agreed with the company, based on evidence from the Cancer Drug Fund, that the median age of people with relapsed or refractory DLBCL treated with CAR T‑cell therapies is 57. But it noted that it was not clear if there would be the same difference in age between real-world and trial data for people with relapsed or refractory mantle cell lymphoma. Illustrative scenario analyses by the ERG showed that even small variations in mean baseline age have a significant impact on the cost-effectiveness estimates. The committee concluded that the age of the patients when treatment starts is a significant area of uncertainty in the cost-effectiveness estimates.\n\n## It is not clear if long-term survivors have the same health-related quality of life as people in the general population of the same age and sex\n\nThe company's model assumed that people who had treatment with autologous anti‑CD19‑transduced CD3+ cells whose disease has not progressed after 5\xa0years of treatment have the same health-related quality of life as the general population. The ERG considered that data from ZUMA‑2 is not enough to support this assumption. It noted that, if long-term survivors are more at risk of mortality than the general population, their health-related quality of life would be lower. The ERG incorporated the company's assumption in its base-case analysis but explored other lower quality-of-life estimates for people who were progression-free for 5\xa0years. It provided illustrative scenario analyses in which the health-related quality of life of long-term survivors was reduced by 10% to 20%. This resulted in higher cost-effectiveness estimates. The clinical experts noted that long-term survivors will have a slightly higher mortality risk and worse health-related quality of life because of the risks associated with CAR T‑cell treatments and the effect of prior therapies. The committee concluded that it was not clear if long-term survivors would have the same health-related quality of life as people in the general population of the same age and sex.\n\n# End of life\n\n## Autologous anti-CD19-transduced CD3+ cells meet both criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that autologous anti‑CD19‑transduced CD3+ cells met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24\xa0months). The company based expected survival without treatment with autologous anti-CD19-transduced CD3+ cells on:\n\nstandard care survival estimated from the matching-adjusted indirect comparison done before technical engagement\n\nreported survival after ibrutinib treatment (mean 3.6\xa0months to 12.5\xa0months)\n\nstandard care survival estimates from economic modelling.All 3 support the assertion that people with relapsed or refractory disease having third-line treatment have a life expectancy of less than 24\xa0months. Extension to life with treatment with autologous anti‑CD19‑transduced CD3+ cells was based on survival estimates from matching-adjusted indirect comparison modelling from the ZUMA‑2 trial data (for which median survival was not reached) and from the company economic model (exact results are confidential and cannot be reported here). The ERG considered that the assumptions also hold for the ERG base case and that the short life-expectancy criterion was met. The committee concluded that treatment with autologous anti-CD19-transduced CD3+ cells meets both criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## The company proposes autologous anti-CD19-transduced CD3+ cells for the Cancer Drugs Fund\n\nThe company submitted a proposal for autologous anti-CD19-transduced CD3+ cells to be considered for the Cancer Drugs Fund rather than routine commissioning, and proposed an accompanying confidential commercial arrangement. The committee considered the ICERs based on this commercial arrangement in its decision-making. The committee understood that it was not considering autologous anti-CD19-transduced CD3+ cells for routine use, and discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum).\n\n## There is a range of possible cost-effectiveness estimates\n\nIn the company's revised base case after technical engagement the deterministic ICER was £46,898 per quality-adjusted life year (QALY) gained for treatment with autologous anti‑CD19‑transduced CD3+ cells compared with standard care. This included a mortality adjustment of 1.09 and the confidential commercial arrangement for autologous anti‑CD19‑transduced CD3+ cells. The ERG's base-case analysis accounted for the lower and upper mortality range of the excess mortality adjustment (2.36 to 4.37) and produced ICERs ranging from £58,223 to £72,920 per QALY gained. Based on the available evidence, the committee concluded that the ICER (with the discount agreed in the commercial arrangement) ranged between £46,898 and £72,920 per QALY gained, but it favoured the lower ERG adjustment of mortality which gave an ICER of £58,223 per QALY gained. The committee recalled the uncertainty around the age of the patient population when treatment starts (see section 3.9) and the health-related quality of life of long-term survivors (see section 3.10) and noted that the ICER range could be wider.\n\n# Cancer Drugs Fund\n\n## Further data collection could address uncertainties in the clinical and cost‑effectiveness evidence\n\nThe committee recalled that it had concluded that autologous anti‑CD19‑transduced CD3+ cells met the criteria to be considered a life-extending treatment at the end of life (see section 3.11) and that the company had proposed autologous anti-CD19-transduced CD3+ cells for use in the Cancer Drugs Fund (see section 3.12). The committee recognised that treatment with autologous anti-CD19-transduced CD3+ cells is innovative and therefore considered if the clinical uncertainty over its use could be addressed by collecting more data. More data from ZUMA‑2 are expected, with additional years of follow up planned. The committee agreed that:\n\nMore data on progression-free, post-progression and overall survival up to 5\xa0years will help clarify if treatment with autologous anti‑CD19‑transduced CD3+ cells improves long-term survival.\n\nUsing autologous anti-CD19-transduced CD3+ cells in the NHS allows data to be collected using the Systemic Anti‑Cancer Therapy (SACT) dataset to get more accurate costs and benefits for its use in clinical practice, as well as the median age of the patients who would be offered treatment with autologous anti-CD19-transduced CD3+ cells.\n\n## Autologous anti-CD19-transduced CD3+ cells meet the criteria to be included in the Cancer Drugs Fund\n\nData from ZUMA‑2 showed that people having treatment with autologous anti-CD19-transduced CD3+ cells have good response rates, overall survival and progression-free survival. The committee noted that the company's revised base-case ICER for autologous anti-CD19-transduced CD3+ cells compared with standard care was below £50,000 per QALY gained. The ERG'S base-case range of ICERs was over £50,000 per QALY gained. The committee acknowledged that the ICERs for autologous anti-CD19-transduced CD3+ cells compared with standard care were not certain, but concluded that the treatment had the plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced. The committee recognised that more data on long-term survival and post-progression survival for treatment with autologous anti‑CD19‑transduced CD3+ cells would allow for a more robust cost-effectiveness estimate. It agreed that the treatment met the criteria to be considered for inclusion in the Cancer Drugs Fund for treating relapsed or refractory mantle cell lymphoma."}
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https://www.nice.org.uk/guidance/ta677
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Evidence-based recommendations on autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory mantle cell lymphoma in adults who have previously had a Bruton’s tyrosine kinase (BTK) inhibitor.
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1d0a5ea30354ee3ddd7546b26171cb6e3e4799a3
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nice
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Dapagliflozin for treating chronic heart failure with reduced ejection fraction
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Dapagliflozin for treating chronic heart failure with reduced ejection fraction
Evidence-based recommendations on dapagliflozin (Forxiga) for symptomatic chronic heart failure with reduced ejection fraction in adults.
# Recommendations
Dapagliflozin is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction in adults, only if it is used as an add-on to optimised standard care with:
angiotensin-converting enzyme (ACE) inhibitors or angiotensin‑2 receptor blockers (ARBs), with beta blockers, and, if tolerated, mineralocorticoid receptor antagonists (MRAs), or
sacubitril valsartan, with beta blockers, and, if tolerated, MRAs.
Start treatment of symptomatic heart failure with reduced ejection fraction with dapagliflozin on the advice of a heart failure specialist. Monitoring should be done by the most appropriate healthcare professional.
These recommendations are not intended to affect treatment with dapagliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with heart failure with reduced ejection fraction may have symptoms that are not controlled well enough despite being on the most appropriate (optimised) treatment. Standard care includes an ACE inhibitor or an ARB, with beta blockers and, if tolerated, an MRA. Alternatively, people may be offered sacubitril valsartan, with beta blockers and, if tolerated, MRAs, if symptoms continue on ACE inhibitors or ARBs.
A clinical trial compared dapagliflozin as an add-on treatment to standard care (based on an ACE inhibitor, ARB or sacubitril valsartan) with standard care alone. Evidence from the trial shows that dapagliflozin lowers the risk of dying from cardiovascular causes, and reduces the likelihood of hospitalisation or an urgent outpatient visit because of heart failure.
There are no trials directly comparing dapagliflozin with sacubitril valsartan. An indirect comparison shows dapagliflozin is likely to be as effective at reducing the risk of death from cardiovascular causes.
The cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So dapagliflozin is recommended as an add-on to optimised standard care for symptomatic chronic heart failure with reduced ejection fraction.
People whose symptoms continue or worsen on optimised doses of standard care based on ACE inhibitors or ARBs can only start sacubitril valsartan under the supervision of a specialist with access to a multidisciplinary team. So dapagliflozin should only be started on advice from a heart failure specialist in primary, secondary or community care.# Information about dapagliflozin
# Marketing authorisation indication
Dapagliflozin (Forxiga, AstraZeneca) has a marketing authorisation 'for the treatment of symptomatic chronic heart failure with reduced ejection fraction'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of dapagliflozin is £36.59 per 28‑tablet pack (excluding VAT; BNF online, accessed November 2020). The annual treatment cost is £476.98. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware of 1 issue that was resolved during the technical engagement stage. It agreed that the probabilistic sensitivity analysis provided at technical engagement should inform the comparison with sacubitril valsartan (issue 5, see technical report page 7).
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 1, pages 3 to 10), and took these into account in its decision making. It discussed issues 1, 2, 3, 4, 6 and 7, which were outstanding after the technical engagement stage.
# The condition
## People with chronic heart failure with reduced ejection fraction would welcome a new treatment option
Heart failure with reduced ejection fraction (HFrEF) is a chronic condition that affects survival and quality of life. The patient experts highlighted the psychological effects of a diagnosis and explained that breathlessness, extreme fatigue and fluid accumulation in particular can be debilitating. Clinical expert submissions to NICE confirmed that HFrEF is associated with high rates of death and hospitalisation and that there is an unmet need for new treatment options. Current treatments aim to manage symptoms and stabilise the disease to prevent further decline in quality of life and to keep people alive longer. The committee heard from clinical experts that despite optimising therapies, many people still have symptoms, including breathlessness. The patient experts said that they would welcome a new option, especially if it could be used early in the treatment pathway. The committee concluded that there is an unmet need for a new treatment option for symptomatic HFrEF and that patients and healthcare professionals would welcome a new treatment option.
# The treatment pathway
## If symptoms worsen or continue on optimised standard care specialist advice is needed
NICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team work collaboratively with the primary care team. It recommends that the specialist multidisciplinary team diagnose heart failure, optimise treatment and manage heart failure not responding to treatment. Recommended drug treatments for newly diagnosed HFrEF include diuretics for congestive symptoms and fluid retention, and an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin‑2 receptor blocker (ARB) when an ACE inhibitor is not tolerated, aiming for maximum tolerated doses. A beta blocker and a mineralocorticoid receptor antagonist (MRA) should also be offered if appropriate and tolerated. The clinical experts said that current clinical practice is to get specialist advice, or refer a patient to specialist care, if symptoms worsen or continue after optimising standard care with ACE inhibitors or ARBs, beta blockers and, if tolerated, MRAs. NICE's guidance says that subsequent treatment with sacubitril valsartan or ivabradine should be started under the supervision of a specialist with access to a multidisciplinary team (see NICE's technology appraisal guidance on sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction and ivabradine for treating chronic heart failure). Treatment with hydralazine plus nitrate or digoxin also requires specialist advice. The clinical experts said that specialist care might include heart failure teams based in the community or GPs with a special interest in heart failure. The committee concluded that current clinical practice involved specialist advice or referral to specialist care if symptoms worsen or continue on optimised standard care based on ACE inhibitors or ARBs.
# Clinical evidence
## The DAPA-HF trial is the key trial for dapagliflozin and is broadly generalisable to NHS clinical practice
DAPA‑HF was a double-blind randomised clinical trial comparing dapagliflozin (a sodium-glucose cotransporter‑2 inhibitor) plus standard care with placebo plus standard care. Standard care was defined by the company as:
ACE inhibitors or ARBs, beta blockers and, if tolerated, MRAs (referred to in this guidance as standard care based on ACE inhibitors or ARBs), or
sacubitril valsartan, plus beta blockers, and, if tolerated, MRAs (referred to in this guidance as standard care based on sacubitril valsartan). People in the trial had HFrEF defined by an ejection fraction of 40% or less who despite being 'optimally treated with pharmacological and/or device therapy' remain symptomatic. Symptomatic HFrEF was defined as New York Heart Association (NYHA) functional class 2 to 4 present for at least 2 months. Eleven per cent of people in the trial had sacubitril valsartan at baseline. Nineteen per cent of patients had digoxin and 5% had ivabradine. Thirty-eight per cent of patients had co-existing atrial fibrillation, 42% had diabetes and 41% had chronic kidney disease. The clinical experts said that the trial findings were generalisable to NHS clinical practice but highlighted several differences between the population in DAPA‑HF and the population in the NHS:
The average age in the full population was 66, which is younger than in the NHS where the average age at diagnosis is 77.
The proportion of men was higher in the trial than in the NHS.
Not all people in the trial were taking NICE guideline-recommended doses of standard care.
More people were taking diuretics in the trial than in the NHS.The ERG said that the characteristics of people in DAPA‑HF, which is a multinational trial, may not reflect that of the population in the NHS. It noted the differences in healthcare systems in different countries. The ERG preferred the European subgroup of the trial, which had an older population (mean age 68) with more severe disease whose background therapies better reflected those in the NHS. However, the European subgroup was over 99% white and was only 45% of the full DAPA‑HF population. The clinical experts explained that the relative clinical effectiveness results were not expected to change as a result of these differences in baseline characteristics. The committee recognised that the absolute risk of complications might differ between the European subgroup and the patients from the rest of the world. It also recognised that larger populations are associated with less uncertainty. The committee concluded that data from the overall DAPA‑HF population were acceptable for decision making, and it was therefore appropriate to use these for the clinical effectiveness analyses.
## The DAPA-HF trial is generalisable to people whose standard care has been optimised
People in the DAPA‑HF trial were clinically stable and optimised on heart failure therapies according to local guidelines. The trial protocol inclusion criteria listed that therapy should have been individually optimised and stable for 4 weeks or more. It also noted that participants should 'be treated with a diuretic regimen aimed at achieving optimal fluid/volume status for that individual'. The clinical experts confirmed that if dapagliflozin were available, clinicians would start dapagliflozin only in people stable on standard heart failure treatments available in the NHS. The company confirmed that this included loop diuretics, which are used together with ACE inhibitors and ARBs based on patient symptoms and clinical presentation. The committee agreed that, in line with the clinical evidence, in the NHS dapagliflozin would be offered to people taking optimised doses of standard care based either on an ACE inhibitor or ARB, or on sacubitril valsartan, and that the DAPA‑HF trial results are generalisable to people whose standard care has been optimised.
## Dapagliflozin plus standard care compared with placebo plus standard care is clinically effective
The primary efficacy outcome in the DAPA‑HF trial was a composite of cardiovascular death, hospitalisation for heart failure or an urgent heart failure visit. Intention-to-treat analyses showed that dapagliflozin plus standard care reduced the incidence of the primary endpoint of composite cardiovascular events by 26% compared with placebo plus standard care (hazard ratio 0.74, 95% confidence interval 0.65 to 0.85; p<0.001). It also reduced the incidence of all the individual components of the composite endpoint. Secondary endpoints included change in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‑TSS) at 8 months and death from any cause. Among people randomised to dapagliflozin, 12% of people died compared with 14% of people randomised to placebo. Cox survival modelling estimated a hazard ratio of 0.83 (95% confidence interval 0.71 to 0.97) in favour of dapagliflozin. The committee concluded that dapagliflozin is clinically effective compared with placebo and reduces the risk of cardiovascular events and all‑cause mortality when added to standard care.
## Risk factors for adverse effects should be identified, and increased monitoring may be needed with dapagliflozin
The frequency and type of most adverse events were broadly similar for people on the dapagliflozin and placebo arms of DAPA‑HF. However, in the DAPA‑HF trial, more people on dapagliflozin had diabetic ketoacidosis and volume depletion, and fewer people had acute kidney injury. The marketing authorisation for dapagliflozin says: 'Before initiating dapagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered.' Dapagliflozin has a separate marketing authorisation as a glucose-lowering agent for type 1 and type 2 diabetes, but the marketing authorisation for HFrEF prohibits prescribing dapagliflozin to people with type 1 diabetes at the dose used for HFrEF. One clinical expert said that additional kidney function monitoring may be needed for dapagliflozin based on its mechanism of action. The marketing authorisation for dapagliflozin also says that for people treated with dapagliflozin for heart failure and type 2 diabetes, a lower dose of insulin or an insulin secretagogue may be needed to reduce the risk of hypoglycaemia. The committee was aware that at times increased monitoring may be needed in people taking dapagliflozin for heart failure, for example, with intercurrent illness to monitor for volume depletion. Non-severe genital infections, a common adverse effect for dapagliflozin in diabetes, were not collected in the DAPA‑HF trial, but all severe adverse events, including severe genital infections, were collected. The company included incidence rates for genital infections in the cost-effectiveness modelling taken from the DECLARE‑TIMI 58 trial, a placebo-controlled cardiovascular outcomes safety trial of dapagliflozin in people with type 2 diabetes. The committee concluded that the safety data from the DAPA‑HF trial with the genital infections data from the DECLARE‑TIMI 58 trial accurately capture the adverse effects of dapagliflozin, but that risk factors for adverse effects should be identified and increased monitoring may be needed.
# Comparators
## ACE inhibitors, ARBs, diuretics, beta blockers and MRAs are not direct comparators alone, but are comparators when used in combination as standard care
The committee heard from a patient expert that they wished dapagliflozin to be used as early as possible in treating heart failure (see section 3.1). But the committee recalled its earlier conclusion, based on the trial evidence presented, that dapagliflozin would be used after standard care is optimised. For this reason, the committee concluded that optimised standard care, rather than the individual components, reflected what patients would otherwise be offered. It agreed that ACE inhibitors, ARBs, diuretics, beta blockers and MRAs were not direct comparators alone but are comparators when used in combination as standard care.
## Ivabradine, digoxin and hydralazine with nitrate are not relevant comparators
NICE's guideline on chronic heart failure in adults: diagnosis and management recommends sacubitril valsartan, ivabradine and hydralazine with nitrate or digoxin as specialist treatments for HFrEF. The final scope for this guidance did not include ivabradine, digoxin and hydralazine with nitrate as relevant comparators for dapagliflozin. The clinical experts explained that these drugs are rarely prescribed in clinical practice for HFrEF. They said that ivabradine is primarily a heart‑rate‑lowering medicine for people with left ventricular systolic disfunction who are in sinus rhythm and have a resting heart rate of over 75 beats per minute. One clinical expert noted that hydralazine with nitrate is used in people with poor kidney function or for whom ACE inhibitors are not suitable. A clinical expert said that digoxin is used in atrial fibrillation and in worsening or severe heart failure with sinus rhythm when reduced kidney function means no other treatments are an option. A clinical expert explained that hydralazine with nitrate and digoxin are generally used in different populations and would not be relevant at this point in the pathway. The company provided pharmacoepidemiologic data from the Clinical Practice Research Datalink which suggests that around 2%, 1% and 11% of people with heart failure have ivabradine, hydralazine with nitrate and digoxin in NHS practice, respectively. However, the committee recognised that these data included people with preserved ejection fraction and that all 3 technologies are licensed for other indications, so the proportion of people taking these medicines in England to treat HFrEF was likely to be lower. The committee concluded that ivabradine, digoxin and hydralazine with nitrate are not relevant comparators for dapagliflozin.
## Sacubitril valsartan is an appropriate comparator
The clinical experts explained that currently they would consider sacubitril valsartan as an option for people whose symptoms continue on optimised standard care based on ACE inhibitors or ARBs. If dapagliflozin were available, the clinical experts noted that specialist teams considering sacubitril valsartan would take into account which treatment was more appropriate based on a person's symptoms and comorbidities. The committee agreed that sacubitril valsartan was an appropriate comparator.
## Optimised standard care based on sacubitril valsartan is also an appropriate comparator
The clinical experts explained that it was likely that for many people symptoms would continue on sacubitril valsartan, so it was reasonable to consider dapagliflozin as an add-on to standard care at this point in the pathway. The committee concluded that, for people who remain symptomatic on sacubitril valsartan, standard care based on sacubitril valsartan is the relevant comparator.
## Optimised standard care based on ACE inhibitors or ARBs is the appropriate comparator for people who cannot take sacubitril valsartan
The committee then considered a population proposed by the company who could not take sacubitril valsartan but could take dapagliflozin. One clinical expert confirmed that they would include people with hypotension or with poor kidney function in the population that cannot have sacubitril valsartan. However, for both sacubitril valsartan and dapagliflozin, there is very limited clinical experience in people with severe kidney impairment (estimated glomerular filtration rate less than 30 ml/min/1.73 m2). The committee noted that people with a left ventricular ejection fraction between 36% and 40% would not be offered sacubitril valsartan, in line with NICE guidance, but could be offered dapagliflozin. The GP committee members said that they would not determine who could and could not take sacubitril valsartan. They said they would refer anyone who continued to have symptoms despite being optimised on standard care based on ACE inhibitors or ARBs to heart failure specialist care. The committee agreed that members of specialist heart failure teams are able to define and identify people who cannot or should not take sacubitril valsartan. It concluded that the appropriate comparator for these people is optimised standard care based on ACE inhibitors or ARBs (see section 3.7).
# Indirect treatment comparison
## The Bucher method is appropriate for an indirect comparison of dapagliflozin with sacubitril valsartan
There were no trials directly comparing dapagliflozin with sacubitril valsartan. To estimate the relative efficacy of dapagliflozin plus standard care based on ACE inhibitors or sacubitril valsartan with beta blockers and, if tolerated, MRAs, the company used a matching-adjusted indirect comparison. This adjusted patient-level data from the subgroup of people in DAPA-HF who received standard care based on ACE inhibitors, to match study-level baseline patient characteristics from PARADIGM‑HF, a randomised controlled trial comparing sacubitril valsartan with enalapril (an ACE inhibitor). The ERG explained that the results of the matching-adjusted indirect comparison were uncertain because the company excluded a large proportion of the DAPA‑HF population when adjusting it to match the baseline characteristics of participants in the PARADIGM‑HF trial. The ERG said that the company had not justified why it had chosen a matching-adjusted indirect comparison. The company also presented an analysis using the alternative Bucher method, which compares treatments without matching baseline characteristics across trials and used the whole subgroup of people in DAPA-HF who had standard care based on ACE inhibitors. The ERG noted that results using both methods were similar, which suggested it was unlikely that the baseline characteristics of participants in the PARADIGM‑HF and DAPA‑HF trial were substantially different and required matching. Because of this, the ERG preferred the Bucher method, which gives more precise estimates, for its analyses. The committee concluded that results from the matching-adjusted indirect comparison were associated with higher uncertainty and that the Bucher method should be used to compare effectiveness of dapagliflozin with sacubitril valsartan.
## Dapagliflozin may be more effective than sacubitril valsartan, but the results are uncertain
The primary endpoint in the indirect comparison was time to first hospitalisation for heart failure or cardiovascular death because these data were available from both the DAPA‑HF and the PARADIGM‑HF trials. The results from the indirect treatment comparison indicated that dapagliflozin was more effective than sacubitril valsartan at delaying cardiovascular events and all‑cause mortality. However, the committee noted that the results were uncertain and included the possibility of no benefit for dapagliflozin compared with sacubitril valsartan (a relative risk of 1.0). The committee was aware that the company originally modelled dapagliflozin as equally effective as sacubitril valsartan in its submission. The committee concluded it would consider both the relative effectiveness results from the Bucher method and the results from assuming equal effectiveness with sacubitril valsartan in its decision making.
# The company's economic model
## The company's model is appropriate for decision making
The company modelled cost effectiveness using a Markov model with 9 states (4 based on symptom severity, split by presence of type 2 diabetes, plus 1 for death). It captured disease severity using the KCCQ‑TSS, which is a disease-specific measure of quality of life. People transitioned through quartiles based on KCCQ‑TSS (0 to 100, with high scores denoting lower symptom burden) and a specific utility and cost was associated with each state. The ERG noted that cut offs for the quartiles chosen by the company to measure KCCQ‑TSS in the model were arbitrary. But it said it expected that using other cut offs or approaches to grouping would minimally affect the cost-effectiveness results. The company also modelled hospitalisation for heart failure, urgent heart failure visits and adverse events based on the incidence in each quartile, and stratified people by whether they had type 2 diabetes at baseline. The model included a treatment effect (relative effectiveness from DAPA‑HF and Bucher indirect treatment comparison) using survival equations. The committee concluded that the company's model structure was appropriate for decision making.
## The KCCQ tool is a reasonable way to measure disease severity
The company's model structure differed from those used in NICE's technology appraisal guidance on sacubitril valsartan and ivabradine. These used a 2‑state dead and alive Markov model and indirectly measured disease severity using the NYHA classification (in survival equations and baseline characteristics). The company said it considered that scores from patient questionnaires, like the KCCQ tool, were more accurate for measuring symptom severity than the NYHA classification, which was based on healthcare professionals' assessments. The clinical experts confirmed that, although NYHA classification is more commonly used in clinical practice, it is more subjective and less sensitive to changes in patient symptoms than the KCCQ tool. The results of a subgroup analysis from DAPA‑HF showed a difference in treatment effect by NYHA classification. The company explained that there was no plausible biological explanation for this finding and results of subgroup analyses in other markers of disease severity (such as prior hospitalisation for heart failure and left ventricular ejection fraction) did not find a difference. In response to technical engagement, the company presented data on health state occupancy over time using the NYHA class for disease severity. This placed most people from the DAPA‑HF control arm in the NYHA class 1 or 2 health state (zero to mild symptoms) over the model time horizon. One clinical expert confirmed that this did not reflect the chronic nature of HFrEF. The company explained that health state occupancy using KCCQ‑TSS better aligned with the expected symptom changes for standard care: initial improvement for 4 to 8 months then stabilisation. The company also said that few people were NYHA class 1 or 4 at baseline so the transition probabilities in these health states would be uncertain. The committee concluded that the KCCQ tool is a reasonable way to classify disease severity and is appropriate for decision making.
# Survival extrapolations for cardiovascular and all-cause mortality
## A Gompertz distribution produces the most plausible survival extrapolations, but the distribution used has limited impact on cost‑effectiveness results
The mortality data from the DAPA‑HF trial were relatively immature because only 12% and 14% of people had died in the dapagliflozin and placebo arms respectively (median follow up was 18 months). The company used a Weibull distribution to extrapolate cardiovascular and all‑cause mortality beyond the end of the trial for the entire duration of the model in its base-case analysis. A clinical expert said that the Weibull curve predicted survival estimates that were aligned with those in NICE's technology appraisal guidance on sacubitril valsartan and their own audit. The ERG confirmed that, based on the observed data, it was plausible to use the Weibull distribution and to assume proportional hazards. However, the Taylor et al. 2019 study of trends in overall heart failure survival in the UK (for reduced and preserved ejection fraction) predicted fewer people would be alive at 1 year, 5 years and 10 years than estimated by the Weibull distribution. The committee noted these data aligned better with the survival estimates predicted using the Gompertz curve, although they may still overestimate survival given the poor prognosis for HFrEF. The company did not validate its survival estimates using epidemiological data. The committee noted that the incremental proportional hazards and treatment effect appeared to be maintained across the different extrapolation methods. Because of this, the choice of distribution to extrapolate survival had little impact on the cost effectiveness of dapagliflozin. The committee concluded that extrapolating survival with a Gompertz distribution is the most plausible for decision making, but that the distribution used has limited impact on cost‑effectiveness results.
# Treatment waning
## Excluding waning of the treatment effect from the model is appropriate
The company modelled the relative survival benefit for dapagliflozin plus standard care as being maintained at the same level for the rest of the person's life. It justified this by noting that the DAPA‑HF trial had no stopping rule for dapagliflozin and NICE's technology appraisal guidance on sacubitril valsartan assumed no waning of effect. Also, the treatment effect for dapagliflozin was stable in DAPA‑HF and the DECLARE‑TIMI 58 trial, the latter of which had a median follow up of 4.2 years. The committee questioned whether it was possible that treatment effect may not be continued over a lifetime, as seen for some diuretic treatments. It noted there was no evidence for or against treatment waning in the long term. Clinical experts and stakeholders confirmed that treatment with dapagliflozin would likely be lifelong. Because the maximum follow-up in the DAPA‑HF trial was 2.3 years, the committee considered the company's scenarios in which the treatment effect of dapagliflozin stopped at 3 years, 5 years and 10 years from starting treatment. However, it noted that cost-effectiveness results were robust to these scenarios. The committee concluded that it is appropriate that the model does not include waning of the treatment effect, and that incorporating this assumption has limited impact on the cost-effectiveness results.
# Utilities
## Utility values from the DAPA-HF trial and the literature should both be considered in decision making
In its initial base case, the company used utilities derived directly from EQ‑5D‑5L questionnaires collected in the DAPA‑HF trial. The company mapped the EQ‑5D‑5L data to EQ‑5D‑3L to estimate mean utility values for all health states, in line with NICE's guide to the methods of technology appraisal. The ERG noted that the company's utility value for KCCQ‑TSS quartile 4 (people with the lowest reported symptom burden) was 0.833. The committee noted that this was higher than the 0.774 utility value for the general population aged 60 to 69 calculated by Sullivan et al. (2011). The clinical experts pointed out that people with heart failure are unlikely to have a better quality of life than the general public for the same age range. For this reason, the ERG preferred a scenario that used the utility value from Sullivan et al. for KCCQ‑TSS quartile 4 and applied the relative differences between quartiles that was observed in the DAPA‑HF study to calculate utilities for quartiles 1 to 3. The committee noted that utility values taken directly from the clinical trial are often preferred but considered the high values from the unadjusted DAPA‑HF utilities to lack face validity. It concluded that it would consider utility values from the DAPA‑HF trial and the literature in its decision making.
# Costs
## Costs used in the company's model are appropriate for decision making
The company's model included costs of treatment with dapagliflozin and sacubitril valsartan at list price, but the committee was aware that the cost of sacubitril valsartan may vary in different settings because of negotiated procurement discounts. The company assumed that treatment costs accrued over a person's lifetime until that person stopped treatment because of adverse events or by choice. The committee was aware that because standard care costs were included in both arms of the DAPA‑HF trial they had limited impact on the overall cost-effectiveness results. Costs were associated with hospitalisation for heart failure, an urgent heart failure visit, death from cardiovascular causes, and having type 2 diabetes at baseline. The company included costs for adverse events including hypoglycaemia, volume depletion, fractures, kidney adverse events and diabetic ketoacidosis as well as genital and urinary tract infections. The committee concluded that the costs used in the company's model were appropriate for decision making.
# Cost-effectiveness estimates
## Dapagliflozin dominates sacubitril valsartan in all scenarios
Dapagliflozin dominated sacubitril valsartan in the company and ERG's base cases (that is, it was less costly and at least equally effective). This was true for all scenarios, including when the company used alternative methods of indirect comparison or if equal clinical effectiveness between dapagliflozin and sacubitril valsartan was assumed. Exact costs for the comparison with sacubitril valsartan are not reported because of varying procurement discounts associated with sacubitril valsartan in different settings. The committee concluded that dapagliflozin added on to optimised standard care based on ACE inhibitors or ARBs is less costly and at least equally effective as optimised sacubitril valsartan with beta blockers and, if tolerated, MRAs.
## Dapagliflozin is cost effective as an add-on to optimised standard care
The committee first considered the population taking dapagliflozin as an add-on to optimised standard care based on ACE inhibitors or ARBs. The company's base-case incremental cost‑effectiveness ratio (ICER; updated at technical engagement) was £6,939 per quality-adjusted life year (QALY) gained. The ICERs for company scenarios ranged from £5,435 to £17,087 per QALY gained. The ERG's preferred assumptions, which used baseline characteristics and the treatment effect from the European subgroup, increased the ICER to around £18,000 per QALY gained. However, the committee recalled that it did not consider the European subgroup the most appropriate for decision making (see section 3.3). The committee agreed that its preferred assumptions to compare dapagliflozin added to optimised standard care (based on ACE inhibitors or ARBs) with optimised standard care (based on ACE inhibitors or ARBs) without dapagliflozin included:
the Gompertz distribution to calculate overall and cardiovascular mortality
the whole DAPA‑HF population for baseline characteristics and treatment effect
no waning of treatment effect
utility values from the DAPA‑HF trial and the literature.Using the above assumptions with utility values from the DAPA-HF trial, the committee's preferred ICER for dapagliflozin was £7,264 per QALY gained as an add-on to optimised standard care based on ACE inhibitors or ARBs. The committee understood that the ICER would be higher if utility values from the literature were used but that this increase would be minimal.The committee then considered the population taking dapagliflozin as an add-on to optimised standard care based on sacubitril valsartan. The cost-effectiveness results are not reported here because of varying procurement discounts associated with sacubitril valsartan in different settings. However, the committee noted that its preferred ICER for this population would be under £10,000 per QALY gained. It concluded that the most plausible ICERs were within what NICE normally considers to be a cost-effective use of NHS resources and that dapagliflozin is cost effective when compared with optimised standard care based on ACE inhibitors or ARBs, or optimised standard care based on sacubitril valsartan.
# Other factors
## Dapagliflozin is innovative and the benefits for people with diabetes and heart failure may not be fully captured in the model
The committee recalled that people with HFrEF have a poor prognosis and that there is an unmet need for treatment options (see section 3.1). The committee noted that it is the first drug of its class to gain regulatory approval for use in heart failure. It also considered that dapagliflozin has a marketing authorisation for the treatment of glycaemic control in people with diabetes, who comprised a large proportion of the DAPA‑HF trial (see section 3.3). The committee recalled that the company had not included additional benefits (for example, prevention of diabetic eye disease) associated with improved glycaemic control for diabetes. The committee concluded that dapagliflozin is innovative and is a step-change in the treatment of HFrEF, and that the benefits for people who also have diabetes may not be fully captured in the model.
## A heart failure specialist should advise on starting dapagliflozin
The committee recalled its earlier conclusion that current clinical practice involved specialist advice or referral to specialist care if symptoms worsen or continue on optimised doses of standard care based on ACE inhibitors or ARBs, to determine the appropriate next treatment. It recalled that regulatory advice for dapagliflozin as a treatment for heart failure is to identify people at high risk of adverse effects before starting treatment (see section 3.6). The company positioned dapagliflozin as an add-on treatment to standard care, highlighting that dapagliflozin could be started before consulting specialist care while people awaited referral. The GPs on the committee said they would not start dapagliflozin without consulting a specialist or heart failure team. The patient expert said that primary care clinicians are familiar with prescribing the drug for type 2 diabetes. However, the committee was aware that the population in the current marketing authorisation for dapagliflozin for heart failure differed from the population for dapagliflozin for diabetes and included people with worse kidney function (with estimated GFR values down to 30 ml/min/1.73 m2). The committee noted that GPs would not be familiar in treating these people with dapagliflozin for diabetes. One clinical expert said that everyone with a new diagnosis of heart failure would see a specialist to start and manage treatment, so people who could have dapagliflozin would already be known to specialist care. The committee concluded that dapagliflozin should be started on advice from a heart failure specialist who can determine the most appropriate treatment.
## Monitoring should be done by the most appropriate healthcare professional
NICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team should work in collaboration with the primary care team to start new medicines that need specialist supervision. NICE's technology appraisal guidance on sacubitril valsartan says that monitoring should be carried out by a heart failure specialist or in primary care by the most appropriate team member. A clinical expert said that people who were taking dapagliflozin for heart failure who also had diabetes might need adjustments in their diabetes medication for safety reasons (see section 3.6). The committee recalled its conclusion that risk factors should be identified and some increased monitoring may be needed for treating heart failure with dapagliflozin. It concluded that monitoring of people who have dapagliflozin for heart failure should be done by the most appropriate healthcare professional from a specialist heart failure multidisciplinary team or primary care team.
## No equalities considerations were identified for dapagliflozin
The committee recalled that dapagliflozin is currently offered to people with diabetes in primary and secondary care. A patient expert explained that, if dapagliflozin were limited to specialist care for heart failure, people with type 2 diabetes would have access to it in primary care, but people who had HFrEF without diabetes would not. The committee considered that the population who had HFrEF were likely to be older and have worse kidney function than people with diabetes alone. The committee recalled standard clinical practice is for a heart failure specialist and a multidisciplinary team to determine the most appropriate second-line treatment to offer. It noted that specialist advice could be given to a primary care healthcare professional, so people would not need to visit a hospital to start dapagliflozin. The committee noted its recommendation applied to all people included in the dapagliflozin for HFrEF marketing authorisation and not only those with comorbid diabetes. It therefore did not consider this an equalities issue.
# Conclusion
## Dapagliflozin is recommended for use in the NHS
The committee agreed that the most plausible ICERs for dapagliflozin compared with all relevant comparators were within what NICE normally considers to be an acceptable use of NHS resources. It therefore concluded that it could recommend dapagliflozin for routine commissioning as an option to treat symptomatic chronic HFrEF as an add-on in people who are already taking optimised standard care based on an ACE inhibitor or ARB, or on sacubitril valsartan.
|
{'Recommendations': 'Dapagliflozin is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction in adults, only if it is used as an add-on to optimised standard care with:\n\nangiotensin-converting enzyme (ACE) inhibitors or angiotensin‑2 receptor blockers (ARBs), with beta blockers, and, if tolerated, mineralocorticoid receptor antagonists (MRAs), or\n\nsacubitril valsartan, with beta blockers, and, if tolerated, MRAs.\n\nStart treatment of symptomatic heart failure with reduced ejection fraction with dapagliflozin on the advice of a heart failure specialist. Monitoring should be done by the most appropriate healthcare professional.\n\nThese recommendations are not intended to affect treatment with dapagliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with heart failure with reduced ejection fraction may have symptoms that are not controlled well enough despite being on the most appropriate (optimised) treatment. Standard care includes an ACE inhibitor or an ARB, with beta blockers and, if tolerated, an MRA. Alternatively, people may be offered sacubitril valsartan, with beta blockers and, if tolerated, MRAs, if symptoms continue on ACE inhibitors or ARBs.\n\nA clinical trial compared dapagliflozin as an add-on treatment to standard care (based on an ACE inhibitor, ARB or sacubitril valsartan) with standard care alone. Evidence from the trial shows that dapagliflozin lowers the risk of dying from cardiovascular causes, and reduces the likelihood of hospitalisation or an urgent outpatient visit because of heart failure.\n\nThere are no trials directly comparing dapagliflozin with sacubitril valsartan. An indirect comparison shows dapagliflozin is likely to be as effective at reducing the risk of death from cardiovascular causes.\n\nThe cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So dapagliflozin is recommended as an add-on to optimised standard care for symptomatic chronic heart failure with reduced ejection fraction.\n\nPeople whose symptoms continue or worsen on optimised doses of standard care based on ACE inhibitors or ARBs can only start sacubitril valsartan under the supervision of a specialist with access to a multidisciplinary team. So dapagliflozin should only be started on advice from a heart failure specialist in primary, secondary or community care.', 'Information about dapagliflozin': "# Marketing authorisation indication\n\nDapagliflozin (Forxiga, AstraZeneca) has a marketing authorisation 'for the treatment of symptomatic chronic heart failure with reduced ejection fraction'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of dapagliflozin is £36.59 per 28‑tablet pack (excluding VAT; BNF online, accessed November 2020). The annual treatment cost is £476.98. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware of 1 issue that was resolved during the technical engagement stage. It agreed that the probabilistic sensitivity analysis provided at technical engagement should inform the comparison with sacubitril valsartan (issue\xa05, see technical report page\xa07).\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa01, pages\xa03 to 10), and took these into account in its decision making. It discussed issues\xa01, 2, 3, 4, 6 and\xa07, which were outstanding after the technical engagement stage.\n\n# The condition\n\n## People with chronic heart failure with reduced ejection fraction would welcome a new treatment option\n\nHeart failure with reduced ejection fraction (HFrEF) is a chronic condition that affects survival and quality of life. The patient experts highlighted the psychological effects of a diagnosis and explained that breathlessness, extreme fatigue and fluid accumulation in particular can be debilitating. Clinical expert submissions to NICE confirmed that HFrEF is associated with high rates of death and hospitalisation and that there is an unmet need for new treatment options. Current treatments aim to manage symptoms and stabilise the disease to prevent further decline in quality of life and to keep people alive longer. The committee heard from clinical experts that despite optimising therapies, many people still have symptoms, including breathlessness. The patient experts said that they would welcome a new option, especially if it could be used early in the treatment pathway. The committee concluded that there is an unmet need for a new treatment option for symptomatic HFrEF and that patients and healthcare professionals would welcome a new treatment option.\n\n# The treatment pathway\n\n## If symptoms worsen or continue on optimised standard care specialist advice is needed\n\nNICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team work collaboratively with the primary care team. It recommends that the specialist multidisciplinary team diagnose heart failure, optimise treatment and manage heart failure not responding to treatment. Recommended drug treatments for newly diagnosed HFrEF include diuretics for congestive symptoms and fluid retention, and an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin‑2 receptor blocker (ARB) when an ACE inhibitor is not tolerated, aiming for maximum tolerated doses. A beta blocker and a mineralocorticoid receptor antagonist (MRA) should also be offered if appropriate and tolerated. The clinical experts said that current clinical practice is to get specialist advice, or refer a patient to specialist care, if symptoms worsen or continue after optimising standard care with ACE inhibitors or ARBs, beta blockers and, if tolerated, MRAs. NICE's guidance says that subsequent treatment with sacubitril valsartan or ivabradine should be started under the supervision of a specialist with access to a multidisciplinary team (see NICE's technology appraisal guidance on sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction and ivabradine for treating chronic heart failure). Treatment with hydralazine plus nitrate or digoxin also requires specialist advice. The clinical experts said that specialist care might include heart failure teams based in the community or GPs with a special interest in heart failure. The committee concluded that current clinical practice involved specialist advice or referral to specialist care if symptoms worsen or continue on optimised standard care based on ACE inhibitors or ARBs.\n\n# Clinical evidence\n\n## The DAPA-HF trial is the key trial for dapagliflozin and is broadly generalisable to NHS clinical practice\n\nDAPA‑HF was a double-blind randomised clinical trial comparing dapagliflozin (a sodium-glucose cotransporter‑2 inhibitor) plus standard care with placebo plus standard care. Standard care was defined by the company as:\n\nACE inhibitors or ARBs, beta blockers and, if tolerated, MRAs (referred to in this guidance as standard care based on ACE inhibitors or ARBs), or\n\nsacubitril valsartan, plus beta blockers, and, if tolerated, MRAs (referred to in this guidance as standard care based on sacubitril valsartan). People in the trial had HFrEF defined by an ejection fraction of 40% or less who despite being 'optimally treated with pharmacological and/or device therapy' remain symptomatic. Symptomatic HFrEF was defined as New York Heart Association (NYHA) functional class\xa02 to 4 present for at least 2\xa0months. Eleven per cent of people in the trial had sacubitril valsartan at baseline. Nineteen per cent of patients had digoxin and 5% had ivabradine. Thirty-eight per cent of patients had co-existing atrial fibrillation, 42% had diabetes and 41% had chronic kidney disease. The clinical experts said that the trial findings were generalisable to NHS clinical practice but highlighted several differences between the population in DAPA‑HF and the population in the NHS:\n\nThe average age in the full population was\xa066, which is younger than in the NHS where the average age at diagnosis is\xa077.\n\nThe proportion of men was higher in the trial than in the NHS.\n\nNot all people in the trial were taking NICE guideline-recommended doses of standard care.\n\nMore people were taking diuretics in the trial than in the NHS.The ERG said that the characteristics of people in DAPA‑HF, which is a multinational trial, may not reflect that of the population in the NHS. It noted the differences in healthcare systems in different countries. The ERG preferred the European subgroup of the trial, which had an older population (mean age\xa068) with more severe disease whose background therapies better reflected those in the NHS. However, the European subgroup was over 99% white and was only 45% of the full DAPA‑HF population. The clinical experts explained that the relative clinical effectiveness results were not expected to change as a result of these differences in baseline characteristics. The committee recognised that the absolute risk of complications might differ between the European subgroup and the patients from the rest of the world. It also recognised that larger populations are associated with less uncertainty. The committee concluded that data from the overall DAPA‑HF population were acceptable for decision making, and it was therefore appropriate to use these for the clinical effectiveness analyses.\n\n## The DAPA-HF trial is generalisable to people whose standard care has been optimised\n\nPeople in the DAPA‑HF trial were clinically stable and optimised on heart failure therapies according to local guidelines. The trial protocol inclusion criteria listed that therapy should have been individually optimised and stable for 4\xa0weeks or more. It also noted that participants should 'be treated with a diuretic regimen aimed at achieving optimal fluid/volume status for that individual'. The clinical experts confirmed that if dapagliflozin were available, clinicians would start dapagliflozin only in people stable on standard heart failure treatments available in the NHS. The company confirmed that this included loop diuretics, which are used together with ACE inhibitors and ARBs based on patient symptoms and clinical presentation. The committee agreed that, in line with the clinical evidence, in the NHS dapagliflozin would be offered to people taking optimised doses of standard care based either on an ACE inhibitor or ARB, or on sacubitril valsartan, and that the DAPA‑HF trial results are generalisable to people whose standard care has been optimised.\n\n## Dapagliflozin plus standard care compared with placebo plus standard care is clinically effective\n\nThe primary efficacy outcome in the DAPA‑HF trial was a composite of cardiovascular death, hospitalisation for heart failure or an urgent heart failure visit. Intention-to-treat analyses showed that dapagliflozin plus standard care reduced the incidence of the primary endpoint of composite cardiovascular events by 26% compared with placebo plus standard care (hazard ratio\xa00.74, 95% confidence interval\xa00.65 to 0.85; p<0.001). It also reduced the incidence of all the individual components of the composite endpoint. Secondary endpoints included change in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‑TSS) at 8\xa0months and death from any cause. Among people randomised to dapagliflozin, 12% of people died compared with 14% of people randomised to placebo. Cox survival modelling estimated a hazard ratio of\xa00.83 (95% confidence interval\xa00.71 to 0.97) in favour of dapagliflozin. The committee concluded that dapagliflozin is clinically effective compared with placebo and reduces the risk of cardiovascular events and all‑cause mortality when added to standard care.\n\n## Risk factors for adverse effects should be identified, and increased monitoring may be needed with dapagliflozin\n\nThe frequency and type of most adverse events were broadly similar for people on the dapagliflozin and placebo arms of DAPA‑HF. However, in the DAPA‑HF trial, more people on dapagliflozin had diabetic ketoacidosis and volume depletion, and fewer people had acute kidney injury. The marketing authorisation for dapagliflozin says: 'Before initiating dapagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered.' Dapagliflozin has a separate marketing authorisation as a glucose-lowering agent for type\xa01 and type\xa02 diabetes, but the marketing authorisation for HFrEF prohibits prescribing dapagliflozin to people with type\xa01 diabetes at the dose used for HFrEF. One clinical expert said that additional kidney function monitoring may be needed for dapagliflozin based on its mechanism of action. The marketing authorisation for dapagliflozin also says that for people treated with dapagliflozin for heart failure and type\xa02 diabetes, a lower dose of insulin or an insulin secretagogue may be needed to reduce the risk of hypoglycaemia. The committee was aware that at times increased monitoring may be needed in people taking dapagliflozin for heart failure, for example, with intercurrent illness to monitor for volume depletion. Non-severe genital infections, a common adverse effect for dapagliflozin in diabetes, were not collected in the DAPA‑HF trial, but all severe adverse events, including severe genital infections, were collected. The company included incidence rates for genital infections in the cost-effectiveness modelling taken from the DECLARE‑TIMI\xa058 trial, a placebo-controlled cardiovascular outcomes safety trial of dapagliflozin in people with type\xa02 diabetes. The committee concluded that the safety data from the DAPA‑HF trial with the genital infections data from the DECLARE‑TIMI\xa058 trial accurately capture the adverse effects of dapagliflozin, but that risk factors for adverse effects should be identified and increased monitoring may be needed.\n\n# Comparators\n\n## ACE inhibitors, ARBs, diuretics, beta blockers and MRAs are not direct comparators alone, but are comparators when used in combination as standard care\n\nThe committee heard from a patient expert that they wished dapagliflozin to be used as early as possible in treating heart failure (see section\xa03.1). But the committee recalled its earlier conclusion, based on the trial evidence presented, that dapagliflozin would be used after standard care is optimised. For this reason, the committee concluded that optimised standard care, rather than the individual components, reflected what patients would otherwise be offered. It agreed that ACE inhibitors, ARBs, diuretics, beta blockers and MRAs were not direct comparators alone but are comparators when used in combination as standard care.\n\n## Ivabradine, digoxin and hydralazine with nitrate are not relevant comparators\n\nNICE's guideline on chronic heart failure in adults: diagnosis and management recommends sacubitril valsartan, ivabradine and hydralazine with nitrate or digoxin as specialist treatments for HFrEF. The final scope for this guidance did not include ivabradine, digoxin and hydralazine with nitrate as relevant comparators for dapagliflozin. The clinical experts explained that these drugs are rarely prescribed in clinical practice for HFrEF. They said that ivabradine is primarily a heart‑rate‑lowering medicine for people with left ventricular systolic disfunction who are in sinus rhythm and have a resting heart rate of over 75\xa0beats per minute. One clinical expert noted that hydralazine with nitrate is used in people with poor kidney function or for whom ACE inhibitors are not suitable. A clinical expert said that digoxin is used in atrial fibrillation and in worsening or severe heart failure with sinus rhythm when reduced kidney function means no other treatments are an option. A clinical expert explained that hydralazine with nitrate and digoxin are generally used in different populations and would not be relevant at this point in the pathway. The company provided pharmacoepidemiologic data from the Clinical Practice Research Datalink which suggests that around 2%, 1% and 11% of people with heart failure have ivabradine, hydralazine with nitrate and digoxin in NHS practice, respectively. However, the committee recognised that these data included people with preserved ejection fraction and that all 3\xa0technologies are licensed for other indications, so the proportion of people taking these medicines in England to treat HFrEF was likely to be lower. The committee concluded that ivabradine, digoxin and hydralazine with nitrate are not relevant comparators for dapagliflozin.\n\n## Sacubitril valsartan is an appropriate comparator\n\nThe clinical experts explained that currently they would consider sacubitril valsartan as an option for people whose symptoms continue on optimised standard care based on ACE inhibitors or ARBs. If dapagliflozin were available, the clinical experts noted that specialist teams considering sacubitril valsartan would take into account which treatment was more appropriate based on a person's symptoms and comorbidities. The committee agreed that sacubitril valsartan was an appropriate comparator.\n\n## Optimised standard care based on sacubitril valsartan is also an appropriate comparator\n\nThe clinical experts explained that it was likely that for many people symptoms would continue on sacubitril valsartan, so it was reasonable to consider dapagliflozin as an add-on to standard care at this point in the pathway. The committee concluded that, for people who remain symptomatic on sacubitril valsartan, standard care based on sacubitril valsartan is the relevant comparator.\n\n## Optimised standard care based on ACE inhibitors or ARBs is the appropriate comparator for people who cannot take sacubitril valsartan\n\nThe committee then considered a population proposed by the company who could not take sacubitril valsartan but could take dapagliflozin. One clinical expert confirmed that they would include people with hypotension or with poor kidney function in the population that cannot have sacubitril valsartan. However, for both sacubitril valsartan and dapagliflozin, there is very limited clinical experience in people with severe kidney impairment (estimated glomerular filtration rate [GFR] less than 30\xa0ml/min/1.73\xa0m2). The committee noted that people with a left ventricular ejection fraction between 36% and 40% would not be offered sacubitril valsartan, in line with NICE guidance, but could be offered dapagliflozin. The GP committee members said that they would not determine who could and could not take sacubitril valsartan. They said they would refer anyone who continued to have symptoms despite being optimised on standard care based on ACE inhibitors or ARBs to heart failure specialist care. The committee agreed that members of specialist heart failure teams are able to define and identify people who cannot or should not take sacubitril valsartan. It concluded that the appropriate comparator for these people is optimised standard care based on ACE inhibitors or ARBs (see section\xa03.7).\n\n# Indirect treatment comparison\n\n## The Bucher method is appropriate for an indirect comparison of dapagliflozin with sacubitril valsartan\n\nThere were no trials directly comparing dapagliflozin with sacubitril valsartan. To estimate the relative efficacy of dapagliflozin plus standard care based on ACE inhibitors or sacubitril valsartan with beta blockers and, if tolerated, MRAs, the company used a matching-adjusted indirect comparison. This adjusted patient-level data from the subgroup of people in DAPA-HF who received standard care based on ACE inhibitors, to match study-level baseline patient characteristics from PARADIGM‑HF, a randomised controlled trial comparing sacubitril valsartan with enalapril (an ACE inhibitor). The ERG explained that the results of the matching-adjusted indirect comparison were uncertain because the company excluded a large proportion of the DAPA‑HF population when adjusting it to match the baseline characteristics of participants in the PARADIGM‑HF trial. The ERG said that the company had not justified why it had chosen a matching-adjusted indirect comparison. The company also presented an analysis using the alternative Bucher method, which compares treatments without matching baseline characteristics across trials and used the whole subgroup of people in DAPA-HF who had standard care based on ACE inhibitors. The ERG noted that results using both methods were similar, which suggested it was unlikely that the baseline characteristics of participants in the PARADIGM‑HF and DAPA‑HF trial were substantially different and required matching. Because of this, the ERG preferred the Bucher method, which gives more precise estimates, for its analyses. The committee concluded that results from the matching-adjusted indirect comparison were associated with higher uncertainty and that the Bucher method should be used to compare effectiveness of dapagliflozin with sacubitril valsartan.\n\n## Dapagliflozin may be more effective than sacubitril valsartan, but the results are uncertain\n\nThe primary endpoint in the indirect comparison was time to first hospitalisation for heart failure or cardiovascular death because these data were available from both the DAPA‑HF and the PARADIGM‑HF trials. The results from the indirect treatment comparison indicated that dapagliflozin was more effective than sacubitril valsartan at delaying cardiovascular events and all‑cause mortality. However, the committee noted that the results were uncertain and included the possibility of no benefit for dapagliflozin compared with sacubitril valsartan (a relative risk of\xa01.0). The committee was aware that the company originally modelled dapagliflozin as equally effective as sacubitril valsartan in its submission. The committee concluded it would consider both the relative effectiveness results from the Bucher method and the results from assuming equal effectiveness with sacubitril valsartan in its decision making.\n\n# The company's economic model\n\n## The company's model is appropriate for decision making\n\nThe company modelled cost effectiveness using a Markov model with 9\xa0states (4\xa0based on symptom severity, split by presence of type\xa02 diabetes, plus\xa01 for death). It captured disease severity using the KCCQ‑TSS, which is a disease-specific measure of quality of life. People transitioned through quartiles based on KCCQ‑TSS (0\xa0to 100, with high scores denoting lower symptom burden) and a specific utility and cost was associated with each state. The ERG noted that cut offs for the quartiles chosen by the company to measure KCCQ‑TSS in the model were arbitrary. But it said it expected that using other cut offs or approaches to grouping would minimally affect the cost-effectiveness results. The company also modelled hospitalisation for heart failure, urgent heart failure visits and adverse events based on the incidence in each quartile, and stratified people by whether they had type\xa02 diabetes at baseline. The model included a treatment effect (relative effectiveness from DAPA‑HF and Bucher indirect treatment comparison) using survival equations. The committee concluded that the company's model structure was appropriate for decision making.\n\n## The KCCQ tool is a reasonable way to measure disease severity\n\nThe company's model structure differed from those used in NICE's technology appraisal guidance on sacubitril valsartan and ivabradine. These used a 2‑state dead and alive Markov model and indirectly measured disease severity using the NYHA classification (in survival equations and baseline characteristics). The company said it considered that scores from patient questionnaires, like the KCCQ tool, were more accurate for measuring symptom severity than the NYHA classification, which was based on healthcare professionals' assessments. The clinical experts confirmed that, although NYHA classification is more commonly used in clinical practice, it is more subjective and less sensitive to changes in patient symptoms than the KCCQ tool. The results of a subgroup analysis from DAPA‑HF showed a difference in treatment effect by NYHA classification. The company explained that there was no plausible biological explanation for this finding and results of subgroup analyses in other markers of disease severity (such as prior hospitalisation for heart failure and left ventricular ejection fraction) did not find a difference. In response to technical engagement, the company presented data on health state occupancy over time using the NYHA class for disease severity. This placed most people from the DAPA‑HF control arm in the NYHA class\xa01 or 2 health state (zero to mild symptoms) over the model time horizon. One clinical expert confirmed that this did not reflect the chronic nature of HFrEF. The company explained that health state occupancy using KCCQ‑TSS better aligned with the expected symptom changes for standard care: initial improvement for 4 to 8\xa0months then stabilisation. The company also said that few people were NYHA class\xa01 or 4 at baseline so the transition probabilities in these health states would be uncertain. The committee concluded that the KCCQ tool is a reasonable way to classify disease severity and is appropriate for decision making.\n\n# Survival extrapolations for cardiovascular and all-cause mortality\n\n## A Gompertz distribution produces the most plausible survival extrapolations, but the distribution used has limited impact on cost‑effectiveness results\n\nThe mortality data from the DAPA‑HF trial were relatively immature because only 12% and 14% of people had died in the dapagliflozin and placebo arms respectively (median follow up was 18\xa0months). The company used a Weibull distribution to extrapolate cardiovascular and all‑cause mortality beyond the end of the trial for the entire duration of the model in its base-case analysis. A clinical expert said that the Weibull curve predicted survival estimates that were aligned with those in NICE's technology appraisal guidance on sacubitril valsartan and their own audit. The ERG confirmed that, based on the observed data, it was plausible to use the Weibull distribution and to assume proportional hazards. However, the Taylor et al. 2019 study of trends in overall heart failure survival in the UK (for reduced and preserved ejection fraction) predicted fewer people would be alive at 1\xa0year, 5\xa0years and 10\xa0years than estimated by the Weibull distribution. The committee noted these data aligned better with the survival estimates predicted using the Gompertz curve, although they may still overestimate survival given the poor prognosis for HFrEF. The company did not validate its survival estimates using epidemiological data. The committee noted that the incremental proportional hazards and treatment effect appeared to be maintained across the different extrapolation methods. Because of this, the choice of distribution to extrapolate survival had little impact on the cost effectiveness of dapagliflozin. The committee concluded that extrapolating survival with a Gompertz distribution is the most plausible for decision making, but that the distribution used has limited impact on cost‑effectiveness results.\n\n# Treatment waning\n\n## Excluding waning of the treatment effect from the model is appropriate\n\nThe company modelled the relative survival benefit for dapagliflozin plus standard care as being maintained at the same level for the rest of the person's life. It justified this by noting that the DAPA‑HF trial had no stopping rule for dapagliflozin and NICE's technology appraisal guidance on sacubitril valsartan assumed no waning of effect. Also, the treatment effect for dapagliflozin was stable in DAPA‑HF and the DECLARE‑TIMI\xa058 trial, the latter of which had a median follow up of 4.2\xa0years. The committee questioned whether it was possible that treatment effect may not be continued over a lifetime, as seen for some diuretic treatments. It noted there was no evidence for or against treatment waning in the long term. Clinical experts and stakeholders confirmed that treatment with dapagliflozin would likely be lifelong. Because the maximum follow-up in the DAPA‑HF trial was 2.3\xa0years, the committee considered the company's scenarios in which the treatment effect of dapagliflozin stopped at 3\xa0years, 5\xa0years and 10\xa0years from starting treatment. However, it noted that cost-effectiveness results were robust to these scenarios. The committee concluded that it is appropriate that the model does not include waning of the treatment effect, and that incorporating this assumption has limited impact on the cost-effectiveness results.\n\n# Utilities\n\n## Utility values from the DAPA-HF trial and the literature should both be considered in decision making\n\nIn its initial base case, the company used utilities derived directly from EQ‑5D‑5L questionnaires collected in the DAPA‑HF trial. The company mapped the EQ‑5D‑5L data to EQ‑5D‑3L to estimate mean utility values for all health states, in line with NICE's guide to the methods of technology appraisal. The ERG noted that the company's utility value for KCCQ‑TSS quartile\xa04 (people with the lowest reported symptom burden) was 0.833. The committee noted that this was higher than the 0.774 utility value for the general population aged\xa060 to 69 calculated by Sullivan et al. (2011). The clinical experts pointed out that people with heart failure are unlikely to have a better quality of life than the general public for the same age range. For this reason, the ERG preferred a scenario that used the utility value from Sullivan et al. for KCCQ‑TSS quartile\xa04 and applied the relative differences between quartiles that was observed in the DAPA‑HF study to calculate utilities for quartiles\xa01 to 3. The committee noted that utility values taken directly from the clinical trial are often preferred but considered the high values from the unadjusted DAPA‑HF utilities to lack face validity. It concluded that it would consider utility values from the DAPA‑HF trial and the literature in its decision making.\n\n# Costs\n\n## Costs used in the company's model are appropriate for decision making\n\nThe company's model included costs of treatment with dapagliflozin and sacubitril valsartan at list price, but the committee was aware that the cost of sacubitril valsartan may vary in different settings because of negotiated procurement discounts. The company assumed that treatment costs accrued over a person's lifetime until that person stopped treatment because of adverse events or by choice. The committee was aware that because standard care costs were included in both arms of the DAPA‑HF trial they had limited impact on the overall cost-effectiveness results. Costs were associated with hospitalisation for heart failure, an urgent heart failure visit, death from cardiovascular causes, and having type\xa02 diabetes at baseline. The company included costs for adverse events including hypoglycaemia, volume depletion, fractures, kidney adverse events and diabetic ketoacidosis as well as genital and urinary tract infections. The committee concluded that the costs used in the company's model were appropriate for decision making.\n\n# Cost-effectiveness estimates\n\n## Dapagliflozin dominates sacubitril valsartan in all scenarios\n\nDapagliflozin dominated sacubitril valsartan in the company and ERG's base cases (that is, it was less costly and at least equally effective). This was true for all scenarios, including when the company used alternative methods of indirect comparison or if equal clinical effectiveness between dapagliflozin and sacubitril valsartan was assumed. Exact costs for the comparison with sacubitril valsartan are not reported because of varying procurement discounts associated with sacubitril valsartan in different settings. The committee concluded that dapagliflozin added on to optimised standard care based on ACE inhibitors or ARBs is less costly and at least equally effective as optimised sacubitril valsartan with beta blockers and, if tolerated, MRAs.\n\n## Dapagliflozin is cost effective as an add-on to optimised standard care\n\nThe committee first considered the population taking dapagliflozin as an add-on to optimised standard care based on ACE inhibitors or ARBs. The company's base-case incremental cost‑effectiveness ratio (ICER; updated at technical engagement) was £6,939 per quality-adjusted life year (QALY) gained. The ICERs for company scenarios ranged from £5,435 to £17,087 per QALY gained. The ERG's preferred assumptions, which used baseline characteristics and the treatment effect from the European subgroup, increased the ICER to around £18,000 per QALY gained. However, the committee recalled that it did not consider the European subgroup the most appropriate for decision making (see section\xa03.3). The committee agreed that its preferred assumptions to compare dapagliflozin added to optimised standard care (based on ACE inhibitors or ARBs) with optimised standard care (based on ACE inhibitors or ARBs) without dapagliflozin included:\n\nthe Gompertz distribution to calculate overall and cardiovascular mortality\n\nthe whole DAPA‑HF population for baseline characteristics and treatment effect\n\nno waning of treatment effect\n\nutility values from the DAPA‑HF trial and the literature.Using the above assumptions with utility values from the DAPA-HF trial, the committee's preferred ICER for dapagliflozin was £7,264 per QALY gained as an add-on to optimised standard care based on ACE inhibitors or ARBs. The committee understood that the ICER would be higher if utility values from the literature were used but that this increase would be minimal.The committee then considered the population taking dapagliflozin as an add-on to optimised standard care based on sacubitril valsartan. The cost-effectiveness results are not reported here because of varying procurement discounts associated with sacubitril valsartan in different settings. However, the committee noted that its preferred ICER for this population would be under £10,000 per QALY gained. It concluded that the most plausible ICERs were within what NICE normally considers to be a cost-effective use of NHS resources and that dapagliflozin is cost effective when compared with optimised standard care based on ACE inhibitors or ARBs, or optimised standard care based on sacubitril valsartan.\n\n# Other factors\n\n## Dapagliflozin is innovative and the benefits for people with diabetes and heart failure may not be fully captured in the model\n\nThe committee recalled that people with HFrEF have a poor prognosis and that there is an unmet need for treatment options (see section\xa03.1). The committee noted that it is the first drug of its class to gain regulatory approval for use in heart failure. It also considered that dapagliflozin has a marketing authorisation for the treatment of glycaemic control in people with diabetes, who comprised a large proportion of the DAPA‑HF trial (see section\xa03.3). The committee recalled that the company had not included additional benefits (for example, prevention of diabetic eye disease) associated with improved glycaemic control for diabetes. The committee concluded that dapagliflozin is innovative and is a step-change in the treatment of HFrEF, and that the benefits for people who also have diabetes may not be fully captured in the model.\n\n## A heart failure specialist should advise on starting dapagliflozin\n\nThe committee recalled its earlier conclusion that current clinical practice involved specialist advice or referral to specialist care if symptoms worsen or continue on optimised doses of standard care based on ACE inhibitors or ARBs, to determine the appropriate next treatment. It recalled that regulatory advice for dapagliflozin as a treatment for heart failure is to identify people at high risk of adverse effects before starting treatment (see section\xa03.6). The company positioned dapagliflozin as an add-on treatment to standard care, highlighting that dapagliflozin could be started before consulting specialist care while people awaited referral. The GPs on the committee said they would not start dapagliflozin without consulting a specialist or heart failure team. The patient expert said that primary care clinicians are familiar with prescribing the drug for type\xa02 diabetes. However, the committee was aware that the population in the current marketing authorisation for dapagliflozin for heart failure differed from the population for dapagliflozin for diabetes and included people with worse kidney function (with estimated GFR values down to 30\xa0ml/min/1.73\xa0m2). The committee noted that GPs would not be familiar in treating these people with dapagliflozin for diabetes. One clinical expert said that everyone with a new diagnosis of heart failure would see a specialist to start and manage treatment, so people who could have dapagliflozin would already be known to specialist care. The committee concluded that dapagliflozin should be started on advice from a heart failure specialist who can determine the most appropriate treatment.\n\n## Monitoring should be done by the most appropriate healthcare professional\n\nNICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team should work in collaboration with the primary care team to start new medicines that need specialist supervision. NICE's technology appraisal guidance on sacubitril valsartan says that monitoring should be carried out by a heart failure specialist or in primary care by the most appropriate team member. A clinical expert said that people who were taking dapagliflozin for heart failure who also had diabetes might need adjustments in their diabetes medication for safety reasons (see section\xa03.6). The committee recalled its conclusion that risk factors should be identified and some increased monitoring may be needed for treating heart failure with dapagliflozin. It concluded that monitoring of people who have dapagliflozin for heart failure should be done by the most appropriate healthcare professional from a specialist heart failure multidisciplinary team or primary care team.\n\n## No equalities considerations were identified for dapagliflozin\n\nThe committee recalled that dapagliflozin is currently offered to people with diabetes in primary and secondary care. A patient expert explained that, if dapagliflozin were limited to specialist care for heart failure, people with type\xa02 diabetes would have access to it in primary care, but people who had HFrEF without diabetes would not. The committee considered that the population who had HFrEF were likely to be older and have worse kidney function than people with diabetes alone. The committee recalled standard clinical practice is for a heart failure specialist and a multidisciplinary team to determine the most appropriate second-line treatment to offer. It noted that specialist advice could be given to a primary care healthcare professional, so people would not need to visit a hospital to start dapagliflozin. The committee noted its recommendation applied to all people included in the dapagliflozin for HFrEF marketing authorisation and not only those with comorbid diabetes. It therefore did not consider this an equalities issue.\n\n# Conclusion\n\n## Dapagliflozin is recommended for use in the NHS\n\nThe committee agreed that the most plausible ICERs for dapagliflozin compared with all relevant comparators were within what NICE normally considers to be an acceptable use of NHS resources. It therefore concluded that it could recommend dapagliflozin for routine commissioning as an option to treat symptomatic chronic HFrEF as an add-on in people who are already taking optimised standard care based on an ACE inhibitor or ARB, or on sacubitril valsartan."}
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https://www.nice.org.uk/guidance/ta679
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Evidence-based recommendations on dapagliflozin (Forxiga) for symptomatic chronic heart failure with reduced ejection fraction in adults.
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c252d4e927610e95d934736d16f5e23e8d1c46f9
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Niraparib for maintenance treatment of advanced ovarian, fallopian tube and peritoneal cancer after response to first-line platinum-based chemotherapy
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Niraparib for maintenance treatment of advanced ovarian, fallopian tube and peritoneal cancer after response to first-line platinum-based chemotherapy
Evidence-based recommendations on niraparib (Zejula) for maintenance treatment of advanced (FIGO stages 3 and 4) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer after response to first-line platinum-based chemotherapy in adults.
# Recommendations
Niraparib is recommended for use within the Cancer Drugs Fund as an option for maintenance treatment for advanced (FIGO stages 3 and 4) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer after response to first-line platinum-based chemotherapy in adults. It is recommended only if the conditions in the managed access agreement for niraparib are followed.
This recommendation is not intended to affect treatment with niraparib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There are no maintenance treatments routinely available for advanced ovarian, fallopian tube or peritoneal cancer that has responded to first-line platinum-based chemotherapy. For some people, maintenance treatment is available through the Cancer Drugs Fund.
Clinical evidence comes from PRIMA, an ongoing clinical trial, which shows that niraparib delays disease progression. But it has not shown whether people having niraparib live longer, because they have not been followed up for long enough.
Because of the clinical uncertainty, the cost-effectiveness estimates are very uncertain. They may be higher than what NICE normally considers an acceptable use of NHS resources. So, niraparib cannot be recommended for routine use in the NHS.
Longer follow-up data from PRIMA could help address the uncertainty about the clinical effectiveness of niraparib in this population. Niraparib has the potential to be a cost-effective use of NHS resources. So, it is recommended for use in the Cancer Drugs Fund while more data from the trial are collected.# Information about niraparib
# Marketing authorisation indication
Niraparib (Zejula, GlaxoSmithKline) has a marketing authorisation in the UK 'as monotherapy for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages 3 and 4) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £4,500 for 56 100‑mg tablets (excluding VAT; BNF online accessed November 2020). The company has a commercial arrangement. This makes niraparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
the first-line treatment response rates from the PRIMA trial were generalisable to rates seen in UK practice (issue 1, see technical report page 2)
the dose of niraparib included in the model for continued treatment after 3 years is appropriate (issue 1, see technical report page 2)
not including the long-term remission assumption in the model is appropriate (issue 7, see technical report page 11).
At technical engagement, the company accepted the ERG's revised costs for heart rate and blood pressure monitoring and the alternative resource-use estimates for progression-free survival in the routine surveillance arm.
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues (issues 1 to 6 and 8 to 12), which were outstanding after the technical engagement stage.
# The condition
## People with ovarian cancer would welcome a new effective maintenance therapy
The patient expert explained that advanced platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer is a devastating condition. Knowing that the disease can relapse is a major psychological burden for people with the disease and their families. For most people without a BRCA1 or BRCA2 gene mutation there are no first-line maintenance treatments available for disease that has responded to platinum-based chemotherapy, although bevacizumab is available for some people through the Cancer Drugs Fund. People who are not eligible for first-line maintenance treatment have routine surveillance until the disease relapses. The patient expert explained that taking a maintenance treatment has a psychological benefit and improves quality of life compared with being on routine surveillance, which can feel like waiting for the cancer to come back. The clinical experts agreed with the patient expert. The committee recognised the need for effective maintenance treatment options after first-line treatment for advanced disease. It concluded that people would welcome new maintenance treatment options.
# Treatment pathway
## There is an unmet need for maintenance treatments after first-line platinum-based chemotherapy
First-line treatment for advanced ovarian, fallopian tube, or primary peritoneal cancer is surgery and platinum-based chemotherapy. Options for surgery are primary debulking surgery before first-line chemotherapy treatment, or interval debulking surgery between cycles of first-line chemotherapy. First-line maintenance treatment with a poly-ADP-ribose polymerase (PARP) inhibitor is available through the Cancer Drugs Fund for people with a BRCA1 or BRCA2 gene mutation. For people without a BRCA1 or BRCA2 gene mutation, there are no first-line PARP inhibitor maintenance treatments. Routine surveillance is the only option for people who are not eligible for maintenance treatment. The clinical experts explained that there is a high unmet need for more maintenance treatment options after first-line treatment for advanced disease. They noted that there is a clear population that would benefit from niraparib maintenance therapy at this point in the treatment pathway. The committee concluded that there is an unmet need for new effective maintenance treatment options after first-line platinum-based chemotherapy.
# Clinical evidence
## The population covered by niraparib's marketing authorisation indication is broader than the population included in PRIMA
PRIMA is a double-blind, randomised controlled trial comparing niraparib with placebo as maintenance treatment of advanced ovarian cancer. It included people with or without a BRCA gene mutation, who had advanced (International Federation of Gynecology and Obstetrics stages 3 and 4) high-grade ovarian, fallopian tube or primary peritoneal cancer that was in response (complete or partial) to first-line platinum-based chemotherapy. The primary end point was progression-free survival based on blinded independent central review. PRIMA excluded people with stage 3 cancer who had no visible residual disease after primary debulking surgery. The rationale for excluding this group was that their prognosis was considered to be better than other groups with advanced ovarian cancer. However, niraparib's marketing authorisation includes all people with stage 3 or 4 high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response to first-line platinum-based chemotherapy. The committee concluded that the population covered by the marketing authorisation indication is broader than the population included in PRIMA.
## Prognosis of stage 3 cancer is likely to be better when there is no visible residual disease after primary debulking surgery, compared with after interval debulking surgery
The ERG commented on the prognosis of stage 3 cancer after surgery. It suggested that the prognosis for no visible residual disease might be similar when achieved by primary debulking surgery and interval debulking surgery. But the clinical experts explained that the prognosis for no visible residual disease after primary debulking surgery might be better than after interval debulking surgery. This is based on evidence from the EORTC-NCIC trial, which compared the outcomes of people with ovarian cancer with no visible residual disease after either type of surgery. The group with the best prognosis in the EORTC-NCIC trial was people with no visible residual disease after primary debulking surgery. However, the clinical experts explained that there is still uncertainty around which type of surgery leads to the best outcomes, and that the biggest prognostic factor is having no visible residual disease. The committee concluded it is likely that the prognosis of stage 3 cancer is better when there is no visible residual disease after primary debulking surgery, compared with after interval debulking surgery.
## The treatment effect of niraparib is likely to be similar irrespective of surgery type
The clinical experts explained that although prognosis is likely to be different after primary debulking surgery compared with interval debulking surgery, they would not expect there to be a difference in the treatment effect of niraparib after either type of surgery. They highlighted that niraparib has been shown to be effective as a first-line maintenance treatment (see section 3.10) and for maintenance treatment for relapsed disease. There is no reason to expect that the outcomes after niraparib treatment would differ because of the type of surgery that had been done, if there is no visible residual disease. The committee concluded that the treatment effect of niraparib is likely to be similar for stage 3 cancer that has no visible residual disease after either primary debulking surgery or interval debulking surgery.
## The proportion of people with stage 3 cancer and no visible residual disease after surgery is highly uncertain
The clinical experts explained that there is variation in the rate of achieving no visible residual disease after surgery in clinical practice in England. They also explained that the rates of primary debulking surgery and interval debulking surgery vary, because neither is widely accepted as the standard of care. They estimated that about 25% to 50% of people with advanced ovarian cancer may have stage 3 cancer and no visible residual disease after primary debulking surgery. However, this estimate is not reliable because there is no evidence available to support it. The committee concluded that the proportion of people with stage 3 cancer and no visible residual disease after surgery is highly uncertain, and there is no robust estimate of the size of this population in clinical practice.
## The PRIMA intention-to-treat analysis is appropriate for decision-making
PRIMA did not include people with stage 3 cancer and no visible residual disease after primary debulking surgery. However, this population is included within the marketing authorisation indication (see section 3.3). Although the prognosis is likely to be different for no visible residual disease after primary debulking surgery compared with interval debulking surgery (see section 3.4), niraparib's treatment effect is unlikely to be different (see section 3.5). The company presented an analysis to adjust for the difference in prognosis between these groups. This used data from a clinical trial (PAOLA‑1) of olaparib (a different PARP inhibitor) to show the treatment effect for a simulated 'PRIMA intention-to-treat population', which excluded people with stage 3 cancer and no visible residual disease after primary debulking surgery, compared with a population that included only these people. The ERG explained that although there is a difference in prognosis between these groups, the effect of this cannot be reliably estimated. And the PAOLA-1 data are not generalisable to PRIMA because of differences in the treatments taken. It explained that even if the treatment effect could be reliably estimated, the proportion of people with stage 3 cancer and no visible residual disease after primary debulking surgery could not be reliably estimated (see section 3.6). The clinical experts agreed that there are no robust estimates of the proportion of people with stage 3 cancer and no visible residual disease irrespective of the type of surgery they had, so it is not possible to reliably adjust the PRIMA intention-to-treat data. The ERG explained that adjusting the PRIMA intention-to-treat data by reweighting the population with stage 3 cancer and no visible residual disease after interval debulking surgery would rely on having an estimate of the proportion of people with stage 3 cancer and no visible residual disease after primary debulking surgery. The committee acknowledged that PRIMA did not include people with stage 3 cancer and no visible residual disease after primary debulking surgery, and there was no reliable method to adjust the PRIMA data to account for this. It concluded that the population in PRIMA does not fully reflect the population who would likely be offered niraparib in clinical practice, but the PRIMA intention-to-treat analysis is appropriate for decision making.
## PRIMA is generalisable to the dosage used in clinical practice
Because of a protocol change during the study, about two-thirds of people in PRIMA took a fixed dose of 300 mg of niraparib and around one-third took an individualised dose of niraparib based on weight and platelet count. The clinical experts explained that individualised dosing would be used in practice because of toxicity concerns, which is reflected in the summary of product characteristics. The company did subgroup analyses of fixed and individualised dosing in PRIMA. These suggested that niraparib increased progression-free survival compared with placebo, irrespective of the type of dosing. The ERG suggested that these analyses should be considered exploratory because they were done post hoc and were non-stratified. The committee agreed that the analyses were uncertain because the individualised dosing group had fewer participants and shorter follow up than the fixed-dose group. Also, PRIMA was not powered to show a difference between the dosing groups. The committee acknowledged that the progression-free survival benefit is more uncertain for the individualised dosing group, as shown by wider confidence intervals. It noted that the summary of product characteristics states that exploratory subgroup analyses of fixed and individualised dosing show comparable efficacy for them both. The clinical experts explained that based on the dose taken by participants in PRIMA, it was likely to be generalisable to clinical practice. They also noted that niraparib's efficacy using individualised dosing is supported by evidence from NOVA (a study of niraparib in relapsed disease). This suggested that a dose of less than 300 mg does not reduce efficacy. The committee concluded that the evidence in PRIMA is generalisable to the dose which will be used in clinical practice.
## Subsequent treatments used in PRIMA are not fully representative of clinical practice, but data are generalisable to clinical practice
Of the participants who had progressed disease in PRIMA, 85% of people on niraparib and 81% on routine surveillance had chemotherapy after progression. The clinical experts explained that this reflects clinical practice, because PRIMA excluded people with stage 3 cancer and no visible residual disease after primary debulking surgery. So, people in PRIMA had a poorer prognosis than the population who would be eligible for niraparib in the NHS. A small percentage of participants in PRIMA had a PARP inhibitor or immunotherapy after first-line niraparib maintenance treatment. The clinical experts explained that this is not representative of clinical practice in England. The committee acknowledged that PRIMA included a small proportion of people having subsequent treatments that are not available in the NHS but concluded that the PRIMA data are generalisable to clinical practice.
# Clinical effectiveness
## Niraparib improves progression-free survival compared with placebo
Median progression-free survival in PRIMA was 13.8 months with niraparib and 8.2 months with placebo. The difference in median progression-free survival was 5.6 months (hazard ratio 0.62, 95% confidence interval 0.50 to 0.76; p<0.001). Subgroup analyses indicated that niraparib increases median progression-free survival compared with placebo for people with or without a BRCA gene mutation. The committee concluded that niraparib improves progression-free survival for people with ovarian cancer that has completely or partially responded to first-line platinum-based chemotherapy.
## PRIMA data on overall survival and time to second progression are immature
Overall survival was a secondary end point in PRIMA. Less than 11% of participants in PRIMA had died at the latest analysis (9.9% in the niraparib arm and 12.6% in the placebo arm). The difference in overall survival was not statistically significant (hazard ratio for death 0.70, 95% confidence interval 0.44 to 1.11) and it is not yet clear whether niraparib will improve overall survival. The clinical experts acknowledged the uncertainty in the results but suggested that niraparib might improve overall survival and may lead to cure in some people. Time from randomisation to disease progression on the next anti-cancer therapy (PFS2) was also a secondary end point in PRIMA. The PFS2 event rate (20%) was low and there was no statistically significant difference between niraparib and placebo (hazard ratio 0.81, 95% confidence interval 0.58 to 1.14). The committee concluded that the data for overall survival and PFS2 for niraparib after first-line treatment are immature and the survival benefit is uncertain.
# The company's economic model
## The company's model structure is appropriate for decision making
The company presented a 3‑state partitioned survival model to estimate the cost effectiveness of niraparib compared with routine surveillance. The 3 health states were progression-free, progressed disease and death. The committee noted that PFS2 data are available in PRIMA. These could have been used to inform a 4‑state model to capture the effect of second progression on quality of life and related costs. The company suggested that using a 4‑state model would add additional uncertainty because the PFS2 data are immature (see section 3.11). The committee concluded that although there are uncertainties with the company's 3‑state model, it is robust enough for decision making.
## The overall-survival estimates in the company's model are highly uncertain
A key driver of the results in the model is the way in which overall-survival estimates for niraparib are derived. The company estimated overall survival for the routine surveillance arm by fitting a log-logistic accelerated failure time model to the observed overall-survival data from PRIMA. The estimates were validated against overall-survival data for people on routine surveillance over 15 years from the University of Edinburgh Ovarian Cancer Database. The company estimated overall survival in the niraparib arm using a hazard ratio derived from assuming a 1:2 ratio for progression-free survival gain to overall-survival gain, and applied this to the log-logistic routine surveillance overall-survival curve. This ratio is based on an assumption that a 1‑month gain in progression-free survival leads to a 2‑month gain in overall survival. The ratio was chosen based on the relationship between progression-free survival and overall survival in a study of olaparib compared with routine surveillance as second-line maintenance treatment (Study 19), which has long-term follow-up data. The ERG considered that there was not sufficient evidence to support the use of a progression-free survival to overall-survival ratio or to determine what ratio would be most appropriate. It explained that the hazard ratio derived from the 1:2 ratio used in the company's model did not reflect the hazard ratio observed for overall survival in PRIMA (see section 3.11). The ERG also explained that it is methodologically inappropriate to apply a hazard ratio to a log-logistic accelerated failure time model, which does not assume proportional hazards. Also, using a hazard ratio assumes a constant treatment effect over time and there is no evidence to support this assumption. The company highlighted that in other studies of olaparib maintenance such as Study 19, overall survival improved for olaparib compared with routine surveillance as more data accumulated during follow up. The committee acknowledged that the PRIMA overall-survival data are very immature. So, it is not known if the long-term results will show improvement in overall survival of a similar magnitude for niraparib as that seen with olaparib in Study 19. The clinical experts considered that the company's assumption that overall-survival benefit is twice the progression-free survival benefit is plausible. But they stated that the overall-survival data from PRIMA are too immature to reliably quantify the overall-survival benefit. Overall-survival data for niraparib are available in PRIMA. The company could have extrapolated long-term overall survival for niraparib, as it did for the routine surveillance arm. The committee was disappointed that these data had not been included in the company's model. The company did not consider it appropriate to extrapolate the overall-survival data from PRIMA, because there were no real-world data that could be used to validate the curve for the treatment arm. The ERG highlighted that any estimation of overall survival should be validated, as should the use of a ratio for progression-free survival gain to overall-survival gain. The committee acknowledged that extrapolated overall-survival from PRIMA data would be uncertain, but the ratio of progression-free survival to overall-survival is also uncertain. It concluded that overall-survival gain may be at least equivalent to progression-free survival gain. But it is highly uncertain whether the overall-survival gain will exceed the progression-free survival gain, or by how much. It concluded that further overall-survival data will reduce the uncertainty.
# Assumptions in the economic model
## Time to treatment discontinuation is modelled appropriately by the company
The summary of product characteristics for niraparib recommends that treatment should be continued until disease progression or toxicity. It does not include a time-limited stopping rule. The company included a stopping rule in its model, which assumed that 15% of people who had not stopped treatment at 3 years would continue to have niraparib. A 3‑year stopping rule was included in PRIMA, but some people took niraparib for longer than 3 years. The ERG noted that the proportion of people who continued taking niraparib after 3 years is unknown, so the ERG's base case did not include treatment discontinuation at 3 years. The clinical experts explained that most people would stop treatment with niraparib at 3 years unless there was evidence of stable, persistent disease. They considered that the proportion of people assumed to stop niraparib at 3 years in the company's model is appropriate. The committee concluded that the company's approach, which assumed a proportion of people stopping treatment at 3 years, is appropriate.
## Age-related utility decrements should be included in the model
The company did not include age-related utility decrements in its base-case analysis. It suggested that this is appropriate because the quality of life measured in PRIMA was consistent across age groups and did not change considerably over a 56‑week period. The ERG explained that the company's approach overestimates both the utility of people as they age and the cost effectiveness of niraparib. The ERG included age-related utility decrements in its analyses. The committee agreed it is reasonable to assume that people's quality of life decreases as they age, which should be reflected in the model. The committee did not consider the company's justification for not including age-related utility decrements to be valid. It concluded that age-related utility decrements should be included in the model.
## Subsequent treatments are modelled appropriately, but data are immature
The ERG noted that the PRIMA data are not mature enough to understand which second-line, third-line and maintenance treatments will be offered to people whose disease relapses. It highlighted the importance of interpreting overall-survival data alongside data on subsequent treatments after disease progression. This may be possible when more mature data becomes available from PRIMA. Because the subsequent treatments in the immature PRIMA data were not wholly representative of the treatment options in clinical practice (see section 3.9), the company obtained the costs for subsequent treatments from key opinion leaders and used these in its model. The committee concluded that the data on subsequent treatments in PRIMA are immature, but the company appropriately included subsequent treatments that are reflective of clinical practice in its model.
# Cost-effectiveness results
## None of the analyses reflect the committee's preferred assumptions
Because of confidential commercial arrangements for subsequent treatments in relapsed disease, none of the cost-effectiveness results are reported here. But none of the company's or ERG's analyses reflected the committee's preferences, which are as follows:
use the PRIMA intention-to-treat population (see section 3.7)
use a progression-free survival gain to overall-survival gain ratio of 1:1 (see section 3.13)
do not include a long-term remission assumption or costs in the progression-free survival health state after 10 years, which was agreed at technical engagement
include the stopping rule with 15% of people still on niraparib at 3 years continuing treatment (see section 3.14)
include age-related utility decrements (see section 3.15)
include the revised costs of monitoring heart rate and blood pressure, which was accepted by the company at technical engagement
include the alternative resource-use estimates for routine surveillance during progression-free survival, which was accepted by the company at technical engagement.
## Niraparib is not recommended for routine use in the NHS
The committee acknowledged that the company's incremental cost-effectiveness ratios (ICERs) were within the range usually considered a cost-effective use of NHS resources. But the committee's preferred ICER was not within the range usually considered a cost-effective use of NHS resources. It noted that the biggest driver of cost effectiveness was the niraparib overall-survival estimate and that this was highly uncertain. Therefore, the committee concluded that the ICER for niraparib compared with routine surveillance was very uncertain, and that it could not recommend niraparib maintenance treatment for routine NHS use in adults with advanced ovarian, fallopian tube and peritoneal cancer after response to first-line platinum-based chemotherapy.
# Cancer Drugs Fund
## Niraparib meets the Cancer Drugs Fund criteria
Having concluded that niraparib could not be recommended for routine use, the committee then considered if it could be recommended as maintenance treatment for advanced ovarian cancer after response to first-line platinum-based chemotherapy within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It noted that:
The company expressed an interest in niraparib being considered for the Cancer Drugs Fund.
Data from PRIMA are immature and median overall survival was not reached in the placebo arm.
PRIMA is still ongoing and further data could help reduce uncertainties about long-term progression-free survival, overall survival and time to second progression.
Overall survival was a key driver of the cost-effectiveness results.
The Systemic Anti-Cancer Therapy dataset could provide data on stage 3 cancer with no visible residual disease after primary debulking surgery, the proportion of people having subsequent treatment and the treatments used.
The company's price for niraparib, including a commercial arrangement, means that it has plausible potential to be cost effective.The committee concluded that niraparib met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended niraparib for use within the Cancer Drugs Fund as an option for people with advanced (FIGO stages 3 and 4) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer after response to first-line platinum-based chemotherapy if the conditions in the managed access agreement are followed. When the guidance is next reviewed the company should use the committee's preferred assumptions as set out in section 3.17, unless new evidence indicates otherwise.
# Innovation
## The model is adequate to capture the benefits of niraparib
The company considered niraparib to be innovative. It explained that there are no PARP inhibitors available as first-line maintenance treatment for people who do not have a BRCA1 or BRCA2 gene mutation. It noted that niraparib will be the first treatment to offer the benefit of maintenance therapy to people with advanced ovarian cancer, irrespective of BRCA mutation status. The clinical experts agreed that niraparib would be a step-change in the first-line treatment of advanced ovarian cancer for people without a BRCA1 or BRCA2 gene mutation. The committee considered that the model included all health-related quality-of-life benefits. It concluded that it had not been presented with evidence of any additional benefits from maintenance treatment with niraparib that had not already been included.
# Other factors
No equality or social value judgements issues were identified.
NICE's advice about life-extending treatments for people with a short life expectancy did not apply.
|
{'Recommendations': 'Niraparib is recommended for use within the Cancer Drugs Fund as an option for maintenance treatment for advanced (FIGO stages 3\xa0and\xa04) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer after response to first-line platinum-based chemotherapy in adults. It is recommended only if the conditions in the managed access agreement for niraparib are followed.\n\nThis recommendation is not intended to affect treatment with niraparib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere are no maintenance treatments routinely available for advanced ovarian, fallopian tube or peritoneal cancer that has responded to first-line platinum-based chemotherapy. For some people, maintenance treatment is available through the Cancer Drugs Fund.\n\nClinical evidence comes from PRIMA, an ongoing clinical trial, which shows that niraparib delays disease progression. But it has not shown whether people having niraparib live longer, because they have not been followed up for long enough.\n\nBecause of the clinical uncertainty, the cost-effectiveness estimates are very uncertain. They may be higher than what NICE normally considers an acceptable use of NHS resources. So, niraparib cannot be recommended for routine use in the NHS.\n\nLonger follow-up data from PRIMA could help address the uncertainty about the clinical effectiveness of niraparib in this population. Niraparib has the potential to be a cost-effective use of NHS resources. So, it is recommended for use in the Cancer Drugs Fund while more data from the trial are collected.', 'Information about niraparib': "# Marketing authorisation indication\n\nNiraparib (Zejula, GlaxoSmithKline) has a marketing authorisation in the UK 'as monotherapy for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages 3 and 4) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £4,500 for 56\xa0100‑mg tablets (excluding VAT; BNF online accessed November\xa02020). The company has a commercial arrangement. This makes niraparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nthe first-line treatment response rates from the PRIMA trial were generalisable to rates seen in UK practice (issue\xa01, see technical report page\xa02)\n\nthe dose of niraparib included in the model for continued treatment after 3\xa0years is appropriate (issue\xa01, see technical report page\xa02)\n\nnot including the long-term remission assumption in the model is appropriate (issue\xa07, see technical report page\xa011).\n\nAt technical engagement, the company accepted the ERG's revised costs for heart rate and blood pressure monitoring and the alternative resource-use estimates for progression-free survival in the routine surveillance arm.\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues (issues\xa01 to 6 and 8 to 12), which were outstanding after the technical engagement stage.\n\n# The condition\n\n## People with ovarian cancer would welcome a new effective maintenance therapy\n\nThe patient expert explained that advanced platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer is a devastating condition. Knowing that the disease can relapse is a major psychological burden for people with the disease and their families. For most people without a BRCA1 or BRCA2 gene mutation there are no first-line maintenance treatments available for disease that has responded to platinum-based chemotherapy, although bevacizumab is available for some people through the Cancer Drugs Fund. People who are not eligible for first-line maintenance treatment have routine surveillance until the disease relapses. The patient expert explained that taking a maintenance treatment has a psychological benefit and improves quality of life compared with being on routine surveillance, which can feel like waiting for the cancer to come back. The clinical experts agreed with the patient expert. The committee recognised the need for effective maintenance treatment options after first-line treatment for advanced disease. It concluded that people would welcome new maintenance treatment options.\n\n# Treatment pathway\n\n## There is an unmet need for maintenance treatments after first-line platinum-based chemotherapy\n\nFirst-line treatment for advanced ovarian, fallopian tube, or primary peritoneal cancer is surgery and platinum-based chemotherapy. Options for surgery are primary debulking surgery before first-line chemotherapy treatment, or interval debulking surgery between cycles of first-line chemotherapy. First-line maintenance treatment with a poly-ADP-ribose polymerase (PARP) inhibitor is available through the Cancer Drugs Fund for people with a BRCA1 or BRCA2 gene mutation. For people without a BRCA1 or BRCA2 gene mutation, there are no first-line PARP inhibitor maintenance treatments. Routine surveillance is the only option for people who are not eligible for maintenance treatment. The clinical experts explained that there is a high unmet need for more maintenance treatment options after first-line treatment for advanced disease. They noted that there is a clear population that would benefit from niraparib maintenance therapy at this point in the treatment pathway. The committee concluded that there is an unmet need for new effective maintenance treatment options after first-line platinum-based chemotherapy.\n\n# Clinical evidence\n\n## The population covered by niraparib's marketing authorisation indication is broader than the population included in PRIMA\n\nPRIMA is a double-blind, randomised controlled trial comparing niraparib with placebo as maintenance treatment of advanced ovarian cancer. It included people with or without a BRCA gene mutation, who had advanced (International Federation of Gynecology and Obstetrics [FIGO] stages 3\xa0and\xa04) high-grade ovarian, fallopian tube or primary peritoneal cancer that was in response (complete or partial) to first-line platinum-based chemotherapy. The primary end point was progression-free survival based on blinded independent central review. PRIMA excluded people with stage\xa03 cancer who had no visible residual disease after primary debulking surgery. The rationale for excluding this group was that their prognosis was considered to be better than other groups with advanced ovarian cancer. However, niraparib's marketing authorisation includes all people with stage 3\xa0or\xa04 high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response to first-line platinum-based chemotherapy. The committee concluded that the population covered by the marketing authorisation indication is broader than the population included in PRIMA.\n\n## Prognosis of stage 3 cancer is likely to be better when there is no visible residual disease after primary debulking surgery, compared with after interval debulking surgery\n\nThe ERG commented on the prognosis of stage\xa03 cancer after surgery. It suggested that the prognosis for no visible residual disease might be similar when achieved by primary debulking surgery and interval debulking surgery. But the clinical experts explained that the prognosis for no visible residual disease after primary debulking surgery might be better than after interval debulking surgery. This is based on evidence from the EORTC-NCIC trial, which compared the outcomes of people with ovarian cancer with no visible residual disease after either type of surgery. The group with the best prognosis in the EORTC-NCIC trial was people with no visible residual disease after primary debulking surgery. However, the clinical experts explained that there is still uncertainty around which type of surgery leads to the best outcomes, and that the biggest prognostic factor is having no visible residual disease. The committee concluded it is likely that the prognosis of stage\xa03 cancer is better when there is no visible residual disease after primary debulking surgery, compared with after interval debulking surgery.\n\n## The treatment effect of niraparib is likely to be similar irrespective of surgery type\n\nThe clinical experts explained that although prognosis is likely to be different after primary debulking surgery compared with interval debulking surgery, they would not expect there to be a difference in the treatment effect of niraparib after either type of surgery. They highlighted that niraparib has been shown to be effective as a first-line maintenance treatment (see section\xa03.10) and for maintenance treatment for relapsed disease. There is no reason to expect that the outcomes after niraparib treatment would differ because of the type of surgery that had been done, if there is no visible residual disease. The committee concluded that the treatment effect of niraparib is likely to be similar for stage\xa03 cancer that has no visible residual disease after either primary debulking surgery or interval debulking surgery.\n\n## The proportion of people with stage 3 cancer and no visible residual disease after surgery is highly uncertain\n\nThe clinical experts explained that there is variation in the rate of achieving no visible residual disease after surgery in clinical practice in England. They also explained that the rates of primary debulking surgery and interval debulking surgery vary, because neither is widely accepted as the standard of care. They estimated that about 25% to 50% of people with advanced ovarian cancer may have stage\xa03 cancer and no visible residual disease after primary debulking surgery. However, this estimate is not reliable because there is no evidence available to support it. The committee concluded that the proportion of people with stage\xa03 cancer and no visible residual disease after surgery is highly uncertain, and there is no robust estimate of the size of this population in clinical practice.\n\n## The PRIMA intention-to-treat analysis is appropriate for decision-making\n\nPRIMA did not include people with stage\xa03 cancer and no visible residual disease after primary debulking surgery. However, this population is included within the marketing authorisation indication (see section\xa03.3). Although the prognosis is likely to be different for no visible residual disease after primary debulking surgery compared with interval debulking surgery (see section\xa03.4), niraparib's treatment effect is unlikely to be different (see section\xa03.5). The company presented an analysis to adjust for the difference in prognosis between these groups. This used data from a clinical trial (PAOLA‑1) of olaparib (a different PARP inhibitor) to show the treatment effect for a simulated 'PRIMA intention-to-treat population', which excluded people with stage\xa03 cancer and no visible residual disease after primary debulking surgery, compared with a population that included only these people. The ERG explained that although there is a difference in prognosis between these groups, the effect of this cannot be reliably estimated. And the PAOLA-1 data are not generalisable to PRIMA because of differences in the treatments taken. It explained that even if the treatment effect could be reliably estimated, the proportion of people with stage\xa03 cancer and no visible residual disease after primary debulking surgery could not be reliably estimated (see section\xa03.6). The clinical experts agreed that there are no robust estimates of the proportion of people with stage\xa03 cancer and no visible residual disease irrespective of the type of surgery they had, so it is not possible to reliably adjust the PRIMA intention-to-treat data. The ERG explained that adjusting the PRIMA intention-to-treat data by reweighting the population with stage\xa03 cancer and no visible residual disease after interval debulking surgery would rely on having an estimate of the proportion of people with stage\xa03 cancer and no visible residual disease after primary debulking surgery. The committee acknowledged that PRIMA did not include people with stage\xa03 cancer and no visible residual disease after primary debulking surgery, and there was no reliable method to adjust the PRIMA data to account for this. It concluded that the population in PRIMA does not fully reflect the population who would likely be offered niraparib in clinical practice, but the PRIMA intention-to-treat analysis is appropriate for decision making.\n\n## PRIMA is generalisable to the dosage used in clinical practice\n\nBecause of a protocol change during the study, about two-thirds of people in PRIMA took a fixed dose of 300\xa0mg of niraparib and around one-third took an individualised dose of niraparib based on weight and platelet count. The clinical experts explained that individualised dosing would be used in practice because of toxicity concerns, which is reflected in the summary of product characteristics. The company did subgroup analyses of fixed and individualised dosing in PRIMA. These suggested that niraparib increased progression-free survival compared with placebo, irrespective of the type of dosing. The ERG suggested that these analyses should be considered exploratory because they were done post hoc and were non-stratified. The committee agreed that the analyses were uncertain because the individualised dosing group had fewer participants and shorter follow up than the fixed-dose group. Also, PRIMA was not powered to show a difference between the dosing groups. The committee acknowledged that the progression-free survival benefit is more uncertain for the individualised dosing group, as shown by wider confidence intervals. It noted that the summary of product characteristics states that exploratory subgroup analyses of fixed and individualised dosing show comparable efficacy for them both. The clinical experts explained that based on the dose taken by participants in PRIMA, it was likely to be generalisable to clinical practice. They also noted that niraparib's efficacy using individualised dosing is supported by evidence from NOVA (a study of niraparib in relapsed disease). This suggested that a dose of less than 300\xa0mg does not reduce efficacy. The committee concluded that the evidence in PRIMA is generalisable to the dose which will be used in clinical practice.\n\n## Subsequent treatments used in PRIMA are not fully representative of clinical practice, but data are generalisable to clinical practice\n\nOf the participants who had progressed disease in PRIMA, 85% of people on niraparib and 81% on routine surveillance had chemotherapy after progression. The clinical experts explained that this reflects clinical practice, because PRIMA excluded people with stage\xa03 cancer and no visible residual disease after primary debulking surgery. So, people in PRIMA had a poorer prognosis than the population who would be eligible for niraparib in the NHS. A small percentage of participants in PRIMA had a PARP inhibitor or immunotherapy after first-line niraparib maintenance treatment. The clinical experts explained that this is not representative of clinical practice in England. The committee acknowledged that PRIMA included a small proportion of people having subsequent treatments that are not available in the NHS but concluded that the PRIMA data are generalisable to clinical practice.\n\n# Clinical effectiveness\n\n## Niraparib improves progression-free survival compared with placebo\n\nMedian progression-free survival in PRIMA was 13.8\xa0months with niraparib and 8.2\xa0months with placebo. The difference in median progression-free survival was 5.6\xa0months (hazard ratio 0.62, 95%\xa0confidence interval 0.50 to 0.76; p<0.001). Subgroup analyses indicated that niraparib increases median progression-free survival compared with placebo for people with or without a BRCA gene mutation. The committee concluded that niraparib improves progression-free survival for people with ovarian cancer that has completely or partially responded to first-line platinum-based chemotherapy.\n\n## PRIMA data on overall survival and time to second progression are immature\n\nOverall survival was a secondary end point in PRIMA. Less than 11% of participants in PRIMA had died at the latest analysis (9.9% in the niraparib arm and 12.6% in the placebo arm). The difference in overall survival was not statistically significant (hazard ratio for death 0.70, 95%\xa0confidence interval 0.44 to 1.11) and it is not yet clear whether niraparib will improve overall survival. The clinical experts acknowledged the uncertainty in the results but suggested that niraparib might improve overall survival and may lead to cure in some people. Time from randomisation to disease progression on the next anti-cancer therapy (PFS2) was also a secondary end point in PRIMA. The PFS2 event rate (20%) was low and there was no statistically significant difference between niraparib and placebo (hazard ratio 0.81, 95%\xa0confidence interval 0.58 to 1.14). The committee concluded that the data for overall survival and PFS2 for niraparib after first-line treatment are immature and the survival benefit is uncertain.\n\n# The company's economic model\n\n## The company's model structure is appropriate for decision making\n\nThe company presented a 3‑state partitioned survival model to estimate the cost effectiveness of niraparib compared with routine surveillance. The 3\xa0health states were progression-free, progressed disease and death. The committee noted that PFS2 data are available in PRIMA. These could have been used to inform a 4‑state model to capture the effect of second progression on quality of life and related costs. The company suggested that using a 4‑state model would add additional uncertainty because the PFS2 data are immature (see section\xa03.11). The committee concluded that although there are uncertainties with the company's 3‑state model, it is robust enough for decision making.\n\n## The overall-survival estimates in the company's model are highly uncertain\n\nA key driver of the results in the model is the way in which overall-survival estimates for niraparib are derived. The company estimated overall survival for the routine surveillance arm by fitting a log-logistic accelerated failure time model to the observed overall-survival data from PRIMA. The estimates were validated against overall-survival data for people on routine surveillance over 15\xa0years from the University of Edinburgh Ovarian Cancer Database. The company estimated overall survival in the niraparib arm using a hazard ratio derived from assuming a 1:2 ratio for progression-free survival gain to overall-survival gain, and applied this to the log-logistic routine surveillance overall-survival curve. This ratio is based on an assumption that a 1‑month gain in progression-free survival leads to a 2‑month gain in overall survival. The ratio was chosen based on the relationship between progression-free survival and overall survival in a study of olaparib compared with routine surveillance as second-line maintenance treatment (Study\xa019), which has long-term follow-up data. The ERG considered that there was not sufficient evidence to support the use of a progression-free survival to overall-survival ratio or to determine what ratio would be most appropriate. It explained that the hazard ratio derived from the 1:2 ratio used in the company's model did not reflect the hazard ratio observed for overall survival in PRIMA (see section\xa03.11). The ERG also explained that it is methodologically inappropriate to apply a hazard ratio to a log-logistic accelerated failure time model, which does not assume proportional hazards. Also, using a hazard ratio assumes a constant treatment effect over time and there is no evidence to support this assumption. The company highlighted that in other studies of olaparib maintenance such as Study\xa019, overall survival improved for olaparib compared with routine surveillance as more data accumulated during follow up. The committee acknowledged that the PRIMA overall-survival data are very immature. So, it is not known if the long-term results will show improvement in overall survival of a similar magnitude for niraparib as that seen with olaparib in Study\xa019. The clinical experts considered that the company's assumption that overall-survival benefit is twice the progression-free survival benefit is plausible. But they stated that the overall-survival data from PRIMA are too immature to reliably quantify the overall-survival benefit. Overall-survival data for niraparib are available in PRIMA. The company could have extrapolated long-term overall survival for niraparib, as it did for the routine surveillance arm. The committee was disappointed that these data had not been included in the company's model. The company did not consider it appropriate to extrapolate the overall-survival data from PRIMA, because there were no real-world data that could be used to validate the curve for the treatment arm. The ERG highlighted that any estimation of overall survival should be validated, as should the use of a ratio for progression-free survival gain to overall-survival gain. The committee acknowledged that extrapolated overall-survival from PRIMA data would be uncertain, but the ratio of progression-free survival to overall-survival is also uncertain. It concluded that overall-survival gain may be at least equivalent to progression-free survival gain. But it is highly uncertain whether the overall-survival gain will exceed the progression-free survival gain, or by how much. It concluded that further overall-survival data will reduce the uncertainty.\n\n# Assumptions in the economic model\n\n## Time to treatment discontinuation is modelled appropriately by the company\n\nThe summary of product characteristics for niraparib recommends that treatment should be continued until disease progression or toxicity. It does not include a time-limited stopping rule. The company included a stopping rule in its model, which assumed that 15% of people who had not stopped treatment at 3\xa0years would continue to have niraparib. A 3‑year stopping rule was included in PRIMA, but some people took niraparib for longer than 3\xa0years. The ERG noted that the proportion of people who continued taking niraparib after 3\xa0years is unknown, so the ERG's base case did not include treatment discontinuation at 3\xa0years. The clinical experts explained that most people would stop treatment with niraparib at 3\xa0years unless there was evidence of stable, persistent disease. They considered that the proportion of people assumed to stop niraparib at 3\xa0years in the company's model is appropriate. The committee concluded that the company's approach, which assumed a proportion of people stopping treatment at 3\xa0years, is appropriate.\n\n## Age-related utility decrements should be included in the model\n\nThe company did not include age-related utility decrements in its base-case analysis. It suggested that this is appropriate because the quality of life measured in PRIMA was consistent across age groups and did not change considerably over a 56‑week period. The ERG explained that the company's approach overestimates both the utility of people as they age and the cost effectiveness of niraparib. The ERG included age-related utility decrements in its analyses. The committee agreed it is reasonable to assume that people's quality of life decreases as they age, which should be reflected in the model. The committee did not consider the company's justification for not including age-related utility decrements to be valid. It concluded that age-related utility decrements should be included in the model.\n\n## Subsequent treatments are modelled appropriately, but data are immature\n\nThe ERG noted that the PRIMA data are not mature enough to understand which second-line, third-line and maintenance treatments will be offered to people whose disease relapses. It highlighted the importance of interpreting overall-survival data alongside data on subsequent treatments after disease progression. This may be possible when more mature data becomes available from PRIMA. Because the subsequent treatments in the immature PRIMA data were not wholly representative of the treatment options in clinical practice (see section\xa03.9), the company obtained the costs for subsequent treatments from key opinion leaders and used these in its model. The committee concluded that the data on subsequent treatments in PRIMA are immature, but the company appropriately included subsequent treatments that are reflective of clinical practice in its model.\n\n# Cost-effectiveness results\n\n## None of the analyses reflect the committee's preferred assumptions\n\nBecause of confidential commercial arrangements for subsequent treatments in relapsed disease, none of the cost-effectiveness results are reported here. But none of the company's or ERG's analyses reflected the committee's preferences, which are as follows:\n\nuse the PRIMA intention-to-treat population (see section\xa03.7)\n\nuse a progression-free survival gain to overall-survival gain ratio of 1:1 (see section\xa03.13)\n\ndo not include a long-term remission assumption or costs in the progression-free survival health state after 10\xa0years, which was agreed at technical engagement\n\ninclude the stopping rule with 15% of people still on niraparib at 3 years continuing treatment (see section\xa03.14)\n\ninclude age-related utility decrements (see section\xa03.15)\n\ninclude the revised costs of monitoring heart rate and blood pressure, which was accepted by the company at technical engagement\n\ninclude the alternative resource-use estimates for routine surveillance during progression-free survival, which was accepted by the company at technical engagement.\n\n## Niraparib is not recommended for routine use in the NHS\n\nThe committee acknowledged that the company's incremental cost-effectiveness ratios (ICERs) were within the range usually considered a cost-effective use of NHS resources. But the committee's preferred ICER was not within the range usually considered a cost-effective use of NHS resources. It noted that the biggest driver of cost effectiveness was the niraparib overall-survival estimate and that this was highly uncertain. Therefore, the committee concluded that the ICER for niraparib compared with routine surveillance was very uncertain, and that it could not recommend niraparib maintenance treatment for routine NHS use in adults with advanced ovarian, fallopian tube and peritoneal cancer after response to first-line platinum-based chemotherapy.\n\n# Cancer Drugs Fund\n\n## Niraparib meets the Cancer Drugs Fund criteria\n\nHaving concluded that niraparib could not be recommended for routine use, the committee then considered if it could be recommended as maintenance treatment for advanced ovarian cancer after response to first-line platinum-based chemotherapy within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It noted that:\n\nThe company expressed an interest in niraparib being considered for the Cancer Drugs Fund.\n\nData from PRIMA are immature and median overall survival was not reached in the placebo arm.\n\nPRIMA is still ongoing and further data could help reduce uncertainties about long-term progression-free survival, overall survival and time to second progression.\n\nOverall survival was a key driver of the cost-effectiveness results.\n\nThe Systemic Anti-Cancer Therapy dataset could provide data on stage\xa03 cancer with no visible residual disease after primary debulking surgery, the proportion of people having subsequent treatment and the treatments used.\n\nThe company's price for niraparib, including a commercial arrangement, means that it has plausible potential to be cost effective.The committee concluded that niraparib met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended niraparib for use within the Cancer Drugs Fund as an option for people with advanced (FIGO stages 3\xa0and\xa04) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer after response to first-line platinum-based chemotherapy if the conditions in the managed access agreement are followed. When the guidance is next reviewed the company should use the committee's preferred assumptions as set out in section\xa03.17, unless new evidence indicates otherwise.\n\n# Innovation\n\n## The model is adequate to capture the benefits of niraparib\n\nThe company considered niraparib to be innovative. It explained that there are no PARP inhibitors available as first-line maintenance treatment for people who do not have a BRCA1 or BRCA2 gene mutation. It noted that niraparib will be the first treatment to offer the benefit of maintenance therapy to people with advanced ovarian cancer, irrespective of BRCA mutation status. The clinical experts agreed that niraparib would be a step-change in the first-line treatment of advanced ovarian cancer for people without a BRCA1 or BRCA2 gene mutation. The committee considered that the model included all health-related quality-of-life benefits. It concluded that it had not been presented with evidence of any additional benefits from maintenance treatment with niraparib that had not already been included.\n\n# Other factors\n\nNo equality or social value judgements issues were identified.\n\nNICE's advice about life-extending treatments for people with a short life expectancy did not apply."}
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https://www.nice.org.uk/guidance/ta673
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Evidence-based recommendations on niraparib (Zejula) for maintenance treatment of advanced (FIGO stages 3 and 4) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer after response to first-line platinum-based chemotherapy in adults.
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46f0134e656f837580b7f62bc16cbd736f80681b
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nice
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Trabectedin for the treatment of advanced soft tissue sarcoma
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Trabectedin for the treatment of advanced soft tissue sarcoma
Evidence-based recommendations on trabectedin (Yondelis) for treating advanced soft tissue sarcoma in adults.
# Guidance
Trabectedin is recommended as a treatment option for people with advanced soft tissue sarcoma if:
treatment with anthracyclines and ifosfamide has failed or
they are intolerant of or have contraindications for treatment with anthracyclines and ifosfamide.Trabectedin is only recommended if the company provides it according to the commercial arrangement.
This recommendation is not intended to affect treatment with trabectedin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Trabectedin (Yondelis, Immedica) is an alkylating agent, which affects cancer cells by damaging DNA. Trabectedin has a UK marketing authorisation for the treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide or who are unsuited to receive these agents. The marketing authorisation was granted under 'exceptional circumstances'. The summary of product characteristics (SPC) states that 'efficacy data are based mainly on liposarcoma and leiomyosarcoma patients'.
Trabectedin is contraindicated in people who have hypersensitivity to trabectedin or to any of the excipients, in those with concurrent serious or uncontrolled infection, in women who are breast-feeding, and in combination with yellow fever vaccine. The SPC states that trabectedin is not indicated for use in children and adolescents, and that creatine phosphokinase, hepatic function and haematological parameters should be monitored regularly during treatment. The SPC lists precautions for use of trabectedin in people with liver or kidney impairment. The SPC reports that the most common adverse reactions are nausea, fatigue, vomiting, weight loss (anorexia), neutropenia, thrombocytopenia, and increases in enzymes in blood indicating abnormal liver function. For full details of adverse events and contraindications, see the SPC.
The SPC for trabectedin states that 'the recommended dose is 1.5 mg/m2 body surface area, administered as an intravenous infusion over 24 hours with a 3-week interval between cycles.' The SPC also states that administration of trabectedin through a central venous line is 'strongly recommended'. Anti-emetic prophylaxis with intravenous dexamethasone (20 mg) must be administered to all patients 30 minutes before trabectedin treatment. Dexamethasone may also have hepatoprotective effects. The acquisition cost of trabectedin is £363.00 for a 250-microgram vial and £1,366.00 for a 1-mg (1,000-microgram) vial (excluding VAT; 'British national formulary' edition 58). At a dose of 1.5 mg/m2, apatient with a body surface area of 1.7 m2 would need approximately 2.5 mg of trabectedin per cycle. One such infusion (using two 1-mg vials and two 250-microgram vials of trabectedin) would cost £3,458. The company has a commercial arrangement. This makes trabectedin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of trabectedin and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer's submission included a phase 2 randomised trial (STS-201) evaluating the efficacy of trabectedin in participants with locally advanced or metastatic soft tissue sarcoma in whom the disease had relapsed or become refractory after treatment with at least 1 anthracycline and ifosfamide, given either in combination or in sequence. All participants had liposarcomas or leiomyosarcomas (L-sarcomas) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial randomised participants to 1 of 2 dosing regimens of trabectedin. One group received the dosage of trabectedin specified in the marketing authorisation (1.5 mg/m2 every 3 weeks as a 24-hour intravenous infusion, n=136) and the other group (n=134) received trabectedin at a dosage of 0.58 mg/m2 every week as a 3-hour intravenous infusion. In addition, the manufacturer's submission presented 3 uncontrolled phase 2 trials of trabectedin. These included a total of 194 participants with soft tissue sarcoma, of whom 104 had L-sarcomas. Participants in all of these studies had an ECOG performance status of 0 or 1. In the absence of relevant comparator data in the included trials, the manufacturer reported historical control data for patients receiving treatments considered to be equivalent to best supportive care (BSC; see sections 3.7 to 3.9). These data were derived from studies in the database of the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC STBSG).
The primary outcome of the STS-201 trial was time to progression (time between randomisation and the first documentation of disease progression or death as a result of progressive disease); secondary outcomes included progression-free survival, overall survival and best overall response. According to the manufacturer, treatment with trabectedin continued as long as participants derived therapeutic benefit, until the disease progressed, or for at least 2 courses of therapy beyond a confirmed response. The design of STS-201 permitted crossover for participants in either arm whose disease progressed. The manufacturer acknowledged that the crossover design of the study affected overall survival.
The median time to progression from intention-to-treat analyses was statistically significantly longer (hazard ratio 0.734, p=0.032) for the licensed dosage of trabectedin, with a time to progression of 3.7 months (95% confidence interval 2.1 to 5.4) compared with 2.3 months (95% CI 2.0 to 3.5) for the comparator dosage of trabectedin. Median overall survival was 13.9 months (95% CI 12.5 to 18.6) for the licensed dosage of trabectedin compared with 11.8 months (95% CI 9.9 to 14.9) for the comparator trabectedin regimen. Median progression-free survival at 3 and 6 months was 51.5% (95% CI 43.0 to 60.1) and 35.5% (95% CI 27.1 to 43.9) respectively for the licensed dosage of trabectedin, compared with 44.7% (95% CI 36.0 to 53.3) and 27.5% (95% CI 19.4 to 35.5) for the comparator trabectedin regimen. The manufacturer reported that in a pre-planned subgroup analysis, efficacy outcomes appeared to be more favourable in patients with liposarcomas than in those with leiomyosarcomas, regardless of the study arm.
The manufacturer reported that the main treatment-related severe (grades 3 and 4) adverse events observed in all studies were transient and reversible, and comprised non-cumulative neutropenia and elevations of hepatic transaminase without clinical consequences. Grade 3 or 4 nausea and vomiting were reported by some participants. The manufacturer stated that unlike with other commonly used cytotoxic agents, no cardiotoxicity or neurotoxicity was observed with trabectedin.
No health-related quality of life data were presented for patients with advanced soft tissue sarcoma and the manufacturer stated that none were obtained from the trials.
Historical control data were used to approximate BSC, with the manufacturer acknowledging the limitations of this approach. To estimate overall survival, data for those in whom treatment with ifosfamide had failed, for those receiving dacarbazine, and for those receiving etoposide were taken from an unpublished analysis of 4 phase 2 studies in the EORTC STBSG database of adults with advanced pre-treated soft tissue sarcoma. To estimate progression-free survival, data for the comparators were taken from a publication reporting on phase 2 studies from the EORTC STBSG database. The studies included in the analysis varied in the treatment given to patients during and before entering the trials. Therefore, the manufacturer selected the pre-treated populations that they considered to be most relevant.
The manufacturer reported that the median overall survival of historical control patients treated with ifosfamide was 6.6 months from start of therapy (95% CI 5.0 to 9.0); a further figure was included by the manufacturer, but was marked as academic-in-confidence and therefore cannot be presented. The manufacturer reported that the median overall survival for those treated with dacarbazine was 6.6 months (95% CI 4.3 to 8.4) and 6.3 months (95% CI 4.4 to 8.9) for those treated with etoposide.
The manufacturer reported that the mean progression-free survival of historical control patients treated with inactive regimens (n=234) was 21% (standard error ± 3%) and 8% (SE ± 2%) at 3 and 6 months respectively. Inactive regimens include treatment with mitozolomide, nimustine, fotemustine, miltefosine, liposomal muramyl tripeptide phosphatidylethanolamide, temozolamide, etoposide, Tomudex or gemcitabine. The corresponding figures for historical control patients treated with active regimens comprising ifosfamide and dacarbazine (n=146) were 39% (SE ± 4%) and 14% (SE ± 3%) respectively.
The manufacturer developed its own economic evaluation, comprising a 2-arm state-transition model. The first arm was designed to capture the costs and outcomes associated with treatment with trabectedin; the second arm was designed to capture the costs and outcomes associated with BSC. Administration of other chemotherapies in addition to BSC was explored in a sensitivity analysis. The model included 4 mutually exclusive health states: progression-free after treatment with trabectedin; progressive disease after treatment with trabectedin; progressive disease with BSC; and death. People treated with trabectedin entered the model in the progression-free state, whereas people treated with BSC entered the model in the progressive disease state. The model cycle length was 1 month with a time horizon of 5 years.
The model used the effectiveness data from the STS-201 trial of trabectedin, which included only participants with L-sarcomas after they had been treated with a regimen containing at least 1 anthracycline and ifosfamide (combined or sequential). To represent the base case, the manufacturer selected effectiveness data from participants receiving a 24-hour infusion of trabectedin every 3 weeks. In a sensitivity analysis, the manufacturer modelled the pooled effectiveness from the 3 initial phase 2 uncontrolled studies of trabectedin. Transition probabilities for the trabectedin arm were estimated from Weibull parameters derived from the patient-level data for time to progression from the STS‑201 trial. Weibull curves were fitted to Kaplan–Meier curves for time to progression and overall survival. The Weibull estimates were considered by the manufacturer to be comparable to the Kaplan–Meier curves. Following a request by the ERG, arising because of differences in patient characteristics between the trabectedin and BSC arms, Weibull curves for trabectedin were re-calculated using age, gender and severity as covariates.
The effectiveness data for patients who receive BSC after failure of anthracyclines and ifosfamide were estimated from pooled data from 4 published trials from the EORTC STBSG database. These data were used in the same manner as the STS-201 data to estimate the transition probabilities (in this case, only from progression to death). In response to requests for clarification, the manufacturer submitted a revised model in which the survival curves were adjusted for the differences in patient characteristics between the trabectedin and BSC arms.
Because no studies of quality of life in patients with soft tissue sarcoma were identified, the manufacturer, following discussion with its clinical experts, used health-state utilities for non-small-cell lung cancer as proxies, assuming comparable prognoses and stages of the 2 diseases. Health-state utilities in progression-free and progressive disease states were assumed to be similar for all patients, irrespective of treatment. The utility values for progression-free and progressive disease health states were assumed to be 0.653 and 0.473 respectively. Admission to hospital as a result of adverse events associated with trabectedin treatment was associated with a utility of 0.610, which was equal to that associated with nausea and vomiting. This was assumed to last 1 month and equated to a quality-adjusted life year (QALY) decrement of 0.004. The utility associated with developing grade 3 or 4 neutropenia was 0.56. This was assumed to last 1 week and equated to a QALY decrement of 0.002. Adverse events were assumed to occur only during the first cycle of trabectedin treatment, and no disutility associated with adverse events was modelled for patients receiving BSC.
Following concerns raised by the ERG about the calculation of the average cost per patient, the manufacturer revised the methodology used to estimate the acquisition cost of the drug. The manufacturer used patient-level data from the STS-201 trial to calculate the average number of 1-mg and 250-microgram vials used for each patient and the proportion of patients receiving trabectedin in each cycle. The ERG stated that the manufacturer's revised response reported a cost per patient of £23,719 with administration costs excluded, and £25,986 with administration costs and a pre-treatment injection of dexamethasone included. The manufacturer obtained management costs for patients in the progressive disease health state from a cost-of-illness study, and assumed that the costs for the progression-free health state, in the absence of data, were half the costs for the progressive disease health state. Additional costs were included when a patient died. Costs of hospitalisation were average costs and were dependent on patients' diagnoses. The manufacturer did not include costs for treating neutropenia, for treating adverse events in the BSC arm, or for patient monitoring.
With discounting at 3.5% per annum, the manufacturer's revised base-case cost-effectiveness results gave an incremental cost-effectiveness ratio (ICER) of £56,985 per QALY gained for trabectedin compared with BSC, based on an incremental cost of £27,145 and an incremental QALY gain of 0.476. The manufacturer explored uncertainty in 1-way sensitivity and probabilistic sensitivity analyses. The ICER appeared most sensitive to changes in estimates of utility.
The manufacturer presented results for additional scenarios:
Using pooled effectiveness for trabectedin from 3 uncontrolled phase 2 trials was associated with an ICER of £50,017 per QALY gained.
Assuming that 33% and 100% of patients receiving BSC receive further chemotherapy was associated with an ICER of £62,044 and £80,279 per QALY gained respectively.
The ERG stated that the revised method used to estimate the cost of trabectedin was, in general, appropriate. It noted, however, that the model may have underestimated the cost of trabectedin because a few participants were still being treated at the end of the follow-up period, yet the model assumed no patients incurred costs beyond follow-up. The ERG also identified a number of errors in the revised model submitted by the manufacturer. These errors were corrected by the ERG and were shown to have limited impact on the results. The ERG's corrections to the manufacturer's model resulted in an ICER of £56,949 per QALY gained for the base case (compared with the manufacturer's figure of £56,985, see section 3.15) and £49,992 per QALY gained for the pooled analysis (from the 3 phase 2 uncontrolled studies of trabectedin).
The ERG expressed strong concerns over the structure of the model in that people treated with trabectedin entered the model in the progression-free health state, whereas those who received BSC entered in the progressive disease health state, which was associated with a lower estimate of utility than the progression-free health state. The manufacturer conducted a revised scenario analysis (based on the revised method to estimate the cost of trabectedin), which assumed that the utility for the progression-free health state (in the BSC arm) was 0.653 for the first cycle and followed a linear decline over the next 4 cycles to reach the utility for progressive disease (0.473). This manufacturer's analysis was associated with an ICER of £61,064 per QALY gained.
In response to comments received during consultation about the way in which utility was modelled, the ERG presented analyses exploring the impact of different assumptions regarding utility on the ICER. These analyses did not include the model correction (described in section 3.18), which was estimated to increase the ICERs by approximately £5,000 per QALY gained. One analysis assumed the same utility value for the progressive disease and progression-free health states, and varied this value between 0.4 and 0.9. This caused the ICER to vary from more than £80,000 per QALY gained (with the utility value for both states set to 0.4) to approximately £40,000 per QALY gained (with the utility value for both states set to 0.9). Another analysis explored the difference in the utilities of the progressive disease and progression-free health states by setting the utility for progression-free to 0.653 (the manufacturer's base case) and varying the utility of progressive disease between 0.473 and 0.653. This had little impact on the ICER. The reverse analysis, which set the utility for progressive disease to 0.473 (the manufacturer's base case) and varied the utility for the progression-free health state between 0.473 and 0.9, produced an ICER range of approximately £46,000 to approximately £70,000 per QALY gained.
The ERG also noted the following uncertainties in the cost-effectiveness estimates presented in the manufacturer's submission:
The comparability of the BSC and trabectedin arms was unclear. The ERG believed that participants in the STS-201 trial were highly selected and would be expected to have a high rate of survival at the time of inclusion.
The data based on historical sources were uncertain and data relating to the natural history of disease may not be appropriate for patients who have contraindications for, or are intolerant of, ifosfamide or anthracyclines.
The ERG was unsure about the comparability of the utility values for patients with soft tissue sarcoma and those with lung cancer, noting that cost-effectiveness results were shown to be sensitive to changes in health-state utilities.
After the second Appraisal Committee meeting, the manufacturer proposed a patient access scheme for trabectedin for the treatment of advanced soft tissue sarcoma when treatment with anthracyclines and ifosfamide has failed or a person is intolerant of or has contraindications for anthracyclines and ifosfamide. Under this patient access scheme, the acquisition cost of trabectedin to the NHS would be capped at 5 cycles of treatment. The acquisition cost of trabectedin for treatment needed after the fifth cycle (that is, cycle 6 and beyond) would be met by the manufacturer. The Department of Health considered this would not place an excessive administrative burden on the NHS and accepted the consideration of this scheme by NICE.
The manufacturer submitted an updated cost-effectiveness model incorporating the patient access scheme. The model assumed reimbursement of the acquisition cost of trabectedin from the sixth treatment cycle onwards, and included additional costs to cover the increased operational costs to the NHS of implementing the scheme. The base-case analysis, which assumed equal utility values for the progression-free and progressive disease health states, produced an ICER of £28,712 per QALY gained. This was based on 41% of patients receiving more than 5 cycles of trabectedin, as observed in the STS-201 trial. The manufacturer also presented the scenario analysis with a higher utility value in the progression-free health state (0.653) than in the progressive disease health state (0.473), and incorporating a linear decline (in the BSC arm) of the value in the progression-free health state to the value of the progressive disease health state (see section 3.18). Incorporating the patient access scheme into this scenario reduced the ICER to £34,484 per QALY gained.
The ERG reviewed the updated analyses from the manufacturer and considered that the model had correctly incorporated the patient access scheme. The ERG reiterated that the scenario analysis that assumed that the utility value in the progression-free health state in the BSC arm followed a linear decline to reach the utility value for progressive disease represented the most appropriate estimation of the ICER. Corrections to minor errors noted in the model resulted in an ICER for this scenario of £34,538 per QALY gained.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of trabectedin, having considered evidence on the nature of advanced soft tissue sarcoma and the value placed on the benefits of trabectedin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
# Clinical effectiveness
The Committee considered the UK treatment pathway for patients with advanced soft tissue sarcoma and noted that trabectedin is licensed for patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The Committee heard from the patient experts and the clinical specialist that there have been no major changes in the treatment of advanced soft tissue sarcoma in the past 20 years and that treatment with trabectedin represents an option for those patients who would otherwise have no licensed treatment options. The Committee heard from the clinical specialist that trabectedin treatment would be managed by specialists in sarcoma units and would usually be administered in an outpatient setting, within existing care structures.
The Committee noted the evidence of clinical effectiveness presented by the manufacturer from the STS-201 trial, which compared 2 dosing regimens for trabectedin and included no alternative treatment as a comparator. The Committee appreciated that because soft tissue sarcoma is a rare condition, the evidence for the comparative effectiveness of trabectedin was limited. The Committee noted that the European Medicines Agency (EMEA) had granted trabectedin marketing authorisation under 'exceptional circumstances' based on evidence from a randomised, uncontrolled phase 2 trial of trabectedin in patients with L−sarcomas. The Committee was aware that there were 3 uncontrolled phase 2 trials that included patients with other types of sarcomas. The Committee heard from the clinical specialist that response to treatment varies according to the type of sarcoma, with some sarcomas being more sensitive to treatment with trabectedin. The Committee was aware that as part of the regulatory process for trabectedin, the manufacturer is committed to exploring the subtypes of soft tissue sarcoma that may best respond to treatment.
The Committee then considered whether the evidence from the 'historical' trials represented patients receiving BSC. Although the Committee was aware of the limitations of historical control data, it noted the 'exceptional circumstances' of the marketing authorisation regarding the difficulties of conducting adequately powered randomised controlled trials against BSC in this patient group, and of exploring factors associated with response to treatment in a reasonable timeframe. The Committee also heard from the clinical specialist that the patients in the 'historical' trials of BSC had been recruited relatively recently, that the general management of advanced soft tissue sarcoma had not changed significantly, and that the duration of the 'historical' control studies was comparable with the trabectedin trial. The Committee therefore concluded that the use of historical controls was appropriate for this disease area but nevertheless needed to be considered with caution.
The Committee noted that there were differences among the patient populations in the randomised trabectedin trial (STS-201) and the 'historical' trials of BSC, mainly with regard to previously received treatment, sarcoma type and ECOG performance status. The clinical specialist informed the Committee that the 3 other uncontrolled phase 2 trials of trabectedin had included patients who were similar to the patients in the 'historical' trials. The Committee therefore accepted that the results could be cautiously generalised to the wider population of patients with advanced soft tissue sarcoma.
The Committee considered the clinical effectiveness data presented by the manufacturer, and noted the median overall survival for patients randomised to the licensed dosage of trabectedin exceeded that for patients receiving BSC. For progression-free survival, patients randomised to the licensed dosage of trabectedin did better than those patients randomised to an active regimen of BSC (see sections 3.4 and 3.9). The Committee noted that there was no evidence on the effectiveness of trabectedin for patients with contraindications for ifosfamide or anthracyclines. The Committee heard from the clinical specialist, however, that a heart or liver impairment that prevents a patient from receiving ifosfamide or anthracyclines would not prevent a patient from receiving trabectedin.
The Committee understood that most adverse effects associated with trabectedin were reversible and non-cumulative. It heard from the clinical specialist and patient experts that there were fewer, less severe and less frequent adverse reactions associated with trabectedin than with the other chemotherapy agents used to treat soft tissue sarcoma. It understood that the adverse effects associated with trabectedin were manageable, but nevertheless important, as with other chemotherapy agents used to treat soft tissue sarcoma. Based on the clinical effectiveness evidence and the testimony from the clinical specialist and patient experts, the Committee concluded that trabectedin is a clinically effective treatment for advanced soft tissue sarcoma for patients in whom both anthracyclines and ifosfamide have failed, or who are unsuited to receive these agents, allowing for reservations about the use of historical control trials.
# Cost effectiveness
The Committee considered evidence on the cost effectiveness of trabectedin for the treatment of advanced soft tissue sarcoma. The Committee noted that overall survival, the acquisition cost of the drug and the utility estimates were the key factors driving the economic model. It heard from the ERG that, given the limited evidence available, the methods used by the manufacturer appeared robust and appropriate. It heard that the administration costs of trabectedin did not greatly affect the outcome of the model. The Committee also heard from the clinical specialist that the scenario submitted by the manufacturer which assumed no benefits of alternative chemotherapy was not clinically plausible. Clinical advice noted that 10% of patients might derive some benefit.
The Committee discussed the estimates of utility used in the model. It accepted the ERG's comment that the model was inappropriate in its assignment of different utility values to the initial health state of patients depending on the treatment to be received (trabectedin or BSC). The Committee heard from the ERG that the scenario analysis presented by the manufacturer was more appropriate, in which the progressive disease health state in the BSC arm was assigned an initial utility value identical to that of the progression-free health state and then declined linearly over the first 4 cycles of the model (see sections 3.18 and 3.23). The Committee agreed that this scenario represented the most plausible base-case estimation of the ICER.
The Committee next considered the appropriateness of the use of utilities associated with non-small-cell lung cancer as proxies for those associated with advanced soft tissue sarcoma, given that no utility values exist for advanced soft tissue sarcoma. The Committee heard from the clinical specialist and patient experts that it is not uncommon for patients with advanced soft tissue sarcoma to maintain a quality of life relatively undiminished by the disease for some time, experiencing a rapid decline of quality of life in the final weeks of life, rather than experiencing continued gradual decline over an extended period of time, as often occurs with non-small-cell lung cancer. It heard from the clinical specialist that it may be reasonable to assume that for some proportion of time, patients with advanced soft tissue sarcoma may therefore experience a higher quality of life than patients with non-small-cell lung cancer at a comparable stage of disease. The Committee accepted that these differences could be associated with a different utility profile for patients with advanced soft tissue sarcoma than for those with non-small-cell lung cancer.
The Committee understood from the ERG's exploratory analyses (see section 3.19) that the way in which utility was modelled influenced the ICER. The Committee had reservations about the use of utility data derived from patients with conditions other than advanced soft tissue sarcoma. The Committee considered that it was very unlikely that the progressive disease and progression-free health states would have the same utility value, and that it was more reasonable to assume a higher utility value for the progression-free state than for the progressive disease state. In the absence of compelling evidence to indicate otherwise, the Committee concluded that the manufacturer's base-case utility values for progression-free (0.653) and progressive disease (0.473) represented the best estimates available.
The Committee accepted that the patient access scheme for trabectedin was implemented correctly by the manufacturer in the updated economic model. The Committee noted that the patient access scheme involved capping the maximum acquisition cost of trabectedin per patient at 5 cycles. The Committee heard from the ERG that ICERs incorporating the patient access scheme were insensitive to changes in the operational costs of the scheme. The Committee concluded that the relevant and most appropriate ICER for trabectedin versus BSC on which to base a decision was approximately £34,500 per QALY gained (incorporating the manufacturer's base-case utility values, whereby the utility value in the progression-free health state in the BSC arm followed a linear decline to reach the utility value for progressive disease, and the patient access scheme, see section 3.23).
The Committee then considered the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of an additional 3 months or more, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.
The Committee discussed whether the benefit provided by trabectedin for the treatment of advanced soft tissue sarcoma fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that the total number of people with advanced soft tissue sarcoma in England and Wales was approximately 500 to 600, and that the number eligible for treatment with trabectedin may be as low as approximately 110 per year. Noting the limitations of analyses based on data from historical control trials, the Committee considered that life expectancy with BSC alone was likely to be approximately 6 months. The Committee considered the evidence from the trabectedin trial (STS-201) and noted the median overall survival for the licensed dosage was 13.9 months, although the Committee was not convinced that this value had not been overestimated. The Committee did, however, agree that trabectedin provided an improvement in the treatment of advanced soft tissue sarcoma and that it was likely that trabectedin would increase overall survival by more than 3 months. The Committee took the view that the estimates of clinical effectiveness informing the best available estimate of the ICER were sufficiently robust to conclude that trabectedin meets the criteria for being a life-extending, end-of-life treatment.
The Committee considered the best available estimate of the base-case ICER to be approximately £34,500 per QALY gained (see section 4.12). The Committee considered this ICER in light of the end-of-life criteria. The Committee considered that the additional weight that would need to be assigned to the original QALY benefits for the ICER to fall within the current threshold range was acceptable. The Committee concluded that, with the patient access scheme, trabectedin should be recommended as a treatment option for people with advanced soft tissue sarcoma in whom treatment with anthracyclines and ifosfamide has failed, or for those who are intolerant to or have contraindications for anthracyclines and ifosfamide.# Recommendations for further research
The Committee recommends that a study estimating utilities using directly observed health-related quality of life values (such as EQ−5D scores) in people with soft tissue sarcoma is conducted.
|
{'Guidance': 'Trabectedin is recommended as a treatment option for people with advanced soft tissue sarcoma if:\n\ntreatment with anthracyclines and ifosfamide has failed or\n\nthey are intolerant of or have contraindications for treatment with anthracyclines and ifosfamide.Trabectedin is only recommended if the company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with trabectedin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology ': "Trabectedin (Yondelis, Immedica) is an alkylating agent, which affects cancer cells by damaging DNA. Trabectedin has a UK marketing authorisation for the treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide or who are unsuited to receive these agents. The marketing authorisation was granted under 'exceptional circumstances'. The summary of product characteristics (SPC) states that 'efficacy data are based mainly on liposarcoma and leiomyosarcoma patients'.\n\nTrabectedin is contraindicated in people who have hypersensitivity to trabectedin or to any of the excipients, in those with concurrent serious or uncontrolled infection, in women who are breast-feeding, and in combination with yellow fever vaccine. The SPC states that trabectedin is not indicated for use in children and adolescents, and that creatine phosphokinase, hepatic function and haematological parameters should be monitored regularly during treatment. The SPC lists precautions for use of trabectedin in people with liver or kidney impairment. The SPC reports that the most common adverse reactions are nausea, fatigue, vomiting, weight loss (anorexia), neutropenia, thrombocytopenia, and increases in enzymes in blood indicating abnormal liver function. For full details of adverse events and contraindications, see the SPC.\n\nThe SPC for trabectedin states that 'the recommended dose is 1.5\xa0mg/m2 body surface area, administered as an intravenous infusion over 24\xa0hours with a 3-week interval between cycles.' The SPC also states that administration of trabectedin through a central venous line is 'strongly recommended'. Anti-emetic prophylaxis with intravenous dexamethasone (20\xa0mg) must be administered to all patients 30\xa0minutes before trabectedin treatment. Dexamethasone may also have hepatoprotective effects. The acquisition cost of trabectedin is £363.00 for a 250-microgram vial and £1,366.00 for a 1-mg (1,000-microgram) vial (excluding VAT; 'British national formulary' [BNF] edition\xa058). At a dose of 1.5\xa0mg/m2, apatient with a body surface area of 1.7\xa0m2 would need approximately 2.5\xa0mg of trabectedin per cycle. One such infusion (using two 1-mg vials and two 250-microgram vials of trabectedin) would cost £3,458. The company has a commercial arrangement. This makes trabectedin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of trabectedin and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission included a phase\xa02 randomised trial (STS-201) evaluating the efficacy of trabectedin in participants with locally advanced or metastatic soft tissue sarcoma in whom the disease had relapsed or become refractory after treatment with at least 1\xa0anthracycline and ifosfamide, given either in combination or in sequence. All participants had liposarcomas or leiomyosarcomas (L-sarcomas) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or 1. The trial randomised participants to 1\xa0of 2 dosing regimens of trabectedin. One group received the dosage of trabectedin specified in the marketing authorisation (1.5\xa0mg/m2 every 3\xa0weeks as a 24-hour intravenous infusion, n=136) and the other group (n=134) received trabectedin at a dosage of 0.58\xa0mg/m2 every week as a 3-hour intravenous infusion. In addition, the manufacturer's submission presented 3 uncontrolled phase\xa02 trials of trabectedin. These included a total of 194\xa0participants with soft tissue sarcoma, of whom 104 had L-sarcomas. Participants in all of these studies had an ECOG performance status of 0\xa0or 1. In the absence of relevant comparator data in the included trials, the manufacturer reported historical control data for patients receiving treatments considered to be equivalent to best supportive care (BSC; see sections\xa03.7 to 3.9). These data were derived from studies in the database of the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC STBSG).\n\nThe primary outcome of the STS-201 trial was time to progression (time between randomisation and the first documentation of disease progression or death as a result of progressive disease); secondary outcomes included progression-free survival, overall survival and best overall response. According to the manufacturer, treatment with trabectedin continued as long as participants derived therapeutic benefit, until the disease progressed, or for at least 2\xa0courses of therapy beyond a confirmed response. The design of STS-201 permitted crossover for participants in either arm whose disease progressed. The manufacturer acknowledged that the crossover design of the study affected overall survival.\n\nThe median time to progression from intention-to-treat analyses was statistically significantly longer (hazard ratio [HR]\xa00.734, p=0.032) for the licensed dosage of trabectedin, with a time to progression of 3.7\xa0months (95%\xa0confidence interval [CI] 2.1 to 5.4) compared with 2.3\xa0months (95%\xa0CI 2.0 to 3.5) for the comparator dosage of trabectedin. Median overall survival was 13.9\xa0months (95%\xa0CI 12.5 to 18.6) for the licensed dosage of trabectedin compared with 11.8\xa0months (95%\xa0CI 9.9 to 14.9) for the comparator trabectedin regimen. Median progression-free survival at 3 and 6\xa0months was 51.5% (95%\xa0CI 43.0 to 60.1) and 35.5% (95%\xa0CI 27.1 to 43.9) respectively for the licensed dosage of trabectedin, compared with 44.7% (95%\xa0CI 36.0 to 53.3) and 27.5% (95%\xa0CI 19.4 to 35.5) for the comparator trabectedin regimen. The manufacturer reported that in a pre-planned subgroup analysis, efficacy outcomes appeared to be more favourable in patients with liposarcomas than in those with leiomyosarcomas, regardless of the study arm.\n\nThe manufacturer reported that the main treatment-related severe (grades\xa03 and 4) adverse events observed in all studies were transient and reversible, and comprised non-cumulative neutropenia and elevations of hepatic transaminase without clinical consequences. Grade\xa03 or 4 nausea and vomiting were reported by some participants. The manufacturer stated that unlike with other commonly used cytotoxic agents, no cardiotoxicity or neurotoxicity was observed with trabectedin.\n\nNo health-related quality of life data were presented for patients with advanced soft tissue sarcoma and the manufacturer stated that none were obtained from the trials.\n\nHistorical control data were used to approximate BSC, with the manufacturer acknowledging the limitations of this approach. To estimate overall survival, data for those in whom treatment with ifosfamide had failed, for those receiving dacarbazine, and for those receiving etoposide were taken from an unpublished analysis of 4\xa0phase\xa02 studies in the EORTC STBSG database of adults with advanced pre-treated soft tissue sarcoma. To estimate progression-free survival, data for the comparators were taken from a publication reporting on phase\xa02 studies from the EORTC STBSG database. The studies included in the analysis varied in the treatment given to patients during and before entering the trials. Therefore, the manufacturer selected the pre-treated populations that they considered to be most relevant.\n\nThe manufacturer reported that the median overall survival of historical control patients treated with ifosfamide was 6.6\xa0months from start of therapy (95%\xa0CI 5.0 to 9.0); a further figure was included by the manufacturer, but was marked as academic-in-confidence and therefore cannot be presented. The manufacturer reported that the median overall survival for those treated with dacarbazine was 6.6\xa0months (95%\xa0CI 4.3 to 8.4) and 6.3\xa0months (95%\xa0CI 4.4 to 8.9) for those treated with etoposide.\n\nThe manufacturer reported that the mean progression-free survival of historical control patients treated with inactive regimens (n=234) was 21% (standard error [SE] ±\xa03%) and 8% (SE\xa0±\xa02%) at 3\xa0and 6\xa0months respectively. Inactive regimens include treatment with mitozolomide, nimustine, fotemustine, miltefosine, liposomal muramyl tripeptide phosphatidylethanolamide, temozolamide, etoposide, Tomudex or gemcitabine. The corresponding figures for historical control patients treated with active regimens comprising ifosfamide and dacarbazine (n=146) were 39% (SE\xa0±\xa04%) and 14% (SE\xa0±\xa03%) respectively.\n\nThe manufacturer developed its own economic evaluation, comprising a 2-arm state-transition model. The first arm was designed to capture the costs and outcomes associated with treatment with trabectedin; the second arm was designed to capture the costs and outcomes associated with BSC. Administration of other chemotherapies in addition to BSC was explored in a sensitivity analysis. The model included 4\xa0mutually exclusive health states: progression-free after treatment with trabectedin; progressive disease after treatment with trabectedin; progressive disease with BSC; and death. People treated with trabectedin entered the model in the progression-free state, whereas people treated with BSC entered the model in the progressive disease state. The model cycle length was 1\xa0month with a time horizon of 5\xa0years.\n\nThe model used the effectiveness data from the STS-201 trial of trabectedin, which included only participants with L-sarcomas after they had been treated with a regimen containing at least 1 anthracycline and ifosfamide (combined or sequential). To represent the base case, the manufacturer selected effectiveness data from participants receiving a 24-hour infusion of trabectedin every 3\xa0weeks. In a sensitivity analysis, the manufacturer modelled the pooled effectiveness from the 3\xa0initial phase\xa02 uncontrolled studies of trabectedin. Transition probabilities for the trabectedin arm were estimated from Weibull parameters derived from the patient-level data for time to progression from the STS‑201 trial. Weibull curves were fitted to Kaplan–Meier curves for time to progression and overall survival. The Weibull estimates were considered by the manufacturer to be comparable to the Kaplan–Meier curves. Following a request by the ERG, arising because of differences in patient characteristics between the trabectedin and BSC arms, Weibull curves for trabectedin were re-calculated using age, gender and severity as covariates.\n\nThe effectiveness data for patients who receive BSC after failure of anthracyclines and ifosfamide were estimated from pooled data from 4\xa0published trials from the EORTC STBSG database. These data were used in the same manner as the STS-201 data to estimate the transition probabilities (in this case, only from progression to death). In response to requests for clarification, the manufacturer submitted a revised model in which the survival curves were adjusted for the differences in patient characteristics between the trabectedin and BSC arms.\n\nBecause no studies of quality of life in patients with soft tissue sarcoma were identified, the manufacturer, following discussion with its clinical experts, used health-state utilities for non-small-cell lung cancer as proxies, assuming comparable prognoses and stages of the 2\xa0diseases. Health-state utilities in progression-free and progressive disease states were assumed to be similar for all patients, irrespective of treatment. The utility values for progression-free and progressive disease health states were assumed to be 0.653 and 0.473 respectively. Admission to hospital as a result of adverse events associated with trabectedin treatment was associated with a utility of 0.610, which was equal to that associated with nausea and vomiting. This was assumed to last 1\xa0month and equated to a quality-adjusted life year (QALY) decrement of 0.004. The utility associated with developing grade\xa03 or 4 neutropenia was 0.56. This was assumed to last 1\xa0week and equated to a QALY decrement of 0.002. Adverse events were assumed to occur only during the first cycle of trabectedin treatment, and no disutility associated with adverse events was modelled for patients receiving BSC.\n\nFollowing concerns raised by the ERG about the calculation of the average cost per patient, the manufacturer revised the methodology used to estimate the acquisition cost of the drug. The manufacturer used patient-level data from the STS-201 trial to calculate the average number of 1-mg and 250-microgram vials used for each patient and the proportion of patients receiving trabectedin in each cycle. The ERG stated that the manufacturer's revised response reported a cost per patient of £23,719 with administration costs excluded, and £25,986 with administration costs and a pre-treatment injection of dexamethasone included. The manufacturer obtained management costs for patients in the progressive disease health state from a cost-of-illness study, and assumed that the costs for the progression-free health state, in the absence of data, were half the costs for the progressive disease health state. Additional costs were included when a patient died. Costs of hospitalisation were average costs and were dependent on patients' diagnoses. The manufacturer did not include costs for treating neutropenia, for treating adverse events in the BSC arm, or for patient monitoring.\n\nWith discounting at 3.5% per annum, the manufacturer's revised base-case cost-effectiveness results gave an incremental cost-effectiveness ratio (ICER) of £56,985 per QALY gained for trabectedin compared with BSC, based on an incremental cost of £27,145 and an incremental QALY gain of 0.476. The manufacturer explored uncertainty in 1-way sensitivity and probabilistic sensitivity analyses. The ICER appeared most sensitive to changes in estimates of utility.\n\nThe manufacturer presented results for additional scenarios:\n\nUsing pooled effectiveness for trabectedin from 3\xa0uncontrolled phase\xa02 trials was associated with an ICER of £50,017 per QALY gained.\n\nAssuming that 33% and 100% of patients receiving BSC receive further chemotherapy was associated with an ICER of £62,044 and £80,279 per QALY gained respectively.\n\nThe ERG stated that the revised method used to estimate the cost of trabectedin was, in general, appropriate. It noted, however, that the model may have underestimated the cost of trabectedin because a few participants were still being treated at the end of the follow-up period, yet the model assumed no patients incurred costs beyond follow-up. The ERG also identified a number of errors in the revised model submitted by the manufacturer. These errors were corrected by the ERG and were shown to have limited impact on the results. The ERG's corrections to the manufacturer's model resulted in an ICER of £56,949 per QALY gained for the base case (compared with the manufacturer's figure of £56,985, see section\xa03.15) and £49,992 per QALY gained for the pooled analysis (from the 3\xa0phase\xa02 uncontrolled studies of trabectedin).\n\nThe ERG expressed strong concerns over the structure of the model in that people treated with trabectedin entered the model in the progression-free health state, whereas those who received BSC entered in the progressive disease health state, which was associated with a lower estimate of utility than the progression-free health state. The manufacturer conducted a revised scenario analysis (based on the revised method to estimate the cost of trabectedin), which assumed that the utility for the progression-free health state (in the BSC arm) was 0.653 for the first cycle and followed a linear decline over the next 4\xa0cycles to reach the utility for progressive disease (0.473). This manufacturer's analysis was associated with an ICER of £61,064 per QALY gained.\n\nIn response to comments received during consultation about the way in which utility was modelled, the ERG presented analyses exploring the impact of different assumptions regarding utility on the ICER. These analyses did not include the model correction (described in section\xa03.18), which was estimated to increase the ICERs by approximately £5,000 per QALY gained. One analysis assumed the same utility value for the progressive disease and progression-free health states, and varied this value between 0.4 and 0.9. This caused the ICER to vary from more than £80,000 per QALY gained (with the utility value for both states set to 0.4) to approximately £40,000 per QALY gained (with the utility value for both states set to 0.9). Another analysis explored the difference in the utilities of the progressive disease and progression-free health states by setting the utility for progression-free to 0.653 (the manufacturer's base case) and varying the utility of progressive disease between 0.473 and 0.653. This had little impact on the ICER. The reverse analysis, which set the utility for progressive disease to 0.473 (the manufacturer's base case) and varied the utility for the progression-free health state between 0.473 and 0.9, produced an ICER range of approximately £46,000 to approximately £70,000 per QALY gained.\n\nThe ERG also noted the following uncertainties in the cost-effectiveness estimates presented in the manufacturer's submission:\n\nThe comparability of the BSC and trabectedin arms was unclear. The ERG believed that participants in the STS-201 trial were highly selected and would be expected to have a high rate of survival at the time of inclusion.\n\nThe data based on historical sources were uncertain and data relating to the natural history of disease may not be appropriate for patients who have contraindications for, or are intolerant of, ifosfamide or anthracyclines.\n\nThe ERG was unsure about the comparability of the utility values for patients with soft tissue sarcoma and those with lung cancer, noting that cost-effectiveness results were shown to be sensitive to changes in health-state utilities.\n\nAfter the second Appraisal Committee meeting, the manufacturer proposed a patient access scheme for trabectedin for the treatment of advanced soft tissue sarcoma when treatment with anthracyclines and ifosfamide has failed or a person is intolerant of or has contraindications for anthracyclines and ifosfamide. Under this patient access scheme, the acquisition cost of trabectedin to the NHS would be capped at 5\xa0cycles of treatment. The acquisition cost of trabectedin for treatment needed after the fifth cycle (that is, cycle\xa06 and beyond) would be met by the manufacturer. The Department of Health considered this would not place an excessive administrative burden on the NHS and accepted the consideration of this scheme by NICE.\n\nThe manufacturer submitted an updated cost-effectiveness model incorporating the patient access scheme. The model assumed reimbursement of the acquisition cost of trabectedin from the sixth treatment cycle onwards, and included additional costs to cover the increased operational costs to the NHS of implementing the scheme. The base-case analysis, which assumed equal utility values for the progression-free and progressive disease health states, produced an ICER of £28,712 per QALY gained. This was based on 41% of patients receiving more than 5 cycles of trabectedin, as observed in the STS-201 trial. The manufacturer also presented the scenario analysis with a higher utility value in the progression-free health state (0.653) than in the progressive disease health state (0.473), and incorporating a linear decline (in the BSC arm) of the value in the progression-free health state to the value of the progressive disease health state (see section 3.18). Incorporating the patient access scheme into this scenario reduced the ICER to £34,484 per QALY gained.\n\nThe ERG reviewed the updated analyses from the manufacturer and considered that the model had correctly incorporated the patient access scheme. The ERG reiterated that the scenario analysis that assumed that the utility value in the progression-free health state in the BSC arm followed a linear decline to reach the utility value for progressive disease represented the most appropriate estimation of the ICER. Corrections to minor errors noted in the model resulted in an ICER for this scenario of £34,538 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of trabectedin, having considered evidence on the nature of advanced soft tissue sarcoma and the value placed on the benefits of trabectedin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee considered the UK treatment pathway for patients with advanced soft tissue sarcoma and noted that trabectedin is licensed for patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The Committee heard from the patient experts and the clinical specialist that there have been no major changes in the treatment of advanced soft tissue sarcoma in the past 20\xa0years and that treatment with trabectedin represents an option for those patients who would otherwise have no licensed treatment options. The Committee heard from the clinical specialist that trabectedin treatment would be managed by specialists in sarcoma units and would usually be administered in an outpatient setting, within existing care structures.\n\nThe Committee noted the evidence of clinical effectiveness presented by the manufacturer from the STS-201 trial, which compared 2\xa0dosing regimens for trabectedin and included no alternative treatment as a comparator. The Committee appreciated that because soft tissue sarcoma is a rare condition, the evidence for the comparative effectiveness of trabectedin was limited. The Committee noted that the European Medicines Agency (EMEA) had granted trabectedin marketing authorisation under 'exceptional circumstances' based on evidence from a randomised, uncontrolled phase\xa02 trial of trabectedin in patients with L−sarcomas. The Committee was aware that there were 3\xa0uncontrolled phase\xa02 trials that included patients with other types of sarcomas. The Committee heard from the clinical specialist that response to treatment varies according to the type of sarcoma, with some sarcomas being more sensitive to treatment with trabectedin. The Committee was aware that as part of the regulatory process for trabectedin, the manufacturer is committed to exploring the subtypes of soft tissue sarcoma that may best respond to treatment.\n\nThe Committee then considered whether the evidence from the 'historical' trials represented patients receiving BSC. Although the Committee was aware of the limitations of historical control data, it noted the 'exceptional circumstances' of the marketing authorisation regarding the difficulties of conducting adequately powered randomised controlled trials against BSC in this patient group, and of exploring factors associated with response to treatment in a reasonable timeframe. The Committee also heard from the clinical specialist that the patients in the 'historical' trials of BSC had been recruited relatively recently, that the general management of advanced soft tissue sarcoma had not changed significantly, and that the duration of the 'historical' control studies was comparable with the trabectedin trial. The Committee therefore concluded that the use of historical controls was appropriate for this disease area but nevertheless needed to be considered with caution.\n\nThe Committee noted that there were differences among the patient populations in the randomised trabectedin trial (STS-201) and the 'historical' trials of BSC, mainly with regard to previously received treatment, sarcoma type and ECOG performance status. The clinical specialist informed the Committee that the 3\xa0other uncontrolled phase\xa02 trials of trabectedin had included patients who were similar to the patients in the 'historical' trials. The Committee therefore accepted that the results could be cautiously generalised to the wider population of patients with advanced soft tissue sarcoma.\n\nThe Committee considered the clinical effectiveness data presented by the manufacturer, and noted the median overall survival for patients randomised to the licensed dosage of trabectedin exceeded that for patients receiving BSC. For progression-free survival, patients randomised to the licensed dosage of trabectedin did better than those patients randomised to an active regimen of BSC (see sections\xa03.4 and 3.9). The Committee noted that there was no evidence on the effectiveness of trabectedin for patients with contraindications for ifosfamide or anthracyclines. The Committee heard from the clinical specialist, however, that a heart or liver impairment that prevents a patient from receiving ifosfamide or anthracyclines would not prevent a patient from receiving trabectedin.\n\nThe Committee understood that most adverse effects associated with trabectedin were reversible and non-cumulative. It heard from the clinical specialist and patient experts that there were fewer, less severe and less frequent adverse reactions associated with trabectedin than with the other chemotherapy agents used to treat soft tissue sarcoma. It understood that the adverse effects associated with trabectedin were manageable, but nevertheless important, as with other chemotherapy agents used to treat soft tissue sarcoma. Based on the clinical effectiveness evidence and the testimony from the clinical specialist and patient experts, the Committee concluded that trabectedin is a clinically effective treatment for advanced soft tissue sarcoma for patients in whom both anthracyclines and ifosfamide have failed, or who are unsuited to receive these agents, allowing for reservations about the use of historical control trials.\n\n# Cost effectiveness\n\nThe Committee considered evidence on the cost effectiveness of trabectedin for the treatment of advanced soft tissue sarcoma. The Committee noted that overall survival, the acquisition cost of the drug and the utility estimates were the key factors driving the economic model. It heard from the ERG that, given the limited evidence available, the methods used by the manufacturer appeared robust and appropriate. It heard that the administration costs of trabectedin did not greatly affect the outcome of the model. The Committee also heard from the clinical specialist that the scenario submitted by the manufacturer which assumed no benefits of alternative chemotherapy was not clinically plausible. Clinical advice noted that 10% of patients might derive some benefit.\n\nThe Committee discussed the estimates of utility used in the model. It accepted the ERG's comment that the model was inappropriate in its assignment of different utility values to the initial health state of patients depending on the treatment to be received (trabectedin or BSC). The Committee heard from the ERG that the scenario analysis presented by the manufacturer was more appropriate, in which the progressive disease health state in the BSC arm was assigned an initial utility value identical to that of the progression-free health state and then declined linearly over the first 4\xa0cycles of the model (see sections\xa03.18 and 3.23). The Committee agreed that this scenario represented the most plausible base-case estimation of the ICER.\n\nThe Committee next considered the appropriateness of the use of utilities associated with non-small-cell lung cancer as proxies for those associated with advanced soft tissue sarcoma, given that no utility values exist for advanced soft tissue sarcoma. The Committee heard from the clinical specialist and patient experts that it is not uncommon for patients with advanced soft tissue sarcoma to maintain a quality of life relatively undiminished by the disease for some time, experiencing a rapid decline of quality of life in the final weeks of life, rather than experiencing continued gradual decline over an extended period of time, as often occurs with non-small-cell lung cancer. It heard from the clinical specialist that it may be reasonable to assume that for some proportion of time, patients with advanced soft tissue sarcoma may therefore experience a higher quality of life than patients with non-small-cell lung cancer at a comparable stage of disease. The Committee accepted that these differences could be associated with a different utility profile for patients with advanced soft tissue sarcoma than for those with non-small-cell lung cancer.\n\nThe Committee understood from the ERG's exploratory analyses (see section\xa03.19) that the way in which utility was modelled influenced the ICER. The Committee had reservations about the use of utility data derived from patients with conditions other than advanced soft tissue sarcoma. The Committee considered that it was very unlikely that the progressive disease and progression-free health states would have the same utility value, and that it was more reasonable to assume a higher utility value for the progression-free state than for the progressive disease state. In the absence of compelling evidence to indicate otherwise, the Committee concluded that the manufacturer's base-case utility values for progression-free (0.653) and progressive disease (0.473) represented the best estimates available.\n\nThe Committee accepted that the patient access scheme for trabectedin was implemented correctly by the manufacturer in the updated economic model. The Committee noted that the patient access scheme involved capping the maximum acquisition cost of trabectedin per patient at 5\xa0cycles. The Committee heard from the ERG that ICERs incorporating the patient access scheme were insensitive to changes in the operational costs of the scheme. The Committee concluded that the relevant and most appropriate ICER for trabectedin versus BSC on which to base a decision was approximately £34,500 per QALY gained (incorporating the manufacturer's base-case utility values, whereby the utility value in the progression-free health state in the BSC arm followed a linear decline to reach the utility value for progressive disease, and the patient access scheme, see section\xa03.23).\n\nThe Committee then considered the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of an additional 3\xa0months or more, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether the benefit provided by trabectedin for the treatment of advanced soft tissue sarcoma fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that the total number of people with advanced soft tissue sarcoma in England and Wales was approximately 500 to 600, and that the number eligible for treatment with trabectedin may be as low as approximately 110 per year. Noting the limitations of analyses based on data from historical control trials, the Committee considered that life expectancy with BSC alone was likely to be approximately 6\xa0months. The Committee considered the evidence from the trabectedin trial (STS-201) and noted the median overall survival for the licensed dosage was 13.9\xa0months, although the Committee was not convinced that this value had not been overestimated. The Committee did, however, agree that trabectedin provided an improvement in the treatment of advanced soft tissue sarcoma and that it was likely that trabectedin would increase overall survival by more than 3\xa0months. The Committee took the view that the estimates of clinical effectiveness informing the best available estimate of the ICER were sufficiently robust to conclude that trabectedin meets the criteria for being a life-extending, end-of-life treatment.\n\nThe Committee considered the best available estimate of the base-case ICER to be approximately £34,500 per QALY gained (see section\xa04.12). The Committee considered this ICER in light of the end-of-life criteria. The Committee considered that the additional weight that would need to be assigned to the original QALY benefits for the ICER to fall within the current threshold range was acceptable. The Committee concluded that, with the patient access scheme, trabectedin should be recommended as a treatment option for people with advanced soft tissue sarcoma in whom treatment with anthracyclines and ifosfamide has failed, or for those who are intolerant to or have contraindications for anthracyclines and ifosfamide.", 'Recommendations for further research': 'The Committee recommends that a study estimating utilities using directly observed health-related quality of life values (such as EQ−5D scores) in people with soft tissue sarcoma is conducted.'}
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https://www.nice.org.uk/guidance/ta185
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Evidence-based recommendations on trabectedin (Yondelis) for treating advanced soft tissue sarcoma in adults.
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e90e831b61e3ed8889a2e14a5370223f34467340
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nice
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Leukomed Sorbact for preventing surgical site infection
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Leukomed Sorbact for preventing surgical site infection
Evidence-based recommendations on Leukomed Sorbact for preventing surgical site infection after caesarean section or vascular surgery.
# Recommendations
Evidence supports the case for adopting Leukomed Sorbact for closed surgical wounds after caesarean section and vascular surgery.
Leukomed Sorbact should be considered as an option for people with wounds that are expected to have low to moderate exudate after caesarean section and vascular surgery. It should be used as part of usual measures to help reduce the risk of surgical site infection. More evidence is needed on the use of Leukomed Sorbact on wounds after other types of surgery.
Cost modelling shows that the reduced rate of surgical site infection with Leukomed Sorbact compared with standard surgical dressings leads to savings of:
£107 per person after caesarean section
£18 per person after vascular surgery.By adopting this technology, the NHS may save up to £5.3 million per year for caesarean section and up to £1.2 million per year for vascular surgery. Cost savings are expected because fewer people will need to stay in hospital for treatment of surgical site infection. For more details, see the NICE resource impact report.
Why the committee made these recommendations
Leukomed Sorbact is an interactive dressing that binds to the microbes that cause surgical site infection so they are removed when the dressing is changed.
Evidence suggests that using Leukomed Sorbact instead of standard dressings after caesarean section and vascular surgery reduces the rate of surgical site infection and leads to cost savings. So Leukomed Sorbact is recommended for wounds expected to have low to moderate exudate.# The technology
# Technology
Leukomed Sorbact (Essity), is a sterile, single-use, bacteria-binding, adhesive-bordered wound dressing. It is used to prevent surgical site infection (SSI) in closed surgical wounds that have low to moderate exudate.
The dressing comprises an absorbent non-woven wound contact pad and an outer transparent adhesive polyurethane film. The pad is made of a white viscose polypropylene and polyester mesh that is coated with the proprietary compound dialkylcarbamoyl chloride (DACC). DACC is hydrophobic, meaning that it does not mix with water and tends to bind to itself or other hydrophobic materials if water is present. In a moist wound, DACC binds to hydrophobic bacteria and fungi that cause SSI. These bound microorganisms are then removed from the wound site when the dressing is changed. Binding to DACC does not cause bacteria to be lysed (broken open), which avoids causing inflammation at the wound site. The polyurethane film is designed to maintain a moist environment and protect the wound from external contamination. The dressing is available in various sizes.
# Innovative aspects
The innovative aspect is the DACC component. This binds and inactivates bacteria through hydrophobic interaction, which helps to reduce colonisation of the wound by potentially harmful microbes.
# Intended use
Leukomed Sorbact is intended to be applied by a surgeon or theatre nurse in the operating theatre after surgery. It can also be used in the early postoperative period when the dressing needs to be replaced.
# Costs
The cost of Leukomed Sorbact is £9.15 per dressing (excluding VAT). There are no other costs for implementing this technology and no training costs. For more details, see the website for Leukomed Sorbact.# Evidence
# Clinical evidence
## The relevant clinical evidence consists of 5 studies, including 3 randomised trials
The external assessment centre (EAC) considered 5 publications:
randomised controlled trial (RCT; Stanirowski et al. 2016a)
pilot RCTs (Totty et al. 2019; Stanirowski et al. 2016b)
non-RCT (Bua et al. 2017) and
unpublished audit (Taylor et al. 2020).The EAC excluded 5 studies identified by the company because 4 did not include Leukomed Sorbact and there were significant uncertainties about the design of 1 study.
## The evidence considered is limited to caesarean section and vascular surgery
Stanirowski et al. 2016a and 2016b were both done in Poland in women having elective or emergency caesarean section. Totty et al. 2019 and Bua et al. 2017 were UK studies in people having vascular surgery. Taylor et al. 2020 contained audit data provided by the company on women having caesarean section in 1 UK health board.
## The evidence suggests Leukomed Sorbact reduces SSI in caesarean section and vascular surgery
Up to 30 days after surgery, surgical site infection (SSI) rates were lower for people having Leukomed Sorbact compared with those having standard dressings. The difference in infection rates was not always statistically significant depending on the trial size. The largest RCT was considered to have the least risk of bias (Stanirowski et al. 2016a). In this study, the SSI rate was 1.8% for Leukomed Sorbact compared with 5.2% for standard dressings at 14 days after caesarean section (statistically significant, p=0.04). In Stanirowski et al. 2016b, the SSI rate was 2.8% for Leukomed Sorbact compared with 9.8% for standard dressings at 14 days after caesarean section (not statistically significant; p=0.08). In Bua et al. 2017, the SSI rate was 1% for Leukomed Sorbact and 10% for standard dressings at 5 to 7 days after vascular surgery (statistically significant, p<0.05). In Totty et al. 2019 and Bua et al. 2017, SSI rates were 16% and 9% at 30 days respectively for Leukomed Sorbact after vascular surgery, compared with 26% and 10% for standard dressings. The differences were not statistically significant (p=0.161 and p=0.83, respectively).
## The evidence suggests that Leukomed Sorbact may reduce antibiotic use
In 3 studies there was less need for antibiotic treatment with Leukomed Sorbact compared with standard dressings (Bua et al. 2017, Stanirowski et al. 2016a and 2016b). In all studies the number of people reported as having antibiotics was low in both arms, and the reported differences were not statistically significant in Stanirowski et al. 2016a (0 in Leukomed Sorbact group, 4 in control group, p=0.13).
## The evidence suggests that Leukomed Sorbact may reduce readmissions from wound complications
In Stanirowski et al. 2016a, women with SSI in the standard dressings group each had 2.9 outpatient hospital visits. Women with SSI in the Leukomed Sorbact group had 4.6 visits, a difference that was statistically significant, p=0.02. However, this was a secondary analysis in a small subgroup of women. The same study found that women with SSI who had Leukomed Sorbact had fewer additional days in hospital (0 days compared with 8.2 days for standard dressings, p=0.22).
# Cost evidence
## The published economic evidence suggests Leukomed Sorbact is cost saving
The economic analysis in the Stanirowski et al. 2016a and Stanirowski et al. 2019 studies showed that Leukomed Sorbact is cost saving when compared with standard surgical dressings. In Stanirowski et al. 2016a, total costs for preventing and treating SSI were 5,775 euros in the standard dressings group compared with 1,065 euros in the Leukomed Sorbact group. In Stanirowski et al. 2019, the same data were used and a decision-analytic model was applied from a UK NHS perspective. This showed a cost saving of £119.07 per person in favour of Leukomed Sorbact.
## The company's cost modelling finds Leukomed Sorbact to be cost saving for caesarean section, vascular surgery and all surgery
The company submitted a simple decision tree model with 2 interventions, Leukomed Sorbact or standard surgical dressings. There were 2 outcomes, SSI or no SSI. The time horizon was 30 days. The company reported base-case cost savings per person with Leukomed Sorbact of £107.43 for caesarean section, £23.55 for vascular surgery, and £20.56 for all surgery. The company's sensitivity analyses found these results to be robust to parameter changes.
## The EAC agrees with the company's cost model but disagrees about including all surgery because of lack of evidence
The EAC agreed with the company's model and its assumptions and made 1 change, to the cost of an SSI episode for vascular surgery. Leukomed Sorbact remained cost saving but the cost savings were lower than those estimated in the company's model for vascular surgery, at £17.82 per patient. The cost savings remained robust to parameter changes. The EAC chose not to model the use of Leukomed Sorbact for all types of surgery because it considered that there was insufficient clinical evidence to do so.# Committee discussion
# Clinical-effectiveness overview
## Leukomed Sorbact reduces SSI after caesarean section
The committee noted that Stanirowski et al. 2016a was a well-performed randomised controlled trial (RCT) with a limited risk of bias. The results showed a statistically significant reduction in surgical site infection (SSI) 14 days after caesarean section with Leukomed Sorbact compared with standard dressings. The committee and clinical experts discussed the relatively low rate of systemic antibiotic use in women who had SSI in this study. The committee considered that this was likely to be explained by the infections being relatively mild. The clinical experts stated that intravenous antibiotics were only needed for treating the most severe SSIs. The committee concluded that using Leukomed Sorbact reduced the rate of SSI after caesarean section compared with standard dressings.
## Leukomed Sorbact reduces SSI after vascular surgery
In the prospective non-randomised Bua et al. 2017 study there were fewer SSIs with Leukomed Sorbact compared with standard dressings at 5 to 7 days and at 30 days. Although the number of people included in the Totty et al. 2019 pilot RCT was relatively small, there were fewer SSIs in those who had Leukomed Sorbact. The committee recognised the limitations of the evidence. But it concluded that the study results and the plausibility of the clinical benefit for this group was sufficient to support the use of Leukomed Sorbact after vascular surgery. It welcomed further research in this area.
## The evidence does not support a broader recommendation to use Leukomed Sorbact in all types of surgery
No evidence was presented to support the use of Leukomed Sorbact in surgery other than caesarean section and vascular surgery. It was noted that Leukomed Sorbact could potentially be particularly useful in plastic surgery and breast surgery, which involve subcutaneous dissection. One clinical expert stated that Leukomed Sorbact is being used after gynaecological surgery at their hospital, but no data are currently available on this use. The committee concluded that the current evidence could not be extrapolated to support the use of Leukomed Sorbact after all types of surgery. It also concluded that it would welcome further research on the use of Leukomed Sorbact in other types of surgery.
## Feedback from clinical experts was positive
Comments from clinical experts about the clinical benefits of Leukomed Sorbact were positive, noting that it seemed to reduce SSI and was easy to use. The clinical experts were broadly optimistic that Leukomed Sorbact may be useful for other types of surgery.
# Other patient benefits or issues
## Using Leukomed Sorbact to reduce SSI risk after caesarean section may enhance recovery
In Stanirowski et al. 2016a, developing SSI led to an increase in mean hospital stay of 8.2 days in the control group. Women with SSI in the Leukomed Sorbact group had more outpatient visits than women with SSI in the control group (4.6 per person compared with 2.9 per person, respectively). This was a secondary analysis in a small subgroup of women. The clinical experts explained that reducing SSI may have additional benefits, such as new mothers being able to care for their babies and a positive effect on postnatal mental health. The committee concluded that reducing the incidence of SSI after caesarean section was likely to reduce the need for prolonged hospital stays and enhance recovery.
## Compared with PICO negative pressure wound therapy, Leukomed Sorbact is comfortable and discreet
The clinical experts reported that people using Leukomed Sorbact had found it to be comfortable and had positive feedback. Unlike the battery-powered PICO, it can be worn while showering and does not make any noise.
# Side effects and adverse events
## Leukomed Sorbact has only uncommon, minor adverse events
The clinical experts noted only 1 report of contact dermatitis after the use of Leukomed Sorbact. The external assessment centre (EAC) identified 1 adverse event registered with the US Food and Drug Administration, in which a person who had a total knee replacement developed a chemical burn after using Leukomed Sorbact. About 1 month after surgery, the person attended the emergency department because of a chemical burn with eschar over the surgical site. The eschar was surgically removed, and the person was discharged after 2 days. This was described in the report as a 'device malfunction' but no other details were reported. The company's submission included an observational study in a poster presentation (Coldwell et al. 2014). In this study there were 2 hypersensitivity reactions to the adhesive in 55 people who had Leukomed Sorbact in an Australian primary care setting.
# Relevance to the NHS
## The studies using Leukomed Sorbact are relevant to the NHS
The Stanirowski et al. 2016a and 2016b studies, which investigated the use of Leukomed Sorbact after caesarean section, were both done in Poland. The clinical experts advised, however, that the care pathway and outcome measures reported in these studies were relevant to an NHS setting. The 2 studies investigating the use of Leukomed Sorbact for vascular surgery (Totty et al. 2019 and Bua et al. 2017) were done in the UK. The committee concluded that the evidence was relevant to the NHS.
# NHS considerations overview
## Most wounds from vascular surgery and caesarean section are expected to have low to moderate exudate
Leukomed Sorbact is indicated when a wound is expected to have low to moderate exudate. The clinical experts advised that this would be most caesarean section or vascular surgery wounds. They also explained that people with wounds at risk of high exudate could usually be identified at the time of surgery and would not have Leukomed Sorbact dressings.
# Cost modelling overview
## The company's cost model is appropriate for caesarean section and vascular surgery but not for other types of surgery
The committee agreed with the EAC that the company's cost model was appropriate for analysing the costs of using Leukomed Sorbact after caesarean section and vascular surgery. It noted that only small adjustments were needed. The committee also agreed with the EAC that cost modelling was inappropriate for an all surgery group because there was no evidence to support the benefits of Leukomed Sorbact for all types of surgery.
## The EAC's base-case analysis shows Leukomed Sorbact is cost saving
The EAC's base-case analysis showed that, compared with standard dressings, using Leukomed Sorbact is cost saving by:
£107.43 per person after caesarean section
£17.82 per person after vascular surgery.The standard surgical dressing used as the comparator in the cost modelling was the Opsite Post‑OP dressing, the best-selling vapour-permeable adhesive film and absorbent sterile pad dressing. The clinical experts confirmed that this standard dressing was widely used in NHS practice.
## The sources for the baseline risk of SSI and the costs of treating SSI after caesarean section and vascular surgery are appropriate
In the company's model, baseline SSI risks for different surgical indications were taken from NHS England or NHS Wales data. The Leukomed Sorbact SSI risk was taken from the pooled results of the clinical studies (Stanirowski et al. 2016a and 2016b for caesarean section; Bua et al. 2017 and Totty et al. 2019 for vascular surgery). The EAC considered the data sources for these inputs appropriate. The cost of SSI in caesarean section was taken from Jenks et al. 2014. The cost of SSI in vascular surgery was taken from an unpublished study (York Health Economics Consortium 2020) but the EAC considered that costs from Jenks et al. 2014 were more appropriate. The committee accepted that these sources were appropriate.
# Main cost drivers
## The company's sensitivity analyses show that the cost saving with Leukomed Sorbact is robust
The company's sensitivity analyses varied the rate of SSI and the costs of Leukomed Sorbact and the comparator. Leukomed Sorbact remained cost saving in all these analyses. The company did 1‑way sensitivity analysis on the cost per SSI episode, varying the cost estimates within their 95% confidence intervals:
For caesarean section, the base-case SSI episode cost was £4,048 and the breakeven point was £350.
For vascular surgery, the base-case SSI episode cost was £3,427 and the breakeven point was £2,000.A second sensitivity analysis investigated the effect of reducing the standard dressing cost by 50% and increasing the cost of Leukomed Sorbact by 100%, or both. For both caesarean section and vascular surgery Leukomed Sorbact remained cost saving.
## The company's scenario analysis reports the breakeven points for reducing SSI risk
The company did a scenario analysis, varying the relative risk reduction by plus or minus 25%:
For caesarean section, the base-case SSI risk was 4.35%, with a relative risk reduction of 67% and an incremental cost per person of -£107.43. The breakeven point for relative risk reduction was 6%.
For vascular surgery, the base-case SSI risk was 2.5%, with a 42% relative risk reduction and an incremental cost per person of -£23.54. The breakeven point for relative risk reduction was 13%.
## The EAC's threshold analyses estimate the breakeven points in the cost model
The EAC did threshold analyses for cost savings from using Leukomed Sorbact after caesarean section and vascular surgery. The breakeven points were estimated for key values in the cost model. For caesarean section:
baseline SSI risk: base case 4.35%, breakeven point 0.39%
relative risk reduction in SSI: base case 67%, breakeven point 6%
SSI episode cost: base case £4,048, breakeven point £362.For vascular surgery:
baseline SSI risk: base case 2.5%, breakeven point 0.93%
relative risk reduction in SSI: base case 42%, breakeven point 16%
SSI episode cost: base case £2,072, breakeven point £1,004.
## Leukomed Sorbact is cost saving across a wide range of SSI costs, device costs, comparator costs and relative risk reduction
There were wide margins for cost neutrality and cost savings. This satisfied the committee that even with some uncertainty around the strength of the clinical evidence, Leukomed Sorbact was highly likely to be cost saving in caesarean section and vascular surgery.
# Further research
## Further research on Leukomed Sorbact would be welcome
The committee noted that a multicentre RCT on the use of Leukomed Sorbact in vascular surgery is being proposed. It welcomed this, as well as the collection of real-world evidence. Also, the committee encouraged further research on using Leukomed Sorbact for a wider range of surgical indications, as well as investigating the effect of Leukomed Sorbact on people with different baseline SSI risks.
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{'Recommendations': 'Evidence supports the case for adopting Leukomed Sorbact for closed surgical wounds after caesarean section and vascular surgery.\n\nLeukomed Sorbact should be considered as an option for people with wounds that are expected to have low to moderate exudate after caesarean section and vascular surgery. It should be used as part of usual measures to help reduce the risk of surgical site infection. More evidence is needed on the use of Leukomed Sorbact on wounds after other types of surgery.\n\nCost modelling shows that the reduced rate of surgical site infection with Leukomed Sorbact compared with standard surgical dressings leads to savings of:\n\n£107\xa0per person after caesarean section\n\n£18\xa0per person after vascular surgery.By adopting this technology, the NHS may save up to £5.3\xa0million per year for caesarean section and up to £1.2\xa0million per year for vascular surgery. Cost savings are expected because fewer people will need to stay in hospital for treatment of surgical site infection. For more details, see the NICE resource impact report.\n\nWhy the committee made these recommendations\n\nLeukomed Sorbact is an interactive dressing that binds to the microbes that cause surgical site infection so they are removed when the dressing is changed.\n\nEvidence suggests that using Leukomed Sorbact instead of standard dressings after caesarean section and vascular surgery reduces the rate of surgical site infection and leads to cost savings. So Leukomed Sorbact is recommended for wounds expected to have low to moderate exudate.', 'The technology': '# Technology\n\nLeukomed Sorbact (Essity), is a sterile, single-use, bacteria-binding, adhesive-bordered wound dressing. It is used to prevent surgical site infection (SSI) in closed surgical wounds that have low to moderate exudate.\n\nThe dressing comprises an absorbent non-woven wound contact pad and an outer transparent adhesive polyurethane film. The pad is made of a white viscose polypropylene and polyester mesh that is coated with the proprietary compound dialkylcarbamoyl chloride (DACC). DACC is hydrophobic, meaning that it does not mix with water and tends to bind to itself or other hydrophobic materials if water is present. In a moist wound, DACC binds to hydrophobic bacteria and fungi that cause SSI. These bound microorganisms are then removed from the wound site when the dressing is changed. Binding to DACC does not cause bacteria to be lysed (broken open), which avoids causing inflammation at the wound site. The polyurethane film is designed to maintain a moist environment and protect the wound from external contamination. The dressing is available in various sizes.\n\n# Innovative aspects\n\nThe innovative aspect is the DACC component. This binds and inactivates bacteria through hydrophobic interaction, which helps to reduce colonisation of the wound by potentially harmful microbes.\n\n# Intended use\n\nLeukomed Sorbact is intended to be applied by a surgeon or theatre nurse in the operating theatre after surgery. It can also be used in the early postoperative period when the dressing needs to be replaced.\n\n# Costs\n\nThe cost of Leukomed Sorbact is £9.15 per dressing (excluding VAT). There are no other costs for implementing this technology and no training costs. For more details, see the website for Leukomed Sorbact.', 'Evidence': "# Clinical evidence\n\n## The relevant clinical evidence consists of 5\xa0studies, including 3\xa0randomised trials\n\nThe external assessment centre (EAC) considered 5\xa0publications:\n\nrandomised controlled trial (RCT; Stanirowski et al. 2016a)\n\npilot RCTs (Totty et al. 2019; Stanirowski et al. 2016b)\n\nnon-RCT (Bua et al. 2017) and\n\nunpublished audit (Taylor et al. 2020).The EAC excluded 5\xa0studies identified by the company because 4 did not include Leukomed Sorbact and there were significant uncertainties about the design of 1\xa0study.\n\n## The evidence considered is limited to caesarean section and vascular surgery\n\nStanirowski et al. 2016a and 2016b were both done in Poland in women having elective or emergency caesarean section. Totty et al. 2019 and Bua et al. 2017 were UK studies in people having vascular surgery. Taylor et al. 2020 contained audit data provided by the company on women having caesarean section in 1\xa0UK health board.\n\n## The evidence suggests Leukomed Sorbact reduces SSI in caesarean section and vascular surgery\n\nUp to 30\xa0days after surgery, surgical site infection (SSI) rates were lower for people having Leukomed Sorbact compared with those having standard dressings. The difference in infection rates was not always statistically significant depending on the trial size. The largest RCT was considered to have the least risk of bias (Stanirowski et al. 2016a). In this study, the SSI rate was 1.8% for Leukomed Sorbact compared with 5.2% for standard dressings at 14\xa0days after caesarean section (statistically significant, p=0.04). In Stanirowski et al. 2016b, the SSI rate was 2.8% for Leukomed Sorbact compared with 9.8% for standard dressings at 14\xa0days after caesarean section (not statistically significant; p=0.08). In Bua et al. 2017, the SSI rate was 1% for Leukomed Sorbact and 10% for standard dressings at 5 to 7\xa0days after vascular surgery (statistically significant, p<0.05). In Totty et al. 2019 and Bua et al. 2017, SSI rates were 16% and 9% at 30\xa0days respectively for Leukomed Sorbact after vascular surgery, compared with 26% and 10% for standard dressings. The differences were not statistically significant (p=0.161 and p=0.83, respectively).\n\n## The evidence suggests that Leukomed Sorbact may reduce antibiotic use\n\nIn 3\xa0studies there was less need for antibiotic treatment with Leukomed Sorbact compared with standard dressings (Bua et al. 2017, Stanirowski et al. 2016a and 2016b). In all studies the number of people reported as having antibiotics was low in both arms, and the reported differences were not statistically significant in Stanirowski et al. 2016a (0 in Leukomed Sorbact group, 4 in control group, p=0.13).\n\n## The evidence suggests that Leukomed Sorbact may reduce readmissions from wound complications\n\nIn Stanirowski et al. 2016a, women with SSI in the standard dressings group each had 2.9\xa0outpatient hospital visits. Women with SSI in the Leukomed Sorbact group had 4.6\xa0visits, a difference that was statistically significant, p=0.02. However, this was a secondary analysis in a small subgroup of women. The same study found that women with SSI who had Leukomed Sorbact had fewer additional days in hospital (0\xa0days compared with 8.2\xa0days for standard dressings, p=0.22).\n\n# Cost evidence\n\n## The published economic evidence suggests Leukomed Sorbact is cost saving\n\nThe economic analysis in the Stanirowski et al. 2016a and Stanirowski et al. 2019 studies showed that Leukomed Sorbact is cost saving when compared with standard surgical dressings. In Stanirowski et al. 2016a, total costs for preventing and treating SSI were 5,775\xa0euros in the standard dressings group compared with 1,065\xa0euros in the Leukomed Sorbact group. In Stanirowski et al. 2019, the same data were used and a decision-analytic model was applied from a UK NHS perspective. This showed a cost saving of £119.07 per person in favour of Leukomed Sorbact.\n\n## The company's cost modelling finds Leukomed Sorbact to be cost saving for caesarean section, vascular surgery and all surgery\n\nThe company submitted a simple decision tree model with 2\xa0interventions, Leukomed Sorbact or standard surgical dressings. There were 2\xa0outcomes, SSI or no SSI. The time horizon was 30\xa0days. The company reported base-case cost savings per person with Leukomed Sorbact of £107.43 for caesarean section, £23.55 for vascular surgery, and £20.56 for all surgery. The company's sensitivity analyses found these results to be robust to parameter changes.\n\n## The EAC agrees with the company's cost model but disagrees about including all surgery because of lack of evidence\n\nThe EAC agreed with the company's model and its assumptions and made 1\xa0change, to the cost of an SSI episode for vascular surgery. Leukomed Sorbact remained cost saving but the cost savings were lower than those estimated in the company's model for vascular surgery, at £17.82 per patient. The cost savings remained robust to parameter changes. The EAC chose not to model the use of Leukomed Sorbact for all types of surgery because it considered that there was insufficient clinical evidence to do so.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Leukomed Sorbact reduces SSI after caesarean section\n\nThe committee noted that Stanirowski et al. 2016a was a well-performed randomised controlled trial (RCT) with a limited risk of bias. The results showed a statistically significant reduction in surgical site infection (SSI) 14\xa0days after caesarean section with Leukomed Sorbact compared with standard dressings. The committee and clinical experts discussed the relatively low rate of systemic antibiotic use in women who had SSI in this study. The committee considered that this was likely to be explained by the infections being relatively mild. The clinical experts stated that intravenous antibiotics were only needed for treating the most severe SSIs. The committee concluded that using Leukomed Sorbact reduced the rate of SSI after caesarean section compared with standard dressings.\n\n## Leukomed Sorbact reduces SSI after vascular surgery\n\nIn the prospective non-randomised Bua et al. 2017 study there were fewer SSIs with Leukomed Sorbact compared with standard dressings at 5 to 7\xa0days and at 30\xa0days. Although the number of people included in the Totty et al. 2019 pilot RCT was relatively small, there were fewer SSIs in those who had Leukomed Sorbact. The committee recognised the limitations of the evidence. But it concluded that the study results and the plausibility of the clinical benefit for this group was sufficient to support the use of Leukomed Sorbact after vascular surgery. It welcomed further research in this area.\n\n## The evidence does not support a broader recommendation to use Leukomed Sorbact in all types of surgery\n\nNo evidence was presented to support the use of Leukomed Sorbact in surgery other than caesarean section and vascular surgery. It was noted that Leukomed Sorbact could potentially be particularly useful in plastic surgery and breast surgery, which involve subcutaneous dissection. One clinical expert stated that Leukomed Sorbact is being used after gynaecological surgery at their hospital, but no data are currently available on this use. The committee concluded that the current evidence could not be extrapolated to support the use of Leukomed Sorbact after all types of surgery. It also concluded that it would welcome further research on the use of Leukomed Sorbact in other types of surgery.\n\n## Feedback from clinical experts was positive\n\nComments from clinical experts about the clinical benefits of Leukomed Sorbact were positive, noting that it seemed to reduce SSI and was easy to use. The clinical experts were broadly optimistic that Leukomed Sorbact may be useful for other types of surgery.\n\n# Other patient benefits or issues\n\n## Using Leukomed Sorbact to reduce SSI risk after caesarean section may enhance recovery\n\nIn Stanirowski et al. 2016a, developing SSI led to an increase in mean hospital stay of 8.2\xa0days in the control group. Women with SSI in the Leukomed Sorbact group had more outpatient visits than women with SSI in the control group (4.6\xa0per person compared with 2.9\xa0per person, respectively). This was a secondary analysis in a small subgroup of women. The clinical experts explained that reducing SSI may have additional benefits, such as new mothers being able to care for their babies and a positive effect on postnatal mental health. The committee concluded that reducing the incidence of SSI after caesarean section was likely to reduce the need for prolonged hospital stays and enhance recovery.\n\n## Compared with PICO negative pressure wound therapy, Leukomed Sorbact is comfortable and discreet\n\nThe clinical experts reported that people using Leukomed Sorbact had found it to be comfortable and had positive feedback. Unlike the battery-powered PICO, it can be worn while showering and does not make any noise.\n\n# Side effects and adverse events\n\n## Leukomed Sorbact has only uncommon, minor adverse events\n\nThe clinical experts noted only 1\xa0report of contact dermatitis after the use of Leukomed Sorbact. The external assessment centre (EAC) identified 1\xa0adverse event registered with the US Food and Drug Administration, in which a person who had a total knee replacement developed a chemical burn after using Leukomed Sorbact. About 1\xa0month after surgery, the person attended the emergency department because of a chemical burn with eschar over the surgical site. The eschar was surgically removed, and the person was discharged after 2\xa0days. This was described in the report as a 'device malfunction' but no other details were reported. The company's submission included an observational study in a poster presentation (Coldwell et al. 2014). In this study there were 2\xa0hypersensitivity reactions to the adhesive in 55\xa0people who had Leukomed Sorbact in an Australian primary care setting.\n\n# Relevance to the NHS\n\n## The studies using Leukomed Sorbact are relevant to the NHS\n\nThe Stanirowski et al. 2016a and 2016b studies, which investigated the use of Leukomed Sorbact after caesarean section, were both done in Poland. The clinical experts advised, however, that the care pathway and outcome measures reported in these studies were relevant to an NHS setting. The 2\xa0studies investigating the use of Leukomed Sorbact for vascular surgery (Totty et al. 2019 and Bua et al. 2017) were done in the UK. The committee concluded that the evidence was relevant to the NHS.\n\n# NHS considerations overview\n\n## Most wounds from vascular surgery and caesarean section are expected to have low to moderate exudate\n\nLeukomed Sorbact is indicated when a wound is expected to have low to moderate exudate. The clinical experts advised that this would be most caesarean section or vascular surgery wounds. They also explained that people with wounds at risk of high exudate could usually be identified at the time of surgery and would not have Leukomed Sorbact dressings.\n\n# Cost modelling overview\n\n## The company's cost model is appropriate for caesarean section and vascular surgery but not for other types of surgery\n\nThe committee agreed with the EAC that the company's cost model was appropriate for analysing the costs of using Leukomed Sorbact after caesarean section and vascular surgery. It noted that only small adjustments were needed. The committee also agreed with the EAC that cost modelling was inappropriate for an all surgery group because there was no evidence to support the benefits of Leukomed Sorbact for all types of surgery.\n\n## The EAC's base-case analysis shows Leukomed Sorbact is cost saving\n\nThe EAC's base-case analysis showed that, compared with standard dressings, using Leukomed Sorbact is cost saving by:\n\n£107.43 per person after caesarean section\n\n£17.82 per person after vascular surgery.The standard surgical dressing used as the comparator in the cost modelling was the Opsite Post‑OP dressing, the best-selling vapour-permeable adhesive film and absorbent sterile pad dressing. The clinical experts confirmed that this standard dressing was widely used in NHS practice.\n\n## The sources for the baseline risk of SSI and the costs of treating SSI after caesarean section and vascular surgery are appropriate\n\nIn the company's model, baseline SSI risks for different surgical indications were taken from NHS England or NHS Wales data. The Leukomed Sorbact SSI risk was taken from the pooled results of the clinical studies (Stanirowski et al. 2016a and 2016b for caesarean section; Bua et al. 2017 and Totty et al. 2019 for vascular surgery). The EAC considered the data sources for these inputs appropriate. The cost of SSI in caesarean section was taken from Jenks et al. 2014. The cost of SSI in vascular surgery was taken from an unpublished study (York Health Economics Consortium 2020) but the EAC considered that costs from Jenks et al. 2014 were more appropriate. The committee accepted that these sources were appropriate.\n\n# Main cost drivers\n\n## The company's sensitivity analyses show that the cost saving with Leukomed Sorbact is robust\n\nThe company's sensitivity analyses varied the rate of SSI and the costs of Leukomed Sorbact and the comparator. Leukomed Sorbact remained cost saving in all these analyses. The company did 1‑way sensitivity analysis on the cost per SSI episode, varying the cost estimates within their 95% confidence intervals:\n\nFor caesarean section, the base-case SSI episode cost was £4,048 and the breakeven point was £350.\n\nFor vascular surgery, the base-case SSI episode cost was £3,427 and the breakeven point was £2,000.A second sensitivity analysis investigated the effect of reducing the standard dressing cost by 50% and increasing the cost of Leukomed Sorbact by 100%, or both. For both caesarean section and vascular surgery Leukomed Sorbact remained cost saving.\n\n## The company's scenario analysis reports the breakeven points for reducing SSI risk\n\nThe company did a scenario analysis, varying the relative risk reduction by plus or minus 25%:\n\nFor caesarean section, the base-case SSI risk was 4.35%, with a relative risk reduction of 67% and an incremental cost per person of -£107.43. The breakeven point for relative risk reduction was 6%.\n\nFor vascular surgery, the base-case SSI risk was 2.5%, with a 42% relative risk reduction and an incremental cost per person of -£23.54. The breakeven point for relative risk reduction was 13%.\n\n## The EAC's threshold analyses estimate the breakeven points in the cost model\n\nThe EAC did threshold analyses for cost savings from using Leukomed Sorbact after caesarean section and vascular surgery. The breakeven points were estimated for key values in the cost model. For caesarean section:\n\nbaseline SSI risk: base case 4.35%, breakeven point 0.39%\n\nrelative risk reduction in SSI: base case 67%, breakeven point 6%\n\nSSI episode cost: base case £4,048, breakeven point £362.For vascular surgery:\n\nbaseline SSI risk: base case 2.5%, breakeven point 0.93%\n\nrelative risk reduction in SSI: base case 42%, breakeven point 16%\n\nSSI episode cost: base case £2,072, breakeven point £1,004.\n\n## Leukomed Sorbact is cost saving across a wide range of SSI costs, device costs, comparator costs and relative risk reduction\n\nThere were wide margins for cost neutrality and cost savings. This satisfied the committee that even with some uncertainty around the strength of the clinical evidence, Leukomed Sorbact was highly likely to be cost saving in caesarean section and vascular surgery.\n\n# Further research\n\n## Further research on Leukomed Sorbact would be welcome\n\nThe committee noted that a multicentre RCT on the use of Leukomed Sorbact in vascular surgery is being proposed. It welcomed this, as well as the collection of real-world evidence. Also, the committee encouraged further research on using Leukomed Sorbact for a wider range of surgical indications, as well as investigating the effect of Leukomed Sorbact on people with different baseline SSI risks."}
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https://www.nice.org.uk/guidance/mtg55
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Evidence-based recommendations on Leukomed Sorbact for preventing surgical site infection after caesarean section or vascular surgery.
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2294ab16b78985dc053beb2c44cb179db1e5a4b9
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nice
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Mepolizumab for treating severe eosinophilic asthma
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Mepolizumab for treating severe eosinophilic asthma
Evidence-based recommendations on mepolizumab (Nucala) for treating severe eosinophilic asthma in adults.
# Recommendations
Mepolizumab, as an add-on therapy, is recommended as an option for treating severe refractory eosinophilic asthma, only if:
it is used for adults who have agreed to and followed the optimised standard treatment plan and
the blood eosinophil count has been recorded as 300 cells per microlitre or more and the person has had at least 4 exacerbations needing systemic corticosteroids in the previous 12 months, or has had continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months or
the blood eosinophil count has been recorded as 400 cells per microlitre or more and the person has had at least 3 exacerbations needing systemic corticosteroids in the previous 12 months (so they are also eligible for either benralizumab or reslizumab).Mepolizumab is recommended only if the company provides it according to the commercial arrangement.
If mepolizumab, benralizumab or reslizumab are equally suitable, start treatment with the least expensive option (taking into account drug and administration costs).
At 12 months:
stop mepolizumab if the asthma has not responded adequately or
continue mepolizumab if the asthma has responded adequately and assess response each year.An adequate response is defined as:
a clinically meaningful reduction in the number of severe exacerbations needing systemic corticosteroids or
a clinically significant reduction in continuous oral corticosteroid use while maintaining or improving asthma control.
These recommendations are not intended to affect treatment with mepolizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
# Why the committee made these recommendations
For severe refractory eosinophilic asthma, standard therapy alone does not work well enough. So people usually also have benralizumab or mepolizumab if:
their blood eosinophil count is 300 cells per microlitre or more and
they have had at least 4 severe exacerbations needing systemic corticosteroids in the previous 12 months or continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months.
People can have benralizumab or reslizumab if their blood eosinophil count is 400 cells per microlitre or more and they have had at least 3 severe exacerbations in the previous 12 months.
There is no evidence directly comparing mepolizumab with benralizumab and reslizumab. But an indirect comparison suggests that it works as well as benralizumab and reslizumab for people with a blood eosinophil count of 400 cells per microlitre or more.
Mepolizumab is cost saving compared with benralizumab and reslizumab. So it is now also recommended for people with a blood eosinophil count of 400 cells per microlitre or more and at least 3 severe exacerbations in the previous 12 months.# Information about mepolizumab
# Marketing authorisation indication
Mepolizumab (Nucala, GlaxoSmithKline) has a marketing authorisation in the UK as an 'add-on treatment for severe refractory eosinophilic asthma in adults, adolescents and children aged 6 years and older'.
# Dosage in the marketing authorisation
Mepolizumab is available as a powder for solution for injection in vials, or as a solution for injection in pre-filled syringes and pre-filled pens. The dosage schedule is available in the summary of product characteristics.
# Price
The list price of mepolizumab is £840 per 100 mg dose (excluding VAT; BNF online, accessed November 2020). The company has a commercial arrangement. This makes mepolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence. The company proposed that this technology be considered in a fast track appraisal using cost-comparison methodology.
# New treatment option
## People with severe eosinophilic asthma will welcome a new treatment option
Severe refractory eosinophilic asthma is a debilitating condition, which does not respond well enough to standard therapy and has many distressing symptoms. Asthma exacerbations can happen without warning, be life threatening, cause fear, and result in hospitalisation and intubation. People with uncontrolled severe eosinophilic asthma are often unable to work and may need help with day-to-day activities because of the symptoms. These physical and psychological pressures negatively affect quality of life. The patient experts highlighted an urgent need for more biological treatments for people who are not eligible for benralizumab or reslizumab or whose asthma does not respond to them. These people would otherwise need more intensive treatment with oral corticosteroids, which are associated with major side effects including diabetes, glaucoma, weight gain, loss of bone density and raised blood pressure. The clinical experts explained that the clinical community would welcome treatment criteria for biologicals to be standardised. The committee concluded that people with severe eosinophilic asthma with a blood eosinophil count of 400 cells per microlitre or more and at least 3 severe asthma exacerbations would welcome a new treatment option.
# Clinical effectiveness
## The indirect treatment comparison of mepolizumab, benralizumab and reslizumab is appropriate
NICE originally recommended mepolizumab for treating severe refractory eosinophilic asthma in adults with:
a blood eosinophil count of 300 cells per microlitre or more and
at least 4 severe exacerbations needing systemic corticosteroids in the past 12 months or if they have had continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months.The company proposed extending this recommendation, in line with NICE's technology appraisal guidance on benralizumab and reslizumab, to include people with:
a blood eosinophil count of 400 cells per microlitre or more and
at least 3 severe exacerbations needing systemic corticosteroids in the past 12 months.The company's evidence submission did not include any head-to-head trials directly comparing mepolizumab with benralizumab and reslizumab. It presented an indirect treatment comparison (ITC) of mepolizumab, benralizumab and reslizumab in severe eosinophilic asthma. The ITC included 9 placebo-controlled studies. The primary outcomes included:
exacerbation needing treatment with oral corticosteroids
exacerbation needing an emergency department visit or hospitalisation
Asthma Control Questionnaire score and change from baseline pre-bronchodilator forced expiratory volume in 1 second.The committee noted the limitations of the company's ITC, namely that potentially relevant studies were omitted. The 75 mg treatment arms from DREAM and MENSA were omitted to ensure that the data reflected the licensed dose of 100 mg. The ERG was unable to fully assess the effect of excluding these on the final efficacy results. It considered that omitting ZONDA and SIRIUS from the ITC was appropriate because of their different primary outcomes. The ERG also noted variation between studies in length of follow up, dosing and administration, asthma severity, blood eosinophil counts and previous exacerbations. But it recognised that most of the pairwise meta-analyses had low heterogeneity. It also noted that corticosteroid reduction was among the outcomes missing from the ITC. However, its clinical advisers suggested that a reduction in exacerbations may also imply a reduction in corticosteroid use so the ERG did not consider this to be an issue. The committee concluded that the ITC of mepolizumab, benralizumab and reslizumab is appropriate.
## There is sufficient evidence that mepolizumab has comparable efficacy to benralizumab and reslizumab
The results of the ITC for the primary outcomes broadly favoured mepolizumab over benralizumab and reslizumab for the subgroups in the trials with an eosinophil count of 400 cells per microlitre or more. But no evidence of a difference between treatments was found when the full trial populations were compared. The analysis for the comparison of mepolizumab with benralizumab and reslizumab was done for people with:
a blood eosinophil count of 400 cells per microlitre or more and
at least 1 severe exacerbation in the reslizumab arm or 2 severe exacerbations in the mepolizumab and benralizumab arms.However, the ERG stated that although this broader subgroup was not exactly aligned to the population being considered, it was closer than any other analysis. The ERG confirmed that there was a low risk that mepolizumab was less effective than benralizumab and reslizumab for severe eosinophilic asthma. The committee concluded that there was sufficient evidence that mepolizumab has comparable efficacy to benralizumab and reslizumab.
# Cost comparison
## A 10-year time horizon is more appropriate for decision making
The company did a cost comparison of mepolizumab with benralizumab and reslizumab. The costs were presented over a 1-year time horizon and were not discounted. The analysis compared:
mepolizumab 100 mg; a powdered vial for mixing, a pre-filled syringe and pre-filled pen, administered subcutaneously every 4 weeks
benralizumab 30 mg; a pre-filled syringe and pre-filled pen, administered subcutaneously every 4 weeks for the first 3 doses, then every 8 weeks and
reslizumab with a weight-dependent dose (assuming a mean weight of 78 kg for the UK adult population); concentrate for intravenous infusion administered every 4 weeks.The analysis included drug, administration and monitoring costs. Oral corticosteroid costs were not included in the analysis. The analysis assumed that there were no differences in adverse event costs based on a Cochrane review that found no excess serious adverse events with any anti-interleukin-5 treatments (such as mepolizumab, benralizumab and reslizumab). It was uncertain whether a 1-year time horizon was sufficient to capture the key differences in costs between treatments. This was particularly because of the loading dose for benralizumab, and differences in dosing frequency and administration costs over time. However, an ERG scenario showed that mepolizumab remained cost saving over a 10-year time horizon. The ERG did not consider monitoring costs to be a key driver of the results. The committee concluded that a 10-year time horizon was more appropriate for decision making.
## Self-administration has a small effect on the cost-comparison results
The committee questioned the proportion of people likely to self-administer the drug and the effect of this on savings with mepolizumab. The company explained that around 97% of people are currently self-administering and only 3% need mepolizumab to be given by a nurse. The clinical experts advised that the largest saving from those self-administering is in secondary care, with savings related to pharmacy and nurse time. However, people being set up for self-administration would need slightly longer appointments. The ERG explained that in the context of the drug costs, administration cost differences have little effect. The committee concluded that self-administration has a small effect on the cost-comparison results and the incremental savings with mepolizumab are mainly related to lower drug costs.
## Mepolizumab results in cost savings when compared with benralizumab and reslizumab
The company's cost comparison included a range of assumptions for:
administration and monitoring costs
-ral corticosteroid use
the comparable safety profile of mepolizumab, benralizumab and reslizumab over a 1-year time horizon.Assuming equivalent effectiveness and based on the list price for all treatments, mepolizumab had incremental cost savings compared with benralizumab and reslizumab. Mepolizumab remained cost saving in the additional ERG scenario over a 10-year time horizon. The committee concluded that, at list price, mepolizumab was cost saving compared with benralizumab and reslizumab for people with an eosinophil count of 400 cells per microlitre or more, and at least 3 severe exacerbations per year. Mepolizumab, benralizumab and reslizumab are available to the NHS with confidential commercial arrangements. The ERG analysis including these commercial arrangements did not change the committee's conclusion.
## Mepolizumab is recommended
The committee concluded that mepolizumab met the criteria to be recommended based on a cost comparison, because the overall health benefits are similar to those of benralizumab and reslizumab. The committee concluded that mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults with:
a blood eosinophil count of 300 cells per microlitre or more and at least 4 exacerbations needing systemic corticosteroids in the previous 12 months or continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months or
a blood eosinophil count of 400 cells per microlitre or more and at least 3 exacerbations needing systemic corticosteroids in the previous 12 months.
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{'Recommendations': 'Mepolizumab, as an add-on therapy, is recommended as an option for treating severe refractory eosinophilic asthma, only if:\n\nit is used for adults who have agreed to and followed the optimised standard treatment plan and\n\nthe blood eosinophil count has been recorded as 300\xa0cells per microlitre or more and the person has had at least 4\xa0exacerbations needing systemic corticosteroids in the previous 12\xa0months, or has had continuous oral corticosteroids of at least the equivalent of prednisolone 5\xa0mg per day over the previous 6\xa0months or\n\nthe blood eosinophil count has been recorded as 400\xa0cells per microlitre or more and the person has had at least 3\xa0exacerbations needing systemic corticosteroids in the previous 12\xa0months (so they are also eligible for either benralizumab or reslizumab).Mepolizumab is recommended only if the company provides it according to the commercial arrangement.\n\nIf mepolizumab, benralizumab or reslizumab are equally suitable, start treatment with the least expensive option (taking into account drug and administration costs).\n\nAt 12\xa0months:\n\nstop mepolizumab if the asthma has not responded adequately or\n\ncontinue mepolizumab if the asthma has responded adequately and assess response each year.An adequate response is defined as:\n\na clinically meaningful reduction in the number of severe exacerbations needing systemic corticosteroids or\n\na clinically significant reduction in continuous oral corticosteroid use while maintaining or improving asthma control.\n\nThese recommendations are not intended to affect treatment with mepolizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\n# Why the committee made these recommendations\n\nFor severe refractory eosinophilic asthma, standard therapy alone does not work well enough. So people usually also have benralizumab or mepolizumab if:\n\ntheir blood eosinophil count is 300\xa0cells per microlitre or more and\n\nthey have had at least 4\xa0severe exacerbations needing systemic corticosteroids in the previous 12\xa0months or continuous oral corticosteroids of at least the equivalent of prednisolone 5\xa0mg per day over the previous 6\xa0months.\n\nPeople can have benralizumab or reslizumab if their blood eosinophil count is 400\xa0cells per microlitre or more and they have had at least 3\xa0severe exacerbations in the previous 12\xa0months.\n\nThere is no evidence directly comparing mepolizumab with benralizumab and reslizumab. But an indirect comparison suggests that it works as well as benralizumab and reslizumab for people with a blood eosinophil count of 400\xa0cells per microlitre or more.\n\nMepolizumab is cost saving compared with benralizumab and reslizumab. So it is now also recommended for people with a blood eosinophil count of 400\xa0cells per microlitre or more and at least 3\xa0severe exacerbations in the previous 12\xa0months.', 'Information about mepolizumab': "# Marketing authorisation indication\n\nMepolizumab (Nucala, GlaxoSmithKline) has a marketing authorisation in the UK as an 'add-on treatment for severe refractory eosinophilic asthma in adults, adolescents and children aged 6\xa0years and older'.\n\n# Dosage in the marketing authorisation\n\nMepolizumab is available as a powder for solution for injection in vials, or as a solution for injection in pre-filled syringes and pre-filled pens. The dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of mepolizumab is £840 per 100\xa0mg dose (excluding VAT; BNF online, accessed November 2020). The company has a commercial arrangement. This makes mepolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence. The company proposed that this technology be considered in a fast track appraisal using cost-comparison methodology.\n\n# New treatment option\n\n## People with severe eosinophilic asthma will welcome a new treatment option\n\nSevere refractory eosinophilic asthma is a debilitating condition, which does not respond well enough to standard therapy and has many distressing symptoms. Asthma exacerbations can happen without warning, be life threatening, cause fear, and result in hospitalisation and intubation. People with uncontrolled severe eosinophilic asthma are often unable to work and may need help with day-to-day activities because of the symptoms. These physical and psychological pressures negatively affect quality of life. The patient experts highlighted an urgent need for more biological treatments for people who are not eligible for benralizumab or reslizumab or whose asthma does not respond to them. These people would otherwise need more intensive treatment with oral corticosteroids, which are associated with major side effects including diabetes, glaucoma, weight gain, loss of bone density and raised blood pressure. The clinical experts explained that the clinical community would welcome treatment criteria for biologicals to be standardised. The committee concluded that people with severe eosinophilic asthma with a blood eosinophil count of 400\xa0cells per microlitre or more and at least 3\xa0severe asthma exacerbations would welcome a new treatment option.\n\n# Clinical effectiveness\n\n## The indirect treatment comparison of mepolizumab, benralizumab and reslizumab is appropriate\n\nNICE originally recommended mepolizumab for treating severe refractory eosinophilic asthma in adults with:\n\na blood eosinophil count of 300\xa0cells per microlitre or more and\n\nat least 4\xa0severe exacerbations needing systemic corticosteroids in the past 12\xa0months or if they have had continuous oral corticosteroids of at least the equivalent of prednisolone 5\xa0mg per day over the previous 6\xa0months.The company proposed extending this recommendation, in line with NICE's technology appraisal guidance on benralizumab and reslizumab, to include people with:\n\na blood eosinophil count of 400\xa0cells per microlitre or more and\n\nat least 3\xa0severe exacerbations needing systemic corticosteroids in the past 12\xa0months.The company's evidence submission did not include any head-to-head trials directly comparing mepolizumab with benralizumab and reslizumab. It presented an indirect treatment comparison (ITC) of mepolizumab, benralizumab and reslizumab in severe eosinophilic asthma. The ITC included 9\xa0placebo-controlled studies. The primary outcomes included:\n\nexacerbation needing treatment with oral corticosteroids\n\nexacerbation needing an emergency department visit or hospitalisation\n\nAsthma Control Questionnaire score and change from baseline pre-bronchodilator forced expiratory volume in 1\xa0second.The committee noted the limitations of the company's ITC, namely that potentially relevant studies were omitted. The 75\xa0mg treatment arms from DREAM and MENSA were omitted to ensure that the data reflected the licensed dose of 100\xa0mg. The ERG was unable to fully assess the effect of excluding these on the final efficacy results. It considered that omitting ZONDA and SIRIUS from the ITC was appropriate because of their different primary outcomes. The ERG also noted variation between studies in length of follow up, dosing and administration, asthma severity, blood eosinophil counts and previous exacerbations. But it recognised that most of the pairwise meta-analyses had low heterogeneity. It also noted that corticosteroid reduction was among the outcomes missing from the ITC. However, its clinical advisers suggested that a reduction in exacerbations may also imply a reduction in corticosteroid use so the ERG did not consider this to be an issue. The committee concluded that the ITC of mepolizumab, benralizumab and reslizumab is appropriate.\n\n## There is sufficient evidence that mepolizumab has comparable efficacy to benralizumab and reslizumab\n\nThe results of the ITC for the primary outcomes broadly favoured mepolizumab over benralizumab and reslizumab for the subgroups in the trials with an eosinophil count of 400\xa0cells per microlitre or more. But no evidence of a difference between treatments was found when the full trial populations were compared. The analysis for the comparison of mepolizumab with benralizumab and reslizumab was done for people with:\n\na blood eosinophil count of 400\xa0cells per microlitre or more and\n\nat least 1\xa0severe exacerbation in the reslizumab arm or 2\xa0severe exacerbations in the mepolizumab and benralizumab arms.However, the ERG stated that although this broader subgroup was not exactly aligned to the population being considered, it was closer than any other analysis. The ERG confirmed that there was a low risk that mepolizumab was less effective than benralizumab and reslizumab for severe eosinophilic asthma. The committee concluded that there was sufficient evidence that mepolizumab has comparable efficacy to benralizumab and reslizumab.\n\n# Cost comparison\n\n## A 10-year time horizon is more appropriate for decision making\n\nThe company did a cost comparison of mepolizumab with benralizumab and reslizumab. The costs were presented over a 1-year time horizon and were not discounted. The analysis compared:\n\nmepolizumab 100\xa0mg; a powdered vial for mixing, a pre-filled syringe and pre-filled pen, administered subcutaneously every 4\xa0weeks\n\nbenralizumab 30\xa0mg; a pre-filled syringe and pre-filled pen, administered subcutaneously every 4\xa0weeks for the first 3\xa0doses, then every 8\xa0weeks and\n\nreslizumab with a weight-dependent dose (assuming a mean weight of 78\xa0kg for the UK adult population); concentrate for intravenous infusion administered every 4\xa0weeks.The analysis included drug, administration and monitoring costs. Oral corticosteroid costs were not included in the analysis. The analysis assumed that there were no differences in adverse event costs based on a Cochrane review that found no excess serious adverse events with any anti-interleukin-5 treatments (such as mepolizumab, benralizumab and reslizumab). It was uncertain whether a 1-year time horizon was sufficient to capture the key differences in costs between treatments. This was particularly because of the loading dose for benralizumab, and differences in dosing frequency and administration costs over time. However, an ERG scenario showed that mepolizumab remained cost saving over a 10-year time horizon. The ERG did not consider monitoring costs to be a key driver of the results. The committee concluded that a 10-year time horizon was more appropriate for decision making.\n\n## Self-administration has a small effect on the cost-comparison results\n\nThe committee questioned the proportion of people likely to self-administer the drug and the effect of this on savings with mepolizumab. The company explained that around 97% of people are currently self-administering and only 3% need mepolizumab to be given by a nurse. The clinical experts advised that the largest saving from those self-administering is in secondary care, with savings related to pharmacy and nurse time. However, people being set up for self-administration would need slightly longer appointments. The ERG explained that in the context of the drug costs, administration cost differences have little effect. The committee concluded that self-administration has a small effect on the cost-comparison results and the incremental savings with mepolizumab are mainly related to lower drug costs.\n\n## Mepolizumab results in cost savings when compared with benralizumab and reslizumab\n\nThe company's cost comparison included a range of assumptions for:\n\nadministration and monitoring costs\n\noral corticosteroid use\n\nthe comparable safety profile of mepolizumab, benralizumab and reslizumab over a 1-year time horizon.Assuming equivalent effectiveness and based on the list price for all treatments, mepolizumab had incremental cost savings compared with benralizumab and reslizumab. Mepolizumab remained cost saving in the additional ERG scenario over a 10-year time horizon. The committee concluded that, at list price, mepolizumab was cost saving compared with benralizumab and reslizumab for people with an eosinophil count of 400\xa0cells per microlitre or more, and at least 3\xa0severe exacerbations per year. Mepolizumab, benralizumab and reslizumab are available to the NHS with confidential commercial arrangements. The ERG analysis including these commercial arrangements did not change the committee's conclusion.\n\n## Mepolizumab is recommended\n\nThe committee concluded that mepolizumab met the criteria to be recommended based on a cost comparison, because the overall health benefits are similar to those of benralizumab and reslizumab. The committee concluded that mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults with:\n\na blood eosinophil count of 300\xa0cells per microlitre or more and at least 4\xa0exacerbations needing systemic corticosteroids in the previous 12\xa0months or continuous oral corticosteroids of at least the equivalent of prednisolone 5\xa0mg per day over the previous 6\xa0months or\n\na blood eosinophil count of 400\xa0cells per microlitre or more and at least 3\xa0exacerbations needing systemic corticosteroids in the previous 12\xa0months."}
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https://www.nice.org.uk/guidance/ta671
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Evidence-based recommendations on mepolizumab (Nucala) for treating severe eosinophilic asthma in adults.
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0dbc328983f482df0b28232e3a5ae7f5acce7415
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nice
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Brolucizumab for treating wet age-related macular degeneration
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Brolucizumab for treating wet age-related macular degeneration
Evidence-based recommendations on brolucizumab (Beovu) for treating wet age-related macular degeneration in adults.
# Recommendations
Brolucizumab is recommended as an option for treating wet age-related macular degeneration in adults, only if, in the eye to be treated:
the best-corrected visual acuity is between 6/12 and 6/96
there is no permanent structural damage to the central fovea
the lesion size is less than or equal to 12 disc areas in greatest linear dimension and
there is recent presumed disease progression (for example, blood vessel growth, as shown by fluorescein angiography, or recent visual acuity changes).It is recommended only if the company provides brolucizumab according to the commercial arrangement.
If patients and their clinicians consider brolucizumab to be one of a range of suitable treatments, including aflibercept and ranibizumab, choose the least expensive (taking into account administration costs and commercial arrangements).
Only continue brolucizumab in people who maintain an adequate response to therapy. Criteria for stopping should include persistent deterioration in visual acuity and identification of anatomical changes in the retina that indicate inadequate response to therapy.
These recommendations are not intended to affect treatment with brolucizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them.
Why the committee made these recommendations
Usual treatment for age-related macular degeneration is aflibercept and ranibizumab. Clinical trial evidence and a network meta-analysis shows that brolucizumab provides similar overall health benefits to these drugs, and is similarly safe. The total costs (including administration) of brolucizumab are the same or less than those of aflibercept and ranibizumab.
Because it has similar costs and overall health benefits to aflibercept and ranibizumab, brolucizumab is recommended as an option for treating adults with wet age-related macular degeneration in line with the previous recommendations in NICE technology appraisals guidance for aflibercept and ranibizumab.# Information about brolucizumab
# Marketing authorisation indication
Brolucizumab (Beovu, Novartis) is indicated 'in adults for the treatment of neovascular (wet) age-related macular degeneration (AMD)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The price of brolucizumab is £816.00 per 120 mg/ml solution for injection in a pre-filled syringe (excluding VAT; BNF). The company has a commercial arrangement. This makes brolucizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), and submissions from other stakeholders. See the committee papers for full details of the evidence.
# Comparators
## Aflibercept and ranibizumab are appropriate comparators
NICE has already produced technology appraisal guidance on aflibercept and ranibizumab in this indication. These treatments are only recommended if all of the following circumstances apply in the eye to be treated:
the best-corrected visual acuity (BCVA) is between 6/12 and 6/96
there is no permanent structural damage to the central fovea
the lesion size is less than or equal to 12 disc areas in greatest linear dimension
there is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes).The committee was aware that the fast track appraisal process only permits recommendations to be made in line with the recommendations of the appraisals for the comparator treatments. So, it understood that any recommendation for brolucizumab would be constrained by these criteria. The company presented a cost-comparison case, in which it proposed that:
the overall health benefits associated with brolucizumab are similar to or greater than those associated with aflibercept and ranibizumab and
the total costs associated with brolucizumab are similar to or lower than those associated with aflibercept and ranibizumab.The committee understood that aflibercept and ranibizumab are standard treatments for wet age-related macular degeneration in the NHS. So, it concluded that aflibercept and ranibizumab were appropriate comparators for this appraisal.
## Bevacizumab cannot be considered as a comparator in this appraisal
The committee was aware that bevacizumab was specified as a comparator in the scope issued by NICE and considered whether the company should have included it as a comparator in its submission. It acknowledged that because bevacizumab has not been appraised by NICE for treating wet age-related macular degeneration it could not be considered as a comparator in the fast track appraisal process. So, it concluded that bevacizumab was not a relevant comparator in this appraisal.
# Clinical effectiveness
## Brolucizumab is non-inferior to aflibercept
The company presented the results from the HAWK and HARRIER trials, comparing the safety and effectiveness of brolucizumab (3 mg and 6 mg) with aflibercept (2 mg). HAWK and HARRIER included adults aged 50 years or more with active choroidal neovascularisation caused by age-related macular degeneration and who had not had anti-vascular endothelial growth factor therapy. The primary outcome was change in BCVA from baseline to week 48. People in HAWK and HARRIER had brolucizumab monthly for the first 3 months then every 8 or 12 weeks, or aflibercept monthly for 3 months then every 8 weeks. The HAWK results showed from baseline to week 48, the least squares mean difference (LSMD) in change in BCVA between brolucizumab (3 mg) and aflibercept was -0.6 (95% confidence interval -2.5 to 1.3). When comparing brolucizumab (6 mg) with aflibercept, the LSMD was -0.2 (95% CI -2.1 to 1.8). The HARRIER trial results showed from baseline to week 48, the LSMD in change in BCVA between brolucizumab (6 mg) and aflibercept was -0.7 (95% CI -2.4 to 1.0). The committee agreed that because there was not a statistically significant difference in the change in BCVA results for brolucizumab and aflibercept the treatments were likely to be similar. But, it questioned whether these results confirmed that brolucizumab could be considered non-inferior to aflibercept. The company explained that there was a pre-defined non-inferiority margin of 4 letters set by the regulator, so the results confirmed brolucizumab was non-inferior to aflibercept. The ERG agreed that the results suggested brolucizumab and aflibercept were similarly effective but questioned whether the frequency and approach to dosing used in HAWK and HARRIER was reflective of clinical practice. It highlighted that most people having treatment for wet age-related macular degeneration in clinical practice would have treatment using a flexible approach such as treat and extend (TREX), pro re nata (PRN; treatment monitored frequently and administered as need), or PRN and extend (PRNX). The committee acknowledged the ERG's concerns but agreed that the results of HAWK and HARRIER were robust. It concluded that brolucizumab is non-inferior to aflibercept.
## Brolucizumab, aflibercept and ranibizumab are similarly effective
To support the HAWK and HARRIER results and estimate the relative effectiveness of brolucizumab compared with ranibizumab, the company presented the results of a network meta-analysis. The network meta-analysis assessed the relative effectiveness of brolucizumab, aflibercept and ranibizumab across 6 outcomes. The network comparing mean change in BCVA from baseline to 1 year contained 13 studies, including HAWK and HARRIER (see section 3.3). The results showed that treatment with brolucizumab (6 mg) every 8 or 12 weeks was similarly effective compared with various aflibercept (2 mg) and ranibizumab (0.5 mg) dosing regimens (every 4, 8 and 12 weeks, PRN, PRNX, and TREX). The committee concluded that the effectiveness of brolucizumab is similar to aflibercept and ranibizumab.
## Adverse events with brolucizumab are likely to be similar to those with aflibercept and ranibizumab
The company explained that the number of ocular and non-ocular adverse events were balanced across brolucizumab and aflibercept treatment groups in HAWK and HARRIER (see section 3.3). It also noted that the results of the network meta-analysis (see section 3.4) showed that adverse events with brolucizumab are similar to aflibercept and ranibizumab. The committee was aware that brolucizumab's summary of product characteristics notes a risk of retinal vasculitis and retinal vascular occlusion. The ERG explained that because these adverse events were rare, it was not likely to affect the view that the overall impact on health of those associated with brolucizumab are similar to those of aflibercept and ranibizumab. The committee concluded that adverse events with brolucizumab are likely to be similar to aflibercept and ranibizumab.
# Overall health benefits
## Brolucizumab provides similar health benefits to aflibercept and ranibizumab
The committee concluded that because changes in BCVA and reports of adverse events with brolucizumab, aflibercept and ranibizumab were similar, the treatments were also likely to provide similar overall health benefits.
# Resource use
## The number of brolucizumab injections in years 1 and 2 should be based on the trial
The company estimated the number of brolucizumab injections in years 1 and 2 from the network meta-analysis, which used pooled data from HAWK and HARRIER and accounted for differences in a random-effects model. The ERG agreed that this approach was appropriate and incorporated the company's estimates in its preferred analysis. The committee concluded that the number of brolucizumab injections in years 1 and 2 should be based on trial data and agreed the company's approach was acceptable.
## The number of comparator injections in years 1 and 2 should be based on TREX regimens
To estimate the number of injections for aflibercept and ranibizumab applied in the model in years 1 and 2, the company used a weighted average approach. This approach weighted the number of injections from different treatment regimens by the amount each regimen was proportionally used in practice. The company obtained estimates of proportions from a survey of 50 healthcare professionals who are retinal specialists. The ERG noted that most people in clinical practice followed a flexible treatment regimen such as TREX and PRN. So, it considered that the company's approach, which pooled different regimens, was unnecessary and presented an alternative approach, which separately estimated year 1 and 2 dose frequencies for TREX and PRN regimens. The committee agreed that because TREX was the most commonly used regimen in practice, it preferred analyses based on this. It concluded that for the comparators, the number of injections in years 1 and 2 should be based on TREX regimens.
## The ERG's approach to estimating the number of injections in year 3 and beyond is preferred
The company assumed that the number of injections given for each treatment in year 3 and beyond would be the same as the number of injections given in year 2. It explained that in absence of longer-term data, it was difficult to assume that effectiveness would be maintained if the number of injections reduced. So, it stated that assuming the number of injections was the same as in year 2 was a reasonable and consistent approach. The ERG explained that if the number of brolucizumab injections was increased because of disease activity in HAWK and HARRIER it could not later be decreased. It highlighted that because of this, the number of brolucizumab injections given in the trials was likely to be an overestimate of the number of injections given in clinical practice. It also highlighted that there were no available data to compare injection numbers across treatments for year 3 and beyond. So, it presented an alternative, based on analysis from NICE's technology appraisal guidance on aflibercept, where the number of injections is assumed to be the same for all treatments in year 3 and beyond. The committee agreed that the company's approach could lead to an overestimate of injection numbers. It also agreed that in the absence of longer-term data to inform estimates of injection numbers in year 3 and beyond, it was reasonable to assume it would be equivalent across treatments. It was uncertain if the year 3 injection numbers estimate from NICE's appraisal of aflibercept were accurate but agreed in the absence of more robust alternatives they were acceptable for decision making. So, it concluded it preferred the ERG's approach, which assumed the same number of injections for all treatments in year 3 and beyond from NICE's appraisal of aflibercept.
# Cost-comparison results
## Brolucizumab can be recommended on the basis of similar health benefits and similar or lower cost
The company presented cost-comparison results for brolucizumab compared with aflibercept and ranibizumab. When taking account of the confidential commercial discounts for all treatments, it showed that the total cost associated with brolucizumab was similar or lower than aflibercept and ranibizumab (the exact results are confidential and cannot be reported here). The committee acknowledged these results but recalled that it preferred the following assumptions incorporated in the ERG's preferred analysis:
comparator injection numbers in year 1 and 2 based on TREX regimen estimates
injection numbers in year 3 and beyond is equivalent for all treatments and based on estimates from NICE's appraisal of aflibercept.Taking account of these assumptions, and the confidential commercial discounts for all treatments, the total cost for brolucizumab was similar or lower than aflibercept and ranibizumab (the exact results are confidential and cannot be reported here). The committee concluded that the criteria for a positive cost comparison were met, because:
the overall health benefits of brolucizumab are similar to those of aflibercept and ranibizumab
the total costs associated with brolucizumab are similar to or lower than those of aflibercept and ranibizumab.The committee therefore recommended brolucizumab, in line with the previous recommendations for aflibercept and ranibizumab, as a cost-effective use of NHS resources for treating wet age-related macular degeneration in adults.
# Other considerations
## The committee considered visual impairment as a disability when formulating its recommendations
The company noted that visual impairment resulting from wet age-related macular degeneration is recognised as a disability. So, the patient population of this appraisal is a protected group under the Equality Act 2010. The committee took the fact that brolucizumab would be used in people with visual impairment into consideration when formulating its recommendations.
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{'Recommendations': 'Brolucizumab is recommended as an option for treating wet age-related macular degeneration in adults, only if, in the eye to be treated:\n\nthe best-corrected visual acuity is between 6/12 and 6/96\n\nthere is no permanent structural damage to the central fovea\n\nthe lesion size is less than or equal to 12\xa0disc areas in greatest linear dimension and\n\nthere is recent presumed disease progression (for example, blood vessel growth, as shown by fluorescein angiography, or recent visual acuity changes).It is recommended only if the company provides brolucizumab according to the commercial arrangement.\n\nIf patients and their clinicians consider brolucizumab to be one of a range of suitable treatments, including aflibercept and ranibizumab, choose the least expensive (taking into account administration costs and commercial arrangements).\n\nOnly continue brolucizumab in people who maintain an adequate response to therapy. Criteria for stopping should include persistent deterioration in visual acuity and identification of anatomical changes in the retina that indicate inadequate response to therapy.\n\nThese recommendations are not intended to affect treatment with brolucizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them.\n\nWhy the committee made these recommendations\n\nUsual treatment for age-related macular degeneration is aflibercept and ranibizumab. Clinical trial evidence and a network meta-analysis shows that brolucizumab provides similar overall health benefits to these drugs, and is similarly safe. The total costs (including administration) of brolucizumab are the same or less than those of aflibercept and ranibizumab.\n\nBecause it has similar costs and overall health benefits to aflibercept and ranibizumab, brolucizumab is recommended as an option for treating adults with wet age-related macular degeneration in line with the previous recommendations in NICE technology appraisals guidance for aflibercept and ranibizumab.', 'Information about brolucizumab': "# Marketing authorisation indication\n\nBrolucizumab (Beovu, Novartis) is indicated 'in adults for the treatment of neovascular (wet) age-related macular degeneration (AMD)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe price of brolucizumab is £816.00 per 120\xa0mg/ml solution for injection in a pre-filled syringe (excluding VAT; BNF). The company has a commercial arrangement. This makes brolucizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), and submissions from other stakeholders. See the committee papers for full details of the evidence.\n\n# Comparators\n\n## Aflibercept and ranibizumab are appropriate comparators\n\nNICE has already produced technology appraisal guidance on aflibercept and ranibizumab in this indication. These treatments are only recommended if all of the following circumstances apply in the eye to be treated:\n\nthe best-corrected visual acuity (BCVA) is between 6/12 and 6/96\n\nthere is no permanent structural damage to the central fovea\n\nthe lesion size is less than or equal to 12\xa0disc areas in greatest linear dimension\n\nthere is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes).The committee was aware that the fast track appraisal process only permits recommendations to be made in line with the recommendations of the appraisals for the comparator treatments. So, it understood that any recommendation for brolucizumab would be constrained by these criteria. The company presented a cost-comparison case, in which it proposed that:\n\nthe overall health benefits associated with brolucizumab are similar to or greater than those associated with aflibercept and ranibizumab and\n\nthe total costs associated with brolucizumab are similar to or lower than those associated with aflibercept and ranibizumab.The committee understood that aflibercept and ranibizumab are standard treatments for wet age-related macular degeneration in the NHS. So, it concluded that aflibercept and ranibizumab were appropriate comparators for this appraisal.\n\n## Bevacizumab cannot be considered as a comparator in this appraisal\n\nThe committee was aware that bevacizumab was specified as a comparator in the scope issued by NICE and considered whether the company should have included it as a comparator in its submission. It acknowledged that because bevacizumab has not been appraised by NICE for treating wet age-related macular degeneration it could not be considered as a comparator in the fast track appraisal process. So, it concluded that bevacizumab was not a relevant comparator in this appraisal.\n\n# Clinical effectiveness\n\n## Brolucizumab is non-inferior to aflibercept\n\nThe company presented the results from the HAWK and HARRIER trials, comparing the safety and effectiveness of brolucizumab (3\xa0mg and 6\xa0mg) with aflibercept (2\xa0mg). HAWK and HARRIER included adults aged 50\xa0years or more with active choroidal neovascularisation caused by age-related macular degeneration and who had not had anti-vascular endothelial growth factor therapy. The primary outcome was change in BCVA from baseline to week\xa048. People in HAWK and HARRIER had brolucizumab monthly for the first 3\xa0months then every 8 or 12\xa0weeks, or aflibercept monthly for 3\xa0months then every 8\xa0weeks. The HAWK results showed from baseline to week\xa048, the least squares mean difference (LSMD) in change in BCVA between brolucizumab (3\xa0mg) and aflibercept was -0.6 (95% confidence interval [CI] -2.5 to 1.3). When comparing brolucizumab (6\xa0mg) with aflibercept, the LSMD was -0.2 (95% CI -2.1 to 1.8). The HARRIER trial results showed from baseline to week\xa048, the LSMD in change in BCVA between brolucizumab (6\xa0mg) and aflibercept was -0.7 (95% CI -2.4 to 1.0). The committee agreed that because there was not a statistically significant difference in the change in BCVA results for brolucizumab and aflibercept the treatments were likely to be similar. But, it questioned whether these results confirmed that brolucizumab could be considered non-inferior to aflibercept. The company explained that there was a pre-defined non-inferiority margin of 4\xa0letters set by the regulator, so the results confirmed brolucizumab was non-inferior to aflibercept. The ERG agreed that the results suggested brolucizumab and aflibercept were similarly effective but questioned whether the frequency and approach to dosing used in HAWK and HARRIER was reflective of clinical practice. It highlighted that most people having treatment for wet age-related macular degeneration in clinical practice would have treatment using a flexible approach such as treat and extend (TREX), pro re nata (PRN; treatment monitored frequently and administered as need), or PRN and extend (PRNX). The committee acknowledged the ERG's concerns but agreed that the results of HAWK and HARRIER were robust. It concluded that brolucizumab is non-inferior to aflibercept.\n\n## Brolucizumab, aflibercept and ranibizumab are similarly effective\n\nTo support the HAWK and HARRIER results and estimate the relative effectiveness of brolucizumab compared with ranibizumab, the company presented the results of a network meta-analysis. The network meta-analysis assessed the relative effectiveness of brolucizumab, aflibercept and ranibizumab across 6 outcomes. The network comparing mean change in BCVA from baseline to 1\xa0year contained 13\xa0studies, including HAWK and HARRIER (see section 3.3). The results showed that treatment with brolucizumab (6\xa0mg) every 8 or 12\xa0weeks was similarly effective compared with various aflibercept (2\xa0mg) and ranibizumab (0.5\xa0mg) dosing regimens (every 4, 8 and 12\xa0weeks, PRN, PRNX, and TREX). The committee concluded that the effectiveness of brolucizumab is similar to aflibercept and ranibizumab.\n\n## Adverse events with brolucizumab are likely to be similar to those with aflibercept and ranibizumab\n\nThe company explained that the number of ocular and non-ocular adverse events were balanced across brolucizumab and aflibercept treatment groups in HAWK and HARRIER (see section 3.3). It also noted that the results of the network meta-analysis (see section 3.4) showed that adverse events with brolucizumab are similar to aflibercept and ranibizumab. The committee was aware that brolucizumab's summary of product characteristics notes a risk of retinal vasculitis and retinal vascular occlusion. The ERG explained that because these adverse events were rare, it was not likely to affect the view that the overall impact on health of those associated with brolucizumab are similar to those of aflibercept and ranibizumab. The committee concluded that adverse events with brolucizumab are likely to be similar to aflibercept and ranibizumab.\n\n# Overall health benefits\n\n## Brolucizumab provides similar health benefits to aflibercept and ranibizumab\n\nThe committee concluded that because changes in BCVA and reports of adverse events with brolucizumab, aflibercept and ranibizumab were similar, the treatments were also likely to provide similar overall health benefits.\n\n# Resource use\n\n## The number of brolucizumab injections in years\xa01 and\xa02 should be based on the trial\n\nThe company estimated the number of brolucizumab injections in years\xa01 and 2 from the network meta-analysis, which used pooled data from HAWK and HARRIER and accounted for differences in a random-effects model. The ERG agreed that this approach was appropriate and incorporated the company's estimates in its preferred analysis. The committee concluded that the number of brolucizumab injections in years\xa01 and 2 should be based on trial data and agreed the company's approach was acceptable.\n\n## The number of comparator injections in years\xa01 and 2 should be based on TREX regimens\n\nTo estimate the number of injections for aflibercept and ranibizumab applied in the model in years\xa01 and\xa02, the company used a weighted average approach. This approach weighted the number of injections from different treatment regimens by the amount each regimen was proportionally used in practice. The company obtained estimates of proportions from a survey of 50 healthcare professionals who are retinal specialists. The ERG noted that most people in clinical practice followed a flexible treatment regimen such as TREX and PRN. So, it considered that the company's approach, which pooled different regimens, was unnecessary and presented an alternative approach, which separately estimated year\xa01 and 2 dose frequencies for TREX and PRN regimens. The committee agreed that because TREX was the most commonly used regimen in practice, it preferred analyses based on this. It concluded that for the comparators, the number of injections in years\xa01 and 2 should be based on TREX regimens.\n\n## The ERG's approach to estimating the number of injections in year\xa03 and beyond is preferred\n\nThe company assumed that the number of injections given for each treatment in year\xa03 and beyond would be the same as the number of injections given in year\xa02. It explained that in absence of longer-term data, it was difficult to assume that effectiveness would be maintained if the number of injections reduced. So, it stated that assuming the number of injections was the same as in year\xa02 was a reasonable and consistent approach. The ERG explained that if the number of brolucizumab injections was increased because of disease activity in HAWK and HARRIER it could not later be decreased. It highlighted that because of this, the number of brolucizumab injections given in the trials was likely to be an overestimate of the number of injections given in clinical practice. It also highlighted that there were no available data to compare injection numbers across treatments for year\xa03 and beyond. So, it presented an alternative, based on analysis from NICE's technology appraisal guidance on aflibercept, where the number of injections is assumed to be the same for all treatments in year\xa03 and beyond. The committee agreed that the company's approach could lead to an overestimate of injection numbers. It also agreed that in the absence of longer-term data to inform estimates of injection numbers in year\xa03 and beyond, it was reasonable to assume it would be equivalent across treatments. It was uncertain if the year\xa03 injection numbers estimate from NICE's appraisal of aflibercept were accurate but agreed in the absence of more robust alternatives they were acceptable for decision making. So, it concluded it preferred the ERG's approach, which assumed the same number of injections for all treatments in year 3 and beyond from NICE's appraisal of aflibercept.\n\n# Cost-comparison results\n\n## Brolucizumab can be recommended on the basis of similar health benefits and similar or lower cost\n\nThe company presented cost-comparison results for brolucizumab compared with aflibercept and ranibizumab. When taking account of the confidential commercial discounts for all treatments, it showed that the total cost associated with brolucizumab was similar or lower than aflibercept and ranibizumab (the exact results are confidential and cannot be reported here). The committee acknowledged these results but recalled that it preferred the following assumptions incorporated in the ERG's preferred analysis:\n\ncomparator injection numbers in year\xa01 and 2 based on TREX regimen estimates\n\ninjection numbers in year\xa03 and beyond is equivalent for all treatments and based on estimates from NICE's appraisal of aflibercept.Taking account of these assumptions, and the confidential commercial discounts for all treatments, the total cost for brolucizumab was similar or lower than aflibercept and ranibizumab (the exact results are confidential and cannot be reported here). The committee concluded that the criteria for a positive cost comparison were met, because:\n\nthe overall health benefits of brolucizumab are similar to those of aflibercept and ranibizumab\n\nthe total costs associated with brolucizumab are similar to or lower than those of aflibercept and ranibizumab.The committee therefore recommended brolucizumab, in line with the previous recommendations for aflibercept and ranibizumab, as a cost-effective use of NHS resources for treating wet age-related macular degeneration in adults.\n\n# Other considerations\n\n## The committee considered visual impairment as a disability when formulating its recommendations\n\nThe company noted that visual impairment resulting from wet age-related macular degeneration is recognised as a disability. So, the patient population of this appraisal is a protected group under the Equality Act 2010. The committee took the fact that brolucizumab would be used in people with visual impairment into consideration when formulating its recommendations."}
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https://www.nice.org.uk/guidance/ta672
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Evidence-based recommendations on brolucizumab (Beovu) for treating wet age-related macular degeneration in adults.
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9cb75b1f551a384f6e1fcdc552a322b78e4c2de5
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nice
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Brain tumours (primary) and brain metastases in over 16s
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Brain tumours (primary) and brain metastases in over 16s
This guideline covers diagnosing, monitoring and managing any type of primary brain tumour or brain metastases in people aged 16 or over. It aims to improve diagnosis and care, including standardising the care people have, how information and support are provided, and palliative care.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Investigation of suspected glioma
## Imaging for suspected glioma
Offer standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as the initial diagnostic test for suspected glioma, unless MRI is contraindicated.
Refer people with a suspected glioma to a specialist multidisciplinary team at first radiological diagnosis for management of their tumour.
Consider advanced MRI techniques, such as MR perfusion and MR spectroscopy, to assess the potential of a high-grade transformation in a tumour appearing to be low grade on standard structural MRI.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on imaging for suspected glioma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Use of molecular markers to determine prognosis or guide treatment for glioma
Report all glioma specimens according to the latest version of the World Health Organization (WHO) classification of tumors of the central nervous system. As well as histopathological assessment, include molecular markers such as:
IDH1 and IDH2 mutations
ATRX mutations to identify IDH mutant astrocytomas and glioblastomas
p/19q codeletion to identify oligodendrogliomas
histone H3.3 K27M mutations in midline gliomas
BRAF fusion and gene mutation to identify pilocytic astrocytoma.
Test all high-grade glioma specimens for MGMT promoter methylation to inform prognosis and guide treatment.
Consider testing IDH-wildtype glioma specimens for TERT promoter mutations to inform prognosis.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on use of molecular markers to determine prognosis or guide treatment for glioma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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# Management of glioma
## Initial surgery for suspected low-grade glioma
The surgical expertise in the multidisciplinary team should include:
access to awake craniotomy with language and other appropriate functional monitoring and
expertise in intraoperative neurophysiological monitoring and
access to neuroradiological support and
access to intraoperative image guidance.
Consider surgical resection as part of initial management (within 6 months of radiological diagnosis) to:
-btain a histological and molecular diagnosis and
remove as much of the tumour as safely possible after discussion of the possible extent of resection at multidisciplinary meeting and with the person with the brain tumour, and their relatives and carers.
If surgical resection is not appropriate, consider biopsy to obtain a histological and molecular diagnosis.
Consider active monitoring without a histological diagnosis, for lesions with radiological features typical of very low-grade tumours, for example, DNET (dysembryoplastic neuroepithelial tumour) or optic pathway glioma.
If people having active monitoring show radiological or clinical disease progression, discuss this at a multidisciplinary team meeting and consider:
surgical resection or
biopsy if surgical resection is not possible.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on initial surgery for suspected low-grade glioma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Further management of newly diagnosed low-grade glioma
After surgery, offer radiotherapy followed by up to 6 cycles of PCV chemotherapy (procarbazine, CCNU and vincristine) for people who:
have a 1p/19q codeleted, IDH-mutated low-grade glioma (oligodendroglioma) and
are aged around 40 or over, or have residual tumour on postoperative MRI.
After surgery, consider radiotherapy followed by up to 6 cycles of PCV chemotherapy for people who:
have a 1p/19q non-codeleted, IDH-mutated low-grade glioma (astrocytoma) and
are aged around 40 or over, or have residual tumour on postoperative MRI.
Consider active monitoring for people who are aged around 40 or under with an IDH‑mutated low‑grade glioma and have no residual tumour on postoperative MRI.
Consider radiotherapy followed by up to 6 cycles of PCV chemotherapy for people with an IDH‑mutated low‑grade glioma who have not had radiotherapy before if they have:
progressive disease on radiological follow‑up or
intractable seizures.
When delivering radiotherapy for people with IDH-mutated low-grade glioma, do not use a treatment dose of more than 54 Gy at 1.8 Gy per fraction.
Be aware that the prognosis for people with histologically confirmed IDH-wildtype grade II glioma may be similar to that of people with glioblastoma if other molecular features are consistent with glioblastoma. Take this into account when thinking about management options.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on further management of newly diagnosed low-grade glioma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Management of newly diagnosed grade III glioma following surgery or if surgery is not possible (or has been declined)
For guidance on using temozolomide for treating newly diagnosed grade III glioma, see the NICE technology appraisal guidance on carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma.
After surgery, offer sequential radiotherapy and 4 to 6 cycles of PCV chemotherapy to people who have:
a Karnofsky performance status of 70 or more and
a newly diagnosed grade III glioma with 1p/19q codeletion (anaplastic oligodendroglioma).
Agree with the person with the anaplastic oligodendroglioma the order of PCV chemotherapy and radiotherapy after discussing the potential advantages and disadvantages of each option with them (see table 1).
PCV first
Radiotherapy first
Overall survival
No clinically important difference.
No clinically important difference.
Progression-free survival
No clinically important difference.
No clinically important difference.
Fertility preservation
Trying to preserve fertility may cause a delay in the start of treatment.
Allows additional time for fertility preservation without delaying treatment.
Planning treatment around important life events
Initially much less contact with the health system, but potentially more fatigue.
Harder to give a precise date for when radiotherapy will start, as people's tolerance of chemotherapy is less predictable.
Initially much more contact with the health system: daily visits to radiotherapy department lasting several weeks.
Timing of start of chemotherapy much more predictable.
After surgery, offer radiotherapy followed by up to 12 cycles of adjuvant temozolomide to people who have:
a Karnofsky performance status of 70 or more and
a newly diagnosed IDH-wildtype or mutated grade III glioma without 1p/19q codeletion (anaplastic astrocytoma).
Do not offer nitrosoureas (for example, CCNU ) concurrently with radiotherapy to people with newly diagnosed grade III glioma.
If asked, advise people with an initial diagnosis of grade III glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:
cannabis oil
immunotherapy
ketogenic diets
metformin
statins
valganciclovir.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of newly diagnosed grade III glioma after surgery, or if surgery is not possible or the person declines surgery .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Management of newly diagnosed grade IV glioma (glioblastoma) following surgery or if surgery is not possible (or has been declined)
The recommendations in this section are also viewable as a visual summary.
For guidance on using temozolomide for treating newly diagnosed grade IV glioma (glioblastoma), see the NICE technology appraisal guidance on carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma.
Offer radiotherapy using 60 Gy in 30 fractions with concomitant temozolomide, followed by up to 6 cycles of adjuvant temozolomide, for people aged around 70 or under who have:
a Karnofsky performance status of 70 or more and
had maximal safe resection, or biopsy when resection is not possible, for a newly diagnosed grade IV glioma (glioblastoma).
Offer radiotherapy using 40 Gy in 15 fractions with concomitant and up to 12 cycles of adjuvant temozolomide for people aged around 70 or over who have:
a Karnofsky performance status of 70 or more and
a newly diagnosed grade IV glioma (glioblastoma) with MGMT methylation.
Consider radiotherapy using 40 Gy in 15 fractions with concomitant and up to 12 cycles of adjuvant temozolomide for people aged around 70 or over who have:
a Karnofsky performance status of 70 or more and
a newly diagnosed grade IV glioma (glioblastoma) without MGMT methylation or for which methylation status is unavailable.
Consider best supportive care alone for people aged around 70 or over who have:
a grade IV glioma (glioblastoma) and
a Karnofsky performance status of under 70.
For people with an initial diagnosis of grade IV glioma (glioblastoma) not covered in recommendations 1.2.19 to 1.2.22, consider the treatment options of:
radiotherapy using 60 Gy in 30 fractions with concurrent and up to 6 cycles of adjuvant temozolomide
radiotherapy alone using 60 Gy in 30 fractions
hypofractionated radiotherapy
up to 6 cycles of temozolomide alone if the tumour has MGMT methylation and the person is aged around 70 or over
best supportive care alone.
Assess the person's performance status throughout the postoperative period and review treatment options for grade IV glioma (glioblastoma) if their performance status changes.
Do not offer bevacizumab as part of management of a newly diagnosed grade IV glioma (glioblastoma).
Do not offer tumour-treating fields (TTF) as part of management of a newly diagnosed grade IV glioma (glioblastoma).
If asked, advise people with an initial diagnosis of grade IV glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:
cannabis oil
immunotherapy
ketogenic diets
metformin
statins
valganciclovir.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of newly diagnosed grade IV glioma (glioblastoma) following surgery, or if surgery is not possible or the person declines surgery .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Management of recurrent high-grade glioma (recurrent grade III and grade IV glioma)
When deciding on treatment options for people with recurrent high-grade glioma, take into account:
Karnofsky performance status
the person's preferences
time from last treatment
tumour molecular markers
what their last treatment was.
Consider PCV or single agent CCNU (lomustine) as an alternative to temozolomide for people with recurrent high-grade glioma.
For guidance on using temozolomide as an option for treating recurrent high-grade glioma, see the NICE technology appraisal guidance on temozolomide for the treatment of recurrent malignant glioma (brain cancer).
Consider best supportive care alone for high-grade glioma if other treatments are not likely to be of benefit, or if the person would prefer this. Refer to the NICE cancer service guidance on improving supportive and palliative care for adults with cancer.
For people with focally recurrent high-grade glioma, the multidisciplinary team should also consider the treatment options of:
further surgery
further radiotherapy.
Do not offer bevacizumab, erlotinib or cediranib, either alone or in combination with chemotherapy, as part of management of recurrent high-grade glioma.
Do not offer tumour treating fields (TTF) as part of management of recurrent high-grade glioma.
If asked, advise people who have recurrent high-grade glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:
cannabis oil
immunotherapy
ketogenic diets
metformin
statins
valganciclovir.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of recurrent grade III and grade IV glioma (recurrent high-grade glioma) .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Genomic biomarker-based treatment for glioma
The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.
## Techniques for resection of glioma
If a person has a radiologically enhancing suspected high-grade glioma and the multidisciplinary team thinks that surgical resection of all enhancing tumour is possible, offer 5‑aminolevulinic acid (5‑ALA)-guided resection as an adjunct to maximise resection at initial surgery.
Consider intraoperative MRI to help achieve surgical resection of both low-grade and high-grade glioma while preserving neurological function, unless MRI is contraindicated.
Consider intraoperative ultrasound to help achieve surgical resection of both low-grade and high-grade glioma.
Consider diffusion tensor imaging overlays in addition to standard neuronavigation techniques to minimise damage to functionally important fibre tracts during resection of both low-grade and high-grade glioma.
Consider awake craniotomy for people with low-grade or high-grade glioma to help preserve neurological function.
Discuss awake craniotomy and its potential benefits and risks with the person and their relatives and carers (as appropriate) so that they can make an informed choice about whether to have it. Only consider the procedure if the person is likely not to be significantly distressed by it.
Involve other specialists as appropriate, such as neuropsychologists and speech and language therapists, before, during and after awake craniotomy.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on techniques for resection of glioma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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# Follow-up for glioma
Offer regular clinical review for people with glioma to assess changes in their physical, psychological and cognitive wellbeing.
Base decisions on the timing of regular clinical reviews and follow‑up imaging for people with glioma on:
any residual tumour
life expectancy
the person's preferences (see table 2 for factors to discuss with them)
treatments used before
treatment options available
tumour subtype.
Possible advantages of more frequent follow‑up
Possible disadvantages of more frequent follow‑up
May identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.
There is no definitive evidence that identifying recurrent disease early improves outcomes.
May help provide information about the course of the illness and prognosis.
May increase anxiety if changes of uncertain significance are detected on imaging.
Some people can find more frequent imaging and hospital contact reassuring.
Provides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).
Some people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.
There may be a financial cost from taking time off work and travelling to appointments.
More imaging and follow‑up is resource intensive for the NHS.
Consider the follow‑up schedule given in table 3 for people with glioma.
Consider standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as part of regular clinical review for people with glioma, to assess for progression or recurrence, unless MRI is contraindicated.
Consider advanced MRI techniques, such as MR perfusion, diffusion tensor imaging and MR spectroscopy, if findings from standard imaging are unclear about whether there is recurrence and early identification is potentially clinically useful.
For people with glioma having routine imaging:
explain to them, and their relatives and carers, that imaging can be difficult to interpret and results can be of uncertain significance and
be aware that having routine imaging and waiting for the results may cause anxiety.
Consider a baseline MRI scan within 72 hours of surgical resection for all types of glioma.
Consider a baseline MRI scan 3 months after the completion of radiotherapy for all types of glioma.
Arrange a clinical review, including appropriate imaging, for people with glioma who develop new or changing neurological symptoms or signs at any time.
Grade of tumour
Clinical review schedule
Grade I
Scan at 12 months, then:
consider discharge if no tumour visible on imaging unless completely-resected pilocytic astrocytoma
consider ongoing imaging at increasing intervals for 15 years for completely-resected pilocytic astrocytoma
consider if ongoing imaging is needed at a rate of once every 1 to 3 years for the rest of the person's life if the tumour is visible on imaging.
Grade II 1p/19q non-codeleted, IDH mutated
Grade II 1p/19q codeleted
Grade III 1p/19q codeleted
From 0 to 2 years, scan at 3 months, then every 6 months
From 2 to 4 years, review annually
From 5 to 10 years, review every 1 to 2 years
For more than 10 years and for the rest of life consider ongoing imaging every 1 to 2 years.
Grade II IDH wildtype
Grade III 1p/19q non-codeleted
Grade IV (glioblastoma)
From 0 to 2 years, review every 3 to 6 months
From 2 to 4 years, review every 6 to 12 months
From 5 to 10 years, review annually
For more than 10 years and for the rest of life - consider ongoing imaging every 1 to 2 years.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for glioma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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# Investigation and management of meningioma
## Investigation of suspected meningioma
Offer standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as the initial diagnostic test for suspected meningioma, unless MRI is contraindicated.
Consider CT imaging for meningioma (if not already performed) to assess bone involvement if this is suspected.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on investigation of suspected meningioma .
Full details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.
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## Management of confirmed meningioma following surgery or if surgery is not possible (or has been declined)
Base management of meningioma after surgery, or if surgery is not possible or the person declines surgery, on the extent of any surgery and grade of meningioma, as described in table 4.
Grade
Completely excised (Simpson 1 to 3)
Incompletely excised (Simpson 4 to 5)
No excision (radiological only diagnosis)
Recurrent
I
Offer active monitoring.
Consider further surgery (if possible), radiotherapy or active monitoring.
Consider active monitoring or radiotherapy.
Consider further surgery or radiotherapy (if not previously used).
II
Offer a choice between active monitoring and radiotherapy.
Consider further surgery (if possible). Offer radiotherapy if surgery is not possible, including if the person declines surgery, or if the tumour is incompletely excised afterwards.
Consider active monitoring or radiotherapy
Consider further surgery and offer radiotherapy (if not previously used).
III
Offer radiotherapy.
Consider further surgery (if possible) and offer radiotherapy.
Consider active monitoring or radiotherapy
Consider further surgery and offer radiotherapy (if not previously used).
Before a decision is made on radiotherapy for meningioma, take into account:
comorbidities
life expectancy
neurological function
-edema
performance status
rate of tumour progression
size and location of tumour
surgical and radiotherapy morbidity
the person's preferences (see table 5 for factors to discuss with them)
treatments used before.
Radiotherapy
No radiotherapy
Control of tumour
There is evidence that radiotherapy is effective in the local control of a tumour.
Receiving no radiotherapy means the tumour may continue to grow.
Risk of developing subsequent symptoms
Controlling the tumour will reduce the risk of developing symptoms from the tumour in the future.
If the tumour grows, it can cause irreversible symptoms such as loss of vision.
Risk of re-treatment
Less risk of needing second surgery compared with no radiotherapy.
Higher risk of needing second surgery compared with radiotherapy.
If the tumour has progressed, then the surgery might be more complex.
If the tumour has progressed, then not all radiotherapy techniques may be possible.
Early side effects of treatment
Early side effects from radiotherapy can include:
fatigue
hair loss
headache
nausea
seizures
skin irritation.
No side effects from treatment.
Late side effects of treatment
Late side effects from radiotherapy can include:
effect on cognition
risk of stroke
risk of radionecrosis
risk of second tumours
cranial nerve effects
hypopituitarism
cataracts.
No side effects from treatment.
Management of side effects
Increased use of steroids to manage side effects.
No side effects from treatment.
When deciding on the radiotherapy technique for people with meningioma, take into account:
the preferences of the person (for example, to minimise the number of appointments or travel distance)
tumour grade
tumour location (proximity to optic nerves, optic chiasm and brainstem)
tumour size. From the suitable radiotherapy techniques, choose the one which maximises the chances of local tumour control while minimising the radiation dose to normal brain tissue.
If the multidisciplinary team thinks that radiotherapy may be appropriate, offer the person the opportunity to discuss the potential benefits and risks with an oncologist.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of confirmed meningioma following surgery, or if surgery is not possible or the person declines surgery .
Full details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.
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## Genomic biomarker-based treatment for meningioma
The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.
# Follow-up for meningioma
Offer regular clinical review for people with meningioma to assess changes in their physical, psychological and cognitive wellbeing.
Base decisions on the timing of regular clinical reviews and follow‑up imaging for people with meningioma on:
any residual tumour
life expectancy
the person's preferences (see table 6 for factors to discuss with them)
treatments used before
treatment options available
tumour grade.
Possible advantages of more frequent follow‑up
Possible disadvantages of more frequent follow‑up
May identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.
There is no definitive evidence that identifying recurrent disease early improves outcomes.
May help provide information about the course of the illness and prognosis.
May increase anxiety if changes of uncertain significance are detected on imaging.
Some people can find more frequent imaging and hospital contact reassuring.
Provides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).
Some people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.
There may be a financial cost from taking time off work and travelling to appointments.
More imaging and follow‑up is resource intensive for the NHS.
Consider the follow‑up schedule given in table 7 for people with meningioma.
Consider standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as part of regular clinical review for people with meningioma, to assess for progression or recurrence, unless MRI is contraindicated.
For people with meningioma having routine imaging, be aware that having routine imaging and waiting for the results may cause anxiety.
Arrange a clinical review, including appropriate imaging, for people with meningioma (including incidental meningioma) who develop new or changing neurological symptoms or signs at any time.
Grade I: no residual tumour
Grade I: residual tumour
Grade I: after radiotherapy
Grade II
Grade III
to 1 years
Scan at 3 months
Scan at 3 months
Scan 6 months after radiotherapy
Scan at 3 months, then 6 to 12 months later
Every 3 to 6 months
to 2 years
Annually
Annually
Annually
Annually
Every 3 to 6 months
to 3 years
Annually
Annually
Annually
Annually
Every 6 to 12 months
to 4 years
Once every 2 years
Annually
Once every 2 years
Annually
Every 6 to 12 months
to 5 years
Once every 2 years
Annually
Once every 2 years
Annually
Every 6 to 12 months
to 6 years
Once every 2 years
Once every 2 years
Once every 2 years
Once every 2 years
Annually
to 7 years
Once every 2 years
Once every 2 years
Once every 2 years
Once every 2 years
Annually
to 8 years
Once every 2 years
Once every 2 years
Once every 2 years
Once every 2 years
Annually
to 9 years
Once every 2 years
Once every 2 years
Once every 2 years
Once every 2 years
Annually
9 years (for the rest of life)
Consider discharge
Consider discharge
Consider discharge
Consider discharge
Annually
For asymptomatic incidental meningioma: scan at 12 months and if no change, consider discharge or scan at 5 years.
Note: the presence of any residual tumour can only be established after the first scan at 3 months.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for meningioma .
Full details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.
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# Investigation of suspected brain metastases
Offer standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as the initial diagnostic test for suspected brain metastases, unless MRI is contraindicated.
To help establish current disease status, offer extracranial imaging (appropriate to the primary tumour type) to people with any radiologically suspected brain metastases that may be suitable for focal treatment.
Perform all intracranial and extracranial diagnostic imaging and, if appropriate, biopsy of extracranial disease, before referral to the neuro-oncology multidisciplinary team.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on investigation of suspected brain metastases .
Full details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.
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# Management of confirmed brain metastases
When choosing management options for brain metastases, take into account:
extracranial disease
leptomeningeal disease
location of metastases
resection cavity size
the number and volume of metastases
the person's preference (based on a discussion of the factors listed in tables 8 and 9)
their age
their performance status
the primary tumour site, type, and molecular profile.
Consider systemic anti-cancer therapy for people who have brain metastases likely to respond effectively, for example, germ cell tumours or small-cell lung cancer.
Consider maximal local therapy with either surgery, stereotactic radiosurgery or stereotactic radiotherapy for people with a single brain metastasis.
Base the choice of treatment for people with a single brain metastasis on:
comorbidities
extent of oedema
location of metastasis
the person's preference (see table 8)
tumour size.
Surgery
Stereotactic radiosurgery / radiotherapy
Overall survival
No clinically important difference.
No clinically important difference.
Risk of needing additional treatment
Risk that stereotactic radiosurgery / radiotherapy may be needed in any case.
Risk that surgery may be needed in any case. However, has higher local control rate than surgery (meaning surgery is less likely after radiotherapy than the other way around).
Key benefit of treatment
Has more rapid control of symptoms.
Additionally, surgery allows for obtaining an up-to-date pathological diagnosis which may guide future treatment, making it more effective.
Has a higher local control rate than surgery, meaning more treatment is less likely to be needed.
Additionally, is an outpatient treatment and does not need a general anaesthetic.
Key risks of treatment
Surgical procedures carry known risks that vary depending on the person and the tumour. These include infection, stroke, a prolonged hospital stay and death.
Surgery is more painful than radiotherapy during recovery.
Radiation carries the risk of delayed effects such as radionecrosis, which might need surgical resection.
There is an increased risk of seizures with this technique, although this appears to mostly affect people who have pre-existing epilepsy.
Steroid use
Early reduction in steroid dose.
Likely to need steroids for longer, and at a higher dose. Steroids have significant side effects when used long-term, such as changes in mood, heart problems and changes in body fat.
Planning treatment around important life events
The wound from the surgery may affect the ability to carry out certain activities in the short term, such as air travel and sport.
The cosmetic appearance of the wound from surgery may be important to some people, and should be discussed.
Some people find the techniques used in radiotherapy challenging or upsetting, especially the equipment which immobilises the head. This is especially likely to be true for people with claustrophobia.
Other considerations
Radiotherapy can reach some areas of the brain that surgery cannot, and might be the only appropriate technique for certain tumour types.
Do not offer adjuvant whole-brain radiotherapy to people with a single brain metastasis treated with stereotactic radiosurgery/radiotherapy or surgery.
See NHS England's clinical commissioning policy on stereotactic radiosurgery and stereotactic radiotherapy to the surgical cavity following resection of cerebral metastases.
Consider stereotactic radiosurgery/radiotherapy for people with multiple brain metastases who have controlled or controllable extracranial disease and Karnofsky performance status of 70 or more. Take into account the number and total volume of metastases.
Do not offer whole-brain radiotherapy to people with:
non-small-cell lung cancer and
brain metastases that are not suitable for surgery or stereotactic radiosurgery/radiotherapy and
a Karnofsky performance status of under 70.
For people with multiple brain metastases who have not had stereotactic radiosurgery/radiotherapy or surgery, decide with them whether to use whole-brain radiotherapy after a discussion with them and their relatives and carers (as appropriate) of the potential benefits and risks (see table 9).
Whole-brain radiotherapy
No whole-brain radiotherapy
Overall survival
No clinically important difference.
No clinically important difference.
Quality of life
Short-term deterioration in quality of life because of treatment.
No impact on quality of life because of treatment, but deterioration because of the disease progression.
Potential benefits
Can stabilise or reduce the brain metastases.
Brain metastases may continue to grow.
Side effects
Temporary hair loss and fatigue. Potential for accelerated cognitive loss because of radiotherapy.
Potential for cognitive loss because of disease progression.
Time commitment
Requires 5 to 10 hospital visits.
No time commitment.
Other considerations
People with non-small-cell lung cancer will not benefit from treatment if their overall prognosis is poor.
Do not offer memantine in addition to whole-brain radiotherapy to people with multiple brain metastases, unless as part of a clinical trial.
Do not offer concurrent systemic therapy to enhance the efficacy of whole-brain radiotherapy to people with multiple brain metastases, unless as part of a clinical trial.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of confirmed brain metastases .
Full details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.
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# Follow-up for brain metastases
Offer regular clinical review for people with brain metastases to assess changes in their physical, psychological and cognitive wellbeing.
Base decisions on the timing of regular clinical reviews and follow‑up imaging for people with brain metastases on:
extracranial disease status
life expectancy
primary cancer
the person's preferences (see table 10 for factors to discuss with them)
treatment options available.
Possible advantages of more frequent follow‑up
Possible disadvantages of more frequent follow‑up
May identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.
There is no definitive evidence that identifying recurrent disease early improves outcomes.
May help provide information about the course of the illness and prognosis.
May increase anxiety if changes of uncertain significance are detected on imaging.
Some people can find more frequent imaging and hospital contact reassuring.
Provides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).
Some people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.
There may be a financial cost from taking time off work and travelling to appointments.
More imaging and follow‑up is resource intensive for the NHS.
Consider the follow‑up schedule given in table 11 for people with brain metastases.
Consider standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as part of regular clinical review for people with brain metastases, to assess for progression or recurrence, unless MRI is contraindicated.
Consider advanced MRI techniques, such as MR perfusion, diffusion tensor imaging and MR spectroscopy, if findings from standard imaging are unclear about whether there is recurrence and early identification is potentially clinically useful.
For people with brain metastases having routine imaging:
explain to them, and their relatives and carers, that imaging can be difficult to interpret and results can be of uncertain significance and
be aware that having routine imaging and waiting for the results may cause anxiety.
Arrange a clinical review, including appropriate imaging, for people with brain metastases who develop new or changing neurological symptoms or signs at any time.
Years after end of treatment
Clinical review schedule
to 1 years
Every 3 months
to 2 years
Every 4 to 6 months
years and onwards
Annually
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for brain metastases .
Full details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.
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# Care needs of people with brain tumours
Be aware that the care needs of people with brain tumours represent a unique challenge, because (in addition to physical disability) the tumour and treatment can have effects on:
behaviour
cognition
personality.
Discuss health and social care support needs with the person with a brain tumour and their relatives and carers (as appropriate). Take into account the complex health and social care support needs people with any type of brain tumour and their relatives and carers may have (for example, psychological, cognitive, physical, spiritual, emotional).
Set aside enough time to discuss the impact of the brain tumour on the person and their relatives and carers (as appropriate), and to elicit and discuss their health and social care support needs.
Health and social care professionals involved in the care of people with brain tumours should address additional complex needs during or at the end of treatment and throughout follow‑up. These include:
changes to cognitive functioning
fatigue
loss of personal identity
loss of independence
maintaining a sense of hope
potential for change in personal and sexual relationships
the challenges of living with uncertainty
the impact of brain tumour-associated epilepsy on wellbeing (see the NICE guideline on epilepsies: diagnosis and management).
Provide a named healthcare professional with responsibility for coordinating health and social care support for people with brain tumours and their relatives and carers, for example, a key worker (often a clinical nurse specialist) as defined in NICE cancer service guidance on improving outcomes for people with brain and other central nervous system tumours.
Give information to the person with a brain tumour and their relatives and carers (as appropriate):
in a realistic and empathetic manner
in suitable formats (written and spoken, with information available to take away), following the principles in the NICE guideline on patient experience in adult NHS services (also see NHS England's guidance on the Accessible Information Standard).
at appropriate times throughout their care pathway.
Explain to the person that they have a legal obligation to notify the Driver and Vehicle Licensing Agency (DVLA) if they have a brain tumour, and that this may have implications for their driving.
Provide and explain clinical results, for example, imaging and pathology reports, to the person with a brain tumour and their relatives and carers (as appropriate) as soon as possible.
Offer supportive care to people with brain tumours and their relatives and carers (as appropriate) throughout their treatment and care pathway
In people aged between 16 and 24 years old, refer to the NICE quality standard on cancer services for children and young people.
Discuss the potential preservation of fertility with people with brain tumours where treatment may have an impact on their fertility (see the recommendations on people with cancer who wish to preserve fertility in NICE's guideline on fertility problems).
If the person with a brain tumour is likely to be in their last year of life, refer to the NICE quality standards on end of life care for adults and, when appropriate, care of dying adults in the last days of life.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on care needs of people with brain tumours .
Full details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.
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# Neurorehabilitation needs of people with brain tumours
Consider referring the person with a brain tumour for a neurological rehabilitation assessment of physical, cognitive and emotional function at diagnosis and every stage of follow‑up.
Offer people with brain tumours and their relatives and carers (as appropriate) information on accessing neurological rehabilitation, and on what needs it can help address.
Give people with brain tumours and their relatives and carers (as appropriate) information on:
neurological rehabilitation options in the community, as an outpatient, or an inpatient and
how to get a neurological rehabilitation assessment.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on neurorehabilitation needs of people with brain tumours .
Full details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.
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# Surveillance for the late-onset side effects of treatment
Be aware that people with brain tumours can develop side effects of treatment months or years after treatment, which can include:
cataracts
cavernoma
cognitive decline
epilepsy
hearing loss
hypopituitarism
infertility
neuropathy (for example, nerve damage causing visual loss, numbness, pain or weakness)
radionecrosis
secondary tumours
SMART (stroke-like migraine attacks after radiotherapy)
stroke.
Assess the person's individual risk of developing late effects when they finish treatment. Record these in their written treatment summary and explain them to the person (and their relatives and carers, as appropriate).
Encourage people who have had cranial radiotherapy to follow a healthy lifestyle, including exercise, a healthy diet and stopping smoking (if applicable), to decrease their risk of stroke. See the NICE guidelines on obesity prevention, physical activity and tobacco: preventing uptake, promoting quitting and treating dependence.
For people who are at risk of stroke, consider checking their blood pressure, HbA1c level and cholesterol profile regularly.
Consider ongoing neuropsychology assessment for people at risk of cognitive decline.
If a person has had a radiotherapy dose that might affect pituitary function, consider checking their endocrine function regularly after the end of treatment.
Consider referring people who are at risk of visual impairment for an ophthalmological assessment.
Consider referring people who are at risk of hearing loss to audiology for a hearing test.
Consider referring the person to stroke services if an MRI during active monitoring identifies asymptomatic ischaemic stroke.
For a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on surveillance for the late-onset side effects of treatment .
Full details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.
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# Terms used in this guideline
## Active monitoring
This is regular clinical and radiological review of a person with a brain tumour or brain metastases who are not currently having treatment for their cancer.
## Regular clinical review
This is outpatient review of the person with a brain tumour or brain metastases at a planned interval from the previous visit in order to assess symptoms and care needs, to provide support and treatment and to perform imaging when appropriate.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Managing glioma: management of IDH wildtype grade II glioma
Does the addition of concurrent and adjuvant temozolomide to radiotherapy improve overall survival in patients with IDH wildtype grade II glioma?
The World Health Organization (WHO) 2016 reclassification of brain tumours recognised that the molecular characteristics of glioma are extremely important in helping differentiate between disease entities with very different outcomes. Although evidence exists to guide management recommendations for certain molecular gliomas, such as codeleted and non-codeleted grade III glioma, currently no studies have investigated the best approach for the management of grade II glioma with IDH wildtype. The biological behaviour of these tumours is more like a high-grade glioma with a much shorter prognosis than IDH-mutated grade II glioma.
Because of this, some clinicians have advocated treating such tumours with concurrent chemoradiation recommended for grade IV glioma (glioblastoma multiforme, GBM). However, there is currently no research evidence to support this approach and this regimen is more intensive and people experience increased acute and late side effects compared to radiotherapy alone.
Research is needed to establish whether or not this approach is beneficial in terms of improved survival, and at what cost in terms of toxicity and, potentially, reduced quality of life.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on managing glioma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Managing glioma: supportive care clinics for low-grade glioma
Does a dedicated supportive care clinic in addition to standard care improve outcomes for people with low-grade gliomas?
People with low-grade gliomas have significant symptoms and complex healthcare needs across multiple physical, cognitive, emotional and social domains. This is often from the initial diagnosis onwards. There are indications from research literature and patient reports that these needs are currently unmet. Helping people with low-grade gliomas maintain their quality of life and function is important, especially as there is currently no cure, because earlier supportive care interventions and care plans may help reduce unplanned or emergency contact with secondary and tertiary providers.
As no research literature exists which establishes the effectiveness of a specific healthcare intervention, uncertainty exists about the most appropriate intervention to address unmet needs and improve patient-reported outcome measures (or to establish whether current healthcare provision can meet these needs). Current uncertainty is likely to have led to variations in service provision across the UK. It is also possible that no specific intervention is available in some areas.
Research is needed to identify whether, in addition to standard care, a specific supportive care intervention can significantly improve patient-reported outcome measures, and if so to establish what this intervention should consist of.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on supportive care clinics for low-grade glioma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Managing glioma: early referral to palliative care for glioblastoma
Does early referral to palliative care improve outcomes for people with glioblastomas in comparison with standard oncology care?
People with grade IV brain tumours (glioblastomas) have a poor prognosis which has not improved in over a decade. Median overall survival is 14–18 months even with gold-standard chemoradiation following surgery.
From initial diagnosis people experience multiple complex symptoms resulting from neurological impairment. These can significantly impact on their quality of life, function and psychological wellbeing. Their caregivers report high levels of distress and carer burden.
The aim of palliative care is to relieve symptoms and improve people's quality of life and function – not just towards the end of life but throughout the duration of illness. There is some evidence that early palliative care referral significantly improves overall survival, quality of life and mood.
Research in this area is important because this group of people have substantial health needs, which use significant healthcare resources. Supportive care interventions such as early palliative care may improve quality of life and function throughout the duration of illness. It may also help people to manage the distress associated with a reduced life expectancy and participate in advanced care planning.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on early referral to palliative care for glioblastoma .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Managing glioma: early detection of recurrence after treatment
Does early detection of recurrence after treatment improve overall survival/outcomes in molecularly stratified glioma?
Prognosis for brain tumours is inherently uncertain, and recent advances in treatment mean many people with a brain tumour will live for a long time after the initial diagnosis. For these individuals, follow‑up is the longest component of their treatment and it is both expensive for the NHS and (sometimes) a burden for the person. There is no high-quality evidence that follow‑up after treatment is beneficial, no high-quality evidence on the optimal frequency of imaging, and clinical uncertainty about whether such follow‑up is likely to alter outcomes of importance to people with tumours (such as overall life expectancy or quality of life).
Research is needed to establish at what point the value of identifying recurrence early is outweighed by the harms of increasing burden to patients.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on the early detection of recurrence after treatment .
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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## Managing meningioma: immediate versus deferred radiotherapy for incompletely excised grade I meningioma
Is immediate or deferred radiotherapy better for incompletely excised grade I meningioma?
There are no randomised studies on the use of radiotherapy/radiosurgery in the treatment of grade I meningioma. Though case series have shown that people with inoperable and incompletely excised grade I meningioma treated with radiotherapy have high rates of control of their tumour, treatment risks significant side effects. The side effects include: neuropathy, radionecrosis, significant oedema, neuro-cognitive effects, increased risk of stroke and secondary tumours. Therefore the timing of treatment is a balance between control of tumour and side effects. It is not known if early treatment has a greater or lesser chance of long-term tumour control or risk of tumour complications, or if this just risks complications of treatment earlier.
People with grade I meningioma have traditionally been overlooked as a priority area for research. This is likely because of the slow nature of the disease resulting in need for long-term follow‑up and the difficulty to obtain funding for radiotherapy-only studies. However, this lack of research is inequitable, hence the reason for its prioritisation by the committee.
A study on this topic would provide clear information to guide clinicians and people with meningiomas, hopefully leading to overall improvement in quality of life. Because of the slow-growing characteristics of grade I meningioma, treatment decisions made early in the management pathway will have long-term effects on the person with the meningioma's overall quality of life outcomes, and potentially overall survival.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on managing meningioma .
Full details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Investigations for suspected glioma: imaging
The discussion below explains how the committee made recommendations 1.1.1–1.1.3.
## Why the committee made the recommendations
The evidence indicated that standard structural MRI is useful in distinguishing high-grade from low-grade glioma. The committee noted that this knowledge will inform management. Based on their experience, the committee recommended a protocol that they defined as a minimum standard for imaging acquisition.
No evidence was found on more advanced MRI techniques. However, the committee agreed that in their experience such techniques can be useful for assessing malignant features of a tumour – in particular, for ensuring that high-grade tumours are not misdiagnosed as low-grade tumours, which could have serious consequences for people who receive suboptimal management as a result. However the committee explained that a specialist multidisciplinary team would be needed to interpret features of the scan and decide management, even if advanced techniques were used.
## How the recommendations might affect practice
Currently, various imaging strategies are used in different centres and depending on the person's circumstances. These recommendations aim to reduce variation in practice, and ensure that images obtained at different sites and using different equipment can be more accurately compared. Some centres may need to change their imaging protocols. This might increase or reduce costs depending on the imaging protocols which are currently in place.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
Return to recommendations
# Investigations for suspected glioma: molecular markers
The discussion below explains how the committee made recommendations 1.1.4–1.1.6.
## Why the committee made the recommendations
Molecular markers are an emerging and important area in the treatment of brain tumours. The committee looked for evidence on these markers but did not find any. However, they noted that there are some molecular markers for which the evidence of benefit if tested is overwhelming, as reported in studies identified in searches for other review questions. This applies in particular for MGMT promoter methylation and TERT promoter mutations in IDH-wildtype glioma, although the committee agreed the evidence was of a higher quality in the first case than the second. The committee agreed that even these markers are not being consistently tested for and that testing should be standardised. Therefore they made recommendations based on their knowledge and experience, highlighting the World Health Organization (WHO) classification, to ensure that all centres follow a consistent process for assessing and interpreting information on molecular markers. This was important, since failure to consistently report molecular markers can mislead clinicians or limit treatment options.
## How the recommendations might affect practice
As testing for molecular markers is relatively new, practice can vary widely and this is to be expected. In principle there should not be a major change, although the time taken to implement the new molecular tests will vary significantly between centres.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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# Management of glioma: initial surgery for low-grade glioma
The discussion below explains how the committee made recommendations 1.2.1–1.2.5.
## Why the committee made the recommendations
There was evidence that optimal resection of a large percentage of the tumour improved survival for people with low-grade glioma. The committee noted that it is sometimes not appropriate to offer maximal safe resection (for example, if the balance of risks and benefits favours not resecting all areas) and that a specialist surgical team should look at the value of doing an operation given its safe extent. They agreed that biopsy should be considered in these cases, based on limited evidence showing improved overall survival after biopsy compared with active monitoring. However, the committee also concluded that some tumours were of such limited risk that the risks of surgery outweighed the possible gain of biopsy or resection.
The committee described how there was no evidence for immediate intervention, but that intervention should not be delayed due to the probability that surgical resection would have benefit for the person with the tumour. They therefore recommended intervention within 6 months, to allow for time to discuss treatment options with the person with the tumour. This also allows for the possibility of a second imaging sequence to be done later to look for progression and to assess for symptom change, as the committee also recognised that a proportion of low-grade gliomas have unfavourable gene profiles (for example, IDH wildtype) that make them more like high-grade tumours from a prognostic perspective.
A small number of people might have had initial treatment before it was standard practice to save a tissue sample for biopsy, and these people would currently be actively monitored. Based on their experience the committee agreed that these people may not need further surgery as long as their condition is stable (that is, they are not showing radiological or clinical disease progression).
## How the recommendations might affect practice
The recommendations are likely to change practice at some centres, and remove unnecessary variation. There are currently differences between centres in which molecular diagnoses are performed and in treatment of very low-risk, low-grade tumours. This is partly because low-grade gliomas may be managed by non-expert surgical teams.
The recommendation about the management of low-grade gliomas that have been managed but then progress is unlikely to substantially change practice, as management would be largely unchanged.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
Return to recommendations
# Management of glioma: further management of low-grade glioma
The discussion below explains how the committee made recommendations 1.2.6–1.2.11.
## Why the committee made the recommendations
There was evidence that PCV chemotherapy (procarbazine, CCNU and vincristine) after radiotherapy improved overall survival and progression-free survival compared with radiotherapy alone. The committee discussed how the evidence for the exact regime was complex, and used their judgement to recommend possible sequence and dose. In addition, the committee noted that there are some circumstances where radiotherapy and PCV might not be appropriate (particularly for the very lowest-concern and highest-concern low-grade tumours) and made recommendations based on their experience in these cases.
The committee included approximate age cut‑offs based on evidence showing that treatment improved survival in people aged around 40 or over with or without residual tumour, and their clinical judgement that treatment would be unlikely to be of benefit for people aged around 40 or under without residual tumour.
The committee found no evidence on the treatment of IDH wildtype grade II glioma. They determined that management of this type of glioma was likely to be different from other low-grade glioma, as IDH wildtype grade II glioma behaves more like a high-grade glioma. The committee therefore made a research recommendation on whether treating this tumour type more like a grade II glioma or grade IV glioma was most beneficial.
## How the recommendations might affect practice
These recommendations aim to standardise practice. They will probably result in the same amounts of chemotherapy and radiotherapy being given, but these treatments will be more precisely targeted and it is possible that they will be given earlier. This would result in more people requiring long-term treatment for the side effects of radiation and chemotherapy. More people are likely to have active monitoring alone, which is not likely to create a resource impact.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
Return to recommendations
# Management of glioma: grade III glioma following surgery
The discussion below explains how the committee made recommendations 1.2.12–1.2.17.
## Why the committee made the recommendations
The committee considered evidence for grade III and grade IV glioma separately.
Based on randomised controlled trial evidence, the committee recommended radiotherapy and either PCV or temozolomide chemotherapy, depending on tumour subtype and performance status, for people with grade III glioma.
Based on the available evidence, the committee recommended that some treatments should not be offered because they were harmful. They also agreed, based on their experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to indicate that certain treatments are beneficial.
## How the recommendations might affect practice
Adjuvant PCV for treating codeleted grade III glioma is standard practice, but adjuvant temozolomide for non-codeleted grade III gliomas is a change in practice. However, some centres may already have started to adopt this as standard care, since the results of the study supporting this treatment were made publicly available in 2016.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
Return to recommendations
# Management of glioma: grade IV glioma following surgery
The discussion below explains how the committee made recommendations 1.2.18–1.2.27.
## Why the committee made the recommendations
The committee considered evidence for grade III and grade IV glioma separately.
The committee saw some evidence demonstrating improved overall survival in some groups of people with grade IV glioma who had radiotherapy with concurrent and adjuvant temozolomide (compared with radiotherapy alone). However, based on their clinical experience they were unsure that these results could be generalised to all people with grade IV glioma, so suggested a range of possible treatments that can be considered for other groups, depending on the exact clinical characteristics of the tumour.
Approximate age cut‑offs for people with grade IV glioma were specified by the committee based on evidence that a radiotherapy dose of 40 Gy did not result in lower survival in people aged around 70 or over compared with a 60 Gy dose. Therefore a lower radiotherapy dose is likely to cause fewer side effects without compromising clinical effectiveness for this group.
The committee were aware that the prognosis of people with a grade IV glioma and a low performance status was poor, and recommended palliative care be considered. However the committee did not find any evidence on whether earlier or later palliative care was most beneficial for people who might need it. They therefore made a research recommendation on this topic, with the aim of finding out the point in the treatment pathway when it would be most beneficial for people with this type of glioma to have palliative care.
Based on the available evidence, the committee recommended that certain treatments should not be offered. This included tumour treating fields (TTF) based on published health economic evidence that they are not an efficient use of NHS resources. They also agreed, based on their clinical experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to suggest that certain treatments are beneficial.
## How the recommendations might affect practice
For younger people with a grade IV glioma and a good performance status, a course of radiotherapy with concurrent and adjuvant temozolomide is standard care. However, for people aged around 70 and over, particularly those with a glioma with methylated MGMT, the use of concurrent and adjuvant temozolomide with 15 fractions of radiotherapy is a change of practice that will probably result in more people being treated. This is a relatively small group of people, and so the recommendation is unlikely to have a significant resource impact.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
Return to recommendations
# Management of glioma: recurrent high-grade glioma
The discussion below explains how the committee made recommendations 1.2.28–1.2.35.
## Why the committee made the recommendations
Based on the available evidence, the committee recommended that treatment options for people with recurrent glioma should include temozolomide, PCV and single-agent CCNU (lomustine). No evidence was found to indicate which of these 3 options is likely to lead to the best outcomes, and on the basis of their clinical experience the committee concluded that the choice of treatment should take several factors into account, including the individual features of the tumour and the preferences of the person. The committee also highlighted the possibility of considering supportive care alone.
Based on the available evidence, the committee recommended that certain treatments should not be offered. This included tumour treating fields (TTF) on the basis of evidence of some clinical benefit but indirect published health economic evidence, in people with newly diagnosed high-grade glioma, that they are not cost effective. They also agreed, based on their clinical experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to suggest that certain treatments are beneficial.
## How the recommendations might affect practice
These recommendations reflect standard treatment for recurrent high-grade glioma, and therefore should not represent a substantial change in practice.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
Return to recommendations
# Management of glioma: techniques for resection of glioma
The discussion below explains how the committee made recommendations 1.2.36–1.2.42.
## Why the committee made the recommendations
There was evidence that 5‑aminolevulinic acid (5‑ALA), intraoperative MRI and diffusion tensor imaging could improve either the extent or safety of resection (particularly the preservation of neurological function). The committee noted that a combination of techniques might be needed to optimise both the extent and safety of resection for a particular surgical plan. The committee concluded that the evidence for MRI could be generalised to intraoperative ultrasound on the basis of their clinical experience, and therefore that clinicians should be able to choose either technique depending on availability.
The evidence for awake craniotomy was equivocal (non-significant differences compared with surgery under general anaesthesia), therefore from the evidence it was not possible to conclude that awake craniotomy would benefit all people with glioma. This is in line with the committee's clinical experience that some people benefit from the procedure (in terms of preserving language, motor and visual function) but others are harmed – particularly from psychological effects which act as a contraindication to awake craniotomy. The committee described how better preoperative procedures could reduce the number of people distressed by the procedure.
## How the recommendations might affect practice
Some techniques recommended by the committee require a very high level of intraoperative skill, and this might have resource implications for hospitals recruiting people with these specialist skills. There is significant variation in the current provision of psychological support for people before and during awake craniotomy, and implementing this could carry a high cost to an individual unit.
If a unit does not have access to intraoperative ultrasound or MRI, the cost of acquiring this equipment could be substantial (MRI is relatively expensive, ultrasound is relatively cheap). However the committee concluded that most units should have access to one or the other already. Therefore the only resource impact would be if a unit currently using intraoperative ultrasound decided that the additional evidence for preservation of neurological function in intraoperative MRI justified the cost of switching machines. However, the committee thought this was unlikely to happen.
Using 5‑ALA is associated with a high cost, and 5‑ALA-guided surgery needs a non-standard fluorescence-detecting microscope. Therefore the resource impact of this recommendation is likely to be high in all settings, and very high in settings without access to a fluorescence-detecting microscope. The anticipated resource impact of this recommendation is greater than £1 million per year.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
Return to recommendations
# Follow-up for glioma
The discussion below explains how the committee made recommendations 1.3.1–1.3.9.
## Why the committee made the recommendations
In the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.
As regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.
The committee believed that a dedicated supportive care clinic could improve outcomes for people with low-grade glioma, but did not find any evidence on this. Therefore they made a research recommendation on improving the long-term outcomes of people with low-grade glioma.
## How the recommendations might affect practice
The recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.
The imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.
Full details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.
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# Investigation of suspected meningioma
The discussion below explains how the committee made recommendations 1.4.1 and 1.4.2.
## Why the committee made the recommendations
Evidence indicated that standard structural MRI is useful in distinguishing high-grade from low-grade glioma, and the committee agreed that it is appropriate to extrapolate from this evidence to a belief that MRI can be used to distinguish meningioma from healthy brain tissue. In the committee's experience, CT scans can be more accurate than MRI for assessing meningioma with bone involvement.
## How the recommendations might affect practice
Currently, various imaging strategies are used depending on the centre and the person's circumstances. These recommendations aim to reduce variation in practice, and ensure that images obtained at different sites and using different equipment can be more accurately compared. Some centres may need to change their imaging protocols as a result, but this should not require the purchase of additional equipment.
Full details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.
Return to recommendations
# Management of confirmed meningioma following surgery or if surgery is not possible (or has been declined)
The discussion below explains how the committee made recommendations 1.4.3–1.4.6.
## Why the committee made the recommendations
Based on limited evidence and their clinical experience, the committee concluded that management of this group of meningiomas will depend on the type of meningioma. They noted that evidence for 1 grade of meningioma could not normally be used to suggest best management for another grade. Therefore the committee made recommendations for each grade of meningioma separately, using evidence if this was available and their judgement if it was not. The committee identified that management could be more conservative if the tumour grade was lower and initial resection more complete, and should be more aggressive if the tumour grade was higher or initial resection more partial.
The committee agreed that the 3 management options – further radiotherapy, surgery and active monitoring – had different balances of benefits and harms in different situations. However they also agreed that serious harm could be done to a person with a tumour if they were over- or under-treated given the risk profile of their tumour, and so made recommendations according to this risk. For example, for a low-grade almost completely-resected tumour (grade I, Simpson 2 excision), radiotherapy or further surgery could expose the person to risk of harm for no expected clinical gain.
Based on limited evidence, the committee made recommendations on how to deliver radiotherapy or radiosurgery where this was appropriate. They used their experience to highlight features of the tumour or preferences of the person that might help select the most appropriate radiotherapy or radiosurgery modality, and explained that the best results would come through minimising the dose of radiation delivered to healthy brain tissue while maximising the chance of local control.
The committee were unable to find evidence comparing different timings of radiotherapy in incompletely excised grade I meningioma. As the disease is slow growing it can be difficult to assess the risks of immediate side effects from treatment compared to the longer-term benefits of tumour control. Therefore the committee made a research recommendation to investigate this topic.
## How the recommendations might affect practice
The recommendations reflect standard practice in many centres, and should make treatment more consistent.
An appointment with an oncologist for all people who may have radiotherapy is not currently standard practice. However, for most people this is likely to mean a change in the timing of their first appointment with an oncologist, rather than many more people having oncologist appointments.
Full details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.
Return to recommendations
# Follow-up for meningioma
The discussion below explains how the committee made recommendations 1.5.1–1.5.6.
## Why the committee made the recommendations
In the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.
As regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.
## How the recommendations might affect practice
The recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.
The imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.
Full details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.
Return to recommendations
# Investigation of suspected brain metastases
The discussion below explains how the committee made recommendations 1.6.1–1.6.3.
## Why the committee made the recommendations
In the absence of evidence, the committee recommended standard structural MRI based on their experience, because it is important to establish the exact number of metastases in the brain, which can guide further treatment. The committee described how failing to establish this could be dangerous. Extracranial imaging, biopsy of the extracranial disease (where indicated) and performing all imaging before multidisciplinary team discussions should ensure that all necessary information is available so that appropriate decisions are made and delays in treatment avoided.
## How the recommendations might affect practice
The recommendations reinforce current best practice and should reduce delays to local intracranial treatment.
Full details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.
Return to recommendations
# Management of confirmed brain metastases
The discussion below explains how the committee made recommendations 1.7.1–1.7.11.
## Why the committee made the recommendations
The committee made recommendations based on the available evidence and their judgement. They described how features of brain metastases, including the number and volume (which is important for establishing prognosis), should be evaluated before starting treatment, and decisions about treatment made on the basis of these features and the person's preferences.
The committee described how systematic anti-cancer therapies were widely used in the management of other types of metastases, and therefore they might be expected to work for brain tumours. In the absence of evidence, the committee recommended considering systematic anti-cancer therapies on the basis of their clinical experience. Whether or not these therapies should be given depends on the type of metastasis: if it is not likely to respond then the side effects would not justify giving the therapy, whereas if the metastasis was likely to respond then the therapy was likely to be beneficial.
Evidence indicated that surgery, stereotactic radiosurgery and stereotactic radiotherapy are effective for treating a single brain metastasis, but there was no evidence to recommend 1 technique over the other. There was some evidence that irradiation of the cavity site improved local control, so the committee recommended it on the basis that improving local control should improve quality of life.
January 2021: the recommendations on this surgical cavity radiosurgery and radiotherapy have been updated. For details see the update information.
For people with multiple brain metastases, the committee described how treatment options are more variable, and that resection, stereotactic radiosurgery, stereotactic radiotherapy and whole-brain radiotherapy could all be considered in certain circumstances.
The committee recommended that neither memantine nor concurrent systemic therapy should be offered to enhance the efficacy of whole-brain radiotherapy, on the basis of evidence of no benefit and a potential risk of harm. However, there were biological reasons to think these treatments might be beneficial in some settings, so the committee agreed these therapies could be offered in the context of a clinical trial to investigate this.
## How the recommendations might affect practice
Current practice varies greatly between centres. Some of the variation reflects clinically relevant factors such as expertise in a particular technique or the patient population. The recommendations should help to standardise care and prevent some harmful and wasteful practices from continuing. Economic modelling identified that the recommendations will likely increase costs, but the committee believed that this was still an efficient use of NHS resources, as the improvement to quality of life was significant.
Full details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.
Return to recommendations
# Follow-up for brain metastases
The discussion below explains how the committee made recommendations 1.8.1–1.8.7.
## Why the committee made the recommendations
In the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.
As regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.
## How the recommendations might affect practice
The recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.
The imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.
Full details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.
Return to recommendations
# Care needs of people with brain tumours
The discussion below explains how the committee made recommendations 1.9.1–1.9.12.
## Why the committee made the recommendations
Based on the evidence and their own experience, the committee determined that people with brain tumours have very specific needs that are often not met. In particular, they highlighted ways in which the care needs of people with brain tumours differ from those of people with other types of cancer, such as the impact on the person's sense of identity and legal requirements related to driving. Losing the ability or legal right to drive can have a profound effect on the patient's independence, employment status and self-esteem. The committee's aim was to improve the support and information offered to people with brain tumours.
The committee described how the care needs of people with brain tumours were often more complex than could be considered in a single guideline. In particular, young people, people wishing to preserve their fertility, and people nearing the end of their life have especially complex needs. In order to address these needs, the committee signposted to existing NICE guidance in the specific area.
## How the recommendations might affect practice
The recommendations should improve care for both people living with brain tumours and their relatives and carers. It is likely that there will be a short-term resource impact in some areas, as supportive care for people with brain tumours is currently variable, with very little support available in some areas.
Full details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.
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# Neurorehabilitation needs of people with brain tumours
The discussion below explains how the committee made recommendations 1.10.1–1.10.3.
## Why the committee made the recommendations
No evidence was found for this topic. Based on their experience, the committee agreed that neurological rehabilitation is likely to be suitable for many people with brain tumours. Given that neurological rehabilitation is time-consuming (especially if the person with a tumour lives a long way from the rehabilitation centre) and sometimes not appropriate, the committee agreed that assessment should be carried out at every stage of diagnosis and follow‑up to identify which, if any, forms of rehabilitation are suitable for the person. The aim of the recommendations is to ensure that neurological rehabilitation is considered at every stage of treatment and follow‑up.
## How the recommendations might affect practice
There is currently variation in practice in assessing whether people with a brain tumour need neurological rehabilitation. Some of this reflects the availability of neurological rehabilitation services. The recommendations reinforce current best practice, and will mean a change in practice in some areas, including where assessment is 'ad hoc' rather than systematic.
People with a brain tumour make up a small percentage of people referred for neurological rehabilitation, so only a small increase in demand on resources is expected. There should not be any extra training needs because professionals already have the knowledge and skills to provide the services.
Full details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.
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# Surveillance for the late-onset side effects of treatment
The discussion below explains how the committee made recommendations 1.11.1–1.11.9.
## Why the committee made the recommendations
No evidence was found for this topic. Some people experience late effects after treatment for a brain tumour. With the possible exception of stroke risk it is unknown if these late effects can be prevented, but the committee agreed that any negative impact can be managed through clinical vigilance and referral into appropriate specialist monitoring pathways. The committee explained that it was important to consider referral for anyone at risk of late effects – not just those at 'high' risk – but that there may be no value in such a referral overall in lower risk groups.
## How the recommendations might affect practice
The recommendations should not significantly alter practice, as they reflect common clinical practice.
Full details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.
Return to recommendations# Context
It is estimated there are around 10,000 new cases of primary brain tumours per year. These tumours come from the brain tissue or its coverings – the meninges. Malignant high-grade gliomas (anaplastic gliomas and glioblastomas) and pre-malignant low-grade gliomas come from the brain tissue glial cells, and make up over 60% of primary brain tumours. Meningiomas make up a further 30%. Although often thought benign, meningiomas can have an acute presentation and are associated with significant long-term neurological morbidity. Because of this, they can behave in a malignant fashion in terms of recurrence and impact.
Over 60% of people with primary brain tumours present at, and are diagnosed by, accident and emergency services rather than from conventional GP or specialist referral. This causes a significant demand on these services. Although primary malignant brain tumours represent only 3% of all cancers, they result in the most life-years lost of any cancer. There is concern that the true incidence of these tumours is rising.
Cancers that have spread to the brain from somewhere else in the body are called secondary brain tumours, or brain metastases. Many different cancer types can spread to the brain, with lung and breast cancers being the most common. More people with systemic cancers are surviving longer and are referred to neuroscience multidisciplinary teams for management of their brain metastases. The number of people needing assessment for cranial treatment is now over 10,000 per year in the UK and rising.
The specialist nature of neuro-imaging and the need for complex diagnostic and reductive surgery emphasises the importance of well-organised service delivery by dedicated units. The singular effects of brain tumours on mental performance (both psychological state and cognitive decline) are a particular challenge to carers and professionals alike, especially in delivering support to people at home. The peak age of presentation of brain cancer is between 65 and 69, and there are concerns that delivery of all services to these older people is suboptimal. There are also concerns that the transition from paediatric to adult units could create a care gap. This would most specifically affects patients who are between 18 and 30 years old.
Survival with malignant brain tumours has remained poor despite some improvements in surgery, radiotherapy and chemotherapy, and a greater understanding of molecular classification. The management of a low-grade glioma that is likely to transform to high grade remains controversial, and presents issues for ongoing care. Follow‑up for people with meningiomas after primary treatment is often long term, and there is variation in both follow‑up and treatments for recurrence.
Conventional whole-brain irradiation as optimal therapy for brain metastases is being challenged by concerns about its effectiveness and toxicity, as well as the availability and immediacy of surgery and stereotactic radiotherapy.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Investigation of suspected glioma\n\n## Imaging for suspected glioma\n\nOffer standard structural MRI (defined as T2\xa0weighted, FLAIR, DWI series and T1\xa0pre- and post-contrast volume) as the initial diagnostic test for suspected glioma, unless MRI is contraindicated.\n\nRefer people with a suspected glioma to a specialist multidisciplinary team at first radiological diagnosis for management of their tumour.\n\nConsider advanced MRI techniques, such as MR perfusion and MR spectroscopy, to assess the potential of a high-grade transformation in a tumour appearing to be low grade on standard structural MRI.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on imaging for suspected glioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Use of molecular markers to determine prognosis or guide treatment for glioma\n\nReport all glioma specimens according to the latest version of the World Health Organization (WHO) classification of tumors of the central nervous system. As well as histopathological assessment, include molecular markers such as:\n\nIDH1 and IDH2 mutations\n\nATRX mutations to identify IDH mutant astrocytomas and glioblastomas\n\np/19q codeletion to identify oligodendrogliomas\n\nhistone H3.3\xa0K27M mutations in midline gliomas\n\nBRAF fusion and gene mutation to identify pilocytic astrocytoma.\n\nTest all high-grade glioma specimens for MGMT promoter methylation to inform prognosis and guide treatment.\n\nConsider testing IDH-wildtype glioma specimens for TERT promoter mutations to inform prognosis.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on use of molecular markers to determine prognosis or guide treatment for glioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n# Management of glioma\n\n## Initial surgery for suspected low-grade glioma\n\nThe surgical expertise in the multidisciplinary team should include:\n\naccess to awake craniotomy with language and other appropriate functional monitoring and\n\nexpertise in intraoperative neurophysiological monitoring and\n\naccess to neuroradiological support and\n\naccess to intraoperative image guidance.\n\nConsider surgical resection as part of initial management (within 6\xa0months of radiological diagnosis) to:\n\nobtain a histological and molecular diagnosis and\n\nremove as much of the tumour as safely possible after discussion of the possible extent of resection at multidisciplinary meeting and with the person with the brain tumour, and their relatives and carers.\n\nIf surgical resection is not appropriate, consider biopsy to obtain a histological and molecular diagnosis.\n\nConsider active monitoring without a histological diagnosis, for lesions with radiological features typical of very low-grade tumours, for example, DNET (dysembryoplastic neuroepithelial tumour) or optic pathway glioma.\n\nIf people having active monitoring show radiological or clinical disease progression, discuss this at a multidisciplinary team meeting and consider:\n\nsurgical resection or\n\nbiopsy if surgical resection is not possible.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on initial surgery for suspected low-grade glioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Further management of newly diagnosed low-grade glioma\n\nAfter surgery, offer radiotherapy followed by up to 6\xa0cycles of PCV chemotherapy (procarbazine, CCNU [lomustine] and vincristine) for people who:\n\nhave a 1p/19q codeleted, IDH-mutated low-grade glioma (oligodendroglioma) and\n\nare aged around 40\xa0or over, or have residual tumour on postoperative MRI.\n\nAfter surgery, consider radiotherapy followed by up to 6\xa0cycles of PCV chemotherapy for people who:\n\nhave a 1p/19q non-codeleted, IDH-mutated low-grade glioma (astrocytoma) and\n\nare aged around 40\xa0or over, or have residual tumour on postoperative MRI.\n\nConsider active monitoring for people who are aged around 40\xa0or under with an IDH‑mutated low‑grade glioma and have no residual tumour on postoperative MRI.\n\nConsider radiotherapy followed by up to 6\xa0cycles of PCV chemotherapy for people with an IDH‑mutated low‑grade glioma who have not had radiotherapy before if they have:\n\nprogressive disease on radiological follow‑up or\n\nintractable seizures.\n\nWhen delivering radiotherapy for people with IDH-mutated low-grade glioma, do not use a treatment dose of more than 54\xa0Gy at 1.8\xa0Gy per fraction.\n\nBe aware that the prognosis for people with histologically confirmed IDH-wildtype grade\xa0II glioma may be similar to that of people with glioblastoma if other molecular features are consistent with glioblastoma. Take this into account when thinking about management options.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on further management of newly diagnosed low-grade glioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Management of newly diagnosed grade\xa0III glioma following surgery or if surgery is not possible (or has been declined)\n\nFor guidance on using temozolomide for treating newly diagnosed grade\xa0III glioma, see the NICE technology appraisal guidance on carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma.\n\nAfter surgery, offer sequential radiotherapy and 4\xa0to 6\xa0cycles of PCV chemotherapy to people who have:\n\na Karnofsky performance status of 70\xa0or more and\n\na newly diagnosed grade\xa0III glioma with 1p/19q codeletion (anaplastic oligodendroglioma).\n\nAgree with the person with the anaplastic oligodendroglioma the order of PCV chemotherapy and radiotherapy after discussing the potential advantages and disadvantages of each option with them (see table\xa01).\n\n\n\nPCV first\n\nRadiotherapy first\n\nOverall survival\n\nNo clinically important difference.\n\nNo clinically important difference.\n\nProgression-free survival\n\nNo clinically important difference.\n\nNo clinically important difference.\n\nFertility preservation\n\nTrying to preserve fertility may cause a delay in the start of treatment.\n\nAllows additional time for fertility preservation without delaying treatment.\n\nPlanning treatment around important life events\n\nInitially much less contact with the health system, but potentially more fatigue.\n\nHarder to give a precise date for when radiotherapy will start, as people's tolerance of chemotherapy is less predictable.\n\nInitially much more contact with the health system: daily visits to radiotherapy department lasting several weeks.\n\nTiming of start of chemotherapy much more predictable.\n\nAfter surgery, offer radiotherapy followed by up to 12\xa0cycles of adjuvant temozolomide to people who have:\n\na Karnofsky performance status of 70\xa0or more and\n\na newly diagnosed IDH-wildtype or mutated grade\xa0III glioma without 1p/19q codeletion (anaplastic astrocytoma).\n\nDo not offer nitrosoureas (for example, CCNU [lomustine]) concurrently with radiotherapy to people with newly diagnosed grade\xa0III glioma.\n\nIf asked, advise people with an initial diagnosis of grade\xa0III glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:\n\ncannabis oil\n\nimmunotherapy\n\nketogenic diets\n\nmetformin\n\nstatins\n\nvalganciclovir.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of newly diagnosed grade III glioma after surgery, or if surgery is not possible or the person declines surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Management of newly diagnosed grade\xa0IV glioma (glioblastoma) following surgery or if surgery is not possible (or has been declined)\n\nThe recommendations in this section are also viewable as a visual summary.\n\nFor guidance on using temozolomide for treating newly diagnosed grade\xa0IV glioma (glioblastoma), see the NICE technology appraisal guidance on carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma.\n\nOffer radiotherapy using 60\xa0Gy in 30\xa0fractions with concomitant temozolomide, followed by up to 6\xa0cycles of adjuvant temozolomide, for people aged around 70\xa0or under who have:\n\na Karnofsky performance status of 70\xa0or more and\n\nhad maximal safe resection, or biopsy when resection is not possible, for a newly diagnosed grade\xa0IV glioma (glioblastoma).\n\nOffer radiotherapy using 40\xa0Gy in 15\xa0fractions with concomitant and up to 12\xa0cycles of adjuvant temozolomide for people aged around 70\xa0or over who have:\n\na Karnofsky performance status of 70\xa0or more and\n\na newly diagnosed grade\xa0IV glioma (glioblastoma) with MGMT methylation.\n\nConsider radiotherapy using 40\xa0Gy in 15\xa0fractions with concomitant and up to 12\xa0cycles of adjuvant temozolomide for people aged around 70\xa0or over who have:\n\na Karnofsky performance status of 70\xa0or more and\n\na newly diagnosed grade\xa0IV glioma (glioblastoma) without MGMT methylation or for which methylation status is unavailable.\n\nConsider best supportive care alone for people aged around 70\xa0or over who have:\n\na grade\xa0IV glioma (glioblastoma) and\n\na Karnofsky performance status of under\xa070.\n\nFor people with an initial diagnosis of grade\xa0IV glioma (glioblastoma) not covered in recommendations\xa01.2.19 to\xa01.2.22, consider the treatment options of:\n\nradiotherapy using 60\xa0Gy in 30\xa0fractions with concurrent and up to 6\xa0cycles of adjuvant temozolomide\n\nradiotherapy alone using 60\xa0Gy in 30\xa0fractions\n\nhypofractionated radiotherapy\n\nup to 6\xa0cycles of temozolomide alone if the tumour has MGMT methylation and the person is aged around 70\xa0or over\n\nbest supportive care alone.\n\nAssess the person's performance status throughout the postoperative period and review treatment options for grade\xa0IV glioma (glioblastoma) if their performance status changes.\n\nDo not offer bevacizumab as part of management of a newly diagnosed grade\xa0IV glioma (glioblastoma).\n\nDo not offer tumour-treating fields (TTF) as part of management of a newly diagnosed grade\xa0IV glioma (glioblastoma).\n\nIf asked, advise people with an initial diagnosis of grade\xa0IV glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:\n\ncannabis oil\n\nimmunotherapy\n\nketogenic diets\n\nmetformin\n\nstatins\n\nvalganciclovir.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of newly diagnosed grade IV glioma (glioblastoma) following surgery, or if surgery is not possible or the person declines surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Management of recurrent high-grade glioma (recurrent grade\xa0III and grade\xa0IV glioma)\n\nWhen deciding on treatment options for people with recurrent high-grade glioma, take into account:\n\nKarnofsky performance status\n\nthe person's preferences\n\ntime from last treatment\n\ntumour molecular markers\n\nwhat their last treatment was.\n\nConsider PCV or single agent CCNU (lomustine) as an alternative to temozolomide for people with recurrent high-grade glioma.\n\nFor guidance on using temozolomide as an option for treating recurrent high-grade glioma, see the NICE technology appraisal guidance on temozolomide for the treatment of recurrent malignant glioma (brain cancer).\n\nConsider best supportive care alone for high-grade glioma if other treatments are not likely to be of benefit, or if the person would prefer this. Refer to the NICE cancer service guidance on improving supportive and palliative care for adults with cancer.\n\nFor people with focally recurrent high-grade glioma, the multidisciplinary team should also consider the treatment options of:\n\nfurther surgery\n\nfurther radiotherapy.\n\nDo not offer bevacizumab, erlotinib or cediranib, either alone or in combination with chemotherapy, as part of management of recurrent high-grade glioma.\n\nDo not offer tumour treating fields (TTF) as part of management of recurrent high-grade glioma.\n\nIf asked, advise people who have recurrent high-grade glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:\n\ncannabis oil\n\nimmunotherapy\n\nketogenic diets\n\nmetformin\n\nstatins\n\nvalganciclovir.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of recurrent grade III and grade IV glioma (recurrent high-grade glioma)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Genomic biomarker-based treatment for glioma\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.\n\n## Techniques for resection of glioma\n\nIf a person has a radiologically enhancing suspected high-grade glioma and the multidisciplinary team thinks that surgical resection of all enhancing tumour is possible, offer 5‑aminolevulinic acid (5‑ALA)-guided resection as an adjunct to maximise resection at initial surgery.\n\nConsider intraoperative MRI to help achieve surgical resection of both low-grade and high-grade glioma while preserving neurological function, unless MRI is contraindicated.\n\nConsider intraoperative ultrasound to help achieve surgical resection of both low-grade and high-grade glioma.\n\nConsider diffusion tensor imaging overlays in addition to standard neuronavigation techniques to minimise damage to functionally important fibre tracts during resection of both low-grade and high-grade glioma.\n\nConsider awake craniotomy for people with low-grade or high-grade glioma to help preserve neurological function.\n\nDiscuss awake craniotomy and its potential benefits and risks with the person and their relatives and carers (as appropriate) so that they can make an informed choice about whether to have it. Only consider the procedure if the person is likely not to be significantly distressed by it.\n\nInvolve other specialists as appropriate, such as neuropsychologists and speech and language therapists, before, during and after awake craniotomy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on techniques for resection of glioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n# Follow-up for glioma\n\nOffer regular clinical review for people with glioma to assess changes in their physical, psychological and cognitive wellbeing.\n\nBase decisions on the timing of regular clinical reviews and follow‑up imaging for people with glioma on:\n\nany residual tumour\n\nlife expectancy\n\nthe person's preferences (see table\xa02 for factors to discuss with them)\n\ntreatments used before\n\ntreatment options available\n\ntumour subtype.\n\nPossible advantages of more frequent follow‑up\n\nPossible disadvantages of more frequent follow‑up\n\nMay identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.\n\nThere is no definitive evidence that identifying recurrent disease early improves outcomes.\n\nMay help provide information about the course of the illness and prognosis.\n\nMay increase anxiety if changes of uncertain significance are detected on imaging.\n\nSome people can find more frequent imaging and hospital contact reassuring.\n\nProvides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).\n\nSome people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.\n\nThere may be a financial cost from taking time off work and travelling to appointments.\n\n–\n\nMore imaging and follow‑up is resource intensive for the NHS.\n\nConsider the follow‑up schedule given in table\xa03 for people with glioma.\n\nConsider standard structural MRI (defined as T2\xa0weighted, FLAIR, DWI series and T1\xa0pre- and post-contrast volume) as part of regular clinical review for people with glioma, to assess for progression or recurrence, unless MRI is contraindicated.\n\nConsider advanced MRI techniques, such as MR perfusion, diffusion tensor imaging and MR spectroscopy, if findings from standard imaging are unclear about whether there is recurrence and early identification is potentially clinically useful.\n\nFor people with glioma having routine imaging:\n\nexplain to them, and their relatives and carers, that imaging can be difficult to interpret and results can be of uncertain significance and\n\nbe aware that having routine imaging and waiting for the results may cause anxiety.\n\nConsider a baseline MRI scan within 72\xa0hours of surgical resection for all types of glioma.\n\nConsider a baseline MRI scan 3\xa0months after the completion of radiotherapy for all types of glioma.\n\nArrange a clinical review, including appropriate imaging, for people with glioma who develop new or changing neurological symptoms or signs at any time.\n\nGrade of tumour\n\nClinical review schedule\n\nGrade\xa0I\n\nScan at 12\xa0months, then:\n\nconsider discharge if no tumour visible on imaging unless completely-resected pilocytic astrocytoma\n\nconsider ongoing imaging at increasing intervals for 15\xa0years for completely-resected pilocytic astrocytoma\n\nconsider if ongoing imaging is needed at a rate of once every 1\xa0to 3\xa0years for the rest of the person's life if the tumour is visible on imaging.\n\nGrade\xa0II 1p/19q non-codeleted, IDH mutated\n\nGrade II 1p/19q codeleted\n\nGrade III 1p/19q codeleted\n\nFrom 0 to 2 years, scan at 3\xa0months, then every 6\xa0months\n\nFrom 2 to 4 years, review annually\n\nFrom 5 to 10 years, review every 1\xa0to 2\xa0years\n\nFor more than 10 years and for the rest of life consider ongoing imaging every 1\xa0to 2\xa0years.\n\nGrade\xa0II IDH wildtype\n\nGrade III 1p/19q non-codeleted\n\nGrade IV (glioblastoma)\n\nFrom 0 to 2 years, review every 3\xa0to 6\xa0months\n\nFrom 2 to 4 years, review every 6\xa0to 12\xa0months\n\nFrom 5 to 10 years, review annually\n\nFor more than 10 years and for the rest of life - consider ongoing imaging every 1\xa0to 2\xa0years.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for glioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n# Investigation and management of meningioma\n\n## Investigation of suspected meningioma\n\nOffer standard structural MRI (defined as T2\xa0weighted, FLAIR, DWI series and T1\xa0pre- and post-contrast volume) as the initial diagnostic test for suspected meningioma, unless MRI is contraindicated.\n\nConsider CT imaging for meningioma (if not already performed) to assess bone involvement if this is suspected.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on investigation of suspected meningioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\n\nLoading. Please wait.\n\n## Management of confirmed meningioma following surgery or if surgery is not possible (or has been declined)\n\nBase management of meningioma after surgery, or if surgery is not possible or the person declines surgery, on the extent of any surgery and grade of meningioma, as described in table\xa04.\n\nGrade\n\nCompletely excised (Simpson 1\xa0to\xa03)\n\nIncompletely excised (Simpson 4\xa0to\xa05)\n\nNo excision (radiological only diagnosis)\n\nRecurrent\n\nI\n\nOffer active monitoring.\n\nConsider further surgery (if possible), radiotherapy or active monitoring.\n\nConsider\xa0active monitoring or radiotherapy.\n\nConsider\xa0further surgery or radiotherapy (if not previously used).\n\nII\n\nOffer a choice between active monitoring and radiotherapy.\n\nConsider further surgery (if possible). Offer radiotherapy if surgery is not possible, including if the person declines surgery, or if the tumour is incompletely excised afterwards.\n\nConsider\xa0active monitoring or radiotherapy\n\nConsider further surgery and offer radiotherapy (if not previously used).\n\nIII\n\nOffer radiotherapy.\n\nConsider further surgery (if possible) and offer radiotherapy.\n\nConsider\xa0active monitoring or radiotherapy\n\nConsider further surgery and offer radiotherapy (if not previously used).\n\nBefore a decision is made on radiotherapy for meningioma, take into account:\n\ncomorbidities\n\nlife expectancy\n\nneurological function\n\noedema\n\nperformance status\n\nrate of tumour progression\n\nsize and location of tumour\n\nsurgical and radiotherapy morbidity\n\nthe person's preferences (see table\xa05 for factors to discuss with them)\n\ntreatments used before.\n\n\n\nRadiotherapy\n\nNo radiotherapy\n\nControl of tumour\n\nThere is evidence that radiotherapy is effective in the local control of a tumour.\n\nReceiving no radiotherapy means the tumour may continue to grow.\n\nRisk of developing subsequent symptoms\n\nControlling the tumour will reduce the risk of developing symptoms from the tumour in the future.\n\nIf the tumour grows, it can cause irreversible symptoms such as loss of vision.\n\nRisk of re-treatment\n\nLess risk of needing second surgery compared with no radiotherapy.\n\nHigher risk of needing second surgery compared with radiotherapy.\n\nIf the tumour has progressed, then the surgery might be more complex.\n\nIf the tumour has progressed, then not all radiotherapy techniques may be possible.\n\nEarly side effects of treatment\n\nEarly side effects from radiotherapy can include:\n\nfatigue\n\nhair loss\n\nheadache\n\nnausea\n\nseizures\n\nskin irritation.\n\nNo side effects from treatment.\n\nLate side effects of treatment\n\nLate side effects from radiotherapy can include:\n\neffect on cognition\n\nrisk of stroke\n\nrisk of radionecrosis\n\nrisk of second tumours\n\ncranial nerve effects\n\nhypopituitarism\n\ncataracts.\n\nNo side effects from treatment.\n\nManagement of side effects\n\nIncreased use of steroids to manage side effects.\n\nNo side effects from treatment.\n\nWhen deciding on the radiotherapy technique for people with meningioma, take into account:\n\nthe preferences of the person (for example, to minimise the number of appointments or travel distance)\n\ntumour grade\n\ntumour location (proximity to optic nerves, optic chiasm and brainstem)\n\ntumour size. From the suitable radiotherapy techniques, choose the one which maximises the chances of local tumour control while minimising the radiation dose to normal brain tissue.\n\nIf the multidisciplinary team thinks that radiotherapy may be appropriate, offer the person the opportunity to discuss the potential benefits and risks with an oncologist.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of confirmed meningioma following surgery, or if surgery is not possible or the person declines surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\n\nLoading. Please wait.\n\n## Genomic biomarker-based treatment for meningioma\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.\n\n# Follow-up for meningioma\n\nOffer regular clinical review for people with meningioma to assess changes in their physical, psychological and cognitive wellbeing.\n\nBase decisions on the timing of regular clinical reviews and follow‑up imaging for people with meningioma on:\n\nany residual tumour\n\nlife expectancy\n\nthe person's preferences (see table\xa06 for factors to discuss with them)\n\ntreatments used before\n\ntreatment options available\n\ntumour grade.\n\nPossible advantages of more frequent follow‑up\n\nPossible disadvantages of more frequent follow‑up\n\nMay identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.\n\nThere is no definitive evidence that identifying recurrent disease early improves outcomes.\n\nMay help provide information about the course of the illness and prognosis.\n\nMay increase anxiety if changes of uncertain significance are detected on imaging.\n\nSome people can find more frequent imaging and hospital contact reassuring.\n\nProvides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).\n\nSome people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.\n\nThere may be a financial cost from taking time off work and travelling to appointments.\n\n–\n\nMore imaging and follow‑up is resource intensive for the NHS.\n\nConsider the follow‑up schedule given in table\xa07 for people with meningioma.\n\nConsider standard structural MRI (defined as T2\xa0weighted, FLAIR, DWI series and T1\xa0pre- and post-contrast volume) as part of regular clinical review for people with meningioma, to assess for progression or recurrence, unless MRI is contraindicated.\n\nFor people with meningioma having routine imaging, be aware that having routine imaging and waiting for the results may cause anxiety.\n\nArrange a clinical review, including appropriate imaging, for people with meningioma (including incidental meningioma) who develop new or changing neurological symptoms or signs at any time.\n\n\n\nGrade I: no residual tumour\n\nGrade I: residual tumour\n\nGrade I: after radiotherapy\n\nGrade II\n\nGrade III\n\nto 1 years\n\nScan at 3\xa0months\n\nScan at 3\xa0months\n\nScan 6\xa0months after radiotherapy\n\nScan at 3\xa0months, then 6\xa0to 12\xa0months later\n\nEvery 3\xa0to 6\xa0months\n\nto 2 years\n\nAnnually\n\nAnnually\n\nAnnually\n\nAnnually\n\nEvery 3\xa0to 6\xa0months\n\nto 3 years\n\nAnnually\n\nAnnually\n\nAnnually\n\nAnnually\n\nEvery 6\xa0to 12\xa0months\n\nto 4 years\n\nOnce every 2\xa0years\n\nAnnually\n\nOnce every 2\xa0years\n\nAnnually\n\nEvery 6\xa0to 12\xa0months\n\nto 5 years\n\nOnce every 2\xa0years\n\nAnnually\n\nOnce every 2\xa0years\n\nAnnually\n\nEvery 6\xa0to 12\xa0months\n\nto 6 years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nAnnually\n\nto 7 years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nAnnually\n\nto 8 years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nAnnually\n\nto 9 years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nOnce every 2\xa0years\n\nAnnually\n\n>9 years (for the rest of life)\n\nConsider discharge\n\nConsider discharge\n\nConsider discharge\n\nConsider discharge\n\nAnnually\n\nFor asymptomatic incidental meningioma: scan at 12 months and if no change, consider discharge or scan at 5 years.\n\nNote: the presence of any residual tumour can only be established after the first scan at 3 months.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for meningioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\n\nLoading. Please wait.\n\n# Investigation of suspected brain metastases\n\nOffer standard structural MRI (defined as T2\xa0weighted, FLAIR, DWI series and T1\xa0pre- and post-contrast volume) as the initial diagnostic test for suspected brain metastases, unless MRI is contraindicated.\n\nTo help establish current disease status, offer extracranial imaging (appropriate to the primary tumour type) to people with any radiologically suspected brain metastases that may be suitable for focal treatment.\n\nPerform all intracranial and extracranial diagnostic imaging and, if appropriate, biopsy of extracranial disease, before referral to the neuro-oncology multidisciplinary team.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on investigation of suspected brain metastases\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\n\nLoading. Please wait.\n\n# Management of confirmed brain metastases\n\nWhen choosing management options for brain metastases, take into account:\n\nextracranial disease\n\nleptomeningeal disease\n\nlocation of metastases\n\nresection cavity size\n\nthe number and volume of metastases\n\nthe person's preference (based on a discussion of the factors listed in tables\xa08 and 9)\n\ntheir age\n\ntheir performance status\n\nthe primary tumour site, type, and molecular profile.\n\nConsider systemic anti-cancer therapy for people who have brain metastases likely to respond effectively, for example, germ cell tumours or small-cell lung cancer.\n\nConsider maximal local therapy with either surgery, stereotactic radiosurgery or stereotactic radiotherapy for people with a single brain metastasis.\n\nBase the choice of treatment for people with a single brain metastasis on:\n\ncomorbidities\n\nextent of oedema\n\nlocation of metastasis\n\nthe person's preference (see table\xa08)\n\ntumour size.\n\n\n\nSurgery\n\nStereotactic radiosurgery / radiotherapy\n\nOverall survival\n\nNo clinically important difference.\n\nNo clinically important difference.\n\nRisk of needing additional treatment\n\nRisk that stereotactic radiosurgery / radiotherapy may be needed in any case.\n\nRisk that surgery may be needed in any case. However, has higher local control rate than surgery (meaning surgery is less likely after radiotherapy than the other way around).\n\nKey benefit of treatment\n\nHas more rapid control of symptoms.\n\nAdditionally, surgery allows for obtaining an up-to-date pathological diagnosis which may guide future treatment, making it more effective.\n\nHas a higher local control rate than surgery, meaning more treatment is less likely to be needed.\n\nAdditionally, is an outpatient treatment and does not need a general anaesthetic.\n\nKey risks of treatment\n\nSurgical procedures carry known risks that vary depending on the person and the tumour. These include infection, stroke, a prolonged hospital stay and death.\n\nSurgery is more painful than radiotherapy during recovery.\n\nRadiation carries the risk of delayed effects such as radionecrosis, which might need surgical resection.\n\nThere is an increased risk of seizures with this technique, although this appears to mostly affect people who have pre-existing epilepsy.\n\nSteroid use\n\nEarly reduction in steroid dose.\n\nLikely to need steroids for longer, and at a higher dose. Steroids have significant side effects when used long-term, such as changes in mood, heart problems and changes in body fat.\n\nPlanning treatment around important life events\n\nThe wound from the surgery may affect the ability to carry out certain activities in the short term, such as air travel and sport.\n\nThe cosmetic appearance of the wound from surgery may be important to some people, and should be discussed.\n\nSome people find the techniques used in radiotherapy challenging or upsetting, especially the equipment which immobilises the head. This is especially likely to be true for people with claustrophobia.\n\nOther considerations\n\n–\n\nRadiotherapy can reach some areas of the brain that surgery cannot, and might be the only appropriate technique for certain tumour types.\n\nDo not offer adjuvant whole-brain radiotherapy to people with a single brain metastasis treated with stereotactic radiosurgery/radiotherapy or surgery.\n\nSee NHS England's clinical commissioning policy on stereotactic radiosurgery and stereotactic radiotherapy to the surgical cavity following resection of cerebral metastases. [amended 2021]\n\nConsider stereotactic radiosurgery/radiotherapy for people with multiple brain metastases who have controlled or controllable extracranial disease and Karnofsky performance status of 70\xa0or more. Take into account the number and total volume of metastases.\n\nDo not offer whole-brain radiotherapy to people with:\n\nnon-small-cell lung cancer and\n\nbrain metastases that are not suitable for surgery or stereotactic radiosurgery/radiotherapy and\n\na Karnofsky performance status of under\xa070.\n\nFor people with multiple brain metastases who have not had stereotactic radiosurgery/radiotherapy or surgery, decide with them whether to use whole-brain radiotherapy after a discussion with them and their relatives and carers (as appropriate) of the potential benefits and risks (see table\xa09).\n\n-\n\nWhole-brain radiotherapy\n\nNo whole-brain radiotherapy\n\nOverall survival\n\nNo clinically important difference.\n\nNo clinically important difference.\n\nQuality of life\n\nShort-term deterioration in quality of life because of treatment.\n\nNo impact on quality of life because of treatment, but deterioration because of the disease progression.\n\nPotential benefits\n\nCan stabilise or reduce the brain metastases.\n\n\n\nBrain metastases may continue to grow.\n\nSide effects\n\nTemporary hair loss and fatigue. Potential for accelerated cognitive loss because of radiotherapy.\n\nPotential for cognitive loss because of disease progression.\n\nTime commitment\n\nRequires 5\xa0to 10\xa0hospital visits.\n\nNo time commitment.\n\nOther considerations\n\nPeople with non-small-cell lung cancer will not benefit from treatment if their overall prognosis is poor.\n\n–\n\nDo not offer memantine in addition to whole-brain radiotherapy to people with multiple brain metastases, unless as part of a clinical trial.\n\nDo not offer concurrent systemic therapy to enhance the efficacy of whole-brain radiotherapy to people with multiple brain metastases, unless as part of a clinical trial.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of confirmed brain metastases\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\n\nLoading. Please wait.\n\n# Follow-up for brain metastases\n\nOffer regular clinical review for people with brain metastases to assess changes in their physical, psychological and cognitive wellbeing.\n\nBase decisions on the timing of regular clinical reviews and follow‑up imaging for people with brain metastases on:\n\nextracranial disease status\n\nlife expectancy\n\nprimary cancer\n\nthe person's preferences (see table\xa010 for factors to discuss with them)\n\ntreatment options available.\n\nPossible advantages of more frequent follow‑up\n\nPossible disadvantages of more frequent follow‑up\n\nMay identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.\n\nThere is no definitive evidence that identifying recurrent disease early improves outcomes.\n\nMay help provide information about the course of the illness and prognosis.\n\nMay increase anxiety if changes of uncertain significance are detected on imaging.\n\nSome people can find more frequent imaging and hospital contact reassuring.\n\nProvides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).\n\nSome people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.\n\nThere may be a financial cost from taking time off work and travelling to appointments.\n\n–\n\nMore imaging and follow‑up is resource intensive for the NHS.\n\nConsider the follow‑up schedule given in table\xa011 for people with brain metastases.\n\nConsider standard structural MRI (defined as T2\xa0weighted, FLAIR, DWI series and T1\xa0pre- and post-contrast volume) as part of regular clinical review for people with brain metastases, to assess for progression or recurrence, unless MRI is contraindicated.\n\nConsider advanced MRI techniques, such as MR perfusion, diffusion tensor imaging and MR spectroscopy, if findings from standard imaging are unclear about whether there is recurrence and early identification is potentially clinically useful.\n\nFor people with brain metastases having routine imaging:\n\nexplain to them, and their relatives and carers, that imaging can be difficult to interpret and results can be of uncertain significance and\n\nbe aware that having routine imaging and waiting for the results may cause anxiety.\n\nArrange a clinical review, including appropriate imaging, for people with brain metastases who develop new or changing neurological symptoms or signs at any time.\n\nYears after end of treatment\n\nClinical review schedule\n\nto 1 years\n\nEvery 3\xa0months\n\nto 2 years\n\nEvery 4\xa0to 6\xa0months\n\nyears and onwards\n\nAnnually\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for brain metastases\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\n\nLoading. Please wait.\n\n# Care needs of people with brain tumours\n\nBe aware that the care needs of people with brain tumours represent a unique challenge, because (in addition to physical disability) the tumour and treatment can have effects on:\n\nbehaviour\n\ncognition\n\npersonality.\n\nDiscuss health and social care support needs with the person with a brain tumour and their relatives and carers (as appropriate). Take into account the complex health and social care support needs people with any type of brain tumour and their relatives and carers may have (for example, psychological, cognitive, physical, spiritual, emotional).\n\nSet aside enough time to discuss the impact of the brain tumour on the person and their relatives and carers (as appropriate), and to elicit and discuss their health and social care support needs.\n\nHealth and social care professionals involved in the care of people with brain tumours should address additional complex needs during or at the end of treatment and throughout follow‑up. These include:\n\nchanges to cognitive functioning\n\nfatigue\n\nloss of personal identity\n\nloss of independence\n\nmaintaining a sense of hope\n\npotential for change in personal and sexual relationships\n\nthe challenges of living with uncertainty\n\nthe impact of brain tumour-associated epilepsy on wellbeing (see the NICE guideline on epilepsies: diagnosis and management).\n\nProvide a named healthcare professional with responsibility for coordinating health and social care support for people with brain tumours and their relatives and carers, for example, a key worker (often a clinical nurse specialist) as defined in NICE cancer service guidance on improving outcomes for people with brain and other central nervous system tumours.\n\nGive information to the person with a brain tumour and their relatives and carers (as appropriate):\n\nin a realistic and empathetic manner\n\nin suitable formats (written and spoken, with information available to take away), following the principles in the NICE guideline on patient experience in adult NHS services (also see NHS England's guidance on the Accessible Information Standard).\n\nat appropriate times throughout their care pathway.\n\nExplain to the person that they have a legal obligation to notify the Driver and Vehicle Licensing Agency (DVLA) if they have a brain tumour, and that this may have implications for their driving.\n\nProvide and explain clinical results, for example, imaging and pathology reports, to the person with a brain tumour and their relatives and carers (as appropriate) as soon as possible.\n\nOffer supportive care to people with brain tumours and their relatives and carers (as appropriate) throughout their treatment and care pathway\n\nIn people aged between 16\xa0and 24\xa0years old, refer to the NICE quality standard on cancer services for children and young people.\n\nDiscuss the potential preservation of fertility with people with brain tumours where treatment may have an impact on their fertility (see the recommendations on people with cancer who wish to preserve fertility in NICE's guideline on fertility problems).\n\nIf the person with a brain tumour is likely to be in their last year of life, refer to the NICE quality standards on end of life care for adults and, when appropriate, care of dying adults in the last days of life.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on care needs of people with brain tumours\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\n\nLoading. Please wait.\n\n# Neurorehabilitation needs of people with brain tumours\n\nConsider referring the person with a brain tumour for a neurological rehabilitation assessment of physical, cognitive and emotional function at diagnosis and every stage of follow‑up.\n\nOffer people with brain tumours and their relatives and carers (as appropriate) information on accessing neurological rehabilitation, and on what needs it can help address.\n\nGive people with brain tumours and their relatives and carers (as appropriate) information on:\n\nneurological rehabilitation options in the community, as an outpatient, or an inpatient and\n\nhow to get a neurological rehabilitation assessment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on neurorehabilitation needs of people with brain tumours\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\n\nLoading. Please wait.\n\n# Surveillance for the late-onset side effects of treatment\n\nBe aware that people with brain tumours can develop side effects of treatment months or years after treatment, which can include:\n\ncataracts\n\ncavernoma\n\ncognitive decline\n\nepilepsy\n\nhearing loss\n\nhypopituitarism\n\ninfertility\n\nneuropathy (for example, nerve damage causing visual loss, numbness, pain or weakness)\n\nradionecrosis\n\nsecondary tumours\n\nSMART (stroke-like migraine attacks after radiotherapy)\n\nstroke.\n\nAssess the person's individual risk of developing late effects when they finish treatment. Record these in their written treatment summary and explain them to the person (and their relatives and carers, as appropriate).\n\nEncourage people who have had cranial radiotherapy to follow a healthy lifestyle, including exercise, a healthy diet and stopping smoking (if applicable), to decrease their risk of stroke. See the NICE guidelines on obesity prevention, physical activity and tobacco: preventing uptake, promoting quitting and treating dependence.\n\nFor people who are at risk of stroke, consider checking their blood pressure, HbA1c level and cholesterol profile regularly.\n\nConsider ongoing neuropsychology assessment for people at risk of cognitive decline.\n\nIf a person has had a radiotherapy dose that might affect pituitary function, consider checking their endocrine function regularly after the end of treatment.\n\nConsider referring people who are at risk of visual impairment for an ophthalmological assessment.\n\nConsider referring people who are at risk of hearing loss to audiology for a hearing test.\n\nConsider referring the person to stroke services if an MRI during active monitoring identifies asymptomatic ischaemic stroke.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on surveillance for the late-onset side effects of treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Active monitoring\n\nThis is regular clinical and radiological review of a person with a brain tumour or brain metastases who are not currently having treatment for their cancer.\n\n## Regular clinical review\n\nThis is outpatient review of the person with a brain tumour or brain metastases at a planned interval from the previous visit in order to assess symptoms and care needs, to provide support and treatment and to perform imaging when appropriate.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Managing glioma: management of IDH wildtype grade\xa0II glioma\n\nDoes the addition of concurrent and adjuvant temozolomide to radiotherapy improve overall survival in patients with IDH wildtype grade\xa0II glioma?\n\nThe World Health Organization (WHO) 2016 reclassification of brain tumours recognised that the molecular characteristics of glioma are extremely important in helping differentiate between disease entities with very different outcomes. Although evidence exists to guide management recommendations for certain molecular gliomas, such as codeleted and non-codeleted grade\xa0III glioma, currently no studies have investigated the best approach for the management of grade\xa0II glioma with IDH wildtype. The biological behaviour of these tumours is more like a high-grade glioma with a much shorter prognosis than IDH-mutated grade\xa0II glioma.\n\nBecause of this, some clinicians have advocated treating such tumours with concurrent chemoradiation recommended for grade\xa0IV glioma (glioblastoma multiforme, GBM). However, there is currently no research evidence to support this approach and this regimen is more intensive and people experience increased acute and late side effects compared to radiotherapy alone.\n\nResearch is needed to establish whether or not this approach is beneficial in terms of improved survival, and at what cost in terms of toxicity and, potentially, reduced quality of life.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on managing glioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Managing glioma: supportive care clinics for low-grade glioma\n\nDoes a dedicated supportive care clinic in addition to standard care improve outcomes for people with low-grade gliomas?\n\nPeople with low-grade gliomas have significant symptoms and complex healthcare needs across multiple physical, cognitive, emotional and social domains. This is often from the initial diagnosis onwards. There are indications from research literature and patient reports that these needs are currently unmet. Helping people with low-grade gliomas maintain their quality of life and function is important, especially as there is currently no cure, because earlier supportive care interventions and care plans may help reduce unplanned or emergency contact with secondary and tertiary providers.\n\nAs no research literature exists which establishes the effectiveness of a specific healthcare intervention, uncertainty exists about the most appropriate intervention to address unmet needs and improve patient-reported outcome measures (or to establish whether current healthcare provision can meet these needs). Current uncertainty is likely to have led to variations in service provision across the UK. It is also possible that no specific intervention is available in some areas.\n\nResearch is needed to identify whether, in addition to standard care, a specific supportive care intervention can significantly improve patient-reported outcome measures, and if so to establish what this intervention should consist of.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on supportive care clinics for low-grade glioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Managing glioma: early referral to palliative care for glioblastoma\n\nDoes early referral to palliative care improve outcomes for people with glioblastomas in comparison with standard oncology care?\n\nPeople with grade\xa0IV brain tumours (glioblastomas) have a poor prognosis which has not improved in over a decade. Median overall survival is 14–18\xa0months even with gold-standard chemoradiation following surgery.\n\nFrom initial diagnosis people experience multiple complex symptoms resulting from neurological impairment. These can significantly impact on their quality of life, function and psychological wellbeing. Their caregivers report high levels of distress and carer burden.\n\nThe aim of palliative care is to relieve symptoms and improve people's quality of life and function – not just towards the end of life but throughout the duration of illness. There is some evidence that early palliative care referral significantly improves overall survival, quality of life and mood.\n\nResearch in this area is important because this group of people have substantial health needs, which use significant healthcare resources. Supportive care interventions such as early palliative care may improve quality of life and function throughout the duration of illness. It may also help people to manage the distress associated with a reduced life expectancy and participate in advanced care planning.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on early referral to palliative care for glioblastoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Managing glioma: early detection of recurrence after treatment\n\nDoes early detection of recurrence after treatment improve overall survival/outcomes in molecularly stratified glioma?\n\nPrognosis for brain tumours is inherently uncertain, and recent advances in treatment mean many people with a brain tumour will live for a long time after the initial diagnosis. For these individuals, follow‑up is the longest component of their treatment and it is both expensive for the NHS and (sometimes) a burden for the person. There is no high-quality evidence that follow‑up after treatment is beneficial, no high-quality evidence on the optimal frequency of imaging, and clinical uncertainty about whether such follow‑up is likely to alter outcomes of importance to people with tumours (such as overall life expectancy or quality of life).\n\nResearch is needed to establish at what point the value of identifying recurrence early is outweighed by the harms of increasing burden to patients.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on the early detection of recurrence after treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\n\nLoading. Please wait.\n\n## Managing meningioma: immediate versus deferred radiotherapy for incompletely excised grade\xa0I meningioma\n\nIs immediate or deferred radiotherapy better for incompletely excised grade\xa0I meningioma?\n\nThere are no randomised studies on the use of radiotherapy/radiosurgery in the treatment of grade\xa0I meningioma. Though case series have shown that people with inoperable and incompletely excised grade\xa0I meningioma treated with radiotherapy have high rates of control of their tumour, treatment risks significant side effects. The side effects include: neuropathy, radionecrosis, significant oedema, neuro-cognitive effects, increased risk of stroke and secondary tumours. Therefore the timing of treatment is a balance between control of tumour and side effects. It is not known if early treatment has a greater or lesser chance of long-term tumour control or risk of tumour complications, or if this just risks complications of treatment earlier.\n\nPeople with grade\xa0I meningioma have traditionally been overlooked as a priority area for research. This is likely because of the slow nature of the disease resulting in need for long-term follow‑up and the difficulty to obtain funding for radiotherapy-only studies. However, this lack of research is inequitable, hence the reason for its prioritisation by the committee.\n\nA study on this topic would provide clear information to guide clinicians and people with meningiomas, hopefully leading to overall improvement in quality of life. Because of the slow-growing characteristics of grade\xa0I meningioma, treatment decisions made early in the management pathway will have long-term effects on the person with the meningioma's overall quality of life outcomes, and potentially overall survival.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on managing meningioma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Investigations for suspected glioma: imaging\n\nThe discussion below explains how the committee made recommendations 1.1.1–1.1.3.\n\n## Why the committee made the recommendations\n\nThe evidence indicated that standard structural MRI is useful in distinguishing high-grade from low-grade glioma. The committee noted that this knowledge will inform management. Based on their experience, the committee recommended a protocol that they defined as a minimum standard for imaging acquisition.\n\nNo evidence was found on more advanced MRI techniques. However, the committee agreed that in their experience such techniques can be useful for assessing malignant features of a tumour – in particular, for ensuring that high-grade tumours are not misdiagnosed as low-grade tumours, which could have serious consequences for people who receive suboptimal management as a result. However the committee explained that a specialist multidisciplinary team would be needed to interpret features of the scan and decide management, even if advanced techniques were used.\n\n## How the recommendations might affect practice\n\nCurrently, various imaging strategies are used in different centres and depending on the person's circumstances. These recommendations aim to reduce variation in practice, and ensure that images obtained at different sites and using different equipment can be more accurately compared. Some centres may need to change their imaging protocols. This might increase or reduce costs depending on the imaging protocols which are currently in place.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Investigations for suspected glioma: molecular markers\n\nThe discussion below explains how the committee made recommendations 1.1.4–1.1.6.\n\n## Why the committee made the recommendations\n\nMolecular markers are an emerging and important area in the treatment of brain tumours. The committee looked for evidence on these markers but did not find any. However, they noted that there are some molecular markers for which the evidence of benefit if tested is overwhelming, as reported in studies identified in searches for other review questions. This applies in particular for MGMT promoter methylation and TERT promoter mutations in IDH-wildtype glioma, although the committee agreed the evidence was of a higher quality in the first case than the second. The committee agreed that even these markers are not being consistently tested for and that testing should be standardised. Therefore they made recommendations based on their knowledge and experience, highlighting the World Health Organization (WHO) classification, to ensure that all centres follow a consistent process for assessing and interpreting information on molecular markers. This was important, since failure to consistently report molecular markers can mislead clinicians or limit treatment options.\n\n## How the recommendations might affect practice\n\nAs testing for molecular markers is relatively new, practice can vary widely and this is to be expected. In principle there should not be a major change, although the time taken to implement the new molecular tests will vary significantly between centres.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Management of glioma: initial surgery for low-grade glioma\n\nThe discussion below explains how the committee made recommendations 1.2.1–1.2.5.\n\n## Why the committee made the recommendations\n\nThere was evidence that optimal resection of a large percentage of the tumour improved survival for people with low-grade glioma. The committee noted that it is sometimes not appropriate to offer maximal safe resection (for example, if the balance of risks and benefits favours not resecting all areas) and that a specialist surgical team should look at the value of doing an operation given its safe extent. They agreed that biopsy should be considered in these cases, based on limited evidence showing improved overall survival after biopsy compared with active monitoring. However, the committee also concluded that some tumours were of such limited risk that the risks of surgery outweighed the possible gain of biopsy or resection.\n\nThe committee described how there was no evidence for immediate intervention, but that intervention should not be delayed due to the probability that surgical resection would have benefit for the person with the tumour. They therefore recommended intervention within 6\xa0months, to allow for time to discuss treatment options with the person with the tumour. This also allows for the possibility of a second imaging sequence to be done later to look for progression and to assess for symptom change, as the committee also recognised that a proportion of low-grade gliomas have unfavourable gene profiles (for example, IDH wildtype) that make them more like high-grade tumours from a prognostic perspective.\n\nA small number of people might have had initial treatment before it was standard practice to save a tissue sample for biopsy, and these people would currently be actively monitored. Based on their experience the committee agreed that these people may not need further surgery as long as their condition is stable (that is, they are not showing radiological or clinical disease progression).\n\n## How the recommendations might affect practice\n\nThe recommendations are likely to change practice at some centres, and remove unnecessary variation. There are currently differences between centres in which molecular diagnoses are performed and in treatment of very low-risk, low-grade tumours. This is partly because low-grade gliomas may be managed by non-expert surgical teams.\n\nThe recommendation about the management of low-grade gliomas that have been managed but then progress is unlikely to substantially change practice, as management would be largely unchanged.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Management of glioma: further management of low-grade glioma\n\nThe discussion below explains how the committee made recommendations 1.2.6–1.2.11.\n\n## Why the committee made the recommendations\n\nThere was evidence that PCV chemotherapy (procarbazine, CCNU [lomustine] and vincristine) after radiotherapy improved overall survival and progression-free survival compared with radiotherapy alone. The committee discussed how the evidence for the exact regime was complex, and used their judgement to recommend possible sequence and dose. In addition, the committee noted that there are some circumstances where radiotherapy and PCV might not be appropriate (particularly for the very lowest-concern and highest-concern low-grade tumours) and made recommendations based on their experience in these cases.\n\nThe committee included approximate age cut‑offs based on evidence showing that treatment improved survival in people aged around 40\xa0or over with or without residual tumour, and their clinical judgement that treatment would be unlikely to be of benefit for people aged around 40\xa0or under without residual tumour.\n\nThe committee found no evidence on the treatment of IDH wildtype grade\xa0II glioma. They determined that management of this type of glioma was likely to be different from other low-grade glioma, as IDH wildtype grade\xa0II glioma behaves more like a high-grade glioma. The committee therefore made a research recommendation on whether treating this tumour type more like a grade\xa0II glioma or grade\xa0IV glioma was most beneficial.\n\n## How the recommendations might affect practice\n\nThese recommendations aim to standardise practice. They will probably result in the same amounts of chemotherapy and radiotherapy being given, but these treatments will be more precisely targeted and it is possible that they will be given earlier. This would result in more people requiring long-term treatment for the side effects of radiation and chemotherapy. More people are likely to have active monitoring alone, which is not likely to create a resource impact.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Management of glioma: grade\xa0III glioma following surgery\n\nThe discussion below explains how the committee made recommendations 1.2.12–1.2.17.\n\n## Why the committee made the recommendations\n\nThe committee considered evidence for grade\xa0III and grade\xa0IV glioma separately.\n\nBased on randomised controlled trial evidence, the committee recommended radiotherapy and either PCV or temozolomide chemotherapy, depending on tumour subtype and performance status, for people with grade\xa0III glioma.\n\nBased on the available evidence, the committee recommended that some treatments should not be offered because they were harmful. They also agreed, based on their experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to indicate that certain treatments are beneficial.\n\n## How the recommendations might affect practice\n\nAdjuvant PCV for treating codeleted grade\xa0III glioma is standard practice, but adjuvant temozolomide for non-codeleted grade\xa0III gliomas is a change in practice. However, some centres may already have started to adopt this as standard care, since the results of the study supporting this treatment were made publicly available in\xa02016.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Management of glioma: grade\xa0IV glioma following surgery\n\nThe discussion below explains how the committee made recommendations 1.2.18–1.2.27.\n\n## Why the committee made the recommendations\n\nThe committee considered evidence for grade\xa0III and grade\xa0IV glioma separately.\n\nThe committee saw some evidence demonstrating improved overall survival in some groups of people with grade\xa0IV glioma who had radiotherapy with concurrent and adjuvant temozolomide (compared with radiotherapy alone). However, based on their clinical experience they were unsure that these results could be generalised to all people with grade\xa0IV glioma, so suggested a range of possible treatments that can be considered for other groups, depending on the exact clinical characteristics of the tumour.\n\nApproximate age cut‑offs for people with grade\xa0IV glioma were specified by the committee based on evidence that a radiotherapy dose of 40\xa0Gy did not result in lower survival in people aged around 70\xa0or over compared with a 60\xa0Gy dose. Therefore a lower radiotherapy dose is likely to cause fewer side effects without compromising clinical effectiveness for this group.\n\nThe committee were aware that the prognosis of people with a grade\xa0IV glioma and a low performance status was poor, and recommended palliative care be considered. However the committee did not find any evidence on whether earlier or later palliative care was most beneficial for people who might need it. They therefore made a research recommendation on this topic, with the aim of finding out the point in the treatment pathway when it would be most beneficial for people with this type of glioma to have palliative care.\n\nBased on the available evidence, the committee recommended that certain treatments should not be offered. This included tumour treating fields (TTF) based on published health economic evidence that they are not an efficient use of NHS resources. They also agreed, based on their clinical experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to suggest that certain treatments are beneficial.\n\n## How the recommendations might affect practice\n\nFor younger people with a grade\xa0IV glioma and a good performance status, a course of radiotherapy with concurrent and adjuvant temozolomide is standard care. However, for people aged around 70\xa0and over, particularly those with a glioma with methylated MGMT, the use of concurrent and adjuvant temozolomide with 15\xa0fractions of radiotherapy is a change of practice that will probably result in more people being treated. This is a relatively small group of people, and so the recommendation is unlikely to have a significant resource impact.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Management of glioma: recurrent high-grade glioma\n\nThe discussion below explains how the committee made recommendations 1.2.28–1.2.35.\n\n## Why the committee made the recommendations\n\nBased on the available evidence, the committee recommended that treatment options for people with recurrent glioma should include temozolomide, PCV and single-agent CCNU (lomustine). No evidence was found to indicate which of these 3\xa0options is likely to lead to the best outcomes, and on the basis of their clinical experience the committee concluded that the choice of treatment should take several factors into account, including the individual features of the tumour and the preferences of the person. The committee also highlighted the possibility of considering supportive care alone.\n\nBased on the available evidence, the committee recommended that certain treatments should not be offered. This included tumour treating fields (TTF) on the basis of evidence of some clinical benefit but indirect published health economic evidence, in people with newly diagnosed high-grade glioma, that they are not cost effective. They also agreed, based on their clinical experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to suggest that certain treatments are beneficial.\n\n## How the recommendations might affect practice\n\nThese recommendations reflect standard treatment for recurrent high-grade glioma, and therefore should not represent a substantial change in practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Management of glioma: techniques for resection of glioma\n\nThe discussion below explains how the committee made recommendations 1.2.36–1.2.42.\n\n## Why the committee made the recommendations\n\nThere was evidence that 5‑aminolevulinic acid (5‑ALA), intraoperative MRI and diffusion tensor imaging could improve either the extent or safety of resection (particularly the preservation of neurological function). The committee noted that a combination of techniques might be needed to optimise both the extent and safety of resection for a particular surgical plan. The committee concluded that the evidence for MRI could be generalised to intraoperative ultrasound on the basis of their clinical experience, and therefore that clinicians should be able to choose either technique depending on availability.\n\nThe evidence for awake craniotomy was equivocal (non-significant differences compared with surgery under general anaesthesia), therefore from the evidence it was not possible to conclude that awake craniotomy would benefit all people with glioma. This is in line with the committee's clinical experience that some people benefit from the procedure (in terms of preserving language, motor and visual function) but others are harmed – particularly from psychological effects which act as a contraindication to awake craniotomy. The committee described how better preoperative procedures could reduce the number of people distressed by the procedure.\n\n## How the recommendations might affect practice\n\nSome techniques recommended by the committee require a very high level of intraoperative skill, and this might have resource implications for hospitals recruiting people with these specialist skills. There is significant variation in the current provision of psychological support for people before and during awake craniotomy, and implementing this could carry a high cost to an individual unit.\n\nIf a unit does not have access to intraoperative ultrasound or MRI, the cost of acquiring this equipment could be substantial (MRI is relatively expensive, ultrasound is relatively cheap). However the committee concluded that most units should have access to one or the other already. Therefore the only resource impact would be if a unit currently using intraoperative ultrasound decided that the additional evidence for preservation of neurological function in intraoperative MRI justified the cost of switching machines. However, the committee thought this was unlikely to happen.\n\nUsing 5‑ALA is associated with a high cost, and 5‑ALA-guided surgery needs a non-standard fluorescence-detecting microscope. Therefore the resource impact of this recommendation is likely to be high in all settings, and very high in settings without access to a fluorescence-detecting microscope. The anticipated resource impact of this recommendation is greater than £1\xa0million per year.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Follow-up for glioma\n\nThe discussion below explains how the committee made recommendations 1.3.1–1.3.9.\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.\n\nAs regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.\n\nThe committee believed that a dedicated supportive care clinic could improve outcomes for people with low-grade glioma, but did not find any evidence on this. Therefore they made a research recommendation on improving the long-term outcomes of people with low-grade glioma.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.\n\nThe imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: investigation, management and follow-up of glioma.\n\nReturn to recommendations\n\n# Investigation of suspected meningioma\n\nThe discussion below explains how the committee made recommendations 1.4.1 and\xa01.4.2.\n\n## Why the committee made the recommendations\n\nEvidence indicated that standard structural MRI is useful in distinguishing high-grade from low-grade glioma, and the committee agreed that it is appropriate to extrapolate from this evidence to a belief that MRI can be used to distinguish meningioma from healthy brain tissue. In the committee's experience, CT scans can be more accurate than MRI for assessing meningioma with bone involvement.\n\n## How the recommendations might affect practice\n\nCurrently, various imaging strategies are used depending on the centre and the person's circumstances. These recommendations aim to reduce variation in practice, and ensure that images obtained at different sites and using different equipment can be more accurately compared. Some centres may need to change their imaging protocols as a result, but this should not require the purchase of additional equipment.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: investigation, management and follow-up of meningioma.\n\nReturn to recommendations\n\n# Management of confirmed meningioma following surgery or if surgery is not possible (or has been declined)\n\nThe discussion below explains how the committee made recommendations 1.4.3–1.4.6.\n\n## Why the committee made the recommendations\n\nBased on limited evidence and their clinical experience, the committee concluded that management of this group of meningiomas will depend on the type of meningioma. They noted that evidence for 1\xa0grade of meningioma could not normally be used to suggest best management for another grade. Therefore the committee made recommendations for each grade of meningioma separately, using evidence if this was available and their judgement if it was not. The committee identified that management could be more conservative if the tumour grade was lower and initial resection more complete, and should be more aggressive if the tumour grade was higher or initial resection more partial.\n\nThe committee agreed that the 3\xa0management options – further radiotherapy, surgery and active monitoring – had different balances of benefits and harms in different situations. However they also agreed that serious harm could be done to a person with a tumour if they were over- or under-treated given the risk profile of their tumour, and so made recommendations according to this risk. For example, for a low-grade almost completely-resected tumour (grade\xa0I, Simpson\xa02 excision), radiotherapy or further surgery could expose the person to risk of harm for no expected clinical gain.\n\nBased on limited evidence, the committee made recommendations on how to deliver radiotherapy or radiosurgery where this was appropriate. They used their experience to highlight features of the tumour or preferences of the person that might help select the most appropriate radiotherapy or radiosurgery modality, and explained that the best results would come through minimising the dose of radiation delivered to healthy brain tissue while maximising the chance of local control.\n\nThe committee were unable to find evidence comparing different timings of radiotherapy in incompletely excised grade\xa0I meningioma. As the disease is slow growing it can be difficult to assess the risks of immediate side effects from treatment compared to the longer-term benefits of tumour control. Therefore the committee made a research recommendation to investigate this topic.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect standard practice in many centres, and should make treatment more consistent.\n\nAn appointment with an oncologist for all people who may have radiotherapy is not currently standard practice. However, for most people this is likely to mean a change in the timing of their first appointment with an oncologist, rather than many more people having oncologist appointments.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: investigation, management and follow-up of meningioma.\n\nReturn to recommendations\n\n# Follow-up for meningioma\n\nThe discussion below explains how the committee made recommendations 1.5.1–1.5.6.\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.\n\nAs regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.\n\nThe imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: investigation, management and follow-up of meningioma.\n\nReturn to recommendations\n\n# Investigation of suspected brain metastases\n\nThe discussion below explains how the committee made recommendations 1.6.1–1.6.3.\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, the committee recommended standard structural MRI based on their experience, because it is important to establish the exact number of metastases in the brain, which can guide further treatment. The committee described how failing to establish this could be dangerous. Extracranial imaging, biopsy of the extracranial disease (where indicated) and performing all imaging before multidisciplinary team discussions should ensure that all necessary information is available so that appropriate decisions are made and delays in treatment avoided.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice and should reduce delays to local intracranial treatment.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: investigation, management and follow-up of brain metastases.\n\nReturn to recommendations\n\n# Management of confirmed brain metastases\n\nThe discussion below explains how the committee made recommendations 1.7.1–1.7.11.\n\n## Why the committee made the recommendations\n\nThe committee made recommendations based on the available evidence and their judgement. They described how features of brain metastases, including the number and volume (which is important for establishing prognosis), should be evaluated before starting treatment, and decisions about treatment made on the basis of these features and the person's preferences.\n\nThe committee described how systematic anti-cancer therapies were widely used in the management of other types of metastases, and therefore they might be expected to work for brain tumours. In the absence of evidence, the committee recommended considering systematic anti-cancer therapies on the basis of their clinical experience. Whether or not these therapies should be given depends on the type of metastasis: if it is not likely to respond then the side effects would not justify giving the therapy, whereas if the metastasis was likely to respond then the therapy was likely to be beneficial.\n\nEvidence indicated that surgery, stereotactic radiosurgery and stereotactic radiotherapy are effective for treating a single brain metastasis, but there was no evidence to recommend 1\xa0technique over the other. There was some evidence that irradiation of the cavity site improved local control, so the committee recommended it on the basis that improving local control should improve quality of life.\n\nJanuary 2021: the recommendations on this surgical cavity radiosurgery and radiotherapy have been updated. For details see the update information.\n\nFor people with multiple brain metastases, the committee described how treatment options are more variable, and that resection, stereotactic radiosurgery, stereotactic radiotherapy and whole-brain radiotherapy could all be considered in certain circumstances.\n\nThe committee recommended that neither memantine nor concurrent systemic therapy should be offered to enhance the efficacy of whole-brain radiotherapy, on the basis of evidence of no benefit and a potential risk of harm. However, there were biological reasons to think these treatments might be beneficial in some settings, so the committee agreed these therapies could be offered in the context of a clinical trial to investigate this.\n\n## How the recommendations might affect practice\n\nCurrent practice varies greatly between centres. Some of the variation reflects clinically relevant factors such as expertise in a particular technique or the patient population. The recommendations should help to standardise care and prevent some harmful and wasteful practices from continuing. Economic modelling identified that the recommendations will likely increase costs, but the committee believed that this was still an efficient use of NHS resources, as the improvement to quality of life was significant.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: investigation, management and follow-up of brain metastases.\n\nReturn to recommendations\n\n# Follow-up for brain metastases\n\nThe discussion below explains how the committee made recommendations 1.8.1–1.8.7.\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.\n\nAs regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.\n\nThe imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: investigation, management and follow-up of brain metastases.\n\nReturn to recommendations\n\n# Care needs of people with brain tumours\n\nThe discussion below explains how the committee made recommendations 1.9.1–1.9.12.\n\n## Why the committee made the recommendations\n\nBased on the evidence and their own experience, the committee determined that people with brain tumours have very specific needs that are often not met. In particular, they highlighted ways in which the care needs of people with brain tumours differ from those of people with other types of cancer, such as the impact on the person's sense of identity and legal requirements related to driving. Losing the ability or legal right to drive can have a profound effect on the patient's independence, employment status and self-esteem. The committee's aim was to improve the support and information offered to people with brain tumours.\n\nThe committee described how the care needs of people with brain tumours were often more complex than could be considered in a single guideline. In particular, young people, people wishing to preserve their fertility, and people nearing the end of their life have especially complex needs. In order to address these needs, the committee signposted to existing NICE guidance in the specific area.\n\n## How the recommendations might affect practice\n\nThe recommendations should improve care for both people living with brain tumours and their relatives and carers. It is likely that there will be a short-term resource impact in some areas, as supportive care for people with brain tumours is currently variable, with very little support available in some areas.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: supporting people living with a brain tumour.\n\nReturn to recommendations\n\n# Neurorehabilitation needs of people with brain tumours\n\nThe discussion below explains how the committee made recommendations 1.10.1–1.10.3.\n\n## Why the committee made the recommendations\n\nNo evidence was found for this topic. Based on their experience, the committee agreed that neurological rehabilitation is likely to be suitable for many people with brain tumours. Given that neurological rehabilitation is time-consuming (especially if the person with a tumour lives a long way from the rehabilitation centre) and sometimes not appropriate, the committee agreed that assessment should be carried out at every stage of diagnosis and follow‑up to identify which, if any, forms of rehabilitation are suitable for the person. The aim of the recommendations is to ensure that neurological rehabilitation is considered at every stage of treatment and follow‑up.\n\n## How the recommendations might affect practice\n\nThere is currently variation in practice in assessing whether people with a brain tumour need neurological rehabilitation. Some of this reflects the availability of neurological rehabilitation services. The recommendations reinforce current best practice, and will mean a change in practice in some areas, including where assessment is 'ad hoc' rather than systematic.\n\nPeople with a brain tumour make up a small percentage of people referred for neurological rehabilitation, so only a small increase in demand on resources is expected. There should not be any extra training needs because professionals already have the knowledge and skills to provide the services.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: supporting people living with a brain tumour.\n\nReturn to recommendations\n\n# Surveillance for the late-onset side effects of treatment\n\nThe discussion below explains how the committee made recommendations 1.11.1–1.11.9.\n\n## Why the committee made the recommendations\n\nNo evidence was found for this topic. Some people experience late effects after treatment for a brain tumour. With the possible exception of stroke risk it is unknown if these late effects can be prevented, but the committee agreed that any negative impact can be managed through clinical vigilance and referral into appropriate specialist monitoring pathways. The committee explained that it was important to consider referral for anyone at risk of late effects – not just those at 'high' risk – but that there may be no value in such a referral overall in lower risk groups.\n\n## How the recommendations might affect practice\n\nThe recommendations should not significantly alter practice, as they reflect common clinical practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: supporting people living with a brain tumour.\n\nReturn to recommendations", 'Context': 'It is estimated there are around 10,000\xa0new cases of primary brain tumours per year. These tumours come from the brain tissue or its coverings – the meninges. Malignant high-grade gliomas (anaplastic gliomas and glioblastomas) and pre-malignant low-grade gliomas come from the brain tissue glial cells, and make up over 60% of primary brain tumours. Meningiomas make up a further 30%. Although often thought benign, meningiomas can have an acute presentation and are associated with significant long-term neurological morbidity. Because of this, they can behave in a malignant fashion in terms of recurrence and impact.\n\nOver 60% of people with primary brain tumours present at, and are diagnosed by, accident and emergency services rather than from conventional GP or specialist referral. This causes a significant demand on these services. Although primary malignant brain tumours represent only 3% of all cancers, they result in the most life-years lost of any cancer. There is concern that the true incidence of these tumours is rising.\n\nCancers that have spread to the brain from somewhere else in the body are called secondary brain tumours, or brain metastases. Many different cancer types can spread to the brain, with lung and breast cancers being the most common. More people with systemic cancers are surviving longer and are referred to neuroscience multidisciplinary teams for management of their brain metastases. The number of people needing assessment for cranial treatment is now over 10,000\xa0per year in the UK and rising.\n\nThe specialist nature of neuro-imaging and the need for complex diagnostic and reductive surgery emphasises the importance of well-organised service delivery by dedicated units. The singular effects of brain tumours on mental performance (both psychological state and cognitive decline) are a particular challenge to carers and professionals alike, especially in delivering support to people at home. The peak age of presentation of brain cancer is between 65\xa0and\xa069, and there are concerns that delivery of all services to these older people is suboptimal. There are also concerns that the transition from paediatric to adult units could create a care gap. This would most specifically affects patients who are between 18\xa0and 30\xa0years old.\n\nSurvival with malignant brain tumours has remained poor despite some improvements in surgery, radiotherapy and chemotherapy, and a greater understanding of molecular classification. The management of a low-grade glioma that is likely to transform to high grade remains controversial, and presents issues for ongoing care. Follow‑up for people with meningiomas after primary treatment is often long term, and there is variation in both follow‑up and treatments for recurrence.\n\nConventional whole-brain irradiation as optimal therapy for brain metastases is being challenged by concerns about its effectiveness and toxicity, as well as the availability and immediacy of surgery and stereotactic radiotherapy.'}
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https://www.nice.org.uk/guidance/ng99
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This guideline covers diagnosing, monitoring and managing any type of primary brain tumour or brain metastases in people aged 16 or over. It aims to improve diagnosis and care, including standardising the care people have, how information and support are provided, and palliative care.
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b31254d767456e59cef5000601f1a5807f97ac77
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nice
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Minimally invasive radical hysterectomy for early stage cervical cancer
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Minimally invasive radical hysterectomy for early stage cervical cancer
Evidence-based recommendations on minimally invasive radical hysterectomy for early stage cervical cancer. This involves removing the uterus, cervix, upper vagina and some lymph nodes.
# Recommendations
Evidence on minimally invasive radical hysterectomy for early stage cervical cancer shows that there are no short-term safety concerns.
The evidence on efficacy for tumours 2 cm or larger shows that minimally invasive radical hysterectomy has shorter disease-free and overall survival compared with open hysterectomy surgery. Therefore, this procedure should not be used for tumours 2 cm or above.
The evidence on efficacy for tumours smaller than 2 cm is inconclusive for disease-free and overall survival compared with open hysterectomy surgery. Therefore, for tumours smaller than 2 cm this procedure should only be used in the context of research. Find out what 'do not use' and 'only in research' mean on the NICE interventional procedures guidance page.
Further research, preferably in the form of randomised controlled trials, should describe details of patient selection, tumour histology and size and surgical technique and report overall survival, disease-free survival, tumour recurrence and patient‑reported outcome measures.# The condition, current treatments and procedure
# The condition
Cervical cancer is the second most common cancer in women under 35 years in the UK. The most common symptoms are abnormal vaginal bleeding or discharge, and discomfort during intercourse.
The International Federation of Gynecology and Obstetrics system is used to stage cervical cancer from 1 to 4. Early stage cervical cancer includes stage 1 (cancer confined to the cervix) to stage 2a (tumour has spread down into the top of the vagina).
# Current treatments
Radical hysterectomy is the most common surgical treatment for cervical cancer. It is conventionally done through an incision in the abdomen or through the vagina. It includes removing the uterus and supporting ligaments, cervix, upper vagina, the pelvic lymph nodes and sometimes the para-aortic lymph nodes.
Radiotherapy may be used, with or without surgery, and is usually combined with chemotherapy.
# The procedure
Minimally invasive radical hysterectomy for early stage cervical cancer is done using general anaesthesia. A uterine manipulator is often inserted through the vagina and attached to the uterus and cervix. The abdomen is insufflated with carbon dioxide, and several small incisions are made to provide access for the laparoscope and surgical instruments. A robot may be used to assist with the procedure. A hysterectomy is done by dividing the round ligaments, accessing the broad ligaments, dividing the uterine vessels and mobilising the uterus. If the ovaries are to be left in position, the utero-ovarian ligaments are transected. The pelvic lymph nodes and sometimes the para-aortic lymph nodes are removed through 1 of the abdominal incisions or through the vagina. The upper vagina, cervix and uterus are removed through the vagina.
The technique is distinct from laparoscopically assisted vaginal hysterectomy, which may include laparoscopic division of the infundibulopelvic ligaments and the uterine vessels before a vaginal hysterectomy is done.
A nerve-sparing radical hysterectomy is a modified technique that preserves pelvic nerves to prevent bladder dysfunction.
The aim is to remove all the cancer. The suggested benefits of the laparoscopic approach are shorter length of stay in hospital, shorter recovery period and minimal abdominal scarring.
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{'Recommendations': "Evidence on minimally invasive radical hysterectomy for early stage cervical cancer shows that there are no short-term safety concerns.\n\nThe evidence on efficacy for tumours\xa02\xa0cm or larger shows that minimally invasive radical hysterectomy has shorter disease-free and overall survival compared with open hysterectomy surgery. Therefore, this procedure should not be used for tumours\xa02\xa0cm or above.\n\nThe evidence on efficacy for tumours smaller than 2\xa0cm is inconclusive for disease-free and overall survival compared with open hysterectomy surgery. Therefore, for tumours smaller than 2\xa0cm this procedure should only be used in the context of research. Find out what 'do not use' and 'only in research' mean on the NICE interventional procedures guidance page.\n\nFurther research, preferably in the form of randomised controlled trials, should describe details of patient selection, tumour histology and size and surgical technique and report overall survival, disease-free survival, tumour recurrence and patient‑reported outcome measures.", 'The condition, current treatments and procedure': '# The condition\n\nCervical cancer is the second most common cancer in women under 35\xa0years in the UK. The most common symptoms are abnormal vaginal bleeding or discharge, and discomfort during intercourse.\n\nThe International Federation of Gynecology and Obstetrics system is used to stage cervical cancer from 1\xa0to\xa04. Early stage cervical cancer includes stage\xa01 (cancer confined to the cervix) to stage\xa02a (tumour has spread down into the top of the vagina).\n\n# Current treatments\n\nRadical hysterectomy is the most common surgical treatment for cervical cancer. It is conventionally done through an incision in the abdomen or through the vagina. It includes removing the uterus and supporting ligaments, cervix, upper vagina, the pelvic lymph nodes and sometimes the para-aortic lymph nodes.\n\nRadiotherapy may be used, with or without surgery, and is usually combined with chemotherapy.\n\n# The procedure\n\nMinimally invasive radical hysterectomy for early stage cervical cancer is done using general anaesthesia. A uterine manipulator is often inserted through the vagina and attached to the uterus and cervix. The abdomen is insufflated with carbon dioxide, and several small incisions are made to provide access for the laparoscope and surgical instruments. A robot may be used to assist with the procedure. A hysterectomy is done by dividing the round ligaments, accessing the broad ligaments, dividing the uterine vessels and mobilising the uterus. If the ovaries are to be left in position, the utero-ovarian ligaments are transected. The pelvic lymph nodes and sometimes the para-aortic lymph nodes are removed through 1\xa0of the abdominal incisions or through the vagina. The upper vagina, cervix and uterus are removed through the vagina.\n\nThe technique is distinct from laparoscopically assisted vaginal hysterectomy, which may include laparoscopic division of the infundibulopelvic ligaments and the uterine vessels before a vaginal hysterectomy is done.\n\nA nerve-sparing radical hysterectomy is a modified technique that preserves pelvic nerves to prevent bladder dysfunction.\n\nThe aim is to remove all the cancer. The suggested benefits of the laparoscopic approach are shorter length of stay in hospital, shorter recovery period and minimal abdominal scarring.'}
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https://www.nice.org.uk/guidance/ipg686
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Evidence-based recommendations on minimally invasive radical hysterectomy for early stage cervical cancer. This involves removing the uterus, cervix, upper vagina and some lymph nodes.
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530179c071e5b7ac63d86cf65d45dab07b445b3d
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nice
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Self-expanding implant insertion into the intersphincteric space for faecal incontinence
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Self-expanding implant insertion into the intersphincteric space for faecal incontinence
Evidence-based recommendations on self-expanding implant insertion into the intersphincteric space for faecal incontinence. This involves inserting implants that expand and press together, forming a ring that creates an artificial sphincter.
# Recommendations
Evidence on the safety and efficacy of self-expanding implant insertion into the intersphincteric space for faecal incontinence is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
NICE encourages further research into self-expanding implant insertion into the intersphincteric space for faecal incontinence. This could be randomised controlled trials or registry-based research to capture long-term outcomes.# The condition, current treatments and procedure
# The condition
Faecal incontinence is an inability to control bowel movements, resulting in the involuntary passage of faeces. The process of defaecation and its control is complex. Causes of incontinence include problems in the colon and rectum (including constipation and diarrhoea), problems with the sphincter muscles (such as damage caused by childbirth or surgery), or nerve damage (such as multiple sclerosis, stroke or spina bifida). Faecal incontinence can also be caused by loss of higher-level cerebral control in conditions such as dementia or severe learning disability.
NICE's guideline on faecal incontinence in adults states that there is no consensus on methods of classifying the symptoms and causes of faecal incontinence. It is most commonly classified according to symptom, character of the leakage, patient group or presumed primary underlying cause. For many people faecal incontinence is the result of a complex interplay of contributing factors, some of which may be relatively simple to reverse. Therefore, a detailed initial assessment and structured approach to management is needed, starting with addressing reversible factors and, only if this fails to restore continence, progressing to specialised management.
# Current treatments
Initial management of faecal incontinence includes interventions related to diet, bowel habit, toilet access and medication. Specialised management options depend on the underlying cause and include pelvic floor muscle training, bowel retraining, specialist dietary assessment and management, biofeedback, electrical stimulation and rectal irrigation. The main surgical treatment is anal sphincter repair. Sacral nerve stimulation may be offered to people for whom sphincter surgery is not appropriate. If a trial of sacral nerve stimulation is unsuccessful, a neosphincter may be considered (stimulated graciloplasty or an artificial anal sphincter).
# The procedure
Self-expanding implant insertion into the intersphincteric space for faecal incontinence is done using local or general anaesthesia, with ultrasound guidance. About 6 to 10 small (2 mm) incisions are made in the perianal skin, equidistant to each other, about 2 cm from the anal margin. An introducer is inserted into each incision in turn, pushed through a short subcutaneous tunnel and into the intersphincteric space. The implant is deployed in the desired position within the intersphincteric space. This is repeated around the entire circumference of the internal anal sphincter. The incisions are sutured with resorbable material. Patients are advised to avoid any heavy physical activity for a few days after surgery. One type of implant is a solid polyacrylonitrile cylinder (non-biological) that becomes thicker, shorter and softer over 1 day to 2 days after implantation. The implants expand and press together, forming a ring that creates an artificial sphincter. The aim is to give the person more control over their ability to control defaecation.
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{'Recommendations': 'Evidence on the safety and efficacy of self-expanding implant insertion into the intersphincteric space for faecal incontinence is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nNICE encourages further research into self-expanding implant insertion into the intersphincteric space for faecal incontinence. This could be randomised controlled trials or registry-based research to capture long-term outcomes.', 'The condition, current treatments and procedure': "# The condition\n\nFaecal incontinence is an inability to control bowel movements, resulting in the involuntary passage of faeces. The process of defaecation and its control is complex. Causes of incontinence include problems in the colon and rectum (including constipation and diarrhoea), problems with the sphincter muscles (such as damage caused by childbirth or surgery), or nerve damage (such as multiple sclerosis, stroke or spina bifida). Faecal incontinence can also be caused by loss of higher-level cerebral control in conditions such as dementia or severe learning disability.\n\nNICE's guideline on faecal incontinence in adults states that there is no consensus on methods of classifying the symptoms and causes of faecal incontinence. It is most commonly classified according to symptom, character of the leakage, patient group or presumed primary underlying cause. For many people faecal incontinence is the result of a complex interplay of contributing factors, some of which may be relatively simple to reverse. Therefore, a detailed initial assessment and structured approach to management is needed, starting with addressing reversible factors and, only if this fails to restore continence, progressing to specialised management.\n\n# Current treatments\n\nInitial management of faecal incontinence includes interventions related to diet, bowel habit, toilet access and medication. Specialised management options depend on the underlying cause and include pelvic floor muscle training, bowel retraining, specialist dietary assessment and management, biofeedback, electrical stimulation and rectal irrigation. The main surgical treatment is anal sphincter repair. Sacral nerve stimulation may be offered to people for whom sphincter surgery is not appropriate. If a trial of sacral nerve stimulation is unsuccessful, a neosphincter may be considered (stimulated graciloplasty or an artificial anal sphincter).\n\n# The procedure\n\nSelf-expanding implant insertion into the intersphincteric space for faecal incontinence is done using local or general anaesthesia, with ultrasound guidance. About 6 to 10\xa0small (2\xa0mm) incisions are made in the perianal skin, equidistant to each other, about 2\xa0cm from the anal margin. An introducer is inserted into each incision in turn, pushed through a short subcutaneous tunnel and into the intersphincteric space. The implant is deployed in the desired position within the intersphincteric space. This is repeated around the entire circumference of the internal anal sphincter. The incisions are sutured with resorbable material. Patients are advised to avoid any heavy physical activity for a few days after surgery. One type of implant is a solid polyacrylonitrile cylinder (non-biological) that becomes thicker, shorter and softer over 1\xa0day to 2\xa0days after implantation. The implants expand and press together, forming a ring that creates an artificial sphincter. The aim is to give the person more control over their ability to control defaecation."}
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https://www.nice.org.uk/guidance/ipg685
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Evidence-based recommendations on self-expanding implant insertion into the intersphincteric space for faecal incontinence. This involves inserting implants that expand and press together, forming a ring that creates an artificial sphincter.
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b45fdbcf5de5b4779ea8a4b1ac590bea425014e4
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nice
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The VAC Veraflo Therapy system for acute infected or chronic wounds that are failing to heal
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The VAC Veraflo Therapy system for acute infected or chronic wounds that are failing to heal
Evidence-based recommendations on the VAC Veraflo Therapy system for acute infected or chronic wounds that are failing to heal.
# Recommendations
The VAC Veraflo Therapy system shows promise for treating acute infected or chronic wounds that are not healing. However there is not enough good-quality evidence to support the case for routine adoption.
Research in the form of a randomised controlled trial is recommended to show clinically meaningful benefits for the VAC Veraflo Therapy system (wound instillation with negative pressure therapy) compared with negative pressure wound therapy alone. A key outcome should be time to wound closure.
Why the committee made these recommendations
Acute infected or chronic wounds are normally cleaned, dead or infected tissue removed, and dressed. Chronic non-healing wounds are usually treated with advanced wound care (such as adsorptive or moisture-donating advanced wound dressings). Some wounds are treated with negative pressure therapy, which uses a pump to draw out excess fluid from the wound. VAC Veraflo Therapy system would generally be considered as an alternative to negative pressure wound therapy without wound instillation.
The VAC Veraflo Therapy system comprises a dressing that covers the wound, attached by tubes to a machine, which delivers the therapy. It uses negative pressure therapy, but also slowly introduces cleansing fluid onto the wound bed (wound instillation therapy). The fluid stays for a time and then is slowly drawn away from the wound, along with wound and tissue fluid. The fluid is delivered in automated treatment cycles allowing the wound to be repeatedly cleaned without needing to remove the dressing.
The clinical evidence for VAC Veraflo Therapy system is mostly low quality. The best available evidence does not show any clinical benefit over negative pressure wound therapy without instillation. Also, the evidence is from the US and does not reflect the way VAC Veraflo Therapy system is used in the NHS. There was not enough evidence to compare VAC Veraflo Therapy system with advanced wound care, and the comparison is of limited relevance because advanced wound care is used in a different part of the care pathway.
Although there are potential benefits for patients and the NHS, more evidence is needed to be certain of VAC Veraflo Therapy system's clinical effectiveness and potential for cost savings compared with negative pressure wound therapy in the NHS. Therefore NICE recommends further research.# The technology
# Technology
VAC Veraflo Therapy system (3M+KCI) uses negative pressure wound therapy and wound instillation with topical solutions to promote wound healing. Wound instillation is a controlled process in which topical solutions are slowly introduced to the wound bed, where they remain for a defined period before being removed using negative pressure. Treatment is delivered in automated treatment cycles, allowing wounds to be repeatedly cleansed without needing to remove the dressing.VAC Veraflo Therapy system has the following components:
VAC Ulta Therapy Unit – delivers VAC Veraflo therapy.
Exudate canister – single-patient use, disposable canister (500 ml or 1,000 ml), which collects fluid.
VAC Veralink Cassette – instillation cassette which connects the topical wound solution container and dressing tubing to the VAC Ulta Therapy Unit.
VAC Veraflo Dressing kit of clinician's choice (VAC Veraflo Dressing, VAC Veraflo Cleanse Dressing or VAC Veraflo Cleanse Choice Dressing). The VAC Veraflo Dressing kits include the appropriate dressing as well as VAC VeraTRAC Pad with tubing, VAC Advanced Drape, and 3M Cavilon No Sting Barrier Film.
Topical wound solution of clinician's choice indicated for topical wound treatment and compatible with VAC Veraflo Dressings and disposable components (most commonly saline; other examples include Dakin's solution and Prontosan).VAC Veraflo Therapy system received a CE mark in March 2017 as a class IIb medical device. Each component part of the system, including sterile foam dressing kits, tube sets, and electrically powered accessories, are also individually CE marked.
# Innovative aspects
VAC Veraflo Therapy system differs from other negative pressure wound therapies because it is designed to apply and remove a cleansing solution, as well as giving automated cycles of negative pressure wound therapy. The technology allows for repeated cleansing without needing to remove the dressing.
# Intended use
VAC Veraflo Therapy system is intended to be used to treat acute infected or chronic wounds that do not respond to standard care and need additional therapy to promote healing and wound closure. Clinical scenarios that result in acutely infected or chronic non-healing wounds include surgical site infections, diabetic foot ulcers, and pressure ulcers, which NICE has published recommendations and advice for.
The technology is used by healthcare professionals, such as surgeons, podiatrists, and tissue viability nurses, in hospital. Healthcare staff using the technology will need training, which is provided by the company.
# Costs
The costs for VAC Veraflo Therapy system (excluding VAT) include:
VAC Veralink canister (average cost for 500 ml and 1,000 ml cannisters £34.06)
VAC Veralink Cassette (£19.37)
VAC Veraflo Dressings (average dressing cost £84.36)
rental of the VAC Ulta Therapy Unit (£16 per day).It is assumed that consumables are changed 3 times a week.For more details, see the website for VAC Veraflo Therapy system.# Evidence
# Clinical evidence
## The main clinical evidence comprises 19 studies
The evidence assessed by the external assessment centre (EAC) included 19 studies, all of which were full-text peer-reviewed publications. Of the included studies, 9 were comparative studies (3 randomised controlled trials and 6 observational studies) and 10 were single-arm observational studies. The comparative evidence included a total of 636 people, of whom 365 had VAC Veraflo Therapy system, 222 had negative pressure wound therapy, and 49 had dressings. For full details of the clinical evidence, see section 3 of the assessment report in supporting documentation.
## There are not enough data to make a meaningful comparison with advanced wound care
Of the 19 studies included by the EAC, only 2 compared VAC Veraflo Therapy system with dressings (Chowdry and Wilhelmi 2019; and Deleyto et al. 2017). Both studies were retrospective, and the EAC said that their methodology and reporting were not high enough quality to have confidence in the results. The EAC concluded that there was not enough evidence to be able to assess the clinical benefit of VAC Veraflo Therapy system over advanced wound care.
## The randomised controlled trial by Kim et al. (2020) is the most robust evidence
The EAC considered the randomised controlled trial by Kim et al. (2020) to be the most informative study. It was in scope, made a relevant comparison (VAC Veraflo Therapy system compared with negative pressure wound therapy), had a relatively large sample size (n=183, randomised), and a relatively high methodological quality. The study included people with acute (28%) or chronic (72%) wounds of various types. These included diabetic ulcers (43%), pressure ulcers (17%) and surgical wounds (13% dehisced and 13% non-dehisced). The EAC considered the other randomised controlled trials by Yang et al. (2017) and Kim et al. (2015) to be of limited relevance.
## The observational comparative studies are generally retrospective and of limited methodological quality
The EAC considered all the comparative observational studies to be of poor methodological quality. It concluded that it was not possible to confidently say that the intervention caused the reported outcomes. Common weaknesses included:
poorly reported patient selection
small sample sizes
use of historical control groups without an adequate description of how these were selected
lack of statistical matching
lack of confidence in how endpoints were measured, recorded and reported.The EAC considered that none of the single-armed studies provided data that could reliably inform estimates of relative treatment effects for wound care in the NHS. This was because several of the studies reported descriptive outcomes only and there was also substantial heterogeneity in study populations and wound characteristics.
## Heterogeneity in the study populations and variation in care pathways make it difficult to generalise data to the NHS
The comparative evidence covered a range of populations. Some studies included people with a specific wound type, while others involved a range. According to the EAC, the heterogeneous nature of the study populations, combined with the relatively small patient numbers for each wound type made interpretation of results in specific patient groups difficult. Also, none of the studies were in the NHS or reported on UK populations.
## The available evidence suggests that VAC Veraflo Therapy system reduces bacterial bioburden but the clinical significance of this is unclear
One randomised controlled trial reported a statistically significant (p=0.02) reduction in bacterial bioburden (the number of bacteria in the wound bed measured in colony forming units) compared with negative pressure wound therapy (Kim et al. 2020). This was measured from the time of initial surgical debridement and first dressing change with VAC Veraflo Therapy system. This was supported by data from a smaller randomised controlled trial (n=20; Yang et al. 2017) and the comparative observational study (Goss et al. 2012), which also reported a reduction in bioburden with VAC Veraflo Therapy system after 7 days of therapy. The EAC highlighted that the clinical significance of this outcome was unclear.
## It is not certain if VAC Veraflo Therapy system has better outcomes than negative pressure wound therapy
One randomised controlled trial reported no significant difference in its primary endpoint: the number of follow-on surgical debridements for VAC Veraflo Therapy system compared with negative pressure wound therapy (Kim et al. 2020). Apart from a reduction in bioburden, there was no significant difference between VAC Veraflo Therapy system and negative pressure wound therapy for any other secondary outcomes. These included the number of inpatient operating room debridements, time until wound closure or coverage, the proportion of wounds closed, and the number of wound complications. The EAC concluded that there was no evidence to support the claims for VAC Veraflo Therapy system of a reduced need for debridement or other follow-on treatments, and improvements in wound healing, compared with negative pressure wound therapy.
## The evidence to support claims of a shorter hospital stay is weak
There was weak evidence to suggest that VAC Veraflo Therapy system is associated with a shorter hospital stay than negative pressure wound therapy in some populations. These included people with acute wounds of the lower limb (Omar et al. 2016), people with infected extremity and trunk wounds (Gabriel et al. 2014, Kim et al. 2014) and people with surgically dehisced wounds (Kim et al. 2020; subgroup analysis only).
## There is no published evidence on health-related quality of life or patient-reported outcome measures
There was no evidence on the following clinical management outcomes: number of dressing changes, number of amputations or skin grafts, staff time, and use of other consumables. There was no published evidence on health-related quality of life or patient-reported outcome measures.
# Cost evidence
## The company's comparators are negative pressure wound therapy and advanced wound care in 4 clinical scenarios
The company presented a cost calculator model that compared VAC Veraflo Therapy system with negative pressure wound therapy or advanced wound care. The model evaluated 4 clinical scenarios (lower limb, mixed wounds, prosthetic implant and surgical site infections) and combined the data to estimate a total cost for the whole population (the base case). The model assumed that surgical debridement was needed after treatment and that operating room visits and operations were for debridement only. It also assumed that consumables needed changing 3 times per week. Nurse training time on VAC Veraflo Therapy system was believed to be negligible and was not included. The main clinical parameters driving the model related to length of hospital stay, length of therapy, and the number of surgical debridements needed. Parameters were derived from 7 comparative studies. When all 3 parameters could not be sourced from the same study, the company applied scaling factors using data from another study. The 3 sources of costs in the model were from the therapies themselves, surgical debridement and hospital stay.
## The company's estimates show cost savings over the comparators
The company's base case results estimated a cost saving using VAC Veraflo Therapy system of £3,251 per patient compared with negative pressure wound therapy. It was £8,312 per patient compared with advanced wound care. The main driver for these cost savings was a shorter hospital stay in the VAC Veraflo Therapy system arm. The company's sensitivity analyses reported that the technology was cost saving in all of the individual scenarios that were used to inform the base case (from £300 to over £13,000). Results from a one-way deterministic sensitivity analysis found that changing individual parameters did not affect the overall direction of cost savings, but that cost savings were most sensitive to parameter or cost changes in length of stay. For full details of the cost evidence, see section 4 of the assessment report in supporting documentation.
## The overall modelling approach used by the company is not appropriate
The EAC said that combining results from different clinical scenarios is not a usual method of establishing a base case. It said that a more appropriate approach would be to use a broader population as the base case, followed by scenario analyses for different subgroups. The EAC did not believe the model population was well defined, noting that the different populations included were likely to overlap. The EAC also noted that the company had used simple averages to estimate parameters in the base case, and these had not been weighted by study sample size or by underlying prevalence. The EAC did not agree with the company's method of estimating missing clinical parameters using scaling factors based on data from different studies. The EAC believed that, because of the amount of structural and parameter uncertainty, the results from the company's sensitivity analyses were uninformative.
## There is a lack of confidence in the informing clinical data
The EAC noted that most of the clinical parameters used in the company model were derived from retrospective studies with low methodological quality. Some of the studies involved people who did not match the scenario described. Three of the studies used by the company were excluded by the EAC in the clinical evaluation because they used a previous version of the technology (VAC Instill).
## The EAC's changes to the model result in VAC Veraflo Therapy system costing more than negative pressure wound therapy
The EAC revised the company's model to address some potential limitations by:
Including 2 new scenarios using relevant data from 2 additional studies (Kim et al. 2020 and Omar et al. 2016). The randomised controlled trial by Kim et al. (2020) was regarded by the EAC as the most robust evidence and was the closest to being considered appropriate for populating parameters on clinical effectiveness.
Only using data reported within a single study for each scenario. In the absence of data, length of stay was assumed to be the same as length of therapy. When a study did not report the number of surgeries or debridements in both arms, no debridement costs were incurred.
Updating technology costs to reflect current prices and excluding additional procedural costs that the company had included for the 'prosthetic implant subgroup'.
Modifying some inputs concerning resource use and rounding techniques.The EAC's base case (which used data from Kim et al. 2020 only) found VAC Veraflo Therapy system to be more costly than negative pressure wound therapy for all cost domains (length of stay, therapy and debridement), with an overall cost difference of £480 per patient. The EAC did not report a base case for VAC Veraflo Therapy system compared with advanced wound care because there were not enough data to inform this analysis.
## It is not certain that VAC Veraflo Therapy system is cost saving
Although the EAC made changes to the company model that aimed to improve accuracy and consistency, its analyses had similar limitations to the company's because there was not enough clinical evidence. The EAC's scenario analyses showed that VAC Veraflo Therapy system was cost saving in all scenarios except for the EAC base case and that cost savings were mainly from shorter hospital stay. Results from probabilistic sensitivity analyses on the base case scenario showed a point estimate cost difference of £471 (95% credible interval -£1,085 to £2,015). The EAC highlighted that, because the credible interval crossed zero, it is not possible to draw conclusions from this analysis. The EAC's probabilistic sensitivity analysis at a scenario level showed that cost savings with VAC Veraflo Therapy system were highly likely in 3 out of 9 scenarios. But there was considerable uncertainty in the other 6 scenarios. Based on these results, the EAC concluded that the cost saving potential is highly uncertain.# Committee discussion
# Clinical-effectiveness overview
## VAC Veraflo Therapy system shows promise but there is not enough evidence of its clinical benefits
The committee noted that the evidence for VAC Veraflo Therapy system compared with negative pressure wound therapy was mainly from retrospective observational studies of low methodological quality. It agreed that, given the substantial heterogeneity in different patients (including age and comorbidities), wound types and wound characteristics, such studies are not an appropriate basis for estimating relative clinical effectiveness. It also noted that the most robust evidence (the randomised controlled trial by Kim et al. 2020) showed no statistically significant clinical benefit for VAC Veraflo Therapy system compared with negative pressure wound therapy. The clinical experts explained that, in their experience, VAC Veraflo Therapy system has shown benefits over standard negative pressure wound therapy for appropriately selected people with difficult to heal wounds. The clinical experts said they had seen a reduction in dressing changes, faster tissue granulation, shorter wound healing time, and a shorter time to surgery. The committee felt that the technology showed promise and plausibility based on clinical expert advice, but that this was not supported by the available evidence. The committee concluded that there was not enough good-quality evidence to make a definitive judgement about the benefits of this technology compared with negative pressure wound therapy or advanced wound care in the NHS.
## Negative pressure wound therapy (without instillation) is the relevant comparator for VAC Veraflo Therapy system
The committee heard from clinical experts that VAC Veraflo Therapy system would normally be used in place of, or as a temporary alternative to, negative pressure wound therapy. The clinical experts explained that advanced wound care was of limited relevance as a comparator because it would be used earlier in the care pathway, and sometimes also after treatment with VAC Veraflo Therapy system or negative pressure wound therapy. The committee considered negative pressure wound therapy to be the most appropriate comparator.
## The evidence is heterogenous in terms of patient population and reporting
The committee noted that the patient populations in the evidence are heterogeneous, involving a mixture of people with different wound types and comorbidities. The clinical experts agreed that the patient population eligible for VAC Veraflo Therapy system is complex and broad. They also highlighted that the clinical pathway for people with non-healing wounds is not clearly defined and that clinical practice varies. The clinical experts said that the decision to offer VAC Veraflo Therapy system requires specialist knowledge and experience. They added that it is used slightly differently in each of their clinics because of the different types of wounds they treat and the different aims of therapy. One expert said that in their clinic VAC Veraflo Therapy system is used after debridement, especially for people who have an infection to help with healing. They also said that VAC Veraflo Therapy system is most commonly used in people with diabetic foot problems before limb salvage. The committee was aware that outcome reporting is particularly problematic in this field because of the heterogenous population and setting, as well as the use of non-standardised definitions and measurements. The committee concluded that the complexity of the population, together with the heterogeneity of the available evidence, makes generalisation of study results difficult.
# Relevance to the NHS
## The best available evidence does not reflect NHS practice
None of the available published studies were done in the UK. The most robust evidence for VAC Veraflo Therapy system came from a multicentre randomised controlled trial done in the US (Kim et al. 2020). One of the clinical experts explained that wound management in the US is likely to be very different from the NHS. The trial (Kim et al. 2020) involved specialist tertiary centres where the aim of treatment is to surgically debride wounds to acute status. Microbiology is then reviewed every 48 hours until definitive or reconstructive surgery can be done to close the wound. In these centres debridement may be done several times until microbiology results are sterile. The clinical experts said that this does not happen in the NHS. They also noted that in most of the included studies chronic wounds were debrided back to an acute wound status before VAC Veraflo Therapy system treatment was applied. Because of this, they said caution was needed when interpreting its clinical efficacy in chronic wounds based on these studies. The clinical experts also explained that in the NHS many people with wounds eligible for treatment with VAC Veraflo Therapy system are not treated by acute surgeons but by tissue viability nurses and vascular clinicians. Other clinical experts also agreed that the care pathway evaluated in Kim et al. (2020) did not fully reflect their experience of using VAC Veraflo Therapy system in the NHS. The committee concluded that the evidence does not fully reflect NHS practice and that data from non-UK studies are likely to have limited generalisability to the NHS.
# Outcome measures
## Length of hospital stay may not be an appropriate primary clinical outcome
The clinical experts said that, given how the technology is used in the NHS, length of hospital stay is likely to be a poor choice of outcome and does not take into account other important clinical outcomes including quicker time to surgery (plastic surgery), better overall wound healing, and reduced negative pressure wound therapy time. One expert said that the technology could increase the patient's length of stay but reduce the overall impact on other services because of faster healing. It was also noted that length of hospital stay may be confounded by other factors, such as hospital discharge procedures and the availability of community care. The clinical experts agreed that, to fully understand the clinical benefits of the technology in the NHS, the entire wound healing journey should be considered. They also agreed that wound closure is the most important outcome. The committee concluded that the outcome of length of hospital stay may not be an appropriate primary clinical outcome.
## There is no evidence on important clinical outcomes
Some important clinical outcomes from the scope had not been reported in the evidence. In particular, none of the published evidence reported health-related quality of life and patient-related outcome measures (such as pain). The committee agreed that this was a substantial omission, and that how VAC Veraflo Therapy system affects patient experience is poorly understood. One clinical expert also explained that improving the quality of granulation tissue in the early healing stages was an important benefit of the technology that was not captured in the evidence. The committee concluded that further research would be helpful on the technology's effect on these outcomes.
# Other patient benefits or issues
## VAC Veraflo Therapy system has plausible benefits for people over standard negative pressure wound therapy
The clinical experts said that people who are offered treatment with VAC Veraflo Therapy system have usually had a non-healing wound for months and that this is likely to have made their quality of life poorer. They explained that when people see the rapidly improved appearance of their wound, which can happen after treatment with VAC Veraflo Therapy system, it can give them much-needed hope. The experts said that in their experience people tend to accept and respond well to therapy. They said other potential benefits were fewer dressing changes, and less wound exudate, odour and spoiling of clothing and bed linen.
## VAC Veraflo Therapy system may benefit people with protected characteristics under the Equality Act
The committee heard that people who are older or physically disabled are more likely to have chronic and complex wounds. People with certain family origins (South Asian, Chinese, black African and African-Caribbean family origins) are more prone to poor wound healing because of their increased risk of diabetes. Age, disability, and race are protected characteristics. The committee also heard, however, that people with serious mental health or cognitive impairment may have difficulty keeping the system in place. The committee concluded that people with disabilities, including those with serious mental health or cognitive impairment, would not be disadvantaged by the recommendations. This is providing that clinicians act in the interest of their patients, in line with their usual responsibilities.
# NHS considerations overview
## VAC Veraflo Therapy system is intended to be used temporarily to promote wound healing
The clinical experts explained that in the NHS VAC Veraflo Therapy system is used as a temporary treatment at a specific point in wound healing to speed up wound healing. They explained that it's usually used for about 2 weeks and that when the wound bed improves, treatment is changed to standard negative pressure wound therapy or standard wound care with dressings. One expert explained that once a wound has a good level of granulation tissue it can be treated with conventional dressings. They said that people are routinely discharged with open wounds that are then managed in community care. The other experts noted that in their experience VAC Veraflo Therapy system is used as a bridging therapy and helps reduce the time between surgical treatments by preparing the wound bed for reconstruction.
## VAC Veraflo Therapy system should be used in hospital by specialist healthcare professionals trained in using it
The clinical experts said that, because of the complexity of the wounds, a multidisciplinary team, including a trust specialist trained in using VAC Veraflo Therapy system, should decide when to offer treatment with VAC Veraflo Therapy system and when to stop it. The clinical experts thought that this level of specialism was not widely available in community care. Also, using the system in community care is difficult because of the frequency of dressing and other consumable changes. The clinical experts said that it is only offered in secondary or tertiary care. One clinical expert added that offering VAC Veraflo Therapy system in a community setting should not be ruled out if appropriate support mechanisms are in place.
## A standard dwell time of 10 minutes and cycle length of 3.5 hours should be considered for VAC Veraflo Therapy system
There was no evidence on the best dwell time and cycle length for VAC Veraflo Therapy system. The clinical experts explained that the instillation fluid needs enough dwell time to infiltrate the wound and for the exudate to mix with the solution for it to be effectively removed. They said that the VAC Ulta device comes with standard manufacturer recommended settings, but that it also enables healthcare professionals to modify settings based on clinical judgement. The clinical experts noted that in their experience the standard setting of 10 minutes dwell time and a 3.5 hour cycle length recommended by the manufacturer is normally appropriate for most wounds. One said that in some situations they increase the number of cycles to every 1 hour to 2 hours at the beginning of therapy to speed up wound healing. The committee concluded the standard settings recommended by the manufacturer were appropriate.
# Cost modelling overview
## Any cost modelling using the available evidence is likely to be flawed
The key clinical parameters that drive cost savings estimates in the economic modelling, such as surgical debridement and length of stay, were very uncertain. This is because the evidence was mainly made up of retrospective observational studies from outside the UK, and because of uncertainties in the relationship between length of stay and length of therapy. The committee noted that there were no well-designed studies in the NHS. It concluded that more research was needed to establish the clinical and cost benefits of VAC Veraflo Therapy system in the NHS and that in the meantime any cost modelling was likely to be flawed.
# Further research
## Randomised controlled trials of VAC Veraflo Therapy system in the NHS are needed
The committee concluded that further research is needed to address uncertainties about the clinical effectiveness of VAC Veraflo Therapy system compared with negative pressure wound therapy alone in the NHS. It advised that research should compare VAC Veraflo Therapy system with negative pressure wound therapy in randomised controlled trials in NHS hospitals. The clinical experts said that there are difficulties with running high-quality trials in wound care. These include nursing time, funding, and difficulty recruiting enough patients because of a possible lack of equipoise (that is, clinicians and trial participants may be unwilling to risk randomisation to a treatment that they believe to be inferior). Despite the challenges, clinical experts said that high-quality randomised controlled trials were still possible and necessary. The committee agreed that the most important outcome should be time to complete wound closure. Other outcomes should include health-related quality of life (including pain outcomes) and length of therapy with VAC Veraflo Therapy system and its impact on length of hospital stay.The committee also encouraged data collection from registries. It agreed that large-scale real-world data collection in the form of registries may help future decision making around the adoption of VAC Veraflo Therapy system. For example, in providing confidence in assumptions made in the economic modelling.
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{'Recommendations': "The VAC Veraflo Therapy system shows promise for treating acute infected or chronic wounds that are not healing. However there is not enough good-quality evidence to support the case for routine adoption.\n\nResearch in the form of a randomised controlled trial is recommended to show clinically meaningful benefits for the VAC Veraflo Therapy system (wound instillation with negative pressure therapy) compared with negative pressure wound therapy alone. A key outcome should be time to wound closure.\n\nWhy the committee made these recommendations\n\nAcute infected or chronic wounds are normally cleaned, dead or infected tissue removed, and dressed. Chronic non-healing wounds are usually treated with advanced wound care (such as adsorptive or moisture-donating advanced wound dressings). Some wounds are treated with negative pressure therapy, which uses a pump to draw out excess fluid from the wound. VAC Veraflo Therapy system would generally be considered as an alternative to negative pressure wound therapy without wound instillation.\n\nThe VAC Veraflo Therapy system comprises a dressing that covers the wound, attached by tubes to a machine, which delivers the therapy. It uses negative pressure therapy, but also slowly introduces cleansing fluid onto the wound bed (wound instillation therapy). The fluid stays for a time and then is slowly drawn away from the wound, along with wound and tissue fluid. The fluid is delivered in automated treatment cycles allowing the wound to be repeatedly cleaned without needing to remove the dressing.\n\nThe clinical evidence for VAC Veraflo Therapy system is mostly low quality. The best available evidence does not show any clinical benefit over negative pressure wound therapy without instillation. Also, the evidence is from the US and does not reflect the way VAC Veraflo Therapy system is used in the NHS. There was not enough evidence to compare VAC Veraflo Therapy system with advanced wound care, and the comparison is of limited relevance because advanced wound care is used in a different part of the care pathway.\n\nAlthough there are potential benefits for patients and the NHS, more evidence is needed to be certain of VAC Veraflo Therapy system's clinical effectiveness and potential for cost savings compared with negative pressure wound therapy in the NHS. Therefore NICE recommends further research.", 'The technology': "# Technology\n\nVAC Veraflo Therapy system (3M+KCI) uses negative pressure wound therapy and wound instillation with topical solutions to promote wound healing. Wound instillation is a controlled process in which topical solutions are slowly introduced to the wound bed, where they remain for a defined period before being removed using negative pressure. Treatment is delivered in automated treatment cycles, allowing wounds to be repeatedly cleansed without needing to remove the dressing.VAC Veraflo Therapy system has the following components:\n\nVAC Ulta Therapy Unit – delivers VAC Veraflo therapy.\n\nExudate canister – single-patient use, disposable canister (500\xa0ml or 1,000\xa0ml), which collects fluid.\n\nVAC Veralink Cassette – instillation cassette which connects the topical wound solution container and dressing tubing to the VAC Ulta Therapy Unit.\n\nVAC Veraflo Dressing kit of clinician's choice (VAC Veraflo Dressing, VAC Veraflo Cleanse Dressing or VAC Veraflo Cleanse Choice Dressing). The VAC Veraflo Dressing kits include the appropriate dressing as well as VAC VeraTRAC Pad with tubing, VAC Advanced Drape, and 3M Cavilon No Sting Barrier Film.\n\nTopical wound solution of clinician's choice indicated for topical wound treatment and compatible with VAC Veraflo Dressings and disposable components (most commonly saline; other examples include Dakin's solution and Prontosan).VAC Veraflo Therapy system received a CE mark in March 2017 as a class IIb medical device. Each component part of the system, including sterile foam dressing kits, tube sets, and electrically powered accessories, are also individually CE marked.\n\n# Innovative aspects\n\nVAC Veraflo Therapy system differs from other negative pressure wound therapies because it is designed to apply and remove a cleansing solution, as well as giving automated cycles of negative pressure wound therapy. The technology allows for repeated cleansing without needing to remove the dressing.\n\n# Intended use\n\nVAC Veraflo Therapy system is intended to be used to treat acute infected or chronic wounds that do not respond to standard care and need additional therapy to promote healing and wound closure. Clinical scenarios that result in acutely infected or chronic non-healing wounds include surgical site infections, diabetic foot ulcers, and pressure ulcers, which NICE has published recommendations and advice for.\n\nThe technology is used by healthcare professionals, such as surgeons, podiatrists, and tissue viability nurses, in hospital. Healthcare staff using the technology will need training, which is provided by the company.\n\n# Costs\n\nThe costs for VAC Veraflo Therapy system (excluding VAT) include:\n\nVAC Veralink canister (average cost for 500\xa0ml and 1,000\xa0ml cannisters £34.06)\n\nVAC Veralink Cassette (£19.37)\n\nVAC Veraflo Dressings (average dressing cost £84.36)\n\nrental of the VAC Ulta Therapy Unit (£16 per day).It is assumed that consumables are changed 3 times a week.For more details, see the website for VAC Veraflo Therapy system.", 'Evidence': "# Clinical evidence\n\n## The main clinical evidence comprises 19 studies\n\nThe evidence assessed by the external assessment centre (EAC) included 19\xa0studies, all of which were full-text peer-reviewed publications. Of the included studies, 9 were comparative studies (3\xa0randomised controlled trials and 6 observational studies) and 10 were single-arm observational studies. The comparative evidence included a total of 636\xa0people, of whom 365 had VAC Veraflo Therapy system, 222 had negative pressure wound therapy, and 49 had dressings. For full details of the clinical evidence, see\xa0section\xa03 of the assessment report in supporting documentation.\n\n## There are not enough data to make a meaningful comparison with advanced wound care\n\nOf the 19\xa0studies included by the EAC, only 2\xa0compared VAC Veraflo Therapy system with dressings (Chowdry and Wilhelmi 2019; and Deleyto et al. 2017). Both studies were retrospective, and the EAC said that their methodology and reporting were not high enough quality to have confidence in the results. The EAC concluded that there was not enough evidence to be able to assess the clinical benefit of VAC Veraflo Therapy system over advanced wound care.\n\n## The randomised controlled trial by Kim et al. (2020) is the most robust evidence\n\nThe EAC considered the randomised controlled trial by Kim et al. (2020) to be the most informative study. It was in scope, made a relevant comparison (VAC Veraflo Therapy system compared with negative pressure wound therapy), had a relatively large sample size (n=183, randomised), and a relatively high methodological quality. The study included people with acute (28%) or chronic (72%) wounds of various types. These included diabetic ulcers (43%), pressure ulcers (17%) and surgical wounds (13% dehisced and 13% non-dehisced). The EAC considered the other randomised controlled trials by Yang et al. (2017) and Kim et al. (2015) to be of limited relevance.\n\n## The observational comparative studies are generally retrospective and of limited methodological quality\n\nThe EAC considered all the comparative observational studies to be of poor methodological quality. It concluded that it was not possible to confidently say that the intervention caused the reported outcomes. Common weaknesses included:\n\npoorly reported patient selection\n\nsmall sample sizes\n\nuse of historical control groups without an adequate description of how these were selected\n\nlack of statistical matching\n\nlack of confidence in how endpoints were measured, recorded and reported.The EAC considered that none of the single-armed studies provided data that could reliably inform estimates of relative treatment effects for wound care in the NHS. This was because several of the studies reported descriptive outcomes only and there was also substantial heterogeneity in study populations and wound characteristics.\n\n## Heterogeneity in the study populations and variation in care pathways make it difficult to generalise data to the NHS\n\nThe comparative evidence covered a range of populations. Some studies included people with a specific wound type, while others involved a range. According to the EAC, the heterogeneous nature of the study populations, combined with the relatively small patient numbers for each wound type made interpretation of results in specific patient groups difficult. Also, none of the studies were in the NHS or reported on UK populations.\n\n## The available evidence suggests that VAC Veraflo Therapy system reduces bacterial bioburden but the clinical significance of this is unclear\n\nOne randomised controlled trial reported a statistically significant (p=0.02) reduction in bacterial bioburden (the number of bacteria in the wound bed measured in colony forming units) compared with negative pressure wound therapy (Kim et al. 2020). This was measured from the time of initial surgical debridement and first dressing change with VAC Veraflo Therapy system. This was supported by data from a smaller randomised controlled trial (n=20; Yang et al. 2017) and the comparative observational study (Goss et al. 2012), which also reported a reduction in bioburden with VAC Veraflo Therapy system after 7\xa0days of therapy. The EAC highlighted that the clinical significance of this outcome was unclear.\n\n## It is not certain if VAC Veraflo Therapy system has better outcomes than negative pressure wound therapy\n\nOne randomised controlled trial reported no significant difference in its primary endpoint: the number of follow-on surgical debridements for VAC Veraflo Therapy system compared with negative pressure wound therapy (Kim et al. 2020). Apart from a reduction in bioburden, there was no significant difference between VAC Veraflo Therapy system and negative pressure wound therapy for any other secondary outcomes. These included the number of inpatient operating room debridements, time until wound closure or coverage, the proportion of wounds closed, and the number of wound complications. The EAC concluded that there was no evidence to support the claims for VAC Veraflo Therapy system of a reduced need for debridement or other follow-on treatments, and improvements in wound healing, compared with negative pressure wound therapy.\n\n## The evidence to support claims of a shorter hospital stay is weak\n\nThere was weak evidence to suggest that VAC Veraflo Therapy system is associated with a shorter hospital stay than negative pressure wound therapy in some populations. These included people with acute wounds of the lower limb (Omar et al. 2016), people with infected extremity and trunk wounds (Gabriel et al. 2014, Kim et al. 2014) and people with surgically dehisced wounds (Kim et al. 2020; subgroup analysis only).\n\n## There is no published evidence on health-related quality of life or patient-reported outcome measures\n\nThere was no evidence on the following clinical management outcomes: number of dressing changes, number of amputations or skin grafts, staff time, and use of other consumables. There was no published evidence on health-related quality of life or patient-reported outcome measures.\n\n# Cost evidence\n\n## The company's comparators are negative pressure wound therapy and advanced wound care in 4 clinical scenarios\n\nThe company presented a cost calculator model that compared VAC Veraflo Therapy system with negative pressure wound therapy or advanced wound care. The model evaluated 4 clinical scenarios (lower limb, mixed wounds, prosthetic implant and surgical site infections) and combined the data to estimate a total cost for the whole population (the base case). The model assumed that surgical debridement was needed after treatment and that operating room visits and operations were for debridement only. It also assumed that consumables needed changing 3 times per week. Nurse training time on VAC Veraflo Therapy system was believed to be negligible and was not included. The main clinical parameters driving the model related to length of hospital stay, length of therapy, and the number of surgical debridements needed. Parameters were derived from 7\xa0comparative studies. When all 3 parameters could not be sourced from the same study, the company applied scaling factors using data from another study. The 3 sources of costs in the model were from the therapies themselves, surgical debridement and hospital stay.\n\n## The company's estimates show cost savings over the comparators\n\nThe company's base case results estimated a cost saving using VAC Veraflo Therapy system of £3,251 per patient compared with negative pressure wound therapy. It was £8,312 per patient compared with advanced wound care. The main driver for these cost savings was a shorter hospital stay in the VAC Veraflo Therapy system arm. The company's sensitivity analyses reported that the technology was cost saving in all of the individual scenarios that were used to inform the base case (from £300 to over £13,000). Results from a one-way deterministic sensitivity analysis found that changing individual parameters did not affect the overall direction of cost savings, but that cost savings were most sensitive to parameter or cost changes in length of stay. For full details of the cost evidence, see\xa0section\xa04 of the assessment report in supporting documentation.\n\n## The overall modelling approach used by the company is not appropriate\n\nThe EAC said that combining results from different clinical scenarios is not a usual method of establishing a base case. It said that a more appropriate approach would be to use a broader population as the base case, followed by scenario analyses for different subgroups. The EAC did not believe the model population was well defined, noting that the different populations included were likely to overlap. The EAC also noted that the company had used simple averages to estimate parameters in the base case, and these had not been weighted by study sample size or by underlying prevalence. The EAC did not agree with the company's method of estimating missing clinical parameters using scaling factors based on data from different studies. The EAC believed that, because of the amount of structural and parameter uncertainty, the results from the company's sensitivity analyses were uninformative.\n\n## There is a lack of confidence in the informing clinical data\n\nThe EAC noted that most of the clinical parameters used in the company model were derived from retrospective studies with low methodological quality. Some of the studies involved people who did not match the scenario described. Three of the studies used by the company were excluded by the EAC in the clinical evaluation because they used a previous version of the technology (VAC Instill).\n\n## The EAC's changes to the model result in VAC Veraflo Therapy system costing more than negative pressure wound therapy\n\nThe EAC revised the company's model to address some potential limitations by:\n\nIncluding 2 new scenarios using relevant data from 2 additional studies (Kim et al. 2020 and Omar et al. 2016). The randomised controlled trial by Kim et al. (2020) was regarded by the EAC as the most robust evidence and was the closest to being considered appropriate for populating parameters on clinical effectiveness.\n\nOnly using data reported within a single study for each scenario. In the absence of data, length of stay was assumed to be the same as length of therapy. When a study did not report the number of surgeries or debridements in both arms, no debridement costs were incurred.\n\nUpdating technology costs to reflect current prices and excluding additional procedural costs that the company had included for the 'prosthetic implant subgroup'.\n\nModifying some inputs concerning resource use and rounding techniques.The EAC's base case (which used data from Kim et al. 2020 only) found VAC Veraflo Therapy system to be more costly than negative pressure wound therapy for all cost domains (length of stay, therapy and debridement), with an overall cost difference of £480 per patient. The EAC did not report a base case for VAC Veraflo Therapy system compared with advanced wound care because there were not enough data to inform this analysis.\n\n## It is not certain that VAC Veraflo Therapy system is cost saving\n\nAlthough the EAC made changes to the company model that aimed to improve accuracy and consistency, its analyses had similar limitations to the company's because there was not enough clinical evidence. The EAC's scenario analyses showed that VAC Veraflo Therapy system was cost saving in all scenarios except for the EAC base case and that cost savings were mainly from shorter hospital stay. Results from probabilistic sensitivity analyses on the base case scenario showed a point estimate cost difference of £471 (95% credible interval -£1,085 to £2,015). The EAC highlighted that, because the credible interval crossed zero, it is not possible to draw conclusions from this analysis. The EAC's probabilistic sensitivity analysis at a scenario level showed that cost savings with VAC Veraflo Therapy system were highly likely in 3 out of 9 scenarios. But there was considerable uncertainty in the other 6 scenarios. Based on these results, the EAC concluded that the cost saving potential is highly uncertain.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## VAC Veraflo Therapy system shows promise but there is not enough evidence of its clinical benefits\n\nThe committee noted that the evidence for VAC Veraflo Therapy system compared with negative pressure wound therapy was mainly from retrospective observational studies of low methodological quality. It agreed that, given the substantial heterogeneity in different patients (including age and comorbidities), wound types and wound characteristics, such studies are not an appropriate basis for estimating relative clinical effectiveness. It also noted that the most robust evidence (the randomised controlled trial by Kim et al. 2020) showed no statistically significant clinical benefit for VAC Veraflo Therapy system compared with negative pressure wound therapy. The clinical experts explained that, in their experience, VAC Veraflo Therapy system has shown benefits over standard negative pressure wound therapy for appropriately selected people with difficult to heal wounds. The clinical experts said they had seen a reduction in dressing changes, faster tissue granulation, shorter wound healing time, and a shorter time to surgery. The committee felt that the technology showed promise and plausibility based on clinical expert advice, but that this was not supported by the available evidence. The committee concluded that there was not enough good-quality evidence to make a definitive judgement about the benefits of this technology compared with negative pressure wound therapy or advanced wound care in the NHS.\n\n## Negative pressure wound therapy (without instillation) is the relevant comparator for VAC Veraflo Therapy system\n\nThe committee heard from clinical experts that VAC Veraflo Therapy system would normally be used in place of, or as a temporary alternative to, negative pressure wound therapy. The clinical experts explained that advanced wound care was of limited relevance as a comparator because it would be used earlier in the care pathway, and sometimes also after treatment with VAC Veraflo Therapy system or negative pressure wound therapy. The committee considered negative pressure wound therapy to be the most appropriate comparator.\n\n## The evidence is heterogenous in terms of patient population and reporting\n\nThe committee noted that the patient populations in the evidence are heterogeneous, involving a mixture of people with different wound types and comorbidities. The clinical experts agreed that the patient population eligible for VAC Veraflo Therapy system is complex and broad. They also highlighted that the clinical pathway for people with non-healing wounds is not clearly defined and that clinical practice varies. The clinical experts said that the decision to offer VAC Veraflo Therapy system requires specialist knowledge and experience. They added that it is used slightly differently in each of their clinics because of the different types of wounds they treat and the different aims of therapy. One expert said that in their clinic VAC Veraflo Therapy system is used after debridement, especially for people who have an infection to help with healing. They also said that VAC Veraflo Therapy system is most commonly used in people with diabetic foot problems before limb salvage. The committee was aware that outcome reporting is particularly problematic in this field because of the heterogenous population and setting, as well as the use of non-standardised definitions and measurements. The committee concluded that the complexity of the population, together with the heterogeneity of the available evidence, makes generalisation of study results difficult.\n\n# Relevance to the NHS\n\n## The best available evidence does not reflect NHS practice\n\nNone of the available published studies were done in the UK. The most robust evidence for VAC Veraflo Therapy system came from a multicentre randomised controlled trial done in the US (Kim et al. 2020). One of the clinical experts explained that wound management in the US is likely to be very different from the NHS. The trial (Kim et al. 2020) involved specialist tertiary centres where the aim of treatment is to surgically debride wounds to acute status. Microbiology is then reviewed every 48 hours until definitive or reconstructive surgery can be done to close the wound. In these centres debridement may be done several times until microbiology results are sterile. The clinical experts said that this does not happen in the NHS. They also noted that in most of the included studies chronic wounds were debrided back to an acute wound status before VAC Veraflo Therapy system treatment was applied. Because of this, they said caution was needed when interpreting its clinical efficacy in chronic wounds based on these studies. The clinical experts also explained that in the NHS many people with wounds eligible for treatment with VAC Veraflo Therapy system are not treated by acute surgeons but by tissue viability nurses and vascular clinicians. Other clinical experts also agreed that the care pathway evaluated in Kim et al. (2020) did not fully reflect their experience of using VAC Veraflo Therapy system in the NHS. The committee concluded that the evidence does not fully reflect NHS practice and that data from non-UK studies are likely to have limited generalisability to the NHS.\n\n# Outcome measures\n\n## Length of hospital stay may not be an appropriate primary clinical outcome\n\nThe clinical experts said that, given how the technology is used in the NHS, length of hospital stay is likely to be a poor choice of outcome and does not take into account other important clinical outcomes including quicker time to surgery (plastic surgery), better overall wound healing, and reduced negative pressure wound therapy time. One expert said that the technology could increase the patient's length of stay but reduce the overall impact on other services because of faster healing. It was also noted that length of hospital stay may be confounded by other factors, such as hospital discharge procedures and the availability of community care. The clinical experts agreed that, to fully understand the clinical benefits of the technology in the NHS, the entire wound healing journey should be considered. They also agreed that wound closure is the most important outcome. The committee concluded that the outcome of length of hospital stay may not be an appropriate primary clinical outcome.\n\n## There is no evidence on important clinical outcomes\n\nSome important clinical outcomes from the scope had not been reported in the evidence. In particular, none of the published evidence reported health-related quality of life and patient-related outcome measures (such as pain). The committee agreed that this was a substantial omission, and that how VAC Veraflo Therapy system affects patient experience is poorly understood. One clinical expert also explained that improving the quality of granulation tissue in the early healing stages was an important benefit of the technology that was not captured in the evidence. The committee concluded that further research would be helpful on the technology's effect on these outcomes.\n\n# Other patient benefits or issues\n\n## VAC Veraflo Therapy system has plausible benefits for people over standard negative pressure wound therapy\n\nThe clinical experts said that people who are offered treatment with VAC Veraflo Therapy system have usually had a non-healing wound for months and that this is likely to have made their quality of life poorer. They explained that when people see the rapidly improved appearance of their wound, which can happen after treatment with VAC Veraflo Therapy system, it can give them much-needed hope. The experts said that in their experience people tend to accept and respond well to therapy. They said other potential benefits were fewer dressing changes, and less wound exudate, odour and spoiling of clothing and bed linen.\n\n## VAC Veraflo Therapy system may benefit people with protected characteristics under the Equality Act\n\nThe committee heard that people who are older or physically disabled are more likely to have chronic and complex wounds. People with certain family origins (South Asian, Chinese, black African and African-Caribbean family origins) are more prone to poor wound healing because of their increased risk of diabetes. Age, disability, and race are protected characteristics. The committee also heard, however, that people with serious mental health or cognitive impairment may have difficulty keeping the system in place. The committee concluded that people with disabilities, including those with serious mental health or cognitive impairment, would not be disadvantaged by the recommendations. This is providing that clinicians act in the interest of their patients, in line with their usual responsibilities.\n\n# NHS considerations overview\n\n## VAC Veraflo Therapy system is intended to be used temporarily to promote wound healing\n\nThe clinical experts explained that in the NHS VAC Veraflo Therapy system is used as a temporary treatment at a specific point in wound healing to speed up wound healing. They explained that it's usually used for about 2\xa0weeks and that when the wound bed improves, treatment is changed to standard negative pressure wound therapy or standard wound care with dressings. One expert explained that once a wound has a good level of granulation tissue it can be treated with conventional dressings. They said that people are routinely discharged with open wounds that are then managed in community care. The other experts noted that in their experience VAC Veraflo Therapy system is used as a bridging therapy and helps reduce the time between surgical treatments by preparing the wound bed for reconstruction.\n\n## VAC Veraflo Therapy system should be used in hospital by specialist healthcare professionals trained in using it\n\nThe clinical experts said that, because of the complexity of the wounds, a multidisciplinary team, including a trust specialist trained in using VAC Veraflo Therapy system, should decide when to offer treatment with VAC Veraflo Therapy system and when to stop it. The clinical experts thought that this level of specialism was not widely available in community care. Also, using the system in community care is difficult because of the frequency of dressing and other consumable changes. The clinical experts said that it is only offered in secondary or tertiary care. One clinical expert added that offering VAC Veraflo Therapy system in a community setting should not be ruled out if appropriate support mechanisms are in place.\n\n## A standard dwell time of 10\xa0minutes and cycle length of 3.5\xa0hours should be considered for VAC Veraflo Therapy system\n\nThere was no evidence on the best dwell time and cycle length for VAC Veraflo Therapy system. The clinical experts explained that the instillation fluid needs enough dwell time to infiltrate the wound and for the exudate to mix with the solution for it to be effectively removed. They said that the VAC Ulta device comes with standard manufacturer recommended settings, but that it also enables healthcare professionals to modify settings based on clinical judgement. The clinical experts noted that in their experience the standard setting of 10\xa0minutes dwell time and a 3.5\xa0hour cycle length recommended by the manufacturer is normally appropriate for most wounds. One said that in some situations they increase the number of cycles to every 1\xa0hour to 2\xa0hours at the beginning of therapy to speed up wound healing. The committee concluded the standard settings recommended by the manufacturer were appropriate.\n\n# Cost modelling overview\n\n## Any cost modelling using the available evidence is likely to be flawed\n\nThe key clinical parameters that drive cost savings estimates in the economic modelling, such as surgical debridement and length of stay, were very uncertain. This is because the evidence was mainly made up of retrospective observational studies from outside the UK, and because of uncertainties in the relationship between length of stay and length of therapy. The committee noted that there were no well-designed studies in the NHS. It concluded that more research was needed to establish the clinical and cost benefits of VAC Veraflo Therapy system in the NHS and that in the meantime any cost modelling was likely to be flawed.\n\n# Further research\n\n## Randomised controlled trials of VAC Veraflo Therapy system in the NHS are needed\n\nThe committee concluded that further research is needed to address uncertainties about the clinical effectiveness of VAC Veraflo Therapy system compared with negative pressure wound therapy alone in the NHS. It advised that research should compare VAC Veraflo Therapy system with negative pressure wound therapy in randomised controlled trials in NHS hospitals. The clinical experts said that there are difficulties with running high-quality trials in wound care. These include nursing time, funding, and difficulty recruiting enough patients because of a possible lack of equipoise (that is, clinicians and trial participants may be unwilling to risk randomisation to a treatment that they believe to be inferior). Despite the challenges, clinical experts said that high-quality randomised controlled trials were still possible and necessary. The committee agreed that the most important outcome should be time to complete wound closure. Other outcomes should include health-related quality of life (including pain outcomes) and length of therapy with VAC Veraflo Therapy system and its impact on length of hospital stay.The committee also encouraged data collection from registries. It agreed that large-scale real-world data collection in the form of registries may help future decision making around the adoption of VAC Veraflo Therapy system. For example, in providing confidence in assumptions made in the economic modelling."}
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https://www.nice.org.uk/guidance/mtg54
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Evidence-based recommendations on the VAC Veraflo Therapy system for acute infected or chronic wounds that are failing to heal.
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192d4d085a7ad7f8ea1754a542331e96771284c8
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nice
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Brigatinib for ALK-positive advanced non-small-cell lung cancer that has not been previously treated with an ALK inhibitor
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Brigatinib for ALK-positive advanced non-small-cell lung cancer that has not been previously treated with an ALK inhibitor
Evidence-based recommendations on brigatinib (Alunbrig) for anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer that has not been previously treated with an ALK inhibitor.
# Recommendations
Brigatinib is recommended, within its marketing authorisation, as an option for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) that has not been previously treated with an ALK inhibitor in adults. It is recommended only if the company provides brigatinib according to the commercial arrangement.
Why the committee made these recommendations
People with ALK-positive advanced NSCLC who have not had an ALK inhibitor before are usually offered alectinib. If a person's ALK status is not known at diagnosis, crizotinib is offered after chemotherapy. Brigatinib may be offered as an alternative to these treatments.
Clinical evidence shows that brigatinib is more effective than crizotinib at delaying disease progression. It suggests that brigatinib extends life more than crizotinib, but this is uncertain. There is no clinical trial evidence directly comparing brigatinib with alectinib. An indirect comparison suggests that brigatinib is as effective as alectinib in delaying disease progression, including in the central nervous system. However, although it appears that brigatinib could extend life as much as alectinib, there is uncertainty because of a lack of long-term data.
Despite the uncertainty, the most likely cost-effectiveness estimates for brigatinib are within what NICE considers an acceptable use of NHS resources. So, brigatinib is recommended.# Information about brigatinib
# Marketing authorisation indication
Brigatinib (Alunbrig, Takeda) has a marketing authorisation for 'the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) previously not treated with an ALK inhibitor'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of brigatinib is £4,900.00 (excluding VAT; BNF accessed November 2020) for the:
starter pack (7 tablets at 90 mg plus 21 tablets at 180 mg)
‑tablet pack at 180 mg. The company has a commercial arrangement. This makes brigatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
it was appropriate to consider alectinib as the main comparator in the appraisal (issue 1, see technical report, page 2)
use of time on treatment to inform duration of treatment was appropriate (issue 5, see technical report, pages 8 to 9)
partitioning disease by central nervous system (CNS) progression to account for the effect of CNS involvement was appropriate (issue 6a, see technical report, pages 9 to 10).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues (issues 2, 3, 4 and 6b; see technical report, pages 3 to 10), which were outstanding after the technical engagement stage.
# Treatment pathway and comparator
## A new treatment option would benefit people with ALK-positive advanced NSCLC that has not been treated with an ALK inhibitor
People with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) tend to be younger and are less likely to have a history of smoking than the wider NSCLC population. Approximately 40% to 50% of all people with NSCLC develop CNS metastases, which can reduce quality of life and how long people live. The patient and clinical experts explained that there are very few treatments available for untreated ALK-positive advanced NSCLC. Most people diagnosed with ALK-positive NSCLC will be offered treatment with alectinib, a second-generation tyrosine kinase inhibitor. The patient and clinical experts further explained that compared with alectinib, brigatinib has a reduced treatment burden (1 tablet per day compared with 8 tablets per day). They noted that in clinical practice, people having alectinib can experience side effects such as sun sensitivity, fatigue and gastrointestinal issues, which can substantially affect their quality of life. The committee concluded that there was a need for more treatment options for people with ALK-positive advanced NSCLC.
## Alectinib is the most appropriate comparator for this appraisal, but crizotinib is also considered
The clinical experts advised that they routinely offer alectinib for untreated ALK-positive advanced NSCLC in line with NICE's technology appraisal guidance on alectinib. NICE also recommends ceritinib and crizotinib for this indication. The clinical experts and the company explained that ceritinib is used for only 1% to 2% of people with ALK-positive NSCLC in the NHS, because CNS metastases have limited response to it. Crizotinib is primarily offered to people with ALK-positive NSCLC who do not have an ALK status at diagnosis, who are a minority. The clinical experts explained that at least 90% of people who receive ALK status at diagnosis will have alectinib. The committee concluded that first-line treatment with alectinib was the most appropriate comparator for this appraisal.
# Clinical-effectiveness evidence
## Brigatinib is more effective than crizotinib, but there is uncertainty on how much brigatinib extends overall survival
The main evidence for brigatinib came from ALTA‑1L, an open-label phase 3 randomised controlled trial that compared brigatinib (n=137) with crizotinib (n=138) in adults with untreated ALK-positive advanced or metastatic NSCLC. The ALTA‑1L trial showed that brigatinib statistically significantly extends progression-free survival compared with crizotinib. The ERG considered that the best overall survival hazard ratio for brigatinib was 0.87 (95% confidence interval 0.40 to 1.80). This suggested that brigatinib is more effective than crizotinib. However, the ERG noted that because of the immaturity of data and the high level of crossover from the crizotinib arm to the brigatinib arm in the trial (see section 3.5), there is uncertainty about the precise improvement in overall survival with brigatinib compared with crizotinib.
## There is no direct evidence for brigatinib compared with alectinib but there is suitable indirect evidence using data from the ALTA-1L and ALEX trials
Because there was no evidence directly comparing brigatinib with alectinib, the company did an indirect treatment comparison that included data from the ALEX trial, an open-label phase 3 randomised controlled trial. ALEX compared alectinib (n=152) with crizotinib (n=151) in adults with untreated ALK-positive advanced NSCLC. The company excluded the ALESIA trial, a randomised, open-label phase 3 study comparing alectinib and crizotinib, from the indirect treatment comparison. This was because it only included people from Asian countries (China, South Korea and Thailand) so was not considered generalisable to the UK. The ERG considered that the ALESIA study should be included. It noted that the European Public Assessment Report for brigatinib states that it is possible to extrapolate clinical-effectiveness data from a population of Asian family origin to a population of mainly European family origin. The clinical experts explained that they did not expect ethnicity to affect clinical outcomes. However, they noted that the ALESIA trial predominately included people from China, who are likely to be offered different subsequent treatments and have access to a healthcare system that is different to the NHS in England. The committee noted that the ALTA‑1L and ALEX trials were well-done studies that were more generalisable to the NHS. Considering this, the committee agreed that it was suitable to exclude the ALESIA trial from the indirect treatment comparison and to use data only from the ALTA‑1L and ALEX trials.
## The unanchored matched-adjusted indirect comparison is not acceptable for decision making
The studies used in the indirect treatment comparison had some key baseline differences. For example, a higher proportion of patients in the ALEX trial had CNS involvement at baseline for both the alectinib and crizotinib arms compared with those in the ALTA‑1L trial. Also, the ALTA‑1L study included patients who had previously had at least 1 full cycle of chemotherapy (26% of patients in the brigatinib arm and 27% of patients in the crizotinib arm). The ALEX trial did not include patients who had chemotherapy before. Because of these differences, the company used matching-adjusted indirect comparisons (MAICs) to compare the efficacy of brigatinib with alectinib. Three methods of indirect treatment comparison (ITC) were used:
unanchored MAIC
anchored MAIC
unweighted Bucher ITC.The unanchored MAIC ignored the crizotinib arms of the ALTA‑1L and ALEX trials and considered the brigatinib and alectinib data as if they were from 2 single-arm studies. The anchored MAIC used crizotinib (the common treatment arm) as an anchor. The unweighted Bucher ITC was included as a baseline reference. All 3 ITC methods resulted in similar progression-free survival results. The hazard ratios were close to 1, showing that brigatinib and alectinib both extend the time before disease progression for a similar amount of time. The ITC results for overall survival varied and had wider confidence intervals than the results for progression-free survival (see section 3.6). The anchored MAIC and unweighted Bucher ITC were adjusted for different crossover scenarios using rank-preserving structural failure model methods to generate additional overall survival results. Because there was high crossover (99%) from the crizotinib arm to the brigatinib arm in the ALTA‑1L study on disease progression, the company believed that the anchored MAIC results could potentially be influenced by bias. So, the company chose to use the unanchored MAIC for its base case. However, the committee noted that the NICE Decision Support Unit technical support document 18 states that when connected evidence with a common comparator is available, only anchored forms of population adjustment may be used. Unanchored population adjustment may only be considered in the absence of a connected network of randomised studies, or when there are only single-arm studies. Also, the ERG explained that reliable unanchored MAIC results rely on the assumption that all prognostic factors and treatment effect modifiers are accounted for, and that this assumption was not considered to have been met in the company's ITCs. The committee concluded that the unanchored MAIC results were not acceptable for decision making.
## There is uncertainty about whether brigatinib produces similar overall survival compared with alectinib
Hazard ratio results from the company's anchored MAICs, unanchored MAICs and unweighted Bucher ITC for overall survival ranged between 0.83 and 1.36 and had wide confidence intervals. The ERG considered all the indirect treatment comparison overall survival results to be uncertain because of the immaturity of the data. It considered the best available overall survival result to be from the anchored MAIC with rank-preserving structural failure time model adjustment for all people who switched treatments during the trials without re-censoring (hazard ratio 1.15; 95% CI 0.62 to 2.12). The overall survival data from the ALTA‑1L trial were immature and median overall survival was not reached in either treatment arm. Also, the committee recognised that overall survival data were confounded by the high proportion of people who crossed over from the crizotinib arm to the brigatinib arm during the study (see section 3.5). The clinical experts commented that, although the survival data were very immature, they would expect to see an increase in survival over time with brigatinib, in the absence of confounding. They noted that brigatinib is a second-generation tyrosine kinase inhibitor with the same mechanism of action as alectinib and that both technologies have shown pre-clinical activity against several ALK mutations. Both brigatinib and alectinib showed an improved efficacy as measured by progression-free survival compared with crizotinib in the ALTA‑1L and ALEX trials, respectively. Also, the company's 3 ITCs all suggested that brigatinib and alectinib led to similar progression-free survival (see section 3.5). Considering the biological and pharmacological similarity of alectinib and brigatinib, and their experience with both technologies in clinical practice, the clinical experts were confident that overall survival with brigatinib could be expected to be similar to alectinib. Also, the committee noted that the 5‑year overall survival outcomes for alectinib exceeded the most optimistic predictions in NICE's technology appraisal guidance on alectinib. The committee accepted that, considering that brigatinib and alectinib have similar mechanisms of action, an increase in progression-free and CNS progression-free survival could plausibly translate to a benefit in overall survival, although uncertainty remains about this. It also accepted that it was plausible for similar overall survival to be seen with brigatinib and alectinib, given the similarities between the 2 treatments.
# Economic approach
## The CNS-progressed disease utility value of 0.52 is accepted, despite its limitations
The multiplier used for the CNS health state was based on a utility value of 0.52 from a 2014 abstract (Roughley et al. 2014). The committee noted that this abstract included a small number of people with brain metastases (n=29), and did not report treatment-related adverse events, comorbidities or age. It noted that the limited information prevented the reliability of the data being investigated. Also, the committee considered that since the abstract was published, there have been various changes in how ALK-positive NSCLC is treated. For example, both alectinib and lorlatinib are recommended as first-line and second-line treatment options, respectively (see NICE's technology appraisal guidance on alectinib and lorlatinib). The committee recognised that these developments are likely to have affected the quality of life of people with ALK-positive NSCLC with CNS involvement. However, the clinical experts confirmed there are no alternative data to use to measure quality of life in this population. The committee concluded that the CNS-progressed disease utility value of 0.52 was accepted, despite its limitations.
## There is not enough evidence to accept a cost comparison with alectinib
The company included a cost-comparison analysis in its submission to help with decision making. The company explained that clinical advice suggested that brigatinib would perform similarly to alectinib in a real-world setting. The clinical experts noted that, based on their experience, both brigatinib and alectinib perform similarly in the clinic. Based on this, they considered brigatinib and alectinib to be clinically equivalent and associated with similar long-term outcomes (see section 3.6). The ERG referred to the wide confidence interval around the overall survival hazard ratios (see section 3.6) and noted that these can only be interpreted as a measure of uncertainty and not as evidence of similarity. Also, the ERG explained that a lack of statistically significant difference in the company's ITCs is not the same as providing statistical evidence that there is no difference between treatments. The committee concluded that there was not enough evidence to consider brigatinib and alectinib to be clinically equivalent, so a cost-comparison approach with alectinib was not suitable.
# Cost-effectiveness results
## The company's base-case ICER comparing brigatinib with alectinib is not considered acceptable
The company's base-case incremental cost-effectiveness ratio (ICER), which did not include the confidential discount for alectinib, showed that brigatinib dominated alectinib (that is, it was more effective and cost less than alectinib). However, this was calculated using the unanchored MAIC overall survival results. The committee recalled that where possible, an anchored MAIC is preferred (NICE Decision Support Unit technical support document 18; see section 3.5). Having considered the evidence and methodological approach, the committee concluded that an anchored MAIC was feasible for the comparison of brigatinib with alectinib so rejected the company's base case using the unanchored MAIC.
## In the company's base case brigatinib dominates crizotinib
In the comparison of brigatinib with crizotinib, the ERG noted that the ALTA‑1L trial results were confounded by crossover. It explained that, although adjustment methods were implemented correctly, a robust analysis of the effect of crossover was not possible because of the immaturity of the overall survival data and the high level of crossover (99%; see section 3.5). Because of this, the ERG did not identify a preferred ICER per quality-adjusted life year (QALY) gained for the comparison with crizotinib. When confidential discounts for both brigatinib and crizotinib were included, the ICERs were below what NICE considers cost effective in the company base case and in the ERG's preferred scenarios (including use of time on treatment to model treatment duration, and use of 3‑year and 5‑year treatment waning for overall survival, progression-free survival and intracranial progression-free survival).
## Considering incremental net monetary benefit analyses to compare brigatinib and alectinib is appropriate for decision making
The company also provided cost-effectiveness results in a net benefit framework. The incremental net monetary benefit of brigatinib was compared with alectinib at threshold values of £20,000 and £30,000 per QALY gained using the confidential discount for brigatinib and list price for alectinib. Using each of the available overall survival results from the anchored MAIC and unweighted Bucher ITC resulted in a positive incremental net monetary benefit at both thresholds of £20,000 and £30,000 per QALY gained, demonstrating cost effectiveness. The ERG considered that the net monetary benefit analyses had been done correctly. It repeated the analyses and included the confidential discount for alectinib, which showed that the net monetary benefit remained positive with all overall survival analyses at the threshold of £20,000 per QALY gained and most overall survival analyses at the threshold of £30,000 per QALY gained. This showed that brigatinib is cost effective compared with alectinib at the range NICE considers an acceptable use of NHS resources. Given the immaturity of the overall survival data and associated uncertainty in the company's base-case analysis, and it being likely that any differences in QALYs between brigatinib and alectinib are small, the committee concluded that net monetary benefit was a useful supplementary analysis to inform the cost-effectiveness of brigatinib compared with alectinib.
## Brigatinib is recommended
The committee considered whether brigatinib would be a cost-effective use of NHS resources for people with ALK-positive advanced NSCLC that has not been previously treated with an ALK inhibitor. Because of the uncertainty about the overall survival benefit of brigatinib (see section 3.6), the ERG did not identify a preferred ICER compared with alectinib. The company submitted additional cost-effectiveness analyses using overall survival data from the anchored MAICs and unweighted Bucher ITC analyses, with and without adjustment for crossover. Using overall survival data generated from these analyses resulted in scenarios where brigatinib was less effective and less costly than alectinib (incorporating the confidential discount for brigatinib and list price for alectinib). The committee noted that, in situations in which an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. The ERG replicated the company's analyses including the confidential discount for alectinib. Each of the plausible analyses (with 1 exception, in which brigatinib dominated alectinib) resulted in ICERs showing that brigatinib was associated with cost savings per QALY lost (exact ICERs are confidential and cannot be reported here). The committee acknowledged that the overall survival data used to generate these ICERs was uncertain (see section 3.6). It noted that even if more mature overall survival data became available, uncertainty would remain because of the high level of crossover in the ALTA‑1L trial. However, it recalled the clinical experts' comments that overall survival with brigatinib could be expected to be similar to alectinib (see section 3.6). The committee also considered comments from the clinical and patient experts describing the burden of taking existing treatments and the effect this had on a person's quality of life (see section 3.1). The committee agreed that extending treatment choices would benefit people. The committee also agreed that brigatinib was a cost-effective use of NHS resources compared with crizotinib for the small number of people who do not have ALK status at diagnosis (see section 3.10). For the comparison with alectinib, it considered the estimated cost-effectiveness results, results of the net monetary benefit analyses, and the views of clinicians and patients. The committee agreed the likelihood of brigatinib being cost effective was high and that the risk to the NHS if this decision is incorrect is very small. So, it recommended brigatinib for people with ALK-positive advanced NSCLC that has not been previously treated with an ALK inhibitor.
# Other considerations
## Equality
No equality or social value judgement issues were identified.
## End of life
NICE's advice about life-extending treatments for people with a short life expectancy did not apply.
## Innovation
The company explained that it considered brigatinib to be innovative. The benefits of brigatinib were considered adequately captured in the model.
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{'Recommendations': "Brigatinib is recommended, within its marketing authorisation, as an option for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) that has not been previously treated with an ALK inhibitor in adults. It is recommended only if the company provides brigatinib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nPeople with ALK-positive advanced NSCLC who have not had an ALK inhibitor before are usually offered alectinib. If a person's ALK status is not known at diagnosis, crizotinib is offered after chemotherapy. Brigatinib may be offered as an alternative to these treatments.\n\nClinical evidence shows that brigatinib is more effective than crizotinib at delaying disease progression. It suggests that brigatinib extends life more than crizotinib, but this is uncertain. There is no clinical trial evidence directly comparing brigatinib with alectinib. An indirect comparison suggests that brigatinib is as effective as alectinib in delaying disease progression, including in the central nervous system. However, although it appears that brigatinib could extend life as much as alectinib, there is uncertainty because of a lack of long-term data.\n\nDespite the uncertainty, the most likely cost-effectiveness estimates for brigatinib are within what NICE considers an acceptable use of NHS resources. So, brigatinib is recommended.", 'Information about brigatinib': "# Marketing authorisation indication\n\nBrigatinib (Alunbrig, Takeda) has a marketing authorisation for 'the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) previously not treated with an ALK inhibitor'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of brigatinib is £4,900.00 (excluding VAT; BNF accessed November 2020) for the:\n\nstarter pack (7\xa0tablets at 90\xa0mg plus 21\xa0tablets at 180\xa0mg)\n\n‑tablet pack at 180\xa0mg. The company has a commercial arrangement. This makes brigatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nit was appropriate to consider alectinib as the main comparator in the appraisal (issue\xa01, see technical report, page\xa02)\n\nuse of time on treatment to inform duration of treatment was appropriate (issue\xa05, see technical report, pages\xa08\xa0to\xa09)\n\npartitioning disease by central nervous system (CNS) progression to account for the effect of CNS involvement was appropriate (issue 6a, see technical report, pages 9\xa0to\xa010).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues (issues\xa02, 3,\xa04 and\xa06b; see technical report, pages 3\xa0to\xa010), which were outstanding after the technical engagement stage.\n\n# Treatment pathway and comparator\n\n## A new treatment option would benefit people with ALK-positive advanced NSCLC that has not been treated with an ALK inhibitor\n\nPeople with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) tend to be younger and are less likely to have a history of smoking than the wider NSCLC population. Approximately 40% to 50% of all people with NSCLC develop CNS metastases, which can reduce quality of life and how long people live. The patient and clinical experts explained that there are very few treatments available for untreated ALK-positive advanced NSCLC. Most people diagnosed with ALK-positive NSCLC will be offered treatment with alectinib, a second-generation tyrosine kinase inhibitor. The patient and clinical experts further explained that compared with alectinib, brigatinib has a reduced treatment burden (1\xa0tablet per day compared with 8\xa0tablets per day). They noted that in clinical practice, people having alectinib can experience side effects such as sun sensitivity, fatigue and gastrointestinal issues, which can substantially affect their quality of life. The committee concluded that there was a need for more treatment options for people with ALK-positive advanced NSCLC.\n\n## Alectinib is the most appropriate comparator for this appraisal, but crizotinib is also considered\n\nThe clinical experts advised that they routinely offer alectinib for untreated ALK-positive advanced NSCLC in line with NICE's technology appraisal guidance on alectinib. NICE also recommends ceritinib and crizotinib for this indication. The clinical experts and the company explained that ceritinib is used for only 1% to 2% of people with ALK-positive NSCLC in the NHS, because CNS metastases have limited response to it. Crizotinib is primarily offered to people with ALK-positive NSCLC who do not have an ALK status at diagnosis, who are a minority. The clinical experts explained that at least 90% of people who receive ALK status at diagnosis will have alectinib. The committee concluded that first-line treatment with alectinib was the most appropriate comparator for this appraisal.\n\n# Clinical-effectiveness evidence\n\n## Brigatinib is more effective than crizotinib, but there is uncertainty on how much brigatinib extends overall survival\n\nThe main evidence for brigatinib came from ALTA‑1L, an open-label phase\xa03 randomised controlled trial that compared brigatinib (n=137) with crizotinib (n=138) in adults with untreated ALK-positive advanced or metastatic NSCLC. The ALTA‑1L trial showed that brigatinib statistically significantly extends progression-free survival compared with crizotinib. The ERG considered that the best overall survival hazard ratio for brigatinib was 0.87 (95% confidence interval [CI] 0.40 to 1.80). This suggested that brigatinib is more effective than crizotinib. However, the ERG noted that because of the immaturity of data and the high level of crossover from the crizotinib arm to the brigatinib arm in the trial (see section\xa03.5), there is uncertainty about the precise improvement in overall survival with brigatinib compared with crizotinib.\n\n## There is no direct evidence for brigatinib compared with alectinib but there is suitable indirect evidence using data from the ALTA-1L and ALEX trials\n\nBecause there was no evidence directly comparing brigatinib with alectinib, the company did an indirect treatment comparison that included data from the ALEX trial, an open-label phase\xa03 randomised controlled trial. ALEX compared alectinib (n=152) with crizotinib (n=151) in adults with untreated ALK-positive advanced NSCLC. The company excluded the ALESIA trial, a randomised, open-label phase\xa03 study comparing alectinib and crizotinib, from the indirect treatment comparison. This was because it only included people from Asian countries (China, South Korea and Thailand) so was not considered generalisable to the UK. The ERG considered that the ALESIA study should be included. It noted that the European Public Assessment Report for brigatinib states that it is possible to extrapolate clinical-effectiveness data from a population of Asian family origin to a population of mainly European family origin. The clinical experts explained that they did not expect ethnicity to affect clinical outcomes. However, they noted that the ALESIA trial predominately included people from China, who are likely to be offered different subsequent treatments and have access to a healthcare system that is different to the NHS in England. The committee noted that the ALTA‑1L and ALEX trials were well-done studies that were more generalisable to the NHS. Considering this, the committee agreed that it was suitable to exclude the ALESIA trial from the indirect treatment comparison and to use data only from the ALTA‑1L and ALEX trials.\n\n## The unanchored matched-adjusted indirect comparison is not acceptable for decision making\n\nThe studies used in the indirect treatment comparison had some key baseline differences. For example, a higher proportion of patients in the ALEX trial had CNS involvement at baseline for both the alectinib and crizotinib arms compared with those in the ALTA‑1L trial. Also, the ALTA‑1L study included patients who had previously had at least 1\xa0full cycle of chemotherapy (26% of patients in the brigatinib arm and 27% of patients in the crizotinib arm). The ALEX trial did not include patients who had chemotherapy before. Because of these differences, the company used matching-adjusted indirect comparisons (MAICs) to compare the efficacy of brigatinib with alectinib. Three methods of indirect treatment comparison (ITC) were used:\n\nunanchored MAIC\n\nanchored MAIC\n\nunweighted Bucher ITC.The unanchored MAIC ignored the crizotinib arms of the ALTA‑1L and ALEX trials and considered the brigatinib and alectinib data as if they were from 2\xa0single-arm studies. The anchored MAIC used crizotinib (the common treatment arm) as an anchor. The unweighted Bucher ITC was included as a baseline reference. All 3\xa0ITC methods resulted in similar progression-free survival results. The hazard ratios were close to 1, showing that brigatinib and alectinib both extend the time before disease progression for a similar amount of time. The ITC results for overall survival varied and had wider confidence intervals than the results for progression-free survival (see section\xa03.6). The anchored MAIC and unweighted Bucher ITC were adjusted for different crossover scenarios using rank-preserving structural failure model methods to generate additional overall survival results. Because there was high crossover (99%) from the crizotinib arm to the brigatinib arm in the ALTA‑1L study on disease progression, the company believed that the anchored MAIC results could potentially be influenced by bias. So, the company chose to use the unanchored MAIC for its base case. However, the committee noted that the NICE Decision Support Unit technical support document\xa018 states that when connected evidence with a common comparator is available, only anchored forms of population adjustment may be used. Unanchored population adjustment may only be considered in the absence of a connected network of randomised studies, or when there are only single-arm studies. Also, the ERG explained that reliable unanchored MAIC results rely on the assumption that all prognostic factors and treatment effect modifiers are accounted for, and that this assumption was not considered to have been met in the company's ITCs. The committee concluded that the unanchored MAIC results were not acceptable for decision making.\n\n## There is uncertainty about whether brigatinib produces similar overall survival compared with alectinib\n\nHazard ratio results from the company's anchored MAICs, unanchored MAICs and unweighted Bucher ITC for overall survival ranged between 0.83 and 1.36 and had wide confidence intervals. The ERG considered all the indirect treatment comparison overall survival results to be uncertain because of the immaturity of the data. It considered the best available overall survival result to be from the anchored MAIC with rank-preserving structural failure time model adjustment for all people who switched treatments during the trials without re-censoring (hazard ratio 1.15; 95% CI 0.62 to 2.12). The overall survival data from the ALTA‑1L trial were immature and median overall survival was not reached in either treatment arm. Also, the committee recognised that overall survival data were confounded by the high proportion of people who crossed over from the crizotinib arm to the brigatinib arm during the study (see section\xa03.5). The clinical experts commented that, although the survival data were very immature, they would expect to see an increase in survival over time with brigatinib, in the absence of confounding. They noted that brigatinib is a second-generation tyrosine kinase inhibitor with the same mechanism of action as alectinib and that both technologies have shown pre-clinical activity against several ALK mutations. Both brigatinib and alectinib showed an improved efficacy as measured by progression-free survival compared with crizotinib in the ALTA‑1L and ALEX trials, respectively. Also, the company's 3\xa0ITCs all suggested that brigatinib and alectinib led to similar progression-free survival (see section\xa03.5). Considering the biological and pharmacological similarity of alectinib and brigatinib, and their experience with both technologies in clinical practice, the clinical experts were confident that overall survival with brigatinib could be expected to be similar to alectinib. Also, the committee noted that the 5‑year overall survival outcomes for alectinib exceeded the most optimistic predictions in NICE's technology appraisal guidance on alectinib. The committee accepted that, considering that brigatinib and alectinib have similar mechanisms of action, an increase in progression-free and CNS progression-free survival could plausibly translate to a benefit in overall survival, although uncertainty remains about this. It also accepted that it was plausible for similar overall survival to be seen with brigatinib and alectinib, given the similarities between the 2\xa0treatments.\n\n# Economic approach\n\n## The CNS-progressed disease utility value of 0.52 is accepted, despite its limitations\n\nThe multiplier used for the CNS health state was based on a utility value of 0.52 from a 2014 abstract (Roughley et al. 2014). The committee noted that this abstract included a small number of people with brain metastases (n=29), and did not report treatment-related adverse events, comorbidities or age. It noted that the limited information prevented the reliability of the data being investigated. Also, the committee considered that since the abstract was published, there have been various changes in how ALK-positive NSCLC is treated. For example, both alectinib and lorlatinib are recommended as first-line and second-line treatment options, respectively (see NICE's technology appraisal guidance on alectinib and lorlatinib). The committee recognised that these developments are likely to have affected the quality of life of people with ALK-positive NSCLC with CNS involvement. However, the clinical experts confirmed there are no alternative data to use to measure quality of life in this population. The committee concluded that the CNS-progressed disease utility value of 0.52 was accepted, despite its limitations.\n\n## There is not enough evidence to accept a cost comparison with alectinib\n\nThe company included a cost-comparison analysis in its submission to help with decision making. The company explained that clinical advice suggested that brigatinib would perform similarly to alectinib in a real-world setting. The clinical experts noted that, based on their experience, both brigatinib and alectinib perform similarly in the clinic. Based on this, they considered brigatinib and alectinib to be clinically equivalent and associated with similar long-term outcomes (see section\xa03.6). The ERG referred to the wide confidence interval around the overall survival hazard ratios (see section\xa03.6) and noted that these can only be interpreted as a measure of uncertainty and not as evidence of similarity. Also, the ERG explained that a lack of statistically significant difference in the company's ITCs is not the same as providing statistical evidence that there is no difference between treatments. The committee concluded that there was not enough evidence to consider brigatinib and alectinib to be clinically equivalent, so a cost-comparison approach with alectinib was not suitable.\n\n# Cost-effectiveness results\n\n## The company's base-case ICER comparing brigatinib with alectinib is not considered acceptable\n\nThe company's base-case incremental cost-effectiveness ratio (ICER), which did not include the confidential discount for alectinib, showed that brigatinib dominated alectinib (that is, it was more effective and cost less than alectinib). However, this was calculated using the unanchored MAIC overall survival results. The committee recalled that where possible, an anchored MAIC is preferred (NICE Decision Support Unit technical support document\xa018; see section\xa03.5). Having considered the evidence and methodological approach, the committee concluded that an anchored MAIC was feasible for the comparison of brigatinib with alectinib so rejected the company's base case using the unanchored MAIC.\n\n## In the company's base case brigatinib dominates crizotinib\n\nIn the comparison of brigatinib with crizotinib, the ERG noted that the ALTA‑1L trial results were confounded by crossover. It explained that, although adjustment methods were implemented correctly, a robust analysis of the effect of crossover was not possible because of the immaturity of the overall survival data and the high level of crossover (99%; see section\xa03.5). Because of this, the ERG did not identify a preferred ICER per quality-adjusted life year (QALY) gained for the comparison with crizotinib. When confidential discounts for both brigatinib and crizotinib were included, the ICERs were below what NICE considers cost effective in the company base case and in the ERG's preferred scenarios (including use of time on treatment to model treatment duration, and use of 3‑year and 5‑year treatment waning for overall survival, progression-free survival and intracranial progression-free survival).\n\n## Considering incremental net monetary benefit analyses to compare brigatinib and alectinib is appropriate for decision making\n\nThe company also provided cost-effectiveness results in a net benefit framework. The incremental net monetary benefit of brigatinib was compared with alectinib at threshold values of £20,000 and £30,000 per QALY gained using the confidential discount for brigatinib and list price for alectinib. Using each of the available overall survival results from the anchored MAIC and unweighted Bucher ITC resulted in a positive incremental net monetary benefit at both thresholds of £20,000 and £30,000 per QALY gained, demonstrating cost effectiveness. The ERG considered that the net monetary benefit analyses had been done correctly. It repeated the analyses and included the confidential discount for alectinib, which showed that the net monetary benefit remained positive with all overall survival analyses at the threshold of £20,000 per QALY gained and most overall survival analyses at the threshold of £30,000 per QALY gained. This showed that brigatinib is cost effective compared with alectinib at the range NICE considers an acceptable use of NHS resources. Given the immaturity of the overall survival data and associated uncertainty in the company's base-case analysis, and it being likely that any differences in QALYs between brigatinib and alectinib are small, the committee concluded that net monetary benefit was a useful supplementary analysis to inform the cost-effectiveness of brigatinib compared with alectinib.\n\n## Brigatinib is recommended\n\nThe committee considered whether brigatinib would be a cost-effective use of NHS resources for people with ALK-positive advanced NSCLC that has not been previously treated with an ALK inhibitor. Because of the uncertainty about the overall survival benefit of brigatinib (see section\xa03.6), the ERG did not identify a preferred ICER compared with alectinib. The company submitted additional cost-effectiveness analyses using overall survival data from the anchored MAICs and unweighted Bucher ITC analyses, with and without adjustment for crossover. Using overall survival data generated from these analyses resulted in scenarios where brigatinib was less effective and less costly than alectinib (incorporating the confidential discount for brigatinib and list price for alectinib). The committee noted that, in situations in which an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. The ERG replicated the company's analyses including the confidential discount for alectinib. Each of the plausible analyses (with 1\xa0exception, in which brigatinib dominated alectinib) resulted in ICERs showing that brigatinib was associated with cost savings per QALY lost (exact ICERs are confidential and cannot be reported here). The committee acknowledged that the overall survival data used to generate these ICERs was uncertain (see section\xa03.6). It noted that even if more mature overall survival data became available, uncertainty would remain because of the high level of crossover in the ALTA‑1L trial. However, it recalled the clinical experts' comments that overall survival with brigatinib could be expected to be similar to alectinib (see section\xa03.6). The committee also considered comments from the clinical and patient experts describing the burden of taking existing treatments and the effect this had on a person's quality of life (see section\xa03.1). The committee agreed that extending treatment choices would benefit people. The committee also agreed that brigatinib was a cost-effective use of NHS resources compared with crizotinib for the small number of people who do not have ALK status at diagnosis (see section\xa03.10). For the comparison with alectinib, it considered the estimated cost-effectiveness results, results of the net monetary benefit analyses, and the views of clinicians and patients. The committee agreed the likelihood of brigatinib being cost effective was high and that the risk to the NHS if this decision is incorrect is very small. So, it recommended brigatinib for people with ALK-positive advanced NSCLC that has not been previously treated with an ALK inhibitor.\n\n# Other considerations\n\n## Equality\n\nNo equality or social value judgement issues were identified.\n\n## End of life\n\nNICE's advice about life-extending treatments for people with a short life expectancy did not apply.\n\n## Innovation\n\nThe company explained that it considered brigatinib to be innovative. The benefits of brigatinib were considered adequately captured in the model."}
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https://www.nice.org.uk/guidance/ta670
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Evidence-based recommendations on brigatinib (Alunbrig) for anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer that has not been previously treated with an ALK inhibitor.
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293897f3eb64462882dc85e0b38c32d172a8af49
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nice
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The PLASMA system for transurethral resection and haemostasis of the prostate
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The PLASMA system for transurethral resection and haemostasis of the prostate
Evidence-based recommendations on the PLASMA system for transurethral resection and haemostasis of the prostate.
# Recommendations
The evidence supports the case for adopting the PLASMA system for bipolar transurethral resection and haemostasis of the prostate. Clinical outcomes are comparable with monopolar transurethral resection of the prostate (mTURP), but PLASMA avoids the risk of transurethral resection syndrome and reduces the need for blood transfusion and the length of hospital stay.
The PLASMA system for prostate resection and haemostasis should be considered as an option for people with symptomatic benign prostatic hyperplasia when surgical intervention is indicated.
Cost modelling estimates that the PLASMA system is cost saving by £459 per procedure compared with mTURP for hospitals that already use an Olympus platform and £343 for those that do not. This assumes a reduced (2-day) length of stay with PLASMA and that 65% of procedures need a second electrode for haemostasis. Evidence suggests there are reduced readmissions with the PLASMA system compared with mTURP. This would increase cost saving to £534 for hospitals that already use an Olympus platform and £418 for those that do not.
Why the committee made these recommendations
The PLASMA system uses electrodes to cut out (resect) prostate tissue and stop any local bleeding afterwards (haemostasis). The electrodes are put into the prostate through the urethra (transurethral). It is a treatment for symptomatic benign prostatic hyperplasia.
The clinical evidence supports using the PLASMA system (which used to be called TURis) for TURP. Clinical outcomes are as good as for conventional mTURP but there is a lesser chance of serious complications. PLASMA also reduces the length of hospital stay. This means that the treatment costs are less than for conventional mTURP.# The technology
# Technology
The PLASMA system (Olympus Medical) consists of an Olympus high frequency (430 kHz plus or minus 20%) generator, a resectoscope (which incorporates the PLASMA active working element and electrode), a telescope, an inner and outer sheath, a light guide cable, and a saline high-frequency cable. The active and return electrode are contained within the resectoscope at the operation site. This means a patient return electrode is not needed because PLASMA uses saline irrigation fluid to conduct electrical current within the resectoscope. The surgeon uses an endoscopic image to guide the electrode assembly through the urethra to the prostate. A loop electrode is used to repeatedly cut out small chippings to create a wider channel through the prostate (generator set to cut) and a roller or button electrode is used to promote haemostasis (generator set to coagulate). Electrodes are available in different sizes. A urethral urinary catheter is inserted at the end of the procedure.
# Innovative aspects
In common with other bipolar systems, the PLASMA system uses saline for irrigation instead of glycine, which is used in the monopolar transurethral resection of the prostate (mTURP) system. Using saline avoids transurethral resection syndrome, a serious adverse event. The PLASMA system has a range of electrodes. Of these, only the loop electrode for resection and the roller or button electrodes for haemostasis are in the scope of this guidance.
# Intended use
The PLASMA system is a bipolar electrosurgery system designed for use when surgical resection and haemostasis is indicated to treat symptomatic benign prostatic hyperplasia.
# Relevant pathway
The relevant NICE Pathway described in the decision problem for this technology is the NICE Pathway on managing lower urinary tract symptoms in men.
# Costs
The typical cost for a PLASMA procedure for resection and haemostasis is estimated as £972. This includes consumables and length of stay.# Evidence
# Clinical evidence
All clinical evidence was reported when the technology was called TURis (transurethral resection in saline). Now it is called the PLASMA system.
## Relevant evidence in original guidance comes from 10 studies and 1 meta-analysis
For the medical technologies guidance on TURis that this guidance replaces, the external assessment centre (EAC) considered 10 unique randomised studies (1,870 people) and 1 meta-analysis from the company. The studies relevant to the decision problem in the scope were:
papers (Akman et al. 2013; Chen et al. 2009; Chen et al. 2010; Fagerstrom et al. 2009; Fagerstrom et al. 2011; Geavlete et al. 2011; Ho et al. 2007; Michielson et al. 2007)
foreign language papers with English abstracts (Rose et al. 2007; Abascal Junquera et al. 2006)
multicentre study published in 4 abstracts (Goh et al. 2009; Gular et al. 2009; Gular et al. 2010a; Gular et al. 2010b).For full details of the clinical evidence, see section 3 of the original assessment report in supporting documentation.
## PLASMA has equivalent clinical effectiveness to mTURP
All studies reported equivalent clinical effectiveness for resection of the prostate for PLASMA compared with monopolar transurethral resection of the prostate (mTURP).
## PLASMA eliminates transurethral resection (TUR) syndrome
No cases of TUR syndrome were seen with PLASMA (Akman et al. 2013; Ho et al. 2007; Fagerstrom et al. 2009 and 2011; Gleavlete et al. 2011; Chen et al. 2009 and 2010).
## PLASMA reduces bleeding
In the 3 studies where it was reported, fewer people needed a blood transfusion in the PLASMA group compared with mTURP (Chen et al. 2009 and 2010; Geavlete et al. 2011).
## PLASMA reduces length of hospital stay
The PLASMA system reduced the length of hospital stay in 2 studies (Chen et al. 2009; Gleavlete et al. 2011).
## New relevant evidence comes from 2 studies in 3 publications, including 1 randomised controlled trial
For the guidance update, the EAC considered 2 new studies reported as 3 papers (156 people) relevant to the decision problem in the scope:
a randomised controlled trial (2 publications: Komura et al. 2014 and 2015)
a prospective observational study (non-randomised comparative study, Karadeniz et al. 2016).For full details of the clinical evidence, see section 3 of the assessment report update in supporting documentation.
## PLASMA reduces the length of hospital stay
Hospitalisation time (mean days) was significantly higher in the mTURP group (3.4) compared with the PLASMA group (2.5; p=0.045; Komura et al. 2014 and 2015).
## PLASMA has been associated with an increased rate of urethral stricture
Komura et al. (2015) reported a rate of urethral stricture at 36 months. This was 4 out of 61 (6.6%) in the mTURP group and 12 out of 63 (19%) in the PLASMA group (p<0.022). Komura et al. (2015) also reported on the anatomical location of the strictures and the treatment. The incidence of urethral stricture was not reported in Karadeniz et al. (2016).
# Cost evidence
## The company provided an executable Excel model of a simple decision tree
For the guidance update, the EAC updated the parameters of the model from the company. For full details of the cost evidence, see the assessment report update in supporting documentation. The company model assumed no change in length of stay for mTURP but a reduced length of stay with PLASMA.
The EAC contacted 3 professional experts and the company. They were asked to comment on whether the assumptions and parameters used in the original model were still valid for the update or whether there were any changes. There was no suggestion that assumptions on the cost of generators or single-use electrodes were invalid. One professional expert advised that there was recent evidence that bipolar TURP was associated with higher rates of strictures and contractures compared with mTURP. See sections 3.12 to 3.15 for additional comments from the professional experts.
## There is uncertainty about whether bipolar electrosurgery is standard care
Two professional experts indicated that most TURP procedures now use bipolar electrosurgery devices as standard care. The company advised that 100 NHS centres were using PLASMA in 2019, compared with 61 in 2015 (England, Scotland, and Wales). A third professional expert indicated that, in his opinion, bipolar should be seen as the 'gold standard' for electrosurgical TURP treatment. However, the experts also reported that other companies that make bipolar systems have been slow to develop reliable devices. This means that hospitals that rely on these companies have been slow to change from monopolar to bipolar TURP as their standard technique.
## Blood transfusion rates and volumes may now be lower
Three professional experts stated that blood transfusion rates and volumes of blood given may be lower now. Two professional experts indicated that the haemoglobin threshold for starting blood transfusion had decreased from 80 g/litre to 70 g/litre. Or, it was restricted to patients who are symptomatic because of blood loss. Two professional experts advised that transfusion rates are very low, probably lower than the 5.8% used for monopolar TURP in the original model. Another indicated that 2.7 units of red blood cells used in the model seemed high and suggested that 1 to 2 units was more likely.
## PLASMA is associated with better haemostasis
There is an overall indication that PLASMA is associated with better haemostasis than mTURP (based on lower blood transfusion rates and increased use of coagulating electrodes). Therefore, a lower rate of admissions for haemorrhage would be expected for PLASMA.
## Using the PLASMA button electrode for vaporisation is out of scope for this guidance but using it for haemostasis is in scope
When used with the generator in cut mode, the PLASMA button electrodes cause transurethral vaporisation of the prostate (TUVP). This uses a plasma effect as an alternative to resection using a loop electrode. All 3 professional experts and the company considered this to be a separate procedure to PLASMA TURP. The evidence base is distinct and the clinical outcome values in the TURP model should not be transferred into a model of PLASMA TUVP compared with mTURP. Previously the model assumed that 22% of PLASMA resections also included using a roller electrode for haemostasis. All 3 professional experts advised that using the button electrode for haemostasis (generator in coagulate mode) after loop resection is now relatively common. Two professional experts stated that they use the PLASMA button electrode for haemostasis after resection with a loop electrode. They suggested that this produces better haemostasis, therefore a lower risk of transfusion and higher chance of treatment as a day case. One professional expert stated that they suspected many of these cases unavoidably caused some vaporisation of prostate tissue, although the primary intention is haemostasis.
## The original base case for PLASMA is cost saving assuming a 0.19-day reduction in length of stay of PLASMA compared with mTURP at sites with an existing Olympus system and cost incurring at other sites
In the original base case, for a 0.19-day reduction in length of stay for PLASMA and 2-day length of stay for mTURP with an existing Olympus system, mTURP costs £1,196.60 and PLASMA costs £1,126.04. This is a cost saving of £70.56. For non-Olympus sites, mTURP costs £1,125.69 and PLASMA costs £1,145.49. This is a cost increase of £19.80. This original base case assumed a second electrode was used for 22% of procedures.
## The updated base case for PLASMA is cost saving with a 2-day length of stay compared with a 3.3-day length of stay for mTURP
For a 3.3-day length of stay with an existing Olympus system, mTURP costs £1,510.32. For a 2-day length of stay with an existing Olympus system, PLASMA costs £1,051.42. This is a cost saving of £458.91. For non-Olympus sites and a 3.3-day length of stay, mTURP costs £1,415.86. For non-Olympus sites and a 2-day length of stay, PLASMA costs £1,073.02. This is a cost saving of £342.84. In the updated base case, 65% of procedures were assumed to need a second electrode for haemostasis.
## PLASMA is cost saving for a 1-day length of stay (day case)
For a 1-day length of stay (day case) for PLASMA and a 3.3-day length of stay for mTURP with an existing Olympus system, mTURP costs £1,510.32 and PLASMA costs £662.42. This is a cost saving of £847.91. For a non-Olympus site, mTURP costs £1,415.86 under these circumstances and PLASMA costs £684.02. This is a cost saving of £731.84. In this scenario, 65% of procedures were assumed to need a second electrode for haemostasis.
## PLASMA is cost saving for a 2-day length of stay when not using a second electrode for haemostasis
The EAC modelled an additional scenario with no second electrode. For a 3.3-day length of stay for mTURP and an existing Olympus site when no second electrode used for haemostasis, the cost is £1,510.32, and PLASMA costs £932.71 for a 2-day length of stay. This gives a cost saving of £577.61. For a 3.3-day length of stay for mTURP and a non-Olympus site with no second electrode, the mTURP cost is £1,415.86 and the PLASMA cost is £954.31 for a 2-day length of stay. This gives a cost saving of £461.55.
## PLASMA is cost saving for a 2-day length of stay when a second electrode is used for haemostasis in 65% of procedures and all-cause readmissions are reduced
The EAC modelled an additional scenario with 65% of procedures needing a second electrode and reduced all-cause readmissions. For mTURP and an existing Olympus site when a second electrode is used for haemostasis in 65% of procedures, the cost is £1,621.25, and PLASMA costs £1,086.94. This is a cost saving of £534.34. For mTURP and a non-Olympus site when a second electrode is used in 65% of procedures, the mTURP cost is £1,526.79 and PLASMA costs £1,108.38. This gives a cost saving of £418.41.# Committee discussion
# Clinical-effectiveness overview
## Previous evidence about clinical outcomes is still relevant now the technology name has changed from TURis to PLASMA
The committee noted that the name change from TURis to PLASMA was not accompanied by any change to the technology. Therefore, they concluded that the previous evidence of equivalent clinical outcomes with monopolar transurethral resection of the prostate (mTURP) is still relevant, and they saw no new contradictory evidence.
## The evidence shows that PLASMA resection with a loop electrode is clinically effective
The committee discussed updated evidence on resection with PLASMA using the loop electrode and it concluded that the procedure is clinically effective. The professional experts advised that it is straightforward to switch from a loop to a roller or button electrode for haemostasis. The committee concluded from the published and expert evidence that using the button and roller electrodes is clinically effective for haemostasis after resection.
## Using a PLASMA button electrode for vaporisation and the PLASMA system for other procedures such as incision and enucleation is not in the scope of this guidance
The professional experts advised that, in most cases after resection with loop electrodes, a separate roller or button electrode is needed to achieve haemostasis. They indicated that, while this will inevitably result in some vaporisation of the prostate, this is not considered as a vaporisation procedure. The committee agreed that using the PLASMA button electrode for vaporisation of the prostate is not covered by the scope and should therefore not be the subject of this assessment. It acknowledged that transurethral vaporisation of the prostate (TUVP) is not recommended in NICE's guideline on management of lower urinary tract symptoms in men. The committee agreed that using the PLASMA system for needle incision or enucleation is also out of scope for this evaluation.
# Side effects and adverse events
## Resection with the PLASMA system may increase the incidence of urethral stricture
The committee noted that 1 study reported a 19% incidence of urethral stricture after PLASMA treatment, compared with 6.6% for mTURP (Komura et al. 2015). The professional experts advised that this higher incidence did not reflect their own experience or practice. They informed the committee that they see urethral stricture in 5% or less of people who have treatment with PLASMA. The committee concluded that, based on the current evidence, it is difficult to be definitive about the incidence of urethral stricture after PLASMA. But, it was reassured that when this condition does develop, treatment is available.
## Serious adverse events are reduced by using the PLASMA system compared with mTURP
The committee considered the incidence of serious adverse events, including transurethral resection (TUR) syndrome and blood transfusion with bipolar and monopolar TURP, during the production of the original guidance (MTG23). The committee noted that the evidence shows that the PLASMA system reduces the risk of TUR syndrome and reduces the need for blood transfusion compared with mTURP. The committee considered that these original conclusions about adverse events are still relevant and that there is no new data that would contradict their previous conclusions.
# Relevance to the NHS
## The PLASMA system and mTURP are used in the NHS
The committee heard that use of the PLASMA system for resection of the prostate has increased in the NHS over the last 5 years, with the number of centres with the potential to offer this treatment rising from around 60 to over 110. The professional experts advised that the use of bipolar TURP is superseding mTURP. However, uptake across the UK is variable, and bipolar TURP is not yet established as standard care. The professional experts advised that mTURP is still used in people with small prostates when prolonged procedures are unlikely and when the incidence of TUR syndrome is likely to be low. The committee concluded that PLASMA and mTURP are both used in the NHS.
## Collecting real-world evidence during post-market surveillance is encouraged
The committee encouraged the collection of real-world clinical data on PLASMA. They considered that this would represent good clinical practice and routine post-market surveillance.
# Cost-modelling overview
## PLASMA can be used with a reduced length of stay
The committee heard that PLASMA is now more expensive than it was when the original guidance was published. This is because of increased costs for components of the PLASMA system, including consumables, and increased inpatient day costs. However, the professional experts advised that PLASMA can now be used with a shorter length of stay. They stated that the length of stay for mTURP had not changed and so 3.3 days was still correct. Assumptions about length of stay for PLASMA were contained in the original model, that is, reduced by 0.19 days compared with mTURP. Accounting for this and the increase in the cost of PLASMA, the treatment would be cost incurring if applied in this way. However, with a reduction in length of stay to 2 days, the technology becomes cost saving. There are even more cost savings when treatment is given as a day case. The professional experts advised that a plausible and conservative length of stay with PLASMA in their practice is 2 days. One professional expert advised that he does the procedure as a day case in most of his patients. The committee concluded that PLASMA can be used with a reduced length of stay compared with mTURP.
## PLASMA can be used with existing compatible equipment to save costs
The committee agreed that sites that already have compatible Olympus equipment for mTURP would be able to use some of this equipment for PLASMA. This could result in greater cost savings for these sites. However, the committee also noted that for sites where purchase of Olympus equipment would be needed for PLASMA treatment to be offered, cost savings would still be possible.
## A second electrode is often needed to stop bleeding (haemostasis)
The professional experts advised that a second electrode is needed to achieve haemostasis in most cases. The EAC modelled this in a scenario of 65% of procedures. It advised that PLASMA is still cost saving under these circumstances.
## A urinary catheter is used after treatment with PLASMA and mTURP
The professional experts advised that a urinary catheter is used after PLASMA and mTURP and that for day-case surgery with PLASMA, the catheter is removed after discharge from hospital in a community setting. The EAC estimated that the cost of catheter placement was included in the procedure costs. The cost of removal of the catheter at an outpatient appointment with a single healthcare professional is £68 (NHS tariff). The cost of removal in community care during a 1-hour appointment is £84 for a band 7 healthcare professional. The EAC advised the committee that neither of these costs for catheter removal would negate the cost savings for PLASMA compared with mTURP.
# Main cost drivers
## Length of stay is the main cost driver
The length of stay was the main driver of cost savings in the model. The committee discussed with professional experts using the PLASMA system for day-case surgery. One professional expert advised that PLASMA was used routinely for day-case TURP in his centre, but the experts acknowledged that this is not the case in all centres. The experts agreed that day-case use of PLASMA is possible, especially in people with low risk.
# Cost savings
## The PLASMA system is cost saving with reduced length of stay
The committee considered an updated base case and 4 additional scenarios presented by the EAC in the assessment report update (see sections 3.16 to 3.20). It agreed that reduced length of stay for the PLASMA system compared with mTURP was plausible. The committee also agreed that even when a second electrode is used to achieve haemostasis, cost savings are still possible with PLASMA because of the reduced hospital stay.
# Equalities
People over 80 years old, especially those with frail health and comorbidities, have been found to have an increased risk of complications after TURP. However, the effectiveness of TURP is the same as in younger people.
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{'Recommendations': 'The evidence supports the case for adopting the PLASMA system for bipolar transurethral resection and haemostasis of the prostate. Clinical outcomes are comparable with monopolar transurethral resection of the prostate (mTURP), but PLASMA avoids the risk of transurethral resection syndrome and reduces the need for blood transfusion and the length of hospital stay.\n\nThe PLASMA system for prostate resection and haemostasis should be considered as an option for people with symptomatic benign prostatic hyperplasia when surgical intervention is indicated.\n\nCost modelling estimates that the PLASMA system is cost saving by £459 per procedure compared with mTURP for hospitals that already use an Olympus platform and £343 for those that do not. This assumes a reduced (2-day) length of stay with PLASMA and that 65% of procedures need a second electrode for haemostasis. Evidence suggests there are reduced readmissions with the PLASMA system compared with mTURP. This would increase cost saving to £534 for hospitals that already use an Olympus platform and £418 for those that do not.\n\nWhy the committee made these recommendations\n\nThe PLASMA system uses electrodes to cut out (resect) prostate tissue and stop any local bleeding afterwards (haemostasis). The electrodes are put into the prostate through the urethra (transurethral). It is a treatment for symptomatic benign prostatic hyperplasia.\n\nThe clinical evidence supports using the PLASMA system (which used to be called TURis) for TURP. Clinical outcomes are as good as for conventional mTURP but there is a lesser chance of serious complications. PLASMA also reduces the length of hospital stay. This means that the treatment costs are less than for conventional mTURP.', 'The technology': '# Technology\n\nThe PLASMA system (Olympus Medical) consists of an Olympus high frequency (430\xa0kHz plus or minus 20%) generator, a resectoscope (which incorporates the PLASMA active working element and electrode), a telescope, an inner and outer sheath, a light guide cable, and a saline high-frequency cable. The active and return electrode are contained within the resectoscope at the operation site. This means a patient return electrode is not needed because PLASMA uses saline irrigation fluid to conduct electrical current within the resectoscope. The surgeon uses an endoscopic image to guide the electrode assembly through the urethra to the prostate. A loop electrode is used to repeatedly cut out small chippings to create a wider channel through the prostate (generator set to cut) and a roller or button electrode is used to promote haemostasis (generator set to coagulate). Electrodes are available in different sizes. A urethral urinary catheter is inserted at the end of the procedure.\n\n# Innovative aspects\n\nIn common with other bipolar systems, the PLASMA system uses saline for irrigation instead of glycine, which is used in the monopolar transurethral resection of the prostate (mTURP) system. Using saline avoids transurethral resection syndrome, a serious adverse event. The PLASMA system has a range of electrodes. Of these, only the loop electrode for resection and the roller or button electrodes for haemostasis are in the scope of this guidance.\n\n# Intended use\n\nThe PLASMA system is a bipolar electrosurgery system designed for use when surgical resection and haemostasis is indicated to treat symptomatic benign prostatic hyperplasia.\n\n# Relevant pathway\n\nThe relevant NICE Pathway described in the decision problem for this technology is the NICE Pathway on managing lower urinary tract symptoms in men.\n\n# Costs\n\nThe typical cost for a PLASMA procedure for resection and haemostasis is estimated as £972. This includes consumables and length of stay.', 'Evidence': "# Clinical evidence\n\nAll clinical evidence was reported when the technology was called TURis (transurethral resection in saline). Now it is called the PLASMA system.\n\n## Relevant evidence in original guidance comes from 10\xa0studies and 1\xa0meta-analysis\n\nFor the medical technologies guidance on TURis that this guidance replaces, the external assessment centre (EAC) considered 10\xa0unique randomised studies (1,870\xa0people) and 1\xa0meta-analysis from the company. The studies relevant to the decision problem in the scope were:\n\npapers (Akman et al. 2013; Chen et al. 2009; Chen et al. 2010; Fagerstrom et al. 2009; Fagerstrom et al. 2011; Geavlete et al. 2011; Ho et al. 2007; Michielson et al. 2007)\n\nforeign language papers with English abstracts (Rose et al. 2007; Abascal Junquera et al. 2006)\n\nmulticentre study published in 4\xa0abstracts (Goh et al. 2009; Gular et al. 2009; Gular et al. 2010a; Gular et al. 2010b).For full details of the clinical evidence, see section\xa03 of the original assessment report in supporting documentation.\n\n## PLASMA has equivalent clinical effectiveness to mTURP\n\nAll studies reported equivalent clinical effectiveness for resection of the prostate for PLASMA compared with monopolar transurethral resection of the prostate (mTURP).\n\n## PLASMA eliminates transurethral resection (TUR) syndrome\n\nNo cases of TUR syndrome were seen with PLASMA (Akman et al. 2013; Ho et al. 2007; Fagerstrom et al. 2009 and 2011; Gleavlete et al. 2011; Chen et al. 2009 and 2010).\n\n## PLASMA reduces bleeding\n\nIn the 3\xa0studies where it was reported, fewer people needed a blood transfusion in the PLASMA group compared with mTURP (Chen et al. 2009 and 2010; Geavlete et al. 2011).\n\n## PLASMA reduces length of hospital stay\n\nThe PLASMA system reduced the length of hospital stay in 2\xa0studies (Chen et al. 2009; Gleavlete et al. 2011).\n\n## New relevant evidence comes from 2\xa0studies in 3\xa0publications, including 1\xa0randomised controlled trial\n\nFor the guidance update, the EAC considered 2\xa0new studies reported as 3\xa0papers (156\xa0people) relevant to the decision problem in the scope:\n\na randomised controlled trial (2\xa0publications: Komura et al. 2014 and 2015)\n\na prospective observational study (non-randomised comparative study, Karadeniz et al. 2016).For full details of the clinical evidence, see section\xa03 of the assessment report update in supporting documentation.\n\n## PLASMA reduces the length of hospital stay\n\nHospitalisation time (mean days) was significantly higher in the mTURP group (3.4) compared with the PLASMA group (2.5; p=0.045; Komura et al. 2014 and 2015).\n\n## PLASMA has been associated with an increased rate of urethral stricture\n\nKomura et al. (2015) reported a rate of urethral stricture at 36\xa0months. This was 4 out of 61 (6.6%) in the mTURP group and 12 out of 63 (19%) in the PLASMA group (p<0.022). Komura et al. (2015) also reported on the anatomical location of the strictures and the treatment. The incidence of urethral stricture was not reported in Karadeniz et al. (2016).\n\n# Cost evidence\n\n## The company provided an executable Excel model of a simple decision tree\n\nFor the guidance update, the EAC updated the parameters of the model from the company. For full details of the cost evidence, see the assessment report update in supporting documentation. The company model assumed no change in length of stay for mTURP but a reduced length of stay with PLASMA.\n\nThe EAC contacted 3 professional experts and the company. They were asked to comment on whether the assumptions and parameters used in the original model were still valid for the update or whether there were any changes. There was no suggestion that assumptions on the cost of generators or single-use electrodes were invalid. One professional expert advised that there was recent evidence that bipolar TURP was associated with higher rates of strictures and contractures compared with mTURP. See sections\xa03.12 to\xa03.15 for additional comments from the professional experts.\n\n## There is uncertainty about whether bipolar electrosurgery is standard care\n\nTwo professional experts indicated that most TURP procedures now use bipolar electrosurgery devices as standard care. The company advised that 100\xa0NHS centres were using PLASMA in 2019, compared with 61 in 2015 (England, Scotland, and Wales). A third professional expert indicated that, in his opinion, bipolar should be seen as the 'gold standard' for electrosurgical TURP treatment. However, the experts also reported that other companies that make bipolar systems have been slow to develop reliable devices. This means that hospitals that rely on these companies have been slow to change from monopolar to bipolar TURP as their standard technique.\n\n## Blood transfusion rates and volumes may now be lower\n\nThree professional experts stated that blood transfusion rates and volumes of blood given may be lower now. Two professional experts indicated that the haemoglobin threshold for starting blood transfusion had decreased from 80\xa0g/litre to 70\xa0g/litre. Or, it was restricted to patients who are symptomatic because of blood loss. Two professional experts advised that transfusion rates are very low, probably lower than the 5.8% used for monopolar TURP in the original model. Another indicated that 2.7\xa0units of red blood cells used in the model seemed high and suggested that 1 to 2\xa0units was more likely.\n\n## PLASMA is associated with better haemostasis\n\nThere is an overall indication that PLASMA is associated with better haemostasis than mTURP (based on lower blood transfusion rates and increased use of coagulating electrodes). Therefore, a lower rate of admissions for haemorrhage would be expected for PLASMA.\n\n## Using the PLASMA button electrode for vaporisation is out of scope for this guidance but using it for haemostasis is in scope\n\nWhen used with the generator in cut mode, the PLASMA button electrodes cause transurethral vaporisation of the prostate (TUVP). This uses a plasma effect as an alternative to resection using a loop electrode. All 3\xa0professional experts and the company considered this to be a separate procedure to PLASMA TURP. The evidence base is distinct and the clinical outcome values in the TURP model should not be transferred into a model of PLASMA TUVP compared with mTURP. Previously the model assumed that 22% of PLASMA resections also included using a roller electrode for haemostasis. All 3\xa0professional experts advised that using the button electrode for haemostasis (generator in coagulate mode) after loop resection is now relatively common. Two professional experts stated that they use the PLASMA button electrode for haemostasis after resection with a loop electrode. They suggested that this produces better haemostasis, therefore a lower risk of transfusion and higher chance of treatment as a day case. One professional expert stated that they suspected many of these cases unavoidably caused some vaporisation of prostate tissue, although the primary intention is haemostasis.\n\n## The original base case for PLASMA is cost saving assuming a 0.19-day reduction in length of stay of PLASMA compared with mTURP at sites with an existing Olympus system and cost incurring at other sites\n\nIn the original base case, for a 0.19-day reduction in length of stay for PLASMA and 2-day length of stay for mTURP with an existing Olympus system, mTURP costs £1,196.60 and PLASMA costs £1,126.04. This is a cost saving of £70.56. For non-Olympus sites, mTURP costs £1,125.69 and PLASMA costs £1,145.49. This is a cost increase of £19.80. This original base case assumed a second electrode was used for 22% of procedures.\n\n## The updated base case for PLASMA is cost saving with a 2-day length of stay compared with a 3.3-day length of stay for mTURP\n\nFor a 3.3-day length of stay with an existing Olympus system, mTURP costs £1,510.32. For a 2-day length of stay with an existing Olympus system, PLASMA costs £1,051.42. This is a cost saving of £458.91. For non-Olympus sites and a 3.3-day length of stay, mTURP costs £1,415.86. For non-Olympus sites and a 2-day length of stay, PLASMA costs £1,073.02. This is a cost saving of £342.84. In the updated base case, 65% of procedures were assumed to need a second electrode for haemostasis.\n\n## PLASMA is cost saving for a 1-day length of stay (day case)\n\nFor a 1-day length of stay (day case) for PLASMA and a 3.3-day length of stay for mTURP with an existing Olympus system, mTURP costs £1,510.32 and PLASMA costs £662.42. This is a cost saving of £847.91. For a non-Olympus site, mTURP costs £1,415.86 under these circumstances and PLASMA costs £684.02. This is a cost saving of £731.84. In this scenario, 65% of procedures were assumed to need a second electrode for haemostasis.\n\n## PLASMA is cost saving for a 2-day length of stay when not using a second electrode for haemostasis\n\nThe EAC modelled an additional scenario with no second electrode. For a 3.3-day length of stay for mTURP and an existing Olympus site when no second electrode used for haemostasis, the cost is £1,510.32, and PLASMA costs £932.71 for a 2-day length of stay. This gives a cost saving of £577.61. For a 3.3-day length of stay for mTURP and a non-Olympus site with no second electrode, the mTURP cost is £1,415.86 and the PLASMA cost is £954.31 for a 2-day length of stay. This gives a cost saving of £461.55.\n\n## PLASMA is cost saving for a 2-day length of stay when a second electrode is used for haemostasis in 65% of procedures and all-cause readmissions are reduced\n\nThe EAC modelled an additional scenario with 65% of procedures needing a second electrode and reduced all-cause readmissions. For mTURP and an existing Olympus site when a second electrode is used for haemostasis in 65% of procedures, the cost is £1,621.25, and PLASMA costs £1,086.94. This is a cost saving of £534.34. For mTURP and a non-Olympus site when a second electrode is used in 65% of procedures, the mTURP cost is £1,526.79 and PLASMA costs £1,108.38. This gives a cost saving of £418.41.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Previous evidence about clinical outcomes is still relevant now the technology name has changed from TURis to PLASMA\n\nThe committee noted that the name change from TURis to PLASMA was not accompanied by any change to the technology. Therefore, they concluded that the previous evidence of equivalent clinical outcomes with monopolar transurethral resection of the prostate (mTURP) is still relevant, and they saw no new contradictory evidence.\n\n## The evidence shows that PLASMA resection with a loop electrode is clinically effective\n\nThe committee discussed updated evidence on resection with PLASMA using the loop electrode and it concluded that the procedure is clinically effective. The professional experts advised that it is straightforward to switch from a loop to a roller or button electrode for haemostasis. The committee concluded from the published and expert evidence that using the button and roller electrodes is clinically effective for haemostasis after resection.\n\n## Using a PLASMA button electrode for vaporisation and the PLASMA system for other procedures such as incision and enucleation is not in the scope of this guidance\n\nThe professional experts advised that, in most cases after resection with loop electrodes, a separate roller or button electrode is needed to achieve haemostasis. They indicated that, while this will inevitably result in some vaporisation of the prostate, this is not considered as a vaporisation procedure. The committee agreed that using the PLASMA button electrode for vaporisation of the prostate is not covered by the scope and should therefore not be the subject of this assessment. It acknowledged that transurethral vaporisation of the prostate (TUVP) is not recommended in NICE's guideline on management of lower urinary tract symptoms in men. The committee agreed that using the PLASMA system for needle incision or enucleation is also out of scope for this evaluation.\n\n# Side effects and adverse events\n\n## Resection with the PLASMA system may increase the incidence of urethral stricture\n\nThe committee noted that 1\xa0study reported a 19% incidence of urethral stricture after PLASMA treatment, compared with 6.6% for mTURP (Komura et al. 2015). The professional experts advised that this higher incidence did not reflect their own experience or practice. They informed the committee that they see urethral stricture in 5% or less of people who have treatment with PLASMA. The committee concluded that, based on the current evidence, it is difficult to be definitive about the incidence of urethral stricture after PLASMA. But, it was reassured that when this condition does develop, treatment is available.\n\n## Serious adverse events are reduced by using the PLASMA system compared with mTURP\n\nThe committee considered the incidence of serious adverse events, including transurethral resection (TUR) syndrome and blood transfusion with bipolar and monopolar TURP, during the production of the original guidance (MTG23). The committee noted that the evidence shows that the PLASMA system reduces the risk of TUR syndrome and reduces the need for blood transfusion compared with mTURP. The committee considered that these original conclusions about adverse events are still relevant and that there is no new data that would contradict their previous conclusions.\n\n# Relevance to the NHS\n\n## The PLASMA system and mTURP are used in the NHS\n\nThe committee heard that use of the PLASMA system for resection of the prostate has increased in the NHS over the last 5\xa0years, with the number of centres with the potential to offer this treatment rising from around 60 to over 110. The professional experts advised that the use of bipolar TURP is superseding mTURP. However, uptake across the UK is variable, and bipolar TURP is not yet established as standard care. The professional experts advised that mTURP is still used in people with small prostates when prolonged procedures are unlikely and when the incidence of TUR syndrome is likely to be low. The committee concluded that PLASMA and mTURP are both used in the NHS.\n\n## Collecting real-world evidence during post-market surveillance is encouraged\n\nThe committee encouraged the collection of real-world clinical data on PLASMA. They considered that this would represent good clinical practice and routine post-market surveillance.\n\n# Cost-modelling overview\n\n## PLASMA can be used with a reduced length of stay\n\nThe committee heard that PLASMA is now more expensive than it was when the original guidance was published. This is because of increased costs for components of the PLASMA system, including consumables, and increased inpatient day costs. However, the professional experts advised that PLASMA can now be used with a shorter length of stay. They stated that the length of stay for mTURP had not changed and so 3.3\xa0days was still correct. Assumptions about length of stay for PLASMA were contained in the original model, that is, reduced by 0.19\xa0days compared with mTURP. Accounting for this and the increase in the cost of PLASMA, the treatment would be cost incurring if applied in this way. However, with a reduction in length of stay to 2\xa0days, the technology becomes cost saving. There are even more cost savings when treatment is given as a day case. The professional experts advised that a plausible and conservative length of stay with PLASMA in their practice is 2\xa0days. One professional expert advised that he does the procedure as a day case in most of his patients. The committee concluded that PLASMA can be used with a reduced length of stay compared with mTURP.\n\n## PLASMA can be used with existing compatible equipment to save costs\n\nThe committee agreed that sites that already have compatible Olympus equipment for mTURP would be able to use some of this equipment for PLASMA. This could result in greater cost savings for these sites. However, the committee also noted that for sites where purchase of Olympus equipment would be needed for PLASMA treatment to be offered, cost savings would still be possible.\n\n## A second electrode is often needed to stop bleeding (haemostasis)\n\nThe professional experts advised that a second electrode is needed to achieve haemostasis in most cases. The EAC modelled this in a scenario of 65% of procedures. It advised that PLASMA is still cost saving under these circumstances.\n\n## A urinary catheter is used after treatment with PLASMA and mTURP\n\nThe professional experts advised that a urinary catheter is used after PLASMA and mTURP and that for day-case surgery with PLASMA, the catheter is removed after discharge from hospital in a community setting. The EAC estimated that the cost of catheter placement was included in the procedure costs. The cost of removal of the catheter at an outpatient appointment with a single healthcare professional is £68 (NHS tariff). The cost of removal in community care during a 1-hour appointment is £84 for a band\xa07 healthcare professional. The EAC advised the committee that neither of these costs for catheter removal would negate the cost savings for PLASMA compared with mTURP.\n\n# Main cost drivers\n\n## Length of stay is the main cost driver\n\nThe length of stay was the main driver of cost savings in the model. The committee discussed with professional experts using the PLASMA system for day-case surgery. One professional expert advised that PLASMA was used routinely for day-case TURP in his centre, but the experts acknowledged that this is not the case in all centres. The experts agreed that day-case use of PLASMA is possible, especially in people with low risk.\n\n# Cost savings\n\n## The PLASMA system is cost saving with reduced length of stay\n\nThe committee considered an updated base case and 4\xa0additional scenarios presented by the EAC in the assessment report update (see sections\xa03.16 to\xa03.20). It agreed that reduced length of stay for the PLASMA system compared with mTURP was plausible. The committee also agreed that even when a second electrode is used to achieve haemostasis, cost savings are still possible with PLASMA because of the reduced hospital stay.\n\n# Equalities\n\nPeople over 80\xa0years old, especially those with frail health and comorbidities, have been found to have an increased risk of complications after TURP. However, the effectiveness of TURP is the same as in younger people."}
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https://www.nice.org.uk/guidance/mtg53
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Evidence-based recommendations on the PLASMA system for transurethral resection and haemostasis of the prostate.
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2966369d5fb5528ba448c1530a88b9517ede3457
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nice
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Encorafenib plus cetuximab for previously treated BRAF V600E mutation-positive metastatic colorectal cancer
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Encorafenib plus cetuximab for previously treated BRAF V600E mutation-positive metastatic colorectal cancer
Evidence-based recommendations on encorafenib (Braftovi) plus cetuximab (Erbitux) for treating BRAF V600E mutation-positive metastatic colorectal cancer in adults who have had previous systemic treatment.
# Recommendations
Encorafenib plus cetuximab is recommended, within its marketing authorisation, as an option for treating BRAF V600E mutation-positive metastatic colorectal cancer in adults who have had previous systemic treatment. It is recommended only if the company provides it according to the commercial arrangements.
Why the committee made these recommendations
Treatment for BRAF V600E mutation-positive metastatic colorectal cancer after previous systemic treatment includes combination chemotherapy, usually FOLFIRI (5‑fluorouracil, folinic acid and irinotecan) followed by trifluridine–tipiracil then best supportive care. Encorafenib plus cetuximab is the first colorectal cancer treatment that targets the BRAF V600E mutation, and could be used second or third line.
Clinical trial evidence shows that encorafenib plus cetuximab increases how long people live compared with FOLFIRI plus cetuximab or irinotecan plus cetuximab. However, these drug combinations are not used in NHS clinical practice, because NICE does not recommend cetuximab beyond first-line treatment for metastatic colorectal cancer. Assumptions are needed to indirectly compare encorafenib plus cetuximab with FOLFIRI or trifluridine–tipiracil using evidence from other clinical trials. This makes the results uncertain.
Encorafenib plus cetuximab meets NICE's criteria for being a life-extending treatment at the end of life. Also, despite the uncertain comparative effectiveness results, the cost-effectiveness estimates are within what is normally considered a cost-effective use of NHS resources. So, it is recommended for routine use in the NHS.# Information about encorafenib plus cetuximab
# Marketing authorisation indication
Encorafenib (Braftovi; Pierre Fabre Ltd) has a marketing authorisation in combination with cetuximab (Erbitux; Merck Serono Ltd) 'for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy'. Because the marketing authorisation did not include triple therapy (encorafenib plus binimetinib and cetuximab), this appraisal only considers dual therapy.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of encorafenib 75 mg is £1,400 for 42 capsules (excluding VAT; BNF online accessed October 2020).The list price of cetuximab 5 mg per millilitre solution for infusion is £890.50 for 100 millilitres (excluding VAT; BNF online accessed October 2020).The companies have commercial arrangements for each of the drugs. These make encorafenib and cetuximab available to the NHS with discounts. The size of the discounts are commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of the discounts.# Committee discussion
The appraisal committee considered evidence submitted by Pierre Fabre Ltd, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The company's adjustment of health utilities for the progression-free health state is more likely to reflect clinical practice.
The company's amended cost for drugs at the start of the model cycle more accurately reflects costs in clinical practice.It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report table 11, page 41), and took these into account in its decision making. It discussed the issues that were outstanding after the technical engagement stage.
# The condition
## There is an unmet need for treatments for BRAF V600E mutation-positive metastatic colorectal cancer
Colorectal cancer is a malignant tumour arising from the lining of the large intestine (colon and rectum). BRAF is a human gene that encodes the protein B‑Raf, which influences cell growth. Metastatic colorectal cancer with a BRAF V600E mutation is a rare type of colorectal cancer. It is associated with a poorer prognosis and has a greater risk of recurring than colorectal cancer without the BRAF mutation. There has been little improvement in survival for BRAF V600E mutation-positive cancer despite improvements for colorectal cancer in general. The clinical experts explained that there are currently no effective treatments for this type of colorectal cancer, and that encorafenib plus cetuximab represents a step change in treatment. The committee concluded that there is an unmet need for treatments for BRAF V600E mutation-positive metastatic colorectal cancer.
## People would welcome an effective treatment option for BRAF V600E mutation-positive metastatic colorectal cancer
Metastatic colorectal cancer is a progressive condition that affects survival and quality of life. The patient experts highlighted the psychological effects of a diagnosis of metastatic BRAF V600E mutation-positive colorectal cancer, and the lasting adverse effects of current treatments such as neuropathic damage. They explained that their cancers responded quickly to triple therapy (encorafenib plus binimetinib and cetuximab) and this was life-changing, whereas they saw little to no response on previous treatment. They noted that their quality of life had improved enormously because the adverse effects of this therapy are manageable compared with other treatments. The committee concluded that both patients and healthcare professionals would welcome an effective new treatment.
# The treatment pathway
## Encorafenib plus cetuximab may be used after 1 or more previous lines of treatment
Encorafenib plus cetuximab has a marketing authorisation for treating metastatic colorectal cancer with a BRAF V600E mutation in people who have had previous systemic treatment. Current NHS treatment options for this type of metastatic colorectal cancer include combination chemotherapy regimens, trifluridine–tipiracil and best supportive care. The committee noted that encorafenib plus cetuximab could be positioned second line or later in the treatment pathway. The clinical experts explained that encorafenib plus cetuximab is the first targeted treatment for this population, and their preference for using it after first-line treatment. The patient experts emphasised the psychological effect of being diagnosed with BRAF V600E mutation-positive metastatic colorectal cancer. They noted that using encorafenib plus cetuximab earlier in the pathway could give people hope of improved outcomes and avoid adverse events associated with current treatments. The committee recognised the clinical and patient experts' preference for using encorafenib plus cetuximab earlier in the treatment pathway. The committee concluded that it may be used after 1 or more previous lines of treatment in clinical practice.
## FOLFIRI and trifluridine–tipiracil are relevant comparators for encorafenib plus cetuximab after 1 previous line of treatment
The clinical experts explained that treatment options for BRAF V600E mutation-positive metastatic colorectal cancer depend on the previous treatments a person has had, their response to these treatments and their preferences. Most people have combination chemotherapy, usually folinic acid, fluorouracil (5‑FU) and oxaliplatin (known as FOLFOX) first line followed by folinic acid, 5‑FU and irinotecan (known as FOLFIRI). The clinical experts explained that these treatments are interchangeable and considered equivalent. A small proportion of people have folinic acid, 5‑FU, irinotecan and oxaliplatin (FOLFOXIRI) first line, so would then have trifluridine–tipiracil as second-line treatment. The clinical experts noted that this was uncommon because of the higher toxicity with FOLFOXIRI than with other combinations. The company explained that encorafenib plus cetuximab could be used instead of FOLFIRI or trifluridine–tipiracil after 1 previous line of treatment. The marketing authorisation for trifluridine–tipiracil allows for its use second line and later. It is the only drug recommended after first-line treatment for metastatic colorectal cancer in the NICE Pathway on colorectal cancer. However, the committee recalled its conclusion in NICE's technology appraisal guidance on trifluridine–tipiracil that, in clinical practice, it would mainly be used in people who have had 2 or more previous lines of treatment when there are no further treatment options. The committee concluded that the relevant comparators after 1 previous line of treatment include both FOLFIRI and trifluridine–tipiracil.
## Irinotecan monotherapy is not a relevant comparator for encorafenib plus cetuximab after 1 previous line of treatment
NICE's scope includes irinotecan monotherapy as a relevant comparator. However, the company excluded it based on expert opinion and a market survey, which found that fewer than 2% of people have irinotecan monotherapy in clinical practice. The clinical experts agreed with the company and explained that, in clinical practice, irinotecan is used as part of FOLFIRI. When used with other treatments, the dose of irinotecan is lower and better tolerated than when used as monotherapy. The clinical experts noted that irinotecan monotherapy is occasionally used when there is a specific intolerance to 5‑FU or a dihydropyrimidine dehydrogenase deficiency resulting in an inability to detoxify 5‑FU in the liver. The committee concluded that irinotecan monotherapy is not a relevant comparator after 1 previous line of treatment.
## Trifluridine–tipiracil is a relevant comparator for encorafenib plus cetuximab after 2 previous lines of treatment
In clinical practice, trifluridine–tipiracil is usually used after 2 previous lines of treatment. The clinical experts explained that it would be appropriate to use encorafenib plus cetuximab instead of trifluridine–tipiracil after 2 previous lines of treatment if neither had been used earlier in the treatment pathway. The committee concluded that trifluridine–tipiracil is a relevant comparator for encorafenib plus cetuximab after 2 previous lines of treatment.
## Best supportive care is not a relevant comparator for encorafenib plus cetuximab
NICE's scope for the appraisal included best supportive care as a relevant comparator. After treatment with trifluridine–tipiracil, there are no other active treatment options and people have best supportive care. The committee recognised that a small group of people with BRAF V600E positive mutations whose disease had relapsed after treatment with trifluridine–tipiracil may be eligible for encorafenib plus cetuximab. The clinical experts agreed that encorafenib plus cetuximab could also be used when no other active treatment options are available. However, they noted that, at this stage, people may not be well enough to have active treatment. The company and ERG agreed that patients eligible for best supportive care would generally not be well enough to have active treatment, including encorafenib plus cetuximab. The committee concluded that best supportive care was not a relevant comparator for encorafenib plus cetuximab.
# Clinical effectiveness of encorafenib plus cetuximab
## Encorafenib plus cetuximab is clinically effective based on BEACON CRC but the comparators in the trial are not used in the NHS
BEACON CRC is a multinational, open-label, randomised, phase 3 trial comparing encorafenib plus cetuximab with the investigator's choice of chemotherapy (FOLFIRI or irinotecan) plus cetuximab. It included people with BRAF V600E mutation-positive metastatic colorectal cancer whose disease had progressed after 1 or 2 previous lines of treatment. The primary endpoints in the trial were for triple therapy (encorafenib plus binimetinib and cetuximab), which is not relevant for this appraisal. Overall survival, progression-free survival and overall response rate for encorafenib plus cetuximab compared with controls were secondary endpoints. Results showed that encorafenib plus cetuximab increased overall survival more than the investigator's choice of either FOLFIRI plus cetuximab or irinotecan plus cetuximab. The clinical experts explained that the control arm of BEACON CRC did not reflect clinical practice in the NHS. This is because epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab, are not recommended beyond first-line treatment for metastatic colorectal cancer in NICE's technology appraisal guidance on cetuximab, bevacizumab and panitumumab. In addition, about 40% of people in the control arm had irinotecan plus cetuximab. The committee recalled that irinotecan monotherapy is not a relevant comparator because it is associated with worse toxicity than FOLFIRI (see section 3.5). It heard that irinotecan monotherapy would not be offered second line with cetuximab. The committee concluded that encorafenib plus cetuximab is clinically effective compared with the comparators in the trial, but these treatments do not reflect NHS clinical practice.
## Cetuximab likely benefits patients so the trial may underestimate the relative effect of encorafenib plus cetuximab compared with FOLFIRI
The committee recalled that cetuximab is not recommended in the NHS beyond first-line treatment for metastatic colorectal cancer. However, the clinical experts at the first committee meeting explained that it is likely to benefit people with BRAF V600E mutation-positive colorectal cancer who have not had an EGFR inhibitor. However, they also noted that there are limited data available for this population, so how much benefit cetuximab has when used with FOLFIRI or irinotecan is unknown. At consultation after the first committee meeting, a consultee cited data from CRYSTAL. This was a randomised controlled phase 3 study comparing cetuximab plus FOLFIRI with FOLFIRI first line in people with KRAS wild-type metastatic colorectal cancer, and in people with known BRAF V600E mutations. Results showed that both populations had improved survival when FOLFIRI was used with cetuximab compared with FOLFIRI alone. The committee recognised that the CRYSTAL study included people who had not had prior treatment. However, the clinical experts and the NHS England lead for the Cancer Drugs Fund explained that the population seen in the NHS would not have had an EGFR inhibitor before. This meant that they would be likely to have a similar benefit to that seen in CRYSTAL. The committee concluded that cetuximab was likely to have added benefit to FOLFIRI and irinotecan in the control arm of BEACON CRC. This meant that the BEACON CRC trial results may have underestimated the relative effectiveness of encorafenib plus cetuximab compared with FOLFIRI alone. It agreed to consider this in its decision making.
## Irinotecan may not be clinically equivalent to FOLFIRI
Treatment in the control arm of BEACON CRC included either FOLFIRI plus cetuximab or irinotecan plus cetuximab. The committee appreciated that if irinotecan and FOLFIRI are equally effective, then it would be satisfied that irinotecan plus cetuximab and FOLFIRI plus cetuximab are also equally effective. The committee was aware that treatment in the control arm was not randomised. Instead, it was allocated according to the investigator's choice, which the committee recognised was a 'blended comparator'. The clinical experts explained that people are offered treatments depending on how their disease reacted to previous treatments, their comorbidities, and personal preference. The committee recalled that 40% of people in the control arm had irinotecan plus cetuximab. It considered whether FOLFIRI and irinotecan were equally effective. The company cited data from 2 clinical trials to support this. The ERG highlighted that the trials were done in patients with unknown BRAF mutation status, so the results may not apply in this population. In its first meeting, the committee was concerned that assuming equivalent effectiveness for FOLFIRI and irinotecan was unproven. At consultation, the company presented results from a stratified log-rank test. The committee was aware that the trial was not powered to detect differences in survival for the control arm. But it noted that the results showed worse survival for people in the BEACON CRC trial who had irinotecan plus cetuximab compared with FOLFIRI plus cetuximab, although the results were uncertain. The ERG noted that the results included the possibility of no difference. The committee was aware of the possibility of confounding by indication. So, it considered the company's multivariate Cox analysis controlling for age, sex, characteristics of the tumour, number of organs involved and prior use of oxaliplatin. This analysis also showed a hazard ratio indicating that patients taking irinotecan plus cetuximab died earlier than those taking FOLFIRI plus cetuximab. The committee noted that these results were uncertain and included the possibility of no difference. The company noted that there were no covariates excluded from the multivariable analysis. The clinical experts explained that most oncologists would view the 2 treatments as having similar efficacy. Also, 1 consultee explained that FOLFIRI is better tolerated. One expert noted that there will likely be clinical reasons (for example, 5‑FU intolerance or not wanting an implanted venous access device necessary to deliver FOLFIRI) as to why investigators chose irinotecan over FOLFIRI. The committee was aware of the lack of evidence for people with BRAF mutations. However, it concluded that irinotecan may not be equivalent to FOLFIRI and took this into consideration in its decision making.
## Comparing encorafenib plus cetuximab with the blended comparator from BEACON does not reflect the comparison with FOLFIRI
The BEACON control arm included investigator's choice plus cetuximab. Investigator's choice included either FOLFIRI or irinotecan. The committee appreciated that the components of the blended comparator have different degrees of benefit, and that this approach averages the clinical effectiveness of the treatments included. It recalled its conclusion that cetuximab is likely to add benefit to FOLFIRI alone, but also that irinotecan is associated with worse toxicity and potentially poorer outcomes than FOLFIRI (see section 3.10). The committee concluded that including a blended comparator in the estimates of clinical effectiveness does not reflect the comparison with FOLFIRI.
# Indirect comparison of encorafenib plus cetuximab with FOLFIRI
## The indirect comparison of encorafenib plus cetuximab with FOLFIRI is useful for decision making
Analyses that adjust for the differences between the trial and clinical practice should inform decision making. The committee noted that BEACON CRC differed from current NHS clinical practice because:
irinotecan was included in the control arm of the trial (see section 3.8)
cetuximab was added to irinotecan and FOLFIRI, which added benefit (see section 3.9)
irinotecan may not be clinically equivalent to FOLFIRI (see section 3.10)
the blended comparator makes the relative effectiveness analyses uncertain (see section 3.11).The committee concluded that BEACON CRC did not reflect the comparison with FOLFIRI. In addition, it concluded that it would take into account the company's indirect comparison of encorafenib plus cetuximab with FOLFIRI to inform decision making.
## Cetuximab and panitumumab are equally effective
The committee recalled that there were no data directly comparing encorafenib plus cetuximab with FOLFIRI or trifluridine–tipiracil. To estimate the relative efficacy of encorafenib plus cetuximab compared with FOLFIRI, the company did an indirect treatment comparison using data from BEACON CRC and data from a subgroup of people with BRAF mutation-positive metastatic colorectal cancer from Peeters et al. (2010 to 2015). Peeters et al. was a randomised controlled trial comparing FOLFIRI alone with FOLFIRI plus panitumumab in people with metastatic colorectal cancer. There were no common comparators between these 2 trials, so assumptions were needed to form a network. The control arm of BEACON CRC (investigator's choice of either FOLFIRI or irinotecan, both plus cetuximab) would have to be considered equivalent to the treatment arm in Peeters et al. (FOLFIRI plus panitumumab) to form a network. The indirect treatment comparison was possible only by assuming equal efficacy for:
cetuximab and panitumumab
FOLFIRI and irinotecan.The committee recalled the conclusion from NICE's technology appraisal guidance on cetuximab and panitumumab that cetuximab and panitumumab were likely to have similar effectiveness in treating RAS wild-type metastatic colorectal cancer. The clinical experts and NHS England's clinical lead for the Cancer Drugs Fund explained that cetuximab and panitumumab should be considered clinically equivalent in the population with BRAF mutation-positive disease. The committee concluded that cetuximab and panitumumab were equally effective.
## The results of the indirect comparison are uncertain because FOLFIRI and irinotecan may not be equally effective
The committee recalled its conclusion that FOLFIRI and irinotecan may not be equally effective (see section 3.10). It noted that an assumption of equivalence was needed to estimate the relative effectiveness of encorafenib plus cetuximab with FOLFIRI using both the BEACON CRC results and the alternative analyses. The committee concluded that the evidence for equal effectiveness of FOLFIRI and irinotecan was uncertain, which made the results of the indirect treatment comparison uncertain.
## All estimates of relative effectiveness for encorafenib plus cetuximab compared with FOLFIRI are uncertain
The committee recalled that the uncertainties associated with BEACON CRC meant the relative efficacy of encorafenib plus cetuximab compared with FOLFIRI could not be accurately estimated. However, it noted that the company's indirect treatment comparison was also highly uncertain. The ERG preferred to use the BEACON CRC data as a proxy for the clinical effectiveness of encorafenib plus cetuximab compared with FOLFIRI, and provided scenarios adjusting for cetuximab's duration of effect. The committee concluded that all relative effectiveness results were uncertain and it would consider this in its decision making.
# Clinical effectiveness of encorafenib plus cetuximab compared with trifluridine–tipiracil
## The RECOURSE trial contributes relevant clinical evidence
There were no studies for trifluridine–tipiracil with comparators common to BEACON CRC. The company and ERG highlighted the lack of data for people with BRAF V600E mutation-positive colorectal cancer. The company identified the RECOURSE trial, a randomised controlled phase 3 trial in people with refractory metastatic colorectal cancer or who could not tolerate standard therapies. It compared trifluridine–tipiracil with placebo, but the company noted that the population included people whose BRAF status was undefined. The company did a naive comparison using data from the trifluridine–tipiracil arm of RECOURSE and from the encorafenib plus cetuximab arm of BEACON CRC. The company did not have access to individual patient-level data from RECOURSE, so instead simulated the data by digitalising the published survival curves. The committee understood that there was a lack of data for this population. Although RECOURSE included a highly heterogenous population compared with the BEACON CRC population, the committee concluded that it was appropriate and relevant to consider as part of the clinical evidence.
## The company's naive comparison of encorafenib plus cetuximab with trifluridine–tipiracil is uncertain
The committee recalled the considerable heterogeneity in potential prognostic factors between the study populations (BEACON CRC and RECOURSE) included in the company's naive comparison of encorafenib plus cetuximab with trifluridine–tipiracil. People in RECOURSE had 4 or more previous lines of treatment compared with 1 or 2 previous lines of treatment in BEACON CRC. After technical engagement, the company presented data from RECOURSE, which suggested that outcomes were better for people who had more lines of treatment compared with those who had fewer lines of treatment. The clinical experts and company explained that, in BEACON CRC, the number of previous treatments was not associated with the effect of encorafenib plus cetuximab. However, the committee noted that the population in RECOURSE had not had testing for BRAF status. The company assumed that about 5% of the RECOURSE trial population had BRAF V600E mutation-positive disease. It also noted the higher mortality associated with BRAF V600E mutation-positive colorectal cancer compared with wild-type colorectal cancer. To adjust the baseline hazard (poorer outcomes for those with BRAF mutation), it applied a hazard ratio to survival outcomes. At the first meeting, the committee concluded that it was appropriate to adjust survival for poorer outcomes in the BRAF population but that the appropriate hazard ratio was uncertain. At consultation, the company amended its choice of hazard ratio from 4.0 to 2.2. It noted that the updated value of 2.2 was derived from a meta-analysis (Safaee et al. 2012) including multiple studies identified by systematic review. The company suggested that it was therefore likely to be more reliable than a single study result. Alternative scenarios were presented by the ERG, which adjusted the baseline mortality using a hazard ratio of 1.8 from MRC Focus (2009). This was a UK randomised trial among people with advanced colorectal cancer who had 1 of 3 treatment strategies, including monotherapy and combination treatment with fluorouracil, irinotecan and oxaliplatin. In addition, the ERG presented an unadjusted analysis that did not adjust for the presence of a BRAF mutation (that is, it naively compared encorafenib plus cetuximab with the intervention arm of RECOURSE). The clinical experts expected survival to be much lower for people who had trifluridine–tipiracil if they had a BRAF V600E mutation than for those with no BRAF V600E mutation. The committee agreed that it was appropriate to adjust for histology because all studies showed poorer outcomes for people with the BRAF V600E mutation. However, it also thought it important to consider other potential confounders. The committee noted that there was considerable range in the hazard ratios provided to adjust survival outcomes for the presence of BRAF mutations. It concluded that the meta-analysis (Safaee et al. 2012) was likely to provide the most reliable hazard ratio.
# Subsequent treatments in BEACON CRC
## Subsequent treatments in BEACON CRC do not reflect NHS clinical practice but may extend life
In the first committee meeting the company noted that people in BEACON CRC had a range of subsequent treatments after disease progression. The committee was aware that some of these treatments had included immunotherapies, which are not available at this point in the pathway in the NHS and may prolong life. The clinical experts explained that, in current NHS clinical practice, there are no active treatments after people have trifluridine–tipiracil. The committee appreciated that, if the subsequent treatments differed by trial arm and prolonged life, then the results of the intention-to-treat analyses would not be generalisable to the NHS. At consultation, the company noted that it was unable to adjust survival outcomes for subsequent treatments but provided details of subsequent treatments by trial arm. Consultees explained that subsequent therapies were unlikely to have prolonged life in the encorafenib plus cetuximab arm. The clinical experts noted that more patients in the control arm of BEACON CRC had had BRAF inhibitors as subsequent therapies, which may have improved survival. So, the effect of encorafenib plus cetuximab may have been underestimated. The committee noted that it would have preferred to see analyses controlling for the effect of subsequent treatments. Nevertheless, it concluded that subsequent treatments were unlikely to have had a large effect on the survival estimates.
# The company's economic model
## The company's model is appropriate for decision making
The company chose a partitioned survival model to estimate the cost effectiveness of encorafenib plus cetuximab. The model included 3 health states reflecting colorectal cancer: progression free, progressed, and dead. The probability of being in a given health state was defined by the area under the curves for progression-free survival, overall survival, and their difference. The model cycle length was 1 month and the time horizon was 10 years. The committee considered the company's model to be appropriate for decision making.
# Modelling overall survival
## The most recent data cut from BEACON CRC should be used to model survival
The company provided an updated data cut (May 2020) from BEACON CRC after technical engagement, which provided an additional 9 months of follow up. The committee considered that additional data on survival outcomes helped when considering the long-term extrapolations, and agreed that it would consider the updated data cut in its decision making.
# Modelling overall survival for encorafenib plus cetuximab compared with FOLFIRI
## A piecewise approach is preferred for modelling overall survival for encorafenib plus cetuximab
Follow up for BEACON CRC was short in relation to the modelled time horizon. The company extrapolated the trial data for the encorafenib plus cetuximab arm, choosing a log-logistic distribution in its base case. The ERG noted that the log-logistic distribution provided the best statistical fit to the trial data, but other distributions had similar statistical fits and none fitted the data well. The committee noted that the hazard function for the BEACON CRC overall survival data showed a change in trajectory (slope of the line) for the hazard rate at 2.8 months. The clinical and patient experts explained that this may have been because disease responds quickly to encorafenib plus cetuximab. The clinical experts said that responses in tumour markers could be seen from as early as 2 weeks after treatment with encorafenib plus cetuximab. The committee was aware that the ERG preferred to fit the extrapolated curve from 2.8 months onwards, using the observed Kaplan–Meier data from the trial up to this point, using a 'piecewise' approach. The committee considered that it was appropriate to model overall survival for encorafenib plus cetuximab using a piecewise approach.
## The generalised gamma distribution should be used to model overall survival for encorafenib plus cetuximab
Having concluded that a piecewise approach was the most appropriate method to model overall survival in the encorafenib plus cetuximab arm, the committee considered the models used by the company and the ERG. At consultation, the company chose the log-logistic model distribution from 2.8 months onwards based on statistical fit. The committee was aware that statistical fit considers only the time period in which the models are fitted to the observed data. It noted the ERG's statements that there were low numbers of people in the trials at risk towards the tail of the Kaplan–Meier curve, and that deciding whether extrapolations are plausible needs clinical input. The ERG highlighted that it was difficult to distinguish between the parametric curves by looking at them, and the 10‑year survival proportions were not negligible for many of the curves. The clinical experts explained that the log-logistic curve could plausibly reflect mortality. However, they pointed out that it represented the upper-bound expected for overall survival. This was because a higher proportion of people than expected were predicted to be alive at 10 years. The committee considered that the Weibull distribution represented the lower-bound of plausible approaches. It concluded that the generalised gamma curve lay between the 2 and most closely reflected what clinical experts expected in clinical practice. It further concluded that the generalised gamma curve, fitted using a piecewise approach, was the most appropriate for extrapolating overall survival.
## Estimates of overall survival for FOLFIRI likely lie between the BEACON CRC control arm and the company's indirect treatment comparison
The committee recalled its conclusion that all estimates of relative effectiveness for encorafenib plus cetuximab compared with FOLFIRI were associated with uncertainties (see section 3.15). At consultation, the company provided updated analyses using the May 2020 data cut from BEACON CRC. The company applied a hazard ratio of 2.56 (95% confidence interval 1.23 to 5.26) from the indirect treatment comparison to the encorafenib plus cetuximab survival curves to generate survival curves for FOLFIRI. The ERG provided scenario analyses that explored the duration of cetuximab effect from none (reflecting use of the BEACON CRC control arm as a proxy for FOLFIRI) to lifetime (reflecting adjustment using the company's indirect treatment comparison). The committee also considered a result from an alternative scenario that used data from the CRYSTAL study (see section 3.9) to provide an indirect treatment comparison. Survival estimates using CRYSTAL data were lower than those from BEACON CRC, but above those of the company's original base case using the indirect treatment comparison. The clinical experts expected survival to be low for people who had FOLFIRI alone, with no one alive at 5 years and fewer than 2% alive at 3 years. The committee noted that results from the indirect treatment comparison and ERG scenario analyses best reflected these estimates. It also noted the preference to use the same hazard function for both treatment arms, which was consistent with the recommendations from NICE's Decision Support Unit. The committee therefore preferred extrapolating with the generalised gamma distribution to compare encorafenib plus cetuximab with FOLFIRI. It concluded that the comparator arm of BEACON CRC needed adjustment for the benefit associated with cetuximab. It further concluded that the most plausible survival estimates for FOLFIRI were likely to lie between the company's indirect treatment comparison and the BEACON CRC control arm.
# Modelling progression-free survival
## Kaplan–Meier data should be used to model progression-free survival
In the company's original submission, a jointly fitted parametric curve was chosen to extrapolate progression-free survival for encorafenib plus cetuximab. The company applied the hazard ratio from the indirect treatment comparison to estimate the FOLFIRI survival outcomes (see section 3.13). The committee noted that none of the parametric models offered a good fit to the progression-free survival data in BEACON CRC. The ERG presented alternative analyses using the raw Kaplan–Meier data because these were relatively mature. The committee considered that it would be preferable to fit a curve to the data, but because this was not possible, using the Kaplan–Meier data was reasonable. At consultation, the company updated its base case to use observed Kaplan–Meier data to model progression-free survival for encorafenib plus cetuximab, but noted that this was not possible for FOLFIRI or trifluridine–tipiracil. The committee concluded that the Kaplan–Meier data should have been used to model progression-free survival if possible. However, it did not think that not doing this had a large effect on the cost-effectiveness results.
# Modelling overall survival for encorafenib plus cetuximab compared with trifluridine–tipiracil
## To estimate cost effectiveness the generalised gamma curve adjusted to account for differences in BRAF mutation status is the most appropriate
Trifluridine–tipiracil is a relevant comparator for second and third-line treatment (see section 3.4 and section 3.6). BEACON CRC showed no difference in treatment effect for encorafenib plus cetuximab in people who had 1 or 2 previous lines of treatment. Therefore, the committee considered it reasonable to assume the same treatment effect for encorafenib plus cetuximab at second and third line. All the results of the company's naive comparison were very uncertain (see section 3.17). The committee recalled that it would consider cost-effectiveness analyses that used a range of hazard ratios to adjust for differences in the populations between BEACON CRC and RECOURSE, based on its earlier conclusion that the hazard ratios vary widely (see section 3.17). It considered the different approaches to extrapolating the curves. It recalled that the generalised gamma curve was the best fit for encorafenib plus cetuximab (see section 3.22), and that the same extrapolation should apply for the comparator arm in line with the NICE Decision Support Unit recommendation. It concluded that the most appropriate curve fit was generalised gamma, and that the RECOURSE overall survival curves should be adjusted to account for differences in BRAF mutation status.
# Subsequent treatments
## Adjusting trial data for subsequent treatments not available in NHS practice is appropriate
The committee recalled that people in BEACON CRC had subsequent treatments that would not be available in NHS clinical practice and which might prolong life (see section 3.18). It was also aware that in the analysis these treatments affected costs in both treatment arms. The company did not attempt to adjust for the additional survival benefit. However, it did provide a scenario accounting for the costs of these treatments. The committee considered that this scenario did not have a large effect on the incremental cost-effectiveness ratio (ICER). Also, it recalled that any survival gain caused by subsequent treatment was likely to lengthen the life of patients in the control arm more than the encorafenib arm (see section 3.18). The committee concluded that subsequent treatments in BEACON CRC were unlikely to have a big effect on the results of the cost-effectiveness analyses.
# Waning of treatment effect
## It is appropriate that the model does not include waning of the treatment effect
The company's model assumed that the relative survival benefit of encorafenib plus cetuximab, compared with current treatment, was maintained at the same level for the rest of a person's life if a person remained in the pre-progression health state. The committee was aware that neither the company nor the ERG had modelled scenarios in which the treatment benefit diminishes in the long term. The clinical experts explained that the benefit of encorafenib plus cetuximab is likely to continue while the person is having treatment. They also noted that there is no stopping rule for the treatment. The committee accepted the clinical experts' comments, and concluded that the company's model need not include waning of the relative treatment effect.
# Utility values in the economic model
## The utility estimates in the company's model are appropriate
BEACON CRC included the EQ‑5D‑5L health questionnaire to measure health-related quality of life. The company mapped the EQ‑5D‑5L data to the EQ‑5D‑3L to estimate mean utility for the pre-progressed and progressed disease health states, in line with NICE's methods guide. After technical engagement, the company applied a utility value from those people who had FOLFIRI plus cetuximab in the clinical trial to people who had FOLFIRI only in the model. The committee noted that the utility value used by the company for the post-progression health state in the encorafenib plus cetuximab arm was slightly lower than for the FOLFIRI arm. The company explained that, although these were different in the modelling, the range of the utilities in each arm overlapped. The ERG also highlighted that the utility values were not collected at the same time point in each arm, which may have affected the results. The committee considered it reasonable that the health utility data collected in BEACON CRC captured decrements for adverse events because they were treatment specific. The committee concluded that the utility estimates used in the company's model were appropriate.
# Costs in the economic model
## Time to treatment discontinuation should be applied in the model
Time to treatment discontinuation determines total acquisition costs for a treatment. At consultation, the company provided scenarios using time to treatment discontinuation for comparisons using the BEACON CRC control arm as a proxy for FOLFIRI. In all other analyses, the company assumed that time to treatment discontinuation was equivalent to progression-free survival. The company explained that it used progression-free survival to model time to treatment discontinuation because the trials used in the indirect and naive treatment comparisons did not report time to treatment discontinuation. The ERG highlighted that using time to treatment discontinuation had a bigger effect on encorafenib plus cetuximab costs than on comparator costs. It also explained that time to treatment discontinuation was available for encorafenib plus cetuximab, so it should have been applied to the treatment arm. The ERG's scenarios applied time to treatment discontinuation to the encorafenib plus cetuximab arm, and made assumptions to include time to treatment discontinuation in the comparator arms. The committee concluded that the ERG's scenarios using time to treatment discontinuation were appropriate for decision making.
## It is appropriate to use mean relative dose intensities in the model
The company used mean relative dose intensities, that is, the ratio of the given dose to the planned dose, in the economic model. The ERG explained its preference for using median values because the trial data are skewed, meaning that the median is higher than the mean. It noted that this may have been caused by some poor outcomes early in the trial. The company explained that it used the mean because it better reflected what will happen in clinical practice. The committee concluded that mean relative dose intensities should be used in the model.
## It is appropriate to assume 10% drug wastage for oral treatments
In its base case, the company assumed sharing vials and no wastage. It provided a scenario analysis that assumed that 10% of patients would waste some capsules in a pack by rounding up to the nearest whole pack. The clinical lead for the Cancer Drugs Fund explained that it was reasonable to assume 10% drug wastage for oral drugs because people may stop taking treatment between clinic visits. But assuming no drug wastage for intravenous drugs would be appropriate because cetuximab and FOLFIRI are common treatments used in the NHS with relatively long shelf lives. The ERG explained that the company wastage scenario did not reflect 10% wastage, because it assumed only 10% of patients waste capsules, rather than all patients waste 10% of capsules. It presented scenario analyses that increased the encorafenib costs by 10% to account for wastage. The committee concluded that the ERG's scenario more accurately represented 10% drug wastage.
# End of life
## Encorafenib plus cetuximab meets the criteria to be considered a life-extending end of life treatment
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The clinical experts explained that the average life expectancy for people with BRAF V600E mutation-positive metastatic colorectal cancer was shorter than 2 years. The committee noted that the median overall survival for the control arm in BEACON CRC was 5.9 months and that the literature suggested that median survival for people with BRAF V600E mutation-positive colorectal cancer was shorter than 12 months. The committee recognised that the mean values would be higher than the median, but would likely remain below 2 years. The committee thought it was plausible that encorafenib plus cetuximab would result in a survival gain of more than 3 months compared with standard care, despite limitations in the comparative evidence base. The median overall survival gain in BEACON CRC was 3.4 months for encorafenib plus cetuximab compared with the investigator's choice. Both the ERG's and the company's modelling estimated a survival gain of more than 3 months. The committee concluded that encorafenib plus cetuximab met the criteria to be considered a life-extending end of life treatment.
# Innovation
## Encorafenib plus cetuximab is an innovative treatment for BRAF V600E mutation-positive metastatic colorectal cancer
The patient and clinical experts explained that encorafenib plus cetuximab represents a step change in treatment for people with BRAF V600E mutation-positive colorectal cancer and there is high unmet need for an effective treatment. The committee was aware that there are no BRAF V600E targeted treatments available for this population. The clinical experts explained that targeted treatment can change the genetic make-up of the tumour, potentially offering targets for other treatment options in the future. The committee noted that the treatment is not a chemotherapy and may transform people's quality of life. The committee concluded that encorafenib plus cetuximab is an innovative treatment for BRAF V600E mutation-positive colorectal cancer.
# Cost-effectiveness estimate
## It is appropriate to make pairwise comparisons rather than incremental analyses
Because of confidential commercial arrangements for encorafenib and cetuximab, none of the cost-effectiveness results are reported here. The committee recalled that the second-line comparators depended on the person's previous treatment, so reflected distinct populations, which made pairwise comparisons appropriate.
## Encorafenib plus cetuximab is effective and innovative, but the cost-effectiveness estimates are uncertain
The committee noted the high level of uncertainty with the clinical and modelling assumptions made by the company and the ERG, specifically:
The control arm of BEACON CRC did not reflect NHS clinical practice (see section 3.8).
There were no head-to-head trials comparing encorafenib plus cetuximab with FOLFIRI or with trifluridine–tipiracil (see section 3.12 and section 3.16).
The company's indirect treatment comparison made several uncertain clinical assumptions, including that FOLFIRI and irinotecan are clinically equivalent (see section 3.13 and section 3.14).
The results of the company's naive comparison were uncertain (see section 3.17).
The analysis does not take into account subsequent treatments used in the trial but not available in the NHS (see section 3.18).The committee acknowledged that the company did not know the price of encorafenib plus cetuximab because cetuximab is supplied by another company and has a confidential discount. The committee recognised that encorafenib plus cetuximab was effective and innovative, but the cost-effectiveness estimates were uncertain.
## Encorafenib plus cetuximab is recommended in the NHS
Because of the level of uncertainty in the clinical evidence, the committee recalled that all the cost-effectiveness results were uncertain. However, it agreed that the most plausible ICER was within what NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life. It therefore concluded that it could recommend encorafenib plus cetuximab for previously treated BRAF V600E mutation-positive colorectal cancer for routine commissioning.
# Equalities
## No equalities issues were identified for encorafenib plus cetuximab
At consultation, several web comments were received stating that the draft guidance discriminated against young people. This was because the average age of patients in BEACON CRC was 60 years, which does not reflect the younger population who would be eligible to have encorafenib plus cetuximab. Clinical experts considered that the age of patients in BEACON CRC reflected the age of patients who would be seen in NHS practice with previously treated BRAF V600E mutation-positive colorectal cancer. They noted that this population would be well enough to have chemotherapy and encorafenib plus cetuximab. The committee was aware that its recommendation applied to everyone covered by the marketing authorisation for encorafenib plus cetuximab, which does not restrict the treatment to any age group. So, it did not consider this an equalities issue. The committee concluded that there were no equalities issues for treatment with encorafenib plus cetuximab.
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{'Recommendations': "Encorafenib plus cetuximab is recommended, within its marketing authorisation, as an option for treating BRAF V600E mutation-positive metastatic colorectal cancer in adults who have had previous systemic treatment. It is recommended only if the company provides it according to the commercial arrangements.\n\nWhy the committee made these recommendations\n\nTreatment for BRAF V600E mutation-positive metastatic colorectal cancer after previous systemic treatment includes combination chemotherapy, usually FOLFIRI (5‑fluorouracil, folinic acid and irinotecan) followed by trifluridine–tipiracil then best supportive care. Encorafenib plus cetuximab is the first colorectal cancer treatment that targets the BRAF V600E mutation, and could be used second or third line.\n\nClinical trial evidence shows that encorafenib plus cetuximab increases how long people live compared with FOLFIRI plus cetuximab or irinotecan plus cetuximab. However, these drug combinations are not used in NHS clinical practice, because NICE does not recommend cetuximab beyond first-line treatment for metastatic colorectal cancer. Assumptions are needed to indirectly compare encorafenib plus cetuximab with FOLFIRI or trifluridine–tipiracil using evidence from other clinical trials. This makes the results uncertain.\n\nEncorafenib plus cetuximab meets NICE's criteria for being a life-extending treatment at the end of life. Also, despite the uncertain comparative effectiveness results, the cost-effectiveness estimates are within what is normally considered a cost-effective use of NHS resources. So, it is recommended for routine use in the NHS.", 'Information about encorafenib plus cetuximab': "# Marketing authorisation indication\n\nEncorafenib (Braftovi; Pierre Fabre Ltd) has a marketing authorisation in combination with cetuximab (Erbitux; Merck Serono Ltd) 'for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy'. Because the marketing authorisation did not include triple therapy (encorafenib plus binimetinib and cetuximab), this appraisal only considers dual therapy.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of encorafenib 75\xa0mg is £1,400 for 42\xa0capsules (excluding VAT; BNF online accessed October 2020).The list price of cetuximab 5\xa0mg per millilitre solution for infusion is £890.50 for 100\xa0millilitres (excluding VAT; BNF online accessed October 2020).The companies have commercial arrangements for each of the drugs. These make encorafenib and cetuximab available to the NHS with discounts. The size of the discounts are commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of the discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Pierre Fabre Ltd, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe company's adjustment of health utilities for the progression-free health state is more likely to reflect clinical practice.\n\nThe company's amended cost for drugs at the start of the model cycle more accurately reflects costs in clinical practice.It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report table\xa011, page\xa041), and took these into account in its decision making. It discussed the issues that were outstanding after the technical engagement stage.\n\n# The condition\n\n## There is an unmet need for treatments for BRAF V600E mutation-positive metastatic colorectal cancer\n\nColorectal cancer is a malignant tumour arising from the lining of the large intestine (colon and rectum). BRAF is a human gene that encodes the protein B‑Raf, which influences cell growth. Metastatic colorectal cancer with a BRAF V600E mutation is a rare type of colorectal cancer. It is associated with a poorer prognosis and has a greater risk of recurring than colorectal cancer without the BRAF mutation. There has been little improvement in survival for BRAF V600E mutation-positive cancer despite improvements for colorectal cancer in general. The clinical experts explained that there are currently no effective treatments for this type of colorectal cancer, and that encorafenib plus cetuximab represents a step change in treatment. The committee concluded that there is an unmet need for treatments for BRAF V600E mutation-positive metastatic colorectal cancer.\n\n## People would welcome an effective treatment option for BRAF V600E mutation-positive metastatic colorectal cancer\n\nMetastatic colorectal cancer is a progressive condition that affects survival and quality of life. The patient experts highlighted the psychological effects of a diagnosis of metastatic BRAF V600E mutation-positive colorectal cancer, and the lasting adverse effects of current treatments such as neuropathic damage. They explained that their cancers responded quickly to triple therapy (encorafenib plus binimetinib and cetuximab) and this was life-changing, whereas they saw little to no response on previous treatment. They noted that their quality of life had improved enormously because the adverse effects of this therapy are manageable compared with other treatments. The committee concluded that both patients and healthcare professionals would welcome an effective new treatment.\n\n# The treatment pathway\n\n## Encorafenib plus cetuximab may be used after 1\xa0or more previous lines of treatment\n\nEncorafenib plus cetuximab has a marketing authorisation for treating metastatic colorectal cancer with a BRAF V600E mutation in people who have had previous systemic treatment. Current NHS treatment options for this type of metastatic colorectal cancer include combination chemotherapy regimens, trifluridine–tipiracil and best supportive care. The committee noted that encorafenib plus cetuximab could be positioned second line or later in the treatment pathway. The clinical experts explained that encorafenib plus cetuximab is the first targeted treatment for this population, and their preference for using it after first-line treatment. The patient experts emphasised the psychological effect of being diagnosed with BRAF V600E mutation-positive metastatic colorectal cancer. They noted that using encorafenib plus cetuximab earlier in the pathway could give people hope of improved outcomes and avoid adverse events associated with current treatments. The committee recognised the clinical and patient experts' preference for using encorafenib plus cetuximab earlier in the treatment pathway. The committee concluded that it may be used after 1\xa0or more previous lines of treatment in clinical practice.\n\n## FOLFIRI and trifluridine–tipiracil are relevant comparators for encorafenib plus cetuximab after 1\xa0previous line of treatment\n\nThe clinical experts explained that treatment options for BRAF V600E mutation-positive metastatic colorectal cancer depend on the previous treatments a person has had, their response to these treatments and their preferences. Most people have combination chemotherapy, usually folinic acid, fluorouracil (5‑FU) and oxaliplatin (known as FOLFOX) first line followed by folinic acid, 5‑FU and irinotecan (known as FOLFIRI). The clinical experts explained that these treatments are interchangeable and considered equivalent. A small proportion of people have folinic acid, 5‑FU, irinotecan and oxaliplatin (FOLFOXIRI) first line, so would then have trifluridine–tipiracil as second-line treatment. The clinical experts noted that this was uncommon because of the higher toxicity with FOLFOXIRI than with other combinations. The company explained that encorafenib plus cetuximab could be used instead of FOLFIRI or trifluridine–tipiracil after 1\xa0previous line of treatment. The marketing authorisation for trifluridine–tipiracil allows for its use second line and later. It is the only drug recommended after first-line treatment for metastatic colorectal cancer in the NICE Pathway on colorectal cancer. However, the committee recalled its conclusion in NICE's technology appraisal guidance on trifluridine–tipiracil that, in clinical practice, it would mainly be used in people who have had 2\xa0or more previous lines of treatment when there are no further treatment options. The committee concluded that the relevant comparators after 1\xa0previous line of treatment include both FOLFIRI and trifluridine–tipiracil.\n\n## Irinotecan monotherapy is not a relevant comparator for encorafenib plus cetuximab after 1\xa0previous line of treatment\n\nNICE's scope includes irinotecan monotherapy as a relevant comparator. However, the company excluded it based on expert opinion and a market survey, which found that fewer than 2% of people have irinotecan monotherapy in clinical practice. The clinical experts agreed with the company and explained that, in clinical practice, irinotecan is used as part of FOLFIRI. When used with other treatments, the dose of irinotecan is lower and better tolerated than when used as monotherapy. The clinical experts noted that irinotecan monotherapy is occasionally used when there is a specific intolerance to 5‑FU or a dihydropyrimidine dehydrogenase deficiency resulting in an inability to detoxify 5‑FU in the liver. The committee concluded that irinotecan monotherapy is not a relevant comparator after 1\xa0previous line of treatment.\n\n## Trifluridine–tipiracil is a relevant comparator for encorafenib plus cetuximab after 2\xa0previous lines of treatment\n\nIn clinical practice, trifluridine–tipiracil is usually used after 2\xa0previous lines of treatment. The clinical experts explained that it would be appropriate to use encorafenib plus cetuximab instead of trifluridine–tipiracil after 2\xa0previous lines of treatment if neither had been used earlier in the treatment pathway. The committee concluded that trifluridine–tipiracil is a relevant comparator for encorafenib plus cetuximab after 2\xa0previous lines of treatment.\n\n## Best supportive care is not a relevant comparator for encorafenib plus cetuximab\n\nNICE's scope for the appraisal included best supportive care as a relevant comparator. After treatment with trifluridine–tipiracil, there are no other active treatment options and people have best supportive care. The committee recognised that a small group of people with BRAF V600E positive mutations whose disease had relapsed after treatment with trifluridine–tipiracil may be eligible for encorafenib plus cetuximab. The clinical experts agreed that encorafenib plus cetuximab could also be used when no other active treatment options are available. However, they noted that, at this stage, people may not be well enough to have active treatment. The company and ERG agreed that patients eligible for best supportive care would generally not be well enough to have active treatment, including encorafenib plus cetuximab. The committee concluded that best supportive care was not a relevant comparator for encorafenib plus cetuximab.\n\n# Clinical effectiveness of encorafenib plus cetuximab\n\n## Encorafenib plus cetuximab is clinically effective based on BEACON\xa0CRC but the comparators in the trial are not used in the NHS\n\nBEACON\xa0CRC is a multinational, open-label, randomised, phase\xa03 trial comparing encorafenib plus cetuximab with the investigator's choice of chemotherapy (FOLFIRI or irinotecan) plus cetuximab. It included people with BRAF V600E mutation-positive metastatic colorectal cancer whose disease had progressed after 1\xa0or\xa02 previous lines of treatment. The primary endpoints in the trial were for triple therapy (encorafenib plus binimetinib and cetuximab), which is not relevant for this appraisal. Overall survival, progression-free survival and overall response rate for encorafenib plus cetuximab compared with controls were secondary endpoints. Results showed that encorafenib plus cetuximab increased overall survival more than the investigator's choice of either FOLFIRI plus cetuximab or irinotecan plus cetuximab. The clinical experts explained that the control arm of BEACON\xa0CRC did not reflect clinical practice in the NHS. This is because epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab, are not recommended beyond first-line treatment for metastatic colorectal cancer in NICE's technology appraisal guidance on cetuximab, bevacizumab and panitumumab. In addition, about 40% of people in the control arm had irinotecan plus cetuximab. The committee recalled that irinotecan monotherapy is not a relevant comparator because it is associated with worse toxicity than FOLFIRI (see section\xa03.5). It heard that irinotecan monotherapy would not be offered second line with cetuximab. The committee concluded that encorafenib plus cetuximab is clinically effective compared with the comparators in the trial, but these treatments do not reflect NHS clinical practice.\n\n## Cetuximab likely benefits patients so the trial may underestimate the relative effect of encorafenib plus cetuximab compared with FOLFIRI\n\nThe committee recalled that cetuximab is not recommended in the NHS beyond first-line treatment for metastatic colorectal cancer. However, the clinical experts at the first committee meeting explained that it is likely to benefit people with BRAF V600E mutation-positive colorectal cancer who have not had an EGFR inhibitor. However, they also noted that there are limited data available for this population, so how much benefit cetuximab has when used with FOLFIRI or irinotecan is unknown. At consultation after the first committee meeting, a consultee cited data from CRYSTAL. This was a randomised controlled phase\xa03 study comparing cetuximab plus FOLFIRI with FOLFIRI first line in people with KRAS wild-type metastatic colorectal cancer, and in people with known BRAF V600E mutations. Results showed that both populations had improved survival when FOLFIRI was used with cetuximab compared with FOLFIRI alone. The committee recognised that the CRYSTAL study included people who had not had prior treatment. However, the clinical experts and the NHS England lead for the Cancer Drugs Fund explained that the population seen in the NHS would not have had an EGFR inhibitor before. This meant that they would be likely to have a similar benefit to that seen in CRYSTAL. The committee concluded that cetuximab was likely to have added benefit to FOLFIRI and irinotecan in the control arm of BEACON\xa0CRC. This meant that the BEACON\xa0CRC trial results may have underestimated the relative effectiveness of encorafenib plus cetuximab compared with FOLFIRI alone. It agreed to consider this in its decision making.\n\n## Irinotecan may not be clinically equivalent to FOLFIRI\n\nTreatment in the control arm of BEACON\xa0CRC included either FOLFIRI plus cetuximab or irinotecan plus cetuximab. The committee appreciated that if irinotecan and FOLFIRI are equally effective, then it would be satisfied that irinotecan plus cetuximab and FOLFIRI plus cetuximab are also equally effective. The committee was aware that treatment in the control arm was not randomised. Instead, it was allocated according to the investigator's choice, which the committee recognised was a 'blended comparator'. The clinical experts explained that people are offered treatments depending on how their disease reacted to previous treatments, their comorbidities, and personal preference. The committee recalled that 40% of people in the control arm had irinotecan plus cetuximab. It considered whether FOLFIRI and irinotecan were equally effective. The company cited data from 2\xa0clinical trials to support this. The ERG highlighted that the trials were done in patients with unknown BRAF mutation status, so the results may not apply in this population. In its first meeting, the committee was concerned that assuming equivalent effectiveness for FOLFIRI and irinotecan was unproven. At consultation, the company presented results from a stratified log-rank test. The committee was aware that the trial was not powered to detect differences in survival for the control arm. But it noted that the results showed worse survival for people in the BEACON\xa0CRC trial who had irinotecan plus cetuximab compared with FOLFIRI plus cetuximab, although the results were uncertain. The ERG noted that the results included the possibility of no difference. The committee was aware of the possibility of confounding by indication. So, it considered the company's multivariate Cox analysis controlling for age, sex, characteristics of the tumour, number of organs involved and prior use of oxaliplatin. This analysis also showed a hazard ratio indicating that patients taking irinotecan plus cetuximab died earlier than those taking FOLFIRI plus cetuximab. The committee noted that these results were uncertain and included the possibility of no difference. The company noted that there were no covariates excluded from the multivariable analysis. The clinical experts explained that most oncologists would view the 2\xa0treatments as having similar efficacy. Also, 1\xa0consultee explained that FOLFIRI is better tolerated. One expert noted that there will likely be clinical reasons (for example, 5‑FU intolerance or not wanting an implanted venous access device necessary to deliver FOLFIRI) as to why investigators chose irinotecan over FOLFIRI. The committee was aware of the lack of evidence for people with BRAF mutations. However, it concluded that irinotecan may not be equivalent to FOLFIRI and took this into consideration in its decision making.\n\n## Comparing encorafenib plus cetuximab with the blended comparator from BEACON does not reflect the comparison with FOLFIRI\n\nThe BEACON control arm included investigator's choice plus cetuximab. Investigator's choice included either FOLFIRI or irinotecan. The committee appreciated that the components of the blended comparator have different degrees of benefit, and that this approach averages the clinical effectiveness of the treatments included. It recalled its conclusion that cetuximab is likely to add benefit to FOLFIRI alone, but also that irinotecan is associated with worse toxicity and potentially poorer outcomes than FOLFIRI (see section\xa03.10). The committee concluded that including a blended comparator in the estimates of clinical effectiveness does not reflect the comparison with FOLFIRI.\n\n# Indirect comparison of encorafenib plus cetuximab with FOLFIRI\n\n## The indirect comparison of encorafenib plus cetuximab with FOLFIRI is useful for decision making\n\nAnalyses that adjust for the differences between the trial and clinical practice should inform decision making. The committee noted that BEACON\xa0CRC differed from current NHS clinical practice because:\n\nirinotecan was included in the control arm of the trial (see section\xa03.8)\n\ncetuximab was added to irinotecan and FOLFIRI, which added benefit (see section\xa03.9)\n\nirinotecan may not be clinically equivalent to FOLFIRI (see section\xa03.10)\n\nthe blended comparator makes the relative effectiveness analyses uncertain (see section\xa03.11).The committee concluded that BEACON\xa0CRC did not reflect the comparison with FOLFIRI. In addition, it concluded that it would take into account the company's indirect comparison of encorafenib plus cetuximab with FOLFIRI to inform decision making.\n\n## Cetuximab and panitumumab are equally effective\n\nThe committee recalled that there were no data directly comparing encorafenib plus cetuximab with FOLFIRI or trifluridine–tipiracil. To estimate the relative efficacy of encorafenib plus cetuximab compared with FOLFIRI, the company did an indirect treatment comparison using data from BEACON\xa0CRC and data from a subgroup of people with BRAF mutation-positive metastatic colorectal cancer from Peeters et al. (2010 to 2015). Peeters et al. was a randomised controlled trial comparing FOLFIRI alone with FOLFIRI plus panitumumab in people with metastatic colorectal cancer. There were no common comparators between these 2\xa0trials, so assumptions were needed to form a network. The control arm of BEACON\xa0CRC (investigator's choice of either FOLFIRI or irinotecan, both plus cetuximab) would have to be considered equivalent to the treatment arm in Peeters et al. (FOLFIRI plus panitumumab) to form a network. The indirect treatment comparison was possible only by assuming equal efficacy for:\n\ncetuximab and panitumumab\n\nFOLFIRI and irinotecan.The committee recalled the conclusion from NICE's technology appraisal guidance on cetuximab and panitumumab that cetuximab and panitumumab were likely to have similar effectiveness in treating RAS wild-type metastatic colorectal cancer. The clinical experts and NHS England's clinical lead for the Cancer Drugs Fund explained that cetuximab and panitumumab should be considered clinically equivalent in the population with BRAF mutation-positive disease. The committee concluded that cetuximab and panitumumab were equally effective.\n\n## The results of the indirect comparison are uncertain because FOLFIRI and irinotecan may not be equally effective\n\nThe committee recalled its conclusion that FOLFIRI and irinotecan may not be equally effective (see section\xa03.10). It noted that an assumption of equivalence was needed to estimate the relative effectiveness of encorafenib plus cetuximab with FOLFIRI using both the BEACON\xa0CRC results and the alternative analyses. The committee concluded that the evidence for equal effectiveness of FOLFIRI and irinotecan was uncertain, which made the results of the indirect treatment comparison uncertain.\n\n## All estimates of relative effectiveness for encorafenib plus cetuximab compared with FOLFIRI are uncertain\n\nThe committee recalled that the uncertainties associated with BEACON\xa0CRC meant the relative efficacy of encorafenib plus cetuximab compared with FOLFIRI could not be accurately estimated. However, it noted that the company's indirect treatment comparison was also highly uncertain. The ERG preferred to use the BEACON\xa0CRC data as a proxy for the clinical effectiveness of encorafenib plus cetuximab compared with FOLFIRI, and provided scenarios adjusting for cetuximab's duration of effect. The committee concluded that all relative effectiveness results were uncertain and it would consider this in its decision making.\n\n# Clinical effectiveness of encorafenib plus cetuximab compared with trifluridine–tipiracil\n\n## The RECOURSE trial contributes relevant clinical evidence\n\nThere were no studies for trifluridine–tipiracil with comparators common to BEACON\xa0CRC. The company and ERG highlighted the lack of data for people with BRAF V600E mutation-positive colorectal cancer. The company identified the RECOURSE trial, a randomised controlled phase\xa03 trial in people with refractory metastatic colorectal cancer or who could not tolerate standard therapies. It compared trifluridine–tipiracil with placebo, but the company noted that the population included people whose BRAF status was undefined. The company did a naive comparison using data from the trifluridine–tipiracil arm of RECOURSE and from the encorafenib plus cetuximab arm of BEACON\xa0CRC. The company did not have access to individual patient-level data from RECOURSE, so instead simulated the data by digitalising the published survival curves. The committee understood that there was a lack of data for this population. Although RECOURSE included a highly heterogenous population compared with the BEACON\xa0CRC population, the committee concluded that it was appropriate and relevant to consider as part of the clinical evidence.\n\n## The company's naive comparison of encorafenib plus cetuximab with trifluridine–tipiracil is uncertain\n\nThe committee recalled the considerable heterogeneity in potential prognostic factors between the study populations (BEACON\xa0CRC and RECOURSE) included in the company's naive comparison of encorafenib plus cetuximab with trifluridine–tipiracil. People in RECOURSE had 4\xa0or more previous lines of treatment compared with 1\xa0or\xa02 previous lines of treatment in BEACON\xa0CRC. After technical engagement, the company presented data from RECOURSE, which suggested that outcomes were better for people who had more lines of treatment compared with those who had fewer lines of treatment. The clinical experts and company explained that, in BEACON\xa0CRC, the number of previous treatments was not associated with the effect of encorafenib plus cetuximab. However, the committee noted that the population in RECOURSE had not had testing for BRAF status. The company assumed that about 5% of the RECOURSE trial population had BRAF V600E mutation-positive disease. It also noted the higher mortality associated with BRAF V600E mutation-positive colorectal cancer compared with wild-type colorectal cancer. To adjust the baseline hazard (poorer outcomes for those with BRAF mutation), it applied a hazard ratio to survival outcomes. At the first meeting, the committee concluded that it was appropriate to adjust survival for poorer outcomes in the BRAF population but that the appropriate hazard ratio was uncertain. At consultation, the company amended its choice of hazard ratio from 4.0\xa0to\xa02.2. It noted that the updated value of\xa02.2 was derived from a meta-analysis (Safaee et al. 2012) including multiple studies identified by systematic review. The company suggested that it was therefore likely to be more reliable than a single study result. Alternative scenarios were presented by the ERG, which adjusted the baseline mortality using a hazard ratio of 1.8 from MRC Focus (2009). This was a UK randomised trial among people with advanced colorectal cancer who had 1\xa0of 3\xa0treatment strategies, including monotherapy and combination treatment with fluorouracil, irinotecan and oxaliplatin. In addition, the ERG presented an unadjusted analysis that did not adjust for the presence of a BRAF mutation (that is, it naively compared encorafenib plus cetuximab with the intervention arm of RECOURSE). The clinical experts expected survival to be much lower for people who had trifluridine–tipiracil if they had a BRAF V600E mutation than for those with no BRAF V600E mutation. The committee agreed that it was appropriate to adjust for histology because all studies showed poorer outcomes for people with the BRAF V600E mutation. However, it also thought it important to consider other potential confounders. The committee noted that there was considerable range in the hazard ratios provided to adjust survival outcomes for the presence of BRAF mutations. It concluded that the meta-analysis (Safaee et al. 2012) was likely to provide the most reliable hazard ratio.\n\n# Subsequent treatments in BEACON\xa0CRC\n\n## Subsequent treatments in BEACON\xa0CRC do not reflect NHS clinical practice but may extend life\n\nIn the first committee meeting the company noted that people in BEACON\xa0CRC had a range of subsequent treatments after disease progression. The committee was aware that some of these treatments had included immunotherapies, which are not available at this point in the pathway in the NHS and may prolong life. The clinical experts explained that, in current NHS clinical practice, there are no active treatments after people have trifluridine–tipiracil. The committee appreciated that, if the subsequent treatments differed by trial arm and prolonged life, then the results of the intention-to-treat analyses would not be generalisable to the NHS. At consultation, the company noted that it was unable to adjust survival outcomes for subsequent treatments but provided details of subsequent treatments by trial arm. Consultees explained that subsequent therapies were unlikely to have prolonged life in the encorafenib plus cetuximab arm. The clinical experts noted that more patients in the control arm of BEACON\xa0CRC had had BRAF inhibitors as subsequent therapies, which may have improved survival. So, the effect of encorafenib plus cetuximab may have been underestimated. The committee noted that it would have preferred to see analyses controlling for the effect of subsequent treatments. Nevertheless, it concluded that subsequent treatments were unlikely to have had a large effect on the survival estimates.\n\n# The company's economic model\n\n## The company's model is appropriate for decision making\n\nThe company chose a partitioned survival model to estimate the cost effectiveness of encorafenib plus cetuximab. The model included 3\xa0health states reflecting colorectal cancer: progression free, progressed, and dead. The probability of being in a given health state was defined by the area under the curves for progression-free survival, overall survival, and their difference. The model cycle length was 1\xa0month and the time horizon was 10\xa0years. The committee considered the company's model to be appropriate for decision making.\n\n# Modelling overall survival\n\n## The most recent data cut from BEACON CRC should be used to model survival\n\nThe company provided an updated data cut (May 2020) from BEACON\xa0CRC after technical engagement, which provided an additional 9\xa0months of follow up. The committee considered that additional data on survival outcomes helped when considering the long-term extrapolations, and agreed that it would consider the updated data cut in its decision making.\n\n# Modelling overall survival for encorafenib plus cetuximab compared with FOLFIRI\n\n## A piecewise approach is preferred for modelling overall survival for encorafenib plus cetuximab\n\nFollow up for BEACON\xa0CRC was short in relation to the modelled time horizon. The company extrapolated the trial data for the encorafenib plus cetuximab arm, choosing a log-logistic distribution in its base case. The ERG noted that the log-logistic distribution provided the best statistical fit to the trial data, but other distributions had similar statistical fits and none fitted the data well. The committee noted that the hazard function for the BEACON\xa0CRC overall survival data showed a change in trajectory (slope of the line) for the hazard rate at 2.8\xa0months. The clinical and patient experts explained that this may have been because disease responds quickly to encorafenib plus cetuximab. The clinical experts said that responses in tumour markers could be seen from as early as 2\xa0weeks after treatment with encorafenib plus cetuximab. The committee was aware that the ERG preferred to fit the extrapolated curve from 2.8\xa0months onwards, using the observed Kaplan–Meier data from the trial up to this point, using a 'piecewise' approach. The committee considered that it was appropriate to model overall survival for encorafenib plus cetuximab using a piecewise approach.\n\n## The generalised gamma distribution should be used to model overall survival for encorafenib plus cetuximab\n\nHaving concluded that a piecewise approach was the most appropriate method to model overall survival in the encorafenib plus cetuximab arm, the committee considered the models used by the company and the ERG. At consultation, the company chose the log-logistic model distribution from 2.8\xa0months onwards based on statistical fit. The committee was aware that statistical fit considers only the time period in which the models are fitted to the observed data. It noted the ERG's statements that there were low numbers of people in the trials at risk towards the tail of the Kaplan–Meier curve, and that deciding whether extrapolations are plausible needs clinical input. The ERG highlighted that it was difficult to distinguish between the parametric curves by looking at them, and the 10‑year survival proportions were not negligible for many of the curves. The clinical experts explained that the log-logistic curve could plausibly reflect mortality. However, they pointed out that it represented the upper-bound expected for overall survival. This was because a higher proportion of people than expected were predicted to be alive at 10\xa0years. The committee considered that the Weibull distribution represented the lower-bound of plausible approaches. It concluded that the generalised gamma curve lay between the\xa02 and most closely reflected what clinical experts expected in clinical practice. It further concluded that the generalised gamma curve, fitted using a piecewise approach, was the most appropriate for extrapolating overall survival.\n\n## Estimates of overall survival for FOLFIRI likely lie between the BEACON\xa0CRC control arm and the company's indirect treatment comparison\n\nThe committee recalled its conclusion that all estimates of relative effectiveness for encorafenib plus cetuximab compared with FOLFIRI were associated with uncertainties (see section\xa03.15). At consultation, the company provided updated analyses using the May 2020 data cut from BEACON\xa0CRC. The company applied a hazard ratio of\xa02.56 (95% confidence interval 1.23\xa0to\xa05.26) from the indirect treatment comparison to the encorafenib plus cetuximab survival curves to generate survival curves for FOLFIRI. The ERG provided scenario analyses that explored the duration of cetuximab effect from none (reflecting use of the BEACON\xa0CRC control arm as a proxy for FOLFIRI) to lifetime (reflecting adjustment using the company's indirect treatment comparison). The committee also considered a result from an alternative scenario that used data from the CRYSTAL study (see section\xa03.9) to provide an indirect treatment comparison. Survival estimates using CRYSTAL data were lower than those from BEACON\xa0CRC, but above those of the company's original base case using the indirect treatment comparison. The clinical experts expected survival to be low for people who had FOLFIRI alone, with no one alive at 5\xa0years and fewer than 2% alive at 3\xa0years. The committee noted that results from the indirect treatment comparison and ERG scenario analyses best reflected these estimates. It also noted the preference to use the same hazard function for both treatment arms, which was consistent with the recommendations from NICE's Decision Support Unit. The committee therefore preferred extrapolating with the generalised gamma distribution to compare encorafenib plus cetuximab with FOLFIRI. It concluded that the comparator arm of BEACON\xa0CRC needed adjustment for the benefit associated with cetuximab. It further concluded that the most plausible survival estimates for FOLFIRI were likely to lie between the company's indirect treatment comparison and the BEACON\xa0CRC control arm.\n\n# Modelling progression-free survival\n\n## Kaplan–Meier data should be used to model progression-free survival\n\nIn the company's original submission, a jointly fitted parametric curve was chosen to extrapolate progression-free survival for encorafenib plus cetuximab. The company applied the hazard ratio from the indirect treatment comparison to estimate the FOLFIRI survival outcomes (see section\xa03.13). The committee noted that none of the parametric models offered a good fit to the progression-free survival data in BEACON\xa0CRC. The ERG presented alternative analyses using the raw Kaplan–Meier data because these were relatively mature. The committee considered that it would be preferable to fit a curve to the data, but because this was not possible, using the Kaplan–Meier data was reasonable. At consultation, the company updated its base case to use observed Kaplan–Meier data to model progression-free survival for encorafenib plus cetuximab, but noted that this was not possible for FOLFIRI or trifluridine–tipiracil. The committee concluded that the Kaplan–Meier data should have been used to model progression-free survival if possible. However, it did not think that not doing this had a large effect on the cost-effectiveness results.\n\n# Modelling overall survival for encorafenib plus cetuximab compared with trifluridine–tipiracil\n\n## To estimate cost effectiveness the generalised gamma curve adjusted to account for differences in BRAF mutation status is the most appropriate\n\nTrifluridine–tipiracil is a relevant comparator for second and third-line treatment (see section\xa03.4 and\xa0section 3.6). BEACON\xa0CRC showed no difference in treatment effect for encorafenib plus cetuximab in people who had 1\xa0or\xa02 previous lines of treatment. Therefore, the committee considered it reasonable to assume the same treatment effect for encorafenib plus cetuximab at second and third line. All the results of the company's naive comparison were very uncertain (see section\xa03.17). The committee recalled that it would consider cost-effectiveness analyses that used a range of hazard ratios to adjust for differences in the populations between BEACON\xa0CRC and RECOURSE, based on its earlier conclusion that the hazard ratios vary widely (see section\xa03.17). It considered the different approaches to extrapolating the curves. It recalled that the generalised gamma curve was the best fit for encorafenib plus cetuximab (see section\xa03.22), and that the same extrapolation should apply for the comparator arm in line with the NICE Decision Support Unit recommendation. It concluded that the most appropriate curve fit was generalised gamma, and that the RECOURSE overall survival curves should be adjusted to account for differences in BRAF mutation status.\n\n# Subsequent treatments\n\n## Adjusting trial data for subsequent treatments not available in NHS practice is appropriate\n\nThe committee recalled that people in BEACON\xa0CRC had subsequent treatments that would not be available in NHS clinical practice and which might prolong life (see section\xa03.18). It was also aware that in the analysis these treatments affected costs in both treatment arms. The company did not attempt to adjust for the additional survival benefit. However, it did provide a scenario accounting for the costs of these treatments. The committee considered that this scenario did not have a large effect on the incremental cost-effectiveness ratio (ICER). Also, it recalled that any survival gain caused by subsequent treatment was likely to lengthen the life of patients in the control arm more than the encorafenib arm (see section\xa03.18). The committee concluded that subsequent treatments in BEACON\xa0CRC were unlikely to have a big effect on the results of the cost-effectiveness analyses.\n\n# Waning of treatment effect\n\n## It is appropriate that the model does not include waning of the treatment effect\n\nThe company's model assumed that the relative survival benefit of encorafenib plus cetuximab, compared with current treatment, was maintained at the same level for the rest of a person's life if a person remained in the pre-progression health state. The committee was aware that neither the company nor the ERG had modelled scenarios in which the treatment benefit diminishes in the long term. The clinical experts explained that the benefit of encorafenib plus cetuximab is likely to continue while the person is having treatment. They also noted that there is no stopping rule for the treatment. The committee accepted the clinical experts' comments, and concluded that the company's model need not include waning of the relative treatment effect.\n\n# Utility values in the economic model\n\n## The utility estimates in the company's model are appropriate\n\nBEACON\xa0CRC included the EQ‑5D‑5L health questionnaire to measure health-related quality of life. The company mapped the EQ‑5D‑5L data to the EQ‑5D‑3L to estimate mean utility for the pre-progressed and progressed disease health states, in line with NICE's methods guide. After technical engagement, the company applied a utility value from those people who had FOLFIRI plus cetuximab in the clinical trial to people who had FOLFIRI only in the model. The committee noted that the utility value used by the company for the post-progression health state in the encorafenib plus cetuximab arm was slightly lower than for the FOLFIRI arm. The company explained that, although these were different in the modelling, the range of the utilities in each arm overlapped. The ERG also highlighted that the utility values were not collected at the same time point in each arm, which may have affected the results. The committee considered it reasonable that the health utility data collected in BEACON\xa0CRC captured decrements for adverse events because they were treatment specific. The committee concluded that the utility estimates used in the company's model were appropriate.\n\n# Costs in the economic model\n\n## Time to treatment discontinuation should be applied in the model\n\nTime to treatment discontinuation determines total acquisition costs for a treatment. At consultation, the company provided scenarios using time to treatment discontinuation for comparisons using the BEACON\xa0CRC control arm as a proxy for FOLFIRI. In all other analyses, the company assumed that time to treatment discontinuation was equivalent to progression-free survival. The company explained that it used progression-free survival to model time to treatment discontinuation because the trials used in the indirect and naive treatment comparisons did not report time to treatment discontinuation. The ERG highlighted that using time to treatment discontinuation had a bigger effect on encorafenib plus cetuximab costs than on comparator costs. It also explained that time to treatment discontinuation was available for encorafenib plus cetuximab, so it should have been applied to the treatment arm. The ERG's scenarios applied time to treatment discontinuation to the encorafenib plus cetuximab arm, and made assumptions to include time to treatment discontinuation in the comparator arms. The committee concluded that the ERG's scenarios using time to treatment discontinuation were appropriate for decision making.\n\n## It is appropriate to use mean relative dose intensities in the model\n\nThe company used mean relative dose intensities, that is, the ratio of the given dose to the planned dose, in the economic model. The ERG explained its preference for using median values because the trial data are skewed, meaning that the median is higher than the mean. It noted that this may have been caused by some poor outcomes early in the trial. The company explained that it used the mean because it better reflected what will happen in clinical practice. The committee concluded that mean relative dose intensities should be used in the model.\n\n## It is appropriate to assume 10% drug wastage for oral treatments\n\nIn its base case, the company assumed sharing vials and no wastage. It provided a scenario analysis that assumed that 10% of patients would waste some capsules in a pack by rounding up to the nearest whole pack. The clinical lead for the Cancer Drugs Fund explained that it was reasonable to assume 10% drug wastage for oral drugs because people may stop taking treatment between clinic visits. But assuming no drug wastage for intravenous drugs would be appropriate because cetuximab and FOLFIRI are common treatments used in the NHS with relatively long shelf lives. The ERG explained that the company wastage scenario did not reflect 10% wastage, because it assumed only 10% of patients waste capsules, rather than all patients waste 10% of capsules. It presented scenario analyses that increased the encorafenib costs by 10% to account for wastage. The committee concluded that the ERG's scenario more accurately represented 10% drug wastage.\n\n# End of life\n\n## Encorafenib plus cetuximab meets the criteria to be considered a life-extending end of life treatment\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The clinical experts explained that the average life expectancy for people with BRAF V600E mutation-positive metastatic colorectal cancer was shorter than 2\xa0years. The committee noted that the median overall survival for the control arm in BEACON\xa0CRC was 5.9\xa0months and that the literature suggested that median survival for people with BRAF V600E mutation-positive colorectal cancer was shorter than 12\xa0months. The committee recognised that the mean values would be higher than the median, but would likely remain below 2\xa0years. The committee thought it was plausible that encorafenib plus cetuximab would result in a survival gain of more than 3\xa0months compared with standard care, despite limitations in the comparative evidence base. The median overall survival gain in BEACON\xa0CRC was 3.4\xa0months for encorafenib plus cetuximab compared with the investigator's choice. Both the ERG's and the company's modelling estimated a survival gain of more than 3\xa0months. The committee concluded that encorafenib plus cetuximab met the criteria to be considered a life-extending end of life treatment.\n\n# Innovation\n\n## Encorafenib plus cetuximab is an innovative treatment for BRAF V600E mutation-positive metastatic colorectal cancer\n\nThe patient and clinical experts explained that encorafenib plus cetuximab represents a step change in treatment for people with BRAF V600E mutation-positive colorectal cancer and there is high unmet need for an effective treatment. The committee was aware that there are no BRAF V600E targeted treatments available for this population. The clinical experts explained that targeted treatment can change the genetic make-up of the tumour, potentially offering targets for other treatment options in the future. The committee noted that the treatment is not a chemotherapy and may transform people's quality of life. The committee concluded that encorafenib plus cetuximab is an innovative treatment for BRAF V600E mutation-positive colorectal cancer.\n\n# Cost-effectiveness estimate\n\n## It is appropriate to make pairwise comparisons rather than incremental analyses\n\nBecause of confidential commercial arrangements for encorafenib and cetuximab, none of the cost-effectiveness results are reported here. The committee recalled that the second-line comparators depended on the person's previous treatment, so reflected distinct populations, which made pairwise comparisons appropriate.\n\n## Encorafenib plus cetuximab is effective and innovative, but the cost-effectiveness estimates are uncertain\n\nThe committee noted the high level of uncertainty with the clinical and modelling assumptions made by the company and the ERG, specifically:\n\nThe control arm of BEACON\xa0CRC did not reflect NHS clinical practice (see section\xa03.8).\n\nThere were no head-to-head trials comparing encorafenib plus cetuximab with FOLFIRI or with trifluridine–tipiracil (see section\xa03.12 and\xa0section 3.16).\n\nThe company's indirect treatment comparison made several uncertain clinical assumptions, including that FOLFIRI and irinotecan are clinically equivalent (see section\xa03.13 and\xa0section 3.14).\n\nThe results of the company's naive comparison were uncertain (see section\xa03.17).\n\nThe analysis does not take into account subsequent treatments used in the trial but not available in the NHS (see section\xa03.18).The committee acknowledged that the company did not know the price of encorafenib plus cetuximab because cetuximab is supplied by another company and has a confidential discount. The committee recognised that encorafenib plus cetuximab was effective and innovative, but the cost-effectiveness estimates were uncertain.\n\n## Encorafenib plus cetuximab is recommended in the NHS\n\nBecause of the level of uncertainty in the clinical evidence, the committee recalled that all the cost-effectiveness results were uncertain. However, it agreed that the most plausible ICER was within what NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life. It therefore concluded that it could recommend encorafenib plus cetuximab for previously treated BRAF V600E mutation-positive colorectal cancer for routine commissioning.\n\n# Equalities\n\n## No equalities issues were identified for encorafenib plus cetuximab\n\nAt consultation, several web comments were received stating that the draft guidance discriminated against young people. This was because the average age of patients in BEACON\xa0CRC was 60\xa0years, which does not reflect the younger population who would be eligible to have encorafenib plus cetuximab. Clinical experts considered that the age of patients in BEACON\xa0CRC reflected the age of patients who would be seen in NHS practice with previously treated BRAF V600E mutation-positive colorectal cancer. They noted that this population would be well enough to have chemotherapy and encorafenib plus cetuximab. The committee was aware that its recommendation applied to everyone covered by the marketing authorisation for encorafenib plus cetuximab, which does not restrict the treatment to any age group. So, it did not consider this an equalities issue. The committee concluded that there were no equalities issues for treatment with encorafenib plus cetuximab."}
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https://www.nice.org.uk/guidance/ta668
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Evidence-based recommendations on encorafenib (Braftovi) plus cetuximab (Erbitux) for treating BRAF V600E mutation-positive metastatic colorectal cancer in adults who have had previous systemic treatment.
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7376dcecd21b89e4a7112e18fdfa03232c8f197a
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nice
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Eating disorders: recognition and treatment
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Eating disorders: recognition and treatment
This guideline covers assessment, treatment, monitoring and inpatient care for children, young people and adults with eating disorders. It aims to improve the care people receive by detailing the most effective treatments for anorexia nervosa, binge eating disorder and bulimia nervosa.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.
In this guideline, 'family members' includes the siblings, children and partners of people with an eating disorder.
# General principles of care
## Improving access to services
Be aware that people with an eating disorder may:
find it difficult or distressing to discuss it with healthcare professionals, staff and other service users
be vulnerable to stigma and shame
need information and interventions tailored to their age and level of development.
Ensure that all people with an eating disorder and their parents or carers (as appropriate) have equal access to treatments (including through self-referral) for eating disorders, regardless of:
age
gender or gender identity (including people who are transgender)
sexual orientation
socioeconomic status
religion, belief, culture, family origin or ethnicity
where they live and who they live with
any physical or other mental health problems or disabilities.
Healthcare professionals assessing people with an eating disorder (especially children and young people) should be alert throughout assessment and treatment to signs of bullying, teasing, abuse (emotional, physical and sexual) and neglect. For guidance on when to suspect child maltreatment, see the NICE guideline on child maltreatment.
## Communication and information
When assessing a person with a suspected eating disorder, find out what they and their family members or carers (as appropriate) know about eating disorders and address any misconceptions.
Offer people with an eating disorder and their family members or carers (as appropriate) education and information on:
the nature and risks of the eating disorder and how it is likely to affect them
the treatments available and their likely benefits and limitations.
When communicating with people with an eating disorder and their family members or carers (as appropriate):
be sensitive when discussing a person's weight and appearance
be aware that family members or carers may feel guilty and responsible for the eating disorder
show empathy, compassion and respect
provide information in a format suitable for them, and check they understand it.
Ensure that people with an eating disorder and their parents or carers (as appropriate) understand the purpose of any meetings and the reasons for sharing information about their care with others.
## Support for people with an eating disorder
Assess the impact of the home, education, work and wider social environment (including the internet and social media) on each person's eating disorder. Address their emotional, education, employment and social needs throughout treatment.
If appropriate, encourage family members, carers, teachers, and peers of children and young people to support them during their treatment.
## Working with family members and carers
Be aware that the family members or carers of a person with an eating disorder may experience severe distress. Offer family members or carers assessments of their own needs as treatment progresses (see the NICE guideline on supporting adult carers), including:
what impact the eating disorder has on them and their mental health
what support they need, including practical support and emergency plans if the person with the eating disorder is at high medical or psychiatric risk.
If appropriate, provide written information for family members or carers who do not attend assessment or treatment meetings with the person with an eating disorder.
## Consent and confidentiality
When working with people with an eating disorder and their family members or carers (as appropriate):
hold discussions in places where confidentiality, privacy and dignity can be respected
explain the limits of confidentiality (that is, which professionals and services have access to information about their care and when this may be shared with others).
When seeking consent for assessments or treatments for children or young people under 16, respect Gillick competence (see the Department of Health and Social Care reference guide) if they consent and do not want their family members or carers involved.
## Training and competencies
Professionals who assess and treat people with an eating disorder should be competent to do this for the age groups they care for.
Health, social care and education professionals working with people with an eating disorder should be trained and skilled in:
negotiating and working with family members and carers
managing issues around information sharing and confidentiality
safeguarding
working with multidisciplinary teams.
Base the content, structure and duration of psychological treatments on relevant manuals that focus on eating disorders.
Professionals who provide treatments for eating disorders should:
receive appropriate clinical supervision
use standardised outcome measures, for example, the Eating Disorder Examination Questionnaire (EDE‑Q)
monitor their competence (for example, by using recordings of sessions, and external audit and scrutiny)
monitor treatment adherence in people who use their service.
## Coordination of care for people with an eating disorder
Take particular care to ensure services are well coordinated when:
a young person moves from children's to adult services (see the NICE guideline on transition from children's to adults' services)
more than one service is involved (such as inpatient and outpatient services, child and family services, or when a comorbidity is being treated by a separate service)
people need care in different places at different times of the year (for example, university students).
# Identification and assessment
People with eating disorders should be assessed and receive treatment at the earliest opportunity.
Early treatment is particularly important for those with or at risk of severe emaciation and such patients should be prioritised for treatment.
## Initial assessments in primary and secondary mental healthcare
Be aware that eating disorders present in a range of settings, including:
primary and secondary healthcare (including acute hospitals)
social care
education
work.
Although eating disorders can develop at any age, be aware that the risk is highest for young men and women between 13 and 17 years of age.
Do not use screening tools (for example, SCOFF) as the sole method to determine whether or not people have an eating disorder.
When assessing for an eating disorder or deciding whether to refer people for assessment, take into account any of the following that apply:
an unusually low or high body mass index (BMI) or body weight for their age
rapid weight loss
dieting or restrictive eating practices (such as dieting when they are underweight) that are worrying them, their family members or carers, or professionals
family members or carers report a change in eating behaviour
social withdrawal, particularly from situations that involve food
-ther mental health problems
a disproportionate concern about their weight or shape (for example, concerns about weight gain as a side effect of contraceptive medication)
problems managing a chronic illness that affects diet, such as diabetes or coeliac disease
menstrual or other endocrine disturbances, or unexplained gastrointestinal symptoms
physical signs of:
malnutrition, including poor circulation, dizziness, palpitations, fainting or pallor
compensatory behaviours, including laxative or diet pill misuse, vomiting or excessive exercise
abdominal pain that is associated with vomiting or restrictions in diet, and that cannot be fully explained by a medical condition
unexplained electrolyte imbalance or hypoglycaemia
atypical dental wear (such as erosion)
whether they take part in activities associated with a high risk of eating disorders (for example, professional sport, fashion, dance, or modelling).
Be aware that, in addition to the points in recommendation 1.2.6, children and young people with an eating disorder may also present with faltering growth (for example, a low weight or height for their age) or delayed puberty.
Do not use single measures such as BMI or duration of illness to determine whether to offer treatment for an eating disorder.
Professionals in primary and secondary mental health or acute settings should assess the following in people with a suspected eating disorder:
their physical health, including checking for any physical effects of malnutrition or compensatory behaviours such as vomiting
the presence of mental health problems commonly associated with eating disorders, including depression, anxiety, self-harm and obsessive-compulsive disorder
the possibility of alcohol or substance misuse
the need for emergency care in people whose physical health is compromised or who have a suicide risk.
## Referral
If an eating disorder is suspected after an initial assessment, refer immediately to a community-based, age-appropriate eating disorder service for further assessment or treatment.
# Treating anorexia nervosa
Provide support and care for all people with anorexia nervosa in contact with specialist services, whether or not they are having a specific intervention. Support should:
include psychoeducation about the disorder
include monitoring of weight, mental and physical health, and any risk factors
be multidisciplinary and coordinated between services
involve the person's family members or carers (as appropriate).
When treating anorexia nervosa, be aware that:
helping people to reach a healthy body weight or BMI for their age is a key goal and
weight gain is key in supporting other psychological, physical and quality of life changes that are needed for improvement or recovery.
When weighing people with anorexia nervosa, consider sharing the results with them and (if appropriate) their family members or carers.
## Psychological treatment for anorexia nervosa in adults
For adults with anorexia nervosa, consider one of:
individual eating-disorder-focused cognitive behavioural therapy (CBT‑ED)
Maudsley Anorexia Nervosa Treatment for Adults (MANTRA)
specialist supportive clinical management (SSCM). Explain to the person what the treatments involve to help them choose which they would prefer.
Individual CBT‑ED programmes for adults with anorexia nervosa should:
typically consist of up to 40 sessions over 40 weeks, with twice-weekly sessions in the first 2 or 3 weeks
aim to reduce the risk to physical health and any other symptoms of the eating disorder
encourage healthy eating and reaching a healthy body weight
cover nutrition, cognitive restructuring, mood regulation, social skills, body image concern, self-esteem, and relapse prevention
create a personalised treatment plan based on the processes that appear to be maintaining the eating problem
explain the risks of malnutrition and being underweight
enhance self-efficacy
include self-monitoring of dietary intake and associated thoughts and feelings
include homework, to help the person practice in their daily life what they have learned.
MANTRA for adults with anorexia nervosa should:
typically consist of 20 sessions, with:
weekly sessions for the first 10 weeks, and a flexible schedule after this
up to 10 extra sessions for people with complex problems
base treatment on the MANTRA workbook
motivate the person and encourage them to work with the practitioner
be flexible in how the modules of MANTRA are delivered and emphasised
when the person is ready, cover nutrition, symptom management, and behaviour change
encourage the person to develop a 'non-anorexic identity'
involve family members or carers to help the person:
understand their condition and the problems it causes and the link to the wider social context
change their behaviour.
SSCM for adults with anorexia nervosa should:
typically consist of 20 or more weekly sessions (depending on severity)
assess, identify, and regularly review key problems
aim to develop a positive relationship between the person and the practitioner
aim to help people recognise the link between their symptoms and their abnormal eating behaviour
aim to restore weight
provide psychoeducation, and nutritional education and advice
include physical health monitoring
establish a weight range goal
encourage reaching a healthy body weight and healthy eating
allow the person to decide what else should be included as part of their therapy.
If individual CBT‑ED, MANTRA or SSCM is unacceptable, contraindicated or ineffective for adults with anorexia nervosa, consider:
-ne of these 3 treatments that the person has not had before or
eating-disorder-focused focal psychodynamic therapy (FPT).
FPT for adults with anorexia nervosa should:
typically consist of up to 40 sessions over 40 weeks
make a patient-centred focal hypothesis that is specific to the individual and addresses:
what the symptoms mean to the person
how the symptoms affect the person
how the symptoms influence the person's relationships with others and with the therapist
in the first phase, focus on developing the therapeutic alliance between the therapist and person with anorexia nervosa, addressing pro-anorexic behaviour and ego-syntonic beliefs (beliefs, values and feelings consistent with the person's sense of self) and building self-esteem
in the second phase, focus on relevant relationships with other people and how these affect eating behaviour
in the final phase, focus on transferring the therapy experience to situations in everyday life and address any concerns the person has about what will happen when treatment ends.
## Psychological treatment for anorexia nervosa in children and young people
Consider anorexia-nervosa-focused family therapy for children and young people (FT‑AN), delivered as single-family therapy or a combination of single- and multi-family therapy. Give children and young people the option to have some single-family sessions:
separately from their family members or carers and
together with their family members or carers.
FT‑AN for children and young people with anorexia nervosa should:
typically consist of 18 to 20 sessions over 1 year
review the needs of the person 4 weeks after treatment begins and then every 3 months, to establish how regular sessions should be and how long treatment should last
emphasise the role of the family in helping the person to recover
not blame the person or their family members or carers
include psychoeducation about nutrition and the effects of malnutrition
early in treatment, support the parents or carers to take a central role in helping the person manage their eating, and emphasise that this is a temporary role
in the first phase, aim to establish a good therapeutic alliance with the person, their parents or carers and other family members
in the second phase, support the person (with help from their parents or carers) to establish a level of independence appropriate for their level of development
in the final phase:
focus on plans for when treatment ends (including any concerns the person and their family have) and on relapse prevention
address how the person can get support if treatment is stopped.
Consider support for family members who are not involved in the family therapy, to help them cope with distress caused by the condition.
Consider giving children and young people with anorexia nervosa additional appointments separate from their family members or carers.
Assess whether family members or carers (as appropriate) need support if the child or young person with anorexia nervosa is having therapy on their own.
If FT‑AN is unacceptable, contraindicated or ineffective for children or young people with anorexia nervosa, consider individual CBT‑ED or adolescent-focused psychotherapy for anorexia nervosa (AFP‑AN).
Individual CBT‑ED for children and young people with anorexia nervosa should:
typically consist of up to 40 sessions over 40 weeks, with:
twice-weekly sessions in the first 2 or 3 weeks
to 12 additional brief family sessions with the person and their parents or carers (as appropriate)
in family sessions and in individual sessions, include psychoeducation about nutrition and the effects of malnutrition
in family sessions:
identify anything in the person's home life that could make it difficult for them to change their behaviour, and find ways to address this
discuss meal plans
aim to reduce the risk to physical health and any other symptoms of the eating disorder
encourage reaching a healthy body weight and healthy eating
cover nutrition, relapse prevention, cognitive restructuring, mood regulation, social skills, body image concern and self-esteem
create a personalised treatment plan based on the processes that appear to be maintaining the eating problem
take into account the person's specific development needs
explain the risks of malnutrition and being underweight
enhance self-efficacy
include self-monitoring of dietary intake and associated thoughts and feelings
include homework, to help the person practice what they have learned in their daily life
address how the person can get support if treatment is stopped.
AFP‑AN for children and young people should:
typically consist of 32 to 40 individual sessions over 12 to 18 months, with:
more regular sessions early on, to help the person build a relationship with the practitioner and motivate them to change their behaviour
to 12 additional family sessions with the person and their parents or carers (as appropriate)
review the needs of the person 4 weeks after treatment begins and then every 3 months, to establish how regular sessions should be and how long treatment should last
in family sessions and in individual sessions, include psychoeducation about nutrition and the effects of malnutrition
focus on the person's self-image, emotions and interpersonal processes, and how these affect their eating disorder
develop a formulation of the person's psychological issues and how they use anorexic behaviour as a coping strategy
address fears about weight gain, and emphasise that weight gain and healthy eating is a critical part of therapy
find alternative strategies for the person to manage stress
in later stages of treatment, explore issues of identity and build independence
towards end of treatment, focus on transferring the therapy experience to situations in everyday life
in family sessions, help parents or carers support the person to change their behaviour
address how the person can get support if treatment is stopped.
## People with anorexia nervosa who are not having treatment
For people with anorexia who are not having treatment (for example, because it has not helped or because they have declined it) and who do not have severe or complex problems:
discharge them to primary care
tell them they can ask their GP to refer them again for treatment at any time.
For people with anorexia who have declined or do not want treatment and who have severe or complex problems, eating disorder services should provide support as covered in the recommendation on providing support and care in the section on treating anorexia nervosa.
## Dietary advice for people with anorexia nervosa
Only offer dietary counselling as part of a multidisciplinary approach.
Encourage people with anorexia nervosa to take an age-appropriate oral multi-vitamin and multi-mineral supplement until their diet includes enough to meet their dietary reference values.
Include family members or carers (as appropriate) in any dietary education or meal planning for children and young people with anorexia nervosa who are having therapy on their own.
Offer supplementary dietary advice to children and young people with anorexia nervosa and their family or carers (as appropriate) to help them meet their dietary needs for growth and development (particularly during puberty).
## Medication for anorexia nervosa
Do not offer medication as the sole treatment for anorexia nervosa.
# Treating binge eating disorder
## Psychological treatment for binge eating disorder in adults
Explain to people with binge eating disorder that psychological treatments aimed at treating binge eating have a limited effect on body weight and that weight loss is not a therapy target in itself. Refer to the NICE guideline on obesity identification, assessment and management for guidance on weight loss and bariatric surgery.
Offer a binge-eating-disorder-focused guided self-help programme to adults with binge eating disorder.
Binge-eating-disorder-focused guided self-help programmes for adults should:
use cognitive behavioural self-help materials
focus on adherence to the self-help programme
supplement the self-help programme with brief supportive sessions (for example, 4 to 9 sessions lasting 20 minutes each over 16 weeks, running weekly at first)
focus exclusively on helping the person follow the programme.
If guided self-help is unacceptable, contraindicated, or ineffective after 4 weeks, offer group eating-disorder-focused cognitive behavioural therapy (CBT‑ED).
Group CBT‑ED programmes for adults with binge eating disorder should:
typically consist of 16 weekly 90‑minute group sessions over 4 months
focus on psychoeducation, self-monitoring of the eating behaviour and helping the person analyse their problems and goals
include making a daily food intake plan and identifying binge eating cues
include body exposure training and helping the person to identify and change negative beliefs about their body
help with avoiding relapses and coping with current and future risks and triggers.
If group CBT‑ED is not available or the person declines it, consider individual CBT‑ED for adults with binge eating disorder.
Individual CBT‑ED for adults with binge eating disorder should:
typically consist of 16 to 20 sessions
develop a formulation of the person's psychological issues, to determine how dietary and emotional factors contribute to their binge eating
based on the formulation:
advise people to eat regular meals and snacks to avoid feeling hungry
address the emotional triggers for their binge eating, using cognitive restructuring, behavioural experiments and exposure
include weekly monitoring of binge eating behaviours, dietary intake and weight
share the weight record with the person
address body-image issues if present
explain to the person that although CBT‑ED does not aim at weight loss, stopping binge eating can have this effect in the long term
advise the person not to try to lose weight (for example, by dieting) during treatment, because this is likely to trigger binge eating.
## Psychological treatment for binge eating disorder in children and young people
For children and young people with binge eating disorder, offer the same treatments recommended for adults with binge eating disorder.
## Medication for binge eating disorder
Do not offer medication as the sole treatment for binge eating disorder.
# Treating bulimia nervosa
Explain to all people with bulimia nervosa that psychological treatments have a limited effect on body weight.
## Psychological treatment for bulimia nervosa in adults
Consider bulimia-nervosa-focused guided self-help for adults with bulimia nervosa.
Bulimia-nervosa-focused guided self-help programmes for adults with bulimia nervosa should:
use cognitive behavioural self-help materials for eating disorders
supplement the self-help programme with brief supportive sessions (for example, 4 to 9 sessions lasting 20 minutes each over 16 weeks, running weekly at first).
If bulimia-nervosa-focused guided self-help is unacceptable, contraindicated, or ineffective after 4 weeks of treatment, consider individual eating-disorder-focused cognitive behavioural therapy (CBT‑ED).
Individual CBT‑ED for adults with bulimia nervosa should:
typically consist of up to 20 sessions over 20 weeks, and consider twice-weekly sessions in the first phase
in the first phase focus on:
engagement and education
establishing a pattern of regular eating, and providing encouragement, advice and support while people do this
follow by addressing the eating disorder psychopathology (for example, the extreme dietary restraint, the concerns about body shape and weight, and the tendency to binge eat in response to difficult thoughts and feelings)
towards the end of treatment, spread appointments further apart and focus on maintaining positive changes and minimising the risk of relapse
if appropriate, involve significant others to help with one-to-one treatment.
## Psychological treatment for bulimia nervosa in children and young people
Offer bulimia-nervosa-focused family therapy (FT‑BN) to children and young people with bulimia nervosa.
FT-BN for children and young people with bulimia nervosa should:
typically consist of 18 to 20 sessions over 6 months
establish a good therapeutic relationship with the person and their family members or carers
support and encourage the family to help the person recover
not blame the person, their family members or carers
include information about:
regulating body weight
dieting
the adverse effects of attempting to control weight with self-induced vomiting, laxatives or other compensatory behaviours
use a collaborative approach between the parents and the young person to establish regular eating patterns and minimise compensatory behaviours
include regular meetings with the person on their own throughout the treatment
include self-monitoring of bulimic behaviours and discussions with family members or carers
in later phases of treatment, support the person and their family members or carers to establish a level of independence appropriate for their level of development
in the final phase of treatment, focus on plans for when treatment ends (including any concerns the person and their family have) and on relapse prevention.
Consider support for family members who are not involved in the family therapy, to help them to cope with distress caused by the condition.
If FT-BN is unacceptable, contraindicated or ineffective, consider individual eating-disorder-focused cognitive behavioural therapy (CBT‑ED) for children and young people with bulimia nervosa.
Individual CBT‑ED for children and young people with bulimia nervosa should:
typically consist of 18 sessions over 6 months, with more frequent sessions early in treatment
include up to 4 additional sessions with parents or carers
initially focus on the role bulimia nervosa plays in the person's life and on building motivation to change
provide psychoeducation about eating disorders and how symptoms are maintained, while encouraging the person to gradually establish regular eating habits
develop a case formulation with the person
teach the person to monitor their thoughts, feelings and behaviours
set goals and encourage the person to address problematic thoughts, beliefs and behaviours with problem-solving
use relapse prevention strategies to prepare for and mitigate potential future setbacks
in sessions with parents and carers, provide education about eating disorders, identify family factors that stop the person from changing their behaviour, and discuss how the family can support the person's recovery.
## Medication for bulimia nervosa
Do not offer medication as the sole treatment for bulimia nervosa.
# Treating other specified feeding and eating disorders (OSFED)
For people with OSFED, consider using the treatments for the eating disorder it most closely resembles.
# Physical therapy for any eating disorder
Do not offer a physical therapy (such as transcranial magnetic stimulation, acupuncture, weight training, yoga or warming therapy) as part of the treatment for eating disorders.
# Physical and mental health comorbidities
Eating disorder specialists and other healthcare teams should collaborate to support effective treatment of physical or mental health comorbidities in people with an eating disorder.
When collaborating, teams should use outcome measures for both the eating disorder and the physical and mental health comorbidities, to monitor the effectiveness of treatments for each condition and the potential impact they have on each other.
## Diabetes
For people with an eating disorder and diabetes, the eating disorder and diabetes teams should:
collaborate to explain the importance of physical health monitoring to the person
agree who has responsibility for monitoring physical health
collaborate on managing mental and physical health comorbidities
use a low threshold for monitoring blood glucose and blood ketones
use outcome measurements to monitor the effectiveness of treatments for each condition and the potential impact they have on each other.
When treating eating disorders in people with diabetes:
explain to the person (and if needed their diabetes team) that they may need to monitor their blood glucose and blood ketones more closely during treatment
consider involving their family members and carers (as appropriate) in treatment to help them with blood glucose control.
Address insulin misuse as part of any psychological treatment for eating disorders in people with diabetes.
Offer people with an eating disorder who are misusing insulin the following treatment plan:
a gradual increase in the amount of carbohydrates in their diet (if medically safe), so that insulin can be started at a lower dose
a gradual increase in insulin doses to avoid a rapid drop in blood glucose levels, which can increase the risk of retinopathy and neuropathy
adjusted total glycaemic load and carbohydrate distribution to meet their individual needs and prevent rapid weight gain
psychoeducation about the problems caused by misuse of diabetes medication
diabetes educational interventions, if the person has any gaps in their knowledge.
For people with suspected hypoglycaemia, test blood glucose:
before all supervised meals and snacks
when using the hypoglycaemia treatment algorithm
after correction doses.
For people with suspected hyperglycaemia or hypoglycaemia, and people with normal blood glucose levels who are misusing insulin, healthcare professionals should test for blood ketones:
when using the hypoglycaemia treatment algorithm
after correction doses.
For people with bulimia nervosa and diabetes, consider monitoring of:
glucose toxicity
insulin resistance
ketoacidosis
-edema.
When diabetes control is challenging:
do not attempt to rapidly treat hyperglycaemia (for example, with increased insulin doses), because this increases the risk of retinopathy and neuropathy
regularly monitor blood potassium levels
do not stop insulin altogether, because this puts the person at high risk of diabetic ketoacidosis.
See the NICE guidelines on type 1 and type 2 diabetes in children and young people, type 1 diabetes in adults and type 2 diabetes in adults for more guidance on:
fluid replacement in children and young people with diabetic ketoacidosis
insulin therapy, insulin delivery (including rotating injection sites within the same body region) and insulin dosage adjustment.
## Comorbid mental health problems
When deciding which order to treat an eating disorder and a comorbid mental health condition (in parallel, as part of the same treatment plan or one after the other), take the following into account:
the severity and complexity of the eating disorder and comorbidity
the person's level of functioning
the preferences of the person with the eating disorder and (if appropriate) those of their family members or carers.
Refer to the NICE guidelines on specific mental health problems for further guidance on treatment.
## Medication risk management
When prescribing medication for people with an eating disorder and comorbid mental or physical health conditions, take into account the impact malnutrition and compensatory behaviours can have on medication effectiveness and the risk of side effects.
When prescribing for people with an eating disorder and a comorbidity, assess how the eating disorder will affect medication adherence (for example, for medication that can affect body weight).
When prescribing for people with an eating disorder, take into account the risks of medication that can compromise physical health due to pre-existing medical complications.
Offer electrocardiogram (ECG) monitoring for people with an eating disorder who are taking medication that could compromise cardiac functioning (including medication that could cause electrolyte imbalance, bradycardia below 40 beats per minute, hypokalaemia, or a prolonged QT interval).
## Substance or medication misuse
For people with an eating disorder who are misusing substances, or over the counter or prescribed medication, provide treatment for the eating disorder unless the substance misuse is interfering with this treatment.
If substance misuse or medication is interfering with treatment, consider a multidisciplinary approach with substance misuse services.
## Growth and development
Seek specialist paediatric or endocrinology advice for delayed physical development or faltering growth in children and young people with an eating disorder.
# Conception and pregnancy for women with eating disorders
Provide advice and education to women with an eating disorder who plan to conceive, to increase the likelihood of conception and to reduce the risk of miscarriage. This may include information on the importance of:
maintaining good mental health and wellbeing
ensuring adequate nutrient intake and a healthy body weight
stopping behaviours such as binge eating, vomiting, laxatives and excessive exercise.
Nominate a dedicated professional (such as a GP or midwife) to monitor and support pregnant women with an eating disorder during pregnancy and in the post-natal period, because of:
concerns they may have specifically about gaining weight
possible health risks to the mother and child
the high risk of mental health problems in the perinatal period.
For women who are pregnant or in the perinatal period and have an eating disorder:
-ffer treatment for their eating disorder as covered in the sections on treating anorexia nervosa, treating binge eating disorder, treating bulimia nervosa and treating other specified feeding and eating disorders (OSFED)
provide monitoring and education as recommended in the section on psychological interventions for eating disorders in the NICE guideline on antenatal and postnatal mental health.
For guidance on providing advice to pregnant women about healthy eating and feeding their baby, see the NICE guideline on maternal and child nutrition.
Consider more intensive prenatal care for pregnant women with current or remitted anorexia nervosa, to ensure adequate prenatal nutrition and fetal development.
# Physical health assessment, monitoring and management for eating disorders
## Physical health assessment and monitoring for all eating disorders
Assess fluid and electrolyte balance in people with an eating disorder who are believed to be engaging in compensatory behaviours, such as vomiting, taking laxatives or diuretics, or water loading.
Assess whether ECG monitoring is needed in people with an eating disorder, based on the following risk factors:
rapid weight loss
excessive exercise
severe purging behaviours, such as laxative or diuretic use or vomiting
bradycardia
hypotension
excessive caffeine (including from energy drinks)
prescribed or non-prescribed medications
muscular weakness
electrolyte imbalance
previous abnormal heart rhythm.
## Management for all eating disorders
Provide acute medical care (including emergency admission) for people with an eating disorder who have severe electrolyte imbalance, severe malnutrition, severe dehydration or signs of incipient organ failure.
For people with an eating disorder who need supplements to restore electrolyte balance, offer these orally unless the person has problems with gastrointestinal absorption or the electrolyte disturbance is severe.
For people with an eating disorder and continued unexplained electrolyte imbalance, assess whether it could be caused by another condition.
Encourage people with an eating disorder who are vomiting to:
have regular dental and medical reviews
avoid brushing teeth immediately after vomiting
rinse with non‑acid mouthwash after vomiting
avoid highly acidic foods and drinks.
Advise people with an eating disorder who are misusing laxatives or diuretics:
that laxatives and diuretics do not reduce calorie absorption and so do not help with weight loss
to gradually reduce and stop laxative or diuretic use.
Advise people with an eating disorder who are exercising excessively to stop doing so.
For guidance on identifying, assessing and managing overweight and obesity, see the NICE guideline on obesity.
## Assessment and monitoring of physical health in anorexia nervosa
GPs should offer a physical and mental health review at least annually to people with anorexia nervosa who are not receiving ongoing treatment for their eating disorder. The review should include:
weight or BMI (adjusted for age if appropriate)
blood pressure
relevant blood tests
any problems with daily functioning
assessment of risk (related to both physical and mental health)
an ECG, for people with purging behaviours and/or significant weight changes
a discussion of treatment options.
Monitor growth and development in children and young people with anorexia nervosa who have not completed puberty (for example, not reached menarche or final height).
## Low bone mineral density in people with anorexia nervosa
Bone mineral density results should be interpreted and explained to people with anorexia nervosa by a professional with the knowledge and competencies to do this.
Before deciding whether to measure bone density, discuss with the person and their family members or carers why it could be useful.
Explain to people with anorexia nervosa that the main way of preventing and treating low bone mineral density is reaching and maintaining a healthy body weight or BMI for their age.
Consider a bone mineral density scan:
after 1 year of underweight in children and young people, or earlier if they have bone pain or recurrent fractures
after 2 years of underweight in adults, or earlier if they have bone pain or recurrent fractures.
Use measures of bone density that correct for bone size (such as bone mineral apparent density ) in children and young people with faltering growth.
Consider repeat bone mineral density scans in people with ongoing persistent underweight, especially when using or deciding whether to use hormonal treatment.
Do not repeat bone mineral density scans for people with anorexia nervosa more frequently than once per year, unless they develop bone pain or recurrent fractures.
Do not routinely offer oral or transdermal oestrogen therapy to treat low bone mineral density in children or young people with anorexia nervosa.
Seek specialist paediatric or endocrinological advice before starting any hormonal treatment for low bone mineral density. Coordinate any treatment with the eating disorders team.
Consider transdermal 17‑β‑estradiol (with cyclic progesterone) for young women (13 to 17 years) with anorexia nervosa who have long-term low body weight and low bone mineral density with a bone age over 15.
Consider incremental physiological doses of oestrogen in young women (13 to 17 years) with anorexia nervosa who have delayed puberty, long-term low body weight and low bone mineral density with a bone age under 15.
Consider bisphosphonates for women (18 years and over) with anorexia nervosa who have long-term low body weight and low bone mineral density. Discuss the benefits and risks (including risk of teratogenic effects) with women before starting treatment.
Advise people with anorexia nervosa and osteoporosis or related bone disorders to avoid high-impact physical activities and activities that significantly increase the chance of falls or fractures.
For guidance on osteoporosis risk assessment, see the NICE guideline on assessing the risk of fragility fractures in osteoporosis.
# Inpatient and day patient treatment
Admit people with an eating disorder whose physical health is severely compromised to a medical inpatient or day patient service for medical stabilisation and to initiate refeeding, if these cannot be done in an outpatient setting.
Do not use an absolute weight or BMI threshold when deciding whether to admit people with an eating disorder to day patient or inpatient care.
When deciding whether day patient or inpatient care is most appropriate, take the following into account:
The person's BMI or weight, and whether these can be safely managed in a day patient service or whether the rate of weight loss (for example, more than 1 kg a week) means they need inpatient care.
Whether inpatient care is needed to actively monitor medical risk parameters such as blood tests, physical observations and ECG (for example, bradycardia below 40 beats per minute or a prolonged QT interval) that have values or rates of change in the concern or alert ranges: refer to box 1 in the Royal College of Psychiatrists' resource on management of really sick patients with anorexia nervosa (MARSIPAN), or Guidance 1 and 2 in the junior MARSIPAN report.
The person's current physical health and whether this is significantly declining.
Whether the parents or carers of children and young people can support them and keep them from significant harm as a day patient.
When reviewing the need for inpatient care as part of an integrated treatment programme for a person with an eating disorder:
do not use inpatient care solely to provide psychological treatment for eating disorders
do not discharge people solely because they have reached a healthy weight.
For people with an eating disorder and acute mental health risk (such as significant suicide risk), consider psychiatric crisis care or psychiatric inpatient care.
Children, young people and adults with an eating disorder who are admitted to day patient or inpatient care should be cared for in age-appropriate facilities (for example, paediatric wards or adolescent mental health services). These should be near to their home, and have the capacity to provide appropriate educational activities during extended admissions.
When a person is admitted to inpatient care for medical stabilisation, specialist eating disorder or liaison psychiatry services should:
keep in contact with the inpatient team to advise on care and management, both during the admission and when planning discharge
keep the person's family members or carers involved
consider starting or continuing psychological treatments for the eating disorder.
Inpatient or day patient services should collaborate with other teams (including the community team) and the person's family members or carers (as appropriate), to help with treatment and transition.
## Refeeding
Ensure that staff of day patient, inpatient, or acute services who treat eating disorders are trained to recognise the symptoms of refeeding syndrome and how to manage it.
Use a standard operating procedure for refeeding that emphasises the need to avoid under-nutrition and refeeding syndrome. Refer to existing national guidance, such as the Royal College of Psychiatrists' MARSIPAN resource and the junior MARSIPAN report.
## Care planning and discharge from inpatient care
Develop a care plan for each person with an eating disorder who is admitted to inpatient care. The care plan should:
give clear objectives and outcomes for the admission
be developed in collaboration with the person, their family members or carers (as appropriate), and the community-based eating disorder service
set out how they will be discharged, how they will move back to community-based care, and what this care should be.
Whether or not the person is medically stable, within 1 month of admission review with them, their parents or carers (as appropriate) and the referring team, whether inpatient care should be continued or stepped down to a less intensive setting.
As part of the review:
assess whether enough progress has been made towards the objectives agreed at admission
agree a schedule for further reviews, with reviews happening at least monthly
take into account the risk that people with an eating disorder can become institutionalised by a long admission, and that a lack of change in their condition could indicate that inpatient treatment is harmful
consider seeking an independent second opinion if healthcare professionals have different views about the benefit of continued inpatient care.
# Using the Mental Health Act and compulsory treatment
If a person's physical health is at serious risk due to their eating disorder, they do not consent to treatment, and they can only be treated safely in an inpatient setting, follow the legal framework for compulsory treatment in the Mental Health Act 1983.
If a child or young person lacks capacity, their physical health is at serious risk and they do not consent to treatment, ask their parents or carers to consent on their behalf and if necessary, use an appropriate legal framework for compulsory treatment (such as the Mental Health Act 1983/2007 or the Children Act 1989).
Feeding people without their consent should only be done by multidisciplinary teams who are competent to do so.
# Terms used in this guideline
## Children
Aged 0 to 12 years.
## Young people
Aged 13 to 17 years.
## Adults
Aged 18 years and over.# Context
Eating disorders are defined by the negative beliefs and behaviours they cause people to have about themselves and their eating, body shape and weight. They can cause people to adopt restricted eating, binge eating and compensatory behaviours (such as vomiting and excessive exercise). The emotional and physical consequences of these beliefs and behaviours maintain the disorder and result in a high mortality rate from malnutrition, suicide and physical issues (such as electrolyte imbalances). This is most common in people with anorexia nervosa. There are also other physical complications (such as osteoporosis) and psychiatric comorbidities (such as anxiety disorders) that affect the wellbeing and recovery of people with an eating disorder and raise the cost of treatment.
Using figures for UK hospital admissions from 2012 to 2013, the eating disorders charity BEAT estimated that there were over 725,000 people with an eating disorder in the UK, approximately 90% of whom were female. However, recent community-based epidemiological studies suggest that as many as 25% of people with an eating disorder are male. Eating disorders most commonly start in adolescence, but can also start during childhood or adulthood. About 15% of people with an eating disorder have anorexia nervosa, which is also more common in younger people. Most people with an eating disorder meet diagnostic criteria for bulimia nervosa, binge eating disorder, or other specified feeding and eating disorder (OSFED). Each disorder is associated with poor quality of life, social isolation, and a substantial impact for family members and carers. Eating disorders are long-lasting conditions if they are not treated.
This guideline covers identifying, assessing, diagnosing, treating and managing eating disorders in people of all ages. It does not cover avoidant/restrictive food intake disorder (ARFID), pica, rumination disorder, or obesity in people who do not have an eating disorder. The guideline makes recommendations for different stages of the care process on identifying eating disorders, ensuring patient safety, supporting people with an eating disorder and their family members and carers, and ensuring people have access to evidence-based care. Given the high level of physical complications and psychological comorbidities, recommendations on care cover both physical care and psychological interventions. The guideline applies to all settings in which NHS care is provided, and to settings in which eating disorders might be identified.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Psychological treatments for binge eating disorder
Compare the clinical and cost effectiveness of individual eating-disorder-focused cognitive behavioural therapy (CBT‑ED) with guided self-help and group CBT‑ED for adults with binge eating disorder.
Compare the clinical and cost effectiveness of individual eating-disorder-focused CBT‑ED with guided self-help and group CBT‑ED for children and young people with binge eating disorder.
## Why this is important
There is little evidence on psychological treatments for people with binge eating disorder. The studies that have been published have not always provided remission outcomes or adequate definitions of remission. While there is some evidence for guided self-help and individual CBT‑ED, only 1 study was identified for individual CBT‑ED and no remission data were available. It is also unclear if individual CBT‑ED is more effective than guided self-help or group CBT‑ED (especially for people that find these treatments ineffective).
There is also no evidence on treatments for children and very little for young people. One study was found on individual CBT‑ED for young people, but only 26 participants were included in the data for remission. Randomised controlled trials should be carried out to compare the clinical and cost effectiveness of psychological treatments for adults, children and young people with binge eating disorder. In adults, the treatment should focus on the effectiveness of individual CBT‑ED compared with guided self-help and group CBT‑ED. For children and young people, the efficacy of eating disorder-focused family therapy could also be compared with individual CBT‑ED and different kinds of self-help (such as internet self-help or guided self-help). Primary outcome measures could include:
remission
binge eating
compensatory behaviours.
There should be at least a 1‑year follow up. Qualitative data could also be collected on the service user's and (if appropriate) their family members' or carers' experience of the treatment. Mediating and moderating factors that have an effect on treatment effectiveness should also be measured, so that treatment barriers can be addressed and positive factors can be promoted.
# Duration and intensity of psychological treatment
What is the effectiveness of treating eating disorders with psychological treatments of reduced duration and reduced intensity, compared with standard treatment?
## Why is this important
The psychological treatments currently recommended consist of a high number of sessions (typically between 20 and 40) delivered over a long period of time. Attending a high number of sessions is a major commitment for a person with an eating disorder and a large cost for services. People may be able to achieve remission with a smaller number of sessions or over a shorter period of time.
Randomised controlled trials of the psychological treatments recommended in this guideline should be carried out to compare whether a reduced number of sessions or a less intensive course is as effective as the recommended number. Primary outcome measures could include:
remission
binge eating
compensatory behaviours
weight or body mass index (BMI; for studies of anorexia nervosa).
There should be at least a 1‑year follow up. Mediating and moderating factors that have an effect on treatment effectiveness should also be measured, so that treatment barriers can be addressed and positive factors can be promoted.
# Predictors of acute physical risk
What clinical and biochemical markers are the best predictors of acute physical risk for people with eating disorders?
## Why this is important
Medical conditions such as bradycardia, hypotension and hypothermia are common in people who are underweight because of an eating disorder. Key markers of medical instability due to underweight such as pulse rate, blood pressure, and degree of underweight are commonly used as indications of risk in people with eating disorders. A number of internationally used risk frameworks are based on these markers and are important in decision making for people with eating disorders (in particular when deciding whether to admit someone, whether to use compulsory care, and how to provide nutrition). The medical markers of acute risk are used throughout this guideline.
Despite their importance, almost all of the conventional risk frameworks are based on consensus with little validation. There is also a shortage of information on the physical factors most associated with mortality in eating disorders. Validated tools (such as Acute Physiology and Chronic Health Evaluation scores) are central to risk prediction in other areas of medical care, and it would be very useful to have a tool like this for eating disorders. Research is therefore needed to validate the range of individual clinical and biochemical markers, both individually and collectively, as predictors for physical harm (including death).
# Treating an eating disorder in people with a comorbidity
What is the impact of comorbidities on treatment outcomes for eating disorders, and what approaches are effective in managing these comorbidities?
## Why this is important
People with an eating disorder often have physical comorbidities (such as diabetes) or mental health comorbidities (such as substance abuse, self-harm or obsessive-compulsive disorder). However, there is little evidence on which treatments work best for people with an eating disorder and a comorbidity. A modified eating disorder therapy that addresses both conditions may avoid the need for different types of therapy (either in parallel or one after the other). Alternatively, a comorbidity may be severe enough that it needs addressing before treating the eating disorder, or treatment solely for the eating disorder may help with the comorbidity.
This is a complex area and likely to depend on the severity of the comorbidity and the eating disorder. There is limited evidence and randomised controlled trials are needed. For example, a trial could randomise people with an eating disorder and the same comorbidity (such as type 1 diabetes) to either a modified eating disorder therapy or a non-modified eating disorder therapy. Primary outcome measures may include:
remission
binge eating
compensatory behaviours
weight or BMI (for studies of anorexia nervosa)
critical outcomes relating to the specific comorbidity.
There should be at least a 1‑year follow up. Mediating and moderating factors that have an effect on treatment effectiveness should also be measured, so that treatment barriers can be addressed and positive factors can be promoted.
# Maintaining benefits after successful treatment of anorexia nervosa
What factors (including comorbidities, personal, social and demographic factors, treatment type, and subsequent relapse prevention interventions) are associated with continued benefit after successful treatment for anorexia nervosa?
## Why this is important
There is a wide range of treatments available for anorexia nervosa. However, they are often ineffective, and even when they are successful there is a high risk of relapse. It is not clear which factors reduce the risk of relapse after successful treatment, or what benefit people receive from further treatment to prevent relapse. There is also little evidence on effective relapse prevention strategies for people in remission.
A series of studies should be done to identify the factors associated with an enduring response to treatment, and to test interventions specifically aimed at preventing relapse in people in remission. Primary outcome measures may include:
time to relapse
weight or BMI.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.\n\nIn this guideline, 'family members' includes the siblings, children and partners of people with an eating disorder.\n\n# General principles of care\n\n## Improving access to services\n\nBe aware that people with an eating disorder may:\n\nfind it difficult or distressing to discuss it with healthcare professionals, staff and other service users\n\nbe vulnerable to stigma and shame\n\nneed information and interventions tailored to their age and level of development.\n\nEnsure that all people with an eating disorder and their parents or carers (as appropriate) have equal access to treatments (including through self-referral) for eating disorders, regardless of:\n\nage\n\ngender or gender identity (including people who are transgender)\n\nsexual orientation\n\nsocioeconomic status\n\nreligion, belief, culture, family origin or ethnicity\n\nwhere they live and who they live with\n\nany physical or other mental health problems or disabilities.\n\nHealthcare professionals assessing people with an eating disorder (especially children and young people) should be alert throughout assessment and treatment to signs of bullying, teasing, abuse (emotional, physical and sexual) and neglect. For guidance on when to suspect child maltreatment, see the NICE guideline on child maltreatment.\n\n## Communication and information\n\nWhen assessing a person with a suspected eating disorder, find out what they and their family members or carers (as appropriate) know about eating disorders and address any misconceptions.\n\nOffer people with an eating disorder and their family members or carers (as appropriate) education and information on:\n\nthe nature and risks of the eating disorder and how it is likely to affect them\n\nthe treatments available and their likely benefits and limitations.\n\nWhen communicating with people with an eating disorder and their family members or carers (as appropriate):\n\nbe sensitive when discussing a person's weight and appearance\n\nbe aware that family members or carers may feel guilty and responsible for the eating disorder\n\nshow empathy, compassion and respect\n\nprovide information in a format suitable for them, and check they understand it.\n\nEnsure that people with an eating disorder and their parents or carers (as appropriate) understand the purpose of any meetings and the reasons for sharing information about their care with others.\n\n## Support for people with an eating disorder\n\nAssess the impact of the home, education, work and wider social environment (including the internet and social media) on each person's eating disorder. Address their emotional, education, employment and social needs throughout treatment.\n\nIf appropriate, encourage family members, carers, teachers, and peers of children and young people to support them during their treatment.\n\n## Working with family members and carers\n\nBe aware that the family members or carers of a person with an eating disorder may experience severe distress. Offer family members or carers assessments of their own needs as treatment progresses (see the NICE guideline on supporting adult carers), including:\n\nwhat impact the eating disorder has on them and their mental health\n\nwhat support they need, including practical support and emergency plans if the person with the eating disorder is at high medical or psychiatric risk.\n\nIf appropriate, provide written information for family members or carers who do not attend assessment or treatment meetings with the person with an eating disorder.\n\n## Consent and confidentiality\n\nWhen working with people with an eating disorder and their family members or carers (as appropriate):\n\nhold discussions in places where confidentiality, privacy and dignity can be respected\n\nexplain the limits of confidentiality (that is, which professionals and services have access to information about their care and when this may be shared with others).\n\nWhen seeking consent for assessments or treatments for children or young people under\xa016, respect Gillick competence (see the Department of Health and Social Care reference guide) if they consent and do not want their family members or carers involved.\n\n## Training and competencies\n\nProfessionals who assess and treat people with an eating disorder should be competent to do this for the age groups they care for.\n\nHealth, social care and education professionals working with people with an eating disorder should be trained and skilled in:\n\nnegotiating and working with family members and carers\n\nmanaging issues around information sharing and confidentiality\n\nsafeguarding\n\nworking with multidisciplinary teams.\n\nBase the content, structure and duration of psychological treatments on relevant manuals that focus on eating disorders.\n\nProfessionals who provide treatments for eating disorders should:\n\nreceive appropriate clinical supervision\n\nuse standardised outcome measures, for example, the Eating Disorder Examination Questionnaire (EDE‑Q)\n\nmonitor their competence (for example, by using recordings of sessions, and external audit and scrutiny)\n\nmonitor treatment adherence in people who use their service.\n\n## Coordination of care for people with an eating disorder\n\nTake particular care to ensure services are well coordinated when:\n\na young person moves from children's to adult services (see the NICE guideline on transition from children's to adults' services)\n\nmore than one service is involved (such as inpatient and outpatient services, child and family services, or when a comorbidity is being treated by a separate service)\n\npeople need care in different places at different times of the year (for example, university students).\n\n# Identification and assessment\n\nPeople with eating disorders should be assessed and receive treatment at the earliest opportunity.\n\nEarly treatment is particularly important for those with or at risk of severe emaciation and such patients should be prioritised for treatment.\n\n## Initial assessments in primary and secondary mental healthcare\n\nBe aware that eating disorders present in a range of settings, including:\n\nprimary and secondary healthcare (including acute hospitals)\n\nsocial care\n\neducation\n\nwork.\n\nAlthough eating disorders can develop at any age, be aware that the risk is highest for young men and women between 13\xa0and 17\xa0years of age.\n\nDo not use screening tools (for example, SCOFF) as the sole method to determine whether or not people have an eating disorder.\n\nWhen assessing for an eating disorder or deciding whether to refer people for assessment, take into account any of the following that apply:\n\nan unusually low or high body mass index (BMI) or body weight for their age\n\nrapid weight loss\n\ndieting or restrictive eating practices (such as dieting when they are underweight) that are worrying them, their family members or carers, or professionals\n\nfamily members or carers report a change in eating behaviour\n\nsocial withdrawal, particularly from situations that involve food\n\nother mental health problems\n\na disproportionate concern about their weight or shape (for example, concerns about weight gain as a side effect of contraceptive medication)\n\nproblems managing a chronic illness that affects diet, such as diabetes or coeliac disease\n\nmenstrual or other endocrine disturbances, or unexplained gastrointestinal symptoms\n\nphysical signs of:\n\n\n\nmalnutrition, including poor circulation, dizziness, palpitations, fainting or pallor\n\ncompensatory behaviours, including laxative or diet pill misuse, vomiting or excessive exercise\n\n\n\nabdominal pain that is associated with vomiting or restrictions in diet, and that cannot be fully explained by a medical condition\n\nunexplained electrolyte imbalance or hypoglycaemia\n\natypical dental wear (such as erosion)\n\nwhether they take part in activities associated with a high risk of eating disorders (for example, professional sport, fashion, dance, or modelling).\n\nBe aware that, in addition to the points in recommendation\xa01.2.6, children and young people with an eating disorder may also present with faltering growth (for example, a low weight or height for their age) or delayed puberty.\n\nDo not use single measures such as BMI or duration of illness to determine whether to offer treatment for an eating disorder.\n\nProfessionals in primary and secondary mental health or acute settings should assess the following in people with a suspected eating disorder:\n\ntheir physical health, including checking for any physical effects of malnutrition or compensatory behaviours such as vomiting\n\nthe presence of mental health problems commonly associated with eating disorders, including depression, anxiety, self-harm and obsessive-compulsive disorder\n\nthe possibility of alcohol or substance misuse\n\nthe need for emergency care in people whose physical health is compromised or who have a suicide risk.\n\n## Referral\n\nIf an eating disorder is suspected after an initial assessment, refer immediately to a community-based, age-appropriate eating disorder service for further assessment or treatment.\n\n# Treating anorexia nervosa\n\nProvide support and care for all people with anorexia nervosa in contact with specialist services, whether or not they are having a specific intervention. Support should:\n\ninclude psychoeducation about the disorder\n\ninclude monitoring of weight, mental and physical health, and any risk factors\n\nbe multidisciplinary and coordinated between services\n\ninvolve the person's family members or carers (as appropriate).\n\nWhen treating anorexia nervosa, be aware that:\n\nhelping people to reach a healthy body weight or BMI for their age is a key goal and\n\nweight gain is key in supporting other psychological, physical and quality of life changes that are needed for improvement or recovery.\n\nWhen weighing people with anorexia nervosa, consider sharing the results with them and (if appropriate) their family members or carers.\n\n## Psychological treatment for anorexia nervosa in adults\n\nFor adults with anorexia nervosa, consider one of:\n\nindividual eating-disorder-focused cognitive behavioural therapy (CBT‑ED)\n\nMaudsley Anorexia Nervosa Treatment for Adults (MANTRA)\n\nspecialist supportive clinical management (SSCM). Explain to the person what the treatments involve to help them choose which they would prefer.\n\nIndividual CBT‑ED programmes for adults with anorexia nervosa should:\n\ntypically consist of up to 40\xa0sessions over 40\xa0weeks, with twice-weekly sessions in the first 2\xa0or\xa03\xa0weeks\n\naim to reduce the risk to physical health and any other symptoms of the eating disorder\n\nencourage healthy eating and reaching a healthy body weight\n\ncover nutrition, cognitive restructuring, mood regulation, social skills, body image concern, self-esteem, and relapse prevention\n\ncreate a personalised treatment plan based on the processes that appear to be maintaining the eating problem\n\nexplain the risks of malnutrition and being underweight\n\nenhance self-efficacy\n\ninclude self-monitoring of dietary intake and associated thoughts and feelings\n\ninclude homework, to help the person practice in their daily life what they have learned.\n\nMANTRA for adults with anorexia nervosa should:\n\ntypically consist of 20\xa0sessions, with:\n\n\n\nweekly sessions for the first 10\xa0weeks, and a flexible schedule after this\n\nup to 10\xa0extra sessions for people with complex problems\n\n\n\nbase treatment on the MANTRA workbook\n\nmotivate the person and encourage them to work with the practitioner\n\nbe flexible in how the modules of MANTRA are delivered and emphasised\n\nwhen the person is ready, cover nutrition, symptom management, and behaviour change\n\nencourage the person to develop a 'non-anorexic identity'\n\ninvolve family members or carers to help the person:\n\n\n\nunderstand their condition and the problems it causes and the link to the wider social context\n\nchange their behaviour.\n\n\n\nSSCM for adults with anorexia nervosa should:\n\ntypically consist of 20\xa0or more weekly sessions (depending on severity)\n\nassess, identify, and regularly review key problems\n\naim to develop a positive relationship between the person and the practitioner\n\naim to help people recognise the link between their symptoms and their abnormal eating behaviour\n\naim to restore weight\n\nprovide psychoeducation, and nutritional education and advice\n\ninclude physical health monitoring\n\nestablish a weight range goal\n\nencourage reaching a healthy body weight and healthy eating\n\nallow the person to decide what else should be included as part of their therapy.\n\nIf individual CBT‑ED, MANTRA or SSCM is unacceptable, contraindicated or ineffective for adults with anorexia nervosa, consider:\n\none of these 3\xa0treatments that the person has not had before or\n\neating-disorder-focused focal psychodynamic therapy (FPT).\n\nFPT for adults with anorexia nervosa should:\n\ntypically consist of up to 40\xa0sessions over 40\xa0weeks\n\nmake a patient-centred focal hypothesis that is specific to the individual and addresses:\n\n\n\nwhat the symptoms mean to the person\n\nhow the symptoms affect the person\n\nhow the symptoms influence the person's relationships with others and with the therapist\n\n\n\nin the first phase, focus on developing the therapeutic alliance between the therapist and person with anorexia nervosa, addressing pro-anorexic behaviour and ego-syntonic beliefs (beliefs, values and feelings consistent with the person's sense of self) and building self-esteem\n\nin the second phase, focus on relevant relationships with other people and how these affect eating behaviour\n\nin the final phase, focus on transferring the therapy experience to situations in everyday life and address any concerns the person has about what will happen when treatment ends.\n\n## Psychological treatment for anorexia nervosa in children and young people\n\nConsider anorexia-nervosa-focused family therapy for children and young people (FT‑AN), delivered as single-family therapy or a combination of single- and multi-family therapy. Give children and young people the option to have some single-family sessions:\n\nseparately from their family members or carers and\n\ntogether with their family members or carers.\n\nFT‑AN for children and young people with anorexia nervosa should:\n\ntypically consist of 18\xa0to 20\xa0sessions over 1\xa0year\n\nreview the needs of the person 4\xa0weeks after treatment begins and then every 3\xa0months, to establish how regular sessions should be and how long treatment should last\n\nemphasise the role of the family in helping the person to recover\n\nnot blame the person or their family members or carers\n\ninclude psychoeducation about nutrition and the effects of malnutrition\n\nearly in treatment, support the parents or carers to take a central role in helping the person manage their eating, and emphasise that this is a temporary role\n\nin the first phase, aim to establish a good therapeutic alliance with the person, their parents or carers and other family members\n\nin the second phase, support the person (with help from their parents or carers) to establish a level of independence appropriate for their level of development\n\nin the final phase:\n\n\n\nfocus on plans for when treatment ends (including any concerns the person and their family have) and on relapse prevention\n\naddress how the person can get support if treatment is stopped.\n\n\n\nConsider support for family members who are not involved in the family therapy, to help them cope with distress caused by the condition.\n\nConsider giving children and young people with anorexia nervosa additional appointments separate from their family members or carers.\n\nAssess whether family members or carers (as appropriate) need support if the child or young person with anorexia nervosa is having therapy on their own.\n\nIf FT‑AN is unacceptable, contraindicated or ineffective for children or young people with anorexia nervosa, consider individual CBT‑ED or adolescent-focused psychotherapy for anorexia nervosa (AFP‑AN).\n\nIndividual CBT‑ED for children and young people with anorexia nervosa should:\n\ntypically consist of up to 40\xa0sessions over 40\xa0weeks, with:\n\n\n\ntwice-weekly sessions in the first 2\xa0or\xa03\xa0weeks\n\nto 12\xa0additional brief family sessions with the person and their parents or carers (as appropriate)\n\n\n\nin family sessions and in individual sessions, include psychoeducation about nutrition and the effects of malnutrition\n\nin family sessions:\n\n\n\nidentify anything in the person's home life that could make it difficult for them to change their behaviour, and find ways to address this\n\ndiscuss meal plans\n\n\n\naim to reduce the risk to physical health and any other symptoms of the eating disorder\n\nencourage reaching a healthy body weight and healthy eating\n\ncover nutrition, relapse prevention, cognitive restructuring, mood regulation, social skills, body image concern and self-esteem\n\ncreate a personalised treatment plan based on the processes that appear to be maintaining the eating problem\n\ntake into account the person's specific development needs\n\nexplain the risks of malnutrition and being underweight\n\nenhance self-efficacy\n\ninclude self-monitoring of dietary intake and associated thoughts and feelings\n\ninclude homework, to help the person practice what they have learned in their daily life\n\naddress how the person can get support if treatment is stopped.\n\nAFP‑AN for children and young people should:\n\ntypically consist of 32\xa0to 40\xa0individual sessions over 12\xa0to 18\xa0months, with:\n\n\n\nmore regular sessions early on, to help the person build a relationship with the practitioner and motivate them to change their behaviour\n\nto 12\xa0additional family sessions with the person and their parents or carers (as appropriate)\n\n\n\nreview the needs of the person 4\xa0weeks after treatment begins and then every 3\xa0months, to establish how regular sessions should be and how long treatment should last\n\nin family sessions and in individual sessions, include psychoeducation about nutrition and the effects of malnutrition\n\nfocus on the person's self-image, emotions and interpersonal processes, and how these affect their eating disorder\n\ndevelop a formulation of the person's psychological issues and how they use anorexic behaviour as a coping strategy\n\naddress fears about weight gain, and emphasise that weight gain and healthy eating is a critical part of therapy\n\nfind alternative strategies for the person to manage stress\n\nin later stages of treatment, explore issues of identity and build independence\n\ntowards end of treatment, focus on transferring the therapy experience to situations in everyday life\n\nin family sessions, help parents or carers support the person to change their behaviour\n\naddress how the person can get support if treatment is stopped.\n\n## People with anorexia nervosa who are not having treatment\n\nFor people with anorexia who are not having treatment (for example, because it has not helped or because they have declined it) and who do not have severe or complex problems:\n\ndischarge them to primary care\n\ntell them they can ask their GP to refer them again for treatment at any time.\n\nFor people with anorexia who have declined or do not want treatment and who have severe or complex problems, eating disorder services should provide support as covered in the recommendation on providing support and care in the section on treating anorexia nervosa.\n\n## Dietary advice for people with anorexia nervosa\n\nOnly offer dietary counselling as part of a multidisciplinary approach.\n\nEncourage people with anorexia nervosa to take an age-appropriate oral multi-vitamin and multi-mineral supplement until their diet includes enough to meet their dietary reference values.\n\nInclude family members or carers (as appropriate) in any dietary education or meal planning for children and young people with anorexia nervosa who are having therapy on their own.\n\nOffer supplementary dietary advice to children and young people with anorexia nervosa and their family or carers (as appropriate) to help them meet their dietary needs for growth and development (particularly during puberty).\n\n## Medication for anorexia nervosa\n\nDo not offer medication as the sole treatment for anorexia nervosa.\n\n# Treating binge eating disorder\n\n## Psychological treatment for binge eating disorder in adults\n\nExplain to people with binge eating disorder that psychological treatments aimed at treating binge eating have a limited effect on body weight and that weight loss is not a therapy target in itself. Refer to the NICE guideline on obesity identification, assessment and management for guidance on weight loss and bariatric surgery.\n\nOffer a binge-eating-disorder-focused guided self-help programme to adults with binge eating disorder.\n\nBinge-eating-disorder-focused guided self-help programmes for adults should:\n\nuse cognitive behavioural self-help materials\n\nfocus on adherence to the self-help programme\n\nsupplement the self-help programme with brief supportive sessions (for example, 4\xa0to\xa09\xa0sessions lasting 20\xa0minutes each over 16\xa0weeks, running weekly at first)\n\nfocus exclusively on helping the person follow the programme.\n\nIf guided self-help is unacceptable, contraindicated, or ineffective after 4\xa0weeks, offer group eating-disorder-focused cognitive behavioural therapy (CBT‑ED).\n\nGroup CBT‑ED programmes for adults with binge eating disorder should:\n\ntypically consist of 16\xa0weekly 90‑minute group sessions over 4\xa0months\n\nfocus on psychoeducation, self-monitoring of the eating behaviour and helping the person analyse their problems and goals\n\ninclude making a daily food intake plan and identifying binge eating cues\n\ninclude body exposure training and helping the person to identify and change negative beliefs about their body\n\nhelp with avoiding relapses and coping with current and future risks and triggers.\n\nIf group CBT‑ED is not available or the person declines it, consider individual CBT‑ED for adults with binge eating disorder.\n\nIndividual CBT‑ED for adults with binge eating disorder should:\n\ntypically consist of 16\xa0to 20\xa0sessions\n\ndevelop a formulation of the person's psychological issues, to determine how dietary and emotional factors contribute to their binge eating\n\nbased on the formulation:\n\n\n\nadvise people to eat regular meals and snacks to avoid feeling hungry\n\naddress the emotional triggers for their binge eating, using cognitive restructuring, behavioural experiments and exposure\n\n\n\ninclude weekly monitoring of binge eating behaviours, dietary intake and weight\n\nshare the weight record with the person\n\naddress body-image issues if present\n\nexplain to the person that although CBT‑ED does not aim at weight loss, stopping binge eating can have this effect in the long term\n\nadvise the person not to try to lose weight (for example, by dieting) during treatment, because this is likely to trigger binge eating.\n\n## Psychological treatment for binge eating disorder in children and young people\n\nFor children and young people with binge eating disorder, offer the same treatments recommended for adults with binge eating disorder.\n\n## Medication for binge eating disorder\n\nDo not offer medication as the sole treatment for binge eating disorder.\n\n# Treating bulimia nervosa\n\nExplain to all people with bulimia nervosa that psychological treatments have a limited effect on body weight.\n\n## Psychological treatment for bulimia nervosa in adults\n\nConsider bulimia-nervosa-focused guided self-help for adults with bulimia nervosa.\n\nBulimia-nervosa-focused guided self-help programmes for adults with bulimia nervosa should:\n\nuse cognitive behavioural self-help materials for eating disorders\n\nsupplement the self-help programme with brief supportive sessions (for example, 4\xa0to 9\xa0sessions lasting 20\xa0minutes each over 16\xa0weeks, running weekly at first).\n\nIf bulimia-nervosa-focused guided self-help is unacceptable, contraindicated, or ineffective after 4\xa0weeks of treatment, consider individual eating-disorder-focused cognitive behavioural therapy (CBT‑ED).\n\nIndividual CBT‑ED for adults with bulimia nervosa should:\n\ntypically consist of up to 20\xa0sessions over 20\xa0weeks, and consider twice-weekly sessions in the first phase\n\nin the first phase focus on:\n\n\n\nengagement and education\n\nestablishing a pattern of regular eating, and providing encouragement, advice and support while people do this\n\n\n\nfollow by addressing the eating disorder psychopathology (for example, the extreme dietary restraint, the concerns about body shape and weight, and the tendency to binge eat in response to difficult thoughts and feelings)\n\ntowards the end of treatment, spread appointments further apart and focus on maintaining positive changes and minimising the risk of relapse\n\nif appropriate, involve significant others to help with one-to-one treatment.\n\n## Psychological treatment for bulimia nervosa in children and young people\n\nOffer bulimia-nervosa-focused family therapy (FT‑BN) to children and young people with bulimia nervosa.\n\nFT-BN for children and young people with bulimia nervosa should:\n\ntypically consist of 18\xa0to 20\xa0sessions over 6\xa0months\n\nestablish a good therapeutic relationship with the person and their family members or carers\n\nsupport and encourage the family to help the person recover\n\nnot blame the person, their family members or carers\n\ninclude information about:\n\n\n\nregulating body weight\n\ndieting\n\nthe adverse effects of attempting to control weight with self-induced vomiting, laxatives or other compensatory behaviours\n\n\n\nuse a collaborative approach between the parents and the young person to establish regular eating patterns and minimise compensatory behaviours\n\ninclude regular meetings with the person on their own throughout the treatment\n\ninclude self-monitoring of bulimic behaviours and discussions with family members or carers\n\nin later phases of treatment, support the person and their family members or carers to establish a level of independence appropriate for their level of development\n\nin the final phase of treatment, focus on plans for when treatment ends (including any concerns the person and their family have) and on relapse prevention.\n\nConsider support for family members who are not involved in the family therapy, to help them to cope with distress caused by the condition.\n\nIf FT-BN is unacceptable, contraindicated or ineffective, consider individual eating-disorder-focused cognitive behavioural therapy (CBT‑ED) for children and young people with bulimia nervosa.\n\nIndividual CBT‑ED for children and young people with bulimia nervosa should:\n\ntypically consist of 18\xa0sessions over 6\xa0months, with more frequent sessions early in treatment\n\ninclude up to 4\xa0additional sessions with parents or carers\n\ninitially focus on the role bulimia nervosa plays in the person's life and on building motivation to change\n\nprovide psychoeducation about eating disorders and how symptoms are maintained, while encouraging the person to gradually establish regular eating habits\n\ndevelop a case formulation with the person\n\nteach the person to monitor their thoughts, feelings and behaviours\n\nset goals and encourage the person to address problematic thoughts, beliefs and behaviours with problem-solving\n\nuse relapse prevention strategies to prepare for and mitigate potential future setbacks\n\nin sessions with parents and carers, provide education about eating disorders, identify family factors that stop the person from changing their behaviour, and discuss how the family can support the person's recovery.\n\n## Medication for bulimia nervosa\n\nDo not offer medication as the sole treatment for bulimia nervosa.\n\n# Treating other specified feeding and eating disorders (OSFED)\n\nFor people with OSFED, consider using the treatments for the eating disorder it most closely resembles.\n\n# Physical therapy for any eating disorder\n\nDo not offer a physical therapy (such as transcranial magnetic stimulation, acupuncture, weight training, yoga or warming therapy) as part of the treatment for eating disorders.\n\n# Physical and mental health comorbidities\n\nEating disorder specialists and other healthcare teams should collaborate to support effective treatment of physical or mental health comorbidities in people with an eating disorder.\n\nWhen collaborating, teams should use outcome measures for both the eating disorder and the physical and mental health comorbidities, to monitor the effectiveness of treatments for each condition and the potential impact they have on each other.\n\n## Diabetes\n\nFor people with an eating disorder and diabetes, the eating disorder and diabetes teams should:\n\ncollaborate to explain the importance of physical health monitoring to the person\n\nagree who has responsibility for monitoring physical health\n\ncollaborate on managing mental and physical health comorbidities\n\nuse a low threshold for monitoring blood glucose and blood ketones\n\nuse outcome measurements to monitor the effectiveness of treatments for each condition and the potential impact they have on each other.\n\nWhen treating eating disorders in people with diabetes:\n\nexplain to the person (and if needed their diabetes team) that they may need to monitor their blood glucose and blood ketones more closely during treatment\n\nconsider involving their family members and carers (as appropriate) in treatment to help them with blood glucose control.\n\nAddress insulin misuse as part of any psychological treatment for eating disorders in people with diabetes.\n\nOffer people with an eating disorder who are misusing insulin the following treatment plan:\n\na gradual increase in the amount of carbohydrates in their diet (if medically safe), so that insulin can be started at a lower dose\n\na gradual increase in insulin doses to avoid a rapid drop in blood glucose levels, which can increase the risk of retinopathy and neuropathy\n\nadjusted total glycaemic load and carbohydrate distribution to meet their individual needs and prevent rapid weight gain\n\npsychoeducation about the problems caused by misuse of diabetes medication\n\ndiabetes educational interventions, if the person has any gaps in their knowledge.\n\nFor people with suspected hypoglycaemia, test blood glucose:\n\nbefore all supervised meals and snacks\n\nwhen using the hypoglycaemia treatment algorithm\n\nafter correction doses.\n\nFor people with suspected hyperglycaemia or hypoglycaemia, and people with normal blood glucose levels who are misusing insulin, healthcare professionals should test for blood ketones:\n\nwhen using the hypoglycaemia treatment algorithm\n\nafter correction doses.\n\nFor people with bulimia nervosa and diabetes, consider monitoring of:\n\nglucose toxicity\n\ninsulin resistance\n\nketoacidosis\n\noedema.\n\nWhen diabetes control is challenging:\n\ndo not attempt to rapidly treat hyperglycaemia (for example, with increased insulin doses), because this increases the risk of retinopathy and neuropathy\n\nregularly monitor blood potassium levels\n\ndo not stop insulin altogether, because this puts the person at high risk of diabetic ketoacidosis.\n\nSee the NICE guidelines on type 1 and type 2 diabetes in children and young people, type 1 diabetes in adults and type 2 diabetes in adults for more guidance on:\n\nfluid replacement in children and young people with diabetic ketoacidosis\n\ninsulin therapy, insulin delivery (including rotating injection sites within the same body region) and insulin dosage adjustment. [2017, amended 2020]\n\n## Comorbid mental health problems\n\nWhen deciding which order to treat an eating disorder and a comorbid mental health condition (in parallel, as part of the same treatment plan or one after the other), take the following into account:\n\nthe severity and complexity of the eating disorder and comorbidity\n\nthe person's level of functioning\n\nthe preferences of the person with the eating disorder and (if appropriate) those of their family members or carers.\n\nRefer to the NICE guidelines on specific mental health problems for further guidance on treatment.\n\n## Medication risk management\n\nWhen prescribing medication for people with an eating disorder and comorbid mental or physical health conditions, take into account the impact malnutrition and compensatory behaviours can have on medication effectiveness and the risk of side effects.\n\nWhen prescribing for people with an eating disorder and a comorbidity, assess how the eating disorder will affect medication adherence (for example, for medication that can affect body weight).\n\nWhen prescribing for people with an eating disorder, take into account the risks of medication that can compromise physical health due to pre-existing medical complications.\n\nOffer electrocardiogram (ECG) monitoring for people with an eating disorder who are taking medication that could compromise cardiac functioning (including medication that could cause electrolyte imbalance, bradycardia below 40\xa0beats per minute, hypokalaemia, or a prolonged QT interval).\n\n## Substance or medication misuse\n\nFor people with an eating disorder who are misusing substances, or over the counter or prescribed medication, provide treatment for the eating disorder unless the substance misuse is interfering with this treatment.\n\nIf substance misuse or medication is interfering with treatment, consider a multidisciplinary approach with substance misuse services.\n\n## Growth and development\n\nSeek specialist paediatric or endocrinology advice for delayed physical development or faltering growth in children and young people with an eating disorder.\n\n# Conception and pregnancy for women with eating disorders\n\nProvide advice and education to women with an eating disorder who plan to conceive, to increase the likelihood of conception and to reduce the risk of miscarriage. This may include information on the importance of:\n\nmaintaining good mental health and wellbeing\n\nensuring adequate nutrient intake and a healthy body weight\n\nstopping behaviours such as binge eating, vomiting, laxatives and excessive exercise.\n\nNominate a dedicated professional (such as a GP or midwife) to monitor and support pregnant women with an eating disorder during pregnancy and in the post-natal period, because of:\n\nconcerns they may have specifically about gaining weight\n\npossible health risks to the mother and child\n\nthe high risk of mental health problems in the perinatal period.\n\nFor women who are pregnant or in the perinatal period and have an eating disorder:\n\noffer treatment for their eating disorder as covered in the sections on treating anorexia nervosa, treating binge eating disorder, treating bulimia nervosa and treating other specified feeding and eating disorders (OSFED)\n\nprovide monitoring and education as recommended in the section on psychological interventions for eating disorders in the NICE guideline on antenatal and postnatal mental health.\n\nFor guidance on providing advice to pregnant women about healthy eating and feeding their baby, see the NICE guideline on maternal and child nutrition.\n\nConsider more intensive prenatal care for pregnant women with current or remitted anorexia nervosa, to ensure adequate prenatal nutrition and fetal development.\n\n# Physical health assessment, monitoring and management for eating disorders\n\n## Physical health assessment and monitoring for all eating disorders\n\nAssess fluid and electrolyte balance in people with an eating disorder who are believed to be engaging in compensatory behaviours, such as vomiting, taking laxatives or diuretics, or water loading.\n\nAssess whether ECG monitoring is needed in people with an eating disorder, based on the following risk factors:\n\nrapid weight loss\n\nexcessive exercise\n\nsevere purging behaviours, such as laxative or diuretic use or vomiting\n\nbradycardia\n\nhypotension\n\nexcessive caffeine (including from energy drinks)\n\nprescribed or non-prescribed medications\n\nmuscular weakness\n\nelectrolyte imbalance\n\nprevious abnormal heart rhythm.\n\n## Management for all eating disorders\n\nProvide acute medical care (including emergency admission) for people with an eating disorder who have severe electrolyte imbalance, severe malnutrition, severe dehydration or signs of incipient organ failure.\n\nFor people with an eating disorder who need supplements to restore electrolyte balance, offer these orally unless the person has problems with gastrointestinal absorption or the electrolyte disturbance is severe.\n\nFor people with an eating disorder and continued unexplained electrolyte imbalance, assess whether it could be caused by another condition.\n\nEncourage people with an eating disorder who are vomiting to:\n\nhave regular dental and medical reviews\n\navoid brushing teeth immediately after vomiting\n\nrinse with non‑acid mouthwash after vomiting\n\navoid highly acidic foods and drinks.\n\nAdvise people with an eating disorder who are misusing laxatives or diuretics:\n\nthat laxatives and diuretics do not reduce calorie absorption and so do not help with weight loss\n\nto gradually reduce and stop laxative or diuretic use.\n\nAdvise people with an eating disorder who are exercising excessively to stop doing so.\n\nFor guidance on identifying, assessing and managing overweight and obesity, see the NICE guideline on obesity.\n\n## Assessment and monitoring of physical health in anorexia nervosa\n\nGPs should offer a physical and mental health review at least annually to people with anorexia nervosa who are not receiving ongoing treatment for their eating disorder. The review should include:\n\nweight or BMI (adjusted for age if appropriate)\n\nblood pressure\n\nrelevant blood tests\n\nany problems with daily functioning\n\nassessment of risk (related to both physical and mental health)\n\nan ECG, for people with purging behaviours and/or significant weight changes\n\na discussion of treatment options.\n\nMonitor growth and development in children and young people with anorexia nervosa who have not completed puberty (for example, not reached menarche or final height).\n\n## Low bone mineral density in people with anorexia nervosa\n\nBone mineral density results should be interpreted and explained to people with anorexia nervosa by a professional with the knowledge and competencies to do this.\n\nBefore deciding whether to measure bone density, discuss with the person and their family members or carers why it could be useful.\n\nExplain to people with anorexia nervosa that the main way of preventing and treating low bone mineral density is reaching and maintaining a healthy body weight or BMI for their age.\n\nConsider a bone mineral density scan:\n\nafter 1\xa0year of underweight in children and young people, or earlier if they have bone pain or recurrent fractures\n\nafter 2\xa0years of underweight in adults, or earlier if they have bone pain or recurrent fractures.\n\nUse measures of bone density that correct for bone size (such as bone mineral apparent density [BMAD]) in children and young people with faltering growth.\n\nConsider repeat bone mineral density scans in people with ongoing persistent underweight, especially when using or deciding whether to use hormonal treatment.\n\nDo not repeat bone mineral density scans for people with anorexia nervosa more frequently than once per year, unless they develop bone pain or recurrent fractures.\n\nDo not routinely offer oral or transdermal oestrogen therapy to treat low bone mineral density in children or young people with anorexia nervosa.\n\nSeek specialist paediatric or endocrinological advice before starting any hormonal treatment for low bone mineral density. Coordinate any treatment with the eating disorders team.\n\nConsider transdermal 17‑β‑estradiol (with cyclic progesterone) for young women (13\xa0to 17\xa0years) with anorexia nervosa who have long-term low body weight and low bone mineral density with a bone age over\xa015.\n\nConsider incremental physiological doses of oestrogen in young women (13\xa0to 17\xa0years) with anorexia nervosa who have delayed puberty, long-term low body weight and low bone mineral density with a bone age under\xa015.\n\nConsider bisphosphonates for women (18\xa0years and over) with anorexia nervosa who have long-term low body weight and low bone mineral density. Discuss the benefits and risks (including risk of teratogenic effects) with women before starting treatment.\n\nAdvise people with anorexia nervosa and osteoporosis or related bone disorders to avoid high-impact physical activities and activities that significantly increase the chance of falls or fractures.\n\nFor guidance on osteoporosis risk assessment, see the NICE guideline on assessing the risk of fragility fractures in osteoporosis.\n\n# Inpatient and day patient treatment\n\nAdmit people with an eating disorder whose physical health is severely compromised to a medical inpatient or day patient service for medical stabilisation and to initiate refeeding, if these cannot be done in an outpatient setting.\n\nDo not use an absolute weight or BMI threshold when deciding whether to admit people with an eating disorder to day patient or inpatient care.\n\nWhen deciding whether day patient or inpatient care is most appropriate, take the following into account:\n\nThe person's BMI or weight, and whether these can be safely managed in a day patient service or whether the rate of weight loss (for example, more than 1\xa0kg a week) means they need inpatient care.\n\nWhether inpatient care is needed to actively monitor medical risk parameters such as blood tests, physical observations and ECG (for example, bradycardia below 40\xa0beats per minute or a prolonged QT interval) that have values or rates of change in the concern or alert ranges: refer to box\xa01 in the Royal College of Psychiatrists' resource on management of really sick patients with anorexia nervosa (MARSIPAN), or Guidance\xa01 and\xa02 in the junior MARSIPAN report.\n\nThe person's current physical health and whether this is significantly declining.\n\nWhether the parents or carers of children and young people can support them and keep them from significant harm as a day patient.\n\nWhen reviewing the need for inpatient care as part of an integrated treatment programme for a person with an eating disorder:\n\ndo not use inpatient care solely to provide psychological treatment for eating disorders\n\ndo not discharge people solely because they have reached a healthy weight.\n\nFor people with an eating disorder and acute mental health risk (such as significant suicide risk), consider psychiatric crisis care or psychiatric inpatient care.\n\nChildren, young people and adults with an eating disorder who are admitted to day patient or inpatient care should be cared for in age-appropriate facilities (for example, paediatric wards or adolescent mental health services). These should be near to their home, and have the capacity to provide appropriate educational activities during extended admissions.\n\nWhen a person is admitted to inpatient care for medical stabilisation, specialist eating disorder or liaison psychiatry services should:\n\nkeep in contact with the inpatient team to advise on care and management, both during the admission and when planning discharge\n\nkeep the person's family members or carers involved\n\nconsider starting or continuing psychological treatments for the eating disorder.\n\nInpatient or day patient services should collaborate with other teams (including the community team) and the person's family members or carers (as appropriate), to help with treatment and transition.\n\n## Refeeding\n\nEnsure that staff of day patient, inpatient, or acute services who treat eating disorders are trained to recognise the symptoms of refeeding syndrome and how to manage it.\n\nUse a standard operating procedure for refeeding that emphasises the need to avoid under-nutrition and refeeding syndrome. Refer to existing national guidance, such as the Royal College of Psychiatrists' MARSIPAN resource and the junior MARSIPAN report.\n\n## Care planning and discharge from inpatient care\n\nDevelop a care plan for each person with an eating disorder who is admitted to inpatient care. The care plan should:\n\ngive clear objectives and outcomes for the admission\n\nbe developed in collaboration with the person, their family members or carers (as appropriate), and the community-based eating disorder service\n\nset out how they will be discharged, how they will move back to community-based care, and what this care should be.\n\nWhether or not the person is medically stable, within 1\xa0month of admission review with them, their parents or carers (as appropriate) and the referring team, whether inpatient care should be continued or stepped down to a less intensive setting.\n\nAs part of the review:\n\nassess whether enough progress has been made towards the objectives agreed at admission\n\nagree a schedule for further reviews, with reviews happening at least monthly\n\ntake into account the risk that people with an eating disorder can become institutionalised by a long admission, and that a lack of change in their condition could indicate that inpatient treatment is harmful\n\nconsider seeking an independent second opinion if healthcare professionals have different views about the benefit of continued inpatient care.\n\n# Using the Mental Health Act and compulsory treatment\n\nIf a person's physical health is at serious risk due to their eating disorder, they do not consent to treatment, and they can only be treated safely in an inpatient setting, follow the legal framework for compulsory treatment in the Mental Health Act\xa01983.\n\nIf a child or young person lacks capacity, their physical health is at serious risk and they do not consent to treatment, ask their parents or carers to consent on their behalf and if necessary, use an appropriate legal framework for compulsory treatment (such as the Mental Health Act\xa01983/2007 or the Children Act\xa01989).\n\nFeeding people without their consent should only be done by multidisciplinary teams who are competent to do so.\n\n# Terms used in this guideline\n\n## Children\n\nAged 0\xa0to 12\xa0years.\n\n## Young people\n\nAged 13\xa0to 17\xa0years.\n\n## Adults\n\nAged 18\xa0years and over.", 'Context': 'Eating disorders are defined by the negative beliefs and behaviours they cause people to have about themselves and their eating, body shape and weight. They can cause people to adopt restricted eating, binge eating and compensatory behaviours (such as vomiting and excessive exercise). The emotional and physical consequences of these beliefs and behaviours maintain the disorder and result in a high mortality rate from malnutrition, suicide and physical issues (such as electrolyte imbalances). This is most common in people with anorexia nervosa. There are also other physical complications (such as osteoporosis) and psychiatric comorbidities (such as anxiety disorders) that affect the wellbeing and recovery of people with an eating disorder and raise the cost of treatment.\n\nUsing figures for UK hospital admissions from 2012 to 2013, the eating disorders charity BEAT estimated that there were over 725,000\xa0people with an eating disorder in the UK, approximately 90% of whom were female. However, recent community-based epidemiological studies suggest that as many as 25% of people with an eating disorder are male. Eating disorders most commonly start in adolescence, but can also start during childhood or adulthood. About 15% of people with an eating disorder have anorexia nervosa, which is also more common in younger people. Most people with an eating disorder meet diagnostic criteria for bulimia nervosa, binge eating disorder, or other specified feeding and eating disorder (OSFED). Each disorder is associated with poor quality of life, social isolation, and a substantial impact for family members and carers. Eating disorders are long-lasting conditions if they are not treated.\n\nThis guideline covers identifying, assessing, diagnosing, treating and managing eating disorders in people of all ages. It does not cover avoidant/restrictive food intake disorder (ARFID), pica, rumination disorder, or obesity in people who do not have an eating disorder. The guideline makes recommendations for different stages of the care process on identifying eating disorders, ensuring patient safety, supporting people with an eating disorder and their family members and carers, and ensuring people have access to evidence-based care. Given the high level of physical complications and psychological comorbidities, recommendations on care cover both physical care and psychological interventions. The guideline applies to all settings in which NHS care is provided, and to settings in which eating disorders might be identified.', 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Psychological treatments for binge eating disorder\n\nCompare the clinical and cost effectiveness of individual eating-disorder-focused cognitive behavioural therapy (CBT‑ED) with guided self-help and group CBT‑ED for adults with binge eating disorder.\n\nCompare the clinical and cost effectiveness of individual eating-disorder-focused CBT‑ED with guided self-help and group CBT‑ED for children and young people with binge eating disorder.\n\n## Why this is important\n\nThere is little evidence on psychological treatments for people with binge eating disorder. The studies that have been published have not always provided remission outcomes or adequate definitions of remission. While there is some evidence for guided self-help and individual CBT‑ED, only 1\xa0study was identified for individual CBT‑ED and no remission data were available. It is also unclear if individual CBT‑ED is more effective than guided self-help or group CBT‑ED (especially for people that find these treatments ineffective).\n\nThere is also no evidence on treatments for children and very little for young people. One study was found on individual CBT‑ED for young people, but only 26\xa0participants were included in the data for remission. Randomised controlled trials should be carried out to compare the clinical and cost effectiveness of psychological treatments for adults, children and young people with binge eating disorder. In adults, the treatment should focus on the effectiveness of individual CBT‑ED compared with guided self-help and group CBT‑ED. For children and young people, the efficacy of eating disorder-focused family therapy could also be compared with individual CBT‑ED and different kinds of self-help (such as internet self-help or guided self-help). Primary outcome measures could include:\n\nremission\n\nbinge eating\n\ncompensatory behaviours.\n\nThere should be at least a 1‑year follow up. Qualitative data could also be collected on the service user's and (if appropriate) their family members' or carers' experience of the treatment. Mediating and moderating factors that have an effect on treatment effectiveness should also be measured, so that treatment barriers can be addressed and positive factors can be promoted.\n\n# Duration and intensity of psychological treatment\n\nWhat is the effectiveness of treating eating disorders with psychological treatments of reduced duration and reduced intensity, compared with standard treatment?\n\n## Why is this important\n\nThe psychological treatments currently recommended consist of a high number of sessions (typically between 20\xa0and\xa040) delivered over a long period of time. Attending a high number of sessions is a major commitment for a person with an eating disorder and a large cost for services. People may be able to achieve remission with a smaller number of sessions or over a shorter period of time.\n\nRandomised controlled trials of the psychological treatments recommended in this guideline should be carried out to compare whether a reduced number of sessions or a less intensive course is as effective as the recommended number. Primary outcome measures could include:\n\nremission\n\nbinge eating\n\ncompensatory behaviours\n\nweight or body mass index (BMI; for studies of anorexia nervosa).\n\nThere should be at least a 1‑year follow up. Mediating and moderating factors that have an effect on treatment effectiveness should also be measured, so that treatment barriers can be addressed and positive factors can be promoted.\n\n# Predictors of acute physical risk\n\nWhat clinical and biochemical markers are the best predictors of acute physical risk for people with eating disorders?\n\n## Why this is important\n\nMedical conditions such as bradycardia, hypotension and hypothermia are common in people who are underweight because of an eating disorder. Key markers of medical instability due to underweight such as pulse rate, blood pressure, and degree of underweight are commonly used as indications of risk in people with eating disorders. A number of internationally used risk frameworks are based on these markers and are important in decision making for people with eating disorders (in particular when deciding whether to admit someone, whether to use compulsory care, and how to provide nutrition). The medical markers of acute risk are used throughout this guideline.\n\nDespite their importance, almost all of the conventional risk frameworks are based on consensus with little validation. There is also a shortage of information on the physical factors most associated with mortality in eating disorders. Validated tools (such as Acute Physiology and Chronic Health Evaluation [APACHE] scores) are central to risk prediction in other areas of medical care, and it would be very useful to have a tool like this for eating disorders. Research is therefore needed to validate the range of individual clinical and biochemical markers, both individually and collectively, as predictors for physical harm (including death).\n\n# Treating an eating disorder in people with a comorbidity\n\nWhat is the impact of comorbidities on treatment outcomes for eating disorders, and what approaches are effective in managing these comorbidities?\n\n## Why this is important\n\nPeople with an eating disorder often have physical comorbidities (such as diabetes) or mental health comorbidities (such as substance abuse, self-harm or obsessive-compulsive disorder). However, there is little evidence on which treatments work best for people with an eating disorder and a comorbidity. A modified eating disorder therapy that addresses both conditions may avoid the need for different types of therapy (either in parallel or one after the other). Alternatively, a comorbidity may be severe enough that it needs addressing before treating the eating disorder, or treatment solely for the eating disorder may help with the comorbidity.\n\nThis is a complex area and likely to depend on the severity of the comorbidity and the eating disorder. There is limited evidence and randomised controlled trials are needed. For example, a trial could randomise people with an eating disorder and the same comorbidity (such as type\xa01 diabetes) to either a modified eating disorder therapy or a non-modified eating disorder therapy. Primary outcome measures may include:\n\nremission\n\nbinge eating\n\ncompensatory behaviours\n\nweight or BMI (for studies of anorexia nervosa)\n\ncritical outcomes relating to the specific comorbidity.\n\nThere should be at least a 1‑year follow up. Mediating and moderating factors that have an effect on treatment effectiveness should also be measured, so that treatment barriers can be addressed and positive factors can be promoted.\n\n# Maintaining benefits after successful treatment of anorexia nervosa\n\nWhat factors (including comorbidities, personal, social and demographic factors, treatment type, and subsequent relapse prevention interventions) are associated with continued benefit after successful treatment for anorexia nervosa?\n\n## Why this is important\n\nThere is a wide range of treatments available for anorexia nervosa. However, they are often ineffective, and even when they are successful there is a high risk of relapse. It is not clear which factors reduce the risk of relapse after successful treatment, or what benefit people receive from further treatment to prevent relapse. There is also little evidence on effective relapse prevention strategies for people in remission.\n\nA series of studies should be done to identify the factors associated with an enduring response to treatment, and to test interventions specifically aimed at preventing relapse in people in remission. Primary outcome measures may include:\n\ntime to relapse\n\nweight or BMI."}
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https://www.nice.org.uk/guidance/ng69
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This guideline covers assessment, treatment, monitoring and inpatient care for children, young people and adults with eating disorders. It aims to improve the care people receive by detailing the most effective treatments for anorexia nervosa, binge eating disorder and bulimia nervosa.
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