Heart failure with preserved ejection fraction (HFPEF) This group of patients with heart failure have a left ventricular ejection fraction greater than 50%, o no alternative cause for the syndrome, o the presence of a non-dilated left ventricle; evidence of structural remodelling (left ventricular hypertrophy or dilated left atrium); or diastolic dysfunction through imaging o and have abnormal biomarkers. The GDG recognises that the two terms HFREF and HFPEF have several limitations. These include the variability of the left ventricular ejection fraction measured by different imaging modalities, and the lack of universal agreement on the threshold of ejection fraction at which these are defined or the exact definition of HFPEF. The GDG also recognised the proposal of another class as heart failure with mid-range ejection fraction (HFMREF). This proposal has not been fully clinically validated and remains the topic of further research 150, 354 . The GDG reviewed the available biomarkers for diagnosis of heart failure. Assays for both B-type natriuretic peptide (BNP) and NT-pro-BNP are commonly available. Other biomarkers have been identified but their utility is unclear. It considered that any marker chosen should be widely available, have an extensive evidence base, and good performance characteristics including high stability in patient samples given transfer times between primary care and central laboratory facilities. Though current practice favours the use of biomarkers for diagnosis rather than monitoring their future use cannot be predicted. Thus, the ability to interconvert between assays based on the same biomarker and the ability to clearly define baseline levels to allow long-term management by monitoring would be prudent to maintain. After consideration of the available assays222 , their performance and and recent publications that inform the rest of the guideline the GDG decided that NT-proBNP should be the favoured biomarker as it was more commonly used, more stable, did not require additional laboratory specimens for ideal performance248 and did not suffer from potential confounding of interpretation by novel therapies (e.g. sacubitril-valsartan)303 . Chronic Heart Failure Introduction NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 2.5 Rationale for the update This guideline is a partial update of NICE Guideline No 108: Chronic Heart Failure in adults . The 2010 guidelines offered advice on best practice for the care of adult patients (aged 18 years or older) who have symptoms or a diagnosis of chronic heart failure. Since and North American374 guidelines, based on new high-quality evidence from randomised controlled trials in diagnosis, treatment and monitoring have been published. A partial update of the existing NICE guideline is necessary to ensure that the recommendations take into account the new evidence available. Diagnosis of heart failure depends on clinical symptoms and signs with imaging usually echocardiography - and increasingly laboratory measured biomarkers such as natriuretic peptides (chapter 5). Technological progress has led to availability of further imaging technologies e.g. cardiac magnetic resonance imaging (chapter 5) and biomarkers which might be used in diagnosis or for monitoring the efficacy and titration of therapies (chapter 8). The National Heart Failure audit highlights the roles that beta-blocker (chapter 6) and mineralocorticoid receptor antagonist (MRA) therapy (chapter 6) are playing in management of heart failure. The evidence base for these treatments has increased over the last 10 years. Despite the high prevalence of ischaemic heart disease in patients with heart failure the role of coronary intervention in patients with heart failure remains unclear (chapter 6). The high incidence of iron deficiency and anaemia in patients with heart failure has prompted trials of iron therapy in heart failure (chapter 6). Patients with co-morbidities have a worse prognosis and some co-morbidities such as atrial fibrillation (chapter 6) or chronic kidney disease can influence the management of heart failure (chapter 6). Non-pharmacological interventions also have a substantial and under-recognised role to play in the management of heart failure. Evidence has accumulated for better outcomes in patients receiving care from cardiology services including specialist heart failure nurses (chapter 9) and in those able to access rehabilitation (chapter 7). The increasing move of complex care from hospital to primary care places a greater emphasis on communication and processes for transition of care (chapter 9) and the ability to manage symptomatic relief in community settings (chapter 10). Developments in information technology and in the use of telephone-based and direct telemonitoring technologies have the potential to further improve delivery of care (chapter 8) 241 . Heart failure is a progressive condition but access to palliative care services remains patchy, with unclear referral criteria (chapter 10), unclear policies on deactivation of implanted devices (chapter 10) and on the use of ancillary therapies such as diuretic regimes (chapter 10) or domiciliary oxygen (chapter 10). The guideline update is intended for use by the following people or organisations: All healthcare professionals People with chronic heart failure and their carers Patient support groups Commissioning organisations Service providers Chronic Heart Failure Development of the guideline NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 3 Development of the guideline 3.1 What is a NICE guideline? NICE guidelines are recommendations for the care of individuals in specific clinical conditions or circumstances within the NHS from prevention and self-care through primary and secondary care to more specialised services. These may also include elements of social care or public health measures. We base our guidelines on the best available research evidence, with the aim of improving the quality of healthcare. We use predetermined and systematic methods to identify and evaluate the evidence relating to specific review questions. NICE guidelines can: provide recommendations for the treatment and care of people by health professionals be used to develop standards to assess the clinical practice of individual health professionals be used in the education and training of health professionals help patients to make informed decisions improve communication between patient and health professional. While guidelines assist the practice of healthcare professionals, they do not replace their knowledge and skills. We produce our guidelines using the following steps: A guideline topic is referred to NICE from NHS England. Stakeholders register an interest in the guideline and are consulted throughout the development process. The scope is prepared by the National Guideline Centre (NGC). The NGC establishes a guideline committee. A draft guideline is produced after the group assesses the available evidence and makes recommendations. There is a consultation on the draft guideline. The final guideline is produced. The NGC and NICE produce a number of versions of this guideline: The full guideline contains all the recommendations, plus details of the methods used and the underpinning evidence. The NICE guideline lists the recommendations. NICE Pathways brings together all connected NICE guidance. This version is the full version. The other versions can be downloaded from NICE at www.nice.org.uk. NICE received the remit for this guideline from NHS England. NICE commissioned the NGC to produce the guideline. The remit for this guideline is: To develop a clinical guideline on the management of chronic heart failure in adults in primary and secondary care. Chronic Heart Failure Development of the guideline NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 3.3 Who developed this guideline? A multidisciplinary guideline committee comprising health professionals and researchers as well as lay members developed this guideline (see the list of guideline committee members and the acknowledgements). The National Institute for Health and Care Excellence (NICE) funds the National Guideline Centre (NGC) and thus supported the development of this guideline. The committee was convened by the NGC and chaired by Anthony Wierzbicki in accordance with guidance from NICE. The group met approximately every 6 weeks during the development of the guideline. At the start of the guideline development process all committee members declared interests including consultancies, fee-paid work, shareholdings, fellowships and support from the healthcare industry. At all subsequent committee meetings, members declared arising conflicts of interest. Members were either required to withdraw completely or for part of the discussion if their declared interest made it appropriate. The details of declared interests and the actions taken are shown in appendix L. Staff from the NGC provided methodological support and guidance for the development process. The team working on the guideline included a project manager, systematic reviewers (research fellows), health economists and information specialists. They undertook systematic searches of the literature, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate and drafted the guideline in collaboration with the committee. 3.3.1 What this guideline covers Groups that will be covered Adults (18 and over) with symptoms or a diagnosis of chronic heart failure (including heart failure with reduced ejection fraction and heart failure with preserved ejection fraction). Areas from the published guideline that will be updated Diagnosing heart failure. o Role of circulating biomarkers (including natriuretic peptides). o Echocardiography and cardiac MRI. Managing chronic heart failure. o Initiation and sequencing of pharmacological therapies including: Isosorbide/hydralazine. Angiotensin-II receptor antagonists (ARBs). Mineralocorticoid receptor antagonists o Fluid balance (optimum fluid and salt intake). Rehabilitation (including Home-based rehabilitation packages that include an exercise element). Monitoring heart failure. o Role of biomarkers (including natriuretic peptides). o Role of echocardiography. o Distance monitoring including telemonitoring. o Self-monitoring. Referral for invasive procedures: o Coronary revascularisation (including coronary artery bypass graft and angioplasty). Chronic Heart Failure Development of the guideline NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Referral and approach to care. o Heart failure multidisciplinary team. o Transfer of care between secondary and primary care services. Information and support. o Information and support on diagnosis and prognosis for people with chronic heart failure, their families and carers. Supportive and palliative care. o Domiciliary oxygen therapy. o Parenteral and intravenous diuretics. o Criteria for withdrawing treatment and device inactivation. Areas not in the published guideline that will be included in the update How to manage chronic heart failure in different subgroups: o People with iron deficiency. o People with chronic kidney disease (estimated glomerular filtration rate [eGFR] less than with or without markers of kidney damage). o People with chronic heart failure and secondary atrial fibrillation. o People aged over 75. Pharmacological therapies. o Beta-blockers in people with chronic heart failure and secondary atrial fibrillation. Palliative care. o Referral to palliative care. o Delivery of diuretics Monitoring heart failure. o Role of cardiac MRI. For further details please refer to the scope in appendix L and the review questions in section 4.1. 3.3.2 What this guideline does not cover Areas from the published guideline that will not be updated Symptoms and signs in diagnosing heart failure. Clinical review and monitoring of serum digoxin. Lifestyle. o Sexual activity, vaccination and air travel. Areas from the published guideline that will be removed General. o Age. o Gender. Pharmacological agents. o Aspirin. Chronic Heart Failure Development of the guideline NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 o Statins. Heart failure caused by valve disease. Management of depression and anxiety. Benefit of other therapies such as homeopathy, reflexology, hydrotherapy, crystal therapy and acupuncture. Referral for invasive procedures. o Implantable cardiac defibrillators. Valve surgery. Non-NHS agencies. Lifestyle. o Smoking and alcohol. 3.3.3 Relationships between the guideline and other NICE guidance NICE guidance that will be updated by this guideline: Chronic heart failure in in adults: management (2010) NICE guidline CG108 NICE technology appraisals to be incorporated in this guidance: Ivabradine for treating chronic heart failure (2012) NICE technology appraisal guidance 267. Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction (2016) NICE technology appraisal [TA388] Related NICE technology appraisals: Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure (2014) NICE technology appraisal guidance [TA314] Related NICE intervenetional procedures guidance Subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death Related NICE guidelines: Medicines optimisation (2015) NICE guideline NG5 Patient experience in adult NHS services (2012) NICE guideline CG138 Medicines adherence (2009) NICE guideline CG76 Acute heart failure: diagnosis and management (2014) Nice guideline [CG187] Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 This chapter sets out in detail the methods used to review the evidence and to develop the recommendations that are presented in subsequent chapters of this guideline. This guidance was developed in accordance with the methods outlined in the NICE guidelines manual, 2014 version.236 Sections 4.1 to 4.3 describe the process used to identify and review clinical evidence (summarised in Figure 3), sections 4.2 and 4.4 describe the process used to identify and review the health economic evidence, and section 4.5 describes the process used to develop recommendations. Figure 3: Step-by-step process of review of evidence in the guideline 4.1 Developing the review questions and outcomes Review questions were developed using a PICO framework (population, intervention, comparison and outcome) for intervention reviews; using a framework of population, index tests, reference standard and target condition for reviews of diagnostic test accuracy; using population, presence or absence of factors under investigation (for example prognostic factors) and outcomes for prognostic reviews; and using a framework of population, setting and context for qualitative reviews. This use of a framework guided the literature searching process, critical appraisal and synthesis of evidence, and facilitated the development of recommendations by the guideline committee. The review questions were drafted by the NGC technical team and refined and validated by the committee. The questions were based on the key clinical areas identified in the scope (appendix L). A total of 26 review questions were identified. Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Full literature searches, critical appraisals and evidence reviews were completed for all the specified review questions. Table 1: Review questions Chapter Type of review Review questions Outcomes 5 Diagnostic In people with suspected heart failure, what thresholds of pro-B-type natriuretic peptide (NT-proBNP) and B- type natriuretic peptide (BNP) are most accurate in identifying heart failure (as indicated by the reference standard)? Diagnostic accuracy of BNP and NT-proBNP: 2x2 tables Specificity Sensitivity PPV/NPV ROC curve or Area under Curve 5 Diagnostic RCT In people with suspected heart failure, what is the clinical and cost effectiveness of N-terminus pro-B-type natriuretic peptide (NT-proBNP) compared to B-type natriuretic peptide (BNP), when each is followed by the appropriate patient pathway, in order to improve patient outcomes? Efficacy outcomes: All-cause mortality Quality of life Unplanned hospitalisation Process outcomes: Number of people receiving echocardiography, i.e., including people who may not have needed it such as those with false positive results Repeat testing / additional testing Secondary accuracy outcomes: Sensitivity / specificity and other test accuracy measures 5 Diagnostic In people with suspected heart failure who also have atrial fibrillation, what thresholds of N-terminus pro-B-type natriuretic peptide (NT-proBNP) and B- type natriuretic peptide (BNP) are most accurate in identifying heart failure (as indicated by the reference standard)? Diagnostic accuracy of BNP and NT-proBNP: 2x2 tables Specificity Sensitivity PPV/NPV ROC curve or Area under Curve 5 Diagnostic RCT In people with suspected heart failure who also have atrial fibrillation, what is the clinical and cost effectiveness of N- terminus pro-B-type natriuretic peptide (NT-proBNP) compared to B-type natriuretic peptide (BNP), when each is followed by the appropriate patient pathway, in order to improve patient outcomes? Efficacy outcomes: All-cause mortality Quality of life Unplanned hospitalisation Process outcomes: Number of people receiving echocardiography, i.e., including people who may not have needed it such as those with false positive results Repeat testing / additional testing Secondary accuracy outcomes: Sensitivity / specificity and other test accuracy measures 5 Diagnostic In people with suspected heart failure who also have chronic kidney disease, Diagnostic accuracy of BNP and NT-proBNP: Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Chapter Type of review Review questions Outcomes what thresholds of N-terminus pro-B- type natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) are most accurate in identifying heart failure (as indicated by the reference standard)? 2x2 tables Specificity Sensitivity PPV/NPV ROC curve or Area under Curve 5 Diagnostic RCT In people with suspected heart failure who also have chronic kidney disease, what is the clinical and cost effectiveness of N-terminus pro-B-type natriuretic peptide (NT-proBNP) compared to B-type natriuretic peptide (BNP), when each is followed by the appropriate patient pathway, in order to improve patient outcomes? Efficacy outcomes: All-cause mortality Quality of life Unplanned hospitalisation Process outcomes: Number of people receiving echocardiography, i.e., including people who may not have needed it such as those with false positive results Repeat testing / additional testing Secondary accuracy outcomes: Sensitivity / specificity and other test accuracy measures 5 Intervention In people with heart failure what is the clinical and cost effectiveness of cardiac MRI followed by the appropriate patient pathway? Critical outcomes: All-cause mortality (time to event) Health-related quality of life at 12 months (continuous) Unplanned hospitalisation (total number of events (rate ratio)) Important outcomes: Adverse events related to test (non-specific fibrosis in the presence of renal dysfunction) Reclassification of specific HF aetiology (including ability to classify previous unclassified patients) Change in management HF medication use HF advanced therapy use, including disease specific therapies Repeat testing / additional testing 6 Intervention What is the clinical and cost effectiveness of salt and/or fluid restriction in people with heart failure? Critical outcomes: Quality of life at 12 months (Continuous) Unplanned hospitalization (Count rate) Important outcomes: Change in weight at 12 months Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Chapter Type of review Review questions Outcomes (Continuous) Change in oedema at 12 months (Continuous) Change in sodium level (Continuous)(in the low baseline sodium strata only) Adverse events - Renal function at 12 months (Dichotomous) Adverse events - Hyperkalaemia at 12 months (Dichotomous) 6 Intervention What is the clinical and cost effectiveness of beta-blockers in the management of chronic heart failure in people with heart failure with reduced ejection fraction (HFREF) and atrial fibrillation? Critical outcomes: All-cause mortality Health-related quality of life Unplanned hospitalisation Important outcomes: Other adverse events (stroke, bradycardia, hypotension) Improvement of NYHA class 6 Intervention What is the clinical and cost effectiveness of mineralocorticoid receptor antagonists in people with heart failure with preserved ejection fraction? Critical outcomes: All-cause mortality Quality of life Unplanned hospitalisation Important outcomes: Improvement of NYHA class Adverse events - Renal function Adverse events Gynaecomastia Adverse events Hypotension Adverse events - Hyperkalaemia 6 Intervention What is the clinical and cost effectiveness of adding a mineralocorticoid receptor antagonist to existing standard first line treatment in people with heart failure with reduced ejection fraction? Critical outcomes: All-cause mortality Quality of life Unplanned hospitalisation Important outcomes: Improvement of NYHA class Adverse events - Renal function Adverse events Gynaecomastia Adverse events Hypotension Adverse events - Hyperkalaemia 6 Intervention What is the clinical and cost effectiveness of iron supplementation in people with chronic heart failure and iron deficiency? Critical outcomes: Mortality Quality of life Unplanned hospitalisation Important outcomes: Improvement in exercise Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Chapter Type of review Review questions Outcomes tolerance Change in haemoglobin in anaemic patients Withdrawal due to adverse events/tolerability Adverse events (hypertension, anaphylaxis/hypersensitivity, stroke, gastrointestinal) 6 Intervention What is the clinical and cost effectiveness of pharmacological interventions for heart failure in people with heart failure who also have chronic kidney disease? Critical outcomes: All-cause mortality Quality of life Unplanned hospitalization Important outcomes: Renal function Adverse events - Bradycardia Adverse events - Arrhythmic events Adverse events - Progression to stage five kidney disease / unplanned dialysis Adverse events - Hypotension Adverse events - Hyperkalaemia 6 Intervention What is the clinical and cost effectiveness of coronary revascularisation with coronary artery bypass grafting or angioplasty in people with heart failure? Critical outcomes: All-cause mortality at 30 days (Time to event) All-cause mortality (Time to event) Quality of life at 12 months (Continuous) Unplanned hospitalisation at 12 months (Count rate) Important outcomes: Additional revascularisation events at 24 months (Count rate) Improvement of NYHA class at 12 months (Dichotomous) Improvement in ejection fraction at 12 months (Dichotomous) Adverse events - stroke at 12 months (Dichotomous) 7 Intervention What is the clinical and cost effectiveness of home-based versus centre-based rehabilitation (that includes an exercise element) for people with heart failure (HF)? Critical outcomes: All-cause mortality CV mortality Health-related quality of life All cause hospitalisation HF-related hospitalisation Important outcomes: Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Chapter Type of review Review questions Outcomes Exercise capacity Adverse events (withdrawal from the exercise programme) Adherence (including maintenance of exercise/physical activity) Health service use 8 Intervention What is the clinical and cost effectiveness of biomarker-based monitoring, monitoring with cardiac MRI, and monitoring with repeated echocardiography in people with heart failure? Critical outcomes: Mortality (Time to event) Quality of life at 12 months (Continuous) Unplanned hospitalisation (all- cause) (Count rate) Important outcomes: Adverse events - hypotension (Dichotomous) Adverse events - hyperkalaemia (Dichotomous) Adverse events - renal function (Continuous) Adverse events - bradycardia (Dichotomous) Adverse events - arrhythmic events (Dichotomous) 8 Intervention What is the clinical and cost effectiveness of biomarker-based monitoring, monitoring with cardiac MRI, and monitoring with repeated echocardiography in people with heart failure who also have CKD? Critical outcomes: Mortality (Time to event) Quality of life at 12 months (Continuous) Unplanned hospitalisation (all- cause) (Count rate) Important outcomes: Adverse events - hypotension (Dichotomous) Adverse events - hyperkalaemia (Dichotomous) Adverse events - renal function (Continuous) Adverse events - bradycardia (Dichotomous) Adverse events - arrhythmic events (Dichotomous) 8 Intervention What is the clinical and cost effectiveness of biomarker-based monitoring, monitoring with cardiac MRI, and monitoring with repeated echocardiography in people with heart failure who also have atrial fibrillation? Critical outcomes: Mortality at during study (Time to event) Quality of life at 12 months (Continuous) Unplanned hospitalisation (all- cause) (Count rate) Important outcomes: Adverse events - hypotension Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Chapter Type of review Review questions Outcomes (Dichotomous) Adverse events - hyperkalaemia (Dichotomous) Adverse events - renal function (Continuous) Adverse events - bradycardia (Dichotomous) Adverse events - arrhythmic events (Dichotomous) 8 Intervention What is the clinical and cost effectiveness of telemonitoring and self- monitoring using telephone technology, compared with usual care, in people with heart failure? Critical outcomes: All-cause mortality during study (dichotomous) Quality of life during study (continuous) All-cause hospitalisations during study (dichotomous) Important outcomes: Adherence to intervention 9 Intervention What competencies should be present in the multidisciplinary teams involved in the outpatient or community-based care of people with heart failure? Critical outcomes: All-cause mortality (Time to event) Quality of life (Continuous) Unplanned hospitalisation (Count rate) Important outcomes: Medicine optimization and adherence Dying in preferred place of death (for palliative care patients) Adverse events hypotension, hyperkalaemia, and renal function Patient and carer experience 9 Qualitative What are the experiences/preferences of staff and patients during transition between different heart failure care settings (including primary, secondary and community care)? Thematic analysis- information synthesised into main review findings. 9 Qualitative What are the information and support needs to be considered when communication a diagnosis and consequent prognosis, to people with heart failure, their families and carers? Thematic analysis- information synthesised into main review findings. 10 Intervention Which route of administration of diuretics (intravenous (IV), subcutaneous or oral) is most clinically and cost effective in people with advanced heart failure who are in the community, including patients receiving Critical outcomes: Quality of life Unplanned hospitalization Important outcomes: Change in dyspnoea Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Chapter Type of review Review questions Outcomes palliative care? Weight change / change in oedema Change in NYHA class Patient and carer satisfaction Time to death (survival) Successful administration of intervention 10 Intervention What is the effectiveness of domiciliary oxygen therapy in people with advanced heart failure? Critical outcomes: Quality of life at 2 weeks (Continuous) Change in dyspnea at 2 weeks (Continuous) Unplanned hospitalization at 4 weeks (Count rate) Unplanned hospitalization at 4 weeks (number of bed days) Patient and carer satisfaction 2 weeks (Continuous) Important outcomes: Change in exercise capacity at 2 weeks (Continuous) Change in NYHA class at 2 weeks (Continuous) 10 Qualitative What criteria should determine when to discuss defibrillator deactivation? Thematic analysis- information synthesised into main review findings. 10 Prognostic In adults with heart failure, which validated risk tools best identify patients with heart failure who are at increased risk of mortality in the short term (up to 1 year)?In adults with heart failure, which validated risk tools best identify patients with heart failure who are at increased risk of mortality in the short term (up to 1 year)? Area under the ROC curve (AUC or c-statistic) Sensitivity, specificity, negative predictive value, positive predictive value Predicted risk versus observed risk (calibration) Other outcomes e.g., D statistic and Brier score Reclassification 4.2 Searching for evidence 4.2.1 Clinical literature search Systematic literature searches were undertaken to identify all published clinical evidence relevant to the review questions. Searches were undertaken according to the parameters stipulated within the NICE guidelines manual 2014.236 Databases were searched using relevant medical subject headings, free-text terms and study-type filters where appropriate. Where possible, searches were restricted to papers published in English. Studies published in languages other than English were not reviewed. All searches were conducted in Medline, Embase, and The Cochrane Library. Additional subject specific databases were used for the qualitative reviews: CINAHL and PsychINFO. All searches were updated on 06.12.17. No papers published after this date were considered. Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Search strategies were quality assured by cross-checking reference lists of highly relevant papers, analysing search strategies in other systematic reviews, and asking committee members to highlight any additional studies. Searches were quality assured by a second information specialist before being run. The questions, the study types applied, the databases searched and the years covered can be found in appendix N. The titles and abstracts of records retrieved by the searches were sifted for relevance, with potentially significant publications obtained in full text. These were assessed against the inclusion criteria. During the scoping stage, a search was conducted for guidelines and reports on the websites listed below from organisations relevant to the topic. Guidelines International Network database (www.g-i-n.net) National Guideline Clearing House (www.guideline.gov) National Institute for Health and Care Excellence (NICE) (www.nice.org.uk) National Institutes of Health Consensus Development Program (consensus.nih.gov) NHS Evidence Search (www.evidence.nhs.uk). Turning Research into Practice (TRIP (www.tripdatabase.com)) Royal College of General Practitioners (www.rcgp.org.uk) All references sent by stakeholders were considered. Searching for unpublished literature was not undertaken. The NGC and NICE do not have access to drug manufacturers unpublished clinical trial results, so the clinical evidence considered by the committee for pharmaceutical interventions may be different from that considered by the MHRA and European Medicines Agency for the purposes of licensing and safety regulation. 4.2.2 Health economic literature search Systematic literature searches were also undertaken to identify health economic evidence within published literature relevant to the review questions. The evidence was identified by conducting a broad search relating to heart failure in the NHS Economic Evaluation Database (NHS EED) and the Health Technology Assessment database (HTA) with no date restrictions (NHS EED ceased to be updated after March 2015). Additionally, the search was run on Medline and Embase using a health economic filter, from September 2009, to ensure recent publications that had not yet been indexed by the economic databases were identified. The quality of life search was run on Medline and Embase using a quality of life filter, from January 2002. Where possible, searches were restricted to papers published in English. Studies published in languages other than English were not reviewed. The health economic search strategies are included in appendix N. The general heart failure economic search was updated on 6 December 2017. No papers published after this date were considered. 4.3 Identifying and analysing evidence of effectiveness Research fellows conducted the tasks listed below, which are described in further detail in the rest of this section: Identified potentially relevant studies for each review question from the relevant search results by reviewing titles and abstracts. Full papers were then obtained. Reviewed full papers against prespecified inclusion and exclusion criteria to identify studies that addressed the review question in the appropriate population, and reported on outcomes of interest (review protocols are included in appendix A). Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Critically appraised relevant studies using the appropriate study design checklist as specified in the NICE guidelines manual.236 Prognostic studies were critically appraised using NGC checklists. Qualitative studies were critically appraised using the GRADE CERQual approach for rating confidence in the body of evidence as a whole and using an NGC checklist for the methodological limitations section of the quality assessment. Extracted key information about interventional study methods and results using Evibase , NGC s purpose-built software. Evibase produces summary evidence tables, including critical appraisal ratings. Key information about non-interventional study methods and results was manually extracted onto standard evidence tables and critically appraised separately (evidence tables are included in appendix F). Generated summaries of the evidence by outcome. Outcome data were combined, analysed and reported according to study design: o Randomised data were meta-analysed where appropriate and reported in GRADE profile tables. o Data from non-randomised studies were presented as a range of values in GRADE profile tables or meta-analysed if appropriate. o Prognostic data were meta-analysed where appropriate and reported in GRADE profile tables. o Diagnostic data studies were meta-analysed where appropriate or presented as a range of values in adapted GRADE profile tables o Qualitative data were synthesised across studies and presented as summary statements with accompanying GRADE CERQual ratings for each review finding. A sample of a minimum of 10% of the abstract lists of the first 3 sifts by new reviewers and those for complex review questions (for example, prognostic reviews) were double-sifted by a senior research fellow and any discrepancies were rectified. All of the evidence reviews were quality assured by a senior research fellow. This included checking: o papers were included or excluded appropriately o a sample of the data extractions o correct methods were used to synthesise data o a sample of the risk of bias assessments. 4.3.1 Inclusion and exclusion criteria The inclusion and exclusion of studies was based on the criteria defined in the review protocols, which can be found in appendix A. Excluded studies by review question (with the reasons for their exclusion) are listed in appendix I. The committee was consulted about any uncertainty regarding inclusion or exclusion. The key population inclusion criterion was: Adults (18 and older) with symptoms or a diagnosis of chronic heart failure (including heart failure with reduced ejection fraction and heart failure with preserved ejection fraction) The key population exclusion criterion was: Diagnostic screening for heart failure in people who are asymptomatic. People with isolated right heart failure. Heart failure in people having chemotherapy. Heart failure in people having treatment for HIV. Heart failure in women who are pregnant. Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Conference abstracts were not included in any of the reviews. Literature reviews, posters, letters, editorials, comment articles, unpublished studies and studies not in English were excluded. 4.3.1.1 Saturation of qualitative studies Data extraction in qualitative reviews is a thorough process and may require more time compared to intervention reviews. It is common practice to stop extracting data once saturation has been reached. This is the point when no new information emerges from studies that match the review protocol. The remaining identified studies are, however, not directly excluded from the review as they nevertheless fit the criteria defined in the review protocol. Any studies for which data were not extracted due to saturation having been reached, but that fit the inclusion criteria of the protocol, were listed in the table for studies identified but not included due to saturation in the appendix for the qualitative evidence review. 4.3.2 Type of studies Randomised trials, non-randomised intervention studies, and other observational studies (including diagnostic or prognostic studies) were included in the evidence reviews as appropriate. For most intervention reviews in this guideline, parallel randomised controlled trials (RCTs) were included because they are considered the most robust type of study design that can produce an unbiased estimate of the intervention effects. Crossover RCTs were not appropriate for any of the intervention reviews . In chronic conditions there is the possibility that the initial treatment permanently alters the disease or the process being investigated. The cardiac rehabilitation review was the exception where only data from the 1st period of cross-over trials was included, unless there was formal evidence of period effects in which case data from both 1st and 2nd periods was included. If non-randomised intervention studies were considered appropriate for inclusion (for example, in prognostic risk tool and diagnostic reviews) the committee stated a priori in the protocol that either certain identified variables must be equivalent at baseline or else the analysis had to adjust for any baseline differences. If the study did not fulfil either criterion it was excluded. Please refer to the review protocols in appendix A for full details on the study design of studies selected for each review question. For diagnostic review questions, diagnostic RCTs, cross-sectional studies and retrospective studies were included. For prognostic review questions, prospective and retrospective cohort studies were included. Case control studies were not included. Where data from non-randomised studies were included, the results for each outcome were presented separately for each study or meta-analysed if appropriate. 4.3.3 Methods of combining clinical studies 4.3.3.1 Data synthesis for intervention reviews Where possible, meta-analyses were conducted using Cochrane Review Manager (RevMan5)283 software to combine the data given in all studies for each of the outcomes of interest for the review question. For some questions stratification was used, and this is documented in the individual review question protocols (see appendix A). Analysis of different types of data Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Dichotomous outcomes Fixed-effects (Mantel-Haenszel) techniques were used to calculate risk ratios (relative risk, RR) for the binary outcomes, which included: All-cause mortality Cardiovascular mortality Unplanned hospitalisation HF related hospitalisation Adverse events (for example stroke, bradycardia, hypotension, arrhythmic events, hyperkalaemia) Change in NYHA class Change in management HF medication use HF advanced therapy use, including disease specific therapies Repeat testing or additional testing Additional revascularisation events Patient and carer satisfaction Successful administration of intervention Withdrawal due to adverse events/tolerability Medicine optimisation and adherence Dying in preferred place of death (for palliative care patients) Adherence to intervention Health service use The absolute risk difference was also calculated using GRADEpro138 software, using the median event rate in the control arm of the pooled results. For binary variables where there were zero events in either arm or a less than 1% event rate, Peto odds ratios, rather than risk ratios, were calculated. Peto odds ratios are more appropriate for data with a low number of events. Continuous outcomes Continuous outcomes were analysed using an inverse variance method for pooling weighted mean differences. These outcomes included: heath-related quality of life (HRQoL) Time to death Change in exercise capacity Improvement in exercise tolerance Change in haemoglobin in anaemic patients Improvement in ejection fraction Change in dyspnoea Weight change or change in oedema Change in sodium level Where the studies within a single meta-analysis had different scales of measurement, standardised mean differences were used (providing all studies reported either change from baseline or final values rather than a mixture of both); each different measure in each study was normalised to the Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 standard deviation value pooled between the intervention and comparator groups in that same study. The means and standard deviations of continuous outcomes are required for meta-analysis. However, in cases where standard deviations were not reported, the standard error was calculated if the p values or 95% confidence intervals (95% CI) were reported, and meta-analysis was undertaken with the mean and standard error using the generic inverse variance method in Cochrane Review software. Where p values were reported as less than , a conservative approach was undertaken. For example, if a p value was reported as p 0.001 , the calculations for standard deviations were based on a p value of 0.001. If these statistical measures were not available then the methods described in section 16.1.3 of the Cochrane Handbook (version 5.1.0, updated March 2011) were applied. 4.3.3.1.1 Generic inverse variance If a study reported only the summary statistic and 95% CI the generic-inverse variance method was used to enter data into RevMan5.283 If the control event rate was reported this was used to generate the absolute risk difference in GRADEpro.138 If multivariate analysis was used to derive the summary statistic but no adjusted control event rate was reported no absolute risk difference was calculated. Statistical heterogeneity was assessed for each meta-analysis estimate by considering the chi- squared test for significance at p<0.1 or an I-squared (I2 ) inconsistency statistic (with an I-squared value of more than 50% indicating significant heterogeneity) as well as the distribution of effects. Where significant heterogeneity was present, predefined subgrouping of studies was carried out as specified a priori in the review protocols (appendix A). If the subgroup analysis resolved heterogeneity within all of the derived subgroups, then each of the derived subgroups were adopted as separate outcomes (providing at least 1 study remained in each subgroup. Assessments of potential differences in effect between subgroups were based on the chi- squared tests for heterogeneity statistics between subgroups. Any subgroup differences were interpreted with caution as separating the groups breaks the study randomisation and as such is subject to uncontrolled confounding. For some questions additional subgrouping was applied, and this is documented in the individual review question protocols (see appendix A). These additional subgrouping strategies were applied independently, so subunits of subgroups were not created, unlike the situation with strata. Other subgrouping strategies were only used if the age category subgroup was unable to explain heterogeneity, then these further subgrouping strategies were applied in order of priority. Again, once a subgrouping strategy was found to explain heterogeneity from all derived subgroups, further subgrouping strategies were not used. If all predefined strategies of subgrouping were unable to explain statistical heterogeneity within each derived subgroup, then a random effects (DerSimonian and Laird) model was employed to the entire group of studies in the meta-analysis. A random-effects model assumes a distribution of populations, rather than a single population. This leads to a widening of the confidence interval around the overall estimate, thus providing a more realistic interpretation of the true distribution of effects across more than 1 population. If, however, the committee considered the heterogeneity was so large that meta-analysis was inappropriate, then the results were described narratively. 4.3.3.1.3 Complex analysis Where studies had used a crossover design, paired continuous data were extracted where possible, and forest plots were generated in RevMan5283 with the generic inverse variance function. When a crossover study had categorical data and the number of subjects with an event in both interventions Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 was known, the standard error (of the log of the risk ratio) was calculated using the simplified Mantel-Haenszel method for paired outcomes. Forest plots were also generated in RevMan5283 with the generic inverse variance function. If paired continuous or categorical data were not available from the crossover studies, the separate group data were analysed in the same way as data from parallel groups, on the basis that this approach would overestimate the confidence intervals and thus artificially reduce study weighting resulting in a conservative effect. Where a meta-analysis included a mixture of studies using both paired and parallel group approaches, all data were entered into using the generic inverse variance function. 4.3.3.2 Data synthesis for diagnostic test accuracy reviews Two separate review protocols were produced to reflect the 2 different diagnostic study designs. 4.3.3.2.1 Diagnostic RCTs Diagnostic RCTs (sometimes referred to as test and treat trials) are a randomised comparison of 2 diagnostic tests, with study outcomes being clinically important consequences of the diagnosis (patient-related outcome measures similar to those in intervention trials, such as mortality). Patients are randomised to receive test A or test B, followed by identical therapeutic interventions based on the results of the test (so someone with a positive result would receive the same treatment regardless of whether they were diagnosed by test A or test B). Downstream patient outcomes are then compared between the 2 groups. As treatment is the same in both arms of the trial, any differences in patient outcomes will reflect the accuracy of the tests in correctly establishing who does and does not have the condition. Data were synthesised using the same methods for intervention reviews (see section 4.3.3.1 above). 4.3.3.2.2 Diagnostic accuracy studies For diagnostic test accuracy studies, a positive result on the index test was found if the patient had values of the measured quantity above or below a threshold value, and different thresholds could be used. The thresholds were prespecified by the committee including whether or not data could be pooled across a range of thresholds. Diagnostic test accuracy measures used in the analysis were: area under the receiver operating characteristics (ROC) curve (AUC), and, for different thresholds (if appropriate), sensitivity and specificity. The threshold of a diagnostic test is defined as the value at which the test can best differentiate between those with and without the target condition. In practice this varies amongst studies. If a test has a high sensitivity then very few people with the condition will be missed (few false negatives). For example, a test with a sensitivity of 97% will only miss 3% of people with the condition. Conversely, if a test has a high specificity then few people without the condition would be incorrectly diagnosed (few false positives). For example, a test with a specificity of 97% will only incorrectly diagnose 3% of people who do not have the condition as positive. For this guideline, sensitivity or specificity was considered more important depending on the test threshold value being considered. For example at standard diagnostic thresholds of BNP and NT-proBNP sensitivity was prioritised as failing to diagnose people who have heart failure may delay the initiation of treatment and increase the risk of unplanned hospitalisations and mortality. While at much higher rule-in thresholds specificity was prioritised as minimising false positives is more important in this context. Coupled forest plots of sensitivity and specificity with their 95% CIs across studies (at various thresholds) were produced for each test, using RevMan5.283 In order to do this, 2 2 tables (the number of true positives, false positives, true negatives and false negatives) were directly taken from the study if given, or else were derived from raw data or calculated from the set of test accuracy statistics. Diagnostic meta-analysis was conducted where appropriate, that is, when 3 or more studies were available per threshold. Test accuracy for the studies was pooled using the bivariate method for the direct estimation of summary sensitivity and specificity using a random-effects approach in WinBUGS Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 The advantage of this approach is that it produces summary estimates of sensitivity and specificity that account for the correlation between the 2 statistics. Other advantages of this method The bivariate method uses logistic regression on the true positives, true negatives, false positives and false negatives reported in the studies. Overall sensitivity and specificity and confidence regions were plotted (using methods outlined by Novielli 2010.284 ) Pooled sensitivity and specificity and their 95% CIs were reported in the clinical evidence summary tables. For scores with fewer than 3 studies, each study s sensitivity and the paired specificity were reported where possible. Heterogeneity or inconsistency amongst studies was visually inspected in the forest plots and pooled diagnostic meta-analysis plots. The following criteria were used for evaluating AUCs: 0.50: worse than chance 0.50 0.60: very poor 0.61 0.70: poor 0.71 0.80: moderate 0.81 0.90: good 0.91 1.00: excellent or perfect test. 4.3.3.3 Data synthesis for risk prediction rules Evidence reviews on risk prediction rules or risk prediction tool results were presented separately for discrimination and calibration. The discrimination data were analysed according to the principles of data synthesis for diagnostic accuracy studies as outlined in section 4.3.3.2.2. Calibration data such as ),if reported,were presented separately to the discrimination data. The results were presented for each study separately along with the quality rating for the study and modified GRADE assessment. 4.3.3.4 Data synthesis for qualitative study reviews The main findings for each included paper were identified and thematic analysis methods were used to synthesise this information into broad overarching themes which were summarised into the main review findings. The evidence was presented in the form of a narrative summary detailing the evidence from the relevant papers and how this informed the overall review finding plus a statement on the level of confidence for that review finding. Considerable limitations and issues around relevance were listed. A summary evidence table with the succinct summary statements for each review finding was produced including the associated quality assessment. 4.3.4 Appraising the quality of evidence by outcomes 4.3.4.1 Intervention reviews The evidence for outcomes from the included RCTs and, where appropriate, non-randomised intervention studies, were evaluated and presented using an adaptation of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox developed by the international GRADE working group (http://www.gradeworkinggroup.org/). The software ) developed by the GRADE working group was used to assess the quality of each outcome, taking into account individual study quality and the meta-analysis results. Each outcome was first examined for each of the quality elements listed and defined in Table 2. Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Table 2: Description of quality elements in GRADE for intervention studies Quality element Description Risk of bias Limitations in the study design and implementation may bias the estimates of the treatment effect. Major limitations in studies decrease the confidence in the estimate of the effect. Examples of such limitations are selection bias (often due to poor allocation concealment), performance and detection bias (often due to a lack of blinding of the patient, healthcare professional or assessor) and attrition bias (due to missing data causing systematic bias in the analysis). Indirectness Indirectness refers to differences in study population, intervention, comparator and outcomes between the available evidence and the review question. Inconsistency Inconsistency refers to an unexplained heterogeneity of effect estimates between studies in the same meta-analysis. Imprecision Results are imprecise when studies include relatively few patients and few events (or highly variable measures) and thus have wide confidence intervals around the estimate of the effect relative to clinically important thresholds. 95% confidence intervals denote the possible range of locations of the true population effect at a 95% probability, and so wide confidence intervals may denote a result that is consistent with conflicting interpretations (for example a result may be consistent with both clinical benefit AND clinical harm) and thus be imprecise. Publication bias Publication bias is a systematic underestimate or overestimate of the underlying beneficial or harmful effect due to the selective publication of studies. A closely related phenomenon is where some papers fail to report an outcome that is inconclusive, thus leading to an overestimate of the effectiveness of that outcome. Other issues Sometimes randomisation may not adequately lead to group equivalence of confounders, and if so this may lead to bias, which should be taken into account. Potential conflicts of interest, often caused by excessive pharmaceutical company involvement in the publication of a study, should also be noted. Details of how the 4 main quality elements (risk of bias, indirectness, inconsistency and imprecision) were appraised for each outcome are given below. Publication or other bias was only taken into consideration in the quality assessment if it was apparent. 4.3.4.1.1 Risk of bias The main domains of bias for RCTs are listed in Table 3. Each outcome had its risk of bias assessed within each study first. For each study, if there were no risks of bias in any domain, the risk of bias was given a rating of 0. If there was risk of bias in just 1 domain, the risk of bias was given a serious rating of 1, but if there was risk of bias in 2 or more domains the risk of bias was given a very serious rating of 2. A weighted average score was then calculated across all studies contributing to the outcome, by taking into account the weighting of studies according to study precision. For example if the most precise studies tended to each have a score of 1 for that outcome, the overall score for that outcome would tend towards 1. Table 3: Principle domains of bias in randomised controlled trials Limitation Explanation Selection bias (sequence generation and allocation concealment) If those enrolling patients are aware of the group to which the next enrolled patient will be allocated, either because of a non-random sequence that is predictable, or because a truly random sequence was not concealed from the researcher, this may translate into systematic selection bias. This may occur if the researcher chooses not to recruit a participant into that specific group because of: knowledge of that participant s likely prognostic characteristics, and a desire for one group to do better than the other. Performance and Patients, caregivers, those adjudicating or recording outcomes, and data analysts Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Limitation Explanation detection bias (lack of blinding of patients and healthcare professionals) should not be aware of the arm to which patients are allocated. Knowledge of the group can influence: the experience of the placebo effect performance in outcome measures the level of care and attention received, and the methods of measurement or analysis all of which can contribute to systematic bias. Attrition bias Attrition bias results from an unaccounted for loss of data beyond a certain level (a differential of 10% between groups). Loss of data can occur when participants are compulsorily withdrawn from a group by the researchers (for example, when a per- protocol approach is used) or when participants do not attend assessment sessions. If the missing data are likely to be different from the data of those remaining in the groups, and there is a differential rate of such missing data from groups, systematic attrition bias may result. Selective outcome reporting Reporting of some outcomes and not others on the basis of the results can also lead to bias, as this may distort the overall impression of efficacy. Other limitations For example: Stopping early for benefit observed in randomised trials, in particular in the absence of adequate stopping rules. Use of unvalidated patient-reported outcome measures. Lack of washout periods to avoid carry-over effects in crossover trials. Recruitment bias in cluster-randomised trials. Indirectness refers to the extent to which the populations, interventions, comparisons and outcome measures are dissimilar to those defined in the inclusion criteria for the reviews. Indirectness is important when these differences are expected to contribute to a difference in effect size, or may affect the balance of harms and benefits considered for an intervention. As for the risk of bias, each outcome had its indirectness assessed within each study first. For each study, if there were no sources of indirectness, indirectness was given a rating of 0. If there was indirectness in just 1 source (for example in terms of population), indirectness was given a serious rating of 1, but if there was indirectness in 2 or more sources (for example, in terms of population and treatment) the indirectness was given a very serious rating of 2. A weighted average score was then calculated across all studies contributing to the outcome by taking into account study precision. For example, if the most precise studies tended to have an indirectness score of 1 each for that outcome, the overall score for that outcome would tend towards 1. Inconsistency refers to an unexplained heterogeneity of results for an outcome across different studies. When estimates of the treatment effect across studies differ widely, this suggests true differences in the underlying treatment effect, which may be due to differences in populations, settings or doses. When heterogeneity existed within an outcome (chi-squared p<0.1, or I2 no plausible explanation could be found, the quality of evidence for that outcome was downgraded. Inconsistency for that outcome was given a serious score of 1 if the I2 was 50 74%, and a very serious score of 2 if the I2 was 75% or more. If inconsistency could be explained based on prespecified subgroup analysis (that is, each subgroup had an I2 <50%), the committee took this into account and considered whether to make separate recommendations on new outcomes based on the subgroups defined by the assumed explanatory Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 factors. In such a situation the quality of evidence was not downgraded for those emergent outcomes. Since the inconsistency score was based on the meta-analysis results, the score represented the whole outcome and so weighted averaging across studies was not necessary. The criteria applied for imprecision were based on the 95% CIs for the pooled estimate of effect, and the minimal important differences (MID) for the outcome. The MIDs are the threshold for appreciable benefits and harms, separated by a zone either side of the line of no effect where there is assumed to be no clinically important effect. If either end of the 95% CI of the overall estimate of effect crossed 1 of the MID lines, imprecision was regarded as serious and a serious score of 1 was given. This was because the overall result, as represented by the span of the confidence interval, was consistent with 2 interpretations as defined by the MID (for example, both no clinically important effect and clinical benefit were possible interpretations). If both MID lines were crossed by either or both ends of the 95% CI then imprecision was regarded as very serious and a very serious score of 2 was given. This was because the overall result was consistent with all 3 interpretations defined by the MID (no clinically important effect, clinical benefit and clinical harm). This is illustrated in Figure 4. As for inconsistency, since the imprecision score was based on the meta-analysis results, the score represented the whole outcome and so weighted averaging across studies was not necessary. The position of the MID lines is ideally determined by values reported in the literature. Anchor- based methods aim to establish clinically meaningful changes in a continuous outcome variable by relating or anchoring them to patient-centred measures of clinical effectiveness that could be regarded as gold standards with a high level of face validity. For example, a MID for an outcome could be defined by the minimum amount of change in that outcome necessary to make patients feel their quality of life had significantly improved . MIDs in the literature may also be based on expert clinician or consensus opinion concerning the minimum amount of change in a variable deemed to affect quality of life or health. For binary variables, any MIDs reported in the literature will inevitably be based on expert consensus, as such MIDs relate to all-or-nothing population effects rather than measurable effects on an individual, and so are not amenable to patient-centred anchor methods. The GC agreed to use these published values for quality of life scores: EQ-5D 0.03 (from Sf-36 mapping),Kansas City 5 (taken from literature) and SF-36 5 (taken from literature). The GC did not support the use of other MIDs as the measures were perceived as unreliable. The GC agreed that it was appropriate to use a reduction of 10 unplanned hospitilisation per 1000 as a clinically important benefit. In the absence of values identified in the literature, the alternative approach to deciding on MID levels is the default method, as follows: For categorical outcomes the MIDs were taken to be RRs of 0.75 and 1.25. For positive outcomes such as patient satisfaction , the RR of 0.75 is taken as the line denoting the boundary between no clinically important effect and a clinically significant harm, whilst the RR of 1.25 is taken as the line denoting the boundary between no clinically important effect and a clinically significant benefit. For negative outcomes such as bleeding , the opposite occurs, so the RR of 0.75 is taken as the line denoting the boundary between no clinically important effect and a clinically significant benefit, whilst the RR of 1.25 is taken as the line denoting the boundary between no clinically important effect and a clinically significant harm. For mortality any change was considered to be clinically important and the imprecision was assessed on the basis of the whether the confidence intervals crossed the line of no effect, that is whether the result was consistent with both benefit and harm. For continuous outcome variables the MID was taken as half the median baseline standard deviation of that variable, across all studies in the meta-analysis. Hence the MID denoting the Chronic Heart Failure Methods NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 minimum clinically significant benefit was positive for a positive outcome (for example, a quality of life measure where a higher score denotes better health), and negative for a negative outcome (for example, a visual analogue scale [VAS] pain score). Clinically significant harms will be the converse of these. If baseline values are unavailable, then half the median comparator group standard deviation of that variable will be taken as the MID. If standardised mean differences have been used, then the MID will be set at the absolute value of +0.5. This follows because standardised mean differences are mean differences normalised to the pooled standard deviation of the 2 groups, and are thus effectively expressed in units of numbers of standard deviations . The 0.5 MID value in this context therefore indicates half a standard deviation, the same definition of MID as used for non-standardised mean differences. The default MID value was subject to amendment after discussion with the committee. If the committee decided that the MID level should be altered, after consideration of absolute as well as relative effects, this was allowed, provided that any such decision was not influenced by any bias towards making stronger or weaker recommendations for specific outcomes. Figure 4: Illustration of precise and imprecise outcomes based on the 95% CI of dichotomous outcomes in a forest plot (Note that all 3 results would be pooled estimates, and would not, in practice, be placed on the same forest plot) 4.3.4.1.5 Overall grading of the quality of clinical evidence Once an outcome had been appraised for the main quality elements, as above, an overall quality grade was calculated for that outcome. The scores (0, 1 or 2) from each of the main quality elements were summed to give a score that could be anything from 0 (the best possible) to 8 (the worst possible). However scores were capped at 3. This final score was then applied to the starting grade that had originally been applied to the outcome by default, based on study design. All RCTs started as High and the overall quality became Moderate, Low or Very Low if the overall score was 1, 2 or 3 points respectively. The significance of these overall ratings is explained in Table 4. The reasons for downgrading in each case were specified in the footnotes of the GRADE tables. 