Hypertension. The clinical management of primary hypertension in adults. Clinical Guideline. February 2011

Transcription

1 Partial update of Clinical Guidelines and Hypertension The clinical management of primary hypertension in adults Clinical Guideline Methods, evidence and recommendations February 0 Draft for Consultation Commissioned by the National Institute for Health and Clinical Excellence

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3 Contents Published by the National Clinical Guideline Centre at The Royal College of Physicians, St Andrews Place, Regents Park, London, NW BT First published 00 National Clinical Guideline Centre - 0 Apart from any fair dealing for the purposes of research or private study, criticism or review, as permitted under the Copyright, Designs and Patents Act,, no part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK. Enquiries concerning reproduction outside the terms stated here should be sent to the publisher at the UK address printed on this page. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore for general use. The rights of National Clinical Guideline Centre to be identified as Author of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act,.

4 Contents Contents Rationale for update... Guideline development group members... Acknowledgments... Acronyms and abbreviations... Introduction... Development of the guideline.... What is a NICE clinical guideline?.... Who developed this guideline?.... What this guideline covers.... What this guideline does not cover.... Relationships between the guideline and other NICE guidance..... Related guidance... 0 Methods.... Developing the review questions and outcomes.... Searching for evidence..... Clinical literature search..... Health economic literature search..... Evidence of effectiveness..... Inclusion/exclusion..... Methods of combining clinical studies..... Appraising the quality of evidence by outcomes..... Grading the quality of clinical evidence..... Study limitations Inconsistency Indirectness Imprecision.... Evidence of cost-effectiveness..... Literature review..... Undertaking new health economic analysis..... Cost-effectiveness criteria.... Developing recommendations..... Research recommendations..... Validation process..... Updating the guideline..... Disclaimer..... Funding...

5 Contents 00 Methods..... Review methods..... Group process..... Evidence statements and recommendations..... Costs and consequences methods..... Clinical evidence..... Cost-effectiveness evidence... Guideline summary.... Algorithms.... Key priorities for implementation.... Full list of recommendations.... Key research recommendations... Measuring blood pressure.... Techniques for measuring blood pressure..... Manual blood pressure measurement.... Cuffs.... White Coat Hypertension.... Blood pressure measurement devices..... Mercury sphygmomanometer..... Aneroid sphygmomanometers..... Automated devices..... Recommendations..... Research recommendation... Diagnosis of Hypertension.... Predicting outcome using clinic, home and ambulatory measurements..... Clinical evidence Clinical evidence Evidence statements clinical Sensitivity and specificity of clinic, home and ambulatory measurements..... Clinical evidence..... Evidence statements clinical.... Cost-effectiveness of clinic, home and ambulatory measurements..... Economic evidence literature review..... Economic evidence - original economic analysis..... Evidence statements economic.... Measurement protocols for diagnosing hypertension Ambulatory blood pressure measurement... 0

6 Contents.. Home blood pressure measurement.... Link from evidence to recommendations.... Recommendations..... Research recommendation... Assessing cardiovascular risk, target organ damage and secondary causes of hypertension..... Hypertension and cardiovascular disease.... Routine clinical investigations..... Urine testing for proteinuria..... Blood electrolyte, urea, creatinine, glucose and total/hdl cholesterol levels.... Cardiovascular Risk Assessment.... Secondary Hypertension..... Renal and renovascular disease..... Pheochromocytoma..... Hyperaldosteronism (primary aldosteronism)..... Cushing's syndrome.... Other identifiable causes of hypertension..... Hypothyroidism..... Hyperthyroidism..... Obstructive sleep apnoea..... Coarctation of aorta..... Acromegaly..... Drugs Recommendations Research recommendation Initiating and monitoring treatment, including blood pressure targets Blood pressure thresholds for initiating pharmacological treatment Clinical evidence Evidence statement - clinical..... Evidence statement economic.... Treatment of people aged 0 years and greater..... Clinical evidence..... Economic evidence..... Evidence statements Clinical..... Evidence statements Health economic Link from evidence to recommendations Recommendations..... Recommendations for research.... Monitoring treatment efficacy...

7 Contents.. Clinical evidence..... Economic evidence..... Link from evidence to recommendations..... Recommendations..... Research recommendations.... Blood pressure targets for treatment..... Clinical evidence..... Health economic evidence..... Evidence statements clinical..... Evidence statements economic..... Link from evidence to recommendations..... Recommendations.... Frequency of review... 0 Integrating the assessment of blood pressure, target organ damage and cardiovascular risk assessment and clinical decision making regarding treatment initiation, treatment and targets... Lifestyle interventions.... Overview..... Managing changes in lifestyle..... Diet..... Exercise..... Relaxation therapies..... Multiple lifestyle interventions..... Alcohol..... Coffee..... Reducing sodium (salt) intake..... Calcium supplements Magnesium supplements Potassium supplementation Combined salt supplements..... Drug therapy versus lifestyle change..... Smoking cessation..... Recommendations... Pharmacological interventions guidance: pharmacological interventions..... Placebo controlled trials rapid pharmacological update: head to head trials..... Clinical evidence statements: head-to-head drug comparisons..... Meta-analysis results summary... 0

8 Contents. 0 update: Pharmacological therapy for hypertension..... Angiotensin-converting enzyme inhibitors (ACEi) versus Angiotensin Receptor Blockers (ARB)..... Diuretics.... Cost-effectiveness analysis..... Methodological introduction..... Results of the health economic model..... Conclusions.... Step two therapy.... Resistant hypertension.... Special groups for consideration..... People aged over 0 years..... Younger people..... Ethnicity..... Chronic kidney disease..... Type and Type diabetes..... Women who are pregnant or breast-feeding.... Stopping treatment.... Link from evidence to recommendations..... Recommendations..... Research recommendations... Patients perspectives.... Introduction.... Discovering hypertension.... Treatment.... Living with hypertension.... Education and adherence..... Compliance with Prescribed Antihypertensive Medication..... Implementing lifestyle measures..... Recommendations... Reference list... 0 Glossary...

9 Introduction 0 Rationale for update This document is a partial update of Clinical Guideline (00) and Clinical Guideline (00) on Essential Hypertension in adults. The sections that have not been amended are integrated with the updated guidance in this document. Both guidelines are available in full in the appendices of the document. The sections that have been updated in 0 are: Diagnosis of Hypertension Initiation and monitoring treatment, including blood pressure targets Pharmacological interventions Improvements in methodology since 00 mean the way information is presented may, at times, be inconsistent (for example, the style of review write-up and 0 recommendations are not graded according to the strength of evidence, unlike those in the 00). New or amended sections of the guideline are indicated with an update panel in the right hand margin.

10 Introduction Guideline development group members Name Bernard Higgins Bryan Williams Helen Williams Jane Northedge John Crimmins Kate Lovibond Mark Caulfield Michaela Watts Naomi Stetson Paul Miller Rachel O Mahony Richard McManus Shelley Mason Terry McCormack Taryn Krause Role Clinical Director, National Clinical Guideline Centre Professor of Medicine, Guideline Development Group Chair Consultant Pharmacist for cardiovascular disease, Southwark Health and Social Care Patient and care representative General Practitioner, Vale of Glamorgan Senior Health Economist, National Clinical Guideline Centre Professor of Clinical Pharmacology, Barts and the London School of Medicine Hypertension Nurse Specialist, Addenbrooke s Hospital, Cambridge Primary Care Nurse, Watling Medical Centre, Burnt Oak Senior Information Scientist, National Clinical Guideline Centre Senior Research Fellow, National Clinical Guideline Centre Professor of Primary Care Cardiovascular Research, University of Birmingham Patient and carer representative General Practitioner, Spring Vale Medical Centre, North Yorkshire Senior Project Manager/Research Fellow, National Clinical Guideline Centre

11 Introduction 0 Acknowledgments The development of this guideline was greatly assisted by the following people: Jill Cobb, Information Scientist, National Clinical Guideline Centre Ralph Hughes, Health Economist, National Clinical Guideline Centre Fatema Limbada, Project Coordinator, National Clinical Guideline Centre Jill Parnham, Director of Operations, National Clinical Guideline Centre David Wondering, Health Economic Lead, National Clinical Guideline Centre Jacoby Patterson, Systematic Reviewer Julie Brown, Systematic Reviewer Richard McManus, Professor of Primary Care Cardiovascular Research, University of Birmingham Sue Jowett, Senior Lecturer in Health Economics, University of Birmingham James Hodgkinson, Research Fellow, University of Birmingham Jonathan Mant, Professor of Primary Care Research, University of Cambridge Una Martin, Reader in Clinical Pharmacology, University of Birmingham Carl Heneghan, Reader in Evidence-Based Medicine, University of Oxford Richard Hobbs, Head of Primary Care Clinical Sciences, University of Birmingham.

12 Introduction Acronyms and abbreviations ANOVA BNF CCA CEA c.f. CI / % CI CUA DH DSA ED EQ-D GDG GP GRADE HES HR HRQoL HTA ICD-0 ICER IQR INMB IRR ITT LOS LR+ LY MD NCGC NHS Analysis of variance British National Formulary Cost-consequences analysis Cost-effectiveness analysis Confer (refer to) Confidence interval / % confidence interval Cost-utility analysis Department of Health Deterministic Sensitivity Analysis Emergency Department EuroQol-D Guideline Development Group General Practitioner Grading of Recommendations Assessment, Development and Evaluation Hospital Episode Statistics Hazard Ratio Health-related quality of life Health technology assessment International Classification of Diseases, 0th edition Incremental cost-effectiveness ratio Interquartile range Incremental Net Monetary Benefit Inter-rater reliability Intention to treat Length of Stay Positive likelihood ratio Life-year Mean difference National Clinical Guideline Centre National Health Service

13 Introduction 0 0 NHSEED NICE NNT NPV OR PICO PPP PPV p.r.n PSA QALY QUADAS RCT ROC RR SD SE SPC SR The NHS Economic Evaluation Database National Institute for Health and Clinical Excellence Number needed to treat Negative predictive value Odds ratio Framework incorporating patients, interventions, comparison and outcome Purchasing Power Parity Positive predictive value Pro re nata Probabilistic sensitivity analysis Quality-adjusted life year Quality assessment tool for diagnostic accuracy studies Randomised controlled trial Receiver operating characteristic Relative risk Standard deviation Standard error Summary of product characteristics Systematic review 0

14 Introduction 0 Introduction This guideline is for the clinical management of primary hypertension in adults (aged greater than years). Hypertension (high blood pressure) is one of the most preventable causes of premature morbidity and mortality world-wide. Hypertension is a major risk factor for stroke (ischaemic and haemorrhagic), myocardial infarction, heart failure, chronic kidney disease, peripheral vasculardisease, cognitive decline and premature death. Untreated hypertension is associated a progressive rise in blood pressure, often culminating in a treatment resistant state due to associated vascular and renal damage. Blood pressure is quantified as diastolic and systolic pressures measured in millimetres of mercury (mmhg). The diastolic pressure represents the pressure during ventricular relaxation in diastole whereas the systolic pressure represents the peak pressure due to ventricular contraction during systole. Either or both pressures have specified upper limits of normal and elevation in either or both pressures are used to define hypertension. 0 Blood pressure is normally distributed in the population and there is no natural cut-point above which "hypertension" definitively exists and below which, it does not. Epidemiological studies demonstrate that the aforementioned disease risk associated with blood pressure is a continuous relationship and above blood pressures of /0mmHg, the risk of cardiovascular events doubles for every 0/0mmHg rise in blood pressure. The threshold blood pressure determining the presence of hypertension is defined as the level of blood pressure above which treatment has been shown to reduce the development or progression of disease. Primary hypertension was previously termed essential hypertension because of a long-standing view that high blood pressure was sometimes essential to perfuse diseased and sclerotic arteries. It is now recognised that the diseased and sclerotic arteries were most often the consequence of the hypertension and thus the term essential hypertension is redundant and the primary hypertension is preferred. Primary hypertension refers to the majority of people with sustained high blood pressure (approximately 0%) encountered in clinical practice, for which there is no obvious, identifiable cause. The remaining 0% are termed "secondary hypertension" for which specific causes for the blood pressure elevation can be determined (for example, Conn's adenoma, renovascular disease, or phaeochromocytoma). Update Primary hypertension is remarkably common in the UK population and the prevalence is strongly influenced by age and lifestyle factors. Systolic and/or diastolic blood pressures may be elevated. Systolic pressure elevation is the more dominant feature of hypertension in older patients and diastolic pressure more commonly elevated in younger patients, (those less than 0 years of age). At least one quarter of the adult population of the UK have hypertension, (blood pressure 0/0mmHg) and more than half of those over the age of 0 years. As the demographics of the UK shifts towards an older, more sedentary and obese population, the prevalence of hypertension and its requirement for treatment will continue to rise. Routine periodic screening for high blood pressure is now commonplace in the UK as part of National Service Frameworks for cardiovascular disease prevention. Consequently, the diagnosis, treatment and follow-up of patients with hypertension is one of the most common interventions in primary care, accounting for approximately % of Primary Care consultation episodes and approximately billion in drug costs in 00. NICE first issued guidance for the management of hypertension in primary care in 00. This was followed by a rapid update of the pharmacological treatment chapter of the guideline in 00. The current partial update of the hypertension guideline is in response to the regular five year review cycle of existing NICE guidance. It began with a scoping exercise which identified key areas of the existing guideline for which new evidence had emerged that was likely to influence or change existing guideline recommendations.

15 Introduction Sections of the guideline that have not been updated continue to stand, however, wherever NICE has subsequently issued new and related guidance relevant to existing recommendations, these have been identified and cross-referred to in this partial update, examples include interventions on lifestyle factors and public health policy recommendations such as smoking cessation, dietary salt restriction, alcohol intake and cardiovascular disease prevention and cardiovascular disease risk assessment. In addition, new NICE guidance developed in areas relevant to hypertension are also highlighted and cross referenced (for example, chronic kidney disease, stroke, diabetes and hypertension in pregnancy). 0 The recommendations that have been reviewed in this partial update of the guideline for the clinical management of primary hypertension in adults, include; blood pressure measurement for the diagnosis of hypertension; blood pressure thresholds for intervention with drug therapy and blood pressure targets for treatment; specific aspects of the recommendations for the pharmacological treatment of hypertension; the treatment of hypertension in the very elderly (people aged greater than 0 years); dilemmas surrounding decision making for treatment of hypertension in younger adults (less than 0 years); the treatment of drug resistant hypertension; and wherever appropriate, the impact of age and ethnicity on treatment recommendations. Update 0 0 Finally, despite the fact that the treatment of hypertension has a large clinical trial evidence base to inform recommendations, an important aspect of the evidence review for guideline development is to identify where gaps in knowledge remain. In so doing, research questions have been identified to prompt the gathering of further evidence to continue the evolution of guidance and clinical practice.

16 Development of the guideline 0 Development of the guideline. What is a NICE clinical guideline? NICE clinical 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. We base our clinical guidelines on the best available research evidence, with the aim of improving the quality of health care. We use predetermined and systematic methods to identify and evaluate the evidence relating to specific review questions. NICE clinical 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. 0 We produce our guidelines using the following steps: Guideline topic is referred to NICE from the Department of Health Stakeholders register an interest in the guideline and are consulted throughout the development process. The scope is prepared by the National Clinical Guideline Centre (NCGC) The NCGC establishes a guideline development group 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. Update 0 0 The NCGC 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 the quick reference guide (QRG) presents recommendations in a suitable format for health professionals information for the public ( understanding NICE guidance or UNG) is written using suitable language for people without specialist medical knowledge. This version is the full version. The other versions can be downloaded from NICE at Who developed this guideline? A multidisciplinary Guideline Development Group (GDG) comprising professional group members and consumer representatives of the main stakeholders developed this guideline (see section on Guideline Development Group Membership and acknowledgements).

17 Development of the guideline 0 The National Institute for Health and Clinical Excellence funds the National Clinical Guideline Centre (NCGC) and thus supported the development of this guideline. The GDG was convened by the NCGC and chaired by Professor Bryan Williams in accordance with guidance from the National Institute for Health and Clinical Excellence (NICE). The group met every four weeks during the development of the guideline. At the start of the guideline development process all GDG members declared interests including consultancies, fee-paid work, share-holdings, fellowships and support from the healthcare industry. At all subsequent GDG meetings, members declared arising conflicts of interest, which were also recorded in Error! Reference source not found. Declarations 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 Error! Reference source not found. Declarations of Interest. Staff from the NCGC provided methodological support and guidance for the development process. The team working on the guideline included a project manager, systematic reviewers, health economists and information scientists. 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 GDG What this guideline covers Adults with hypertension ( years and older). Particular consideration will be given to the needs of black people of African and Caribbean descent and minority ethnic groups where these differ from the needs of the general population. People aged 0 years or older. Ambulatory monitoring. Home blood pressure monitoring. Blood pressure thresholds for intervention and targets for treatment. First-line therapy options, for example angiotensin-converting enzyme inhibitors versus angiotension receptors blockers. Calcium-channel blockers versus diuretics as preferred components in step two of the treatment algorithm, for example, combination therapy. Adherence to medication. Provision of appropriate information and support. Resistant hypertension (that is, fourth-line therapy). Response to blood pressure lowering drugs according to age and ethnicity. Update 0 0 For further details please refer to Error! Reference source not found. Scope and Error! Reference source not found. Review questions.. What this guideline does not cover People with diabetes. Children and young people (younger than years). Pregnant women. Secondary causes of hypertension (for example, Conn's adenoma, phaeochromocytoma and renovascular hypertension).

18 Development of the guideline People with accelerated hypertension (that is, severe acute hypertension associated grade III retinopathy and encephalopathy). People with acute hypertension or high blood pressure in emergency care settings. Prevention of hypertension. Screening for hypertension. Specialist management of secondary hypertension (that is, hypertension arising from other medical conditions). Non-pharmacological interventions.. Relationships between the guideline and other NICE guidance Related guidance Chronic heart failure. NICE clinical guideline 0 (00). Available from Hypertension in pregnancy. NICE clinical guideline 0 (00). Available from Prevention of cardiovascular disease at population level. NICE public health guidance (00). Available from Type diabetes. NICE clinical guideline (00, updated March 00 and September 00). Available from Medicines adherence. NICE clinical guideline (00). Available from Chronic kidney disease. NICE clinical guideline (00). Available from Stroke. NICE clinical guideline (00). Available from Lipid modification. NICE clinical guideline (00, reissued 00). Available from Continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome. NICE technology appraisal guidance (00). Available from MI: secondary prevention. NICE clinical guideline (00). Available from Obesity. NICE clinical guideline (00). Available from Atrial fibrillation. NICE clinical guideline (00). Available from Update 0

19 0 Methods 0 0 Methods This guidance was developed in accordance with the methods outlined in the NICE Guidelines Manual 00.. Developing the review questions and outcomes Review questions were developed in a PICO framework (patient, intervention, comparison and outcome) for intervention reviews, and with a framework of population, index tests, reference standard and target condition for reviews of diagnostic test accuracy. This was to guide the literature searching process and to facilitate the development of recommendations by the guideline development group (GDG). They were drafted by the NCGC technical team and refined and validated by the GDG. The questions were based on the key clinical areas identified in the scope (Error! Reference source not found. Scope) and a list can be found in Error! Reference source not found. Review Questions. Further information on the outcome measures examined follows this section.. Searching for evidence.. Clinical literature search 0 Systematic literature searches were undertaken to identify evidence within published literature in order to answer the review questions as per The Guidelines Manual (00). Clinical databases were searched using relevant medical subject headings, free-text terms and study type filters where appropriate. Studies published in languages other than English were not reviewed. All searches were conducted on core databases, MEDLINE, Embase, Cinahl and The Cochrane Library. All searches were updated on th November 00. No papers after this date were considered. Search strategies were checked by looking at reference lists of relevant key papers, checking search strategies in other systematic reviews and asking the GDG for known studies. The questions, the study types applied, the databases searched and the years covered can be found in Error! Reference source not found. Literature search strategies. Update 0 0 During the scoping stage, a search was conducted for guidelines and reports on the websites listed below and via organisations relevant to the topic. Searching for grey literature or unpublished literature was not undertaken. All references sent by stakeholders were considered. Guidelines International Network database ( National Guideline Clearing House ( National Institute for Health and Clinical Excellence (NICE) ( National Institutes of Health Consensus Development Program (consensus.nih.gov/) National Library for Health ( Call for evidence The GDG decided to initiate a call for evidence for meta analyses, based on a systematic review, that include studies that use ambulatory blood pressure measurement as the reference standard and report sensitivity and specificity of home and/or clinic blood pressure measurement, as they believed that important evidence existed that would not be identified by the standard searches. The NCGC contacted all registered stakeholders and asked them to submit any relevant published or unpublished evidence.

20 0 Methods 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 the guideline population in the NHS economic evaluation database (NHS EED), the Health Economic Evaluations Database (HEED) and health technology assessment (HTA) databases from 00 onwards to find anything published since the original guideline. There were two questions not covered in either the original guideline or the previous rapid update, for which additional searches with no date restrictions were carried out. Additionally, the search was run on MEDLINE and Embase, with a specific economic filter, from 00, to ensure recent publications that had not yet been indexed by these databases were identified. Studies published in languages other than English were not reviewed. Where possible, searches were restricted to articles published in English language.the search strategies for health economics are included in Error! Reference source not found. Literature search strategies. All searches were updated on th November 00. No papers published after this date were considered.... Call for evidence The GDG decided to initiate a call for evidence for cost-effectiveness analyses from a UK perspective, using methods in line with the NICE reference case, comparing ambulatory, home and clinic blood pressure measurement in the diagnosis of hypertension, as they believed that important evidence existed that would not be identified by the standard searches. The NCGC contacted all registered stakeholders and asked them to submit any relevant published or unpublished evidence Evidence of effectiveness The Research Fellow: 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 pre-specified inclusion / 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 Error! Reference source not found.review protocols). Critically appraised relevant studies using the appropriate checklist as specified in The Guidelines Manual Extracted key information about the study s methods and results into evidence tables (evidence tables are included in Appendix D: Evidence tables clinical studies and Appendix G: Evidence tables health economic studies. Generated summaries of the evidence by outcome (included in the relevant chapter write-ups): o Randomised studies: meta analysed, where appropriate and reported in GRADE profiles (for clinical studies) see below for details o Observational studies: data has been presented for individual studies narratively or in summary tables (GRADE profiles have not been generated) o Diagnostic studies: data has been presented for individual studies narratively or in summary tables (GRADE profiles have not been generated) o Qualitative studies: each study summarised in a table where possible, otherwise presented in a narrative. Update 0.. Inclusion/exclusion See the review protocols in Error! Reference source not found. Review Protocols for full details.

21 0 Methods 0.. Methods of combining clinical studies Data synthesis for intervention reviews Where possible, meta-analyses were conducted to combine the results of studies for each review question using Cochrane Review Manager (RevMan) software. Fixed-effects (Mantel -Haenszel) techniques were used to calculate risk ratios (relative risk) for the following binary outcomes: angioedema. Where reported, time-to-event data was presented as a hazard ratio for the following binary outcomes: mortality, stroke, MI, heart failure, new onset diabetes, vascular procedures, angina requiring hospitalisation, study drug withdrawal. The continuous outcome blood pressure (mmhg)] was analysed using an inverse variance method for pooling weighted mean differences and where the studies had different scales, standardised mean differences were used. No quality of life outcome data was reported by any of the studies included in the 0 update reviews Statistical heterogeneity was assessed by considering the chi-squared test for significance at p<0. or an I-squared inconsistency statistic of >0% to indicate significant heterogeneity. Where significant heterogeneity was present, we carried out sensitivity analysis based on the quality of studies, with particular attention paid to allocation concealment, blinding and loss to follow-up (missing data). In cases where there was inadequate allocation concealment, unclear blinding, high loss to follow-up ( 0% missing data for studies years follow-up and 0% for those with > years follow-up) or differential missing data, this was examined in a sensitivity analysis. For the latter, the duration of follow up was also taken into consideration prior to including in a sensitivity analysis. 0 0 Assessments of potential differences in effect between subgroups were based on the chi-squared tests for heterogeneity statistics between subgroups. If no sensitivity analysis was found to completely resolve statistical heterogeneity then a random effects (DerSimonian and Laird) model was also explored to provide a more conservative estimate of the effect. The means and standard deviations of continuous outcomes were required for meta-analysis. However, in cases where standard deviations were not reported, the standard error was calculated if the p-values or % confidence intervals were reported and meta-analysis was undertaken with the mean and standard error using the generic inverse variance method in Cochrane Review Manager (RevMan) software. Where p values were reported as less than, a conservative approach was undertaken. For example, if the p value was reported as p 0.00, the calculations for standard deviations will be based on a p value of If these statistical measures were un available then the methods described in section.. of the Cochrane Handbook Missing standard deviations were applied as the last resort. Update Appraising the quality of evidence by outcomes The evidence for outcomes from the included RCT 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 ( The software (GRADEpro) 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. The summary of findings was presentedas an evidence profile, a single table that includes details of the quality assessment as well as pooled outcome data, where appropriate, an absolute measure of intervention effect and the summary of quality of evidence for that outcome. In this table, the columns for intervention and control indicate the sum of the sample size for continuous outcomes. For binary outcomes such as number of patients with an adverse event, the event rates (n/n: number of patients with events divided by sum of number of patients) are shown with percentages. Reporting or publication bias was only taken into consideration in the quality assessment and included in the Clinical Study Characteristics table if it was apparent.

22 0 Methods Each outcome was examined separately for the quality elements listed and defined in Table and each graded using the quality levels listed in Table : The main criteria considered in the rating of these elements are discussed below (see.. Grading of Evidence). Footnotes were used to describe reasons for grading a quality element as having serious or very serious problems. The ratings for each component were summed to obtain an overall assessment for each outcome. GRADE is currently designed only for randomised trials and observational studies. Table : Quality element Limitations Inconsistency Indirectness Imprecision Publication bias Description of quality elements in GRADE for intervention studies. Description 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. Inconsistency refers to an unexplained heterogeneity of results. Indirectness refers to differences in study population, intervention, comparator and outcomes between the available evidence and the review question, or recommendation made. Results are imprecise when studies include relatively few patients and few events and thus have wide confidence intervals around the estimate of the effect relative to the clinically important threshold. Publication bias is a systematic underestimate or an overestimate of the underlying beneficial or harmful effect due to the selective publication of studies. 0 Table : Levels of quality elements in GRADE Level Description None There are issues with the evidence Serious The issues are serious enough to downgrade the outcome evidence by one level Very serious The issues are serious enough to downgrade the outcome evidence by two levels Update 0 0 Table : Level High Moderate Low Very low Overall quality of outcome evidence in GRADE Description Further research is very unlikely to change our confidence in the estimate of effect Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Any estimate of effect is very uncertain.. Grading the quality of clinical evidence After results were pooled, the overall quality of evidence for each outcome was considered. The following procedure was adopted when using GRADE:. A quality rating was assigned, based on the study design. RCTs start HIGH and observational studies as LOW.. The rating for RCTs was then downgraded for the specified criteria: Study limitations, inconsistency, indirectness, imprecision and reporting bias. These criteria are detailed below. Due to the wide diversity of study design, data reported and data analysis methods of the observational studies that were included in this guideline, it was very difficult to compare studies

23 0 Methods 0 for quality and therefore observational studies were not downgraded or upgraded in GRADE, and all remained as LOW quality evidence.. The downgraded marks were then summed and the overall quality rating was revised. For example, all RCTs started as HIGH and the overall quality became MODERATE, LOW or VERY LOW if, or points were deducted respectively.. The reasons or criteria used for downgrading were specified in the footnotes. The details of criteria used for each of the main quality element are discussed further in the following sections.. to../.. [if section for publication bias is relevant]... Study limitations The main limitations for randomised controlled trials are listed in Table. Table : Limitation Allocation concealment Lack of blinding Incomplete accounting of patients and outcome events Selective outcome reporting Other limitations Study limitations of randomised controlled trials Explanation Those enrolling patients are aware of the group to which the next enrolled patient will be allocated (major problem in pseudo or quasi randomised trials with allocation by day of week, birth date, chart number, etc) Patient, caregivers, those recording outcomes, those adjudicating outcomes, or data analysts are aware of the arm to which patients are allocated Loss to follow-up not accounted and failure to adhere to the intention to treat principle when indicated Reporting of some outcomes and not others on the basis of the results For example: Stopping early for benefit observed in randomised trials, in particular in the absence of adequate stopping rules Use of unvalidated patient-reported outcomes Carry-over effects in cross-over trials Recruitment bias in cluster randomised trials Update Inconsistency Inconsistency refers to an unexplained heterogeneity of results. When estimates of the treatment effect across studies differ widely (i.e. heterogeneity or variability in results), this suggests true differences in underlying treatment effect. When heterogeneity exists (Chi square p<0. or I- squared inconsistency statistic of >0%), but no plausible explanation can be found, the quality of evidence was downgraded by one or two levels, depending on the extent of uncertainty to the results contributed by the inconsistency in the results. If inconsistency could be explained based on pre-specified subgroup analysis, the GDG took this into account and considered whether to make separate recommendations based on the identified explanatory factors, i.e. population and intervention. Where subgroup analysis gave a plausible explanation of heterogeneity, the quality of evidence was not downgraded...0 Indirectness Directness refers to the extent to which the populations, intervention, comparisons and outcome measures are similar to those defined in the inclusion criteria for the reviews. Indirectness is 0

24 0 Methods 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... Imprecision The criteria applied for imprecision are based on the confidence intervals for pooled or the best estimate of effect as illustrated in Figure and outlined in Table. Table : Criteria applied to determine precision Dichotomous and continuous outcomes The % confidence interval (or alternative estimate of precision) around the pooled or best estimate of effect:. Does not cross either of the two minimal important difference (MID) thresholds (the threshold lines for appreciable benefit or harm); defined as precise Rating for precision: imprecision Update 0. Crosses one of the two MID thresholds (appreciable benefit or appreciable harm); defined as imprecise Rating for precision: serious. Crosses both of the two MID thresholds ( appreciable benefit and appreciable harm); defined as imprecise Rating for precision: very serious

25 0 Methods Figure : Illustration of precise and imprecise outcomes based on the confidence interval of outcomes in a forest plot MID MID NO SERIOUS IMPRECISION SERIOUS IMPRECISION - VERY SERIOUS IMPRECISION Appreciable benefit (AEs and harmful outcomes) / appreciable harm (effectiveness and beneficial outcomes) Non-appreciable benefit or harm Appreciable harm (AEs and harmful outcomes) / appreciable benefit (effectiveness and beneficial outcomes) MID = minimal important difference determined for each outcome. The MIDs are the threshold for appreciable benefits and harms. The confidence intervals of the top five points of the diagram (within the green sector or within the purple sector) are considered precise because the upper and lower limits of the point estimate (diamond shapes) do not cross the pre-defined MID. Conversely, the bottom three points of the diagram are considered imprecise because the upper and lower limits of the point estimates (diamonds) for each of them cross the pre-defined MID and reduce the certainty of the result. The following are the MID for the outcomes in this guideline (as agreed by the GDG). Table : MIDs for the outcomes used in this guidance Outcome Relative risk reduction Mortality from any cause 0% Stroke (ischaemic or haemorrhagic) 0% Myocardial infarction (MI) (including, where reported, silent MI) 0% Update 0

26 0 Methods Outcome Relative risk reduction Heart failure 0% New onset diabetes 0% Vascular procedures (including both coronary and carotid artery procedures) 0% Angina requiring hospitalisation 0% Health-related quality of life (to use what is reported by trials) Major adverse cardiac and cerebrovascular events (MAACE): fatal and nonfatal MI, fatal and non-fatal stroke, hospitalised angina, hospitalised heart failure, revascularisation (and different composites of this outcome) Study drug withdrawal rates (surrogate for adverse effects of drug treatment and for adherence Angioedema in black people of African and Caribbean descent 0% Blood pressure As defined in literature for each specific QoL measure % 0% mmhg. Evidence of cost-effectiveness Evidence on cost-effectiveness related to the key clinical issues being addressed in the guideline was sought. The health economist undertook: A systematic review of the economic literature New cost-effectiveness analysis in priority areas.. Literature review 0 The Health Economist: Identified potentially relevant studies for each review question from the economic search results by reviewing titles and abstracts full papers were then obtained. Reviewed full papers against pre-specified inclusion / exclusion criteria to identify relevant studies (see below for details). Critically appraised relevant studies using the economic evaluations checklist as specified in The Guidelines Manual. Extracted key information about the study s methods and results into evidence tables (evidence tables are included in Error! Reference source not found. Evidence tables health economic studies. Generated summaries of the evidence in NICE economic evidence profiles (included in the relevant chapter write-ups) see below for details. Update 0 0 Inclusion/exclusion Full economic evaluations (studies comparing costs and health consequences of alternative courses of action: cost utility, cost-effectiveness, cost-benefit and cost-consequence analyses) and comparative costing studies that addressed the review question in the relevant population were considered potentially applicable as economic evidence. Studies were excluded if they only reported cost per hospital (not per patient), or only reported average cost effectiveness without disaggregated costs and effects. Abstracts, posters, reviews, letters/editorials, foreign language publications and unpublished studies were excluded. Studies judged to have an applicability rating of not applicable were excluded (this included studies that took the perspective of a non-oecd country).

27 0 Methods 0 Remaining studies were prioritised for inclusion based on their relative applicability to the development of this guideline and the study limitations. For example, if a high quality, directly applicable UK analysis was available other less relevant studies may have been excluded and this is noted in the relevant section. For more details about the assessment of applicability and methodological quality see the economic evaluation checklist (The Guidelines Manual, Appendix H and the health economics research protocol in Error! Reference source not found. Review protocols. When no relevant economic analyses were identified in the economic literature review, relevant UK NHS unit costs were presented to the GDG to inform consideration of cost effectiveness. NICE economic evidence profiles The NICE economic evidence profile has been used to summarise cost and cost-effectiveness estimates. The economic evidence profile shows, for each economic study, an assessment of applicability and methodological quality, with footnotes indicating the reasons for the assessment. These assessments were made by the health economist using the economic evaluation checklist from The Guidelines Manual, Appendix H. It also shows incremental costs, incremental outcomes (for example, QALYs) and the incremental cost-effectiveness ratio from the primary analysis, as well as information about the assessment of uncertainty in the analysis. See Table for more details. If a non-uk study was included in the profile, the results were converted into pounds sterling using the appropriate purchasing power parity. 0 Table : Item Study Limitations Applicability Other comments Incremental cost Incremental effects ICER Content of NICE economic profile Description First author name, reference, date of study publication and country perspective. An assessment of methodological quality of the study(a): Minor limitations the study meets all quality criteria, or the study fails to meet one or more quality criteria, but this is unlikely to change the conclusions about cost effectiveness. Potentially serious limitations the study fails to meet one or more quality criteria, and this could change the conclusion about cost effectiveness Very serious limitations the study fails to meet one or more quality criteria and this is very likely to change the conclusions about cost effectiveness. Studies with very serious limitations would usually be excluded from the economic profile table. An assessment of applicability of the study to the clinical guideline, the current NHS situation and NICE decision-making(a): Directly applicable the applicability criteria are met, or one or more criteria are not met but this is not likely to change the conclusions about cost effectiveness. Partially applicable one or more of the applicability criteria are not met, and this might possibly change the conclusions about cost effectiveness. Not applicable one or more of the applicability criteria are not met, and this is likely to change the conclusions about cost effectiveness. Particular issues that should be considered when interpreting the study. The mean cost associated with one strategy minus the mean cost of a comparator strategy. The mean QALYs (or other selected measure of health outcome) associated with one strategy minus the mean QALYs of a comparator strategy. Incremental cost-effectiveness ratio: the incremental cost divided by the respective QALYs gained. Update 0