Hypertension nice 2011

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Hypertension nice 2011

  1. 1. 1 Partial update of Clinical Guidelines 18 and 34 Hypertension The clinical management of primary hypertension in adults Clinical Guideline Methods, evidence and recommendations February 2011 Draft for Consultation Commissioned by the National Institute for Health and Clinical Excellence
  2. 2. Hypertension (partial update) Contents1 Published by the National Clinical Guideline Centre at The Royal College of Physicians, 11 St Andrews Place, Regents Park, London, NW1 4BT First published 2004 © National Clinical Guideline Centre - 2011 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, 1988, 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, 1988. Draft for consultation
  3. 3. Hypertension (partial update)ContentsContentsRationale for update .................................................................................................................... 6Guideline development group members ....................................................................................... 7Acknowledgments ....................................................................................................................... 8Acronyms and abbreviations ........................................................................................................ 91 Introduction ........................................................................................................................112 Development of the guideline ..............................................................................................13 2.1 What is a NICE clinical guideline? ....................................................................................... 13 2.2 Who developed this guideline? .......................................................................................... 13 2.3 What this guideline covers .................................................................................................. 14 2.4 What this guideline does not cover .................................................................................... 14 2.5 Relationships between the guideline and other NICE guidance ......................................... 15 2.5.1 Related guidance ................................................................................................. 153 2011 Methods .....................................................................................................................16 3.1 Developing the review questions and outcomes................................................................ 16 3.2 Searching for evidence ........................................................................................................ 16 3.2.1 Clinical literature search ...................................................................................... 16 3.2.2 Health economic literature search ...................................................................... 17 3.2.3 Evidence of effectiveness .................................................................................... 17 3.2.4 Inclusion/exclusion .............................................................................................. 17 3.2.5 Methods of combining clinical studies ................................................................ 18 3.2.6 Appraising the quality of evidence by outcomes ................................................ 18 3.2.7 Grading the quality of clinical evidence............................................................... 19 3.2.8 Study limitations .................................................................................................. 20 3.2.9 Inconsistency ....................................................................................................... 20 3.2.10 Indirectness ......................................................................................................... 20 3.2.11 Imprecision .......................................................................................................... 21 3.3 Evidence of cost-effectiveness ............................................................................................ 23 3.3.1 Literature review ................................................................................................. 23 3.3.2 Undertaking new health economic analysis ........................................................ 25 3.3.3 Cost-effectiveness criteria ................................................................................... 25 3.4 Developing recommendations ............................................................................................ 25 3.4.1 Research recommendations ................................................................................ 26 3.4.2 Validation process ............................................................................................... 26 3.4.3 Updating the guideline ........................................................................................ 26 3.4.4 Disclaimer ............................................................................................................ 26 3.4.5 Funding ................................................................................................................ 26Draft for consultation 1
  4. 4. Hypertension (partial update)Contents4 2004 Methods .....................................................................................................................27 4.1.1 Review methods .................................................................................................. 27 4.1.2 Group process ...................................................................................................... 29 4.1.3 Evidence statements and recommendations ...................................................... 29 4.1.4 Costs and consequences ...................................................................................... 31 4.2 2006 methods ..................................................................................................................... 32 4.2.1 Clinical evidence .................................................................................................. 32 4.2.2 Cost-effectiveness evidence ................................................................................ 345 Guideline summary ..............................................................................................................35 5.1 Algorithms ........................................................................................................................... 35 5.2 Key priorities for implementation....................................................................................... 35 5.3 Full list of recommendations .............................................................................................. 36 5.4 Key research recommendations ......................................................................................... 426 Measuring blood pressure....................................................................................................43 6.1 Techniques for measuring blood pressure ......................................................................... 43 6.1.1 Manual blood pressure measurement ................................................................ 43 6.2 Cuffs .................................................................................................................................... 44 6.3 White Coat Hypertension.................................................................................................... 45 6.4 Blood pressure measurement devices ................................................................................ 45 6.4.1 Mercury sphygmomanometer............................................................................. 46 6.4.2 Aneroid sphygmomanometers ............................................................................ 46 6.4.3 Automated devices .............................................................................................. 46 6.4.4 Recommendations ............................................................................................... 47 6.4.5 Research recommendation ................................................................................. 487 Diagnosis of Hypertension ...................................................................................................49 7.1 Predicting outcome using clinic, home and ambulatory measurements ........................... 49 7.1.1 Clinical evidence 2004 ......................................................................................... 49 7.1.2 Clinical evidence 2011 ......................................................................................... 50 7.1.3 Evidence statements – clinical............................................................................. 50 7.2 Sensitivity and specificity of clinic, home and ambulatory measurements ........................ 52 7.2.1 Clinical evidence .................................................................................................. 52 7.2.2 Evidence statements – clinical............................................................................. 52 7.3 Cost-effectiveness of clinic, home and ambulatory measurements................................... 53 7.3.1 Economic evidence – literature review ............................................................... 53 7.3.2 Economic evidence - original economic analysis................................................. 54 7.3.3 Evidence statements – economic ........................................................................ 59 7.4 Measurement protocols for diagnosing hypertension ....................................................... 60 7.4.1 Ambulatory blood pressure measurement ......................................................... 60Draft for consultation 2
  5. 5. Hypertension (partial update)Contents 7.4.2 Home blood pressure measurement ................................................................... 83 7.5 Link from evidence to recommendations ........................................................................... 89 7.6 Recommendations .............................................................................................................. 93 7.6.1 Research recommendation ................................................................................. 948 Assessing cardiovascular risk, target organ damage and secondary causes of hypertension ...95 8.1.1 Hypertension and cardiovascular disease ........................................................... 95 8.2 Routine clinical investigations ............................................................................................. 96 8.2.1 Urine testing for proteinuria................................................................................ 96 8.2.2 Blood electrolyte, urea, creatinine, glucose and total/HDL cholesterol levels ... 96 8.3 Cardiovascular Risk Assessment ......................................................................................... 97 8.4 Secondary Hypertension ..................................................................................................... 97 8.4.1 Renal and renovascular disease .......................................................................... 97 8.4.2 Pheochromocytoma ............................................................................................ 98 8.4.3 Hyperaldosteronism (primary aldosteronism) .................................................... 98 8.4.4 Cushings syndrome ............................................................................................. 98 8.5 Other identifiable causes of hypertension.......................................................................... 99 8.5.1 Hypothyroidism ................................................................................................... 99 8.5.2 Hyperthyroidism .................................................................................................. 99 8.5.3 Obstructive sleep apnoea .................................................................................... 99 8.5.4 Coarctation of aorta............................................................................................. 99 8.5.5 Acromegaly .......................................................................................................... 99 8.5.6 Drugs .................................................................................................................. 100 8.5.7 Recommendations ............................................................................................. 100 8.5.8 Research recommendation ............................................................................... 1009 Initiating and monitoring treatment, including blood pressure targets ................................ 101 9.1 Blood pressure thresholds for initiating pharmacological treatment .............................. 101 9.1.1 Clinical evidence ................................................................................................ 101 9.1.2 Evidence statement - clinical ............................................................................. 116 9.1.3 Evidence statement – economic........................................................................ 116 9.2 Treatment of people aged 80 years and greater .............................................................. 116 9.2.1 Clinical evidence ................................................................................................ 116 9.2.2 Economic evidence ............................................................................................ 119 9.2.3 Evidence statements – Clinical .......................................................................... 119 9.2.4 Evidence statements – Health economic .......................................................... 120 9.2.5 Link from evidence to recommendations.......................................................... 120 9.2.6 Recommendations ............................................................................................. 122 9.2.7 Recommendations for research ........................................................................ 123 9.3 Monitoring treatment efficacy.......................................................................................... 124Draft for consultation 3
  6. 6. Hypertension (partial update)Contents 9.3.1 Clinical evidence ................................................................................................ 124 9.3.2 Economic evidence ............................................................................................ 125 9.3.3 Link from evidence to recommendations.......................................................... 126 9.3.4 Recommendations ............................................................................................. 126 9.3.5 Research recommendations .............................................................................. 127 9.4 Blood pressure targets for treatment ............................................................................... 127 9.4.1 Clinical evidence ................................................................................................ 127 9.4.2 Health economic evidence ................................................................................ 141 9.4.3 Evidence statements – clinical........................................................................... 141 9.4.4 Evidence statements – economic ...................................................................... 142 9.4.5 Link from evidence to recommendations.......................................................... 142 9.4.6 Recommendations ............................................................................................. 144 9.5 Frequency of review.......................................................................................................... 14410 Integrating the assessment of blood pressure, target organ damage and cardiovascular risk assessment and clinical decision making regarding treatment initiation, treatment and targets ........................................................................................................................ 14511 Lifestyle interventions ....................................................................................................... 147 11.1 Overview ........................................................................................................................... 147 11.1.1 Managing changes in lifestyle............................................................................ 149 11.1.2 Diet .................................................................................................................... 149 11.1.3 Exercise .............................................................................................................. 151 11.1.4 Relaxation therapies .......................................................................................... 152 11.1.5 Multiple lifestyle interventions.......................................................................... 154 11.1.6 Alcohol ............................................................................................................... 156 11.1.7 Coffee................................................................................................................. 157 11.1.8 Reducing sodium (salt) intake ........................................................................... 157 11.1.9 Calcium supplements......................................................................................... 159 11.1.10 Magnesium supplements .................................................................................. 160 11.1.11 Potassium supplementation .............................................................................. 160 11.1.12 Combined salt supplements .............................................................................. 162 11.1.13 Drug therapy versus lifestyle change................................................................. 162 11.1.14 Smoking cessation ............................................................................................. 164 11.1.15 Recommendations ............................................................................................. 16412 Pharmacological interventions ........................................................................................... 166 12.1 2004 guidance: pharmacological interventions ................................................................ 169 12.1.1 Placebo controlled trials .................................................................................... 169 12.2 2006 rapid pharmacological update: head to head trials ................................................. 177 12.2.1 Clinical evidence statements: head-to-head drug comparisons ....................... 177 12.2.2 Meta-analysis results summary ......................................................................... 180Draft for consultation 4
  7. 7. Hypertension (partial update)Contents 12.3 2011 update: Pharmacological therapy for hypertension ................................................ 182 12.3.1 Angiotensin-converting enzyme inhibitors (ACEi) versus Angiotensin Receptor Blockers (ARB) .................................................................................... 182 12.3.2 Diuretics ............................................................................................................. 186 12.4 Cost-effectiveness analysis ............................................................................................... 214 12.4.1 Methodological introduction ............................................................................. 214 12.4.2 Results of the health economic model .............................................................. 216 12.4.3 Conclusions ........................................................................................................ 217 12.5 Step two therapy............................................................................................................... 218 12.6 Resistant hypertension ..................................................................................................... 222 12.7 Special groups for consideration....................................................................................... 225 12.7.1 People aged over 80 years................................................................................. 225 12.7.2 Younger people.................................................................................................. 225 12.7.3 Ethnicity ............................................................................................................. 225 12.7.4 Chronic kidney disease ...................................................................................... 231 12.7.5 Type 1 and Type 2 diabetes ............................................................................... 232 12.7.6 Women who are pregnant or breast-feeding.................................................... 232 12.8 Stopping treatment ........................................................................................................... 233 12.9 Link from evidence to recommendations ......................................................................... 234 12.9.1 Recommendations ............................................................................................. 242 12.9.2 Research recommendations .............................................................................. 24413 Patients’ perspectives ........................................................................................................ 245 13.1 Introduction ...................................................................................................................... 245 13.2 Discovering hypertension ................................................................................................. 245 13.3 Treatment ......................................................................................................................... 245 13.4 Living with hypertension ................................................................................................... 246 13.5 Education and adherence ................................................................................................. 246 13.5.1 Compliance with Prescribed Antihypertensive Medication .............................. 246 13.5.2 Implementing lifestyle measures ...................................................................... 248 13.5.3 Recommendations ............................................................................................. 24914 Reference list..................................................................................................................... 25015 Glossary ............................................................................................................................ 299Draft for consultation 5
  8. 8. Hypertension (partial update) Introduction 1 Rationale for update 2 This document is a partial update of Clinical Guideline 18 (2004) and Clinical Guideline 34 (2006) on 3 Essential Hypertension in adults. The sections that have not been amended are integrated with the 4 updated guidance in this document. Both guidelines are available in full in the appendices of the 5 document. 6 The sections that have been updated in 2011 are: 7 Diagnosis of Hypertension 8 Initiation and monitoring treatment, including blood pressure targets 9 Pharmacological interventions10 Improvements in methodology since 2006 mean the way information is presented may, at times, be11 inconsistent (for example, the style of review write-up and 2011 recommendations are not graded12 according to the strength of evidence, unlike those in the 2006).13 New or amended sections of the guideline are indicated with an ‘update’ panel in the right hand14 margin.151617 Draft for consultation 6
  9. 9. Hypertension (partial update) Introduction1 Guideline development group members2 Name Role Bernard Higgins Clinical Director, National Clinical Guideline Centre Bryan Williams Professor of Medicine, Guideline Development Group Chair Helen Williams Consultant Pharmacist for cardiovascular disease, Southwark Health and Social Care Jane Northedge Patient and care representative John Crimmins General Practitioner, Vale of Glamorgan Kate Lovibond Senior Health Economist, National Clinical Guideline Centre Mark Caulfield Professor of Clinical Pharmacology, Barts and the London School of Medicine Michaela Watts Hypertension Nurse Specialist, Addenbrooke’s Hospital, Cambridge Naomi Stetson Primary Care Nurse, Watling Medical Centre, Burnt Oak Paul Miller Senior Information Scientist, National Clinical Guideline Centre Rachel O’Mahony Senior Research Fellow, National Clinical Guideline Centre Richard McManus Professor of Primary Care Cardiovascular Research, University of Birmingham Shelley Mason Patient and carer representative Terry McCormack General Practitioner, Spring Vale Medical Centre, North Yorkshire Taryn Krause Senior Project Manager/Research Fellow, National Clinical Guideline Centre345 Draft for consultation 7
  10. 10. Hypertension (partial update) Introduction 1 Acknowledgments 2 The development of this guideline was greatly assisted by the following people: 3 Jill Cobb, Information Scientist, National Clinical Guideline Centre 4 Ralph Hughes, Health Economist, National Clinical Guideline Centre 5 Fatema Limbada, Project Coordinator, National Clinical Guideline Centre 6 Jill Parnham, Director of Operations, National Clinical Guideline Centre 7 David Wondering, Health Economic Lead, National Clinical Guideline Centre 8 Jacoby Patterson, Systematic Reviewer 9 Julie Brown, Systematic Reviewer10 Richard McManus, Professor of Primary Care Cardiovascular Research, University of Birmingham11 Sue Jowett, Senior Lecturer in Health Economics, University of Birmingham12 James Hodgkinson, Research Fellow, University of Birmingham13 Jonathan Mant, Professor of Primary Care Research, University of Cambridge14 Una Martin, Reader in Clinical Pharmacology, University of Birmingham15 Carl Heneghan, Reader in Evidence-Based Medicine, University of Oxford16 Richard Hobbs, Head of Primary Care Clinical Sciences, University of Birmingham.17 Draft for consultation 8
  11. 11. Hypertension (partial update) Introduction 1 Acronyms and abbreviations 2 ANOVA Analysis of variance 3 BNF British National Formulary 4 CCA Cost-consequences analysis 5 CEA Cost-effectiveness analysis 6 c.f. Confer (refer to) 7 CI / 95% CI Confidence interval / 95% confidence interval 8 CUA Cost-utility analysis 9 DH Department of Health10 DSA Deterministic Sensitivity Analysis11 ED Emergency Department12 EQ-5D EuroQol-5D13 GDG Guideline Development Group14 GP General Practitioner15 GRADE Grading of Recommendations Assessment, Development and Evaluation16 HES Hospital Episode Statistics17 HR Hazard Ratio18 HRQoL Health-related quality of life19 HTA Health technology assessment20 ICD-10 International Classification of Diseases, 10th edition21 ICER Incremental cost-effectiveness ratio22 IQR Interquartile range23 INMB Incremental Net Monetary Benefit24 IRR Inter-rater reliability25 ITT Intention to treat26 LOS Length of Stay27 LR+ Positive likelihood ratio28 LY Life-year29 MD Mean difference30 NCGC National Clinical Guideline Centre31 NHS National Health Service Draft for consultation 9
  12. 12. Hypertension (partial update) Introduction 1 NHSEED The NHS Economic Evaluation Database 2 NICE National Institute for Health and Clinical Excellence 3 NNT Number needed to treat 4 NPV Negative predictive value 5 OR Odds ratio 6 PICO Framework incorporating patients, interventions, comparison and outcome 7 PPP Purchasing Power Parity 8 PPV Positive predictive value 9 p.r.n Pro re nata10 PSA Probabilistic sensitivity analysis11 QALY Quality-adjusted life year12 QUADAS Quality assessment tool for diagnostic accuracy studies13 RCT Randomised controlled trial14 ROC Receiver operating characteristic15 RR Relative risk16 SD Standard deviation17 SE Standard error18 SPC Summary of product characteristics19 SR Systematic review202122 Draft for consultation 10
  13. 13. Hypertension (partial update) Introduction 1 1 Introduction 2 This guideline is for the clinical management of primary hypertension in adults (aged greater than 18 3 years). Hypertension (high blood pressure) is one of the most preventable causes of premature 4 morbidity and mortality world-wide. 5 Hypertension is a major risk factor for stroke (ischaemic and haemorrhagic), myocardial infarction, 6 heart failure, chronic kidney disease, peripheral vasculardisease, cognitive decline and premature 7 death. Untreated hypertension is associated a progressive rise in blood pressure, often culminating in 8 a treatment resistant state due to associated vascular and renal damage. 9 Blood pressure is quantified as diastolic and systolic pressures measured in millimetres of mercury10 (mmHg). The diastolic pressure represents the pressure during ventricular relaxation in diastole11 whereas the systolic pressure represents the peak pressure due to ventricular contraction during12 systole. Either or both pressures have specified upper limits of normal and elevation in either or both13 pressures are used to define hypertension.14 Blood pressure is normally distributed in the population and there is no natural cut-point above15 which "hypertension" definitively exists and below which, it does not. Epidemiological studies16 demonstrate that the aforementioned disease risk associated with blood pressure is a continuous17 relationship and above blood pressures of 115/70mmHg, the risk of cardiovascular events doubles18 for every 20/10mmHg rise in blood pressure. The threshold blood pressure determining the presence19 of hypertension is defined as the level of blood pressure above which treatment has been shown to20 reduce the development or progression of disease. Primary hypertension was previously termed21 “essential hypertension” because of a long-standing view that high blood pressure was sometimes22 “essential” to perfuse diseased and sclerotic arteries. It is now recognised that the diseased and Update 201123 sclerotic arteries were most often the consequence of the hypertension and thus the term “essential24 hypertension” is redundant and the “primary hypertension” is preferred. Primary hypertension refers25 to the majority of people with sustained high blood pressure (approximately 90%) encountered in26 clinical practice, for which there is no obvious, identifiable cause. The remaining 10% are termed27 "secondary hypertension" for which specific causes for the blood pressure elevation can be28 determined (for example, Conns adenoma, renovascular disease, or phaeochromocytoma).29 Primary hypertension is remarkably common in the UK population and the prevalence is strongly30 influenced by age and lifestyle factors. Systolic and/or diastolic blood pressures may be elevated.31 Systolic pressure elevation is the more dominant feature of hypertension in older patients and32 diastolic pressure more commonly elevated in younger patients, (those less than 50 years of age). At33 least one quarter of the adult population of the UK have hypertension, (blood pressure34 ≥140/90mmHg) and more than half of those over the age of 60 years. As the demographics of the UK35 shifts towards an older, more sedentary and obese population, the prevalence of hypertension and36 its requirement for treatment will continue to rise.37 Routine periodic screening for high blood pressure is now commonplace in the UK as part of National38 Service Frameworks for cardiovascular disease prevention. Consequently, the diagnosis, treatment39 and follow-up of patients with hypertension is one of the most common interventions in primary40 care, accounting for approximately 12% of Primary Care consultation episodes and approximately £141 billion in drug costs in 2006 .42 NICE first issued guidance for the management of hypertension in primary care in 2004. This was43 followed by a rapid update of the pharmacological treatment chapter of the guideline in 2006. The44 current partial update of the hypertension guideline is in response to the regular five year review45 cycle of existing NICE guidance. It began with a scoping exercise which identified key areas of the46 existing guideline for which new evidence had emerged that was likely to influence or change47 existing guideline recommendations. Draft for consultation 11
  14. 14. Hypertension (partial update) Introduction 1 Sections of the guideline that have not been updated continue to stand, however, wherever NICE has 2 subsequently issued new and related guidance relevant to existing recommendations, these have 3 been identified and cross-referred to in this partial update, examples include interventions on 4 lifestyle factors and public health policy recommendations such as smoking cessation, dietary salt 5 restriction, alcohol intake and cardiovascular disease prevention and cardiovascular disease risk 6 assessment. In addition, new NICE guidance developed in areas relevant to hypertension are also 7 highlighted and cross referenced (for example, chronic kidney disease, stroke, diabetes and 8 hypertension in pregnancy). 9 The recommendations that have been reviewed in this partial update of the guideline for the clinical10 management of primary hypertension in adults, include; blood pressure measurement for the Update 201111 diagnosis of hypertension; blood pressure thresholds for intervention with drug therapy and blood12 pressure targets for treatment; specific aspects of the recommendations for the pharmacological13 treatment of hypertension; the treatment of hypertension in the very elderly (people aged greater14 than 80 years); dilemmas surrounding decision making for treatment of hypertension in younger15 adults (less than 40 years); the treatment of drug resistant hypertension; and wherever appropriate,16 the impact of age and ethnicity on treatment recommendations.17 Finally, despite the fact that the treatment of hypertension has a large clinical trial evidence base to18 inform recommendations, an important aspect of the evidence review for guideline development is19 to identify where gaps in knowledge remain. In so doing, research questions have been identified to20 prompt the gathering of further evidence to continue the evolution of guidance and clinical practice. Draft for consultation 12
  15. 15. Hypertension (partial update) Development of the guideline 1 2 Development of the guideline 2 2.1 What is a NICE clinical guideline? 3 NICE clinical guidelines are recommendations for the care of individuals in specific clinical conditions 4 or circumstances within the NHS – from prevention and self-care through primary and secondary 5 care to more specialised services. We base our clinical guidelines on the best available research 6 evidence, with the aim of improving the quality of health care. We use predetermined and 7 systematic methods to identify and evaluate the evidence relating to specific review questions. 8 NICE clinical guidelines can: 9 provide recommendations for the treatment and care of people by health professionals10 be used to develop standards to assess the clinical practice of individual health professionals11 be used in the education and training of health professionals12 help patients to make informed decisions13 improve communication between patient and health professional14 While guidelines assist the practice of healthcare professionals, they do not replace their knowledge15 and skills.16 We produce our guidelines using the following steps:17 Guideline topic is referred to NICE from the Department of Health18 Stakeholders register an interest in the guideline and are consulted throughout the development19 process. Update 201120 The scope is prepared by the National Clinical Guideline Centre (NCGC)21 The NCGC establishes a guideline development group22 A draft guideline is produced after the group assesses the available evidence and makes23 recommendations24 There is a consultation on the draft guideline.25 The final guideline is produced.26 The NCGC and NICE produce a number of versions of this guideline:27 the full guideline contains all the recommendations, plus details of the methods used and the28 underpinning evidence29 the NICE guideline lists the recommendations30 the quick reference guide (QRG) presents recommendations in a suitable format for health31 professionals32 information for the public (‘understanding NICE guidance’ or UNG) is written using suitable33 language for people without specialist medical knowledge.34 This version is the full version. The other versions can be downloaded from NICE at www.nice.org.uk3536 2.2 Who developed this guideline?37 A multidisciplinary Guideline Development Group (GDG) comprising professional group members and38 consumer representatives of the main stakeholders developed this guideline (see section on39 Guideline Development Group Membership and acknowledgements). Draft for consultation 13
  16. 16. Hypertension (partial update) Development of the guideline 1 The National Institute for Health and Clinical Excellence funds the National Clinical Guideline Centre 2 (NCGC) and thus supported the development of this guideline. The GDG was convened by the NCGC 3 and chaired by Professor Bryan Williams in accordance with guidance from the National Institute for 4 Health and Clinical Excellence (NICE). 5 The group met every four weeks during the development of the guideline. At the start of the 6 guideline development process all GDG members declared interests including consultancies, fee-paid 7 work, share-holdings, fellowships and support from the healthcare industry. At all subsequent GDG 8 meetings, members declared arising conflicts of interest, which were also recorded in Error! 9 Reference source not found. Declarations of Interest.10 Members were either required to withdraw completely or for part of the discussion if their declared11 interest made it appropriate. The details of declared interests and the actions taken are shown in12 Error! Reference source not found. Declarations of Interest.13 Staff from the NCGC provided methodological support and guidance for the development process.14 The team working on the guideline included a project manager, systematic reviewers, health15 economists and information scientists. They undertook systematic searches of the literature,16 appraised the evidence, conducted meta analysis and cost effectiveness analysis where appropriate17 and drafted the guideline in collaboration with the GDG.1819 2.3 What this guideline covers20 Adults with hypertension (18 years and older). Update 201121 Particular consideration will be given to the needs of black people of African and Caribbean22 descent and minority ethnic groups where these differ from the needs of the general population.23 People aged 80 years or older.24 Ambulatory monitoring.25 Home blood pressure monitoring.26 Blood pressure thresholds for intervention and targets for treatment.27 First-line therapy options, for example angiotensin-converting enzyme inhibitors versus28 angiotension receptors blockers.29 Calcium-channel blockers versus diuretics as preferred components in step two of the treatment30 algorithm, for example, combination therapy.31 Adherence to medication.32 Provision of appropriate information and support.33 Resistant hypertension (that is, fourth-line therapy).34 Response to blood pressure lowering drugs according to age and ethnicity.35 For further details please refer to Error! Reference source not found. Scope and Error! Reference36 source not found. Review questions.37 2.4 What this guideline does not cover38 People with diabetes.39 Children and young people (younger than 18 years).40 Pregnant women.41 Secondary causes of hypertension (for example, Conns adenoma, phaeochromocytoma and42 renovascular hypertension). Draft for consultation 14
  17. 17. Hypertension (partial update) Development of the guideline 1 People with accelerated hypertension (that is, severe acute hypertension associated grade III 2 retinopathy and encephalopathy). 3 People with acute hypertension or high blood pressure in emergency care settings. 4 Prevention of hypertension. 5 Screening for hypertension. 6 Specialist management of secondary hypertension (that is, hypertension arising from other 7 medical conditions). 8 Non-pharmacological interventions. 9 2.5 Relationships between the guideline and other NICE guidance10 2.5.1 Related guidance11 Chronic heart failure. NICE clinical guideline 108 (2010). Available from12 www.nice.org.uk/guidance/CG10813 Hypertension in pregnancy. NICE clinical guideline 107 (2010). Available from14 www.nice.org.uk/guidance/CG10715 Prevention of cardiovascular disease at population level. NICE public health guidance 25 (2010). Update 201116 Available from www.nice.org.uk/guidance/PH2517 Type 2 diabetes. NICE clinical guideline 87 (2009, updated March 2010 and September 2010).18 Available from www.nice.org.uk/guidance/CG8719 Medicines adherence. NICE clinical guideline 76 (2009). Available from20 www.nice.org.uk/guidance/CG7621 Chronic kidney disease. NICE clinical guideline 73 (2008). Available from22 www.nice.org.uk/guidance/CG7323 Stroke. NICE clinical guideline 68 (2008). Available from www.nice.org.uk/guidance/CG6824 Lipid modification. NICE clinical guideline 67 (2008, reissued 2010). Available from25 www.nice.org.uk/guidance/CG6726 Continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea27 syndrome. NICE technology appraisal guidance 139 (2008). Available from28 www.nice.org.uk/guidance/TA13929 MI: secondary prevention. NICE clinical guideline 48 (2007). Available from30 www.nice.org.uk/guidance/CG4831 Obesity. NICE clinical guideline 43 (2006). Available from www.nice.org.uk/guidance/CG4332 Atrial fibrillation. NICE clinical guideline 36 (2006). Available from www.nice.org.uk/CG3633 . Draft for consultation 15
  18. 18. Hypertension (partial update) 2011 Methods 1 3 2011 Methods 2 This guidance was developed in accordance with the methods outlined in the NICE Guidelines 3 Manual 2009.427 4 3.1 Developing the review questions and outcomes 5 Review questions were developed in a PICO framework (patient, intervention, comparison and 6 outcome) for intervention reviews, and with a framework of population, index tests, reference 7 standard and target condition for reviews of diagnostic test accuracy. This was to guide the literature 8 searching process and to facilitate the development of recommendations by the guideline 9 development group (GDG). They were drafted by the NCGC technical team and refined and validated10 by the GDG. The questions were based on the key clinical areas identified in the scope (Error!11 Reference source not found. Scope) and a list can be found in Error! Reference source not found.12 Review Questions. Further information on the outcome measures examined follows this section.13 3.2 Searching for evidence14 3.2.1 Clinical literature search15 Systematic literature searches were undertaken to identify evidence within published literature in16 order to answer the review questions as per The Guidelines Manual (2009).427 Clinical databases Update 201117 were searched using relevant medical subject headings, free-text terms and study type filters where18 appropriate. Studies published in languages other than English were not reviewed. All searches were19 conducted on core databases, MEDLINE, Embase, Cinahl and The Cochrane Library. All searches were20 updated on 29th November 2010. No papers after this date were considered .21 Search strategies were checked by looking at reference lists of relevant key papers, checking search22 strategies in other systematic reviews and asking the GDG for known studies. The questions, the23 study types applied, the databases searched and the years covered can be found in Error! Reference24 source not found. Literature search strategies.25 During the scoping stage, a search was conducted for guidelines and reports on the websites listed26 below and via organisations relevant to the topic. Searching for grey literature or unpublished27 literature was not undertaken. All references sent by stakeholders were considered.28 Guidelines International Network database (www.g-i-n.net)29 National Guideline Clearing House (www.guideline.gov/)30 National Institute for Health and Clinical Excellence (NICE) (www.nice.org.uk)31 National Institutes of Health Consensus Development Program (consensus.nih.gov/)32 National Library for Health (www.library.nhs.uk/)33 3.2.1.1 Call for evidence34 The GDG decided to initiate a ‘call for evidence’ for meta analyses, based on a systematic review,35 that include studies that use ambulatory blood pressure measurement as the reference standard and36 report sensitivity and specificity of home and/or clinic blood pressure measurement, as they believed37 that important evidence existed that would not be identified by the standard searches. The NCGC38 contacted all registered stakeholders and asked them to submit any relevant published or39 unpublished evidence. Draft for consultation 16
  19. 19. Hypertension (partial update) 2011 Methods 1 3.2.2 Health economic literature search 2 Systematic literature searches were also undertaken to identify health economic evidence within 3 published literature relevant to the review questions. The evidence was identified by conducting a 4 broad search relating to the guideline population in the NHS economic evaluation database (NHS 5 EED), the Health Economic Evaluations Database (HEED) and health technology assessment (HTA) 6 databases from 2003 onwards to find anything published since the original guideline. There were two 7 questions not covered in either the original guideline or the previous rapid update, for which 8 additional searches with no date restrictions were carried out. Additionally, the search was run on 9 MEDLINE and Embase, with a specific economic filter, from 2009, to ensure recent publications that10 had not yet been indexed by these databases were identified. Studies published in languages other11 than English were not reviewed. Where possible, searches were restricted to articles published in12 English language.The search strategies for health economics are included in Error! Reference source13 not found. Literature search strategies. All searches were updated on 29th November 2010. No14 papers published after this date were considered.15 3.2.2.1 Call for evidence16 The GDG decided to initiate a ‘call for evidence’ for cost-effectiveness analyses from a UK17 perspective, using methods in line with the NICE reference case, comparing ambulatory, home and18 clinic blood pressure measurement in the diagnosis of hypertension, as they believed that important19 evidence existed that would not be identified by the standard searches. The NCGC contacted all20 registered stakeholders and asked them to submit any relevant published or unpublished evidence.21 3.2.3 Evidence of effectiveness Update 201122 The Research Fellow:23 Identified potentially relevant studies for each review question from the relevant search results24 by reviewing titles and abstracts – full papers were then obtained.25 Reviewed full papers against pre-specified inclusion / exclusion criteria to identify studies that26 addressed the review question in the appropriate population and reported on outcomes of27 interest (review protocols are included in Error! Reference source not found.Review protocols).28 Critically appraised relevant studies using the appropriate checklist as specified in The Guidelines29 Manual 42730 Extracted key information about the study’s methods and results into evidence tables (evidence31 tables are included in Appendix D: Evidence tables – clinical studies and Appendix G: Evidence32 tables – health economic studies.33 Generated summaries of the evidence by outcome (included in the relevant chapter write-ups):34 o Randomised studies: meta analysed, where appropriate and reported in GRADE profiles (for35 clinical studies) – see below for details36 o Observational studies: data has been presented for individual studies narratively or in37 summary tables (GRADE profiles have not been generated)38 o Diagnostic studies: data has been presented for individual studies narratively or in summary39 tables (GRADE profiles have not been generated)40 o Qualitative studies: each study summarised in a table where possible, otherwise presented in a41 narrative.42 3.2.4 Inclusion/exclusion43 See the review protocols in Error! Reference source not found. Review Protocols for full details. Draft for consultation 17
  20. 20. Hypertension (partial update) 2011 Methods 1 3.2.5 Methods of combining clinical studies 2 Data synthesis for intervention reviews 3 Where possible, meta-analyses were conducted to combine the results of studies for each review 4 question using Cochrane Review Manager (RevMan5) software. Fixed-effects (Mantel -Haenszel) 5 techniques were used to calculate risk ratios (relative risk) for the following binary outcomes: 6 angioedema. Where reported, time-to-event data was presented as a hazard ratio for the following 7 binary outcomes: mortality, stroke, MI, heart failure, new onset diabetes, vascular procedures, 8 angina requiring hospitalisation, study drug withdrawal. The continuous outcome blood pressure 9 (mmHg)] was analysed using an inverse variance method for pooling weighted mean differences and10 where the studies had different scales, standardised mean differences were used. No quality of life11 outcome data was reported by any of the studies included in the 2012 update reviews12 Statistical heterogeneity was assessed by considering the chi-squared test for significance at p<0.1 or13 an I-squared inconsistency statistic of >50% to indicate significant heterogeneity. Where significant14 heterogeneity was present, we carried out sensitivity analysis based on the quality of studies, with15 particular attention paid to allocation concealment, blinding and loss to follow-up (missing data). In16 cases where there was inadequate allocation concealment, unclear blinding, high loss to follow-up (≥17 20% missing data for studies ≤2 years follow-up and ≥30% for those with >2 years follow-up) or18 differential missing data, this was examined in a sensitivity analysis. For the latter, the duration of19 follow up was also taken into consideration prior to including in a sensitivity analysis.20 Assessments of potential differences in effect between subgroups were based on the chi-squared21 tests for heterogeneity statistics between subgroups. If no sensitivity analysis was found to22 completely resolve statistical heterogeneity then a random effects (DerSimonian and Laird) model Update 201123 was also explored to provide a more conservative estimate of the effect.24 The means and standard deviations of continuous outcomes were required for meta-analysis.25 However, in cases where standard deviations were not reported, the standard error was calculated if26 the p-values or 95% confidence intervals were reported and meta-analysis was undertaken with the27 mean and standard error using the generic inverse variance method in Cochrane Review Manager28 (RevMan5) software. Where p values were reported as “less than”, a conservative approach was29 undertaken. For example, if the p value was reported as “p ≤0.001”, the calculations for standard30 deviations will be based on a p value of 0.001. If these statistical measures were un available then31 the methods described in section 16.1.3 of the Cochrane Handbook ‘Missing standard deviations’32 were applied as the last resort.33 3.2.6 Appraising the quality of evidence by outcomes34 The evidence for outcomes from the included RCT studies were evaluated and presented using an35 adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE)36 toolbox’ developed by the international GRADE working group37 (http://www.gradeworkinggroup.org/). The software (GRADEpro) developed by the GRADE working38 group was used to assess the quality of each outcome, taking into account individual study quality39 and the meta-analysis results. The summary of findings was presentedas an ‘evidence profile,’ a40 single table that includes details of the quality assessment as well as pooled outcome data, where41 appropriate, an absolute measure of intervention effect and the summary of quality of evidence for42 that outcome. In this table, the columns for intervention and control indicate the sum of the sample43 size for continuous outcomes. For binary outcomes such as number of patients with an adverse44 event, the event rates (n/N: number of patients with events divided by sum of number of patients)45 are shown with percentages. Reporting or publication bias was only taken into consideration in the46 quality assessment and included in the Clinical Study Characteristics table if it was apparent. Draft for consultation 18
  21. 21. Hypertension (partial update) 2011 Methods 1 Each outcome was examined separately for the quality elements listed and defined in Table 1 and 2 each graded using the quality levels listed in Table 2: The main criteria considered in the rating of 3 these elements are discussed below (see 3.2.7 Grading of Evidence). Footnotes were used to 4 describe reasons for grading a quality element as having serious or very serious problems. The 5 ratings for each component were summed to obtain an overall assessment for each outcome. 6 GRADE is currently designed only for randomised trials and observational studies. 7 Table 1: Description of quality elements in GRADE for intervention studies. Quality element Description Limitations 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 Inconsistency refers to an unexplained heterogeneity of results. Indirectness Indirectness refers to differences in study population, intervention, comparator and outcomes between the available evidence and the review question, or recommendation made. Imprecision 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 Publication bias is a systematic underestimate or an overestimate of the underlying beneficial or harmful effect due to the selective publication of studies. 8 9 Table 2: Levels of quality elements in GRADE Update 2011 Level Description None There are no serious 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 levels1011 Table 3: Overall quality of outcome evidence in GRADE Level Description High Further research is very unlikely to change our confidence in the estimate of effect Moderate Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low 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 Very low Any estimate of effect is very uncertain1213 3.2.7 Grading the quality of clinical evidence14 After results were pooled, the overall quality of evidence for each outcome was considered. The15 following procedure was adopted when using GRADE:16 1. A quality rating was assigned, based on the study design. RCTs start HIGH and observational17 studies as LOW.18 2. The rating for RCTs was then downgraded for the specified criteria: Study limitations,19 inconsistency, indirectness, imprecision and reporting bias. These criteria are detailed below. Due20 to the wide diversity of study design, data reported and data analysis methods of the21 observational studies that were included in this guideline , it was very difficult to compare studies Draft for consultation 19
  22. 22. Hypertension (partial update) 2011 Methods 1 for quality and therefore observational studies were not downgraded or upgraded in GRADE, and 2 all remained as LOW quality evidence. 3 3. The downgraded marks were then summed and the overall quality rating was revised. For 4 example, all RCTs started as HIGH and the overall quality became MODERATE, LOW or VERY LOW 5 if 1, 2 or 3 points were deducted respectively. 6 4. The reasons or criteria used for downgrading were specified in the footnotes. 7 The details of criteria used for each of the main quality element are discussed further in the following 8 sections 3.3.5 to 3.3.8/3.3.9 [if section for publication bias is relevant]. 9 3.2.8 Study limitations10 The main limitations for randomised controlled trials are listed in Table 4.11 Table 4: Study limitations of randomised controlled trials Limitation Explanation Allocation Those enrolling patients are aware of the group to which the next enrolled patient concealment will be allocated (major problem in “pseudo” or “quasi” randomised trials with allocation by day of week, birth date, chart number, etc) Lack of blinding Patient, caregivers, those recording outcomes, those adjudicating outcomes, or data analysts are aware of the arm to which patients are allocated Incomplete Loss to follow-up not accounted and failure to adhere to the intention to treat accounting of principle when indicated patients and Update 2011 outcome events Selective outcome Reporting of some outcomes and not others on the basis of the results reporting 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 outcomes Carry-over effects in cross-over trials Recruitment bias in cluster randomised trials12 3.2.9 Inconsistency13 Inconsistency refers to an unexplained heterogeneity of results. When estimates of the treatment14 effect across studies differ widely (i.e. heterogeneity or variability in results), this suggests true15 differences in underlying treatment effect. When heterogeneity exists (Chi square p<0.1 or I- squared16 inconsistency statistic of >50%), but no plausible explanation can be found, the quality of evidence17 was downgraded by one or two levels, depending on the extent of uncertainty to the results18 contributed by the inconsistency in the results.19 If inconsistency could be explained based on pre-specified subgroup analysis, the GDG took this into20 account and considered whether to make separate recommendations based on the identified21 explanatory factors, i.e. population and intervention. Where subgroup analysis gave a plausible22 explanation of heterogeneity, the quality of evidence was not downgraded.23 3.2.10 Indirectness24 Directness refers to the extent to which the populations, intervention, comparisons and outcome25 measures are similar to those defined in the inclusion criteria for the reviews. Indirectness is Draft for consultation 20
  23. 23. Hypertension (partial update) 2011 Methods1 important when these differences are expected to contribute to a difference in effect size, or may2 affect the balance of harms and benefits considered for an intervention.3 3.2.11 Imprecision4 The criteria applied for imprecision are based on the confidence intervals for pooled or the best5 estimate of effect as illustrated in Figure 1 and outlined in Table 5.6 Table 5: Criteria applied to determine precision Dichotomous and continuous outcomes Update 2011 The 95% confidence interval (or alternative estimate of precision) around the pooled or best estimate of effect: 1. 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: ‘no serious imprecision’ 2. Crosses one of the two MID thresholds (appreciable benefit or appreciable harm); defined as imprecise Rating for precision: ‘serious’ 3. Crosses both of the two MID thresholds ( appreciable benefit and appreciable harm); defined as imprecise Rating for precision: ‘very serious’7 Draft for consultation 21
  24. 24. Hypertension (partial update) 2011 Methods Figure 1: Illustration of precise and imprecise outcomes based on the confidence interval of outcomes in a forest plot MID MID NO SERIOUS IMPRECISION SERIOUS IMPRECISION -1 VERY SERIOUS IMPRECISION -2 0.75 1.0 1.25 Appreciable benefit Non-appreciable benefit or harm Appreciable harm (AEs and (AEs and harmful harmful outcomes) / outcomes) / appreciable benefit appreciable harm (effectiveness and beneficial (effectiveness and outcomes) beneficial outcomes)1 MID = minimal important difference determined for each outcome. The MIDs are the threshold for2 appreciable benefits and harms. The confidence intervals of the top five points of the diagram3 (within the green sector or within the purple sector) are considered precise because the upper and4 lower limits of the point estimate (diamond shapes) do not cross the pre-defined MID. Conversely,5 the bottom three points of the diagram are considered imprecise because the upper and lower limits6 of the point estimates (diamonds) for each of them cross the pre-defined MID and reduce the Update 20117 certainty of the result.8 The following are the MID for the outcomes in this guideline (as agreed by the GDG).9 Table 6: MIDs for the outcomes used in this guidance Outcome Relative risk reduction Mortality from any cause 10% Stroke (ischaemic or haemorrhagic) 10% Myocardial infarction (MI) (including, where reported, silent MI) 10% Draft for consultation 22
  25. 25. Hypertension (partial update) 2011 Methods Outcome Relative risk reduction Heart failure 10% New onset diabetes 10% Vascular procedures (including both coronary and carotid artery procedures) 10% Angina requiring hospitalisation 10% Health-related quality of life (to use what is reported by trials) As defined in literature for each specific QoL measure Major adverse cardiac and cerebrovascular events (MAACE): fatal and non- 15% fatal 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 10% and for adherence Angioedema in black people of African and Caribbean descent 10% Blood pressure 5 mmHg 1 3.3 Evidence of cost-effectiveness 2 Evidence on cost-effectiveness related to the key clinical issues being addressed in the guideline was 3 sought. The health economist undertook: 4 A systematic review of the economic literature 5 New cost-effectiveness analysis in priority areas 6 3.3.1 Literature review 7 The Health Economist: 8 Identified potentially relevant studies for each review question from the economic search results 9 by reviewing titles and abstracts – full papers were then obtained.10 Reviewed full papers against pre-specified inclusion / exclusion criteria to identify relevant studies11 (see below for details). Update 201112 Critically appraised relevant studies using the economic evaluations checklist as specified in The13 Guidelines Manual.42714 Extracted key information about the study’s methods and results into evidence tables (evidence15 tables are included in Error! Reference source not found. Evidence tables – health economic16 studies.17 Generated summaries of the evidence in NICE economic evidence profiles (included in the18 relevant chapter write-ups) – see below for details.19 Inclusion/exclusion20 Full economic evaluations (studies comparing costs and health consequences of alternative courses21 of action: cost–utility, cost-effectiveness, cost-benefit and cost-consequence analyses) and22 comparative costing studies that addressed the review question in the relevant population were23 considered potentially applicable as economic evidence.24 Studies were excluded if they only reported cost per hospital (not per patient), or only reported25 average cost effectiveness without disaggregated costs and effects. Abstracts, posters, reviews,26 letters/editorials, foreign language publications and unpublished studies were excluded. Studies27 judged to have an applicability rating of ‘not applicable’ were excluded (this included studies that28 took the perspective of a non-OECD country). Draft for consultation 23
  26. 26. Hypertension (partial update) 2011 Methods 1 Remaining studies were prioritised for inclusion based on their relative applicability to the 2 development of this guideline and the study limitations. For example, if a high quality, directly 3 applicable UK analysis was available other less relevant studies may have been excluded and this is 4 noted in the relevant section. 5 For more details about the assessment of applicability and methodological quality see the economic 6 evaluation checklist (The Guidelines Manual, Appendix H 427 and the health economics research 7 protocol in Error! Reference source not found. Review protocols. 8 When no relevant economic analyses were identified in the economic literature review, relevant UK 9 NHS unit costs were presented to the GDG to inform consideration of cost effectiveness.10 NICE economic evidence profiles11 The NICE economic evidence profile has been used to summarise cost and cost-effectiveness12 estimates. The economic evidence profile shows, for each economic study, an assessment of13 applicability and methodological quality, with footnotes indicating the reasons for the assessment.14 These assessments were made by the health economist using the economic evaluation checklist from15 The Guidelines Manual, Appendix H.427 It also shows incremental costs, incremental outcomes (for16 example, QALYs) and the incremental cost-effectiveness ratio from the primary analysis, as well as17 information about the assessment of uncertainty in the analysis. See Table 7 for more details.18 If a non-UK study was included in the profile, the results were converted into pounds sterling using19 the appropriate purchasing power parity.46420 Table 7: Content of NICE economic profile Update 2011 Item Description Study First author name, reference, date of study publication and country perspective. Limitations 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. Applicability 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. Other comments Particular issues that should be considered when interpreting the study. Incremental cost The mean cost associated with one strategy minus the mean cost of a comparator strategy. Incremental effects The mean QALYs (or other selected measure of health outcome) associated with one strategy minus the mean QALYs of a comparator strategy. ICER Incremental cost-effectiveness ratio: the incremental cost divided by the respective QALYs gained. Draft for consultation 24
  27. 27. Hypertension (partial update) 2011 Methods Item Description Uncertainty A summary of the extent of uncertainty about the ICER reflecting the results of deterministic or probabilistic sensitivity analyses, or stochastic analyses of trial data, as appropriate. 1 a) Limitations and applicability were assessed using the economic evaluation checklist from The Guidelines Manual, 427 2 Appendix H 3 3.3.2 Undertaking new health economic analysis 4 As well as reviewing the published economic literature for each review question, as described above, 5 new cost-effectiveness analysis was undertaken by the Health Economist in priority areas. Priority 6 areas were agreed by the GDG after formation of the review questions and consideration of the 7 available health economic evidence. 8 Additional data for the analysis were identified as required through additional literature searches 9 undertaken by the Health Economist, and discussion with the GDG. Model structure, inputs and10 assumptions were explained to and agreed by the GDG members during meetings, and they11 commented on subsequent revisions. Results were presented in GDG meetings for discussion and12 interpretation.13 The priority area identified for new economic analysis was diagnosis of hypertension – see ‘Error!14 Reference source not found. Error! Reference source not found.’ for full methods. The 2006 cost-15 effectiveness analysis of drug treatment was also updated – see ‘Error! Reference source not found.16 Error! Reference source not found.’ for full methods.17 3.3.3 Cost-effectiveness criteria18 NICE’s report ‘Social value judgements: principles for the development of NICE guidance’ sets out the Update 201119 principles that GDGs should consider when judging whether an intervention offers good value for20 money.426,42721 In general, an intervention was considered to be cost effective if either of the following criteria22 applied (given that the estimate was considered plausible):23 a) The intervention dominated other relevant strategies (that is, it was both less costly in terms of24 resource use and more clinically effective compared with all the other relevant alternative25 strategies), or26 b) The intervention cost less than £20,000 per quality-adjusted life-year (QALY) gained compared27 with the next best strategy.28 If the GDG recommended an intervention that was estimated to cost more than £20,000 per QALY29 gained, or did not recommend one that was estimated to cost less than £20,000 per QALY gained,30 the reasons for this decision are discussed explicitly in the ‘from evidence to recommendations’31 section of the relevant chapter with reference to issues regarding the plausibility of the estimate or32 to the factors set out in the ‘Social value judgements: principles for the development of NICE33 guidance’.42634 3.4 Developing recommendations35 Over the course of the guideline development process, the GDG was presented with:36 Evidence tables of the clinical and economic evidence reviewed from the literature. All evidence37 tables are in Error! Reference source not found. Evidence Tables – Clinical studies and Error!38 Reference source not found.Evidence tables – health economic studies.39 Summary of clinical and economic evidence and quality Draft for consultation 25
  28. 28. Hypertension (partial update) 2011 Methods 1 Forest plots and summary ROC curves 2 A description of the methods and results of the cost-effectiveness analysis undertaken for the 3 guideline 4 The main considerations specific to each recommendation are outlined in the link from evidence to 5 recommendation section preceding the recommendation section. 6 3.4.1 Research recommendations 7 When areas were identified for which good evidence was lacking, the guideline development group 8 considered making recommendations for future research. Decisions about inclusion were based on 9 factors such as:10 the importance to patients or the population11 national priorities12 potential impact on the NHS and future NICE guidance13 ethical and technical feasibility14 3.4.2 Validation process15 The guidance is subject to an eight week public consultation and feedback as part of the quality16 assurance and peer review the document. All comments received from registered stakeholders are17 responded to in turn and posted on the NICE website when the pre-publication check of the full18 guideline occurs.19 3.4.3 Updating the guideline20 Following publication, and in accordance with the NICE guidelines manual, NICE will ask a National21 Collaborating Centre or the National Clinical Guideline Centre to advise NICE’s Guidance executive22 whether the evidence base has progressed significantly to alter the guideline recommendations and23 warrant an update.24 3.4.4 Disclaimer25 Health care providers need to use clinical judgement, knowledge and expertise when deciding26 whether it is appropriate to apply guidelines. The recommendations cited here are a guide and may27 not be appropriate for use in all situations. The decision to adopt any of the recommendations cited28 here must be made by the practitioners in light of individual patient circumstances, the wishes of the29 patient, clinical expertise and resources.30 The National Clinical Guideline Centre disclaims any responsibility for damages arising out of the use Update 201131 or non-use of these guidelines and the literature used in support of these guidelines.32 3.4.5 Funding33 The National Clinical Guideline Centre was commissioned by the National Institute for Health and34 Clinical Excellence to undertake the work on this guideline.3536 Draft for consultation 26
  29. 29. Hypertension (partial update) 2004 Methods 1 4 2004 Methods 2 4.1.1 Review methods 3 The aim of reviewing was to identify and synthesise relevant published and unpublished evidence to 4 allow recommendations to be evidence-based wherever possible.621 The search was carried out using 5 the electronic databases MEDLINE, EMBASE and CENTRAL, attempting to locate systematic reviews 6 and meta-analyses, and original randomised trials using a combination of subject heading and free 7 text searches. We made extensive use of high quality recent review articles and bibliographies, as 8 well as contact with subject area experts. New searches were concentrated in areas of importance to 9 the guideline development process, for which existing systematic reviews were unable to provide10 valid or up to date answers. The expert knowledge and experience of group members also backed up11 the search of the literature.12 Electronic searches used a sensitive search strategy based on a combination of text and index terms13 to locate randomised controlled trials of treatments relevant to the guideline. If data necessary for14 our analyses were not reported, we wrote to authors or sponsoring agencies. We are grateful to15 investigators and sponsors who provided unpublished information to aid our work.16 We assessed the quality of relevant studies retrieved and their ability to provide valid answers to the17 clinical questions addressed by the group. Assessment of study quality concentrated on internal18 validity (the extent to which the study measured what it intended to measure), external validity (the19 extent to which study findings could be generalised to other treatment settings) and construct20 validity (the extent to which measurement corresponded to theoretical understanding of a disease). 1382122 Table 8: Quality Criteria for Randomised Controlled Trials Appropriateness of inclusion and exclusion criteria Concealment of allocation Blinding of patients Blinding of health professionals Blinding of data collectors/outcome assessors Completeness and length of follow up Appropriateness of outcome measures23 Once data had been abstracted from individual papers and their quality assessed, the information24 was synthesised. Individual trials often have an insufficient sample size to identify significant25 outcomes with confidence80, so where appropriate, the results of randomised studies were26 combined using meta-analytic techniques 174. Questions were answered using the best evidence27 available. When considering the effect of an intervention, if this could be addressed by the best study28 design then weaker designs were not reviewed. Where studies were of poor quality, or contained29 patient groups considered likely to have different responses, the effects of inclusion or exclusion30 were examined in sensitivity analyses. No trials that met our inclusion criteria were excluded from31 the primary analyses. However, where data on relevant outcomes were not available, these studies32 could not be included, thus leading to the potential for publication bias.33 Review criteria34 Scoping work revealed a vast number of trials of pharmaceutical interventions. Recent work suggests35 that study size is a useful proxy for study quality.188,222 Consequently to achieve the task in the36 timescale provided we reviewed only those pharmaceutical studies which enrolled 200 or more37 patients. Since the prime motivation for treatment in hypertension, an asymptomatic condition, is Draft for consultation 27

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