Cochrane Database of Systematic Reviews Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction (Review) Martin N, Manoharan K, Thomas J, Davies C, Lumbers RT Martin N, Manoharan K, Thomas J, Davies C, Lumbers RT. Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction. Cochrane Database of Systematic Reviews 2018, Issue 6. Art. No.: CD012721. DOI: 10.1002/14651858.CD012721.pub2. www.cochranelibrary.com Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction (Review) Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER....................................... 1 ABSTRACT ...................................... 1 PLAINLANGUAGESUMMARY . 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . ..... 4 BACKGROUND .................................... 6 OBJECTIVES ..................................... 7 METHODS ...................................... 7 Figure1. ..................................... 9 RESULTS....................................... 11 Figure2. ..................................... 14 Figure3. ..................................... 15 ADDITIONALSUMMARYOFFINDINGS . 20 DISCUSSION ..................................... 27 AUTHORS’CONCLUSIONS . 28 ACKNOWLEDGEMENTS . 29 REFERENCES ..................................... 29 CHARACTERISTICSOFSTUDIES . 57 DATAANDANALYSES. 164 Analysis 1.1. Comparison 1 Beta-blockers versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR). 166 Analysis 1.2. Comparison 1 Beta-blockers versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR)...................................... 167 Analysis 1.3. Comparison 1 Beta-blockers versus placebo or no treatment, Outcome 3 All-cause mortality (RR). 168 Analysis 1.4. Comparison 1 Beta-blockers versus placebo or no treatment, Outcome 4 Quality of life (Minnesota). 168 Analysis 1.5. Comparison 1 Beta-blockers versus placebo or no treatment, Outcome 5 Withdrawal due to adverse event. 169 Analysis 2.1. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR). 170 Analysis 2.2. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR). 171 Analysis 2.3. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 3 Heart failure hospitalisation (HR). 172 Analysis 2.4. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 4 Hyperkalaemia. 173 Analysis 2.5. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 5 All-cause mortality(RR). ................................. 174 Analysis 2.6. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 6 Quality of life. ..................................... 175 Analysis 2.7. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 7 Quality of life(KCCQ)................................... 176 Analysis 2.8. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 8 Quality of life(Minnesota).. 177 Analysis 2.9. Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 9 Withdrawal duetoadverseevent. 178 Analysis 3.1. Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR). 179 Analysis 3.2. Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR). 180 Analysis 3.3. Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 3 Hyperkalaemia. 181 Analysis 3.4. Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 4 All- causemortality(RR). 181 Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction i (Review) Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.5. Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 5 Quality oflife(Minnesota).. 182 Analysis 3.6. Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 6 Withdrawal due to adverse event. 183 Analysis 4.1. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 1 Cardiovascular mortality(RR). ................................. 184 Analysis 4.2. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 2 Cardiovascular mortality(HR). ................................. 185 Analysis 4.3. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 3 Heart failure hospitalisation(RR). 185 Analysis 4.4. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 4 Heart failure hospitalisation(HR). 186 Analysis 4.5. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 5 Hyperkalaemia. 187 Analysis 4.6. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 6 All-cause mortality (RR)...................................... 188 Analysis 4.7. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 7 All-cause mortality (HR). .................................... 189 Analysis 4.8. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 8 Quality of life (Minnesota). .................................. 190 Analysis 4.9. Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 9 Withdrawal due to adverseevent................................... 191 APPENDICES ..................................... 191 CONTRIBUTIONSOFAUTHORS . 195 DECLARATIONSOFINTEREST . 195 SOURCESOFSUPPORT . 195 DIFFERENCES BETWEEN PROTOCOL AND REVIEW . .... 196 Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction ii (Review) Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction Nicole Martin1, Karthick Manoharan2, James Thomas3, Ceri Davies4, R Thomas Lumbers5 1Farr Institute of Health Informatics Research, University College London, London, UK. 2Emergency Department, John Radcliffe Hospital, London, UK. 3EPPI-Centre, Social Science Research Unit, UCL Institute of Education, University College London, London, UK. 4Department of Cardiology, Barts Heart Centre, St Bartholomew’s Hospital, London, UK. 5Institute of Health Informatics, University College London, London, UK Contact address: R Thomas Lumbers, Institute of Health Informatics, University College London, London, UK. [email protected]. Editorial group: Cochrane Heart Group. Publication status and date: New, published in Issue 6, 2018. Citation: Martin N, Manoharan K, Thomas J, Davies C, Lumbers RT.Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction. Cochrane Database of Systematic Reviews 2018, Issue 6. Art. No.: CD012721. DOI: 10.1002/14651858.CD012721.pub2. Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT Background Beta-blockers and inhibitors of the renin-angiotensin aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction. There is uncertainty whether these treatments are beneficial for people with heart failure with preserved ejection fraction and a comprehensive review of the evidence is required. Objectives To assess the effects of beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with heart failure with preserved ejection fraction. Search methods We searched CENTRAL, MEDLINE, Embase and two clinical trial registries on 25 July 2017 to identify eligible studies. Reference lists from primary studies and review articles were checked for additional studies. There were no language or date restrictions. Selection criteria We included randomised controlled trials with a parallel group design enrolling adult participants with heart failure with preserved ejection fraction, defined by a left ventricular ejection fraction of greater than 40 percent. Data collection and analysis Two review authors independently selected studies for inclusion and extracted data. The outcomes assessed included cardiovascular mortality, heart failure hospitalisation, hyperkalaemia, all-cause mortality and quality of life. Risk ratios (RR) and, where possible, hazard ratios (HR) were calculated for dichotomous outcomes. For continuous data, mean difference (MD) or standardised mean difference (SMD) were calculated. We contacted trialists where neccessary to obtain missing data. Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction 1 (Review) Copyright © 2018 The Cochrane Collaboration. Published by John