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Do beta-blockers and inhibitors of the renin–angiotensin aldosterone system improve outcomes in patients with heart failure and left ventricular ejection fraction >40%?
  1. R Thomas Lumbers1,2,3,
  2. Nicole Martin1,
  3. Karthick Manoharan4,
  4. James Thomas5,
  5. L Ceri Davies3
  1. 1Institute of Health Informatics, University College London, London, UK
  2. 2Health Data Research UK, London, UK
  3. 3Barts Heart Centre, St. Bartholomew’s Hospital, London, UK
  4. 4Department of Cardiology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK
  5. 5EPPI-Centre, University College London, London, UK
  1. Correspondence to Dr R Thomas Lumbers, Institute of Health Informatics, University College London, London WC1E 6BT, UK; t.lumbers{at}

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Approximately half of all patients with heart failure have preserved left ventricular ejection fraction (LVEF), yet in contrast to heart failure with reduced ejection fraction (HFrEF), no treatments have yet been shown to be effective at improving outcomes.1 Neurohumoral activation is observed in heart failure across the full spectrum of left ventricular function2; however, pharmacological inhibition of the renin–angiotensin aldosterone system (RAAS) has only been shown to improve survival and reduce hospitalisation in HFrEF.1 We therefore performed a Cochrane systematic review and meta-analysis to synthesize all available evidence to investigate the effects of RAAS inhibition in heart failure patients with a LVEF >40%. This patient population comprises both heart failure with mid-range ejection fraction (40%–49%) and heart   failure with preserved ejection fraction (HFpEF, >50%), as defined in current guidelines1.


We searched for randomised controlled trials (RCTs) investigating pharmacological neurohumoral inhibition with beta-blockers (BB), ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), mineralocorticoid receptor antagonists (MRA) and angiotensin receptor–neprilysin inhibitors, in adult patients (≥ 18  years  old) with heart failure and LVEF >40%. We searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials on 25 July 2017. The primary outcomes were cardiovascular (CV) mortality, heart failure hospitalisation and hyperkalaemia; and the secondary outcomes were all-cause mortality, quality of life (measured using either the Minnesota Living with Heart Failure (MLHF) Questionnaire or Kansas City Cardiomyopathy Questionnaire). We undertook meta-analysis for each drug class and outcome. when data were available from more than one clinical trial. We used a fixed-effect model unless heterogeneity was high (I²≥50%) when a random-effect model was used. We assessed the quality of evidence for each comparison using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology. The review was conducted in accordance with the guidelines provided in the Cochrane Handbook,3 and reported findings …

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