Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials

John G F Cleland; Karina V Bunting; Marcus D Flather; Douglas G Altman; Jane Holmes; Andrew J S Coats; Luis Manzano; John J V McMurray; Frank Ruschitzka; Dirk J van Veldhuisen; Thomas G von Lueder; Michael Böhm; Bert Andersson; John Kjekshus; Milton Packer; Alan S Rigby; Giuseppe Rosano; Hans Wedel; Åke Hjalmarson; John Wikstrand; Dipak Kotecha; Beta-blockers in Heart Failure Collaborative Group

doi:10.1093/eurheartj/ehx564

Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials

Eur Heart J. 2018 Jan 1;39(1):26-35. doi: 10.1093/eurheartj/ehx564.

Authors

John G F Cleland¹, Karina V Bunting², Marcus D Flather³, Douglas G Altman⁴, Jane Holmes⁴, Andrew J S Coats⁵, Luis Manzano⁶, John J V McMurray⁷, Frank Ruschitzka⁸, Dirk J van Veldhuisen⁹, Thomas G von Lueder^{10

11}, Michael Böhm¹², Bert Andersson¹³, John Kjekshus¹⁴, Milton Packer¹⁵, Alan S Rigby¹⁶, Giuseppe Rosano^{17

18}, Hans Wedel¹⁹, Åke Hjalmarson¹³, John Wikstrand²⁰, Dipak Kotecha^{21

11}; Beta-blockers in Heart Failure Collaborative Group

Affiliations

¹ Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
² Institute of Cardiovascular Sciences, University of Birmingham, Vincent Drive, Birmingham B15?2TT, UK.
³ Norwich Medical School, Faculty of Medicine and Health Science, University of East Anglia, Norwich NR4 7TJ, UK.
⁴ Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX1 2JD, UK.
⁵ San Raffaele Pisana Scientific Institute, Via della Pisana, 235, 00163 Rome, Italy.
⁶ Internal Medicine Department, Hospital Universitario Ramón y Cajal, Universidad de Alcalá (IRYCIS), Plaza de San Diego, 28801 Alcalá de Henares, Madrid, Spain.
⁷ Institute of Cardiovascular and Medical Sciences, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
⁸ Klinik für Kardiologie, UniversitätsSpital Zürich, Universitätstrasse 8, 8006 Zürich, Switzerland.
⁹ Department of Cardiology, University Medical Centre Groningen, University of Groningen, PO box 30.001 9700 RB Groningen, The Netherlands.
¹⁰ Department of Cardiology, Oslo University Hospital, PO Box 4950 Nydalen N-0424 Oslo, Norway.
¹¹ Centre of Cardiovascular Research and Education in Therapeutics, Monash University, 99 Commercial Road, Melbourne, Victoria 3004, Australia.
¹² Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Str. 100, 66421 Homburg/Saar, Germany.
¹³ Department of Cardiology, Sahlgrenska University Hospital and Gothenburg University, Blå stråket 5, 413 45 Gothenburg, Sweden.
¹⁴ Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Problemveien 7, 0315 Oslo, Norway.
¹⁵ Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 Hall St, Dallas TX 75226, USA.
¹⁶ Hull York Medical School, Faculty of Health Sciences, University of Hull, Kingston-upon-Hull, HU6 7RX, UK.
¹⁷ Cardiovascular and Cell Science Institute, St George's University of London, SW17 0RE, UK.
¹⁸ Department of Medical Sciences, IRCCS San Raffaele Pisana, Via della Pisana, 235, 00163 Roma, Italy.
¹⁹ Health Metrics, Sahlgrenska Academy, University of Gothenburg, Box 100, S-405 30 Gothenburg, Sweden.
²⁰ Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Bruna Stråket 16, 413 45 Gothenburg, Sweden.
²¹ Institute of Cardiovascular Sciences, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.

Abstract

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials.

Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis.

Conclusion: Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.

Keywords: Atrial fibrillation; Beta-blockers; Ejection fraction; Heart failure; Mortality; Sinus rhythm.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Adrenergic beta-Antagonists / therapeutic use*
Aged
Atrial Fibrillation
Double-Blind Method
Female
Heart Failure* / drug therapy
Heart Failure* / mortality
Heart Failure* / physiopathology
Humans
Male
Middle Aged
Placebos
Randomized Controlled Trials as Topic
Stroke Volume / physiology*

Substances

Adrenergic beta-Antagonists
Placebos

Abstract

Publication types

MeSH terms

Substances

Grants and funding