Author + information
- Received February 2, 2017
- Revision received March 31, 2017
- Accepted April 2, 2017
- Published online April 30, 2017.
- Dipak Kotecha, PhD1,2,
- Marcus D. Flather, MBBS3,
- Douglas G. Altman, DSc4,
- Jane Holmes, PhD4,
- Giuseppe Rosano, PhD5,
- John Wikstrand, PhD6,
- Milton Packer, MD7,
- Andrew J.S. Coats, DSc8,
- Luis Manzano, MD9,
- Michael Böhm10,
- Dirk J. van Veldhuisen11,
- Bert Andersson, PhD12,
- Hans Wedel, PhD13,
- Thomas G. von Lueder, PhD2,14,
- Alan S. Rigby, MSc15,
- Åke Hjalmarson, PhD12,
- John Kjekshus, PhD16,
- John G.F. Cleland, MD17,∗ (, )
- Beta-Blockers in Heart Failure Collaborative Group
- 1University of Birmingham Institute of Cardiovascular Sciences, Birmingham, UK
- 2Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Australia
- 3Norwich Medical School, University of East Anglia, Norwich, UK
- 4Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- 5Department of Medical Sciences, IRCCS San Raffaele Pisana, Italy and Cardiovascular and Cell Science Institute, St George’s University of London, Roma, UK
- 6Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
- 7Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, USA
- 8Monash University, Melbourne, Australia and University of Warwick, Warwick, UK
- 9Internal Medicine Department, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain
- 10Universitätsklinikum des Saarlandes, Homburg, Saar, Germany
- 11Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
- 12Department of Cardiology, Sahlgrenska University Hospital and Gothenburg University, Gothenburg
- 13Health Metrics, Sahlgrenska Academy, University of Gothenburg
- 14Department of Cardiology, Oslo University Hospital, Oslo, Norway
- 15Academic Cardiology, Castle Hill Hospital, Kingston upon Hull, UK
- 16Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Norway
- 17Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, Glasgow, UK
- ↵∗Correspondence to John G.F. Cleland, MD Robertson Institute of Biostatistics and Clinical Trials Unit University of Glasgow, University Avenue Glasgow, G12 8QQ, UK Telephone: (44)(1482) 46 1776 Fax: (44)(1482) 46 177.
Background The relationship between mortality and heart rate remains unclear for patients with heart failure and reduced ejection fraction (HFrEF) in either sinus rhythm or atrial fibrillation (AF).
Objective To investigate the prognostic importance of heart rate in HFrEF in randomized controlled trials (RCTs) comparing beta-blockers and placebo.
Methods The Beta-blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual-patient data from eleven double-blind RCTs. The primary outcome was all-cause mortality, analysed with Cox proportional hazard ratios (HR) modelling heart rate measured at baseline and approximately six-months post-randomization.
Results A higher heart rate at baseline was associated with greater all-cause mortality in patients with sinus rhythm (n=14,166; adjusted HR 1.11 per 10 beats/minute; 95% CI 1.07-1.15, p<0.0001), but not in AF (n=3,034; HR 1.03 per 10 beats/minute; 0.97-1.08, p=0.38). Beta-blockers reduced ventricular rate by 12 beats/minute in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomised to beta-blockers (HR 0.73 versus placebo, 95% CI 0.67-0.79; p<0.001), regardless of baseline heart rate (interaction p=0.35). Beta-blockers had no effect on mortality in patients with AF (HR 0.96, 95% CI 0.81-1.12; p=0.58) at any heart rate (interaction p=0.48). A lower achieved resting heart rate, irrespective of treatment, was associated with better prognosis only for patients in sinus rhythm (HR 1.16 per 10 beats/minute increase, 95% CI 1.11-1.22; p<0.0001).
Conclusions Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with HFrEF in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm.
Disclosures: All authors have completed the ICMJE uniform disclosure form (www.icmje.org/coi_disclosure.pdf) and declare:
DK reports grants from Menarini, during the conduct of the study; non-financial support from Daiichi Sankyo and personal fees from AtriCure, outside the submitted work; and Chief Investigator for the RAte control Therapy Evaluation in Atrial Fibrillation (RATE-AF) Trial. MDF reports personal fees from AstraZeneca and grants from Novartis, all outside the submitted work. JW reports an appointment as Study team physician for MERIT-HF at AstraZeneca beside his role as Assistant Director for the Wallenberg Laboratory for Cardiovascular Research at Gothenburg University, Sweden. MP reports personal fees from Amgen, Admittance Technologies, Bayer, Boehringer Ingelheim, BioControl, Celyad, Daiichi Sankyo, AstraZeneca, Cardiorentis, CardioKinetix, Relypsa, Novartis, Sanofi, Takeda and ZS Pharma, all outside the submitted work. MB reports personal fees from Servier, Medtronic, Bayer and Pfizer, all outside the submitted work. BA reports personal fees from Servier, outside the submitted work. HW reports personal fees from Astra-Zeneca, during the conduct of the study. JGFC reports grants, personal fees and non-financial support from GlaxoSmithKline, during the conduct of the study. DGA, JH, GR, AJSC, LM, DJvV, TGvL, ASR, AH and JK have nothing to disclose.
Funding: Menarini Farmaceutica Internazionale provided an unrestricted research grant for administrative costs, GlaxoSmithKline provided data extraction support and IRCCS San Raffaele a collaborative research grant. None of the pharmaceutical groups had any role in data analysis or manuscript preparation. The Steering Committee Lead (DK) and the Centre for Statistics in Medicine, Oxford, UK (DGA and JH), had full access to all the data and had joint responsibility for the decision to submit for publication after discussion with all the named authors. DK is funded by a National Institute for Health Research (NIHR) Career Development Fellowship (CDF-2015-08-074). The opinions expressed are those of the authors and do not represent the NIHR or the UK Department of Health.
Contributors: DK participated in the design of the study, leads the collaborative group and performed data management, statistical analysis and manuscript preparation. JH and DGA independently performed the primary statistical analyses. JGFC participated in evaluation of results and manuscript preparation. LM and MDF participated in the design and coordination of the study. All other named authors read, revised and approved the final manuscript.
- Received February 2, 2017.
- Revision received March 31, 2017.
- Accepted April 2, 2017.