Original Investigation
Heart Rate and Rhythm and the Benefit of Beta-Blockers in Patients With Heart Failure

https://doi.org/10.1016/j.jacc.2017.04.001Get rights and content
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Abstract

Background

The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF).

Objectives

This analysis explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo.

Methods

The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization.

Results

A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval [CI]: 1.07 to 1.15; p < 0.0001) but not in AF (n = 3,034; HR: 1.03 per 10 beats/min; 95% CI: 0.97 to 1.08; p = 0.38). Beta-blockers reduced ventricular rate by 12 beats/min in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomized to beta-blockers (HR: 0.73 vs. placebo; 95% CI: 0.67 to 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 to 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/min increase, 95% CI: 1.11 to 1.22; p < 0.0001).

Conclusions

Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm.

Key Words

atrial fibrillation
intention-to-treat analysis
randomized controlled trials

Abbreviations and Acronyms

AF
atrial fibrillation
CI
confidence interval
HFrEF
heart failure with reduced left ventricular ejection fraction
HR
hazard ratio
IPD
individual patient data
IQR
interquartile range
LVEF
left ventricular ejection fraction
RCT
randomized controlled trial

Cited by (0)

Menarini Farmaceutica Internazionale provided an unrestricted research grant for administrative costs. GlaxoSmithKline provided data extraction support and a collaborative research grant to IRCCS San Raffaele. None of the pharmaceutical groups had any role in data analysis or manuscript preparation. The Steering Committee lead (Dr. Kotecha) and the Centre for Statistics in Medicine (Drs. Altman and Holmes) 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. Dr. Kotecha 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 U.K. Department of Health. Dr. Kotecha has received grants from Menarini, during the conduct of the study; nonfinancial support from Daiichi-Sankyo; personal fees from AtriCure; and has served as chief investigator for the RATE-AF (Rate Control Therapy Evaluation in Atrial Fibrillation) trial. Dr. Flather has received personal fees from AstraZeneca; and grants from Novartis. Dr. Wikstrand has an appointment as study team physician for MERIT-HF at AstraZeneca. Dr. Packer has received personal fees from Amgen, Admittance Technologies, Bayer, Boehringer Ingelheim, BioControl, Celyad, Daiichi-Sankyo, AstraZeneca, Cardiorentis, CardioKinetix, Relypsa, Novartis, Sanofi, Takeda, and ZS Pharma. Dr. Böhm has received personal fees from Servier, Medtronic, Bayer, and Pfizer. Dr. Andersson has received personal fees from Servier. Dr. Wedel has received personal fees from AstraZeneca. Prof. Cleland has received grants from Amgen and Novartis; personal fees from Novartis and Servier; and nonfinancial support from GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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