Heart rate, heart rhythm and prognostic benefits of beta-blockers in heart failure: individual patient-data meta-analysis

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. Abstract 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. Meta-analysis of individual-patient data from eleven double-blind randomized trials found that higher baseline heart rate was associated with greater all-cause mortality for those in sinus rhythm, but not for those in AF. Mortality was lower for patients in sinus rhythm assigned beta-blockers (HR 0.73, 95% CI 0.67-0.79; p<0.001), regardless of baseline heart rate. 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. A lower achieved resting heart rate 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).