Heart Rate, Rhythm, Beta-Blockers, and Heart Failure
What is the prognostic importance of heart rate in heart failure with reduced ejection fraction (HRrEF) in randomized controlled trials comparing beta-blockers and placebo?
The study authors belonging to the Beta-Blockers in Heart Failure Collaborative Group pooled individual patient data from 11 major randomized controlled trials comparing beta-blockers to placebo in patients with HF in order to investigate further their efficacy and safety. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HRs) modeling heart rate measured at baseline and approximately 6 months post-randomization. Their analysis used heart rate as a continuous variable and also categorized into prespecified clinical groups (<70, 70-90, and >90 bpm). Effect modification was assessed using p values from interaction terms fitted in the multivariate models.
The final study cohort included 14,313 patients in sinus rhythm and 3,065 in AF, after exclusions. The investigators found that a higher heart rate at baseline was associated with greater all-cause mortality in patients with sinus rhythm (n = 14,166; adjusted hazard ratio [HR], 1.11 per 10 bpm; 95% confidence interval [CI], 1.07-1.15; p < 0.0001), but not in atrial fibrillation (AF) (n = 3,034; HR, 1.03 per 10 bpm; 95% CI, 0.97-1.08; p = 0.38). Beta-blockers reduced ventricular rate by 12 bpm 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, 0.67-0.79; 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 bpm increase, 95% CI, 1.11-1.22; p < 0.0001). In patients with underlying sinus rhythm, the baseline heart rate was associated with all-cause mortality, with an HR of 1.11 per 10 bpm (95% CI, 1.07-1.15; p < 0.0001), adjusted for baseline variables and treatment allocation.
The authors concluded that regardless of pretreatment 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.
The findings of this study demonstrating that beta-blockers improve prognosis in those with underlying sinus rhythm but not AF suggest that modulation of sympathetic activity may not completely explain the survival benefits of these agents. This is supported by the data that there was no survival benefit with anti-adrenergic agents such as moxonidine. Earlier studies reporting that decreasing heart rate has not shown to have survival benefits with ivabradine suggest that the efficacy of beta-blockers is not entirely due to reduction in heart rate. Further studies are needed to determine the mechanism for the efficacy of beta-blockers in HFrEF patients with sinus rhythm.
Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure
Keywords: Adrenergic beta-Antagonists, Arrhythmias, Cardiac, Atrial Fibrillation, Heart Failure, Heart Rate, Stroke Volume, Prognosis, Randomized Controlled Trials as Topic
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