Role of Rhythm Control With Antiarrhythmic Agents in Heart Failure With Preserved Ejection Fraction: Insights From the AFFIRM Trial

Background Atrial fibrillation (AF) is common in heart failure with preserved ejection fraction (HFpEF) and optimal therapeutic strategies remain unknown. This post-hoc analysis of the AFFIRM trial evaluates the risks and benefits of rhythm versus rate control with antiarrhythmic drugs (AADs) in patients with and without HFpEF. Methods In the AFFIRM trial, which randomized patients with AF to either rhythm or rate control, HFpEF was identified using European Society of Cardiology criteria, excluding patients with reduced ejection fraction or missing echocardiography. Cox models and generalized linear mixed models analyzed mortality and AF recurrence, stratified by HFpEF status. Specifically, the effects of amiodarone, class Ic antiarrhythmics, and sotalol were assessed. Results Among 2540 patients, 56% had HFpEF (mean age 71 years, 46% female). Rhythm control with AADs did not significantly affect all-cause mortality (hazard ratio [HR] 1.21, 95% confidence interval [CI] 0.98–1.48, P = .073) compared with rate control. However, a significant interaction was found with HFpEF status ( P interaction < .001), showing 31% higher mortality risk in patients with HFpEF randomized to rhythm versus rate control (HR 1.31, 95% CI 1.02–1.68, P = .033). Rhythm control increased sinus rhythm at 1 year (odds ratio [OR] 4.75, 95% CI 3.95–5.71, P < .001), with no treatment effect diminution by HFpEF. In HFpEF, but not in non-HFpEF, class Ic antiarrhythmics and sotalol appeared to increase mortality (HR 2.25, 95% CI 0.92–5.46, P = .054, P for interaction = 0.041). Conclusions Approximately half of the AF patients included in this AFFIRM subanalysis have HFpEF. While rhythm control may help to maintain sinus rhythm, class Ic antiarrhythmics and sotalol are associated with higher all-cause mortality in HFpEF, urging caution in their use. As a post-hoc analysis, our findings require further validation.