Cardiac myosin inhibitors (CMIs), including mavacamten and aficamten, have demonstrated improvements in hemodynamics and symptoms in hypertrophic cardiomyopathy (HCM). However, observational data have suggested a potential increase in atrial fibrillation (AF) risk. A systematic review and random-effects meta-analysis of randomized controlled trials (RCTs) published in Journal of Cardiovascular Electrophysiology was conducted to evaluate incident AF risk with CMIs and to examine differences compared with real-world findings.

A comprehensive search of MEDLINE, Scopus, and CENTRAL through November 25, 2025 identified eight RCTs (n=1581) comparing CMIs with placebo or active control. Event counts were pooled as risk ratios (RRs) with 95% confidence intervals. Across included trials, CMIs were not associated with increased AF risk (RR 1.11; 95% CI 0.62-1.98; I²=0%). Consistent findings were reported across CMI agents (mavacamten and aficamten) and across HCM subtypes, including obstructive and non-obstructive forms.

Trial eligibility criteria limited inclusion of higher-risk AF populations. Seven of eight RCTs excluded patients with uncontrolled, persistent, or permanent AF, five excluded paroxysmal AF at screening, and one excluded any prior AF history. Baseline left atrial enlargement was generally mild to moderate, suggesting underrepresentation of patients with advanced atrial remodeling. These factors may contribute to differences between RCT findings and observational reports.

Current randomized evidence does not indicate an increased AF risk with CMIs. Differences in patient selection and rhythm monitoring between RCTs and observational cohorts may contribute to these discrepancies.