Disopyramide has long been used in obstructive hypertrophic cardiomyopathy (oHCM) to reduce hypercontractility, while aficamten selectively inhibits cardiac myosin to directly reduce myosin–actin interaction. An analysis of REDWOOD-HCM Cohort 3 (open-label), SEQUOIA-HCM (placebo-controlled), and FOREST-HCM (open-label) published in the JACC: Heart Failure evaluated the safety and efficacy of concomitant use and withdrawal strategies in symptomatic patients receiving background disopyramide.

Fifty unique patients contributed 93 treatment segments across four groups: disopyramide plus aficamten with aficamten withdrawal (n=29), disopyramide plus placebo (n=20), aficamten plus disopyramide with subsequent disopyramide withdrawal (n=17), and continued combination therapy (n=27). Mean disopyramide dose was 331 ± 146 mg/day.

Adding aficamten to disopyramide reduced left ventricular outflow tract (LVOT) gradients (resting Δ −27.0 ± 3.6 mmHg; Valsalva Δ −39.2 ± 5.0 mmHg; both P<0.0001), improved symptoms (≥1 NYHA class improvement in 77.8% [95% CI 61.0–94.5]; P<0.0001), increased Kansas City Cardiomyopathy Questionnaire score (12.3 ± 3.3; P<0.001), and reduced NT-proBNP ratio (0.35; 95% CI 0.26–0.48; P<0.0001). Placebo showed no significant change.

Withdrawal of aficamten led to recurrence of obstruction and biomarker increases, whereas disopyramide withdrawal during aficamten therapy did not reduce efficacy. No safety events or atrial fibrillation occurred with withdrawal.

As pooled analyses of clinical trials, findings demonstrate associations within controlled trial settings. The sample size of the analysis was small with 50 unique patients and the two trials included were open-label.