Key Points:
- Beta-blockers are widely used as first-line therapy for obstructive hypertrophic cardiomyopathy (HCM), despite limited evidence supporting their efficacy.
- In the MAPLE-HCM trial, aficamten monotherapy significantly improved exercise capacity, symptoms, and cardiac biomarkers compared with metoprolol in patients with symptomatic obstructive HCM.
- Benefits of aficamten were observed even in newly diagnosed or treatment-naïve patients, with no major safety concerns.
Beta-blockers are the most commonly prescribed first-line therapy for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), although they do not target the underlying hypercontractility driving the disease. Aficamten, a next-generation cardiac myosin inhibitor, directly modulates contractility and has shown clinical benefit in prior trials. However, whether aficamten outperforms beta-blockers as initial therapy had not been tested until the MAPLE-HCM trial.
Presented during a Hot Line session at the European Society of Cardiology (ESC) Congress 2025 and simultaneously published in the New England Journal of Medicine, the MAPLE-HCM trial directly compared aficamten to metoprolol as monotherapy in patients with symptomatic obstructive HCM. The double-blind, double-dummy, phase 3 trial randomized 175 patients at 71 centers across five continents to receive either aficamten (5–20 mg) or metoprolol (50–200 mg), titrated to maximally tolerated doses.
Eligible participants had New York Heart Association (NYHA) class II–III symptoms, a Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) ≤90, and impaired exercise capacity based on peak oxygen uptake <100% of age- and sex-predicted norms.
At 24 weeks, aficamten significantly increased peak oxygen uptake by 1.1 mL/kg/min, while metoprolol was associated with a decline of 1.2 mL/kg/min. This resulted in a least-squares mean difference of 2.3 mL/kg/min in favor of aficamten (95% CI: 1.5 to 3.1; p<0.001). Improvements were consistent across all prespecified subgroups, including those who were treatment-naïve at baseline.
Aficamten was also associated with greater improvement in NYHA class (≥1 class improvement in 51.1% vs. 26.4% with metoprolol) and in health status, as measured by KCCQ-CSS (mean increase of 15.8 vs. 8.7 points). Hemodynamic benefits included greater reductions in left ventricular outflow tract (LVOT) gradient, left atrial volume index, and NT-proBNP.
Safety profiles were similar between groups, with treatment-emergent adverse events occurring in 73.9% of aficamten-treated patients and 75.9% of those on metoprolol. Serious adverse events were infrequent (8.0% with aficamten vs. 6.9% with metoprolol).
Commenting on the findings, principal investigator Dr. Pablo Garcia-Pavia (Madrid, Spain) stated, “By directly comparing aficamten and metoprolol, the MAPLE-HCM trial expands our understanding of how aficamten may be optimally integrated into the management of patients with obstructive HCM. As monotherapy, aficamten delivered superior improvements in exercise capacity and symptoms compared with beta-blockers.”
Funded by Cytokinetics, MAPLE-HCM provides the first head-to-head evidence that a myosin inhibitor can outperform traditional beta-blockers in symptomatic obstructive HCM, potentially reshaping first-line treatment approaches.