Aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics and decreasing symptoms among patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), according to results from the MAPLE-HCM trial presented at ESC Congress 2025 and simultaneously published in NEJM.

Researchers randomly assigned 88 patients to receive aficamten (daily dose of 5 mg to 20 mg) plus placebo and 87 patients to receive metoprolol (at a daily dose of 50 mg to 200 mg) plus placebo. The primary endpoint was the change in peak oxygen uptake at week 24. Secondary endpoints included improvement at week 24 in New York Heart Association (NYHA) functional class and changes at week 24 in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient after the Valsalva maneuver, NT-proBNP level, left atrial volume index, and left ventricular mass index.

Results showed a change in peak oxygen uptake of 1.1 ml per kilogram of body weight per minute in the aficamten group at week 24 compared with −1.2 ml per kilogram per minute in the metoprolol group. Significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index were also observed in patients receiving aficamten than those receiving metoprolol.

"The effect of aficamten on exercise capacity appeared to be consistent across all prespecified subgroups, including among patients with a new diagnosis or who had not previously received treatment, those with longstanding HCM, and those with a known pathogenic sarcomere variant," said the study authors. They added that no significant differences in left ventricular mass index or adverse events were observed between the two groups.

"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," said Pablo Garcia-Pavia, MD, the trial's principal investigator. "Currently, myosin inhibitor therapy is recommended as a second-line treatment for patients with persistent symptoms on beta-blockers. But here we show that aficamten – as monotherapy and as first-line therapy – demonstrated greater improvements in exercise capacity and symptoms than beta-blockers."

In a related editorial comment, Amrut V. Ambardekar, MD, FACC, notes that moving forward, "Additional investigations are needed to determine the pathophysiological mechanisms underlying nonobstructive HCM in order to target alternate mechanisms of myocardial dysfunction, such as diastolic function, cellular energetics, subendocardial ischemia, or fibrosis."

In a related review article, Eugene Braunwald, MD, MACC, highlights ongoing research involving the diagnosis, and management of HCM, and notes that there are important short-term questions that should be addressed regarding cardiac myosin inhibitors in the meantime. Among them: "Because the action of these agents ceases shortly after their discontinuation, will lifetime administration be necessary in patients with obstructive HCM? If so, in which subgroup? Will there be a role for cardiac myosin inhibitors in children with obstructive HCM? Can these drugs have a role in reducing the incidence of the patient profile that is gene positive and phenotype positive with left ventricular outflow-tract obstruction and has the accompanying risk of sudden cardiac death or ventricular dysfunction (or both)?"