Aficamten treatment was associated with significant improvements in exercise capacity and symptoms compared with metoprolol in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), according to late-breaking research presented in a Hot Line session today at ESC Congress 2025 and simultaneously published inNew England Journal of Medicine. “Beta-blockers are commonly used to treat patients with symptomatic obstructive HCM, but they do not directly affect the underlying pathophysiology of the disease and evidence for their efficacy is limited,” explained Principal Investigator, Doctor Pablo Garcia-Pavia from Hospital Universitario Puerta de Hierro Majadahonda and Centro Nacional de Investigaciones Cardiovasculares (CNIC), both in Madrid, Spain. “Aficamten is a cardiac myosin inhibitor that reduces the damaging hypercontractility associated with obstructive HCM. Aficamten improved peak oxygen uptake compared with placebo in patients with persistent symptoms despite beta-blockers in a recent phase III trial2 but whether aficamten is superior to beta-blockers is unknown. The MAPLE-HCM trial was designed to compare aficamten with metoprolol, as monotherapy, in patients with symptomatic obstructive HCM, some of whom were treatment naïve.” This randomised, double-blind, double-dummy phase III trial was conducted across 71 sites in North America, South America, Europe, Israel and China. Adults with symptomatic obstructive HCM were randomised 1:1 to receive aficamten (uptitrated from 5 to 20 mg as tolerated) or metoprolol (uptitrated from 50 to 200 mg as tolerated). Eligible patients had symptoms and impaired functional capacity, as evidenced by New York Heart Association (NYHA) functional class II or III, a Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) ≤90, and age- and sex-predicted peak oxygen uptake <100%. The primary end point was change in peak oxygen uptake, as assessed by cardiopulmonary exercise testing, at 24 weeks. Among 175 participants who underwent randomisation, the mean age was 58 years and 42% were women. Around one-third of participants (30%) were defined as newly diagnosed or treatment naïve. The majority in both groups were titrated to the highest doses of aficamten or metoprolol. At 24 weeks, the primary endpoint of peak oxygen uptake increased by 1.1 mL/kg/min (95% confidence interval [CI] 0.5 to 1.7) in the aficamten group and decreased by 1.2 mL/kg/min (95% CI −1.72 to −0.8) in the metoprolol group, resulting in a significant difference between the two groups in favour of aficamten (least-squares mean difference of 2.3 mL/kg/min; 95% CI 1.5 to 3.1; p<0.001). The effect of aficamten on exercise capacity appeared consistent across all prespecified subgroups, including newly diagnosed or treatment-naïve patients. At 24 weeks, aficamten was associated with symptom and health status improvements compared with metoprolol: the proportion of patients who had ≥1 class improvement in NYHA functional class was 51.1% vs. 26.4%, respectively, and the least-squares mean changes in KCCQ-CSS were 15.8 and 8.7 points, respectively. Patients who received aficamten also had significant improvements in haemodynamics, namely left ventricular outflow tract gradient and left atrial volume index, and in NT-proBNP (an adverse prognostic indicator) compared with patients who received metoprolol. Regarding safety, at least one treatment-emergent adverse event was reported by 73.9% and 75.9% of patients treated with aficamten and metoprolol, respectively. Serious adverse events occurred in 8.0% of participants in the aficamten group and 6.9% in the metoprolol group. Concluding, Doctor Garcia-Pavia said: “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. 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.” Pablo Garcia-Pavia, Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy, New England Journal of Medicine, DOI: 10.1056/NEJMoa2504654.