Exercise Performance With Aficamten vs Metoprolol in Obstructive Hypertrophic Cardiomyopathy

Importance: Patients with obstructive hypertrophic cardiomyopathy (oHCM) endure life-altering exercise limitations. Current treatment guidelines recommend β-blockers as first-line therapy primarily based on expert opinion. The Metoprolol vs Aficamten in Patients with Left Ventricular Outflow Tract Obstruction on Exercise Capacity in HCM (MAPLE-HCM) trial characterizes comprehensive exercise response to aficamten monotherapy vs β-blockade (metoprolol). Objective: To determine the effect of aficamten compared with metoprolol across all stages of exercise using 16 quantitative measures in individuals with oHCM. Design, Setting, and Participants: This was a prespecified secondary analysis of the MAPLE-HCM study, a phase 3, randomized, active-control trial conducted from June 2023 to March 2025 with data analyzed between May and July 2025 at 71 sites in North America, South America, Europe, Israel, and China. Patients with symptomatic oHCM with objective evidence of exercise intolerance (peak oxygen uptake [pVO2] <100% of predicted) were included. Those with a history of atrial fibrillation (paroxysmal or persistent), medical indication for β-blockers or calcium channel blockers prohibiting drug discontinuation, or intolerance or medical contraindication to β-blockers were excluded. Intervention: Randomized 1:1 to titrated aficamten (5-20 mg daily) or matching titrated metoprolol (50-200 mg daily) for 24 weeks. Main Outcomes and Measures: The main outcomes were submaximal exercise minute ventilation (VE)/carbon dioxide output (VCO2) slope and anaerobic threshold; peak exercise duration, workload, heart rate and heart rate reserve; and postexercise oxygen recovery rates; and composite variables, such as circulatory power. Results: Of 175 randomized participants (mean [SD] age, 57.7 [13.2] years; 102 [58.3%] male), 165 (94%) had core laboratory-validated exercise tests at baseline and week 24. Compared with metoprolol, aficamten treatment improved multiple stages of exercise; including submaximal exercise VE/VCO2 slope (-2.8; 95% CI, -4.0 to -1.5; P < .001) and anaerobic threshold (76 mL/min; 95% CI, 41 to 111; P < .001); peak workload (8 watts; 95% CI, 3 to 13; P = .003); the time required for VO2 to recover by 12.5% postexercise (-11 seconds; 95% CI, -16 to -5; P < .001); and circulatory power (819 mm Hg × mL/min per kg; 95% CI, 569 to 1070; P < .001). Large improvements (≥3.0 mL/kg/min) in peak VO2 were more common with aficamten compared with metoprolol (17 [20.5%] vs 3 [3.7%], respectively; odds ratio, 6.8; 95% CI, 2.0 to 22.5; P < .001). In contrast, large reductions in peak VO2 (≥3.0 mL/kg/min) were significantly more common with metoprolol than aficamten (17 [20.7%] vs 2 [2.4%], respectively; odds ratio, 10.6; 95% CI, 2.6 to ∞; P < .001). Conclusions and Relevance: This prespecified analysis of MAPLE-HCM demonstrated monotherapy with aficamten was superior to metoprolol in promoting adaptation to multiple phases of exercise in patients with symptomatic oHCM and supports aficamten as first-line therapy for oHCM. Trial Registration: ClinicalTrials.gov Identifier: NCT05767346.