Aficamten Outperforms Metoprolol Across All Phases of Exercise in Obstructive HCM

Aficamten monotherapy produced broader and more consistent improvements in exercise capacity than metoprolol across submaximal, peak, and recovery phases of exercise in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), according to a prespecified secondary analysis of the phase 3 MAPLE-HCM trial published in JAMA Cardiology.

“Patients with obstructive hypertrophic cardiomyopathy (oHCM) endure life-altering exercise limitations,” wrote the researchers of the study. “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).”

The phase 3, randomized, double-blind, double-dummy trial enrolled 175 adults with symptomatic oHCM at 71 sites across North America, South America, Europe, Israel, and China between June 2023 and March 2025. Participants had a left ventricular outflow tract gradient of at least 30 mm Hg at rest or 50 mm Hg with Valsalva maneuver; New York Heart Association (NYHA) class II to III symptoms; and objective exercise intolerance, defined by reduced peak oxygen uptake relative to predicted values. Patients with a history of atrial fibrillation or a medical need for β-blockers or calcium channel blockers were excluded. Participants were randomized 1:1 to titrated aficamten (5-20 mg daily) or titrated metoprolol (50-200 mg daily) for 24 weeks. Of the 175 randomized participants, 165 (94%) had core laboratory–validated exercise tests at both baseline and week 24.

Across 16 prespecified CPET measures, aficamten showed superiority to metoprolol at nearly every stage of exercise. In submaximal exercise, aficamten improved ventilatory efficiency (minute ventilation [VE]/carbon dioxide output [VCO₂] slope: −2.8; 95% CI, −4.0 to −1.5; P < .001) and oxygen uptake at the anaerobic threshold (76 mL/min; 95% CI, 41 to 111; P < .001) relative to metoprolol. At peak exercise, aficamten improved peak oxygen uptake (pVO₂) (2.3 mL/kg/min; 95% CI, 1.5 to 3.1; P < .001), peak workload (8 watts; 95% CI, 3 to 13; P = .003), exercise duration, and heart rate reserve, while metoprolol was associated with deterioration in most peak-performance metrics over the same period. Post exercise, aficamten sped recovery of oxygen uptake at all 4 time points assessed, including a reduction of 11 seconds (95% CI, −16 to −5; P < .001) in the time required for a 12.5% recovery. A composite measure integrating circulatory power, ventilatory power, and a combined oxygen-uptake/ventilatory-efficiency z score also favored aficamten (between-group z score difference, 0.45; 95% CI, 0.31-0.59; P < .001).

In a responder analysis, large improvements in pVO₂ (≥3.0 mL/kg/min) were more than 6 times as likely with aficamten than metoprolol (20.5% vs 3.7%; OR, 6.8; 95% CI, 2.0-22.5; P < .001), while large reductions in pVO₂ were more than 10 times as likely with metoprolol (20.7% vs 2.4%; odds ratio, 10.6; P < .001). The number needed to treat for a large pVO₂ improvement while avoiding large worsening was 2.8 with aficamten relative to metoprolol.

The investigators noted that metoprolol lowered peak heart rate by a mean of 23 beats per minute, consistent with prior invasive hemodynamic data showing that β-blockade can reduce peak cardiac output despite modest gains in stroke volume. Aficamten, by contrast, preserved heart rate reserve during exercise without altering resting heart rate, a pattern the authors said underscores the often-overlooked role of chronotropic response in exercise intolerance among patients with oHCM.

Limitations include the 24-week trial duration, which precludes conclusions about long-term outcomes, and the exclusion of asymptomatic patients with oHCM. Ten participants (5.7%) lacked valid week 24 CPET data due to technical failures, protocol deviations, or adverse events, including 1 death in the aficamten group.

“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,” wrote the researchers.

Managed Care Considerations

Whether these findings translate into a first-line role for aficamten in practice will depend heavily on payer coverage policy, which has so far been restrictive for this drug class. An analysis from the Tufts Center for the Evaluation of Value and Risk in Health examined payer coverage of mavacamten, the first approved cardiac myosin inhibitor for oHCM, 1 year after its 2022 approval and found substantial variation across plans in step therapy requirements, approval durations, and reauthorization criteria. The analysis attributed these restrictions to the drug's high price, uncertain long-term benefit, and unfavorable cost-effectiveness and projected that aficamten and other next-generation myosin inhibitors would likely face similar access barriers. The analysis suggested that future cardiac myosin inhibitors, including aficamten, could face similar utilization management requirements, with coverage criteria potentially reflecting registration trial eligibility criteria.²

References

1. Lewis GD, Garcia-Pavia P, Masri A, et al. Exercise performance with aficamten vs metoprolol in obstructive hypertrophic cardiomyopathy: the MAPLE-HCM randomized clinical trial. JAMA Cardiol. Published online June 17, 2026. doi:10.1001/jamacardio.2026.1730
2. Variation in payer coverage of mavacamten (Camzyos) for hypertrophic cardiomyopathy: one year post approval. Center for the Evaluation of Value and Risk in Health, Tufts Medical Center. August 9, 2023. Accessed June 19, 2026. https://cevr.tuftsmedicalcenter.org/news/variation-in-payer-coverage-of-mavacamten-camzyos-for-hypertrophic-cardiomyopathy-one-year-post-approval