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Metoprolol Versus Aficamten in Patients With Left Ventricular Outflow Tract Obstruction on Exercise Capacity in HCM - MAPLE-HCM
Contribution To Literature:
The MAPLE-HCM trial showed that, among patients with symptomatic obstructive HCM, aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics, and decreasing symptoms.
Study Design
Patients were randomly assigned in a 1:1 ratio to receive aficamten (daily dose of 5-20 mg) plus placebo or metoprolol (daily dose of 50-200 mg) plus placebo.
- Total number of enrollees: 175
- Duration of follow-up: 24 weeks
- Mean patient age: 58.0 years
- Percentage female: 41.7%
Inclusion criteria:
- Adults 18-85 years with symptomatic obstructive hypertrophic cardiomyopathy (HCM) (left ventricular [LV] wall thickness ≥15 mm or ≥13 mm with disease causing genetic variant or family history).
- Left ventricular ejection fraction (LVEF) ≥60%.
- Left ventricular outflow tract (LVOT) gradient ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva maneuver.
- New York Heart Association (NYHA) class II or III, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) ≤90 and age- and sex-predicted peak oxygen uptake ≤100%.
Exclusion criteria:
- Septal reduction therapy within 6 months of screening.
- Current or recent disopyramide (<4 weeks) or mavacamten (<8 weeks) use.
- Significant valvular heart disease (other than systolic anterior motion).
- Paroxysmal or persistent atrial fibrillation or atrial flutter.
- Syncope, symptomatic or sustained ventricular tachyarrhythmia with exercise within 6 months.
- Obstructive coronary artery disease or history of myocardial infarction.
- Estimated glomerular filtration rate <30 mL/min/1.73 m2
- Hepatic enzyme levels >3x upper limit of normal.
Other salient features/characteristics:
- Mean LVOT gradient 47 mm Hg at rest, 74 mm Hg after Valsalva
- Mean LVEF 68%
- Median NT-proBNP 468 pg/mL
Principal Findings:
The outcomes evaluated differences in change between the aficamten and metoprolol groups.
Primary outcome:
- Change in peak oxygen uptake at week 24: 2.3 mL/kg/min (95% CI, 1.5 to 3.1, p<0.001)
Secondary outcomes:
- Improvement in NYHA class at week 24: 25% (95% CI, 11 to 39, p<0.001)
- KCCQ-CCS at week 24: 6.9 (95% CI, 2.6 to 11.3, p=0.002)
- LVOT gradient after Valsalva: –34.9 mm Hg (95% CI, –43.4 to –26.4, p<0.001)
- Proportional change in NT-proBNP level: 0.19 (95% CI, 0.15 to 0.24, p<0.001)
- Left atrial volume index: –7.0 mL/m2 (95% CI, –9.1 to –4.9, p<0.001)
- LV mass index: –4.9 g/m2 (95% CI, –11.7 to 2.0, p=0.16)
Safety:
- Serious adverse events: 7 patients (8%) in aficamten vs. 6 patients (7%) in metoprolol arm. These included death following brief viral illness, pericarditis, and atrial fibrillation in the aficamten arm.
- Adverse events resulting in dose reductions: 1 patient (1%) in aficamten vs. 4 patients (5%) in metoprolol arm.
- Mean LVEF difference between aficamten vs. metoprolol group: –4.2% (95% CI, –5.3% to –3.1%).
Interpretation:
In this phase 3 study in symptomatic obstructive HCM patients, cardiac myosin inhibitor aficamten monotherapy significantly improved peak oxygen uptake, and reduced symptoms and LVOT gradient after Valsalva compared to metoprolol monotherapy with no significant serious medication-related adverse events.
This study suggests that aficamten may be a reasonable addition as a myosin inhibitor to our armamentarium treating symptomatic obstructive HCM, especially considering a better performance compared to a well-known beta-blocker, metoprolol, which is the current first-line treatment according to many international guidelines. Further studies with longer follow-up are needed to explore the efficacy and safety of this medication.
References:
Presented by Dr. Pablo Garcia-Pavia at the European Society of Cardiology Congress, Madrid, Spain, Aug. 30, 2025.
Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure
Keywords: ESC Congress, ESC25, Cardiomyopathy, Hypertrophic, Heart Failure
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