Metoprolol Versus Aficamten in Patients With Left Ventricular Outflow Tract Obstruction on Exercise Capacity in HCM - MAPLE-HCM

Nov 09, 2025
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Author/Summarized by Author:
Ufuk Vardar, MD
Summary Reviewer:
Fred M. Kusumoto, MD, FACC; Mays Ali, MD
Date Updated:
11/09/2025
Original Posted Date:
09/24/2025
References

Highlighted text has been updated as of Nov. 9, 2025.

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 in 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%).

Multi-domain efficacy analysis:
At 24 weeks, aficamten treatment led to greater benefits in all five efficacy outcome measures reflecting obstructive HCM disease burden, including complete hemodynamic response, symptom improvement, cardiac biomarker response, enhanced exercise capacity, and favorable cardiac remodeling. Numbers needed to treat ranged from 1.5 to 5.0 vs. metoprolol treatment. Aficamten-treated patients were much more likely to be either positive (3-4 outcome measures) or complete (all five measures) responders vs. metoprolol (78% vs. 3%, respectively; p<0.001).

Health status analysis:
At 24 weeks, greater health status improvements were observed in patients taking aficamten vs. metoprolol, with a mean difference in KCCQ-CCS of +7.8 points (p<0.001) and Seattle Angina Questionnaire Summary score of +4.6 points (p=0.063). Large clinical improvements (≥20 points) were more common with aficamten than metoprolol (38.6% vs. 18.4%), suggesting a number needed to treat of 4.9 (95% CI, 3.0-13.9) for one participant to feel much better with aficamten than metoprolol.

Biomarker analysis:
At 24 weeks, mean NT-proBNP decreased by 73% with aficamten and increased by 42% with metoprolol (treatment effect, −81%; p<0.001). Mean high-sensitivity cardiac troponin I (hs-cTnI) decreased by 43% with aficamten and by 17% with metoprolol (treatment effect, −28%, p=0.001). The correlation between changes in NT-proBNP vs. Valsalva LVOT gradient, rest LVOT gradient, and KCCQ-CSS were +0.44, +0.48, and −0.26 (all p<0.05). The correlation between change in biomarkers and change in peak oxygen uptake was significant for NT-proBNP (−0.42, p<0.001), but not hs-cTnI (−0.11, p=0.22). Biomarkers reverted to baseline levels after washout in both treatment groups.

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.

A patient-level multi-domain efficacy analysis revealed that treatment with aficamten vs. metoprolol led to superior and rapid treatment benefits across multiple clinically relevant outcome measures of disease burden, supporting aficamten as monotherapy for patients with obstructive HCM. Moreover, a patient-reported health status analysis showed that aficamten is a highly effective therapeutic option providing greater symptomatic and functional improvement than metoprolol after 24 weeks for this patient population.

A biomarker analysis demonstrated that aficamten significantly reduced NT-proBNP and hs-cTnI vs. metoprolol. Reduction in NT-proBNP levels significantly improved exercise capacity, LVOT gradient, and health status, providing insights into the mechanism of clinical benefit of aficamten vs. metoprolol.

References:

Wang A, Garcia-Pavia P, Masri A, et al. Aficamten in Obstructive Hypertrophic Cardiomyopathy: A Multi-Domain, Patient-Level Analysis of the MAPLE-HCM Trial. J Am Coll Cardiol. Published online Nov. 8, 2025. doi:10.1016/j.jacc.2025.10.057.

Nassif M, Garcia-Pavia P, Masri A, et al. Effect of Aficamten vs Metoprolol on Patient-Reported Health Status in Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. Published online Nov. 7, 2025. doi:10.1016/j.jacc.2025.10.059.

Presented by Drs. Michael Nassif, Andrew Wang, and Neal K. Lakdawala at the American Heart Association Scientific Sessions (AHA 2025), New Orleans, LA, Nov. 7-9, 2025.

Garcia-Pavia P, Maron MS, Masri A, et al. Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy. N Engl J Med. Published online Aug. 30, 2025. doi:10.1056/NEJMoa2504654.

Editorial: Ambardekar AV. Expanding the Role of Myosin Inhibition in Hypertrophic Cardiomyopathy – A Tale of Two Conditions. N Engl J Med. Published online Aug. 30, 2025. doi:10.1056/NEJMe2512100.

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, AHA Annual Scientific Sessions, AHA25


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