Exercise Performance With Aficamten vs Metoprolol in Obstructive Hypertrophic Cardiomyopathy: Insights from the MAPLE-HCM Phase 3 Randomized Trial

Highlights

• The MAPLE-HCM trial is the first large-scale, head-to-head, phase 3 randomized trial comparing aficamten, a selective cardiac myosin inhibitor, with metoprolol, the longstanding first-line β-blocker therapy for symptomatic oHCM.
• Aficamten monotherapy demonstrated superior improvements in multiple exercise parameters, including peak oxygen uptake (pVO2), submaximal ventilation efficiency (VE/VCO2 slope), anaerobic threshold, and circulatory power, compared with metoprolol.
• Beyond exercise capacity, aficamten showed enhanced patient-reported health status and quality of life, significant reductions in left ventricular outflow tract gradients (LVOT-G), and favorable echocardiographic remodeling compared with metoprolol.
• Safety profiles were comparable, with aficamten exhibiting modest reductions in left ventricular ejection fraction consistent with its mechanism but without adverse hemodynamic compromise.

Background

Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by pathologic left ventricular hypertrophy, dynamic LVOT obstruction, and resultant exercise intolerance with symptoms including dyspnea and exertional fatigue. Exercise limitation profoundly impairs quality of life and is associated with adverse prognosis. For decades, β-blockers such as metoprolol have been the first-line pharmacologic therapy, recommended primarily based on expert consensus rather than robust comparative efficacy data. These agents reduce heart rate and myocardial contractility, partially mitigating LVOT obstruction but do not directly modify underlying hypercontractility.

Recent development of cardiac myosin inhibitors, including aficamten, offers a novel mechanism by selectively reducing sarcomere hypercontractility. Early phase studies showed additive benefits on LVOT gradients and symptomatic improvement when added to standard care, but the effect of aficamten as monotherapy compared directly to β-blockers remained undetermined. The MAPLE-HCM trial addresses this critical knowledge gap.

Key Content

Study Design and Population

MAPLE-HCM was a phase 3, international, double-blind, randomized controlled trial conducted at 71 sites across North America, South America, Europe, Israel, and China from June 2023 to March 2025. It enrolled 175 adults with symptomatic oHCM, confirmed LVOT obstruction (≥30 mm Hg resting or ≥50 mm Hg with Valsalva), and objective exercise intolerance (pVO2 <100% predicted). Patients with atrial fibrillation or contraindications to β-blockers were excluded. Participants were randomized 1:1 to titrated aficamten (5-20 mg daily) or metoprolol (50-200 mg daily) for 24 weeks.

Exercise Performance Outcomes

Using cardiopulmonary exercise testing, aficamten significantly outperformed metoprolol across 16 quantitative exercise measures. Key findings from secondary analysis included:

• Smaller VE/VCO2 slope indicating improved ventilatory efficiency at submaximal exercise (mean difference -2.8; P < .001).
• Higher anaerobic threshold (mean +76 mL/min; P < .001), reflecting better endurance capacity.
• Increased peak workload by 8 watts (P = .003) and enhanced circulatory power (+819 mm Hg × mL/min/kg; P < .001), a composite of cardiac output and oxygen uptake.
• Accelerated postexercise oxygen recovery kinetics (VO2 recovery -11 seconds faster; P < .001), indicating improved cardiopulmonary reserve.
• Notably, 20.5% of aficamten-treated patients had large improvements in peak VO2 (≥3.0 mL/kg/min) versus 3.7% in the metoprolol group (OR 6.8; P < .001). Conversely, large declines in peak VO2 were more frequent with metoprolol (20.7% vs 2.4%; OR 10.6; P < .001).

This comprehensive exercise evaluation confirms aficamten fosters superior functional adaptation across exercise phases.

Patient-Reported Outcomes and Symptomatology

Patient-centered outcomes were assessed via validated instruments including the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Seattle Angina Questionnaire (SAQ). Analysis revealed:

• Aficamten improved KCCQ Overall Summary Scores by 7.8 points over metoprolol at 24 weeks (P < .001), with more patients achieving very large clinically meaningful improvements.
• Fewer patients on aficamten reported worsening health status.
• SAQ Physical Limitation scale improvements were also significantly greater (+10.1 points; P = .001).

These findings underscore aficamten’s impact on symptoms and health-related quality of life beyond objective exercise metrics.

Echocardiographic and Biomarker Findings

Cardiac structure and function were rigorously assessed by core-lab echocardiography:

• Aficamten substantially reduced resting and Valsalva maneuver LVOT gradients by approximately 30-35 mm Hg more than metoprolol (P < .001).
• Left atrial volume index decreased by 7.0 mL/m2 (P < .001), reflecting reduced atrial pressure and remodeling.
• Markers of diastolic function (E/e’ ratios) improved significantly.
• Modest reductions in left ventricular ejection fraction (mean -4%) and global strain measures occurred with aficamten, consistent with its negative inotropic mechanism but without compromising cardiac output.
• Mitral valve systolic anterior motion and mitral regurgitation also improved with aficamten therapy.
• N-terminal pro-B-type natriuretic peptide levels declined more with aficamten, indicating reduced myocardial stress.

Collectively, these findings demonstrate aficamten’s favorable reverse remodeling and physiological impact on oHCM pathophysiology.

Safety and Tolerability

Adverse events were comparable between groups, with aficamten generally well tolerated. Some reduction in ejection fraction warrants monitoring but was not associated with clinical heart failure or adverse hemodynamics in the short term.

Contextualizing With Historical and Complementary Evidence

Prior to MAPLE-HCM, β-blockers were recommended based on longstanding clinical use and observational evidence but lacked direct comparative trials. Earlier trials of aficamten (including SEQUOIA-HCM) demonstrated its benefits as an add-on therapy. MAPLE-HCM now provides the strongest evidence favoring aficamten over β-blockers as monotherapy.

The trial also advances oHCM management by providing comprehensive multi-domain efficacy data, including objective exercise physiology, patient-reported outcomes, echocardiography, and biomarkers in a diverse, international cohort.

Expert Commentary

The MAPLE-HCM results represent a paradigm shift for symptomatic oHCM management. Aficamten’s targeted myosin inhibition directly addresses the pathogenic hypercontractility of oHCM, resulting in more effective LVOT obstruction reduction and improved exercise tolerance than traditional β-blockade.

Importantly, the improvements are clinically meaningful across vulnerable patient-centric domains like function, quality of life, and symptom burden, bridging the gap between physiological endpoints and lived experience.

Despite reduction in LVEF with aficamten, careful monitoring and dose titration afford a favorable therapeutic window without compromising cardiac output. This contrasts with β-blockers, which carry risks of bradycardia and exercise limitation.

Clinicians should consider aficamten as a first-line monotherapy in appropriate oHCM patients, especially those intolerant or inadequately managed by β-blockers. The comprehensive data set supports guideline updates to reflect this new evidence.

Limitations include the 24-week follow-up period; longer-term safety and durability require ongoing study. Exclusion of patients with atrial fibrillation may limit generalizability.

Future research directions include evaluating aficamten in broader patient populations, combination strategies, and comparative effectiveness against invasive septal reduction therapies.

Conclusion

The MAPLE-HCM randomized trial robustly establishes aficamten monotherapy as superior to metoprolol in improving exercise performance, patient-reported health status, and cardiac hemodynamics in symptomatic obstructive hypertrophic cardiomyopathy. These findings support aficamten’s role as a new first-line therapeutic option that directly targets oHCM pathophysiology with rapid, clinically meaningful benefits.

This advance heralds a new era in pharmacologic management of oHCM, emphasizing precision molecular targeting over nonspecific β-adrenergic blockade, with profound implications for improving patient outcomes and quality of life.

References

• 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. 2026 Jun 17. PMID: 42307914.
• Heitner SB, Jacoby DL, Judge DP, et al. Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy. N Engl J Med. 2025 Sep 11;393(10):949-960. PMID: 40888697.
• Lewis GD, Masri A, Garcia-Pavia P, et al. Effect of Aficamten vs Metoprolol on Patient-Reported Health Status in Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2026 Mar 3;87(8):1046-1058. PMID: 41493295.
• Lewis GD, Garcia-Pavia P, Masri A, et al. Aficamten in Obstructive Hypertrophic Cardiomyopathy: A Multidomain, Patient-Level Analysis of the MAPLE-HCM Trial. J Am Coll Cardiol. 2026 Mar 3;87(8):1029-1042. PMID: 41348072.
• Masri A, Garcia-Pavia P, Heitner SB, et al. Effect of Aficamten Compared With Metoprolol on Echocardiographic Measures in Symptomatic Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM. J Am Coll Cardiol. 2025 Dec 16;86(24):2452-2467. PMID: 40932433.