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Exercise Performance With Aficamten vs Metoprolol in Obstructive Hypertrophic Cardiomyopathy: The MAPLE-HCM
Gregory D Lewis1, Pablo Garcia-Pavia2,3, Ahmad Masri4
1Mass General Brigham Heart and Vascular Institute, Boston, Massachusetts.
Insights
Aficamten significantly improved exercise capacity in patients with obstructive hypertrophic cardiomyopathy (oHCM) compared to metoprolol. This study suggests aficamten may be a superior first-line treatment option for oHCM, enhancing multiple stages of exercise response.
Area of Science:
- Cardiology
- Exercise Physiology
- Pharmacology
Background:
- Obstructive hypertrophic cardiomyopathy (oHCM) severely limits patients' exercise capacity.
- Current treatment guidelines for oHCM recommend beta-blockers based primarily on expert opinion, lacking robust comparative data.
- The MAPLE-HCM trial investigated the efficacy of aficamten versus metoprolol in patients with oHCM.
Purpose of the Study:
- To compare the effects of aficamten and metoprolol on comprehensive exercise response in patients with symptomatic oHCM.
- To evaluate 16 quantitative exercise measures across all exercise stages.
- To determine the potential of aficamten as a first-line therapy for oHCM.
Main Methods:
- A prespecified secondary analysis of the phase 3, randomized MAPLE-HCM trial.
- 175 patients with symptomatic oHCM and exercise intolerance were randomized 1:1 to aficamten or metoprolol for 24 weeks.
- Exercise response was assessed using 16 quantitative measures, including submaximal and peak exercise parameters, and oxygen recovery.
Main Results:
- Aficamten demonstrated superior improvements in multiple exercise stages compared to metoprolol, including submaximal VE/VCO2 slope and anaerobic threshold.
- Patients on aficamten showed greater improvements in peak workload and circulatory power.
- Large improvements in peak VO2 were significantly more common with aficamten, while large reductions were more frequent with metoprolol.
Conclusions:
- Aficamten monotherapy proved superior to metoprolol in enhancing exercise adaptation across multiple phases in patients with symptomatic oHCM.
- These findings support aficamten as a potential first-line therapy for obstructive hypertrophic cardiomyopathy.
- The study provides robust evidence for aficamten's efficacy in improving exercise capacity in oHCM patients.
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.
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