Efficacy of Aficamten vs Metoprolol According to Pretrial Beta-Blocker Treatment in Obstructive Hypertrophic Cardiomyopathy
Fernándo DomínguezRoberto Barriales-VillaBrian L. ClaggettAnne DybroJunbo GeNeal K. LakdawalaMartin S. MaronAhmad MasriBela MerkelyZ. Michael MiaoAjith NairMichael E. NassifMaria Luisa Peña-PeñaP. Christian SchulzeAndrew WangSheila M. HegdeGregory D. LewisPerry ElliottRegina SohnStephen B. HeitnerDaniel L. JacobyStuart KupferFady I. MalikIndrias BerhaneAmy WohltmanMichael A. FiferPablo Garcia-Pavia
Key result
Aficamten improves exercise capacity vs metoprolol, boosting peak oxygen uptake ~1.9 mL/kg/min in prior beta-blocker users.
- MD +1.9 mL/kg/min
- 95% CI 0.9-2.8
- P<0.001
- n=175
Why the study?
The impact of pretrial standard-of-care medications, including beta-blockers, on the comparative efficacy of aficamten versus metoprolol in obstructive hypertrophic cardiomyopathy was unknown.
Does aficamten improve exercise capacity compared to metoprolol in patients with obstructive hypertrophic cardiomyopathy, regardless of pretrial beta-blocker use?
Key Points
- To evaluate the efficacy of aficamten monotherapy compared with metoprolol across patient subgroups categorized by pretrial beta-blocker and standard-of-care medication exposure.
- Secondary analysis of the phase 3 MAPLE-HCM randomized trial (NCT05767346) comparing aficamten (5–20 mg/d) with metoprolol (50–200 mg/d) over 24 weeks in 175 randomized adults.
- Outcomes were evaluated across three pretrial medical therapy subgroups: no beta-blockers at screening (BB-no, n=52), beta-blockers at screening (BB-yes, n=123), and no standard-of-care therapy for ≥12 months (SOC-no, n=22).
- Aficamten significantly improved peak oxygen uptake compared with metoprolol in both the BB-no group (+3.1 mL/kg/min; 95% CI: 1.8–4.5 mL/kg/min; P < 0.001) and BB-yes group (+1.9 mL/kg/min; 95% CI: 0.9–2.8 mL/kg/min; P < 0.001; P for interaction = 0.133).
Study Design
Type
RCT (n=175)
Randomization
randomized
Structured PICO
Does aficamten improve exercise capacity compared to metoprolol in patients with obstructive hypertrophic cardiomyopathy, regardless of pretrial beta-blocker use?
P
Population
175 adults with symptomatic obstructive hypertrophic cardiomyopathy were randomized to aficamten or metoprolol for 24 weeks to evaluate efficacy based on pretrial medical therapy.
I
Intervention
Aficamten (5-20 mg/d) for 24 weeks
C
Comparator
Metoprolol (50-200 mg/d) for 24 weeks
O
Outcome
Exercise capacity (peak oxygen uptake) at 24 weekssurrogate
Main Result
Mean Difference: 1.9 (95% CI 0.9–2.8)
p-value: p=<0.001
Aficamten is superior to metoprolol for improving exercise capacity in obstructive hypertrophic cardiomyopathy, independent of prior beta-blocker or standard-of-care therapy.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“By directly comparing aficamten and metoprolol, the MAPLE-HCM trial expands our understanding of how aficamten may be optimally integrated into the management of patients with obstructive HCM. Currently, myosin inhibitor therapy is recommended as a second-line treatment for patients with persistent symptoms on beta-blockers. But here we show that aficamten—as monotherapy and as first-line therapy—demonstrated greater improvements in exercise capacity and symptoms than beta-blockers.”
“The divergent effects of monotherapy with aficamten or metoprolol on exercise performance lends support to consideration of aficamten as first-line monotherapy to augment functional capacity in patients with symptomatic oHCM.”
“Because the action of these agents ceases shortly after their discontinuation, will lifetime administration be necessary in patients with obstructive HCM? If so, in which subgroup? Will there be a role for cardiac myosin inhibitors in children with obstructive HCM? Can these drugs have a role in reducing the incidence of the patient profile that is gene positive and phenotype positive with left ventricular outflow-tract obstruction and has the accompanying risk of sudden cardiac death or ventricular dysfunction (or both)?”
Implication
Supports aficamten regardless of pretrial beta-blocker use; extends MAPLE-HCM applicability to pretreated oHCM patients.
Abstract
BACKGROUND: The MAPLE-HCM trial demonstrated the superiority of monotherapy with aficamten vs metoprolol at improving clinical endpoints in obstructive hypertrophic cardiomyopathy (oHCM). The impact of pretrial use of standard-of-care (SOC) medications, including beta-blockers (BBs), was unknown. OBJECTIVES: The aim of this study was to evaluate the efficacy of aficamten by pretrial medical therapy. METHODS: Participants were randomized to aficamten (5-20 mg/d) or metoprolol (50-200 mg/d) for 24 weeks. Exercise capacity and other efficacy endpoints were examined by pretrial medical therapy: 1) BB-no: participants not receiving any BB therapy at screening; 2) BB-yes: participants on BB at screening, regardless of duration of exposure; and 3) SOC-no: participants without SOC therapy for ≥12 months before screening. Groups 1 and 3 overlapped, as all SOC-no participants were also included in the BB-no group. RESULTS: A total of 175 patients were randomized. At screening, 52 participants were BB-no, 123 BB-yes, and 22 SOC-no. The overall mean age was 58 years; 41.7% of patients were women. The mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. Aficamten demonstrated consistent benefits across multiple efficacy endpoints compared with metoprolol, independent of pretrial medical therapy. Aficamten improved exercise capacity (peak oxygen uptake) compared with metoprolol: BB-no: +3.1 mL/kg/min (95% CI: 1.8-4.5 mL/kg/min; P < 0.001); BB-yes: +1.9 mL/kg/min (95% CI: 0.9-2.8 mL/kg/min; P < 0.001) (P for interaction = 0.133); and SOC-no: +4.1 mL/kg/min (95% CI: 2.2-6.0 mL/kg/min; P < 0.001). CONCLUSIONS: Aficamten was superior to metoprolol regardless of BB use at screening or prior SOC medications. This supports the primary study results and suggests no confounding by BB resistance. Consequently, aficamten can be considered an early treatment option independent of prior SOC history. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM [MAPLE-HCM; NCT05767346).
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Cite This Study
Domínguez et al. (2026) conducted an RCT in obstructive hypertrophic cardiomyopathy (oHCM) (n=175). Aficamten vs. Metoprolol (50-200 mg/d) was evaluated on Exercise capacity (peak oxygen uptake) difference in patients on pretrial beta-blockers (BB-yes) (MD +1.9 mL/kg/min, 95% CI 0.9-2.8, p=<0.001). Aficamten improved exercise capacity compared with metoprolol regardless of pretrial beta-blocker use, including a 1.9 mL/kg/min increase in peak oxygen uptake for those on prior beta-blockers (P<0.001).