Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy (MAPLE-HCM)

Authors, Journal, Affiliations, Type, DOI

• Authors: Pablo Garcia-Pavia, Martin S. Maron, Ahmad Masri, Bela Merkely, Michael E. Nassif, et al., for the MAPLE-HCM Investigators
• Journal: New England Journal of Medicine
• Affiliations: Hospital Universitario Puerta de Hierro, Madrid (lead); co-investigators from Brigham and Women's/Harvard, Lahey Hospital, Oregon Health and Science University, Duke, MGH, UCL; sponsored by Cytokinetics
• Type: Phase 3, international, double-blind, double-dummy, head-to-head randomized clinical trial
• DOI: 10.1056/NEJMoa2504654

Overview

MAPLE-HCM was the first direct head-to-head phase 3 RCT comparing aficamten monotherapy (5–20 mg/day) vs metoprolol monotherapy (50–200 mg/day) in 175 patients with symptomatic obstructive HCM (71 sites; 24 weeks). Aficamten was superior on the primary endpoint (peak VO2 difference +2.3 ml/kg/min; P<0.001), with improvement in all prespecified secondary endpoints (NYHA, KCCQ-CSS, Valsalva LVOTO gradient, NT-proBNP, LAVi) except LV mass index. In contrast, metoprolol — despite robust heart rate reduction (−23.4 bpm) — did not improve LVOTO gradient, NT-proBNP, LAVi, or peak VO2, highlighting that beta-blocker benefit in obstructive HCM is largely chronotropic (symptomatic) rather than hemodynamic. Safety was favorable for aficamten: only 1% LVEF <50% vs 0% metoprolol. These results challenge the Class I first-line status of beta-blockers and position cardiac myosin inhibitors as superior monotherapy for obstructive HCM.

Keywords

Hypertrophic cardiomyopathy, obstructive HCM, aficamten, metoprolol, beta-blockers, cardiac myosin inhibitor, peak oxygen uptake, LVOTO gradient, head-to-head trial

Key Takeaways

Background and Rationale

• Beta-blockers have been first-line therapy for symptomatic obstructive HCM for ~60 years since Cohen and Braunwald (1967) showed beta-blockade reduces LVOTO; however, evidence base is limited to small, single-center, placebo-controlled studies
• Aficamten (CK-3773274) is a next-in-class cardiac myosin inhibitor with a shallow dose-response relationship facilitating individualized dose adjustment and no clinically important drug-drug interactions
• Prior SEQUOIA-HCM trial (NEJM 2024) showed aficamten superior to placebo when added to background standard therapy including beta-blockers
• MAPLE-HCM was designed to determine if aficamten as monotherapy is superior to metoprolol as monotherapy — directly challenging guideline step-care paradigm

Trial Design

• Phase 3, double-blind, double-dummy, head-to-head RCT; 71 sites in North America, Brazil, Europe, Israel, and China; June 2023 – August 2024
• N=175: 88 aficamten, 87 metoprolol (1:1 randomization); double-dummy design (each group receives active drug + placebo for the other drug)
• Eligibility: HCM (LV wall ≥15 mm or ≥13 mm with gene variant/family history), LVEF ≥60%, resting LVOTO ≥30 mmHg or Valsalva LVOTO ≥50 mmHg, NYHA II–III, KCCQ-CSS ≤90, peak VO2 <100% predicted
• Prior standard medications washed out in 76% of patients (up to 2 weeks before screening)
• Two subgroups: Group 1 = new diagnosis/no prior treatment ≤12 months; Group 2 = chronic HCM with prior standard therapy >12 months
• Aficamten dose: starting 5 mg, escalated to maximum 20 mg; metoprolol starting 50 mg, escalated to maximum 200 mg
• Treatment period 24 weeks; followed by 4-week washout

Patient Characteristics

• Mean age 58 years; 58.3% men; 42% women; 20% non-White
• Baseline mean LVOTO: 47 mmHg rest; 74 mmHg Valsalva
• Mean LVEF 68%; 70.3% NYHA class II; median NT-proBNP 468 pg/mL
• 30.3% had new diagnosis or no prior treatment
• ~10% each with prior mavacamten exposure or prior SRT (capped at enrollment)
• Most patients required/received maximum doses: aficamten 76% on 15–20 mg; metoprolol 63% on 150–200 mg

Primary Efficacy — Peak VO2 (Highly Significant)

• Peak VO2 change: +1.1 ml/kg/min (95% CI 0.5–1.7) with aficamten; −1.2 ml/kg/min (95% CI −1.7 to −0.8) with metoprolol
• Between-group difference: +2.3 ml/kg/min (95% CI 1.5–3.1; P<0.001)
• Peak heart rate change: +4.7 bpm aficamten vs −23.4 bpm metoprolol — confirming that metoprolol failed to improve VO2 despite marked chronotropic effect
• Effect consistent across all prespecified subgroups (sex, age, BMI, NYHA class, LVEF, NT-proBNP, CPET method, disease duration, LVOTO severity, KCCQ, sarcomere variant status)

Secondary Endpoints — All Significant Except LV Mass Index

• NYHA improvement ≥1 class: 51% aficamten vs 26% metoprolol (P<0.01)
• KCCQ-CSS change: +15.8 (95% CI 12.5–19.0) aficamten vs +8.7 (95% CI 5.3–12.1) metoprolol; difference +6.9 points (P=0.002)
• Valsalva LVOTO gradient: −40.7 mmHg aficamten vs −3.8 mmHg metoprolol (difference −34.9 mmHg; P<0.001)
• Resting LVOTO gradient (exploratory): difference 29.6 mmHg favoring aficamten
• NT-proBNP: 81% relative difference favoring aficamten (P<0.001) — aficamten reduced NT-proBNP substantially; metoprolol increased it (proportional change 0.3 aficamten vs 1.4 metoprolol pg/mL)
• LAVi: −3.8 ml/m² aficamten vs +2.8 ml/m² metoprolol (difference −7.0 ml/m²; P<0.001) — reverse LA remodeling vs progressive LA enlargement
• LV mass index: −6.9 aficamten vs −3.8 metoprolol (P=NS — only secondary endpoint not significant)
• All benefits disappeared after 4-week washout

Safety — Favorable Profile for Aficamten

• Serious adverse events: 8% aficamten vs 7% metoprolol (similar)
• Any adverse event: 74% aficamten vs 76% metoprolol (similar)
• LVEF <50% (core lab): 1 patient (1%) aficamten; 0 metoprolol — transient and asymptomatic
• LVEF difference between groups: −4.2 percentage points (95% CI −5.3 to −3.1) — expected on-target pharmacodynamic effect of myosin inhibition
• Dose reduction for adverse events or algorithm: 5% aficamten vs 30% metoprolol — metoprolol much more frequently dose-limited
• 1 sudden death in aficamten group after brief viral illness (not drug-attributed by investigators)
• Metoprolol dose reduced to 0 mg in 12% due to intolerable side effects at lowest dose

Critical Mechanistic Insight — What Beta-Blockers Actually Do

• Despite reducing heart rate by 23.4 bpm (on-target pharmacodynamic effect), metoprolol did NOT improve:
  • Peak VO2 (decreased by 1.2 ml/kg/min)
  • LVOTO gradient (−3.8 mmHg, not significant)
  • NT-proBNP (increased by metoprolol)
  • LAVi (increased by 2.8 ml/m²)
• Beta-blockers improve subjective outcomes (NYHA class, KCCQ-CSS) likely via heart rate slowing → longer diastolic filling → improved forward output at rest, but do not address the underlying sarcomere hypercontractility or dynamic LVOTO
• This mechanistic dissociation undermines the hemodynamic rationale for beta-blockers as first-line therapy

Implications for Treatment Guidelines

• Current AHA 2024 and ESC 2023 guidelines recommend beta-blockers as Class I step-1 therapy; cardiac myosin inhibitors as Class I step-3 (AHA) or Class IIa step-4 (ESC) — only after beta-blockers have failed
• MAPLE-HCM provides the first direct RCT evidence that cardiac myosin inhibitor monotherapy produces greater objective improvement than beta-blocker monotherapy
• These data may support repositioning aficamten as potential first-line therapy, particularly for patients who are beta-blocker intolerant, have contraindications, or have predominantly hemodynamically driven symptoms
• Results are consistent across newly diagnosed/treatment-naïve patients (Group 1) and chronic HCM patients (Group 2)

Limitations of the Document

• Relatively short 24-week treatment period — long-term outcomes (SCD, HF hospitalisation, all-cause mortality) not assessed
• Double-dummy design does not fully blind investigators to treatment due to metoprolol's obvious chronotropic effect (HR difference)
• Cannot exclude that other beta-blockers (atenolol, nadolol) may have different effects than metoprolol
• Metoprolol dose-adjustment protocol may differ from clinical practice
• Some imbalances at baseline: aficamten group more frequently enrolled in North America, higher baseline NT-proBNP, more sarcomeric variants, more hypertension

Key Concepts Mentioned

• concepts/LVOTO — primary pathophysiology addressed; aficamten reduces LVOTO, metoprolol does not despite HR reduction
• concepts/Sarcomere-Biology — cardiac myosin inhibition as the mechanistic target; aficamten reduces cross-bridge cycling
• concepts/Septal-Reduction-Therapy — context: beta-blockers and myosin inhibitors are alternatives before considering SRT

Key Entities Mentioned

• entities/Aficamten — drug under study; proven superior to metoprolol as monotherapy in obstructive HCM
• entities/HCM — obstructive subtype; treatment algorithm implications
• entities/Mavacamten — same drug class (cardiac myosin inhibitor); MAPLE-HCM is the first head-to-head trial vs beta-blockers for either myosin inhibitor

Wiki Pages Updated

• wiki/sources/aficamten-maplehcm-nejm-2025.md — created
• wiki/entities/Aficamten.md — created (new entity page)
• wiki/entities/HCM.md — LVOTO management section updated with MAPLE-HCM evidence
• wiki/entities/Mavacamten.md — pipeline note updated to reflect aficamten now phase 3 approved
• wiki/concepts/LVOTO.md — pharmacological management section updated; new contradiction added
• wiki/sourceindex.md — entry added
• wiki/wikiindex.md — Aficamten entity added