Efficacy and safety of cardiac myosin inhibitors in obstructive hypertrophic cardiomyopathy: systematic review and comprehensive frequentist and Bayesian meta-analyses of Phase 3 randomized controlled trials

Abstract

Aims: Data on cardiac myosin inhibitors (CMIs) in obstructive hypertrophic cardiomyopathy (oHCM) are rapidly emerging. This systematic review and meta-analysis evaluated the efficacy and safety of CMIs in randomized placebo-controlled trials. Methods: Phase 3 randomized placebo-controlled trials published up to 22-Apr-2025 were included. Outcomes extracted included symptoms, cardiopulmonary exercise testing (CPET), biomarkers, transthoracic echocardiography (TTE), cardiovascular magnetic resonance (CMR), and safety data. Frequentist (common/fixed effect, random) and Bayesian meta-analyses were performed using trial-level data to pool estimates of effects. Results: Four randomized placebo-controlled trials involving 726 patients with oHCM were included (444 mavacamten/placebo, 282 aficamten/placebo). Trial follow-up durations ranged from 16 to 30 weeks. In common/fixed effects meta-analyses, CMIs were associated with a greater proportion achieving ≥1 NYHA improvement [difference 36 % (95 % CI 29, 43)] and an increase in KCCQ-CSS [8.4 (6.6, 10.2) points] versus placebo. CMIs significantly improved several CPET parameters including increased peak oxygen consumption [1.6 (1.0, 2.1) mL/kg/min] and reduced VE/VCO2 [-2.0 (-2.7, -1.3)]. CMIs significantly reduced NT-proBNP [-79 % (-81 %, -77 %)] and hs-cTnI [-50 % (-54 %, -46 %)]. CMIs led to significant reductions in resting LVOT-G [-40 (-45, -35) mmHg] and favourable cardiac remodelling in other TTE and CMR parameters. Although CMIs increased the likelihood of LVEF <50 %, consistent with its known mechanism of action, none of these patients developed heart failure. No significant differences were seen in safety outcomes. Conclusions: Mavacamten and aficamten significantly improve symptoms, enhance exercise performance, improve cardiac biomarkers, reduce LVOT obstruction, and promote favourable cardiac remodelling. These findings suggest a class effect of CMIs. PROSPERO registration: CRD42024582096