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

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.