Cardiac Myosin Inhibitors for Obstructive Hypertrophic Cardiomyopathy: A Meta-analysis of Randomized Placebo-Controlled Trials.

Background: Cardiac myosin inhibitors (CMI) have emerged as the first disease-specific, noninvasive therapy with promising results in patients with hypertrophic cardiomyopathy. However, its role in obstructive hypertrophic cardiomyopathy (oHCM) remains uncertain, especially in secondary endpoints of randomized controlled trials (RCTs).

Methods: We systematically searched PubMed, Embase, Web of Science, and Clinicaltrials.gov from inception to June 2024 for RCTs comparing CMI versus placebo in patients with oHCM. We applied a random-effects model to evaluate efficacy and safety outcomes and primary or secondary outcomes of RCTs.

Results: We included five RCTs comprising 767 patients, of whom 402 (52.5%) were randomized to CMI. Relative to placebo, CMI were associated with a higher rate of improvement of at least one New York Heart Association (NYHA) functional class [risk ratio (RR) 2.33; 95% confidence interval (CI) 1.92-2.82]. In addition, CMI reduced resting left ventricular outflow tract (LVOT) [mean difference (MD) - 42.51 mmHg; 95% CI - 59.27 to - 25.75] and the provoked LVOT gradients (MD - 46.12 mmHg; 95% CI - 55.70 to - 36.54). However, CMI significantly increased the risk of reaching a left ventricular ejection fraction below 50% (RR 4.80; 95% CI 1.42-16.20), affecting 8% of patients during long-term follow-up of up to 120 weeks. There was no significant interaction across subgroups of class representatives, pointing to a class effect. The benefit-risk analysis indicated a larger benefit for NYHA class improvement than risk for systolic dysfunction.

Conclusion: In patients with oHCM, mavacamten and aficamten as a class improve clinical and hemodynamic endpoints compared with placebo, albeit with a higher incidence of a reduction in left ventricular ejection fraction.

Registration: PROSPERO CRD42023468079.