Cardiac Myosin Inhibitors in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy

Introduction/Background Symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) is associated with impaired functional capacity, heart failure symptoms, and reduced quality of life despite conventional medical therapy. While therapeutic advances in hypertrophic cardiomyopathy, including cardiac myosin inhibitors (CMi), have primarily focused on obstructive disease, treatment of nHCM remains largely limited to symptom control. Early randomized evidence in nHCM focused predominantly on mavacamten, with more recent trials evaluating aficamten. However, the overall efficacy and safety of CMi in nHCM remain uncertain. Research Questions/Hypothesis: To determine whether CMi improve health-related quality of life and exercise capacity while maintaining a comparable safety profile to placebo or standard care in adults with symptomatic nHCM. Methods/Approach: We performed a systematic review and meta-analysis of randomized controlled trials comparing mavacamten or aficamten with placebo or standard care in adults with symptomatic nHCM. MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception through February 2026. Random-effects models were used to pool mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs), with serious adverse events (SAEs) analyzed using raw event data from the included studies. Primary outcomes included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), peak oxygen uptake (VO 2 peak) as secondary outcome was serious adverse events (SAEs). All analyses were performed using the software R (version 4.5.3). Results/Data: Three randomized trials involving 1155 participants were included, 329 patients were treated with mavacamten and 258 with aficamten. The overall mean age was 54.7 ± 14.4 years, 49% were women, 69% and 31% had New York Heart Association (NYHA) class II and III symptoms, respectively. Compared with placebo or standard care, CMi significantly improved KCCQ-CSS (MD 2.1 points; 95% CI 0.3-4.0) and VO 2 peak (MD 0.5 mL/kg/min; 95% CI 0.2-0.8). There was no significant difference in the risk of SAEs (RR 1.09; 95% CI 0.75-1.59). Sensitivity analyses demonstrated consistent findings across included studies. Heterogeneity for these results were low, with maximum of I 2 = 15%. Conclusion: In symptomatic nHCM, cardiac myosin inhibitors improve health-related quality of life and functional capacity without increasing SAEs. These findings suggest cardiac myosin inhibitors as an effective therapeutic strategy for symptomatic nHCM.