Cardiac Myosin Inhibitors in Adults with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background: Cardiac myosin inhibitors (CMIs) directly target sarcomeric hypercontractility and have demonstrated clinical efficacy in obstructive hypertrophic cardiomyopathy (HCM). In symptomatic nonobstructive HCM (nHCM), the phase 3 randomized controlled trials (RCT) differed in whether their primary efficacy endpoints reached statistical significance, although the direction and magnitude of treatment effects were broadly comparable. We therefore conducted a systematic review and meta-analysis to synthesize the randomized evidence on the efficacy and safety of CMIs in symptomatic nHCM. Methods: We systematically searched for randomized placebo-controlled trials evaluating CMIs in adults with symptomatic nHCM according to PRISMA guidance and a prospectively registered protocol (PROSPERO CRD420261466576). Primary efficacy outcomes were changes from baseline in peak oxygen uptake (pVO2) and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), assessed at each trial's primary endpoint. Secondary outcomes included improvement by at least 1 New York Heart Association (NYHA) functional class and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP). The safety outcome was LVEF <50%. Random-effects models were used to pool mean differences (MDs), risk ratios (RRs), and ratios of geometric mean changes. Results: Three RCTs comprising 1,156 participants were included: MAVERICK-HCM, ODYSSEY-HCM, and ACACIA-HCM. Compared with placebo, CMIs were associated with improvements in pVO2 (MD, 0.55 mL/kg/min; 95% CI, 0.22-0.87; I2=0%; P=0.001) and KCCQ-CSS (MD, 2.71 points; 95% CI, 0.87-4.55; I2=0%; P=0.004). Improvement by at least 1 NYHA functional class was more frequent with CMIs (RR, 1.29; 95% CI, 1.03-1.62; I2=24.3%; P=0.024). Across the two phase 3 trials, CMIs reduced NT-proBNP (ratio of geometric mean changes, 0.42; 95% CI, 0.39-0.46; I2=0%; P<0.001), while LVEF <50% occurred more frequently with CMIs (RR, 12.77; 95% CI, 5.98-27.27; I2=0%; P<0.001). Conclusions: In this meta-analysis of randomized trials in symptomatic nHCM, CMIs' pooled estimates favoured CMIs over placebo for improvements in exercise capacity, health status, and NYHA functional class, together with a marked reduction in NT-proBNP. These potential benefits were accompanied by an increased risk of LVEF reduction below 50%.