Pooling three randomized controlled trials — MAVERICK-HCM, ODYSSEY-HCM, and ACACIA-HCM — across 1,156 adults with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM), cardiac myosin inhibitors (CMIs) produced statistically significant gains in peak oxygen uptake (+0.55 mL/kg/min), quality-of-life scores (+2.71 KCCQ-CSS points), and NYHA functional class improvement (29% more likely than placebo). NT-proBNP, a cardiac stress biomarker, fell by 58% versus placebo. However, CMIs elevated the risk of left ventricular ejection fraction dropping below 50% by nearly 13-fold.
CMIs like mavacamten and aficamten have reshaped obstructive HCM management by directly dampening sarcomeric hypercontractility — a mechanistically elegant target. Their application to nHCM is less established, partly because the disease's pathophysiology differs: obstruction is absent, yet diastolic dysfunction and exercise intolerance remain debilitating. This meta-analysis is among the first to synthesize randomized evidence specifically for nHCM, lending statistical power where individual trials diverged on significance. The effect sizes, while real, are modest in absolute terms — the VO2 gain is clinically meaningful but modest relative to obstructive HCM data. The 13-fold LVEF suppression risk demands careful patient selection and monitoring protocols before broader adoption. Importantly, this is a preprint posted on medRxiv and has not yet undergone peer review, so findings should be interpreted cautiously. Assuming peer validation, this work could support regulatory discussions for nHCM indications currently lacking approved therapies — an incremental but clinically important advance.
