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Study Summary

EXPLORER-HCM was a randomized, double-blind, phase 3 trial designed to assess the safety and efficacy of mavacamten (a small-molecule inhibitor of the cardiac myosin ATPase) to improve exercise capacity and symptoms in patients with hypertrophic cardiomyopathy (HCM) and reduce left ventricular outflow tract (LVOT) gradient. In a 1:1 fashion, 251 enrolled patients were randomized to receive either mavacamten (N = 123) or placebo (N = 128). Follow-up was 30 weeks. Almost all patients (N = 231, 92%) were on background β-blocker or calcium-channel blocker therapy. The primary outcome, a >1.5ml/kg/min increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction OR a 3.0ml/kg/min increase in pVO2 without NYHA class worsening, occurred in 37% of patients who received mavacamten verses 17% in those who received placebo (P = 0.005; see accompanying Hurst's Central Illustration). Patients who received mavacamten also had a greater reduction in post-exercise LVOT gradient (-36 mmHg; 95% CI -43.2 to -28.1 mmHg, P <0.0001) and improved Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (+9.1; 95% CI 5.5-12.7, P <0.0001) as compared to placebo. There were no safety signals or major toxicity differences as compared to placebo.


Study Strengths: This was the first study to investigate the use of a novel disease-specific therapy for patients with obstructive HCM in a randomized, placebo-controlled trial.

Study Limitations: Follow-up in this study was only 30 weeks; therefore, the long-term benefit and safety profile of mavacamten is unknown. Very few younger or non-white patients were included. This study did not investigate the effect of mavacamten on significant clinical end points, including hospitalization, arrhythmia, or mortality. Only 20% of patients were on calcium channel blockers and 25% were not on β-blockers. Patients on concomitant β-blockers experienced less of an effect. The time of day and food consumption prior to echocardiograms was not controlled, which could impact LVOT gradients. This study did not investigate the use of mavacamten in patients with more-advanced forms of HCM, including those receiving disopyridamole, recent septal reduction therapy, with NYHA class IV symptoms, or a history of syncope or ventricular tachycardia.

Next Steps/Clinical Perspective: After 30 weeks of mavacamten therapy, patients had improved exercise capacity and reduced LVOT gradients compared to placebo, without significant adverse side effects. Longer-term follow-up on the efficacy and safety of mavacamten is needed. Future studies should also investigate the effect of mavacamten on cardiac clinical end points, such as hospitalization and mortality. Mavacamten may turn out to be an appealing alternative to septal reduction therapy.

Trial Reference

Olivotto  I, Oreziak  A, Barriales-Villa  R,  et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet doi:10.1016/S0140-6736(20)31792-X.

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