BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.

1st Department of Arrhythmia National Institute of Cardiology Warsaw Poland

Cardiomyopathy Unit Azienda Ospedaliera Universitaria Careggi Florence Italy

Centro de Investigación Biomédica en Red Madrid Spain

Complexo Hospitalario Universitario de A Coruña A Coruña Spain

Department of Cardiology Aarhus University Hospital Aarhus Denmark

Department of Cardiology Hospital Universitario Puerta de Hierro Madrid Spain

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Cardiovascular Diseases Mayo Clinic Arizona Phoenix AZ USA

Department of Internal Medicine Division of Cardiovascular Medicine University of Michigan Ann Arbor MI USA

Department of Internal Medicine Section of Cardiovascular Medicine Yale University New Haven CT USA

Department of Medicine Division of Cardiovascular Medicine Stanford University School of Medicine Stanford CA USA

Division of Cardiology and Structural Heart Diseases Medical University of Silesia Katowice Poland

Division of Cardiology University of California San Francisco San Francisco CA USA

Division of Cardiology Veterans Affairs Palo Alto Healthcare System Palo Alto CA USA

Division of Cardiovascular Medicine Brigham and Women's Hospital Boston MA USA

Duke University School of Medicine Durham NC USA

HCMBeat Los Angeles CA USA

Inherited Cardiac Disease Unit University Hospital Virgen de la Arrixaca Murcia Spain

Intermountain Medical Center Heart Institute Intermountain Medical Center Murray UT USA

Knight Cardiovascular Institute Oregon Health and Science University Portland OR USA

MyoKardia Brisbane CA USA

Servizo Galego de Saúde A Coruña Spain

Stanford University Palo Alto CA USA

Unidad de Cardiopatías Familiares Instituto de Investigación Biomédica de A Coruña A Coruña Spain

Universidad Francisco de Vitoria Pozuelo de Alarcón Madrid Spain

Universidade da Coruña A Coruña Spain

University of Florence Florence Italy

University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

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