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BackgroundOne of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility.MethodsIn this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24.ResultsA total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups.ConclusionsAmong patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM number, NCT05186818.).

Original publication




Journal article


The New England journal of medicine

Publication Date





1849 - 1861


From Lahey Hospital and Medical Center, Burlington (M.S.M.), and the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School (B.C., S.D.S.), the Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School (J.L.J., G.D.L.), and the Baim Institute for Clinical Research (J.L.J.), Boston - all in Massachusetts; Oregon Health and Science University, Portland (A.M.); the University of Missouri Kansas City Healthcare Institute for Innovations in Quality and Saint Luke's Mid America Heart Institute, Kansas City (M.E.N., J.A.S.); Complejo Hospitalario Universitario de A Coruña, Instituto de Investigación Biomédica de A Coruña, Centro de Investigación Biomédica en Red de Enfermedades Cardiovaculares (CIBERCV)-Instituto de Salud Carlos III, A Coruña (R.B.-V.), and Hospital Universitario Puerta de Hierro de Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares, Madrid (P.G.-P.) - both in Spain; Chaim Sheba Medical Center, Ramat Gan and Tel Aviv University, Tel Aviv, Israel (M.A.); Hospital Companhia União Fabril Descobertas, Lisbon, Portugal (N.C.); Northwestern University Feinberg School of Medicine, Chicago (L.C.); the School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow (C.J.C., M.M.Y.L.), and Radcliffe Department of Medicine, University of Oxford, Oxford (H.W.) - both in the United Kingdom; Charité Campus Virchow-Klinikum, Berlin (H.-D.D.); Département de Cardiologie, Hôpital Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Paris (A.A.H.); Beijing Anzhen Hospital, Capital Medical University, Beijing (C.-S.M.); the Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam (M.M.) and Zwolle (M.S.) - both in the Netherlands; Meyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Florence, Italy (I.O.); National Institute of Cardiology, Warsaw, Poland (A.O.); University of Pennsylvania Perelman School of Medicine, Philadelphia (A.T.O.); the Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, and the Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen (J.T.-H.); the Department of Cardiology, Motol University Hospital, Prague, Czech Republic (J.V.); Cytokinetics, South San Francisco (D.L.J., S.B.H., S.K., F.I.M., L.M., A.W.), and the University of California, San Francisco, San Francisco (T.P.A.) - both in California.


SEQUOIA-HCM Investigators, Humans, Cardiomyopathy, Hypertrophic, Ventricular Outflow Obstruction, Benzylamines, Uracil, Cardiac Myosins, Exercise Test, Valsalva Maneuver, Double-Blind Method, Oxygen Consumption, Exercise Tolerance, Adult, Aged, Middle Aged, Female, Male