Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy

Garcia-Pavia, Pablo M.D., Ph.D.
Maron, Martin S. M.D.
Masri, Ahmad M.D.
Merkely, Bela M.D.
Nassif, Michael E. M.D.
Peña-Peña, Maria Luisa M.D.
Barriales-Villa, Roberto M.D., Ph.D.
Bilen, Ozlem M.D.
Burroughs, Melissa M.D.
Claggett, Brian Ph.D.
Costabel, Juan Pablo M.D.
de Barros Correia, Edileide M.D.
Dybro, Anne M. M.D., Ph.D.
Elliott, Perry M.B., B.S., M.D.
Hegde, Sheila M. M.D.
Lakdawala, Neal K. M.D.
Lewis, Gregory D. M.D.
Mann, Amy B.A.
Miao, Zi Michael M.S.
Nair, Ajith M.D.
Poulsen, Steen H. M.D.
Reant, Patricia M.D., Ph.D.
Schulze, Christian P. M.D.
Solomon, Scott D. M.D.
Wang, Andrew M.D.
Sohn, Regina M.D., Ph.D.
Berhane, Indrias Ph.D.
Heitner, Stephen B. M.D.
Jacoby, Daniel L. M.D.
Kupfer, Stuart M.D.
Malik, Fady I. M.D., Ph.D.
Wohltman, Amy M.E.
Fifer, Michael A. M.D.

¹Hospital Universitario Puerta de Hierro de Majadahonda, Instituto Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares (CIBERCV), Madrid
²Centro Nacional de Investigaciones Cardiovasculares, Madrid
³Lahey Hospital and Medical Center, Burlington, MA
⁴Oregon Health and Science University, Portland
⁵Heart and Vascular Center, Semmelweis University, Budapest, Hungary
⁶University of Missouri Kansas City Healthcare Institute for Innovations in Quality, Kansas City
⁷Saint Luke's Mid America Heart Institute, Kansas City, MO
⁸General Hospital of H.U. Virgen Del Rocio, Seville, Spain
⁹Complexo Hospitalario Universitario A Coruña, Instituto de Investigación Biomédica de A Coruña, CIBERCV-Instituto de Salud Carlos III, A Coruña, Spain
¹⁰Emory University Medical Center, Atlanta
¹¹Wellstar Center for Cardiovascular Care, Hiram, GA
¹²Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston
¹³Instituto Cardiovascular de Buenos Aires, Buenos Aires
¹⁴Dante Pazzanese Institute of Cardiology, São Paulo
¹⁵Aarhus Hospital University, Aarhus, Denmark
¹⁶Department of Inherited Cardiovascular Diseases, St. Bartholomew's Hospital, Institute of Cardiovascular Science, University College London, London
¹⁷Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston
¹⁸Colorado Springs, CO
¹⁹Texas Heart Institute at Baylor College of Medicine, Houston
²⁰University Hospital Center of Bordeaux, Centre d'Investigation Clinique Plurithématique 1401, University of Bordeaux, Bordeaux, France
²¹University Hospital Jena, Friedrich-Schiller-University, Jena, Germany
²²Duke University Medical Center, Durham, NC
²³Cytokinetics, South San Francisco, CA
²⁴Massachusetts General Hospital, Harvard Medical School, Boston

Pablo Garcia-Pavia can be contacted at [email protected] or at the Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Manuel de Falla 2, Majadahonda, Madrid 28222, Spain.

^*A list of the MAPLE-HCM investigators is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on August 30, 2025, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Cytokinetics.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

New England Journal of Medicine 393(10):p 949-960, September 11, 2025. | DOI: 10.1056/NEJMoa2504654

ABSTRACT

BACKGROUND

Beta-blockers have been the initial treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM) despite limited evidence of their efficacy. Aficamten is a cardiac myosin inhibitor that reduces left ventricular outflow tract gradients, improves exercise capacity, and decreases HCM symptoms when added to standard medications. Whether aficamten as monotherapy provides greater clinical benefit than beta-blockers as monotherapy remains unknown.

METHODS

We conducted an international, double-blind, double-dummy trial in which adults with symptomatic obstructive HCM were randomly assigned in a 1:1 ratio to receive aficamten (at a daily dose of 5 mg to 20 mg) plus placebo or metoprolol (at a daily dose of 50 mg to 200 mg) plus placebo. The primary end point was the change in peak oxygen uptake at week 24; secondary end points were improvement at week 24 in New York Heart Association (NYHA) functional class and changes at week 24 in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient after the Valsalva maneuver, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, left atrial volume index, and left ventricular mass index.

RESULTS

A total of 88 patients were assigned to the aficamten group and 87 to the metoprolol group. The mean age of the patients was 58 years, 58.3% were men, and the mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. At 24 weeks, the change in the peak oxygen uptake was 1.1 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.5 to 1.7) in the aficamten group and −1.2 ml per kilogram per minute (95% CI, −1.7 to −0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; P<0.001). Patients who received aficamten had significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index than patients who received metoprolol. No significant difference in left ventricular mass index was observed. Adverse events appeared to be similar in the two treatment groups.

CONCLUSIONS

Among patients with symptomatic obstructive HCM, aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics and decreasing symptoms. (Funded by Cytokinetics; MAPLE-HCM ClinicalTrials.gov number, NCT05767346.)