Exercise Performance With Aficamten vs Metoprolol in Obstructive Hypertrophic Cardiomyopathy
Year: 2026
Type: article
Abstract: Importance: Patients with obstructive hypertrophic cardiomyopathy (oHCM) endure life-altering exercise limitations. Current treatment guidelines recommend β-blockers as first-line therapy primarily based on expert opinion. The Metoprolol vs Aficamten in Patients with Left Ventricular Outflow Tract Obstruction on Exercise Capacity in HCM (MAPLE-HCM) trial characterizes comprehensive exercise response to aficamten monotherapy vs β-blockade (metoprolol). Objective: To determine the effect of aficamten compared with metoprolol across all stages of exercise using 16 quantitative measures in individuals with oHCM. Design, Setting, and Participants: This was a prespecified secondary analysis of the MAPLE-HCM study, a phase 3, randomized, active-control trial conducted from June 2023 to March 2025 with data analyzed between May and July 2025 at 71 sites in North America, South America, Europe, Israel, and China. Patients with symptomatic oHCM with objective evidence of exercise intolerance (peak oxygen uptake [pVO2] <100% of predicted) were included. Those with a history of atrial fibrillation (paroxysmal or persistent), medical indication for β-blockers or calcium channel blockers prohibiting drug discontinuation, or intolerance or medical contraindication to β-blockers were excluded. Intervention: Randomized 1:1 to titrated aficamten (5-20 mg daily) or matching titrated metoprolol (50-200 mg daily) for 24 weeks. Main Outcomes and Measures: The main outcomes were submaximal exercise minute ventilation (VE)/carbon dioxide output (VCO2) slope and anaerobic threshold; peak exercise duration, workload, heart rate and heart rate reserve; and postexercise oxygen recovery rates; and composite variables, such as circulatory power. Results: Of 175 randomized participants (mean [SD] age, 57.7 [13.2] years; 102 [58.3%] male), 165 (94%) had core laboratory-validated exercise tests at baseline and week 24. Compared with metoprolol, aficamten treatment improved multiple stages of exercise; including submaximal exercise VE/VCO2 slope (-2.8; 95% CI, -4.0 to -1.5; P < .001) and anaerobic threshold (76 mL/min; 95% CI, 41 to 111; P < .001); peak workload (8 watts; 95% CI, 3 to 13; P = .003); the time required for VO2 to recover by 12.5% postexercise (-11 seconds; 95% CI, -16 to -5; P < .001); and circulatory power (819 mm Hg × mL/min per kg; 95% CI, 569 to 1070; P < .001). Large improvements (≥3.0 mL/kg/min) in peak VO2 were more common with aficamten compared with metoprolol (17 [20.5%] vs 3 [3.7%], respectively; odds ratio, 6.8; 95% CI, 2.0 to 22.5; P < .001). In contrast, large reductions in peak VO2 (≥3.0 mL/kg/min) were significantly more common with metoprolol than aficamten (17 [20.7%] vs 2 [2.4%], respectively; odds ratio, 10.6; 95% CI, 2.6 to ∞; P < .001). Conclusions and Relevance: This prespecified analysis of MAPLE-HCM demonstrated monotherapy with aficamten was superior to metoprolol in promoting adaptation to multiple phases of exercise in patients with symptomatic oHCM and supports aficamten as first-line therapy for oHCM. Trial Registration: ClinicalTrials.gov Identifier: NCT05767346.
Source: JAMA Cardiology
Authors: Gregory D. Lewis, Pablo Garcia-Pavia, Ahmad Masri, Bela Merkely, Michael E. Nassif, Maria Luisa Peña-Peña, Roberto Barriales-Villa, Ozlem Bilen, Melissa Burroughs, Brian Claggett, Juan Pablo Costabel, Edileide de Barros Correia, Anne M. Dybro, Ian J. Kulac, Neal K. Lakdawala, Amy Mann, Martin S. Maron, Shaina McGinnis, Ajith Nair, Chloe Newlands, Steen H. Poulsen, Patricia Reant, P. Christian Schulze, Scott D. Solomon, Andrew Wang, Regina Sohn, Indrias Berhane, Stephen B. Heitner, Daniel L. Jacoby, Stuart Kupfer, Fady I. Malik, Amy Wohltman, Michael A. Fifer, Perry M. Elliott, MAPLE-HCM Investigators, Ahmad Masri, Andrew Wang, Mark Sherrid, Jacob Kelly, Anjali Owens, Omar Wever-Pinzon, Michael Nassif, Theodore Abraham, Sherif Nagueh, Florian Rader, Timothy Wong, Matthew Martinez, Neal Lakdawala, Milind Desai, Zainal Hussain, Albree Tower-Rader, Sara Saberi, Lubna Choudhury, Sounok Sen, Patrick Bering, Marshall Brinkley, Srihari Naidu, Mathew Maurer, Sumeet Mitter, Ozlem Bilen, Jorge Silva Enciso, Beatrice Musumeci, Michele Emdin, Mattia Targetti, Michelle Michels, Christian Knackstedt, Roberto Barriales-Villa, Pablo Garcia Pavia, Juan Ramón Gimeno Blanes, Rafael Jesus Hidalgo Urbano, Luis Miguel Rincón Diaz, Tomas Vicente Ripoll Vera, David Zemanek, Morten Jensen, Jens Mogensen, Jens Thune, Henning Bundgaard, Jean-Noël Trochu, Gilbert Habib, Patricia Reant, Albert Hagege, Damien Logeart, Veselin Mitrovic, Frank Edelmann, Tim Seidler, Benjamin Meder, Paul Christian Schulze, Stephan Stoerk, Tienush Rassaf, Bela Merkely, Michael Arad, Majdi Halabi, Donna Zfat-Zwas, Xavier Piltz, Artur Oreziak, Wojciech Wojakowski, Alexandra Toste, José Mesquita Bastos, Perry Elliott, Masliza Mahmod, Caroline Coats, Rob Cooper, William Bradlow, Antonis Pantazis, Maria Teresa Tome Esteban, Changsheng Ma, Qingchun Zeng, Yushi Wang, Yan Shu, Xiang Cheng, Mulei Chen, Kui Hong, Zuyi Yuan, Haibo Yang, Chunli Shao, Xiaodong Li, Yuhui Zhang
Institutions: Mass General Brigham, Spanish National Centre for Cardiovascular Research, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario Puerta de Hierro Majadahonda, Centro de Investigación Biomédica en Red, Oregon Health & Science University, Hausdorff Center for Mathematics, Semmelweis University, Saint Luke's Hospital, University of Missouri–Kansas City, Hospital Universitario Virgen del Rocío, Instituto de Salud Carlos III, Complexo Hospitalario Universitario A Coruña, Instituto de Investigación Biomédica de A Coruña, Emory University, WellStar Health System, Brigham and Women's Hospital, Harvard University, Instituto Cardiovascular de Buenos Aires, Instituto Dante Pazzanese de Cardiologia, Aarhus University Hospital, Lahey Hospital and Medical Center, Baylor College of Medicine, Université de Bordeaux, Centre Hospitalier Universitaire de Bordeaux, Centre d'Investigation Clinique Plurithématique de Bordeaux, Jena University Hospital, Friedrich Schiller University Jena, Duke Medical Center, Cytokinetics (United States), Massachusetts General Hospital, St Bartholomew's Hospital, University College London
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7165023499