Effect of Aficamten Compared With Metoprolol on Echocardiographic Measures in Symptomatic Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM
- PMID: 40932433
- DOI: 10.1016/j.jacc.2025.08.022
Effect of Aficamten Compared With Metoprolol on Echocardiographic Measures in Symptomatic Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM
Abstract
Background: Beta-blockers have formed the mainstay of first-line therapy for symptomatic obstructive hypertrophic cardiomyopathy (HCM) for decades. Aficamten, compared with placebo, lowered left ventricular outflow tract gradients (LVOT-G), improved measures of left ventricular (LV) diastolic function, and showed evidence of favorable remodeling when added to standard of care medical therapy in SEQUOIA-HCM. The comparative effectiveness of monotherapy with aficamten vs metoprolol was investigated in MAPLE-HCM.
Objectives: This study evaluated the effect of monotherapy with aficamten compared with metoprolol on cardiac structure and function in participants enrolled in the MAPLE-HCM study.
Methods: Serial echocardiograms and other clinical measures were collected over 24 weeks in participants receiving escalating doses of aficamten 5 to 20 mg or metoprolol 50 to 200 mg.
Results: The study enrolled 175 participants (mean age 58 ± 13 years, 42% women, 80% White, 14% Asian). Mean left ventricular ejection fraction (LVEF) was 68% ± 4% with resting and Valsalva LVOT-G of 47 ± 29 mm Hg and 74 ± 33 mm Hg, respectively. Compared with metoprolol, aficamten decreased resting LVOT-G (-30 mm Hg [95% CI: -37 to -23 mm Hg]; P < 0.001) and Valsalva LVOT-G (-35 mm Hg [95% CI: -44 to -26 mm Hg]; P < 0.001); reduced left atrial volume index (left atrial volume index -7.0 mL/m2 [95% CI: -9.1 to -4.8 mL/m2]; P < 0.001); and improved E/e' (lateral E/e' -2.8 [95% CI: -4.0 to -1.6]; P < 0.001; septal E/e' -3.1 [95% CI: -4.5 to -1.7]; P < 0.001). Maximal wall thickness decreased (-1.0 mm [95% CI: -1.8 to -0.2 mm]; P = 0.02). LVEF, absolute LV global longitudinal strain, and absolute global circumferential strain decreased (LVEF -4% [95% CI: -5% to -3%]; global longitudinal strain -1.2% [95% CI: -1.8% to -0.5%]; global circumferential strain -2.5% [95% CI: -3.7% to -1.3%]; all P < 0.001) with no significant change in resting cardiac output between groups. Mitral valve systolic anterior motion and mitral regurgitation significantly decreased with aficamten at week 24.
Conclusions: In addition to lowering Valsalva LVOT-G and left atrial volume index, treatment with aficamten compared with metoprolol over 24 weeks led to improvement in measures of LV diastolic function, mitral valve systolic anterior motion, and mitral regurgitation. Aficamten therapy resulted in modest reduction in LVEF compared with metoprolol. These exploratory findings further support the overall superiority of therapy with aficamten over metoprolol demonstrated in MAPLE-HCM with evidence of favorable changes in multiple echocardiographic measures of cardiac structure and function in patients with symptomatic obstructive HCM. (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM [MAPLE-HCM]; NCT05767346).
Keywords: aficamten; diastolic function; echocardiography; hypertrophic cardiomyopathy; metoprolol.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Funding Support and Author Disclosures The MAPLE-HCM study was funded by Cytokinetics, Inc. Representatives of Cytokinetics have been involved in the design and conduct of the study reported in this paper. The study design was supported by the funder and aided by the coauthors. Data analysis and manuscript drafting was completed independently but reviewed by the funder. Dr Hegde has received advisory board fees from Cytokinetics; and her institution has received fees for core laboratory services from Cytokinetics and Bristol Myers Squibb. Dr X Wang’s institution has received fees for core laboratory services from Cytokinetics and Bristol Myers Squibb. Dr Garcia-Pavia has received speaker fees from Bristol Myers Squibb; and has received consulting fees from Biomarin, Bristol Myers Squibb, Cytokinetics, Edgewise, Rocket Pharmaceuticals, and Lexeo. Dr Masri has received research grants from Pfizer, Ionis, Attralus, Cytokinetics, and Janssen; and has received consulting fees from Cytokinetics, Bristol Myers Squibb, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Edgewise, Rocket, Lexeo, Prothena, BioMarin, AstraZeneca, Avidity, Neurimmune, and Tenaya. Dr Merkely has received advisory board fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, Duke Clinical Institute, Medtronic, and Novartis. Prof Merkely's institution has received fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, Duke Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and VIFOR Pharma. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Olivotto has received speakers’ bureau fees from Boston Scientific, Amicus, and Novartis; has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, and Rocket Pharma; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, and Boston Scientific. Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Bilen has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Burroughs has received consulting fees from Bristol Myers Squibb, Cytokinetics, and Novartis. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and has served on a data and safety monitoring board for Novo Nordisk. Dr Costabel has received speakers’ bureau fees from Bristol Myers Squibb and Pfizer; and has received consulting fees from Bristol Myers Squibb, Cytokinetics, and Pfizer. Dr Dybro has received speaker fees from Pfizer and Bristol Myers Squibb. Dr Elliott has received consulting fees from Bristol Myers Squibb, Pfizer, and Cytokinetics; has received speaker fees from Pfizer; and has received an unrestricted grant from Sarepta. Dr Lakdawala has received consulting fees from Pfizer, Bristol Myers Squibb, Cytokinetics, Tenaya, Akros, Neuvocor, and Alexion; and has received unrestricted research support from Pfizer and Bristol Myers Squibb. Dr Mann has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Maron has received consultant/advisor fees from Imbria, Edgewise, and BioMarin; and has received steering committee fees for SEQUOIA-HCM from Cytokinetics. Dr Poulsen has received consulting fees from Pfizer and BridgeBio. Dr Reant has received consulting fees from Cytokinetics, Bristol Myers Squibb, Pfizer, Alnylam, Amicus Therapeutics, and Sanofi. Dr Schulze has received grants from Boehringer Ingelheim, Abiomed Inc, Edwards Inc, Cytosorb Inc, and Boston Scientific; has received consulting fees and/or honoraria from Bayer, AstraZeneca, Daiichi-Sankyo, Novartis, Actelion, Roche, Sanofi Aventis, Pharmacosmos, Medtronic, Thoratec, Boehringer Ingelheim, Heartware, Coronus, Cytokinetics, Lilly, Abbott, Boston Scientific, St Jude Medical, Abiomed, and the German Cardiac Society; has performed trial committee work for Abbott, Abiomed, and Cytokinetics; and has received research support from the German Research Foundation, Else-Kröner-Fresenius Foundation, the Federal Ministry of Education and Research, Germany, and the European Commission. Dr A Wang has received consulting fees from Bristol Myers Squibb, Cytokinetics, and BioMarin; has been involved in speakers' bureaus for Bristol Myers Squibb; and has received institutional research grants from Bristol Myers Squibb and Cytokinetics. Drs Sohn, Berhane, Heitner, Jacoby, Kupfer, Malik, and Wohltman are employees and shareholder of Cytokinetics, Inc. Dr Fifer has received consulting fees from Bristol Myers Squibb, Cytokinetics, Edgewise Therapeutics, and Viz.ai; and has received research grants from Bristol Myers Squibb and Novartis. Dr Solomon has received grants from Actelion, Amgen, Bellerophon, Bristol Myers Squibb, Cytokinetics, Alnylam, AstraZeneca, Bayer, Celladon, and Eidos; and has received consultant/adviser fees from Abbott, Akros, Amgen, AstraZeneca, Boehringer Ingelheim, Cardior, Corvia, Daiichi Sankyo, Lilly, MyoKardia, Roche, Quantum Genomics, Janssen, Tenaya, Dinagor, CellProThera, American Regent, Lexicon, Akros, Action, Alnylam, Arena, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Merck, Novartis, Theracos, Cardurion, Cardiac Dimensions, Sanofi-Pasteur, Tremeau, Modera, Sarepta, Anacardio, and Puretech Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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