Concomitant Aficamten and Disopyramide in Symptomatic Obstructive Hypertrophic Cardiomyopathy

• DOI: 10.1016/j.jchf.2025.03.008
• Publication Date: 2025-04-03T04:01:58Z
• Authors: Ahmad Masri; Martin S. Maron; Theodore P. Abraham; Michael E. Nassif; Roberto Barriales...; Ozlem Bilen; Caroline J. Coats; Perry Elliott; Pablo Garcia-Pavia; Daniele Massera; Iacopo Olivotto; Artur Oreziak; Anjali Tiku Owens; Sara Saberi; Scott D. Solomon; Albree Tower-Rader; Stephen B. Heitner; Daniel L. Jacoby; Chiara Melloni; Jenny Wei; Mark V. Sherrid; Iacopo Olivotto; Michelle Michels; Roberto Barriales...; Pablo Garcia-Pavia; Theodore P. Abraham; Lubna Choudhury; Christopher Kramer; Neal K. Lakdawala; Martin S. Maron; Ahmad Masri; Sherif F. Nagueh; Anjali Tiku Owens; Florian Rader; Sara Saberi; Mark V. Sherrid; John D. Symanski; Albree Tower-Rader; Aslan Turer; Andrew Wang; Timothy Wong; Yuhui Zhang; Haibo Yang; Chunli Shao; Zuyi Yuan; Qingchun Zeng; Xiaodong Li; Changsheng Ma; Yushi Wang; Yan Shu; Mulei Chen; Ling Tao; Xinli Li; Jingfeng Wang; Zaixin Yu; Xiang Cheng; Kui Hong; David Zemanek; Henning Bundgaard; Jens Thune; Morten Jensen; Jens Mogensen; Albert Hagège; Gilbert Habib; Philippe Charron; Thibault Lhermusier; Jean-Noël Trochu; Patricia Reant; Damien Logeart; Veselin Mitrovic; Tarek Bekfani; Frank Edelman; Tim Seidler; Benjamin Meder; Paul Christian Sc...; Stephan Stoerk; Tienush Rassaf; Bela Merkely; Donna Zfat-Zwas; Michael Arad; Majdi Halabi; Offir Paz; Xavier Piltz; Mattia Targetti; Marco Metra; Marco Canepa; Beatrice Musumeci; Michele Emdin; Michelle Michels; Ahmad Amin; Christian Knackstedt; Artur Oreziak; Wojciech Wojakowski; Dariusz Dudek; Alexandra Toste; José Mesquita Bastos; Roberto Barriales...; Pablo Garcia Pavia; Juan Ramón Gimeno...; Rafael Jesus Hida...; Ana Garcia Alvarez; Luis Miguel Rincó...; Tomas Vicente Rip...; Perry Elliott; Caroline Coats; Robert Cooper; Masliza Mahmod; William Bradlow; Antonis Pantazis; Maria Teresa Tome...; Ahmad Masri; Michael E. Nassif; Ali Marian; David Owens; Matthew Wheeler; Frank McGrew; Richard Bach; Omar Wever-Pinzon; Elias Collado; Aslan Turer; Bashar Hannawi; Jeffrey Geske; Anjali Tiku Owens; John D. Symanski; Christopher Kramer; Nitasha Sarswat; Ferhaan Ahmad; Theodore P. Abraham; Jeremy Markowitz; Neal Lakdawala; Lubna Choudhury; Sandeep Jani; Douglas M. Brinkley; Ozlem Bilen; Craig Asher; Sitaramesh Emani; Abhinav Sharma; David Fermin; Melissa Lyle; David Raymer; Andrew Darlington; Martin S. Maron; Christopher Nielsen; Andrew Wang; Sherif F. Nagueh; Matthew Martinez; Milind Desai; Albree Tower-Rader; Jacob Kelly; Florian Rader; Sounok Sen; Patrick Bering; Mathew Maurer; Sumeet Mitter; Mark V. Sherrid; Timothy Wong; Zainal Hussain; Sara Saberi; Srihari Naidu; Jorge Silva Enciso; David Zemanek; Henning Bundgaard; Morten Jensen; Jens Mogensen; Jens Thune; Erwan Donal; Gilbert Habib; Albert Hagege; Damien Logeart; Patricia Reant; Jean-Noël Trochu; Soeren Brandenburg; Frank Edelman; Benjamin Meder; Tienush Rassaf; Paul Christian Sc...; Stefan Stoerk; Bela Merkely; Michael Arad; Majdi Halabi; Xavier Piltz; Donna Zfat-Zwas; Michele Emdin; Beatrice Musumeci; Christian Knackstedt; Michelle Michels; Artur Oreziak; Wojciech Wojakowski; José Mesquita Bastos; Alexandra Toste; William Bradlow; Caroline Coats; Robert Cooper; Perry Elliott; Antonis Pantazis; Betty Raman; Maria Teresa Tome...; Theodore P. Abraham; Kia Afshar; Said Alsidawi; Patrick Bering; Ozlem Bilen; Douglas M. Brinkley; Lubna Choudhury; Andrew Darlington; Milind Desai; Stavros Drakos; Bashar Hannawi; Zainal Hussain; Jacob Kelly; Christopher Kramer; Neal Lakdawala; Matthew Martinez; Ahmad Masri; Sumeet Mitter; Noah Moss; Sherif F. Nagueh; Srihari Naidu; Michael E. Nassif; Anjali Tiku Owens; Florian Rader; Sriram Ravi; Ethan Rowin; Sara Saberi; Sounok Sen; Mark V. Sherrid; Jorge Silva Enciso; Albree Tower Rader; Aslan Turer; Andrew Wang; Shepard Weiner; Timothy Wong; Mark Zenker
• Keywords: Disopyramide; Concomitant; Obstructive hypertrophic cardiomyopathy

Disopyramide, used in obstructive hypertrophic cardiomyopathy (oHCM) for its negative inotropic properties mediated by reduction cytosolic calcium, has been recommended decades as an option to relieve resistant obstruction. Aficamten is a selective cardiac myosin inhibitor that reduces hypercontractility directly reducing myosin-actin interaction. This study aims investigate the safety and efficacy of concomitant use withdrawal disopyramide patients with symptomatic oHCM receiving aficamten. Patients enrolled REDWOOD-HCM Cohort 3 (open-label), SEQUOIA-HCM (placebo-controlled), FOREST-HCM (open-label) were analyzed. The authors identified 4 groups, each despite background therapy who received: 1) plus aficamten subsequent per protocol (Diso-Afi Withdrawal); 2) placebo (Diso-Pbo); 3) (Afi-Diso 4) continued both (Diso+Afi Continuous). Assessments performed at baseline, after or add-on therapy, washout (except week 24 Diso+Afi Continuous group). Overall, 50 unique from trials enrolled, resulting 93 subjects (segments) across groups: Diso-Afi Withdrawal (n = 29), Diso-Pbo 20), Afi-Diso 17), 27); mean dose was 331 ± 146 mg/d. addition alleviated left ventricular outflow tract (LVOT) obstruction (resting: change [Δ] least squares -27.0 3.6, Valsalva: Δ -39.2 5.0, P < 0.0001), symptoms (≥1 NYHA functional class improvement: 77.8% [95% CI: 61.0-94.5]; 0.0001; Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score: 12.3 3.3 [P 0.001]), reduced N-terminal pro-B-type natriuretic peptide ratio: 0.35 0.26-0.48]; 0.0001, there no significant placebo. while on resulted return LVOT obstruction, worsening symptoms, increase NT-proBNP baseline values. Conversely, did not impact efficacy. There events associated withdrawal, episodes atrial fibrillation withdrawal. In this cohort persistent combination safe well tolerated but enhance clinical vs alone. For such patients, treatment may be considered discontinue disopyramide. (Dose-finding Study Evaluate Safety, Tolerability, PK, PD CK-3773274 Adults With HCM [REDWOOD-HCM]; NCT04219826) (Aficamten Placebo Symptomatic Obstructive Hypertrophic [SEQUOIA-HCM]; NCT05186818) (Open-label Extension Long-term Safety Tolerability [FOREST-HCM]; NCT04848506).