PMID- 35798455 OWN - NLM STAT- MEDLINE DCOM- 20220711 LR - 20230510 IS - 1558-3597 (Electronic) IS - 0735-1097 (Linking) VI - 80 IP - 2 DP - 2022 Jul 12 TI - Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. PG - 95-108 LID - S0735-1097(22)04997-X [pii] LID - 10.1016/j.jacc.2022.04.048 [doi] AB - BACKGROUND: Septal reduction therapy (SRT), surgical myectomy or alcohol ablation, is recommended for obstructive hypertrophic cardiomyopathy (oHCM) patients with intractable symptoms despite maximal medical therapy, but is associated with morbidity and mortality. OBJECTIVES: This study sought to determine whether the oral myosin inhibitor mavacamten enables patients to improve sufficiently to no longer meet guideline criteria or choose to not undergo SRT. METHODS: Patients with left ventricular (LV) outflow tract (LVOT) gradient >/=50 mm Hg at rest/provocation who met guideline criteria for SRT were randomized, double blind, to mavacamten, 5 mg daily, or placebo, titrated up to 15 mg based on LVOT gradient and LV ejection fraction. The primary endpoint was the composite of the proportion of patients proceeding with SRT or who remained guideline-eligible after 16 weeks' treatment. RESULTS: One hundred and twelve oHCM patients were enrolled, mean age 60 +/- 12 years, 51% men, 93% New York Heart Association (NYHA) functional class III/IV, with a mean post-exercise LVOT gradient of 84 +/- 35.8 mm Hg. After 16 weeks, 43 of 56 placebo patients (76.8%) and 10 of 56 mavacamten patients (17.9%) met guideline criteria or underwent SRT, difference (58.9%; 95% CI: 44.0%-73.9%; P < 0.001). Hierarchical testing of secondary outcomes showed significant differences (P < 0.001) favoring mavacamten, mean differences in post-exercise peak LVOT gradient -37.2 mm Hg; >/=1 NYHA functional class improvement 41.1%; improvement in patient-reported outcome 9.4 points; and NT-proBNP and cardiac troponin I between-groups geometric mean ratio 0.33 and 0.53. CONCLUSIONS: In oHCM patients with intractable symptoms, mavacamten significantly reduced the fraction of patients meeting guideline criteria for SRT after 16 weeks. Long-term freedom from SRT remains to be determined. (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy [VALOR-HCM]; NCT04349072). CI - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Desai, Milind Y AU - Desai MY AD - Hypertrophic Cardiomyopathy Center, Cleveland Clinic, Cleveland, Ohio, USA; Department of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Coordinating Center for Clinical Research, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA. FAU - Owens, Anjali AU - Owens A AD - Division of Cardiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Geske, Jeffrey B AU - Geske JB AD - Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA. FAU - Wolski, Kathy AU - Wolski K AD - Department of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Coordinating Center for Clinical Research, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA. FAU - Naidu, Srihari S AU - Naidu SS AD - Department of Cardiology, Westchester Medical Center, Valhalla, New York, USA. FAU - Smedira, Nicholas G AU - Smedira NG AD - Hypertrophic Cardiomyopathy Center, Cleveland Clinic, Cleveland, Ohio, USA; Department of Cardiothoracic Surgery, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA. FAU - Cremer, Paul C AU - Cremer PC AD - Department of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Coordinating Center for Clinical Research, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA. FAU - Schaff, Hartzell AU - Schaff H AD - Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota, USA. FAU - McErlean, Ellen AU - McErlean E AD - Department of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Coordinating Center for Clinical Research, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA. FAU - Sewell, Christina AU - Sewell C AD - Department of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Coordinating Center for Clinical Research, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA. FAU - Li, Wanying AU - Li W AD - MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Brisbane, California, USA. FAU - Sterling, Lulu AU - Sterling L AD - MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Brisbane, California, USA. FAU - Lampl, Kathy AU - Lampl K AD - MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Brisbane, California, USA. FAU - Edelberg, Jay M AU - Edelberg JM AD - MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Brisbane, California, USA. FAU - Sehnert, Amy J AU - Sehnert AJ AD - MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Brisbane, California, USA. FAU - Nissen, Steven E AU - Nissen SE AD - Department of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Coordinating Center for Clinical Research, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address: nissens@ccf.org. LA - eng SI - ClinicalTrials.gov/NCT04349072 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - J Am Coll Cardiol JT - Journal of the American College of Cardiology JID - 8301365 RN - EC 3.6.4.1 (Myosins) SB - IM CIN - J Am Coll Cardiol. 2022 Jul 12;80(2):109-110. PMID: 35798444 CIN - Expert Opin Investig Drugs. 2023 Jan;32(1):1-4. PMID: 36625220 MH - Aged MH - *Cardiomyopathy, Hypertrophic/therapy MH - Female MH - Humans MH - Male MH - Middle Aged MH - *Myosins/antagonists & inhibitors MH - Stroke Volume MH - Treatment Outcome MH - Ventricular Function, Left/physiology OTO - NOTNLM OT - mavacamten OT - obstructive HCM OT - randomized clinical trial OT - septal reduction COIS- Funding Support and Author Disclosures The VALOR-HCM study was funded by MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Funding support for open access was provided by MyoKardia Inc, a wholly owned subsidiary of Bristol Myers Squibb. The Cleveland Clinic Center for Clinical (C5) Research received funding for the trial, but none of the C5 Research personnel received any honoraria from the sponsor. Dr Desai serves as a consultant for Myokardia (now MyoKardia Inc, a wholly owned subsidiary of Bristol Myers Squibb) and Medtronic. Drs Owens and Naidu serve as consultants for MyoKardia Inc, a wholly owned subsidiary of Bristol Myers Squibb and Cytokinetics. Drs Li, Sterling, Lampl, and Sehnert are employees of MyoKardia Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Edelberg is a former employee of MyoKardia Inc, a wholly owned subsidiary of Bristol Myers Squibb. The sponsor had no role in the decision to submit the manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. EDAT- 2022/07/08 06:00 MHDA- 2022/07/12 06:00 CRDT- 2022/07/07 21:03 PHST- 2022/04/01 00:00 [received] PHST- 2022/04/08 00:00 [accepted] PHST- 2022/07/07 21:03 [entrez] PHST- 2022/07/08 06:00 [pubmed] PHST- 2022/07/12 06:00 [medline] AID - S0735-1097(22)04997-X [pii] AID - 10.1016/j.jacc.2022.04.048 [doi] PST - ppublish SO - J Am Coll Cardiol. 2022 Jul 12;80(2):95-108. doi: 10.1016/j.jacc.2022.04.048.