Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy
Milind Y Desai, Anjali Owens, Jeffrey B Geske, Kathy Wolski, Srihari S Naidu, Nicholas G Smedira, Paul C Cremer, Hartzell Schaff, Ellen McErlean, Christina Sewell, Wanying Li, Lulu Sterling, Kathy Lampl, Jay M Edelberg, Amy J Sehnert, Steven E Nissen, Milind Y Desai, Anjali Owens, Jeffrey B Geske, Kathy Wolski, Srihari S Naidu, Nicholas G Smedira, Paul C Cremer, Hartzell Schaff, Ellen McErlean, Christina Sewell, Wanying Li, Lulu Sterling, Kathy Lampl, Jay M Edelberg, Amy J Sehnert, Steven E Nissen
Abstract
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).
Keywords: mavacamten; obstructive HCM; randomized clinical trial; septal reduction.
Conflict of interest statement
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.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed