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

doi:10.1016/j.jacc.2022.04.048

Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy

J Am Coll Cardiol. 2022 Jul 12;80(2):95-108. doi: 10.1016/j.jacc.2022.04.048.

Authors

Milind Y Desai¹, Anjali Owens², Jeffrey B Geske³, Kathy Wolski⁴, Srihari S Naidu⁵, Nicholas G Smedira⁶, Paul C Cremer⁴, Hartzell Schaff⁷, Ellen McErlean⁴, Christina Sewell⁴, Wanying Li⁸, Lulu Sterling⁸, Kathy Lampl⁸, Jay M Edelberg⁸, Amy J Sehnert⁸, Steven E Nissen⁹

Affiliations

¹ 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.
² Division of Cardiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
⁴ 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.
⁵ Department of Cardiology, Westchester Medical Center, Valhalla, New York, USA.
⁶ Hypertrophic Cardiomyopathy Center, Cleveland Clinic, Cleveland, Ohio, USA; Department of Cardiothoracic Surgery, Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁷ Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota, USA.
⁸ MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Brisbane, California, USA.
⁹ 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.

PMID: 35798455
DOI: 10.1016/j.jacc.2022.04.048

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.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Cardiomyopathy, Hypertrophic* / therapy
Female
Humans
Male
Middle Aged
Myosins* / antagonists & inhibitors
Stroke Volume
Treatment Outcome
Ventricular Function, Left / physiology

Substances

Myosins

Associated data

ClinicalTrials.gov/NCT04349072