Mavacamten and Septal Reduction Therapy in Patients With Symptomatic oHCM

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Researchers sought to examine the effect of mavacamten on the need for septal reduction therapy in patients with obstructive hypertrophic cardiomyopathy.

Mavacamten reduces the need for septal reduction therapy at 16 weeks among symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM), according to a study published in the Journal of the American College of Cardiology.

Investigators sought to assess whether the addition of mavacamten to maximally tolerated medical therapy would allow patients with severely symptomatic oHCM to improve enough so that they no longer met guideline criteria for septal reduction therapy or could choose not to receive septal reduction therapy.

The Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy (VALOR-HCM; Identifier: NCT04349072) trial is a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial conducted at 19 sites in the United States.

Study participants were treated with maximally tolerated medical therapy and referred for consideration of septal reduction therapy, either surgical myectomy or alcohol septal ablation, within 12 months. Patients had to meet 2011 American College of Cardiology/American Heart Association guideline criteria for septal reduction therapy. The patients were aged 18 years or older, with severe dyspnea or chest pain despite maximally tolerated medical therapy and New York Heart Association (NYHA) functional class III/IV or class II with exertional syncope or near syncope.

The participants were randomly assigned in a 1:1 ratio to mavacamten 5 mg/day or placebo once daily by mouth. Randomization was stratified according to type of septal reduction therapy recommended and NYHA functional class.

The primary endpoint is the composite of eligibility for septal reduction therapy according to the 2011 guidelines or the patient’s decision to have septal reduction therapy after 16 weeks of treatment.

A total of 112 highly symptomatic oHCM patients (mean age, 60±12 years; 51% men; 93% ≥NYHA functional class III) were enrolled from July 2020 to October 2021. Of these patients, 56 received mavacamten (mean age, 59.8±14.2 years; 51.8% men; 85.7% White), and 56 received placebo (mean age, 60.9±10.5 years; 50.0% men; 92.9% White).

The participants had severe dynamic left ventricular outflow tract (LVOT) obstruction with a mean resting gradient of 49±30.9 mm Hg, a Valsalva gradient of 76±30.2 mm Hg, and a post-exercise LVOT gradient of 84±35.8 mm Hg on maximally tolerated medical therapy. Thirty-two percent of patients received combination therapy (including disopyramide).

After 16 weeks of treatment, 76.8% of patients who received placebo continued to meet guideline criteria for septal reduction therapy or chose to have the procedure vs 17.9% of patients who received mavacamten (treatment difference, 58.9%; 95% CI, 44.0%-73.9%; P <.001).

Statistically significant differences favoring mavacamten are found in hierarchical testing of all prespecified secondary outcomes comparing mavacamten with placebo (all P <.001), including the following:

  • Post-exercise LVOT gradient (mean difference, -37.2 mm Hg; 95% CI, -48.1 to -26.2 mm Hg)
  • The proportion of participants who have 1 class or higher of NYHA functional class improvement (41.1%; 95% CI, 24.5%-57.7%)
  • The change in patient-reported Kansas City Cardiomyopathy Questionnaire 23-item Clinical Summary Score (9.4 points; 95% CI, 4.9-14.0 points)
  • Geometric mean ratios for change in N-terminal pro–B-type natriuretic peptide (0.33; 95% CI, 0.26-0.42)
  • Cardiac troponin I levels (0.53; 95% CI, 0.41-0.70)

Mavacamten is well-tolerated, with 3.6% patients having left ventricular ejection fraction of less than 50% that led to temporary drug discontinuation in the mavacamten group and none in the placebo group.

Among several study limitations, the primary endpoint is driven solely by a decrease in guideline eligibility for septal reduction therapy and not by the decision of patients not to have septal reduction therapy. In addition, participants are randomized for 16 weeks of treatment, and the long-term safety of mavacamten has not been determined in this patient group. Furthermore, the study includes predominantly White patients from high-volume HCM centers with established septal reduction therapy.

“In highly symptomatic obstructive HCM patients meeting guideline criteria for [septal reduction therapy], the addition of mavacamten to maximally tolerated background medical therapy significantly reduced guideline eligibility for [septal reduction therapy] after 16 weeks of treatment,” wrote the investigators. “The study also demonstrated significant reduction in LVOT gradients in mavacamten-treated patients, improvements in NYHA functional classification, and quality-of-life measures. The safety of mavacamten and effect on outcomes during long-term administration remain to be determined.”

Disclosure: The VALOR-HCM study was funded by MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 


Desai MY, Owens A, Geske JB, et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol. Published online July 4, 2022. doi: 10.1016/j.jacc.2022.04.048