Dose-Blinded Myosin Inhibition in Patients with Obstructive HCM Referred for Septal Reduction Therapy: Outcomes Through 32-Weeks

Background: Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial examined the effect of mavacamten on the need for SRT through Week 32 in oHCM.

Methods: A double-blind randomized placebo-controlled multicenter trial at 19 US sites included oHCM patients on maximal tolerated medical therapy referred for SRT, with left ventricular outflow tract (LVOT) gradient ≥50 mmHg at rest or provocation (enrollment 7/202010/2021). The group initially randomized to mavacamten continued the drug for 32 weeks and the placebo group crossed over to dose-blinded mavacamten from Week 16 to 32. Dose titrations were based on investigator-blinded echocardiographic assessment of LVOT gradient and LV ejection fraction. The principal endpoint was proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups.

Results: From the 112 randomized oHCM patients, 108 (mean age 60.3 years, 50% men and 94% in New York Heart Association [NYHA] class III/IV) qualified for Week 32 evaluation (56 in original mavacamten and 52 in placebo crossover group). After 32 weeks, 6/56 (10.7%) patients in original mavacamten and 7/52 (13.5%) in placebo crossover group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting LVOT gradient (-33.0 mmHg 95% confidence interval [CI] -41.1 to -24.9) and Valsalva LVOT gradient (-43.0 mmHg, 95% CI -52.1 to -33.9) was observed in the original mavacamten group. A similar reduction in resting (-33.7 mmHg, 95% CI -42.2 to -25.2) and Valsalva gradients (-52.9 mmHg, 95% CI -63.2 to -42.6) was quantified in the crossover group after 16 weeks of mavacamten. After 32 weeks, ≥1 NYHA class improvement was observed in 48/53 (90.6%) of original mavacamten and 35/50 (70%) after 16 weeks in the crossover group.

Conclusions: In severely symptomatic oHCM patients, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients crossed over from placebo after 16 weeks.

Trial Registration: URL: Clinicaltrials.gov Unique Identifier: NCT04349072

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