VALOR-HCM: Treatment with mavacamten decreased need for septal reduction therapy in patients with hypertrophic cardiomyopathy.

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By Leah Kosyakovsky, MD on

Key Points:

    • In the VALOR-HCM study, patients with severely symptomatic obstructive HCM on maximally tolerated medical therapy were treated with either mavacamten (a novel cardiac myosin inhibitor) or placebo. The primary outcome was composite of patient decision to proceed with SRT or continue to meet 2011 ACC/AHA guideline eligibility for SRT after 16 weeks. Pre-specified secondary analyses included a) change in post-exercise LVOT gradient, b) number of patients with a ≥1 class of NYHA improvement, c) change in KCCQ clinical summary score, d) change in NT-proBNP, and e) change in Troponin I.
    • Treatment with mavacamten reduced the primary endpoint, which was largely driven by guideline eligibility for SRT 17.9% of patients were eligible for SRT therapy at 16 weeks in the mavacamten arm, compared to 76.8% in the placebo arm. Mavacamten also led to a reduction in resting and Valsalva LVOT gradient, troponin and BNP, and KCCQ score.

Patients with obstructive hypertrophic cardiomyopathy (HOCM) suffer from a high burden of symptoms and are at risk of progression to advanced heart failure as well as sudden cardiac death. If patients have failed conservative medical therapy with negative inotropic agents, they are referred for septal reduction therapies (SRT), including either surgical septal myectomy or alcohol septal ablation. A novel medical therapy, mavacamten, has been developed specifically for the medical management of HOCM;  the mechanism of action is via direct cardiac myosin inhibition and reduction of excessive contractility. In a breaking presentation at the 2022 American College of Cardiology Conference today, Dr. Milind Desai (Cleveland Clinic, Cleveland) and his team presented the results of the “Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy” (VALOR-HCM) trial.

The VALOR-HCM study (NCT04349072) was a randomized, double-blind, placebo-controlled, multi-center study conducted across 19 centers in the United States. Patients were treated with either mavacamten or placebo in addition to optimal medical therapy for a total of 16 weeks. All recruited patients were adults with documented HCM with maximum septal wall thickness ≥15 mm (or ≥13 mm with family history of HCM); all patients had to have severe symptoms refractory to maximally tolerated medical therapy. Patients were also required to have an EF >60%, a Valsalva-induced LVOT gradient >50mm Hg, and had to have been referred for SRT in the past 12 months. Some relevant exclusion criteria included previous SRT, permanent atrial fibrillation off anticoagulation (or not optimally rate controlled), or paroxysmal atrial fibrillation with the arrythmia identified at screening.

A total of 112 patients were randomized; 56 received mavacamten and 56 received placebo. All patients received a baseline echocardiogram, stress echocardiogram, and SRT evaluation. Baseline age was 60, and baseline resting LVOT gradient was 51.2mmHg in the mavacamten arm and 46.3 mmHg in the placebo arm. Patients in the mavacamten arm were initiated on 5mg daily, and the doses were titrated based on repeat echocardiogram performed at 8 and 12 weeks. At 8 weeks, the new doses could range from 2.5-10mg daily; at 12 weeks, the range was 2.5-15mg daily. At 16 weeks, all patients were subject to repeat echocardiogram, stress echocardiogram, and SRT evaluation. The primary outcome was a composite of patient decision to proceed with SRT or continue to meet 2011 ACC/AHA guideline eligibility for SRT after 16 weeks, which was significantly reduced in the mavacamten arm (treatment difference 58.93 (43.99,73.87), p <0.0001). 17.9% of patients were eligible for SRT therapy at 16 weeks in the mavacamten arm, compared to 76.8% in the placebo arm; 63% of patients in the mavacamten group improved by at least 1 NYHA class, compared to 21% in the placebo group. Pre-specified secondary analyses, tested hierarchically, included: a) change in post-exercise LVOT gradient, b) number of patients with a ≥1 class of NYHA improvement, c) change in KCCQ clinical summary score, d) change in NT-proBNP, and e) change in Troponin I. Mavacamten treatment resulted in reduced resting (-33.4 mm Hg (95% CI, -42.3, -24.5), p<0.001) and Valsalva-induced (-47.6 mm Hg (95% CI, -58.2, -37.0), p<0.001) LVOT gradient compared to placebo. Mavacamten treatment also resulted in lower KCCQ-23 summary score, BNP, and troponin I compared to placebo (all p<0.001). There were no significant selected adverse events in the mavacamten group; specifically, no patients experienced CHF, syncope, or SCD.

When discussing the implications of the study at the ACC, Dr. Desai stated: “As for limitations, the primary endpoint was driven by reduction in guideline eligibility for SRT, but 95% of patients in the study have chosen to continue with medical therapy as opposed to proceeding with SRT. Long-term results will be available in due course. The duration of randomization was only 16 weeks, because these are highly symptomatic patients….whether myosin inhibition can allow patients to avoid SRT during the long-term remains uncertain. Long-term safety also needs to be ascertained.”