Key Points:
- In patients with treatment-refractory symptomatic obstructive hypertrophic cardiomyopathy (HCM), invasive septal reduction therapies (SRT)—alcohol septal ablation or surgical myectomy—are often the last resort for symptom management. Septal reduction therapies are limited in availability and associated with procedural risks.
- The VALOR-HCM trial demonstrated that mavacamten significantly reduced the need for SRT in severely symptomatic HCM patients at 16, 32, and 56 weeks.
- At 128 weeks, mavacamten provided sustained freedom from SRT, with nearly 90% of patients remaining on long-term therapy.
Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder affecting between 1 in 200 and 1 in 500 individuals. It places patients at increased risk for progressive dyspnea, heart failure, atrial fibrillation, and sudden cardiac death. Traditionally, symptomatic HCM patients unresponsive to medical therapies such as β-blockers, calcium channel blockers, or disopyramide are recommended for septal reduction therapy (SRT), including surgical myectomy or alcohol septal ablation. These procedures aim to alleviate left ventricular outflow tract (LVOT) obstruction, improve symptoms, and enhance quality of life. However, achieving optimal outcomes often requires access to limited high-volume specialized centers, and SRT carries risks of procedural complications.
The VALOR-HCM trial (NCT04349072) is a phase 3 placebo-controlled study investigating mavacamten, a first-in-class selective allosteric and reversible cardiac myosin inhibitor, in patients with symptomatic obstructive HCM referred for SRT. The trial demonstrated that mavacamten, when added to maximally tolerated medical therapy, significantly reduced symptom burden and improved quality of life, allowing patients to defer SRT for up to 56 weeks. Similar benefits were observed in patients who crossed over to active treatment after 16 weeks.
During a featured science session at the American Heart Association 2024 Scientific Sessions on November 18, 2024, Dr. Miland Desai from the Cleveland Clinic in Ohio presented the 128-week follow-up results from the VALOR-HCM trial with simultaneous publication in Circulation..
A total of 112 symptomatic obstructive HCM patients referred for SRT were enrolled across 19 U.S. centers. Participants were randomized to receive mavacamten or placebo for 16 weeks, followed by an open-label extension where placebo patients crossed over to mavacamten for up to 128 weeks. Dosing was personalized based on serial echocardiographic assessments of LVOT gradients and left ventricular ejection fraction (LVEF). The primary endpoint was the proportion of patients undergoing SRT or remaining guideline-eligible for SRT by week 128. Secondary endpoints included changes in New York Heart Association (NYHA) functional class, LVOT gradients, and adverse events.
At 128 weeks, 108 of 112 patients qualified for evaluation. Of these, only 17 patients (15.7%) met the composite endpoint of proceeding with SRT or remaining eligible for it. Most patients (80.5%) experienced at least a one-class improvement in NYHA functional status, with nearly half (48.1%) achieving a two-class improvement. Sustained reductions in LVOT gradients were observed, with mean reductions of 38.2 mm Hg (resting) and 59.4 mm Hg (Valsalva).
By study conclusion, 95 of 108 patients (88%) transitioned to commercial mavacamten, highlighting the therapy’s tolerability and real-world applicability. The safety profile remained favorable despite extended treatment duration. LVEF <50% was observed in 15 patients (13.8%; incidence rate: 5.41 per 100 patient-years), including 2 cases with LVEF ≤30% and 1 treatment-related death. Importantly, 80% of these patients were able to continue therapy with dose adjustments. New-onset atrial fibrillation occurred in 11 patients (10.2%; incidence rate: 4.55 per 100 patient-years).
Reflecting on the study, Dr. Desai remarked, “The take-home message is that the drug is highly effective. Nine out of ten patients who were referred for cardiac surgery or alcohol ablation no longer needed it. And this was not a short-term fluke; we have demonstrated that in the long term, most patients maintain sustained improvements in cardiac remodeling, symptoms, and LVOT gradients.”