VALOR-HCM: Mavacamten reduces need for septal reduction therapy in obstructive HCM
WASHINGTON — The cardiac myosin inhibitor mavacamten, compared with placebo, reduced the need for septal reduction therapy in patients with obstructive hypertrophic cardiomyopathy, according to results of the VALOR-HCM trial.
Mavacamten (Bristol Myers Squibb) also improved symptoms, biomarker levels and quality of life metrics compared with placebo, Milind Y. Desai, MD, MBA, director of the Hypertrophic Cardiomyopathy Center and director of clinical operations at Cleveland Clinic’s Heart Vascular and Thoracic Institute and professor of medicine at Cleveland Clinic Lerner College of Medicine, said during a presentation at the American College of Cardiology Scientific Session.
Septal reduction therapy, in the form of surgical myectomy or alcohol septal ablation, is indicated for patients with obstructive hypertrophic cardiomyopathy (HCM) who have “intractable symptoms despite maximal medical therapy,” Desai said.
“Current therapies are not designed for obstructive hypertrophic cardiomyopathy,” he said. “Although septal reduction therapy improves long-term survival, symptoms and quality of life, optimal results require specialized care that is not widely available. Accordingly, there is an unmet need for noninvasive alternatives to septal reduction therapy in highly symptomatic obstructive HCM patients.”
The researchers randomly assigned 112 patients with obstructive HCM (mean age, 60 years; 49% women; 92.9% with NYHA class III HF or higher) to receive mavacamten or placebo. All patients underwent echocardiography, stress echocardiography and a septal reduction therapy evaluation at baseline and 16 weeks, with additional echocardiograms at 4 weeks, 8 weeks and 12 weeks, Desai said. The mavacamten group was started on a dose of 5 mg daily and were titrated at 8 weeks and 12 weeks, he said.
The primary endpoint was a decision to proceed with septal reduction therapy or guideline-based eligibility for septal reduction therapy at 16 weeks.
The primary endpoint occurred in 17.9% of the mavacamten group compared with 76.8% of the placebo group (treatment difference, 58.93; 95% CI, 43.99-73.87; P < .0001). The primary endpoint was driven by guideline-based eligibility for septal reduction therapy, as only two patients from each group decided to have septal reduction therapy at the end of the study, Desai said.
Desai said mavacamten also met the following secondary endpoints:
- improvement in resting left ventricular outflow tract (LVOT) gradient (difference, –33.4 mm Hg; 95% CI, –42.3 to –24.5; P < .001);
- improvement by at least one NYHA class (mavacamten, 63%; placebo, 21%) and improvement by at least two NYHA classes (mavacamten, 27%; placebo, 2%; P for both < .001);
- N-terminal pro-B natriuretic peptide geometric mean ratio difference (0.33; 95% CI, 0.26-0.45; P < .001);
- Valsalva LVOT gradient (difference, –47.6 mm Hg; 95% CI, –58.2 to 37; P < .001)
- Kansas City Cardiomyopathy Questionnaire-23 score (difference, 9.4; 95% CI, 4.9-14; P < .001); and
- troponin I geometric mean ratio difference (0.53; 95% CI, 0.41-0.7).
Adverse event rates were low, there were no permanent treatment discontinuations due to LV ejection fraction falling below 30% and there were no cases of congestive HF, syncope or sudden cardiac death, Desai said, noting the difference between the groups in LVEF was not significant.
“In obstructive HCM patients with intractable symptoms who were referred for septal reduction therapy, administration of the first-in-class cardiac myosin inhibitor mavacamten, titrated using echocardiography, significantly reduced the need for a septal reduction therapy procedure at 16 weeks and showed treatment benefits for all prespecified secondary endpoints,” Desai said.
Perspective
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Mavacamten is a game changer in obstructive HCM, as seen in the VALOR-HCM trial. Mavacamten is a target inhibitor of cardiac myosin; thus, it decreases the excessive contractility that patients with obstructive HCM experience. This trial showed significant improvement in symptoms, degree of LVOT gradient and cardiac markers, delaying or avoiding the need for septal reduction therapies by 16 weeks with really minor side effects. Remember, septal reduction therapies are not available to everyone; they need to be performed at experienced centers by experienced performers. A lot of minority patients will have not access to these centers. Thus, mavacamten will allow us to improve the health of many patients and select those who truly require septal reduction therapies.
Another point to consider is that a lot of these patients are young and receive a shocking diagnosis than will change their lives. To require surgery and implantable cardioverter defibrillator placement may be a hard pill to swallow all at once. Maybe this therapy will also give time to patients to adjust better to their diagnosis.
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Desai MY, et al. Joint American College of Cardiology/Journal of the American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2022; Washington, D.C. (hybrid meeting).