VALOR-HCM Substudy: Mavacamten Improves Left Ventricular Diastolic Function

Treatment with the myosin inhibitor mavacamten improves measures of diastolic function in patients with severe symptomatic obstructive hypertrophic cardiomyopathy (HCM) independent of reductions in left ventricular outflow tract (LVOT) gradients and mitral regurgitation.

So finds a subanalysis of the phase 3 VALOR-HCM study, which previously showed that the novel drug therapy reduced patients’ need for invasive septal reduction therapy. The new subanalysis, published in Circulation: Cardiovascular Imaging, also demonstrated that diastolic improvement correlated with gains in New York Heart Association (NYHA) class, quality-of-life measures and cardiac biomarkers at 16 weeks.

“Clinical improvement with mavacamten appears to be partly mediated by improved diastolic function,” says Cleveland Clinic cardiologist Paul Cremer, MD, MS, first author of the substudy. “This finding has important implications for the use of diastolic assessment to determine prognosis, evaluate treatments and study in other conditions.”

VALOR-HCM and mavacamten in brief

VALOR-HCM is a double-blind, randomized, placebo-controlled crossover VALOR-HCM trial conducted at Cleveland Clinic and 19 other U.S. sites to evaluate mavacamten’s effects among 112 patients with obstructive HCM. All patients had severe symptoms despite maximally tolerated medical therapy and had been referred for septal reduction therapy.

Results after 32 weeks of the trial were recently published online in Circulation and summarized in a prior Consult QD post. Most notably, more than 85% of patients no longer met guideline criteria for septal reduction therapy after mavacamten therapy. The treatment also reduced LVOT gradient and improved clinical function (reduction of ≥ 1 NYHA class) in 90% of patients at 32 weeks. A long-term extension of the trial is ongoing.

Based on results from the first 16 weeks of the VALOR-HCM study, the FDA approved mavacamten (Camzyos®) for adults with symptomatic obstructive HCM in April 2022, making it the first medication approved for this indication. The drug selectively inhibits cardiac myosin, decreasing the number of excess myosin-actin cross bridges in heart muscle that lead to hypercontractility. Although mavacamten improves ventricular compliance, an important factor in heart failure in obstructive HCM, its specific effects on diastolic function have not been well studied.

Subanalysis design and findings

The substudy evaluated 98 patients (51 of whom took mavacamten) from VALOR-HCM who had diastolic dysfunction grade assessment at baseline and week 16. Principal findings of echocardiographic diastolic function parameters over that time period included the following:

• 4% of treated patients (15/51) had at least a one-grade improvement in diastolic function, compared with 12.8% of patients randomized to placebo (6/47) (P = 0.05).
• Average E/e′ ratio (an index used to evaluate left ventricular filling pressure) decreased by 14.1% in patients treated with mavacamten while it increased by 5.3% in patients treated with placebo (P < 0.001).
• Indexed left atrial volumes (LAVi) decreased by 10.3% in treated patients while it increased by 1.4% in the placebo group (P = 0.003).

Mavacamten-associated improvements in E/e′ ratio and LAVi were independent of LVOT gradient reduction and mitral regurgitation improvement. In addition, decreased average E/e′ ratio was associated with all the secondary clinical and biomarker endpoints in the VALOR-HCM study, including:

• Improvement in NYHA functional class (r = –31, P = 0.002)
• Improvement in Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score (KCCQ-23 CSS) (r= –22, P = 0.03)
• Reduction in NT-proBNP (r = 0.58, P < 0.001)

Change in LAVi had no significant correlation with improvements in NYHA functional class or change in KCCQ-23 CSS, but weakly correlated with improved NT-proBNP level (r = 0.20, P = 0.04).

Key takeaways and implications

Dr. Cremer notes two major conclusions from the study:

• Mavacamten treatment is associated with improved E/e′ ratio and LAVi, independent of LVOT gradient reduction and improved mitral regurgitation.
• Average E/e′ ratio reductions are correlated with improved clinical function measures and NT-proBNP.

As this was a small exploratory substudy, Dr. Cremer emphasizes that its results should be considered hypothesis-generating. He adds that the findings should be confirmed in studies with longer follow-up, and suggests that they also be assessed in nonobstructive HCM and other cardiac conditions.

He highlights two important implications suggested by these findings. “First, average E/e′ ratio may be a preferred surrogate diastology imaging endpoint in future studies of myosin inhibition in HCM,” he says. “Also, changes in average E/e′ ratio should be considered as a preferred diastolic measure to inform prognosis in obstructive HCM.”

“The clinical benefit of mavacamten is likely partially related to improved ventricular compliance, so effective treatments for obstructive HCM should improve diastolic function in addition to relieving LVOT obstruction and reducing mitral regurgitation,” adds VALOR-HCM principal investigator Milind Desai, MD, MBA, Director of Cleveland Clinic’s Hypertrophic Cardiomyopathy Center and senior author of this subanalysis. “This suggests new avenues of investigation for therapy.”