Reduced need for surgical intervention in obstructive HCM with cardiac myosin inhibitor

Mavacamten As An Alternative To Surgical Septal Myectomy Or Alcohol Ablation In Patients With Severely Symptomatic Obstructive Hypertrophic Cardiomyopathy

Presented at ACC.22 by Prof. Milind Desai, MD (Cleveland, OH, USA)

Introduction and methods

Background

There is a need for specific and noninvasive therapies for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). Mavacamten is a selective cardiac myosin inhibitor that targets the underlying pathophysiology of obstructive HCM. It reduces cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation. It has been shown that mavacamten improves LVOT gradient, quality of live and physical function. However, the effect of mavacamten on the need for septal reduction therapy (SRT) remained unknown.

Methods

VALOR-HCM was a multicenter, phase 3, double-blind, placebo-controlled trial in adults with obstructive HCM with severe symptoms despite maximally-tolerated medical therapy. All patients were eligible for SRT based on the 2011 ACC/AHA guideline and have been referred for SRT within the past 12 months and were actively considering scheduling the procedure. A total of 112 patients were randomized to receive either mavacamten (n=56) or placebo (n=56) for 16 weeks. Patients underwent a clinical exam and echocardiogram at baseline, every month and at 16 weeks. The starting dose of mavacamten was 5 mg QD, and was titrated at weeks 8 (to 10 mg, 5 mg, or 2.5 mg) and 12 (to 15 mg, 10 mg, 5 mg or 2.5 mg). Titration was based on echocardiogram measures of LVEF and LVOT gradient at rest and Valsalva provocation.

Outcomes

The primary endpoint was a composite of the patient’s decision to proceed with SRT or continue to meet 2011 ACC/AHA guideline eligibility for SRT after 16 weeks. Secondary outcomes included change in post-exercise LVOT gradient, proportion of patients with a ≥1 class of NYHA improvement, change in KCCQ clinical summary score, change in NT-proBNP and change in Troponin I.

Main results

Primary outcome

• At 16 weeks, 10 out of 56 (17.9%) patients on mavacamten vs. 43 out of 56 (76.8%) patients on placebo were still eligible for, or choose to receive, SRT (P<0.0001).

Secondary outcomes

• In the mavacamten group, 63% of patients improved ≥1 NYHA Class and 27% improved ≥2 NYHA classes, compared with 21% and 2% in the placebo group.
• Treatment with mavacamten improved the resting and Valsalva LVOT gradient at 16 weeks, compared to placebo (resting LVOT gradient difference: -33.4 mmHg, 95% CI -42.3 to - 24.5, P<0.001; Valsalva LVOT gradient difference: -47.6 mmHg, 95% CI, -58.2 to -37.0, P<0.001).
• Mavacamten also improved KCCQ clinical summary score, NT-proBNP and troponin I compared to placebo at 16 weeks (KCCQ-23 CSS difference: 9.4, 95% CI 4.9 to 14.0; NT-proBNP geometric mean ratio difference: 0.33, 95% CI 0.26 to 0.45; Troponin I geometric mean ratio difference: 0.53, 95% CI 0.41 to 0.70; All P<0.001).
• There was no significant difference in LVEF between the two treatment groups at 16 weeks.

Safety

• Mavacamten was well tolerated, with no serious adverse events of CHF, syncope or sudden cardiac death in the trial.
• Two patients in the mavacamten group had a reduction in LVEF to <50% and had to stop the drug temporarily until LVEF recovered. Both patients were able to restart mavacamten at a lower dose.

Conclusion

In patients with symptomatic obstructive hypertrophic cardiomyopathy, mavacamten significantly reduced the proportion of patients who were eligible for, or choose to receive, septal reduction therapy at 16 weeks. Treatment with mavacamten also resulted in significant improvements in LVOT gradient, quality of live as measured by KCCQ clinical summary score, NT-proBNP and troponin I.

-Our coverage of ACC.22 is based on the information provided during the congress-

Watch the video with Milind Desai about this study