Mavacamten in the Treatment of HCM in Patients Referred for Septal Reduction
Extended 56-week follow-up of patients with hypertrophic cardiomyopathy (HCM) resistant to current pharmacotherapy in the VALOR-HCM study confirmed the lasting benefit of mavacamten – the first representative of a new class of selective reversible cardiac myosin inhibitors – as a new pharmacological treatment option reducing the need for invasive procedures.
Treatment Options for HCM
Hypertrophic cardiomyopathy (HCM) is an inherited genetic disorder of the myocardium characterized by primary hypertrophy of the left ventricle. In two-thirds of cases, it is accompanied by obstruction of the left ventricular outflow tract (LVOT). Previously, treatment utilized beta-blockers, verapamil, or the antiarrhythmic disopyramide, with invasive treatment being the only other option. Septal reduction therapy (SRT) is performed through surgical septal myectomy or alcohol ablation. Although this invasive therapy extends overall survival time, alleviates symptoms, and improves the quality of life for patients, long-term specialized care is needed following the procedure.
A new pharmacotherapy option is now represented by mavacamten, the first in a class of selective reversible cardiac myosin inhibitors. Its mechanism of action involves modulation of the number of myosin heads that can enter into a contraction state, thereby reducing (or normalizing in HCM) the likelihood of forming systolic and residual diastolic cross-bridges during contraction. In patients with HCM, inhibition of cardiac myosin with mavacamten normalizes contractility, reduces LVOT dynamic obstruction, and improves cardiac filling pressures.
Methodology, Progress, and Goals of the VALOR-HCM Study
The efficacy and safety of mavacamten were assessed in a randomized, double-blind, multicenter phase III clinical trial, VALOR-HCM. Patients with HCM, older than 18 years, with severe symptoms unresponsive to maximum tolerated pharmacotherapy, and classified as NYHA III–IV were included. Additional inclusion criteria included a maximum septal thickness > 15 mm or > 13 mm in patients with a positive family history of HCM, a dynamic LVOT gradient (resting or provoked) ≥ 50 mmHg, a left ventricular ejection fraction (LVEF) ≥ 60%, and an indication for invasive SRT within the last 12 months.
The primary composite monitored criterion included the patient's decision to undergo SRT and the suitability of SRT according to the AHA/ACC 2021 guidelines. Efficacy monitoring involved changes in clinical parameters (LVOT gradient, NYHA classification, quality of life according to KCCQ-23 CCS), laboratory markers (NT-proBNP, cardiac troponin I), and echocardiographic parameters (left ventricular mass index, left atrial volume index, and E/e´ of the septum) compared to baseline. Safety monitoring looked at the incidence of sudden cardiac death, a decrease in LVEF to < 50%, hospitalization for heart failure, and atrial fibrillation or ventricular tachyarrhythmias.
After 16 weeks of double-blind use of mavacamten or placebo, all patients in the study received mavacamten until week 56.
Results
After 16 weeks, the incidence of the primary monitored criterion was 18% in the mavacamten group compared to 77% in the placebo group. Of the 112 enrolled, 108 (98%) patients continued with long-term mavacamten treatment, 20% of whom also used disopyramide. After 56 weeks, the persistent effect of mavacamten was evident, with the incidence of the primary monitored criterion being 8.9% in patients randomized to mavacamten from the start of the study and 19.2% in those switched from placebo to mavacamten after 16 weeks. The resting LVOT gradient decreased by 34.0 mmHg in the group randomized to mavacamten and by 33.2 mmHg in those switched to mavacamten from placebo; the provoked LVOT gradient decreased by 45.6 mmHg and 54.6 mmHg, respectively. The NYHA class decreased by ≥ 1 in 93% and 73% of patients, and the KCCQ-CSS score increased by 11.7 and 14.1 points, respectively. Both groups also saw reductions in NT-proBNP levels (by 376 and 423 ng/l) and troponin I levels (by 7.0 and 6.2 ng/l), with improvements in all monitored echocardiographic parameters.
No patients randomized to mavacamten discontinued treatment due to a drop in LVEF below 30% or below 50% on two consecutive measurements despite dose reduction, whereas this occurred in 3 patients originally randomized to placebo. At least one instance of LVEF < 50% was detected in 12 (11.8%) patients, including 7 (12.5%) from the original mavacamten group and 5 (9.6%) switched from placebo to mavacamten. Other adverse events included atrial fibrillation in 3 cases, congestive heart failure in 1, and ventricular tachyarrhythmia in 1 case.
Conclusion and Discussion
The results of the extended follow-up in the VALOR-HCM study demonstrate the sustained benefit of mavacamten after 56 weeks of treatment. Mavacamten significantly reduces the need for invasive treatment (SRT) and improves all monitored parameters – resting and provoked LVOT gradient, NYHA class, quality of life according to KCCQ-CSS, laboratory biomarkers, and echocardiographic findings.
Mavacamten is now a therapeutic option for patients with symptomatic HCM and LVOT refractory to previous pharmacotherapy. Due to the possible transient reduction in LVEF, evaluation before mavacamten initiation and regular monitoring during treatment are required. Further studies evaluating the efficacy and safety of long-term use of this drug are needed.
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Source: Desai M. I., Owens A., Wolski K. et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol 2023; 8 (10): 968−977, doi: 10.1001/jamacardio.2023.3342.
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