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Replacing septal reduction therapy with mavacamten for HCM

Presented By
Prof. Milind Desai, Cleveland Clinic, USA
ACC 2022
Phase 3, VALOR-HCM
Initial data from the VALOR-HCM trial indicated that targeted therapy for hypertrophic cardiomyopathy (HCM) with mavacamten, a small molecule inhibitor of β-cardiac myosin, is likely to be the new standard of care.

Prof. Milind Desai (Cleveland Clinic, OH, USA) presented the first findings from the multicentre, double-blind, placebo-controlled, randomised, phase 3 VALOR-HCM (NCT04349072) trial [1,2]. The primary endpoint was a composite of the patient’s preference to proceed with septal reduction therapy (SRT) before the end of week 16 or remain guideline-eligible for SRT at week 16. Secondary efficacy endpoints included change from baseline to week 16 in post-exercise left ventricular outflow tract obstruction (LVOT), New York Heart Association (NYHA) Classification, Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, and cardiac troponin.

The results presented by Prof. Desai included 112 patients with obstructive HCM, with a maximum septal wall thickness on echocardiography of ≥15 mm or ≥13 mm with family history, who were refractory to maximally tolerated medical therapy (46% on β-blockers; 20% on disopyramide). All participants had been referred for SRT (87% to myectomy) within the prior 12 months. Prof. Desai reported that of the 56 participants randomised to receive mavacamten (starting dose 5 mg), after 16 weeks, only 17.9% of patients remained guideline-eligible to receive SRT (defined as LVOT gradient of ≥50 mmHg and NYHA class III–IV) compared with 76.8% of the placebo arm [P<0.0001].

All of the secondary endpoints of postexercise LVOT, NYHA Classification, KCCQ score, and NT-proBNP, and troponin levels were also improved with mavacamten versus placebo (all P<0.001). Of clinical importance, NYHA Classification improved by 1 or 2 classes in 63% in the mavacamten arm, compared with 27% in the placebo arm.

No severe adverse events were noted with mavacamten. Two participants needed to temporarily pause mavacamten due to an ejection fraction of <50%. Nausea and a rash were reported in a few participants.

If performed in an experienced centre, SRT is a “very safe and excellent procedure,” Prof. Desai noted; however, not without risk. The average US mortality with SRT is 5.9% and can be as high as 16% at low-volume centres.

In conclusion, VALOR-HCM obviates the need for SRT in severely symptomatic drug-refractory HCM patients with a 16-week course of mavacamten, using clinically-driven endpoints.

    1. Desai MY, et al. Mavacamten As An Alternative To Surgical Septal Myectomy Or Alcohol Ablation In Patients With Severely Symptomatic Obstructive Hypertrophic Cardiomyopathy. Abstract 402-09, ACC 2022, 2–4 April, Washington DC, USA.

    2. Desai MY, et al. Am Heart J. 2021 Sep;239:80–89.


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