Evaluation of the hypothetical risk of sudden cardiac death in obstructive HCM patients treated with mavacamten using the HCM Risk-SCD score

Background Hypertrophic cardiomyopathy (HCM) is associated with an increased risk of sudden cardiac death (SCD). Risk stratification may be performed using the HCM Risk-SCD score, which has been validated in cohorts of patients treated with first-line medical therapy (beta-blockers or calcium channel blockers). Mavacamten, a novel selective cardiac myosin inhibitor, has been shown to reduce left ventricular outflow tract obstruction (LVOTO) and to promote reverse remodeling. Its influence on the estimated HCM Risk-SCD score, which incorporates echocardiographic parameters that may change with therapy, remains unclear. Objective To assess hypothetical changes in the estimated HCM Risk-SCD score in patients with obstructive HCM treated with mavacamten. Methods We conducted a prospective observational study including all patients with HCM treated with mavacamten who had been on a stable dose for at least 3 months. Clinical data and transthoracic echocardiograms were reviewed to collect maximal wall thickness (MWT), left atrial diameter (LAD), and maximal LVOTO. The HCM Risk-SCD score was calculated using the ESC online tool. Comparisons were assessed using the Wilcoxon signed-rank test. Results Forty patients were included [58% male; median age 62 (61–71) years and follow-up 7 (3–12) months]. Echocardiographic parameters improved significantly in comparison to baseline, with reductions in maximal LVOTO [84 (68–129) vs. 5 (0–39) mmHg; p<0.001], MWT [18 (16–20) vs. 15 (14–18) mm; p<0.001], and LAD [43 (39–47) vs. 40 (36–44) mm; p=0.008]. Mavacamten was associated with a significant reduction in the HCM Risk-SCD score, decreasing from 2.4 (1.7–4.7) to 1.5 (1.1–2.6) %, corresponding to an absolute change of −0.9 (−2.0 to −0.5) % and a relative reduction of −40 (−52 to −26) % (p<0.001) (central figure). At baseline, four patients had a high estimated 5-year SCD risk (>6%) – all of whom had an implantable cardioverter-defibrillator. During follow-up, three were reclassified in the low-risk category (<4%), while one remained in the high-risk group. No patient transitioned into a higher risk category after treatment. Per-patient decomposition of the HCM Risk-SCD reduction showed that most of the improvement was driven by changes in LVOTO (median −0.52%), with smaller contributions from MWT (−0.29%) and LAD (−0.08%). Conclusion Mavacamten was associated with a significant reduction in the estimated HCM Risk-SCD score. Whether this improvement translates into a true reduction in the 5-year SCD incidence remains uncertain. External validation in large multicenter cohorts with long-term follow-up is required to determine whether the decrease in the hypothetical risk corresponds to reduced mortality.Central figure