Echocardiographic Changes With Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy: Exploratory Insights From the ODYSSEY-HCM Trial.

BACKGROUND

Symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) lacks approved therapies. The ODYSSEY-HCM trial (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy; NCT05582395), the largest to date in HCM patients, evaluating the efficacy of mavacamten in symptomatic adults with nHCM, did not demonstrate improvements in its primary endpoints (functional capacity and patient-reported health status).

OBJECTIVES

This exploratory analysis of the phase 3, randomized, placebo-controlled trial evaluated echocardiographic changes in nHCM patients from baseline to week 48.

METHODS

Symptomatic nHCM patients were randomized to placebo or mavacamten (5 mg/d, titrated between 1 and 15 mg based on left ventricular ejection fraction [LVEF]). Echocardiographic assessments of LV systolic/diastolic function and left atrial (LA) function were performed at baseline and week 48.

RESULTS

Among 580 randomized patients (mean age 56 ± 15 years, 45.9% women), baseline measures included LVEF (65.8 ± 4%), maximal LV wall thickness (20.8 ± 4 mm), LV mass index (122.3 ± 31 g/m), average E/e' (13.3 ± 6), and LV-global longitudinal strain (-13.2 ± 4%). LA parameters included volume index (43.5 ± 16 mL/m), reservoir strain (19.1 ± 9%), and conduit strain (-11.6 ± 6%). At week 48, there was significant placebo-corrected treatment difference with patients on mavacamten demonstrating significant reduction in maximal LV wall thickness (-2.1 mm [95% CI: -2.5 to -1.7 mm]), LV mass index (-3.8 g/m [95% CI: -7.1 to -0.5 g/m]), and E/e' (-1.3 [95% CI: -2.0 to -0.7]), with a -5.3% [95% CI: -5.9% to -4.1%]; P < 0.01) reduction in LVEF. A reduction in LVEF <50% occurred in 62 patients (21.5%) in the mavacamten arm vs 5 (1.7%) in the placebo arm and recovered following drug interruption. Patients in the mavacamten group maintaining LVEF ≥50% throughout the study (n = 212) demonstrated an improvement in LV-global longitudinal strain at week 48 (-0.4% [95% CI: -0.8% to -0.05%]; P < 0.05). LA functional parameters including contractile (-1.1% [95% CI: -1.8% to -0.4%]) and conduit (-1.4% [95% CI: -0.6% to -2.3%]) strain also improved significantly at week 48 (P < 0.05), whereas LA volume was significantly reduced in patients without atrial fibrillation (-2.6 mL/m [95% CI: -4.7 to -1.11 mL/m]; P = 0.009).

CONCLUSIONS

Symptomatic nHCM patients treated with mavacamten demonstrated directional improvements in markers of LV diastolic and LA function, modest regression in LV hypertrophy-related parameters, but 1 in 5 demonstrated an LVEF <50%, which reversed following therapy interruption.