Effect of Aficamten Compared With Metoprolol on Echocardiographic Measures in Symptomatic Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM.

Background: Beta-blockers have formed the mainstay of first-line therapy for symptomatic obstructive hypertrophic cardiomyopathy (HCM) for decades. Aficamten, compared with placebo, lowered left ventricular outflow tract gradients (LVOT-G), improved measures of left ventricular (LV) diastolic function, and showed evidence of favorable remodeling when added to standard of care medical therapy in SEQUOIA-HCM. The comparative effectiveness of monotherapy with aficamten vs metoprolol was investigated in MAPLE-HCM.

Objectives: This study evaluated the effect of monotherapy with aficamten compared with metoprolol on cardiac structure and function in participants enrolled in the MAPLE-HCM study.

Methods: Serial echocardiograms and other clinical measures were collected over 24 weeks in participants receiving escalating doses of aficamten 5 to 20 mg or metoprolol 50 to 200 mg.

Results: The study enrolled 175 participants (mean age 58 ± 13 years, 42% women, 80% White, 14% Asian). Mean left ventricular ejection fraction (LVEF) was 68% ± 4% with resting and Valsalva LVOT-G of 47 ± 29 mm Hg and 74 ± 33 mm Hg, respectively. Compared with metoprolol, aficamten decreased resting LVOT-G (-30 mm Hg [95% CI: -37 to -23 mm Hg]; P < 0.001) and Valsalva LVOT-G (-35 mm Hg [95% CI: -44 to -26 mm Hg]; P < 0.001); reduced left atrial volume index (left atrial volume index -7.0 mL/m² [95% CI: -9.1 to -4.8 mL/m²]; P < 0.001); and improved E/e' (lateral E/e' -2.8 [95% CI: -4.0 to -1.6]; P < 0.001; septal E/e' -3.1 [95% CI: -4.5 to -1.7]; P < 0.001). Maximal wall thickness decreased (-1.0 mm [95% CI: -1.8 to -0.2 mm]; P = 0.02). LVEF, absolute LV global longitudinal strain, and absolute global circumferential strain decreased (LVEF -4% [95% CI: -5% to -3%]; global longitudinal strain -1.2% [95% CI: -1.8% to -0.5%]; global circumferential strain -2.5% [95% CI: -3.7% to -1.3%]; all P < 0.001) with no significant change in resting cardiac output between groups. Mitral valve systolic anterior motion and mitral regurgitation significantly decreased with aficamten at week 24.

Conclusions: In addition to lowering Valsalva LVOT-G and left atrial volume index, treatment with aficamten compared with metoprolol over 24 weeks led to improvement in measures of LV diastolic function, mitral valve systolic anterior motion, and mitral regurgitation. Aficamten therapy resulted in modest reduction in LVEF compared with metoprolol. These exploratory findings further support the overall superiority of therapy with aficamten over metoprolol demonstrated in MAPLE-HCM with evidence of favorable changes in multiple echocardiographic measures of cardiac structure and function in patients with symptomatic obstructive HCM. (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM [MAPLE-HCM]; NCT05767346).