LAUSR

Background: Women with obstructive hypertrophic cardiomyopathy (oHCM) often present with a greater burden of disease and worse prognosis. Whether there are sex-related differences in response to aficamten is unknown. Methods: We performed a pre-specified subgroup analysis of sex differences in the doubleblind, randomized-controlled SEQUOIA-HCM trial of aficamten versus placebo in patients with oHCM. Baseline characteristics were compared using t-test for continuous variables and C2 test for categorical variables. Prespecified primary (change in peak oxygen uptake, pVO2) and secondary end points from baseline to end of treatment (week 24) were analyzed using linear regression models, adjusted for baseline values, beta-blocker use, and exercise mode. Results: Of the 282 participants, women (n=115) were older (64 years-old in women vs. 56 years-old in men), had lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), higher NT-proBNP levels, and lower pVO2 at baseline. Women had smaller left ventricular (LV) chamber sizes, higher E/e' ratios, and higher LV outflow tract (LVOT) gradients. At 24 weeks, there was a significant treatment-related increase in pVO2 in women (+1.5, [+0.7 to +2.4] and men (+2.0 [+0.9 to +3.0])). Both women and men had significant treatment-related decreases in LVOT gradients at rest and with Valsalva, with no sex-bytreatment interaction at week 24 (p-interaction ³ 0.13). There was a significant improvement in KCCQ-CSS in women (11 [6 to 15]) and men (6 [2 to 9], p-interaction = 0.08). Women had a greater reduction in lateral E/e' ratio (p-interaction = 0.01). The geometric mean proportional reduction in NT-proBNP were similar in women and men (p-interaction = 0.10). Conclusions: Women enrolled in SEQUOIA-HCM were older with worse baseline health status, higher NT-proBNP, and higher LVOT gradients compared to men. Despite these differences, both men and women derived significant benefits in the primary and secondary end points following treatment with aficamten.