Abstract 4146512: Modifiability of Post-Exercise Oxygen Uptake Recovery Patterns: A Substudy of the SEQUOIA-HCM Randomized Trial

Background: Recent heart failure studies show that post-exercise VO 2 recovery (VO 2 Rec) patterns track closely with exercise cardiac output and outcomes, but not with peripheral oxygen (O 2 ) extraction. In patients with obstructive hypertrophic cardiomyopathy (oHCM), studies of VO 2 Rec changes with effective cardio-specific interventions are lacking. We hypothesized that treatment with aficamten, a next-in-class cardiac myosin inhibitor, would shorten VO 2 Rec in patients with oHCM. Methods: SEQUOIA-HCM is the pivotal phase 3 trial of aficamten in symptomatic patients with oHCM (New York Heart Association functional class [NYHA FC] II-III, peak VO 2 [pVO 2 ] ≤90% predicted, respiratory exchange ratio ≥1.05). Patients were randomized 1:1 to aficamten or placebo for 24 weeks with the primary endpoint of change from baseline (BL) in pVO 2 . For this analysis, VO 2 Rec was measured as the time taken after exercise cessation for VO 2 to decline by 12.5% (t 12.5% ), 25%, or 50% of pVO 2 . Response rates for achieving clinically meaningful threshold reductions (>15 seconds) in t 12.5% , and correlations with changes in cardiac function (echocardiographic parameters/cardiac biomarkers) were assessed. Results: Among 282 randomized patients (mean age 59.1±12.9 years, 115 female [41%]), 263 (93%) had CPETs at BL and W24 with VO 2 Rec values as shown ( Table ). At W24, t 12.5% improved by 8sec (95% CI, -12, -5sec, p<0.001) in the aficamten group compared to the placebo group. Those treated with aficamten were more likely to improve t 12.5% by ≥15sec (OR 3.7 95% CI 1.9-6.9, NNT=4.8) than those on placebo. Shortening of t 12.5% correlated with reduced NT-proBNP, high-sensitivity cardiac troponin I, left ventricular outflow tract gradient, and improved NYHA FC and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (all p<0.005). Conclusion: This is the first study to establish that VO 2 Rec is modifiable in response to cardio-specific intervention (aficamten) in patients with oHCM. VO 2 Rec (t 12.5% ) shortened proportionally and in parallel with other metrics of improved cardiac function, underscoring the benefits of aficamten for oHCM, and supporting inclusion of VO 2 Rec as a routine metric for evaluating cardio-specific interventions for oHCM.