The Threshold for a Clinically Meaningful Improvement in Cardiopulmonary Exercise Testing Measures for Patients With...

Peak oxygen uptake (pVO₂) is a predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing drug therapies in obstructive hypertrophic cardiomyopathy (oHCM). Characterizing changes in pVO₂ that patients perceive as meaningful has not been determined.

Data from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. Patients were randomized 1:1 to daily aficamten (5-20mg) or placebo (SEQUOIA-HCM, n=282), and 1:1 to aficamten (5-20mg) or metoprolol (50-200mg) (MAPLE-HCM, n=175).

change from baseline to week 24 (Δ) in pVO₂ using Patient Global Impression of Change with anchor-based analysis to define minimal important difference.

At week 24, ΔpVO₂ (95% CI) corresponding to no change, 1-category improvement, and 1-category worsening were -0.05 (-0.58, 0.48), +0.35 (-0.22, 0.91), and -0.61 (-1.36, 0.13) mL/kg/min, respectively. Minute ventilation to carbon dioxide production ratio (VE/VCO₂) slope (95% CI) corresponding to no change, 1-category improvement, and 1-category worsening were 0.16 (-0.59, 0.90), -1.15 (-1.89, -0.42), and 0.88 (-0.42, 2.19), respectively. In a responder analysis using the new threshold, 60% of aficamten-treated vs 31% of placebo- or metoprolol-treated patients achieved ΔpVO₂ ≥0.35 (odds ratio [OR], 3.4 [95% CI: 2.3, 4.9], P<.001). Consistent findings were seen with VE/VCO₂ responder analysis.

Changes in pVO₂ of +0.35 and -0.61 mL/kg/min were associated with small improvement and worsening, respectively. Applying this new threshold resulted in excellent differentiation of treatment effect. These data provide a measure of clarity for interpreting changes in pVO₂ following interventions.

SEQUOIA-HCM (NCT05186818); MAPLE-HCM (NCT05767346).