The Threshold for a Clinically Meaningful Improvement in Cardiopulmonary Exercise Testing Measures for Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND

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

METHODS

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

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

RESULTS

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.

CONCLUSIONS

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.

CLINICAL TRIAL REGISTRATION: SEQUOIA-HCM (NCT05186818); MAPLE-HCM (NCT05767346).