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

BACKGROUND Peak oxygen uptake (pVO 2 ) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO 2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODS Data from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. A total of 282 patients were randomized 1:1 to aficamten (5–20 mg daily) or matching placebo in SEQUOIA-HCM, and 175 patients were randomized 1:1 to aficamten (5-20mg daily) or to metoprolol (50–200 mg) in MAPLE-HCM; follow-up in both trials was 24 weeks. Primary outcome was change from baseline to week 24 (Δ) in pVO 2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULTS At week 24, ΔpVO 2 (mL/kg/min) that corresponded to no change, one-category improvement, and one-category worsening were –0.05 (95% CI, –0.58 to 0.48), +0.35 (95% CI, –0.22 to 0.91), and –0.61 (95% CI, –1.36 to 0.13), respectively. Similarly, minute ventilation to carbon dioxide production ratio (VE/VCO 2 ) slope that corresponded to no change, one-category improvement, and one-category worsening were 0.16 (95% CI, –0.59 to 0.90), –1.15 (95% CI, – 1.89 to –0.42), and 0.88 (95% CI, –0.42 to 2.19), respectively. In a responder analysis using this new threshold for pVO 2 , 60% of patients receiving aficamten achieved a ΔpVO 2 ≥0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3–4.9], P <0.001). Consistent findings were seen with VE/VCO 2 responder analysis. CONCLUSIONS Changes in pVO 2 of +0.35 and –0.61 mL/kg/min were associated with a small but perceptible clinical improvement and worsening, respectively, in patients with oHCM. Applying this newly defined threshold resulted in excellent differentiation of treatment effect in a clinical trial. These novel data provide a measure of clarity to patients and clinicians regarding the interpretation of changes in pVO 2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Clinical Trial Registration SEQUOIA-HCM ( NCT05186818 ; https://clinicaltrials.gov/study/NCT05186818?term=sequoia-hcm&rank=1 ); MAPLE-HCM ( NCT05767346 ; https://clinicaltrials.gov/study/NCT05767346?term=maple-hcm&rank=1 ) Clinical Perspective What Is New? Using pooled data from over 440 patients with symptomatic obstructive hypertrophic cardiomyopathy enrolled in two phase 3 clinical trials, we define, for the first time, the minimally important difference for peak oxygen uptake (pVO 2 ) and ventilatory efficiency (VE/VCO 2 ) using patient-anchored and distribution-based methodologies. A change in pVO 2 of +0.35 mL/kg/min and a change in VE/VCO 2 of –1.15 represent the minimal thresholds associated with patient-perceived clinical improvement. Responder analyses using these thresholds demonstrated robust differentiation between aficamten and placebo/metoprolol, with an odds ratio exceeding 3 for achieving a meaningful improvement in pVO 2 . What Are the Clinical Implications? These newly defined thresholds bridge the gap between statistically significant changes in cardiopulmonary exercise testing measures and clinically meaningful benefit as perceived by patients with obstructive hypertrophic cardiomyopathy. Clinicians can use these benchmarks to contextualize individual patient responses to medical therapy, informing shared decision-making regarding treatment continuation or modification. These data provide a standardized, patient-centered framework for designing and interpreting primary end points in future hypertrophic cardiomyopathy clinical trials.