The Threshold for a Clinically Meaningful Improvement in Cardiopulmonary Exercise Testing Measures for Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy.
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Authors
Masri A.
Lewis G.D.
BarrialesVilla R.
Claggett B.L.
Coats C.J.
Elliott P.
Hagege A.
Kulac I.J.
GarciaPavia P.
Fifer M.A.
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2026
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BACKGROUND: Peak oxygen uptake (pVO2) 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 pVO2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHOD(S): 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 (DELTA) in pVO2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULT(S): At week 24, DELTApVO2 (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/VCO2) 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 pVO2, 60% of patients receiving aficamten achieved a DELTApVO2 >=0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3-4.9], P >=0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3-4.9], P2 responder analysis. CONCLUSION(S): Changes in pVO2 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 pVO2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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