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Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial

MMY. Lee, A. Masri, ME. Nassif, R. Barriales-Villa, TP. Abraham, BL. Claggett, CJ. Coats, JR. Gimeno, IJ. Kulac, I. Landsteiner, C. Ma, MS. Maron, I. Olivotto, AT. Owens, SD. Solomon, J. Veselka, DL. Jacoby, SB. Heitner, S. Kupfer, FI. Malik, L....

. 2024 ; 9 (11) : 990-1000. [pub] 20241101

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, randomizované kontrolované studie, klinické zkoušky, fáze III, multicentrická studie

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003678

IMPORTANCE: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. OBJECTIVE: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. INTERVENTIONS: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. RESULTS: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). CONCLUSIONS AND RELEVANCE: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05186818.

Citace poskytuje Crossref.org

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$a Barriales-Villa, Roberto $u Complexo Hospitalario Universitario A Coruña, INIBIC, CIBERCV-ISCIII, A Coruña, Spain
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$a Claggett, Brian L $u Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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$a Coats, Caroline J $u School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland
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$a Gimeno, Juan Ramón $u Cardiac Department, University Hospital Virgen Arrixaca, CIBERCV, ERN Guard-Heart, Murcia, Spain
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$a Olivotto, Iacopo $u Meyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Florence, Italy
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$a Owens, Anjali T $u University of Pennsylvania Perelman School of Medicine, Philadelphia
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