• Paul Clift, Felix Berger, Lars Sondergaard, Petra Antonova, Patrick Disney, Jeremy Nicolarsen, Jean-Benoît Thambo, Tomkiewicz PajakLidiaLDepartment of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland., Jou-Kou Wang, Schophuus JensenAnnetteADepartment of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Michela Efficace, Michael Friberg, Diana Haberle, Verena Walter, and Yves d'Udekem.
• Adult Congenital Heart Disease Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom. Electronic address: Paul.Clift@uhb.nhs.uk.
• J. Thorac. Cardiovasc. Surg. 2024 Aug 29.

ObjectivesThe efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL).MethodsPatients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies.ResultsIn RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was -0.16 ± 2.86 versus -0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, -0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point.ConclusionsThe primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

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