Results of the FUEL Trial

• Type of Material: Article
• Authors: David J Goldberg, Childrens Hospital of Philadelphia; Victor Zak, New England Research Institutes; Bryan H Goldstein, Cincinnati Children’s Hospital, Medical Center; Kurt R Schumacher, CS Mott Childrens Hospital; Jonathan Rhodes, Children’s Hospital Boston; Daniel J Penny, Texas Childrens Hosp; Christopher Petit, Emory University; Salil Ginde, Medical College of Wisconsin; Shaji C Menon, University of Utah; Seong-H Kim, Sejong General Hospital; Gi Beom Kim, Seoul National University Children's Hospital; Todd T Nowlen, Phoenix Childrens Hosp; Michael DiMaria, University of Colorado Aurora; Benjamin P Frischhertz, Vanderbilt University; Jonathan B Wagner, Childrens Mercy Kansas City; Kimberly E McHugh, Medical University of South Carolina; Brian W McCrindle, University of Toronto; Amanda J Shillingford, Nemours Alfred I DuPont Hospital Children; Arash A Sabati, Los Angeles Childrens Hospital; Anji T Yetman, University of Nebraska; Anitha S John, Childrens National Health System; Marc E Richmond, Columbia University; Mathhew D Files, Seattle Childrens Hospital; R Mark Payne, Riley Hospital Children; Andrew S Mackie, Stollery Childrens Hospital; Christopher K Davis, Rady Childrens Hospital San Diego; Shabana Shahanavaz, St Louis Childrens Hospital; Kevin D Hill, Duke Childrens Pediat & Congenital Heart Ctr; Ruchira Garg, Cedars Sinai Medical Center; Jeffrey P Jacobs, Johns Hopkins All Childrens Hosp; Michelle S Hamstra, Cincinnati Childrens Hosp Med Ctr; Stacy Woyciechowski, Childrens Hospital of Philadelphia; Kathleen A Rathge, Cincinnati Children’s Hospital, Medical Center; Michael G McBride, Childrens Hospital of Philadelphia; Peter C Frommelt, Medical College of Wisconsin; Mark W Russell, C.S. Mott Children’s Hospital, Ann Arbor; Elaine M Urbina, Cincinnati Children’s Hospital, Medical Center; James L Yeager, Mezz Pharma Co Ltd; Victoria L Pemberton, National Heart, Lung, and Blood Institute, NIH, Bethesda; Mario P Stylianou, National Heart, Lung, and Blood Institute, NIH, Bethesda; Gail D Pearson, National Heart, Lung, and Blood Institute, NIH, Bethesda; Stephen M Paridon, Childrens Hospital of Philadelphia
• Language: English
• Date: 2020-02-25
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019, Wolters Kluwer Health
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044352
• Title of Journal or Parent Work: CIRCULATION
• Volume: 141
• Issue: 8
• Start Page: 641
• End Page: 651
• Grant/Funding Information: Funding for this project was provided by grants from the National Heart, Lung, and Blood Institute (HL135646, HL135665, HL135666, HL135678, HL135680, HL135682, HL135683, HL135685, HL135689, HL135691) and by Mezzion Pharma Co. Ltd. (Seoul, Republic of Korea). (Funded by Mezzion Pharma Co. Ltd., and conducted by the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network).
• Keywords: FONTAN OPERATION; Fontan procedure; phosphodiesterase 5 inhibitor; Peripheral Vascular Disease; exercise test; ADOLESCENTS; congenital; Cardiac & Cardiovascular Systems; EXERCISE CAPACITY; heart defects; Science & Technology; DIASTOLIC DYSFUNCTION; SINGLE VENTRICLE; ADULTS; PULMONARY VASCULAR-RESISTANCE; HEART-FAILURE; Life Sciences & Biomedicine; Cardiovascular System & Cardiology; LONG-TERM SURVIVAL; SILDENAFIL

Abstract

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included betweengroup differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus-9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus-0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.