Faculty Collaboration Database

Results of the FUEL Trial. Circulation 2020 Feb 25;141(8):641-651

Date

11/19/2019

Pubmed ID

31736357

Pubmed Central ID

PMC7042084

DOI

10.1161/CIRCULATIONAHA.119.044352

Scopus ID

2-s2.0-85081102578 (requires institutional sign-in at Scopus site)   84 Citations

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 between-group 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.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Author List

Goldberg DJ, Zak V, Goldstein BH, Schumacher KR, Rhodes J, Penny DJ, Petit CJ, Ginde S, Menon SC, Kim SH, Kim GB, Nowlen TT, DiMaria MV, Frischhertz BP, Wagner JB, McHugh KE, McCrindle BW, Shillingford AJ, Sabati AA, Yetman AT, John AS, Richmond ME, Files MD, Payne RM, Mackie AS, Davis CK, Shahanavaz S, Hill KD, Garg R, Jacobs JP, Hamstra MS, Woyciechowski S, Rathge KA, McBride MG, Frommelt PC, Russell MW, Urbina EM, Yeager JL, Pemberton VL, Stylianou MP, Pearson GD, Paridon SM, Pediatric Heart Network Investigators

Authors

Peter C. Frommelt MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Salil Ginde MD, MPH Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Child
Double-Blind Method
Drug Administration Schedule
Exercise
Female
Fontan Procedure
Heart Diseases
Heart Rate
Humans
Male
Natriuretic Peptide, Brain
Oxygen Consumption
Phosphodiesterase 5 Inhibitors
Placebo Effect
Pyrimidines
Sulfonamides
Thrombosis
Treatment Outcome