Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial.

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 Fontan Udenafil Exercise Longitudinal (FUEL) Trial 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 sub-maximal exercise at the ventilatory anaerobic threshold (VAT), the myocardial performance index (MPI), the natural log of the reactive hyperemia index (lnRHI), and serum brain-type natriuretic peptide (BNP). Results:Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomized 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 endpoint for 21 participants with missing data (11 randomized to udenafil and 10 to placebo). Among randomized 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 VAT demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33 ±185 (3.2%) vs -9 ±193 (-0.9%) mL/min, p=0.012), ventilatory equivalents of carbon dioxide (-0.8 vs -0.06, p=0.014), and work rate (+3.8 vs +0.34 Watts, p=0.021). There was no difference in change of MPI, lnRHI, or serum BNP 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://clinicaltrials.gov Unique Identifier: NCT02741115.