Results of the 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 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 an improvement in myocardial performance index (–0.02 vs 0.01, P =0.030), but no change in 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.

Pulmonary Vasodilator Therapy in Children with Single Ventricle Physiology: Effects on Saturation and Pulmonary Arterial Pressure

“…Handler et al [ 32 ] showed significant decrease in pulmonary vascular resistance and increase in saturation with subcutaneous treprostinil for 17 children with single ventricle. A recently published large randomized controlled trial by Goldberg et al demonstrated that udenafil compared to placebo had a modest positive effect on oxygen saturations and measures of submaximal exercise performance in adolescents after total cavopulmonary connection palliation, but udenafil was not shown to improve the primary outcome measure of peak oxygen consumption [ 33 ]. The patients in our cohort by comparison were far more symptomatic at baseline with a high proportion of risk factors for pulmonary vascular dysfunction and therefore may have a greater potential for benefit.…”

Superior Cavopulmonary Connection: Its Physiology, Limitations, and Anesthetic Implications

“…[99][100][101][102][103] The most recent trial of a longacting phosphodiesterase inhibitor (udenafil) in Fontan patients was again unable to demonstrate a statistically significant improvement in oxygen consumption at peak exercise, although some secondary exercise endpoints had small improvements. 104…”

Heart failure in congenital heart disease: management options and clinical challenges

“…However, a significant improvement in NYHA class, 6-minute walking distance, and peak VO2 was described, as well as a small but significant reduction in mean pulmonary artery pressure [82]. The recently published FUEL trial exploring the use of udenafil versus placebo in 400 Fontan patients (mean age 15,5 ± 2 years) showed no significant effect on improvement in oxygen consumption at peak exercise [83]. However, in the udenafil group a significant improvement in the oxygen consumption, work rate, and ventilatory efficiency at the anaerobic threshold was observed.…”