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 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.

Keywords: Fontan procedure; exercise test; heart defects, congenital; phosphodiesterase 5 inhibitor.

Figures

Figure 1.

Randomization and Treatment of FUEL Participants. Peak VO2 denotes oxygen consumption at peak exercise. RER denotes respiratory exchange ratio.

Figure 2.

Oxygen consumption at peak exercise. Panel A demonstrates the difference in the change in mean peak VO2 from Baseline to Week 26 along with the standard deviation for each treatment arm. Panel B demonstrates the percentage of participants (y axis) who demonstrated improvement in peak VO2 by the reference percentage or greater (x axis).

Figure 2.

Oxygen consumption at peak exercise. Panel A demonstrates the difference in the change in mean peak VO2 from Baseline to Week 26 along with the standard deviation for each treatment arm. Panel B demonstrates the percentage of participants (y axis) who demonstrated improvement in peak VO2 by the reference percentage or greater (x axis).

Figure 3.

Oxygen consumption at the ventilatory anaerobic threshold. Panel A demonstrates the difference in the change in mean VO2 at VAT from Baseline to Week 26 along with the standard deviation for each treatment arm. Panel B demonstrates the percentage of participants (y axis) who demonstrated improvement in VO2 at VAT by the reference percentage or greater (x axis).

Figure 3.

Oxygen consumption at the ventilatory anaerobic threshold. Panel A demonstrates the difference in the change in mean VO2 at VAT from Baseline to Week 26 along with the standard deviation for each treatment arm. Panel B demonstrates the percentage of participants (y axis) who demonstrated improvement in VO2 at VAT by the reference percentage or greater (x axis).

Figure 4.

Work at the ventilatory anaerobic threshold. Panel A demonstrates the difference in the change in mean work rate at VAT from Baseline to Week 26 along with the standard deviation for each treatment arm. Panel B demonstrates the percentage of participants (y axis) who demonstrated improvement in work rate by the reference percentage or greater (x axis).

Figure 4.

Work at the ventilatory anaerobic threshold. Panel A demonstrates the difference in the change in mean work rate at VAT from Baseline to Week 26 along with the standard deviation for each treatment arm. Panel B demonstrates the percentage of participants (y axis) who demonstrated improvement in work rate by the reference percentage or greater (x axis).