Revisiting the Effect of Udenafil on Exercise Performance in Patients With Fontan Circulation: Results of a Post Hoc Analysis of the FUEL Trial

BACKGROUND: In the FUEL (Fontan Udenafil Exercise Longitudinal) trial, a positive treatment effect was identified for outcomes at the ventilatory anaerobic threshold but not for the primary outcome, oxygen consumption (Vo 2) at peak exercise. This disparate response may be explained by the physiologic challenge of improving peak Vo 2 in participants with near-normal baseline exercise performance.

METHODS: Participants were divided into subgroups by baseline predicted peak Vo 2 (<80% versus ≥80%). Treatment effect was evaluated in those with a baseline peak Vo 2 <80% predicted and linear regression was performed to examine the interaction between subgroup and response to therapy for the primary and secondary outcomes.

RESULTS: Of the 379 participants with paired exercise data, 302 (80%) had a baseline peak Vo 2 <80% predicted. In this subgroup, the primary outcome of peak Vo 2 improved significantly after 6 months of udenafil treatment, when compared with placebo (0.23±4.17 mL/kg per min versus -0.90±3.74 mL/kg per min; P=0.021). Secondary outcome measures, including Vo 2 at ventilatory anaerobic threshold ( P=0.023), work at ventilatory anaerobic threshold ( P=0.032), and the myocardial performance index ( P=0.007) were all significantly improved as well. A significant interaction was found between exercise subgroups and response to udenafil for peak Vo 2 ( P=0.036) but not for other outcomes.

CONCLUSIONS: In this post hoc subgroup analysis, after exclusion of patients with Fontan circulation with near-normal baseline peak Vo 2, a positive treatment effect of udenafil was identified for the primary outcome of peak Vo 2. The interaction between baseline peak Vo 2 and treatment may have influenced the outcome of the FUEL trial.

REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT0274115.