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

Abstract

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 (Vo₂) at peak exercise. This disparate response may be explained by the physiologic challenge of improving peak Vo₂ in participants with near-normal baseline exercise performance.

Methods: Participants were divided into subgroups by baseline predicted peak Vo₂ (<80% versus ≥80%). Treatment effect was evaluated in those with a baseline peak Vo₂ <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 Vo₂ <80% predicted. In this subgroup, the primary outcome of peak Vo₂ 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 Vo₂ 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 Vo₂ (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 Vo₂, a positive treatment effect of udenafil was identified for the primary outcome of peak Vo₂. The interaction between baseline peak Vo₂ and treatment may have influenced the outcome of the FUEL trial.

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

Keywords: Fontan; exercise; udenafil.