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Clinical Trial
. 2025 Aug 19;14(16):e041348.
doi: 10.1161/JAHA.125.041348. Epub 2025 Aug 12.

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

David J Goldberg  1 , Victor Zak  2 , Chenwei Hu  2 , Adam M Lubert  3 , Rahul H Rathod  4 , Daniel J Penny  5 , Robert Whitehill  6 , Kurt R Schumacher  7 , Salil Ginde  8 , Michelle Ploutz  9 , Gi Beom Kim  10 , Todd T Nowlen  11 , Michael V DiMaria  12 , Benjamin P Frischhertz  13 , Jonathan B Wagner  14 , Kimberly E McHugh  15 , Brian W McCrindle  16 , Mark J Cartoski  17 , Jon Detterich  18 , Anji T Yetman  19 , Anitha S John  20 , Marc E Richmond  21 , Matthew Files  22 , R Mark Payne  23 , Andrew S Mackie  24 , Christopher K Davis  25 , William B Orr  26 , Ruchira Garg  27 , Kevin D Hill  28 , Jennifer S Yauck  8 , Michael G McBride  1 , James Yeager  29 , Gail D Pearson  30 , Stephen M Paridon  1 , Bryan H Goldstein  31
Affiliations
Clinical Trial

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

David J Goldberg et al. J Am Heart Assoc. .

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.

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Conflict of interest statement

D.G. has consulted for and received grant funding from Mezzion Pharma Co. Ltd., and National Heart, Lung, and Blood Institute and is a coinventor on a method of use for udenafil in adolescents who have undergone the Fontan procedure. D.P. received a consulting fee from Mezzion Pharma Co. Ltd. J.W. receives funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. B.M. is a consultant for Janssen, Chiesi, Esperion, Ultragenyx, and Amryt Pharma. K.H. receives funding from the National Centers for Advancing Translational Sciences. J.Y. was an employee of Mezzion Pharma Co. Ltd. S.P. received grant funding from the National Heart, Lung, and Blood Institute. B.G. is a consultant for Mezzion Pharma Co. Ltd., Medtronic, W. L. Gore, and PECA Labs. The remaining authors have no disclosures to report.

Figures

Figure 1
Figure 1. Box and whisker plot demonstrating a comparison of change in peak Vo 2 between participants treated with placebo and those treated with udenafil for participants with baseline peak Vo 2 ≤80% predicted.
Vo 2 indicates oxygen consumption.
Figure 2
Figure 2. Box and whisker plot demonstrating a comparison of change in Vo 2 at the ventilatory anaerobic threshold between participants treated with placebo and those treated with udenafil for participants with baseline peak Vo 2 ≤80% predicted.
Vo 2 indicates oxygen consumption.
Figure 3
Figure 3. Box and whisker plot demonstrating a comparison of change in work at the VAT between participants treated with placebo and those treated with udenafil for participants with baseline peak Vo 2 ≤80% predicted.
VAT indicates ventilatory anaerobic threshold; Vo 2, oxygen consumption.
Figure 4
Figure 4. Box and whisker plot demonstrating a comparison of change in ventilatory equivalents of carbon dioxide at the ventilatory anaerobic threshold between participants treated with placebo and those treated with udenafil for participants with baseline peak Vo 2 ≤80% predicted.
VE/VCO2 indicates ratio of minute ventilation to minute carbon dioxide production Vo 2 oxygen consumption.
See this image and copyright information in PMC

References

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