Abstract
The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.
Trial Registration NCT0274115.
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Acknowledgements
The authors would like to recognize Dr. Jonathan Rhodes, in memoriam, for his contribution to this work and for his career dedicated to children with heart disease. He will be missed, but his contributions will not be forgotten.
Funding
Funding for this project was provided by the National Heart, Lung, and Blood Institute (HL135646, HL135665, HL135666, HL135678, HL135680, HL135682, HL135683, HL135685, HL135689, HL135691) and by Mezzion Pharma Co. Ltd. (Seoul, Republic of Korea). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; the U.S. Department of Health and Human Services; or Mezzion Pharma Co. Ltd.
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DG wrote the main manuscript and provided figures. CH and VZ provided statistical analysis. All other authors reviewed analyses, provided critical review, and edited the manuscript.
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DG received grant funding from Mezzion and NHLBI and is a co-inventor on a method of use for udenafil in adolescents who have undergone Fontan, CH none, AL none, RR none, DP received a consulting fee from Mezzion Pharma Co. Ltd., CP none, KS none, SG none, RW none, JY none, GK none, TK none, MD none, BF none, JW receives funding from the National Center for Advancing Translational Science, KM none, BM is a consultant for Janssen, Chiesi, Esperion, Ultragenyx, and Amryt Pharma, MC none, JD none, AY none, AJ none, MR none, DY none, RP none, AM none, CD none, SS none, KH receives funding from the National Center for Advancing Translational Sciences, MA none, VZ none, MM none, BG is a consultant for Mezzion Pharma, Medtronic, W.L. Gore, and PECA Labs, GP none, and SP received grant funding from NHLBI.
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Goldberg, D.J., Hu, C., Lubert, A.M. et al. The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis. Pediatr Cardiol 44, 1691–1701 (2023). https://doi.org/10.1007/s00246-023-03204-y
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DOI: https://doi.org/10.1007/s00246-023-03204-y