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FUEL trial: Udenafil improves some exercise measurements in Fontan

Presented by
Dr David Goldberg, Childrenā€™s Hospital of Philadelphia, USA
AHA 2019
In The Fontan Udenafil Exercise Longitudinal Trial (FUEL), udenafil treatment was not associated with an improvement in oxygen consumption at peak exercise in patients with Fontan physiology; however, multiple measures of exercise performance at the ventilatory anaerobic threshold did show marked improvements.

Dr David Goldberg (Childrenā€™s Hospital of Philadelphia, USA) presented the 30-centre phase 3 clinical trial that attempted to address a problem resulting from the Fontan physiology, which can lead to deterioration of cardiovascular efficiency associated with a decline in exercise performance [1]. The researchers hypothesised that udenafil may improve exercise performance. The primacy efficacy endpoint of this study was a between-group difference in the change in oxygen consumption (VO2) from baseline to 26 weeks at peak exercise. Key secondary endpoints included myocardial performance index, exercise measures at ventilatory equivalents of CO2 at anaerobic threshold, brain natriuretic peptide, and reactive hyperaemia index.

Between 2017 and 2019, adolescents with Fontan physiology (n=400) were randomised to either udenafil 87.5 mg twice daily or placebo. The mean age was 15.5 Ā±2 years, and 60% of participants were male. All 400 participants were included in the primary analysis with imputation of the 26-week endpoint for 21 participants with missing data (i.e. 11 randomised to udenafil and 10 to placebo).

The primary efficacy endpoint was not met: peak oxygen consumption was not significantly changed, increasing by 44 Ā±245 mL/min (2.8%) in the udenafil arm and declining by 3.7 Ā±228 mL/min (-0.2%) in the placebo arm (P=0.071). However, improvements in the udenafil group versus the placebo group were evident in some of the secondary endpoints, including mean oxygen consumption (+33 Ā±185 [3.2%] vs -9 Ā±193 [-0.9%] mL/min, respectively; P=0.012), ventilatory equivalents of CO2 (-0.8 vs -0.06, respectively; P=0.014), and work rate (+3.8 vs +0.34 Watts, respectively; P=0.021). No differences were observed in the other secondary endpoints.

In conclusion, although the primary endpoint was not met, some benefits from udenafil treatment were observed in the secondary efficacy endpoints in patients with Fontan physiology, which may warrant further investigation.

1. Goldberg DJ et al. Longitudinal results from the Pediatric Heart Network: effect of udenafil on exercise performance after Fontan. LBS.05, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.

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