American Heart Association

American Heart Association

November 18, 2019
3 min read

FUEL: Udenafil improves certain exercise performance after Fontan palliation in adolescents

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David J. Goldberg

PHILADELPHIA — Udenafil in adolescents after Fontan surgery did not significantly improve oxygen consumption at peak exercise, although it did significantly improve exercise performance at the ventilatory anaerobic threshold, according to data from the FUEL trial presented at the American Heart Association Scientific Sessions.

Results from this trial were also published in Circulation.

“Our study extends recent findings highlighting the importance of submaximal exercise in the understanding of Fontan physiology,” David J. Goldberg, MD, cardiologist in the Cardiac Center and Fetal Heart Program and associate professor of pediatrics at Children’s Hospital of Philadelphia, said during the presentation. “Unlike VO2, submaximal exercise is not constrained by the physiologic ceiling of central venous pressure inherent in exercise physiology after Fontan palliation. Submaximal exercise has real implications for day-to-day activities of adolescents with Fontan physiology.”

Researchers analyzed data from 400 adolescents with Fontan physiology who were currently treated with anticoagulation and achieved maximum effort on a baseline exercise test.

“The FUEL trial was the largest trial of a medication in adolescents with single-ventricle heart disease who had undergone Fontan,” Goldberg told Healio. “Before the FUEL trial, medical therapy had been extrapolated from adult heart failure, which is quite a bit different from physiology after Fontan.”

FUEL participants were assigned 87.5 mg udenafil (Mezzion Pharma) twice per day (n = 200; mean age, 15 years; 44% girls) or matching placebo (n = 200; mean age, 16 years; 36% girls). Exercise performance was assessed in both groups.

Udenafil is a novel phosphodiesterase-5 (PDE5) inhibitor that has undergoing phase 1/2 testing in adolescents after Fontan,” Goldberg said during the presentation. “[Udenafil] 87.5 mg twice daily was associated with the highest average serum concentration with no dose-limiting adverse events.”

The primary endpoint was change in peak VO2 from baseline to 26 weeks. Key secondary endpoints included myocardial performance index, exercise measures at ventilatory anaerobic threshold, brain natriuretic peptide and reactive hyperemia index. The primacy efficacy endpoint was defined as a between-group difference in the change in VO2 from baseline to 26 weeks.

There was a decline among patients assigned udenafil or placebo in VO2 indexed to body weight during a 6-month period, although it was attenuated in adolescents assigned udenafil (–0.23 mL/kg/min vs. –0.89 mL/kg/min, respectively; P = .092). Patients assigned udenafil had a greater improvement in unindexed peak VO2 compared with those assigned placebo (44 mL/min vs. –3.7 mL/min; P = .071). No significant differences were seen in peak heart rate (P = .56) or peak oxygen saturation (P = .21) between both groups.


The udenafil group had greater improvements in measures at the ventilatory anaerobic threshold compared with the placebo group including oxygen consumption (33 mL/min vs. –9 mL/min; P = .012), work rate (3.8 W vs. 0.34 W; P = .021) and ventilatory efficiency (–0.8 vs. –0.06; P = .014).

There were no significant changes regarding the other secondary outcomes between the groups.

Compared with placebo, more patients assigned udenafil had headache/migraine (35% vs. 25%; P = .049), facial flushing (16% vs. 6%; P = .002) and increased erection for boys (12% vs. 2%; P = .002). There was also a trend for nosebleeds in the udenafil group vs. placebo group (6% vs. 2%; P = .053).

“For the first time, we have evidence-based medicine to support the use of a pharmacologic agent for children with Fontan physiology,” Goldberg told Healio.

“This is really a first step,” he added. “We need to have longer-term follow-up of kids who are taking udenafil to see if it truly lives up to the potential that we think it has. The main thing is getting the drug approved and available. Once it’s approved and available, then we can develop a registry where we follow the trajectory of treated kids over a longer time period.”

During the discussant portion of the presentation, Craig Sable, MD, associate division chief of cardiology and director of echocardiography at Children’s National in Washington, D.C., said, “In adults with congenital heart disease, we know that maximal VO2 of approximately 45% to 50% of predicted is the threshold value for increased risk of heart failure and death. A medicine that addresses the central deficiencies of Fontan physiology and results in improved exercise performance may allow for a longer period of symptom-free survival.” – by Darlene Dobkowski


Goldberg DJ, et al. Late Breaking Science V: Challenges in Heart Failure Management. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Goldberg DJ, et al. Circulation. 2019;doi:10.1161/CIRCULATIONAHA.119.044352.

Disclosures: The trial was financially supported by Mezzion Pharma. Goldberg reports he received grant support from Mezzion Pharma and is a co-inventor of patent US10137128B2. Sable reports no relevant financial disclosures.