Pediatric drug trial finds benefit in teens with heart defect

Results from NIH-funded trial could extend patients’ well-being.

Teenagers born with a single working ventricle of the heart — a rare defect that cannot be completely corrected — showed a significant improvement in their ability to sustain moderate exercise after treatment with udenafil, a drug that helps improve blood flow, according to a new study.

The trial was funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, and conducted in partnership with Mezzion Pharma. The publication appears online on Nov. 17 in Circulation and coincides with the study’s presentation at the American Heart Association scientific conference in Philadelphia.

With single ventricle defects, the heart struggles to pump oxygenated blood to the rest of the body. Children with the congenital condition—often called “blue babies”—typically undergo a series of three palliative procedures, culminating in the Fontan operation to help stabilize the circulation of blood.

Although these procedures usually produce favorable outcomes in childhood, the body’s ability to distribute blood and oxygen deteriorates throughout adolescence and early adulthood. This deterioration often leads to a decline in exercise capacity and an increase in the likelihood of heart failure symptoms, hospitalization and death.

Researchers say the findings from the Fontan Udenafil Exercise Longitudinal (FUEL) trial could help improve exercise capacity and delay morbidity and mortality in individuals who have undergone the Fontan operation.

“The current study uses a novel approach that focuses on exercise performance metrics rather than specifically focusing on cardiac function,” said Gail Pearson, M.D., Sc.D., associate director of NHLBI’s Division of Cardiovascular Sciences, and director of the Pediatric Heart Network (PHN). “Using exercise performance metrics to measure the effect of udenafil may help kids stave off adverse consequences of the Fontan that manifest in the form of poor exercise performance.”

The primary aim of the trial was to determine the effect of udenafil on peak exercise performance over a six-month period in adolescents who have undergone the Fontan operation. Secondary outcomes included sub-maximal exercise capacity and cardiovascular function.

From July 2016 to May 2018, the trial enrolled 400 participants who were 15 years old on average. They were enrolled at 30 sites that are part of the PHN, as well auxiliary sites in the United States, Canada, and South Korea. Half of the individuals who had undergone the Fontan operation were randomly assigned to udenafil, which they received twice a day; the other half was assigned to a placebo.

Participants pedaled on a special exercise bicycle while wearing a mask that measured oxygen consumption. Researchers programmed the bicycle to increase resistance to assess exercise capacity.

Six months after the start of treatment, participants in the udenafil group did not significantly improve in peak exercise performance, but significantly improved in their ability to sustain sub-maximal exercise measured by oxygen consumption (+33 mL/min), compared to patients in the placebo group (-9 mL/min). The researchers say this level of exertion, which is near to the exertion often encountered in normal recreation and activities of daily living, may be the more relevant measurement for those who have undergone the Fontan operation. This finding was also supported by superior gains in the body’s ability to exhale carbon dioxide and to produce more power needed when changing from aerobic to anaerobic activity.

“Data from the trial show that udenafil improved the ability to perform a moderate level of exercise,” said David Goldberg, M.D., cardiologist in the Cardiac Center and Fetal Heart Program at Children’s Hospital of Philadelphia, and the study’s lead author. “The study’s findings should translate into improved wellness, which was what we are aiming for in this patient population.”

The researchers reported no changes in measures of overall heart function in the individuals who have undergone the Fontan operation taking udenafil or in those taking the placebo. Those taking udenafil tolerated it well, with few experiencing serious adverse events.

“Our hope is that udenafil will give people who have undergone the Fontan procedure sustained improvement over time,” said Stephen Paridon, M.D., medical director of the exercise physiology laboratory at Children’s Hospital of Philadelphia and a study co-author. “Although this study took place over a six month period, ongoing studies are looking at the long-term effects and safety profile of udenafil in these individuals.”

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit www.nhlbi.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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