Primary endpoint missed, but other outcomes point to overall benefit
PHILADELPHIA – A novel treatment designed to allow teenagers who survived so-called Fontan heart reconstruction surgery as babies to have better exercise function failed to achieve its primary endpoint in a large placebo-controlled trial reported here.
Patients treated with the investigative agent udenafil – an investigational phosphodiesterase-5 inhibitor – did not improve VO2 peak, the volume of oxygen that the body can utilize during physical exertion, said David Goldberg, MD, of Children's Hospital of Pennsylvania, Philadelphia.
In the 26-week study called the FUEL (Fontan Udenafil Exercise Longitudinal) Trial, peak VO2 decreased 0.83% from a baseline of 27.8 mL/kg/min with udenafil at 87.5 mg twice daily compared to a decline of 4.5% from 20.0 mL/kg/min at baseline in a placebo group, which favored the active drug but missed statistical significance (P=0.092), Goldberg reported at the American Heart Association's annual scientific meeting. The results were also published simultaneously in Circulation.
However, at an AHA press conference, Goldberg suggested that udenafil could still be important in treating the teenagers in his study because the drug appeared to improve other exercise measures that may be clinically meaningful to these Fontan survivors.
Patients treated with udenafil achieved a 33-mL/min improvement in VO2 at the ventilatory anaerobic threshold (VAT) compared with a 9-mL/min reduction in the placebo (P=0.012), Goldberg reported. He also said the work rate at VAT also improved compared to placebo (P=0.021), increasing by 3.8 watts among those on udenafil compared to an increase of 0.34 watts among the patients assigned to placebo.
Goldberg noted that when children are born with heart defects that leave them with only one functional ventricle, these so-called "blue babies" undergo Fontan procedures as palliation. While this procedure works well during childhood, "cardiovascular efficiency deteriorates over time, associated with a decline in exercise performance and the accrual of Fontan-associated morbidities."
He said that the FUEL researchers sought to utilize udenafil's vasodilator properties to modulate pulmonary vascular resistance, one of the factors tied to post-Fontan deterioration. The research team randomized 400 patients 1:1 to receive udenafil or placebo.
Participants's mean age was about 15; 40% were female; 80% were white; and mean body mass index was 22.
"Treatment with udenafil was well-tolerated and safe, with adverse events limited to those known to be associated with phosphodiesterase5 inhibitors," Goldberg said. Adverse effects more common with udenafil included headaches, facial flushing, and, among males, erections.
"Our study extends recent findings highlighting the importance of sub-maximal exercise and the understanding of Fontan physiology, and unlike peak VO2, sub-maximal exercise is not constrained by the physiologic ceiling of central venous pressure inherent in exercise physiology after Fontan palliation," Goldberg said. "An improvement in sub-maximal exercise has real implications for day-to-day activity of adolescents with Fontan physiology. This is the first large clinical trial to show improvements in measures of clinically relevant exercise performance in those with single ventricle disease after Fontan palliation."
Discussant Craig Sable, MD, of Children's National Health System and George Washington University in Washington, D.C., said the missed primary endpoint might not be that relevant in Fontan patients.
"The max VO2 has generally been accepted as a marker of hospitalization and death but it may be not ideal as a measure in single ventricles," he said. "There is a limited ability to increase cardiac output to meet exercise need because of the lack of sub-pulmonary pumping ventricle which limits the ability to increase cardiac output. There is a unique physiologic ceiling for max VO2 in the Fontan population."
Sable suggested that VO2 at VAT is a more suitable measure of effectiveness of the intervention than the primary endpoint.
"A mediation that addresses the central deficiencies of Fontan physiology and results in improved exercise performance may allow for a longer period of symptom free survival," he said. "Specifically, people are improved in their daily work which is much more important than at peak exercise."
Udenafil is available as a treatment for erectile dysfunction in Korea, the Philippines, and Russia. It has not been approved by the FDA. Goldberg said that an extension trial with udenafil is ongoing to study long-term safety.
The study was sponsored by Mezzion and the National Heart, Lung, and Blood Institute.
Goldberg disclosed a relationships with Mezzion Pharma.
Sable disclosed no relevant relationships with industry.
Source Reference: Goldberg D, et al "Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial" Circulation 2019; DOI: 10.1161/CIRCULATIONAHA.119.044352.
Read the original article on Medpage Today: