FUEL trial: Post-Fontan udenafil shows mixed results

PHILADELPHIA – In adolescents who have had a Fontan procedure for congenital heart disease, a randomized trial of the phosphodiesterase type 5 inhibitor udenafil showed that it achieved improved exercise performance but did not lead to significant improvement in oxygen levels or myocardial performance.

That’s according to results of the Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal Trial (FUEL) presented at the American Heart Association scientific sessions. “Treatment with udenafil was not associated with a statistically significant improvement in oxygen consumption at peak exercise, but it was associated with statistically significant improvements in exercise performance at the ventilatory anaerobic threshold,” said David J. Goldberg, MD, of Children’s Hospital of Philadelphia in reporting the FUEL results. The results were published simultaneously in Circulation (2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044352).

“This is the first large clinical trial to show improvement in measures of clinically relevant exercise performance in those with single-ventricle heart disease after Fontan palliation,” he said.

FUEL enrolled 400 male and female adolescents with a single functional ventricle after Fontan surgical palliation. In these patients, pulmonary vascular resistance (PVR) is critical for the efficient flow of blood through the lungs without the benefit of a ventricular pump. “While this circulation is typically stable through childhood, cardiovascular efficiency deteriorates over time, associated with a decline in exercise performance and the accrual of Fontan-associated morbidities,” Dr. Goldberg said. “Given the importance of pulmonary vascular resistance, modulators of PVR make sense as potential therapies.”

FUEL evaluated the effect of udenafil 87.5 mg twice daily versus placebo in post-Fontan patients who’d been on anticoagulation or antiplatelet therapy. The treatment group had a higher percentage of female patients (44% vs. 36% on placebo), but all other baseline characteristics were similar between the two groups.

While the trial found the drug was well tolerated and safe, with side effects typical of PDE5 inhibitors, it did not lead to changes in myocardial performance index, reactive hyperemia index, or log brain natriuretic peptide, Dr. Goldberg said.

At 6 months, both groups showed a decline in exercise data, “as expected,” Dr. Goldberg said. “But that decline was attenuated in the group receiving udenafil,” he said, with peak oxygen consumption declining an average of 0.23 and 0.89 mL/kg per minute in the treatment and placebo groups, respectively (P = 0.092).

Total oxygen consumption, however, actually improved in the udenafil group and declined in the placebo group, 44 mL/min on average versus –3.7 mL/min (P = 0.071).

“There was no significant difference in the change in peak heart rate or the change in peak oxygen saturation between the groups,” Dr. Goldberg said. But three measures at the ventilatory aerobic threshold (VAT) – oxygen consumption, work rate, and ventilation/carbon dioxide output – all showed statistically significant improvement in exercise performance.

“This has important clinical implications,” Dr. Goldberg said of the study findings. “Our study extends recent findings in highlighting the importance of submaximal exercise in the understanding of Fontan physiology. And unlike peak oxygen consumption, submaximal exercise is not constrained by the physiologic ceiling of central venous pressure inherent in exercise physiology after Fontan palliation.”

Maximum oxygen consumption at VAT is likely a more relevant measure after Fontan palliation than is central venous pressure, discussant Craig A. Sable, MD, a pediatric cardiologist in Potomac, Md., noted in his comments. “This is because VAT occurs at about 70% of maximum VO₂ [oxygen consumption] in Fontan as opposed to 55% in two-ventricle physiology,” Dr. Sable said.

In adults with congenital heart disease, maximal VO₂ of 45%-50% of predicted levels portends increased risk of heart failure and death. “Therefore, a medication 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.

In an invited commentary in Circulation (2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044512), Marc Gewillig, MD, and Alexander van de Bruaene, MD, of University Hospitals Leuven (Belgium) said that the findings of FUEL and other trials of pulmonary vasodilators after Fontan leave “open for debate” whether the treatment effects of a 3%-5% improvement in oxygen consumption is clinically meaningful for adolescents. “For failing Fontan patients (not studied in FUEL), these improvements are minimal but maybe relevant,” the commentators wrote. But the studies do not resolve whether that’s enough to prevent further decline.

Dr. Goldberg disclosed receiving research grants from trial sponsor Mezzion Pharmaceuticals and the National Heart Lung and Blood Institute. Dr. Sable, Dr. Gewillig, and Dr. van de Bruaene have no financial relationships to disclose.

SOURCE: Goldberg D. AHA 2019, Late Breaking Science Session 5.

PHILADELPHIA – In adolescents who have had a Fontan procedure for congenital heart disease, a randomized trial of the phosphodiesterase type 5 inhibitor udenafil showed that it achieved improved exercise performance but did not lead to significant improvement in oxygen levels or myocardial performance.

That’s according to results of the Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal Trial (FUEL) presented at the American Heart Association scientific sessions. “Treatment with udenafil was not associated with a statistically significant improvement in oxygen consumption at peak exercise, but it was associated with statistically significant improvements in exercise performance at the ventilatory anaerobic threshold,” said David J. Goldberg, MD, of Children’s Hospital of Philadelphia in reporting the FUEL results. The results were published simultaneously in Circulation (2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044352).

“This is the first large clinical trial to show improvement in measures of clinically relevant exercise performance in those with single-ventricle heart disease after Fontan palliation,” he said.

FUEL enrolled 400 male and female adolescents with a single functional ventricle after Fontan surgical palliation. In these patients, pulmonary vascular resistance (PVR) is critical for the efficient flow of blood through the lungs without the benefit of a ventricular pump. “While this circulation is typically stable through childhood, cardiovascular efficiency deteriorates over time, associated with a decline in exercise performance and the accrual of Fontan-associated morbidities,” Dr. Goldberg said. “Given the importance of pulmonary vascular resistance, modulators of PVR make sense as potential therapies.”

FUEL evaluated the effect of udenafil 87.5 mg twice daily versus placebo in post-Fontan patients who’d been on anticoagulation or antiplatelet therapy. The treatment group had a higher percentage of female patients (44% vs. 36% on placebo), but all other baseline characteristics were similar between the two groups.

While the trial found the drug was well tolerated and safe, with side effects typical of PDE5 inhibitors, it did not lead to changes in myocardial performance index, reactive hyperemia index, or log brain natriuretic peptide, Dr. Goldberg said.

At 6 months, both groups showed a decline in exercise data, “as expected,” Dr. Goldberg said. “But that decline was attenuated in the group receiving udenafil,” he said, with peak oxygen consumption declining an average of 0.23 and 0.89 mL/kg per minute in the treatment and placebo groups, respectively (P = 0.092).

Total oxygen consumption, however, actually improved in the udenafil group and declined in the placebo group, 44 mL/min on average versus –3.7 mL/min (P = 0.071).

“There was no significant difference in the change in peak heart rate or the change in peak oxygen saturation between the groups,” Dr. Goldberg said. But three measures at the ventilatory aerobic threshold (VAT) – oxygen consumption, work rate, and ventilation/carbon dioxide output – all showed statistically significant improvement in exercise performance.

“This has important clinical implications,” Dr. Goldberg said of the study findings. “Our study extends recent findings in highlighting the importance of submaximal exercise in the understanding of Fontan physiology. And unlike peak oxygen consumption, submaximal exercise is not constrained by the physiologic ceiling of central venous pressure inherent in exercise physiology after Fontan palliation.”

Maximum oxygen consumption at VAT is likely a more relevant measure after Fontan palliation than is central venous pressure, discussant Craig A. Sable, MD, a pediatric cardiologist in Potomac, Md., noted in his comments. “This is because VAT occurs at about 70% of maximum VO₂ [oxygen consumption] in Fontan as opposed to 55% in two-ventricle physiology,” Dr. Sable said.

In adults with congenital heart disease, maximal VO₂ of 45%-50% of predicted levels portends increased risk of heart failure and death. “Therefore, a medication 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.

In an invited commentary in Circulation (2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044512), Marc Gewillig, MD, and Alexander van de Bruaene, MD, of University Hospitals Leuven (Belgium) said that the findings of FUEL and other trials of pulmonary vasodilators after Fontan leave “open for debate” whether the treatment effects of a 3%-5% improvement in oxygen consumption is clinically meaningful for adolescents. “For failing Fontan patients (not studied in FUEL), these improvements are minimal but maybe relevant,” the commentators wrote. But the studies do not resolve whether that’s enough to prevent further decline.

Dr. Goldberg disclosed receiving research grants from trial sponsor Mezzion Pharmaceuticals and the National Heart Lung and Blood Institute. Dr. Sable, Dr. Gewillig, and Dr. van de Bruaene have no financial relationships to disclose.

SOURCE: Goldberg D. AHA 2019, Late Breaking Science Session 5.

PHILADELPHIA – In adolescents who have had a Fontan procedure for congenital heart disease, a randomized trial of the phosphodiesterase type 5 inhibitor udenafil showed that it achieved improved exercise performance but did not lead to significant improvement in oxygen levels or myocardial performance.

That’s according to results of the Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal Trial (FUEL) presented at the American Heart Association scientific sessions. “Treatment with udenafil was not associated with a statistically significant improvement in oxygen consumption at peak exercise, but it was associated with statistically significant improvements in exercise performance at the ventilatory anaerobic threshold,” said David J. Goldberg, MD, of Children’s Hospital of Philadelphia in reporting the FUEL results. The results were published simultaneously in Circulation (2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044352).

“This is the first large clinical trial to show improvement in measures of clinically relevant exercise performance in those with single-ventricle heart disease after Fontan palliation,” he said.

FUEL enrolled 400 male and female adolescents with a single functional ventricle after Fontan surgical palliation. In these patients, pulmonary vascular resistance (PVR) is critical for the efficient flow of blood through the lungs without the benefit of a ventricular pump. “While this circulation is typically stable through childhood, cardiovascular efficiency deteriorates over time, associated with a decline in exercise performance and the accrual of Fontan-associated morbidities,” Dr. Goldberg said. “Given the importance of pulmonary vascular resistance, modulators of PVR make sense as potential therapies.”

FUEL evaluated the effect of udenafil 87.5 mg twice daily versus placebo in post-Fontan patients who’d been on anticoagulation or antiplatelet therapy. The treatment group had a higher percentage of female patients (44% vs. 36% on placebo), but all other baseline characteristics were similar between the two groups.

While the trial found the drug was well tolerated and safe, with side effects typical of PDE5 inhibitors, it did not lead to changes in myocardial performance index, reactive hyperemia index, or log brain natriuretic peptide, Dr. Goldberg said.

At 6 months, both groups showed a decline in exercise data, “as expected,” Dr. Goldberg said. “But that decline was attenuated in the group receiving udenafil,” he said, with peak oxygen consumption declining an average of 0.23 and 0.89 mL/kg per minute in the treatment and placebo groups, respectively (P = 0.092).

Total oxygen consumption, however, actually improved in the udenafil group and declined in the placebo group, 44 mL/min on average versus –3.7 mL/min (P = 0.071).

“There was no significant difference in the change in peak heart rate or the change in peak oxygen saturation between the groups,” Dr. Goldberg said. But three measures at the ventilatory aerobic threshold (VAT) – oxygen consumption, work rate, and ventilation/carbon dioxide output – all showed statistically significant improvement in exercise performance.

“This has important clinical implications,” Dr. Goldberg said of the study findings. “Our study extends recent findings in highlighting the importance of submaximal exercise in the understanding of Fontan physiology. And unlike peak oxygen consumption, submaximal exercise is not constrained by the physiologic ceiling of central venous pressure inherent in exercise physiology after Fontan palliation.”

Maximum oxygen consumption at VAT is likely a more relevant measure after Fontan palliation than is central venous pressure, discussant Craig A. Sable, MD, a pediatric cardiologist in Potomac, Md., noted in his comments. “This is because VAT occurs at about 70% of maximum VO₂ [oxygen consumption] in Fontan as opposed to 55% in two-ventricle physiology,” Dr. Sable said.

In adults with congenital heart disease, maximal VO₂ of 45%-50% of predicted levels portends increased risk of heart failure and death. “Therefore, a medication 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.

In an invited commentary in Circulation (2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044512), Marc Gewillig, MD, and Alexander van de Bruaene, MD, of University Hospitals Leuven (Belgium) said that the findings of FUEL and other trials of pulmonary vasodilators after Fontan leave “open for debate” whether the treatment effects of a 3%-5% improvement in oxygen consumption is clinically meaningful for adolescents. “For failing Fontan patients (not studied in FUEL), these improvements are minimal but maybe relevant,” the commentators wrote. But the studies do not resolve whether that’s enough to prevent further decline.

Dr. Goldberg disclosed receiving research grants from trial sponsor Mezzion Pharmaceuticals and the National Heart Lung and Blood Institute. Dr. Sable, Dr. Gewillig, and Dr. van de Bruaene have no financial relationships to disclose.

SOURCE: Goldberg D. AHA 2019, Late Breaking Science Session 5.