Fontan Udenafil Exercise Longitudinal - FUEL

Nov 17, 2019
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Funded by Mezzion Pharma Co. Ltd., and conducted by the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network
Date Presented:
11/17/2019
Date Published:
11/17/2019
Date Updated:
11/17/2019
Original Posted Date:
11/17/2019
References

Contribution To Literature:

The FUEL trial showed that udenafil is not superior to placebo at improving oxygen consumption at peak exercise among compensated patients with Fontan physiology.

Description:

The goal of the trial was to assess the safety and efficacy of udenafil, a long-acting phosphodiesterase type 5 (PDE5) inhibitor, among patients who had Fontan physiology.

Study Design

Eligible patients were randomized in a 1:1 fashion to either udenafil 87.5 mg BID (n = 200) or placebo (n = 200). Patients were stratified by ventricular morphology (left ventricle [LV] vs. right ventricle [RV] or mixed).

  • Total number of enrollees: 400
  • Duration of follow-up: 26 weeks
  • Mean patient age: 15 years
  • Percentage female: 40%

Inclusion criteria:

  • Age 12-18 years
  • Prior Fontan procedure
  • No prior treatment with a PDE5 inhibitor
  • Weight ≥40 kg
  • Height ≥132 cm

Exclusion criteria:

  • Severe ventricular dysfunction
  • Severe atrioventricular valve insufficiency
  • Prior clinical exercise test in which peak oxygen consumption was <50% of predicted for age and sex

Other salient features/characteristics:

  • Predominant ventricular morphology: RV 45%, LV 47%
  • Patent fenestration: 35%

Principal Findings:

The primary outcome of change in oxygen consumption at peak exercise between baseline and week 26, for udenafil vs. placebo was 44 ml/min (2.8%) vs. -3.7 ml/min (-0.2%), p = 0.071.

Secondary outcomes for udenafil vs. placebo:

  • No mortality in either arm
  • Diastolic blood pressure change: -2.9 vs. 0.2 mm Hg, p = 0.003
  • Oxygen saturation: 0.5% vs. -0.3%, p = 0.002
  • Oxygen consumption at anaerobic threshold: 33 ml/min vs. -9.0 ml/min, p = 0.012
  • Headache: 34.5% vs. 25.0%, p = 0.049

Interpretation:

The results of this trial indicate that udenafil, a long-acting PDE5 inhibitor, is not superior to placebo in improving oxygen consumption at peak exercise among compensated patients with Fontan physiology. Improvements were, however, noted in diastolic blood pressure and a few measures of exercise performance at the ventilatory anaerobic threshold.

The Fontan operation is essentially a palliative procedure that connects the superior vena cava/inferior vena cava to the pulmonary arteries; late pump failure is a common issue. Since the pulmonary vasculature is an important source of resistance to flow, pulmonary vasodilators appeared to show promise in smaller studies. This trial suggests that the treatment effects on peak oxygen are modest and perhaps of borderline significance clinically.

References:

Goldberg D, Zak V, Goldstein B, et al. Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial. Circulation 2019;Nov 17:[Epub ahead of print].

Editorial: Gewillig M, De Bruaene AV. FUELing the Search for Medical Therapies in Late Fontan Failure. Circulation 2019;Nov 17:[Epub ahead of print].

Presented by Dr. David J. Goldberg at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.

Keywords: AHA Annual Scientific Sessions, AHA19, Blood Pressure, Cyclic Nucleotide Phosphodiesterases, Type 5, Diastole, Exercise, Fontan Procedure, Heart Defects, Congenital, Oxygen Consumption, Pediatrics, Phosphodiesterase 5 Inhibitors, Vasodilator Agents


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