The Quest to Find the Right FUEL: Are We Close?

By Shahnawaz Amdani, MD, and Kenneth Zahka, MD

It is becoming increasingly evident that the long-term issues encountered in Fontan patients are secondary to long-standing elevations in central venous pressure (CVP) and diminished cardiac output (CO). In this physiology, pulmonary vascular resistance (PVR) is an important determinant of both upstream (CVP) and downstream (CO) effects.1 Hence, modulation of PVR can have important effects in these patients.

To that end, there are now a few studies that have evaluated different classes of pulmonary vasodilators in Fontan patients: (a) phosphodiesterase (PDE) 5 inhibitors, such as sildenafil;2-7 (b) endothelin receptor antagonists, such as macitentan and bosentan;8,9 and (c) Iloprost, a synthetic prostacyclin analogue.10

Studies using a endothelin receptor antagonists in Fontan patients have shown a reduction in PVR,8 improvement in cardiac index8 and exercise parameters (oxygen uptake, oxygen pulse, anaerobic threshold and exercise time).8,9 Use of Iloprost has also been shown to result in improvement in peak oxygen uptake in Fontan patients. Interestingly, Iloprost led to improvement in all nine (100%) patients who had VO2 <30 ml/kg/min, suggestive of severe exercise limitation, as compared with three out of six (50%) patients who had VO2 >30 ml/kg/min.10

Studies using sildenafil have shown a reduction in PVR and pulmonary resistance index3-5 and improvement in myocardial performance index,6 cardiac output/index,4,5,7 exercise parameters (six-minute walk test distance, oxygen uptake and ventilator efficiency)2,3,7 and NYHA functional class.3

The latest study

The Fontan Udenafil Exercise Longitudinal (FUEL) trial evaluated the effect of udenafil, a long-acting PDE5 inhibitor, on exercise performance and other cardiovascular and functional outcomes over a 6-month period in Fontan patients. This phase 3, international, multi-center trial included 400 patients – 200 in each treatment arm. 11,12

Adolescents (aged 12-18) who had undergone the Fontan procedure were randomly assigned to a treatment group (87.5 mg of udenafil twice daily) or a placebo group. Investigators made several exclusions, including the following:

• Patients with severe ventricular dysfunction assessed by echocardiography within 6 months prior to enrollment.
• Maximum oxygen uptake of < 50% predicted for age and gender at enrollment.
• Admitted for acute decompensated heart failure in the last 12 months.
• Undergoing evaluation for heart transplant or listed for transplant.
• Those with active plastic bronchitis or protein losing enteropathy in the last three years.
• A history of liver cirrhosis.
• A history of PDE-5 inhibitor use or any other medications for treatment of pulmonary hypertension in the three months before study onset.

Also in the FUEL study, hemodynamic assessments (measurement of Fontan pressures, PVR index, transpulmonary gradient [TPG] and cardiac index) were not performed before or after initiation of udenafil.

The authors did not find an improvement in oxygen consumption at peak exercise; however, udenafil use was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.12

Our approach is unchanged

First and foremost, the patients that were studied in this trial differ from patients in our clinical practice. As Fontan failure specialists at Cleveland Clinic Children’s, we often see patients that have one or many of the exclusions mentioned above.

In our practice, Fontan patients that are put on sildenafil have hemodynamic evidence of increased PVR, severe ventricular dysfunction, worsening New York Heart Association (NYHA) functional class, liver cirrhosis and active protein losing enteropathy or plastic bronchitis. Before we start sildenafil, we meticulously study their hemodynamics to gauge their Fontan pressures, PVR index/TPG and cardiac index. Clinically, patients who have seen maximum benefit in our practice are those with elevated PVR index/TPG and low cardiac index. Hence, unfortunately the FUEL study does not change our day-to-day practice.

As we’ve outlined above, there are various studies using sildenafil with almost all showing some benefit in PVR, myocardial performance, cardiac output, exercise parameters and NYHA functional class. There are other studies using other pulmonary vasodilators showing benefit in this patient population when used in the right cohort. As shown in the iloprost study,10 we suspect a greater degree of improvement would have been seen in Fontan patients with significant exercise limitation (oxygen uptake < 50% predicted for age and gender), a cohort that was excluded in the FUEL study.

Future directions

The real question for us is: Would the results be different if the inclusion criteria were altered to include the Fontan patients with severe exercise limitation (oxygen uptake < 50% of predicted for age and gender), severe ventricular dysfunction, patients admitted with recent acute decompensated heart failure, those with evidence of abnormal lymphatics (protein losing enteropathy or plastic bronchitis) or cirrhosis? Also are PDE-5 inhibitors of significant benefit only in those with abnormal hemodynamics (elevated PVR index/TPG and low cardiac index)? Future studies that evaluate the use of pulmonary vasodilators in sicker Fontan cohorts — or those with hemodynamic suggestion of elevated PVR — may help answer these questions.

We commend the Fontan patients, their families and the authors of the FUEL study for trying to answer a clinically important question.

References

1. Gewillig M, Brown SC, van de Bruaene A, Rychik J. Providing a framework of principles for conceptualising the Fontan circulation. Acta Paediatr. 2019 Nov. [Epub ahead of print]
2. Goldberg DJ, French B, McBride MG, et al. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation. 2011;123(11):1185-1193.
3. Mori H, Park IS, Yamagishi H, et al. Sildenafil reduces pulmonary vascular resistance in single ventricular physiology. Int J Cardiol. 2016;221:122-7.
4. Tunks RD, Barker PC, Benjamin DK, Jr. et al. Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med. 2014;15(1):28-34.
5. Van De Bruaene A, La Gerche A, Claessen G, et al. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging. 2014;7:265-73.
6. Goldberg DJ, French B, Szwast AL, et al. Impact of sildenafil on echocardiographic indices of myocardial performance after the Fontan operation. Pediatr Cardiol. 2012;33(5):689-96.
7. Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M, Picchio FM. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 2008;29(13):1681-7.
8. Agnoletti G, Gala S, Ferroni F, et al. Endothelin inhibitors lower pulmonary vascular resistance and improve functional capacity in patients with Fontan circulation. J Thorac Cardiovasc Surg. 2017;153(6):1468-1475.
9. Hebert A, Mikkelsen UR, Thilen U, et al. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. Circulation. 2014;130(23):2021-30.
10. Rhodes J, Ubeda-Tikkanen A, Clair M, et al. Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstration of concept. Int J Cardiol. 2013;168:2435-40.
11. Goldberg DJ, Zak V, Goldstein BH et al. Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial. Am Heart J. 2018;201:1-8.
12. Goldberg DJ, Zak V, Goldstein BH, et al. Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial. Circulation. 2019 Nov. [Epub ahead of print]