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Drug therapy in the prevention of failure of the Fontan circulation: a systematic review

  • Nathalie J. Oldenburger (a1), Arenda Mank (a1), Jonathan Etnel (a2), Johanna J. M. Takkenberg (a2) and Willem A. Helbing (a1)...



The Fontan circulation is the optimal treatment for patients with univentricular hearts. These patients are at high risk of circulatory failure. There is no consensus on the optimal drug treatment for the prevention of failure of the Fontan circulation. The aim of this systematic review was to provide an overview of evidence for drug therapy used in the prevention of Fontan circulatory failure.


We searched the Embase database for articles that reported drug therapy in Fontan patients. Studies published between 1997 and 2014 were included if efficacy or safety of medication was assessed, drug therapy aimed to prevent or treat failure of the Fontan circulation, and if the full text was available. Case reports were excluded.


A total of nine studies were included with a total of 267 Fontan patients; four studies evaluated the medication sildenafil, one iloprost, three bosentan, and one enalapril. Among all, two sildenafil studies reported improvement in exercise capacity, one in exercise haemodynamics, and one in ventricular performance. In the largest study of bosentan, an increase in exercise capacity was found. Enalapril did not result in improvements.


The studies analysed in this review suggest that bosentan, sildenafil, and iloprost may improve exercise capacity at the short term. Given the limitations of the studies, more, larger, placebo-controlled studies with longer follow-up periods are needed to better understand which drug therapies are effective in the prevention of failure of the Fontan circulation.


Corresponding author

Correspondence to: W. A. Helbing, MD, PhD, Department of Paediatrics, Division of Paediatric Cardiology, Erasmus Medical Centre, Sophia Children’s Hospital, Sp-2.457, PO Box 2060, 3000 CB Rotterdam, The Netherlands. Tel: +31 10 703 62 64; E-mail:


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Both authors contributed equally.



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1. Gewillig, M. The Fontan circulation. Heart 2005; 91: 839846.
2. Driscoll, DJ, Offord, KP, Feldt, RH, Schaff, HV, Puga, FJ, Danielson, GK. Five- to fifteen-year follow-up after Fontan operation. Circulation 1992; 85: 469496.
3. Gentles, TL, Gauvreau, K, Mayer, JE Jr, et al. Functional outcome after the Fontan operation: factors influencing late morbidity. J Thorac Cardiovasc Surg 1997; 114: 392403; discussion 4–5.
4. d’Udekem, Y, Iyengar, AJ, Galati, J, et al. Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand. Circulation 2014; 130 (Suppl 1): S32S38.
5. Deal, BJ, Jacobs, ML. Management of the failing Fontan circulation. Heart 2012; 98: 10981104.
6. Giardini, A, Hager, A, Pace Napoleone, C, Picchio, FM. Natural history of exercise capacity after the Fontan operation: a longitudinal study. Ann Thorac Surg 2008; 85: 818821.
7. Stickland, MK, Welsh, RC, Petersen, SR, et al. Does fitness level modulate the cardiovascular hemodynamic response to exercise? J Appl Physiol 2006; 100: 18951901.
8. Goldberg, DJ, Avitabile, CM, McBride, MG, Paridon, SM. Exercise capacity in the Fontan circulation. Cardiol Young 2013; 23: 824830.
9. Caruthers, RL, Kempa, M, Loo, A, et al. Demographic characteristics and estimated prevalence of Fontan-associated plastic bronchitis. Pediatr Cardiol 2013; 34: 256261.
10. Feldt, RH, Driscoll, DJ, Offord, KP, et al. Protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg 1996; 112: 672680.
11. Ghanayem, NS, Berger, S, Tweddell, JS. Medical management of the failing Fontan. Pediatr Cardiol 2007; 28: 465471.
12. Anderson, PA, Breitbart, RE, McCrindle, BW, et al. The Fontan patient: inconsistencies in medication therapy across seven pediatric heart network centers. Pediatr Cardiol 2010; 31: 12191228.
13. Moher, D, Liberati, A, Tetzlaff, J, Altman, DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009; 62: 10061012.
14. Higgins, JPT, Green, S. Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The Cochrane collaboration, 2011. Retrieved from www.cochrane-handbookorg.
15. 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: 11851193.
16. 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: 689696.
17. Tunks, RD, Barker, PC, Benjamin, DK Jr, et al. Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med 2014; 15: 2834.
18. Kouatli, AA, Garcia, JA, Zellers, TM, Weinstein, EM, Mahony, L. Enalapril does not enhance exercise capacity in patients after Fontan procedure. Circulation 1997; 96: 15071512.
19. 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: 24352440.
20. 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: 20212030.
21. 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: 16811687.
22. Schuuring, MJ, Vis, JC, van Dijk, AP, et al. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Fail 2013; 15: 690698.
23. Hager, A, Weber, R, Muller, J, Hess, J. Predictors of sildenafil effects on exercise capacity in adolescents and adults with Fontan circulation. Clin Res Cardiol 2014; 103: 641646.
24. Ovaert, C, Thijs, D, Dewolf, D, et al. The effect of bosentan in patients with a failing Fontan circulation. Cardiol Young 2009; 19: 331339.
25. Van De Bruaene, A, La Gerche, A, Claessen, G, et al. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging 2014; 7: 265273.
26. Kempny, A, Dimopoulos, K, Uebing, A, et al. Reference values for exercise limitations among adults with congenital heart disease. Relation to activities of daily life – single centre experience and review of published data. Eur Heart J 2012; 33: 13861396.
27. Diller, GP, Giardini, A, Dimopoulos, K, et al. Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J 2010; 31: 30733083.
28. Argiento, P, Chesler, N, Mule, M, et al. Exercise stress echocardiography for the study of the pulmonary circulation. Eur Respir J 2010; 35: 12731278.
29. Khambadkone, S, Li, J, de Leval, MR, Cullen, S, Deanfield, JE, Redington, AN. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circulation 2003; 107: 32043208.
30. Nemoto, S, Sasaki, T, Ozawa, H, et al. Oral sildenafil for persistent pulmonary hypertension early after congenital cardiac surgery in children. Eur J Cardiothorac Surg 2010; 38: 7177.
31. Duffels, MG, van der Plas, MN, Surie, S, et al. Bosentan in pulmonary arterial hypertension: a comparison between congenital heart disease and chronic pulmonary embolism. Neth Heart J 2009; 17: 334338.
32. Roche, SL, Redington, AN. Right ventricle: wrong targets? Another blow for pharmacotherapy in congenital heart diseases. Circulation 2013; 127: 314316.



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