Use of ACE inhibitors in Fontan: Rational or irrational?☆,☆☆
Introduction
We are now facing a growing population of children, adolescents and young adults who have survived a Fontan procedure [1]. There are no current guidelines identifying optimal care in this population. The Australia and New Zealand Fontan Registry was established to identify outcomes after Fontan surgery and to encourage research that would assess treatment strategies aimed at increasing longevity and quality of life in this population [2]. In an earlier report of outcomes from the Registry, we found that 26% of patients were being treated with an angiotensin-converting enzyme (ACE) inhibitor at last follow-up [3]. There is no current evidence supporting the use of ACE inhibitors in patients with a single ventricle circulation; only a few small studies have been performed, none of which have focused on long-term outcomes [4], [5], [6], [7]. We sought to identify the rationale for the use of ACE inhibitors in Fontan patients in Australia and New Zealand and if possible, evaluate the cost and impact of their use.
Section snippets
Methods
The Australia and New Zealand Fontan Registry, created in 2008, is a binational, population-based registry that collects the clinical data of all patients who have undergone a Fontan procedure in either country, as well as those who had their Fontan procedure overseas and are now followed within the region [2]. There were 1444 hospital survivors of a Fontan procedure in Australia and New Zealand between January 1975 and May 2015. During post-discharge follow-up of these patients there were 129
Results
At most recent follow up, 36% of the participants in the Australia and New Zealand Fontan Registry were taking an ACE inhibitor (457/1268) and 0.4% were taking an ARB (5/1268). The characteristics of those who were taking an ACE-inhibitor or ARB, compared to those who were not, are summarized in Table 1.
The most commonly prescribed agent of the two classes was lisinopril (54%, 248/462), followed by enalapril (24%, 111/462), cilazapril (5%, 23/462), perindopril (5%, 21/462), captopril (5%,
Discussion
Despite no proven indications for their use in single ventricle palliation, we have demonstrated that a high proportion of patients with a Fontan circulation are treated with ACE inhibitors in our region.
A limited number of trials have investigated the benefits of ACE inhibitors in the Fontan population, the majority of which were underpowered and focused on short-term outcomes [5], [6], [7], [10], [11]. No study has shown ACE inhibitors to be effective in improving exercise capacity, growth
Conclusion
Despite a paucity of evidence supporting the use of ACE inhibitors in patients with a Fontan circulation, more than a third of the patients within our region are currently taking one of these agents. Only a third of the patients identified had a well-recognised indication for ongoing treatment. A significant proportion of the remaining two thirds appeared to be treated on the assumption that long-term administration of ACE inhibitors would improve long-term outcomes in patients after Fontan
Disclosures
All other authors have nothing to disclose with regard to commercial support.
Conflicts of interest
Yves d'Udekem is consultant for MSD and Actelion. David S Celermajer report consulting fees from Actelion.
Acknowledgements
The authors thank Murdoch Childrens Research Institute for infrastructure support. The authors also acknowledge Fontan Registry management and research assistants for their invaluable support in the creation and maintenance of the Registry, as well as support in data gathering for this paper and to Belinda Bortone for administrative support. The authors acknowledge support provided to the Murdoch Childrens Research Institute by the Victorian Government's Operational Infrastructure Support
References (27)
- et al.
Is captopril useful in decreasing pleural drainage in children after modified Fontan operation?
Am. J. Cardiol.
(1999) - et al.
Factors influencing perioperative morbidity during palliation of the univentricular heart
Ann. Thorac. Surg.
(1995) - et al.
Factors influencing pleural effusion after Fontan operation: an analysis with 95 patients
Chin. Med. Sci. J.
(2010) - et al.
Risk factors for persistent pleural effusions after the extracardiac Fontan procedure
J. Thorac. Cardiovasc. Surg.
(2004) - 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) - et al.
The Australia and New Zealand Fontan registry: description and initial results from the first population-based Fontan registry
Intern. Med. J.
(2014) Annual Report
- et al.
The use and misuse of ACE inhibitors in patients with single ventricle physiology
Heart, Lung and Circulation
(Oct 27 2015) - et al.
Enalapril in infants with single ventricle: results of a multicenter randomized trial
Circulation
(2010) - et al.
Enalapril does not enhance exercise capacity in patients after Fontan procedure
Circulation
(1997)
Effect of anti-heart failure therapy on diastolic function in children with single-ventricle circulations
Cardiol. Young
Department of Health, Australian Government
Pharmaceutical Mangement Agency (PHARMAC)
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2022, American Journal of CardiologyCitation Excerpt :In the study by Anderson et al11 the use of ACE inhibitors in pediatric Fontan patients correlated with severe atrioventricular valve regurgitation and right ventricular morphology but not with the presence of ventricular dysfunction. In fact, in the study by Wilson et al12 2/3 of the patients receiving enalapril did not have systolic ventricular dysfunction indicating that in most Fontan patients ACE inhibitors are prescribed as a preventive therapy, although proof of effectiveness is lacking. In this study, we showed that a 3-month enalapril treatment had no demonstrable impact on exercise capacity, nor on systolic or diastolic function in pediatric Fontan patients with moderate-good systolic ventricular function.
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2022, American Heart JournalCitation Excerpt :It is possible that there are difference in case mix and/or propensity to prescribe medications between PHN and other centers. In a contemporary study from the Australia/New Zealand Fontan Registry the likelihood of ACEi/ARB prescription (36%) was similar to our study population.10 The similarities with this contemporary cohort could be seen as supporting an era effect, but the Australia/New Zealand Fontan is also an unselected sample of Fontan survivors, so the same issues of case mix and practice variation may apply.
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2020, Annals of Thoracic Surgery
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
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Acknowledgement of Grant Support: The Australia and New Zealand Fontan Registry is funded by grants from the National Health and Medical Research Council (NHMRC; Project Grants 1012241, 1047923, 1065794). The authors acknowledge support provided to the Murdoch Childrens Research Institute by the Victorian Government's Operational Infrastructure Support Programme. Yves d'Udekem is a NHMRC Clinician Practitioner Fellow (1082186). The Victorian Government's Operational Infrastructure Support Programme supported this research project.