Review
The Use and Misuse of ACE Inhibitors in Patients with Single Ventricle Physiology

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Background

There are no clear guidelines for the use of angiotensin-converting enzyme (ACE) inhibitors in patients with single ventricle physiology, especially after the Fontan procedure. Despite this, ACE inhibitors are widely prescribed within the single ventricle population.

Objective

We decided to review the literature to better establish the efficacy of ACE inhibitors in the single ventricle population and summarise their indications.

Methods

A review of the literature was conducted to identify relevant articles describing use of ACE inhibitors in single ventricle patients both before and after the Fontan procedure.

Results

A search in the Ovid MEDLINE and Embase databases identified a total of 140 articles, of which 31 were deemed relevant to the review.

Conclusions

There is little published evidence supporting the use of ACE inhibitors in patients with single ventricle physiology. Based on the current literature, it is possible that ACE inhibitors are overprescribed in patients with single ventricle physiology. The coordination of large, prospective studies through initiatives such as the Australia and New Zealand Fontan Registry is necessary to guide the appropriate use of ACE inhibitors in the single ventricle population.

Introduction

Patients born with single ventricle physiology who cannot be offered bi-ventricular repair can now reach adulthood provided they undergo a series of operations in childhood [1]. After the Fontan procedure, the last in this series, both vena cavae are connected directly to the pulmonary arteries, bypassing a subpulmonary ventricle and connecting the systemic and pulmonary circulation in series. It seems today that the majority of patients undergoing a Fontan procedure will survive the first three decades of life, but their future thereafter remains uncertain [1]. Up to 40% of patients will suffer from significant adverse events such as failure of their circulation, stroke, thrombo-embolic events or arrhythmia within the first decade following Fontan [2]. Patients who have undergone a Fontan procedure have a decreased cardiac output, and therefore the Fontan circulation has been compared to a model of heart failure [3], [4]. It has even been suggested that progressive diastolic dysfunction of the systemic ventricle of these patients may contribute to the observed late failure of their circulation [5]. Angiotensin-converting enzyme (ACE) inhibitors are considered a cornerstone of heart failure treatment in adults with acquired heart disease. It has therefore seemed intuitively sound to treat single ventricle patients with these agents to prolong life and improve functional status. While the rationale for this approach seems clear, the evidence to justify ACE inhibitor therapy in these patients may be lacking.

The Australian and New Zealand Fontan Registry is a binational, population-based registry that collects the clinical data of all patients in the region who have undergone a Fontan procedure. At the beginning of February 2015, there were a total of 1,426 patients listed in the ANZ Fontan Registry [6]. A recent report from the Registry found that 36% of patients living with a Fontan circulation within our region were currently taking an ACE inhibitor [7]. Other investigators have reported similarly high proportions of patients with single ventricle physiology being treated with ACE inhibitors. A Paediatric Heart Network study reported that 57% of their patients were taking an ACE inhibitor after Fontan [8]. A survey administered to Canadian cardiologists revealed that one in five of the respondents would routinely use ACE inhibitors in patients with a Fontan circulation, whilst others would restrict their indication to atrio-ventricular or semi-lunar valve regurgitation, reduced systolic or diastolic ventricular function, abnormal diastolic parameters, elevated central venous pressure, decreased exercise tolerance, protein-losing enteropathy or poor functional status [9]. We decided to review the literature to better delineate the efficacy of ACE inhibitors in patients born with a single functional ventricle.

Section snippets

Methods

A literature search was conducted on 2nd February 2015 to identify primary resources published in the OvidSP MEDLINE (R) and Embase databases between 1988 and 2014, pertaining to the use of angiotensin-converting enzyme inhibitors in single ventricle patients or in patients with a Fontan circulation. The following thesaurus terms were used: angiotensin-converting enzyme inhibitors, Fontan procedure, heart single ventricle, heart ventricles/abnormalities and heart defects/congenital. Randomised

Results

A total of 70 and 87 articles were identified in the Ovid MEDLINE and Embase databases respectively. Of these 157 articles, there were 17 duplicates, leaving a total of 140 potential articles for review. A screening of the abstracts identified 31 relevant publications, according to the methods listed above, including three randomised controlled trials. A summary of the major studies is included in Table 1.

Interstage Weight Gain

Follow-up studies in children with single ventricle physiology demonstrate impairment in somatic development during early childhood and persisting into adolescence [10], [11], [12]. Whilst medications that reduce afterload may improve weight gain in infants with other forms of congenital heart disease, [13], [14], [15] there is little evidence to suggest that the same is true for patients with a single functional ventricle.

A multicentre randomised double-blind study of 230 infants aged less

Post-Bidirectional Cavopulmonary Shunt

The bidirectional cavopulmonary shunt (BCPS) is the second stage of single ventricle palliation and involves connection of the superior vena cava to the pulmonary arteries.

Post-operative Pleural Effusions

Pleural effusions after Fontan procedure increase length of stay and increase time with draining tube thoracotomies. Suggestions of a hormonal basis for this fluid retention [28] have prompted a number of enquiries into the potential role of ACE inhibitors on reducing the duration of post-operative pleural drainage. Importantly, no study has shown a decrease in duration of pleural drainage with administration of ACE inhibitors in patients following the Fontan procedure.

Only one prospective

Discussion

There is little evidence in the current literature supporting the use of ACE inhibitors in patients with single ventricle physiology. The use of these agents has not been shown to significantly improve growth parameters or ventricular systolic function in patients born with a single functional ventricle, nor has a beneficial effect for ventricular remodelling been demonstrated. A potential role for ACE inhibitors in reducing the severity of post-operative pleural effusions after BCPS has been

Conclusion

Despite a considerable scarcity of evidence supporting the use of ACE inhibitors in single ventricle patients, there still seems to be a relatively large proportion taking regular ACE inhibitor therapy. This comes in spite of numerous suggestions from the literature that ACE inhibitors are of limited efficacy in this population, and may be detrimental to those with Fontan physiology [26], [31], [32], [33], [50]. Based on the current literature, ACE inhibitors may be overprescribed in patients

Disclosures

Yves d’Udekem is a NHMRC Clinician Practitioner Fellow (1082186). The Victorian Government's Operational Infrastructure Support Program supported this research project.

Financial Assistance

None declared.

Conflicts of Interest

Yves d’Udekem is a consultant for companies MSD and Actelion.

Acknowledgements

The authors thank our research assistants, Dr Aneta Kotevski, Ms Janina Chapman, Ms Ingrid King, Ms Charlotte Verrall, Ms Megan Upjohn and Ms Lisa Cowcher for their invaluable assistance in the creation and maintenance of the Registry and to Belinda Bortone for administrative support. The authors acknowledge support provided to the Murdoch Children's Research Institute by the Victorian Government's Operational Infrastructure Support Program.

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