Eplerenone in systemic right ventricle: Double blind randomized clinical trial. The evedes study,☆☆

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Abstract

Background

There is no proven pharmacological strategy for the treatment of the failing systemic right ventricle (SRV) but myocardial fibrosis may play a role in its pathophysiology.

Methods

We designed a double-blind, placebo-controlled clinical trial to assess the effects of eplerenone 50 mg during 12 months on cardiac magnetic resonance parameters (SRV mass and ejection fraction) and neurohormonal and collagen turnover biomarker (CTB) levels.

Results

Twenty six patients with atrial switch repair for transposition of the great arteries were randomized to eplerenone (n = 14) or placebo (n = 12) and 14 healthy volunteers served as controls for comparison of baseline neurohormones and CTB levels. The study population showed a good baseline profile in terms of SRV mass (57.4 ± 17 g/m2) and ejection fraction (54.9 ± 7.5%). However, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), C terminal propeptide of type I procollagen (CICP) and C-terminal Telopeptide of type I Collagen (ICTP) were significantly elevated when compared to healthy controls. After one year of treatment, a trend toward reduction of CICP, N-terminal pro-Matrix Metalloproteinase 1 (NT-proMMP1), Tissue Inhibitor of Metalloproteinases 1 (TIMP1) and galectin 3 levels and a lower increase in ICTP in patients under eplerenone was observed. The reduction of SRV mass and the improvement of SRV function with eplerenone were not conclusive.

Conclusions

Patients with SRV treated with eplerenone showed an improvement of an altered baseline CTB profile suggesting that reduction of myocardial fibrosis might be a therapeutic target in these patients.

Introduction

Although the current surgical procedure of choice for the repair of the transposition of the great arteries (TGA) is the arterial switch, there is a considerable number of adult patients followed up at the congenital cardiac clinics that underwent the atrial switch procedure (AtS) during childhood. Despite the overall good survival of these patients into adulthood, the majority leading a normal life [1], [2], [3], [4], heart failure has been identified as a major problem in the long term [5], [6] since the morphologic right ventricle is on the systemic position. However, when it comes to the management of the failing systemic right ventricle (SRV), questions arise. The promising results offered by β-blockers in some studies are far from conclusive [5], [7], [8], [9] and the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers has brought divergent results [10], [11], [12], [13], [14], [15].

Myocardial fibrosis has been identified in patients with SRV by cardiac magnetic resonance (CMR) and it seems to correlate with poorer ventricular function and worse prognosis [16], [17]. Aldosterone, one of the most widely studied neurohormones in systemic left ventricular remodeling and failure is known to stimulate the mineralocorticoid receptor in cardiomyocytes, endothelial cells and fibroblasts inducing myocardial and vascular fibrosis. This inflammatory response is a direct humoral effect, rather than secondary to hemodynamic changes [18], [19], [20], [21]. Experimental studies have demonstrated that, regardless the dose, treatment with aldosterone antagonists can reduce myocardial fibrosis [19], [20], [21], [22], [23] and even reduce ventricular hypertrophy in hypertensive patients presumably due to reduction of fibrotic tissue [24]. Our study was therefore designed to assess the effects of eplerenone, a selective aldosterone antagonist, on myocardial mass and fibrosis of systemic right ventricles.

Section snippets

Study population

This study started as a collaborative study between the Adult Congenital Cardiac Units of Vall d'Hebron University Hospital and Santa Creu i Sant Pau University Hospital. By the end of the study both units merged into a single tertiary referral which is Adult Congenital Heart Disease Unit for the Autonomous Community of Catalonia. The protocol was approved by the Ethics Review Board of both centers and written informed consent was obtained from each patient before enrollment. This investigation

Results

During 18 months of time-frame recruitment, only 27 out of a total sample size of 110 patients signed the informed consent to participate (Fig. 1), thus leading to discontinuation because of insufficient recruitment. In addition, one patient withdrew informed consent before randomization, thus 26 patients were randomized to eplerenone (n = 14) or placebo (n = 12). We next present the clinical, cardiac MRI, neurohormonal, and functional results of these 26 patients.

Discussion

Although this randomized clinical trial has to be considered as non-conclusive regarding its primary endpoint due to insufficient recruitment, it is the first to evaluate the effect of an aldosterone antagonist on patients with SRV. In summary, while our cohort of patients with SRV was in a good clinical situation and showed only a modest degree of ventricular hypertrophy when compared to previously published series, they exhibited a pattern of altered collagen turnover and neurohormonal

Limitations and strengths of the study

The main limitation of our study is the low number of patients enrolled because of the refusal of the patients to participate. Their very good clinical situation, the fear of side-effects and a self-negation of their chronic condition likely influenced the low rate of participation despite our efforts. It has to be pointed out, however, that baseline characteristics of consenting patients and those who refused to participate compared well in terms of age (26.4 ± 5.4 vs 26.6 ± 4.2, p = 0.9), sex

Conclusion

Despite an overall baseline good situation, our cohort of patients with SRV exhibits an altered baseline CTB profile and neurohormonal activation. Although the small sample size prevents from any conclusive statement, our results suggest that patients with SRV could hypothetically benefit from the treatment with eplerenone in terms of SRV hypertrophy reduction, and SRV function and CTB profile improvement. Moreover, the reduction of myocardial fibrosis in these patients might be a therapeutic

Acknowledgments

We wish to acknowledge the support of Purificación Cascant and Maria Teresa Fernandez in the data collection process and Maite Domingo in the blood samples' collection.

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      However, given the significant dropout rate, there was a risk of type II error. Potential for type II error was also high in the study by Dos et al. (19), which analyzed the effect of eplerenone in a randomized, double-blind, controlled trial. It had significant underrecruitment, with only 26 of the estimated 117 patients being recruited.

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    Funding Sources: This study was funded through a grant from the Instituto de Salud Carlos III, Ministry of Science and Innovation, Spain (grant EC07/90112). Eplerenone was donated by Pfizer Spain.

    ☆☆

    Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00703352.

    1

    This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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