Randomised trial of ramipril in repaired tetralogy of Fallot and pulmonary regurgitation: The APPROPRIATE study (Ace inhibitors for Potential PRevention Of the deleterious effects of Pulmonary Regurgitation In Adults with repaired TEtralogy of Fallot)

Babu-Narayan, Sonya V.; Uebing, Anselm; Davlouros, Periklis A.; Kemp, Michael; Davidson, Simon; Dimopoulos, Konstantinos; Bayne, Stephanie; Pennell, Dudley J.; Gibson, Derek G.; Flather, Marcus; Kilner, Philip J.; Li, Wei; Gatzoulis, Michael A.

doi:10.1016/j.ijcard.2010.09.057

« Previous Next »International Journal of Cardiology
Volume 154, Issue 3 , Pages 299-305, 9 February 2012

Randomised trial of ramipril in repaired tetralogy of Fallot and pulmonary regurgitation:

The APPROPRIATE study (Ace inhibitors for Potential PRevention Of the deleterious effects of Pulmonary Regurgitation In Adults with repaired TEtralogy of Fallot)

Sonya V. Babu-Narayan
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
- National Heart and Lung Institute, Imperial College London, UK
Anselm Uebing
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
Periklis A. Davlouros
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
Michael Kemp
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
Simon Davidson
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
Konstantinos Dimopoulos
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
- National Heart and Lung Institute, Imperial College London, UK
Stephanie Bayne
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
Dudley J. Pennell
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
- National Heart and Lung Institute, Imperial College London, UK
Derek G. Gibson
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
Marcus Flather
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
- National Heart and Lung Institute, Imperial College London, UK
Philip J. Kilner
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
- National Heart and Lung Institute, Imperial College London, UK
Wei Li
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
- National Heart and Lung Institute, Imperial College London, UK
Michael A. Gatzoulis
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK
- National Heart and Lung Institute, Imperial College London, UK
- Corresponding author. NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London; Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel.: +44 20 7351 8602; fax: +44 20 7351 8629.

Received 20 June 2010; accepted 25 September 2010. published online 25 October 2010.

Abstract

Background

Optimal treatment for stable repaired tetralogy of Fallot (rTOF) patients with pulmonary regurgitation (PR) and related right ventricular (RV) dilatation, including timing of valve implantation, remains uncertain. We sought to study tolerability of the angiotensin-converting-enzyme (ACE) inhibitor ramipril and its effects on cardiovascular function in these patients.

Methods

Clinically stable rTOF patients with moderate/severe PR were included. A double-blinded, placebo-controlled study of 6months of ramipril vs placebo was performed. All patients underwent cardiovascular magnetic resonance (CMR), echocardiography, neurohormonal analysis, and objective cardiopulmonary exercise testing at baseline and follow-up.

Primary endpoint

The main aim was to detect changes in RV function (primary endpoint CMR-derived RV ejection fraction).

Results

Seventy-two patients were enrolled and 64 qualified for the final analysis.

There was no difference in the primary endpoint RV ejection fraction. RV long-axis shortening significantly improved in the ramipril group compared to placebo (RV: 2.3±3.8 vs 0.02±2.7mm; P=0.017) as did LV long-axis shortening (1.9±4.5 vs −0.2±3.7mm respectively; P=0.030). No clear differences were detected between ramipril and placebo for other measures. In a subgroup of patients with restrictive RV physiology, ramipril resulted in decrease in LV end-systolic volume index and increase in LVEF (−2.4±5.0 vs 2.7±3.6mL/m²; P=0.005, 2.5±5.0 vs −1.3±3.5%; P=0.03). Ramipril did not cause adverse events and was well tolerated.

Conclusions

Ramipril is a well tolerated therapy, improves biventricular function in patients with rTOF and may have a particular role in patients with restrictive RV physiology. Larger, longer-term studies are needed to determine if ACE inhibitors can improve both ventricular remodelling and clinical outcomes. (ISRCTN: 97515585)

Keywords: Randomised controlled trials, Congenital heart disease, Tetralogy of Fallot, Pulmonary regurgitation, ACE inhibitor, Fibrosis