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Archives of cardiovascular diseases
Volume 102, n° 2
pages 89-96 (février 2009)
Doi : 10.1016/j.acvd.2008.10.012
Received : 8 June 2008 ;  accepted : 20 October 2008
Angiotensin-converting enzyme inhibition with perindopril in patients with prior myocardial infarction and/or revascularization: A subgroup analysis of the EUROPA trial
Inhibition de l’enzyme de conversion chez les patients avec un antécédent d’infarctus du myocarde ou de revascularisation : une analyse de sous-groupe de l’étude EUROPA
 

Michel E. Bertrand a, , Kim M. Fox b, Willem J. Remme c, Roberto Ferrari d, Maarten L. Simoons e
a Hôpital cardiologique, boulevard du Prof.-Leclercq, 59037 Lille, France 
b Royal Brompton and National Heart Hospitals, London, UK 
c Sticares Cardiovascular Research Foundation, Rotterdam, The Netherlands 
d Department of Cardiology, University of Ferrara and Salvatore Maugeri Foundation, IRCCS, Ferrara, Italy 
e Erasmus University, Rotterdam, The Netherlands 

Corresponding author. Fax: +33 320 00 65 09.
Summary
Background

The European trial on Reduction Of cardiac events with perindopril in patients with stable coronary Artery disease (EUROPA) demonstrated the benefits of perindopril with respect to secondary prevention of cardiovascular risk in patients with stable coronary artery disease.

Aims

To describe the clinical effects of perindopril in a subpopulation of patients from EUROPA with a history of myocardial infarction and/or revascularization.

Patients and methods

Of the 12,218 patients in the EUROPA study, 10,962 had a history of myocardial infarction and/or revascularization. In this EUROPA subpopulation, 7910 patients had a history of myocardial infarction and 6709 had a history of revascularization. Patients were randomized to treatment with perindopril 8mg/day or placebo. The primary endpoint was a composite of cardiovascular mortality, myocardial infarction and resuscitated cardiac arrest.

Results

After a mean follow-up of 4.2 years, treatment with perindopril 8mg/day was associated with a 22.4% reduction in the primary endpoint compared with placebo (p <0.001) in patients with a history of myocardial infarction. Patients with a history of myocardial revascularization showed a 17.3% reduction in the primary endpoint with perindopril versus placebo (p <0.05). In the combined population of patients with a history of myocardial infarction and/or revascularization, treatment with perindopril produced a 22.4% reduction in the primary endpoint compared with placebo (p <0.001).

Conclusions

This study confirms the benefits of a high dose of angiotensin-converting enzyme inhibitor for the secondary prevention of cardiovascular risk among patients with a history of myocardial infarction and/or revascularization.

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Résumé
Objectifs

L’étude EUROPA a démontré les bénéfices du perindopril dans le cadre de la prévention secondaire du risque cardiovasculaire chez les patients avec une athérosclérose coronaire stable. Le but de cet article est de rapporter les principaux résultats d’un sous-groupe de l’étude EUROPA chez les patients avec un antécédent d’infarctus du myocarde et/ou de revascularisation myocardique.

Patients et méthodes

Parmi les 12 218 patients de l’étude EUROPA, 10 902 avaient un antécédent d’infarctus du myocarde (n =7910) et/ou de revascularisation myocardique (n =6709). Cette population a été randomisée en deux groupes, l’un recevant 8mg/j de périndopril et le second recevant un placebo. L’objectif primaire combinait la mortalité cardiovasculaire, l’infarctus myocardique ou un arrêt cardiaque récupéré.

Résultats

Avec un suivi moyen de 4,2 ans, on note que la prescription de perindopril (8mg/j) chez les patients avec un antécédent d’infarctus du myocarde détermine une réduction significative de l’objectif principal : 22,4 % (p <0,001). Cette réduction est de 17,3 % (p =0,035) chez les patients ayant fait l’objet d’une revascularisation myocardique. Elle est de 22,4 % chez les patients ayant fait l’objet d’un infarctus du myocarde et/ou d’une revascularisation myocardique.

Conclusions

Les résultats de cette étude confirment les bénéfices d’une dose élevée d’inhibiteur de l’enzyme de conversion pour la prévention secondaire des risques cardiovasculaires chez les patients avec un antécédent d’infarctus et/ou de revascularisation.

The full text of this article is available in PDF format.

Keywords : Angiotensin-converting enzyme inhibitor, Coronary artery disease, Secondary prevention, Myocardial infarction, Perindopril, Revascularization

Mots clés : Inhibiteur de l’enzyme de conversion de l’angiotensine, Maladie coronaire, Prévention cardiovasculaire, Prévention secondaire, Infarctus du myocarde, Perindopril, Revascularisation myocardique


Abbreviations

ACE : Angiotensin-converting enzyme
CABG : Coronary artery bypass graft
CAD : Coronary artery disease
MI : Myocardial infarction
PCI : Percutaneous coronary intervention
RRR : Relative risk reduction

Introduction

CAD remains one of the leading causes of cardiovascular mortality [1]. However, over recent years, its impact on morbidity and mortality has decreased due to major advances in the management of acute coronary syndromes, surgical techniques for myocardial revascularization (CABG orPCI) and secondary prevention. The basis of treatment for the prevention of recurrence of major cardiovascular events has been the use of combinations of antiplatelet drugs, beta-blockers (in the case of history of MI) and statins. More recently, various studies have demonstrated the benefits of ACE inhibitors for secondary prevention in stable CAD. Four major clinical trials have been published in this field [2, 3, 4, 5]. These trials were followed by three meta-analyses [6, 7, 8] in more than 33,000 subjects, which confirmed the importance of ACE inhibitors for secondary prevention in stable CAD. ACE inhibitors were found to significantly reduce total mortality by approximately 15%, cardiovascular mortality by approximately 20% and the occurrence of MI by 18 to 20%. These results were due essentially to the effects of two ACE inhibitors – ramipril and perindopril.

The Food and Drug Administration and the European Medicines Agency currently recommend perindopril for stable CAD patients with a history of MI and/or revascularization. Although the results for the subpopulation of patients with a history of revascularization in the European trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease (EUROPA) have been published previously [9], this is not the case for patients with a history of MI. The aim of this article, which is a post-hoc analysis, is to describe the clinical effects of perindopril on the combined subpopulations of CAD patients from EUROPA with a history of MI and/or revascularization.

Patients and methods
Study population

The EUROPA methodology has been described elsewhere in detail [3]. Briefly, the trial enrolled 12,218 men and women greater than or equal to 18 years of age, with documented evidence of CAD and without clinical evidence of heart failure. Evidence of CAD consisted of any of the following: history of MI greater than 3 months before screening, revascularization greater than 6 months before screening and stenosis of greater than 70% in at least one of the major coronary arteries as assessed by coronary angiography. Criteria for exclusion from study entry were clinical signs of heart failure, hypotension, uncontrolled hypertension, use of ACE inhibitors or angiotensin receptor blockers within the last month and impaired renal function and/or serum potassium greater than 5.5mmol/L. In the EUROPA cohort, 90% of the patients (n =10,962) had a history of MI and/or a history of revascularization. This subpopulation can be classified into three groups: patients with a history of MI (n =7910); patients with a history of revascularization (n =6709); and patients with a history of MI and/or revascularization (n =10,962).

Study design

EUROPA was a multicenter, double-blind, placebo-controlled trial. EUROPA started with a run-in period during which patients received perindopril 4mg/day orally each morning in addition to their normal treatment for 2 weeks, followed by perindopril 8mg/day orally each morning for a further 2 weeks if the 4mg dose was well tolerated. Patients greater than 70 years of age received perindopril 2mg/day in the first week, then 4mg/day in the second week and 8mg/day in the last 2 weeks. At the end of the run-in period, patients were assigned randomly to treatment with either perindopril 8mg/day or placebo once daily for at least 3 years. Patients were seen at 3, 6 and 12 months, and then every 6 months for the rest of the trial duration.

Study endpoints

The primary endpoint was a composite of cardiovascular death, non-fatal MI and resuscitated cardiac arrest. The secondary endpoints were a composite of total mortality, non-fatal MI, hospitalization for unstable angina and resuscitated cardiac arrest; a composite of cardiovascular mortality and non-fatal MI; and the individual components of these secondary endpoints plus coronary revascularization, stroke and admission for heart failure. Diagnosis of MI was based on the current recommendations of the European Society of Cardiology and the American College of Cardiology [10]. The study included four committees, an Executive Committee, a Steering Committee, a Data and Safety Monitoring Board, and a Critical Event Committee (for death and MI).

Statistical analyses

The log-rank test was used in an intention-to-treat analysis for the time to first occurrence of the primary endpoint. The Kaplan-Meier method was used to analyse distribution of events over time and the Cox proportional-hazards model was used to assess risk reduction for the primary and secondary endpoints. Descriptive statistics are presented for the baseline population. A p -value of less than 0.05 was considered to be significant.

Results

The results for the endpoints are discussed below, grouped as follows: patients with a history of MI; patients with a history of revascularization; and patients with a history of MI and/or revascularization. Within each group there were no relevant differences in the baseline characteristics of patients treated with perindopril or placebo (Table 1, Table 2, Table 3).

Patients with history of MI

Among the patients with a history of MI (n =7910, mean age 59.6±9.5 years), 46.2% had a history of revascularization and 65.5% were being treated with beta-blockers (Table 1). The cumulative incidence of the primary endpoint in patients receiving perindopril (n =3962) or placebo (n =3948) during the trial is shown in Figure 1A. At the end of the trial, there was a significant RRR of 22.4% in the primary endpoint (p <0.001); the incidence was 8.9% in the perindopril group versus 11.3% in the placebo group (Table 4). Perindopril also reduced the recurrence of MI significantly compared with placebo (5.6% versus 7.6%; 27.9% reduction; p =0.001). Although the incidence of heart failure was low, there was a significant reduction with perindopril compared with placebo (1.1% versus 2.2%; 47.6% reduction; p <0.001).



Figure 1


Figure 1. 

A. Patients with history of MI. B. Patients with history of revascularization. C. Patients with history of MI or revascularization.

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Patients with history of revascularization

Among the patients with previous revascularization (n =6709), 54.5% also had a history of MI (Table 2). A history of PCI was noted in 53.3% of patients and a history of CABG was noted in 53.5% of patients. Thus, over time, some patients underwent both procedures. The cumulative incidence of the primary endpoint for perindopril (n =3340) and placebo (n =3369) throughout the trial is shown in Figure 1B. The incidence of the primary endpoint at the end of trial was 6.6% in the perindopril group versus 8.0% in the placebo group (RRR 17.3%; p <0.05) (Table 4) [9]. The incidence of MI was also significantly lower with perindopril versus placebo (4.6% versus 5.9%; p <0.05). The incidence of heart failure was 40.3% lower in the perindopril group than in the placebo group (0.7% versus 1.2%; p <0.05).

In this study, 1648 patients with no history of MI underwent revascularization with CABG. In this patient subgroup, perindopril was associated with a tendency to reduce the primary endpoint by 18%, although this trend did not reach statistical significance (p =0.28). Among the 1585 patients with no history of MI who underwent PCI, perindopril showed a significant benefit in terms of the primary endpoint (RRR 34.2%; p <0.05). For the overall group of 3047 patients with no history of previous MI who underwent revascularization, there was also a tendency for perindopril to reduce the primary endpoint by 23%, although this did not reach statistical significance (p =0.074).

Patients with history of MI and/or revascularization

Among the large subpopulation with a history of MI and/or revascularization (n =10,962), 72.2% had history of MI and 61.2% had a history of revascularization (Table 3). The cumulative incidence of the primary endpoint during the trial for perindopril (n =5485) and placebo (n =5477) is shown in Figure 1C. At the end of the trial, perindopril was associated with a lower incidence of the primary endpoint compared with placebo (7.9% versus 10.1%; RRR 22.4%; p <0.001) (Table 4). The total mortality rate was 6.2% with perindopril and 6.8% with placebo (p =0.211). The cardiovascular mortality rates were 3.6 and 4.1%, respectively (p =0.19). The incidence of MI was also significantly lower with perindopril compared with placebo (5.1% versus 7.0%; p <0.001). Finally, the incidence of heart failure was 1.7% with placebo compared with 1.0% with perindopril (p <0.005).

Impact of risk factors and associated cardiovascular treatments

The beneficial effects of perindopril were independent of the presence of cardiovascular risk factors at baseline in all study groups (Table 5). In the EUROPA subpopulation with a history of MI and/or revascularization, the benefit of perindopril was additional to the effects of secondary prevention with antiplatelet drugs and lipid-lowering drugs (Table 6).

Tolerability

Of the 10,962 EUROPA patients with a history of MI and/or a history of revascularization, 21.5% left the study prematurely, and in similar proportions in the perindopril and placebo groups (Table 7). However, it should be noted that these figures concern patients who were not excluded in the run-in period. Perindopril treatment was well tolerated compared with placebo. The main reason for stopping treatment with perindopril was cough (2.7% versus 0.5% in the placebo group). At 3 years, 95.3% of the patients receiving perindopril and 95.4% of the patients receiving placebo were still taking the medication; most patients receiving perindopril were still taking the full 8mg/day dose and only 5% had reduced the dose to 4mg/day.

Discussion

The results of this subpopulation analysis of the EUROPA trial show that treatment with perindopril is associated with a significant 22.4% RRR in the primary endpoint compared with placebo (p <0.001) in patients with a history of MI and/or revascularization. The RRR in the primary endpoint was 22.4% in patients with a history of MI and 17.3% in patients with a history of revascularization (p <0.001 and p <0.05, respectively). The incidence of MI and heart failure was reduced significantly with perindopril treatment in all study groups. These beneficial effects of perindopril were independent of baseline cardiovascular risk factors, and were seen even with other secondary prevention in CAD, including antiplatelet and lipid-lowering agents. The European Medicines Agency and the Food and Drug Administration gave an indication for the appropriate use of perindopril in CAD patients with a history of MI and/or revascularization, and our results support this recommendation.

It is interesting to compare the time of study entry with the timing of any preceding cardiovascular events in these subpopulations. Of the 64% of patients with a history of MI, one third had had an MI greater than 5 years before study entry, 47% had had an MI between 1 and 5 years before study entry and the remainder had had an MI between 3 months and 1 year before study entry. Enrolment in the study was thus well beyond the acute phase of MI during which various other trials and meta-analyses have shown clearly the benefits of ACE inhibitors for patients with left ventricular dysfunction [11, 12].

According to study protocol, revascularized patients could only be enlisted if the procedure had been performed greater than 6 months beforehand. A recent study has shown that the prescription of high-dose quinapril during the 10 days after CABG was not beneficial and may even have had a deleterious effect [13]. This is in contrast with the clinical benefits of perindopril in the revascularized patients in our study, and may be due to patients being recruited 6 months after the procedure. However, long-term use of quinapril in low-risk CAD patients undergoing PCI also failed to show any beneficial effects [4].

Although patients in this EUROPA substudy were enrolled if they had had an MI greater than 3 months or revascularization greater than 6 months before entry into the study, the secondary prevention benefits obtained suggest that perindopril should be prescribed as soon as possible after either of these events. Indeed, it has been shown clearly that target doses of prescribed medication for secondary prevention are maintained closely at the time of the initial event during hospitalization, but that this is less true for a medication prescribed some time after the critical event [14].

Finally, the results of this analysis were obtained using a high dose of ACE inhibitor (8mg), which was well tolerated. Experimental trials have shown that the beneficial effects of ACE inhibitors on atherogenesis and secondary prevention are obtained primarily with high doses. It is impossible to extrapolate the results of the EUROPA study [3] to lower doses. As with all clinical studies, the results in terms of clinical efficacy and safety in a large-scale clinical trial cannot be transferred to other agents. In conclusion, the results of this EUROPA substudy confirm the benefits of perindopril 8mg/day in patients with a history of MI and/or revascularization.

Conflict of interest

The EUROPA study was funded by Servier. Drs Bertrand, Fox, Remme, Ferrari, and Simoons declare having received research grants and honoraria from Servier.

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