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Archives of cardiovascular diseases
Volume 102, n° 2
pages 81-83 (février 2009)
Doi : 10.1016/j.acvd.2008.12.004
Received : 16 December 2008 ;  accepted : 16 December 2008
Should angiotensin-converting enzyme inhibitors be used in all patients with coronary artery disease or restricted to those with a history of myocardial infarction or myocardial revascularization?
Faut-il prescrire des IEC chez tous les coronariens ou restreindre leur utilisation aux patients ayant des antécédents d’infarctus ou de revascularisation myocardique ?

Nicolas Danchin
Division of coronary artery disease and intensive cardiac care, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France 

Keywords : Coronary artery disease, ACE-inhibitors, Randomized controlled trial, Subgroup analysis

Mots clés : Maladie coronaire, Inhibiteurs de l’enzyme de conversion, Études randomisées, Analyse de sous-groupe

Everyone agrees that angiotensin-converting enzyme (ACE) inhibitors should be used in patients with coronary artery disease and either left ventricular dysfunction or a history of heart failure [1]. In contrast, whether they should be prescribed in all patients with coronary artery disease when they have preserved left ventricular function is debated. The most recent guidelines [2, 3] advocate the use of ACE-inhibitors for patients with no left ventricular dysfunction when they have concomitant conditions such as hypertension or diabetes (class IA). The recommendation is less strong, however, when these patients have no such concomitant conditions (class IIa). The basis for these recommendations is derived from cost/benefits analyses, and from subgroup analyses such as the one presented here by Bertrand et al. [4].

In their analysis from the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (Europa) data, Bertrand et al. [4] show that treatment with perindopril 8mg resulted in a consistent reduction in the primary endpoint of the trial (cardiovascular mortality, acute myocardial infarction or resuscitated cardiac arrest), both for patients with previous myocardial infarction (risk reduction of 22%) and for those with a history of myocardial revascularization (risk reduction of 17%). Specifically, the occurrence of myocardial infarction was reduced significantly in both populations, as was the occurrence of heart failure, another secondary endpoint of the trial. Moreover, the results were consistent according to risk factor subgroups (patients with or without hypertension, diabetes mellitus or hypercholesterolemia), as it was in patients with or without lipid-lowering and antiplatelet medications at baseline.

Overall, these results are hardly surprising, as risk reduction for the primary endpoint in the Europa trial was 20%, and patients with a history of either myocardial infarction or myocardial revascularization comprised 90% of the total trial population [5].

The real question raised by the present analysis, however, goes beyond the results presented here and is the following: do these results actually mean that the benefit of ACE-inhibitors in patients with stable coronary artery disease who have no evidence of left ventricular dysfunction is confined to those with a history of myocardial infarction and/or a history of myocardial revascularization? A positive answer to this question would obviously justify the current recommendations which consider that, when left ventricular function is not impaired, ACE-inhibitor treatment is mandatory in patients with associated conditions only.

A detailed analysis of the data available from the Europa trial [5], but also from the Heart outcomes prevention evaluation (Hope) trial [6], however, does not warrant such a conclusion. To convincingly restrict the benefits of ACE-inhibitor therapy to patients with previous myocardial infarction or revascularization would mean that patients meeting none of these criteria would behave differently compared with those who did. This is clearly not the case. In the Europa trial [5], the magnitude of the benefit of perindopril treatment was somewhat greater in patients without a history of myocardial revascularization compared with those with such a history, while, though slightly less, the magnitude of the effect was not significantly different in patients with or without a history of previous myocardial infarction. Likewise, in the Hope trial [6], there was absolutely no difference in the favorable effect of ramipril, when patients were categorized among those with or without a history of myocardial infarction. In the combined analysis of the individual data from the Europa and Hope trials, there was even a trend to a greater benefit in patients without a history of myocardial revascularization (p for interaction=0.078) [7].

These observations emphasize the limitations of subgroup analyses from large, randomized trials. Presenting positive results in specific subgroups from a trial that documents positive results in the whole population may falsely hint at a lack of efficacy of the medication studied in the other subgroups. Indeed, subgroup analyses are exploratory only and, whether positive or negative, cannot be considered definite proof of the efficacy of a given medication (or lack thereof). In the present case, the feeling left by reading the paper by Bertrand et al. [4] might wrongly be that the benefits of perindopril do not exist in other populations than those assessed here. In fact, three meta-analyses of long-term trials of patients with stable coronary artery disease without heart failure or left ventricular dysfunction show that this should not be the case [7, 8, 9]. All three found a positive effect of these medications on cardiovascular mortality, myocardial infarction and stroke; in addition, myocardial revascularization, heart failure and new onset diabetes mellitus are significantly decreased. Additionally, and importantly, all-cause mortality is also significantly decreased by 14%. Adding the recently published results of the Ischemia management with accupril post bypass graft via inhibition of the converting enzyme (Imagine) trial [10], which showed no benefit of the early and prolonged treatment with quinapril in patients undergoing coronary artery bypass surgery, does not substantially change the conclusions of the meta-analysis (Figure 1, Table 1).

Figure 1

Figure 1. 

Updated meta-analysis of the long-term trials comparing ACE-inhibitors and placebo in coronary artery disease patients without heart failure or left ventricular dysfunction. Abbreviations: CV=cardiovascular; MI=myocardial infarction.


In summary, there is convincing evidence of the efficacy of ACE-inhibitor therapy in patients with coronary artery disease, even when left ventricular dysfunction, previous myocardial infarction or previous myocardial revascularization are absent. This simple message should not be blurred by the present subgroup study from Bertrand et al.


Dr Danchin has received speaking and consulting fees from Servier, who manufactures perindopril, and from all major companies manufacturing ACE-inhibitors.

 Angiotensin-converting enzyme inhibition with perindopril in patients with prior myocardial infarction and/or revascularization: A subgroup analysis of the EUROPA trial, Bertrand M.E., Fox K.M., Remme W.J., Ferrari R., Simoons M.L., doi:10.1016/j.acvd.2008.10.012


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Danchin N., Cucherat M., Thuillez C., and al. Angiotensin-converting enzyme inhibitors in patients with coronary artery disease and absence of heart failure or left ventricular systolic dysfunction: an overview of long-term randomized controlled trials Arch Intern Med 2006 ;  166 : 787-796 [cross-ref]
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