Cardiovascular Drugs and Therapy 20 11–12 2006

C© 2006 Springer Science + Business Media, Inc. Manufactured in the United States.

DOI: 10.1007/s10557-006-7297-8

EDITORIAL

ACE-Inhibition for Secondary Prevention of CardiovascularEvents—Should We Change Our Recommendation AfterPEACE?

Roberto FerrariChair of Cardiology, University of Ferrara, Corso Giovecca 203,44100, Ferrara

Published online: 23 March 2006

The review of A.A. Voors and colleagues published inthis number of Cardiovascular Drug and Therapy ad-dresses an important topic of cardiovascular medicine:The current role of ACE-inhibitors for secondaryprevention [1].

The authors suggest to reconsider the recommenda-tion of the European Society of Cardiology task forceto the use of ACE-inhibitors for secondary preventionlabelled as Class I level of evidence A. After the pub-lication of the prevention of events with angiotensin-converting enzyme inhibition (PEACE) trial [2], theybelieve that the level of evidence is not so strong, there-fore the labelling of the recommendation should be Class1,B. They conclude that ACE-inhibition, presumably ir-respective of drug or dose, is not of value in low riskpatients with CAD treated with other (statins) provenpreventative therapies.

From a pathophysiological point of view, they ar-gue that only patients with an activated local renin-angiotensin system will benefit from therapy with ACE-inhibitors. The major risk factors for CVD, includinghigh cholesterol and blood pressure, are all associatedwith activation of tissue ACE. Baseline serum choles-terol and blood pressure were lower in PEACE than inEUROPA and HOPE, therefore local renin-angiotensinsystem of the PEACE patients could have been less ac-tivated compared to that of HOPE and EUROPA pa-tients. This would explain the lack of Trandolapril effectsin PEACE.

This hypothesis is certainly interesting, but there aresome points which should be considered before acceptingit.

The major risk factors for CVD in all populationare elevated levels of cholesterol, and blood pressure,diabetes, tobacco exposure, obesity, insufficient dietaryfruits and vegetables and lack of regular exercise [3].There is ample evidence that these factors should notbe considered individually as their inter-relationshipis complex, continuous and extends over a wide range,including “normal” levels. Moreover, clinical trials ofcholesterol and blood pressure lowering agents, includ-ing ACE-inhibitors, suggest that the benefit obtained

depends primarily on the magnitude of cholesterol andblood pressure lowering, irrespective of their baselinelevel [4,5]. Interestingly, the magnitude of low pres-sure lowering in HOPE, EUROPA and PEACE wasremarkably similar [2,6,7].

In HOPE, consistently with the contemporaneousregistry, fewer patients received anti-platelet drugs,lipid lowering agents and beta-blockers (76%, 29%and 40% patients, respectively) than in EUROPA andPEACE [2,6,7]. In EUROPA, at baseline the use ofthese medications was 92%, 58% and 62% respectively.At 3 years follow up, the use of lipid lowering agentsincreased to 69% [7]. In PEACE, at baseline 91% pa-tients received anti-platelet agents, 70% lipid loweringagent and 60% ß-blockers [2]. Thus, in PEACE the useof lipid lowering agents at baseline but not at the endof the study, was slightly higher than in EUROPA. Themodest magnitude of the difference could hardly ex-plain absence of local ACE-activation and, consequentlyof Trandolapril inefficacy. Moreover in HOPE and EU-ROPA the benefits were observed whether or not pa-tients were taking statins at baseline [6,7]. Experimen-tally, both ACE-inhibitors and statins improve endothe-lial eNOS expression and reduce apoptosis with a conse-quent retard in the onset and progression of aterogena-sis. Their combination has been shown to exert a sinergiceffect [8]. Clinically, it has been shown that combinationof statin and ACE-inhibitors is more effective in the re-duction of acute coronary events and revascularizationthan each drug alone, supporting their complementarypleiotrophic effects [9]. Thus, if anything, the higher useof statins in PEACE should have increased the efficacyof Trandolapril.

Although similar in terms of baseline characteristics,the PEACE population had more frequently undergonerevascularization than those of HOPE and EUROPA.Nonetheless, in EUROPA, ACE inhibition reduced car-

Address for correspondence: Roberto Ferrari , MD, Chair ofCardiology, University of Ferrara, Corso Giovecca 203, 44100,Ferrara. Tel.: +39.0532.24.20.11; Fax: +39.0532.24.18.85; E-mail:fri@dns.unife.it

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diac outcomes to a similar degree in patients with andwithout revascularization. In patients with prior revas-cularization in EUROPA perindopril reduced the risk atcardiac events to similar extent as in the overall popula-tion (relative risk reduction—17.3%, p = 0.035). In ad-dition, prior revascularization does not guarantee lowerrisk cardiac outcome nor influence the underlying dis-ease.

One possible explanation of the discrepancies amongthe three studies may rely in dose regimes of the testeddrugs, and in differences in trial designs. In HOPEand EUROPA, patients were assigned to receive highdoses of Ramipril (10 mg) and Perindopril (8 mg). Thesedoses were achieved raqpidly and in a high proportionof patients. In PEACE, Trandolapril was delivered at4 mg, a dose that in the earlier TRACE study [10] wasassociated with a 22% reduction in all cause mortalitywith only a trend toward decreased incidence of MI dur-ing a 2 year follow up. The target dose was only reached6 months after randomisation and 57.8% of patientsassigned to Trandolapril received target dose at 3 years.Furthermore, the event rate was lower than predicted.As a result, revascularization, a relative soft end pointthat depends on practice styles and is an insensitiveto treatment, was added to the primary end point asthe trial progressed. The % of patients lost to follow upwas greater in PEACE than in EUROPA (1.6%, 0.02%respectively). Thus in PEACE, less than 60% of thepatients had received the target dose of Trandolapril,and the most frequent component of the new compositeend point could not be directly affected by the activedrug.

It follows that the PEACE results cannot be em-ployed to the effects of Ramipril or Perindopril in pa-tients in which they were tested in HOPE and in EU-ROPA, nor justify a generally reduction in the levelof evidence of the recommendation to the use of ACE-inhibitors in secondary prevention. This would be justi-fied only by results provided by the totality of the dataand not only by those of a single trial designed to ran-domize over 14000 patients but concluded with a muchsmaller sampler size with the incorporation of a less sen-sitive primary end point and in the presence of low com-pliance.

A careful review of the totality of data providedfrom these three large trials shows that ACE-inhibitortherapy does indeed reduce all cause death by about14% and major vascular events by about 19% in a widerange of patients with vascular disease and preserved

LV function, including those receiving other cardiac andcardiovascular protective therapies (statins, aspirin, ß-blockers), people of various ages, including the elderly,men and women and those with or without a historyof hypertension, diabetes and peripheral arterial dis-ease, independently from baseline characteristics. Forthis reason, the recommendation should remain Class1A, as originally suggested.

References

1. Voors AA, Van Velduisen DJ, Van Gilst WH. The current roleof ACE-inhibitors for secondary prevention; from pathogenesisto clinical practice CITATION this issue.

2. Braunwald E, Domanski MJ, Fowler SE, et al. PEACE trialinvestigators.angiotensin-converting-enzyme in stable coro-nary artery disease. N Engl J Med 2004;351:2058–2068.

3. Yusuf S, Hawken S, Ounpuu S. Effect of potentially mod-ifiable risk factors associated with myocardial infarction in52 countries (the INTERHEART Study): Case-control study.Lancet 2004;364:937–952.

4. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statinson low density lipoprotein cholesterol, ischemic heart dis-ease, and stroke: Systematic review and meta-annalysis. BMJ2003;326:1423.

5. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dosecombination treatment with blood pressure lowering drugs:Analysis of 354 randomised trials. BMJ 2003;28;326:1427.

6. Heart outcomes prevention evaluation investigators effects ofan angiotensin-converting-enzyme inhibitor, ramipril, on car-diovascular events in high-risk patients. The heart outcomeprevention evaluation study investigators. N Engl J Med2003;342:145–153.

7. EUROPA Investigatos Efficacy of perindopril in reduction ofcardiovascular events among patients with stable coronaryartery disease: Randomised, double-blind, placebo-controlled,multicentre trial (the EUROPA study). Lancet 2003;362:782–788.

8. Oubina MP, de las Heras N, Cediel E, et al. Synergistic ef-fect of angiotensin-converting enzyme (ACE) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibition on in-flammatory markers in atheroscleroticrabbits. ClinSci(Lond)2003;105:655–662.

9. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. Effectsof statins and ACE inhibitors alone and in combination on clin-ical outcome in patients with coronary heart disease. J HumHypertens 2004;18:781–788.

10. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trialof the angiotensin-converting-enzyme inhibitor trandolapril inpatients with left ventricular dysfunction after myocardial in-farction. Trandolapril Cardiac Evaluation (TRACE) StudyGroup. N Engl J Med 1995;333:1670–1676.