Reconsider the management of all coronary artery disease patients: Importance of the EUROPA trial
Sticares Cardiovascular Research Foundation, Rhoon, The Netherlands
1 W.J. Remme, MD PhD, Sticares Foundation, PO Box 882, 3160 AB Rhoon, The Netherlands.
Abstract
In patients at risk for cardiovascualr disease or with ischemic cardiomyopathy ACE inhibitors have been shown to reduce ischaemic events. Whether similar beneficial effects occur in the larger population of patients with coronary artery disease (CAD), but a low risk profile and without left ventricular dysfunction and/or heart failure, is unknown.
The anti-atherosclerotic effects of ACE inhibition are due to a dual mode of action, inhibition of angiotensin II production and enhancing bradykinin formation. As a result, ACE inhibitors reduce smooth muscle cell proliferation, improve vascular endothelial function, decrease palque rupture, enhance fibronlysis, modulate cytokine activation and lead to anti-inflammatory and anti-oxidative effects. ACE inhibitors are also anti-hypertensive agents that reduce left ventricular hypertrophy and myocardial oxygen demand. It is therefore to be expected that, together, these multiple effects may lead to marked secondary prevention in all patients with CAD, irrespective of cardiac function or further risk profile.
The EUROPA study aims at investigating this hypothesis. The primary objective of EUROPA is a reduction in cardiovascular death, non-fatal myocardial infarction and/or successful resuscitation during an approximate 4-year randomized, double-blind study in over 12000 patients, comparing the ACE inhibitor perindopril with placebo. It aims to prove that ACE inhibition with perindopril will lead to secondary prevention of cardiovascular events in all patients with CAD.
Key Words: Angiotensin-converting enzyme inhibition Angiotensin II Atherosclerosis Bradykinin Coronary artery disease EUROPA Myocardial ischemia Perindopril Secondary prevention
References
- The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiostensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145153
[Abstract/Free Full Text] - PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regime among 6,105 individuals with previous stroke or transient ischemic attack. Lancet. 2001;358:10331041[CrossRef][Web of Science][Medline]
- Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONCENSUS). N Engl J Med. 1987;316:14291435[Web of Science][Medline]
- SOLVD Investigators. Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293302[Abstract]
- Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303310[Abstract]
- SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685691[Abstract]
- Pfeffer MA, Braunwald E, Moyé LA, SAVE investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1992;327:669677[Abstract]
- Kober L, Torp-Pederson C, Carlsen JE, et alTRACE Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333:1671676
- Rutherford JD, Pfeffer MA, Moye LA, et al. Effects of captopril on ischemic events after myocardial infacrtion. Results of the Survival And Ventricular Enlargement trial. Circulation. 1994;90:17311738
[Abstract/Free Full Text] - Yusuf S, Pepine CJ, Garces C, et al. Effects of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992;340:11731178[CrossRef][Web of Science][Medline]
- Schieffer B, Schieffer E, Hilfiker-Kleiner D, et al. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques; potential, implication for inflammation and plaque instability. Circulation. 2000;101:13721378
[Abstract/Free Full Text] - Bachetti T. Is bradykinin important for the clinical out-come? Dialoques Cardiovasc Med. 2000;5:8792
- Mombouli JV, Illiano S, Nagao T, Scott-Burden T, Vanhoutte PM. Potentiation of endothelium-dependent relaxations to bradykinin by angiotensin I converting enzyme inhibitors in canine coronary arteries involves both endothelium-derived and hyperpolarizing factors. Circ Res. 1992;71:137144
[Abstract/Free Full Text] - Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin- converting enzyme inhibitors in human. Circulation. 1997;95:11151118
[Abstract/Free Full Text] - Fogari R, Mugellini A, Zoppi A, et al. Losartan and perindopril effects on plasma plasminogen activator inhibitor-1 and fibrinogen in hypertensive type 2 diabetic patients. Am J Hypertens. 2002;15:316320[CrossRef][Web of Science][Medline]
- Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA, HEART study investigators. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation. 1997;96:442447
[Abstract/Free Full Text] - Farhy RD, Carretero OA, Ho K-L, Scicli AG. Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res. 1993;72:12021210
[Abstract/Free Full Text] - Fennessy PA, Campbell JH, Mendelsohn FAO, Campbell GR. Angiotensin-covering enzyme inhibitors and atherosclerosis: relevance of animal models to human disease. Clin Exp Pharamacol Physiol. 1996;23(suppl 1):530532
- Morawietz H, Rueckschloss U, Niemann B, et al. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation. 1999;100:899902
[Abstract/Free Full Text] - Gomma AH, Fox KM, EUROPA investigators. The EUROPA trial: design, baseline demography and status of then substudies. Cardiovasc Drugs Ther. 2001;15:169179[CrossRef][Web of Science][Medline]
- Remme WJ. Effect of ACE inhibition on neurohormones. Eur Heart J. 1998;19(suppl J):J16J23
- Pfeffer MA, Domanski M, Rosenberg Y, et al. Prevention of events with angiotensin-converting enzyme inhibitors (the PEACE Study design). Am J Cardiol. 1998;82:25H30H[Web of Science][Medline]
- Asmar RG, Pannier B, Santoni JP, et al. Reversion of cardiac hypertrophy and reduced arterial compliance after converting enzyme in essential hypertension. Circulation. 1988;78:941950
[Abstract/Free Full Text] - Antoni I, Lerebours G, Nitenberg A. Angiotensin converting enzyme inhibition restores flow-dependent and cold-pressure test-induced dilations in coronary arteries of hypertensive patiets. Circulation. 1996;94:31153122
[Abstract/Free Full Text] - Thybo NK, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvaany MJ. Effect of antihypertensive treatment on small arteries of patients with previous untreated essential hypertension. Hypertension. 1995;25:471481
- Rolland PH, Charpiot P, Friggi A, et al. Effects of angiotensin-converting enzyme inhibition with perindopril on hemodynamics, arterial structure, and wall rheology in the hindquarters of atherosclerotic mini pigs. Am J Cardiol. 1993;71:22E27E[CrossRef][Medline]
- Remme WJ, Kruijssen HACM, Look MP, Bootsma M, De Leeuw PW. Systematic and cardiac neuroendocrine activation and severity of myocardial ischemia in humans. J Am Coll Cardiol. 1994;23:8291[Abstract]
- Bartels LG, van den Hevrel AdFM, van Veldhuisen DJ, van der Ent M, Remme WJ. Acute anti-ischemic effects of perindoprilat in men with coronary artery disease and their relation with Left ventricular function. Am J Cardiol. 1999;83:332336[CrossRef][Web of Science][Medline]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||