Abstract
Background: Angiotensin-converting enzyme inhibitors do reduce both mortality and morbidity in patients with left ventricular dysfunction, recent myocardial infarction and hypertension. However, the long-term effects in patients with coronary artery disease have not been established. The EUROPA study is designed to assess the long-term (3–4 years) effects of perindopril on the reduction of cardiac events in patients with proven stable coronary artery disease but with no evidence of heart failure.
Study Design and Methods: EUROPA is a 12236 patient, randomised, double-blind, placebo-controlled and multicentre trial. EUROPA had an initial run-in period of 4 weeks during which patients received 4 and then 8 mg of perindopril daily to assess tolerance to maximum dose. This was followed by a double-blind randomisation to either perindopril or placebo. Patients were followed-up at 3 and 6 months and then 6 monthly until the last patient included in the main study completes the 3-year follow-up. EUROPA includes five sub-studies. Each of these sub-studies investigates the effects of perindopril on a different aspect of coronary artery disease: endothelial dysfunction, atherosclerosis progression or regression, diabetes mellitus, inflammation, thrombosis, neurohormonal activation. Patients are characterised genetically to assess characteristics associated with improved or unfavourable outcome. The final results of EUROPA will be available in 2002.
Similar content being viewed by others
References
Fennessy PA, Campbell JH, Mendelsohn FAO, et al. Angiotensin-converting enzyme inhibitors and atherosclerosis: Relevance of animal models to human disease. Clin Exp Pharmacol Physiol 1996; 23(Suppl 1): 530-32.
Curzen NP, Fox KM. Do ACE inhibitors modulate atherosclerosis? Eur Heart J 1997; 18:15 30-35.
Aberg G, Ferrer P. Effects of captopril on atherosclerosis in cynomolgus monkeys. Cardiovasc Pharmacol 1990; 15(Suppl 5): 656-72.
Pfeffer MA, Braunwald E, Maye LA, et al. On behalf of the SAVE investigators: Effects of captopril on mortality and morbility in patients with left ventricular dysfunction. N. Engl J Med 1992; 327: 669-77.
The 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: 293-02.
The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N. Engl J Med 1987; 316: 1429-35.
The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-53.
Fox KM, Henderson JR, Bertrand ME, et al. The European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA). Eur Heart J 1998; 19(Suppl J): J52-55.
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: 25H-30H.
Simoons ML, Vos J, de Feyter PJ, et al. EUROPA substudies, confirmation of pathophysiological concepts. Eur Heart J 1998; 19(Suppl J): J56-60.
McMurray J. TheACEInhibitor/Myocardial InfarctionTrials. From Clinical Trials to Clinical Practice. Beckenham, Kent: Publishing Initiatives Books, 1995.
The SOLVD Investigators. Effects of enalapril on survival in patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327:6 85-91.
Pfeffer MA, Braunwald E, Moyes LA, et al. Effects of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992; 327:6 69-77.
Young JB. Reduction of ischemic events with angiotensin converting enzyme inhibitors: Lessons and controversy emerging from recent clinical trials. Cardiovasc Drugs Thera 1995; 9: 89-102.
Remme WJ, Bartels GL. Antiischemic effects of converting enzyme inhibitors: Underlying mechanisms and future prospects. Eur Heart J 1995; 16(Suppl I): 87-95.
Brilla CG, Weber KT. Reactive and reparative myocardial fibrosis in arterial hypertension in the rat. Cardiovasc Res 1992; 26:6 71-77.
Brilla CG, Janiki JS, Weber KT. Cardioreparative effects of lisinopril in rats with genetic hypertension and left ventricular hypertrophy. Circulation 1991; 5:17 71-79.
Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effects of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 319(2): 80-86.
Linz W, Scholkens BA, Ganten D. Converting enzyme inhibition specifically prevents the development and induces the regression of cardiac hypertrophy in rats. Clin and Exper Hyper 1989; A11(7): 1325-50.
Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation 1997; 95: 1115-18.
Mancini GBJ, Henry GC, Macaya C, et al. Angiotensinconverting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing Endothelial Dysfunction) study. Circulation 1996; 94: 258-65.
Chobanian AV, Haudenschild CC, Nickerson C, Drago R. Antiatherogenic effect of captopril in the Watanable heritable hyperlipidic rabbit. Hypertension 1990; 15: 327-31.
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: 22E-27E.
Rakugi H, Jacob HJ, Krieger JE, Ingelfinger JR, Pratt RE. Vascular injury induces angiotensinogen gene expression in the media and neointima. Circulation 1993; 87: 283-90.
Powell JS, Clozel JP, Muller RKM, et al. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989; 245: 186-88.
MERCATOR (The Multicenter European Research trial with Cilazapril after Angioplasty to prevent Transluminal coronary Obstruction and Restenosis) Study Group. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR randomized, double-blind placebo controlled trial. Circulation 1992; 86: 100-10.
Texter M, Lees RS, Pitt B, et al. The Quinapril Ischemic Events Trial (QUIET) design and methods: Evaluation of chronic ACE inhibitor therapy after coronary artery intervention. Cardiovasc Drugs Thera 1993; 7: 273-82.
Rakugi H, Wang DS, Dzau VJ. Potential importance of tissue angiotensin converting enzyme inhibition in preventing neointima formation. Circulation 1994; 90: 449-55.
Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaugham DE. Stimulation of Plasminogen activator inhibitor in vivoby infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin systems and fibrinolytic function. Circulation 1993; 87: 1969-73.
Remme WJ, De Leeuw PW, Bootsma M, Look MP, Kruijssen DACM. Systemic neurohumoral activation and vasoconstruction during pacing-induced acute myocardial ischemia in patients with stable angina pectoris. Am J Cardiol 1991; 68: 181-86.
Remme WJ, Kruijssen DACM, Look MP, Bootsma M, De Leeuw W. Systemic and cardiac neuroendocrine activation and severity of myocardial ischemia in humans. J Am Coll Cardiol 1994; 23: 82-91.
Bartels L, Remme WJ, van der ENT M, Kruijkssen D. ACE inhibitors reduce myocardial ischemia through modulation of ischemia-induced catecholamine activation. Experience with perindoprilat. J Am Coll Cardiol 1993; 21(2): 19A.
Vincent M, Redmond G, Portevin B. Stereoselective synthesis of a new perhydroindole derivative of chiral iminodiacid, a potent inhibitor of angiotensin converting enzyme. Tetrahedron Lett 1982; 23: 77.
Suraniti S, Berrut G, Marre M, Fressinaud PH. Antihypertensive efficacy and acceptability of perindopril in elderly hypertensive patients. Am J Cardiol 1993; 71: 28E-31E.
Dyker AG, Grosset DG, Lees KR. Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke. Stroke 1997; 28; 580-83.
MacFadyen RJ, Lees KR, Reid JL. Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: A placebo controlled study. Br Heart J 1991; 66: 206-11.
Squire IB, MacFadyen RJ, Reid JL, Devlin A, Lees KR. Differing early blood pressure and renin-angiotensin system responses to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure. J Cardiovasc Pharmacol 1996; 27: 657-66.
Asmar RG, Pannier B, Santoni JP, et al. Reversion of cardiac hypertrophy and reduced arterial compliance after converting enzyme inhibition in essential hypertension. Circulation 1988; 78: 941-50.
Antony I, Lerebours G, Nitenberg A. Angiotensinconverting enzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary arteries of hypertensive patients. Circulation 1996; 94: 3115-22.
Dexler H, Kurs S, Jeserich M, Munzel T, Hornig B. Effect of chronic angiotensin-converting enzyme inhibition on endothelial function in patients with chronic heart failure. Am J Cardiol 1995; 76: 13E-18E.
Nakashima M, Mombouli JV, Taylor AA, Vanhoutte PM. Endothelium-dependent hyperpolarization caused by bradykinin in human coronary arteries. J Clin Invest 1993; 92: 2867-71.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gomma, A.H., Fox, K.M. The EUROPA Trial: Design, Baseline Demography and Status of the Substudies. Cardiovasc Drugs Ther 15, 169–179 (2001). https://doi.org/10.1023/A:1011131130922
Issue Date:
DOI: https://doi.org/10.1023/A:1011131130922