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Cardiovascular Drugs and Therapy 15 169–179 2001
 Kluwer Academic Publishers. Printed in The Netherlands
The EUROPA Trial: Design, Baseline Demography
and Status of the Substudies
On behalf of the EUROPA Investigators
Abba H. Gomma and Kim M. Fox
Cardiology Department, Royal Brompton Hospital,
London
the incidence of myocardial infarction [4–6]. The cur- inhibitors do reduce both mortality and morbidity in pa-
rent generation of large ACE inhibitor/atherosclerosis tients with left ventricular dysfunction, recent myocardial
studies (HOPE [7], EUROPA [8] and PEACE [9]) infarction and hypertension. However, the long-term effects
include 4–5 years follow up. HOPE results have already in patients with coronary artery disease have not been es-
been published and showed a favourable effect of ACE tablished. The EUROPA study is designed to assess the long-
inhibition. This trial studied high-risk patients of vascu- term (3–4 years) effects of perindopril on the reduction
lar disease who did not necessarily suffer from coronary of cardiac events in patients with proven stable coronary
artery disease but with no evidence of heart failure.
artery disease. In contrast, EUROPA and PEACE will Study Design and Methods: EUROPA is a 12236 pa-
demonstrate the long-term effects of ACE inhibition in tient, randomised, double-blind, placebo-controlled and
patients with proven coronary artery disease, not par- multicentre trial. EUROPA had an initial run-in period of 4
ticularly at high-risk. This paper examines the prelim- weeks during which patients received 4 and then 8 mg of
inary baseline and demographic findings of EUROPA perindopril daily to assess tolerance to maximum dose. This
and also details on its sub-studies. Recruitment was was followed by a double-blind randomisation to either
completed in February 1999 and in June 1999 for the perindopril or placebo. Patients were followed-up at 3 and
patients entering the substudies. 12236 patients have 6 months and then 6 monthly until the last patient included
been randomised and the results are expected to be in the main study completes the 3-year follow-up. EUROPA
reported in 2002.
includes five sub-studies. Each of these sub-studies inves-
tigates the effects of perindopril on a different aspect of
coronary
mellitus, inflammation, thrombosis, neurohormonal acti-
The study organization
vation. Patients are characterised genetically to assess
EUROPA is a multicentre European trial, involving characteristics associated with improved or unfavourable
424 centres in 24 countries (Austria, Belgium, outcome. The final results of EUROPA will be available in
Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Key Words. coronary artery disease, diabetes, EUROPA,
angiotensin-converting enzyme inhibitors, perindopril
Portugal, Spain, Slovakia, Sweden, Switzerland,Turkey and the United Kingdom; See Appendix).
The study population
The study recruited men and women aged ≥18 yearswithout clinical evidence of heart failure and with Coronary artery disease is the most important cause evidence of coronary artery disease documented by of death in the western world. Although there has either previous MI for at least 3 months prior to been considerable success in relieving the symptoms the selection visit, percutaneous or surgical coronary of angina only statins and aspirin have been shown to revascularisation for at least 6 months before the selec- improve mortality.
tion visit or angiographic evidence of ≥70% narrowing Angiotensin-converting enzyme (ACE) inhibitors have well-established roles in the reduction of mor-tality and morbidity in patients with heart failure, re- Address for Correspondence: K.M. Fox, Cardiology Department, cent myocardial infarction (MI) and hypertension. In Royal Brompton Hospital, Sydney Street, London SW3 6NP, recent years, it has been suggested to extend these in- United Kingdom. Tel.: +44 20 7351 8645; Fax: +44 20 7351 8643.
dications to coronary artery disease, because the drugs have been shown to be effective in reversing atheroscle-rosis in animal models [1–3] and because in earlier heartfailure studies ACE inhibitors significantly lowered Revision submitted 20 April 2001; accepted 23 April 2001 Gomma and Fox of ≥1 major coronary artery. Men were also recruited Table 1. Exclusion criteria
if they had history of chest pain and a positive exercisetest or regional wall motion abnormalities during strees Women of child-bearing potential without contraception;Participation in a drug or device trial within the previous 30 days; echocardiography or nuclear scintigraphy or with tran- Compliance with the treatment or the visits likely to be sient perfusion defects during scintigraphy perfusion imaging. Patients were not scheduled for coronary Patients who previously did not tolerate ACE inhibitors because revascularisation procedures at the time of selection visit and informed consents were obtained from all pa- A history of alcohol or drug abuse; tients. Exclusion criteria are reported in Table 1.
Clinical signs of heart failure requiring treatment;Supine hypotension with a systolic blood pressure <110 mm Hg;Uncontrolled treated hypertension, as defined by a systolic The study design
blood pressure >180 mm Hg and/or a diastolic EUROPA is a large simple study (Fig. 1). The study blood pressure >100 mm Hg; comprises of a first run-in period of two weeks during Clinically significant obstructive valvular disease; which patients received perindopril 4 mg/day in addi- tion to their usual medication, a second run-in period of Use of ACE inhibitors within one month before the first two weeks during which patients received perindopril 8 mg/day in addition to their usual medication provided Use of angiotensin II receptor inhibitors within one month that the 4 mg/day of perindopril was well tolerated in prior to the first selection visit; the first run-in period. Patients 70 years or older started Renal failure with serum creatinine >150 mumol/ l; with 2 mg/day the first week, 4 mg/day the second, and Bilateral renal artery stenosis; 8 mg/day the last 2 weeks of the run-in period, if well Serum potassium >5.0 mmol/ l;Liver disease: ASAT or ALAT >3 times the upper normal values; tolerated. At the end of the run-in period, a double-blind A history of stroke or cerebral transient ischemic attacks within treatment period of at least 36 months started during the preceding 3 months; which patients receive either perindopril 8 mg/day or Any other serious disease likely to interfere with the conduct placebo. Patients will continue in the study until the last patient included completes the 3-year follow-upperiod.
3, 6 and 12 months and thereafter at 6 monthly interval.
Patients were seen at 2 and 4 weeks during the run-in Follow-up is scheduled to end in March 2002 at which period. Following randomisation patients are seen at time average duration of follow-up will be 3.5 years.
Fig. 1. EUROPA study Design.
The EUROPA Trial The study end-points
Table 3. Concomitant medications of the randomised patients
The primary objective of EUROPA is to assess theeffect of perindopril on the combined end-point of No drug treatment Platelets inhibitors total mortality, non-fatal acute myocardial infarction, Oral anticoagulants hospital admission for unstable angina pectoris and car- diac arrest with successful resuscitation and alive after 28 days thereafter.
The secondary objectives are to assess the effect of perindopril in reducing the rate of the following events: total mortality, cardiac mortality, cardiac mortality and non fatal acute MI, cardiac mortality, non fatal MI and Other vasodilators unstable angina pectoris (UA), fatal and non fatal MI Potassium sparing diuretics and UA, non fatal MI, UA, cardiac arrest with success- ful resuscitation and alive 28 days thereafter, revascu- Lipid lowering agents larisation (CABG or PTCA), heart failure and stroke.
Other drug treatment The study power and sample size
determination
In calculating the sample size for EUROPA, the follow-
Table 4. Reasons for drop-outs during the screening period
ing assumptions were made: with a primary event rate Intolerance (including cough) of 4% per year, in order to detect a relative reduction of 16% with a power of greater than 90% and a two- sided type I error rate of 0.05, 750 events are required in the control group. Assuming an average follow-up Study event (including angina of 3 years and 9 months, a total of 10500 patients are without hospitalisation) ‘Other' or ‘unknown' Between screening and randomisation, 10.9% of pa- tients were excluded from the trial. The reasons pro- At the end of the recruitment period, which was June vided for drop-outs are shown in Table 4.
1999, 12236 patients had been randomised. Their aver- The number of patients in whom the study drug has age age was 61 years (range 24–90); 83% were male.
been withdrawn after randomisation is low indicating Their histories showed that 62% had suffered a pre- good tolerance to perindopril. Mostly are for reaching vious myocardial infarction, 60% documented >70% a study end-point but a very small number (2.4%) are coronary stenosis, 54% previous revascularisation, 15% for intolerance including cough.
had a history of diabetes mellitus or impaired glu-cose tolerance, 26% hypertension and 63% hyper- cholesterolaemia as shown in Table 2.
A number of sub-studies have been undertaken. The The majority, 76%, had no evidence of angina and purpose of these sub-studies is to develop a better only 4.4% of the patients were enrolled with coronary understanding of the actions of perindopril in coro- artery disease documented solely by a history of chest nary artery disease. These sub-studies investigate pain or abnormal stress test. At entry, 91.9% of the the effects of the drug on neurohormonal activation, randomised patients were on platelet inhibitors, 62.6% thrombosis, endothelium, inflammation and coronary on beta blockers and 47.5% on statins as shown in anatomy. In view of the known effects of ACE inhibitors in diabetes, this population has been specifically investi-gated. Finally, the genetic characterisation of the studypopulation will be studied.
Table 2. EUROPA study baseline characteristics
PERTINENT [10] (PERindopril-Thrombosis, In- Mean age (range) (years) flammatioN, Endothelial dysfunction and Neurohor- monal activation Trial) evaluates the predictive value Documented coronary artery disease: ≥70% of several plasma and serum markers associated with atherosclerosis and the effects of perindopril on their Previous myocardial infarction (%) levels. These markers are fibrinogen as a marker for Previous revascularisation (%) coagulation, C-reactive protein (CRP) as a marker Diabetes mellitus or impaired glucose tolerance (%) for inflammation, D-dimer for thrombogenesis, von Willebrand factor (vWf ) for endothelial activation/ coagulation, Cromogranin A (CgA) for neurohormonal Gomma and Fox activation and Nitric Oxide synthase (ecNOS) for PERSUADE (PERindopril SUbstudy in Coronary endothelial function. In addition, angiotensin convering Artery Disease and diabEtes) [10] is a substudy that ex- enzyme activity is measured.
amines diabetic patients in EUROPA (15% of the study This substudy has two parts: Part A includes 345 patients and compares the effect of perindopril and The main efficacy variable in this substudy is to de- placebo on these plasma markers at baseline and after termine the effects of perindopril in diabetic popula- one year of treatment.
tion in terms of the primary and secondary end-points.
Part B which includes 1282 patients, evaluates The primary end-points are those of the EUROPA whether the effect of perindopril on CRP and vWf is study. We will also detect the progression of diabetic related to its effect on cardiovascular endpoints, both nephropathy as assessed by albumin:creatinine ratio.
primary and secondary.
PERGENE is a sub-study that will look at the ge- PERFECT (PERindopril Function of the Endothe- netic characterisation of all patients in the EUROPA lium in Coronary artery disease Trial) [10]: Forearm population. A sample of blood is taken from every circulation and flow-mediated vasodilatation of the EUROPA patient which is stored to the end of the brachial artery reflect endothelial functional changes study, when the most up-to-date gene polymorphism similar to those in the coronary arteries of patients with will be explored.
coronary artery disease. In this sub-study, blood flowin the brachial artery will be measured using B-mode imaging with Duplex scanning with a 7–10 MHz lineararray transducer. Scanning is performed at rest, during ACE inhibitors confer unequivocal beneficial effects and for 5 minutes after four minutes of ischaemia and in treating patients with all degrees of ischaemic during and for 10 minutes after cold pressure testing.
heart failure (as demonstrated in CONSENSUS-1, Consecutive studies are carried out during the run-in VHeFT-I, VHeFT-II and SOLVD), asymptomatic left period, at the time of randomisation and at 6, 12, 24, ventricular dysfunction (SOLVD) and after acute my- and 36 months thereafter. At baseline and at the end of ocardial infarction (ISIS-4, SAVE, GISSI-3, AIRE, the study nitroglycerin is administered sublingually to SMILE, TRACE) [11]. SOLVD [12] and SAVE [13] study non-endothelial dependent vasodilation. Plasma trials demonstrated that patients receiving ACE in- levels of von Willebrand factor are assessed during each hibitors have less myocardial ischaemic events on long- term therapy. This delay in the reduction of ischaemic The primary end-point is the percentage change in events suggests that ACE inhibitors may have struc- the flow-mediated vasodilation of the brachial artery tural effects, affecting the underlying pathophysiol- between baseline and 36 months and also the percent- ogy for coronary atherosclerosis, rather than the acute age change in neurohormonal-mediated vasoconstric- haemodynamic effects. The possible mechanisms for tion of the brachial artery.
this observed anti-ischaemic effects of ACE inhibition A total of 345 patients have been enrolled in this are discussed below.
PERSPECTIVE (PERindopril'S Prospective Ef- Structural cardiac and vascular effects
fect on Coronary aTherosclerosis by angiographical and ACE inhibitors may reduce myocardial ischaemia IntraVascular ultrasound Evaluation) [10] aims to in- through several different mechanisms [14,15]. Firstly, vestigate the effects of perindopril administration on ACE inhibitors induce cardioprotective effects, which the progression and regression of coronary atheroscle- are related to a reduction in inappropriate cardiac rosis using qualitative coronary angiography (QCA) hypertrophy and a decrease in cardiac enlargement.
and intravascular ultrasound (IVUS). QCA provides Under conditions of volume or pressure overload or fol- reproducible assessment of the coronary arterial di- lowing myocardial infarction, cardiac ACE expression mensions with main outcome parameters of mean lu- increases and enhances local tissue angiotensin II for- men diameter and minimal lumen diameter whereas mation. Angiotensin II has growth promoting effects IVUS main parameters are plaque volume, plaque and may stimulate cardiac fibrosis, either directly or area and lumen area. 319 patients have been recruited through activation of aldosterone [16]. Reduction of from those within the main study needing angiogra- cardiac tissue angiotensin II by ACE inhibition may phy. The primary objective of this sub-study is to com- counteract cardiac remodelling following long-term pare the effects of perindopril and placebo on the pro- overloading of the heart or following an infarct [17,18].
gression and regression of coronary atherosclerosis This effect is direct and does not result from blood pres- after 36 months of treatment as measured by QCA.
sure reduction or other indirect effects of the ACE The secondary objective is to compare the effects of inhibition [19]. In addition, ACE inhibition leads to perindopril and placebo on the progression and re- increased bradykinin production. Bradykinin induces gression of plaque and lumen changes following a 36- nitric oxide production and increases prostaglandin month treatment as measured by IVUS and the devel- formation which may be involved in bradykinin's anti- opment of new lesions as detected by using QCA and proliferative effects. Whereas the anti-remodelling ef- fect of the ACE inhibitor results in an improvement The EUROPA Trial of cardiac function and hemodynamics, the extra therefore may improve endogenous fibrinolytic func- spin off, in particular the volume effect, relates to tion in man, although this needs further confirmation.
a decrease in myocardial oxygen demand, less is-chaemia and an improvement of myocardial energetics.
Neurohormonal effects of ACE inhibition
Secondly, long-term administration of ACE inhibitors which may add to their anti-ischaemic profile
may result in vasculoprotective effects. Of these, an In addition to the structural effects on the vasculature improvement or even normalisation of endothelial described above, ACE inhibitors may exert functional dysfunction is probably the most important. In vitro effects which are more direct, but are likely to become studies indicate that ACE inhibition improves endothe- more prominent with time when endothelial function lial nitric oxide production, which appears related to its effect on bradykinin formation. In animal models, Episodes of stress-induced myocardial ischaemia re- in which endothelial dysfunction is induced, ACE in- sult in activation of the sympathetic system with an hibition improves endothelial function, an effect which increase in circulating levels of norepinephrine and is counteracted by bradykinin antagonists. In humans epinephrine, unrelated to the presence or absence of with hypertension or heart failure and endothelial dys- angina [30,31]. More severe ischaemia stimulates the function, the latter improves following ACE inhibitor circulating renin-angiotensin system [31]. The increase therapy [20]. In particular, the TREND [21] study indi- in these circulating vasoconstricting neurohormones cated that 6-month treatment with the ACE inhibitor, results in systemic vasoconstriction, particularly in the quinapril, significantly improved coronary endothelial absence of normal endothelium. Thus, a vicious circle function in normotensive patients with moderate coro- ensues whereby ischaemia-induced neurohormonal ac- nary artery disease and without heart failure. Besides tivation leads to systemic vasoconstriction, an increase their effect on endothelial function, ACE inhibitors in after-load and in myocardial oxygen demand, and have anti-proliferative and, possibly, anti-atherogenic to coronary vasoconstriction, at least in the coronary properties [22,23]. The expression of ACE and an- lesion area, further jeopardising coronary flow. ACE in- giotensinogen increases following angioplasty in small hibition limits this neurohormonal activation and vaso- animal models [24] and precedes neointima prolifera- constriction during ischaemia [15].
tion. ACE inhibition diminishes intimal hyperplasia in As angiotensin II is a potent direct systemic and these models, again linked to its effect on bradykinin coronary vasoconstrictor, we may expect a direct ef- degradation [25]. Yet, in human coronary angioplasty fect through a reduction in circulating angiotensin II trials, 6-month ACE inhibition failed to prevent subse- following ACE inhibition. Moreover, bradykinin has a quent restenosis [26], which may be related to timing of direct vasodilator effect and suppresses platelet adhe- onset of treatment or to the fact that the main mecha- sion and aggregation (via the release of nitric oxide and nism of restenosis after balloon angioplasty is vascular remodelling and the drug was mainly directed to pre- ACE inhibition with enalaprilat has been shown to vent neo-intimal hyperplasia or due to the fact that the ameliorate pacing-induced angina [15], while perindo- vascular lesion which results from balloon procedures prilat lessens angina and post-anginal left ventricu- is so significant that neither repair nor prevention of lar filling pressure. Perindoprilat also reverses the stenosis recurrence is to be expected from any pharma- increase in arterial norepinephrine levels during is- cological intervention. The latter may also be the reason chaemia and significantly diminishes net cardiac nore- for lack of clinical improvement observed in the QUIET pinephrine release, compared with placebo [32]. As a trial, in which patients were treated with quinapril result of this, systemic vasoconstriction is reduced and or placebo for a period of 3 years after coronary an- myocardial ischaemia diminishes. It is likely that this gioplasty [27]. Although there was a trend towards acute effect of the ACE inhibitor may become more reduction of events, the combined primary endpoint of pronounced and more efficient with ongoing treatment cardiovascular death, non-fatal MI, revascularisation when endothelial function improves. This may explain procedures and hospitalisation for unstable angina why the reduction in ischaemic events such as observed was not significantly reduced ( p = 0.6). Indeed, in large clinical trials takes a relatively long time to be- animal studies suggest that the ACE inhibitor come discernible.
dosage needed to produce anti-proliferative effect In summary, ACE inhibitors may reduce myocar- exceeds that causing changes in blood pressure dial ischaemia through various mechanisms which induce inhibition of angiotensin II production, anti-adrenergic properties and bradykinin formation. Asa consequence, ACE inhibitors improve endothelial function over time. In addition, ACE inhibitors avoid ACE inhibitors may induce antiplatelet effects through cardiac remodelling with a reduction in ventricu- bradykinin. Moreover, they may improve the bal- lar volume, mass and wall stress, together lead- ance between plasminogen activator inhibitor-1 (PAI- ing to a reduction in myocardial oxygen demand 1) and tissue type plasminogen activator (t-PA), also and, possibly, an improvement in subendocardial flow.
favouring anti-thrombotic effects [29]. ACE inhibitors Animal experiments clearly indicate anti-proliferative Gomma and Fox and anti-atherogenic properties. In addition, ACE in- Table 5. EUROPA v HOPE (Demography)
hibitors may have antiplatelet effects (bradykinin) andimprove the balance between plasminogen activator inhibitor-1 and tissue type plasminogen activator.
Total patients randomised These properties could lead to plaque stabilisation and prevent plaque rupture. Finally, ACE inhibitors mod- ulate ischaemia-induced neurohormonal activation, Evidence of coronary artery disease (%) coronary and systemic vasoconstriction. As such Previous myocardial infarction (%) they could override coronary vasoconstriction in the Previous revascularization (%) lesion area, particularly in unstable angina. These Peripheral vascular disease findings and observations gave a stimulus for large Stroke or transient ischemic attack controlled trials which examine the long-term effects Peripheral vascular disease (%) of ACE inhibitors in patients with stable coronary artery disease as studied in EUROPA or in patients Diabetes mellitus (%) at high risk of cardiovascular events as studied inHOPE.
In the EUROPA trial, perindopril has been used plus one other cardiovascular risk factor without evi- which is a long-acting ACE inhibitor first synthesised dence of heart failure were randomly assigned to re- [33] in the early 1980s and now registered in over ceive ramipril (10 mg once daily orally) or matching 100 countries worldwide with the hypertension and placebo. The trial was a two-by-two factorial study heart failure indications. It is well tolerated even in evaluating both ramipril and vitamin E. Ramipril at risk patients such as the elderly [34] or patients significantly reduces the rate of deaths, MI, and with recent ischaemic stroke, in whom it causes no stroke in a broad range of high-risk patients who are change in cerebral circulation [35]. Perindopril at the not known to have a low ejection fraction or heart initiating dose of 2 mg in heart failure has been demon- failure [7].
strated in several controlled studies to minimise the Comparison of the demographics of HOPE with risk of first dose hypotension [36,37]. The effects of those of EUROPA illustrates the rather different pa- perindopril on cardiovascular remodelling are well doc- tient populations of the two studies. HOPE patients umented: perindopril improves arterial compliance in were not required to have coronary artery disease; it large arteries and restores the structure of small was enough for them to have diabetes and one clinical resistance arteries [38]. In addition, perindopril re- risk factor (smoking, for example). Consequently, the stores flow-mediated coronary vasodilation in hyper- proportion of diabetic patients was strikingly higher tensive patients [39] and reverses the endothelial dys- than in EUROPA. Also, there were more patients with function observed in patients with heart failure [40].
hypertension, peripheral vascular disease and stroke in These effects are produced via potentiation of the bradykinin-mediated release, not only of nitric oxide In contrast, documentation of coronary artery dis- but also endothelium-derived hyperpolarisation factor ease is essential for EUROPA and the ratio of diabetic [41]. Perindopril has been shown to reduce myocar- patients in EUROPA represents the true incidence dial ischaemia relative to placebo treatment in pac- of diabetes in coronary artery disease population.
ing induced angina, furthermore the increase in ar- Table 5 shows the demography of the two studies. Two terial norepinephrine levels is reversed and the net of the important questions which were raised as a re- cardiac norepinephrine release is signficantly dimin- sult of the HOPE trial are: what will be the effect of ished [32]. In an experimental model of atherosclero- ACE inhibition in patients who are not at high risk? sis, perindopril significantly modified the atheroscle- and the second question is: can the beneficial effects of rotic process [23]: a reduction in the atherosclerotic ramipril shown in HOPE be reproduced by other ACE lesion size, a decrease in lipid-laden macrophages and inhibitors? These questions and many others will be less fragmentation of arterial elastic tissue were seen.
answered when EUROPA results are available.
Furthermore, perindopril not only reduced the size ofthe lesions but made them more stable and less likelyto rupture.
Therefore, we have an extensive body of evidence from both animal and human research that support thehypothesis for the EUROPA trial that perindopril Executive Committee will improve the clinical outcome in patients with Pr Bertrand M.
Pr Remme W. J.
stable coronary artery disease. The mechanisms dis- (The Netherlands) cussed above are verified in the different EUROPA Pr Ferrari R.
Pr Simoons M.
(The Netherlands) In the HOPE trial, a total of 9297 high-risk pa- tients who had evidence of vascular disease or diabetes The EUROPA Trial Steering Committee Dr Herman A.
Dr Povolny J.
Pr Aldershville J., Pr Bassand J.P.
Dr Hradec J.
Ass. Pr Rosolova H.
Dr Hildebrandt P.
Dr Jansky P.
Pr Semrad B.
Dr Jirmar R.
Pr Sochor K.
Dr Spacek R.
Pr Toutouzas P.
Dr Erikssen J.
Dr Krejcova H.
Dr Spinar J.
Dr Kvasnak M.
Dr Stipal R.
Pr Erhardt L.
Pr Kalnins U.
Dr Maratka T.
Dr Stuchlik K.
Dr Marcinek G.
Pr Grybauskas P.
Pr Keltai M.
Dr Moravcova J.
Dr Nedbal P.
Dr Vaclavicek A.
Pr L ¨uscher T.
Dr Peterka K.
Dr Vojtisek P.
Pr Sechtem U.
Pr Nieminen M.
Dr Markenvard J.
Dr Meibom J.
Pr Paulus W.
Dr Norgaard A.
Dr Mulcahy D.
Dr Hildebrandt P.
Dr Scheibel M.
Pr Riecansky I.
Dr Kristensen K.
Dr Madsen J.K.
Pr Ozsaruhan O.
Pr Tavazzi L.
Pr Providencia L.
Pr Teesalu R.
Pr Widimsky P.
Dr Vahulaa V.
Pr Ruzyllo W.
Pr Soler-Soler J.
Dr Itkonen A.
Dr Juvonen J.
Dr Nieminen M.S.
Dr Karmakoski J.
Dr Savola R.
Dr Kilkki E.
Dr Koskela E.
Dr Voipio-Pulkki L.M.
Pr Julian D.
Pr Dargie H.
Dr Kotila M.J.
Pr Murray G.
Pr K ¨ubler W.
Dr Apffel F.
Dr Guillot J.P.
Dr Attali P.
Dr Hanania G.
End Point Validation Committee Dr Lelguen C.
Pr Duprez D.
Pr Thygesen K.
Pr Bassand J.P.
Dr Berthier Y.
Dr Mansourati J.
Dr Bertrand M.
Dr Dambrine P.
Dr Danchin N.
Pr Quiret J.C.
Dr Decoulx E.
Pr Raynaud P.
Dr Deshayes P.
Dr Rondepierre D.
Dr Fouche R.
Dr Roynard J.L.
Pr Drexel H.
Dr Genest M.
Dr Van Belle E.
Dr Gombotz G.
Dr Stoeckl G.
Dr Godard S.
Dr Veyrat A.
Pr Gaudron P.
Pr Sechtem U.
Pr Duprez D.
Dr Materne P.
Pr Karsch K.R.
Pr Sigel H.A.
Pr Heyndrickx G.H.
Pr Van Mieghem W.
Pr Legrand V.
Pr Rettig-St ¨urmer G.
Pr Riessen R.
Pr Von Schacky C.
Pr Rutsch W.
Dr Winkelmann B.R.
Dr Branny M.
Dr Florian J.
Dr Francek L.
Dr Christakos S.
Pr Geleris P.
Dr Charouzek J.
Pr Cokkinos D.
Dr Georgiadis S.
Dr Drazka J.
Pr Havranek P.
Dr Feggos S.
Pr Gialafos J.
Gomma and Fox Pr Goudevenos I.
Pr Papazoglou N.
Pr Vincenzi M.
Dr Zavatteri G.
Dr Kardara D.
Dr Skoufas P.
Dr Volterrani M.
Dr Kardaras F.
Pr Stamatelopoulos S.
Dr Karidis C.
Dr Stambola S.
Dr Kelesides C.
Dr Stavridis A.
Dr Gailiss E.
Dr Ozolina M.A.
Dr Kyriakidis M.
Dr Syribeis S.
Dr Gersamija A.
Dr Skards J.
Dr Koliopoulos N.
Pr Vardas P.
Dr Kalnins U.
Pr Kremastinos D.
Dr Vassiliadis I.
Dr Liberi S.
Dr Voudris V.
Pr Manolis A.
Pr Zacharoulis A.
Pr Baubiniene A.
Pr Kirkutis A.
Dr N. Pyrgakis V.
Dr Zobolos S.
Pr Berukstis E.
Pr Marcinkus R.
Dr Papasteriadis E.
Dr Zouras C.
Dr Grigoniene L.
Dr Milvidaite I.
Pr Grybauskas P.
Dr Vasiliauskas D.
Pr Kibarskis A.
Dr Berenyi I.
Dr Reiber I.
Dr Csendes E.
Dr Rusznak M.
Dr Aalders J.C.A.
Dr Slob F.D.
Dr Bruggeling W.A.J.
Dr Smits W.C.G.
Dr Gelesz E.
Dr Bucx J.J.J.
Dr Spierenburg H.A.M.
Dr Janosi A.
Dr Tarjan J.
Dr De Feyter P.J.
Dr Suttorp M.J.
Dr Tihanyi L.
Dr De Leeuw M.J.
Dr Karpati P.
Dr De Waard D.E.P.
Dr Van Beek G.J.
Dr De Weerd G.J.
Dr Van Daele M.E.R.M.
Dr Pinter I.
Dr Veress G.
Dr De Zwaan C.
Dr Van Den Merkhof L.F.M.
Dr Dijkgraaf R.
Dr Van Den Toren E.W.
Dr Barton J.
Dr Meany T.B.
Dr Droste H.T.
Dr Van Hessen M.W.J.
Dr Mulcahy D.
Dr Freericks M.P.
Dr Van Langeveld R.A.M.
Dr Quigley P.
Dr Hagoort-Kok A.W.
Dr Van Loo L.W.H.
Dr Kearney P.
Dr Jap W.T.J.
Dr Van Nierop P.R.
Dr Jochemsen G.M.
Dr Van Rey F.J.W.
Dr Kiemeney K.
Dr Van Straalen M.J.
Dr Azzolini P.
Dr Giannetto M.
Dr Kuijer P.J.P.
Dr Barone G.
Dr Giannuzzi P.
Dr Mannaerts H.F.J.
Dr Werner H.A.
Pr Barsotti A.
Dr Giordano A.
Dr Piek J.J.
Dr Westendorp J.J.C.
Dr Bellone E.
Dr Giovannini E.
Dr Saelman J.P.M.
Dr Zwiers G.
Pr Borghetti A.
Pr Iacono A.
Pr Simoons M.L.
Pr Branzi A.
Dr Brunelli C.
Pr Ippoliti G.
Dr Capponi E.
Dr Leghissa R.
Dr Erikssen J.
Dr Capucci A.
Dr Lorusso R.
Dr Casaccia M.
Pr Marzilli M.
Pr Casali G.
Dr Minutiello L.
Dr Achremczyk P.
Dr Cecchetti E.
Dr Moretti G.
Dr Adamus J.
Majnigier M.
Dr Mosele G.M.
Dr Janion M.
Dr Celegon L.
Pr Pasotti C.
Dr Jaworska K.
Dr Chimini C.
Dr Pettinati G.
Soltysiak H.
Dr Kaszewska I.
Dr Colombo A.
Pr Pezzano A.
Dr Bubinski R.
Dr Kleinrok A.
Dr Corsini G.
Dr Polimeni M.R.
Pr Ceremuzynski L.
Dr Kornacewicz Jach Z.
Pr Cucchini F.
Pr Portaluppi F.
Pr Cieslinski A.
Dr Krawczyk W.
Pr Dalla Volta S.
Dr Dariusz D.
Dr Krynicki R.
Dr De Luca I.
Dr Deptulski T.
Dr Krzciuk M.
Pr De Servi S.
Dr Sanguinetti M.
Dr Drewla P.
Dr Krzeminska-Pakula M.
Dr Delise P.
Dr Santini M.
Dr Drozdowski P.
Pr Di Donato M.
Dr Severi S.
Dr Dubiel J.S.
Dr Kuzniar J.
Dr Di Giacomo U.
Dr Sinagra G.
Dr Legutko J.
Dr Di Pasquale G.
Dr Tantalo L.
Dr Galewicz M.
Pr Liszewska-Pfejfer D.
Pr Fiorentini C.
Pr Tavazzi L.
Dr Ghlebus K.
Pr Loboz-Grudzien K.
Dr Vajola S.F.
Pr Halawa B.
Pr Musial W.
The EUROPA Trial Pr Opolski G.
Dr Targonski R.
Dr Templin W.
Pr Acart ¨urk E.
Pr Ozturk M.
Pr Piwowarska W.
Dr Tendera M.
Dr Guzelsoy D.
Pr Sansoy V.
Dr Pulkowski G.
Pr Turkoglu C.
Dr Radziszewski B.
Dr Trusz-Gluza M.
Ozsaruhan O.
Pr y ¨uksel H.
Pr Romanski B.
Pr Ruzyllo W.
Dr Rynkiewicz A.
Pr Adgey A.A.J.
Dr Jennings K.
Pr Wodniecki J.
Dr Jones C.J.H.
Pr Slowinski S.
Dr Zalewski M.
Dr Al-Khafaji M.
Dr Smielak-Korombel W.
Pr Ball S.G.
Dr Keeling P.
Dr Birkhead J.
Dr Kooner J.
Dr Lawson C.
Pr Carrageta M.
Dr Leitao Marques A.
Dr Bowker T.
Dr Levy R.D.
Dr Coelho Gil J.
Dr Santos Andrade Dr Ferreira R.
Dr Bridges A.
Pr Lorimer A.R.
Dr Seabra-Gomes R.
Dr Buchalter M.
Dr Marshall H.
Dr Buchalter B.
Dr Mclachlan B.
Dr Calder B.
Dr Montgomery H.
Dr Palinsky M.
Dr Cooke R.A.
Dr Morley C.
Dr Belicova M.
Dr Murdoch D.L.
Dr Buksarova E.
Dr Renker B.
Dr Cowell R.
Dr Muthusamy R.
Pr Riecansky I.
Dr Curzen N.P.
Dr Oakley G.D.
Dr Gonsorcik J.
Dr Sefara P.
Dr Davidson C.
Dr Davies E.
Dr Pohl J.E.F.
Dr Kamensky G.
Dr Davies J.
Dr Purvis J.
Dr Karvaj M.
Dr Szakacs M.
Dr De Belder M.
Dr Szentivanyi M.
Dr Ramsdale D.
Dr Doig J.C.
Dr Findlay I.N.
Dr Roberts D.H.
Dr Rowlands D.
Dr Jodar Lorente L.
Dr Francis C.M.
Dr Rozkovec A.
Salcedo J.M.
Dr Glancy J.M.
Dr Saltissi S.
Dr Alonso Orcajo N.
Dr Schofield P.M.
Dr Ancillo Garcia P.
Dr Macaya De Miguel C.
Dr Greenwood T.W.
Dr Auge Sanpera J.M.
Dr Maroto Montero J.
Dr Groves P.
Dr Shapiro L.M.
Dr Ayuela Azcarate J.
Dr Martinez Romero P.
Dr Hall A.S.
Dr Bardaji Mayor J.L.
Dr Navarro Lopez F.
Dr Hamilton G.
Dr Stephens J.
Dr Bertomeu Martinez V.
Dr Noriega Peiro F.
Dr Hillman R.
Dr Sutherland S.
Dr Blanco Coronado J.L.
Dr Olague De Ros J.
Dr Holdright D.
Dr Swan J.W.
Dr Bros Caimari R.
Dr Orellana Mas J.
Dr Hubbard W.
Dr Shakespeare C.
Dr Bruguera Cortada J.
Dr Paz Bermejo M.A.
Dr Travill C.
Dr Tildesley G.
Dr Caparros Valderrama J.
Dr Placer Peralta L.J.
Dr Hutton I.
Dr Travill C.
Dr De Armas Trujillo D.
Dr Ilsley C.
Dr Watson R.D.S.
Dr Del Rio Ligorit A.
Dr Wilkinson P.
Dr Espinosa Caliani J.S.
Dr Salvador Sanz A.
Dr Fernandez Aviles F.
Dr Segui Bonnin J.
Dr Garcia Guerrero J.J.
Dr Simarro Martin E.
Dr Garcia Lopez D.
Dr Sobrino Daza J.
Dr Gonzalez Cocina E.
Dr Valles Belsue F.
Dr Guallar Urena C.
1. Fennessy PA, Campbell JH, Mendelsohn FAO, et al. Angio- tensin-converting enzyme inhibitors and atherosclerosis: Relevance of animal models to human disease. Clin Exp Dr Ekdahl S.
Pharmacol Physiol 1996;23(Suppl 1):530–32.
Dr Erhardt L.
Dr Persson S.
2. Curzen NP, Fox KM. Do ACE inhibitors modulate athero- Dr Forslund L.
sclerosis? Eur Heart J 1997;18:1530–35.
3. Aberg G, Ferrer P. Effects of captopril on atherosclerosis in cynomolgus monkeys. Cardiovasc Pharmacol 1990;15 Dr Pieper M.
Pr Moccetti T.
(Suppl 5):656–72.
Gomma and Fox 4. Pfeffer MA, Braunwald E, Maye LA, et al. On behalf of the 22. Chobanian AV, Haudenschild CC, Nickerson C, Drago R. An- SAVE investigators: Effects of captopril on mortality and tiatherogenic effect of captopril in the Watanable heritable morbility in patients with left ventricular dysfunction. N.
hyperlipidic rabbit. Hypertension 1990;15:327–31.
Engl J Med 1992;327:669–77.
23. Rolland PH, Charpiot P, Friggi A, et al. Effects of 5. The SOLVD Investigators. Effects of enalapril on survival angiotensin-converting enzyme inhibition with perindopril in patients with reduced left ventricular ejection fractions on hemodynamics, arterial structure, and wall rheology in and congestive heart failure. N Engl J Med 1991;325:293– the hindquarters of atherosclerotic mini pigs. Am J Cardiol 6. The CONSENSUS Trial Study Group. Effects of enalapril 24. Rakugi H, Jacob HJ, Krieger JE, Ingelfinger JR, Pratt on mortality in severe congestive heart failure. N. Engl J RE. Vascular injury induces angiotensinogen gene expres- sion in the media and neointima. Circulation 1993;87:283– 7. The Heart Outcomes Prevention Evaluation Study Inves- tigators. Effects of an angiotensin-converting enzyme in- 25. Powell JS, Clozel JP, Muller RKM, et al. Inhibitors of angio- hibitor, ramipril, on cardiovascular events in high-risk pa- tensin-converting enzyme prevent myointimal proliferation tients. N Engl J Med 2000;342:145–53.
after vascular injury. Science 1989;245:186–88.
8. Fox KM, Henderson JR, Bertrand ME, et al. The European 26. MERCATOR (The Multicenter European Research trial trial on reduction of cardiac events with perindopril in with Cilazapril after Angioplasty to prevent Transluminal stable coronary artery disease (EUROPA). Eur Heart J coronary Obstruction and Restenosis) Study Group. Does the new angiotensin converting enzyme inhibitor cilaza- 9. Pfeffer MA, Domanski M, Rosenberg Y, et al. Prevention of pril prevent restenosis after percutaneous transluminal events with angiotensin-converting enzyme inhibitors (the coronary angioplasty? Results of the MERCATOR ran- PEACE Study design). Am J Cardiol 1998;82:25H–30H.
domized, double-blind placebo controlled trial. Circulation 10. Simoons ML, Vos J, de Feyter PJ, et al. EUROPA substud- ies, confirmation of pathophysiological concepts. Eur Heart 27. Texter M, Lees RS, Pitt B, et al. The Quinapril Ischemic J 1998;19(Suppl J):J56–60.
Events Trial (QUIET) design and methods: Evaluation of 11. McMurray J. The ACE Inhibitor/Myocardial Infarction Tri- chronic ACE inhibitor therapy after coronary artery inter- als. From Clinical Trials to Clinical Practice. Beckenham, vention. Cardiovasc Drugs Thera 1993;7:273–82.
Kent: Publishing Initiatives Books, 1995. 28. Rakugi H, Wang DS, Dzau VJ. Potential importance of tis- 12. The SOLVD Investigators. Effects of enalapril on survival sue angiotensin converting enzyme inhibition in preventing in patients with reduced left ventricular ejection fractions.
neointima formation. Circulation 1994;90:449–55.
N Engl J Med 1992;327:685–91.
29. Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams 13. Pfeffer MA, Braunwald E, Moyes LA, et al. Effects of capto- GH, Vaugham DE. Stimulation of Plasminogen activator pril on mortality and morbidity in patients with left ventric- inhibitor in vivo by infusion of angiotensin II. Evidence ular dysfunction after myocardial infarction. N Engl J Med of a potential interaction between the renin-angiotensin systems and fibrinolytic function. Circulation 1993;87:1969– 14. Young JB. Reduction of ischemic events with angiotensin converting enzyme inhibitors: Lessons and controversy 30. Remme WJ, De Leeuw PW, Bootsma M, Look MP, Kruijssen emerging from recent clinical trials. Cardiovasc Drugs Thera DACM. Systemic neurohumoral activation and vasocon- struction during pacing-induced acute myocardial ischemia 15. Remme WJ, Bartels GL. Antiischemic effects of convert- in patients with stable angina pectoris. Am J Cardiol ing enzyme inhibitors: Underlying mechanisms and future prospects. Eur Heart J 1995;16(Suppl I): 87–95.
31. Remme WJ, Kruijssen DACM, Look MP, Bootsma M, 16. Brilla CG, Weber KT. Reactive and reparative myocardial De Leeuw W. Systemic and cardiac neuroendocrine activa- fibrosis in arterial hypertension in the rat. Cardiovasc Res tion and severity of myocardial ischemia in humans. J Am Coll Cardiol 1994;23:82–91.
17. Brilla CG, Janiki JS, Weber KT. Cardioreparative effects of 32. Bartels L, Remme WJ, van der ENT M, Kruijkssen D.
lisinopril in rats with genetic hypertension and left ventric- ACE inhibitors reduce myocardial ischemia through mod- ular hypertrophy. Circulation 1991;5:1771–79.
ulation of ischemia-induced catecholamine activation. Ex- 18. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald perience with perindoprilat. J Am Coll Cardiol 1993;21(2): E. Effects of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 33. Vincent M, Redmond G, Portevin B. Stereoselective synthe- sis of a new perhydroindole derivative of chiral iminodiacid, 19. Linz W, Scholkens BA, Ganten D. Converting enzyme inhibi- a potent inhibitor of angiotensin converting enzyme. Tetra- tion specifically prevents the development and induces the hedron Lett 1982;23:77.
regression of cardiac hypertrophy in rats. Clin and Exper 34. Suraniti S, Berrut G, Marre M, Fressinaud PH. Antihyper- tensive efficacy and acceptability of perindopril in elderly 20. Hornig B, Kohler C, Drexler H. Role of bradykinin in me- hypertensive patients. Am J Cardiol 1993;71:28E–31E.
diating vascular effects of angiotensin-converting enzyme 35. Dyker AG, Grosset DG, Lees KR. Perindopril reduces blood inhibitors in humans. Circulation 1997;95:1115–18.
pressure but not cerebral blood flow in patients with recent 21. Mancini GBJ, Henry GC, Macaya C, et al. Angiotensin- cerebral ischemic stroke. Stroke 1997;28;580–83.
converting enzyme inhibition with quinapril improves en- 36. MacFadyen RJ, Lees KR, Reid JL. Differences in first dose dothelial vasomotor dysfunction in patients with coronary response to angiotensin converting enzyme inhibition in artery disease. The TREND (Trial on Reversing Endothe- congestive heart failure: A placebo controlled study. Br lial Dysfunction) study. Circulation 1996;94:258–65.
Heart J 1991;66:206–11.
The EUROPA Trial 37. Squire IB, MacFadyen RJ, Reid JL, Devlin A, Lees and cold pressor test-induced dilations in coronary KR. Differing early blood pressure and renin-angiotensin arteries of hypertensive patients. Circulation 1996;94:3115– system responses to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure. J Cardiovasc 40. Dexler H, Kurs S, Jeserich M, Munzel T, Hornig B. Effect of chronic angiotensin-converting enzyme inhibition on en- 38. Asmar RG, Pannier B, Santoni JP, et al. Reversion of cardiac dothelial function in patients with chronic heart failure. Am hypertrophy and reduced arterial compliance after convert- J Cardiol 1995;76:13E–18E.
ing enzyme inhibition in essential hypertension. Circulation 41. Nakashima M, Mombouli JV, Taylor AA, Vanhoutte PM.
39. Antony I, Lerebours G, Nitenberg A. Angiotensin- bradykinin in human coronary arteries. J Clin Invest converting enzyme inhibition restores flow-dependent

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