The EUROPA Trial: Design, Baseline Demography and Status of the Substudies
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Cardiovascular Drugs and Therapy 15 169–179 2001
C 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
Summary. Background: Angiotensin-converting enzyme 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
of cardiac events in patients with proven stable coronary lar disease who did not necessarily suffer from 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
includes five sub-studies. Each of these sub-studies inves- reported in 2002.
tigates the effects of perindopril on a different aspect of
coronary artery disease: endothelial dysfunction,
atherosclerosis progression or regression, diabetes Methodology
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
2002.
Czech Republic, Denmark, Estonia, Finland, France,
Germany, Greece, Hungary, Ireland, Italy, Latvia,
Key Words. coronary artery disease, diabetes, EUROPA, Lithuania, The Netherlands, Norway, Poland,
angiotensin-converting enzyme inhibitors, perindopril Portugal, Spain, Slovakia, Sweden, Switzerland,
Turkey and the United Kingdom; See Appendix).
The study population
Introduction The study recruited men and women aged ≥18 years
without 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 E-mail: d.curcher@rbh.nthames.nhs.uk
have been shown to be effective in reversing atheroscle-
rosis in animal models [1–3] and because in earlier heart
failure studies ACE inhibitors significantly lowered Revision submitted 20 April 2001; accepted 23 April 2001
169170 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 exercise
Women of child-bearing potential without contraception;
test or regional wall motion abnormalities during strees
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 inadequate;
imaging. Patients were not scheduled for coronary Patients who previously did not tolerate ACE inhibitors because
revascularisation procedures at the time of selection of side effects;
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 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- Hypertrophic cardiomyopathy;
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 selection visit;
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;
Serum potassium >5.0 mmol/ l;
8 mg/day the last 2 weeks of the run-in period, if well
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 of the study;
last patient included completes the 3-year follow-up
period.
Follow-up assessment 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 171
The study end-points Table 3. Concomitant medications of the randomised patients
The primary objective of EUROPA is to assess the
No drug treatment 0.3%
effect of perindopril on the combined end-point of
Platelets inhibitors 91.9%
total mortality, non-fatal acute myocardial infarction, Oral anticoagulants 4.5%
hospital admission for unstable angina pectoris and car- Nitrates 44.2%
diac arrest with successful resuscitation and alive after Beta blockers 62.6%
28 days thereafter. Calcium blockers 32.3%
The secondary objectives are to assess the effect of Digitalis 1.6%
perindopril in reducing the rate of the following events: ACE inhibitors 0.0%
total mortality, cardiac mortality, cardiac mortality and ATII blockers 0.0%
non fatal acute MI, cardiac mortality, non fatal MI and Other vasodilators 4.0%
unstable angina pectoris (UA), fatal and non fatal MI Potassium sparing diuretics 2.1%
Other diuretics 7.6%
and UA, non fatal MI, UA, cardiac arrest with success-
Anti-arrhythmics 2.3%
ful resuscitation and alive 28 days thereafter, revascu- Lipid lowering agents 55.8%
larisation (CABG or PTCA), heart failure and stroke. Statins 47.5%
Other drug treatment 32.2%
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) 2.4%
of 4% per year, in order to detect a relative reduction Hypotension 1.9%
of 16% with a power of greater than 90% and a two- Creatinine/potassium rise 0.9%
sided type I error rate of 0.05, 750 events are required Poor compliance 0.8%
in the control group. Assuming an average follow-up Study event (including angina 0.5%
of 3 years and 9 months, a total of 10500 patients are without hospitalisation)
required. ‘Other’ or ‘unknown’ 4.4%
Results Between screening and randomisation, 10.9% of pa-
Recruitment 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- EUROPA sub-studies
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
Table 3. in diabetes, this population has been specifically investi-
gated. Finally, the genetic characterisation of the study
population will be studied.
Table 2. EUROPA study baseline characteristics
PERTINENT [10] (PERindopril-Thrombosis, In-
Mean age (range) (years) 61 (24–90) flammatioN, Endothelial dysfunction and Neurohor-
Males (%) 83 monal activation Trial) evaluates the predictive value
Documented coronary artery disease: ≥70% 60 of several plasma and serum markers associated with
stenosis (%) atherosclerosis and the effects of perindopril on their
Previous myocardial infarction (%) 62 levels. These markers are fibrinogen as a marker for
Previous revascularisation (%) 54 coagulation, C-reactive protein (CRP) as a marker
Diabetes mellitus or impaired glucose tolerance (%) 15
for inflammation, D-dimer for thrombogenesis, von
Hypertension (%) 26
Hypercholesterolaemia (%) 63
Willebrand factor (vWf ) for endothelial activation/
coagulation, Cromogranin A (CgA) for neurohormonal172 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 population). 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 flow in the brachial artery will be measured using B-mode Discussion imaging with Duplex scanning with a 7–10 MHz linear array 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- study. 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. substudy. 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- IVUS. fect of the ACE inhibitor results in an improvement
The EUROPA Trial 173
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 recovers.
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 prostacyclin).
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
[28]. induce inhibition of angiotensin II production, anti-
adrenergic properties and bradykinin formation. As
a consequence, ACE inhibitors improve endothelial
Anti-thrombotic effects 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-proliferative174 Gomma and Fox
and anti-atherogenic properties. In addition, ACE in- Table 5. EUROPA v HOPE (Demography)
hibitors may have antiplatelet effects (bradykinin) and
EUROPA HOPE
improve the balance between plasminogen activator
inhibitor-1 and tissue type plasminogen activator. Total patients randomised 12236 9297
These properties could lead to plaque stabilisation and Mean age (range) 61 (24–90) 66 (>55)
prevent plaque rupture. Finally, ACE inhibitors mod- Females (%) 17 27
ulate ischaemia-induced neurohormonal activation, Evidence of coronary artery disease (%) 100 81
coronary and systemic vasoconstriction. As such Previous myocardial infarction (%) 62 53
they could override coronary vasoconstriction in the Previous revascularization (%) 54 44
lesion area, particularly in unstable angina. These Peripheral vascular disease 7 43
Stroke or transient ischemic attack 3 10.8
findings and observations gave a stimulus for large
Hypertension (%) 26 47
controlled trials which examine the long-term effects Peripheral vascular disease (%) 7 43
of ACE inhibitors in patients with stable coronary Stroke (%) 3 11
artery disease as studied in EUROPA or in patients Diabetes mellitus (%) 15 38
at high risk of cardiovascular events as studied in
HOPE.
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 HOPE.
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 of
the lesions but made them more stable and less likely
to rupture. Appendix
Therefore, we have an extensive body of evidence
from both animal and human research that support the
hypothesis 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- (France) (The Netherlands)
cussed above are verified in the different EUROPA Pr Ferrari R. Pr Simoons M.
substudies. (Italy) (The Netherlands)
In the HOPE trial, a total of 9297 high-risk pa- Dr Fox K.
tients who had evidence of vascular disease or diabetes (United Kingdom)The EUROPA Trial 175
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. France Dr Jansky P. Pr Semrad B.
Denmark Pr Eha J. Dr Jirmar R. Pr Sochor K.
Pr Cokkinos D., Estonia Dr Jokl I. Dr Spacek R.
Pr Toutouzas P. Dr Erikssen J. Dr Krejcova H. Dr Spinar J.
Greece Norway Dr Kvasnak M. Dr Stipal R.
Pr Erhardt L. Pr Kalnins U. Dr Maratka T. Dr Stuchlik K.
Sweden Latvia Dr Marcinek G. Dr Sulda M.
Pr Grybauskas P. Pr Keltai M. Dr Moravcova J. Dr Ulman J.
Lithuania Hungary Dr Nedbal P. Dr Vaclavicek A.
Pr Karsch K., Pr Lüscher T. Dr Peterka K. Dr Vojtisek P.
Pr Sechtem U. Switzerland Denmark
Germany Pr Nieminen M. Dr Bjerregard- Dr Markenvard J.
Pr Klein W. Finland Andersen H. Dr Meibom J.
Austria Pr Paulus W. Dr Dorff B. Dr Norgaard A.
Dr Mulcahy D. Belgium Dr Hildebrandt P. Dr Scheibel M.
Ireland Pr Riecansky I. Dr Kristensen K.
Pr Oto A., Slovakia Dr Madsen J.K.
Pr Ozsaruhan O. Pr Santini U.,
Turkey Pr Tavazzi L. Estonia
Pr Providencia L. Italy Dr Eha J. Pr Teesalu R.
Portugal Pr Widimsky P. Dr Leht A. Dr Vahulaa V.
Pr Ruzyllo W. Czech Republic
Poland Finland
Pr Soler-Soler J. Dr Itkonen A. Dr Melin J.
Spain Dr Juvonen J. Dr Nieminen M.S.
Dr Karmakoski J. Dr Savola R.
Dr Kilkki E. Dr Terho T.
Safety Committee
Dr Koskela E. Dr Voipio-Pulkki L.M.
Pr Julian D. Pr Dargie H.
Dr Kotila M.J.
United Kingdom United Kingdom
Pr Murray G. Pr Kübler W. France
United Kingdom Germany Dr Apffel F. Dr Guillot J.P.
Dr Attali P. Dr Hanania G.
End Point Validation Committee Dr Baron B. Dr Lelguen C.
Pr Duprez D. Pr Thygesen K. Pr Bassand J.P. Dr Leroy F.
Belgium Denmark Dr Berthier Y. Dr Mansourati J.
Pr Steg G. Dr Bertrand M. Dr Mery D.
France Dr Dambrine P. Dr Michel
Dr Danchin N. Pr Quiret J.C.
Dr Decoulx E. Pr Raynaud P.
Investigators
Dr Deshayes P. Dr Rondepierre D.
Austria Dr Fouche R. Dr Roynard J.L.
Pr Drexel H. Pr Klein W. Dr Genest M. Dr Van Belle E.
Dr Gombotz G. Dr Stoeckl G. Dr Godard S. Dr Veyrat A.
Germany
Belgium
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.
Dr Lauer B. Pr Simon R.
Pr Legrand V.
Pr Rettig-Stürmer G. Dr Stork S.
Pr Riessen R. Pr Von Schacky C.
Czech Republic Pr Rutsch W. Dr Winkelmann B.R.
Dr Bocek P. Dr Fabik L.
Dr Branny M. Dr Florian J. Greece
Dr Cech M. Dr Francek L. Dr Christakos S. Pr Geleris P.
Dr Charouzek J. Dr Groch L. Pr Cokkinos D. Dr Georgiadis S.
Dr Drazka J. Pr Havranek P. Dr Feggos S. Pr Gialafos J.176 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 Zogno M.
Dr Kardaras F. Pr Stamatelopoulos S.
Dr Karidis C. Dr Stambola S. Latvia
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. Lithuania
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.
Hungary Pr Kibarskis A.
Dr Berenyi I. Dr Polak G.
Dr Bocsa Z. Dr Reiber I. The Netherlands
Dr Csendes E. Dr Rusznak M. Dr Aalders J.C.A. Dr Slob F.D.
Dr Edes I. Dr Simon A. Dr Bruggeling W.A.J. Dr Smits W.C.G.
Dr Gelesz E. Dr Simon K. 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 Kalo E. Dr Tihanyi L. Dr De Leeuw M.J. Dr Tan T.B.
Dr Karpati P. Dr Timar S. Dr De Waard D.E.P. Dr Van Beek G.J.
Dr Pap I. Dr Toth K. 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.
Ireland 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 Crean P. Dr Mulcahy D. Dr Freericks M.P. Dr Van Langeveld R.A.M.
Dr Daly K. 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.
Italy Dr Kiemeney K. Dr Van Straalen M.J.
Dr Azzolini P. Dr Giannetto M. Dr Kuijer P.J.P. Dr Vos J.
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 Inama G.
Dr Brunelli C. Pr Ippoliti G. Norway
Dr Capponi E. Dr Leghissa R. Dr Erikssen J.
Dr Capucci A. Dr Lorusso R.
Dr Casaccia M. Pr Marzilli M. Poland
Pr Casali G. Dr Minutiello L. Dr Achremczyk P. Dr Jakubowska-
Dr Cecchetti E. Dr Moretti G. Dr Adamus J. Majnigier M.
Dr Ceci V. Dr Mosele G.M. Dr Baska J. Dr Janion M.
Dr Celegon L. Pr Pasotti C. Pr Bolinska- 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. Pr Proto C. Dr Dariusz D. Dr Krynicki R.
Dr De Luca I. Dr Riva S. 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 Kuch J.
Pr Di Donato M. Dr Severi S. Dr Dubiel J.S. Dr Kuzniar J.
Dr Di Giacomo U. Dr Sinagra G. Dr Dudek D. 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 Gaddi O. Dr Vajola S.F. Pr Halawa B. Pr Musial W.The EUROPA Trial 177
Pr Opolski G. Dr Targonski R. Turkey
Pr Pasyk S. Dr Templin W. Pr Acartürk E. Pr Ozturk M.
Pr Piwowarska W. Dr Tendera M. Dr Guzelsoy D. Pr Sansoy V.
Dr Pulkowski G. Dr Tracz W. Dr Oto A. Pr Turkoglu C.
Dr Radziszewski B. Dr Trusz-Gluza M. Pr Özsaruhan O. Pr yüksel H.
Pr Romanski B. Dr Turek P.
Pr Ruzyllo W. Dr Tyminska- United-Kingdom
Dr Rynkiewicz A. Sedek K. Pr Adgey A.A.J. Dr Jennings K.
Dr Skura M. Pr Wodniecki J. Dr Ahsan A. Dr Jones C.J.H.
Pr Slowinski S. Dr Zalewski M. Dr Al-Khafaji M. Pr Joy M.
Dr Smielak-Korombel W. Dr Zinka E. Pr Ball S.G. Dr Keeling P.
Dr Birkhead J. Dr Kooner J.
Portugal Dr Boon N. 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 Brack M. Dr Lip G.
Dr Ferreira R. C.M. Dr Bridges A. Pr Lorimer A.R.
Dr Seabra-Gomes R. Dr Buchalter M. Dr Marshall H.
Dr Buchalter B. Dr Mclachlan B.
Slovakia Dr Calder B. Dr Montgomery H.
Pr Bada V. Dr Palinsky M. Dr Cooke R.A. Dr Morley C.
Dr Belicova M. Dr Pella D. Dr Corr L. Dr Murdoch D.L.
Dr Buksarova E. Dr Renker B. Dr Cowell R. Dr Muthusamy R.
Dr Dukat A. Pr Riecansky I. Dr Curzen N.P. Dr Oakley G.D.
Dr Gonsorcik J. Dr Sefara P. Dr Davidson C. Dr Penny W.
Dr Jonas P. Dr Sojka G. Dr Davies E. Dr Pohl J.E.F.
Dr Kamensky G. Dr Sulej P. Dr Davies J. Dr Purvis J.
Dr Karvaj M. Dr Szakacs M. Dr De Belder M. Dr Pye M.
Dr Micko K. Dr Szentivanyi M. Dr Dhiya L. Dr Ramsdale D.
Pr Mikes Z. Dr Doig J.C. Dr Reid D.
Dr Findlay I.N. Dr Roberts D.H.
Spain Dr Fox K. Dr Rowlands D.
Dr Aguirre Dr Jodar Lorente L. Dr Francis C.M. Dr Rozkovec A.
Salcedo J.M. Dr Lopez Garcia- Dr Glancy J.M. Dr Saltissi S.
Dr Alonso Orcajo N. Aranda V. Dr Glen S. Dr Schofield P.M.
Dr Ancillo Garcia P. Dr Macaya De Miguel C. Dr Greenwood T.W. Dr Scott M.
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 Silke B.
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 Rodriguez Dr Ilsley C. Dr Watson R.D.S.
Dr Del Rio Ligorit A. Padial L. Dr Innes M. Dr Wilkinson P.
Dr Espinosa Caliani J.S. Dr Salvador Sanz A. Dr James M.
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.
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