To assess the long-term effects (four years) of ACE-inhibitor therapy
with perindopril on the reduction of cardiac events in patients with
proven stable coronary artery disease with/without signs of ischaemia, but
heart failure, irrespective of age, cardiovascular risk profile or
Study design and randomisation
This is a double-blind, randomised, placebo-controlled, multicentre trial. Patient
recruitment into the study began in October 1997 and the follow-up ended in April
2003. 12,218 patients were randomised.
The study comprised an initial run-in period of two weeks during which patients
received perindopril 4 mg once daily in addition to their existing medication(s).
This was followed by a second two-week period during which patients received
perindopril 8 mg once daily in addition to existing medication(s) on condition
that the previous 4 mg once daily dose of perindopril was well tolerated.
Patients aged 70 years or older started on a lower dose. They received perindopril
2 mg once daily in the first week, 4 mg once daily in the second
week and 8 mg once daily for the following two weeks, if the drug was well
The four-week run-in period was then followed by a double-blind treatment
period during which time patients received either perindopril 8 mg once daily
or placebo for at least four years.
Examinations - Follow up
Patients were seen at two and four weeks during the initial four-week run-in
period before being randomly assigned to one of the two treatment groups.
Following randomisation, patients were examined at three, six and 12 months
and thereafter at six-monthly intervals. Follow up ended in April 2003, at
which time the average duration of treatment was four years.
12,218 patients aged 26 to 89 years (mean age 60 years) without clinical evidence
of heart failure were recruited and randomised if they had documented coronary
artery disease, which was defined as either:
infarction (MI) at least three months prior to the
selection visit (65%)
Percutaneous or surgical
coronary revascularisation at least six months
before the selection visit (55%)
of at least 70% narrowing of at least one major coronary
Male patients (85% of the study population) with a history of chest pain (4%)
were also recruited if they had either:
Positive exercise test
Regional wall motion
abnormalities during stress echocardiography or nuclear
defects during nuclear imaging.
The analysis of the baseline characteristics of patients recruited into the study
85% were male
65% had suffered a previous MI
61% had coronary artery
stenosis (angiographic evidence of =70% narrowing
at least one major coronary artery) removed in media materials)
55% had undergone previous
12% had diabetes
27% had hypertension
63% had hypercholesterolaemia
or received treatment for hypercholesterolaemia.
Patients received either perindopril 8 mg/day or placebo in addition to their
existing medication(s). Existing medications included:
Platelet inhibitors (93% of the patient population)
Lipid-lowering agents (58%)
Cardiovascular death, MI and cardiac arrest with successful
MI (fatal and non-fatal)
Unstable angina pectoris
(PTCA or CABG)
Various sub-studies have been incorporated into the EUROPA trial to assess the
effects of perindopril in patients with diabetes, as well as to provide data
on the exact mechanism(s) by which this drug may reduce morbidity and mortality
in coronary artery disease:
PERSUADE (PERindopril SUbstudy in coronary Artery Disease
and diabEtes): this
sub-study is examining patients (almost 1500) taking part in
EUROPA who also have diabetes (12% of the study population). In addition
to the objectives of
the main EUROPA trial, this study will also detect the progression
of diabetic nephropathy in this patient population.
PERSPECTIVE (PERindopril’S Prospective Effect
on Coronary aTherosclerosis
by angiographical and IntraVascular ultrasound Evaluation):
this sub-study is investigating the effects of perindopril (almost 400 patients)
on the progression and regression of coronary
atherosclerosis using qualitative coronary angiography (QCA)
and intravascular ultrasound (IVUS).
PERFECT (PERindopril Function of the Endothelium
in Coronary artery disease
Trial): this sub-study is examining the effect of perindopril
(almost 300 patients) on endothelial function by measuring forearm
circulation and flow-mediated
vasodilatation of the brachial artery in response to perindopril
PERTINENT (PERindopril – Thrombosis, InflammatioN, Endothelial
dysfunction and Neurohormonal activation Trial): this sub-study
is designed to evaluate the predictive value of several plasma
and serum markers associated with
atherosclerosis and the effects of perindopril on their levels
(almost 1300 patients).
PERGENE (PERindopril and GENEtic characterisation of coronary artery disease
patients): this sub-study is looking at the genetic characterisation of all
patients in the EUROPA study population.
These sub-studies will provide valuable scientific knowledge on the origin
and development of coronary artery disease and, in particular, how perindopril
may exert its beneficial actions in patients with the disease.
The announcement of these sub-studies will follow in the future.
Study results (Click
The results of the EUROPA study were announced at the European
Society of Cardiology (ESC) meeting in Vienna, 31 August, 2003.