Download PERTINENT (a substudy of the EUROPA trial): a persistent legacy

EDITORIAL
Cardiovascular Research (2012) 96, 202–203
doi:10.1093/cvr/cvs178
PERTINENT (a substudy of the EUROPA trial):
a persistent legacy
EXPERTS’ PERSPECTIVE
Juan Carlos Kaski 1* and Luciano Consuegra-Sanchez 2
1
Cardiovascular Sciences Research Centre, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK; and 2Cardiology Department,
Hospital Universitario de Santa Lucia, Cartagena, Spain
Online publish-ahead-of-print 19 July 2012
This editorial refers to an article by C. Ceconi et al. 9 published in Cardiovascular Research in 2007. It is accompanied
by a retrospective editorial by two authors of that original
article, R. Ferrari and C. Ceconi, pp. 204 –207, this issue, as
part of this Spotlight on Landmark Papers in Cardiovascular
Research.
Endothelial activation and dysfunction—usually associated with traditional cardiovascular disease risk factors and increased oxidative
stress—initiate the atherosclerotic process. In patients with coronary
artery disease (CAD), endothelial dysfunction results in abnormal
coronary artery vasomotion, increased leucocyte adhesion to the vascular wall, platelet activation, and the release of pro-inflammatory
molecules, all of which contribute to both the atherogenic process
and atheromatous plaque growth. These events largely result from
reduced nitric oxide (NO) production and bioavailability as well as
the reduced expression and activity of endothelial nitric oxide synthase (eNOS), which can itself become a pro-atherogenic stimulus
promoting an increase in oxidative stress.1,2 Prior to the publication
of the EUROPA trial, several relatively small studies had suggested a
correlation between coronary endothelial dysfunction and the occurrence of adverse events in patients with CAD.3 – 5 The important goal
of improving endothelial dysfunction stimulated the development of
therapies aimed at reversing or slowing down the processes leading
to atherogenesis and vascular dysfunction. In this regard, the large
EUROPA trial6 made an important contribution to the field. The
study assessed whether the administration of the angiotensinconverting enzyme (ACE) inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and
no apparent heart failure. They recruited 13 655 patients (mean age
60 years; 85% male) with a history of a previous myocardial infarction
(64%), angiographic evidence of CAD (61%), coronary revascularization (55%), or a positive stress test only (5%). A total of 12 218
patients entered the study and were randomly assigned to perindopril
8 mg od (n ¼ 6110), or matching placebo (n ¼ 6108). The mean
follow-up was 4.2 years and the primary endpoint was cardiovascular
death, myocardial infarction, or cardiac arrest; 603 (10%) patients in
the placebo group and 488 (8%) in the perindopril group experienced
the primary endpoint, indicating a 20% relative risk reduction (95% CI:
9–29, P ¼ 0.0003) with the use of perindopril. These results strongly
suggested that ACE inhibitors—perindopril specifically—can improve
clinical outcome beyond the context of an acute myocardial infarction, as patients in the EUROPA trial were considered to be ‘stable’
and ‘low risk’.
Although the benefits of perindopril were apparently due to blood
pressure lowering, mechanisms other than blood pressure reduction
could have also played a role. Of interest, a post hoc analysis of the
EUROPA study showed that the greatest relative risk reduction of
the primary endpoint, i.e. 32%, was achieved in those patients with
the lowest blood pressure at baseline (,120 mmHg)7 in whom the
medication did not reduce the blood pressure further. Improvements
in ventricular remodelling could have been another plausible reason
for the improvement in the outcome, but the assessment of LV systolic function was not mandatory at study entry and it was assessed
in only 58% of the patients, thus representing a potential limitation
of the study. Another post hoc analysis8 just limited to patients with
a preserved ejection fraction showed that perindopril achieved a
slightly lower (16%) reduction in the primary endpoint compared
with that achieved in the whole EUROPA population.
The important implications of the EUROPA findings and uncertainty
as to the true mechanisms responsible for the remarkable beneficial
effects of perindopril in these patients represented the basis for
another landmark study, the PERindopril Thrombosis, InflammatioN,
Endothelial dysfunction, and Neurohormonal activation Trial (PERTINENT), whose results were published in Cardiovascular Research in 2007.9
PERTINENT was specifically designed to assess the effects of perindopril on endothelial function and to provide further explanations as to
the reason for the improved clinical outcome in the EUROPA trial.
In PERTINENT, blood from 1200 EUROPA patients was withdrawn
at baseline and after 1 year of treatment with either perindopril or
placebo to measure the von Willebrand factor and from 45 healthy
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
* Corresponding author. Tel: +44 2087255939; fax: +44 2087253328, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected].
203
Editorial
subjects and 87 EUROPA patients to study endothelial function at the
cellular level in painstaking in vitro experiments with human umbilical
vein endothelial cells. In this setting, the authors determined protein
expression/activity of eNOS and the rate of cell apoptosis. Plasma
levels of angiotensin II, bradykinin, tumour necrosis factor-a, and
nitrite/nitrate were also measured. The occurrence of cardiovascular
events correlated with von Willebrand factor concentrations at the
baseline (P ¼ 0.013) and significantly decreased after 1 year’s treatment (P , 0.001). Perindopril up-regulated protein expression and
activity of eNOS (19 and 27%, respectively; P , 0.05) and reduced
the rate of apoptosis by 31% (P , 0.05). There was also a significant
reduction in levels of angiotensin II, and tumour necrosis factor-a and
an increase in bradykinin and nitrite/nitrate concentrations. These
results indicated that abnormal endothelial function is present in
patients with stable CAD and this can be counteracted by ACE inhibition with perindopril. Taken together, findings in EUROPA and PERTINENT suggest a clear link between CAD and endothelial
dysfunction and a beneficial effect of perindopril in this setting.
However, other trials in a similar clinical setting, i.e. CAD without
heart failure, such as the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial,10 failed to show a significant
benefit with the use of the ACE inhibitor, trandolapril. Differences
regarding the pharmacological properties of the ACE inhibitors used,
tissue affinity and lipophilicity for example, might have at least partially
accounted for the different effects reported in the EUROPA vs. the
PEACE trials, but this remains controversial. Perhaps a more important
reason may be that the dose of perindopril (8 mg od) in the EUROPA
trial was achieved in 93% of patients, while in the PEACE study fewer
than 69% of the patients received the highest dose of trandolapril
(4 mg) at any time during the trial. It could therefore be speculated
that to achieve the beneficial effects seen in the EUROPA trial,
higher doses are more effective.
The results of the EUROPA trial—and the subsequent mechanistic basis for these findings provided by PERTINENT—certainly influenced clinical practice at the time, and some of its legacy has
extended further to current clinical practice. Indeed, ACE inhibitors
are currently recommended in European guidelines11,12 for the secondary prevention of ischaemic events in patients admitted with
non-ST and ST elevation acute coronary syndrome, and they are
also recommended for the long-term prevention of adverse cardiovascular events in patients undergoing myocardial revascularization
(class II A).13 Thus the EUROPA trial, documenting the beneficial
effects of ACE inhibition in stable CAD, and PERTINENT, providing
a rational explanation for these intriguing findings, represent land-
mark trials. These two complementary studies, addressing crucial
pharmacotherapy and mechanistic issues, have opened new
avenues for research into the prevention and treatment of ischaemic
heart disease and its complications, as well as shedding light onto
the pathogenesis of atherosclerosis and the reasons for the beneficial effects of ACE inhibition in this setting.
Conflict of interest: none declared.
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