OUP user menu

PERTINENT (a substudy of the EUROPA trial): a persistent legacy
EXPERTS' PERSPECTIVE

Juan Carlos Kaski, Luciano Consuegra-Sanchez
DOI: http://dx.doi.org/10.1093/cvr/cvs178 202-203 First published online: 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.35 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 angiotensin-converting 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= 6110), or matching placebo (n= 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= 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 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-α, and nitrite/nitrate were also measured. The occurrence of cardiovascular events correlated with von Willebrand factor concentrations at the baseline (P= 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-α 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 landmark 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.

Footnotes

  • The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.

References

View Abstract