Perindopril, thrombosis, inflammation, endothelial dysfunction, and neurohormonal activation trial, a subanalysis of EUROPA - PERTINENT
The goal of the trial was to evaluate the effect of the ACE inhibitor perindopril compared with placebo on endothelial function in patients with stable coronary artery disease (CAD) enrolled in the EUROPA trial.
Treatment with perindopril would improve endothelial function compared with placebo in patients with stable CAD enrolled in the EUROPA trial.
Patients Enrolled: 87
Mean Follow Up: One year
Mean Patient Age: Mean age 60 years
Enrollment in the EUROPA trial
Main inclusion criteria were documented CAD (prior MI >3 months, percutaneous coronary intervention/coronary artery bypass graft >6 months, stenosis on angiography ≥70%, males with chest pain, and positive exercise treadmill test or stress test); no scheduled revascularization; and no clinical signs of heart failure
A subgroup of patients enrolled in the EUROPA trial were included in the present substudy. Briefly, the EUROPA trial randomized patients to either perindopril (8 mg per day) or placebo and showed a reduction in cardiovascular events in the perindopril arm. Patients in the substudy underwent blood draws at baseline and one year. Serum samples in 43 patients in the perindopril group and 44 patients in the placebo group were analyzed for apoptosis, endothelial nitric oxide synthase (ecNOS) activation and expression, angiotensin II, tumor necrosis factor alpha, and other markers of endothelial function. Serum samples from age-matched controls (n=45) without CAD were also analyzed for apoptosis. Von Willebrand factor (vWF) was measured in 1,157 patients.
ecNOS activity did not differ in the perindopril and placebo groups at baseline (2.4 vs. 2.5, respectively), but was higher in the perindopril group at one-year follow-up (3.3 vs. 2.9, p<0.05). There was no difference between treatment groups in ecNOS expression at baseline (7.1 vs. 7.4) or one year (8.7 vs. 7.6, p=NS). Apoptosis at baseline did not statistically differ in the perindopril and placebo groups (6.8% vs. 7.8%, respectively). At one-year follow-up, apoptosis was lower in the perindopril group compared with the placebo group (4.7% vs. 7.0%, p<0.05). Bax/Bc1-2 ratio, the pro- to anti-apoptosis ratio, also did not differ by treatment group at baseline (0.8 vs. 0.9), but was lower at one-year follow-up (0.4 vs. 0.7, p<0.01).
The healthy control group had higher levels of ecNOS activity (3.5) and ecNOS expression (3.9), and lower levels of apoptosis (1.3%) and Bax/Bc1-2 ratio (0.3) compared with the baseline levels in stable CAD trial patients (p<0.01 for each).
In the larger subset of patients with vWF data, there was no difference by treatment group in baseline vWF (142 for perindopril vs. 145 for placebo, p=NS). At one-year follow-up, vWF was lower in the perindopril group compared with placebo (128 vs. 135, p<0.05). When dichotomized by the median vWF (median=142), the rate of events was higher in patients with vWF above the median than below the median.
Among a subgroup of patients enrolled in the EUROPA trial with stable CAD, treatment with the ACE inhibitor perindopril was associated with improved endothelium function at one year, as assessed by lower apoptosis and vWF compared with placebo.
The EUROPA trial demonstrated a reduction in cardiovascular events in the perindopril arm that went beyond the expected effect from the reduction in blood pressure. The data from the present study provide a potential vascular or antiatherosclerotic mechanistic explanation for the excess benefit observed in the overall EUROPA trial. Higher rates of apoptosis are a marker of poorer endothelium function and may reflect the onset of atherosclerosis.
Other studies have shown an improvement in endothelial function with ACE inhibitors via an indirect measure, but the present study used the more direct measure of endothelium function of apoptosis. Additionally, the study showed that stable CAD was associated with a significantly higher rate of apoptosis than healthy control patients.
Scientific Committee of the PERTINENT Sub-Study, EUROPA-PERTINENT Investigators. PERTINENT--perindopril-thrombosis, inflammation, endothelial dysfunction and neurohormonal activation trial: a sub-study of the EUROPA study. Cardiovasc Drugs Ther. 2003 Jan;17(1):83-91.
Ferrari R. PERTINENT: Perindopril, thrombosis, inflammation, endothelial dysfunction, and neurohormonal activation trial, a subanalysis of EUROPA. Paper presented at the European Society of Cardiology Congress 2004, 29 August-1 September, Munich, Germany.
Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Heart Failure, Novel Agents, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease
Keywords: Perindopril, Coronary Artery Disease, Apoptosis, Follow-Up Studies, Atherosclerosis, Blood Pressure, Tumor Necrosis Factor-alpha, Constriction, Pathologic, Percutaneous Coronary Intervention, von Willebrand Factor, Nitric Oxide Synthase Type III, Chest Pain, Heart Failure, Coronary Artery Bypass, Exercise Test
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