Perindopril Substudy in Coronary Artery Disease and Diabetes: the Diabetic Substudy of EUROPA - PERSUADE

Description:

The goal of the study was to evaluate the effect of treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril compared with placebo on cardiovascular (CV) events in the diabetic and nondiabetic subgroups of patients with stable coronary artery disease (CAD) in the EUROPA trial.

Hypothesis:

In low-risk stable CAD patients with or without diabetes, treatment with the ACE inhibitor perindopril will be associated with reduced CV events.

Study Design

Patients Enrolled: 12,218
Mean Follow Up: Mean 4.2 years
Mean Patient Age: Mean age 62 years in the diabetic population
Female: 18

Patient Populations:

Age >18 years; documented CAD (prior MI >3 months, PCI/CABG >6 months, stenosis on angiography ≥70%, and males with chest pain and positive exercise treadmill test or stress test); no scheduled revascularization; and no clinical signs of HF

Primary Endpoints:

Composite of CV mortality, nonfatal MI, and cardiac arrest

Secondary Endpoints:

Composite of total death, nonfatal MI, and cardiac arrest; heart failure (HF); revascularization (percutaneous coronary intervention [PCI]/coronary artery bypass graft [CABG]); and stroke

Drug/Procedures Used:

Following a four-week, open-label run-in phase, patients were randomized to perindopril (8 mg/day, n=6,110) or placebo (n=6,108). Both insulin-dependent and noninsulin-dependent diabetics were included in the diabetic cohort (12% of the overall study population, n=1,502). The trial was conducted in 424 European countries.

Principal Findings:

Baseline characteristics were similar in the diabetic cohort compared with the overall study population, with the exception of a higher frequency of treated hypertension (27% in the entire overall population, 38% in the diabetic perindopril group, and 41% in the diabetic placebo group) and history of noncoronary vascular disease (7% in the entire overall population, 14% in the diabetic perindopril group, and 12% in the diabetic placebo group).

The primary composite endpoint of CV mortality, nonfatal myocardial infarction (MI), and cardiac arrest was higher in the diabetic cohort versus the nondiabetic cohort (14.1% vs. 8.2%), as was all-cause mortality (11.1% vs. 6.5%), CV death (7.1% vs. 3.8%), and MI (8.9% vs. 6.0%).

In the diabetic cohort of patients, the primary endpoint trended lower in the perindopril arm versus control (relative risk reduction [RRR] 19%, p=0.131). The secondary endpoint of fatal or nonfatal MI also trended lower in the perindopril arm versus control (RRR 23%, p=0.143), as did heart failure hospitalization (RRR 46%, p=0.06). The RRRs were similar in the diabetic subgroup and the overall population.

Unlike the overall study population, where the treatment effect on the primary outcome was evident between 1-2 years, the treatment effect in the diabetic subgroup was not evident until ~3 years. The number needed to treat to prevent one CV death over four years was 27 patients in the diabetic subgroup.

Interpretation:

Among diabetic patients with stable CAD, treatment with the ACE inhibitor perindopril was associated with a nonsignificant trend toward reduction in the primary endpoint of CV mortality, nonfatal MI, and cardiac arrest compared with placebo.

As would be expected, the event rates were higher in the diabetic subgroup. However, the high risk of events did not result in a higher risk reduction with perindopril in the diabetic patients, which had similar risk reductions as the overall study population. The presenter speculated that the longer delay in the treatment effect in the diabetic subgroup may reflect the diffuse vascular disease present in diabetes.

References:

Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML; EUROPA Investigators. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J. 2005 Jul;26(14):1369-78.

Presented by Dr. Kim M. Fox at the American College of Cardiology Annual Scientific Session, March 2004.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Statins, Acute Heart Failure, Hypertension

Keywords: Perindopril, Insulin, Myocardial Infarction, Coronary Artery Disease, Risk Reduction Behavior, Constriction, Pathologic, Heart Arrest, Chest Pain, Heart Failure, Hypertension, Diabetes Mellitus, Exercise Test


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