Prevention of Events With Angiotensin-Converting Enzyme Inhibition Trial - PEACE

Description:

The goal of the trial was to evaluate the efficacy of the angiotensin-converting enzyme (ACE) inhibitor trandolapril compared with placebo for reduction in atherosclerotic complications among patients with stable coronary artery disease without heart failure.

Hypothesis:

Treatment with the ACE inhibitor trandolapril would reduce the rate of the composite endpoint of death from cardiovascular causes or nonfatal myocardial infarction (MI) among patients with stable coronary artery disease.

Study Design

Patients Enrolled: 8,290
Mean Follow Up: Median 4.8 years
Mean Patient Age: Mean age 64 years
Female: 18
Mean Ejection Fraction: Baseline ejection fraction 58%

Patient Populations:

Age ≥50 years; coronary artery disease documented by either MI at least three months prior to enrollment, CABG, or PCI at least three months prior to enrollment, or ≥50% native artery stenosis on coronary angiography; left ventricular ejection fraction >40%, normal left ventriculogram, or absence of left ventricular wall-motion abnormalities on echocardiography; and toleration of the medication and successful completion of the run-in phase

Exclusions:

Current use of or need for an ACE inhibitor, contraindication to ACE inhibitors, current use of an angiotensin II-receptor antagonist, hospitalization for unstable angina in prior two months, valvular heart disease requiring surgery, CABG or PCI within prior three months, planned elective revascularization, serum creatinine >2.0 mg/dl, serum potassium >5.5 mmol/l, or limited chance of five-year survival

Primary Endpoints:

Composite of death from cardiovascular causes, nonfatal MI, or coronary revascularization. The primary endpoint initially was death from cardiovascular causes or nonfatal MI, but the endpoint was expanded during the trial to also include coronary revascularization in order to reduce the sample size needed and keep the trial adequately powered.

Secondary Endpoints:

Composite of death from cardiovascular causes or nonfatal MI

Drug/Procedures Used:

Patients were randomized to the ACE inhibitor trandolapril (target dose of 4 mg/day) (n=4,158) or placebo (n=4,132). Patients were followed for four years.

Principal Findings:

Baseline characteristics were well matched between the treatment groups. Baseline ejection fraction was 58% in both groups, with only 15% of patients in each group having an ejection fraction of >40% to <50%. Lipid-lowering medications were used in 70% of patients, while aspirin was used in 90% and beta-blockers in 60%.

Among patients in the trandolapril group, either trandolapril or an open-label ACE inhibitor was taken in 81.9% of patients at one year and 74.5% at three years. In the placebo group, an ACE inhibitor was used in 1.5% of patients at one year and 8.3% at three years.

Blood pressure declined by 4.4/3.6 mm Hg in the trandolapril group and 1.4/2.4 mm Hg in the placebo group at three years (p<0.001 for treatment comparison). The primary endpoint of cardiovascular death, MI, or coronary revascularization was not significantly different between treatment arms (21.9% for trandolapril vs. 22.5% for placebo, hazard ratio [HR] 0.96, p=0.43). There was also no difference in any of the subgroups analyzed.

None of the individual components of the composite endpoint differed, including cardiovascular death (3.5% vs. 3.7%, p=0.67), nonfatal MI (5.3% each, p=1.0), coronary artery bypass graft (CABG) (6.5% vs. 7.1%, p=0.24), or percutaneous coronary intervention (PCI) (12.4% vs. 12.0%, p=0.65). All-cause mortality was reported in 7.2% of trandolapril patients and 8.1% of placebo patients (p=0.13). The post-hoc analysis of new onset diabetes was lower in the trandolapril arm (9.8% vs. 11.5%, HR 0.83, p=0.01), as was congestive heart failure as the primary cause of hospitalization or death (2.8% vs. 3.7%, HR 0.75, p=0.02).

Side effects leading to study drug discontinuation were higher in the trandolapril group (14.4% vs. 6.5%, p<0.001). Both cough (39.1% vs. 27.5%, p<0.01) and syncope (4.8% vs. 3.9%, p=0.04) were higher in the trandolapril group.

Interpretation:

Among patients with stable coronary artery disease and without heart failure, treatment with the ACE inhibitor trandolapril was not associated with a reduction in the primary endpoint of cardiovascular death, nonfatal MI, or coronary revascularization compared with placebo at a median follow-up of 4.8 years.

The SAVE and SOLVD studies demonstrated a benefit with an ACE inhibitor in patients with symptomatic and asymptomatic heart failure. Additionally, in the HOPE trial, use of the ACE inhibitor ramipril was associated with a reduction in death from cardiovascular causes, nonfatal MI, or stroke in high-risk patients with vascular disease or diabetes who did not have heart failure compared with placebo. Likewise, in the EUROPA trial of patients with stable coronary artery disease, treatment with the ACE inhibitor perindopril was associated with a reduction in death from cardiovascular causes, nonfatal MI, or cardiac arrest compared with placebo. Given the similar patient population to EUROPA, the authors hypothesized that a potential reason for the lack of benefit with an ACE inhibitor in the present trial may be due to more intensive management of baseline risk factors. A larger proportion of patients in the present study were treated with lipid-lowering medication at baseline, and a larger proportion underwent coronary revascularization prior to enrollment. Further supporting this hypothesis is the fact that the event rate in the PEACE trial was lower than EUROPA or HOPE.

References:

Braunwald E, Domanski MJ, Fowler SE, et al., on behalf of the PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-68.

Presented by Marc Pfeffer at the American Heart Association Scientific Sessions, November 2004, New Orleans, LA.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Lipid Metabolism, Statins, Acute Heart Failure, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Echocardiography/Ultrasound, Nuclear Imaging

Keywords: Perindopril, Coronary Artery Disease, Myocardial Infarction, Stroke, Follow-Up Studies, Lipids, Syncope, Risk Factors, Blood Pressure, Constriction, Pathologic, Heart Arrest, Ramipril, Percutaneous Coronary Intervention, Coronary Angiography, Indoles, Heart Failure, Stroke Volume, Coronary Artery Bypass, Cough, Diabetes Mellitus, Echocardiography


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