PEACE

Clinical Question

In patients with CAD and LVEF >=40%, does ACE inhibition reduce a composite outcome of cardiovascular death, nonfatal MI, and need for revascularization?

Bottom Line

CAD patients with prior MI/CABG/PCI or angiography >50% stenosis do not have overall mortality benefits from trandolapril. New diabetes was significantly less likely in trandolapril group (9.8% vs 11.5%)

Guidelines

In SAVE and SOLVD trials, ACE inhibitors were shown to decrease the incidence of death and MI in patients with decreased LVEF. TRACE study demonstrated 22% reduction in all-cause mortality at 2 years with use of trandolapril 4 mg/day vs placebo among post-MI patients with LVEF of 35%.

Design

• Randomized, double-blind, placebo-controlled, multicenter trial
• N= 8290 number of patients randomized
  • Trandalopril N=4158
  • Placebo N=4132
• Setting: 187 sites in US, Canada, Italy
• Enrollment: 11/1996- 6/2000
• Mean follow-up: 4.8 years
• Analysis: intention to treat; run-in period allowed exclusion of noncompliant patients
• Power: 90% power to detect 18% relative reduction in primary end point at 0.05 level of significance
• Primary outcome: Originally decreased death from cardiovascular cause or nonfatal MI; switched in 1997 to include coronary revascularization due to inability to recruit 14,100 patients

Population

Inclusion Criteria

• 50+ yo
• CAD documented by prior MI, CABG or angioplasty (>3 mo before enrollment) or >50% obstruction on angiography
• LVEF >40%
• >= 80% of treatment compliance in run-in phase

Exclusion Criteria

• Current use of ACE or ARB
• Hospitalization for unstable angina in prior 2 mo
• Valvular heart disease requiring surgery
• CABG or angioplasty within 3 mo
• Serum Cr >2.0 mg/dL, K > 5.5 mmol/L
• limited chance of 5 yr survival
• Female of childbearing age not using contraception

Baseline Characteristics

• Age 64 yr (Trandolapril), 64 (placebo)
• Female 19%, 17%
• US and Puerto Rico 58%, 58%
• Diabetes 18%, 16%
• Blood pressure 134/78, 133/78
• EF 58%, 58%
• Serum creatinine 1.0
• Serum cholesterol 192
• EF 58%, 58%
• Medications: CCB 36%, 35%

Beta-blocker 60%, 60% Aspirin or antiplatelet 90%, 91% Lipid lowering drug 70%, 70% Diuretic 13%, 13% Digitalis 4%, 4% Antiarrhythmic 2%, 2% Anticoagulant 5%, 5% Insulin 4%, 4%

Interventions

Placebo vs trandolapril 2 mg qd, increased to 4 mg at 6 month visit.

Outcomes

Primary Outcomes

Death from CV causes, nonfatal MI, or PCI occurred in 21.9% of trandolapril patients and 22.5% of placebo (HR 0.96, 95%CI 0.88-1.06)

Secondary Outcomes

Mean blood pressure decreased by 4.4 mmHg systolic in trandolapril group and 1.4 in placebo group (average baseline 133/78, p<0.001) Death from any cause occurred in 7.2% of treatment group and 8.1% placebo (HR 0.89, 95%CI 0.76-1.04) CHF as a primary cause of hospitalization or death occurred in 2.8% of treatment group and 3.7% of placebo (HR 0.75, 95%CI 0.59-0.95, p=0.02)

Subgroup Analysis

Onset of new diabetes occurred in 9.8% of treatment group and 11.5% of placebo (HR 0.83, 95%CI 0.72-0.96, p=0.01)

Adverse Events

Cough: 39.1 percent in treatment vs. 27.5 percent in placebo, P<0.01 Syncope: 4.8 percent in treatment group vs. 3.9 percent, P=0.04 Angioedema: 5 patients in placebo group (2 receiving ACE inhibitors d/t diabetes) and 8 patients in trandolapril group

Criticisms

• In 2002 (2-6 years after enrollment), patients in placebo group with diabetes and either proteinuria or HTN & microalbuminuria were started on ACE inhibitors; this may have reduced the effect size. However, subgroup analysis censoring data from when patients with diabetes were started on ACE inhibitors did not change results.
• Exclusion of patients on basis of run-in phase meant study was not actually intention-to-treat. Selecting for the most compliant patients in this manner likely skewed towards more positive findings.
• Small proportion of female patients included in study decreases external validity.
• Absence of effect of ACE inhibitor in CAD (opposite findings of HOPE and EUROPA) may be due to more lenient inclusion criteria; coronary angiography >50% may not be predictive of functional stenosis. Alternately, exclusion criteria are stricter in removing patients hospitalized for unstable angina. Finally, many more patients in this later study were on statins vs HOPE (28.6%) and EUROPA (57.8%)

Funding

National Heart, Lung, and Blood Institute, Knoll Pharmaceuticals and Abbott Laboratories

Further Reading

HOPE and EUROPA trials