News:IMAGINE reported: early ACE inhibitor therapy in low risk CABG patients associated with worse early outcomes

December 15, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

IMAGINE was a randomized, blinded, international trial of quinapril (40 mg/day) vs. placebo in 2553 stable non-diabetic patients with left ventricular ejection fractions (EF) > 40% who underwent coronary artery bypass grafting (CABG). They screened over 32,000 patients, and excluded almost 29,500 patients, mostly for “other reasons”. Among the 1280 patients randomized to quinapril, 444 discontinued study drug, around half because of adverse reaction. Patients in both study arms did not differ statistically in any measured baseline characteristic. The study conducted an intention to treat analysis, with a primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, coronary revascularization, unstable angina, documented angina, stroke, congestive heart failure that required hospitalization. Median follow-up was almost 3 years.

The incidence of the primary endpoint was 13.7% in the quinapril group and 12.2% in the placebo group (HR 1.15, CI 0.92 to 1.42, p = 0.212). However, a closer look at the data demonstrated that within the first 3-months, the primary endpoint was more common in the quinapril group (HR 1.52, CI 1.03 to 2.26, p=0.036). After three months, the two groups had very similar outcomes. The main difference in the first 3-months appears to be the incidence of documented angina not requiring hospitalization, which was more common in the quinapril arm (2% vs. 1.1%, p=0.079). Adverse events were more frequent in the quinapril group including hypotension (12% vs. 5.5%), cough (21% vs. 11%). Hypotension was a common problem within the first three months of treatment with quinapril (9.2% vs. 3.9%).

The benefit of ACE-I in patients with reduced EF, diabetes, and non-low-risk patients post acute coronary syndromes is well-established. The PEACE trial recently addressed the incremental benefit to adding trandolapril to optimal medical management of stable coronary artery disease patients with preserved ejection fraction and found no benefit. The IMAGINE trial addressed the role of ACE-I in low-risk CABG patients without diabetes, and likewise found no benefit. The Achilles heel of the study was the increase in angina early after treatment initiation. It is interesting to speculate that perhaps hypotension contributed to this outcome. This was a relatively small study with a low event rate and a large (~30%) drop-out rate in the active arm, making it difficult to discern a small treatment effect.

This study was funded by Pfizer Canada, the Netherlands, Belgium, and France.

1. Jean L. Rouleau, Wayne J. Warnica, Richard Baillot, Pierre J. Block, Sidney Chocron, David Johnstone, Martin G. Myers, Cristina-Dana Calciu, Sonia Dalle-Ave, Pierre Martineau, Christine Mormont, Wiek H. van Gilst, and for the IMAGINE (Ischemia Management with Accupril post-bypass Graft via Inhibition of the coNverting Enzyme) Investigators. Effects of Angiotensin-Converting Enzyme Inhibition in Low-Risk Patients Early After Coronary Artery Bypass Surgery. Circulation 2007: published online before print December 10, 2007, 10.1161/CIRCULATIONAHA.106.685073.