STOCKHOLM — The initiation of ACE inhibitor therapy within 7 days of coronary artery bypass graft surgery does not improve clinical outcomes in low-risk patients without a conventional indication for it, Dr. Wiek H. van Gilst, said at the annual congress of the European Society of Cardiology.
In fact, just the opposite was observed in the 2,553-patient Ischemia Management With Accupril Post Bypass Graft via Inhibition of Angiotensin-Converting Enzyme (IMAGINE) trial, conducted in Europe and Canada. The incidence of ischemic events was 52% greater in the quinapril (Accupril) group than with placebo during the first 3 months of follow-up, although at the end of the full 43 months, there was no significant difference between the two treatment groups, noted Dr. van Gilst, professor of cardiovascular and clinical pharmacology at University Medical Center, in Groningen, the Netherlands.
The rationale behind the IMAGINE trial was that the post-coronary artery bypass graft (CABG) period is known to be a time of increased local and systemic inflammation, thrombotic activity, and endothelial dysfunction, and ACE inhibitors have been shown to curb endothelial dysfunction and exert an anti-inflammatory effect. The hypothesis of the study was that quinapril, at a target dose of 40 mg once daily, would slow atherosclerotic progression and reduce ischemic events.
This specific issue had not been examined before. The earlier Heart Outcomes Prevention Evaluation (HOPE), European Trial on Reduction of Cardiac Events With Perindopril in Stable CAD (EUROPA), and Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trials included collectively more than 9,200 patients who had undergone CABG, and those patients experienced a significant reduction in ischemic events. In those trials, however, recent CABG was an exclusion criterion.
The primary end point in IMAGINE was a composite of cardiovascular death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, hospitalization for unstable angina, documented angina not requiring hospitalization, stroke, and congestive heart failure requiring hospitalization. The relative risk of this combined end point was 15% greater in the quinapril group, a rate not significantly higher than with placebo.
IMAGINE participants had higher rates of ?-blocker, statin, and antiplatelet therapy usage than did patients in any previous clinical trial. Moreover, none of the participants had a low ejection fraction or other indication for an ACE inhibitor, which made this a very low-risk group. In fact, they were at lower risk of ischemic events than was the age-matched general population, according to Dr. van Gilst.
Discussant Dr. Michel E. Bertrand, called the IMAGINE results “somewhat surprising.” He noted that every component of the composite end point save one—nonfatal MI—trended in favor of placebo.
Dr. Bertrand, professor of cardiology at the University of Lille (France), proposed that the quinapril target dose may have been too high. The mean daily dose was 28 mg. The 12% incidence of hypotension and 21% rate of cough in the quinapril group were also relatively high. It may be that the substantial quinapril dose led to an increase in the release of bradykinin, further promoting inflammation in a postsurgical population that had an ongoing highly active inflammatory process, with a resultant increase in ischemic events.
He also said that the negative results could have been due to a molecule-specific effect of quinapril. IMAGINE was not the first negative trial involving quinapril in patients undergoing coronary intervention.
Yet another possibility is that starting an ACE inhibitor within 1 week of CABG is just too soon, Dr. Bertrand said.
IMAGINE was sponsored by Pfizer Inc., which markets Accupril.
Bruce Jancin