IMAGINE: Ischemia Management With Accupril Post Bypass Graft via Inhibition of Angiotensin Converting Enzyme

Linda Brookes, MSc

Disclosures

October 24, 2005

Editorial Collaboration

Medscape &

Presenter: Wiek H. van Gilst, PhD (University Hospital Medical Center, Groningen, The Netherlands)

According to the results of the Ischemia Management with Accupril Post Bypass Graft via Inhibition of Angiotensin Converting Enzyme (IMAGINE) trial, early treatment after coronary artery bypass grafting (CABG) with an angiotensin converting enzyme (ACE) inhibitor may not improve outcome.[1] This surprising conclusion appears to contradict previous evidence from trials such as the Heart Outcomes Prevention Evaluation (HOPE),[2] European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA),[3] and the Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE),[4] which showed a benefit of ACE inhibitor treatment in post-CABG patients.

Study Rationale

Although CABG remains the revascularization treatment of choice for patients with severely symptomatic or life-threatening coronary artery disease (CAD), 9% to 25% of the patients who have undergone CABG experience a recurrent ischemic event such as death, recurrent infarction, angina, or repeat revascularization. IMAGINE was the first large clinical trial to investigate the role of preventing ischemic events early after CABG.

The hypothesis underlying the trial was based on 2 considerations (pro and con) of the way ACE inhibitors are understood to work:

  1. Pro — In favor of ACE inhibition early post-CABG, the pathophysiologic processes that occur during the CABG procedure may affect endothelial function in the graft, and these would be most active in the early phase after surgery. Use of an ACE inhibitor early post-CABG might improve endothelial function, reduce activation of local and systemic inflammatory and coagulation processes, and reduce progression of local and systemic atherosclerosis.

  2. Con — On the other hand, it was also recognized that the effect of ACE inhibition might be to further decrease blood pressure or enhance postoperative renal impairment in patients with low blood pressure and changing intravascular volumes.

A Canadian-led international study, IMAGINE was set up to address whether ACE inhibition with quinapril 40 mg daily initiated within 7 days in post-CABG patients who did not have a current indication for an ACE inhibitor would reduce ischemic clinical events.[5]

Patients

Patients eligible for IMAGINE were adults aged > 18 years who were still hospitalized and in stable condition ≤ 7 days post CABG (≤ 10 days in France) with a left ventricular ejection fraction (LVEF) > 40% determined within 6 months before surgery. Patients were ineligible if they had a clinical need for treatment with an ACE inhibitor or an angiotensin receptor blocker (ARB), if they had undergone valve replacement during CABG, if they had high serum potassium (≥ 5.6 mmol/L) or creatinine (> 200 micromol/L) levels, or if they had significant perioperative myocardial infarction (MI).

Between November 1999 and September 2004, a total of 2553 patients (mean age 61 years, 13% women, 96% white) were enrolled at 39 sites in Canada, 10 in Belgium, 9 in The Netherlands, and 9 in France.

The IMAGINE patient population was well treated overall, with 84% on beta-blockers, 90% on lipid-lowering agents, and 98% on aspirin or antiplatelet agents. Patients had normal LV function, blood pressure, renal function, and lipids (Table 1).

Table 1. Baseline Measurements (Mean Values)
Quinapril Placebo
LVEF (%) 60 60
Blood pressure (mm Hg) 70/122 70/121
Creatinine (micromol/L) 87 87
Total cholesterol 4.9 4.9
LDL-cholesterol 2.9 2.9
HDL-cholesterol 1.1 1.1
Triglycerides 2.2 2.3
HDL = high-density lipoprotein; LDL = low-density lipoprotein; LVEF = left ventricular ejection fraction
Treatment

According to the design of the study, patients were to be randomly assigned to placebo or quinapril, titrated up to a dose of 40 mg daily where possible, within 7 days after CABG. Actual randomization took place within a mean of 4 days, and the average dose of quinapril was 28 mg. Treatment compliance with study medication was > 80%. Patients were scheduled to be followed closely for a minimum of 12 months after randomization; median follow-up period was 2.95 years.

Blood Pressure

Over a mean follow-up of 44 months, blood pressure increased in both study groups but increased by a mean of 4.8 mm Hg more in systolic blood pressure (SBP) and 2.7 mm Hg more in diastolic blood pressure (DBP) in the quinapril group vs the placebo group. This was true despite the fact that blood pressure dropped early in the study in the quinapril group and during the first 3 months hypotension was significantly more frequent in the quinapril group than in the placebo group (9.2% vs 3.9%, P < .01). After 3 months, the hypotension was less frequent in each group (3.0% vs 1.7%, respectively, P = .047).

Primary Endpoint

With all confidence intervals fairly wide and spanning 1.0, no statistically significant difference was seen between the 2 treatment groups in the primary composite endpoint (P = .21) or in the individual components of the primary endpoint (Table 2).

Table 2. Primary Composite Endpoint and Components
Endpoint HR 95% CI
Primary composite endpoint 1.15 0.92-1.42
Primary endpoint components
Cardiovascular death or resuscitated cardiac arrest 1.18 0.40-1.46
Nonfatal MI 0.76 0.85-1.93
Coronary revascularization 1.28 0.77-1.83
Hospitalization for unstable angina 1.19 0.95-1.8
Documented angina not requiring hospitalization 1.28 0.95-1.73
Stroke 1.07 0.52-2.21
Congestive heart failure requiring hospitalization 1.09 0.53-2.26
CI = confidence interval; HR = hazard ratio; MI = myocardial infarction

Prespecified analysis of events during the first 3-month period of the trial vs the period after 3 months showed that the quinapril-treated group experienced about 50% more primary events compared with the placebo group (Table 3). During the chronic phase, however, there was no difference between the 2 study groups.

Table 3. Primary Composite Endpoint Before and After the First 3 Months of the Study
Primary Composite Endpoint HR 95% CI P Value
First 3 months 1.52 1.03-2.26 .04
After 3 months 1.08 0.85-1.39 .52
CI = confidence interval; HR = hazard ratio
Safety

Apart from hypotension during the first 3 months of the study, the only adverse event that was significantly more frequent in the quinapril group was cough (P < .01).

Interpretation

Prof. van Gilst pointed out that compared with previous studies of ACE inhibitors in patients with stable CAD, the risk of all-cause mortality and cardiovascular mortality at baseline was lower in the IMAGINE patients. Applying the primary endpoints used in the HOPE, EUROPA, and PEACE trials to the IMAGINE study showed benefit for quinapril for cardiovascular death/MI/stroke (HOPE), cardiovascular death/MI/cardiac arrest (EUROPA), and cardiovascular death/MI/coronary revascularization (PEACE), but only for the period following the first 3 months of follow-up.

Prof. van Gilst and IMAGINE co-principal investigator Jean-Lucien Rouleau, MD (University of Montreal, Canada), believe that their results should not change the recommendations for the use of an ACE inhibitor in chronic stable CAD, but they suggest that there may not be any absolute benefit of an ACE inhibitor in very low-risk populations.

Reasons for "Surprising" Results

The European Society of Cardiology-designated discussant Michel E. Bertrand, MD (University of Lille, France), emphasized that the IMAGINE results do not contradict the favorable results obtained with ACE inhibitors (ramipril and perindopril) in secondary prevention of stable patients with CAD in the HOPE and EUROPA trials. He suggested that the short time between surgery and randomization might be one reason for the lack of benefit with the ACE inhibitor in IMAGINE. He pointed out that the time between CABG and randomization to treatment was much longer in the HOPE, EUROPA, and PEACE trials, which all showed a relative risk reduction with the ACE inhibitor in the post-CABG patients (Table 4).

Table 4. Time Between CABG and Randomization in Trials of Other ACE Inhibitors
HOPE EUROPA PEACE
Time post CABG > 4 y > 6 mo > 3 mo
No. of CABG patients 2399 3578 3232
Relative risk reduction 11% 17% 4.7%
CABG = coronary artery bypass grafting

He noted that the QUinapril On Vascular ACE and Determinants of ISchemia (QUO VADIS) trial,[6] which could be regarded as the pilot trial for IMAGINE, randomized patients to quinapril 40 mg/day 4 weeks before surgery and showed a risk reduction of 77%, a result he described, however, as "too good to be believed."

Prof. Bertrand also pointed out that the patients in IMAGINE were a relatively low-risk population (only 39% with a history of MI and 10% with diabetes) and that the primary endpoint combination of 7 major adverse cardiovascular events mixing soft and hard endpoints was very complex. He also suggested that quinapril might have a molecule-specific effect that could account for the IMAGINE result.

References
  1. van Gilst WH. IMAGINE -- Ischemia Management with Accupril post bypass Graft via Inhibition of angiotensin coNverting enzyme. Program and abstracts of the European Society of Cardiology Congress 2005; September 3-7, 2005; Stockholm, Sweden. Hotline II.

  2. The HOPE study investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.

  3. Fox KM. EURopean Trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicenter trial (the EUROPA study). Lancet. 2003;362:782-788.

  4. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-2068.

  5. Warnica JW, Gilst WV, Baillot R, et al. Ischemia Management with Accupril post bypass Graft via Inhibition of angiotensin coNverting enzyme (IMAGINE): a multicenter randomized trial - design and rationale. Can J Cardiol. 2002;18:1191-1200.

  6. Oosterga M, Voors AA, Pinto YM, et al. Effects of quinapril on clinical outcome after coronary artery bypass grafting (The QUO VADIS Study). QUinapril on Vascular Ace and Determinants of Ischemia. Am J Cardiol. 2001;87:542-546.

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