Ischemia Management With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme - IMAGINE

Description:

The goal of this trial was to test the effects of early angiotensin-converting enzyme (ACE) inhibitor initiation after coronary artery bypass surgery (CABG) in patients with preserved left ventricular function, and no clear indication for ACE inhibitor therapy.

Hypothesis:

ACE inhibitor therapy initiated early after CABG would reduce the rate of coronary ischemic events, stroke, and congestive cardiac failure.

Study Design

Study Design:

Patients Screened: 32,032
Patients Enrolled: 2,553
Mean Follow Up: 2.95 years
Mean Patient Age: 61 years
Female: 13
Mean Ejection Fraction: 60

Patient Populations:

• Post-CABG within 7 to 10 days
• Stable after surgery, as per investigator judgment
• Still hospitalized
• Age ≥18 years
• Left ventricular ejection fraction ≥40% within 6 months before surgery

Exclusions:

• Intolerance or any contraindication to ACE inhibitor of history of angioedema
• Insulin-dependent diabetes mellitus, or type 2 diabetes with microalbuminuria
• Investigator determines that ACE inhibitor or angiotensin-receptor blocker is otherwise needed
• Current need for post-CABG urgent intervention
• Valve replacement during index CABG
• Significant valve stenosis or cardiomyopathy
• Serum K ≥5.6 mmol/L
• Primary hyperaldosteronism
• Serum creatinine >2.26 mg%, suspected renal artery stenosis, solitary kidney, renal transplant
• Serious concomitant disease, such as cancer, AIDS, or sepsis
• Systolic blood pressure >160 mm Hg or diastolic blood pressure >90 mm Hg despite treatment
• Systolic blood pressure <100 mm Hg
• Significant perioperative myocardial infarction, defined as CK-MB >100 U/L, troponin I >20 mcg/L, or new Q waves or left bundle branch block with corresponding wall motion abnormality, or prolonged postoperative hypotension (>48 hours) requiring intravenous inotropic support
• Pregnancy, breast-feeding, or inadequate contraception
• Investigational drug use <30 days
• Drug abuse, alcohol abuse, or inability to adhere to protocol

Primary Endpoints:

Time to first occurrence of any of the composite of:
• Cardiovascular death or resuscitated cardiac arrest
• Nonfatal myocardial infarction
• Coronary revascularization
• Unstable angina that requires hospitalization
• Documented angina that does not require hospitalization
• Stroke
• Congestive heart failure

Secondary Endpoints:

• Time to occurrence of the composite of cardiovascular death or resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, or stroke
• Incidence of any of the above secondary endpoints
• Time to first occurrence of the composite primary endpoint with the addition of transient ischemic attack and any cardiovascular event that required hospitalization
• Incidence of any of the above secondary endpoints
• Time to occurrence of death from any cause

Drug/Procedures Used:

The IMAGINE trial randomized patients undergoing CABG to either quinapril 10 or 20 mg/day or placebo within 7 to 10 days following surgery. All other current conventional therapy was continued.

Concomitant Medications:

Concomitant medications at 3 months included beta-blockers (79%), lipid-lowering therapy (90%), and aspirin/antiplatelet agent (97%).

Principal Findings:

A total of 2,553 patients were randomized, with 1,280 assigned to the quinapril arm and 1,273 assigned to the placebo arm. The baseline characteristics were fairly similar between the two arms. The mean age was 61 ± 10 years. The incidence of the primary composite endpoint (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, unstable angina or heart failure requiring hospitalization, documented angina, and stroke) was 13.7% in the quinapril group and 12.2% in the placebo group (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.92-1.42; p = 0.212) over a median follow-up of 2.95 years. The incidence of the primary composite endpoint increased significantly in the first 3 months after CABG in the quinapril group (HR, 1.52; 95% CI, 1.03-2.26; p = 0.0356). Adverse events also increased in the quinapril group, particularly during the first 3 months after CABG, including hypotension and cough.

Interpretation:

In patients at low risk of cardiovascular events after CABG, routine early initiation of ACE inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG; however, it increases the incidence of adverse events, particularly early after CABG. This study represents another surprising negative result in a placebo-controlled trial, and emphasizes why empiric decisions need to be avoided and evidence-based choices are so important. While ACE inhibitor given within 7 days of surgery has no value in very low-risk post-CABG patients, this does not imply that classic indications should not be followed. It is not clear why there was an increased event rate (predominantly angina and unstable angina and need for repeat CABG) with quinapril in the first 3 months. One simple posit is the effect of relative hypotension on bypass graft patency, which was not assessed.

References:

Rouleau JL, Warnica WJ, Baillot R, et al., on behalf of 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 2008;117:24-31.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Implantable Devices, SCD/Ventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure

Keywords: Isoquinolines, Myocardial Infarction, Stroke, Follow-Up Studies, Ventricular Function, Left, Hypotension, Tetrahydroisoquinolines, Heart Arrest, Saphenous Vein, Heart Failure, Confidence Intervals, Cough, Coronary Artery Bypass


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