Effects of Angiotensin-Converting Enzyme Inhibition in Low-Risk Patients Early After Coronary Artery Bypass Surgery
Background— Early after coronary artery bypass surgery (CABG), activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors.
Methods and Results— The Ischemia Management with Accupril post–bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial tested whether early initiation (≤7 days) of an angiotensin-converting enzyme inhibitor after CABG reduced cardiovascular events in stable patients with left ventricular ejection fraction ≥40%. The trial was a double-blind, placebo-controlled study of 2553 patients randomly assigned to quinapril, target dose 40 mg/d, or placebo, who were followed up to a maximum of 43 months. The mean (SD) age was 61 (10) years. The incidence of the primary composite end point (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 1.15, 95% confidence interval 0.92 to 1.42, P=0.212) over a median follow-up of 2.95 years. The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group (hazard ratio 1.52, 95% confidence interval 1.03 to 2.26, P=0.0356). Adverse events also increased in the quinapril group, particularly during the first 3 months after CABG.
Conclusions— In patients at low risk of cardiovascular events after CABG, routine early initiation of angiotensin-converting enzyme 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. Thus, early after CABG, initiation of angiotensin-converting enzyme inhibitor therapy should be individualized and continually reassessed over time according to risk.
Received December 18, 2006; accepted October 15, 2007.
The benefits of angiotensin-converting enzyme (ACE) inhibitors in reducing coronary ischemic events and survival in patients with low/moderate-risk to high-risk coronary artery disease1–3 are impressive. In low-risk patients with preserved left ventricular systolic function and modern conventional therapy, such as those in the Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial,4 the evidence for benefit from the addition of an ACE inhibitor is less compelling. The lack of benefit of an ACE inhibitor in the PEACE study has been interpreted by some as identifying the limits beyond which ACE inhibitors are no longer of benefit in patients with coronary artery disease. Alternatively, because the 95% confidence intervals (CIs) for both total and cardiovascular mortality overlap for PEACE and studies that demonstrate benefits with ACE inhibitors in patients with coronary artery disease and preserved systolic function, others have interpreted the results of the PEACE study as simply being the play of chance.
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The surgical procedure of CABG results in endothelial denudation and dysfunction and early activation of the renin-angiotensin system.5–8 Because ACE inhibitors both reduce activation of the renin-angiotensin system and improve endothelial function,9 it has been postulated that they may reduce coronary ischemic events after CABG.10 Alternatively, ACE inhibitors given during the dynamic, relatively fragile early post-CABG period could result in hypotension, renal dysfunction, and graft occlusion.
The results of one small study, the Effects of Quinapril on Clinical Outcome After Coronary Artery Bypass Grafting (QUO VADIS) trial,10 suggest that an ACE inhibitor started preoperatively and continued postoperatively reduces recurrent ischemia at 1 year of follow-up, with most of the benefit attributable to a decrease in recurrent angina. Although this secondary analysis of the QUO VADIS study was promising, it was a small study and simply hypothesis generating.11 Therefore, the goal of the Ischemia Management with Accupril post–bypass Graft via Inhibition of angiotensin coNverting Enzyme (IMAGINE) study was to test whether ACE inhibitor therapy initiated within the hospital phase after CABG would reduce the rate of coronary ischemic events, stroke, and congestive heart failure in patients with preserved left ventricular function and no clear indication for ACE inhibitor therapy who were receiving current conventional therapy.12
The design of the IMAGINE study has been described previously12 and is summarized here. The IMAGINE study is a double-blind, placebo-controlled, parallel-group, randomized, multicenter, international study conducted in patients who have undergone CABG. The research protocol was approved by the ethics committees of all participating institutions, and all patients gave written informed consent. The data were collected and analyzed by an independent clinical research organization (i3 Innovus).
The inclusion and exclusion criteria are summarized in Table 1. Patients were screened for eligibility and randomized in the hospital within 7 days after CABG, except for patients in France, where randomization could occur within 10 days after CABG.
Starting November 6, 2001, given the increasing evidence of benefit of ACE inhibitors in patients with diabetes mellitus and renal disease,13 all patients requiring insulin or who had type II diabetes mellitus and microalbuminuria were no longer eligible for the study. Those already in the trial were treated according to the clinical judgment of the treating physician.
Conduct of the Trial
Of patients screened in 57 sites in Canada, the Netherlands, Belgium, or France between November 1999 and September 2004, 2553 (≈5% of patients screened and 13% of eligible patients; Figure 1) were randomized postoperatively to 1 of 2 arms: quinapril, either 10 or 20 mg according to the judgment of the investigator, or placebo. Randomization was done centrally and was unstratified, block based, and computer generated. If tolerated, doses were uptitrated to 40 mg of quinapril or its placebo equivalent within the hospital, or if not tolerated, doses were uptitrated later, after hospital discharge. Patients were followed up for 24 months, at which time they were invited to continue until 43 months of follow-up or to withdraw if they did not wish to extend their participation in the trial (n=53). In the 3 European countries, except for 2 centers in the Netherlands, randomization was stopped and study closure performed between September and December 2003. Study closure for the remaining centers occurred between February and May 2005. The minimum follow-up was 6 months, and the maximum follow-up was 43 months.
The original primary end point consisted of time to first occurrence of any of the composite of cardiovascular death or resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, unstable angina that required hospitalization, and documented angina that did not require hospitalization. On January 14, 2003, owing to a lower than expected event rate, the steering committee concluded that the required number of end points would likely not be reached without modification of the primary end point. Stroke and congestive heart failure that required hospitalization were thus added to the primary end point, and sample size was increased to 2500 patients.
The secondary end points included (1) time to first occurrence of the composite of cardiovascular death or resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, or stroke; (2) incidence of any of the above-mentioned secondary end points; (3) time to first occurrence of the composite primary end point with the addition of transient ischemic attack and any cardiovascular event that required hospitalization; (4) incidence of any secondary end points included in item 3; and (5) time to occurrence of death due to any cause. All end points were adjudicated in a blinded fashion by an end-point committee on the basis of predefined definitions for each end point.
The original sample size of 2204 patients was based on a composite event rate of 18% in the placebo group and had 80% power to detect a 25% relative reduction in the incidence of the primary end point when the log-rank test was used at the 0.05 level of significance. With the final sample size of 2553 patients, the study had 80% power to detect a 25% relative reduction in the incidence of the primary end point, assuming a 14.6% incidence of the primary end point in the placebo group when the log-rank test was used at the 0.05 level of significance. Cox regression analysis was used to examine the influence of potential important covariates. The study was end-point driven to continue until 325 subjects experienced a primary end point. The sample-size calculations assumed a 7% rate of discontinuation of active treatment and 7% rate of crossover to active treatment over the average follow-up.
The data and safety committee reviewed the data related to safety and the primary end point using the Haybittle-Peto stopping rule.14 For the 2 interim analyses, at 50% and 75% of the expected number of end points, a P<0.001 for benefit was required to limit the statistical penalty. Statistical analyses of the primary and secondary end points followed the intention-to-treat principle. A further analysis of the primary end point for the periods of 0 to 3 months and 3 to 43 months was prespecified. All reported probability values are 2-sided.
Time-to-event data were captured for the primary end point and for individual component end points even after the first primary end point had been experienced. For individual end points, time to first occurrence of the end point was calculated regardless of whether it was the first event that occurred in the patient.
Hazard ratios and 2-sided CIs were estimated from the univariate Cox proportional hazards regression model (Table 2). The probability value was obtained from the log-rank test comparing the time to event occurrence between treatment groups. The Cox proportional hazards regression model, which used the mean-of-covariates method, included the effects of age (continuous); history of hypertension, diabetes mellitus, myocardial infarction, stroke, or CABG; smoking status; peripheral vascular disease; use of β-blockers, lipid-lowering drugs, or antiplatelet drugs; arterial conduit with CABG; country of surgery; and creatinine (continuous). Assumptions of proportional hazard used the log-negative log plot and the treatment×time (time-dependent) interaction term. Cumulative event rates were calculated by the Kaplan–Meier method for the primary end point and displayed graphically (Figures 2 and 3⇓).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Of the 2553 patients who underwent randomization, 1280 were assigned to receive quinapril and 1273 to receive matching placebo. Baseline characteristics (Table 3) were similar in both treatment groups. Mean age was 61 years, 13% were women, 10% had diabetes mellitus, 3% had previous CABG, and 18% had previous percutaneous coronary intervention. Left ventricular ejection fraction was 60%.
There were 3.2 grafts per patient, and 39% of patients had 2 or more arterial conduits. Two percent of patients had minimally invasive surgery, and 19% had off-pump surgery. The mean time of randomization was 4 (SD 2) days after CABG.
Follow-Up and Compliance
Median follow-up was 2.95 years. One patient given quinapril and 4 patients given placebo were lost to follow-up.
Sixty-three percent of patients (1616 of 2553 patients) were randomized to the 10-mg dose of study medication and 36% (921/2553) to the 20-mg dose. At discharge from hospital, 4.5% of patients randomized to quinapril were no longer taking the study medication, whereas 32.5% were taking the 10-mg dose, 44% were taking the 20-mg dose, and 19% were taking the 40-mg dose. Of patients randomized to placebo, at discharge, 2.6% were no longer taking study medication, 32.2% were taking the 10-mg dose, 43% were taking the 20-mg dose, and 22% were taking the 40-mg dose. Among patients randomized to quinapril, 81% were taking quinapril or an open-label ACE inhibitor at 1 year, 81% at 2 years, and 81% at 3 years. Among patients randomized to placebo, 5% were taking an ACE inhibitor at 1 year, 8% at 2 years, and 11% at 3 years. Of patients taking quinapril, 67% were taking 40 mg at 1 year, 66% at 2 years, and 66% at 3 years. The average dose among patients taking quinapril was 33±10 mg. Average dose was calculated as the total amount of quinapril taken divided by the total number of days the patient was taking study medication.
Medications, Blood Pressure, and Cholesterol
No differences existed in medications taken before or after CABG between groups. Before CABG, 91% of subjects were taking aspirin, 65% were taking a statin, 79% were taking a β-blocker, 23% were taking an ACE inhibitor or angiotensin receptor blocker, and 37% were taking a calcium channel blocker. After randomization, over the entire study period, the use of antiplatelet agents averaged 95%, whereas lipid-lowering drug use averaged 85% (statins 83%), and β-blocker use averaged 63%. Mean arterial pressure over the course of the study averaged 125/74 mm Hg for patients randomized to quinapril versus 129/76 mm Hg for placebo, which represents a mean reduction of systolic arterial pressure of 3.9 mm Hg (95% CI 2.96 to 4.97 mm Hg) and a mean reduction of diastolic arterial pressure of 2.1 mm Hg (95% CI 1.50 to 2.62, P<0.001) with quinapril. At the end of the study, the plasma concentrations of lipids were similar in both groups: total cholesterol 161 mg/dL, LDL 95 mg/dL, HDL 48 mg/dL, and triglycerides 151 mg/dL.
Primary End Point
The incidence of the primary end point was 12.2% in the placebo group and 13.7% in the quinapril group (hazard ratio 1.15, 95% CI 0.92 to 1.42, P=0.212; Table 2; Figure 2). Adjustment for baseline characteristics (age, sex, and history of myocardial infarction or stroke, diabetes mellitus, or previous CABG) did not alter the results (hazard ratio 1.14, 95% CI 0.92 to 1.42, P=0.225). No difference in the primary end point was found when patients were divided according to prespecified subgroups, age, sex, diabetes mellitus, systolic blood pressure, plasma cholesterol, and the use of β-blocker, lipid-lowering, or antiplatelet therapy. When individual components of the primary end point were considered separately (Table 2), no difference between treatment groups was found. The per-protocol analysis of the primary composite end point also did not alter the results (hazard ratio 1.24, 95% CI 0.97 to 1.58, P=0.090).
When only the first 3 months were considered, the incidence of the primary end point was 3.2% in the placebo group, and 4.8% in the quinapril group (hazard ratio 1.52, 95% CI 1.03 to 2.26, P=0.036; Table 4; Figure 3). When events after the first 3 months were considered, the incidence of the primary end point was 10.0% in the placebo group and 10.7% in the quinapril group (hazard ratio 1.08, 95% CI 0.85 to 1.39, P=0.522; Figure 3).
Secondary Outcomes and Other End Points
None of the differences in prespecified secondary end points reached statistical significance. The incidence of new-onset diabetes mellitus (2.4% versus 3.1%, difference −0.8%, 95% CI −0.5% to −2%) and of new-onset atrial fibrillation (after randomization; 7.9% versus 8.9% for placebo and quinapril, respectively; difference 1%, 95% CI −1.2% to 3.1%) was similar in both groups.
Adverse events with quinapril versus placebo were more frequent for hypotension (12% versus 5.5%, difference 6.5%, CI 4.5% to 8.5%) and cough (21% versus 11%, difference 10%, 95% CI 7.2% to 12.7%) and less frequent for hypertension (7% versus 11%, difference −4%, 95% CI −6.4% to 2.0%; all P<0.001). Ninety-six patients randomized to 10 mg of quinapril and 60 patients randomized to 20 mg had hypotension. Forty-nine patients randomized to 10 mg of placebo and 22 patients randomized to 20 mg had hypotension, which suggests that the excess of hypotension with quinapril occurs regardless of initial dose. No difference was found in frequency of renal dysfunction or syncope between groups. With quinapril, hypotension was a particularly frequent adverse event during the first 3 months of therapy (9.2% versus 3.9%, difference 5.3%, 95% CI 3.4% to 6.9%, P<0.001), but it was also present after the first 3 months (5.3% versus 2.3%, difference 3.0%, 95% CI 1.5 to 4.3%, P<0.001).
The results of the IMAGINE study, which represented up to 60% of patients undergoing CABG in IMAGINE centers during the study period, do not support the hypothesis that starting an ACE inhibitor early after CABG improves outcome in low-risk patients with preserved left ventricular function, intensive contemporary medical therapy, and no clear indication for the use of an ACE inhibitor. Indeed, the higher incidence of adverse events with quinapril during the first 3 months after CABG indicates that caution is warranted when an ACE inhibitor is initiated early (≤7 days) after CABG in a population such as that of the IMAGINE study.
The early post-CABG period is very dynamic, with activation of the renin-angiotensin system, fluid shifts from one compartment to another, coagulation disturbances, and an incidence of early graft closure that varies from 10% to 15%.6 Before IMAGINE, the only study to evaluate the effects of ACE inhibitors during the early post-CABG period was the small QUO VADIS study, which suggested that ACE inhibitors were useful, particularly in reducing the risk of angina. As frequently occurs, the results of the large IMAGINE study do not corroborate the earlier, smaller QUO VADIS trial,15 which indicates that at least in low-risk patients treated with contemporary therapy, early initiation of an ACE inhibitor after CABG has no benefit, and this strategy may even be associated with an increase in adverse events. Whether the results of IMAGINE would have been different had the ACE inhibitor been initiated before the surgery and continued during and after CABG, as was done in QUO VADIS, remains speculative, but it may be that such a strategy would only have led to further adverse effects, particularly those associated with hypotension.
During the first 3 months after CABG, the increase in the primary end point with quinapril was largely the result of an increased risk of the combination of recurrent angina and unstable angina (36 versus 21 events, P=0.060). This early trend toward increased angina and increased need for revascularization persisted throughout the study. Whether this increase in angina was simply a play of chance or the result of therapy with quinapril is uncertain, but clearly, the beneficial results of QUO VADIS on recurrent angina were not reproduced.
The IMAGINE study differs from other large ACE inhibitor studies of patients with coronary artery disease in that it assessed early intervention in patients after CABG, a population that was purposefully avoided by previous studies. It also excluded patients with diabetes mellitus, who are known to benefit from ACE inhibitors, those dependent on insulin, and those with microalbuminuria. Patients in IMAGINE were treated intensively with contemporary therapy and had recent optimal coronary revascularization with a high use of arterial conduits. Together, this resulted in a particularly low cardiovascular event rate. Indeed, the annual cardiovascular mortality rate of 0.46% in the placebo group of IMAGINE was much lower than that of the PEACE (0.77%), EUROPA (EUropean trial of Reduction Of cardiac events with Perindopril in stable coronary Artery disease; 0.97%), and HOPE (Heart Outcomes Prevention Evaluation; 1.85%) studies. If one starts counting events 3 months after CABG, the annual cardiovascular mortality rate in IMAGINE patients fell further, to 0.34%, one third of that of EUROPA and half of that of the PEACE study. The excellent outcome of patients in the IMAGINE study is far superior to that reported in contemporary registries, which underscores the relatively low-risk nature of the patients involved.16
The results of the IMAGINE study should not modify the interpretation of the previously published large studies (HOPE, EUROPA, and PEACE). IMAGINE is a much smaller study than the previous 3 large studies and was underpowered to test outcomes other than the primary objective of the study. In patient-years, follow-up in IMAGINE ranged from 13% to 16% of that of the larger studies, and the incidence of comparable hard events was even lower, ranging from 5.5% to 6.9% of that of the larger studies. Nevertheless, if one does an exploratory analysis and considers only harder end points that occurred after the first 3 months, the results of IMAGINE are entirely consistent with those of the previous larger studies, which suggests that ACE inhibitors may indeed have benefits in very-low-risk patients. The hazard ratio in IMAGINE for the HOPE primary composite end point of cardiovascular death, myocardial infarction, and stroke was 0.82 (95% CI 0.50 to 1.35), similar to that of HOPE (0.78, 95% CI 0.70 to 0.86), and the hazard ratio for the EUROPA primary composite end point of cardiovascular death, cardiac arrest, and myocardial infarction was 0.81 (95% CI 0.45 to 1.43), similar to that of EUROPA (0.80, 95% CI 0.71 to 0.90). However, because of the extremely low event rate in this patient population, one must question the cost-effectiveness, if a relative benefit exists, of giving an ACE inhibitor to such patients, even 3 months after CABG.
The results of IMAGINE suggest that in patients at low risk of cardiovascular events, the initiation of an ACE inhibitor can and probably should be delayed beyond 7 days after CABG. The IMAGINE trial did not address the question of when an ACE inhibitor should be initiated within 7 days after CABG in the large group of patients in whom it is clearly indicated, but the results suggest that if initiated early, ACE inhibitors should be administered with some care and in very small doses to avoid the early adverse events documented in IMAGINE.
The results of the IMAGINE trial are consistent with those of previous studies and thus should not modify the present recommendations that an ACE inhibitor be considered in every patient with vascular disease.17 Indeed, ACE inhibitors continue to be indicated in post-CABG patients in whom they have proved to be of benefit, such as those with low-to-moderate or high-risk coronary artery disease or any other clear indication for use of an ACE inhibitor. However, due to a very low event rate, the absolute benefits of an ACE inhibitor, if any, are small in IMAGINE-like patients, such that individualized therapy, based on the patient’s associated risk factors, is recommended.
We thank Anna Nozza for her expert statistical advice and help.
Sources of Funding
This project was supported by Pfizer Canada, the Netherlands, Belgium, and France.
Dr Rouleau has received a research grant from Pfizer for the IMAGINE study; has served on the speakers’ bureau for Pfizer; has received honoraria from Novartis; and has served on the data safety monitoring board of a study sponsored by Pfizer. Dr Warnica has received research grants from Sanofi-Aventis for the ORIGIN and IMPROVE-IT studies and has received honoraria from Pfizer. Dr Baillot has served on the speakers’ bureau for Pfizer. Dr Block has received a research grant from Pfizer for the IMAGINE study. Dr Chocron has served on the speakers’ bureau for Pfizer and has received honoraria from the advisory board of Pfizer. Dr Johnstone has served on the speakers’ bureau for the Canadian Cardiovascular Society and has worked as a consultant for Pfizer on the advisory board for IMAGINE. Dr Myers has received a research grant from Pfizer for the IMAGINE study; has served on the speakers’ bureau for Pfizer and Servier; has received honoraria from Servier and Boehringer Ingelheim; and has worked as a consultant for Servier, Pfizer, and Boehringer Ingelheim. Drs Calciu and Martineau are employees of Pfizer Canada Inc and as such are granted stock options from Pfizer. Dr Dalle-Ave has ownership interest in AstraZeneca. Dr Mormont is an employee of Pfizer Canada Inc. Dr van Gilst has received an unrestricted grant from Pfizer.
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The Ischemia Management with Accupril post–bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) study suggests that although angiotensin-converting enzyme (ACE) inhibitors are useful in the therapy of patients with coronary artery disease, it would appear that in patients with preserved left ventricular function (ejection fraction ≥40%) and without a clear indication for an ACE inhibitor (uncontrolled hypertension, diabetes with microalbuminuria or insulin dependency), early (≤7 days after coronary artery bypass grafting) initiation of an ACE inhibitor is not beneficial and may even increase the incidence of adverse events over the early (3 months) postoperative period. Indeed, the results of the IMAGINE study suggest that in such low-risk patients, it may be wise to delay the initiation of an ACE inhibitor beyond 7 days after coronary artery bypass grafting unless a specific indication other than the presence of coronary artery disease exists. The results of IMAGINE also suggest that if early initiation of an ACE inhibitor after coronary artery bypass grafting is indicated, it should be done with care. Finally, the results of the IMAGINE study do not modify the present recommendations for the use of ACE inhibitors in stable patients with coronary artery disease; however, owing to the very low event rate in IMAGINE-like patients, the absolute benefits of ACE inhibitors, if any, would be so small that individualized therapy, depending on the patient’s associated risk factors, is recommended.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00269243.
The online-only Data Supplement, consisting of lists of the committee members, investigators, and research coordinators who participated in the IMAGINE trial, is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.106.685073/DC1.