The association between preoperative use of angiotensin-converting enzyme (ACE) inhibitors and outcomes after coronary artery bypass grafting (CABG) remain controversial. Our aim was to study in-hospital outcomes after isolated CABG in patients on preoperative ACE inhibitors. A retrospective analysis of 8,889 patients who underwent isolated CABG from 2000 through 2011 was conducted. The primary outcome of interest was the incidence of major adverse events (MAEs) defined as a composite of mortality, postoperative renal dysfunction, myocardial infarction, stroke, and atrial fibrillation during index hospitalization. The secondary outcome was the incidence of individual outcomes included in MAEs. Logistic regression analyses were performed. Of 8,889 patients, 3,983 (45%) were on preoperative ACE inhibitors and 4,906 (55%) were not. Overall incidence of MAEs was 38.1% (n = 1,518) in the ACE inhibitor group compared to 33.6% (n = 1,649) in the no-ACE inhibitor group. Preoperative use of ACE inhibitors was independently associated with MAEs (odds ratio 1.13, 95% confidence interval 1.03 to 1.24), most of which was driven by a statistically significant increase in postoperative renal dysfunction (odds ratio 1.18, 95% confidence interval 1.03 to 1.36) and atrial fibrillation (odds ratio 1.15, 95% confidence interval 1.05 to 1.27). In-hospital mortality, postoperative myocardial infarction, and stroke were not significantly associated with preoperative ACE inhibitor use. Analyses performed after excluding patients with low ejection fractions yielded similar results. In conclusion, preoperative ACE inhibitor use was associated with an increased risk of MAEs after CABG, in particular postoperative renal dysfunction and atrial fibrillation.
The long-term effects of angiotensin-converting enzyme (ACE) inhibitors in decreasing cardiovascular events and mortality in patients with coronary artery disease have been well established. However, their role in the preoperative setting and their effects on postoperative outcome remain controversial. The Quinapril on Clinical Outcome after Coronary Artery Bypass Grafting (QUO-VADIS) study demonstrated a decreased incidence of mortality and cardiac events at a median follow-up of 1 year in patients started on quinapril preoperatively (7 to 28 days) before coronary artery bypass grafting (CABG). Rady and Ryan, in a cohort of 11,330 subjects, found that ACE inhibitor therapy before CABG did not cause adverse immediate postoperative outcomes. Paradoxically, the Ischemia Management with Accupril postbypass Graft via Inhibition of the Converting Enzyme (IMAGINE) investigators showed worse outcomes in the ACE inhibitor group in the early period after CABG. These studies are limited because they mostly evaluated outcomes in patients undergoing CABG who were recently started on ACE inhibitors rather than on long-term ACE inhibitor therapy. In addition, the composite end points in some of these studies did not include postoperative renal insufficiency, myocardial infarction (MI), and stroke. Thus the aim of our study was to determine early in-hospital outcomes after isolated CABG in patients on ACE inhibitors before CABG. We hypothesized that ACE inhibitor use before isolated CABG was not associated with favorable outcomes.
Methods
We conducted a retrospective analysis of consecutive patients who underwent isolated CABG at the St. Luke’s Episcopal Hospital from January 1, 2000 through July 31, 2011. All preoperative and intraoperative data were extracted from the Texas Heart Institute database (THIRD-Base ). Of 11,068 patients who underwent CABG, 2,179 were excluded because they underwent associated procedures including valve repair, left ventricular aneurysm, and aortic root repair. Thus the final sample consisted of 8,889 patients. Preoperative ACE inhibitor use was defined as a patient taking ACE inhibitors until the day of CABG. Patients on any ACE inhibitors (lisinopril, enalapril, ramipril, quinapril, benazepril, or perindopril) irrespective of dose were included in the analyses.
We used the following preoperative patient characteristics in our analyses: age (continuous variable), gender, race, body mass index (continuous variable), smoking status, diabetes mellitus, hypertension, unstable angina, previous MI, history of atrial fibrillation, peripheral vascular disease, cerebrovascular accident, preoperative renal insufficiency (serum creatinine level >2 mg/dl), β-blocker use, statin use, low left ventricular ejection fraction (<35%), New York Heart Association class, need for urgent or repeat surgery, need for intra-aortic balloon pump, and aortic cross-clamp time.
The primary outcome of interest was the incidence of major adverse events (MAEs) during the time of index hospitalization for cardiac surgery. A MAE was defined as the composite of mortality, postoperative renal dysfunction, MI, stroke, and atrial fibrillation. The secondary study outcomes studied were the individual components of MAEs and included (1) mortality, defined as death during hospitalization after CABG surgery; (2) postoperative renal dysfunction, defined as a serum creatinine level >2 mg/dl (if normal before surgery) or an increase of 1.5 times preoperative creatinine levels, (3) atrial fibrillation as evidenced by a rhythm strip or 12-lead electrocardiogram showing atrial fibrillation of any duration in the postoperative period; (4) postoperative MI as appearance of new Q waves >0.04 ms in ≥2 contiguous leads on electrocardiogram and an increase of total creatinine phosphokinase ≥5 times the upper limit of normal; and (5) stroke as any evidence of a new neurologic deficit confirmed by computed tomography or magnetic resonance imaging.
We initially performed unadjusted analyses to determine whether preoperative ACE inhibitor use was associated with MAEs. To further control for potential confounders, we performed multivariate analyses adjusting for the following variables: age >65 years, male gender, African-American race, body mass index, diabetes mellitus, hypertension, low ejection fraction (<35%), New York Heart Association class III or IV symptoms, previous MI, cerebrovascular accident, peripheral vascular disease and renal insufficiency, β-blocker use, statin use, urgent CABG, repeat CABG, aortic cross-clamp time >80 minutes, and preoperative need for intra-aortic balloon pump. Similar adjustment models were used for the individual secondary outcomes. These adjusted analyses were performed to determine if ACE inhibitor use was independently associated with MAEs or the individual secondary outcomes.
All statistical analyses were performed using SAS 9.1 (SAS Institute, Cary, North Carolina). We compared discrete variables using chi-square test and t test for continuous variables. A p value <0.05 was considered statistically significant. The study protocol was approved by the institutional review board at Baylor College of Medicine and St. Luke’s Episcopal Hospital.
Results
Of 8,889 patients included in this study, 3,983 (45%) were on preoperative ACE inhibitors (“ACE inhibitor group”) and 4,906 (55%) were not on preoperative ACE inhibitors (“no-ACE inhibitor group”). As presented in Table 1 , patients who received ACE inhibitors were more likely to be women, older, African-American and have marginally higher body mass index compared with the no-ACE inhibitor group. They also had a higher prevalence of smoking, hypertension, diabetes mellitus, peripheral vascular disease, previous MI, renal insufficiency, and ejection fraction <35%. Beta-blocker and statin use was significantly higher in patients receiving ACE inhibitors compared to those not on ACE inhibitors preoperatively.
| Variable | Preoperative ACE Inhibitors | p Value | |
|---|---|---|---|
| Yes (n = 3,983) | No (n = 4,906) | ||
| Age (years) | 64.17 ± 10.44 | 63.61 ± 10.69 | 0.007 |
| Men | 2,964 (74.42%) | 3,747 (76.38%) | 0.03 |
| African-American | 419 (10.52%) | 413 (8.42%) | 0.0007 |
| Body mass index (kg/m 2 ) | 29.49 ± 5.78 | 28.59 ± 5.54 | <0.0001 |
| Smoker | 2,035 (51.14%) | 2,403 (49.02%) | 0.047 |
| Diabetes mellitus | 1,964 (49.31%) | 1,622 (33.06%) | <0.0001 |
| Hypertension | 3,732 (93.70%) | 3,752 (76.48%) | <0.0001 |
| Unstable angina pectoris | 1,717 (43.11%) | 2,212 (45.09%) | 0.06 |
| Previous myocardial infarction | 1,679 (42.15%) | 1,949 (39.73%) | 0.02 |
| History of atrial fibrillation | 219 (6.67%) | 258 (7.08%) | 0.50 |
| Peripheral vascular disease | 930 (23.35%) | 955 (19.47%) | <0.0001 |
| Cerebrovascular disease | 309 (7.76%) | 334 (6.81%) | 0.08 |
| Renal insufficiency | 796 (19.98%) | 843 (17.18%) | 0.0007 |
| Ejection fraction <35% | 617 (15.49%) | 565 (11.52%) | <0.0001 |
| New York Heart Association class III or IV | 2,677 (67.21%) | 3,464 (70.61%) | 0.0006 |
| Redo coronary bypass | 343 (8.61%) | 387 (7.89%) | 0.097 |
| Urgent coronary bypass | 1,439 (36.13%) | 1,797 (36.63%) | 0.63 |
| Preoperative need for intra-aortic balloon pump | 256 (5.22%) | 196 (4.92%) | 0.53 |
| Aortic cross-clamp time >80 minutes | 1,220 (30.63%) | 1,447 (29.49%) | 0.25 |
| Statin use | 2,360 (71.89%) | 2,124 (57.91%) | <0.0001 |
| β-Blocker use | 2,351 (59.03%) | 2,491 (50.77%) | <0.0001 |
Table 2 presents the incidence of the primary and individual secondary outcomes. Overall incidence of MAEs (primary outcome) was 38.1% (n = 1,518) in those on ACE inhibitors compared to 33.6% (n = 1,649) in those not on preoperative ACE inhibitors. For the individual secondary outcomes, incidences of postoperative renal dysfunction and postoperative atrial fibrillation were higher in the ACE inhibitor group compared to the no-ACE inhibitor group.
| Outcome | Preoperative ACE Inhibitors | p Value ⁎ | |
|---|---|---|---|
| Yes (n = 3,983) | No (n = 4,906) | ||
| Major adverse events | 1,518 (38.1%) | 1,649 (33.6%) | <0.0001 |
| In-hospital mortality | 144 (3.62%) | 199 (4.06%) | 0.29 |
| Postoperative renal dysfunction | 522 (13.1%) | 495 (10.1%) | <0.0001 |
| Postoperative stroke | 123 (3.1%) | 125 (2.6%) | 0.14 |
| Postoperative atrial fibrillation | 1,062 (26.7%) | 1,166 (23.8%) | 0.0018 |
| Postoperative myocardial infarction | 144 (3.62%) | 146 (2.98%) | 0.09 |
⁎ Unadjusted (see Tables 3 and 4 for adjusted analyses).
Table 3 lists the independent predictors associated with MAEs. Age >65 years, male gender, diabetes mellitus, body mass index, hypertension, urgent CABG, redo CABG, aortic cross-clamp time >80 minutes, and need for intra-aortic balloon pump were independently associated with MAEs. Preoperative ACE inhibitor use was associated with a 13% increase in the risk of MAEs in the fully adjusted model.
| Variable | OR (95% CI) | p Value |
|---|---|---|
| Age >65 years | 1.91 (1.74–2.09) | <0.0001 |
| Diabetes mellitus | 1.16 (1.06–1.28) | 0.0016 |
| Cerebrovascular accident | 1.23 (1.03–1.46) | 0.019 |
| Peripheral vascular disease | 1.35 (1.20–1.50) | <0.0001 |
| Renal insufficiency | 1.89 (1.68–2.11) | <0.0001 |
| Low ejection fraction | 1.33 (1.16–1.51) | <0.0001 |
| Urgent coronary artery bypass grafting | 1.29 (1.18–1.42) | <0.0001 |
| Redo coronary artery bypass grafting | 1.32 (1.13–1.55) | 0.0006 |
| Aortic cross clamp time >80 minutes | 1.20 (1.09–1.32) | 0.0003 |
| Preoperative need for intra-aortic balloon pump | 1.38 (1.12–1.69) | 0.0021 |
| Use of preoperative angiotensin-converting enzyme inhibitor | 1.13 (1.03–1.24) | 0.0063 |
⁎ Major adverse events adjusted for age <65 years, male gender, African-American race, body mass index, diabetes mellitus, hypertension, New York Heart Association class III or IV symptoms; previous myocardial infarction cerebrovascular accident, peripheral vascular disease, renal insufficiency, β-blocker use, statin use, urgent coronary artery bypass grafting, redo coronary artery bypass grafting, need for preoperative intra-aortic balloon pump, and aortic cross-clamp time >80 minutes.
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