Influence of Preoperative Lipid-Lowering Therapy on Postoperative Outcome in Patients Undergoing Coronary Artery Bypass Grafting

Influence of Preoperative Lipid-Lowering Therapy on Postoperative Outcome in Patients Undergoing Coronary Artery Bypass Grafting Brian D. Powell, MDa,*, Kevin A. Bybee, MDd, Uma Valeti, MDc, Randal J. Thomas, MDa, Stephen L. Kopecky, MDa, Charles J. Mullany, MB, MSb, and R. Scott Wright, MDa Statin therapy has recently been shown to decrease adverse perioperative events in patients undergoing vascular surgery. The potential beneficial effect of lipid-lowering therapy in patients undergoing coronary artery bypass grafting (CABG) is not well known. This was an observational analysis of 4,739 patients who underwent first-time isolated CABG at a single institution from 1995 to 2001. Patients were categorized into 2 groups based on treatment with a lipid-lowering agent within 30 days before surgery. Univariate and multivariate analyses were used to determine the association between lipid-lowering therapy and survival to hospital discharge. Patients in the lipid-lowering group (n ⴝ 2,334) tended to be younger (mean age 66 ⴞ 10 vs 68 ⴞ 10 years), were more likely to be diabetic (31% vs 28%), and on ␤ blockers (77% vs 70%) than patients in the nonlipid-lowering group (n ⴝ 2,405). In-hospital mortality was significantly lower in the lipid-lowering group than in the nonlipid-lowering therapy group (1.4% vs 2.2%, odds ratio 0.62, 95% confidence interval 0.40 to 0.96, p ⴝ 0.03). A multivariable model demonstrated a loss of statistical significance for the effect of lipid-lowering therapy on in-hospital mortality (adjusted odds ratio 0.83, 95% confidence interval 0.5 to 1.37, p ⴝ 0.46). In conclusion, preoperative use of lipid-lowering therapy in patients undergoing CABG appears safe and is associated with improved survival to hospital discharge compared with patients not receiving lipid-lowering therapy. However, patient risk factors and other cardioprotective medication use associated with the use of preoperative lipid-lowering therapy appear to explain the association with improved survival. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:785–789)

Lipid-lowering medications slow progression of atherosclerosis in bypass grafts and decrease the number of long-term cardiovascular events in patients after coronary artery bypass grafting (CABG).1– 4 However, lipid-lowering therapy was initiated ⱖ3 months after bypass surgery in these trials. There are few published data evaluating the effect of preoperative lipid-lowering therapy on early postoperative outcomes after CABG or on the safety of lipid-lowering medications during the perioperative period.5– 8 Statins have been associated with decreased perioperative cardiac complications in patients undergoing vascular surgery,9 and in 1 observational study were associated with improved outcomes soon after CABG.5 It is plausible that preoperative lipid-lowering therapy, in particular hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins), could have beneficial effects in the early postoperative period. Statins have beneficial effects on endothelial function and plaque stabilization, decrease markers of inflammation, and attenuate myocardial ischemia-reperfusion injury.10 –16 In this Divisions of aCardiovascular Diseases and bCardiothoracic Surgery, Mayo Clinic, Rochester, and cDepartment of Cardiology, St. Paul Heart Clinic, St. Paul, Minnesota; and dMid America Heart Institute, Cardiovascular Consultants; Kansas City, Missouri. Manuscript received August 9, 2006; revised manuscript received and accepted October 30, 2006. This work was supported by a grant from Merck & Co., Inc., Whitehouse Station, New Jersey. *Corresponding author: Tel: 507-284-3545; fax: 507-284-1203. E-mail address: [email protected] (B.D. Powell). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.10.036

study, we analyzed the association between preoperative lipid-lowering therapy and early postoperative outcomes in patients undergoing CABG. Methods Study design: This study was an observational study including 4,739 consecutive patients who underwent firsttime isolated CABG at our institution from January 1, 1995 to December 31, 2001. Patients were classified to 1 of 2 groups depending on whether or not they had received lipid-lowering medication within the 30 days before CABG. We evaluated the association between preoperative lipidlowering therapy and postoperative outcomes. This study was approved by the institutional review board. All patients had previously granted permission for use of their medical records for research purposes. Study data: Data used in this analysis were retrieved from the Mayo Clinic Cardiothoracic Surgery database. This database includes prospectively collected information on all patients undergoing cardiothoracic surgery at the Mayo Clinic (Rochester, Minnesota). This database includes data entered as part of the Society of Thoracic Surgeons Database project and other prespecified clinical data. Within the database, patients were coded as having cerebrovascular disease if they had a previous cerebrovascular accident, residual ischemic neurologic deficit, transient ischemic attack, or documented stenosis ⱖ75% in the common and/or internal carotid circulation. Patients were coded www.AJConline.org

786

The American Journal of Cardiology (www.AJConline.org)

Table 1 Patient characteristics Variables

Age (yrs), (mean ⫾ SD) Women Smoker Diabetes mellitus Hypercholesterolemia (total cholesterol ⬎200 mg/dl) Renal failure Dialysis Cerebrovascular accident Previous myocardial infarction Time of myocardial infarction before surgery ⬍6 h 6–24 h 1–7 d 8–21 d ⬎21 d Previous arrhythmia (within 2 wks) Cardiogenic shock NYHA class I/II heart failure Surgery status—elective Preoperative medications Antiarrhythmics Angiotensin converting-enzyme inhibitors Anticoagulants Antiplatelets (including aspirin) ␤ blockers Calcium channel blockers Digitalis

Antihyperlipidemics

p Value

No (n ⫽ 2,405)

Yes (n ⫽ 2,334)

68 ⫾ 10 550 (23%) 1,521 (63%) 666 (28%) 1,487 (62%) 105 (4%) 23 (1%) 149 (6%) 1,147 (48%)

66 ⫾ 10 596 (26%) 1,512 (65%) 729 (31%) 2,284 (98%) 101 (4%) 16 (1%) 158 (7%) 1,040 (45%)

23 (2%) 46 (4%) 357 (31%) 143 (13%) 578 (50%) 350 (15%) 58 (2%) 2,105 (88%) 2,024 (84%)

10 (1%) 16 (2%) 247 (24%) 109 (10%) 653 (63%) 256 (11%) 26 (1%) 1,997 (86%) 1,932 (83%)

⬍0.001 ⬍0.001 0.04 0.2

149 (6%) 762 (32%) 1,265 (53%) 2,135 (89%) 1,688 (70%) 802 (33%) 263 (11%)

90 (4%) 930 (40%) 1,002 (43%) 2,150 (97%) 1,812 (77%) 818 (35%) 189 (8%)

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.22 ⬍0.001

⬍0.001 0.03 0.28 0.01 ⬍0.001 0.95 0.3 0.42 0.03 ⬍0.001

NYHA ⫽ New York Heart Association.

as having renal insufficiency if the preoperative serum creatinine level was ⱖ2.0 mg/dl. Hypercholesterolemia was defined as a serum total cholesterol level ⱖ200 mg/dl and/or low-density lipoprotein level ⬎130 mg/dl and/or treatment with a cholesterol-lowering medication. Outcome measurements: All-cause in-hospital mortality after CABG was the primary outcome measurement. Prespecified secondary outcomes included rates of cerebrovascular events, reoperation for bleeding, and postoperative atrial fibrillation. Adverse cerebrovascular events were defined as a cerebral vascular accident or transient ischemic attack, which was diagnosed by a neurologist during the postoperative hospitalization period. Statistical analysis: Continuous variables are reported as means ⫾ SDs and as medians. Categorical variables are reported as percentages. Wilcoxon rank-sum tests were used in univariate analysis of continuous data. Chi-square test was used in univariate analysis of categorical data. Univariate and multivariate associations of demographic, clinical, and therapeutic variables with the end points were assessed by logistic regression. Multivariate models were calculated using stepwise logistic regression, with entry and retention in the model set at significance levels of 0.15 and 0.05, respectively. Odds ratios (ORs) and their associated 95% confidence intervals (CIs) were then estimated. A p value ⬍0.05 was considered statistically significant.

Table 2 Procedural characteristics Characteristic

No. of distal anastamoses Internal mammary graft used Aortic cross-clamp time (min)

Preoperative Lipid-lowering Therapy Yes (n ⫽ 2,334)

No (n ⫽ 2,405)

3 (3, 4) 2,243 (96%) 48 (36, 60)

3 (3, 4) 2,304 (96%) 49 (36, 61)

p Value

0.04 0.60 0.15

Values are medians (25th, 75th percentiles) or numbers of patients (percentages).

Results Patient characteristics: Of the 4,739 patients, 2,334 (49%) had received a lipid-lowering agent within the 30 days before CABG, whereas the remaining 2,405 (51%) had not received lipid-lowering therapy within this period. Demographic and clinical data of the 2 groups are presented in Table 1. A random sample of 100 patients in the lipidlowering group demonstrated that 86% were on a statin as their lipid-lowering agent. Patients in the lipid-lowering group tended to be younger, were more likely to be diabetic, and more likely to use ␤ blockers than those in the nonlipid-lowering group (Table 1). Patients on lipid-lowering therapy were less likely to have had a recent myocardial infarction (27% vs

Coronary Artery Disease/Preoperative Lipid-Lowering Therapy in CABG Table 3 Univariate logistic results for in-hospital mortality Variable

OR

95% CI

p Value

Age Women Ejection fraction ⬍50% Hypercholesterolemia Diabetes mellitus Dialysis Smoker NYHA class III/IV heart failure Cerebrovascular accident Previous myocardial infarction Previous arrhythmia (within 2 wks) Cardiogenic shock No. of vessels diseased* Surgery status—elective Date of admission, 4 levels Angiotensin-converting enzyme inhibitors† Anticoagulants† Aspirin‡ ␤ blockers† Calcium channel blockers† Digitalis† Lipid-lowering medication†

1.08 1.82 1.42 0.63 1.53 6.52 1.44 2.51 2.68 1.86 1.47 8.25 1.86 0.29 0.85 1.54

1.05–1.11 1.17–2.85 0.9–2.26 0.39–1.01 0.99–2.38 2.26–18.76 0.89–2.31 1.01–6.22 1.47–4.89 1.2–2.88 0.84–2.59 4.1–16.6 1.05–3.32 0.18–0.45 0.68–1.05 1–2.37

⬍0.001 0.01 0.13 0.06 0.06 ⬍0.001 0.14 0.05 ⬍0.001 0.01 0.18 ⬍0.001 0.03 ⬍0.001 0.13 0.05

2.25 0.69 0.80 1.36 1.90 0.62

1.42–3.55 0.4–1.2 0.5–1.28 0.88–2.1 1.06–3.4 0.4–0.96

⬍0.001 0.19 0.35 0.17 0.03 0.03

There were 4,739 patients with 80 events. * Vessels with ⬎50% stenosis on angiography. † Medication within 30 days before surgery. ‡ Medication within 7 days before surgery. Abbreviation as in Table 1.

37%, p ⬍0.01). Surgical procedural characteristics were similar in the 2 groups (Table 2). Outcome measurements: Clinical characteristics associated with increased risk of death after CABG are listed in Table 3. Medications associated with decreased risk of death after CABG included lipid-lowering medications (Table 3). The observed in-hospital mortality rates were low in the 2 groups. Unadjusted in-hospital mortality was significantly lower in patients receiving lipid-lowering therapy than in patients not receiving preoperative lipid-lowering therapy (1.4% vs 2.2%, OR 0.62, 95% CI 0.40 to 0.96, p ⫽ 0.03). This resulted in an observed 36% relative decrease in all-cause in-hospital mortality in patients receiving preoperative lipid-lowering therapy (Figure 1). However, after adjustment for the variables listed in Table 4, this association lost statistical significance (adjusted OR 0.83, 95% CI 0.5 to 1.37, p ⫽ 0.46). Risk factors for increased mortality included female gender, diabetes, dialysis, and cardiogenic shock (Table 4). Aspirin use was associated with lower mortality, consistent with previous studies.17,18 There was no significant difference between groups with regard to postoperative adverse cerebrovascular events (2.6% vs 3.0%, p ⫽ 0.48), reoperation for bleeding (3.3% vs 3.3%, p ⫽ 0.91), or postoperative atrial fibrillation (28.8% vs 30.5%, p ⫽ 0.18). Discussion The present study evaluated the association between preoperative lipid-lowering therapy and postoperative outcomes

787

in a large group of patients who underwent first-time isolated CABG. We found that taking a lipid-lowering medication before CABG appears to be safe. It was associated with a 0.8% absolute risk decrease and a 36% decrease in the risk of postoperative in-hospital mortality. However, patient risk factors and other cardioprotective medication use associated with the use of preoperative lipid-lowering therapy appear to explain the association with improved survival. The mechanism by which lipid-lowering agents might improve survival after CABG could not be assessed in our analysis. However, pharmacologic lowering of serum cholesterol has been shown to improve long-term cardiovascular outcomes in patients with coronary artery disease regardless of baseline low-density lipoprotein levels.19 Cholesterol lowering decreases the rate of low-density lipoprotein oxidation with a subsequent decrease in lipid accumulation within coronary plaque. In addition, statins have many pleiotropic effects that may play a role in cardiovascular protection, including improvement of endothelial function, decreased inflammatory mediators, decreased platelet activation and aggregation, and attenuation of myocardial ischemia-reperfusion injury.7,11,14 –16 These mechanisms may be beneficial acutely in patients undergoing coronary artery bypass surgery. Several animal studies have shown that statin pretreatment decreases infarct size and leukocyte infiltration into ischemic myocardium in models of experimental myocardial infarction and ischemia-reperfusion injury.20 –23 Several recently published studies have shown that statin therapy immediately after presentation with an acute coronary syndrome is associated with a decrease in short-term adverse cardiovascular events.21,24 –27 In addition, statin pretreatment decreases the risk and extent of procedure-related myocardial infarction in patients undergoing percutaneous coronary revascularization.28 Dontani et al6 reported a retrospective analysis of 323 patients who underwent CABG. Their findings suggested a potential benefit of preoperative statin therapy, but the small number of total adverse events limited the analysis. Clark et al8 reported a retrospective analysis with findings of lower mortality in patients who received a statin before cardiac surgery. Pan et al5 in a cohort of 1,663 patients, found that statin therapy before isolated CABG was independently associated with a lower risk of mortality at 30 days after surgery. The mortality rate of 3.75% in the study by Pan et al5 was higher than that in our study (2.2% in the nonlipidlowering medication group). However, despite our larger sample, we were unable to show that lipid-lowering therapy is independently associated with lower postoperative mortality. Ali et al29 analyzed the effect of preoperative statin use in a higher risk CABG population of patients with unstable angina. They found results similar to those of the present study with lower in-hospital mortality in the statin group; however, patients on statins had a lower risk profile. After adjustment for other risk factors, statin use was not associated with a significant decrease in mortality. Other studies have demonstrated improved survival in patients who received aspirin or ␤-blocker therapy before CABG.17,18,30 Even with multivariate analysis, it may be difficult to separate the independent effects of

788

The American Journal of Cardiology (www.AJConline.org)

Figure 1. In-hospital mortality after CABG. LLT ⫽ lipid-lowering therapy. Table 4 Multivariate results for in-hospital mortality Variable

Age Women Diabetes Dialysis No. of diseased vessels Cardiogenic shock, preoperative Lipid-lowering medication† Aspirin* Anticoagulants† ␤ blockers† Angiotensin-converting enzyme inhibitors†

In-Hospital Mortality OR

95% CI

p Value

1.08 1.82 1.82 10.83 2.05 3.44 0.83 0.57 1.86 0.7 1.31

1.05–1.11 1.12–2.98 1.15–2.88 3.39–34.57 1.01–4.15 1.34–8.85 0.50–1.37 0.32–1.01 1.11–3.12 0.42–1.17 0.8–2.14

⬍0.001 0.02 0.01 ⬍0.001 0.05 ⬍0.001 0.46 0.05 0.02 0.17 0.28

There were 4,739 patients with 80 events. * Medication within 7 days before surgery. † Medication within 30 days before surgery.

aspirin, ␤ blockers, and lipid-lowering agents on postoperative survival. Our study adds to findings of previous studies suggesting that use of preoperative statin therapy may have beneficial effects in patients undergoing CABG. Limitations of our study include the retrospective nature of our analysis and that preoperative lipid-lowering therapy was not a randomized assignment. As a result, there may have been treatment bias in the lipid-lowering group. We attempted to adjust for these differences using logistic regression. However, unmeasured differences between groups cannot be accounted for without randomization. Precise characterization of lipid-lowering therapy could not be ascertained from our database; therefore, the exact distribution and dosages of lipid-lowering agents used by the analyzed patients could not be determined. However, a random sampling of patients in the lipid-lowering group showed that most (86%) were on a statin as their lipid-lowering agent before CABG.

1. Knatterud GL, Rosenberg Y, Campeau L, Geller NL, Hunninghake DB, Forman MA, Forrester JS, Gobel FL, Herd JA, Hickey A, et al. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Circulation 2000; 102:157–165. 2. Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A, Taskinen MR. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation 1997;96:2137–2143. 3. Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA 1990;264:3013–3017. 4. Campeau L, Knatterud GL, Domanski M, Hunninghake DB, White CW, Geller NL, Rosenberg Y. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary artery bypass grafts. N Eng J Med 1997;336:153–162. 5. Pan W, Pintar T, Anton J, Lee VV, Vaughn WK, Collard CD. Statins are associated with a reduced incidence of perioperative mortality after coronary artery bypass graft surgery. Circulation 2004;110(suppl):II45–II-49. 6. Dontani MI, Elnicki DM, Jain AC, Gibson CM. Effect of preoperative statin therapy and cardiac outcomes after coronary artery bypass grafting. Am J Cardiol 2000;86:1128 –1130. 7. Christenson JT. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG. Eur J Cardiothorac Surg 1999;15:394 –399. 8. Clark L, Ikonomidis J, Crawford F, Crumbley A, Kratz J, Stroud M, Woolson R, Buruce J, Nicholas J, Lackland D, Zile M, Spinale F. Preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery: an 8-year retrospective cohort study. J Thorac Cardiovasc Surg 2006; 131:679 – 685. 9. Callahan KO, Katsimaglis G, Tepper MR, Ryan J, Mosby C, Ioannidis JP, Danias PG. Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery. J Am Coll Cardiol 2005;45:336 –342. 10. Chello M, Carassiti M, Agro F, Mastroroberto P, Pugliese G, Colonna D, Covino E. Simvastatin blunts the increase of circulating adhesion molecules after coronary artery bypass surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesthes 2004;18:605– 609. 11. O’Driscoll G, Green D, Taylor R. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997;95:1126 –1131. 12. Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes:

Coronary Artery Disease/Preoperative Lipid-Lowering Therapy in CABG

13.

14.

15. 16.

17. 18. 19.

20. 21.

the RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation 1999;99:3227–3233. Bustos C, Hernandez-Presa M, Ortego M, Tunon J, Ortega L, Perez F, Diaz C, Hernandez G, Edgido J. HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis. J Am Coll Cardiol 1998;32:2057–2064. Beigel Y, Fuchs J, Snir M, Green P, Lurie Y, Djaldetti M. Lovastatin therapy in hypercholesterolemia: effect on fibrinogen, hemorheologic parameters, platelet activity, and red blood cell morphology. J Clin Pharmacol 1991;31:512–517. Brull DJ, Sanders J, Rumley A, Lowe G, Humphries SE, Montgomery HE. Statin therapy and the acute inflammatory response after coronary artery bypass grafting. Am J Cardiol 2001;88:431– 433. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of staatin therapy on C-reactive protein levels. The Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286:64 –70. Ferguson TB, Coombs LP, Peterson ED. Preoperative beta-blocker use and mortality and morbidity following CABG surgery in North America. JAMA 2002;287:2221–2227. Mangano DT, Group MSoPIR. Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002;347:1309 –1317. Collins R, Armitage J, Parish S, Sleight P, Peto R, Group HPS. Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005–2016. Ikeda Y, Young LH, Lefer AM. Rosuvastatin, a new HMG-CoA reductase inhibitor, protects ischemic reperfused myocardium in normocholesterolemic rats. J Cardiovasc Pharm 2003;41:649 – 656. Lefer DJ, Scalia R, Jones SP, Sharp BR, Hoffmeyer MR, Farvid AR, Gibson MF, Lefer AM. HMG-CoA reductase inhibition protects the diabetic myocardium from ischemia-reperfusion injury. FASEB J 2001;15:1454 –1456.

789

22. Wayman NS, Ellis BL, Thiemermann C. Simvastatin reduces infarct size in a model of acute myocardial ischemia and reperfusion in the rat. Med Sci Monit 2003;9(suppl):BR155–BR159. 23. Rendig SV, Symons JD, Amsterdam EA. Effects of statins on myocardial and coronary artery response to ischemia-reperfusion. Can J Phys Pharmacol 2003;81:1064 –1071. 24. Arntz H, Wunderlich W, Schnitzer L, Stern R, Fischer F, Agrawal R, Linderer T, Schultheiss HP. Short- and long-term effects of intensified versus conventional antilipidemic therapy in patients with coronary heart disease. Results from the Lipid-Coronary Artery Disease (L-CAD) Study. Zeitschr Kardiol 1999;88:582–590. 25. Bybee K, Wright R, Williams B, Murphy J, Holmes D Jr, Kopecky S. Effect of concomitant or very early statin administration on in-hospital mortality and re-infarction rates in patients with acute myocardial infarction. Am J Cardiol 2001;87:771–774. 26. Schwarzt GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on early recurrent ischemc events in acute coronary syndrome: the MIRACL study. JAMA 2001;285:1711–1718. 27. Kayikcioglu M, Can L, Kultursay H, Payzin S, Turkoglu C. Early use of pravastatin in patients with acute myocardial infarction undergoing coronary angioplasty. Acta Cardiol 2002;57:295–302. 28. Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciasco G. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA study. Circulation 2004;110:674 – 678. 29. Ali I, Buth K. Preoperative statin use and in-hospital outcomes following heart surgery in patients with unstable angina. Eur J Cardiothorac Surg 2005;27:1051–1056. 30. Bybee K, Powell B, Valeti V, Rosales A, Kopecky S, Mullany C, Wright R. Pre-operative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting. Circulation 2005;112(suppl I):I-286 –I-292.