Journal of the American College of Cardiology Vol. 36, No. 4, by the American College of Cardiology ISSN /00/$20.

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1 Journal of the American College of Cardiology Vol. 36, No. 4, by the American College of Cardiology ISSN /00/$20.00 Published by Elsevier Science Inc. PII S (00) Diabetes and Outcomes of Coronary Artery Byass Graft Surgery in Patients With Severe Left Ventricular Dysfunction: Results from The CABG Patch Trial Database William Whang, MD, MS, J. Thomas Bigger, Jr., MD, FACC, for The CABG Patch Trial Investigators and Coordinators New York, New York OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS We examined the relationshi between diabetes mellitus and outcomes after coronary artery byass graft (CABG) surgery in atients with severe left ventricular (LV) dysfunction. Although diabetes is associated with oor outcomes after CABG surgery among unselected atients, the relationshi between diabetes and mortality after CABG surgery among atients with LV dysfunction is less certain. Using data from The CABG Patch Trial, a study of imlantable cardiac defibrillator theray, we analyzed 900 atients with ejection fraction 0.36 who underwent CABG surgery from 1990 to Diabetics comrised 38% of the atients, and 48% of diabetics were rescribed insulin. Diabetes was associated with hyertension, eriheral vascular disease, history of stroke, clinical heart failure and rales on hysical exam. Diabetics were at higher risk for ostoerative suerficial sternal wound infection and renal failure. With an average follow-u time of months, actuarial all-cause mortality 48 months after CABG surgery was 26% in diabetics and 24% in nondiabetics ( 0.66, log-rank test). Diabetes was not associated with long-term mortality in Cox multile regression analyses. Actuarial re-hositalization rates 48 months after CABG surgery were 85% in diabetics and 69% in nondiabetics ( , log-rank test). Diabetics had a 44% higher risk of re-hositalization for any cause ( ) and a 24% higher risk of re-admission for cardiac causes ( 0.05). Unexectedly, fewer arrhythmic events were found in diabetics. Diabetes was not a redictor of mortality after CABG surgery among atients with LV dysfunction desite associated comorbidities. However, diabetes was associated with increased ostoerative comlications and re-hositalization. (J Am Coll Cardiol 2000;36: ) 2000 by the American College of Cardiology Diabetes is a risk factor for coronary artery disease (CAD) and heart failure (1,2). Investigators have osited several ossible mechanisms for the association between diabetes and heart disease, including abnormalities in liid metabolism, nitric oxide activity, latelet function, coagulation and autonomic function (3 7). Not only is diabetes a risk factor for CAD, but observational studies have also linked it with worse outcomes after revascularization via coronary artery byass graft (CABG) surgery (8 13). The higher mortality among diabetics after revascularization is felt to be consistent with more severe atherosclerosis associated with diabetic heart disease, ossibly in the form of more diffuse distal CAD that continues to jeoardize myocardium. The association between diabetes and mortality after CABG surgery among atients with left ventricular (LV) dysfunction is less conclusive. Some studies that examined atients with reduced LV ejection fractions (LVEFs) have identified diabetes as a risk factor for mortality (9,14); others have not (15 17). In this study we assessed the long-term From the Deartment of Medicine, New York Presbyterian Hosital, Columbia University, New York, New York. Manuscrit received November 5, 1999; revised manuscrit received March 15, 2000, acceted Aril 28, results of CABG surgery in diabetic atients with LV dysfunction using data from a multicenter trial. We tested two rimary hyotheses: 1) among atients with LV dysfunction who undergo CABG, diabetes is an indeendent redictor of mortality, both all-cause and cardiac; 2) diabetes is a redictor of the risk of re-hositalization, due to all causes and cardiac causes. METHODS Data collection. We erformed a cohort analysis of data collected for The CABG Patch Trial, a randomized study of rohylactic imlantable cardiac defibrillators (ICDs) in high risk coronary heart disease atients undergoing CABG surgery from 1990 to 1996 (18). Criteria for inclusion in the trial included the following: age less than 80 years, LVEF less than 0.36 and an abnormal signal averaged electrocardiogram (ECG). In the main trial, 71,855 atients were screened for inclusion, and 900 atients were randomized and followed for an average of months. Patients were excluded from the trial on the basis of the following: diabetes mellitus with oor blood glucose control or recurrent infections, history of sustained ventricular tachycardia or fibrillation,

2 JACC Vol. 36, No. 4, 2000 October 2000: Whang et al. Diabetes and CABG Surgery 1167 Abbreviations and Acronyms CABG coronary artery byass graft CAD coronary artery disease ECG electrocardiogram ICD imlantable cardiac defibrillator LV left ventricular LVEF left ventricular ejection fraction revious or concomitant aortic or mitral valve surgery, concomitant cerebrovascular surgery, serum creatinine greater than 3 mg er deciliter, emergency coronary byass surgery, noncardiovascular condition with exected survival less than two years or inability to attend follow-u visits. Nurse coordinators at the 37 clinical centers involved in the trial ascertained whether atients had ever been diagnosed with diabetes and whether treatment included insulin. In obtaining information about early ostoerative outcomes, need for mechanical suort was defined as the use of an intra-aortic balloon um or LV assist device on exit from the oerating room, and renal failure was defined as renal dysfunction severe enough to require hemodialysis or eritoneal dialysis (19). After the index hositalization for CABG surgery, follow-u visits were scheduled every three months. Data on hositalizations included the reason for hositalization, whether for a cardiac roblem and whether a definite/robable myocardial infarction, congestive heart failure or ventricular arrhythmias occurred during the hosital stay. An indeendent events committee classified each death that occurred according to whether the mechanism of death was cardiac in nature, for examle, due to arrhythmia, myocardial um failure or cardiac rocedure (20). Statistical analysis. We collected information on baseline demograhic, clinical, angiograhic and intraoerative risk factors for ostoerative comlications, long-term mortality and re-hositalization. We examined differences in baseline variables between diabetic and nondiabetic atients via chi-square tests, with a correction for continuity for dichotomous variables. From our candidate redictors for mortality/morbidity, we used chi-square tests to select indeendent variables for multile logistic regression models of erioerative comlications and log-rank tests to select variables for Cox multile regression models in the case of long-term outcomes. We used backwards stewise regression, with mandatory inclusion of diabetes status, to select models for arsimony. Diabetes status was reresented via two searate models for each outcome one model in which all diabetics were groued together and another in which atients treated with insulin and those treated with oral hyoglycemics or diet were groued searately. We used chi-square tests for nested models to test whether the relationshi between diabetes and outcome significantly differed deending on the tye of treatment for diabetes. Kalan-Meier curves were constructed to comare unadjusted time to death or re-hositalization between diabetics and nondiabetics. All statistical tests were erformed to reject the null hyothesis at a nominal alha level of All analyses were erformed using SAS Version RESULTS Patient characteristics. Among the 900 atients studied, 344 (38%) of the atients were diabetic at the time of CABG surgery (Table 1); 48% of the diabetic atients were treated with insulin. Average follow-u time was months among diabetics and months among nondiabetics. Comared with atients without diabetes, diabetics were more likely to be women, obese and less likely to have a history of tobacco use. Hyertension, eriheral vascular disease, history of stroke, clinical heart failure and rales on hysical exam were more revalent among diabetics. Diabetics and nondiabetics did not significantly differ in their severity of angina, LVEF, resence of left main or trile vessel disease or use of internal mammary artery grafts as conduits. Mean LVEF was in both diabetics and nondiabetics. Before CABG surgery, diabetics were more likely to be treated with angiotensin convertingenzyme inhibitors, diuretics and digoxin and less likely to be treated with beta-adrenergic blocking agents (Table 1). Postoerative comlications. In analyses of erioerative comlications, diabetes was associated with an increased risk of suerficial sternal wound infection and renal failure requiring dialysis (Table 2). The odds of suerficial sternal wound infection were 3.31 times greater ( 0.05) and the odds of renal failure were 2.24 times greater ( 0.05) for diabetic atients than for atients without diabetes. There was a trend toward higher risk for these outcomes among atients treated with insulin than there was among atients treated with oral hyoglycemic agents; however, chi-square tests for the interaction between tye of treatment and both suerficial sternal wound infection and renal failure were not statistically significant. Insulin theray was associated with an increased use of mechanical suort (intra-aortic balloon um or LV assist device). Neither dee sternal wound infection nor neumonia was associated with diabetes in multivariable logistic regression models. There was an increased risk of dee sternal wound infection and neumonia among ICD atients; there was no significant interaction between ICD use and diabetes in regression models of either outcome. Mortality. There were 198 total deaths, 157 cardiac deaths and 43 arrhythmic deaths. The actuarial total mortality rate at 48 months after CABG surgery was 26% in diabetics and 24% in atients without diabetes ( 0.66, log-rank test; Fig. 1). Cardiac and arrhythmic death rates were 19.4% and 6.1%, resectively, in diabetics and 20.7% and 6.9% in atients without diabetes. Diabetes was not significantly associated either with cardiac or arrhythmic mortality by log-rank test. Neither diabetes nor treatment with insulin was signifi-

3 1168 Whang et al. JACC Vol. 36, No. 4, 2000 Diabetes and CABG Surgery October 2000: Table 1. Baseline/Intraoerative Characteristics Among Patients With and Without Diabetes* Variable Diabetes (n 344) No Diabetes (n 556) Odds Age 65 (%) Men (%) Cardiovascular history Hyertension (%) Cholesterol 200 (%) Smoking (%) Periheral vascular disease (%) Stroke (%) COPD (%) Previous CABG surgery (%) Heart failure No heart failure (%) Ref. Class I/II (%) Class III/IV (%) Angina No angina (%) Ref. Class I/II (%) Class III/IV (%) Physical findings Body mass index 30 (%) Rales (%) LVEF 0.20 (%) Ref to 0.30 (%) (%) LVEDP 12 mm Hg (%) Left main disease (%) Trile vessel disease (%) Use of IMA graft (%) ICD grou (%) ACEI (%) Diuretic (%) Digoxin (%) All three (%) Beta-blocker theray (%) *Data were less than the full 900 observations for the following comarisons: cholesterol (n 245 for atients with diabetes, n 400 for atients without diabetes), smoking (n 344, 555), COPD (n 343, 552), history of CABG surgery (n 344, 555), heart failure (n 344, 553), angina (n 319, 523), LVEDP (n 267, 449), left main disease (n 318, 515). ACEI angiotensin converting-enzyme inhibitor; CABG coronary artery byass graft; COPD chronic obstructive ulmonary disease; ICD imlantable cardiac defibrillator; IMA internal mammary artery; LVEDP left ventricular end-diastolic ressure; LVEF left ventricular ejection fraction; Ref. reference. cantly associated with increased long-term mortality in Cox multile regression analyses (Table 3). Age, history of stroke, clinical heart failure, history of revious CABG surgery and body mass index 30 were indeendent, significant redictors of long-term ostoerative mortality in diabetics and in nondiabetics. In analyses of cardiac mortality, diabetes was not a significant redictor of the risk of death due to any cardiac cause. There was a strong trend toward less arrhythmic mortality among diabetics in multile regression analyses; however, it was not statistically significant. As has been reorted reviously (18), defibrillator theray had no effect on long-term mortality, nor was there a significant interaction between defibrillator theray and diabetes. Re-hositalization. The actuarial rate of re-hositalization at 12 months was 54% among diabetics and 41% among nondiabetics; the corresonding rates at 48 months were 85% and 69%, resectively ( , log-rank test; Fig. 2). The elased time before 50% of the diabetic grou was hositalized was 23.7 months; the corresonding time among nondiabetics was 44.8 months. After adjustment for other variables, diabetes was associated with a statistically significant 44% increase in the relative risk of rehositalization (Table 4). Although there was a trend toward a higher risk of re-hositalization for atients treated with insulin than there was for atients treated with oral agents or nonharmacologic theray, tests for the interaction between tye of diabetes treatment and re-hositalization were not statistically significant. Diabetes also was associated with a 24% increase in the risk of re-admission for cardiac reasons. For initial re-hositalizations, the odds that the admission was for noncardiac reasons were 48% higher among diabetics than they were among nondiabetics (Table 5). Re-hositalization was less likely to be due to arrhythmias among diabetics, and relatively fewer

4 JACC Vol. 36, No. 4, 2000 October 2000: Whang et al. Diabetes and CABG Surgery 1169 Table 2. Multivariable Logistic Regression Models for Perioerative Comlications by Outcome* Variable Odds Odds Mechanical suort Diabetes Insulin Oral agent/diet LVEDP 12 mm Hg Previous CABG Suerficial sternal wound infection Diabetes Insulin Oral agent/diet Dee sternal wound infection Diabetes Insulin Oral agent/diet ICD Renal failure Diabetes Insulin Oral agent/diet Age Previous CABG surgery Pneumonia Diabetes Insulin Oral agent/diet ICD *There were two searate logistic regression models for each outcome, one model in which all diabetics were groued together and another in which atients treated with insulin and atients treated with oral hyoglycemics or diet were groued searately. Data were missing for models measuring mechanical suort after byass (n 715). CABG coronary artery byass graft; ICD imlantable cardiac defibrillator; LVEDP left ventricular end-diastolic ressure; not included. ventricular arrhythmias occurred during hositalization of atients with diabetes (Table 5). DISCUSSION In a cohort study of 900 atients in The CABG Patch Trial, we tested two hyotheses of the link between diabetes and outcomes after CABG surgery: 1) among atients with LV dysfunction who undergo CABG, diabetes is an indeendent redictor of mortality, both all-cause and cardiac; and 2) diabetes is a redictor of the risk of rehositalization, due to all causes and cardiac causes. Our study samle comrised 344 diabetics and 556 nondiabetics with low ejection fraction ( 0.36); aroximately half of the atients had clinical heart failure, and 198 died during the follow-u eriod. Half the atients in the study received ICD theray, but ICD theray had no effect on survival. Contrary to our first hyothesis, the long-term risk of death after CABG surgery was not significantly different for diabetics comared with nondiabetics, desite higher rates of comorbidities such as hyertension, heart failure, eriheral vascular disease and history of stroke among diabetics. However, diabetes was associated with a higher risk of rehositalization, including those for cardiac reasons. Comarisons with other studies. Previous studies have included diabetes as an exlanatory variable for mortality after CABG surgery among atients with reduced LV function with varying results. As art of a larger study of CABG surgery in diabetics, Morris and colleagues (9) included aroximately 870 atients with ejection fraction 0.40, of whom about 27% were diabetic. Five-year mortality was 34% among diabetics and 20% among nondiabetics ( 0.02). Trachiotis and colleagues (14) examined Figure 1. Post-CABG survival by diabetes status ( 0.66, log-rank test). Dotted line no diabetes; solid line diabetes. Figure 2. Freedom from initial hositalization ost-cabg by diabetes status ( , log-rank test). Dotted line no diabetes; solid line diabetes.

5 1170 Whang et al. JACC Vol. 36, No. 4, 2000 Diabetes and CABG Surgery October 2000: Table 3. Multivariable Cox Regression Models for Mortality* All-cause Mortality (n 198) Cardiac Mortality (n 157) Arrhythmic Mortality (n 43) Variable Diabetes Insulin Oral agent/diet Age (NS) (NS) (NS) (NS) Body mass index (NS) (NS) (NS) (NS) (NS) (NS) (NS) (NS) Stroke (NS) (NS) (NS) (NS) (NS) (NS) (NS) (NS) Heart failure Periheral vascular disease (NS) (NS) (NS) (NS) (NS) (NS) (NS) (NS) Previous CABG surgery (NS) (NS) (NS) (NS) IMA graft (NS) (NS) (NS) (NS) (NS) (NS) (NS) (NS) ICD grou (NS) (NS) (NS) (NS) (NS) (NS) (NS) (NS) *There were two searate Cox roortional hazard models for each outcome, one model in which all diabetics were groued together and another in which atients treated with insulin and atients treated with oral hyoglycemics or diet were groued searately. Variables labeled (NS) were not significantly related to the articular outcome in single variable analyses and were droed before stewise multivariable analyses. CABG coronary artery byass graft; ICD imlantable cardiac defibrillator; IMA internal mammary artery; not included. long-term survival after CABG surgery in 11,830 atients, of whom 156 atients had ejection fraction 0.25, and 588 atients had ejection fraction 0.25 to In an analysis inclusive of all the atients regardless of ventricular function, diabetes was associated with a 59% increase in the relative risk of death ( ). Gill and colleagues (15) found that among 166 atients with ejection fraction 0.31, during 4.75 years of follow-u, diabetes was not associated with reduced survival after CABG surgery. Kaul and colleagues (16) measured outcomes in 210 atients with LVEF 0.20 who underwent CABG surgery at University of Alabama from 1987 to During an average follow-u of 43 months, diabetes was not significantly associated with excess long-term mortality. Milano and colleagues (17) studied outcomes among 118 atients with ejection fraction 0.25, of whom 33% were diabetic. Diabetes was not associated with long-term mortality in single variable analyses. Exlanations for lack of mortality findings. The lack of a relationshi between diabetes and mortality after CABG surgery in our analysis has multile otential exlanations. Our study had adequate ower to detect an association of diabetes mellitus with long-term cumulative mortality. The mortality rate was 26% at 48 months after CABG surgery among diabetics, giving us aroximately 80% ower to detect a 35% relative difference or a 9% absolute difference in mortality at a two-tailed alha level of It is ossible that diabetes does not contribute to the underlying force of mortality after CABG surgery in ischemic cardiomyoathy to as large an extent as it does in CAD with reserved ventricular function. Alternatively, diabetic atients with ventricular dysfunction may derive a larger benefit from revascularization of jeoardized myocardium and, therefore, have similar lifesans as nondiabetics after surgery. Morbidity findings. Although the risk of death was not higher for diabetics in our study, diabetes was clearly a risk factor for morbidity after CABG surgery. There was a strong association with erioerative comlications including renal failure, suerficial sternal wound infection and use of mechanical circulatory suort. The association with sternal wound infection is consistent with revious studies of CABG surgery in diabetic atients (21 25). The association between sternal wound infection and eicardial ICD use in our analysis has been documented in-deth by Sotnitz and colleagues (19) and may result artly from reorting bias. The time to ostoerative re-hositalization was significantly shorter for diabetics. The one year re-hositalization rate was 54% among diabetics comared with 41% in nondiabetics. It took almost twice as long for atients in the nondiabetic grou to reach a 50% re-hositalization rate comared with those in the diabetic grou (44.8 vs months, resectively). Hositalizations for noncardiac causes comrised a higher roortion of re-admissions among diabetics. However, in the context of a much higher overall re-hositalization rate, there was a higher relative

6 JACC Vol. 36, No. 4, 2000 October 2000: Whang et al. Diabetes and CABG Surgery 1171 Table 4. Multivariable Cox Regression Models for Hositalization Variable Hositalization for Any Reason Hositalization for Cardiac Reason Diabetes Insulin Oral agent/diet Age Stroke Heart failure ICD *There were two searate Cox roortional hazard models for each outcome, one model in which all diabetics were groued together and another in which atients treated with insulin and atients treated with oral hyoglycemics or diet were groued searately. ICD imlantable cardiac defibrillator; not included. risk of cardiac hositalization among diabetics, which is consistent with our second hyothesis regarding excess morbidity. The imlications of our findings for long-term resource use and costs are significant and have yet to be fully quantified. Arrhythmic events. The CABG Patch Trial is the only study, to our knowledge, of atients after CABG surgery that has rosectively collected data on ventricular arrhythmias and arrhythmic death during long-term follow-u. The adjusted risk for arrhythmic death in diabetics was almost half that in nondiabetics, although with 43 total arrhythmic deaths, this was not a statistically significant finding. Arrhythmia was less often the reason for initial re-hositalizations after CABG surgery in diabetics, and substantially fewer ventricular arrhythmias occurred during hositalizations in diabetics. Given the ast evidence that has linked autonomic dysfunction with diabetes, we exected more, not less, arrhythmic events among the diabetics in our study. About 40% of diabetics with and without ischemic heart disease have cardiac autonomic nerve dysfunction, that is, reduced arasymathetic and increased symathetic modulation of RR intervals (7,26,27), and diabetics with autonomic neuroathy are at increased risk of death comared with diabetics without autonomic neuroathy (28). In addition, rolongation of the QT interval has been noted in diabetic atients with autonomic neuroathy (29,30) and ischemic heart disease (31). However, all the atients in our study had severe LV dysfunction, and the diabetics had a higher revalence of heart failure. The UK-Heart study showed that, among heart failure atients, reduced heart rate variability was the best redictor of death due to heart failure but did not redict sudden cardiac death (32). Ischemic cardiomyoathy may interact with the effect of diabetes and autonomic neuroathy on arrhythmic events. Also, diabetics could benefit more from revascularization than nondiabetics, articularly with resect to their arrhythmic substrate. Further studies are needed to examine the incidence and significance of ventricular arrhythmias after CABG surgery in diabetics. Study limitations. One otential disadvantage of this analysis is the fact that diabetic atients with oor blood glucose control or recurrent infections and atients with serum creatinine 3 mg/dl were excluded from the trial. These two grous resectively comrised about 0.6% and 0.5% of the 71,855 screened atients in the enrollment cascade (33). Thirty-eight ercent of the 900 atients in the trial had diabetes, a larger ercentage than most revious observational studies of CABG surgery. Another limitation of this study was that the extent of glucose control, in terms of serum glucose levels or glycosylated hemoglobin levels, was not available from our database. In addition, the retrosective nature of our analysis limited the strength of inferences from the data. However, the multicenter exerience rovided by our samle strengthens its generalizability. Conclusions. Our analysis indicates that diabetes is not a strong redictor of mortality after CABG surgery among Table 5. Characteristics of Initial Post-CABG Hositalizations Among Diabetics and Nondiabetics* Diabetes (n 236) No diabetes (n 324) Odds Reason for hositalization Arrhythmia (%) Other cardiac (%) Noncardiac (%) Related to ICD (%) Cardiac events during hositalization Myocardial infarct (%) Ventricular arrhythmias (%) Heart failure (%) *Data were less than the full 560 observations for the following comarisons: ventricular arrhythmias (n 533), heart failure (n 557). ICD imlantable cardiac defibrillator.

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