Diabetes has long been described as an independent

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1 Effect of Risk-Adjusted Diabetes on Mortality and Morbidity After Coronary Artery Bypass Surgery Chandrasahekhar Kubal, MRCS, Arun K. Srinivasan, FRCS, Antony D. Grayson, BS, Brian M. Fabri, FRCS(Ed), and John A. C. Chalmers, FRCS Departments of Cardiothoracic Surgery and Research and Development, The Cardiothoracic Centre, Liverpool, United Kingdom Background. Diabetes is commonly regarded as a risk factor for mortality and morbidity after coronary artery bypass surgery. Methods. Between April 1997 and December 2002, 6,033 consecutive patients underwent isolated coronary artery bypass surgery. Eight hundred and fourteen (13.5%) patients had diabetes (530 oral-dependent, 284 insulindependent). Patients with diet-controlled diabetes were classified as nondiabetics. Deaths occurring over time were described using Kaplan-Meier techniques. To control for differences in patient characteristics, we constructed a propensity score (for diabetes) and this was included along with the comparison variable in multivariate logistic regression and Cox proportional hazards analyses. Results. In-hospital mortality was significantly higher for diabetic patients in the univariate analyses; however, this association disappeared after adjusting for the propensity score. Further analyses found that insulin-dependent diabetes was associated with an increased incidence of acute renal failure (adjusted odds ratio 4.15; p 0.002), deep sternal wound infection (adjusted odds ratio 2.96; p 0.039), and prolonged postoperative stay (adjusted odds ratio 1.60; p 0.017). Oral-controlled diabetes was not associated with any of these outcomes. Four hundred and ninety-eight (8.3%) deaths occurred during the study follow-up. After adjusting for patient characteristics, the adjusted hazard ratio of midterm mortality for diabetes was 1.35; p Conclusions. Insulin-dependent diabetes has a significant impact on in-hospital morbidity. Although diabetic patients are not at increased risk of in-hospital mortality, longevity is significantly decreased during a five-year follow-up period. (Ann Thorac Surg 2005;79:1570 6) 2005 by The Society of Thoracic Surgeons Diabetes has long been described as an independent risk factor for the development of coronary artery disease after adjusting for other risk factors such as age, hypertension, hypercholesterolemia, and smoking [1]. Itis common in adult patients requiring cardiac operations, and the proportion of diabetic patients undergoing coronary artery bypass grafting (CABG) is steadily increasing [2, 3]. Diabetes is recognized as a risk factor for adverse outcomes after CABG, especially with regard to longterm survival [4, 5]. However, the impact of diabetes on in-hospital mortality has been changing over time according to the Society of Cardiothoracic Surgeons of Great Britain and Ireland [2]. Furthermore, Calafiore and colleagues [6] found no significant difference between diabetic and nondiabetic patients with respect to allcause in-hospital and five-year mortality after CABG. In this report we assess the impact of diabetes on mortality and morbidity in a contemporary series of CABG patients, while adjusting for patient and disease characteristics. Accepted for publication Oct 20, Address reprint requests to Mr Grayson, The Cardiothoracic Centre- Liverpool, Thomas Drive, Liverpool, L14 3PE, United Kingdom; tony.grayson@ctc.nhs.uk. Material and Methods Patient Population and Data We performed a retrospective study on a total of 6,033 consecutive patients undergoing CABG between April 1, 1997 and December 31, 2002 at the Cardiothoracic Centre-Liverpool. Patients undergoing CABG that was combined with a heart valve repair or replacement, resection of a ventricular aneurysm, or other surgical procedures were not included. Definitions and data collection methods have been previously published [7] and are available from As part of routine clinical practice, data were collected prospectively during the patient s admission on the following variables: age, sex, body mass index, urgency of operation, prior cardiac surgery, Canadian Cardiovascular Society angina class, history of myocardial infarction, smoking, diabetes, hypercholesterolemia, hypertension, peripheral vascular disease, cerebrovascular disease, respiratory disease, renal dysfunction, as well as the extent of coronary disease, and left ventricular ejection fraction. The number and type of grafts, and the use of cardiopulmonary bypass (CPB) during the procedure were also collected. In-hospital mortality, defined as death with the same hospital admission, was noted at discharge. Reexploration for bleeding was defined as bleeding that required surgical reoperation after initial departure from the operating the by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg KUBAL ET AL 2005;79: EFFECT OF DIABETES ON OUTCOMES AFTER CABG Table 1. Patient and Disease Characteristics (n 5219) p Value Age at operation (years) 64.8 ( ) 64.3 ( ) 0.41 Female sex (%) Body mass index (kg/m 2 ) 28.8 ( ) 27.3 ( ) Angina class IV (%) Previous MI (%) Current smoker (%) Hypercholesterolemia (%) Hypertension (%) Peripheral vascular disease (%) Cerebrovascular disease (%) Renal dysfunction (%) Respiratory disease (%) Three-vessel disease (%) Left-main stenosis 50% (%) Ejection fraction 30% (%) Emergent procedure (%) Prior CABG (%) CARDIOVASCULAR Continuous variables are shown as median with 25th and 75th percentiles. Categorical variables are shown as a percentage. CABG coronary artery bypass grafting; MI myocardial infarction. ater. Postoperative stroke was defined as a new focal neurologic deficit and comatose state occurring postoperatively that persisted for greater than 24 hours after its onset and was noted before discharge. We excluded confused states, transient events, and intellectual impairment from our study to avoid any subjective bias. Acute renal failure was defined as patients requiring new postoperative dialysis support. Postoperative myocardial infarction was defined as a new Q wave postoperatively in two or more contiguous leads on an electrocardiogram or a significant rise in postoperative cardiac enzymes (creatine kinase-mb greater than 2 times upper limit of normal) combined with hemodynamic and echocardiographic signs of myocardial infarction. Sternal wound infection was defined in accord with the published evidence-based guidelines by the Centers for Disease Control and Prevention [8]. Postoperative atrial arrhythmia was defined as the occurrence of new atrial arrhythmia in the absence of preoperative persistent or paroxysmal atrial arrhythmias. Patient Follow-Up Patient records were linked to the National Strategic Tracing Service (NSTS), which records all deaths in the United Kingdom. To establish current vital status, patients were matched to the NSTS based on patient name, National Health Service number, date of birth, gender, and postcode. Statistical Methods Continuous variables are shown as median with 25th and 75th percentiles and categorical variables are shown as a percentage. Comparisons were made with Wilcoxon rank sum tests and 2 tests as appropriate. The Parsonnet risk stratification score [5] was calculated for each patient, to assess overall risk to both study groups, and was modified to a regional standard [7]. Logistic regression analysis was undertaken to risk adjust in-hospital outcomes [9]. Deaths occurring as a function of time were described using the product limit methodology of Kaplan and Meier [10]. Cox proportional hazards analysis was used to calculate adjusted hazard ratios (HR) [11]. Differences in case-mix between patients with diabetes and those without were controlled for by constructing a propensity score [12]. The propensity score was the probability that a patient had diabetes, and was constructed from the variables listed in Table 1 (C statistic 0.77). Once the propensity score is constructed for each patient, there are three ways of using the score for comparisons: matching, stratification, and multivariable adjustment. We have used multivariable adjustment because matching would have reduced the study size and stratification can be difficult to interpret. The propensity score is then included along with the comparison variable (diabetes vs no diabetes) in multivariable analyses of outcome. The propensity score adjusts for the case-mix differences between the two groups, which are evident in Table 1 [12]. Our analyses were supplemented by repeating them on only first-time multivessel CABG patients, and also adjusting for the use of CPB and year of operation. In all instances, our conclusions remained the same and therefore the results are not shown. In all cases a p value less than 0.05 was considered significant. All statistical analysis was performed retrospectively with SAS for Windows Version 8.2 (SAS Institute, Cary, NC).

3 1572 KUBAL ET AL Ann Thorac Surg EFFECT OF DIABETES ON OUTCOMES AFTER CABG 2005;79: Table 2. Operative Characteristics (n 5219) p Value Number of grafts (n/patient) 4 (3 4) 4 (3 4) 0.46 LIMA use (%) RIMA use (%) BIMA use (%) Radial artery use (%) Total arterial revascularization (%) Cardiopulmonary bypass time (m) [on-pump only] 112 (92 132) 110 (91 130) 0.19 Aortic cross-clamp time (m) [on-pump only] 63 (48 80) 62 (47 78) 0.53 Off-pump CABG (%) Continuous variables are shown as median with 25th and 75th percentiles. Categorical variables are shown as a percentage. BIMA bilateral internal mammary artery; CABG coronary artery bypass grafting; LIMA left internal mammary artery; RIMA right internal mammary artery. Results Patient Characteristics Overall, 814 (13.5%) patients were classified as diabetic, with 530 oral-dependent and 284 insulin-dependent. Two hundred and seventeen patients had diet-controlled diabetes, and were classified for this study as nondiabetics. Table 1 shows patient and disease characteristics based on the presence of diabetes. Diabetic patients were significantly more likely to be female, obese, have severe angina symptoms, hypertension, peripheral vascular disease, cerebrovascular disease, renal dysfunction, respiratory disease, and triple-vessel disease, as well as a poor ejection fraction. Interestingly, diabetics were less likely to have had prior cardiac surgery, had less left main stem stenosis, and were less likely to be current smokers. The modified Parsonnet scores for diabetics and nondiabetics were 4.2 (25th and 75th percentiles: 3.1 to 6.2) and 2.1 (25th and 75th percentiles: 1.0 to 4.2), respectively (p 0.001). Table 2 shows operative characteristics based on Table 3. Propensity Score for Diabetes Coefficient Standard Error p Value Body mass index a Peripheral vascular disease Renal dysfunction Hypertension Ejection fraction 30% Angina class IV Current smoker Respiratory disease Left main stenosis 50% Cerebrovascular disease Prior CABG Intercept a For each additional unit. CABG coronary artery bypass grafting. the presence of diabetes. The variables identified as predictors for diabetic group membership are shown in Table 3 along with the coefficients, standard errors, and intercept value. In-Hospital Mortality and Morbidity Table 4 shows the crude postoperative outcomes between diabetic and nondiabetic patients. In-hospital mortality was significantly higher for diabetic patients in the univariate analyses; however, this association disappeared after adjusting for the propensity score (Table 5). The incidence of acute renal failure and deep sternal wound infection were significantly higher in diabetic patients (Table 4), which remained unchanged after adjusting for the propensity score (Table 5). Prolonged postoperative stay was also more frequent in diabetic patients in both the univariate (Table 4) and multivariable (Table 5) analyses. On further analyses, insulin-dependent diabetes was associated with more acute renal failure (adjusted odds ratio [OR] 4.15 (95% confidence intervals [CI] 1.68 to 10.2; p 0.002), deep sternal wound infection (adjusted OR 2.96 [95% CI 1.06 to 8.26]; p 0.039), and prolonged postoperative stay (adjusted OR 1.60 [95% CI 1.09 to 2.36]; p 0.017). Oral-controlled diabetes was not associated with any of these outcomes. Midterm Survival Four hundred and ninety-four (8.2%) deaths occurred during the study with a total follow-up period of 20,523 patient years (mean follow-up of 3.4 years). The number of patients at risk of death during the follow-up period for both study groups is shown in Figure 1. The crude HR of midterm mortality for diabetic patients was 1.73 (95% CI 1.39 to 2.15; p 0.001). Freedom from death in diabetic patients at 30 days, 1, 2, 3, 4, and 5 years was 96.4%, 93.5%, 90.9%, 88.4%, 85.9%, and 83.6%, respectively, compared with 98.1%, 96.1%, 94.6%, 93.1%, 91.7%, and 90.3% for patients with no diabetes (Fig 1). After adjusting for the propensity score, the adjusted HR of midterm mortality

4 Ann Thorac Surg KUBAL ET AL 2005;79: EFFECT OF DIABETES ON OUTCOMES AFTER CABG Table 4. Postoperative Data Based on Existence of Diabetes (n 5219) Crude OR (95% CI) 1573 p Value CARDIOVASCULAR In-hospital mortality (%) ( ) Myocardial infarction (%) ( ) Stroke (%) ( ) Atrial arrhythmia (%) ( ) 0.33 Acute renal failure (%) ( ) Deep SWI (%) ( ) Reoperative for bleeding (%) ( ) 0.98 Postoperative stay 14 days (%) ( ) CI confidence intervals; OR odds ratio; SWI sternal wound infection. for diabetic patients was 1.35 (95% CI 1.06 to 1.71, p 0.013). Further analysis revealed that survival between the type of diabetes (insulin or oral therapy) was similar during the follow-up period. Comment Diabetes and Patient Characteristics Currently, 2.1% of the total world population may have diabetes but this may increase to more than 3% by the year 2010 [13]. The World Health Organization has estimated that the global burden of diabetes is increasing from 135 million in 1995 to 299 million by the year 2025 [14]. The prevalence of coronary artery disease ranges from 13.0% to 43.0% in patients with diabetes in the UK [15, 16]. This would suggest that there will be a corresponding increase in the number of patients with diabetes who will need coronary intervention in the future. There has been a steady increase in the number of patients with diabetes undergoing isolated CABG across the UK and the US [2, 3]. Within our own institution, the proportion of diabetic patients has increased to 18.1% in the calendar year 2003, which is more in keeping with the proportion of diabetics receiving CABG in the US. In the Northwest of England, the percentage of insulin-dependent diabetics undergoing isolated CABG almost doubled, increasing from 2.8% to 5.0% between 1997 and 2001 (see This increase in surgical activity is not only explained by a rise in the prevalence of diabetes, but can also partly be explained by improvements in the treatment of diabetics. In the UK, diabetic patients were twice as likely to die after CABG compared to nondiabetics; however, over the last five years there has been a 60% reduction in the operative mortality, practically eliminating this additional risk [2]. In this large observational study we found that diabetic patients had significantly different patient and disease characteristics. Patients with diabetes were significantly more likely to be female, obese, have severe angina symptoms, hypertension, peripheral vascular disease, cerebrovascular disease, renal dysfunction, respiratory disease, and triple-vessel disease, as well as a poor ejection fraction. Various angiographic studies have demonstrated that diabetic patients have more diffuse coronary artery disease compared to nondiabetics [17]. Echocardiographic studies also support our finding that diabetics are more likely to have poor left ventricular dysfunction [18]. This may be related to a higher incidence of transmural infarction in diabetic patients [19] and to an increased prevalence of silent ischemia associated with autonomic neuropathy [20]. In-Hospital Mortality and Morbidity The increased crude in-hospital mortality seen in diabetic patients is explained by the difference in case mix. Table 5. Postoperative Data Based on Existence of Diabetes (n 5219) a Adjusted OR (95% CI) p Value In-hospital mortality (%) ( ) 0.57 Myocardial infarction (%) ( ) 0.23 Stroke (%) ( ) 0.64 Atrial arrhythmia (%) ( ) 0.79 Acute renal failure (%) ( ) Deep SWI (%) ( ) Reoperative for bleeding (%) ( ) 0.78 Postoperative stay 14 days (%) ( ) a Adjusted for the propensity score. CI confidence intervals; OR odds ratio; SWI sternal wound infection.

5 1574 KUBAL ET AL Ann Thorac Surg EFFECT OF DIABETES ON OUTCOMES AFTER CABG 2005;79: Fig 1. Observed survival after coronary artery bypass surgery denotes diabetes-no; denotes diabetes-yes. After risk adjusting for propensity score this difference disappears, supporting the belief that the previously recognized risk of diabetes on in-hospital mortality [5] is no longer applicable. This finding concurs with that of Calafiore and colleagues [6] who found no significant difference in all-cause in-hospital mortality. However, they did find a significant difference with respect to cardiac-related deaths, an outcome which we are unable to assess. As with other reports [21 25], diabetic patients were found to have significantly higher incidences of postoperative renal insufficiency. More importantly, after further analyses, we were able to show that the significant increase in postoperative dialysis support was specifically associated with insulin-dependent diabetes. Previous work from our institution also found that insulin-dependent diabetes was an independent risk factor for developing acute renal failure in all cardiac surgery cases with an adjusted OR of 3.31 (95% CI 1.75 to 6.26; p 0.001) [21]. Previous studies have reported an association between diabetes and sternal wound infections [24 27]. Trick and colleagues [26] found that diabetic patients with a preoperative blood glucose level of 200 mg/dl had a significantly higher chance of developing deep sternal wound infections. Lu and colleagues [27], as with this present report, identified insulin-dependent diabetes as an independent risk factor for developing deep sternal wound infections, along with prolonged mechanical ventilation and history of peripheral vascular disease. Strategies to lower the incidence of acute renal failure and sternal wound infection in diabetic patients should be strongly encouraged. Off-pump CABG has been shown to significantly reduce the incidence of renal failure requiring dialysis by Magee and colleagues [28] in a series of 2,891 diabetic patients. This finding is also supported by Srinivasan and colleagues [29], who found over a 60% reduction in postoperative renal dysfunction in diabetic patients who received off-pump CABG compared to conventional on-pump CABG. Furnary and colleagues [30] demonstrated that tight control of blood glucose levels with intravenous insulin infusion throughout the perioperative period reduced the incidence of wound complications. Before undertaking this study, no rigorous protocols were in place within our institution to ensure the tight control of blood glucose levels preoperatively. If the preoperative routine investigations reveal blood sugar levels broadly within acceptable figures surgery will go ahead. However, intraoperatively and during the postoperative period strict glucose management is adhered to with blood glucose level maintained at between 6 and 8 mmol/l using intravenous insulin. This protocol is continued into the postoperative period until the patient returns to their preoperative diabetic management. Interestingly, we found no association between diabetes and postoperative stroke. This finding differs from reports by Szabo and colleagues [25] and Herlitz and colleagues [31] who all found the incidence of stroke to be significantly increased in diabetic patients. Due to the fact that the proportion of patients undergoing off-pump CABG was significantly different between our study groups, and that previous reports have shown significant reductions in stroke when avoiding CPB [32, 33], we performed further analyses adjusting for the avoidance of CPB. However, this did not significantly alter our conclusions that diabetes was not associated with the development of neurologic events. Diabetes was also not associated with postoperative myocardial infarctions, atrial arrhythmia, and reexploration for bleeding. Midterm Survival Calafiore and colleagues [6] concluded that diabetes was not associated with either all-cause or cardiac-related late survival. This finding is at odds with our experience. Although we are unable to assess the impact of cardiacrelated deaths, we have found a significant reduction in midterm survival for diabetic patients. The risk-adjusted survival rates at five years was 86.9% for diabetics compared to 90.1% for nondiabetics (p 0.013). The type of diabetes, insulin or oral dependent, did not, however, have any additional impact on this finding. We speculate that one of the reasons for the nonsignificant finding by Calafiore and colleagues [6] with respect to late mortality might be due to an incomplete risk-adjusted analyses. Calafiore and colleagues used a stepwise Cox proportional hazards model to select significant predictors of late mortality, but certain patient characteristics which may contribute to systematic bias were not adjusted for. However, as with our study, adjusting for a propensity score or balancing score, as we have done, not only adjusts for significant factors but augments them with other variables, even if not significant. The aim is to balance the patient characteristics in both study groups by incorporating everything that may relate to potential systematic bias [12]. Several other reports also confirm an increase in late mortality for diabetic patients in line with our findings [24, 25, 34]. Progression of disease in native coronaries and failure of the left ventricular function to improve after revascularization [18] may be factors responsible for worse

6 Ann Thorac Surg KUBAL ET AL 2005;79: EFFECT OF DIABETES ON OUTCOMES AFTER CABG midterm survival in diabetic patients, and measures to improve on these factors are important. The patient management needs to be emphasized with strict glycemic control, treatment of concomitant cardiovascular risk factors, aggressive lipid lowering, and antiplatelet therapy. In diabetes, a switch from carbohydrate oxidation to free fatty acid oxidation affects cardiac function [35]. Therefore, metabolic and nutritional considerations are equally important. The American Heart Association guidelines indicate that it is paramount to achieve strict control of diabetic status, as well as other strategies for secondary prevention [36]. Various studies have indicated that secondary prevention is not rigidly followed [37] and this can have major implications on long-term survival of diabetic patients after CABG. Along with glycemic control (HbA1c less than 7%), other general guidelines of particular importance include the following: dietary modifications (to lower total caloric, saturated fat, and cholesterol intake, maintain appropriate intake of nutrients and fiber), exercise, cessation of smoking, weight reduction, control of hyperlipidemia with statins (low density lipoprotein [LDL] cholesterol less than 100 mg/dl], control of blood pressure (less than 130/80), use of angiotensinconverting enzyme inhibitors, and blockers. The Cholesterol and Recurrent Events Trial in a subgroup analysis has shown effectiveness of pravastatin in lowering the risk of recurrent coronary events in diabetics [38]. Involvement of primary healthcare providers in monitoring glycemic control, along with adherence to other secondary prevention guidelines, may be beneficial. Education and counseling of the patient and family members is equally important. Study Limitations There are some limitations which may affect the conclusions drawn from this study. First, this is an observational study and by its retrospective nature cannot account for the unknown variables affecting the outcomes that are not correlated strongly with the variables used in the risk adjustment. However, retrospective comparisons with propensity score adjustment are recognized as highly robust and may in some cases be more widely acceptable than randomized control trials. This is particularly true in this case, as it is not possible to randomize a patient to be either diabetic or nondiabetic [12]. A further limitation of the study is the fact that we have not assessed the impact of cardiac-related deaths or other midterm outcomes, such as graft patency. Clinical Implications This study carries valuable information for the treatment of diabetic patients with surgical revascularization. Surgeons are often asked to provide short-term and longterm mortality rates, along with morbidity outcomes, for possible CABG surgery, to patients and families. This study provides contemporary and accurate data to surgical clinicians for the purposes of patient consent. Also highlighted is the importance of strict adherence to secondary prevention for diabetic patients after hospital discharge. Conclusions In conclusion, insulin-dependent diabetes has a significant impact on in-hospital morbidity with regard to acute renal failure and deep sternal wound infection. As a result, diabetes is also associated with a prolonged postoperative stay. Although diabetic patients are not at increased risk of in-hospital mortality, midterm mortality is significantly increased for these patients, irrespective of the type of diabetes, during a five-year follow-up period. We would like to acknowledge the cooperation of all the Consultant Cardiac Surgeons at the Cardiothoracic Centre- Liverpool: Doctors John A. C. Chalmers, Walid C. Dihmis, Brian M. Fabri, Elaine M. Griffiths, Neeraj K. Mediratta, Richard D. Page, D. Mark Pullan, Abbas Rashid, and W. Ian Weir. We would also like to thank Janet Deane, who maintains the quality and ensures completeness of data collected in our Cardiac Surgery Registry. References Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham Study. Circulation 1979;59: The Society of Cardiothoracic Surgeons of Great Britain and Ireland. National adult cardiac surgical database report ; May Ferguson TB Jr, Hammill BG, Peterson ED, DeLong ER, Grover FL. A decade of change risk profiles and outcomes for isolated coronary artery bypass grafting procedures, Ann Thorac Surg 2002;73: Eagle KA, Guyton RA, Davidoff R, et al. 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