Diabetes mellitus (DM) has been identified as an independent

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1 Diabetes Does Not Affect Long-Term Results After Total Arterial Off-Pump Coronary Revascularization Ho Young Hwang, MD, Jae-Sung Choi, MD, PhD, and Ki-Bong Kim, MD, PhD Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul; and Dongguk University Hospital, Goyang, Korea Background. We evaluated the influence of diabetes mellitus (DM) on 5-year angiographic results and longterm clinical outcomes in patients who underwent total arterial off-pump coronary revascularization for multivessel coronary disease. Methods. Between January 1998 and July 2004, total arterial revascularization for multivessel coronary disease was performed in 558 patients; 247 patients were diabetic (DM group) and 311 were nondiabetic (NDM group). Follow-up duration was months. Longterm survival, cardiac deaths, and major advanced cardiovascular or cerebral events were studied. Effects of DM on early, 1-year, and 5-year graft patency rates were compared using the generalized linear mixed model. Results. No differences in operative mortality and morbidity were observed. Overall survival in the DM group was significantly lower (p 0.004), with 10-year survival rates of 78.5% (vs 88.1% in the NDM group). Independent risk factors for long-term survival included smoking, chronic renal failure, and preoperative left ventricular dysfunction, but not DM itself. No differences in freedom from cardiac death were found between the 2 groups (p 0.171). Freedom from reintervention and major adverse cardiovascular and cerebral events were also similar between the groups. Early, 1-year, and 5-year postoperative angiographic patency rates in the DM group were 98.2%, 95.3%, and 94.6%, respectively. Those of the NDM group were 98.6%, 94.7%, and 90.5%. Diabetes mellitus did not affect graft patency rates. Conclusions. Diabetes mellitus did not affect 5-year angiographic results, long-term survival, and clinical events in patients with multivessel coronary disease who underwent total arterial off-pump revascularization. (Ann Thorac Surg 2010;90:1180 6) 2010 by The Society of Thoracic Surgeons Diabetes mellitus (DM) has been identified as an independent risk factor for development of coronary atherosclerosis [1]. Adverse effects of DM on surgical outcomes in patients who underwent coronary artery bypass grafting (CABG) have been reported, although controversy exists [2 6]. Previous studies have indicated that the arterial conduit may have a positive impact on maintenance of its biologic integrity and improvement of surgical outcomes in diabetic patients [7 9]. With renewed interest in off-pump CABG (OPCAB) since the mid-1990s, some authors have found reduced surgical morbidity in diabetic patients undergoing OPCAB compared with conventional CABG, although survival advantages were controversial [10 12]. The aim of this study was to evaluate whether or not diabetes has an influence on 5-year graft patency and long-term clinical outcomes in patients with multivessel coronary disease who underwent total arterial revascularization without the use of cardiopulmonary bypass. Material and Methods Accepted for publication May 10, Address correspondence to Dr Kim, Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, 28 Yeongeon-dong, Jongno-gu, Seoul , Korea; address : kimkb@snu.ac.kr. The study protocol was reviewed by the Institutional Review Board and approved as a minimal risk retrospective study (Approval Number: H ) that did not require individual consent based on the institutional guidelines for waiving consent. Patient Characteristics Between January 1998 and July 2004, 738 patients underwent isolated OPCAB in our institution. Among these, 558 (75.6%; male to female 419:139) patients with multivessel coronary disease who underwent total arterial OPCAB were enrolled in this study. Patients with single-vessel disease or patients who underwent OPCAB using saphenous vein grafting were excluded. Two hundred thirty six patients who had been previously diagnosed as diabetic and requiring pharmacologic glycemic control were included in the diabetic group. Eleven patients without a previous diagnosis of DM but with elevated glucose levels at admission (fasting glucose level 126 mg/dl; 2-hour glucose level after a meal during glucose tolerance test 200 mg/dl) were also included in the diabetic group (DM group; n 247). One hundred seventy one patients required oral drugs and 76 patients were treated with insulin therapy. Three hundred eleven patients were nondiabetic (NDM group). Preoperative characteristics were similar, except that there were more patients with left ventricular dysfunction, chronic renal failure, and peripheral vascular obstructive disease in the DM group (Table 1) by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg HWANG ET AL 2010;90: EFFECT OF DM ON TOTAL ARTERIAL OPCAB 1181 Table 1. Patient Characteristics Variables Total (n 558) DM group (n 247) NDM group (n 311) p Age (years) Male/Female 419: :69 241: Unstable/stable angina 442: :52 245: Risk factors, n (%) Smoking 253 (45%) 102 (41%) 151 (49%) Hypertension 351 (63%) 163 (66%) 188 (61%) Overweight (BMI 25 kg/m 2 ) 238 (43%) 100 (41%) 138 (44%) Dyslipidemia 150 (27%) 66 (27%) 84 (27%) History of stroke 70 (13%) 36 (15%) 34 (11%) Chronic renal failure 33 (6%) 27 (11%) 6 (2%) LV dysfunction (EF 0.35) 34 (6%) 21 (9%) 13 (4%) PVOD 83 (15%) 48 (19%) 35 (11%) Three-vessel disease 392 (70%) 180 (73%) 212 (68%) Left main disease 182 (33%) 71 (29%) 111 (36%) BMI body mass index; DM diabetes mellitus; EF ejection fraction; LV left ventricle; NDM nondiabetic; PVOD peripheral vascular obstructive disease. Operative Strategy Basic principles and surgical procedures for OPCAB have been previously described [13]. A left internal thoracic artery (ITA) graft was used in almost all patients (n 556, 99.6%). Other arterial conduits included the right ITA (n 441), right gastroepiploic artery (n 346), and radial artery (n 9). All patients refrained from aspirin therapy (300 mg/day) on the day before surgery, and resumed it 1 day postoperatively. Bilateral ITAs were used more frequently in the NDM group (DM vs NDM, 74.1% vs 82.3%; p 0.018). Right gastroepiploic arteries were used more frequently in the DM group (70.0% vs 55.6%; p 0.001). Radial arteries were seldom used in either group (n 9, 1.6%). There were no differences between the groups in the number of distal anastomoses (DM vs NDM, vs ; p 0.508). Perioperative Management of Diabetes Mellitus Mixtures of intravenous insulin, glucose, and potassium (GIK regimen) were administered before surgery for all previously diagnosed patients with DM. The starting solution usually included 7 units of insulin in 500 ml of 5% dextrose containing 15 meq potassium and was infused at a rate of 80 ml/hour. The target glucose level ranged from 90 to 150 mg/dl, and the serum potassium level was maintained between 4.0 and 5.5 mmol/l. Blood glucose level was monitored hourly during the intraoperative and immediate postoperative periods. Infusion was stopped and the preoperative glucose control regimen was resumed once oral intake was established, usually on the first postoperative day. Evaluation of Long-Term Clinical Outcomes Patients underwent regular postoperative follow-up through the outpatient clinic at 3 or 4 month intervals, and were contacted by telephone for confirmation of their condition if the last clinic visit was not conducted at the scheduled time. Clinical and angiographic follow-up was completed on August 31, Follow-up was complete in 96.5% (530 of 549) of survivors, with a follow-up duration of months. Operative mortality was defined as death within 30 days. Cardiac death was defined as any death related to cardiac events, including sudden death during follow-up. Major adverse cardiovascular or cerebral events (MACCE) included acute myocardial infarction, coronary reintervention, death from any cause, and cerebrovascular accident. Evaluation of Angiographic Patency Early, 1-year, and 5-year follow-up coronary angiograms were performed regardless of patients angina symptoms. Patients who died, refused angiographic evaluation, or had renal function impairment were excluded from angiographic follow-up. However, patients with renal replacement therapy were included in angiographic follow-up. Early postoperative angiograms for evaluation of the anastomotic sites and patency of the grafts were performed in 97.1% (542 of 558) of all patients on postoperative days. One-year ( months) and 5-year ( months) angiograms were performed in 94.8% (499 of 526) and 80.1% (375 of 468) of all patients who were followed up for more than 1 year and 5 years, respectively. All 375 patients who underwent 5-year follow-up angiograms had both early and 1-year angiograms, and were enrolled for serial comparison of graft patency. More patients in the NDM group underwent follow-up angiograms (DM vs NDM; 74.0% [142 of 192] vs 84.4% [233 of 276]; p 0.005). One physician initially reviewed all coronary angiograms and consensus was reached after review. Graft patency was graded in the manner described by FitzGibbon and colleagues [14]. Steno-occlusion was defined as occluded or as stenosis of 75% of graft diameter or greater.

3 1182 HWANG ET AL Ann Thorac Surg EFFECT OF DM ON TOTAL ARTERIAL OPCAB 2010;90: Statistical Analysis Statistical analysis was performed using the SPSS software package (version 12.0; SPSS Inc, Chicago, IL) and SAS (version 9.1; Cary, NC). Data were expressed as mean standard deviation, median and ranges, or proportions. Comparison between the 2 groups was performed with the 2 test or Fisher exact test for categoric variables and the Student t test for continuous variables. Survival rates were estimated using the Kaplan-Meier method and comparisons between groups were performed using the log-rank test or Cox regression model. The Cox proportional hazard model was adopted for analysis of risk factors for overall late mortality and late cardiac death. Univariate variables with p values less than 0.05 were entered into the analysis. The generalized linear mixed model was adopted for analysis of the effects of DM, graft type, and revascularized territory on graft patency rates. To correct baseline differences, the propensity score of having diabetes was adjusted in the model. Underlying characteristics considered in estimation of propensity scores were the following: (1) age; (2) gender; (3) smoking status; (4) presence of obesity (body mass index 25 kg/m 2 ); (5) hypertension; (6) dyslipidemia; (7) chronic renal failure; (8) left ventricular dysfunction; (9) acute myocardial infarction; (10) left main coronary artery disease; (11) 3-vessel disease; (12) history of percutaneous coronary intervention; (13) emergent surgery; and (14) peripheral vascular obstructive disease. Kaplan-Meier curves were drawn using Prism software (version 5.0; GraphPad Software Inc, La Jolla, CA). A p value of less than 0.05 was considered statistically significant. Results Early Clinical Results Operative mortalities were 2.0% (5 of 247) in the DM group and 1.6% (5 of 311) in the NDM group (p 0.756). Early clinical outcomes including atrial fibrillation, perioperative myocardial infarction, mediastinitis, and cerebrovascular accident were similar between the 2 groups (Table 2). Fig 1. Overall survival of patients with and without diabetes mellitus. (DM diabetes mellitus group; NDM nondiabetes mellitus group.) Long-Term Survival Among 548 survivors, late death occurred in 72 (13.1%) patients, including 20 cardiac deaths. Overall survival rate was lower in the DM group than in the NDM group, with 10-year survival rates of 78.5% and 88.1%, respectively (p 0.004; Fig 1). Age-adjusted survival was also lower in the DM group (p 0.006). The survival rate for patients with insulin-treated DM was not significantly different from those with non-insulin treated DM (p 0.919). Multivariate analysis revealed that after age adjustment, smoking history, chronic renal failure, and preoperative left ventricular dysfunction, but not DM itself, were independent risk factors for long-term survival (Table 3). However, there were no significant differences in the incidence of late cardiac death between the groups, with 10-year freedom from cardiac death rates of 94.6% and 96.6%, respectively (DM vs NDM, p 0.109; Fig 2). Similar results were observed between patients with insulin-treated DM and those with non insulin-treated DM (p 0.836). Chronic renal failure and left ventricular dysfunction were significant risk factors Table 2. Early Mortality and Morbidities Variable Total (n 558) DM group (n 247) NDM group (n 311) p Mortality 10 (1.8%) 5 (2.0%) 5 (1.6%) Morbidities Atrial fibrillation 112 (20.1%) 56 (22.7%) 56 (18%) Perioperative myocardial infarction 32 (5.7%) 8 (3.2%) 20 (6.4%) Bleeding reoperation 22 (3.9%) 9 (3.6%) 13 (4.2%) Acute renal failure 11 (2.0%) 6 (2.4%) 5 (1.6%) Mediastinitis 3 (0.5%) 3 (1.2%) 0 (0%) Low cardiac output syndrome 1 (0.2%) 0 (0%) 1 (0.3%) Stroke 1 (0.2%) 0 (0%) 1 (0.3%) DM diabetes mellitus; NDM nondiabetic.

4 Ann Thorac Surg HWANG ET AL 2010;90: EFFECT OF DM ON TOTAL ARTERIAL OPCAB 1183 Table 3. Independent Predictors of Late Mortality Univariate Multivariate Variable p p Hazard Ratio [95% CI] Age Diabetes mellitus [ ] Chronic renal failure [ ] Smoking [ ] LV dysfunction [ ] PVOD [ ] BMI 25 kg/m [ ] Hypertension Dyslipidemia Female gender Left main disease Three-vessel disease Previous PCI Emergency BMI body mass index; CI confidence interval; LV left ventricular; PCI percutaneous coronary intervention; PVOD peripheral vascular obstructive disease. for age-adjusted long-term cardiac deaths (p 0.001, hazard ratio 6.67 and p 0.004, hazard ratio 2.66, respectively). Freedom From Reintervention and MACCE Sixty eight patients underwent coronary reintervention including 3 reoperations at months after surgery. Reintervention-free survival was similar between the 2 groups, with 10-year freedom from reintervention rates of 86.4% and 84.0%, respectively (DM vs NDM, p 0.509; Fig 3). A trend toward higher reintervention rates beyond 5 years after surgery was observed in the insulin-treated DM group, but it was not statistically significant (p Fig 3. Reintervention-free survival in patients with and without diabetes. (DM diabetes mellitus group; NDM nondiabetes mellitus group.) 0.173; Fig 4). There were no differences in freedom from MACCE at 10 years between the DM and NDM groups (66.2% vs 71.9%, p 0.111; Fig 5) and between the insulin-treated DM and noninsulin-treated DM groups (62.4% vs 67.6%, p 0.324). Early, 1-year, and 5-year Angiographic Patency In the DM group, early, 1-year, and 5-year postoperative patency rates were 98.2% (724 of 737), 95.3% (609 of 639), and 94.6% (417 of 441), respectively. Patency rates of the NDM group were 98.6% (899 of 912), 94.7% (826 of 872), and 90.5% (628 of 694). Analysis of patency rates according to graft type showed that patency rates of left ITA grafts at early, 1 year, and 5 years postoperatively were 99.2%, 95.8%, and 93.0%, respectively. Patency rates of right ITA grafts were 99.5%, 97.1%, and 93.2% and those of right gastroepiploic artery grafts were 98.8%, 92.9%, Fig 2. Late cardiac deaths in patients with and without diabetes. (DM diabetes mellitus group; NDM nondiabetes mellitus group.) Fig 4. Comparison of freedom from reintervention in diabetic patients according to insulin requirement. (DM diabetes mellitus group; NDM nondiabetes mellitus group.)

5 1184 HWANG ET AL Ann Thorac Surg EFFECT OF DM ON TOTAL ARTERIAL OPCAB 2010;90: Fig 5. Freedom from major adverse cardiovascular or cerebral events (MACCE) in diabetes mellitus (DM) and nondiabetes mellitus (NDM) groups. and 88.3%, respectively (Table 4). The generalized linear mixed model revealed that the presence of DM and type of arterial conduit did not affect patency rates in any of the 3 time periods. Patency rates of grafts anastomosed to the left anterior descending territory were higher than those connected to the left circumflex and right coronary artery territories at 1 year and 5 years after OPCAB (Table 5). Comment The present study demonstrated four important findings. First, not DM, but chronic renal failure and left ventricular dysfunction showed a negative impact on long-term survival in patients who underwent OPCAB with total arterial grafting. Second, freedom from cardiac death was similar between diabetic and nondiabetic patients. Third, freedom from MACCE, including reintervention, was similar, regardless of diabetic status. Fourth, DM did not influence the early, 1-year, and 5-year postoperative angiographic patency rates of the grafts. Previous studies have demonstrated poor early or late clinical outcomes, including mortality and freedom from reintervention in patients with DM who underwent CABG compared with those without DM [2 5]. However, controversy still exists [15, 16]. Since the renewal of interest in OPCAB in the mid-1990s, some authors have reported reduced surgical morbidity in diabetic patients undergoing OPCAB compared with conventional CABG, although they failed to demonstrate any survival advantage [10 12]. Previous studies have indicated that the arterial conduit might have a positive impact on maintenance of its biologic integrity and improvement of surgical outcomes in diabetic patients [7 9]. Anatomic patterns of coronary artery disease in DM patients are more complicated. Patients with DM frequently have left main or multivessel coronary disease. Lesions are more diffuse and luminal diameters are small in segments adjacent to obstructive lesions [17 19]. In order to control this bias, we only enrolled patients with multivessel coronary Table 4. Angiographic Patency Rates According to Graft Types and Revascularized Territories in the DM and NDM Groups Graft Territory Group No. of Anastomoses Early 1 Year 5 Years Left ITA Total % 95.8% 93.0% DM % 97.7% 96.0% NDM % 94.6% 91.3% Right ITA Total % 97.1% 93.2% DM % 98.1% 96.8% NDM % 96.5% 91.0% RGEA Total % 92.9% 88.3% DM % 93.6% 89.0% NDM % 92.4% 87.8% Radial artery Total % 88.9% 88.9% DM 0 NDM % 88.9% 88.9% LAD Total % 97.6% 95.5% DM % 98.6% 97.6% NDM % 96.9% 94.1% LCX Total % 95.1% 90.4% DM % 96.5% 93.7% NDM % 94.3% 88.5% RCA Total % 91.7% 86.7% DM % 93.3% 88.8% NDM % 90.7% 85.3% DM diabetes mellitus; ITA internal thoracic artery; LAD left anterior descending artery; LCX left circumflex artery; NDM nondiabetic; RCA right coronary artery; RGEA right gastroepiploic artery.

6 Ann Thorac Surg HWANG ET AL 2010;90: EFFECT OF DM ON TOTAL ARTERIAL OPCAB 1185 Table 5. Effects of Diabetes, Use of Grafts Other Than the Left ITA, and Revascularized Territories Other Than the LAD Territory on Graft Patency at Early, 1 Year, and 5 Years After Surgery Early 1 Year 5 Year Variable OR [95% CI] p OR [95% CI] p OR [95% CI] p DM a 2.03 [ ] [ ] [ ] Right ITA b 2.86 [ ] [ ] [ ] RGEA b 2.81 [ ] [ ] [ ] RA b 0.42 [ ] [ ] LCX c 2.36 [ ] [ ] [ ] RCA c 0.19 [ ] [ ] [ ] a Odds ratio of graft patency in the DM group compared to the NDM group; b Odds ratio of graft patency of right ITA or RGEA grafts compared to reference grafts (left ITA); c Odds ratio of patency of grafts anastomosed to the LCX or RCA territory compared with those anastomosed to the LAD territory. CI confidence interval; DM diabetes mellitus; ITA internal thoracic artery; LAD left anterior descending artery; LCX left circumflex artery; OR odds ratio; RA radial artery; RCA right coronary artery; RGEA right gastroepiploic artery. disease; proportions of patients with three-vessel coronary disease and left main coronary disease were similar between the 2 groups. This may have resulted in a somewhat higher incidence of diabetes in the present study than that of previous reports, which ranged from 14% to 30% [2 5]. Our treatment strategies for CABG include routine off-pump revascularization for most of our patients, exclusive use of total arterial graft with skeletonization, particularly in patients with diabetes or in younger patients. In our early experience, we avoided use of bilateral ITA grafts in DM patients out of concern for possible mediastinal infection, although it was controversial [20]. This explained the reason for more frequent use of bilateral ITA grafts in the NDM group when compared with the DM group. As demonstrated in the previous study [15], DM did not affect early clinical outcomes. Early mortality and postoperative complications, including atrial fibrillation, perioperative myocardial infarction, mediastinitis, and cerebrovascular accident were similar between the 2 groups. Overall longterm survival rate was lower in the DM group, with 10-year survival rates of 78.5% compared with 88.1% in the NDM group. Multivariate analysis revealed that it was not DM itself, but rather chronic renal failure, preoperative left ventricular dysfunction, and smoking that were independent risk factors for age-adjusted longterm survival. This was in agreement with other reports [3, 21] demonstrating that comorbidities of DM, such as chronic renal failure, peripheral vascular obstructive disease, and low left ventricular ejection fraction were independent risk factors for long-term survival. In addition, freedom from cardiac death was similar between the DM and NDM groups, and between patients with insulin-treated DM and those taking oral drugs. Again, chronic renal failure and left ventricular dysfunction were significant risk factors for late cardiac death. A previous study documented lower freedom from percutaneous intervention rates in DM patients, with a 10-year reintervention-free survival rate of 83% compared with 86% in non-dm patients [2]. However, a randomized controlled trial [22] revealed a similar 7-year freedom from reintervention rate in the DM group and the non-dm group (87.8% vs 88.9%). The present study showed an 86.4% reintervention-free survival rate at 10 years in the DM group and this was not statistically different from that of the NDM group. In addition, freedom from MACCE was not different between the 2 groups. Few studies have compared long-term angiographic patency of bypass grafts between patients with DM and those without DM who underwent CABG. In the Bypass Angioplasty Revascularization Investigation trial [23], graft patency assessed with angiograms performed 4 years after CABG showed that the percentages of ITA grafts (89% vs 85%) and vein grafts (71% vs 75%) free of stenosis were similar between patients with and without DM. In their study, however, only 37% of the patient population underwent follow-up angiograms. Since we began performing OPCAB at our institution in 1998, we have performed early postoperative graft angiography in almost all of our OPCAB patients to assess the accuracy of the anastomosis and graft patency. In addition, 1-year and 5-year follow-up coronary angiograms were performed regardless of patients angina symptoms. We evaluated graft patency at 5 years after surgery in 80.1% of patients followed up for more than 5 years. Baseline characteristics in patients with diabetes were different from those without DM. In addition, fewer patients in the DM group underwent 5-year angiograms than in the NDM group. This may have affected the results as a selection bias and the high angiographic patency rates demonstrated in the DM group. To correct these biases, the propensity score of having diabetes was adjusted in the generalized linear mixed model. The present study demonstrated that diabetes did not affect early and 1-year angiographic patency (p and 0.252). The UK prospective diabetes study [24] demonstrated that strict control of glycemia reduced microvascular complications and acute cardiac events. In addition, the Post Coronary Artery Bypass Graft Trial [25] reported that aggressive reduction of plasma lipids significantly reduced ischemic complications and improved permeability of aortocoronary grafts. The favorable angiographic results in the present study might be due to the fact that we strictly controlled glucose and lipid levels in all DM patients

7 1186 HWANG ET AL Ann Thorac Surg EFFECT OF DM ON TOTAL ARTERIAL OPCAB 2010;90: beginning in the immediate postoperative period. Preoperative comorbidities such as chronic renal failure or left ventricular dysfunction, not DM itself, were found to influence long-term survival and cardiac-related death in patients with multivessel disease treated with total arterial OPCAB. Freedom from MACCE, including coronary reintervention, was also similar between the DM and NDM groups. Medically controlled diabetes did not have negative effects on early, 1-year, and 5-year angiographic patency rates. There are limitations to the present study that must be recognized. First, the present study was not performed in a prospective manner, although all consecutive patients with multivessel disease who underwent OPCAB using total arterial grafts were included. There were some baseline differences between the 2 groups and these might have affected the results, although multivariate analysis and adjustment of the propensity score were performed to minimize this bias. Second, some of the patients treated with oral hypoglycemic agents at the time of surgery started insulin therapy during the follow-up period and some patients were diagnosed as new onset diabetes during admission for surgery. These were not evaluated in this study and this could have affected the clinical and angiographic comparison between groups. Measurement of hemoglobin A1 c level, one of the predicting factors for postoperative adverse outcomes in diabetic patients undergoing cardiac operations, was not performed preoperatively on all patients and was not included in the risk factor analysis. Finally, we did not compare these results with those of on-pump CABG or those of CABG using saphenous vein grafts. 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