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J Thorac Cardiovasc Surg 2006;132:802-810
© 2006 The American Association for Thoracic Surgery
Surgery for Acquired Cardiovascular Disease |
Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom.
Received for publication December 2, 2005; revisions received May 10, 2006; accepted for publication May 17, 2006. * Address for reprints: R. Ascione, MD, ChM, FRCS, FETCS, Reader in Cardiac Surgery Sciences, Bristol Heart Institute, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom. (Email: r.ascione{at}bristol.ac.uk).
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Abstract |
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Methods and Results: Patients who underwent first-time coronary artery bypass grafting from April 1996 to October 2003 were classified into diabetic and nondiabetic groups. Data were prospectively collected and retrospectively analyzed. A total of 5259 patients were studied, and of these 877 (17%) were diabetic. Patients with diabetes were more likely to be female, have a higher body mass index, be in an advanced New York Heart Association class and Canadian Cardiovascular Society class, have a history of congestive heart failure, have a poor ejection fraction, renal failure, and more extensive coronary artery disease than the nondiabetic group (P < .001 for all). In-hospital mortality was 2.2% and 1% for diabetic and nondiabetic patients, respectively; however, diabetes was not found to be an independent risk factor for in-hospital mortality (odds ratio = 1.63; 95% confidence interval 0.92-2.88; P = .089). Postoperative complications were comparable in the two groups, with only renal, neurologic, and gastrointestinal complications significantly associated with diabetes (all P 
.05). There was no association between diabetes mellitus and postoperative infective complications. Diabetes remained an independent predictor of 5-year mortality (hazard ratio 1.55; 95% confidence interval 1.22-1.96; P < .001) and of lower 5-year cardiac-related event-free survival.
Conclusion: Despite a worsening cohort, diabetic patients could be surgically revascularized with low morbidity and mortality, comparable with control patients. The negative effect of diabetes mellitus on the longer-term mortality and morbidity remains a problem.
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Introduction |
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Diabetes has been recognized as a major risk factor for atherosclerosis,1,2
and its prevalence is on the rise owing to an increasingly aged and obese population.3 Currently, patients with diabetes mellitus represent about 20% of patients undergoing coronary artery bypass graft (CABG) surgery,4-6 and in the past diabetes has been associated with increased in-hospital morbidity and mortality.7-9 Over the years, reports have maintained the superiority of CABG surgery over percutaneous coronary intervention as the preferred method of coronary revascularization in diabetic patients.10-13 In the past decade, however, there has been a significant worsening of the risk profile of surgical patients,14 to whom the results of previous studies cannot be uncritically applied. In our own institution, the Parsonnet risk score increased from a median of 4 (interquartile range 2-8) in 1996 to 6 (interquartile range 3-11) in 2002 (P < .001), the percentage of patients with diabetes has risen from 15% in 1996 to 20% of patients treated in 2002, and the surgical population is aging. In 1996, 39% of patients were over 65 years; by 2002 this had risen to 49% of patients. Hence, there is a need to update continuously the performance of surgical revascularization in diabetic patients.
The aim of this study was to investigate the effect of diabetes mellitus on in-hospital and midterm clinical outcomes in patients operated on in the current era of CABG surgery.
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Methods |
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Anesthetic and Surgical Management
Anesthetic and surgical techniques were as reported previously.15 For conventional CABG operations, a standard cardiopulmonary bypass circuit was used and systemic temperature was maintained between 34°C and 36°C. Myocardial protection was achieved with intermittent antegrade warm blood cardioplegia. For off-pump coronary artery bypass (OPCAB) procedures, the technique was as previously reported,16 and its use was based on surgeon preference. At the end of surgery, patients were transferred to the cardiac intensive care unit and were extubated as soon as they met the following criteria: hemodynamic stability, no excessive bleeding (<80 mL/h), normothermia, and consciousness with pain control.
Management of Medication
Preoperative medications, including antidiabetic agents, statins, ß-blockers, diuretics, antihypertensives, and calcium channel blockers, were routinely omitted on the day of surgery. Aspirin was omitted 3 days before surgery. Angiotensin-converting enzyme inhibitors were withdrawn on the evening before the operation. Aspirin (300 mg) was given 4 hours after the operation if chest tube drainage was less than 100 mL/h and decreasing. On the first postoperative day, all patients began receiving enoxaparin (20 mg), which was stopped at discharge, and aspirin (300 mg), which was reduced to 75 mg after 3 months. On day 1, statins, ß-blockers, diuretics, antihypertensives, and angiotensin-converting enzyme inhibitors were all restarted, according to a standard unit protocol, which is based on accurate monitoring of blood pressure and renal function. After discharge, these drugs are prescribed and monitored by the family physician and through routine visits to the cardiology department outpatient clinic.
At our institution we aim to maintain the blood glucose levels in diabetic patients between 5 and 8 mmol/L. Preoperatively, diabetic patients are started on a standard sliding scale insulin infusion, which is maintained for the first 48 hours postoperatively. They are then switched to their baseline antidiabetic medications, which are reviewed by a diabetologist until discharge and managed by the family physician, with regular visit to the diabetes outpatient clinic, after discharge. For nondiabetic patients, the use of sliding scale insulin infusion is triggered by blood glucose levels greater than 10 mmol/L.
Data Collection, Monitoring, Follow-up, and Definitions
Patients were considered to be diabetic on the basis of history, regardless of duration of disease and need for diabetic medications. Perioperative death was defined as any death occurring in the hospital (ie, in patients who had not been discharged after the operation). In-hospital complications were recorded and defined as previously reported.15,17
Information about the vital status was obtained from the National Health Service Strategic Tracing Service (NSTS). Follow-up with respect to cardiac-related events was by a standard questionnaire to the patient and to the patient's family physician, as previously reported.18 Nonfatal cardiac-related events included the following: (1) the need for a further coronary revascularization procedure (whether reoperation or percutaneous transluminal coronary angioplasty), (2) patient-reported hospital attendance for myocardial infarction or recurrent angina, or (3) report of cardiac-related hospital admission by the patient or the family physician. In analyses of patient and cardiac event-free survival, patients who had not experienced an event were censored at the date of last follow-up.
Statistical Analysis
Baseline and operative characteristics were compared with a 
2 or Fisher exact test (categorical variables) or the Mann-Whitney test (continuous variables). Outcomes for the respective diabetic and nondiabetic subgroups were compared both with and without adjusting for possible confounding, using logistic or Cox regression (Stata version 8.2; Stata Corporation, College Station, Tex), depending on whether the outcome was a binary or a time-to-event variable. Variables included in the adjusted analyses were chosen because they showed imbalance between the two groups and/or they were thought to affect the outcome. The same variables were included in all the risk-adjusted analyses presented (see Table 4
footnote for details). Some potential confounders (eg, age and body mass index) were dichotomized. Model assumptions were checked and, where untenable, alternative models were explored. The number of prognostic variables and outcomes of interest resulted in a large number of statistical comparisons. No correction was made for multiple comparisons, but confidence intervals and exact P values are presented throughout. The interpretation of the findings takes into account the consistency of the findings and their magnitude, as well as their statistical significance.
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Results |
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Table 3 shows the risk factors for in-hospital mortality. The presence of diabetes mellitus was not found to be an independent predictor of in-hospital mortality on multivariate analysis (P = .089). On the contrary, age older than 65 years, female sex, history of congestive heart failure, renal failure, ejection fraction less than 50%, left main stem disease, and urgent operation were independent predictors of in-hospital death.
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Table 4 shows the effect of diabetes on nonfatal outcomes. After adjustment for differences in prognostic variables, diabetic patients had a significantly higher chance of having neurologic, renal, and gastrointestinal complications after CABG surgery. OPCAB surgery was found to be associated with fewer neurologic complications (OR = 0.58; 95% CI 0.38-0.89; P = .012), but not renal complications (P = .18) or gastrointestinal complications (P = .82) on multivariate analysis. For all in-hospital outcomes, including mortality, the outcome for patients with insulin-dependent diabetes was similar to that for diabetic patients not dependent on insulin (P 
.17).
Midterm Clinical Outcomes
Overall, 99% of the study cohort was successfully matched to the NSTS database. The remaining patients were censored at hospital discharge. Median follow-up was 3 years in both groups. Diabetic patients had a significantly lower 5-year survival than did nondiabetic patients (adjusted hazard ratio [HR] = 1.55; 95% CI 1.22-1.96; P < .001) (Figure 1). Other patient factors identified as independent predictors of 5-year all-cause mortality were advanced age (>65 years), renal failure, preoperative arrhythmias, ejection fraction less than 50%, left main stem disease, advanced Canadian Cardiovascular Society class, the presence of congestive heart failure, and smoking less than 1 month before surgery (P .032).
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Discussion |
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The in-hospital mortality in our study for diabetic patients compared favorably with the literature, despite the worsening of case-mix in the current surgical era (over the period of this study the median Parsonnet risk score increased from 4 to 6 and the numbers of older patients and of diabetic patients treated increased). Thourani and associates9 reported on 2278 diabetic patients who underwent CABG surgery from 1978 to 1993 with an observed mortality of 3.9% and found diabetes to be an independent predictor of in-hospital mortality. Several other studies in the late 1980s had similar findings, reporting mortality rates as high as 5%.4,7,8 North American multicenter registry data on 41,663 diabetic patients who underwent CABG surgery in 1997 reported a 30-day mortality of 3.7%.6 Two recent studies by Szabo,19 Kubal,20 and their associates (similar to our study period) agreed with our findings, reporting mortalities of 2.6% and 2.4% for their diabetic populations, respectively. The older series are not contemporary with respect to internal thoracic artery use, which was less than 50%, and modern perfusion and anesthetic techniques. The North American series did not specify blood glucose management in the perioperative period, which is now recognized to lead to a better outcome.21 In contrast, this study and both contemporary series mentioned previously had a strict postoperative glucose management protocol. Over 30% of our patients in both groups underwent revascularization without the use of cardiopulmonary bypass. The use of OPCAB surgery was based on surgeon preference, and it did not depend on either the preoperative diabetic status or the distribution of coronary disease. OPCAB surgery was associated with fewer neurologic complications (P = .012) but did not affect the incidence of renal complications (P = .18). Magee and colleagues22 compared diabetic and nondiabetic patients who underwent OPCAB surgery and showed a lower observed mortality for diabetic patients and an even lower observed mortality for nondiabetic patients compared with the on-pump group, although this did not translate as a significant benefit for diabetic patients after risk adjustment. Similarly, Kubal and colleagues20 used OPCAB surgical technique in 21.7% of diabetic patients and had the lowest reported mortality rate of 2.4% for a diabetic series to date.
After adjustment for differences in risk profile between diabetic and nondiabetic patients, renal, neurologic and gastrointestinal complications showed significant effect sizes. These risks might be minimized by more thoughtful management, for example, with specific attention to preoperative noninvasive vascular evaluation of carotid and renal arteries, elimination or minimization of intraoperative aortic manipulation, preoperative volume replacement, and the timing of angiotensin-converting enzyme inhibitor therapy in patients with preoperative renal insufficiency.
Previous reports in the literature generally report an increased short-term mortality and morbidity in CABG patients, which includes cardiovascular, infective, and respiratory complications.6,9,20 Whereas in our study the probability of an increased risk of in-hospital death for patients with diabetes mellitus was greater than .05, a 63% increased risk was observed, which could occur by chance in around 10% of studies (P = .092). The 95% CI further suggests that the true in-hospital mortality risk could be as much as 187% higher for a diabetic compared with a nondiabetic patient. With a 17% prevalence of diabetes in our population and a low 1% in-hospital mortality rate among nondiabetic patients, a study of more than 16,000 patients would be needed to identify a 63% rise in mortality risk for persons with diabetes as statistically significant with 80% power.
The predisposition of diabetic patients to infective complications after cardiac surgery has been often suggested.6,23-27 We did not find an independent association between diabetes and infective complications (OR = 1.27; 95% CI 0.85-1.91; P = .24). Angiopathy, neuropathy, and hyperglycemia associated with diabetes are identified as the main reasons for predisposition to infections.28 Impaired host defense mechanisms such as impaired wound healing, impaired granulocyte function, decreased cellular immunity, impaired complement function, and decreased lymphokine response may be influenced by glycemic control.28-30 Our results might be due to the active control of blood glucose in diabetic patients with insulin infusion during the early postoperative period. Others have suggested that this reduces mortality and complications.21,26,31,32 Controlling blood glucose levels at less than 11.1 mmol/L (200 mg/dL) in diabetic patients leads to significantly fewer postoperative complications, including in-hospital death.24,25,33 Furthermore, Fish and associates25 found that, in diabetic patients, a blood glucose level less than 11.1 mmol/L carried a 36% higher risk and a blood glucose level of 13.9 mmol/L or more carried a 63% higher risk of infective complications.
Diabetes was found to be an independent predictor of 5-year mortality and lower cardiac event-free survival, despite key patient risk factors, including diabetes, hypertension, and hypercholesterolemia being managed in the long-term by the family physician and cardiologist. However, we cannot provide data on the long-term management of other factors that could potentially influence late mortality and cardiac event-free survival, such as obesity and lack of exercise. This finding is in keeping with the other reports in the literature.6,9,19,34-36 The negative impact of diabetes mellitus on long-term outcome is probably influenced by several factors. First are the end-organ effects of diabetes and the influence of the insulin-resistant syndrome on the progression of comorbidities. Second is the presence of more complex diffuse coronary artery disease. Third is the rapid progression of coronary artery disease and occurrence of new atherosclerotic lesions in the native vessels in diabetic patients with insulin-resistant syndrome. Fourth, type-2 diabetes mellitus in particular affects the morphology of the bypass conduits and may be a factor in late conduit failure. Similar to our study on follow-up, Thourani and associates9 found no difference in the incidence of myocardial infarction and need for reintervention up to 10 years after CABG.
Historically, surgery has been considered the treatment of choice for diabetic patients with multivessel coronary disease.5 More recently, there has been the advent of drug-eluting stents, and several trials are ongoing to assess the impact of this technique for diabetic patients.37
The limitation of this study is that it was a retrospective analysis, although the data were collected prospectively. At the time of data collection, this analysis had not been planned. It is possible that the differences or similarities observed between the groups were a result of unforeseen confounders. However, multivariate analysis is a theoretically sound statistical method of accounting for differences between groups in the absence of random allocation. Also, this study was based on a large cohort of patients from a single institution, which adds to the power of these results.
In conclusion, despite the worsening case-mix, the early mortality and morbidity of diabetic patients undergoing CABG surgery has significantly improved and is comparable with those of nondiabetic patients. These improvements could be due to modern surgical, anesthetic, and cardopulmonary techniques, as well as to postoperative blood glucose management strategies.
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Footnotes |
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References |
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This article has been cited by other articles:
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  S. Castelvecchio, M. Ranucci, M. Di Donato, and L. Menicanti Diabetes mellitus and long-term outcome in heart failure patients after surgical ventricular restoration. Ann. Thorac. Surg., November 1, 2009; 88(5): 1451 - 1456. [Abstract] [Full Text] [PDF]
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 T. Alserius, N. Hammar, T. Nordqvist, and T. Ivert Improved survival after coronary artery bypass grafting has not influenced the mortality disadvantage in patients with diabetes mellitus. J. Thorac. Cardiovasc. Surg., November 1, 2009; 138(5): 1115 - 1122. [Abstract] [Full Text] [PDF]
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P. Nardi, A. Pellegrino, A. Scafuri, D. Colella, C. Bassano, P. Polisca, and L. Chiariello Long-term outcome of coronary artery bypass grafting in patients with left ventricular dysfunction. Ann. Thorac. Surg., May 1, 2009; 87(5): 1401 - 1407. [Abstract] [Full Text] [PDF]
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M. E. Halkos, O. M. Lattouf, J. D. Puskas, P. Kilgo, W. A. Cooper, C. D. Morris, R. A. Guyton, and V. H. Thourani Elevated Preoperative Hemoglobin A1c Level is Associated With Reduced Long-Term Survival After Coronary Artery Bypass Surgery Ann. Thorac. Surg., November 1, 2008; 86(5): 1431 - 1437. [Abstract] [Full Text] [PDF]
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B. Marcheix, F. Vanden Eynden, P. Demers, D. Bouchard, and R. Cartier Influence of Diabetes Mellitus on Long-Term Survival in Systematic Off-Pump Coronary Artery Bypass Surgery Ann. Thorac. Surg., October 1, 2008; 86(4): 1181 - 1188. [Abstract] [Full Text] [PDF]
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M. E. Halkos, J. D. Puskas, O. M. Lattouf, P. Kilgo, F. Kerendi, H. K. Song, R. A. Guyton, and V. H. Thourani Elevated preoperative hemoglobin A1c level is predictive of adverse events after coronary artery bypass surgery J. Thorac. Cardiovasc. Surg., September 1, 2008; 136(3): 631 - 640. [Abstract] [Full Text] [PDF]
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 P. E. Antunes, J. F. de Oliveira, and M. J. Antunes Coronary surgery in patients with diabetes mellitus: a risk-adjusted study on early outcome. Eur. J. Cardiothorac. Surg., August 1, 2008; 34(2): 370 - 375. [Abstract] [Full Text] [PDF]
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 F. Filsoufi, P. B. Rahmanian, J. G. Castillo, J. I. Mechanick, S. K. Sharma, and D. H. Adams Diabetes is not a risk factor for hospital mortality following contemporary coronary artery bypass grafting Interactive CardioVascular and Thoracic Surgery, December 1, 2007; 6(6): 753 - 758. [Abstract] [Full Text] [PDF]
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 S. Mohammadi, F. Dagenais, P. Mathieu, J. G. Kingma, D. Doyle, S. Lopez, R. Baillot, J. Perron, E. Charbonneau, E. Dumont, et al. Long-Term Impact of Diabetes and Its Comorbidities in Patients Undergoing Isolated Primary Coronary Artery Bypass Graft Surgery Circulation, September 11, 2007; 116(11_suppl): I-220 - I-225. [Abstract] [Full Text] [PDF]
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