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Ann Thorac Surg 2003;76:1149-1154
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Coronary artery bypass grafting in Type II diabetic patients: a comparison between insulin-dependent and non-insulin-dependent patients at short- and mid-term follow-up

^a Department of Cardiology and Cardiovascular Surgery, Catholic University of the Sacred Heart, Rome, Italy

Accepted for publication April 9, 2003.

^* Address reprint requests to Dr Luciani, Dipartimento di Medicina Cardiovascolare, Cattedra di Cardiochirurgia, Università Cattolica del Sacro Cuore, Largo Francesco Vito n. 1, Rome, Italy.
e-mail: nicola.luciani{at}tiscalinet.it

	Abstract

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BACKGROUND: Diabetes is a well-established risk factor for coronary artery disease, and it is associated with an increased rate of early and late adverse events after myocardial revascularization by coronary artery bypass grafting.

METHODS: A prospective follow-up study was done to evaluate the short-term and mid-term outcomes of type II diabetic patients who had coronary artery bypass grafting at our institution between 1996 and May 1999. A total of 200 patients, 100 insulin-dependent diabetic patients (group I) and 100 non-insulin-dependent diabetic patients (group II), met the inclusion criteria of the study and were included in the clinical follow-up study.

RESULTS: The characteristics of the patients of the two groups were similar for baseline clinical angiographic and operative characteristics. In particular, no significant differences in cardiopulmonary bypass and aortic cross-clamping times were noted between the two groups. The number grafts per patient was similar between the two groups. There were no in-hospital deaths, but postoperative complications were different among the two series. In fact, 33% of patients in group I had at least one major complication compared with 20% in group II (p = 0.037). The cumulative number of complications was 148 in group I and 69 in group II, and the mean number of complications per patient was 4.5 and 3.5 in groups I and II, respectively. The major differences in perioperative complication rates were found in the need for prolonged (> 24 hours) ventilation, occurrence of respiratory or renal insufficiency, and mediastinitis. The mean length of stay in the intensive care unit and for total hospitalization were longer in group I than group II (4.3 ± 2.8 days versus 2.8 ± 2.7 days [p = 0.010] and 11.1 ± 2.2 days versus 7.2 ± 2.4 group II [p < 0.05], respectively). At long-term follow-up, group I patients had a significantly higher mortality rate (29% versus 10%, p < 0.001). Moreover, overall late cardiac and noncardiac complication rates were significantly higher in group I than II (37% versus 22%, p = 0.02). In the multivariate analysis including several preoperative and operative variables, treatment by insulin, advanced age (> 75 years), left ventricular dysfunction (left ventricular ejection fraction < 35%), and complex lesions at coronary angiography (American Heart Association lesion classification type C lesion) were found as independent predictors of increased mortality.

CONCLUSIONS: Our data show that patients with insulin-dependent type II diabetes who had coronary artery bypass grafting have a significantly higher rate of major postoperative complications with an extremely unfavorable short- and long-term prognosis. Diabetic patients on insulin treatment should be considered high-risk candidates for coronary artery bypass grafting and require intense perioperative and long-term monitoring. Further studies will be necessary to investigate whether such conclusions may be appropriate for newer surgical strategies such as off-pump operation.

	Introduction

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Diabetes is a well-established risk factor for atherosclerotic coronary heart disease [1]. Coronary artery disease is not only more prevalent in diabetic patients (55%) compared with the rest of the population (2% to 4%) but tends to be more extensive, involving multiple vessels and being rapidly progressive [2]. Moreover, diabetes is also a significant risk factor for early [3] and late adverse outcome after myocardial revascularization with coronary artery bypass grafting (CABG) [4].

Although several authors have considered insulin treatment in type II diabetics to be an additional risk factor for development of coronary artery disease [5, 6], there are no data in the literature that describe the need for insulin treatment in type II diabetic patients as a clear additional risk factor in patients who undergo CABG. The aim of our study was therefore to assess the short- and mid-term prognosis of type II diabetics who had CABG, comparing insulin-dependent patients with non-insulin-dependent patients.

	Material and methods

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Patient population
A prospective registry study to evaluate outcomes of type II diabetic patients who had CABG was started at our institution in January 1996 and ended in May 1999 (DIabete Mellito Outcome: DIMO study). All patients with type II diabetes treated by oral antidiabetic medication or insulin scheduled to undergo isolated CABG were prospectively enrolled in this registry. In all patients the diagnosis of type II diabetes was made by a consultant in internal medicine based on clinical and laboratory analyses, such as fasting glucose levels, oral glucose tolerance test, and insulinemia, according to the criteria of the American Society of Diabetes [7]. Nine hundred eighty diabetic patients were studied. These patients were screened for inclusion criteria in one of the two following groups and for several exclusion criteria. Patients treated by insulin for at least 1 month before CABG were eligible for group I (insulin-dependent diabetics), whereas diabetic patients with no previous insulin treatment who were taking oral antidiabetic medication were eligible for group II (non-insulin-dependent diabetics). The following exclusion criteria were applied in order to maximize homogeneity and comparability between groups: clinical diagnosis of type I diabetes or of maturity onset diabetes of the young, unclear diagnosis of diabetes, patients with intermittent insulin therapy or recent institution of insulin treatment (< 1 month), associated cardiac or noncardiac surgical procedures at CABG time and re-CABG. After such screening procedures, a total of 200 cases were included in the study—100 in group I and 100 in group II.

Patients' preoperative data and risk factors for adverse outcomes, according to the EUROSCORE algorithm [8] are reported in Table 1. Angiographic characteristics with the lesion definition type for each patient (type A, B, or C according to the American Heart Association lesion classification at coronary angiography) [9] are reported in Table 2.

Grafting to the left anterior descending artery was performed using the left internal mammary artery in all cases. The great saphenous vein or other arterial conduits were grafted on the remaining target coronary vessels, when necessary. At the end of cardiopulmonary bypass, anticoagulation was reversed by protamine sulfate (1 to 1.5 mg per 100 IU/heparin).

Statistical analysis
The ² or Fisher exact test was used to compare discrete variables of the two groups. Continuous variables (presented as mean ± standard deviation) were compared by parametric or nonparametric tests (t test and Mann-Whithney U test). Multivariable analysis by the generalized linear model (using the default identity link available on the Statistical Package for Social Sciences SPSS 10.0) was performed using a model which included the following preprocedural and procedural variables: gender, advanced age (> 75 years), New York Heart Association and Canadian Class score functional classes, previous acute myocardial infarction and stroke, renal insufficiency, coronary lesion classification, multivessel coronary disease, left main coronary artery disease, significant left ventricular dysfunction (left ventricular ejection fraction < 35%), and urgent revascularization. Statistical significance was defined as p less than 0.05. The predicted risk of operative mortality was calculated for each patient using the EUROSCORE algorithm [8], and mean predicted risk scores were calculated for each group for comparison.

Definitions
Acute myocardial infarction was defined as 1) electrocardiographic ST segment or T wave alterations with or without echocardiographic evidence of new areas of regional hypo-dyskinesia associated with 2) elevation of creatine kinase-MB fraction (> 4%) with or without appearance of new Q waves on the electrocardiogram. Renal insufficiency was defined as a postoperative increase in serum creatinine level of at least 2 mg/dL or an increase of more than 100% of preoperative creatinine levels. Respiratory insufficiency was defined as hypoxemia (partial arterial oxygen pressure < 60 mm Hg in room air). Intraoperative stroke was defined as a new focal neurologic deficit or coma that became evident at the moment the patient awakened from the anesthesia, lasting more than 24 hours, associated with computed tomographic demonstration of recent ischemic cerebral lesion. Postoperative stroke was defined as a new focal neurologic deficit or coma lasting more than 24 hours, which became evident after a normal awakening of the patient from the anesthesia and an apparently normal postoperative neurologic examination, associated with computed tomography demonstration of recent ischemic cerebral lesion. Sepsis was defined according to the established criteria of fever or hypotermia, leucocytosis or leucopenia, and tachycardia and tachypnea due to systemic infection. Mediastinitis was defined as a deep sternal wound infection associated with fever and sternal wound instability. Hemorrhagic postoperative complications were defined as the need for blood transfusions with or without surgical revision of the wound for bleeding. Emergent revascularization was defined on the basis of clinical and instrumental evidence of one or more of the following: unstable angina not responsive to medical therapy, hemodynamic instability with refractory hypotension, and use of intraaortic balloon pump.

Endpoint
The primary endpoint was all causes of mortality during the in-hospital course or at long-term follow-up. Preestablished secondary endpoints included all major postoperative complications, including nonfatal acute myocardial infarction, nonfatal stroke, sepsis, shock, reoperation for graft failure, mediastinitis, respiratory insufficiency, and renal insufficiency, and minor postoperative complications, including mechanical ventilation for more than 24 hours, inotropic support for more than 24 hours, reoperation for bleeding, and necessity of blood transfusion.

Additional analysis was performed on the duration of stay in the intensive care unit and overall hospital stay and on the need for increasing doses of insulin treatment in group I patients or need for insulin treatment in group II patients.

Follow-up
All living patients were evaluated at follow-up visits for at least 36 months after the procedure with a scheduled in-hospital visit at 6, 12, 24, and 36 months and additional visits when clinically indicated. Clinical evaluation included performance of an electrocardiogram, a transthoracic echocardiogram, and a functional test by either echo-dobutamine or myocardial stress perfusional nuclear scan within 12 months of the procedure (mean, 7 months).

	Results

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Preoperative and operative characteristics
The two groups were similar according to clinical characteristics such as age, risk factors, previous myocardial infarction, and history of congestive heart failure (Table 1). However, there were more men in group I versus group II (although this difference did not reach statistical significance, p = 0.12), and group I patients were more likely to have had manifestation of cerebrovascular disease (56% versus 11%, p < 0.001) and to have significant carotid artery disease (35% versus 16%, p = 0.002), although this difference was no longer significant when only the rate of previous stroke was considered (16% versus 8%, p = 0.08). Moreover, group I patients were significantly more likely to have left main disease (38% versus 4%, p < 0.001); they also had a trend toward higher prevalence of significant left ventricular dysfunction (34% versus 22%, p = 0.06). The EUROSCORE algorithm [8] in the overall population was 8.3 ± 0.8 with no significant difference between the groups (p = 0.68). Angiographic characteristics were similar in the two groups, and type C lesions were noted in 150 patients (78 in group I, 72 in group II, p = 0.89). Most of the procedures were performed on an elective basis. However, 90 patients (45%), 50 in group I and 40 in group II, were urgently revascularized because of clinical instability. True emergent CABG, however, was not performed in this series (Table 2).

Operative results are given in Table 3. No significant differences in cardiopulmonary bypass and aortic cross-clamping times were noted between the two groups. The combination of antegrade and retrograde cardioplegic perfusion was significantly more prevalent in group I than group II, probably because this group had more patients with left main involvement or left ventricular dysfunction.

Early results
The postoperative course of the 200 patients is summarized in Table 4. There were no in-hospital deaths. Seven patients (3.5%, 4 in group I and 3 in group II, p > 0.05) had a nonfatal acute myocardial infarction during the postoperative period. A significantly higher number of patients in group I had respiratory insufficiency (17 in group I and 1 in group II, p < 0.001) and renal insufficiency (all 18 in group I, p < 0.001).

Mediastinitis complicated the postoperative course significantly more often in group I than group II (8 in group I and 2 in group II, p = 0.05).

Eighteen patients (10 in group I and 8 in group II; p > 0.05) required surgical revision of the wound. Forty-five patients (25 in group I and 20 in group II; p > 0.05) required transfusion of at least one unit of packed red blood cells.

Overall, 53 patients had at least one postoperative major complication. This rate was significantly higher in group I (33%) than group II (20%, p = 0.037). Group I also had a greater overall cumulative complication rate (148 complications in group I versus 69 in group II; p < 0.05). No gender-dependent differences in outcomes were found in comparing the two groups.

The mean length of stay in the intensive care unit and the total duration of postoperative hospitalization was significantly longer in group I than group II (4.3 ± 2.8 days versus 2.8 ± 2.7 days [p = 0.01] and 11.1 ± 2.2 days versus 7.2 ± 2.4 [p < 0.05], respectively).

Forty-five patients in group II required insulin treatment in the postoperative period because of uncontrolled hyperglycemia, and 75 patients in group I required a significant increase in total insulin dose (28 U versus 18 U; p < 0.01).

Mid-term follow-up
All living patients were followed up to 3 years after the procedure (Fig 1). There were 39 late deaths (19.5%). Group I patients had a significantly higher mortality rate than those in group II (29% versus 10%; p < 0.001). Cardiac-related deaths were 24% in group I and 7% in group II (p < 0.001). In the multivariable analysis of several preoperative and operative characteristics, insulin-dependent diabetes, advanced age (> 75 years), significant left ventricular dysfunction (left ventricular ejection fraction < 35%), and type C lesion at preoperative angiogram were independent predictors of death at long-term follow-up.

View larger version (9K): [in this window] [in a new window]   Fig 1. Actuarial survival curve at 3 years follow-up. Group I (diamonds) = insulin-dependent type II diabetes patients; group II (squares) = non-insulin-dependent type II diabetes patients. *p < 0.05.

Insulin-dependent diabetics (group I) had a higher incidence of renal insufficiency (7% vs 0%, p = 0.007) and more rapid development of diabetic retinopathy with a higher incidence of partial or complete visual loss at midterm follow-up (22% of group I vs 3% of group II; p < 0.001).

The need for further revascularization either by a repeat CABG or coronary angioplasty was similar in the two groups (6% in both groups).

At mid-term follow-up, 14 patients (14%) in group II required permanent insulin treatment and 22 patients (22%) in group I required a significant increase of insulin dose (Table 5 ).

	Comment

Top Abstract Introduction Material and methods Results Comment References

Our data show that diabetics on insulin therapy have a significantly worse outcome during the postoperative period as well as at mid-term follow-up. In fact, insulin-treated diabetics had a threefold higher mortality rate at 3 years compared with diabetics taking oral antidiabetics.

Salomon and colleagues [12] compared insulin-dependent and non-insulin-dependent diabetic patients to nondiabetics and found that the perioperative mortality rate was significantly higher in diabetics but not different between insulin-dependent and non insulin-dependent patients.

Stewart and associates [13] reported that diabetics treated with oral hypoglycemic agents or with diet alone had clinical outcomes and management costs similar to those of nondiabetics, suggesting that most of the adverse events and adjunctive costs in diabetics are confined to insulin-treated diabetics. Indeed, they also reported that the insulin-requiring diabetic patients had a significantly longer in-hospital stay and more major complications compared with insulin-free diabetic patients and with the nondiabetic population. In a multivariate analysis they showed that preoperative insulin use was an independent risk factor for worse postoperative outcome. Their study, however, was limited by the retrospective design of the protocol.

The results of our study clearly suggest that insulin treatment in type II diabetic patients who had CABG identifies a group of patients at high risk for short-term and mid-term complications. Indeed, in our series, insulin-dependent patients not only had a significantly higher mid-term mortality rate, but also had more perioperative complications. Patients on insulin treatment had, compared with the non-insulin-dependent patients, a significantly higher incidence of mediastinitis, renal insufficiency, respiratory insufficiency, and need for prolonged mechanical ventilation. Moreover, the present study includes exclusively type II diabetics, whereas other studies included type I diabetics, who indeed have a different natural history.

Finally, our data reflect the current time strategy for CABG in diabetics, whereas data previously reported by Salomon and colleagues [12] were from patients who had CABG in the 1980s, before the introduction of warm heart operations and wider use of internal thoracic artery grafts, which are two important confounding factors.

Interestingly, the analysis of hospitalization length, which was significantly longer in patients requiring insulin treatment, may be useful for addressing cost-efficacy issues.

Limitations of our study need to be addressed. The small number of patients is certainly one of the major limitations. Other limitations include single-center experience and cardiopulmonary bypass strategy in all cases. Further studies are required to evaluate this issue in larger series and using novel surgical strategies, such as off-pump coronary artery bypass grafting, an approach [14] that is becoming the choice in many cases of high risk myocardial revascularization.[10]

	References

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