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Ann Thorac Surg 2007;83:93-99
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Impact of Diabetes on Five-Year Outcomes of Patients With Multivessel Coronary Artery Disease

^a Heart Institute, University of São Paulo, São Paulo, Brazil
^b Mayo Clinic, Rochester, Minnesota

Accepted for publication August 28, 2006.

^_* Address correspondence to Dr Hueb, Clinical Division, Heart Institute (InCor), University of São Paulo, Av Dr Enéas de Carvalho Aguiar, 44 Sala 114, São Paulo 05403.000, Brazil. (Email: whady.hueb{at}incor.usp.br; mass{at}incor.usp.br).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: Diabetes mellitus is a major cause of coronary artery disease. Despite improvement in the management of patients with stable coronary artery disease, diabetes remains a major cause of increased morbidity and mortality. Although coronary artery bypass grafting surgery (CABG) and percutaneous coronary intervention are widely used, no conclusive evidence exists that either treatment modality is better than medical therapy alone for the treatment of stable single- or multivessel coronary disease in patients with diabetes.

METHODS: We compared medical therapy, percutaneous coronary intervention, and CABG in 499 diabetic patients (38.5%) and 799 nondiabetic patients (61.5%) with single- or multivessel coronary disease. The composite primary endpoint was cardiac-related death, Q-wave myocardial infarction, or refractory angina requiring revascularization.

RESULTS: We treated 1,298 patients with either CABG (n = 524), percutaneous coronary intervention (n = 378), or medical therapy (n = 396). More deaths occurred among patients with diabetes than among patients without diabetes, regardless of which option was used (p < 0.001). When treatment modalities were stratified according to the number of diseased vessels, CABG was shown to be more beneficial for patients with diabetes and multivessel disease than for patients with diabetes and single-vessel disease (p < 0.001). However, when stratified by treatment, patients with diabetes receiving medical therapy had a worse prognosis than patients with diabetes treated with CABG (p = 0.005).

CONCLUSIONS: All three therapeutic regimens resulted in high rates of cardiac-related deaths among patients with diabetes compared with patients without diabetes. Moreover, we observed better outcomes among patients with diabetes and multivessel coronary artery disease undergoing CABG regarding the primary endpoint at 5-year follow-up.

	Introduction

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The atherosclerotic process is usually more significant in persons with diabetes mellitus than in nondiabetic persons. Several factors involved in the pathogenesis of atherosclerosis in patients with diabetes trigger complications. Consequently, the revascularization strategies in these patients carry an increased risk of restenosis or acute occlusion of the bypass graft [1, 2].

The Bypass Angioplasty Revascularization Investigation (BARI) [3], a trial comparing long-term survival among patients with multivessel disease and severe angina or ischemia who underwent coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) with a balloon, reported better survival rates for the subgroup of patients with diabetes treated with CABG than for those treated with PTCA. Recently, the Arterial Revascularization Therapies Study (ARTS) reported 5-year outcomes of patients with multivessel coronary artery disease treated with stents versus CABG. Repeated revascularization was significantly higher among diabetic than nondiabetic patients randomly allocated to the stenting arm than among those randomly assigned to the CABG arm [4].

Thus, the aim of this study was to prospectively compare the long-term follow-up of medical treatment, CABG, and PCI for patients with single- or multivessel stable coronary artery disease and preserved left ventricular function, with and without diabetes.

	Patients and Methods

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Patient Selection and Study Protocol
A total of 20,769 patients who had the presumptive clinical diagnosis of coronary artery disease and who underwent coronary angiography were screened at the Heart Institute of the University of São Paulo between May 1995 and May 2000. Of these, 18,692 patients (90%) did not meet the clinical or angiographic requirements for study inclusion. The most frequent reasons for exclusion were normal coronary artery anatomy, association with valvular heart disease, previous PCI or CABG, and ventricular dysfunction. The remaining 2,077 patients (10%) who had the medical indications for revascularization procedures, either PCI or CABG were enrolled in the Medicine, Angioplasty or Surgery Study (MASS) database. Of these patients, 1,466 were not randomized because they refused to participate as randomized patients, but they agreed to participate in the observational follow-up study. Of these patients, 168 were lost to follow-up; therefore, 1,298 nonrandomized patients were followed up in this present study. All patients granted informed consent for the study.

The MASS protocol, including details regarding aims, patient recruitment, inclusion and exclusion criteria, data collection, procedural guidelines, and definitions has been published previously [5]. Briefly, clinically eligible patients who consented to enter the study were prospectively followed up for 5 years. Ischemia was documented by either stress testing or the typical stable angina assessment of the Canadian Cardiovascular Society (class II or III). Patients were enrolled in this study if the surgeon and interventionist agreed that revascularization could be attained by either strategy. The study population included 499 patients with diabetes mellitus. Exclusion criteria included unstable angina, ventricular aneurysm requiring surgical repair, left ventricular ejection fraction of less than 45%, a history of PCI or CABG, and left main coronary artery stenosis. Patients gave written informed consent and then were assigned to surgery, angioplasty, or medical treatment only. The Ethics Committee of the Heart Institute approved the trial, and all procedures were performed in accordance with the Helsinki Declaration.

Treatment Intervention
An optimal medical regimen consisted of a stepped approach using nitrates, aspirin, ß-blockers, calcium-channel blockers, angiotensin-converting enzyme inhibitors, hydroxymethylglutaryl-coenzyme-A reductase inhibitors, or a combination of these drugs. Insulin and oral hypoglycemic agents were also used in patients with diabetes.

The Heart Institute provided these medicines free of charge. Patients were then assigned to continue with aggressive medical therapy alone or to undergo PCI or CABG concurrently with medical therapy (MT). Devices used for catheter-based therapeutic strategies, including stents, lasers, directional atherectomy, and balloon angioplasty, were available to the interventionist. Angioplasty was performed according to a standard protocol. Glycoprotein IIb/IIIa agents were not used. Complete revascularization was accomplished, if technically feasible, with saphenous vein grafts, internal mammary arteries, and other conduits such as radial or gastroepiploic arteries, preferably using the left internal mammary artery to graft the left anterior descending coronary artery. Equivalent revascularization was encouraged but not mandatory.

Five-Year Clinical Follow-Up
Adverse and other clinical events were tracked from written informed consent. Patients were assessed at follow-up visits every 3 months during the first year and subsequently every other 6 months until 5-year clinical follow-up.

Clinical Endpoints
The predefined primary endpoint was the combined endpoints of the incidence of cardiac-related mortality, MI, or refractory angina requiring revascularization within 5 years of follow-up. The secondary endpoints included angina status and occurrence of a stroke or cerebrovascular accident.

Statistical Analysis
Statistical analysis was performed with SPSS software (SPSS, Chicago, Illinois). Differences in clinical and demographic baseline characteristics between patients with and without diabetes and among treatment groups within the registry were assessed by ² or Fisher’s exact test for dichotomous variables, and by t tests or Wilcox tests for continuous variables. Event-free survival was estimated by the Kaplan-Meier method, and differences among groups were assessed with the log-rank test. Cox’s proportional hazards methods was used to develop models of 5-year mortality rates in all patients.

Variables included in the multivariate model were age, hypertension, diabetes mellitus, sex, hyperlipidemia, number of vessels diseased, and treatment allocation. All tests were two-tailed, and p less than 0.05 was considered statistically significant.

	Results

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Baseline Characteristics of Source Population
Of the 1,298 patients included in this analysis, 524 (40.4%) underwent initial CABG, 378 (29.1%) were assigned to undergo PTCA, and 396 (30.5%) received MT only. Of these, 499 patients had diabetes mellitus (38.5%) and 799 did not (61.5%). Moreover, 214 patients (16.5%) had single-vessel disease, 420 (32.5%) had two-vessel disease, and 664 (51%) had three-vessel disease. The number of diseased vessels and the treatment received upon registry enrollment in the patients with diabetes is depicted in Table 1. The vital status of all assigned patients was ascertained in May 2005. The minimum duration of follow-up was 5 years. Enrolling patients into one of the three treatment options created balanced treatment groups, as shown in Table 2. The cumulative survival rates at 5-year follow-up were 88.2% for CABG, 89.0% for PCI, and 83.3% for MT, including patients with and without diabetes. After adjusting for age, sex, hypertension, smoking, low-density lipoprotein cholesterol, and single-vessel and multivessel coronary artery disease, overall freedom from death, myocardial infarction, and repeat revascularization were not different between MT and PCI groups (11.11% in PCI group versus 16.66% in MT group, p = 0.025; relative risk [RR], 1.382; 95% confidence interval [CI]: 1.042 to 1.834). Whereas in the CABG and MT arms there was significant difference between the groups (11.11% in CABG group versus 16.66% in MT group, p < 0.001; RR, 0.398; 95% CI: 0.281 to 0.564), the incidence of cardiac death was not significantly different between PCI and MT groups (16.7% in MT group versus 11.1% in PCI group, p = 0.845; RR, 0.948; 95% CI: 0.558 to 1.611) or between CABG and MT groups (11.8% in CABG group versus 16.66% in MT group, p = 0.052; RR, 0.585; 95% CI: 0.341 to 1,003). Specific analyses were performed on diabetic versus nondiabetic patients. At 5 years, there was statistical significance between the groups (p = 0.012; RR, 1.778; 95% CI: 1.135 to 2.784), even if in the three groups, we did not find statistical differences relating to diabetic patients in the MT group (40%), PCI group (32%), or CABG group (42%; p = 0.052).

Surgical Therapy
Of the 524 patients assigned to the CABG group, 519 (99%) underwent CABG treatment. The multivessel patients who underwent CABG had an average of 3.4 ± 0.9 vessels bypassed. All intended vessels were grafted in 78% of the patients. At least one internal thoracic artery was used for grafting in 94% of patients, and two internal thoracic arteries associated with radial arteries were used in 41% of patients. During the 5-year follow-up, 18 patietns (3.4%) had an uncomplicated MI, 6 (2.09%) underwent PCI, and 8 (1.5%) underwent a new CABG owing to refractory angina. In addition, 62 patients (11.8%) died of cardiac death and 20 other patients (3.0%) had a cerebrovascular accident during the 5-year follow-up. During this period, 45 patienst (8.6%) were lost to follow-up.

Coronary Angioplasty
Of 378 patients assigned to the PCI group, 371 (97%) received the assigned treatment, 6 (1.7%) underwent CABG as their initial treatment owing to unstable angina before the percutaneous interventions, and 2 (0.5%) died before treatment.

Moreover, 3 patients (0.8%) received MT because they refused the PCI procedure. Each patient who underwent PCI had an average of 2.2 ± 0.8 vessels dilated. Multivessel PCI was performed in 298 patients (81%). Immediate angiographic success was achieved in 94% of patients in whom PCI was attempted, and at least one stent was implanted in 301 patients (82%). Complete revascularization was achieved in 61% of patients. Two additional patients (0.5%) in whom PCI was uncomplicated but unsuccessful were referred for elective CABG during the initial hospitalization and 2 other patients (0.5%) required repeat PCI before discharge. During 5-year follow-up, 77 patients (20.4%) underwent further PCI and 37 (9.8%) underwent CABG. Nevertheless, during this follow-up period, 33 patients (8.7%) had an uncomplicated MI, 10 (2.6%) had a cerebrovascular accident, and 42 (11.1%) died of cardiac death. During this period, 14 patients (3.7%) were lost to follow-up.

Event-Free Survival
Significant differences were noted between the cumulative cardiac-related mortality among patients with versus patients without diabetes, regardless of the therapeutic option assigned. Estimates of 5-year survival were 83.8% for diabetic patients and 89.1% for nondiabetic patients at the time of entry (p = 0.005; Fig 1). On the other hand, the rates of combined event-free survival had a favorable tendency toward the nondiabetic patients, regardless of the treatment allocated (p = 0.054; Fig 2). When we stratified our analysis by the treatment assigned to the patients, we observed that both event-free survival and event-free combined endpoints had a significant treatment difference at 5 years. That is, patients treated with MT had a worse prognosis than patients who underwent CABG, regardless of the number of diseased arteries. Five-year survival rates were 87.4% for diabetic patients assigned to CABG, 86.7% for those assigned to PCI, and 76.6% for those assigned to MT (p < 0.0001; Fig 3). Five-year rates of event-free combined endpoints were 84.7% for patients assigned to CABG, 61.7% for those assigned to PCI, and 61.4% for those assigned to MT (p = 0.015; Fig 4). Next, we combined CABG and PCI as an interventional strategy and compared it with MT. Interestingly, we found that MT was associated with increased mortality and combined endpoints (p = 0.003 and p = 0.047, respectively). In the Cox proportional hazards analysis, we observed that diabetic patients had a relative risk increase of 1.62 for cardiac death (p = 0.011) and of 1.3 for combined events (p = 0.019) compared with nondiabetic patients. Cox proportional hazards analysis confirmed a relative increase in risk of 1.62 for cardiac death (p = 0.011) and 1.3 for combined events (p = 0.019) in the case of diabetic patients when compared with nondiabetic patients.

View larger version (21K): [in this window] [in a new window]   Fig 1. Probability of survival free of cardiac-related death for diabetic and nondiabetic patients. (DM = diabetes mellitus; NDM = without diabetes mellitus; Yr = year.)

View larger version (20K): [in this window] [in a new window]   Fig 2. Probability of event-free survival for diabetic and nondiabetic patients. (DM = diabetes mellitus; NDM = without diabetes mellitus; Yr = year.)

View larger version (22K): [in this window] [in a new window]   Fig 3. Probability of survival free of cardiac-related death among diabetic patients in three treatment groups: medical therapy (MT), coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI). (Yr = year.)

View larger version (23K): [in this window] [in a new window]   Fig 4. Probability of event-free survival among diabetic patients in three treatment groups: medical therapy (MT), coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI). (Yr = year.)

Single-Vessel Disease
Of the 214 patients with single-vessel disease, no difference was noted in the combined endpoint events or according to the therapy received, regardless of diabetes status. In this group, 14 patients had cardiac-related deaths, 14 had nonfatal MI, and 42 needed repeat revascularization at 5-year follow-up (Table 3). Considering repeated CABG and PCI together as an interventional approach versus MT for diabetic patients, we observed a worse prognosis for patients undergoing MT. The incidence of combined endpoints was 24.1% and 34.3%, respectively (p = 0.016). However, analyzing only cardiac deaths, no statistical difference was noted between diabetic and nondiabetic patients (p = 0.439).

Three-Vessel Disease
Of the 664 patients with three-vessel disease, we observed that regardless of the type of therapy received, the probability of being free of cardiac mortality was worse in diabetic patients compared with nondiabetic patients (81.4% versus 87.8%, respectively; p = 0.018). In this group, 99 patients had cardiac-related deaths, 39 had nonfatal MI, and 88 needed repeat revascularization at 5-year follow-up (Table 3). Considering repeat CABG and PCI together as an interventional approach versus MT in diabetic patients, we observed a worse prognosis for patients receiving MT. The incidence of combined endpoints was 21.5% and 33.3%, respectively (p < 0.001). In addition, even when we compared just CABG and MT in this subgroup of patients, we observed that the difference remained statistically significant between the two groups, namely, MT patients have the worst prognosis.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The MASS registry results indicate that patients with diabetes mellitus have a significantly greater 5-year cardiac mortality than do patients without diabetes. Regarding the treatment strategy, we observed better outcomes with CABG compared with outcomes with PCI or MT in diabetic patients, mainly in patients with three-vessel disease. Within either the diabetic or nondiabetic group, however, no significant difference in mortality occurred among those assigned to PCI, CABG, or MT. Nevertheless, combined endpoint events were more probable among diabetic patients receiving MT only.

The BARI trial recruited 1,829 patients with multivessel disease, of whom 353 had diabetes. Percutaneous intervention had an outcome comparable to that of surgery among nondiabetic patients but worse 5-year mortality among diabetic patients [3]. In addition, this benefit of CABG over the PTCA seen at 5 years in diabetic patients was more pronounced at 7 years. However, post hoc analysis of the Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI) [6] and the Emory Angioplasty Versus Surgery Trial (EAST) [2] demonstrated nonsignificant differences in survival regarding diabetes status. Furthermore, in these trials, balloon angioplasty alone was the only percutaneous revascularization strategy. Bare metal stenting was not performed, which compromised the results because it is well known that the incidence of restenosis after PCI is lower with stents than with the balloon.

More recently, the ARTS trial reported 5-year outcomes in patients with multivessel coronary artery disease treated with stenting versus CABG [7]. Among their 208 diabetic patients, nonsignificant mortality differences occurred in stent patients compared with CABG patients. Within the stent group, the overall mortality was significantly higher in diabetic than in nondiabetic patients. Conversely, there was no significant difference in mortality between diabetic and nondiabetic patients in the CABG group. However, repeat revascularization was higher among diabetic patients randomly assigned to the stent arm than among those in the CABG arm (42.9% versus 10, 9%, respectively) compared with the nondiabetic patients (27.5 % versus 8.4%, respectively; both p < 0.001).

Our study demonstrated a significant difference in cardiac mortality rate for diabetic patients compared with that for nondiabetic patients, regardless of the number of diseased vessel or the treatment allocation (p = 0.005). On the other hand, when we analyzed the probability of being free of combined events, we found a trend toward a worse prognosis only for diabetic patients (p = 0.074). Next, we stratified our analysis of diabetic patients regarding the treatment received, and we showed a worse prognosis for combined endpoint events among those receiving medical therapy or undergoing PCI than among those undergoing CABG treatment, regardless of the number of diseased vessel (p = 0.0001). In addition, we also found higher mortality rates among diabetic patients treated by medical therapy compared with any intervention strategy, regardless of the number of diseased vessels (p = 0.003). Furthermore, analysis based on number of diseased vessels and diabetes status demonstrated a significant difference for triple-vessel disease but not for single-or two-vessel disease for mortality. Fewer deaths were found among diabetic patients when they received the surgical strategy (p = 0.018).

In regard to repeat interventions, the diabetic patients receiving MT compared with those receiving PCI or CABG had a significantly worse prognosis in all subsets of the number of diseased vessels (p = 0.001).

Previous studies comparing outcomes of diabetic patients have grouped together all patients with single- or multivessel disease as well as patients with different left ventricular functions, and that may have masked subgroup differences [8]. The percentage of diabetic patients in these data ranges from 20% to 30%. So it is important to point out that among our population with diabetes, we found patients with different prognostic characteristics related to the number of diseased vessels as well as to diabetes status, such as duration of disease, use of insulin or oral hypoglycemic drugs, or diet only to control diabetes, and the presence of microvascular and other macrovascular disease, all of which may influence the results. Conversely, our diabetic patients were more likely to be female than were nondiabetic patients, and they were older, had higher triglyceride levels, increased frequency of hypertension, and had more three-vessel disease than did nondiabetic patients. On the other hand, nondiabetic patients had a higher frequency of current smoking and higher low-density lipoprotein cholesterol levels. In this context, we cannot rule out all these variables when we are analyzing coronary artery disease prognosis associated with diabetes. Indeed, we used statistical adjustment, and even after adjusting for all the variables related to mortality or combined events in the univariate analysis, diabetes was still an independent predictor of a worse prognosis in our study population.

	Acknowledgments

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Financial support was provided by a research grant from the Zerbini Foundation, São Paulo, Brazil.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

1. Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW. Coronary angioplasty in diabetic patientsThe investigators of the National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation 1996;94:1818-1825.[Abstract/Free Full Text]
2. Stein B, Weintraub WS, Gebhart SP, et al. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty Circulation 1995;91:979-989.[Abstract/Free Full Text]
3. The Bypass Angioplasty Revascularization Investigation (BARI) Influence of diabetes on 5-year mortality in a randomized trial comparing CAGB and PTCA in patients with multivessel disease Circulation 1997;96:1761-1769.[Abstract/Free Full Text]
4. Abizaid A, Costa MA, Centemero M, et al. Arterial Revascularization Therapy Study Group Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary disease patients: insights from the Arterial Revascularizations Therapy Study (ARTS) trial Circulation 2001;104:533-538.[Abstract/Free Full Text]
5. Hueb W, Soares PR, Gersh BJ, et al. The Medicine, Angioplasty or Surgery Study (MASS II): a randomized, controlled clinical trial of three therapeutic strategies for multivessel coronary artery disease J Am Coll Cardiol 2004;43:1743-1751.[Abstract/Free Full Text]
6. CABRI Trial Participants First-year results of CABRI (Coronary Angioplasty versus Bypass Revascularization Investigation) Lancet 1995;346:1179-1184.[Medline]
7. Serruys PW, Ong ATL, Herwerden LA, et al. Five year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial Am J Cardiol 2005;46:575-581.
8. Califf RM, Harrell Jr FE, Lee KL, et al. The evolution of medical therapy for coronary disease: a 15-year perspective JAMA 1989;261:2077-2086.[Abstract/Free Full Text]

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