Percutaneous Coronary Interventions in Diabetic Patients: Is Complete Revascularization Important?

ABSTRACT: Background. The long-term prognosis of diabetic patients with multivessel coronary artery disease (CAD) treated by surgical or percutaneous coronary revascularization is significantly worse as compared to non-diabetics. Lower rates of complete revascularization may be one factor that influences the poor long-term outcome in the diabetic population. Our study assessed the impact of complete revascularization on the long-term prognosis in diabetic patients with CAD treated by percutaneous coronary intervention (PCI). The study included 658 consecutive diabetic patients (mean age, 60.9 ± 10.1 years) who underwent PCI. Multivessel disease was present in 352 patients (53.5%). Revascularization was complete in 94 (26.7%) and incomplete in 258 (73.3%) patients with multivessel disease. Reasons for incomplete revascularization included angioplasty of only the culprit lesion (43.4%); small vessel size (22.8%); moderate lesion, defined as diameter stenosis 50–69% (18.6%); chronic total occlusion of the non-intervened vessel (6.6%); and others (8.5%). Overall survival rate at 5 years was 87.4%. Patients who underwent complete revascularization had a 94.5% survival rate, compared to 83.0% for those with incomplete revascularization (p p = 0.003). Our data suggest that complete myocardial revascularization may improve the long-term prognosis after PCI of diabetic patients with multivessel CAD.

Key words: coronary artery disease, restenosis, revascularization, stents

Coronary artery disease (CAD) is a major complication and the leading cause of death in diabetic patients, with an increased mortality risk of 1.5–3.8% for men and 2.6–4.7% for women, as compared to individuals without diabetes.^1–3 In subjects with multivessel CAD who undergo coronary artery revascularization, the long-term prognosis of diabetic patients is significantly worse compared to non-diabetics.^4–14 In a subgroup analysis of the Bypass Angioplasty Revascularization Investigation,^5,8,11 diabetic patients receiving insulin and/or oral hypoglycemia agents who underwent percutaneous or surgical revascularization had a significantly worse 5-year survival as compared to non-diabetic patients (73.1% versus 91.3%; p 8,11 Similar results have been observed in the Emory Angioplasty Versus Surgery Trial, in the Arterial Revascularization Therapies Study and in other large trials.^12–17 While the mechanisms of the worse long-term outcome in diabetic patients undergoing revascularization as compared to non-diabetics are multifactorial, including more diffuse atherosclerotic disease, increased rates of restenosis, and an increased procoagulant state, one of the possible factors may be related to incomplete revascularization. Few studies have assessed the relationship between completeness of revascularization and long-term prognosis of patients with CAD, providing inconsistent findings. One study¹⁸ demonstrated the positive effect of complete surgical revascularization on the long-term prognosis only in a subset of high-risk patients with severe angina and markedly reduced left ventricle function. As for percutaneous techniques, observational studies have shown an improvement in event-free survival in patients with complete versus incomplete revascularization,^19–23 while others failed to show such a difference.²⁴ The majority of these studies revealed the increased rate of consequent surgical revascularization in the group with incomplete versus complete revascularization.^23,25–27 Even less information is available concerning the influence of complete revascularization on the long-term outcome in diabetic patients undergoing PCI. Limited data regarding this issue were obtained from subgroup analysis applied to series comparing percutaneous versus surgical revascularization.^28,29 The aim of our study was to assess the effect of completeness of revascularization by PCI on the long-term prognosis in diabetic patients with CAD. Methods Study population. Between January 1992 and December 1999, a total of 4,847 percutaneous interventions were performed at our center and data were prospectively entered into our database. Diabetes mellitus was diagnosed before the hospitalization for the index procedure, and was treated with insulin, oral hypoglycemic agents or diet. Patients who underwent PCI in the setting of acute myocardial infarction (MI) were excluded. The endpoints of the study were major adverse cardiac events (MACE): cardiac death, Q-wave MI, coronary artery bypass graft surgery (CABG) and repeat-PCI. Follow-up data were collected during hospital visits, from telephone interviews or the referring physician and were source documented. Information regarding death was obtained from the Ministry of Internal Affairs database. Coronary angiography and angioplasty procedures. Coronary angiography and angioplasty were performed in a routine fashion according to current guidelines with conventional catheter-based systems. Vessel and lesion measurements were obtained using a computerized quantitative analysis system (Quantcor QCA) using the catheter as the object of calibration. Left ventricular ejection fraction (LVEF) was determined from the pre-PCI ventriculogram. Angiographic flow was scored according to the classification of the Thrombolysis in Myocardial Infarction (TIMI) study group.³⁰ PCI was performed using standard techniques. All patients were treated with aspirin 75–250 mg as early as possible before the procedure. A 10,000 U bolus of heparin was given after sheath insertion; thereafter, heparin boluses were administered during the procedure in a dose sufficient to maintain an activated clotting time greater than 250 seconds. After the procedure was completed, heparin was discontinued and the sheath was removed 4 hours later. In cases of intracoronary stent implantation, ticlopidine was started immediately after the procedure (250 mg twice daily) and was prescribed for a period of 3 weeks. Aspirin (75–250 mg daily) was continued indefinitely. Stents were hand-crimped on a balloon or premounted on a delivery system. After stent deployment, further high-pressure balloon inflations (> 12 atmospheres) were typically applied. Definitions. Multivessel CAD was defined as >= 50% diameter reduction by online QCA analysis in 2 or more arteries supplying 2 or more of the 3 major coronary territories, with reference diameters of the arteries adjacent to the site of stenosis > 1.5 mm. Complete revascularization was declared when there was no residual stenosis > 50% in any major coronary artery or their large branches unless a bypass graft fed the territory distal to a diseased segment. Both definitions were adopted from the Arterial Revascularization Therapies Study.¹⁶ Q-wave MI was diagnosed when there was elevation in creatinine kinase to twice the normal level with new pathological Q-waves on the electrocardiogram. MACE were defined as cardiac death, Q-wave MI, CABG or repeat PCI. Statistical analysis. Continuous variables are expressed as mean values and standard deviations. The t-test was used to estimate differences between mean values. Categorical data were compared using the Chi-square test. Kaplan-Meier curves were used to estimate the time to occurrence of MACE. Mean, standard deviation and 95% confidence interval (CI) of MACE-free survival were calculated for each group. Multivariate regression analysis of predictors of 1-year death and MACE was performed using logistic regression with stepwise selection, with entry and exit criteria of p p-value p = 0.06) toward a higher incidence of previous MI in the group with incomplete revascularization. In-hospital MACE were observed in 10 patients (1.6%), including 5 cases of death (0.8%) and 5 cases of non-fatal Q-wave MI (0.8%). Long-term outcome. With a mean follow-up of 3.1 ± 1.7 years, overall MACE were observed in 209/658 patients (31.8%), including 60 cases of death (9.1%), most of which (53/60) were cardiac-related. In the group with complete revascularization, 8/94 patients died (8.5%), 7 of them of cardiac-related causes (7.5%). Of 258 patients with incomplete revascularization, there were 52 deaths (20.1%), 46 of them cardiac-related (17.8%) and 6 not cardiac-related (2.3%). A total of 20/658 patients (3%) had a Q-wave MI and 148 (22.5%) underwent repeat revascularization, the majority of them by repeat PCI (121 cases; 18.4%). By univariate analysis, multivessel disease, incomplete revascularization and LVEF p = NS) and MACE (38.5% and 38.5%, respectively; p = NS) at follow-up. Overall 5-year survival rate for diabetics with multivessel disease was 87.4%, significantly higher in the group with complete revascularization (94.5%) and LVEF > 40% (92%) as compared to patients with incomplete revascularization (83%) and LVEF p = 0.003 and p = 0.00001, respectively) (Figures 1 and 2). Similar results were obtained regarding the rates of 5-year survival free from myocardial infarction. Within the entire group of patients with multivessel CAD, 84.5% were free from death or MI. The rates were much lower in the subgroup with incomplete compared to complete revascularization (79.9% and 92.9%, respectively; p = 0.001) (Figure 3) and in patients with LVEF 40% (58.3% and 89.6%, respectively; p = 0.00001). In the subgroup with LVEF p = 0.005). Treatment modality did not have an impact on survival. Patients treated with diet, oral hypoglycemic agents or insulin had similar rates of death and MACE at follow-up (Table 3). By multivariate analysis (Table 4), incomplete revascularization was the most powerful independent predictor of mortality at follow-up, followed by left ventricular dysfunction, female gender and age > 60 years. Independent predictors of MACE at follow-up included incomplete revascularization (RR, 2.08; 95% CI, 1.27–3.45; p = 0.004) and left ventricular dysfunction (RR, 1.57; 95% CI, 1.18–2.08; p = 0.002). Discussion Diabetes mellitus is a well-recognized disease that is associated with worse outcome after surgical or percutaneous revascularization in patients with CAD.^{4–11,13–15} The reasons for higher mortality rates, greater incidence of MI and the need for additional revascularization procedures in diabetics treated with percutaneous or surgical revascularization are multifactorial. Diffuse atherosclerotic disease, more distal stenosis, rapid progression of the disease in both grafted and non-grafted native arteries and within saphenous vein grafts, increased procoagulant state, an accelerated form of neointimal hyperplasia in response to the vascular injury and other factors have been proposed as explanations for the worse prognosis in diabetic patients undergoing revascularization for multivessel CAD.^31–34 Completeness of myocardial revascularization may be one of the factors influencing the long-term outcome of these patients. To date, studies specifically addressing the relationship between completeness of revascularization and long-term prognosis in patients with multivessel CAD treated with revascularization are few and have provided conflicting results. Our study focused on the effect of incomplete revascularization on mortality and other MACE in diabetic patients. Incomplete myocardial revascularization and poor left ventricular systolic function were strong independent predictors of both mortality and total MACE at follow-up in diabetic patients with multivessel CAD. The definition of complete and not functionally adequate revascularization was used in the present study. The former specifies the successful dilatation of all significant stenosis in vessels that are of sufficient size (> 1.5 mm in diameter), while the latter claims that these vessels must supply viable myocardium. The definition of complete revascularization was preferred in our study, since the evaluation of viable myocardium is often difficult and requires additional diagnostic methods. Other investigators²¹ have addressed the issue of functional revascularization in view of the limitation of PCI to treat chronic total occlusions. The vessels supplying infarcted territory identified by akinesis of the corresponding regions were considered non-viable and, hence, functionally unimportant. Faxon et al.²¹ compared 1-year outcomes in 3 groups of consecutive patients with multivessel CAD who underwent PCI: 1) those who underwent complete revascularization: no residual stenosis >= 70% in any major epicardial vessel; 2) incomplete revascularization: stenosis >= 70% in a major segment; and 3) incomplete but functionally adequate: successful dilatation of all 70% stenosis in bypassable vessels (supporting viable myocardium). The rates of MACE (death, MI and bypass surgery) were highest in the group with incomplete revascularization and did not differ significantly among the arms with complete and incomplete but functionally adequate revascularization. In a retrospective analysis of 3,372 non-randomized surgical patients with three-vessel CAD from the CASS surgical registry,¹⁸ the effect of complete revascularization was evident in the subgroup of patients with severe angina (Canadian Cardiovascular Society grade 3–4) and markedly reduced left ventricle function (Completeness of revascularization and PCI. Data regarding the impact of incomplete revascularization on the long-term prognosis after PCI are controversial.^19–27 In a series of 286 patients with multivessel CAD who underwent PCI, Reeder et al.²⁴ did not find a significant difference in the rate of death, death/MI and grade of angina pectoris in subgroups with or without > 1 residual stenosis (70%) at a mean period of 26.2 months. The same authors showed that a greater proportion of patients with incomplete revascularization underwent CABG at follow-up, while patients with complete revascularization more frequently required re-PCI. Similar results were presented in series by Vandormael et al.,²⁵ Deligonul et al.²⁶ and Shaw et al.²⁷ At the same time, several studies revealed a trend to^21,23 or significantly better survival^20,22 in the group with complete versus incomplete revascularization. As for the diabetic population, the effect of complete revascularization on the long-term prognosis is less known. Limited data are available from subgroup analysis of retrospective series that assessed percutaneous versus surgical revascularization in diabetic patients.^28,32 O’Keefe et al.²⁸ compared the results of surgical versus percutaneous revascularization in 1,938 diabetic patients and found that incomplete revascularization together with the use of sulfonylurea agents represented major factors independently associated with worse long-term outcomes after angioplasty. Gum et al.²⁹ compared the long-term outcomes in 525 diabetic patients with multivessel CAD treated by CABG versus PCI. Complete revascularization was achieved in a larger portion of surgically managed patients as compared to the angioplasty treated group (79% versus 42%, respectively; p p = 0.04) and repeat revascularization procedures (8% versus 64%; p = 0.001). A trend for better survival was observed in the former compared to the latter (30% versus 37%, respectively; p = 0.08). Notably, only the completeness of revascularization and not the type of revascularization (surgical versus percutaneous) was predictive of late mortality. Obviously, these data support a hypothesis that at least some of the mortality differences between surgical and PCI groups in diabetic patients may be related to higher incomplete revascularization rates in the PCI arms. Study limitations. This is a non-randomized, retrospective, observational study with all the inherent limitations of such a trial. The reasons for incomplete revascularization were retrospectively defined. Incomplete revascularization was declared based on the anatomical rather than the functional principle due to the reasons discussed above. Some of the patients included in the study were considered poor candidates for surgery and therefore underwent PCI. This may partially explain the rather high mortality rates in the whole group at follow-up. The correlation of glycemic control (i.e., glycosylated hemoglobin) and long-term prognosis would have provided valuable data regarding the adequacy of glycemic control, but was not available. Conclusion. The results from the present study suggest that complete percutaneous coronary revascularization is associated with improved long-term outcomes in diabetic patients with multivessel CAD. While this study may suggest that we should strive to achieve complete revascularization during PCI in diabetic patients, further randomized studies need to be conducted to prove this hypothesis. Acknowledgments. The authors thank Mr. Boris Futerman, MSc, for his helpful statistical review and Mrs. M. Perlmutter for her assistance in the preparation of this paper.