Diabetes mellitus is an independent risk factor for the development of coronary artery disease (CAD) (1). When diabetic patients develop clinical manifestations of CAD, their prognosis for survival is worse than that of similar patients without diabetes (2 – 5). Diabetic patients treated for CAD with percutaneous transluminal coronary angioplasty (PTCA) appear to have a particularly unfavorable prognosis compared to nondiabetics. Subgroup analysis of the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial demonstrated that diabetic patients with multivessel coronary disease treated with PTCA had a five-year mortality rate of 35% compared to 9% for patients without diabetes (6). Subsequent randomized trials and observational studies have confirmed the reduced survival of diabetics compared to nondiabetics undergoing PTCA (7 – 10). Since the acquisition of these data, coronary stents have become standard treatment for patients with obstructive coronary disease undergoing percutaneous coronary intervention (PCI). Stents reduce the acute risks related to abrupt vessel closure associated with PTCA (11) as well as the long-term adverse outcomes associated with the development of restenosis (12, 13). In addition, inhibitors of the platelet glycoprotein (GP) IIb/IIIa receptor were not available at the time of BARI. These agents reduce the composite endpoint of mortality and myocardial infarction (MI) following PCI (14 – 19) and abciximab, in particular, has been reported to reduce long-term mortality in diabetics following PCI (20). There is little data available to assess the impact of these two recent treatment advances on the survival of unselected diabetics undergoing PCI outside the setting of randomized clinical trials. The purpose of the current study was thus to determine whether contemporary techniques have eliminated the difference in long-term survival between diabetics and nondiabetics undergoing PCI for CAD.

The study population was drawn from a cohort of 3,834 consecutive patients undergoing PCI from January 1, 1998 to October 1, 1999 at one of three tertiary medical centers in New York City. From this group, 997 diabetic patients were identified, accounting for 26.0% of the total population undergoing PCI. These 997 diabetic patients were then matched to nondiabetic patients on three different criteria: decade of age, gender and extent of coronary disease (one-, two- or three-vessel). Matches to all three criteria were found for 857 diabetic patients. Thus, the final study population consisted of 857 diabetics and 857 nondiabetics.

Patient data was recorded prospectively on standardized forms and entered into a computerized database. The data fields are identical to those of the standardized reports submitted to the New York State Department of Health on every PCI performed in New York State. The defined elements in these reports include information on patient demographics, clinical characteristics, pre-intervention risk factors, procedural information, in-hospital outcome, and discharge status. All fields are defined in a data dictionary.

The primary endpoint was all-cause mortality following discharge from the hospital for the index PCI as determined from the Social Security Death Index. This index has been shown to be highly specific and unbiased (21, 22). Follow-up was for a mean of 2.4 years for nondiabetic as well as diabetic patients.

All procedural decisions, including device selection and adjunctive pharmacotherapy were made at the discretion of the individual physician performing PCI. Stents were deployed at high pressure and patients were maintained on ticlopidine or clopidogrel for four weeks in addition to aspirin following implantation unless contraindicated. Angiographic assessments were made at the individual hospital and generally were obtained by visual assessment. Cardiac enzymes (creatine kinase and creatine kinase MB isoenzyme or troponin) were obtained by protocol before and at eight and 24 hours following PCI.

At the time of the procedure, patients were classified as diabetic if they were being treated with oral hypoglycemics or insulin, or if they had a history of elevated (> 140 mg/dL) fasting blood glucose on more than two separate occasions in conjunction with ongoing dietary measures. Ejection fraction (EF) was recorded prior to the cardiac procedure. Missing values for EF were replaced by the mean EF for the nondiabetic or diabetic cohort. A coronary vessel was considered diseased when it contained at least one lesion with > 50% stenosis. Intravenous GP IIb/IIIa inhibitor treatment was administration of abciximab, eptifibatide or tirofiban during or within three hours following PCI. Post-procedural MI was defined as creatine kinase values greater than 2.5 times the upper limit of normal or the development of new Q waves on the electrocardiogram following PCI.

Baseline characteristics of nondiabetics and diabetics are presented in Table 1. Diabetics had a greater mean body mass index and were less commonly white than nondiabetics. Hypertension, electrocardiographic left ventricular hypertrophy, prior congestive heart failure, renal insufficiency (creatinine > 2.5 mg/dl) and renal failure requiring dialysis were all more common in diabetics whereas active smoking was less frequent in diabetics. There were no significant differences between nondiabetics and diabetics with regard to prior history of stroke, MI or peripheral vascular disease. Prior bypass surgery or PCI had been performed with similar frequency in nondiabetics and diabetics.

Features of the clinical presentation are summarized in Table 2. The frequency of presentation with acute MI was similar in nondiabetics and diabetics, as was the recent use of thrombolytic therapy. More diabetic than nondiabetic patients presented with unstable angina (74% vs. 69%, P = 0.047). Congestive heart failure on admission was more common in diabetics than nondiabetics (7.6% vs. 3.7%, P = 0.001).

Procedural information is displayed in Table 3. As a result of case matching there was no difference in extent of coronary disease between groups. One-, two- or three-vessel CAD was present in 43%, 33% and 24% of each group, respectively. The mean ejection fraction was 51.3% in nondiabetics and 49.6% in diabetics (P = 0.005). The use of heparin or intravenous nitroglycerin was similar in both groups. Stents and atherectomy devices were used with similar frequency. Platelet GP IIb/IIIa antagonists were administered to 24% of nondiabetic and diabetic patients. Procedural success was high and not different between groups. Complications of PCI including emergency bypass surgery, post-procedure MI, abrupt closure, stent thrombosis and vascular complications requiring surgery were uncommon and not significantly different between groups. There was a trend toward higher in-hospital mortality in diabetic patients (0.8% vs. 0.2%, P = 0.095) (Table 4).

During 2.4 years of follow-up, mortality was 6.0% (51 deaths) for nondiabetic patients and 11.4% (97 deaths) for diabetic patients who were discharged alive following their PCI (P < 0.001) (Figure 1). After adjustment for baseline differences between nondiabetics and diabetics including body mass index, race, hypertension, left ventricular hypertrophy, smoking, prior or current CHF, previous bypass surgery, renal insufficiency or dialysis and ejection fraction, diabetes remained independently associated with an increased mortality hazard (Hazard Ratio (HR), 1.70; 95% Confidence Intervals (CI), 1.20 – 2.3, P = 0.003).

The impact of stents on out-of-hospital survival of nondiabetics and diabetics is presented in Figures 2a and 2b. Stent placement was not associated with improved survival of nondiabetics or diabetics. For nondiabetics survival was 93.6% for patients who received a stent and 95.6% for patients not treated with a stent (P = 0.32) (Figure 2a). After adjustment for baseline differences among nondiabetics treated with or without a stent, there was a trend toward a mortality hazard among nondiabetic patients receiving a stent (HR, 2.73; 95% CI, 0.97 – 7.63; P = 0.056). For diabetics survival was 89.5% for those who received a stent and 85.6% for those who did not undergo stent implantation (P = 0.15) (Figure 2b). After adjustment for differences in prognostic characteristics between diabetics treated with or without a stent, stent placement resulted in no significant effect on the hazard of mortality (HR, 1.24; 95% CI, 0.77 – 2.02; P = 0.373).

Figures 3a and 3b displays the survival of nondiabetics and diabetics as a function of whether they were treated with GP IIb/IIIa inhibitors at the time of PCI. GP IIb/IIIa inhibitors did not improve survival among nondiabetics or diabetics. Survival for nondiabetics treated with GP IIb/IIIa inhibitors was 95.2% compared to 93.7% for patients not treated with GP IIb/IIIa inhibitors (P = 0.50) (Figure 3a). After adjustment for differences in prognostic characteristics between nondiabetics treated with or without GP IIb/IIIa inhibitors, GP IIb/IIIa inhibitor treatment was associated with an insignificant increase in the hazard of mortality (HR, 1.55; 95% CI, 0.72 – 3.31; P = 0.26). For diabetics survival was 88.4% for those treated with GP IIb/IIIa inhibitors compared to a survival of 88.6% for untreated patients (P = 0.76) (Figure 3b). After adjustment for differences in prognostic characteristics between diabetics treated with and without GP IIb/IIIa inhibitors, no significant effect of GP IIb/IIIa inhibitor therapy on the hazard of mortality was observed (HR, 1.10; 95% CI, 0.67 – 1.82; P = 0.70).

The most important finding of this analytical cohort study was a significantly increased hazard of mortality following contemporary PCI in diabetics compared to nondiabetics after both groups were matched for age, gender and extent of CAD and identifiable residual confounders were controlled for by multivariate modeling. By design, the 70% increase in mortality risk among diabetics was entirely due to deaths occurring following discharge from the hospital. Of concern is the fact that this survival disadvantage occurred in a population three-quarters of which had single- or double-vessel CAD. Furthermore, two of the most important recent advances in interventional cardiology, the development of coronary stents and GP IIb/IIIa inhibitors, did not appear to improve long-term survival for diabetics. These findings are of considerable public health significance as the prevalence of diabetes is expected to double by the year 2025 (23). Thus, unless important advances are realized, the burden of cardiovascular disease imparted by diabetes will also increase dramatically.

The presence of diabetes has long been associated with higher rates of long-term adverse events for patients undergoing PTCA. Stein et al (8) documented a significant reduction in five-year survival for diabetics compared to nondiabetics undergoing PTCA at Emory University in the 1980s. In a population with less three-vessel CAD than the present study, five-year unadjusted mortality was 7% for nondiabetics and 12% for diabetics with an adjusted hazard ratio of 1.51. Analysis of the Duke University database of patients undergoing PTCA with two- or three-vessel CAD from 1984 – 1990 yielded similar findings (9). After five years of follow-up, diabetics undergoing PTCA had an adjusted mortality of 14% compared to 8% for nondiabetic patients. The National Heart Lung and Blood Institute PTCA registry of procedures performed in 1985-6 documented a doubling of nine-year unadjusted mortality in diabetics compared to nondiabetics (36% versus 18%) (10). High restenosis rates, persistent hemostatic abnormalities and uninterrupted progression of atherosclerosis are all factors that potentially contribute to the poor outcomes seen among diabetics treated with PTCA.

The risk of restenosis is significantly greater for diabetic than nondiabetic patients following PTCA (8, 10, 24 – 30). Although restenosis has been associated with an increased requirement for revascularization procedures it has not been shown to be a direct cause of late mortality in the PTCA population in general (12, 13). However, among diabetics a unique feature of restenosis following PTCA is its frequent association with complete occlusion of the previously treated coronary artery (31). In its occlusive form, restenosis in diabetics is a major determinant of long-term mortality (31). Compared to PTCA, coronary stent implantation has been demonstrated in randomized clinical trials to reduce restenosis and the subsequent requirement for revascularization for patients with a relatively narrow spectrum of coronary lesions (12, 13). Although stents appear to achieve a reduction in restenosis compared to PTCA in diabetics (32), even with stents, diabetics appear to have increased restenosis compared to nondiabetic patients (33, 34). The largest prior study of outcomes following stent placement in diabetics from early in the development of coronary stent equipment, techniques and pharmacotherapy documented an increase in late mortality among diabetics compared to nondiabetics (34).

Altered hemostasis may also contribute to the increase in adverse outcomes among diabetics with CAD. Platelets from diabetics demonstrate abnormal platelet aggregation and enhanced shear-induced platelet adhesion (35). These functional abnormalities of the platelet in diabetics have been linked to increased levels of cell surface adhesion molecules including the GP IIb/IIIa receptor (36). Thus, inhibitors of the GP IIb/IIIa receptor have been advocated for treatment of diabetic patients undergoing PCI (20). However, no prospectively derived randomized trial data exists to support this position. A retrospective analysis of abciximab-treated diabetic patients enrolled in three randomized trials demonstrated reduced one-year mortality among diabetics treated with the combination of coronary stents and the GP IIb/IIIa inhibitor, abciximab (20). However, the mechanism of long-term benefit from short-term treatment remains unclear. Furthermore, it is unexplained why this benefit did not extend to nondiabetics or diabetics treated with balloon angioplasty in the same database (20). In contrast, a large single center study found no effect of abciximab on late mortality following PCI in unselected diabetics (37). Although the current study involved the use of all three approved GP IIb/IIIa inhibitors in 1999, in 1998 only abciximab was available for use. Analysis of outcomes of patients treated in 1998 alone did not reveal an improvement in survival for diabetics (or nondiabetics) treated with abciximab (data not shown). Thus, neither abciximab nor GP IIb/IIIa inhibitor treatment in general was associated with improved survival for diabetic patients.

Not only have diabetics been demonstrated to have an increase in late mortality following PTCA, they also experience an increase in nonfatal MI compared to nondiabetics (8, 10). Thus, diabetics appear to have a greater volume of atherosclerotic plaque and an increased propensity for atherosclerotic plaque rupture than nondiabetics. Focal treatments of atherosclerosis as are achieved by all percutaneous approaches may leave behind many untreated potentially vulnerable plaques in diabetics. On the other hand, bypass surgery has the potential advantage of providing an alternative conduit to myocardium in the event of rupture of a vulnerable plaque, most of which occur in proximal portions of the coronary arteries. Thus, the choice of revascularization procedures is especially important in populations with accelerated atherosclerosis and plaque instability such as diabetics. The results of BARI demonstrated a five-year mortality of 9% in diabetics with multivessel disease randomized to bypass surgery and 35% mortality for those assigned to PTCA (6). Of importance, 44% of patients randomized to PTCA in BARI had three-vessel CAD. Because randomized trials of PCI versus bypass surgery contain relatively few diabetic patients who are highly selected and not a subgroup for prespecified analysis, investigators have relied upon “real world” registry data to explore the merits of percutaneous versus surgical revascularization for diabetics with multivessel disease. Large registries of thousands of patients undergoing revascularization by PCI or bypass surgery have tended to show an improvement in survival of diabetics referred for CABG but only one has demonstrated a statistically significant survival benefit for diabetic patients treated with bypass surgery rather than PCI (38). The disparate results of BARI and registry data may be due to the fact that, outside of the setting of a randomized trial, patients referred for surgery tend to have more extensive CAD and those referred for PCI less extensive CAD. With only 24% of diabetic patients in the current study having three-vessel CAD, the referral of these patients for PCI appears consistent with practice patterns in other large registries. Yet the reduced survival of diabetics with predominantly one- and two-vessel CAD in this study raises the question of whether bypass surgery should be considered for diabetic patients with less extensive CAD. Regardless of the revascularization modality, aggressive attempts to control progression of atherosclerosis by addressing not only the hyperglycemia, but also smoking cessation and the dyslipidemias, obesity and hypertension that frequently accompany diabetes should be implemented in all diabetics with CAD (39).

Several limitations should be borne in mind when interpreting the results of the current study. First, as this was not a randomized trial, unidentifiable confounders may have been responsible for the increased mortality in diabetics rather than diabetes itself. Thus, inferences about causation in any observational study must be made with caution. Second, our database does not allow the identification of the specific type of diabetes therapy each patient received. Several studies have suggested that the outcome of insulin-dependent diabetics undergoing PCI is worse than that of diabetics treated with oral agents or dietary restriction (6, 8, 33). Finally, we measured only mortality as our outcome of interest. As a result we cannot speculate on the mechanism of the increased mortality observed in diabetics.

In one of the largest series of diabetic patients to date we found patients with diabetes and moderate CAD treated with contemporary PCI techniques have significantly reduced survival after 2.4 years compared to nondiabetics. Since neither coronary stent placement nor GP IIb/IIIa inhibitors improved survival for diabetics, our results suggest the findings of BARI are still relevant to contemporary practice. A randomized trial of surgical revascularization versus PCI may be required to determine the optimum treatment for diabetics with less extensive CAD than those enrolled in BARI.

2. Stamler J, Vaccaro O, Neaton JD, et al, for the Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care 1993;16:434–444.

3. Kannel W. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J 1985;110:1100–1107.

4. Mak KH, Moliterno DJ, Granger CB, et al. For the GUSTO-1 Investigators. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. J Am Coll Cardiol 1997;30:171–179.

5. Malmberg K, Yusuf S, Gerstein HC, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000;102:1014–1019.

6. The BARI Investigators. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI). Circulation 1997;96:1761–1769.

7. Kurbaan AS, Bowker TJ, Ilsley CD, et al. Difference in the mortality of the CABRI diabetic and nondiabetic populations and its relation to coronary artery disease and the revascularization mode. Am J Cardiol 2001;87:947–950.

8. 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.

9. Barsness GW, Peterson ED, Ohman EM, et al. Relationship between diabetes mellitus and long-term survival after coronary bypass and angioplasty. Circulation 1997;96:2551–2556.

10. Kip KE, Faxon DP, Detre KM, et al. Coronary angioplasty in diabetic patients: the National, Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation 1996;94:1818–1825.

11. Narins CR, Holmes DR, Jr, Topol EJ. A call for provisional stenting: the balloon is back. Circulation 1998;97:1298–1305.

12. Fischman DL, Leon M, Baim D, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994;331:496–501.

13. Serruys PW, De Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331:489–495.

14. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956–961.

15. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockage and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689–1696.

16. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349:1429–1435.

17. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade.Lancet 1998;352:87–92.

18. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997;349:1422–1428.

19. ESPRIT Investigators. Novel dosing regimen in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial. Lancet 2000;356:2037–2044.

20. Bhatt DL, Marso SP, Lincoff AM, et al. Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol 2000;35:922–928.

21. Boyle CA, Decoufle P. National sources of vital status information: extent of coverage and possible selectivity in reporting. Am J Epidemiol 1990;131:160–168.

22. Newman TB, Brown AN. Use of commercial record linkage software and vital statistics to identify patient deaths. J Am Med Inform Assoc 1997;4:233–237.

23. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care 1998;21:1414–1431.

24. Holmes DR Jr, Vliestra RE, Smith HC, et al. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA Registry of the National Heart, Lung and Blood Institute. Am J Cardiol 1984;53:77C–81C.

25. Myler RK, Topol EJ, Shaw RE, et al. Multiple vessel coronary angioplasty: classification, results, and patterns of restenosis in 494 consecutive patients. Cathet Cardiovasc Diagn 1987;13:1–15.

26. Vandormeal MG, Deligonul U, Kern MJ, et al. Multilesion coronary angioplasty: clinical and angiographic follow-up. J Am Coll Cardiol 1987;10:246–252.

27. Hollman J, Badhwa K, Beck GJ, et al. Risk factors for recurrent stenosis following successful coronary angioplasty. Clev Clin J Med 1989;56:517–523.

28. Quigley PJ, Hlatky MA, Hinohara T, et al. Repeat percutaneous transluminal coronary angioplasty and predictors of recurrent stenosis. Am J Cardiol 1989;63:409–413.

29. Deligonul U, Vandormeal M, Kern MJ, et al. Repeat coronary angioplasty and predictors of recurrent stenosis. Am J Cardiol 1989;117:997–1002.

30. Weintraub WS, Kosinski AS, Brown CL, et al. Can restenosis after coronary angioplasty be predicted from clinical variables? J Am Coll Cardiol 1993;21:6–14.

31. Van Belle E, Ketelers R, Bauters C, et al. Patency of percutaneous transluminal coronary angioplasty sites at 6-month angiographic follow-up: a key determinant of survival in diabetics after coronary balloon angioplasty. Circulation 2001;103:1218–1224.

32. Van Belle E, Bauters C, Hubert E, et al. Restenosis rates in diabetic patients: A comparison of coronary stenting and balloon angioplasty in native coronary vessels. Circulation 1997;96:1454–1460.

33. Abizaid A, Kornowski R, Mintz GS, et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998;32:58–589.

34. Elezi S, Kastrati A, Pache J et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol 1998;32:1866–1873.

35. Knobler H, Savion N, Shenkman B, et al. Shear-induced platelet adhesion and aggregation on subendothelium are increased in diabetic patients. Thromb Res 1998;90:181–190.

36. Tschoepe D, Roesen P, Kaufmann L, et al. Evidence for abnormal platelet glycoprotein expression in diabetes mellitus. Eur J Clin Invest 1990;20:166–170.

37. Velianou JL, Mathew V, Wilson SH, et al. Effect of abciximab on late adverse events in patients with diabetes undergoing stent implantation. Am J Cardiol 2000;86:106–1068.

38. Niles NW, McGrath PD, Malenka D, et al. Survival of patients with diabetes and multivessel coronary artery disease after surgical or percutaneous coronary revascularization: results of a large regional prospective study. J Am Coll Cardiol 2001;37:1008–1015.