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(Circulation. 1998;97:1912-1920.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Diabetes Mellitus, Glycoprotein IIb/IIIa Blockade, and Heparin

Evidence for a Complex Interaction in a Multicenter Trial

Neal S. Kleiman, MD; A. Michael Lincoff, MD; Dean J. Kereiakes, MD; Dave P. Miller, MS; Frank V. Aguirre, MD; Keaven M. Anderson, PhD; Harlan F. Weisman, MD; Robert M. Califf, MD; Eric J. Topol, MD; ; for the EPILOG Investigators

From Baylor College of Medicine and the Methodist Hospital, Houston, Tex (N.S.K.); The Carl and Edith Lindner Center for Clinical Cardiovascular Research and the University of Cincinnati (Ohio) College of Medicine (D.J.K.), Ischemia Research and Education Foundation, San Francisco, Calif (D.P.M.); Cleveland (Ohio) Clinic Foundation (A.M.L., E.J.T.); St. Louis (Mo) University Medical Center (F.V.A.); Centocor Inc, Malvern, Pa (K.M.A., H.F.W.); and Duke Clinical Research Institute, Durham, NC (R.M.C.).

	Abstract

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Background—After angioplasty, major complications and ischemic events occur more frequently in diabetic than nondiabetic patients. To determine whether treatment with abciximab is effective in reducing these events in diabetics, we analyzed characteristics and outcomes of diabetic patients enrolled in a large multicenter study (EPILOG).

Methods and Results—Of 2792 patients enrolled, 638 (23%) were diabetic. Diabetic patients were older, shorter, and heavier; more likely to be female and have three-vessel disease, prior coronary artery bypass graft surgery, a history of hypertension, or a recent myocardial infarction; and less likely to be current smokers than their nondiabetic counterparts. During hospitalization, death, myocardial infarction, or urgent revascularization occurred in 7.1% of diabetics and 7.5% of nondiabetics. By 6 months, the composite of death and myocardial infarction had occurred in 8.8% of diabetic patients and 7.4% of nondiabetics, whereas death, myocardial infarction, or revascularization had occurred in 27.2% and 22.6%, respectively. Abciximab treatment reduced death or myocardial infarction among diabetic and nondiabetic patients (hazard ratios, 0.28 [95% confidence interval (CI), 0.13 to 0.57] and 0.47 [95% CI, 0.33 to 0.70] at 30 days for diabetics and nondiabetics, respectively, and 0.36 [95% CI, 0.21 to 0.61] and 0.60 [95% CI, 0.44 to 0.82] at 6 months for diabetics and nondiabetics, respectively). Abciximab reduced target vessel revascularization among nondiabetic patients (hazard ratio, 0.78 [95% CI, 0.63 to 0.96]) but not among diabetics (hazard ratio, 1.4 [95% CI, 0.94 to 2.08]). When standard- and low-dose heparin adjuncts were compared, diabetics receiving abciximab with standard-dose heparin had marginally greater reductions in the composite of death and myocardial infarction and in target vessel revascularization than diabetics assigned to abciximab with low-dose heparin.

Conclusions—Abciximab treatment in diabetic patients led to a reduction in the composite of death and myocardial infarction, which was at least as great as that seen in nondiabetic patients. However, target vessel revascularization was reduced in nondiabetic but not diabetic patients. This effect may be associated in part with lower doses of heparin. These differences may be related to differences in the platelet and coagulation systems between diabetics and nondiabetics, the greater extent of coronary artery disease in diabetics, or patient selection and management factors.

Key Words: angioplasty • abciximab • diabetes mellitus • revascularization • platelets

	Introduction

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Diabetes mellitus is not only a critical risk factor for coronary artery disease¹ but also an important predictor of prognosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Diabetic patients have been reported to be at increased risk to develop complications of the procedure during hospitalization and to have higher rates of recurrence and decreased infarct-free survival after hospital discharge.^{2 3 4} In long-term follow-up, diabetic patients undergoing percutaneous rather than surgical revascularization had nearly a threefold increase in late mortality.²

Inhibition of platelet aggregation with abciximab, a monoclonal antibody directed against the glycoprotein (GP) IIb/IIIa receptor on the platelet surface, has been demonstrated to reduce the risk of ischemic complications in patients with high-risk characteristics undergoing PTCA⁵ and to reduce the combined risk of death, myocardial infarction, or revascularization of the target vessel at 6 months.⁶ A second study, EPILOG, recently indicated that this risk reduction could be extended to patients undergoing routine elective angioplasty, while the safety profile could be improved when the dose of heparin given with abciximab was reduced.⁷ Because a variety of reports have suggested that markers of the soluble coagulation cascade are altered and that levels of platelet activation may be higher in diabetics than nondiabetics,^{8 9 10 11} we decided to examine the clinical outcome of diabetic and nondiabetic patients undergoing PTCA in the EPILOG study.

	Methods

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Details of the main trial have been published previously.⁷ Briefly, patients undergoing elective coronary angioplasty or directional atherectomy were eligible for enrollment if they did not have a contraindication to treatment with abciximab and were not undergoing planned stent placement or rotational atherectomy. All patients received 325 mg of oral aspirin before the procedure. Patients were randomized to receive one of three treatments: standard-dose heparin and a placebo for abciximab, weight-adjusted standard-dose heparin and abciximab, or weight-adjusted low-dose heparin and abciximab. Abciximab was administered as a bolus of 0.25 mg/kg followed by an infusion of 0.07 mg · kg^-1 · h^-1 for 12 hours. Patients assigned to weight-adjusted standard-dose heparin received an initial dose of 100 U/kg. An activated clotting time (ACT) was then determined, and subsequent doses were given as needed to maintain an ACT >300 seconds. Patients assigned to receive weight-adjusted low-dose heparin were given an initial bolus of 70 U/kg. The resultant ACT was recorded, but further bolus doses were not given unless the ACT was <200 seconds. Treatment assignment was blinded. To keep the study blind, all heparin doses were administered and ACTs were recorded by an unblinded observer who was not involved in the management of the patient or subsequent data recording. All patients had a 12-lead ECG performed on enrollment in the study, at hospital discharge, at 30 days, and at 6 months. In addition, blood was drawn for determination of creatine kinase and its MB isoenzymes immediately after the PTCA was begun and every 8 hours thereafter for the first 24 hours. Myocardial infarctions and urgent revascularizations were reviewed individually by a blinded adjudication committee. Six-month status was ascertained by telephone contact.

The primary end point of the study was the composite of death, myocardial infarction, or urgent revascularization at 30 days. The 6-month end point was the composite of death, myocardial infarction, or any revascularization procedure. Myocardial infarction was defined as the development of pathological Q waves on the ECG or elevation of the creatine kinase beyond three times normal with an accompanying elevation in the MB isoenzyme. Target vessel revascularization included repeated PTCA of any segment in the vessel dilated at the time of enrollment in EPILOG or surgical bypass of that vessel.

Information concerning diabetic status was obtained from the case report form. Patients were classified as diabetic on the basis of a history of pathological elevations in the blood sugar. Diabetic patients were further subcategorized on the basis of the presence or absence of insulin dependence and a history of diabetic retinopathy.

Statistical Methods
The statistical design of the trial has been described previously.⁷ Time-to-event analyses used Kaplan-Meier product limit estimates, reference bounds for equality,¹² Cox proportional-hazards models, and the log-rank statistic. Multiple regression analyses did not identify any confounding variables associated with the relationship of diabetes, abciximab, heparin dosing, and the study end points, so all presented estimates are unadjusted. Categorical variables are described as a percentage of nonmissing data. Continuous variables are presented as mean±SD or as median and interquartile range.

	Results

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Baseline Characteristics and In-Hospital Events
Of the 2792 patients enrolled in EPILOG, 638 (23%) were diabetic. Demographic characteristics of diabetic and nondiabetic patients are displayed in Table 1. In general, diabetic patients tended to be older, shorter, and heavier; more likely to be female, have three-vessel coronary artery disease, and have a history of prior CABG, hypertension, or a recent myocardial infarction; and were less likely to be current smokers than their nondiabetic counterparts. Among diabetics, baseline clinical characteristics were evenly distributed among all three treatment allocations (data not shown). There were no differences in angiographic lesion morphology of the target lesions in diabetic and nondiabetic patients (Table 2). Diabetics tended to receive higher heparin doses than nondiabetics; however, when the heparin doses were corrected for body weight, the doses were nearly identical, yielding procedural ACTs that were similar in both groups (Table 3). Two hundred fourteen diabetics (23%) and 424 nondiabetics (23%) were discharged on lipid-lowering agents. Clinical outcomes during hospitalization are shown in Table 4. There were no differences in any elements of the composite primary outcome between diabetics and nondiabetics. Insulin-dependent diabetics and those with diabetic retinopathy did not appear to fare worse than non–insulin-dependent diabetics (data not shown). The peak creatine kinase enzyme ratios were also similar between diabetics and nondiabetics, indicating that the infarctions that did occur were roughly of similar size. Unplanned or "bailout" stenting was performed in 12% of nondiabetics and 11% of diabetics.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical Characteristics by Diabetic Status

View this table: [in this window] [in a new window]   Table 2. Overall Target Lesion Morphology by Diabetic Status

View this table: [in this window] [in a new window]   Table 3. Heparin Dose and Activated Clotting Time

View this table: [in this window] [in a new window]   Table 4. In-Hospital Outcome by Diabetic Status

Early Treatment Efficacy
Beginning the first day after angioplasty, abciximab produced a marked reduction in the composite rates of death and myocardial infarction in both diabetic and nondiabetic patients. Events at 30 days are shown in Table 5. The composite end point occurred slightly more frequently in diabetics than nondiabetics. Q-wave myocardial infarction occurred in 0.4% of diabetics receiving placebo and 0.5% of diabetics receiving abciximab (P=.9) and in 0.9% and 0.4% (P=.21) in nondiabetics assigned to placebo and abciximab, respectively. In contrast, abciximab reduced rates of non–Q-wave infarction from 8.0% to 2.9% in diabetics (P<.001) and from 7.9% to 3.6% in nondiabetics (P<.001). In each of these four groups, more than two thirds of the non–Q-wave infarctions were classified as "large" (ie, creatinine kinase more than five times the upper limit of normal). The early effect of abciximab with low-dose heparin, reflected in the hazard ratio, was nearly identical between diabetics and nondiabetics. However, diabetics appeared to have a greater reduction in the hazard than nondiabetics when treated with abciximab combined with standard-dose heparin. These findings were true of both the primary end-point cluster and the secondary composite of death or myocardial infarction.

View this table: [in this window] [in a new window]   Table 5. Thirty-Day Efficacy by Diabetic Status

Outcomes at 6 Months
Death or Myocardial Infarction
By 6 months, the primary composite was more frequent among diabetic than nondiabetic patients (Fig 1), and there was a trend toward more frequent occurrence of the composite of death and myocardial infarction among diabetics (Table 6). At the 6-month point, the hazard of the composite of death and myocardial infarction was still reduced by abciximab in both diabetics and nondiabetics (Fig 2A). The rate of Q-wave infarction was reduced from 2.3% to 1.7% in diabetics (P=.62) and 1.4% to 1.3% in nondiabetics (P=.77), while non–Q-wave infarction was reduced from 9.9% to 2.9% (P<.001) and 8.0% to 4.2% (P<.001) in diabetics and nondiabetics, respectively. Among diabetics receiving abciximab, the composite rate of death and myocardial infarction tended to be lower in patients assigned to standard-dose heparin (Fig 2B). Diabetics treated with abciximab and standard-dose heparin had a greater reduction in the composite risk of death or myocardial infarction than did nondiabetics treated with the same regimen.

View larger version (31K): [in this window] [in a new window]   Figure 1. A, Kaplan-Meier survival estimates for the composite of death, myocardial infarction (MI), or revascularization according to diabetic status. In this and subsequent figures, the shaded area represents the reference bounds for equivalence (P>.05) between the two groups. B, Kaplan-Meier survival estimates for the composite end point according to diabetic status and treatment assignment among nondiabetics. The curves diverge sharply after 1 month, whereas among diabetics, the curves do not change. DM indicates diabetes mellitus.

View this table: [in this window] [in a new window]   Table 6. Six-Month Efficacy by Diabetic Status

View larger version (27K): [in this window] [in a new window]   Figure 2. A, Kaplan-Meier survival estimates for death or myocardial infarction (MI) among diabetic patients and nondiabetic patients in the placebo and combined abciximab groups. Abciximab reduced the event rates in diabetics to levels equivalent to those in nondiabetics. B, Kaplan-Meier survival estimates for death or myocardial infarction among diabetic patients assigned to abciximab, according to heparin dose assignment. DM indicates diabetes mellitus; Std, standard.

Target Vessel Revascularization at 6 Months
Repeated percutaneous revascularization was performed in 368 patients; 87% of these procedures were performed on the target vessel in nondiabetics and 87% in diabetics. Among diabetic patients, 35% of target vessel revascularizations were coronary artery bypass operations regardless of the treatment assignment, whereas among nondiabetics, the respective proportions were 35% in the placebo group, 29% in the group receiving abciximab and low-dose heparin, and 28% among patients assigned to abciximab and high-dose heparin. Target vessel revascularization was more common among diabetics than nondiabetics in all treatment groups except those assigned to placebo.

The hazard for the composite primary end point of death, myocardial infarction, and revascularization was reduced equivalently in both diabetics and nondiabetics treated with abciximab and standard-dose heparin. However, in patients assigned to abciximab and low-dose heparin, this hazard was reduced only in nondiabetics. Examination of the components of the 6-month end point reveals that target vessel revascularization was more common among diabetics who received abciximab than placebo, particularly among those receiving low-dose heparin (Table 6). In contradistinction, in nondiabetic patients, the frequency of target vessel revascularization was reduced by abciximab, especially in combination with low-dose heparin. Among diabetic patients, there was a relatively steep increase in the frequency of target vessel revascularization between 2 and 4 months after the index procedure. This rise was due primarily to an increase in repeated PTCA and appeared particularly dramatic in diabetic patients treated with abciximab but was less pronounced in diabetic patients assigned to placebo (Fig 3). There was a trend toward more frequent target vessel revascularization in diabetic patients treated with abciximab and low-dose heparin compared with diabetics receiving abciximab and standard-dose heparin (23.5% versus 19.1%, P=.29; Fig 4).

View larger version (34K): [in this window] [in a new window]   Figure 3. A, Kaplan-Meier survival estimates for target vessel revascularization in placebo-treated patients according to diabetic status. In this group, the rate of revascularization was not higher among diabetics. B, Kaplan-Meier survival estimates for target vessel revascularization in abciximab-treated patients according to diabetic status. The rate of revascularization among diabetics was higher than in nondiabetics.

View larger version (35K): [in this window] [in a new window]   Figure 4. Kaplan-Meier survival estimates of target vessel revascularization in diabetic patients receiving abciximab according to heparin treatment assignment. Std indicates standard.

	Discussion

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As the population ages, it is likely that the number of diabetic patients undergoing PTCA will increase. In the first NHLBI-sponsored PTCA registry, 9% of patients had diabetes mellitus¹³; in the second registry, this proportion had risen to 12%,³ and in the Bypass Angioplasty Revascularization Investigation, 19% of patients were diabetic.² In contrast, 23% of patients in EPILOG had diabetes. The principal findings of the present analysis are threefold. First, we have determined that with current angioplasty techniques, the in-hospital event rates for diabetic patients are comparable to those for nondiabetic patients, whereas longer-term rates of death, myocardial infarction, or revascularization are increased in diabetic patients. Second, and perhaps most important, we found that treatment of diabetic patients with a bolus and infusion of abciximab produced a reduction in the risk of death or myocardial infarction that began soon after angioplasty, was maintained at 6 months, and was at least as great as that seen in nondiabetic patients. Although the composite rate of death and myocardial infarction was greater in diabetics than nondiabetics, treatment with abciximab reduced these events to levels comparable to the rates in nondiabetics. The third important finding of this study is the observation that diabetic patients treated with abciximab may have a greater heparin requirement than their nondiabetic counterparts, as reflected in rates of death or myocardial infarction at both 30 days and 6 months and in target vessel revascularization at 6 months.

These findings deserve several comments. First, it is clear that treatment with abciximab produced a robust reduction in catastrophic events, namely the composite of death and myocardial infarction, among both diabetic and nondiabetic patients. The differing outcome responses to heparin dose regimen among the two subgroups are puzzling. Although the confidence limits are broad, the greater beneficial effect of standard-dose heparin for diabetics is present in all outcome measures examined. Some speculation on potential mechanisms therefore seems indicated. It is unlikely that this effect is explained by gross differences in heparin metabolism because the ACT responses indicate that similar levels of anticoagulation were achieved with similar doses of heparin in diabetics and nondiabetics. A variety of other perturbations have been reported in the coagulation systems of diabetic patients that might affect platelet function, including larger platelets,⁸ greater expression of P-selectin,¹⁴ higher platelet surface density of GP IIb/IIIa,^{8 9} altered thromboxane metabolism,¹⁵ and higher levels of circulating fibrinogen,¹⁰ vitronectin,^{16 17} and thrombin–antithrombin III complexes,¹⁸ as well as more extensive endothelial dysfunction.^{19 20} Diabetic patients also have higher mortality in the acute coronary syndromes²¹ and in general have more extensive coronary artery disease than do nondiabetics. These differences may be reflected in the makeup of the target coronary arterial lesions. For example, Silva and colleagues²² reported that when subjected to angioscopy before PTCA, diabetic patients were more likely than nondiabetic patients to have plaque ulceration and evidence of red or fibrin-rich thrombus. Thus, it is conceivable that bona fide differences exist in the coagulation systems of both patient groups and that the lesions in patients with diabetes may be more likely to be include fibrin-rich thrombi and thus require a higher dose of thrombin inhibitor. A higher level of platelet activation manifest by greater surface expression of GP IIb/IIIa might have led to lower levels of receptor occupancy in patients treated with the same dose of abciximab. In the setting of incomplete GP IIb/IIIa receptor blockade coupled with a greater likelihood of a fibrin-rich thrombus, there may be a greater requirement for a thrombin inhibitor to prevent thrombotic complications of PTCA.

Other clinical features of diabetic patients enrolled in EPILOG may have also contributed to the observed differences. Diabetic patients in this trial were more likely than nondiabetics to have had a recent infarction or to have received heparin within the prior week and may therefore have had diminished levels of antithrombin III resulting, in a higher heparin requirement. In addition, patient selection bias may have played an important role. Although the intent of the trial was to encourage the enrollment of low-risk rather than high-risk patients, the clinical threshold for referring diabetic patients for PTCA may have been higher; thus, more acutely ill patients among the diabetics may have been selected.

The findings concerning target vessel revascularization are also unexpected. To understand them better, it is helpful to compare event rates in EPILOG with those previously reported. In the second NHLBI registry, higher rates of death and myocardial infarction were evident in diabetic patients during and after the initial hospitalization. The rates of revascularization did not begin to diverge until 6 months after the index angioplasty, when the rate of repeated angioplasty was 13.8% in nondiabetics and 16.7% in diabetics and the respective rates of coronary artery bypass were 10.4% and 12%. Thus, 29% of diabetics and 24% of nondiabetics had a repeated procedure by the end of 6 months.³ Within a study of a novel pharmacological agent, the most appropriate comparator would be the placebo-treated group. In the first large study of abciximab, EPIC, the rates of target vessel revascularization at 6 months were 22% and 18% for diabetic and nondiabetic patients, respectively, whereas in EPILOG the respective rates were 15.5% and 18.9%. The rate in nondiabetic patients in EPILOG therefore appears to be lower than in earlier studies of PTCA and more in line with the concurrent BENESTENT-2 trial in which repeated PTCA rates of 19.5% were reported in patients treated with standard angioplasty,²³ whereas the rate in diabetics in EPILOG is even lower. The results of both of these studies suggest that advances in the performance of PTCA, probably because of better imaging, better dilation catheters, and provisional stent implantation, have reduced the complications and recurrence rates after PTCA. In particular, the rate of target vessel revascularization in diabetic patients in EPILOG was considerably lower than those seen previously in diabetics. This low rate may be a chance finding and may in part explain the failure of abciximab to further lower the rate of revascularization in diabetics. It is also possible that the enhanced early protection afforded by abciximab against the composite of death and myocardial infarction may have led to a paradoxical increase in revascularization procedures by providing a larger pool of survivors with viable myocardium. Other potential explanations include patient selection or different methods of ascertainment.

The pathophysiological point of view offers another potential explanation. Abciximab is able to antagonize the _Vß₃ (vitronectin) receptor on platelets and smooth muscle cells in addition to its ability to inhibit ligand binding to the platelet _IIß₃ (GP IIb/IIIa) receptor. The former receptor modulates phenotypic alterations and migration in smooth muscle cells and has been theorized to permit the contribution of smooth muscle cells to the process of restenosis after angioplasty.^{24 25} The plasma half-life of abciximab is extremely brief²⁶ since it is believed to be adsorbed rapidly onto the platelet surface. Conceivably, then, a higher density of GP IIb/IIIa receptor density expressed on the surface of platelets in diabetic patients might leave less abciximab available to binding to smooth muscle vitronectin receptors.

Study Limitations
The principal limitation of this analysis lies in its size. Although diabetic patients made up 23% of patients enrolled in EPILOG, comparison between the event rates in three treatment groups is still limited by the relatively wide confidence limits imposed by dividing patients into multiple groups. In addition, ascertainment of the duration of diabetes and adequacy of diabetic control would have been helpful but was not possible. Finally, the current analysis was not prespecified at the time of protocol design and thus, in the absence of truly dramatic differences between groups, should be viewed as resulting in a variety of new hypotheses to be tested rather than in novel therapeutic recommendations.

Clinical Implications
The higher long-term event rates in diabetic patients mandate an increased level of vigilance after coronary angioplasty, even when the procedure is successful. Although the more common current use of intracoronary stents may contribute to lowering revascularization rates among diabetics, more frequent follow-up and perhaps exercise testing nonetheless appear to be indicated. The evidence presented in this analysis strongly supports the use of abciximab for the prevention of ischemic events in both diabetic and nondiabetic patients, particularly with respect to the prevention of death and myocardial infarction. Nevertheless, despite the low event rates in the placebo group, the difference in outcomes, particularly target vessel revascularization with regard to heparin dosing, should raise a note of caution concerning heparin dosing in diabetics. The marginally higher rate of revascularization in patients receiving low-dose heparin, combined with the lower composite rate of death and myocardial infarction in patients assigned to standard dose heparin, led to a 6-month composite event rate that was statistically lower in diabetic patients assigned to abciximab with standard-dose heparin compared with abciximab with low-dose heparin. A definitive recommendation concerning heparin dosing in diabetics receiving abciximab will have to await confirmation from a second trial of abciximab in diabetic patients and longer-term follow-up in the current patient population.

	Footnotes

 
Reprint requests to Neal S. Kleiman, MD, 6565 Fannin, MS F-1090, Houston, TX 77030.

Guest editor for this article was David O. Williams, MD, Rhode Island Hospital, Providence.

Received June 13, 1997; revision received December 29, 1997; accepted January 14, 1998.

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