doi: 10.1161/01.CIR.0000055653.52489.E9
(Circulation. 2003;107:1556.)
© 2003 American Heart Association, Inc.
Special Review |
Important Triad in Cardiovascular Medicine
Diabetes, Coronary Intervention, and Platelet Glycoprotein IIb/IIIa Receptor Blockade
From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to A. Michael Lincoff, MD, Associate Professor of Medicine, Department of Cardiovascular Medicine, Desk F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail LincofA{at}ccf.org
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Introduction |
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 Top Introduction Glycoprotein IIb/IIIa Inhibitors...SummaryReferences |
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Diabetes mellitus is a potent risk factor for greater prevalence, complexity, and complications of cardiovascular disease, and diabetics thus constitute a sizable proportion of patients for whom coronary revascularization is required. However, both percutaneous and surgical revascularization techniques are associated with particular challenges in this population. Diabetics typically have an increased likelihood of restenosis and repeat revascularization procedures after stenting compared with their non-diabetic counterparts.1 Trends toward higher death rates in diabetics have also been observed over 1 year or longer after stenting,1–4 and patients with diabetes thus remain one of the few groups for whom percutaneous coronary intervention (PCI) does not yet provide survival benefit commensurate with that of coronary artery bypass surgery.5–7 Diabetes mellitus is also a predictor of elevated mortality risk and accelerated disease progression after surgical revascularization.5,8,9
The processes leading to adverse prognosis after revascularization in diabetics are likely multifactorial and relate to widespread atheroma, small vessel vasculopathy, impaired collateral formation, exuberant neointimal hyperplasia, and adverse remodeling.10,11 There is also evidence that hypercoagulability contributes to accelerated atherosclerosis and exaggerated injury response after revascularization in diabetics.11–13 Diabetes is associated with increased levels of circulating fibrinogen, thrombin, and factor VII, and with diminished plasma fibrinolytic and antithrombin III activity. Moreover, platelets in diabetic patients are increased in size, are more frequently activated, and exhibit greater adhesiveness, thromboxane synthesis, glycoprotein (GP) IIb/IIIa expression, and mitogenic activity.
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Glycoprotein IIb/IIIa Inhibitors and Diabetes |
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TopIntroductionGlycoprotein IIb/IIIa Inhibitors...SummaryReferences |
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Adjunctive antiplatelet therapy with GP IIb/IIIa blockade reduces the incidence of acute ischemic events by as much as 35% to 50% among the broad population of patients undergoing elective or urgent PCI,14 and evidence supporting long-term suppression of mortality with at least one of these inhibitors, abciximab, has been accrued as well.3,15,16 The benefits of GP IIb/IIIa inhibitors in this setting seem to be complementary to those of stenting, with the latter influencing endpoints related to mechanical disruption of atherosclerotic plaque or restenosis at the interventional site but having little impact on mortality or myocardial infarction. Given that the pathogenesis of cardiovascular complications of diabetes may be due at least in part to heightened coagulation and platelet activity, there are rationale to believe that GP IIb/IIIa blockade may have enhanced efficacy among patients with diabetes undergoing PCI. Unfortunately, published analyses of the diabetic patient subsets from the various GP IIb/IIIa trials have assessed different agents and forms of percutaneous revascularization (stent versus non-stent) and used different endpoints and durations of follow-up, thus contributing to a perception of inconsistency within the body of evidence for benefit of GP IIb/IIIa blockade among diabetic patients. A more systematic approach to the clinical trial data set, however, clarifies many of these apparent discrepancies.
Different "ischemic" endpoints do not necessarily relate to the same pathophysiological processes, and composite endpoints incorporating diverse events may therefore fail to appropriately reflect therapeutic efficacy. The GP IIb/IIIa inhibitor trials have typically used a composite of death, myocardial infarction, or urgent revascularization by 30 days as the primary endpoint, events which occur as a result of thrombosis, embolization, or mechanical plaque disruption during PCI. Over the follow-up period to 6 months or 1 year, however, revascularization events due principally to restenosis, a process distinct from acute thrombosis or vascular dissection, become dominant. For example, among patients in the placebo group of one recent trial of eptifibatide during stenting, myocardial infarction rates increased by only an absolute 0.7% between 30 days and 6 months, whereas target vessel revascularization (TVR) rates increased by an absolute 7.1% during that same interval.17 Thus, durability of benefit after 30 days with regard to acute ischemic events is best assessed using an endpoint confined to death or myocardial infarction, whereas an independent influence on restenosis would be reflected by separate determination of TVR rates. Finally, multiple processes contribute to long-term mortality, typically evaluated at 1 year or more, with the caveat that individual interventional trials seldom have statistical power to detect less than a major mortality benefit.
Of the trials of GP IIb/IIIa blockade during PCI, 5 have reported detailed outcome for diabetic versus non-diabetic patients. The Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC),18,19 Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG),20,21 and Evaluation of Platelet Inhibition in STENTing (EPISTENT)3,22–24 trials compared abciximab to placebo among patients undergoing non-stent interventions (EPIC, EPILOG, and 1 arm of EPISTENT) or stenting (2 arms of EPISTENT). The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT)2,17,25,26 trial compared eptifibatide to placebo and the do Tirofiban And ReoPro Give similar Efficacy Trial (TARGET)27 compared tirofiban to abciximab during stenting. The proportions of patients with diabetes in these trials ranged from 20% to 24%, with inconsistent differentiation within the databases among those treated with insulin, oral agents, or dietary therapy. The total data set for the 4 placebo-controlled trials consists of 2099 diabetic and 7252 non-diabetic patients, with an additional 1117 and 3692 patients with and without diabetes, respectively, in the active-control TARGET trial.
Figure 1 illustrates the treatment effect of GP IIb/IIIa blockade with abciximab or eptifibatide relative to placebo on the acute 30-day endpoint of death, myocardial infarction, or urgent revascularization after PCI in diabetic and non-diabetic patients. The magnitude of risk reduction with GP IIb/IIIa inhibition was similar for patients with or without diabetes, with no evidence of enhanced or diminished benefit in either patient subgroup. Moreover, event rates did not consistently or significantly vary between those with or without diabetes, a finding concordant with other contemporary studies showing similar risk for short-term ischemic complications after PCI in diabetic and non-diabetic patients. In TARGET, the advantage of abciximab over tirofiban with regard to the primary 30-day endpoint was observed for patients with (14% relative risk reduction) and without (22% relative risk reduction) diabetes. Durability of the treatment effect of abciximab or eptifibatide on the endpoint of death or myocardial infarction over 6 months is also depicted in Figure 1, with comparable risk reductions observed in diabetic and non-diabetic patients.
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Outcome at 6 months with regard to TVR, the clinical surrogate for restenosis, is shown in Figure 2. The baseline (placebo group) risk for TVR was higher among diabetics than non-diabetics in all trials except EPILOG, in keeping with previous studies demonstrating an increased likelihood of restenosis among diabetic patients. The lower TVR rate among diabetics in the placebo group of EPILOG21 was likely a chance spurious finding. In contrast to the consistent influence of GP IIb/IIIa inhibition on acute ischemic events (Figure 1), the effect of these agents on 6-month rates of TVR varied considerably among trials and between diabetic or non-diabetic subgroups (Figure 2). After balloon angioplasty or atherectomy in EPIC, a benefit of abciximab on TVR was apparent in patients without diabetes, but not in those with diabetes. In EPILOG, neither diabetic nor non-diabetic patients experienced a reduction in TVR rates with abciximab. Conversely, in EPISTENT, abciximab therapy was associated with a significant 50% decrease in TVR rates after stenting among diabetics but not among non-diabetics, a finding confirmed by improved angiographic indices of restenosis in the angiographic substudy of that trial.23,24 In the ESPRIT trial, there was no effect of eptifibatide on TVR after stenting in either diabetic or non-diabetic patients.
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It thus remains unclear whether GP IIb/IIIa blockade diminishes the likelihood of restenosis in any patient subgroup or with any type of interventional procedure. It is tempting to hypothesize on the basis of the EPISTENT results that abciximab may exert a selective effect on neointimal hyperplasia (the predominant mechanism of restenosis after stenting) in the patient subgroup known to be at high risk for this process (diabetics); support for this concept could also be derived from the subgroup of 53 patients with diabetes in the Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up (ADMIRAL) trial,28 in whom randomization to abciximab rather than placebo during primary stenting for acute myocardial infarction was associated with a significant decrease in 6-month rates of TVR (12.5 versus 0%, P=0.049). The lack of influence of eptifibatide on TVR among diabetics in the ESPRIT trial, however, argues against an important effect of GP IIb/IIIa blockade on restenosis, unless such an effect is also mediated by blockade of the 
vß3 or Mß2 receptors. Such non-specific binding is unique to abciximab among the GP IIb/IIIa inhibitors,29,30 but fails to explain why TVR rates were not improved by abciximab relative to tirofiban (a highly-selective GP IIb/IIIa inhibitor) among diabetics in TARGET (10.8% with abciximab versus 8.8% with tirofiban, P=0.257).
The potential for GP IIb/IIIa blockade to diminish mortality was first demonstrated by the results of the EPISTENT trial, in which a significant 60% reduction in 1-year mortality was observed with abciximab among stented patients.3 The finding of long-term mortality benefit with abciximab during PCI was corroborated by pooled analyses of the different abciximab interventional trials,15,16 wherein death rates were significantly diminished by 20% to 30% over 3 years or longer. By multivariate analysis, diabetes was shown to be an independent predictor of mortality and of the magnitude of survival advantage imparted by abciximab therapy,31 with mortality reduction particularly apparent among diabetic patients treated with stents.32 The body of evidence supporting mortality benefit with eptifibatide is substantially smaller than that for abciximab. Nevertheless, both the EPISTENT3 and ESPRIT2 trials suggested that mortality reduction with abciximab or eptifibatide after stenting is enhanced in diabetic relative to non-diabetic patients (Figure 3), a benefit which strikingly seems to neutralize the higher mortality risk after PCI among diabetics. Death rates in diabetic patients at 1 year were not different between tirofiban and abciximab groups in TARGET (2.1 versus 2.9%, respectively), although the statistical power of this non-inferiority comparison was quite limited.
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A meta-analysis of over 29 000 patients enrolled in 6 large-scale trials of empiric GP IIb/IIIa blockade for non-ST-elevation acute coronary syndromes further supports the linkage between diabetes and survival advantage with these agents.33 Among 6458 diabetic patients, treatment with GP IIb/IIIa inhibitors was associated with a significant reduction in 30-day mortality (6.2 versus 4.6%, P=0.007), a benefit which was particularly marked in the subset of patients who underwent PCI during the index hospitalization (4.0 versus 1.2%, P=0.002). In contrast, no reduction in death rates was observed with GP IIb/IIIa blockade among non-diabetic patients.
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Summary |
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TopIntroductionGlycoprotein IIb/IIIa Inhibitors...SummaryReferences |
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The randomized trial data set provides consistent evidence for a marked reduction in acute ischemic events by GP IIb/IIIa blockade during PCI, the magnitude of which is similar in diabetic and non-diabetic patients. Whether there are quantitative differences in this treatment effect among the 3 GP IIb/IIIa inhibitors continues to be a point of controversy. The impact of GP IIb/IIIa blockade on "clinical restenosis" among diabetic or non-diabetic patients remains unknown. With the introduction into clinical practice of drug-eluting stents, restenosis may no longer be a major limitation of percutaneous revascularization in patients with diabetes. What emerges then as the most compelling argument for GP IIb/IIIa inhibition during PCI in diabetics is the distinctive late mortality advantage; in this regard, abciximab remains the reference standard, with a body of long-term mortality data unmatched by other agents. GP IIb/IIIa blockade in combination with drug-eluting stents has the potential for true complementarity to optimize outcome after revascularization in this important high-risk group of patients.
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Acknowledgments |
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Dr Lincoff has received research funding from Eli Lilly, Centocor, and COR-Millennium Pharmaceuticals.
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References |
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TopIntroductionGlycoprotein IIb/IIIa Inhibitors...SummaryReferences |
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