doi: 10.1161/01.CIR.0000151355.07568.B4
(Circulation. 2004;110:3618-3620.)
© 2004 American Heart Association, Inc.
Editorial |
Diabetes, Coronary Intervention, and Platelet Glycoprotein IIb/IIIa Blockade
The Triad Revisited
From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to A. Michael Lincoff, MD, Professor of Medicine, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, F25, Cleveland, OH 44195. E-mail lincofa{at}ccf.org
Key Words: Editorials • diabetes mellitus • coronary disease • revascularization • platelet-derived factors
Diabetes mellitus is associated with inferior outcome after percutaneous coronary intervention (PCI).1 Platelet glycoprotein IIb/IIIa (GP IIb/IIIa) inhibition is an important adjunctive therapy during PCI and may be particularly so in patients with diabetes mellitus.2 Platelet GP IIb/IIIa inhibitors are potent antithrombotic agents, and in several large-scale clinical trials with balloon angioplasty and coronary stenting, these agents have produced a consistent and marked reduction in both 30-day ischemic events and long-term (up to 1 to 3 years) mortality.3 In most cases, a greater magnitude of survival benefit with abciximab has been observed in patients with diabetes as compared with patients without diabetes.3–5 Furthermore, clinical risk stratification with diabetes and other variables reliably predicts abciximab benefit for late survival, thereby validating the important mortality benefits (nearly 3 lives saved per 100 patients treated) with abciximab use in high-risk patients during PCI.6 This large body of evidence has led to the widespread acceptance of platelet GP IIb/IIIa inhibitors to neutralize the excessive mortality associated with PCI among patients with diabetes as compared with patients without diabetes.
See p 3627
The introduction of clopidogrel has changed the landscape of clinical outcomes in PCI. In patients with diabetes, clopidogrel has been shown to be superior to aspirin in reducing recurrent ischemic events.7 The use of preprocedural clopidogrel can attenuate the increase in C-reactive protein and other inflammatory markers after PCI, even in the presence of abciximab.8,9 Pretreatment with clopidogrel (300 to 600 mg) has been suggested to reduce ischemic events during PCI, and long-term (1 year) clopidogrel therapy has been shown to reduce long-term clinical events.10 Recently, the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment) study found no benefit with abciximab therapy versus placebo in low- and intermediate-risk patients undergoing PCI who received high-dose pretreatment clopidogrel (600 mg loading dose of clopidogrel at least 2 hours before the procedure).11 Notably, patients under medical treatment for diabetes were excluded from enrollment in the ISAR-REACT study because of previous data suggesting enhanced mortality benefit with abciximab in patients with diabetes undergoing PCI.
In this issue of Circulation, Mehilli and colleagues12 report intriguing results from the ISAR-SWEET (Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics?) study. Using the same protocol as in ISAR-REACT, they gave 701 patients with diabetes a 600-mg bolus dose of clopidogrel at least 2 hours before PCI, and the patients were randomized to receive either abciximab or placebo during PCI, followed by at least 6 months of clopidogrel after PCI.12 Abciximab did not reduce the primary end point of death and myocardial infarction (MI) over placebo (8.3% versus 8.6%, respectively, P=0.91) at 1-year follow-up. The study did show a significant reduction in the incidence of target vessel revascularization (TVR) in the abciximab group as compared with the placebo group (23.2% versus 30.4%, respectively, P=0.03) by 1 year. This reduction in the revascularization rate was consistent with the lower incidence of binary angiographic restenosis in the abciximab group as compared with the placebo group (28.9% versus 37.8%, respectively, P=0.01) at follow-up angiography.
How do we put these data in context with the large body of evidence about abciximab use during PCI in patients with diabetes? The discrepancies in event rates in the cohorts with diabetes between the ISAR-SWEET study and previous studies were apparent. In the pooled analysis of the EPIC (Evaluation of c7E3 Fab for Prevention of Ischemic Complications), EPILOG (Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade), and EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting) trials of 1462 patients with diabetes, abciximab treatment reduced the 1-year all-cause mortality rate from 4.5% to 2.5% (P=0.033) and reduced the 1-year MI rate from 11.6% to 6.0% (P=0.022).3 In contrast, in the ISAR-SWEET trial, the 1-year mortality rates remained higher than previously reported—4.8% in the abciximab group and 5.1% in the placebo group (P=0.86)—perhaps because of the older age and higher prevalence of multivessel coronary disease in the study population. The 1-year MI rates in ISAR-SWEET (4.8% in the abciximab group and 4.3% in the placebo group, P=0.72) were far lower than previously reported in the pooled analysis, however. This reduction in long-term MI incidence may have resulted from long-term clopidogrel therapy, in concordance with previous studies.10
To the credit of the investigators, the majority of patients in the ISAR-SWEET trial were discharged on not only aspirin (98%) and clopidogrel (100%), but also on angiotensin-converting enzyme inhibitors (90% to 91%), ß-blockers (93% to 94%), and statins (86% to 88%), drugs that have been consistently shown to improve survival and reduce ischemic events in patients with coronary artery disease. Moreover, improvements in pharmacotherapy for diabetes mellitus, such as thiazolidinediones, may suppress markers of inflammatory responses13 and reduce restenosis rates,14,15 further improving overall long-term survival in patients with diabetes. Therefore, intensification of these adjunctive therapies also may have narrowed the differences in long-term clinical outcomes seen in previous studies.
Early (within 48 hours) postprocedural MI accounts for only a small proportion (18%) of the observed mortality benefit of abciximab at 1 year.16 Several studies have suggested that the early rise in systemic markers of inflammation after angioplasty can be diminished by abciximab use.17,18 The recent demonstration of augmented platelet inhibition of fibrinogen binding via lower glycation of platelet membrane proteins by GP IIb/IIIa inhibitors in patients with diabetes also supports this concept.19 Given that some researchers have speculated that part of the long-term benefit of abciximab may come from its antiinflammatory effects, the potential antiinflammatory actions of treatment with clopidogrel may be particularly relevant among patients with diabetes undergoing PCI, further reducing a discernible treatment effect of abciximab.
It is important to recognize that the findings of ISAR-SWEET should not be viewed as definitively excluding a beneficial effect of abciximab in this population of patients with diabetes, particularly given the large previous dataset that linked abciximab with reduction in mortality. This trial was statistically powered for a combined end point of death and MI and a 50% risk reduction. Because the actual primary end point event rate of 8.4% was lower than expected (14%), Mehilli and colleagues estimate that they had only a 69% power to detect 50% risk reduction.12 The statistical power to detect a mortality reduction is even less than that for the composite end point. Although the authors did not provide the odds ratio for mortality based on time-to-event analysis, we can estimate from 
2 statistics a mortality odds ratio for the treatment effect of abciximab in the ISAR-SWEET study of 0.93 with a 95% confidence interval of 0.5 to 1.9. In other words, these data cannot exclude as much as a 50% decrease (or, alternatively, a 90% increase) in mortality with abciximab therapy. Therefore, the sample size limitations, which have been described for the composite primary end point in the article, are particularly relevant for the more important end point for abciximab therapy in people with diabetes—mortality.
The observation that abciximab was associated with a reduction in angiographic restenosis rates and TVR versus the lack of mortality reduction is an unexpected finding in the ISAR-SWEET study. Typically and consistently, the risk of TVR and angiographic restenosis is found to be higher in people with diabetes as compared with people without diabetes after PCI, but the influence of abciximab on 6-month rates of TVR varied considerably in previous studies. In previous placebo-controlled trials of abciximab during coronary intervention, GP IIb/IIIa blockade was found to reduce TVR rates after balloon angioplasty in patients without diabetes only in the EPIC trial,20 to have no influence on TVR in patients with or without diabetes after balloon angioplasty in EPILOG,21 or to reduce TVR and angiographic restenosis in patients with diabetes only after stenting in the EPISTENT5,22 and ADMIRAL (Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-Up) trials.23 Because of these inconsistent results, most cardiologists do not consider an antirestenotic effect to be a compelling reason to use abciximab during PCI. The significant reduction in angiographic restenosis and TVR in ISAR-SWEET is interesting and raises the question of whether abciximab acts on clopidogrel-independent mechanisms in suppressing neointimal hyperplasia. Two potential examples of such mechanisms suggested by the authors include antiinflammatory effects on leukocyte Mac-124 and antiproliferative effects on the vitronectin receptor on platelets and smooth muscles.25 Although this may be a something of a moot point given the broad use of drug-eluting stents, pharmacological suppression of restenosis may still be valuable because TVR and restenosis rates remain higher in patients with diabetes even when drug-eluting stents are used.26
The results of ISAR-SWEET are certainly provocative. It is conceivable that with the current excellent pharmacotherapy, including pretreatment and prolonged postprocedural therapy with clopidogrel, overall lower rates of ischemic events may undermine the benefits of abciximab in selected patients with diabetes. On the other hand, with the large body of evidence from clinical trials conducted before the ISAR-SWEET trial, it remains difficult to dismiss what has been a compelling argument for late mortality benefit of GP IIb/IIIa inhibitors in patients with diabetes or other high-risk patients undergoing PCI.6 Whether we can continue to generalize this concept of a diminished mortality benefit of abciximab in a broad PCI population with diabetes remains unclear. Unless future studies confirmed a lack of efficacy with abciximab with current interventional practice, we believe that the potential benefits of abciximab should not be withheld from patients at high risk, with or without diabetes, for late mortality. Intriguing observations in restenosis reduction in ISAR-SWEET also may generate further interest in the exploration of platelet-dependent or platelet-independent mechanisms of preventing long-term restenosis in patients with diabetes mellitus.
Disclosure
Dr Lincoff has received research support from Eli Lilly and Centocor. Dr Tang is a consultant for Takeda, GlaxoSmithKline, and Amylin Pharmaceuticals.
Footnotes
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
References
1. Stein B, Weintraub WS, Gebhart SP, Cohen-Bernstein CL, Grosswald R, Liberman HA, Douglas JS Jr, Morris DC, King SB III. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation. 1995; 91: 979–989.
2. Lincoff AM. Important triad in cardiovascular medicine: diabetes, coronary intervention, and platelet glycoprotein IIb/IIIa receptor blockade. Circulation. 2003; 107: 1556–1559.
3. Bhatt DL, Marso SP, Lincoff AM, Wolski KE, Ellis SG, Topol EJ. Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol. 2000; 35: 922–928.
4. Roffi M, Chew DP, Mukherjee D, Bhatt DL, White JA, Heeschen C, Hamm CW, Moliterno DJ, Califf RM, White HD, Kleiman NS, Theroux P, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation. 2001; 104: 2767–2771.
5. Marso SP, Lincoff AM, Ellis SG, Bhatt DL, Tanguay JF, Kleiman NS, Hammoud T, Booth JE, Sapp SK, Topol EJ. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation. 1999; 100: 2477–2484.
6. Kereiakes DJ, Lincoff AM, Anderson KM, Achenbach R, Patel K, Barnathan E, Califf RM, Topol EJ; EPIC Investigators; EPILOG investigators; EPISTENT investigators. Abciximab survival advantage following percutaneous coronary intervention is predicted by clinical risk profile. Am J Cardiol. 2002; 90: 628–630.[CrossRef][Medline] [Order article via Infotrieve]
7. Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol. 2002; 90: 625–628.[CrossRef][Medline] [Order article via Infotrieve]
8. Vivekananthan DP, Bhatt DL, Chew DP, Zidar FJ, Chan AW, Moliterno DJ, Ellis SG, Topol EJ. Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol. 2004; 94: 358–360.[CrossRef][Medline] [Order article via Infotrieve]
9. Quinn MJ, Bhatt DL, Zidar F, Vivekananthan D, Chew DP, Ellis SG, Plow E, Topol EJ. Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2004; 93: 679–684.[CrossRef][Medline] [Order article via Infotrieve]
10. Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288: 2411–2420.
11. Kastrati A, Mehilli J, Schuhlen H, Dirschinger J, Dotzer F, ten Berg JM, Neumann FJ, Bollwein H, Volmer C, Gawaz M, Berger PB, Schomig A; Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med. 2004; 350: 232–238.
12. Mehilli J, Kastrati A, Schühlen H, Dibra A, Dotzer F, von Beckerath N, Bollwein H, Pache J, Dirschinger J, Berger PP, Schomig A; the Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation. 2004; 110: 3627–3635.
13. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation. 2002; 106: 679–684.
14. Osman A, Otero J, Brizolara A, Waxman S, Stouffer G, Fitzgerald P, Uretsky BF. Effect of rosiglitazone on restenosis after coronary stenting in patients with type 2 diabetes. Am Heart J. 2004; 147: e23.[CrossRef][Medline] [Order article via Infotrieve]
15. Choi D, Kim SK, Choi SH, Ko YG, Ahn CW, Jang Y, Lim SK, Lee HC, Cha BS. Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes. Diabetes Care. 2004; 27: 2654–2660.
16. Anderson KM, Califf RM, Stone GW, Neumann FJ, Montalescot G, Miller DP, Ferguson JJ III, Willerson JT, Weisman HF, Topol EJ. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol. 2001; 37: 2059–2065.
17. Lincoff AM, Kereiakes DJ, Mascelli MA, Deckelbaum LI, Barnathan ES, Patel KK, Frederick B, Nakada MT, Topol EJ. Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization. Circulation. 2001; 104: 163–167.
18. Kereiakes DJ. Inflammation as a therapeutic target: a unique role for abciximab. Am Heart J. 2003; 146: S1–S4.[CrossRef][Medline] [Order article via Infotrieve]
19. Keating FK, Whitaker DA, Sobel BE, Schneider DJ. Augmentation of inhibitory effects of glycoprotein IIb-IIIa antagonists in patients with diabetes. Thromb Res. 2004; 113: 27–34.[CrossRef][Medline] [Order article via Infotrieve]
20. Lincoff AM, Califf RM, Anderson KM, Weisman HF, Aguirre FV, Kleiman NS, Harrington RA, Topol EJ. Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularization. EPIC Investigators. Evaluation of 7E3 in Preventing Ischemic Complications. J Am Coll Cardiol. 1997; 30: 149–156.[Abstract]
21. Kleiman NS, Lincoff AM, Kereiakes DJ, Miller DP, Aguirre FV, Anderson KM, Weisman HF, Califf RM, Topol EJ. Diabetes mellitus, glycoprotein IIb/IIIa blockade, and heparin: evidence for a complex interaction in a multicenter trial. EPILOG Investigators. Circulation. 1998; 97: 1912–1920.
22. Lincoff AM, Califf RM, Moliterno DJ, Ellis SG, Ducas J, Kramer JH, Kleiman NS, Cohen EA, Booth JE, Sapp SK, Cabot CF, Topol EJ. Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. Evaluation of Platelet IIb/IIIa Inhibition in Stenting Investigators. N Engl J Med. 1999; 341: 319–327.
23. Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P, Boulenc JM, Morice MC, Maillard L, Pansieri M, Choussat R, Pinton P; ADMIRAL Investigators. Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med. 2001; 344: 1895–1903.
24. Neumann FJ, Zohlnhofer D, Fakhoury L, Ott I, Gawaz M, Schomig A. Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol. 1999; 34: 1420–1426.
25. Tam SH, Sassoli PM, Jordan RE, Nakada MT. Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and alpha(v)beta3 integrins. Circulation. 1998; 98: 1085–1091.
26. Scheen AJ, Warzee F. Diabetes is still a risk factor for restenosis after drug-eluting stent in coronary arteries. Diabetes Care. 2004; 27: 1840–1841.
Related Articles:
Circulation 2004 110: 3627-3635.
Circulation 2004 110: 3627-3635.
This article has been cited by other articles:
 |
|
 |
|
  V K Bhatia and C Di Mario Darwin and the survival of the fittest in modern interventional cardiology Heart, August 1, 2006; 92(8): 1017 - 1018. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Gurm, I. J. Sarembock, D. J. Kereiakes, J. J. Young, R. A. Harrington, N. Kleiman, F. Feit, K. Wolski, J. A. Bittl, R. Wilcox, et al. Use of Bivalirudin During Percutaneous Coronary Intervention in Patients With Diabetes Mellitus: An Analysis From the Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 Trial J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1932 - 1938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Abciximab Adds No Benefit to Clopidogrel in Diabetes Patients Who Undergo PCI Journal Watch Cardiology, February 18, 2005; 2005(218): 3 - 3. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||