Comparison of Two Platelet Glycoprotein IIb/IIIa Inhibitors, Eptifibatide and Abciximab: Outcomes, Complications and Thrombocyto

The development of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors has been a major advance in reducing ischemic complications among a broad spectrum of patients undergoing percutaneous coronary intervention (PCI).1–9 Currently, three intravenous GP IIb/IIIa inhibitors, abciximab (ReoPro, Johnson and Johnson, Malvern, Pennsylvania), eptifibatide (Integrilin, Cor Therapeutics, South San Francisco, California) and tirofiban (Aggrastat, Merck, West Point, Pennsylvania) are approved by the United States Food and Drug Administration (FDA) for medical management of acute coronary syndromes and as adjunctive therapy during PCI.10,11 The cost of abciximab is threefold that of eptifibatide or tirofiban, and in an era of strict healthcare budgets, the advantages are obvious. However, considerable structural and pharmacological differences exist among abciximab and the other 2 agents, and it has been suggested that this difference might account for the proven effectiveness of abciximab as an adjunctive PCI treatment.12,13 The recently completed study entitled “Do Tirofiban and ReoPro Give Similar Efficacy Trial (TARGET)13 demonstrated the superiority of abciximab over tirofiban in preventing major ischemic events in patients undergoing PCI, as reflected by the lower incidence of the composite endpoint of death, nonfatal myocardial infarction, or urgent target vessel revascularization and by the incidence of the individual endpoints. With respect to eptifibatide and abciximab, there has not been a clinical trial that directly compared the efficacy of these drugs and there have been very few retrospective and/or observational studies that compared these 2 drugs.14,15 Therefore, the aim of this study is to compare the clinical efficacy and complication rates of eptifibatide to abciximab in a “real life” setting in the era of third-generation stents that are used in 70–80% of cases. Methods Patients. Between January 2000 and December 2001, a total of 642 consecutive patients underwent PCI at our institution and were treated concomitantly with either abciximab or eptifibatide. Data concerning baseline clinical and angiographic characteristics, revascularization procedures and in-hospital outcomes were obtained from chart review. All patients underwent PCI according to current clinical guidelines with conventional steerable guidewire systems. The operator selected interventional devices and GP IIb/IIIa inhibitor at the time of the procedure. Eptifibatide was given as a double bolus of 180 µg/kg administered 10 minutes apart and as a continuous infusion of 2 µg/kg per minute started at the same time as the first bolus and continued for 18–24 hours. Abciximab was given as a bolus dose of 0.25 mg/kg, followed by an infusion of 0.125 µg/kg per minute (maximum, 10 µg/minute) for 12 hours. All patients received aspirin 75–325 mg daily for at least 24 hours before the procedure and continued indefinitely afterward. Patients who underwent stenting were treated concomitantly with clopidogrel 75 mg daily for 4 weeks per the routine protocol. Weight-adjusted heparin dosage was administered during the procedure in order to maintain an activated clotting time of 200–250 seconds, and was routinely discontinued at the end of the procedure. Complete blood count was performed 2 and 4 hours after the procedure in all patients, and more frequently if required. Endpoints. The primary endpoint was the composite of in-hospital death (all-cause mortality), urgent target vessel revascularization (TVR) or emergency coronary artery bypass surgery due to angioplasty failure or recurrent ischemia. Procedural success was defined as a final diameter stenosis 5 g/dl (or >= 15% in hematocrit), any intracranial bleeding or the need for > 2 units of blood transfused. Vascular complications were defined as the presence of a large hematoma, fistula or pseudoaneurysm formation, retroperitoneal bleeding or the need for surgical vascular repair. Statistical analysis. Statistical significance of the differences between treatment groups for the composite of events, individual endpoints or bleeding complications was assessed with the Chi-square test (or Fisher’s exact test if small numbers were expected). Normally distributed variables (e.g., age) are presented as means ± standard deviation (SD) and were compared using a two-sample t-test. A multivariate logistic regression model was used to determine the relative risk (with 95% confidence intervals) of developing the composite endpoint. The model included all baseline demographic, clinical characteristics and treatment (abciximab versus eptifibatide, acute myocardial infarction as the index diagnosis, gender, age, diabetes, myocardial infarction, hypertension or chronic renal failure). A p-value of less than 0.05 was considered to indicate statistical significance. Data were analyzed using SPSS statistical software 10.1 (SPSS, Chicago, Illinois). Results Baseline clinical characteristics. Between January 1, 2000 and December 31, 2001, a total of 2,142 PCIs were performed at our institution. Of these patients, a total of 642 (30%) received either eptifibatide (n = 342) or abciximab (n = 300) concomitantly during the procedure. Baseline clinical characteristics of both groups are shown in Table 1. Both groups were similar, except for a higher incidence of diabetes in the eptifibatide group (35% versus 26%; p = 0.01). Acute coronary syndrome was the most common diagnosis in the eptifibatide group (67%) and abciximab group (62%). In both groups, eighty-eight percent of the patients underwent stenting, with at least 1 stent placed, and 96% of the lesions involved native coronary arteries. Angiographic, procedural and stent characteristics were similar in both groups (Table 2). Clinical outcomes. In-hospital adverse clinical events and bleeding complications are shown in Table 3. The incidence of the primary endpoint was 2.3% in the eptifibatide group and 2% in the abciximab group (p = 0.7). There was no significant difference in the rates of in-hospital complications between the groups. Abciximab therapy was associated with a significantly higher rate of thrombocytopenia (Table 3), including 5 patients who developed profound thrombocytopenia ( 65 (OR: 1.09; CI: 1.02–1.20; p = 0.005) were the only independent predictors of the composite endpoint. Discussion The present study represents a retrospective analysis of a consecutive series of patients who were treated with platelet GP IIb/IIIa receptor inhibitors during PCI at a single center. Thus, the patient population represents the “real-world” clinical practice of platelet GP IIb/IIIa inhibitor treatment during PCI in a specialized primary as well as a referral center. Considerable clinical trials have been conducted with abciximab and eptifibatide, but none have directly compared the efficacy and safety of these 2 drugs. The composite clinical endpoints (death/urgent target vessel revascularization) occurred in 2.3% versus 2% of patients by hospital discharge in the eptifibatide and abciximab groups, respectively (p = 0.8). Thrombocytopenia and bleeding complications are potential side effects of GP IIb/IIIa inhibitors. In the present study, there was a significantly higher incidence of thrombocytopenia (Study limitations. These results need to be evaluated in the context of several primary limitations. Previous clinical trials have reported important differences between the 2 drugs relative to placebo in reducing the incidence of periprocedural MI; however, dosing regimens may have been suboptimal. Cardiac enzymes are not routinely obtained after the procedure at our institution. Therefore, we could not assess the true incidence of periprocedural MI in either group. In addition, this is a retrospective analysis rather than a prospective study, raising the possibility of treatment selection bias, and therefore is hypothesis-generating only. However, the groups of patients were similar in all clinical characteristics except for a higher rate of diabetes in the eptifibatide group. While the number of patients in this study was the largest in the literature directly comparing these 2 drugs, it is still limited in its ability to detect a small difference in events. Conclusion. In this retrospective data analysis, the overall rates of both clinical adverse events and bleeding complications were comparable between the patients who received abciximab or eptifibatide as adjunctive therapy during PCI. None of the patients treated with eptifibatide developed clinically significant thrombocytopenia, whereas abciximab administration was associated with an increased incidence of mild and profound thrombocytopenia. Despite immediate cessation of treatment upon detection of thrombocytopenia as our strategy, abciximab-induced thrombocytopenia was not associated with an increased risk in bleeding complications or major adverse events. Therefore, in spite of different mechanisms of action and drug kinetics, eptifibatide and abciximab were found comparable in clinical efficacy and clinical complication rates in this “real-life” scenario in the modern stent era.

1. 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. 2. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary intervention. N Engl J Med 1997;336:1689–1696. 3. 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. 4. Tcheng JE, Harrington RA, Kottke-Marchant K, et al., for the IMPACT Investigators. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker integrilin in elective coronary intervention. Circulation 1995;91:2151–2157. 5. 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. 6. Brener SJ, Barr LA, Burchenal JE, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation 1998;98:734–741. 7. 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. 8. The RESTORE Investigators. Effects of glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445–1453. 9. The ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): A randomised, placebo-controlled trial. Lancet 2000;356:2037–2044. 10. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–198. 11. Truong KM, Amankwa K, Kucukarslan S. Platelet glycoprotein IIb/IIIa receptor inhibitors in patients with acute coronary syndromes or undergoing percutaneous coronary interventions: A review. Clin Ther 2001;23:1145–1165. 12. Proimos G. Platelet aggregation inhibition with glycoprotein IIb/IIIa inhibitors. J Thromb Thrombolysis 2001;11:99–110. 13. Topol EJ, Moliterno DJ, Herrmann HC, et al., for the TARGET Investigators. Do Tirofiban and ReoPro Give Similar Efficacy Trial. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001;344:1888–1894. 14. Kimmelstiel C, Phang R, Rehman A, et al. Short-term comparative outcomes associated with the use of GP IIb/IIIa antagonists in patients undergoing coronary intervention. J Thromb Thrombolysis 2001;11:203–209. 15. The PRICE Investigators. Comparative 30-day economic and clinical outcomes of platelet glycoprotein IIb/IIIa inhibitor use during elective percutaneous coronary intervention. The Prairie ReoPro versus Integrilin Cost Evaluation (PRICE) Trial. Am Heart J 2001;141:402–409. 16. Brown DL, Fann, CSJ, Chang CJ. Meta-analysis of effectiveness and safety of abciximab versus eptifibatide or tirofiban in percutaneous coronary intervention. Am J Cardiol 2001;87:537–541. 17. Dasgupta H, Blankenship JC, Wood GC, et al. Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: A pooled analysis. Am Heart J 2000;140:206–211. 18. The PRISM Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study. N Engl J Med 1998;338:1498–1505. 19. The PRISM-PLUS Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q wave myocardial infarction. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study. N Engl J Med 1998;339:415. 20. The PURSUIT Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Study. N Engl J Med 1998;339:436–443. 21. Hongo RH, Brent BN. Association of eptifibatide and acute profound thrombocytopenia. Am J Cardiol 2001;88:428–431. 22. Paradiso-Hardy FL, Madan M, Radhakrishnan S, et al. Severe thrombocytopenia possibly related to readministration of eptifibatide. Cathet Cardiovasc Interv 2001;54:63–67. 23. Peter K, Straub A, Kohler B, et al. Platelet activation as a potential mechanism of GP IIb/IIIa inhibitor-induced thrombocytopenia. Am J Cardiol 1999;84:519–524. 24. Peter K, Schwarz M, Ylanne J, et al. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (aIIb/b3) inhibitors. Blood 1998;92:3240–3249.