The Impact of GP IIb/IIIa Inhibitors During Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction Patients

In the last decade, primary percutaneous coronary intervention (PCI) has emerged as a superior strategy compared to thrombolytic therapy for coronary reperfusion in acute myocardial infarction patients.^1–4 It is associated with lower mortality and reinfarction rates, less recurrent ischemia, fewer hospital readmissions and less need for repeated revascularization, as compared to thrombolytic therapy, both within the first 30 days and during long-term follow-up. Nevertheless, recurrent ischemia and the need for further improvement in survival rates emphasized the need to find new techniques and adjunctive pharmacological therapy in order to reduce these events .^1,4–6 The combined use of stents and platelet glycoprotein (GP) IIb/IIIa inhibitors has been validated in patients undergoing elective PCI,^7,8 but there has been ample controversy regarding their use in the setting of acute myocardial infarction (AMI). Several studies have assessed the role of GP IIb/IIIa inhibitors as an adjunctive therapy in AMI with conflicting results regarding their routine use during stenting.^5,9,10 The aim of the present study was to compare the outcomes of ST-segment elevation AMI patients who underwent primary PCI and were concomitantly treated with GP IIb/IIIa inhibitors versus patients who were not treated with GP IIb/IIIa inhibitors. Methods Patient population and methods. Since January 1996, we prospectively included in an ongoing registry all consecutive ST-segment elevation AMI patients who underwent primary PCI. We retrospectively analyzed the clinical and angiographic characteristics and outcomes of AMI patients concomitantly treated with and without GP IIb/IIIa inhibitors during primary PCI. All patients underwent coronary intervention via the transfemoral approach according to current guidelines with conventional catheter-based systems. Weight-adjusted heparin dosage was administered at the beginning of the procedure in order to maintain an activated clotting time of 250–300 seconds and was routinely discontinued at the end of the procedure. Patients received aspirin 200–325 mg before the procedure and continued indefinitely afterwards. Patients who underwent stenting were treated concomitantly with ticlopidine 250 mg twice daily, or clopidogrel 75 mg/day for 4 weeks. GP IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) were initiated during the catheterization after crossing of the culprit lesion with the guidewire, and were administered at the operator’s discretion according to standard doses: eptifibatide (Integrilin^®, COR Therapeutics, South San Francisco, California) bolus 180 µg/kg, followed by a second bolus of 180 µg/kg after 10 minutes and by a 2.0 µg/kg/hour continuous infusion; abciximab (ReoPro^®, Centocor, B.V. Leiden, The Netherlands) bolus 0.25 µg/kg, followed by 0.125 µg/kg/min infusion; and tirofiban (Aggrastat^®, Merck & Co., Inc., Whitehouse Station, New Jersey) was administered intravenously with a loading dose of 0.4 µg/kg/minute for 30 minutes, followed by infusion of 0.1 µg/kg/minute. Maintenance infusions were given for 14–16 hours. Femoral access sheaths were removed manually 4 hours after the procedure. Definitions. ST-segment elevation AMI was defined as the presence of ST-elevation > 0.1 mV in at least two contiguous precordial leads, or two adjacent limb leads in patients who had symptoms consistent with AMI. We included in the registry patients who presented within 12 hours from symptom onset and who were not treated by pharmacological reperfusion therapy. Angiographic success was defined as 5 g/dL. Minor bleeding was defined as clinically overt signs of hemorrhage, with a drop in hemoglobin of 4 cm at the vascular access site. Baseline demographics, angiographic features, and in-hospital outcomes were prospectively recorded and entered into a dedicated database. Mortality records were obtained from hospital and state records. Statistical analysis. Continuous variables are presented as mean ± SD and dichotomous variables as percentages. Differences between the two groups were compared using an unpaired Student's t-test for continuous variables and the Chi-square test for dichotomous variables. Survival was estimated by the Kaplan-Meier method. The Cox proportional-hazards model was used to calculate relative risk ratios and 95% confidence intervals of prognostic factors affecting survival after adjustment for the following baseline clinical characteristics: age, gender, Killip class, three-vessel disease, anterior MI, GP IIbIIIa inhibitors, and year of procedure. Data were analyzed with Excel (version 2002; Microsoft), GraphPad Prism (version 3.0; GraphPad Software, Inc.) and Statview statistical package. The level selected for statistical significance was set at probability value p 1 (RR: 8.8, CI = 3.4–22.6; p Previous studies. In previous randomized trials that assessed the value of GP IIb/IIIa administration during primary PCI, such as the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC), ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT), and Intracoronary Stenting and Antithrombotic Regimen (ISAR-2); GP IIb/IIIa inhibitors were initiated in the catheterization suite.^5,9,12 Despite proving a significant benefit on the short-term outcomes, they failed to show a benefit after 6 months. In the RAPPORT study, treatment with abciximab improved 30-day outcomes, mostly by reducing target vessel revascularization rates and the composite endpoint of death, reinfarction, or urgent target vessel revascularization (p = 0.03).9 Likewise, in the ISAR-2 trial, adjunctive therapy with abciximab during stenting improved the 30-day composite of death, re-infarction, or target vessel revascularization (5.0% versus 10.5% in placebo; p = 0.04).¹² After 6 months, no benefit was observed compared to the placebo group. In contrast to these trials, 26% of the patients in the Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up (ADMIRAL) trial received abciximab early and before the initiation of the procedure as an upstream therapy in the emergency room or ambulance.¹⁰ As compared with placebo, abciximab significantly reduced the incidence of the primary endpoint at 30 days (composite of death, reinfarction, or urgent revascularization of the target vessel; 6% versus 14.6% in the placebo group). Also, a non-significant 55% reduction in mortality at 6 months was observed in patients who had been randomized to the abciximab arm. These superior results could have been related to the early administration of abciximab. The CADILLAC trial was the largest study to address the use of GP IIb/IIIa inhibitors during primary PCI.^5,13 This study assessed the effectiveness of adding coronary stents or GP IIb/IIIa inhibitors, or both, to balloon angioplasty during AMI. In this study, stenting alone was superior to percutaneous balloon angioplasty, and stenting alone was not inferior to balloon angioplasty plus abciximab. Abciximab treatment was associated with a significant reduction in the composite endpoint of death, MI, ischemia-driven target vessel revascularization, or disabling stroke at 30 days. Subacute thrombosis also was significantly reduced with abciximab treatment. At 12 months, however, rates of the composite endpoint did not differ significantly between the groups.^5,13 Smaller studies performed with eptifibatide and tirofiban have shown an improvement in coronary blood flow in patients treated with these drugs.^14,15 Conversely, in the recently published Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) trial16, early initiation of tirofiban did not have a significant impact on coronary blood flow or clinical outcomes when compared to initiation of tirofiban during the procedure. The benefit of early administration of GP IIb/IIIa inhibitors in AMI, therefore, has not been established. In our patients, GP IIb/IIIa inhibitors were initiated during the procedure following the diagnostic angiography and before the initiation of the interventional procedure itself. The significant improvement in survival in these patients is encouraging. It is important to note that there are some differences between our patients and those in the above-mentioned trials. In some of those trials, stents were used only as a bail-out therapy (RAPPORT), and in others (CADILLAC), only one type of stent was used, whereas in our center, the diversity of stents available probably enabled optimal stent selection. Furthermore, the marginally improved clinical outcomes observed with adjunctive therapy using GP IIb/IIIa inhibitors in AMI is usually offset by an increased rate of bleeding complications. In our registry, the rate of bleeding and vascular complications was low and not significantly different between the two groups. Although the use of upstream GP IIb/IIIa inhibitors was not addressed in our study, upstream therapy does not seem to increase the risk of bleeding complications and might have a beneficial role regarding outcomes. We believe that if there is an early decision to use GP IIb/IIIa inhibitors, they should be given as early as possible (ambulance or emergency room), especially if there is a chance of a delay prior to the procedure. Limitations. There are several limitations in the present study. This was a retrospective analysis, and thus the results and conclusions are subject to the limitations inherent in all such reports. Although the number of patients referred to primary PCI as a reperfusion strategy is growing at our institution, we aim to perform primary PCI in patients who are considered to have a large area of myocardium under jeopardy, such as patients with anterior wall MI, extensive posterior infarction, or those patients with hemodynamic compromise. Given the ambiguity of the beneficial effects of GP IIb/IIIa inhibitors during primary PCI in AMI patients, interventional cardiologists might have different views concerning their use, and therefore their administration may vary according to the operator and his/her individual performance. Still, operator decisions involving the use of GP IIb/IIIa inhibitors could include factors that were not incorporated into the analysis. Thus, the concomitant use of GP IIb/IIIa inhibitors in AMI patients who underwent primary PCI had a favorable impact in the short- and long-term outcomes, without a significant increase in vascular and bleeding complications.

1. Zijlstra F, Hoorntje JC, de Boer MJ, Reiffers S, Miedema K, Ottervanger JP et al. Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1999;341:1413–1419. 2. Nunn CM, O'Neill WW, Rothbaum D, Stone GW, O'Keefe J, Overlie P et al. Long-term outcome after primary angioplasty: report from the primary angioplasty in myocardial infarction (PAMI-I) trial. J Am Coll Cardiol 1999;33:640–646. 3. Grines C, Patel A, Zijlstra F, et al. Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute myocardial infarction: Six-month follow up and analysis of individual patient data from randomized trials. Am Heart J 2003;145:47–57. 4. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1993;328:673–679. 5. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957–966. 6. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003;361:13–20. 7. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. The EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1998;352:87–92. 8. O'Shea JC, Buller CE, Cantor WJ, et al. Long-term efficacy of platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention. J Am Med Assoc 2002;287:618–621. 9. Brener SJ, Barr LA, Burchenal JE, Katz S, George BS, Jones AA et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation 1998;98:734–741. 10. Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001;344:1895–1903. 11. Van de WF, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003;24:28–66. 12. Neumann FJ, Kastrati A, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction. J Am Coll Cardiol 2000;35:915–921. 13. Tcheng JE, Kandzari DE, Grines CL, et al. Benefits and risks of abciximab use in primary angioplasty for acute myocardial infarction: The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Circulation 2003;108:1316–1323. 14. Cutlip DE, Cove CJ, Irons D, et al. Emergency room administration of eptifibatide before primary angioplasty for ST-elevation acute myocardial infarction and its effect on baseline coronary flow and procedure outcomes. Am J Cardiol 2001;88:62–64. 15. Lee DP, Herity NA, Hiatt BL, et al. Adjunctive platelet glycoprotein IIb/IIIa receptor inhibition with tirofiban before primary angioplasty improves angiographic outcomes: Results of the TIrofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) pilot trial. Circulation 2003;107:1497-1501. 16. Van't Hof AW, Ernst N, De Boer MJ, et al. Facilitation of primary coronary angioplasty by early start of a glycoprotein 2b/3a inhibitor: results of the ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial. Eur Heart J 2004;25:837–846. 17. Martinez-Rios MA, Rosas M, Gonzalez H, Pena-Duque MA, Martinez-Sanchez C, Gaspar J et al. Comparison of reperfusion regimens with or without tirofiban in ST-elevation acute myocardial infarction. Am J Cardiol 2004;93:280–287. 18. Yip HK, Wu CJ, Chang HW, et al. Impact of tirofiban on angiographic morphologic features of high-burden thrombus formation during direct percutaneous coronary intervention and short-term outcomes. Chest 2003;124:962–968. 19. Merlini PA, Rossi M, Menozzi A, et al. Thrombocytopenia caused by abciximab or tirofiban and its association with clinical outcome in patients undergoing coronary stenting. Circulation 2004;109:2203–2206.