Integrating GP IIb/IIIa Inhibition into Treatment Strategies for Acute ST-Elevation Myocardial Infarction (Part II)

“Facilitated fibrinolysis”: GP IIb/IIIa inhibitors and fibrinolytic therapy in ST-elevation infarction. Considering the abundant platelet-rich thrombus present in almost all patients with acute myocardial infarction, it is intuitive that platelet inhibition with GP IIb/IIIa antagonists may be effective in this syndrome. In addition to their antiplatelet effects; however, GP IIb/IIIa inhibitors also augment intrinsic fibrinolysis, establishing a dual role for their application in acute myocardial infarction. GP IIb/IIIa inhibitors independently exhibit some intrinsic clot-dissolving activity,22,23 and preclinical studies have demonstrated the benefit of combining GP IIb/IIIa blockade with heparin and fibrinolytic therapy in acute coronary occlusion.43,44 Theoretical advantages of “facilitated fibrinolysis” include a reduction in plasminogen activator-mediated platelet aggregability, earlier infarct-vessel patency, increased safety, and less frequent reocclusion. With plasminogen activators, fibrinolysis occurs, exposing greater amounts of thrombin that generates even further thrombin production in an autocatalytic fashion (Figure 5).45 Moreover, thrombin is the most potent activator of platelets, promoting an even more prothrombotic condition. Not only are platelets resistant to the actions of fibrinolytics, but they secrete large amounts of platelet activator inhibitor-1 (PAI-1) that antagonize the effects of these agents. Along with aspirin, pharmacologic strategies incorporating fibrinolysis with GP IIb/IIIa inhibition may therefore overcome “thrombolytic resistance”.46 Until recently, large investigations of GP IIb/IIIa antagonists in acute myocardial infarction were precluded by overriding concern for bleeding, particularly hemorrhagic stroke induced by combining GP IIb/IIIa inhibition with aspirin, heparin, and fibrinolytic therapy. However, the rates of hemorrhagic stroke have been low in trials of GP IIb/IIIa antagonists for ACS,47–49 and several early studies of combination therapy with reduced-dose fibrinolytic therapy in acute myocardial infarction ensured acceptable safety with improved clinical outcomes. Conversely, the increased risk of major bleeding observed in trials evaluating full-dose fibrinolytic therapy with GP IIb/IIIa antagonists called for a reappraisal of fibrinolytic dosing. In patients treated with the monoclonal antibody m7E3 following alteplase, the dose-finding TAMI-8 study identified the relationship between GP IIb/IIIa receptor occupancy and platelet inhibition.50 Although doses achieving 80–90% platelet inhibition were considered optimal, major bleeding was considerably higher in patients receiving combination therapy. Combining several doses of eptifibatide with reduced-dose alteplase in the IMPACT-AMI trial, Ohman and coworkers reported significantly higher rates of TIMI grade 3 flow at 90 minutes with the highest eptifibatide dosing regimen compared with alteplase alone (66% vs. 39%; p = 0.006) without an increased bleeding risk (Figure 6).51 In a subsequent trial combining full-dose streptokinase with eptifibatide and no heparin, TIMI 3 flow at 90 minutes was achieved in 44–53% of patients randomized to three escalated dosages of eptifibatide, compared with 38% of patients receiving placebo.52 Although a dose-dependent relationship with bleeding risk was observed (requiring discontinuation of the highest eptifibatide treatment arm), rates of intracranial hemorrhage did not differ among treatment groups. The PARADIGM trial also evaluated either full-dose alteplase or streptokinase with simultaneous administration of lamifiban.53 Despite the more rapid ST-segment resolution associated with combined therapy, no clear benefit with regard to mortality was observed, and major bleeding was significantly greater with combination therapy. The sample sizes for these trials, however, were modest. With the aim of reducing hemorrhagic complications, more recent studies have evaluated the safety and efficacy of GP IIb/IIIa inhibition combined with reduced-dose fibrinolytic therapy. The TIMI-14 investigators reported the results of a dose-ranging study randomizing 888 patients with acute myocardial infarction to abciximab alone or abciximab combined with reduced-dose regimens of alteplase or streptokinase.25 At 60 minutes, angiography showed a significantly higher incidence of TIMI grade 3 flow in the infarct vessel for those assigned to abciximab and alteplase compared with alteplase alone (Figure 6) (72% vs. 43%; p = 0.0009). Similarly, the SPEED trial reported encouraging results for patients enrolled in this dose-ranging trial of full-dose abciximab with reduced doses of reteplase.26 Early reperfusion by angiography was achieved in a dose-dependent manner with TIMI grade 3 flow present in up to 62% of patients given abciximab and reteplase (Figure 6). In the second phase of the SPEED trial comparing combined abciximab and reteplase versus reteplase alone, TIMI 3 flow at 60–90 minutes was achieved in 61% of patients treated with a 60 U/kg heparin bolus and abciximab-reteplase compared to 47% for reteplase alone (p = 0.05 for comparison). Based on an earlier dose finding study yielding a TIMI 3 flow rate of 78% at 90 minutes with combined eptifibatide and alteplase, the INTRO-AMI dose confirmation phase demonstrated improved patency with combined therapy compared to alteplase alone (56% with eptifibatide/alteplase vs. 40% with alteplase; p 75 years old assigned to abciximab therapy were more likely to the achieve the combined safety and efficacy endpoint compared with UFH-treated patients (p = 0.001). However, in a subgroup analysis, elderly patients receiving combination therapy in GUSTO V tended to have more frequent intracranial hemorrhage (2.1% with combination therapy vs. 1.1% with alteplase alone; p = 0.069), reflecting similar findings in the ASSENT-3 trial (2.6% with combination therapy vs. 0.7% with tPA-TNK alone for patients > 75 years; p = 0.26). Results from the INTRO-AMI trial likewise showed a nonsignificant 3% intracranial hemorrhage rate among patients receiving the higher dose eptifibatide regimen combined with reduced dose fibrinolysis.54 Results from more recent studies examining the benefit of combination therapy are forthcoming. In the ENTIRE-TIMI 23 study,57 a total of 461 patients were randomized to one of four treatment strategies: 1) full-dose tPA-TNK plus UFH, 2) full-dose tPA-TNK plus enoxaparin, 3) reduced dose enoxaparin, tPA-TNK and abciximab, and 4) reduced dose UFH, tPA-TNK plus abciximab. Unlike ASSENT 3, neither TIMI 3 flow nor ST-segment resolution differed between the treatment groups at 60 minutes (Figure 6), although a trend for later improved epicardial flow with abciximab was observed. Although the study was not statistically powered to determine clinical efficacy, the occurrence of 30-day death, nonfatal (re)infarction, and major bleeding was lowest among regimens that included enoxaparin. In the dose-finding INTEGRITI trial, a regimen of high-dose, double-bolus eptifibatide with reduced dose tPA-TNK in the dose confirmation phase was associated with trends toward improved epicardial patency and ST-segment resolution compared with reduced dosages of both eptifibatide and tPA-TNK (Figure 6).58 Similar to previous trials of combination therapy, however, this regimen also resulted in greater bleeding and need for transfusion, thus precluding any current recommendations for its use as standard therapy. New strategies for ST-elevation MI: “Facilitated PCI”. Facilitated PCI, or the strategy of planned early PCI following pharmacological reperfusion therapy, has the potential to fuse the best aspects of fibrinolysis and primary angioplasty together for the management of ST-elevation MI. First, a pharmacological approach may achieve TIMI 3 flow rates as early as 60 minutes following administration. In addition to epicardial patency, treatment with GP IIb/IIIa antagonists may improve distal microvascular flow and myocardial perfusion. Alternatively, primary angioplasty is able to achieve higher rates of epicardial artery flow compared with fibrinolytic therapy, but generally at later time points. An initial approach to pharmacologic reperfusion therapy in the emergency department or at institutions without interventional facilities may also offer more “active” treatment during delays associated with patient transport for primary PCI. As a combined approach, facilitated PCI may therefore help resolve the controversy focusing on which strategy provides the best outcomes based on TIMI 3 flow rates and clinical events. Clinical trials demonstrating improved outcomes among acute MI patients with a patent infarct-related artery prior to percutaneous revascularization have provided further support for facilitated PCI. Percutaneous intervention following initial pharmacologic reperfusion therapy may not only identify those patients with incomplete reperfusion but provide added benefit with mechanical revascularization. For example, among patients receiving GP IIb/IIIa inhibition and/or fibrinolytic therapy in the TIMI 10B and 14 trials, those with TIMI 0 or 1 flow who underwent “rescue” PCI tended to have lower 30-day mortality than patients treated medically (6% vs. 17%; p = 0.28).59 However, even among patients with TIMI 2 or 3 flow, performance of adjunctive PCI was associated with significantly lower 30-day mortality and/or reinfarction compared with a strategy of delayed revascularization (odds ratio 0.46, 95% confidence interval 0.24–0.57; p = 0.02). With a greater likelihood for epicardial artery patency, facilitated PCI may also improve patient stability and reduce peri-MI complications such as shock. In an analysis of 1,490 patients undergoing primary angioplasty, the finding of initial TIMI 2 or 3 flow prior to intervention was associated with reduced infarct size, improved ventricular function, and greater early survival compared with patients having incomplete reperfusion.60 These data are consistent with 1) a previous report from 2,507 patients in the PAMI trials,61 in which early and late mortality were strikingly reduced in patients with spontaneously occurring pre-procedural TIMI 3 flow, independent of the final TIMI flow (Figure 8); 2) the randomized PACT trial, in which early reperfusion with reduced dose t-PA resulted in greater early recovery of left ventricular function,62 and 3) the meta-analysis demonstrating that mortality is decreased when thrombolytic therapy is initiated pre-hospital as compared to the emergency room.63 Recently, the SPEED investigators described the outcomes for 323 patients who underwent PCI approximately one hour following reperfusion therapy and compared them with a similar cohort who did not undergo early revascularization (Figure 9).64 For the facilitated therapy group, procedural success was 88%, and the 30-day composite endpoint of death, reinfarction, and urgent TVR occurred in 5.6% of patients. Although these findings are more descriptive than comparative, they are encouraging, since earlier trials consistently demonstrated lower immediate procedural success rates, higher mortality, and higher rates of reinfarction, bypass surgery, and bleeding with early PCI following fibrinolytic therapy.65 Similar to the SPEED study, the experience from other trials (ENTIRE-TIMI 23, INTEGRITI) permitting early PCI following pharmacologic reperfusion therapies is awaited. Also, more dedicated trials are underway examining the benefit of early PCI following treatment in the ADVANCE-MI trial with eptifibatide/tPA-TNK and in the FINESSE trial with abciximab/reteplase. Conclusion. Either alone or in combination with other pharmacologic and catheter-based interventions, much progress has been made in the treatment of AMI patients with GP IIb/IIIa inhibition. Clinical trials evaluating both catheter-based and pharmacologic strategies that incorporate GP IIb/IIIa inhibition have demonstrated enhanced epicardial flow, improved microvascular perfusion, and sustained vessel patency. Treatment with GP IIb/IIIa inhibitors has now transitioned to an era somewhere between continued rapid growth (e.g., adoption into routine therapy) and maturity (e.g., novel indications, new trials) as recent results from clinical trials have extended their application to both pharmacologic and catheter-based treatment strategies for acute ST-elevation MI. Given the increased mortality associated with reinfarction following fibrinolytic therapy, therapies that decrease the incidence of recurrent ischemia and infarct artery reocclusion are essential.66 However, despite the reductions in early reinfarction and recurrent ischemia observed with abciximab in GUSTO V, these benefits did not translate to improved survival at one year (8.38% vs. 8.38%; p = NS).67 Until a survival benefit with combined fibrinolytic and GP IIb/IIIa therapy is established, further value beyond the observed reduction in ischemic complications, including both acceptable safety and costs, will need to be established before combination therapy is promoted as routine therapy for acute MI in the absence of primary angioplasty. Additional study is also needed to clarify the disparity between the absence of decreased mortality yet improved TIMI 3 flow. Possible explanations include an overall low-risk study population eligible for clinical trials, persistent impairment of adequate myocardial perfusion, limitations in the interpretation between biomarker results and mortality reduction, or a continued need to identify the optimal antiplatelet and fibrinolytic combination regimen. Other important issues for study with combination therapy include the increased risk of bleeding (particularly among elderly and high-risk patients), the complexity of dosing regimens, and the emphasis on accelerated treatment protocols for prompt administration. The ideal combination of fibrinolytic, antithrombin, and GP IIb/IIIa inhibitor is also uncertain. Clinical results from forthcoming trials should therefore further clarify the safety and efficacy of combined therapy in addition to its potential as a cost-effective measure. Integration of most effective pharmacology with percutaneous revascularization strategies also remains an unresolved issue. The improvements in ventricular function, early recurrent ischemia, and both early and intermediate survival with GP IIb/IIIa inhibition in primary PCI support the use of these agents as adjunctive therapy to mechanical revascularization, particularly with timely administration prior to arrival in the catheterization laboratory. Whether the early performance of angiography and catheter-based intervention following combination therapy for ST-elevation MI will yield favorable outcomes similar to the experience in non-ST-elevation ACS (TIMI 18-TACTICS)68 is less definitive. However, considering the importance of prompt restoration of flow in the infarct-related artery, the collective experience with fibrinolysis and primary PCI has fostered the concept of “facilitated PCI,” and randomized trials evaluating the safety and efficacy of this strategy are underway. Regardless of the treatment strategy, effective platelet inhibition appears to be a critical element in rising above the “ceiling of reperfusion” and past the limitations of current therapies. While the available data should facilitate the use of adjunctive GP IIb/IIIa inhibitors as part of initial anti-thrombotic therapy for primary PCI, results from future trials should further refine the role of these agents as part of treatment algorithm for the initial pharmacologic management of patients with acute MI. Appendix A. List of referenced clinical trials acronyms. ADMIRAL: Abciximab with Percutaneous Transluminal Coronary Angioplasty and Stent in Acute Myocardial Infarction ADVANCE-MI: Addressing the Value of Facilitated Angioplasty After Combination Therapy or Eptifibatide Monotherapy in Acute Myocardial Infarction ASSENT-3: Assessment of the Safety and Efficacy of a New Thrombolytic-3 CADILLAC: Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications DANAMI-2: Danish Multicenter Randomized Trial on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction EPIC: Evaluation of 7E3 for the Prevention of Ischemic Complications ENTIRE-TIMI 23: Enoxaparin and TNK-TPA with or without GP IIb/IIIa Inhibitor as Reperfusion strategy in ST Elevation MI FINESSE: Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events GRAPE: Glycoprotein Receptor Antagonist Patency Evaluation Pilot Study IMPACT-AMI: Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II INTRO-AMI: Integrilin and Reduced Dose of Thrombolysis in Acute Myocardial Infarction INTEGRITI: Integrilin and Tenecteplase in Acute Myocardial Infarction ISAR-2: Intracoronary Stenting and Antithrombotic Regimen-2 PACT: Primary Angioplasty Compatibility Trial PAMI: Primary Angioplasty in Myocardial Infarction PARADIGM: Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial infarction RAPPORT: ReoPro and Primary PTCA Organization and Randomized Trial SPEED: Strategies for Patency Enhancement in the Emergency Department STOP-AMI: Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction TAMI-8: Thrombolysis in Acute Myocardial Infarction-8 TIMI 10B: Thrombolysis in Myocardial Infarction 10B TIMI 14: Thrombolysis in Myocardial Infarction 14

1. Lange RA, Hillis LD, Grines CL. Should thrombolysis or primary angioplasty be the treatment of choice for acute myocardial infarction? N Engl J Med 1996;335:1311-1312. 2. Andersen HR. The Danish Multicenter Randomized Trial on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction. Paper presented at: American College of Cardiology Scientific Sessions; March 2002; Atlanta, Georgia. 3. Herrmann HC. Triple therapy for acute myocardial infarction: Combining fibrinolysis, platelet IIb/IIIa inhibition, and percutaneous coronary intervention. Am J Cardiol 2000;85:10C–16C. 4. The GUSTO Investigators. An international randomized trial comparing four throm-bolytic regimens consisting of tissue plasminogen activator, streptokinase, or both for acute myocardial infarction. N Engl J Med 1993;329:673–682. 5. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615–1622. 6. Meijer A, Verheugt FWA, Werter CPJP, et al. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: A prospective placebo-controlled angiographic study. Circulation 1993;87:1524–1530. 7. Berkowitz SD, Granger CB, Pieper KS, et al., for the GUSTO Investigators. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation 1997;95:2508–2516. 8. Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993;87:1792–1805. 9. Cannon CP, Gibson CM, McCabe CH, et al. TNK–tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: Results of the TIMI 10B Trial. Circulation 98:2805–2814. 10. Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation 1996;94:891–898. 11. den Heijer P, Vermeer F, Ambrosioni E, et al., for the InTime Investigators. Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: A double-blind, randomized angiographic trial of lanoteplase versus alteplase. Circulation 1998;98:2117–2125. 12. The GUSTO III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries III Trial. N Engl J Med 1997;337:1118–1123. 13. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomized trial. Lancet 1999;354:716–722. 14. The In-TIME II Investigators. Intravenous NPA for the treatment of infracting myocardium early: InTIME-II, a double-blind comparison of single-bolus lanoteplase vs. accelerated alteplase for the treatment of patients with acute myocardial infarction. Eur Heart J 2000;21:1996–1997. 15. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndrome. N Engl J Med 1992;326:242–250,310–318. 16. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995;332:1553–1559. 17. Phillips DR, Charo IF, Parisi LV, Fitzgerald LA. The platelet membrane glycoprotein IIb-IIIa complex. Blood 1988;71:831–843. 18. Pytela R, Pierschbacher MD, Ginsberg MH, et al. Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp specific adhesion receptors. Science 1986;231:1559-1562. 19. Coller BS, Peerschke EI, Scudder LE, Sullivan CA. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest 1983;72:325–338. 20. Adgey JAA. Overview of the results of clinical trials with glycoprotein IIb/IIIa inhibitors. Am Heart J 1998;135(Suppl):S43–S55. 21. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation 1987;76:142–154. 22. Gold HK, Garabedian HD, Dinsmore RE, at al. Restoration of coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators: Observations in animals and humans. Circulation 1997;95:1755–1759. 23. Reverter JC, Beguin S, Kessels H, et al. Inhibition of platelet-medicated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody: Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and clinical restenosis. J Clin Invest 1996;98:863–874. 24. van den Merkhof LFM, Zijlstra F, Olsson H, et al. Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1999;33:1528–1532. 25. Antman EM, Giugliano RP, Gibson CM, et al., for the TIMI-14 Investigators. Abciximab facilitate the rate and extent of thrombolysis. Results of the TIMI 14 trial. Circulation 1999;99:2720–2732. 26. Strategies for Patency Enhancement in the Emergency Department (SPEED) Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation 2000;101:2788–2794. 27. 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. 28. Lefkovits J, Ivanhoe RJ, Califf RM, et al. for the EPIC Investigators. Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (abciximab) on acute and six-month outcomes after percutaneous transluminal coronary angioplasty for acute myocardial infarction. Am J Cardiol 1996;77:1045–1051. 29. 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. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation 1998;98:734–741. 30. 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. 31. Montalescot G, Barragan P, Wittenberg O, et al. for the ADMIRAL Investigators. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001;344:1895–1903. 32. Stone GW, Grines CL, Cox DA, et al. A prospective, randomized trial comparing primary balloon angioplasty with or without abciximab to primary stenting with or without abciximab in acute myocardial infarction — primary endpoint analysis from the CADILLAC Trial. N Engl J Med 2002;346:957–966. 33. Gibson CM, Goel M, Cohen DJ, et al. Six-month angiographic and clinical follow-up of patients prospectively randomized to receive either tirofiban or placebo during angioplasty in the RESTORE trial. Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis. J Am Coll Cardiol 1998;32:28–34. 34. Roe MT, Ohman EM, Maas ACP, et al. Shifting the open-artery hypothesis downstream: The quest for optimal reperfusion. J Am Coll Cardiol 2001;37:9–18. 35. van’t Hof A, Liem A, de Boer M, Zijlstra F. Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Lancet 1997;350:615–619. 36. Claeys MJ, Bosmans J, Veenstra L, et al. Determinants and prognostic implications of persistent ST-segment elevation after primary angioplasty for acute myocardial infarction: Importance of microvascular reperfusion injury on clinical outcomes. J Am Coll Cardiol 1999;99:1972–1977. 37. Gibson CM, de Lemos JA, Murphy SA, et al., for the TIMI Study Group. Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: A TIMI 14 substudy. Circulation 2001;103:2550–2554. 38. de Lemos JA, Antman EM, Gibson CM, et al., for the TIMI 14 Investigators. Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction: Observations from the TIMI 14 Trial. Circulation 2000;101:239–243. 39. Schomig A, Kastrati A, Dirschinger J, et al. Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Study Investigators. N Engl J Med 2000;343:385–391. 40. Kastrati A, Mehilli J, Dirschinger J, et al. Myocardial salvage after coronary stenting plus abciximab versus fibrinolysis plus abciximab in patients with acute myocardial infarction: A randomised trial. Lancet 2002;359:920–925. 41. Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 1998;98:2695–2701. 42. The ERASER Investigators. Acute platelet inhibition with abciximab does not reduce in-stent restenosis. Circulation 1999;100:799–806. 43. Yasuda T, Gold HK, Fallon JT, et al. Monoclonal antibody against platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. J Clin Invest 1988;81:1284–1291. 44. Gold HK, Coller BS, Yasuda T, et al. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GP IIb/IIIa antibody in a canine preparation. Circulation 1988;77:670–677. 45. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: Emerging platelet preeminence. Circulation 1998;97:211–218. 46. Cannon CP. Overcoming thrombolytic resistance. Rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction. J Am Coll Cardiol 1999;34:1395–1402. 47. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose hebparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689–1696. 48. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy): A randomised, placebo-controlled trial. Lancet 2000;356:2037–2044. 49. 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. 50. Kleiman NS, Ohman EM, Califf RM, et al. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapy: results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study. J Am Coll Cardiol 1993;22:381–389. 51. Ohman EM, Kleiman NS, Gacioch G, et al. for the IMPACT-AMI Investigators. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction: Results of a randomized; placebo-controlled, dose-ranging trial. Circulation 1997;95:846–854. 52. Ronner E, van Kesteren HAM, Zijnen P, et al. Combined therapy with streptokinase and integrilin. J Am Coll Cardiol 1998;31:191A. 53. The PARADIGM Investigators. Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: Results of the platelet aggregation receptor antagonist dose investigation and reperfusion gain in myocardial infarction (PARADIGM) trial. J Am Coll Cardiol 1998;32:2003–2010. 54. Ferguson JJ. Meeting highlights: Highlights of the 21st Congress of the European Society of Cardiology. Circulation 1999;100:e126–e131. 55. The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: The ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605–613. 56. GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination therapy with reduced fibrinolytic therapy and glycoprotein IIb/IIIa inhibition: The GUSTO V randomised trial. Lancet 2001;357:1905–1914. 57. Antman EM, Gibson M, Heidbuchel H, et al. for the ENTIRE-TIMI 23 Investigators. Fibrinolysis with adjunctive enoxaparin with or without abciximab — results of the ENTIRE-TIMI 23 Trial. Circulation 2001;104:II-538A. 58. Giugliano RP, Roe MT, Harrington RA, et al. Combination reperfusion therapy with eptifibatide and reduced dose tenecteplase for ST-elevation myocardial infarction: Results of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) Phase II angiographic trial. J Am Coll Cardiol 2002 (in press). 59. Schweiger MJ, Cannon CP, Murphy SA, et al., for the TIMI 10B and 14 Investigators. Early coronary intervention following pharmacologic therapy for acute myocardial infarction (the combined TIMI 10B-TIMI 14 experience). Am J Cardiol 2001;88:831–836. 60. Brodie BR, Stuckey TD, Hansen C, Muncy D. Benefit of coronary reperfusion before intervention on outcomes after primary angioplasty for acute myocardial infarction. Am J Cardiol 2000;85:13–18. 61. Stone GW, Cox D, Garcia E, et al. Normal flow (TIMI-3) before mechanical reperfusion therapy is an independent determinant of survival on acute myocardial infarction. Analysis from the Primary Angioplasty in Myocardial Infarction Trials. Circulation 2001;104:636–641. 62. Ross AM, Coyne KS, Reiner JS, et al. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT trial. J Am Coll Cardiol 1999;34:1954–1962. 63. Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis. JAMA 2000;283:2686–2892. 64. Herrmann HC, Moliterno DJ, Ohman EM, et al. Facilitation of early percutaneous coronary intervention after reteplase with or without abciximab in acute myocardial infarction. Results from the SPEED (GUSTO-4 Pilot) Trial. J Am Coll Cardiol 2000;36:1489–1496. 65. Topol EJ, George BS, Califf RM, et al. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987;317:581–588. 66. Hudson MP, Granger CB, Topol EJ, et al. Early reinfarction after fibrinolysis: Experience from the Global Utilization of Streptokinase and Tissue Plasminogen Activator (alteplase) for Occluded Coronary Arteries (GUSTO I) and Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO III) trials. Circulation 2001;104:1229–1235. 67. Lincoff AM. 1-year results from the GUSTO V trial. Paper presented at: XIVth World Congress of Cardiology; May 2002; Sydney, Australia. 68. Cannon CP, Weintraub WS, Demopoulos LA, et al., for the TACTICS-TIMI 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879–1887.