Acute Coronary Syndromes

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

David E. Kandzari, MD and Matthew T. Roe, MD, MHS
David E. Kandzari, MD and Matthew T. Roe, MD, MHS
Overview. Against the background of established clinical benefit in non-ST segment elevation acute coronary syndromes (ACS) and elective percutaneous revascularization, recent trials examining the role of glycoprotein (GP) IIb/IIIa inhibition in acute myocardial infarction (AMI) have been based on the rationale that effective platelet inhibition is fundamental to reperfusion strategies designed to restore myocardial perfusion, limit infarct size, and improve survival. Despite advances in the care of high-risk patients with acute ST-elevation MI, limitations of current standard therapies underscore the need for further improvement. Although primary angioplasty and stenting achieves successful reperfusion in more than 90% of cases, limited availability, time delays, and procedural inexperience are shortcomings associated with this treatment strategy.1 In spite of these limitations, transfer of AMI patients to an institution capable of performing primary percutaneous coronary intervention (PCI) may yield improved outcomes compared with prompt administration of fibrinolytic therapy. Compared with fibrinolytic therapy, a strategy that allowed up to 3 hours delay for transfer to hospitals performing primary PCI in the DANAMI-2 trial was still associated with significant reductions in the 30-day occurrence of death, recurrent infarction, or disabling stroke (13.7% vs. 8.0% for the composite endpoint; p = 0.0003).2 Alternatively, fibrinolytic therapy is limited by the failure to achieve normal antegrade Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in 40% or more of patients, early and late reocclusion of the infarct vessel in approximately 10% and 30% of patients, respectively, and iatrogenic hemorrhagic risks, including intracranial bleeding in approximately 1% of patients.3–7 Although TIMI 3 flow may be initially achieved in approximately half of patients receiving fibrinolytic therapy alone, appraisal of impaired microvascular flow, reocclusion, and intermittent (or incomplete) patency have unveiled the “illusion of reperfusion,” with most patients experiencing incomplete epicardial and/or microvascular perfusion following fibrinolytic therapy.8 In spite of results from contemporary trials evaluating fibrinolytic therapy with low-molecular-weight heparins or direct thrombin inhibitors, a “ceiling of reperfusion” has been achieved with standard fibrinolytic and antithrombotic therapy (Figure 1).9–14 Despite the development of 1) newer-generation, more fibrin-specific fibrinolytic agents and 2) novel antithrombin therapies, the current threshold of efficacy with pharmacologic therapies (~ 6% mortality, ~ %50 TIMI 3 flow; Figure 1) has motivated trials of adjunctive GP IIb/IIIa inhibition in acute MI with the intent of further improving the safety and efficacy. The purpose of this review is to present a rationale for the use of GP IIb/IIIa inhibitors as adjunctive therapy to fibrinolysis and primary angioplasty, examine the results from recent trials of GP IIb/IIIa inhibition in patients with acute MI, and describe future directions for clinical investigation. Role of GP IIb/IIIa in acute coronary syndromes. The pathogenesis of ACS is characterized by atherosclerotic plaque rupture, platelet activation and aggregation, and resultant thrombus formation.15,16 In atherosclerotic coronary vessels, plaque rupture exposes the subendothelium, precipitating thrombus formation. Platelets first adhere to the subendothelium by binding to class I glycoproteins. In the presence of thrombin and other agonists such as adenosine or epinephrine, platelet activation occurs, effecting a conformational change in the GP IIb/IIIa receptor and platelet degranulation. This releases serotonin, adenosine diphosphate (ADP), and other vasoactive substances, which stimulate further platelet activation and recruitment. The conformational change in the GP IIb/IIIa receptor allows binding of fibrinogen and von Willebrand factor, producing platelet aggregation and thrombus formation. The subsequent clinical presentation is determined by whether the thrombotic mass is occlusive, sub-occlusive, or non-obstructive, and is influenced by collateral flow, baseline left ventricular function, amount of jeopardized myocardium, diabetes, and other factors. As a result, patients may experience severe angina with ST-segment elevation, non-ST elevation MI, or unstable angina without elevations of cardiac markers. The role of the GP IIb/IIIa receptor as the final common pathway for platelet aggregation made its inhibition a pivotal transition from bench work to clinical practice.17,18 In 1983, Coller and coworkers first reported a murine monoclonal antibody that blocked the IIb/IIIa receptor.19 These findings led to the engineering of a chimeric monoclonal antibody, abciximab (ReoPro), which was first studied in patients undergoing high-risk PCI.20 Since then, several other inhibitors that mimic the arginine-glycine-aspartic acid (RGD) binding sequences of the GP IIb/IIIa receptor have also undergone extensive clinical investigation. These include the synthetic cyclic heptapeptide eptifibatide (Integrilin) as well as peptidomimetics such as tirofiban (Aggrastat) and lamifiban (Ro 44-9883). Despite differences in pharmacodynamics, the common role of these drugs is to inhibit platelet function by occupying the fibrinogen binding site. GP IIb/IIIa inhibition and PCI in ST-elevation myocardial infarction. Recent trials have established evidence supporting GP IIb/IIIa inhibition as adjunctive therapy for primary PCI in acute ST-segment elevation myocardial infarction. Addition of GP IIb/IIIa blockade to PCI for ST-elevation myocardial infarction has substantially lowered the incidence of recurrent ischemic events and improved early survival, ventricular function, and vessel patency. Observations from early studies evaluating the use of GP IIb/IIIa inhibitors prior to primary PCI yielded TIMI 3 flow rates that exceeded previously reported rates of reperfusion with aspirin and heparin and were comparable to full-dose streptokinase.21 Based on the clinical observation that abciximab exhibited intrinsic anticoagulant and clot-dissolving activity,22,23 the GRAPE investigators showed that rates of TIMI grade 2/3 flow occurred in approximately 40% patients treated with abciximab prior to angioplasty.24 More recently, nearly one-third of patients randomized to abciximab alone in the TIMI 14 (32%) and SPEED (27%) trials experienced grade TIMI 3 flow at 90 minutes.25,26 Although treatment with GP IIb/IIIa inhibitors alone is not ideally suited to achieve early reperfusion, such observations reaffirm the potential of abciximab to restore infarct-artery patency prior to mechanical revascularization. Aside from epicardial artery patency, pivotal trials demonstrating improved clinical outcomes with abciximab in unstable angina patients undergoing PCI also lead to studies extending the role of GP IIb/IIIa inhibitors in percutaneous revascularization for acute MI. Among the 893 patients in the EPIC trial27 with evolving myocardial infarction or unstable angina, abciximab was associated with an approximate 30% reduction in death, nonfatal myocardial infarction, or recurrent ischemic complications at 30 days (7.0% vs. 12.8%, 95% confidence interval 0.5–1.1). For the 64 AMI patients undergoing primary or rescue angioplasty,28 treatment with abciximab resulted in an 83% reduction in 30-day death, reinfarction or urgent revascularization. (26.1% vs. 4.5%; p = 0.06). Similarly, in the RAPPORT trial, patients with acute infarction given abciximab in the catheterization laboratory before primary angioplasty experienced significant reductions in 30-day and 6-month death, reinfarction, or urgent revascularization (5.6% vs. 11.2% at 30 days; p = 0.03).29 In the ISAR-2 trial,30 a total of 401 AMI patients within 48 hours of symptom onset for whom rescue or primary PCI were planned were randomized to abciximab bolus plus infusion or control. Abciximab as an adjunct to coronary stenting improved 30-day clinical outcomes (5.0% vs. 10.5%; p = 0.038 for the composite of death, reinfarction, or target lesion revascularization). At one year, although the absolute reduction in the composite endpoint was maintained with abciximab therapy, this early benefit no longer remained statistically significant, largely due to the accrual of restenotic events and the need for repeat revascularization. More recently, the ADMIRAL study demonstrated that abciximab improved early and late TIMI 3 flow (post-PCI TIMI 3 flow, 95.1% for abciximab vs. 86.7% for placebo; p = 0.04; Figure 2), was associated with higher left ventricular ejection fraction (57.0 ± 10.4% vs. 53.9 ± 10.4%; p GP IIb/IIIa inhibition in AMI: Improving myocardial perfusion and downstream microvascular function. New angiographic techniques, including the TIMI myocardial blush score, as well as noninvasive diagnostic tests (e.g., continuous ST segment monitoring, contrast echocardiography) have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success.34 Although many events can be identified by angiography, such as side branch occlusion or the no-reflow phenomenon, a substantial number of “angiographically silent” events occur at the level of myocardial perfusion. Persistent ST-segment elevation following primary PCI, for example, is associated with reduced left ventricular function and increased mortality.35,36 Despite epicardial vessel patency, disrupted microvascular function and inadequate myocardial perfusion are often the result of thromboembolic debris. To date, a number of studies examining the potential benefit of myocardial perfusion with GP IIb/IIIa antagonists have demonstrated improvements in distal microcirculatory flow. In the TIMI 14 study, patients treated with combined abciximab and fibrinolytic therapy experienced more rapid and complete restoration of epicardial flow as well as angiographically-evident thrombus.37 However, when comparing all patients with 60-minute TIMI 3 flow, combination therapy also resulted in more complete ST-segment resolution.38 Since these findings were independent of the fibrinolytic agent used, an additional mechanism by which abciximab improved myocardial perfusion was proposed; by preventing microvascular obstruction from platelet thromboemboli and the proaggregatory effects of fibrinolysis, abciximab may improve myocardial and microvascular perfusion in addition to epicardial flow. In the single-center open label randomized STOP-AMI trial, the combination of stenting plus abciximab was shown to enhance myocardial salvage and markedly improve event-free survival at 30 days and 1 year compared with accelerated t-PA.39 Similarly, among 162 AMI patients randomized to primary PCI with abciximab or a pharmacologic strategy of reduced-dose alteplase with full-dose abciximab, coronary stenting plus abciximab resulted in significantly greater myocardial salvage and infarct size measured by nuclear imaging at 11 days post-infarction.40 Although 6-month survival tended to favor patients randomized to the invasive strategy, overall survival did not significantly differ in this modest-sized study. Neumann et al. also explored the effects of abciximab on myocardial recovery and coronary flow following stenting in AMI patients.41 In that study, 200 patients within 48 hours of onset of AMI in whom a primary or rescue stent strategy was planned were randomized to a bolus plus 12-hour infusion abciximab regimen or control. Patients treated with abciximab had a lower composite rate of in-hospital death, reinfarction or urgent TVR (9.2% vs. 2.0%; p NOTE: SEE "PART II" OF THIS ARTICLE FOR CONTINUATION
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.