- Email: [email protected]
IIIa receptor blockade for the treatment of acute myocardial infarction
Low-dose fibrinolytics and glycoprotein IIb/IIIa receptor blockade for the treatment of acute myocardial infarction Maurizio Ferrario, MD, Alessandra Repetto, MD, Stefano Lucreziotti, MD, and Diego Ardissino, MD Pavia, Italy
Systemic fibrinolysis and primary coronary angioplasty represent the cornerstone of the pharmacologic management and of the interventional approach, respectively, of patients with acute myocardial infarction (MI). They have been demonstrated to be highly effective, although their action is hampered by some critical limitations; moreover, their association is prohibitive, owing to the well-documented prothrombotic effect of lytics that greatly increases thrombotic complications of interventional procedures. Platelet glycoprotein (GP) IIb/IIIa blockade has inaugurated a new era in the treatment of coronary artery disease, thanks to its potent antiaggregatory action. The administration of GP IIb/IIIa inhibitors in patients with acute MI is now under active investigation, particularly during interventional procedures and in combination with fibrinolytic agents. The anticoagulant and dethrombotic actions of this potent antiplatelet intervention suggest that its use associated with a low-dose lytic therapy could enhance reperfusion efficacy and reduce reocclusion rate, possibly decreasing hemorrhagic complications. Experimental and preliminary data are encouraging and confirm a role for combined treatment. Ongoing large, ramdomized, controlled clinical trials will clarify the real significance of this promising strategy.
related vessel remains biologically unstable, as documented by both an angiographic reocclusion rate up to 30% and the fact that up to 20% of patients have clinical episodes of recurrent myocardial ischemia during the course of hospitalization. Finally, it is associated with a moderately high occurrence of major hemorrhagic complications including a statistically low but clinically important 0.5% to 1% rate of intracranial hemorrhage.6 The rate of complications has recently slightly increased, probably because of relaxation of exclusion criteria with the aim of extending the benefits of the therapy to a larger number of patients.7 The significant incidence and clinical significance of resistance to fibrinolytics and reocclusion after successful reperfusion remain the weak points of the systemic lytic approach, as pointed out by the higher mortality rate of patients without satisfactory coronary recanalization in the short-term follow-up (13% vs 4%).5,8,9 Recent studies with new and more refined fibrinolytic drugs have failed to document any significant clinical improvement, making further advances by this standard strategy unlikely.
Standard fibrinolytic therapy
Perception of these limitations has encouraged the use of mechanical, catheter-based reperfusion interventions in addition to lytics, including rescue and early percutaneous transluminal coronary angioplasty (PTCA) performed immediately or a few days after fibrinolytic therapy. Unfortunately, the clinical results of the efforts aimed at routinely completing standard thrombolysis with mechanical revascularization have been discouraging, and there has been a high incidence of local hemorrhagic and coronary thrombotic complications associated with the procedure.10-16 Given the unsatisfactory results of PTCA after fibrinolytics, primary PTCA was developed as the only reperfusion intervention in evolving MI, without any previous lytic treatment.17-19 It has been proved to be superior to thrombolysis for achieving rapid coronary patency (patency >90%, TIMI grade 3 flow rate >70%), with a low incidence of severe hemorrhagic complications. However, it is still a matter of discussion whether these striking immediate angiographic results translate into sustained clinical advan-
Rapid dissolution of an occlusive intracoronary thrombus by fibrinolytic agents is the aim of standard medical care for patients with acute MI (AMI) observed 6 to 12 hours after symptom onset.1-4 The intravenous thrombolytic approach leads to 20% relative decrease in 30day mortality rates if compared with no lytic therapy,5,6 and this result is substantially independent of the agent and the clinical characteristics of the patient. Nevertheless, fibrinolytic treatment is hampered by some critical limitations: Adequate coronary patency is achieved in only approximately 50% of patients at 90 minutes; furthermore, it is not always sustained because the infarctFrom Divisione di Cardiologia, IRCCS Policlinico S. Matteo. Reprint requests: Diego Ardissino, MD, Divisione di Cardiologia, Ospedale Maggiore di Parma, Università di Parma, V. Gramsci 14, Parma, Italy. (Am Heart J 1999;138:S121-S125.) Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/98537
Lytics and percutaneous transluminal coronary angioplasty
American Heart Journal August 1999
S122 Ferrario et al
tages, which have been well documented at 1 month but seem to decline after 6 months of follow-up, probably because of the high rate of coronary reocclusion (13%) and restenosis (40%).20 As a consequence, the current strategy for facing AMI consists of a dichotomic approach: pharmacologic reperfusion based on systemic fibrinolysis, which is feasible but has a number of absolute and relative contraindications, discrete results, and definite severe hemorrhagic complications; and mechanical reperfusion by PTCA, which is more effective, at least in the early phase, but unpractical because it is highly dependent on the presence of an expensive logistics network and the skill of the operator. The reason by which these two approaches do not work together may have something to do with one of the possible explanations for the incomplete efficacy of fibrinolytics: the paradoxical prothrombotic effects of thrombolytic agents.21-23 This effect is important because it amplifies the procoagulant state already present in acute coronary syndromes24,25 and shifts the balance between prothrombotic and antithrombotic processes toward thrombosis by counteracting the direct action of the drug and creating a prohibitive environment for interventional procedures. The mechanism of this behavior is not completely clarified, although increased local thrombin concentration appears to play a pivotal role. Fibrinolytic therapy dissolves a thrombus mainly by lysing its fibrin network and thus exposing its thrombin content to the plasma environment. Thrombin exerts an autocatalytic action mainly through the activation of factor V and acts directly as a potent procoagulant at multiple levels of the coagulative cascade. A further, recently proposed, associated mechanism for increased lytic-induced thrombin generation is the plasmin-induced activity of the kallikrein-factor XII system, which is related to direct thrombin-associated factor XII activation.26 The markedly increased thrombin concentration induced by lytics not only acts as a prothrombotic stimulus but also may result in reduced activity of the fibrinolytic cascade by proteolytic activation of the recently discovered plasmatic zymogen Thrombin Activable Fibrinolysis Inhibitor (TAFI), which is converted to a potent carboxypeptidase that inhibits fibrinolysis when exposed to the thrombin-thrombomodulin complex.27
Lytics, platelets, and antiplatelet treatment Another one of the major prothrombotic mechanisms is thrombin-mediated platelet activation. Platelets play a primary role at the beginning of coronary thrombus formation by adhering to the exposed subendothelium and aggregating into the white clot28,29 as well as releasing a number of procoagulant and proaggregatory
substances including inhibitors of plasmin, such as plasminogen activator inhibitor-1. Moreover, their membranes offer an ideal phospholipidic surface on which plasma coagulation factors can efficiently interact.30 Fibrinolytics do not directly dissolve platelet aggregates; on the contrary, they lead to an increased platelet activation and aggregation by thrombin generation that is ultimately proportional to their lytic activity. The standard medical approach to AMI includes aspirin as the antiplatelet agent. Its clinical efficacy is as well known3 as its limits, the most important of which is its weak and incomplete antiaggregatory effect. At pharmacologic dosages, aspirin blocks the cyclo-oxygenase enzyme, only one of the multiple mechanisms leading to the activation of GP IIb/IIIa, a membrane integrin molecule that acts as the final common receptor for a number of the adhesive proteins (principally fibrinogen) mediating aggregation. The substances able to block, or to compete with the ligands of, platelet GP IIb/IIIa receptors directly and substantially inhibit the platelet-platelet interaction induced by virtually all of the agonists and potently prevent the formation of the intraluminal white thrombus without affecting adhesion. Moreover, the red component of the intracoronary thrombus also may be reduced. The functional correlations between activated platelets and the plasma phase of coagulation suggests that a potent antiplatelet intervention could greatly diminish thrombin generation and ultimately exert a significant anticoagulant effect. Recently, another major beneficial effect has been proposed for GP IIb/IIIa antagonists: that is, the ability to reduce thrombus load without creating a concomitant prothrombotic stimulus. This “dethrombotic” action is thought to be based on the ability to displace the fibrinogen already bound to the GP IIb/IIIa receptor in the fibrinogen-platelet network because the affinity constant of the blocking agent is greater than that of fibrinogen binding. Furthermore, two other indirect mechanisms associated with platelet inhibition may facilitate the dissolution of a forming thrombus: the decreased activity of factor XIII, which is critical for fibrin stabilization and the subsequent clot retraction together with the “inside” message of GP IIb/IIIa receptor activation to the platelets, and the decreased activity of the plasminogen activator inhibitor. The former action leaves the clot soft and more penetrable by lytics, and the latter makes the thrombolytic pathway more efficient.
New antiplatelet agents A clinically heterogenous group of these ideal substances is now available for clinical evaluation. They include a chimeric antibody fragment directed against the receptor (abciximab), cyclic peptide inhibitors (integrelin), and smaller synthetic nonpeptide mole-
American Heart Journal Volume 138, Number 2, Part 2
cules mainly for parenteral short-term infusion (tirofiban, lamifiban) but recently also available for oral long-term administration (sibrafiban, orbofiban, and others). Abciximab is the only one that is approved for clinical use and was initially tested in the setting of percutaneous coronary interventions at high risk for thrombotic complications, for which it showed a significantly prolonged clinical beneficial effect (up to 3 years of follow-up).31-33 Other agents have been studied in the different clinical context of unstable angina and non–Q-wave myocardial infarction, giving somewhat different but directionally consistent results that favor the new approach.34-37 Considered as a whole, the data from the major randomized placebo-controlled clinical trials in patients at high risk for coronary thrombotic occlusion because of spontaneous or procedural atherosclerotic plaque damage document an overall 20% decrease in the death and nonfatal infarction rate at 30 days in the groups treated with GP IIb/IIIa inhibitors associated with standard therapy than in those receiving standard aspirin plus heparin alone. Physiopathologic considerations and clinical data from studies involving thousands of patients with acute coronary syndromes strongly support the potential usefulness of GP IIb/IIIa antagonists also as an adjunct to thrombolytic therapy in AMI.
Lytics and GP IIb/IIIa antagonists Over the last 10 years, a number of observations obtained in the animal (mainly dog) models have shown that the association of fibrinolytic agents with abciximab in experimental AMI leads to more rapid, complete, and sustained coronary reperfusion, without any significant increase in hemorrhagic complications.38-40 They also suggest that these beneficial effects could be obtained even if the lytic doses were reduced to half those used in the standard regimens, thus decreasing the number of hemorrhagic complications and further improving the net clinical benefit and cost of the therapy. Strongly stimulated by such compelling experimental data, the use of GP IIb/IIIa inhibitors as an adjunct therapy to lytics in patients with ST-segment elevation MI is now under active investigation. Three small clinical pilot studies evaluating the combined therapy at full lytic doses have so far been published.41-43 In the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 Pilot Study, abciximab was administered to 60 patients at ascending doses and at different times (from 3 to 15 hours) after the initiation of recombinant tissue-type plasminogen activator (r-TPA) infusion. This safety study showed that the profound inhibition of platelet aggregation induced by the drug was not associated with a higher bleeding rate than that observed in 10 control patients. Although not designed
Ferrario et al S123
to examine the efficacy of abciximab, the study indicated an acute (90 minutes) coronary patency rate (TIMI grade 2-3 flow) of approximately 90% in the combined therapy group versus approximately 55% in the lytics group, as well as a surprisingly low rate of ischemic events in the patients who were treated with the higher dose of GP IIb/IIIa inhibitor. The Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) Trial was a randomized, double-blind, placebo-controlled study that compared the reperfusion rate of the infarct-related artery in 353 patients with AMI treated with fibrinolytic therapy (rTPA or streptokinase at full doses) plus lamifiban or lytics alone in comparison with placebo. Lamifiban improved patency and reduced the time to steady-state reperfusion studied by means of continuous 12-lead STsegment electrocardiographic monitoring; however, the bleeding rate in the patients treated with the combined therapy was higher, and there was no clear improvement in clinical outcome. The authors concluded that a larger sample of patients was needed to draw any significant conclusions about the clinical efficacy of the drug in this setting. In the Integrelin to Manage Platelet Aggregation to Combat Thrombosis After Myocardial Infarction (IMPACT-AMI) Trial, the association of different doses of integrelin with full-dose r-TPA was compared with rTPA alone in 180 patients with AMI within the 6 hours after the onset of symptoms. Integrelin improved the primary angiographic end point (percentage of patients with TIMI grade 3 flow) from 39% to 66% in comparison with placebo, and the median time to ST-segment recovery was reduced from 116 minutes to 65 minutes. No significant differences were observed in the incidence of severe bleeding or of a complex composite clinical end point (death, reinfarction, stroke, pulmonary edema, new heart failure, or revascularization procedures). The authors suggest that the study was too small to fully address the safety and real clinical efficacy of the association, although one intracranial hemorrhage occurred with the highest dose of GP IIb/IIIa inhibitor. Data derived from previous studies of GP IIb/IIIa inhibitors (not associated with lytics) have indicated the critical role of heparin in hemorrhagic events, but the prohemorrhagic potential of full-dose lytics plus potent antiplatelet agents is a fundamental issue because it could exceed the antithrombotic advantage and reduce the net clinical benefit of the combined approach. This important safety concern still has to be definitively addressed. Another aspect suggesting that it is worth exploring the potential efficacy of GP IIb/IIIa inhibitors in conjunction with reduced doses of fibrinolytics is the possibility of avoiding the creation of the unfavorable prothrombotic milieu related to the level of plasminogen
American Heart Journal August 1999
S124 Ferrario et al
activation induced by the drug. This substantial beneficial effect might modify the current dichotomic approach to AMI by overcoming the need to make an immediate choice between the alternative options of systemic fibrinolysis or primary PTCA, and maximizing the advantages of their sequential use. On the basis of this novel strategic scenario, patients with AMI could be rapidly treated with the low-dose lytic and GP IIb/IIIa antagonist combination, in order to obtain the best pharmacological result, and subsequently transferred to the catheterization laboratory for coronary angiography and catheter revascularization, if necessary, without any treatment delay and in the most effective antithrombotic condition—thus dramatically reducing procedural complications. Two large, multicenter, randomized studies are currently comparing the clinical effects of the combined treatment (abciximab plus low-dose thrombolytic) and full-dose thrombolytic alone, both associated with aspirin and heparin. Both studies are preliminary dosefinding and dose-confirmation phase II trials with a rather complex design aimed at identifying the most promising approach to test against standard lytic therapy in a subsequent phase III trial. The TIMI-14 phase II study is extremely articulate. It initially considered 14 different reperfusion regimens, including r-TPA alone, abciximab alone, and a number of reduced-dose fibrinolytic therapies based on different kinds of lytics (r-TPA, streptokinase, reteplase [r-PA]) at different doses and according to different strategies of administration, associated with abciximab, aspirin, and reduced-dose heparin. Very low heparin administration was also studied, as well as low-dose bolus abciximab. The preliminary results confirm that abciximab plus reduced-dose fibrinolytic (50 mg r-TPA) and low-dose heparin increases TIMI grade 3 flow from 45% to 67% at 60 minutes and from 58% to 73% at 90 minutes in comparison with the full-dose lytic approach. No increased risk of bleeding complications was observed; on the contrary, an unacceptable hemorrhagic risk was associated with streptokinase therapy.44 The GUSTO IV Pilot study (SPEED) evaluated escalating doses of only one fibrinolytic agent (r-PA) in conjunction with abciximab against abciximab alone or full-dose r-PA alone, in all cases associated with aspirin and low-dose heparin. The preliminary results indicate that the new treatment (r-PA 5U plus 5U plus abciximab) induces an early and complete reperfusion (TIMI grade 3 flow at 60 minutes 68%), without any significant increase in hemorrhagic complications.45 The phase III TIMI-14 and GUSTO-IV AMI trials are ongoing. In each of these studies the most promising new drug combination will be tested against standard lytic therapy to evaluate its potential advantages with regard to hard clinical end points. In particular, the primary objective of the GUSTO-IV AMI trial is to compare
the effect of abciximab associated with 5 U r-PA plus 5 U double bolus plus low-dose, weight-adjusted heparin versus conventional 10 U plus 10 U double bolus r-PA with standard-dose heparin (as control) on short-term (30 days) all-cause mortality. Their results should define the significance of this combined pharmacologic strategy.
References 1. De Wood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303(16):897-902. 2. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-401. 3. ISIS-2 (Second international study of infarct survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 1988;2:349-60. 4. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indication for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994;343:311-22. 5. 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;329:1615-22. 6. Simes RJ, Topol EJ, Holmes DR, et al, for the GUSTO-I Investigators. The link between the angiographic substudy and mortality outcomes in a large randomized trial myocardial reperfusion: the importance of early and complete infarct artery reperfusion. Circulation 1995;91:1923-8. 7. GUSTO-III Investigators. An international, randomized comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997;337:1118-23. 8. Ohman EM, Sigmon K, Wall TC. Why do people die after thrombolytic therapy? Circulation 1989;80(suppl II):II-349. 9. Ohman EM, Califf RM, Topol EJ, et al. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction: TAMI study group. Circulation 1990;82:781-91. 10. Topol EJ, Califf RM, George BS, et al, for the Thrombolysis and Angioplasty in Myocardial Infarction Study Group. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987;317:581-8. 11. Simoons ML, Arnold AER, Betriu A, et al. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous transluminal coronary angioplasty. Lancet 1988;1:197-203. 12. TIMI Research Group. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction: TIMI-IIA results. JAMA 1988;260:2849-58. 13. Holmes DR, Topol EJ. Reperfusion momentum: lessons from the randomized trials of immediate coronary angioplasty for acute myocardial infarction. J Am Coll Cardiol 1989;14:1572-8. 14. SWIFT Trial Study Group. SWIFT trial of delayed elective intervention vs conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. Br Med J 1991;302:555-60. 15. Califf RM, Topol EJ, George BG, et al. Characteristics and outcome
American Heart Journal Volume 138, Number 2, Part 2
16.
17.
18.
19.
20.
21.
22.
23.
24. 25. 26.
27.
28.
29.
30. 31.
32.
of patients in whom reperfusion with intravenous tissue-type plasminogen activator fails: results of the thrombolysis and angioplasty in myocardial infarction: TAMI I trial. Circulation 1988;77:1090-9. Abbottsmith CW, Topol EJ, George BG, et al. Fate of patients with acute myocardial infarction with patency of the infarct-related vessel achieved with successful thrombolysis vs rescue angioplasty. J Am Coll Cardiol 1990;16:770-8. Gibbons RJ, Holmes DR, Reeder GS, et al. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction. N Engl J Med 1993;328:685-91. Ziljistra F, Jan de Boer M, Hoorntje JCA, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993;328:680-4. Grines RJ, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673-9. The GUSTO II Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator and recombinant hirudin with heparin for acute myocardial infarction. N Engl J Med 1997;336:1621-8. Rapold JH, De Bono D, Arnold AER, et al, for the European Cooperative Study Group. Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase: correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. Circulation 1992;85:928-34. Rapold JH, Brimaudo V, Declerck PJ, et al. Plasma levels of plasminogen activator inhibitor type 1, B-thromboglobulin and fibrinopeptide A before, during and after treatment of acute myocardial infarction with alteplase. Blood 1991;78:1490-5. Merlini PA, Bauer KA, Oltrona L, et al. Thrombin generation and activity during thrombolysis and concomitant heparin therapy in patients with acute myocardial infarction. J Am Coll Cardiol 1995;25(1):203-9. Rennie JA, Ogston D. Changes in coagulation factors following acute myocardial infarction in man. Haemostasis 1976;5:258-64. Gidron E, Margalit R, Oliven A, et al. Effect of myocardial infarction on components of fibrinolytic system. Br Heart J 1977;39:19-24. Hoffmeister HM, Szabo S, Kastner C, et al. Thrombolytic therapy in acute myocardial infarction: comparison of procoagulant effects of streptokinase and alteplase regimens with focus on the kallikrein system and plasmin. Circulation 1998;98:2527-33. Wang W, Boffa MB, Bajzar L, et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998;273(42):27176-81. Fuster V, Lewis A. Conner memorial lecture: mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994;90:2126-46. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242-50. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: emerging platelet preeminence. Circulation 1998;97:211-8. 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;330:956-61. The EPILOG Investigators. Effect of the platelet glycoprotein IIb/IIIa
Ferrario et al S125
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
receptor inhibitor abciximab with lower heparin dosages on ischemic complications of percutaneous coronary revascularization. N Engl J Med 1997;336:1689-96. The CAPTURE Investigators. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 1997;349:1429-35. Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498-505. Theroux P. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM-PLUS) Study Investigators. Inhibition of the glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and nonQ wave myocardial infarction. N Engl J Med 1998;338:1488-97. The PARAGON Investigators. International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina. Circulation 1998;97:2386-95. The PURSUIT Trial Investigators. Inhibition of glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndrome. N Engl J Med 1998;339:436-43. 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;77:670-7. Yasuda T, Gold HK, Leinbach RC, et al. Lysis of plasminogen activator-resistant platelet-rich coronary artery thrombus with combined bolus injection of recombinant tissue-type plasminogen activator and antiplatelet GP IIb/IIIa antibody. J Am Coll Cardiol 1990;7:1728-35. Mickelson JK, Simpson PJ, Cronin M, et al. Anti-platelet antibody 7E3 Fab prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model. Circulation 1990;81:617-27. 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;22:381-9. 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(7):2003-10. 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. Circulation 1997;95:846-54. Antman EM, Giugliano RP, McCabe CH, et al, for the TIMI 14 Investigators. Abciximab (ReoPro) potentiates thrombolysis in ST elevation myocardial infarction: results of the TIMI 14 Trial. J Am Coll Cardiol 1998;31:191A. Ohman EM, Lincoff AM, Bode C, et al. Enhanced early reperfusion at 60 minutes with low-dose reteplase combined with full dose abciximab in acute myocardial infarction: preliminary results from the GUSTO-4 Pilot (SPEED) dose-ranging trial. Circulation 1998;98: [Suppl.I]:504.
Systemic fibrinolysis and primary coronary angioplasty represent the cornerstone of the pharmacologic management and of the interventional approach, respectively, of patients with acute myocardial infarction (MI). They have been demonstrated to be highly effective, although their action is hampered by some critical limitations; moreover, their association is prohibitive, owing to the well-documented prothrombotic effect of lytics that greatly increases thrombotic complications of interventional procedures. Platelet glycoprotein (GP) IIb/IIIa blockade has inaugurated a new era in the treatment of coronary artery disease, thanks to its potent antiaggregatory action. The administration of GP IIb/IIIa inhibitors in patients with acute MI is now under active investigation, particularly during interventional procedures and in combination with fibrinolytic agents. The anticoagulant and dethrombotic actions of this potent antiplatelet intervention suggest that its use associated with a low-dose lytic therapy could enhance reperfusion efficacy and reduce reocclusion rate, possibly decreasing hemorrhagic complications. Experimental and preliminary data are encouraging and confirm a role for combined treatment. Ongoing large, ramdomized, controlled clinical trials will clarify the real significance of this promising strategy.
related vessel remains biologically unstable, as documented by both an angiographic reocclusion rate up to 30% and the fact that up to 20% of patients have clinical episodes of recurrent myocardial ischemia during the course of hospitalization. Finally, it is associated with a moderately high occurrence of major hemorrhagic complications including a statistically low but clinically important 0.5% to 1% rate of intracranial hemorrhage.6 The rate of complications has recently slightly increased, probably because of relaxation of exclusion criteria with the aim of extending the benefits of the therapy to a larger number of patients.7 The significant incidence and clinical significance of resistance to fibrinolytics and reocclusion after successful reperfusion remain the weak points of the systemic lytic approach, as pointed out by the higher mortality rate of patients without satisfactory coronary recanalization in the short-term follow-up (13% vs 4%).5,8,9 Recent studies with new and more refined fibrinolytic drugs have failed to document any significant clinical improvement, making further advances by this standard strategy unlikely.
Standard fibrinolytic therapy
Perception of these limitations has encouraged the use of mechanical, catheter-based reperfusion interventions in addition to lytics, including rescue and early percutaneous transluminal coronary angioplasty (PTCA) performed immediately or a few days after fibrinolytic therapy. Unfortunately, the clinical results of the efforts aimed at routinely completing standard thrombolysis with mechanical revascularization have been discouraging, and there has been a high incidence of local hemorrhagic and coronary thrombotic complications associated with the procedure.10-16 Given the unsatisfactory results of PTCA after fibrinolytics, primary PTCA was developed as the only reperfusion intervention in evolving MI, without any previous lytic treatment.17-19 It has been proved to be superior to thrombolysis for achieving rapid coronary patency (patency >90%, TIMI grade 3 flow rate >70%), with a low incidence of severe hemorrhagic complications. However, it is still a matter of discussion whether these striking immediate angiographic results translate into sustained clinical advan-
Rapid dissolution of an occlusive intracoronary thrombus by fibrinolytic agents is the aim of standard medical care for patients with acute MI (AMI) observed 6 to 12 hours after symptom onset.1-4 The intravenous thrombolytic approach leads to 20% relative decrease in 30day mortality rates if compared with no lytic therapy,5,6 and this result is substantially independent of the agent and the clinical characteristics of the patient. Nevertheless, fibrinolytic treatment is hampered by some critical limitations: Adequate coronary patency is achieved in only approximately 50% of patients at 90 minutes; furthermore, it is not always sustained because the infarctFrom Divisione di Cardiologia, IRCCS Policlinico S. Matteo. Reprint requests: Diego Ardissino, MD, Divisione di Cardiologia, Ospedale Maggiore di Parma, Università di Parma, V. Gramsci 14, Parma, Italy. (Am Heart J 1999;138:S121-S125.) Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/98537
Lytics and percutaneous transluminal coronary angioplasty
American Heart Journal August 1999
S122 Ferrario et al
tages, which have been well documented at 1 month but seem to decline after 6 months of follow-up, probably because of the high rate of coronary reocclusion (13%) and restenosis (40%).20 As a consequence, the current strategy for facing AMI consists of a dichotomic approach: pharmacologic reperfusion based on systemic fibrinolysis, which is feasible but has a number of absolute and relative contraindications, discrete results, and definite severe hemorrhagic complications; and mechanical reperfusion by PTCA, which is more effective, at least in the early phase, but unpractical because it is highly dependent on the presence of an expensive logistics network and the skill of the operator. The reason by which these two approaches do not work together may have something to do with one of the possible explanations for the incomplete efficacy of fibrinolytics: the paradoxical prothrombotic effects of thrombolytic agents.21-23 This effect is important because it amplifies the procoagulant state already present in acute coronary syndromes24,25 and shifts the balance between prothrombotic and antithrombotic processes toward thrombosis by counteracting the direct action of the drug and creating a prohibitive environment for interventional procedures. The mechanism of this behavior is not completely clarified, although increased local thrombin concentration appears to play a pivotal role. Fibrinolytic therapy dissolves a thrombus mainly by lysing its fibrin network and thus exposing its thrombin content to the plasma environment. Thrombin exerts an autocatalytic action mainly through the activation of factor V and acts directly as a potent procoagulant at multiple levels of the coagulative cascade. A further, recently proposed, associated mechanism for increased lytic-induced thrombin generation is the plasmin-induced activity of the kallikrein-factor XII system, which is related to direct thrombin-associated factor XII activation.26 The markedly increased thrombin concentration induced by lytics not only acts as a prothrombotic stimulus but also may result in reduced activity of the fibrinolytic cascade by proteolytic activation of the recently discovered plasmatic zymogen Thrombin Activable Fibrinolysis Inhibitor (TAFI), which is converted to a potent carboxypeptidase that inhibits fibrinolysis when exposed to the thrombin-thrombomodulin complex.27
Lytics, platelets, and antiplatelet treatment Another one of the major prothrombotic mechanisms is thrombin-mediated platelet activation. Platelets play a primary role at the beginning of coronary thrombus formation by adhering to the exposed subendothelium and aggregating into the white clot28,29 as well as releasing a number of procoagulant and proaggregatory
substances including inhibitors of plasmin, such as plasminogen activator inhibitor-1. Moreover, their membranes offer an ideal phospholipidic surface on which plasma coagulation factors can efficiently interact.30 Fibrinolytics do not directly dissolve platelet aggregates; on the contrary, they lead to an increased platelet activation and aggregation by thrombin generation that is ultimately proportional to their lytic activity. The standard medical approach to AMI includes aspirin as the antiplatelet agent. Its clinical efficacy is as well known3 as its limits, the most important of which is its weak and incomplete antiaggregatory effect. At pharmacologic dosages, aspirin blocks the cyclo-oxygenase enzyme, only one of the multiple mechanisms leading to the activation of GP IIb/IIIa, a membrane integrin molecule that acts as the final common receptor for a number of the adhesive proteins (principally fibrinogen) mediating aggregation. The substances able to block, or to compete with the ligands of, platelet GP IIb/IIIa receptors directly and substantially inhibit the platelet-platelet interaction induced by virtually all of the agonists and potently prevent the formation of the intraluminal white thrombus without affecting adhesion. Moreover, the red component of the intracoronary thrombus also may be reduced. The functional correlations between activated platelets and the plasma phase of coagulation suggests that a potent antiplatelet intervention could greatly diminish thrombin generation and ultimately exert a significant anticoagulant effect. Recently, another major beneficial effect has been proposed for GP IIb/IIIa antagonists: that is, the ability to reduce thrombus load without creating a concomitant prothrombotic stimulus. This “dethrombotic” action is thought to be based on the ability to displace the fibrinogen already bound to the GP IIb/IIIa receptor in the fibrinogen-platelet network because the affinity constant of the blocking agent is greater than that of fibrinogen binding. Furthermore, two other indirect mechanisms associated with platelet inhibition may facilitate the dissolution of a forming thrombus: the decreased activity of factor XIII, which is critical for fibrin stabilization and the subsequent clot retraction together with the “inside” message of GP IIb/IIIa receptor activation to the platelets, and the decreased activity of the plasminogen activator inhibitor. The former action leaves the clot soft and more penetrable by lytics, and the latter makes the thrombolytic pathway more efficient.
New antiplatelet agents A clinically heterogenous group of these ideal substances is now available for clinical evaluation. They include a chimeric antibody fragment directed against the receptor (abciximab), cyclic peptide inhibitors (integrelin), and smaller synthetic nonpeptide mole-
American Heart Journal Volume 138, Number 2, Part 2
cules mainly for parenteral short-term infusion (tirofiban, lamifiban) but recently also available for oral long-term administration (sibrafiban, orbofiban, and others). Abciximab is the only one that is approved for clinical use and was initially tested in the setting of percutaneous coronary interventions at high risk for thrombotic complications, for which it showed a significantly prolonged clinical beneficial effect (up to 3 years of follow-up).31-33 Other agents have been studied in the different clinical context of unstable angina and non–Q-wave myocardial infarction, giving somewhat different but directionally consistent results that favor the new approach.34-37 Considered as a whole, the data from the major randomized placebo-controlled clinical trials in patients at high risk for coronary thrombotic occlusion because of spontaneous or procedural atherosclerotic plaque damage document an overall 20% decrease in the death and nonfatal infarction rate at 30 days in the groups treated with GP IIb/IIIa inhibitors associated with standard therapy than in those receiving standard aspirin plus heparin alone. Physiopathologic considerations and clinical data from studies involving thousands of patients with acute coronary syndromes strongly support the potential usefulness of GP IIb/IIIa antagonists also as an adjunct to thrombolytic therapy in AMI.
Lytics and GP IIb/IIIa antagonists Over the last 10 years, a number of observations obtained in the animal (mainly dog) models have shown that the association of fibrinolytic agents with abciximab in experimental AMI leads to more rapid, complete, and sustained coronary reperfusion, without any significant increase in hemorrhagic complications.38-40 They also suggest that these beneficial effects could be obtained even if the lytic doses were reduced to half those used in the standard regimens, thus decreasing the number of hemorrhagic complications and further improving the net clinical benefit and cost of the therapy. Strongly stimulated by such compelling experimental data, the use of GP IIb/IIIa inhibitors as an adjunct therapy to lytics in patients with ST-segment elevation MI is now under active investigation. Three small clinical pilot studies evaluating the combined therapy at full lytic doses have so far been published.41-43 In the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 Pilot Study, abciximab was administered to 60 patients at ascending doses and at different times (from 3 to 15 hours) after the initiation of recombinant tissue-type plasminogen activator (r-TPA) infusion. This safety study showed that the profound inhibition of platelet aggregation induced by the drug was not associated with a higher bleeding rate than that observed in 10 control patients. Although not designed
Ferrario et al S123
to examine the efficacy of abciximab, the study indicated an acute (90 minutes) coronary patency rate (TIMI grade 2-3 flow) of approximately 90% in the combined therapy group versus approximately 55% in the lytics group, as well as a surprisingly low rate of ischemic events in the patients who were treated with the higher dose of GP IIb/IIIa inhibitor. The Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) Trial was a randomized, double-blind, placebo-controlled study that compared the reperfusion rate of the infarct-related artery in 353 patients with AMI treated with fibrinolytic therapy (rTPA or streptokinase at full doses) plus lamifiban or lytics alone in comparison with placebo. Lamifiban improved patency and reduced the time to steady-state reperfusion studied by means of continuous 12-lead STsegment electrocardiographic monitoring; however, the bleeding rate in the patients treated with the combined therapy was higher, and there was no clear improvement in clinical outcome. The authors concluded that a larger sample of patients was needed to draw any significant conclusions about the clinical efficacy of the drug in this setting. In the Integrelin to Manage Platelet Aggregation to Combat Thrombosis After Myocardial Infarction (IMPACT-AMI) Trial, the association of different doses of integrelin with full-dose r-TPA was compared with rTPA alone in 180 patients with AMI within the 6 hours after the onset of symptoms. Integrelin improved the primary angiographic end point (percentage of patients with TIMI grade 3 flow) from 39% to 66% in comparison with placebo, and the median time to ST-segment recovery was reduced from 116 minutes to 65 minutes. No significant differences were observed in the incidence of severe bleeding or of a complex composite clinical end point (death, reinfarction, stroke, pulmonary edema, new heart failure, or revascularization procedures). The authors suggest that the study was too small to fully address the safety and real clinical efficacy of the association, although one intracranial hemorrhage occurred with the highest dose of GP IIb/IIIa inhibitor. Data derived from previous studies of GP IIb/IIIa inhibitors (not associated with lytics) have indicated the critical role of heparin in hemorrhagic events, but the prohemorrhagic potential of full-dose lytics plus potent antiplatelet agents is a fundamental issue because it could exceed the antithrombotic advantage and reduce the net clinical benefit of the combined approach. This important safety concern still has to be definitively addressed. Another aspect suggesting that it is worth exploring the potential efficacy of GP IIb/IIIa inhibitors in conjunction with reduced doses of fibrinolytics is the possibility of avoiding the creation of the unfavorable prothrombotic milieu related to the level of plasminogen
American Heart Journal August 1999
S124 Ferrario et al
activation induced by the drug. This substantial beneficial effect might modify the current dichotomic approach to AMI by overcoming the need to make an immediate choice between the alternative options of systemic fibrinolysis or primary PTCA, and maximizing the advantages of their sequential use. On the basis of this novel strategic scenario, patients with AMI could be rapidly treated with the low-dose lytic and GP IIb/IIIa antagonist combination, in order to obtain the best pharmacological result, and subsequently transferred to the catheterization laboratory for coronary angiography and catheter revascularization, if necessary, without any treatment delay and in the most effective antithrombotic condition—thus dramatically reducing procedural complications. Two large, multicenter, randomized studies are currently comparing the clinical effects of the combined treatment (abciximab plus low-dose thrombolytic) and full-dose thrombolytic alone, both associated with aspirin and heparin. Both studies are preliminary dosefinding and dose-confirmation phase II trials with a rather complex design aimed at identifying the most promising approach to test against standard lytic therapy in a subsequent phase III trial. The TIMI-14 phase II study is extremely articulate. It initially considered 14 different reperfusion regimens, including r-TPA alone, abciximab alone, and a number of reduced-dose fibrinolytic therapies based on different kinds of lytics (r-TPA, streptokinase, reteplase [r-PA]) at different doses and according to different strategies of administration, associated with abciximab, aspirin, and reduced-dose heparin. Very low heparin administration was also studied, as well as low-dose bolus abciximab. The preliminary results confirm that abciximab plus reduced-dose fibrinolytic (50 mg r-TPA) and low-dose heparin increases TIMI grade 3 flow from 45% to 67% at 60 minutes and from 58% to 73% at 90 minutes in comparison with the full-dose lytic approach. No increased risk of bleeding complications was observed; on the contrary, an unacceptable hemorrhagic risk was associated with streptokinase therapy.44 The GUSTO IV Pilot study (SPEED) evaluated escalating doses of only one fibrinolytic agent (r-PA) in conjunction with abciximab against abciximab alone or full-dose r-PA alone, in all cases associated with aspirin and low-dose heparin. The preliminary results indicate that the new treatment (r-PA 5U plus 5U plus abciximab) induces an early and complete reperfusion (TIMI grade 3 flow at 60 minutes 68%), without any significant increase in hemorrhagic complications.45 The phase III TIMI-14 and GUSTO-IV AMI trials are ongoing. In each of these studies the most promising new drug combination will be tested against standard lytic therapy to evaluate its potential advantages with regard to hard clinical end points. In particular, the primary objective of the GUSTO-IV AMI trial is to compare
the effect of abciximab associated with 5 U r-PA plus 5 U double bolus plus low-dose, weight-adjusted heparin versus conventional 10 U plus 10 U double bolus r-PA with standard-dose heparin (as control) on short-term (30 days) all-cause mortality. Their results should define the significance of this combined pharmacologic strategy.
References 1. De Wood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303(16):897-902. 2. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-401. 3. ISIS-2 (Second international study of infarct survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 1988;2:349-60. 4. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indication for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994;343:311-22. 5. 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;329:1615-22. 6. Simes RJ, Topol EJ, Holmes DR, et al, for the GUSTO-I Investigators. The link between the angiographic substudy and mortality outcomes in a large randomized trial myocardial reperfusion: the importance of early and complete infarct artery reperfusion. Circulation 1995;91:1923-8. 7. GUSTO-III Investigators. An international, randomized comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997;337:1118-23. 8. Ohman EM, Sigmon K, Wall TC. Why do people die after thrombolytic therapy? Circulation 1989;80(suppl II):II-349. 9. Ohman EM, Califf RM, Topol EJ, et al. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction: TAMI study group. Circulation 1990;82:781-91. 10. Topol EJ, Califf RM, George BS, et al, for the Thrombolysis and Angioplasty in Myocardial Infarction Study Group. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987;317:581-8. 11. Simoons ML, Arnold AER, Betriu A, et al. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous transluminal coronary angioplasty. Lancet 1988;1:197-203. 12. TIMI Research Group. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction: TIMI-IIA results. JAMA 1988;260:2849-58. 13. Holmes DR, Topol EJ. Reperfusion momentum: lessons from the randomized trials of immediate coronary angioplasty for acute myocardial infarction. J Am Coll Cardiol 1989;14:1572-8. 14. SWIFT Trial Study Group. SWIFT trial of delayed elective intervention vs conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. Br Med J 1991;302:555-60. 15. Califf RM, Topol EJ, George BG, et al. Characteristics and outcome
American Heart Journal Volume 138, Number 2, Part 2
16.
17.
18.
19.
20.
21.
22.
23.
24. 25. 26.
27.
28.
29.
30. 31.
32.
of patients in whom reperfusion with intravenous tissue-type plasminogen activator fails: results of the thrombolysis and angioplasty in myocardial infarction: TAMI I trial. Circulation 1988;77:1090-9. Abbottsmith CW, Topol EJ, George BG, et al. Fate of patients with acute myocardial infarction with patency of the infarct-related vessel achieved with successful thrombolysis vs rescue angioplasty. J Am Coll Cardiol 1990;16:770-8. Gibbons RJ, Holmes DR, Reeder GS, et al. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction. N Engl J Med 1993;328:685-91. Ziljistra F, Jan de Boer M, Hoorntje JCA, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993;328:680-4. Grines RJ, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673-9. The GUSTO II Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator and recombinant hirudin with heparin for acute myocardial infarction. N Engl J Med 1997;336:1621-8. Rapold JH, De Bono D, Arnold AER, et al, for the European Cooperative Study Group. Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase: correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. Circulation 1992;85:928-34. Rapold JH, Brimaudo V, Declerck PJ, et al. Plasma levels of plasminogen activator inhibitor type 1, B-thromboglobulin and fibrinopeptide A before, during and after treatment of acute myocardial infarction with alteplase. Blood 1991;78:1490-5. Merlini PA, Bauer KA, Oltrona L, et al. Thrombin generation and activity during thrombolysis and concomitant heparin therapy in patients with acute myocardial infarction. J Am Coll Cardiol 1995;25(1):203-9. Rennie JA, Ogston D. Changes in coagulation factors following acute myocardial infarction in man. Haemostasis 1976;5:258-64. Gidron E, Margalit R, Oliven A, et al. Effect of myocardial infarction on components of fibrinolytic system. Br Heart J 1977;39:19-24. Hoffmeister HM, Szabo S, Kastner C, et al. Thrombolytic therapy in acute myocardial infarction: comparison of procoagulant effects of streptokinase and alteplase regimens with focus on the kallikrein system and plasmin. Circulation 1998;98:2527-33. Wang W, Boffa MB, Bajzar L, et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998;273(42):27176-81. Fuster V, Lewis A. Conner memorial lecture: mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994;90:2126-46. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242-50. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: emerging platelet preeminence. Circulation 1998;97:211-8. 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;330:956-61. The EPILOG Investigators. Effect of the platelet glycoprotein IIb/IIIa
Ferrario et al S125
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
receptor inhibitor abciximab with lower heparin dosages on ischemic complications of percutaneous coronary revascularization. N Engl J Med 1997;336:1689-96. The CAPTURE Investigators. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 1997;349:1429-35. Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498-505. Theroux P. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM-PLUS) Study Investigators. Inhibition of the glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and nonQ wave myocardial infarction. N Engl J Med 1998;338:1488-97. The PARAGON Investigators. International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina. Circulation 1998;97:2386-95. The PURSUIT Trial Investigators. Inhibition of glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndrome. N Engl J Med 1998;339:436-43. 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;77:670-7. Yasuda T, Gold HK, Leinbach RC, et al. Lysis of plasminogen activator-resistant platelet-rich coronary artery thrombus with combined bolus injection of recombinant tissue-type plasminogen activator and antiplatelet GP IIb/IIIa antibody. J Am Coll Cardiol 1990;7:1728-35. Mickelson JK, Simpson PJ, Cronin M, et al. Anti-platelet antibody 7E3 Fab prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model. Circulation 1990;81:617-27. 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;22:381-9. 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(7):2003-10. 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. Circulation 1997;95:846-54. Antman EM, Giugliano RP, McCabe CH, et al, for the TIMI 14 Investigators. Abciximab (ReoPro) potentiates thrombolysis in ST elevation myocardial infarction: results of the TIMI 14 Trial. J Am Coll Cardiol 1998;31:191A. Ohman EM, Lincoff AM, Bode C, et al. Enhanced early reperfusion at 60 minutes with low-dose reteplase combined with full dose abciximab in acute myocardial infarction: preliminary results from the GUSTO-4 Pilot (SPEED) dose-ranging trial. Circulation 1998;98: [Suppl.I]:504.