“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
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