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IIIa inhibitor therapy in acute ST-segment elevation myocardial infarction: current practice and future trends
The Use of Glycoprotein IIb/IIIa Inhibitor Therapy in Acute ST-Segment Elevation Myocardial Infarction: Current Practice and Future Trends Kevin R. Campbell,
MD,
E. Magnus Ohman, MD, Warren Cantor, A. Michael Lincoff, MD
MD,
and
The goal of therapy in acute myocardial infarction is complete and timely restoration of coronary blood flow. Current strategies for reperfusion fail to achieve ideal results and resolution of ischemia in all patients. The platelet plays a pivotal role in the pathophysiology of an acute myocardial infarction, and antiplatelet therapy has been shown to improve clinical outcomes. The final common pathway for platelet activation and aggregation in acute myocardial infarction is the activation of the glycoprotein (GP) IIb/IIIa receptor. Newer reperfusion strategies target the GP IIb/IIIa receptor, thereby preventing the prothrombotic effects of platelets in an acute myocardial infarction. In the past decade, several strategies targeting the use of GP IIb/IIIa inhibitors have been evaluated. GP IIb/IIIa inhibitors have been shown to improve angiographic Thrombolysis in Myocardial Infarction (TIMI) 3 flow rates when used as reperfusion therapy given with heparin and aspirin as compared with heparin and aspirin alone. When GP IIb/IIIa inhibitors are used with full-dose fibrinolytics, early studies have suggested a trend toward more rapid and more complete reperfusion in an acute myocardial infarction.
Later trials have examined the use of GP IIb/IIIa inhibitors in conjunction with reduced-dose fibrinolytics. Results from TIMI 14 and Global Use of Strategies to Open occluded arteries–IV pilot trials support the use of combination therapy with reduced- dose fibrinolytics and the GP IIb/IIIa inhibitor abciximab. Given the promising role of GP IIb/IIIa inhibitor therapy in acute myocardial infarction, investigators questioned the need for concomitant antithrombin therapy. However, data from several investigations suggest that antithrombin therapy is required when GP IIb/IIIa inhibitors are used with fibrinolytics, although it appears that the dose of heparin may be reduced. Finally, recent investigations have addressed the safety and efficacy of facilitated early percutaneous intervention. In this strategy, patients presenting with an acute myocardial infarction are treated with reduced-dose fibrinolytics and GP IIb/IIIa inhibitors and are taken to the interventional cardiac catheterization laboratory within the first 60 minutes of therapy. 䊚2000 by Excerpta Medica, Inc. Am J Cardiol 2000;85:32C–38C
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ful reperfusion.3 In contrast, studies evaluating primary angioplasty during an acute MI suggest that TIMI grade 3 flow is achieved in 80% of cases when performed in all centers. This rate of reperfusion is significantly less in more complex patients and in the hands of less-experienced operators. Furthermore, primary angioplasty confers a 10 –13% risk of reocclusion and is associated with several procedural complications.4,5 Given that neither strategy provides ideal reperfusion and resolution of ischemia in all patients, there are many investigations underway to evaluate novel approaches to achieve coronary reperfusion that is more complete and more expedient with less risk of reocclusion and reinfarction. Pathologic mechanisms involved in the acute coronary syndrome include plaque rupture, subsequent platelet aggregation, and thrombosis. The atherosclerotic plaque is covered by a fibrous cap that ruptures and exposes highly thrombogenic contents such as collagen, fibronectin, fibrinogen, and other substances to platelets.6 The platelets are stimulated and adhesion, activation, and aggregation subsequently occur. The aggregated platelets form a surface that promotes the generation of thrombin, which in turn converts
he goal of therapy in acute myocardial infarction (MI) is complete and timely restoration of coronary blood flow.1 In current practice, the 2 means for achieving reperfusion are primary percutaneous coronary angioplasty and medical fibrinolysis. Data from the Fibrinolytic Therapy Trialists’ (FTT) Collaborative group demonstrate that fibrinolytic agents improve survival by nearly 30% if given within 6 hours of symptom onset and by 50% if given within the first 2 hours of presentation.2,3 However, current fibrinolytic strategies fail to restore normal anterograde flow (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) at 60 minutes in almost 60% of cases. An additional 20% of patients fail to reperfuse at the myocardial tissue level. Moreover, 4 – 6% of patients experience early reinfarction despite initially successFrom the Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina, USA (KRC, EMO, WC); and Cleveland Clinic Foundation, Cleveland, Ohio, USA (AML). Dr. Campbell is funded by the Division of Cardiology at Duke University Medical Center. Dr. Cantor is funded by a grant from the Royal College of Physicians and Surgeons of Canada. Address for reprints: E. Magnus Ohman, MD, Duke Clinical Research Institute, 2400 Pratt Street, Room 0311, Durham, NC 27705.
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©2000 by Excerpta Medica, Inc. All rights reserved.
0002-9149/00/$ – see front matter PII S0002-9149(00)00877-8
fibrinogen to fibrin. The fibrin generation further stimulates platelet activation and a cycle of the prothrombotic state develops which results in occlusion of the coronary artery and the clinical phenomenon of an acute MI. Given the pivotal role of the platelet in the pathophysiology of acute MI, it is not surprising that antiplatelet therapies have been investigated and have been shown to improve clinical outcomes. Aspirin inhibits platelet activation by the cyclooxygenase pathway, but platelet activation continues to occur by other pathways. Unlike activation, platelet aggregation occurs by only one pathway and requires the binding of fibrinogen or von Willebrand factor to the specific glycoprotein IIb/IIIa (GP IIb/IIIa) receptor on the platelet surface.7 Platelet activation induces a conformational change in the receptor and allows for binding to fibrinogen or von Willebrand factor and subsequent aggregation. It would therefore seem reasonable that a strategy that targets the final common pathway for platelet aggregation via the GP IIb/IIIa receptor would most likely prevent the prothrombotic effects of platelets in acute MI. In the past decade, many advances have been made in the area of platelet inhibition in acute MI culminating in the development, evaluation, and clinical use of drugs that specifically inhibit the GP IIb/IIIa receptor on the platelet. Recent investigations have examined the use of combinations of GP IIb/IIIa inhibitors and fibrinolytic agents in establishing superior reperfusion success in acute MI. This review will focus on the trials leading up to these most recent investigations and closely examine current trials with an emphasis on new pharmacologic combinations to establish reperfusion. The purpose of this article is: (1) to review the use of GP IIb/IIIa inhibitors alone in the treatment of acute MI; (2) to review the use of GP IIb/IIIa inhibitors as adjunct therapy to both full- and reduced-dose fibrinolytics in acute MI; (3) to provide a rationale for the continued use of antithrombin therapy in conjunction with GP IIb/IIIa inhibition; and (4) to provide a brief update of preliminary data from current trials evaluating the use of combination therapy for facilitated percutaneous coronary intervention.
GLYCOPROTEIN IIB/IIIA INHIBITORS ALONE FOR REPERFUSION IN ACUTE MI Several investigators have pursued the use of GP IIb/IIIa inhibitors as sole reperfusion therapy in acute MI. Early researchers helped to provide a link to the role of the platelet and platelet-generated substances to the vascular biology of an acute MI. Platelets are at the core of the coronary thrombus and play a large role in the progression of the acute coronary syndrome. Willerson et al8 demonstrated that the platelet and specific platelet mediators such as serotonin and thromboxanes were essential to the pathophysiology of the acute coronary syndrome. These investigators were able to document the dynamic responsiveness and ongoing release of prothrombotic mediators by the platelet in the canine model of an acute coronary syndrome.8 This early work led to more sophisticated
animal experiments that focused on the effects of platelet inhibition on the progression of an acute MI. Animal experiments by Gold et al9 used a dog model of left anterior descending coronary artery occlusion to evaluate the efficacy of placebo, aspirin alone, or aspirin plus a GP IIb/IIIa inhibitor (c7E3) in establishing reperfusion. All dogs received heparin, and the results demonstrated that in the group treated with aspirin plus GP IIb/IIIa inhibitors there was an 80% reperfusion rate at 50 minutes. In none of the animals in the other 2 groups was any degree of reflow established.9 This early work sparked interest in the potential use of GP IIb/IIIa inhibitors without fibrinolytics and/or percutaneous intervention to establish adequate reperfusion in acute MI. Following these data, several clinical trials in humans explored GP IIb/IIa inhibitors alone in response to frequent delays in getting patients with acute MI to the catheterization laboratory for primary percutaneous transluminal coronary angioplasty (Figure 1). In the early 1990s, multiple clinical trials began to investigate the role of GP IIb/IIIa inhibition in humans in non–ST-elevation acute coronary syndromes. Altogether, ⬎10 clinical trials, which included ⬎35,000 patients, have been performed. Some of these trials involved patients with unstable angina or non–Q-wave MI as well as patients undergoing percutaneous coronary interventions. Strikingly, all of these trials demonstrated benefit in the reduction of the composite of death or MI for the combination of GP IIb/IIIa inhibitor versus placebo. The Glycoprotein Receptor Antagonist in MI Patency Evaluation (GRAPE) trial was designed to evaluate the early use of GP IIb/IIIa inhibitors in inducing reperfusion before primary percutaneous transluminal coronary angioplasty for acute MI.10 The trial included 60 patients with acute MI and planned primary percutaneous transluminal coronary angioplasty. The patients were given aspirin, heparin, and an abciximab bolus and infusion in the emergency department. In the catheterization laboratory, coronary patency (as evidenced by TIMI grade 2 or 3 flow) at 45 minutes after drug administration was nearly 40% with complete reperfusion (TIMI grade 3 flow) in 18%. Standard therapy, which included aspirin and heparin, had an overall patency rate of only 27% and TIMI grade 3 flow rates of only 8%.10 These findings suggested a dethrombosis role of the GP IIb/IIIa inhibitors. These early findings prompted the inclusion of GP IIb/IIIa inhibitors alone in the design of multiple clinical trials in acute MI. Although some of these trials are currently ongoing, preliminary results have shed some light on the reperfusion capabilities of the GP IIb/IIIa inhibitors alone. Although designed to evaluate combination therapy with thrombolytic agents, the TIMI-14 trial and the Strategies for Patency Enhancement in the Emergency Department (SPEED) trial— which is the Global Use of Strategies to Open occluded arteries (GUSTO)–IV pilot study—included control arms in which patients were treated with abciximab, aspirin, and heparin without concomitant fibrinolytic agents before catheterization.11,12 REVASCULARIZATION IN ACUTE MI AND STROKE
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FIGURE 1. Angiographic patency rates when abciximab is given for acute myocardial infarction (MI) as sole reperfusion therapy. The results of 6 separate studies with angiography done at 5 different time points are shown in the graph. The light gray bars indicate the Thrombolysis in Myocardial Infarction (TIMI)-3 flow rates and the dark gray bars indicate the patency (TIMI 2–3 flow) rates at the different time points. The number of patients assessed at each time point is provided under the study names.
In the dose-finding phase of TIMI-14, patients were randomized within 12 hours of acute MI to receive either standard-dose tissue plasminogen activator (t-PA), reduced-dose t-PA plus abciximab, streptokinase plus abciximab, or abciximab alone. Results from TIMI-14 revealed that only 32% of patients treated with abciximab alone had TIMI grade 3 flow in the infarct-related artery at 90 minutes as compared with 57% of patients treated with t-PA alone.13 Although this rate was low, it exceeded previously reported rates of TIMI grade 3 flow in patients treated with heparin and aspirin and was similar to those reported for abciximab given in conjunction with streptokinase. Furthermore, data from the combination arms of the study revealed significant improvements in artery patency rates and provided more support for the utility of GP IIb/IIIa inhibitors in acute MI.13 These results will be discussed further in another section of this review. In the SPEED trial, patients were randomized to abciximab alone, abciximab plus reteplase (r-PA), and r-PA alone.12,14 The abciximab-alone arm again provided an opportunity to evaluate the efficacy of GP IIb/IIIa inhibitors as sole reperfusion therapy in acute MI. Coronary angiography was performed at 60 minutes and angiographic data from SPEED revealed that 52% of the abciximab-only patients had either TIMI grade 2 or 3 flow as compared with nearly 76% of patients who received combination therapy with rPA.14,15
GLYCOPROTEIN IIB/IIIA INHIBITORS AS ADJUNCT TO FIBRINOLYTIC THERAPY IN ACUTE MI In the early 1990s, many animal studies were conducted to evaluate safety and efficacy of the combination of GP IIb/IIIa inhibitors and fibrinolytics. Us34C THE AMERICAN JOURNAL OF CARDIOLOGY姞
ing a canine model, Gold et al15 demonstrated an increase in speed of reperfusion and a decrease in fibrinolytic dose when combining c7E3 and t-PA. Other groups were able to replicate these findings, and further animal studies were able to demonstrate the ability of combination therapy to prevent reocclusion after successful thrombolysis.16 These animal studies demonstrated that the use of fibrinolytic agents in conjunction with GP IIb/IIIa inhibitors in an experimental model of acute MI led to more rapid, more complete, and more sustained coronary reperfusion without any significant increase in bleeding risks. These promising animal experiments prompted study in human subjects. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI)– 8 pilot study was the first human investigation to evaluate the combined use of GP IIb/IIIa inhibitors with fibrinolytics in acute MI.17 TAMI-8 included 60 patients presenting within 6 hours of acute MI. The patients were given t-PA (3-hour infusion) followed 15 hours later by a bolus and infusion of c7E3 (abciximab). Patients were given varying doses of c7E3 starting at 0.1 mg/kg and sequentially increasing to 0.25 mg/kg. As safety data were acquired, the timing of c7E3 administration was shortened to 3 hours after t-PA initiation. Aspirin was given as early as possible and full-dose heparin was given to the groups receiving c7E3 at 15 hours and reduced-dose heparin was given to the groups receiving c7E3 at 3 hours after fibrinolytic.17 Angiographic TIMI flow grade as well as clinical parameters such as death, reinfarction, and need for urgent intervention were the primary endpoints examined in the trial. Safety issues such as major bleeding episodes and thrombocytopenia were also analyzed. Results revealed TIMI grade 2 or 3 flow in 56% of the control
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patients and in 92% and 96% of patients receiving any or the highest dose of c7E3, respectively.17 The rate of major bleeding was comparable in the groups, with no significant increase in the patients given higher doses of c7E3. However, of the patients who underwent coronary artery bypass graft surgery after infarction, the bleeding rates in the c7E3 patients were higher.17 This study, although small in size, spurred other investigations into the expanded role of GP IIb/IIIa inhibitors in acute MI. The Integrelin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction (IMPACT-AMI) trial evaluated the role of eptifibatide as an adjunct to t-PA, aspirin, and heparin in acute MI.18 The trial included 180 patients enrolled within 6 hours of acute MI. In the dose-finding phase, the subjects were randomized to receive either placebo or eptifibatide in increasing doses within 10 minutes of front-loaded t-PA. In a second phase, the patients were randomized to receive either placebo or the highest dose of eptifibatide from phase I that was considered safe. The rate of TIMI grade 3 flow at 90 minutes was the primary endpoint. Multiple secondary endpoints were examined, including composite of death, reinfarction, need for revascularization, congestive heart failure, and bleeding. Angiographic results revealed that 66% of eptifibatide patients and 39% of control patients had TIMI grade 3 flow.18 The incidence of death and reinfarction was 7.3% for the placebo-treated patients, 8% for the patients treated with eptifibatide, and 7.8% for the group treated with the highest eptifibatide doses. The composite outcome was seen in 41.8% of the placebo group, 44.8% in the eptifibatide patients, and 43.1% in the highest-dose eptifibatide group. Of note, the median time to ST segment recovery by continuous 12lead electrocardiographic monitoring was reduced from 116 minutes to 65 minutes in the eptifibatide group. As in TAMI-8, there was no increased bleeding rate, although the trial was not sufficiently powered to detect differences in clinical outcomes. However, the results of IMPACT-AMI did suggest possible benefits gained with the addition of GP IIb/IIIa inhibitors to fibrinolytic therapy in acute MI. Other investigators led by Simoons19 evaluated the combination of eptifibatide with streptokinase for acute MI in a similar double-blinded, placebo-controlled trial. The 181 patients in this study were randomized to receive escalating doses of eptifibatide in addition to streptokinase. The results demonstrated that the rate of TIMI grade 2 or 3 flow was improved with eptifibatide and that TIMI grade 3 flow alone was significantly improved as well.19 However, the improved reperfusion rates with escalating doses of eptifibatide were associated with unusually high bleeding rates in patients receiving the higher doses of a GP IIb/IIIa inhibitor. The difference in bleeding rates in this trial using streptokinase and an earlier trial using t-PA began to prompt interest in the precise interactions between the GP IIb/IIIa inhibitors and different fibrinolytic agents.19 Another trial, The Platelet Aggregation Receptor
Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) trial, investigated the use of lamifiban in conjunction with fibrinolytic therapy in acute MI.20 The study consisted of 3 phases and initially enrolled patients within 12 hours of acute MI. They received heparin, aspirin, and lamifiban in addition to streptokinase or t-PA. In the second phase, patients were randomized to either lamifiban bolus and 24- or 48-hour infusion or placebo. The primary endpoints were clinical outcome, safety issues, and clinical markers of reperfusion. All patients who received the GP IIb/IIIa inhibitor demonstrated improvement in the speed and stability of reperfusion as compared with placebo using continuous ST-segment monitoring. As in the previous trials, PARADIGM was not sufficiently powered to detect differences in clinical outcomes.20 However, bleeding outcomes were still worth noting. Two intracranial hemorrhages occurred in patients receiving lamifiban and a fibrinolytic, whereas none occurred in the placebo group. There were more major bleeding episodes, mainly from the gastrointestinal tract or coronary artery bypass graft related in the lamifiban group, and increased bleeding was seen with both t-PA and streptokinase. When taken all together, the results of the early trials of combining GP IIb/IIIa inhibitors with fibrinolytics suggest more rapid and more complete reperfusion in acute MI. However, despite the apparent improvements in TIMI grade 3 flow rates and clinical outcomes, none of the trials was large enough to draw statistically significant conclusions regarding clinical endpoints.
LOW-DOSE FIBRINOLYTIC THERAPY WITH ABCIXIMAB The bleeding complications that occurred when GP IIb/IIIa inhibitors were used in conjunction with fulldose fibrinolytic therapy in the prior trials, along with in vitro evidence suggesting lower fibrinolytic dose requirements when used with GP IIb/IIIa inhibitors, prompted the next phase of clinical trials. TIMI-14, which was mentioned in the previous section, addressed the combination of abciximab and t-PA or streptokinase on reperfusion in acute MI.11,13 The SPEED trial evaluated the combination of abciximab and r-PA.12,14 A third trial, INTRO-AMI, has recently begun enrolling patients and is evaluating the combination of eptifibatide and t-PA (Table I). TIMI-14 randomized patients within 12 hours of acute MI to receive either t-PA alone, abciximab alone, reduced-dose t-PA with abciximab, or reduceddose streptokinase with abciximab. Results from this phase II trial support the use of combination therapy with abciximab and reduced-dose thrombolytic.11,13 The group treated with reduced-dose streptokinase and abciximab showed only a modest improvement in TIMI 3 flow at 90 minutes as compared with abciximab alone, with an increase in bleeding complications. However, in patients given t-PA and abciximab, TIMI grade 3 flow was achieved in 77% of patients at 90 minutes as compared with 62% with t-PA alone.11,13 Overall patency in the infarct-related artery REVASCULARIZATION IN ACUTE MI AND STROKE
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TABLE I Studies of Glycoprotein (GP) IIb/IIIa Inhibitor as Adjunct to Fibrinolytic Therapy
Full-dose fibrinolytic therapy
Reduced-dose fibrinolytic therapy
Trial
Patients (n)
GP IIb/IIIa Inhibitor
Fibrinolytic Agent
Results of Combination Therapy Compared with Fibrinolytic Alone
TAMI-817 IMPACT-AMI18 PARADIGM20 Ronner et al19 SPEED14 TIMI-1413 INTRO-AMI FASTER INTEGRITY
68 180 345 181 528 888 NA NA NA
m7E3 Eptifibatide Lamifiban Eptifibatide Abciximab Abciximab Eptifibatide Tirofiban Eptifibatide
t-PA t-PA t-PA/SK SK r-PA t-PA/SK t-PA TNK TNK
1 Patency at 5 days (92% vs 56%) 1 TIMI-3 flow, 2 time to ST recovery 2 time to ST recovery 1 bleeding 1 TIMI-3 flow (61% vs 47%) 1 TIMI-3 flow (72% vs 43%) Pending Pending Pending
IMPACT-AMI ⫽ Integrelin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction trial; NA ⫽ not available; PARADIGM ⫽ Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction trial; SK ⫽ streptokinase; SPEED ⫽ Strategies for Patency Enhancement in the Emergency Department trial; TAMI ⫽ Thrombolysis and Angioplasty in Myocardial Infarction study; TIMI ⫽ Thrombolysis in Myocardial Infarction; t-PA ⫽ tissue plasminogen activator.
was achieved in 94% of patients receiving combination therapy as compared with 78% in the group receiving fibrinolytic therapy alone. Complications such as major bleeding were similar in the combination-therapy group and control group at only 6% in each. Although complication rates were low, these small studies lacked the statistical power to address the risk of infrequent complications such as intracranial hemorrhage. In a later phase of the TIMI-14 trial, patients were randomized to receive either full-dose, double-bolus r-PA plus abciximab or reduced-dose r-PA plus abciximab. Although not reaching statistical significance, a trend toward higher TIMI grade 3 flow was observed in the group treated with 5 ⫹ 5 U/kg r-PA plus abciximab as compared with full-dose r-PA alone. Data from the phase II trial TIMI-14, support the use of GP IIb/IIIa inhibitors in combination with reduced-dose fibrinolytic therapy in improving speed and completeness of reperfusion in acute MI. Although the most efficacious dose of fibrinolytic is not yet determined, there are several ongoing trials that should help to better answer this question. The SPEED investigators enrolled 530 patients randomized within 6 hours of acute MI to receive either abciximab alone or abciximab and single or double boluses of r-PA before acute intervention.12,14 The primary endpoint of the trial was defined as TIMI grade 3 flow in the infarct-related artery at 60-minute catheterization. The secondary endpoints included 30day composite outcomes of death and reinfarction, death, reinfarction, and need for repeat revascularization procedures as well as the safety of abciximab as evidenced by incidence of hemorrhage, thrombocytopenia, need for blood products, or 30-day rate of intracranial hemorrhage. In the first phase of the study, the goal was to determine the appropriate dose of r-PA. Once the dose-finding stage was completed, a confirmation stage directly compared combination therapy with r-PA alone in 150 patients with the same primary endpoint as the pilot. The results demonstrated improvements in early TIMI grade 3 flow with r-PA (5 ⫹ 5 U/kg) and abciximab. In the dose-finding and confirmation stages of SPEED, the combination 36C THE AMERICAN JOURNAL OF CARDIOLOGY姞
of reduced-dose r-PA and abciximab produced 60minute TIMI 3 flow rates of 68%, thus providing evidence of early and complete reperfusion. When combining patients with either TIMI grade 2 or 3 flow rates, this number reaches almost 83% of patients in that particular treatment group compared with t-PA alone.12,14 Moreover, there was no significant increase in hemorrhagic complications with the combination therapy. After the completion of the confirmation stage, GUSTO-IV, the large-scale, international trial will compare the combination of abciximab and r-PA with conventional r-PA on 30-day mortality.
RATIONALE FOR THE NEED FOR CONCOMITANT ANTITHROMBIN THERAPY Unfractionated heparin has long been considered an integral adjunct to fibrinolytic therapy despite a paucity of randomized clinical data to support its routine use.21 Heparin increases the risk of intracranial hemorrhage and other bleeding complications. There is evidence from experimental studies that GP IIb/IIIa inhibitors help prevent fibrinolytic-induced thrombin generation. Therefore, researchers have begun to question whether antithrombin therapy can be reduced or eliminated when GP IIb/IIIa inhibitors are used.22 GP IIb/IIIa antagonists have been shown to not completely inhibit thrombin generation in vitro.22 In the IMPACT-AMI study, eptifibatide had no effect on thrombin generation when heparin was delayed.18 Immediate heparin administration not only reduced thrombin generation, but also improved the rate of TIMI grade 3 flow. Further insight into heparin dosing has been provided by the SPEED and TIMI-14 studies. Patients randomized to receive the combination of low-dose t-PA or r-PA were treated with either lowdose (60 U/kg) or very low-dose (40 U/kg in SPEED, 30 U/kg in TIMI-14) heparin. In both studies, a trend toward lower TIMI-3 flow rates with very low-dose heparin was observed (Figure 2). In the SPEED study, no difference in major bleeds was seen between the 2 groups. However, the TIMI-14 study observed a lower rate of bleeding complications when very-low-dose heparin was used. In summary, antithrombin therapy
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FIGURE 2. Impact of heparin dose on Thrombolysis in Myocardial Infarction (TIMI)-3 flow rates. The TIMI-3 flow rates at 60 minutes from the SPEED14 and TIMI-1413 studies are shown for full-dose fibrinolytic therapy with conventional heparin doses and for the combined fibrinolytic and glycoprotein IIb/IIIa therapy groups with low-dose and very-low-dose heparin. In both trials, the TIMI-3 flow rate was diminished slightly when the dose of heparin was reduced from 60 to 30 – 40 U/kg. Abc ⴝ abciximab; Hep ⴝ heparin.
is required when GP IIb/IIIa inhibitors are combined with fibrinolytic therapy. Lower doses of heparin than conventionally used appear to be effective in this setting, although the optimal dose remains to be determined. Very low doses of heparin may improve the safety profile of the combined-therapy approach, possibly at the cost of reduced efficacy. Low-molecularweight heparin may be a safer and more effective alternative, and is being evaluated in ongoing studies.
THE USE OF COMBINATION THERAPY FOR FACILITATED PERCUTANEOUS INTERVENTION In the early thrombolytic trials in the mid 1980s, immediate angioplasty did not confer any benefit over more conservative strategies for acute MI therapy. Since the time of these trials, many advances in percutaneous intervention have been made and more adjunctive therapies and devices are readily available. For these reasons, there is a great difference in opinion today as to the timing and indications for primary percutaneous transluminal coronary angioplasty. In the SPEED trial, early percutaneous intervention was strongly encouraged and angiographic data were analyzed in all treatment groups.12,14 This allowed investigators to evaluate the efficacy of early intervention when preceded by thrombolysis, GP IIb/IIIa inhibitor therapy, or combinations of both. Facilitated percutaneous coronary intervention, a term adopted by the SPEED investigators, was used to describe early percutaneous intervention after pharmacologic therapy for reperfusion in the acute MI patient.23 The investigators hypothesized that facilitated percutaneous coronary intervention with modern interventional devices and techniques and GP IIb/IIIa inhibitors would improve angiographic outcomes in patients with acute MI. The investigators enrolled 323 patients who underwent percutaneous coronary intervention at
approximately 60 minutes after fibrinolysis and adjunctive reperfusion therapy was initiated. Clinical outcomes such as ischemic events, angiographic results, and major bleeding episodes were compared between the early–percutaneous coronary intervention and no–percutaneous coronary intervention patients.23 Furthermore, the outcomes of patients taken for percutaneous coronary intervention who had TIMI grade 1 or 0 were compared with those patients with TIMI grade 2 or 3 flow rates. Lastly, the outcomes among all 3 treatment groups undergoing percutaneous coronary intervention were also compared. Preliminary results indicate that patients undergoing early percutaneous coronary intervention had a high procedural success rate at 88% and had a 30-day composite outcome of death, MI, or urgent repeat revascularization of only 5.6%.23 The complication rate in these patients was significantly lower than in patients who did not undergo early percutaneous coronary intervention. The SPEED trial suggests that early percutaneous coronary intervention facilitated by pretreatment with reduced-dose r-PA and abciximab is safe and may be very effective. It appears that GP IIb/IIIa inhibitors play a vital role in reperfusion both before, during, and immediately after early percutaneous revascularization. This approach may provide the most efficient and the most effective reperfusion studied to date in the acute MI patient. However, the SPEED data must be confirmed in a large-scale, randomized, controlled trial designed specifically to address the question of the efficacy of facilitated percutaneous coronary intervention compared with primary angioplasty in MI.
CONCLUSION Trials have investigated multiple adjunctive therapies to improve both reperfusion and outcome in acute MI. Lessons learned from these trials have suggested REVASCULARIZATION IN ACUTE MI AND STROKE
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that platelet inhibition with GP IIb/IIIa inhibitors may be a key component in improving outcomes in acute MI patients undergoing percutaneous revascularization. Although platelet inhibition appears to be the focus of our many current trials, there is much yet to be learned about optimal strategies for reperfusion in acute MI. The role of thrombin inhibition or passivation of the coagulation cascade is not yet completely understood. Primary angioplasty using GP IIb/IIIa inhibitors is an effective reperfusion strategy. However, not all centers can perform early intervention in a timely fashion, and the skill of all operators is variable among institutions. GP IIb/IIIa inhibitors do have an effect in reperfusion in acute MI but do not provide complete reperfusion in all patients when used alone. The use of GP IIb/IIIa inhibitors in conjunction with reduced-dose thrombolytic therapy appears to have great promise and early data indicate that this strategy may provide the best reperfusion rates to date.24 In reviewing the data from the 2 latest trials, we see the highest patency rates were observed in the groups that received GP IIb/IIIa inhibitors and the 30-minute continuous infusion of t-PA or the divided bolus of r-PA in TIMI-14 and in SPEED, respectively.11–14 When completed, however, the GUSTO-IV trial should provide definitive answers about evaluation of the efficacy of combined GP IIb/IIIa inhibitors and fibrinolytic therapy. GUSTO-IV AMI [acute MI] will enroll 17,000 patients who present within 6 hours of an acute MI and randomize them to receive either conventional r-PA and standard heparin or reduced-dose r-PA, abciximab, and heparin. The endpoint in this trial will be all-cause mortality at 30 days. Pending final results from GUSTO-IV AMI we should have improved strategies for therapy in acute MI. As we move into the new millennium in cardiovascular medicine and the care of the acute MI patient, multiple clinical trials are being designed to provide insight into the most efficient, most complete, and most reliable means of providing reperfusion therapy. 1. 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. 2. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: 673– 682. 3. 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;343:311–322. 4. The GUSTO-IIb Angioplasty Substudy Investigators. An international randomized trial of 1138 patients comparing primary coronary angioplasty versus tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997;336:1621–1628. 5. Ellis SG, Topol EJ, Gallison L, Grines CL, Langburd AB, Bates ER, Walton JA Jr, O’Neill WW. Predictors of success for coronary angioplasty performed for acute myocardial infarction. J Am Coll Cardiol 1998;12:1407–1415. 6. Fuster V, Badimon L, Badimon JJ, Cheseboro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (second of two parts). N Engl J Med 1992;326:310 –318. 7. Coller BS. Antiplatelet agents in the prevention and therapy of thrombosis. Annu Rev Med 1992;43:171–180.
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8. Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM. Specific platelet mediators and unstable coronary artery lesions. Circulation 1989;80:198 –205. 9. Gold HK, Garabedian HD, Dinsmore RE, Guerrero LJ, Cigarroa JE, Palacios IF, Leinbach RC. 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. 10. van den Merkhof LF, Zijlstra F, Olsson H, Grip L, Veen G, Bar FW, van den Brand MJ, Simoons ML, Verheugt FW. Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty. Results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study. J Am Coll Cardiol 1999;33:1528 –1532. 11. Antman EM, Giugliano RP, McCabe CH, Gibson M, Adgey AJJ, Ghali M, Coussement P, Anderson KM, Sherer J, Van de Werf F, Braunwald E, for the TIMI 14 Investigators. Abciximab (ReoPro) potentiates thrombolysis in ST elevation myocardial infarction: results from the TIMI 14 trial (abstract). J Am Coll Cardiol 1998;31:191A. 12. Ohman EM, Lincoff AM, Bode C, Bachinsky WB, Ardissimo D, Matteo PS, Betriu A, Schildcrout JS, Sketch M, Topol EJ. Enhanced early reperfusion at 60 minutes with low-dose reteplase combined with full-dose abciximab in acute myocardial infarction: preliminary results form the GUSTO-4 Pilot (SPEED) dose-ranging trial. Circulation 1998;98(suppl I):504. 13. Antman EM, Giugliano RP, Gibson CM, McCabe CH, Coussement P, Kleiman NS, Vahanian A, Adgey AA, Menown I, Rupprecht HJ, Van der Wieken R, Ducas J, Scherer J, AndersonK, Van de Werf F, Braunwald E, for the TIMI 14 investigators. Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. Circulation 1999;99: 2720 –2732. 14. Ohman EM. SPEED. Presented at the 48th Annual Scientific Sessions of the American College of Cardiology: March 7-10, 1999, New Orleans, LA. 15. Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D. 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 1998;77:670 – 677. 16. Yasuda T, Gold HK, Leinbach RC, Yaoita H, Fallon JT, Guerrero L, Napier MA, Bunting S, Collen D. Kistrin, a polypeptide platelet GP IIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activatior in a canine preparation. Circulation 1991;83:1038 –1047. 17. Kleiman NS, Ohman EM, Califf RM, George BS, Kereiakes D, Aguirre FV, Weisman H, Schaible T, Topol EJ. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 fab following thrombolytic therapy: results of the TAMI-8 pilot study. J Am Coll Cardiol 1993;22:381–389. 18. Ohman EM, Kleiman NS, Gacioch G, Worley SJ, Navetta FI, Talley JD, Anderson HV, Ellis SG, Cohen MD, Spriggs D, Miller M, Kereiakes D, Yakubov S, Kitt MM, Sigmon KN, Califf RM, Krucoff MW, Topol EJ, for the IMPACTAMI 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. 19. Ronner E, van Kesteren HAM, Zijnen P, Tebbe U, Molhoek P, Cuffie C, Veltri E, Lorenz T, Neuhaus K, Simoons ML. Combined therapy with streptokinase and Integrelin (abstract). J Am Coll Cardiol 1998;31:191A. 20. 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. 21. Collins R, Peto R, Baigent C, Sleight P. Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J Med 1997;336:847– 860. 22. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: emerging platelet preeminence. Circulation 1998;97:211–218. 23. Herrmann HC, Moliterno DJ, Bode C, Betriu A, Lincoff AM, Ohman EM. Combination abciximab and reduced-dose reteplase facilitates early PCI in acute MI: results from the SPEED trial. Circulation 1999;100(suppl 1):I-188. 24. Greenbaum AB, Harrington RA, Ohman EM. The use of glycoprotein IIb/IIIa inhibition in acute myocardial infarction. In: Lincoff AM, Topol EJ, eds. Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa in Cardiovascular Disease. Philadelphia: Williams & Wilkins, 1999:229 –249. 25. Cigarroa JE, Ferrel MA, Collen DJ, Leinbach RC. Enhanced endogenouscoronary thrombolysis during acute myocardial infarction following selective platelet receptor blockade with ReoPro (abstract). Circulation 1996;94:I-553. 26. Gold HK, Kereiakes DJ, Dinsmore RE, Martin LH, Lausten D, Broderick TM, Anderson KM, Garabedian HD, Leinbach RC. A randomized, placebocontrolled crossover trial of Reopro alone or combined with low-dose plasminogen activator for coronary reperfusion in patients with acute myocardial infarction: preliminary results (abstract). Circulation 1997;96:I-473. 27. Makkar R, Eigler N, Goff B, Fry E, Barr L, D’Haem C, Fischell T, Litvack F. Primary reperfusion in acute myocardial infarction with reopro and heparin: interim results of ReoMI pilot study (abstract). J Am Coll Cardiol 1998;31:94-A.
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MD,
E. Magnus Ohman, MD, Warren Cantor, A. Michael Lincoff, MD
MD,
and
The goal of therapy in acute myocardial infarction is complete and timely restoration of coronary blood flow. Current strategies for reperfusion fail to achieve ideal results and resolution of ischemia in all patients. The platelet plays a pivotal role in the pathophysiology of an acute myocardial infarction, and antiplatelet therapy has been shown to improve clinical outcomes. The final common pathway for platelet activation and aggregation in acute myocardial infarction is the activation of the glycoprotein (GP) IIb/IIIa receptor. Newer reperfusion strategies target the GP IIb/IIIa receptor, thereby preventing the prothrombotic effects of platelets in an acute myocardial infarction. In the past decade, several strategies targeting the use of GP IIb/IIIa inhibitors have been evaluated. GP IIb/IIIa inhibitors have been shown to improve angiographic Thrombolysis in Myocardial Infarction (TIMI) 3 flow rates when used as reperfusion therapy given with heparin and aspirin as compared with heparin and aspirin alone. When GP IIb/IIIa inhibitors are used with full-dose fibrinolytics, early studies have suggested a trend toward more rapid and more complete reperfusion in an acute myocardial infarction.
Later trials have examined the use of GP IIb/IIIa inhibitors in conjunction with reduced-dose fibrinolytics. Results from TIMI 14 and Global Use of Strategies to Open occluded arteries–IV pilot trials support the use of combination therapy with reduced- dose fibrinolytics and the GP IIb/IIIa inhibitor abciximab. Given the promising role of GP IIb/IIIa inhibitor therapy in acute myocardial infarction, investigators questioned the need for concomitant antithrombin therapy. However, data from several investigations suggest that antithrombin therapy is required when GP IIb/IIIa inhibitors are used with fibrinolytics, although it appears that the dose of heparin may be reduced. Finally, recent investigations have addressed the safety and efficacy of facilitated early percutaneous intervention. In this strategy, patients presenting with an acute myocardial infarction are treated with reduced-dose fibrinolytics and GP IIb/IIIa inhibitors and are taken to the interventional cardiac catheterization laboratory within the first 60 minutes of therapy. 䊚2000 by Excerpta Medica, Inc. Am J Cardiol 2000;85:32C–38C
T
ful reperfusion.3 In contrast, studies evaluating primary angioplasty during an acute MI suggest that TIMI grade 3 flow is achieved in 80% of cases when performed in all centers. This rate of reperfusion is significantly less in more complex patients and in the hands of less-experienced operators. Furthermore, primary angioplasty confers a 10 –13% risk of reocclusion and is associated with several procedural complications.4,5 Given that neither strategy provides ideal reperfusion and resolution of ischemia in all patients, there are many investigations underway to evaluate novel approaches to achieve coronary reperfusion that is more complete and more expedient with less risk of reocclusion and reinfarction. Pathologic mechanisms involved in the acute coronary syndrome include plaque rupture, subsequent platelet aggregation, and thrombosis. The atherosclerotic plaque is covered by a fibrous cap that ruptures and exposes highly thrombogenic contents such as collagen, fibronectin, fibrinogen, and other substances to platelets.6 The platelets are stimulated and adhesion, activation, and aggregation subsequently occur. The aggregated platelets form a surface that promotes the generation of thrombin, which in turn converts
he goal of therapy in acute myocardial infarction (MI) is complete and timely restoration of coronary blood flow.1 In current practice, the 2 means for achieving reperfusion are primary percutaneous coronary angioplasty and medical fibrinolysis. Data from the Fibrinolytic Therapy Trialists’ (FTT) Collaborative group demonstrate that fibrinolytic agents improve survival by nearly 30% if given within 6 hours of symptom onset and by 50% if given within the first 2 hours of presentation.2,3 However, current fibrinolytic strategies fail to restore normal anterograde flow (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) at 60 minutes in almost 60% of cases. An additional 20% of patients fail to reperfuse at the myocardial tissue level. Moreover, 4 – 6% of patients experience early reinfarction despite initially successFrom the Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina, USA (KRC, EMO, WC); and Cleveland Clinic Foundation, Cleveland, Ohio, USA (AML). Dr. Campbell is funded by the Division of Cardiology at Duke University Medical Center. Dr. Cantor is funded by a grant from the Royal College of Physicians and Surgeons of Canada. Address for reprints: E. Magnus Ohman, MD, Duke Clinical Research Institute, 2400 Pratt Street, Room 0311, Durham, NC 27705.
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©2000 by Excerpta Medica, Inc. All rights reserved.
0002-9149/00/$ – see front matter PII S0002-9149(00)00877-8
fibrinogen to fibrin. The fibrin generation further stimulates platelet activation and a cycle of the prothrombotic state develops which results in occlusion of the coronary artery and the clinical phenomenon of an acute MI. Given the pivotal role of the platelet in the pathophysiology of acute MI, it is not surprising that antiplatelet therapies have been investigated and have been shown to improve clinical outcomes. Aspirin inhibits platelet activation by the cyclooxygenase pathway, but platelet activation continues to occur by other pathways. Unlike activation, platelet aggregation occurs by only one pathway and requires the binding of fibrinogen or von Willebrand factor to the specific glycoprotein IIb/IIIa (GP IIb/IIIa) receptor on the platelet surface.7 Platelet activation induces a conformational change in the receptor and allows for binding to fibrinogen or von Willebrand factor and subsequent aggregation. It would therefore seem reasonable that a strategy that targets the final common pathway for platelet aggregation via the GP IIb/IIIa receptor would most likely prevent the prothrombotic effects of platelets in acute MI. In the past decade, many advances have been made in the area of platelet inhibition in acute MI culminating in the development, evaluation, and clinical use of drugs that specifically inhibit the GP IIb/IIIa receptor on the platelet. Recent investigations have examined the use of combinations of GP IIb/IIIa inhibitors and fibrinolytic agents in establishing superior reperfusion success in acute MI. This review will focus on the trials leading up to these most recent investigations and closely examine current trials with an emphasis on new pharmacologic combinations to establish reperfusion. The purpose of this article is: (1) to review the use of GP IIb/IIIa inhibitors alone in the treatment of acute MI; (2) to review the use of GP IIb/IIIa inhibitors as adjunct therapy to both full- and reduced-dose fibrinolytics in acute MI; (3) to provide a rationale for the continued use of antithrombin therapy in conjunction with GP IIb/IIIa inhibition; and (4) to provide a brief update of preliminary data from current trials evaluating the use of combination therapy for facilitated percutaneous coronary intervention.
GLYCOPROTEIN IIB/IIIA INHIBITORS ALONE FOR REPERFUSION IN ACUTE MI Several investigators have pursued the use of GP IIb/IIIa inhibitors as sole reperfusion therapy in acute MI. Early researchers helped to provide a link to the role of the platelet and platelet-generated substances to the vascular biology of an acute MI. Platelets are at the core of the coronary thrombus and play a large role in the progression of the acute coronary syndrome. Willerson et al8 demonstrated that the platelet and specific platelet mediators such as serotonin and thromboxanes were essential to the pathophysiology of the acute coronary syndrome. These investigators were able to document the dynamic responsiveness and ongoing release of prothrombotic mediators by the platelet in the canine model of an acute coronary syndrome.8 This early work led to more sophisticated
animal experiments that focused on the effects of platelet inhibition on the progression of an acute MI. Animal experiments by Gold et al9 used a dog model of left anterior descending coronary artery occlusion to evaluate the efficacy of placebo, aspirin alone, or aspirin plus a GP IIb/IIIa inhibitor (c7E3) in establishing reperfusion. All dogs received heparin, and the results demonstrated that in the group treated with aspirin plus GP IIb/IIIa inhibitors there was an 80% reperfusion rate at 50 minutes. In none of the animals in the other 2 groups was any degree of reflow established.9 This early work sparked interest in the potential use of GP IIb/IIIa inhibitors without fibrinolytics and/or percutaneous intervention to establish adequate reperfusion in acute MI. Following these data, several clinical trials in humans explored GP IIb/IIa inhibitors alone in response to frequent delays in getting patients with acute MI to the catheterization laboratory for primary percutaneous transluminal coronary angioplasty (Figure 1). In the early 1990s, multiple clinical trials began to investigate the role of GP IIb/IIIa inhibition in humans in non–ST-elevation acute coronary syndromes. Altogether, ⬎10 clinical trials, which included ⬎35,000 patients, have been performed. Some of these trials involved patients with unstable angina or non–Q-wave MI as well as patients undergoing percutaneous coronary interventions. Strikingly, all of these trials demonstrated benefit in the reduction of the composite of death or MI for the combination of GP IIb/IIIa inhibitor versus placebo. The Glycoprotein Receptor Antagonist in MI Patency Evaluation (GRAPE) trial was designed to evaluate the early use of GP IIb/IIIa inhibitors in inducing reperfusion before primary percutaneous transluminal coronary angioplasty for acute MI.10 The trial included 60 patients with acute MI and planned primary percutaneous transluminal coronary angioplasty. The patients were given aspirin, heparin, and an abciximab bolus and infusion in the emergency department. In the catheterization laboratory, coronary patency (as evidenced by TIMI grade 2 or 3 flow) at 45 minutes after drug administration was nearly 40% with complete reperfusion (TIMI grade 3 flow) in 18%. Standard therapy, which included aspirin and heparin, had an overall patency rate of only 27% and TIMI grade 3 flow rates of only 8%.10 These findings suggested a dethrombosis role of the GP IIb/IIIa inhibitors. These early findings prompted the inclusion of GP IIb/IIIa inhibitors alone in the design of multiple clinical trials in acute MI. Although some of these trials are currently ongoing, preliminary results have shed some light on the reperfusion capabilities of the GP IIb/IIIa inhibitors alone. Although designed to evaluate combination therapy with thrombolytic agents, the TIMI-14 trial and the Strategies for Patency Enhancement in the Emergency Department (SPEED) trial— which is the Global Use of Strategies to Open occluded arteries (GUSTO)–IV pilot study—included control arms in which patients were treated with abciximab, aspirin, and heparin without concomitant fibrinolytic agents before catheterization.11,12 REVASCULARIZATION IN ACUTE MI AND STROKE
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FIGURE 1. Angiographic patency rates when abciximab is given for acute myocardial infarction (MI) as sole reperfusion therapy. The results of 6 separate studies with angiography done at 5 different time points are shown in the graph. The light gray bars indicate the Thrombolysis in Myocardial Infarction (TIMI)-3 flow rates and the dark gray bars indicate the patency (TIMI 2–3 flow) rates at the different time points. The number of patients assessed at each time point is provided under the study names.
In the dose-finding phase of TIMI-14, patients were randomized within 12 hours of acute MI to receive either standard-dose tissue plasminogen activator (t-PA), reduced-dose t-PA plus abciximab, streptokinase plus abciximab, or abciximab alone. Results from TIMI-14 revealed that only 32% of patients treated with abciximab alone had TIMI grade 3 flow in the infarct-related artery at 90 minutes as compared with 57% of patients treated with t-PA alone.13 Although this rate was low, it exceeded previously reported rates of TIMI grade 3 flow in patients treated with heparin and aspirin and was similar to those reported for abciximab given in conjunction with streptokinase. Furthermore, data from the combination arms of the study revealed significant improvements in artery patency rates and provided more support for the utility of GP IIb/IIIa inhibitors in acute MI.13 These results will be discussed further in another section of this review. In the SPEED trial, patients were randomized to abciximab alone, abciximab plus reteplase (r-PA), and r-PA alone.12,14 The abciximab-alone arm again provided an opportunity to evaluate the efficacy of GP IIb/IIIa inhibitors as sole reperfusion therapy in acute MI. Coronary angiography was performed at 60 minutes and angiographic data from SPEED revealed that 52% of the abciximab-only patients had either TIMI grade 2 or 3 flow as compared with nearly 76% of patients who received combination therapy with rPA.14,15
GLYCOPROTEIN IIB/IIIA INHIBITORS AS ADJUNCT TO FIBRINOLYTIC THERAPY IN ACUTE MI In the early 1990s, many animal studies were conducted to evaluate safety and efficacy of the combination of GP IIb/IIIa inhibitors and fibrinolytics. Us34C THE AMERICAN JOURNAL OF CARDIOLOGY姞
ing a canine model, Gold et al15 demonstrated an increase in speed of reperfusion and a decrease in fibrinolytic dose when combining c7E3 and t-PA. Other groups were able to replicate these findings, and further animal studies were able to demonstrate the ability of combination therapy to prevent reocclusion after successful thrombolysis.16 These animal studies demonstrated that the use of fibrinolytic agents in conjunction with GP IIb/IIIa inhibitors in an experimental model of acute MI led to more rapid, more complete, and more sustained coronary reperfusion without any significant increase in bleeding risks. These promising animal experiments prompted study in human subjects. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI)– 8 pilot study was the first human investigation to evaluate the combined use of GP IIb/IIIa inhibitors with fibrinolytics in acute MI.17 TAMI-8 included 60 patients presenting within 6 hours of acute MI. The patients were given t-PA (3-hour infusion) followed 15 hours later by a bolus and infusion of c7E3 (abciximab). Patients were given varying doses of c7E3 starting at 0.1 mg/kg and sequentially increasing to 0.25 mg/kg. As safety data were acquired, the timing of c7E3 administration was shortened to 3 hours after t-PA initiation. Aspirin was given as early as possible and full-dose heparin was given to the groups receiving c7E3 at 15 hours and reduced-dose heparin was given to the groups receiving c7E3 at 3 hours after fibrinolytic.17 Angiographic TIMI flow grade as well as clinical parameters such as death, reinfarction, and need for urgent intervention were the primary endpoints examined in the trial. Safety issues such as major bleeding episodes and thrombocytopenia were also analyzed. Results revealed TIMI grade 2 or 3 flow in 56% of the control
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patients and in 92% and 96% of patients receiving any or the highest dose of c7E3, respectively.17 The rate of major bleeding was comparable in the groups, with no significant increase in the patients given higher doses of c7E3. However, of the patients who underwent coronary artery bypass graft surgery after infarction, the bleeding rates in the c7E3 patients were higher.17 This study, although small in size, spurred other investigations into the expanded role of GP IIb/IIIa inhibitors in acute MI. The Integrelin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction (IMPACT-AMI) trial evaluated the role of eptifibatide as an adjunct to t-PA, aspirin, and heparin in acute MI.18 The trial included 180 patients enrolled within 6 hours of acute MI. In the dose-finding phase, the subjects were randomized to receive either placebo or eptifibatide in increasing doses within 10 minutes of front-loaded t-PA. In a second phase, the patients were randomized to receive either placebo or the highest dose of eptifibatide from phase I that was considered safe. The rate of TIMI grade 3 flow at 90 minutes was the primary endpoint. Multiple secondary endpoints were examined, including composite of death, reinfarction, need for revascularization, congestive heart failure, and bleeding. Angiographic results revealed that 66% of eptifibatide patients and 39% of control patients had TIMI grade 3 flow.18 The incidence of death and reinfarction was 7.3% for the placebo-treated patients, 8% for the patients treated with eptifibatide, and 7.8% for the group treated with the highest eptifibatide doses. The composite outcome was seen in 41.8% of the placebo group, 44.8% in the eptifibatide patients, and 43.1% in the highest-dose eptifibatide group. Of note, the median time to ST segment recovery by continuous 12lead electrocardiographic monitoring was reduced from 116 minutes to 65 minutes in the eptifibatide group. As in TAMI-8, there was no increased bleeding rate, although the trial was not sufficiently powered to detect differences in clinical outcomes. However, the results of IMPACT-AMI did suggest possible benefits gained with the addition of GP IIb/IIIa inhibitors to fibrinolytic therapy in acute MI. Other investigators led by Simoons19 evaluated the combination of eptifibatide with streptokinase for acute MI in a similar double-blinded, placebo-controlled trial. The 181 patients in this study were randomized to receive escalating doses of eptifibatide in addition to streptokinase. The results demonstrated that the rate of TIMI grade 2 or 3 flow was improved with eptifibatide and that TIMI grade 3 flow alone was significantly improved as well.19 However, the improved reperfusion rates with escalating doses of eptifibatide were associated with unusually high bleeding rates in patients receiving the higher doses of a GP IIb/IIIa inhibitor. The difference in bleeding rates in this trial using streptokinase and an earlier trial using t-PA began to prompt interest in the precise interactions between the GP IIb/IIIa inhibitors and different fibrinolytic agents.19 Another trial, The Platelet Aggregation Receptor
Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) trial, investigated the use of lamifiban in conjunction with fibrinolytic therapy in acute MI.20 The study consisted of 3 phases and initially enrolled patients within 12 hours of acute MI. They received heparin, aspirin, and lamifiban in addition to streptokinase or t-PA. In the second phase, patients were randomized to either lamifiban bolus and 24- or 48-hour infusion or placebo. The primary endpoints were clinical outcome, safety issues, and clinical markers of reperfusion. All patients who received the GP IIb/IIIa inhibitor demonstrated improvement in the speed and stability of reperfusion as compared with placebo using continuous ST-segment monitoring. As in the previous trials, PARADIGM was not sufficiently powered to detect differences in clinical outcomes.20 However, bleeding outcomes were still worth noting. Two intracranial hemorrhages occurred in patients receiving lamifiban and a fibrinolytic, whereas none occurred in the placebo group. There were more major bleeding episodes, mainly from the gastrointestinal tract or coronary artery bypass graft related in the lamifiban group, and increased bleeding was seen with both t-PA and streptokinase. When taken all together, the results of the early trials of combining GP IIb/IIIa inhibitors with fibrinolytics suggest more rapid and more complete reperfusion in acute MI. However, despite the apparent improvements in TIMI grade 3 flow rates and clinical outcomes, none of the trials was large enough to draw statistically significant conclusions regarding clinical endpoints.
LOW-DOSE FIBRINOLYTIC THERAPY WITH ABCIXIMAB The bleeding complications that occurred when GP IIb/IIIa inhibitors were used in conjunction with fulldose fibrinolytic therapy in the prior trials, along with in vitro evidence suggesting lower fibrinolytic dose requirements when used with GP IIb/IIIa inhibitors, prompted the next phase of clinical trials. TIMI-14, which was mentioned in the previous section, addressed the combination of abciximab and t-PA or streptokinase on reperfusion in acute MI.11,13 The SPEED trial evaluated the combination of abciximab and r-PA.12,14 A third trial, INTRO-AMI, has recently begun enrolling patients and is evaluating the combination of eptifibatide and t-PA (Table I). TIMI-14 randomized patients within 12 hours of acute MI to receive either t-PA alone, abciximab alone, reduced-dose t-PA with abciximab, or reduceddose streptokinase with abciximab. Results from this phase II trial support the use of combination therapy with abciximab and reduced-dose thrombolytic.11,13 The group treated with reduced-dose streptokinase and abciximab showed only a modest improvement in TIMI 3 flow at 90 minutes as compared with abciximab alone, with an increase in bleeding complications. However, in patients given t-PA and abciximab, TIMI grade 3 flow was achieved in 77% of patients at 90 minutes as compared with 62% with t-PA alone.11,13 Overall patency in the infarct-related artery REVASCULARIZATION IN ACUTE MI AND STROKE
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TABLE I Studies of Glycoprotein (GP) IIb/IIIa Inhibitor as Adjunct to Fibrinolytic Therapy
Full-dose fibrinolytic therapy
Reduced-dose fibrinolytic therapy
Trial
Patients (n)
GP IIb/IIIa Inhibitor
Fibrinolytic Agent
Results of Combination Therapy Compared with Fibrinolytic Alone
TAMI-817 IMPACT-AMI18 PARADIGM20 Ronner et al19 SPEED14 TIMI-1413 INTRO-AMI FASTER INTEGRITY
68 180 345 181 528 888 NA NA NA
m7E3 Eptifibatide Lamifiban Eptifibatide Abciximab Abciximab Eptifibatide Tirofiban Eptifibatide
t-PA t-PA t-PA/SK SK r-PA t-PA/SK t-PA TNK TNK
1 Patency at 5 days (92% vs 56%) 1 TIMI-3 flow, 2 time to ST recovery 2 time to ST recovery 1 bleeding 1 TIMI-3 flow (61% vs 47%) 1 TIMI-3 flow (72% vs 43%) Pending Pending Pending
IMPACT-AMI ⫽ Integrelin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction trial; NA ⫽ not available; PARADIGM ⫽ Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction trial; SK ⫽ streptokinase; SPEED ⫽ Strategies for Patency Enhancement in the Emergency Department trial; TAMI ⫽ Thrombolysis and Angioplasty in Myocardial Infarction study; TIMI ⫽ Thrombolysis in Myocardial Infarction; t-PA ⫽ tissue plasminogen activator.
was achieved in 94% of patients receiving combination therapy as compared with 78% in the group receiving fibrinolytic therapy alone. Complications such as major bleeding were similar in the combination-therapy group and control group at only 6% in each. Although complication rates were low, these small studies lacked the statistical power to address the risk of infrequent complications such as intracranial hemorrhage. In a later phase of the TIMI-14 trial, patients were randomized to receive either full-dose, double-bolus r-PA plus abciximab or reduced-dose r-PA plus abciximab. Although not reaching statistical significance, a trend toward higher TIMI grade 3 flow was observed in the group treated with 5 ⫹ 5 U/kg r-PA plus abciximab as compared with full-dose r-PA alone. Data from the phase II trial TIMI-14, support the use of GP IIb/IIIa inhibitors in combination with reduced-dose fibrinolytic therapy in improving speed and completeness of reperfusion in acute MI. Although the most efficacious dose of fibrinolytic is not yet determined, there are several ongoing trials that should help to better answer this question. The SPEED investigators enrolled 530 patients randomized within 6 hours of acute MI to receive either abciximab alone or abciximab and single or double boluses of r-PA before acute intervention.12,14 The primary endpoint of the trial was defined as TIMI grade 3 flow in the infarct-related artery at 60-minute catheterization. The secondary endpoints included 30day composite outcomes of death and reinfarction, death, reinfarction, and need for repeat revascularization procedures as well as the safety of abciximab as evidenced by incidence of hemorrhage, thrombocytopenia, need for blood products, or 30-day rate of intracranial hemorrhage. In the first phase of the study, the goal was to determine the appropriate dose of r-PA. Once the dose-finding stage was completed, a confirmation stage directly compared combination therapy with r-PA alone in 150 patients with the same primary endpoint as the pilot. The results demonstrated improvements in early TIMI grade 3 flow with r-PA (5 ⫹ 5 U/kg) and abciximab. In the dose-finding and confirmation stages of SPEED, the combination 36C THE AMERICAN JOURNAL OF CARDIOLOGY姞
of reduced-dose r-PA and abciximab produced 60minute TIMI 3 flow rates of 68%, thus providing evidence of early and complete reperfusion. When combining patients with either TIMI grade 2 or 3 flow rates, this number reaches almost 83% of patients in that particular treatment group compared with t-PA alone.12,14 Moreover, there was no significant increase in hemorrhagic complications with the combination therapy. After the completion of the confirmation stage, GUSTO-IV, the large-scale, international trial will compare the combination of abciximab and r-PA with conventional r-PA on 30-day mortality.
RATIONALE FOR THE NEED FOR CONCOMITANT ANTITHROMBIN THERAPY Unfractionated heparin has long been considered an integral adjunct to fibrinolytic therapy despite a paucity of randomized clinical data to support its routine use.21 Heparin increases the risk of intracranial hemorrhage and other bleeding complications. There is evidence from experimental studies that GP IIb/IIIa inhibitors help prevent fibrinolytic-induced thrombin generation. Therefore, researchers have begun to question whether antithrombin therapy can be reduced or eliminated when GP IIb/IIIa inhibitors are used.22 GP IIb/IIIa antagonists have been shown to not completely inhibit thrombin generation in vitro.22 In the IMPACT-AMI study, eptifibatide had no effect on thrombin generation when heparin was delayed.18 Immediate heparin administration not only reduced thrombin generation, but also improved the rate of TIMI grade 3 flow. Further insight into heparin dosing has been provided by the SPEED and TIMI-14 studies. Patients randomized to receive the combination of low-dose t-PA or r-PA were treated with either lowdose (60 U/kg) or very low-dose (40 U/kg in SPEED, 30 U/kg in TIMI-14) heparin. In both studies, a trend toward lower TIMI-3 flow rates with very low-dose heparin was observed (Figure 2). In the SPEED study, no difference in major bleeds was seen between the 2 groups. However, the TIMI-14 study observed a lower rate of bleeding complications when very-low-dose heparin was used. In summary, antithrombin therapy
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FIGURE 2. Impact of heparin dose on Thrombolysis in Myocardial Infarction (TIMI)-3 flow rates. The TIMI-3 flow rates at 60 minutes from the SPEED14 and TIMI-1413 studies are shown for full-dose fibrinolytic therapy with conventional heparin doses and for the combined fibrinolytic and glycoprotein IIb/IIIa therapy groups with low-dose and very-low-dose heparin. In both trials, the TIMI-3 flow rate was diminished slightly when the dose of heparin was reduced from 60 to 30 – 40 U/kg. Abc ⴝ abciximab; Hep ⴝ heparin.
is required when GP IIb/IIIa inhibitors are combined with fibrinolytic therapy. Lower doses of heparin than conventionally used appear to be effective in this setting, although the optimal dose remains to be determined. Very low doses of heparin may improve the safety profile of the combined-therapy approach, possibly at the cost of reduced efficacy. Low-molecularweight heparin may be a safer and more effective alternative, and is being evaluated in ongoing studies.
THE USE OF COMBINATION THERAPY FOR FACILITATED PERCUTANEOUS INTERVENTION In the early thrombolytic trials in the mid 1980s, immediate angioplasty did not confer any benefit over more conservative strategies for acute MI therapy. Since the time of these trials, many advances in percutaneous intervention have been made and more adjunctive therapies and devices are readily available. For these reasons, there is a great difference in opinion today as to the timing and indications for primary percutaneous transluminal coronary angioplasty. In the SPEED trial, early percutaneous intervention was strongly encouraged and angiographic data were analyzed in all treatment groups.12,14 This allowed investigators to evaluate the efficacy of early intervention when preceded by thrombolysis, GP IIb/IIIa inhibitor therapy, or combinations of both. Facilitated percutaneous coronary intervention, a term adopted by the SPEED investigators, was used to describe early percutaneous intervention after pharmacologic therapy for reperfusion in the acute MI patient.23 The investigators hypothesized that facilitated percutaneous coronary intervention with modern interventional devices and techniques and GP IIb/IIIa inhibitors would improve angiographic outcomes in patients with acute MI. The investigators enrolled 323 patients who underwent percutaneous coronary intervention at
approximately 60 minutes after fibrinolysis and adjunctive reperfusion therapy was initiated. Clinical outcomes such as ischemic events, angiographic results, and major bleeding episodes were compared between the early–percutaneous coronary intervention and no–percutaneous coronary intervention patients.23 Furthermore, the outcomes of patients taken for percutaneous coronary intervention who had TIMI grade 1 or 0 were compared with those patients with TIMI grade 2 or 3 flow rates. Lastly, the outcomes among all 3 treatment groups undergoing percutaneous coronary intervention were also compared. Preliminary results indicate that patients undergoing early percutaneous coronary intervention had a high procedural success rate at 88% and had a 30-day composite outcome of death, MI, or urgent repeat revascularization of only 5.6%.23 The complication rate in these patients was significantly lower than in patients who did not undergo early percutaneous coronary intervention. The SPEED trial suggests that early percutaneous coronary intervention facilitated by pretreatment with reduced-dose r-PA and abciximab is safe and may be very effective. It appears that GP IIb/IIIa inhibitors play a vital role in reperfusion both before, during, and immediately after early percutaneous revascularization. This approach may provide the most efficient and the most effective reperfusion studied to date in the acute MI patient. However, the SPEED data must be confirmed in a large-scale, randomized, controlled trial designed specifically to address the question of the efficacy of facilitated percutaneous coronary intervention compared with primary angioplasty in MI.
CONCLUSION Trials have investigated multiple adjunctive therapies to improve both reperfusion and outcome in acute MI. Lessons learned from these trials have suggested REVASCULARIZATION IN ACUTE MI AND STROKE
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that platelet inhibition with GP IIb/IIIa inhibitors may be a key component in improving outcomes in acute MI patients undergoing percutaneous revascularization. Although platelet inhibition appears to be the focus of our many current trials, there is much yet to be learned about optimal strategies for reperfusion in acute MI. The role of thrombin inhibition or passivation of the coagulation cascade is not yet completely understood. Primary angioplasty using GP IIb/IIIa inhibitors is an effective reperfusion strategy. However, not all centers can perform early intervention in a timely fashion, and the skill of all operators is variable among institutions. GP IIb/IIIa inhibitors do have an effect in reperfusion in acute MI but do not provide complete reperfusion in all patients when used alone. The use of GP IIb/IIIa inhibitors in conjunction with reduced-dose thrombolytic therapy appears to have great promise and early data indicate that this strategy may provide the best reperfusion rates to date.24 In reviewing the data from the 2 latest trials, we see the highest patency rates were observed in the groups that received GP IIb/IIIa inhibitors and the 30-minute continuous infusion of t-PA or the divided bolus of r-PA in TIMI-14 and in SPEED, respectively.11–14 When completed, however, the GUSTO-IV trial should provide definitive answers about evaluation of the efficacy of combined GP IIb/IIIa inhibitors and fibrinolytic therapy. GUSTO-IV AMI [acute MI] will enroll 17,000 patients who present within 6 hours of an acute MI and randomize them to receive either conventional r-PA and standard heparin or reduced-dose r-PA, abciximab, and heparin. The endpoint in this trial will be all-cause mortality at 30 days. Pending final results from GUSTO-IV AMI we should have improved strategies for therapy in acute MI. As we move into the new millennium in cardiovascular medicine and the care of the acute MI patient, multiple clinical trials are being designed to provide insight into the most efficient, most complete, and most reliable means of providing reperfusion therapy. 1. 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. 2. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: 673– 682. 3. 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;343:311–322. 4. The GUSTO-IIb Angioplasty Substudy Investigators. An international randomized trial of 1138 patients comparing primary coronary angioplasty versus tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997;336:1621–1628. 5. Ellis SG, Topol EJ, Gallison L, Grines CL, Langburd AB, Bates ER, Walton JA Jr, O’Neill WW. Predictors of success for coronary angioplasty performed for acute myocardial infarction. J Am Coll Cardiol 1998;12:1407–1415. 6. Fuster V, Badimon L, Badimon JJ, Cheseboro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (second of two parts). N Engl J Med 1992;326:310 –318. 7. Coller BS. Antiplatelet agents in the prevention and therapy of thrombosis. Annu Rev Med 1992;43:171–180.
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8. Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM. Specific platelet mediators and unstable coronary artery lesions. Circulation 1989;80:198 –205. 9. Gold HK, Garabedian HD, Dinsmore RE, Guerrero LJ, Cigarroa JE, Palacios IF, Leinbach RC. 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. 10. van den Merkhof LF, Zijlstra F, Olsson H, Grip L, Veen G, Bar FW, van den Brand MJ, Simoons ML, Verheugt FW. Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty. Results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study. J Am Coll Cardiol 1999;33:1528 –1532. 11. Antman EM, Giugliano RP, McCabe CH, Gibson M, Adgey AJJ, Ghali M, Coussement P, Anderson KM, Sherer J, Van de Werf F, Braunwald E, for the TIMI 14 Investigators. Abciximab (ReoPro) potentiates thrombolysis in ST elevation myocardial infarction: results from the TIMI 14 trial (abstract). J Am Coll Cardiol 1998;31:191A. 12. Ohman EM, Lincoff AM, Bode C, Bachinsky WB, Ardissimo D, Matteo PS, Betriu A, Schildcrout JS, Sketch M, Topol EJ. Enhanced early reperfusion at 60 minutes with low-dose reteplase combined with full-dose abciximab in acute myocardial infarction: preliminary results form the GUSTO-4 Pilot (SPEED) dose-ranging trial. Circulation 1998;98(suppl I):504. 13. Antman EM, Giugliano RP, Gibson CM, McCabe CH, Coussement P, Kleiman NS, Vahanian A, Adgey AA, Menown I, Rupprecht HJ, Van der Wieken R, Ducas J, Scherer J, AndersonK, Van de Werf F, Braunwald E, for the TIMI 14 investigators. Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. Circulation 1999;99: 2720 –2732. 14. Ohman EM. SPEED. Presented at the 48th Annual Scientific Sessions of the American College of Cardiology: March 7-10, 1999, New Orleans, LA. 15. Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D. 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 1998;77:670 – 677. 16. Yasuda T, Gold HK, Leinbach RC, Yaoita H, Fallon JT, Guerrero L, Napier MA, Bunting S, Collen D. Kistrin, a polypeptide platelet GP IIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activatior in a canine preparation. Circulation 1991;83:1038 –1047. 17. Kleiman NS, Ohman EM, Califf RM, George BS, Kereiakes D, Aguirre FV, Weisman H, Schaible T, Topol EJ. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 fab following thrombolytic therapy: results of the TAMI-8 pilot study. J Am Coll Cardiol 1993;22:381–389. 18. Ohman EM, Kleiman NS, Gacioch G, Worley SJ, Navetta FI, Talley JD, Anderson HV, Ellis SG, Cohen MD, Spriggs D, Miller M, Kereiakes D, Yakubov S, Kitt MM, Sigmon KN, Califf RM, Krucoff MW, Topol EJ, for the IMPACTAMI 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. 19. Ronner E, van Kesteren HAM, Zijnen P, Tebbe U, Molhoek P, Cuffie C, Veltri E, Lorenz T, Neuhaus K, Simoons ML. Combined therapy with streptokinase and Integrelin (abstract). J Am Coll Cardiol 1998;31:191A. 20. 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. 21. Collins R, Peto R, Baigent C, Sleight P. Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J Med 1997;336:847– 860. 22. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: emerging platelet preeminence. Circulation 1998;97:211–218. 23. Herrmann HC, Moliterno DJ, Bode C, Betriu A, Lincoff AM, Ohman EM. Combination abciximab and reduced-dose reteplase facilitates early PCI in acute MI: results from the SPEED trial. Circulation 1999;100(suppl 1):I-188. 24. Greenbaum AB, Harrington RA, Ohman EM. The use of glycoprotein IIb/IIIa inhibition in acute myocardial infarction. In: Lincoff AM, Topol EJ, eds. Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa in Cardiovascular Disease. Philadelphia: Williams & Wilkins, 1999:229 –249. 25. Cigarroa JE, Ferrel MA, Collen DJ, Leinbach RC. Enhanced endogenouscoronary thrombolysis during acute myocardial infarction following selective platelet receptor blockade with ReoPro (abstract). Circulation 1996;94:I-553. 26. Gold HK, Kereiakes DJ, Dinsmore RE, Martin LH, Lausten D, Broderick TM, Anderson KM, Garabedian HD, Leinbach RC. A randomized, placebocontrolled crossover trial of Reopro alone or combined with low-dose plasminogen activator for coronary reperfusion in patients with acute myocardial infarction: preliminary results (abstract). Circulation 1997;96:I-473. 27. Makkar R, Eigler N, Goff B, Fry E, Barr L, D’Haem C, Fischell T, Litvack F. Primary reperfusion in acute myocardial infarction with reopro and heparin: interim results of ReoMI pilot study (abstract). J Am Coll Cardiol 1998;31:94-A.
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