Author + information
- Received December 13, 2002
- Revision received March 26, 2003
- Accepted April 10, 2003
- Published online July 2, 2003.
- ↵*Reprint requests and correspondence:
Dr. Mark J. Eisenberg, Divisions of Cardiology and Clinical Epidemiology, Jewish General Hospital/McGill University, 3755 Cote Ste. Catherine Road/Suite A-118, Montreal, Quebec H3T 1E2, Canada.
Glycoprotein (GP) IIb/IIIa inhibitors have been extensively studied in the setting of percutaneous coronary intervention (PCI) and in the management of non–ST-segment elevation acute coronary syndromes. However, the use of GP IIb/IIIa inhibitors is less well established in the setting of acute ST-segment elevation myocardial infarction (MI). Multiple nonrandomized studies suggest that combination therapy with GP IIb/IIIa inhibitors and thrombolytic agents leads to increased rates of TIMI 3 flow. However, two clinical trials involving over 22,000 patients demonstrated that combination therapy is associated with only modest reductions in major adverse cardiac events, does not reduce mortality, and is associated with an increase in bleeding. In the setting of primary PCI, four clinical trials involving over 3,000 patients demonstrated that GP IIb/IIIa inhibition results in a significant decrease in the need for urgent target vessel revascularization but not in reductions of death or recurrent MI. Thus, GP IIb/IIIa inhibition may provide only limited benefits in the setting of acute ST-segment elevation MI.
Three glycoprotein (GP) IIb/IIIa inhibitors are currently available: abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). These agents have been extensively studied in the setting of percutaneous coronary intervention (PCI) and in the management of non–ST-segment elevation acute coronary syndromes. However, there have been relatively few studies of these agents in the setting of acute ST-segment elevation myocardial infarction (MI), and their use in this setting is less well established. The purpose of this paper is to examine the current literature on the efficacy and safety of GP IIb/IIIa inhibition in the setting of acute ST-segment elevation MI.
Several studies have examined whether GP IIb/IIIa inhibitors alone can be used to improve Thrombolysis In Myocardial Infarction (TIMI) flow in the setting of acute ST-segment elevation MI (1–4). These studies demonstrate that, in patients who receive GP IIb/IIIa inhibitors, up to 32% develop TIMI 3 flow by 90 min after administration. In contrast, thrombolytic agents achieve TIMI 3 flow in up to 57% of patients (1–3,5). Although thrombolytic agents lead to higher rates of TIMI 3 flow, they paradoxically increase platelet aggregation (6,7). Hence, the theoretical foundation was laid for the use of combination therapy with a thrombolytic agent plus a GP IIb/IIIa inhibitor. It was hoped that this combination would increase reperfusion rates, allow for reduced thrombolytic dosages, and decrease bleeding complications.
Early studies suggested that combination therapy does, in fact, lead to increased reperfusion rates over thrombolytics alone. In the Integrelin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction (IMPACT-AMI) study, all patients received accelerated alteplase (≤100 mg) with or without the addition of eptifibatide and then underwent angiography at 90 min (8). Rates of TIMI 3 flow improved with the addition of eptifibatide (66% vs. 39%, p = 0.006), and rates of TIMI 2 and 3 flow also improved (87% vs. 69%, p = 0.01). The TIMI 14 investigators reported similar results (5). They found that the combination of tissue plasminogen activator (50 mg) plus abciximab improved TIMI 3 flow at 60 min (72% vs. 43%, p = 0.0009). Results from other studies, such as Integrelin and Reduced-dose Thrombolytics in Acute Myocardial Infarction (INTRO AMI) and Strategies for Patency Enhancement in the Emergency Department (SPEED), also reported higher rates of TIMI 3 flow in patients receiving combination therapy (3,4)(Fig. 1).
Only two randomized trials have examined the impact of combination therapy on clinical events (Table 1). The Global Utilization of Strategies to open Occluded Coronary Arteries-V (GUSTO-V) trial compared thrombolytic therapy alone versus the combination of abciximab plus thrombolytic therapy in the setting of acute ST-segment elevation MI (9). A total of 16,588 patients were randomized within 6 h of the onset of chest pain to full dose reteplase or to half dose reteplase plus full dose abciximab. Patients in both arms of the trial received unfractionated heparin. The primary end point was mortality. At 30 days, the investigators found no difference between the two treatment arms in terms of the primary end point (reteplase 5.9% vs. combination 5.6%, p = 0.43). Similarly, no significant difference was seen in the occurrence of stroke (0.3% vs. 0.2%, respectively, p = 0.37). In addition, none of the prespecified subgroups (e.g., women, elderly, diabetics, anterior MI) appeared to have a clinical benefit with combination therapy in terms of mortality. However, the investigators did observe that combination therapy was associated with modest reductions in the rates of certain prespecified complications such as reinfarction (3.5% vs. 2.3%, p < 0.0001), ventricular fibrillation (3.5% vs. 2.7%, p = 0.01), and ventricular septal defect (0.3% vs. 0.2%, p = 0.05).
Although combination therapy was associated with modest reductions in some clinical events, rates of bleeding and need for transfusion were significantly higher with combination therapy. Severe bleeding occurred in 0.5% of patients receiving thrombolytic therapy alone versus 1.1% of patients receiving combination therapy (p < 0.0001). Transfusions were required in 4.0% of patients who received thrombolytic therapy alone versus 5.7% of patients who received combination therapy (p < 0.0001). Mild to severe bleeding occurred in 13.7% of patients who received thrombolytic therapy alone versus almost 25% of patients who received combination therapy (p < 0.0001). Importantly, among patients > 75 years of age, intracranial hemorrhage occurred less frequently with thrombolytic therapy than with combination therapy (1.1% vs. 2.1%, p = 0.069) (9).
The GUSTO-V investigators recently published their one-year follow-up results (10). Similar to their mortality results at 30 days, no mortality benefit was seen at one year for patients treated with reteplase alone versus combination therapy (8.4% vs. 8.4%, respectively, p > 0.99) (10). Thus, the GUSTO-V trial demonstrated that combination therapy with half-dose reteplase plus full-dose abciximab leads to only modest clinical benefits but at the cost of increased bleeding complications.
The Assessment of the Safety and Efficacy of a New Thrombolytic-III (ASSENT-III) trial also examined the use of combination therapy in the setting of acute ST-segment elevation MI (11). A total of 6,095 patients were randomized in this trial <6 h from the onset of chest pain. Patients were randomized to one of three arms: 1) full dose tenecteplase-tissue plasminogen activator plus standard dose unfractionated heparin, 2) full dose tenecteplase-tissue plasminogen activator plus low-molecular-weight heparin (enoxaparin), and 3) half dose tenecteplase-tissue plasminogen activator plus full dose abciximab. The primary outcome was a composite of death, reinfarction, and refractory ischemia. The investigators found that patients who received unfractionated heparin had significantly higher rates of the primary end point than those who received enoxaparin or abciximab (15.4% vs. 11.4% and 11.1%, respectively, p = 0.0001 for unfractionated heparin vs. pooled). For the secondary composite end point, which was composed of the primary end point plus intracranial hemorrhage and major bleeding, the enoxaparin group (13.8%) fared slightly better than the abciximab group (14.2%) while the unfractionated heparin group (17.0%) was inferior (p = 0.008 for unfractionated heparin versus pooled) (2). Major bleeding events were seen most commonly in the abciximab group (4.3%), then in the enoxaparin group (3.0%), and lastly in the heparin group (2.2%) (p = 0.0005 for abciximab vs. pooled). Patients in each of the three groups had an intracranial hemorrhage rate of 0.9%. Thus, while combination therapy was more efficacious than tenecteplase-tissue plasminogen activator plus unfractionated heparin, tenecteplase-tissue plasminogen activator plus enoxaparin was associated with clinical benefits similar to those with combination therapy but with lower rates of bleeding.
Thus, both the GUSTO-V and ASSENT-III trials showed comparable results. Combination therapy consisting of a half dose thrombolytic agent plus full dose abciximab was not found to be superior to full dose thrombolytic therapy. Although both trials suggested a modest clinical benefit with combination therapy, bleeding complications were increased. In addition, ASSENT-III suggested that thrombolytic therapy plus low-molecular-weight heparin provided similar clinical outcomes as combination therapy but without the higher bleeding complications.
Primary PCI has been found to be superior to thrombolytic therapy in multiple randomized trials (12–15). Because of the increasing use of primary PCI, investigation into the utility of GP IIb/IIIa inhibition in this setting is germane (16). Four clinical trials have examined the use of GP IIb/IIIa inhibition in the setting of primary PCI (Table 2). The Reopro in Acute Myocardial Infarction and Primary PTCA Organization and Randomized (RAPPORT) trial compared GP IIb/IIIa inhibition versus placebo in the setting of primary PCI (17). A total of 482 patients underwent primary PCI within 12 h of chest pain onset. Patients received either abciximab as an intravenous bolus followed by a 12-h infusion or placebo bolus and infusion. The primary end point of death, recurrent MI, and target vessel revascularization was significantly reduced by abciximab at both 30 days (5.8% vs. 11.2%, p = 0.03) and 6 months (11.6% vs. 17.8%, p = 0.05). However, there was no difference in the composite of death or MI at 30 days (4.6% vs. 5.8%, p = 0.52) or 6 months (8.7% vs. 11.2%, p = 0.36). Thus, the reduction in the primary end point was driven by the reduction in the need for urgent target vessel revascularization at 30 days (1.7% vs. 6.6%, p = 0.006) and at 6 months (3.3% vs. 8.7%, p = 0.01).
The Intracoronary Stenting and Antithrombotic Regimen-2 (ISAR-2) trial compared abciximab plus heparin versus heparin alone on restenosis after primary stent implantation in the setting of acute MI (18). This study was a single blind trial involving 401 patients with ST-segment elevation MI who underwent cardiac catheterization and stent implantation within 48 h of the onset of chest pain. For the primary end point of restenosis, the ISAR-2 investigators found that there was no impact with GP IIb/IIIa inhibition. However, the investigators also reported on clinical event rates at both 30 days and 6 months. They found that the composite end point of death, recurrent MI, and ischemic target lesion revascularization was reduced in the heparin plus abciximab group at 30 days (5.0% vs. 10.5%, p = 0.038). There was also a nonsignificant reduction in the secondary composite end point of death or recurrent MI (2.5% vs. 6.0%, p = 0.08). At six months, however, a significant reduction in the composite end point was no longer present (p = 0.17). Thus, in the ISAR-2 trial, abciximab exerted beneficial effects at 30 days by reducing the rate of major cardiac events (primarily ischemic target lesion revascularization), but this finding was no longer present at 6 months.
The Abciximab Before Direct Angioplasty and Stenting in MI Regarding Acute and Long-term Follow-up (ADMIRAL) trial was the first to examine the use of GP IIb/IIIa inhibition using contemporary primary PCI techniques (19). The purpose of this trial was to compare primary PCI with stenting plus abciximab versus primary PCI with stenting alone. The trial enrolled 300 patients with ST-segment elevation MI randomized within 12 h of the onset of chest pain. Patients received either abciximab or placebo before arterial sheath insertion and cardiac catheterization. The investigators found a significant reduction in the composite outcome of death, recurrent MI, and urgent target vessel revascularization at both 30 days (abciximab 6.0% vs. placebo 14.6%, p = 0.01) and 6 months (7.4% vs. 15.9%, p = 0.02). As in the RAPPORT trial, however, the reduction in the primary end point was solely driven by the reduction in urgent target vessel revascularization. There was a significant reduction in urgent target vessel revascularization at 30 days (1.3% vs. 6.6%, p = 0.02) and at 6 months (2.0% vs. 6.6%, p = 0.049), while there was no reduction in death or recurrent MI.
The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial examined the interaction between stenting and GP IIb/IIIa inhibition in the setting of primary PCI (20). A total of 2,082 patients were randomized in a two-by-two factorial design to one of four arms: balloon angioplasty alone (n = 518), balloon angioplasty plus abciximab (n = 528), stenting alone (n = 512), and stenting plus abciximab (n = 524). In comparison with the ADMIRAL trial, abciximab was given only at the time of angioplasty. The investigators found that rates of TIMI 3 flow were similar in each of the four arms of the trial after PCI and that there were no differences in either death or recurrent MI. There was a substantial reduction in ischemic target vessel revascularization with the use of stenting and a further modest reduction with the addition of abciximab. At six months, patients who received stenting plus abciximab had an ischemic target vessel revascularization rate of 5.2% versus 8.3% in patients who received stenting alone (p = 0.47). For the composite of major adverse cardiac events, there was a substantial reduction for patients who received stents. However, the addition of abciximab did not appear to provide additional clinical benefit. Thus, routine stent implantation during primary PCI resulted in lower rates of clinical events when compared with balloon angioplasty alone. The use of abciximab reduced the rates of ischemic target vessel revascularization after both balloon angioplasty and stenting. Abciximab did not, however, significantly improve TIMI flow rates after either balloon angioplasty or stenting. The relative lack of benefit of abciximab in the CADILLAC trial may have been due to its later administration compared with its early administration in the ADMIRAL trial.
It is important to note that abciximab is not the only GP IIb/IIIa inhibitor that has been examined in the setting of primary PCI. The Emergency Room Administration of Eptifibatide before Primary Angioplasty (RAPIER) study involved the use of eptifibatide in patients with acute ST-segment elevation MI (21). Patients in the early treatment arm received administration of epitfibatide in the emergency room, and another dose on arrival in the catheterization laboratory. Patients in the late treatment arm only received eptifibatide in the catheterization laboratory. The TIMI 2 and 3 flow rates at the time of angiography were higher in the early treatment arm (56.7% vs. 13.3%, respectively, p = 0.001). Unfortunately, the RAPIER study was not a randomized trial, and the study was underpowered to examine clinical events.
We pooled the results of the four trials examining the use of abciximab in the setting of primary PCI (Table 3). We divided the trials into those that examined balloon angioplasty alone and those that examined angioplasty plus stenting. It is important to note that, in the balloon angioplasty trials, stents were used as a bail-out treatment, and, consequently, only 14.5% of patients in the RAPPORT trial and 16.0% of patients in the balloon angioplasty arm of the CADILLAC trial received stents. Of the patients enrolled in the stent trials, 99.0% in ISAR-2, 92.0% in ADMIRAL, and 98.0% in the stent arm of CADILLAC received at least one stent (17–20).
At 30 days, the use of abciximab resulted in significant reductions in the composite end point of death, recurrent MI, and urgent target vessel revascularization in both the balloon angioplasty and stent groups. The reduction in the composite end point was driven by substantial reductions in rates of urgent target vessel revascularization, and there was no major difference between the angioplasty and stent groups. At six months, results were similar. Abciximab use was associated with a 27% reduction in composite events, but this outcome was solely driven by the reduction in urgent target vessel revascularization. From our pooled results, it is apparent that abciximab use in the setting of primary PCI is associated with a substantial reduction in urgent target vessel revascularization at 30 days, and this result still persists at 6 months. We further calculated that 37 patients need to be treated with a GP IIb/IIIa inhibitor in order to prevent one urgent target vessel revascularization at 30 days, and 33 patients need to be treated to prevent one urgent target vessel revascularization at six months.
Although GP IIb/IIIa inhibitors have been closely studied in the setting of both PCI and non–ST-segment elevation acute coronary syndromes, relatively few studies have examined their use in the setting of acute ST-segment elevation MI. Because GP IIb/IIIa inhibitors are potent suppressors of platelet aggregation and because acute MI is due to platelet-dependent thrombus formation, there is a good theoretical foundation for the use of GP IIb/IIIa inhibitors in this setting. However, clinical trials examining the combination of GP IIb/IIIa inhibitors with thrombolytic agents have been disappointing. Combination therapy has not been found to reduce mortality, is only associated with modest reductions in some clinical events, and has been associated with increased rates of bleeding. In the setting of primary PCI, results have been somewhat more promising. The use of GP IIb/IIIa inhibitors in this setting leads to substantial reductions in rates of urgent target vessel revascularization. However, reductions in death and recurrent MI have not been demonstrated.
The authors thank Ms. Laura Gioia and Mr. Philippe Violette for their help in the preparation of this manuscript, as well as the reviewers for their helpful comments.
☆ Dr. Eisenberg is a Physician-Scientist of the Quebec Foundation for Health Research.
- Abciximab Before Direct Angioplasty and Stenting in MI Regarding Acute and Long-term Follow-up
- Assessment of the Safety and Efficacy of a New Thrombolytic-III
- Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications
- Global Utilization of Strategies to open Occluded Coronary Arteries-V
- Integrelin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction
- INTRO AMI
- Integrelin and Reduced-dose Thrombolytics in Acute Myocardial Infarction
- Intracoronary Stenting and Antithrombotic Regimen-2
- myocardial infarction
- percutaneous coronary intervention
- Reopro in Acute Myocardial Infarction and Primary PTCA Organization and Randomized Trial
- Strategies for Patency Enhancement in the Emergency Department
- Thrombolysis In Myocardial Infarction
- Received December 13, 2002.
- Revision received March 26, 2003.
- Accepted April 10, 2003.
- American College of Cardiology Foundation
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