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Synopsis: Available data would suggest that abciximab is the superior agent for use in percutaneous coronary intervention and retains its potent anti-platelet effects despite pretreatment with tirofiban or eptifibatide.
Source: Lev EI, et al. Circulation. 2001;37:84.
Three glycoprotein (GP) IIb-IIIa inhibitors, the long-acting monoclonal antibody, abciximab (ReoPro®—Centocor/Lilly), and 2 short-acting small molecules tirofiban (Aggrastat®—Merck), and eptifibatide (Integrilin®—Cor/Key), have been FDA approved for the treatment of patients with coronary artery disease. Tirofiban and eptifibatide have been shown to be effective in the prevention of ischemic complications in the medical therapy of patients with acute coronary syndromes (ACS) and, therefore, are being used with increasing frequency. Abciximab is the only GP IIb-IIIa inhibitor that has been shown to reduce short-and long-term ischemic complications in patients undergoing percutaneous coronary intervention (PCI) but, in contrast, appears to offer no benefit as medical therapy in ACS. However, in clinical practice, many patients who initially present with ACS, particularly those at highest risk, will eventually undergo PCI. Thus, it often remains difficult to predict which agent will ultimately provide the most beneficial for a given patient.
Lev and colleagues, therefore, sought to determine whether patients receiving medical therapy with a small-molecule GP IIb-IIIa inhibitor could subsequently be treated with abciximab. This small study was designed to assess the efficacy and safety of 20-24 hours of tirofiban or eptifibatide, overlapping with abciximab administration at the time of PCI.
Fifty patients with ACS or recent (< 2 weeks) MI, who were scheduled to undergo PCI within 24 hours, were enrolled in the study. All patients received heparin and aspirin. They were divided into 3 consecutive groups: 25 received tirofiban (bolus and 20-24 hour infusion) followed by abciximab at the time of PCI, 10 received eptifibatide (bolus and 20-24 hour infusion) followed by abciximab at the time of PCI, and 15 received only abciximab (control group) at the time of PCI. Heparin was discontinued after PCI, and all patients receiving stents were treated with 4 weeks of clopidogrel post-procedure.
Efficacy was assessed using several different assays of platelet function in vitro. GP IIb-IIIa receptor binding was measured to assess for any interference with abciximab binding by the small molecule agents. These assays were performed at multiple time points before, during, and after GP IIb-IIIa inhibitor administration. Safety was assessed by serial complete blood counts for evidence of bleeding or thrombocytopenia, need for transfusion, and evidence of clinical bleeding events, as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.
There were no significant differences in baseline demographics between groups. Forty-six patients received coronary stents, and all PCI procedures were deemed successful. The addition of abciximab to tirofiban resulted in additional antiplatelet effects by all assay methods. The addition of abciximab to eptifibatide resulted in additional reduction of platelet function by the surface deposition assay only. The degree of platelet inhibition was greater for either combination therapy than for abciximab alone. Neither tirofiban nor eptifibatide interfered with abciximab binding to the GP IIb-IIIa receptor.
There were no statistically significant differences in safety outcomes among the groups, and complication rates were comparable to or lower than those published in previous clinical trials. There were no major bleeding events or transfusions required in any of the groups. Mild mucocutaneous bleeding occurred in 5 tirofiban-abciximab treated patients, 1 eptifibatide-abciximab treated patient, and 1 control patient. No patient developed severe thromboytopenia (< 50,000 cells/mL). Mild thrombocytopenia developed in 1 patient receiving tirofiban-abciximab, 5 control patients, and in none of the patients receiving eptifibatide-abciximab.
Comment by Sarah M. Vernon, MD
Available data would suggest that abciximab is the superior agent for use in PCI, given the magnitude and durability of benefit demonstrated in the EPIC, EPLILOG, and EPISTENT trials, while both eptifibatide and tirofiban have been shown to have a more modest benefit in multiple trials for patients with ACS. Furthermore, in all of the previously published trials, each of these agents has proved to be of particular benefit for the highest risk subgroups of patients. Within the last several months, initial results of from GUSTO IV, evaluating abciximab in ACS, TACTICS (TIMI 18), and TARGET have become available. In the context of previously published literature, the results from these more recent clinical trials have raised almost as many questions as they answer. In GUSTO IV, 48 hours of abciximab as medical therapy resulted in no reduction in ischemic complications (and a concerning trend toward increased mortality) in patients with ACS. TACTICS demonstrated the superiority of an early invasive strategy vs. an early conservative strategy in the management of patients with ACS treated with tirofiban. TARGET demonstrated superior outcomes for abciximab compared with tirofiban, in the first published head-to-head comparison of GP IIb-IIIa inhibitors for patients undergoing PCI. Thus, there are more data supporting the use of the short-acting small molecule drugs (tirofiban and eptifibatide) in ACS and abciximab in PCI. However, given that the highest risk ACS patients, those most likely to suffer ischemic complications and most likely to benefit from GP IIb-IIIa inhibition, are also the most likely to ultimately require PCI, a conundrum arises. Despite large amounts of data from many randomized trials, it remains difficult to determine which agent to administer to which patient and in what time frame.
The study by Lev et al is important in that it is the first published to evaluate the combination of abciximab and intravenous GP IIb-IIIa inhibitor therapy in vivo. Lev et al acknowledge that this study has obvious and significant limitations, most notably small sample size and the consecutive (nonrandomized, nonblinded) pattern of treatment group assignment. Despite these limitations, the study suggests that abciximab retains its potent antiplatelet effects in the presence of pretreatment with tirofiban or eptifibatide. While the small sample size make the data assessing safety of combination therapy less convincing, the study also suggests that medical therapy with tirofiban or eptifibatide can be safely overlapped with abciximab should such a patient ultimately require PCI. These results, while preliminary, are compelling, and in time may be borne out when data from larger randomized trials assessing combination therapy become available.