Eptifibatide

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Abstract
Eptifibatide, a cyclic peptide, is a highly specific, intravenously administered glycoprotein (GP) IIb/IIIa receptor antagonist. By preventing fibrinogen binding to the GP IIb/IIIa receptor, eptifibatide inhibits platelet aggregation and prevents thrombus formation. Clinically, the drug is used as an adjunct to heparin and aspirin. The PURSUIT trial, conducted in >10 000 patients with unstable angina or non-Q-wave myocardial infarction (MI), showed that eptifibatide (180 μg/kg bolus then 2 μg/kg/min infusion for ≤72 hours) reduces the 30-day risk of death or nonfatal MI, with this benefit apparent at 96 hours. The absolute reduction in this end-point of 1.5% persisted at 6 months. The drug is effective in patients undergoing percutaneous coronary intervention (PCI), and, as shown in the North American subgroup, in patients in whom medical management is appropriate. Eptifibatide is also beneficial in patients undergoing PCI, whether or not they have unstable angina or non-Q-wave MI. In a dosage of 135 μg/kg then 0.5 μg/kg/min for 24 hours, eptifibatide reduced the 30-day risk of a combined end-point (death, nonfatal MI and urgent or emergency coronary interventions) by 2.5% (absolute reduction) in patients undergoing PCI in the IMPACT-II trial, when measured by per-protocol (patients treated), but not intent-to-treat, analysis. The drug also decreased the incidence of abrupt vessel closure and ischaemic cardiovascular complications in the first 24 hours (the period of greatest risk). Bleeding episodes are the most common adverse event associated with eptifibatide therapy. Although the incidence of major bleeding is increased with eptifibatide, most bleeding episodes are minor and occur at the vascular access site. The drug is not associated with an excess of intracranial bleeds, stroke or thrombocytopenia, does not appear to increase bleeding risk in patients undergoing coronary artery bypass graft (CABG), and does not cause antibody formation. Limited data suggest that eptifibatide may improve coronary flow when combined with alteplase in patients with acute Q-wave MI, but the possibility of increased bleeding with eptifibatide plus thrombolytics should be borne in mind. Conclusions: Intravenous eptifibatide, when combined with aspirin and heparin, reduces the 30-day risk of ischaemic events in patients with unstable angina and non-Q-wave MI and decreases ischaemic cardiovascular complications at the time of greatest risk in patients undergoing PCI. With its acceptable tolerability profile eptifibatide is a suitable option as a short term adjunct in these clinical settings. Whether eptifibatide in combination with fibrolysis may improve outcome in patients with acute Q-wave MI has yet to be determined. Atherosclerotic plaque rupture or fissure followed by platelet activation, platelet aggregation and thrombus formation is the pathophysiology common to all forms of acute coronary syndromes (ACS) [unstable angina, non-Q-wave myocardial infarction (MI) and acute Q-wave MI]. This process is also a primary cause of abrupt vessel closure in patients undergoing percutaneous coronary intervention (PCI). Spontaneous plaque rupture exposes the subendothelium to thrombogenic substances and initiates platelet activation. Activation of the platelet glycoprotein (GP) IIb/IIIa receptor is the final common pathway for platelet aggregation. Platelet activation promotes conformational changes in the GP IIb/IIIa receptor, permitting fibrinogen to bind with these sites. Fibrinogen causes cross-linking of platelets, leading to the development of platelet-rich arterial thrombi. Eptifibatide is a highly specific antagonist of the GP IIb/IIIa receptor. The drug dose-dependently inhibits ex vivo platelet aggregation in patients with ACS and inhibits fibrinogen binding to adenosine diphosphate (ADP)-activated platelets, as shown in healthy volunteers and patients undergoing PCI. ADP-induced platelet aggregation is inhibited as early as 5 minutes after starting an eptifibatide infusion, persists for the duration of the infusion and returns to normal within 4 to 8 hours in patients with ACS. >80% inhibition of platelet aggregation has been achieved with an eptifibatide bolus of 180 μg/kg and an infusion rate of 2 μg/kg/min. Eptifibatide produces 2- to 4-fold greater inhibition of platelet aggregation when assayed using citrate anticoagulation (which chelates Ca++, thereby increasing eptifibatide binding to the GP IIb/IIIa receptor) than when using a nonchelating anticoagulant. Conversely, using TRAP (thrombin receptor agonist peptide) rather than ADP as a platelet agonist may underestimate the effects of eptifibatide on platelet aggregation by about 25%. These findings may have hindered the accurate determination of eptifibatide dosages used in early clinical trials. Eptifibatide increases bleeding times approximately 2- to 4-fold compared with baseline in patients with unstable angina or non-Q-wave MI as well as those undergoing PCI. Bleeding times return toward normal 1 hour after stopping the infusion. Eptifibatide displays linear, dose-proportional pharmacokinetics. Steady state is achieved within 4 to 6 hours. Eptifibatide is about 25% bound to plasma proteins. Most of a dose of eptifibatide excreted in the urine is recovered as the parent drug, the deamidated metabolite and several more polar metabolites. No major eptifibatide metabolites have been detected in human plasma. About 40% of total body clearance occurs via renal mechanisms. Systemic clearance assessed by population pharmacokinetics was 9.1 L/h in patients undergoing PCI. Eptifibatide clearance is predicted to be decreased and plasma concentrations to be increased in patients with severe renal impairment (serum creatinine >2 to 4 mg/dl) and in older patients (>60 years). Elimination half-life was about 2.5 hours to 2.8 hours in patients undergoing PCI. Patients with unstable angina or non-Q-wave MI (medically managed or undergoing PCI). As shown by the PURSUIT trial conducted in >10 000 patients, eptifibatide (180 μg/kg bolus then 2 μg/kg/min infusion for ≤72 hours) significantly reduces the short term (30-day) risk of death or nonfatal MI in patients with unstable angina or non-Q-wave MI. The absolute reduction of 1.5% (relative reduction of 16.5%), compared with placebo, in this primary end-point was evident at 96 hours and persisted at 7, 30 and 180 days. The incidence of the individual events of death or MI in the eptifibatide group did not differ significantly from that with placebo at 30 days. Prior aspirin use and concomitant heparin therapy is associated with improved outcome during eptifibatide treatment. The efficacy of eptifibatide varied according to geographical location: factors such as gender, age, heparin use and the type and rate of interventions may have been responsible. In the total population of patients managed medically (not undergoing PCI), the 7% decrease in relative risk of combined end-point with eptifibatide was not significant versus placebo. However, patients treated in North America, who underwent interventions more frequently than in other regions, had a significant and pronounced decrease in risk when the overall population was considered and when evaluating the sub-group who were managed medically. Patients undergoing PCI. Eptifibatide has shown efficacy in patients undergoing PCI. In the IMPACT-II trial, conducted in patients undergoing elective or urgent PCI, eptifibatide (135 μg/kg then 0.5 or 0.75 μg/kg/min for 24 hours) reduced the incidence of acute complications (composite of death, MI, and need for PCI) relative to placebo within 24 hours of starting the infusion. Abrupt vessel closure was also significantly less frequent with the lower eptifibatide dosage than with placebo, as assessed by per-protocol analysis. Eptifibatide (administered in the lower dosage regimen) was associated with a significant 2.5% absolute (22% relative) reduction in the primary combined end-point at 30 days when measured by per-protocol (but not intent-to-treat) analysis. Data from IMPACT-I and the PURSUIT trial add weight to these findings. Eptifibatide is beneficial in patients with or without unstable angina or non-Q-wave MI who undergo PCI (‘high risk’ and ‘low risk’, respectively). Patients with acute Q-wave MI. Experience with eptifibatide in acute Q-wave MI is limited. Eptifibatide (180 μg/kg bolus then 0.75 μg/kg/min infusion for 24 hours) plus accelerated alteplase significantly increased TIMI grade 3 flow and shortened time to ST-segment recovery, compared with placebo, in the IMPACT-AMI trial. No clear benefit was gained by adding eptifibatide to a streptokinase regimen. Most bleeding episodes during eptifibatide therapy are minor and develop most often at the vascular access (femoral puncture) site. Variability in the incidence of bleeding among clinical trials may be due to various risk factors (e.g. advanced age, female gender, larger heparin doses, major coronary dissection and interventions) and differences in eptifibatide dosages used. The incidence of major bleeding is increased with eptifibatide, as shown by the PURSUIT trial: more eptifibatide (10.6%) than placebo (9.1%) recipients had major bleeding and required red blood cell transfusion (relative risk 1.3). Combining eptifibatide with thrombolytics appears to increase bleeding risk. On the other hand, eptifibatide is not associated with an excess of intracranial bleeds, stroke or thrombocytopenia, does not appear to increase bleeding risk in patients undergoing coronary artery bypass graft (CABG), and does not cause antibody formation. In patients with unstable angina or non-Q-wave MI. The recommended dosage of eptifibatide is 180 μg/kg given as an intravenous bolus as soon as possible after diagnosis, then 2 μg/kg/min as a continuous intravenous infusion administered until hospital discharge or CABG is started. Maximum duration should be 72 hours. In patients with these syndromes who undergo PCI, consideration can be given to decreasing the eptifibatide infusion rate to 0.5 μg/kg/min during the procedure. The infusion should be continued for a further 20 to 24 hours, to a maximum of 96 hours of eptifibatide therapy. In patients undergoing PCI but not presenting with unstable angina or non-Q-wave MI. An intravenous bolus of eptifibatide 135 μg/kg is administered immediately prior to starting PCI followed by 0.5 μg/kg/min given by continuous infusion for 20 to 24 hours. Dosage adjustment is not needed in the elderly or in patients with mild to moderate renal dysfunction (serum creatinine <2 mg/dl). Caution should be used when administering eptifibatide with other drugs affecting haemostasis. Eptifibatide is contraindicated in patients with bleeding abnormalities, stroke, severe hypertension or severe renal impairment.