Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic group: Antithrombotic agent (platelet aggregation inhibitors excl. heparin)
ATC code: B01AC16
Eptifibatide, a synthetic cyclic heptapeptide containing six amino acids, including one cysteine amide and one mercaptopropionyl (desamino cysteinyl) residue, is an inhibitor of platelet aggregation and belongs to the class of RGD (arginine-glycine-aspartate)-mimetics.
Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive ligands to the glycoprotein (GP) IIb/IIIa receptors.
Eptifibatide inhibits platelet aggregation in a dose- and concentration-dependent manner as demonstrated by ex vivo platelet aggregation using adenosine diphosphate (ADP) and other agonists to induce platelet aggregation. The effect of eptifibatide is observed immediately after administration of a 180 microgram/kg intravenous bolus. When followed by a 2.0 microgram/kg/min continuous infusion, this regimen produces a >80% inhibition of ADP-induced ex vivo platelet aggregation, at physiologic calcium concentrations, in more than 80% of patients.
Platelet inhibition was readily reversed, with a return of platelet function towards baseline (>50% platelet aggregation) 4 hours after stopping a continuous infusion of 2.0 microgram/kg/min. Measurements of ADP-induced ex vivo platelet aggregation at physiologic calcium concentrations (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone anticoagulant) in patients presenting with unstable angina and Non Q-Wave Myocardial Infarction showed a concentration-dependent inhibition with an IC50 (50% inhibitory concentration) of approximately 550 ng/ml and an IC80 (80% inhibitory concentration) of approximately 1,100 ng/ml.
There is limited data with regards to platelet inhibition in patients with renal impairment. In patients with moderate renal impairment, (creatinine clearance 30–50mL/min) 100% inhibition was achieved at 24 hours following administration of 2 microgram/kg/min. In patients with severe renal impairment (creatinine clearance <30mL/min) administered 1microgram/kg/min, 80% inhibition was achieved in more than 80% of patients at 24 hours.
The pivotal clinical trial for Unstable Angina (UA)/Non-Q Wave Myocardial Infarction (NQMI) was PURSUIT. This study was a 726-center, 27-country, double-blind, randomised, placebo-controlled study in 10,948 patients presenting with UA or NQMI. Patients could be enrolled only if they had experienced cardiac ischemia at rest (≥ 10 minutes) within the previous 24 hours and had:
Patients were randomised to either placebo, eptifibatide 180 microgram/kg bolus followed by a 2.0 microgram/kg/min infusion (180/2.0), or eptifibatide 180 microgram/kg bolus followed by a 1.3 microgram/kg/min infusion (180/1.3).
The infusion was continued until hospital discharge, until the time of coronary artery bypass grafting (CABG) or for up to 72 hours, whichever occurred first. If PCI was performed, the eptifibatide infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours.
The 180/1.3 arm was stopped after an interim analysis, as prespecified in the protocol, when the two active-treatment arms appeared to have a similar incidence of bleeding.
Patients were managed according to the usual standards of the investigational site; frequencies of angiography, PCI and CABG therefore differed widely from site to site and from country to country. Of the patients in PURSUIT, 13% were managed with PCI during eptifibatide infusion, of whom approximately 50% received intracoronary stents; 87% were managed medically (without PCI during eptifibatide infusion).
The vast majority of patients received acetylsalicylic acid (75-325 mg once daily). Unfractionated heparin was administered intravenously or subcutaneously at the physician’s discretion, most commonly as an intravenous bolus of 5,000 U followed by a continuous infusion of 1,000 U/h. A target aPTT of 50-70 seconds was recommended. A total of 1,250 patients underwent PCI within 72 hours after randomisation, in which case they received intravenous unfractionated heparin to maintain an activated clotting time (ACT) of 300-350 seconds.
The primary endpoint of the study was the occurrence of death from any cause or new myocardial infarction (MI) (evaluated by a blinded Clinical Events Committee) within 30 days of randomisation. The component MI could be defined as asymptomatic with enzymatic elevation of CK-MB or new Q wave.
Compared to placebo, eptifibatide administered as 180/2.0 significantly reduced the incidence of the primary endpoint events (table 1): this represents around 15 events avoided for 1,000 patients treated:
Table 1. Incidence of Death/CEC-Assessed MI («Treated as Randomised» Population):
| Time | Placebo | Eptifibatide | p-Value |
|---|---|---|---|
| 30 days | 743/4,697 (15.8%) | 667/4,680 (14.3%) | 0.0346a^ |
a: Pearson’s chi-square test of difference between placebo and eptifibatide.
Results on the primary endpoint were principally attributed to the occurrence of myocardial infarction. The reduction in the incidence of endpoint events in patients receiving eptifibatide appeared early during treatment (within the first 72-96 hours) and this reduction was maintained through 6 months, without any significant effect on mortality.
Patients most likely to benefit from eptifibatide treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina. According to epidemiological findings, a higher incidence of cardiovascular events has been associated with certain indicators, for instance:
PURSUIT was conducted at a time when the standard of care of managing acute coronary syndromes was different from that of present times in terms of thienopyridine use and the routine use of intracoronary stents.
ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with eptifibatide Therapy) was a double-blind, randomised, placebo-controlled trial (n=2,064) for nonurgent PCI with intracoronary stenting.
All patients received routine standard of care and were randomised to either placebo or eptifibatide (2 bolus doses of 180 microgram/kg and a continuous infusion until discharge from hospital or a maximum of 18-24 hours).
The first bolus and the infusion were started simultaneously, immediately before the PCI procedure and were followed by a second bolus 10 minutes after the first. The rate of infusion was 2.0 microgram/kg/min for patients with serum creatinine ≤175 micromols/l or 1.0 microgram/kg/min for serum creatinine >175 up to 350 micromols/l.
In the eptifibatide arm of the trial, virtually all patients received aspirin (99.7%), and 98.1% received a thienopyridine, (clopidogrel in 95.4% and ticlopidine in 2.7%). On the day of PCI, prior to catheterization, 53.2% received a thienopyridine (clopidogrel 52.7%; ticlopidine 0.5%) – mostly as a loading dose (300 mg or more). The placebo arm was comparable (aspirin 99.7%, clopidogrel 95.9%, ticlopidin 2.6%).
The ESPRIT trial used a simplified regimen of heparin during PCI that consisted of an initial bolus of 60 units/kg, with a target ACT of 200-300 seconds. The primary endpoint of the trial was death (D), MI, urgent target vessel revascularisation (UTVR), and acute antithrombotic rescue with GP IIb/IIIa inhibitor therapy (RT) within 48 hours of randomisation.
MI was identified per the CK-MB core laboratory criteria. For this diagnosis, within 24 hours after the index PCI procedure, there had to be at least two CK-MB values ≥3 x the upper limit of normal; thus, validation by the CEC was not required. MI could also be reported following CEC adjudication of an investigator report.
The primary endpoint analysis [quadruple composite of death, MI, urgent target vessel revascularisation (UTVR) and thrombolytic bail-out (TBO) at 48 hours] showed a 37% relative and 3.9% absolute reduction in the eptifibatide group (6.6% events versus 10.5%, p = 0.0015). Results on the primary endpoint were mainly attributed to the reduction of enzymatic MI occurrence, identified as the occurrence of early elevation of cardiac enzymes after PCI (80 out of 92 MIs in the placebo group vs. 47 out of 56 MIs in the eptifibatide group). The clinical relevance of such enzymatic MIs is still controversial.
Similar results were also obtained for the 2 secondary endpoints assessed at 30 days: a triple composite of death, MI and UTVR, and the more robust combination of death and MI.
The reduction in the incidence of endpoint events in patients receiving eptifibatide appeared early during treatment. There was no increased benefit thereafter, up to 1 year.
Administration of eptifibatide by intravenous bolus and infusion causes up to a 5-fold increase in bleeding time. This increase is readily reversible upon discontinuation of the infusion with bleeding times returning towards baseline in approximately 6 (2-8) hours. When administered alone, eptifibatide has no measurable effect on prothrombin time (PT) or activated partial thromboplastin time (aPTT).
EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome) was a study of early routine eptifibatide versus placebo (with delayed provisional use of eptifibatide in the catheterization laboratory) used in combination with antithrombotic therapies (ASA, UFH, bivalirudin, fondaparinux or low molecular weight heparin), in subjects with high-risk NSTE ACS. Patients were to undergo an invasive strategy for further management after receiving study drug for 12 to 96 hours. Patients could be medically managed, proceed to coronary artery bypass graft (CABG), or undergo percutaneous coronary intervention (PCI). Unlike the approved posology in the EU, the study used a double bolus of study drug (separated by 10 minutes) before the infusion.
Early routine eptifibatide in this high-risk NSTE-ACS optimally-treated population who were managed with an invasive strategy did not result in a statistically significant reduction in the composite primary endpoint of rate of death, MI, RI-UR, and TBO within 96 hours compared with a regimen of delayed provisional eptifibatide (9.3% in early eptifibatide patients vs. 10.0% in patients assigned to delayed provisional eptifibatide; odds ratio=0.920; 95% CI=0.802-1.055; p=0.234). GUSTO severe/life threatening bleeding was uncommon and comparable in both treatment groups (0.8%). GUSTO moderate or severe/life threatening bleeding occurred significantly more often with early routine eptifibatide (7.4% vs. 5.0% in delayed provisional eptifibatide group; p <0.001). Similar differences were noted for TIMI major haemorrhage (118 [2.5%] in early routine use vs. 83 [1.8%] in delayed provisional use; p=0.016).
No statistically significant benefit of early routine eptifibatide strategy was demonstrated in the subgroup of patients who were managed medically or during the medical management periods prior to PCI or CABG.
In a post hoc analysis of the EARLY ACS trial the risk benefit of dose reduction in patients with moderate renal impairment is inconclusive. The primary endpoint event rate was 11.9% in patients who received a reduced dose (1microgram/kg/min) vs 11.2% in patients who received the standard dose (2microgram/kg/min) when eptifibatide was administered in the early routine fashion (p=0.81). With delayed provisional eptifibatide administration, the event rates were 10% vs 11.5% in patients who received reduced dose and standard dose respectively (p=0.61). TIMI major bleeding occurred in 2.7% of patients who received a reduced dose (1microgram/kg/min) vs 4.2% of patients who received the standard dose (2microgram/kg/min) when eptifibatide was administered in the early routine fashion (p=0.36). With delayed provisional eptifibatide administration, the TIMI major events were 1.4% vs 2.0% in patients who received reduced dose and standard dose respectively (p=0.54). There were no notable differences observed with GUSTO severe bleeding rates.
The pharmacokinetics of eptifibatide are linear and dose proportional for bolus doses ranging from 90 to 250 microgram/kg and infusion rates from 0.5 to 3.0 microgram/kg/min. For a 2.0 microgram/kg/min infusion, mean steady-state plasma eptifibatide concentrations range from 1.5 to 2.2 microgram/ml in patients with coronary artery disease. These plasma concentrations are achieved rapidly when the infusion is preceded by a 180 microgram/kg bolus. The extent of eptifibatide binding to human plasma protein is about 25%. In the same population, plasma elimination half-life is approximately 2.5 hours, plasma clearance 55 to 80 ml/kg/hr and volume of distribution of approximately 185 to 260 ml/kg.
In healthy subjects, renal excretion accounted for approximately 50% of total body clearance; approximately 50% of the amount cleared is excreted unchanged. In patients with moderate to severe renal insufficiency (creatinine clearance <50 ml/min), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels are approximately doubled.
No formal pharmacokinetic interaction studies have been conducted. However, in a population pharmacokinetic study there was no evidence of a pharmacokinetic interaction between eptifibatide and the following concomitant medicinal products: amlodipine, atenolol, atropine, captopril, cefazolin, diazepam, digoxin, diltiazem, diphenhydramine, enalapril, fentanyl, furosemide, heparin, lidocaine, lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, and warfarin.
Toxicology studies conducted with eptifibatide include single and repeated dose studies in the rat, rabbit and monkey, reproduction studies in the rat and rabbit, in vitro and in vivo genetic toxicity studies, and irritation, hypersensitivity and antigenicity studies. No unexpected toxic effects for an agent with this pharmacologic profile were observed and findings were predictive of clinical experience, with bleeding effects being the principal adverse event. No genotoxic effects were observed with eptifibatide.
Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits at total daily doses of up to 36 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of impaired fertility or harm to the foetus due to eptifibatide. Reproduction studies in animal species where eptifibatide shows a similar pharmacologic activity as in humans are not available. Consequently these studies are not suitable to evaluate the toxicity of eptifibatide on reproductive function (see section 4.6).
The carcinogenic potential of eptifibatide has not been evaluated in long-term studies.
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