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Eptifibatide

Eptifibatide is a competitive antagonist of the GPIIb/IIIa receptor. It is a synthetic small-molecule inhibitor that fits directly into the Arg-Gly-Asp binding pocket of the GPIIb/IIIa receptor, directly competing with the binding of ligands such as fibrinogen and vWF.46 Eptifibatide rapidly dissociates from its receptor, is cleared by the kidney largely as active drug, and has a plasma half-life of approximately 1.5 to 2.5 hours. The return of hemostatic platelet function is largely dependent on clearance of the drug from plasma. Cessation of drug infusion restores platelet function and, in patients with normal renal function, normal hemostasis returns within 15 to 30 minutes after drug discontinuation. Unlike abciximab, however, the platelet inhibitory effect of eptifibatide is not significantly influenced by platelet transfusion.46

Eptifibatide has demonstrated efficacy and safety in patients with non-ST-segment elevation ACS or undergoing PCI in a number of randomized clinical trials. Most recently, the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial demonstrated that early administration of eptifibatide vs. provisional eptifibatide after angiography (delayed eptifibatide) resulted in similar 30-day rates of death, MI, urgent revascularization, or thrombotic complications during PCI in patients with non-ST-segment elevation ACS undergoing invasive management.47 Major and minor bleeding rates were significantly higher with early eptifibatide vs. delayed eptifibatide. Overall, these findings do not support the use of upstream compared with ad hoc GPIIb/IIIa inhibition in ACS patients undergoing PCI.

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Eptifibatide

Eptifibatide is a cyclic heptapeptide competitive inhibitor of platelet glycoprotein IIb/IIIa. Eptifibatide binding to the IIb/IIIa receptor is reversible and the drug's efficacy is dependent on maintaining a high serum concentration, which allows a steady state of IIb/IIIa receptor blockade. In patients with acute coronary syndrome, eptifibatide is given as a bolus of 180 μg/kg followed by a continuous infusion of 2 μg/kg/min. In patients with a creatinine clearance less than 50 mL/minute, the continuous infusion is given as 1 μg/kg/min. High levels of platelet inhibition occurs within 1 hour, with platelet function normalizing 4 to 8 hours after discontinuation. It is secreted primarily in urine.

The benefit of eptifibatide in patients with acute coronary syndrome was established in the PURSUIT trial. This randomized placebo-controlled trial included 10,948 ACS patients without STEMI. Most patients received aspirin and heparin, and were then randomized to receive a placebo or eptifibatide (intravenous bolus of 180 μg/kg followed by an infusion at 1.3 or 2.0 μg/kg/min). The duration of therapy extended to 72 hours (or 96 if intervention occurred later in the hospitalization) or until the patient left the hospital. The primary end point was a composite of death and nonfatal MI at 30 days. In the eptifibatide group, there was a 1.5% absolute reduction in the incidence of the primary end point (14.2% versus 15.7%, p = 0.04), with this effect occurring in most major subgroups.43,61 Further investigation of the PURSUIT cohort reveals that eptifibatide reduced the rates of death and MI in patients before and after PCI, in stented and nonstented patients and those who did not undergo PCI, though the reduction in primary events appears greater in patients who had an early PCI.62

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Eptifibatide

Eptifibatide is an inhibitor of platelet glycoprotein IIb/IIIa.

Hematologic

Eptifibatide can cause thrombocytopenia (52A–54A) in an estimated 0.2% of patients (55A). In 305 patients taking eptifibatide there were four cases of acute thrombocytopenia (platelet count less than 100 × 109/l) (56c). One had been previously exposed to eptifibatide. The platelet counts fell within 6 hours of the first dose and recovered within 6–30 hours after withdrawal. There were no adverse outcomes from thrombocytopenia. Proposed mechanisms include sequestration of platelets in the liver and an interaction of eptifibatide with naturally-occurring antibodies to ligand-induced binding sites on glycoprotein IIb/IIIa (55A).

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A 61-year-old woman with acute coronary syndrome was given heparin and eptifibatide and developed thrombocytopenia (platelet count 2.0 × 109/l) and severe refractory hypotension (57A). There were no heparin-induced antibodies, but eptifibatide-dependent antibodies specific for platelets were detected.

The authors attributed the thrombocytopenia and the hypotension to the eptifibatide antibodies.

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Eptifibatide.

Eptifibatide is a cyclic heptapeptide competitive inhibitor of platelet GP IIb/IIIa. Eptifibatide binding to the IIb/IIIa receptor is reversible and the drug's efficacy is dependent on maintaining a high serum concentration that allows a steady state of IIb/IIIa receptor blockade. In ACS patients, eptifibatide is given as an IV bolus of 180 µg/kg followed by a continuous infusion of 2 µg/kg per minute. In patients with a creatinine clearance less than 50 ml/minute, the continuous infusion is given at 1 µg/kg per minute. High levels of platelet inhibition occur within 1 hour, with platelet function normalizing 4 to 8 hours after discontinuation. It is primarily secreted in the urine.

The benefit of eptifibatide in patients with acute coronary syndrome was established in the Inhibition of Platelet Glycoprotein IIb/IIIa with Eptifibatide in Patients with Acute Coronary Syndrome (PURSUIT) trial. This randomized, placebo-controlled trial included 10,948 NSTE-ACS patients. Most patients received aspirin and heparin, and were then randomized to receive placebo or eptifibatide (IV bolus of 180 µg/kg followed by an infusion at 1.3 or 2 µg/kg per minute). The duration of therapy extended to 72 hours (or 96 hours if PCI occurred later in the hospitalization) or until the patient left the hospital. The primary endpoint was a composite of death and nonfatal MI at 30 days. In the eptifibatide group, there was a 1.5% absolute reduction in the incidence of the primary endpoint (14.2 vs. 15.7%; P = .04), with this effect occurring in most major subgroups.48,49 Further investigation of the PURSUIT cohort revealed that eptifibatide reduced the rates of death and MI in patients before and after PCI, in stented and nonstented patients and in those who did not undergo PCI, although the reduction in primary events appeared greater in patients who had an early PCI.50

The Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST Segment Elevation Acute Coronary Syndrome (EARLY-ACS) trial is an important experiment examining the role of eptifibatide and IIb/IIIa inhibitors in contemporary management of ACS in which P2Y12 inhibitor use is widespread. Patients were randomly assigned to either early, pre-PCI double-bolus eptifibatide or delayed, provisional eptifibatide at the time of PCI. Upstream preprocedure clopidogrel was administered in 75% of the population. Upstream eptifibatide therapy did not result in a significant reduction in the primary efficacy endpoint (a composite of death, MI, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during PCI at 96 hours). However, the risk of major bleeding in the early eptifibatide group was 2.6% compared to 1.8% (P = .02) in the delayed provisional group (Fig. 36.5).51 Thus the use of GP IIb/IIIa receptor antagonists has significantly shifted from an upstream drug to an adjunctive medication given at the time of PCI, usually in a bailout fashion.

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Chapter

Introduction

Eptifibatide is a highly selective cyclic heptapeptide antagonist of the glycoprotein IIb/IIIa receptor that is used to inhibit platelet aggregation and thrombosis. There is no evidence of cross binding with vitronectin receptors. Eptifibatide is employed in combination with aspirin and/or heparin in the treatment of acute coronary syndrome and for the treatment of patients undergoing percutaneous coronary intervention (PCI). The effects of eptifibatide are mediated through reversible inhibition of the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to glycoprotein IIb/IIIa.

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Eptifibatide

Pharmacodynamics.

Eptifibatide (Integrilin) is a nonimmunogenic cyclic heptapeptide with an active pharmacophore that is derived from the structure of barbourin, a platelet GPIIb/IIIa inhibitor from the venom of the southeastern pigmy rattlesnake.124 In a pilot study of the use of eptifibatide in PCI, patients were randomly assigned to one of four eptifibatide dosing schedules: 180-µg/kg bolus with 1-µg/kg/min infusion; 135-µg/kg bolus with 0.5-µg/kg/min infusion; 90-µg/kg bolus with 0.75-µg/kg/min infusion; or 135-µg/kg bolus with 0.75-µg/kg/min infusion.125 All patients were given aspirin and unfractionated heparin and received the study drug for 18 to 24 hours. The two highest bolus doses produced more than 80% inhibition of ADP-mediated platelet aggregation within 15 minutes of administration in a majority of patients (>75%). A constant infusion of 0.75 µg/kg/min maintained the antiplatelet effect, whereas an infusion of 0.50 µg/kg/min allowed gradual recovery of platelet function. In all dosing groups, platelet function as measured returned to more than 50% of baseline within 4 hours of terminating the infusion.125

Pharmacokinetics.

The plasma half-life of eptifibatide is 10 to 15 minutes, and clearance is predominantly renal (75%) and, to less degree, hepatic (25%). The antiplatelet effect has a rapid onset and is rapidly reversible.

Clinical experience.

The Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II (IMPACT-II) trial126 enrolled 4010 patients who were undergoing elective, urgent, or emergent PCI. Patients were assigned to receive placebo, a bolus of 135 µg/kg eptifibatide followed by an infusion of 0.5 µg/kg/min for 20 to 24 hours, or a bolus of 135 µg/kg with a 0.75 µg/kg/min infusion. By 30 days, the composite end point (death, MI, unplanned revascularization, stent placement for abrupt closure) occurred in 11.4%, 9.2%, and 9.9% of patients, respectively. Although the benefit of treatment was maintained at 6 months, the differences between groups were not statistically significant.

The Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis—After Myocardial Infarction (IMPACT-AMI) study127 was designed to determine the effect of eptifibatide on coronary arterial patency when used adjunctively with alteplase (recombinant tissue plasminogen activator). A total of 132 patients with MI received alteplase, heparin, and aspirin and were randomly assigned to receive either a bolus and continuous infusion of eptifibatide at one of six dosages or placebo. The dosages ranged from 36 to 180 µg/kg for the bolus and from to 0.2 to 0.75 µg/kg/min for the infusion. The study drug was started within 24 hours of the MI. The groups receiving the highest dose of eptifibatide had more complete reperfusion (TIMI grade 3 flow) and shorter mean time to ST segment recovery than placebo-treated patients. The rate of composite clinical events (death, reinfarction, revascularization, heart failure, hypertension, stroke) was relatively high in all groups: 44.8% in eptifibatide-treated patients and 41.8% in placebo-treated patients.

The Platelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy (PURSUIT) trial122 included patients who had experienced non–ST segment elevation ACS with symptoms within 24 hours and had shown electrocardiographic changes (indicative of ischemia) within 12 hours. A total of 10,948 patients were randomly assigned to receive eptifibatide (180-µg/kg bolus plus 1.3-µg/kg/min infusion, or 180-µg/kg bolus plus 2.0-µg/kg/min infusion) or placebo for up to 3 days, in addition to unfractionated heparin (for most patients) and aspirin. The 30-day event rate of death or nonfatal MI was 14.2% in those given eptifibatide and 15.7% in those receiving placebo (1.5% absolute reduction). A reduction in MI or death (composite) in the eptifibatide group was observed at later time points.

The Enhanced Suppression of the Platelet GPIIb/IIIa Receptor with Integrilin Trial (ESPRIT) was designed to test the hypothesis that a minimum threshold of 80% GPIIb/IIIa receptor blockade was required for benefit.128 A total of 2064 patients received either eptifibatide (three 180-µg/kg boluses 10 minutes apart, continuous infusion of 2.0 µg/kg/min for 18 to 24 hours) or placebo before PCI. The trial was terminated early due to efficacy because patients receiving eptifibatide had a 4.0% absolute reduction in death, MI, urgent target vessel revascularization, or “bailout” GPIIb/IIIa antagonist use within 48 hours compared with patients given placebo. Major events were significantly lower at 30 days as well.

The Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes (EARLY-ACS) trial randomly assigned 9492 patients with NSTEMI/unstable angina to a strategy of early, routine administration of eptifibatide or delayed, provisional administration. The primary composite end point of death, MI, recurrent ischemia requiring urgent revascularization, or thrombotic complication during PCI occurred at similar rates in both groups; however, there was significantly higher bleeding and transfusion requirements in the early-administration group.129

Conversely, the ISAR-REACT 2 study randomly assigned 2022 patients with NSTEMI scheduled to undergo PCI to receive either abciximab or placebo on top of a background therapy of 600 mg of oral clopidogrel loading. A reduction in the primary composite end point of 30-day death, MI, or urgent revascularization was demonstrated for abciximab (RR, 0.75; 95% CI, 0.58 to 0.97; P = 0.3) without an increase in major or minor bleeding.130 GPIIb/IIIa inhibitors are given a class I recommendation for upstream (preprocedural) use in patients with NSTEMI/unstable angina who are unable to take thienopyridines and a class IIa recommendation for use in addition to thienopyridines in patients at moderate to high risk of adverse events who are undergoing coronary angiography with intent to perform PCI.

Although the EARLY-ACS trial excluded patients with STEMI, multiple contemporary investigations, including a meta-analysis, have examined the role of routine administration of GPIIb/IIIa inhibitors in patients with STEMI and have shown no clear mortality benefit associated with this strategy.131

Agent-specific characteristics.

The duration of platelet inhibition following drug discontinuation and the potential for reversing the pharmacologic effects are particularly important properties in cases of emergent surgery and major hemorrhagic complications. In general, a return of platelet function toward a physiologic state (≤50% inhibition) occurs within 4 hours following the cessation of tirofiban and eptifibatide administration. In contrast, 12 hours are required for return of platelet function with abciximab. Some of the delay in return of physiologic platelet function after abciximab termination may be counterbalanced by its low free plasma concentrations and drug/receptor ratio. These properties are responsible for the rapid return of hemostatic potential following platelet transfusions (and may also limit platelet-inhibiting potential with marked mobilization of GPIIb/IIIa receptors from intraplatelet storage pools). In contrast, the persistence of high plasma concentrations observed with the small-molecule inhibitors limit the effectiveness of platelet transfusions. Fibrinogen supplementation (with fresh frozen plasma or cryoprecipitate) is the more logical choice for restoration of hemostatic potential, given the competitive nature of binding and the relative availability of platelet GPIIb/IIIa receptors.132

Current recommendations.

The 2016 ACCF/AHA PCI guidelines do not recommend administration of upstream platelet GPIIb/IIIa antagonists in patients with STEMI (class III, level of evidence B).77

In the era of P2Y12 receptor antagonist use, there is no clear evidence supporting the routine use of platelet GPIIb/IIIa receptor antagonists in elective PCI. Although previously GPIIb/IIIa receptor antagonists were widely used in diabetic patients, a meta-analysis of 22 studies conducted in the era of stenting and upstream thienopyridine use revealed that administration of GPIIb/IIIa receptor antagonists modestly decreased nonfatal MI without an increase in major bleeding, but with greater rates of minor bleeding and thrombocytopenia.54 As a result, the 2011 ACCF/AHA guidelines have given administration of a GPIIb/IIIa antagonist in patients undergoing elective PCI who are pretreated with clopidogrel, a class IIb recommendation with level of evidence B.49

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6.03.1.5 Eptifibatide

Eptifibatide (Integrilin, Millennium Pharmaceuticals) is an FDA-approved glycoprotein IIb/IIIa antagonist for anticoagulant activity. It is a platelet aggregation inhibitor indicated for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. This antagonist is a cyclic heptapeptide derived from Cys-rich snake venom that is a 73-amino acid-containing disintegrin protein. Truncation of the long peptide to a short loop, in addition to other modifications like guanylation at Lys side chain and deamination at the N-terminus, resulted in a highly potent therapeutic peptide.7

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Eptifibatide

A cyclic peptide, this drug produces selective inhibition. With a loading dose of 180 µg/kg and a continuous infusion of 2 µg/kg per minute, the time to maximum IPA (80% inhibition) is about 15 minutes. The serum half-life is approximately 2.5 hours, and it undergoes renal elimination. Eptifibatide dissociates rapidly from platelets; thus free drug is likely to be present for several hours after its discontinuation. Transfusion of platelets is not likely to be helpful in reversing platelet inhibition because free circulating drug will rapidly bind to the new platelets. Drug reversal in this case is achieved primarily by stopping the medication and may take several hours.

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Pharmacodynamics.

Eptifibatide (Integrilin) is a nonimmunogenic cyclic heptapeptide with an active pharmacophore that is derived from the structure of barbourin, a platelet GPIIb/IIIa inhibitor from the venom of the southeastern pigmy rattlesnake.124 In a pilot study of the use of eptifibatide in PCI, patients were randomly assigned to one of four eptifibatide dosing schedules: 180-µg/kg bolus with 1-µg/kg/min infusion; 135-µg/kg bolus with 0.5-µg/kg/min infusion; 90-µg/kg bolus with 0.75-µg/kg/min infusion; or 135-µg/kg bolus with 0.75-µg/kg/min infusion.125 All patients were given aspirin and unfractionated heparin and received the study drug for 18 to 24 hours. The two highest bolus doses produced more than 80% inhibition of ADP-mediated platelet aggregation within 15 minutes of administration in a majority of patients (>75%). A constant infusion of 0.75 µg/kg/min maintained the antiplatelet effect, whereas an infusion of 0.50 µg/kg/min allowed gradual recovery of platelet function. In all dosing groups, platelet function as measured returned to more than 50% of baseline within 4 hours of terminating the infusion.125

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Therapeutics

Eptifibatide is used for the treatment of acute coronary syndrome and for the treatment of patients undergoing percutaneous coronary intervention, including those undergoing intracoronary stenting. For acute coronary syndrome, eptifibatide decreases the likelihood of death or new myocardial infarction. Eptifibatide is usually administered in combination with aspirin and heparin.

The results from a small clinical trial in patients undergoing coronary artery bypass grafting cessation of eptifibatide 4 h before surgery results in less bleeding and transfusions than 2 h before surgery Dyke et al (2007).

There is no apparent difference in early outcomes of patients treated with eptifibatide compared with patients treated with abciximab patients undergoing primary perutaneous coronary intervention Gurm et al (2008).

Indications

Empty Cell	Value	Units	Prep. and Route of Admin.	Reference	Comments
Acute Coronary Syndrome
Dosage	180	μg/kg	i.v. bolus	Sifton (2002)	Eptifibatide therapy should not exceed 72 h. Maintenance dose is reduced in renal failure. Treatment with eptifibatide is usually coupled with concomitant aspirin and heparin therapy.
Dosage	2.0	μg/kg/min	i.v. continuous infusion	Sifton (2002)	Eptifibatide therapy should not exceed 72 h. Maintenance dose is reduced in renal failure. Treatment with eptifibatide is usually coupled with concomitant aspirin and heparin therapy.
Percutaneous Coronary Intervention (PCI)
Dosage	180	μg/kg	i.v. bolus	Sifton (2002)	An intravenous bolus of 180 μg/kg administered immediately before the initiation of PCI followed by a continuous infusion of 2.0 μg/kg/min and a second 180-μg/kg bolus 10 min after the first bolus. Infusion should be continued for 12 to 24 h. Maintenance dose is reduced in renal failure. Treatment with eptifibatide is usually coupled with concomitant aspirin and heparin therapy.
Dosage	2.0	μg/kg/min	i.v. bolus	Sifton (2002)	An intravenous bolus of 180 μg/kg administered immediately before the initiation of PCI followed by a continuous infusion of 2.0 μg/kg/min and a second 180-μg/kg bolus 10 min after the first bolus. Infusion should be continued for 12 to 24 h. Maintenance dose is reduced in renal failure. Treatment with eptifibatide is usually coupled with concomitant aspirin and heparin therapy.

Contraindications

Eptifibatide is contraindicated in patents with severe hypertension, who have experienced a stroke within 30 days or who have a history of hemorrhagic stroke. It is also contraindicated for those undergoing major surgery and those with a history of bleeding diathesis or evidence of active abnormal bleeding within the previous 30 days. Current or planned administration of another parenteral glycoprotein IIb/IIIa inhibitor, dependency on renal dialysis, and known hypersensitivity to any component of the product are also contraindications for its use Sifton (2002).

Adverse Effects

Bleeding is the most common complication encountered with eptifibatide therapy. Most major bleeding associated with its use has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract. Eptifibatide therapy has also been associated with cerebral, gastrointestinal, and pulmonary hemorrhage Sifton (2002).

Agent-Agent Interactions

Name	Mode of Interaction
Thrombolytics	Because eptifibatide inhibits platelet aggregation, it must be used with caution when it is employed with other drugs that affect hemostasis Sifton (2002).
Other glycoprotein IIb/IIIa	There would be additive pharmacologic effects when administering eptifibatide with our inhibitors of glycoprotein IIb/IIIa Sifton (2002).

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