VA Class:BL117

ATC Class:B01AC16

AHFS Class:

• Platelet-aggregation Inhibitors 20:12.18

Generic Name(s):

• Eptifibatide

Chemical Name:

• Cyclic(1-6)-disulfide- N ⁶amidino- N ²-(3-mercaptopropionyl)-l-lysylglycyl-l-α-aspartyl-l-tryptophyl-l-prolyl-l-cysteinamide

Molecular Formula:

• C₃₅H₄₉N₁₁O₉S₂

Eptifibatide, a selective platelet-aggregation inhibitor,1,2,3,10,11,71 has been referred to as a platelet glycoprotein (GP) IIb/IIIa-receptor inhibitor.2,6,7,11,14,26,37,44,48,50

Non-ST-Segment-Elevation Acute Coronary Syndromes

Eptifibatide is used with anticoagulant therapy (e.g., heparin [referring throughout this monograph to unfractionated heparin], low molecular weight heparin), aspirin, and a P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) to reduce the risk of acute cardiac ischemic events (death and/or myocardial infarction [MI]) in patients with unstable angina or non-ST-segment-elevation MI (NSTEMI) (i.e., non-ST-segment-elevation acute coronary syndromes [NSTE ACS]), both in patients who are to receive medical management and those undergoing percutaneous coronary intervention (PCI).1,4,8,40,72,113,994,995,1100 In clinical trials of eptifibatide, NSTE ACS was defined by prolonged symptoms of cardiac ischemia (at least 10 minutes' duration within the previous 24 hours) that were associated with transient ST-segment changes (ST elevation of 0.6-1 mm or ST depression exceeding 0.5 mm), T-wave inversion (exceeding 1 mm), or increased cardiac (MB) fraction of creatine kinase (CK, creatine phosphokinase, CPK);1,8,72 patients who had MI associated with Q waves or persistent (30 minutes' duration or longer)8,37 ST-segment elevation exceeding 1 mm were not included in these studies.1,8,37,72 NSTEMI and unstable angina clinically may be indistinguishable at initial presentation and are managed similarly.8,69,72,74,78 Almost all patients in clinical trials of eptifibatide received concomitant therapy with aspirin and IV heparin,1,4,8,10,11,40,47 and the efficacy and safety of eptifibatide without adjunctive aspirin and/or heparin therapy have not been established.1,8,56

Platelet glycoprotein (GP) IIb/IIIa-receptor inhibitors are used as an adjunct to standard therapeutic measures for managing NSTE ACS.8,30,43,72 These measures include therapy with aspirin and a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor), nitrates (e.g., nitroglycerin), anticoagulant therapy (e.g., low molecular weight heparins, heparin), and β-blockers followed by either conservative medical management or early aggressive management, such as angiographic evaluation and revascularization procedures (e.g., PCI, coronary artery bypass grafting [CABG], coronary artery stent implantation) as required.8,30,43,72,104,113,991 Several meta-analyses of studies indicate that adjunctive therapy with a GP IIb/IIIa-receptor inhibitor can reduce the incidence of cardiac ischemic events, including subsequent MI and death in patients with NSTE ACS.16,40,43,49,52,56 Benefits of GP IIb/IIIa-receptor inhibitors on mortality principally occur early during therapy (i.e., the first 48-96 hours).1,8,10,16,49,95,96,97

The benefit of aspirin for secondary prevention of ischemic events in patients with unstable angina has been demonstrated in several studies and pooled analyses.30,43,57,63,64,65,68 Many clinicians recommend that all patients with NSTE ACS receive aspirin as soon as possible after hospital admission and then continued indefinitely unless they have documented hypersensitivity or other definite contraindication (e.g., active or recent major bleeding, peptic ulcer disease).30,104,113,991,1100 (See Non-ST-Segment-Elevation Acute Coronary Syndromes under Thrombosis: Coronary Artery Disease and Myocardial Infarction, in Uses, in Aspirin 28:08.04.24.) The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) state that in patients with NSTE ACS in whom an initial invasive management strategy is planned, an additional antiplatelet agent (either clopidogrel or a GP IIb/IIIa-receptor inhibitor given IV) should be administered prior to diagnostic angiography (“upstream”) as an adjunct to aspirin therapy.991 Eptifibatide or tirofiban is the preferred GP IIb/IIIa-receptor inhibitor for this use; abciximab is indicated only if there is no appreciable delay before angiography and PCI is likely to be performed.991 The American College of Chest Physicians (ACCP) states that a clear risk-benefit ratio has not been established for the use of GP IIb/IIIa-receptor inhibitors in patients with ACS who are not routinely scheduled for early revascularization.1016

In patients with NSTE ACS with elevated troponin concentrations who were managed with conservative medical therapy, GP IIb/IIIa-receptor inhibitors were equally effective in men and women.128 However, in women with NSTE ACS who are not at high risk for acute cardiac ischemic events (e.g., no elevated troponin concentrations) and are managed with a conservative strategy, eptifibatide and tirofiban appear to show little benefit and may possibly have detrimental effects; these agents are not recommended by AHA in women at lower risk for adverse cardiac events.128

The current labeled indication for eptifibatide in patients with NSTE ACS is based principally on the results of a large, international, placebo-controlled study, the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) study.1,40,43 In the PURSUIT study, therapy with eptifibatide (180-mcg/kg IV loading dose followed by continuous IV infusion of 2 mcg/kg per minute until hospital discharge or initiation of CABG, up to 72 hours or a maximum of 96 hours in patients undergoing PCI) reduced the combined incidence of death or nonfatal MI at 30 days (the primary composite clinical end point).1,4,8,43

Beneficial effects of eptifibatide in the PURSUIT study were evident within 72 hours of initiating the infusion and persisted for up to 6 months (based on ischemic events evaluated by a blinded clinical events committee for the first 30 days and on investigator-reported events thereafter up to 6 months).1,4,8 The combined incidence of death or nonfatal MI in the overall study was reduced from 7.6% to 5.9% at 3 days, from 11.6% to 10.1% at 7 days, from 15.7% to 14.2% at 30 days, and from 13.6% to 12.1% at 6 months.1,4,8,40,43 This absolute reduction of approximately 1.5% in clinical events was maintained at all time points measured,8,43,56,72 while relative reductions in risk declined from 22% at 3 days to 12.9 and 9.6% at 7 and 30 days, respectively.43,56 The decline in relative benefit over time is related to the continued random occurrence of ischemic events in both placebo and treatment groups after achievement of a constant absolute risk reduction with eptifibatide therapy. 8,72,81 The incidences of the individual end points of death or new MI for eptifibatide or placebo were not different at 30 days, although MI was less frequent with eptifibatide therapy at 96 hours.1,43

Most patients in the PURSUIT study received adjunctive therapy with oral aspirin (75-325 mg once daily) and IV or subcutaneous heparin.1,4,8,40,47 In patients receiving medical management alone (i.e., those not undergoing PCI), heparin sodium (generally an IV loading dose of 5000 units followed by IV infusion of 1000 units per hour) was given to maintain a target activated partial thromboplastin time (aPTT) of 50-70 seconds.1,4,40,43 Patients undergoing PCI were given IV heparin (loading dose followed by IV infusion) to maintain an activated clotting time (ACT) of 300-350 seconds.1,4 (See Dosage and Administration: Dosage.)

The efficacy of eptifibatide in the PURSUIT study varied according to use of concomitant therapy or procedures and by gender, age, and geographic region.1,4,8,40,43,46,47,79,80 In this study, about 13% of patients underwent PCI during infusion of eptifibatide, while the remainder received medical management alone.1,43 For patients who underwent early PCI (within 72 hours after randomization) during eptifibatide infusion, the reduction in adverse ischemic events (nonfatal MI only) was evident prior to the procedure (i.e., during medical management).1,4,40,43,46,47,72,84 Patients undergoing early PCI experienced a 5.1% absolute reduction (31% relative reduction) in the combined clinical end point of death or nonfatal MI at 30 days;8,40,43 reduction in this clinical end point also was maintained over 6 months.8 Of those who received medical management alone, the incidence of clinical events was not appreciably reduced (1.1% absolute reduction, 7% relative reduction).4,8,40,43,46

Subgroup analyses in the PURSUIT study suggested that patients who used aspirin prior to (within 2 weeks of) study entry were less likely to have had a MI (versus unstable angina) at study enrollment but more likely to have worse long-term outcomes (death or MI) than patients who reported no prior aspirin use;8,43,54,72 however, there was no evidence that prior aspirin use influenced the efficacy of eptifibatide.54

The effects of eptifibatide therapy in the PURSUIT study did not appear to be influenced by patient age, but in patients outside North America the drug appeared less beneficial in women than in men.1,4,40,43,79 Results were heterogenous among patients in the various geographic regions (US and Canada, Western Europe, Eastern Europe, Latin America) of the study, possibly because of the practice-based nature of the study and the diverse pharmacologic and regional interventional strategies used to manage NSTE ACS.1,4,8,43,79,82 Patients treated in the US, who were the most homogeneous large subgroup in the study with regard to baseline characteristics (except ethnic background) and approach to patient management, achieved greater benefit than the overall study population.8,40,43,56 Eptifibatide therapy was associated with less benefit than placebo in women in Latin America and Eastern and Western Europe, while in the US and Canada men and women achieved similar benefit.1,79 These findings may reflect genuine biologic interactions between eptifibatide and gender, interactions between eptifibatide and international differences in concomitant therapy (e.g., timing and rate of interventions employed) given to men and women, or chance occurrences; the relative contributions of these possible factors are unknown.1,4,8,43,79

Acute Ischemic Complications of Percutaneous Coronary Intervention

Eptifibatide also is used with anticoagulant therapy (e.g., heparin, low molecular weight heparin), aspirin, and a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) to reduce the risk of acute ischemic complications (death, MI, and/or the need for urgent revascularization procedures) in patients undergoing PCI, including coronary artery stenting.1,4,8,10,11,16,43,995 Despite advances in percutaneous revascularization techniques, abrupt closure of a coronary vessel that occurs during PCI still is associated with substantial morbidity (e.g., MI).61,62 GP IIb/IIIa-receptor inhibitors such as eptifibatide are used to minimize PCI-related ischemic complications and improve the risk-benefit ratio of these procedures.61 Studies involving eptifibatide or another GP IIb/IIIa-receptor inhibitor (i.e., abciximab) have demonstrated consistent reductions in the risk of composite ischemic events (death, MI, need for revascularization procedures) at 30 days in patients with or without NSTE ACS undergoing PCI.55,56,104

The current labeled indication for eptifibatide in patients undergoing PCI is based principally on the results of large, multicenter, placebo-controlled studies in patients undergoing PCI alone in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) study or with coronary artery stenting in the Enhanced Suppression of the Platelet IIb/IIIa receptor with Integrilin Therapy (ESPRIT) study.1,10,43,117,118 In the IMPACT-II study, therapy with eptifibatide (135-mcg/kg IV loading dose immediately before PCI, followed by 0.5-0.75 mcg/kg per minute by continuous IV infusion for 20-24 hours after PCI) reduced the combined incidence of death, nonfatal MI, or the need for urgent intervention at 30 days (the primary composite clinical end point) in patients undergoing elective, urgent, or emergency PCI (e.g., balloon angioplasty, directional atherectomy, transluminal extraction catheter atherectomy, rotational ablation angioplasty, excimer-laser angioplasty).1,4,8,10,11,16,43 All patients received adjunctive therapy with aspirin (75-325 mg given 1-24 hours prior to the procedure), and IV heparin sodium (an IV loading dose of 100 units/kg prior to initiation of the study drug followed by up to 2000 units of heparin sodium every 15 minutes by IV injection) was given to achieve and maintain an ACT of 300-350 seconds.1,8,10,11,72 The primary clinical end point of death, nonfatal MI (defined as an increase in the cardiac MB fraction of creatine kinase to 3 times the upper limit of normal or development of Q waves of at least 0.04 seconds' duration in 2 or more contiguous ECG leads), or urgent intervention (e.g., abrupt closure of a coronary artery followed by CABG, coronary artery stent implantation, repeat PCI) occurred in approximately 6.6% of patients receiving the lower-dose regimen of eptifibatide (135-mcg/kg IV loading dose and 0.5 mcg/kg per minute by IV infusion) versus 9.6% of placebo recipients (31% relative reduction in clinical events) at 24 hours, and in 9.1 or 11.6% of patients receiving the lower-dose regimen of eptifibatide or placebo, respectively, at 30 days (22% relative reduction in clinical events).1,8,10,11,16,49 However, for patients receiving any amount of study drug (excluding those who did not receive study drug or coronary intervention), the decrease in ischemic complications at 30 days was statistically significant only in the low-dose group (those receiving the 135-mcg/kg IV loading dose and 0.5 mcg/kg per minute infusion).1,2,10,11,16 There was no clustering of ischemic events in the 24-48 hours after discontinuance of the eptifibatide infusion, indicating no rebound effect associated with termination of eptifibatide therapy.10,16 Most clinical end-point events (63%) reported in the IMPACT-II study occurred within the first 6 hours after coronary intervention.10,11,12

Unexpected findings in the IMPACT-II study include the inability to prospectively determine outcome according to risk (i.e., the beneficial effect of eptifibatide was more pronounced in low-risk than in high-risk patients) and the lack of a dose-response effect with eptifibatide therapy (i.e., no improvement in clinical efficacy with the higher-dose compared with the lower-dose regimen, and no reduction in bleeding risk with the lower-dose regimen).8,11,16,49,60 Because the assay used to determine inhibition of platelet aggregation and adjust eptifibatide dosage in the IMPACT-II study involved anticoagulation with citrate (which binds calcium), binding of eptifibatide to the GP IIb/IIIa-receptor was exaggerated relative to that occurring at physiologic concentrations of calcium.2,3,8,11,16,20,37,55 Use in subsequent studies (e.g., PURSUIT) of the anticoagulant d-phenylalanyl-l-propyl-l-arginine chloromethyl ketone (PPACK), which does not affect extracellular calcium concentrations in ex vivo platelet-aggregation assays, indicates that inhibition of platelet aggregation may not have been optimal at the eptifibatide dosages employed in the IMPACT-II study.2,3,7,8,10,11,16,83 (See Pharmacology.) An alternative explanation for the lack of improved outcome with the higher infusion rate of eptifibatide in the IMPACT-II trial may be the likelihood that the IV loading dose, rather than the infusion rate, was the principal determinant of plasma eptifibatide concentration at the time of greatest risk of ischemic events (within 6 hours after initiation of therapy).2,10,16,43,49,83

In a subsequent multicenter placebo-controlled study (ESPRIT) in which the dosage of eptifibatide (2 IV loading doses of 180 mcg/kg given 10 minutes apart with a continuous infusion of 2 mcg/kg per minute initiated after the first loading dose) was 3-4 times higher than that in the IMPACT-II study in patients undergoing non-urgent coronary artery stenting, therapy with the drug reduced the primary end point (the combined incidences of death, nonfatal MI, and urgent target-vessel revascularization or rescue therapy with open-label drug for thrombotic complications of PCI) at 30 days and 1 year.1,117,118 All patients received adjunctive therapy with aspirin, clopidogrel, or ticlopidine, and IV heparin sodium (60 units/kg) was given as an IV loading dose followed by additional doses (10-40 units/kg) to achieve and maintain an ACT of 200-300 seconds.1,117,118 The combined clinical end point occurred in 7.5% of patients receiving eptifibatide versus 11.7% of placebo recipients, respectively, at 30 days.1 However, use of rescue therapy for threatened thrombotic complications (e.g., abrupt vessel closure, no reperfusion, coronary thrombosis) is likely to have reduced composite clinical end-point events in the placebo group.117 Benefits of eptifibatide appeared to be maintained during long-term follow-up as indicated by attainment of the primary end point in 14.3 or 18.5% of eptifibatide or placebo recipients, respectively, at 6 months and in 17.5 or 22.1% of eptifibatide or placebo recipients, respectively, at 1 year.1

Randomized controlled studies, including a meta-analysis of 16 randomized trials involving approximately 10,000 patients with ST-segment-elevation MI (STEMI) undergoing primary PCI, generally have failed to demonstrate benefits of GP IIb/IIIa-receptor blockade similar to those observed in patients with NSTE ACS.994,1016 ACCF, AHA, the Society for Cardiovascular Angiography and Interventions (SCAI), and other experts currently do not recommend the routine use of GP IIb/IIIa-receptor inhibitors in patients with STEMI undergoing PCI; however, selective use of these drugs as an adjunct to heparin may be reasonable in certain high-risk patients (e.g., those with large anterior MI and/or large thrombus).994,1016 Studies evaluating the use of GP IIb/IIIa-receptor inhibitors in patients with NSTE ACS undergoing PCI have demonstrated reductions in ischemic outcomes, particularly in patients with high-risk features (e.g., elevated troponin); therefore, ACCF/AHA/SCAI states that it may be useful to administer a GP IIb/IIIa-receptor inhibitor at the time of PCI as an adjunct to heparin therapy in such high-risk patients who are not receiving bivalirudin and who are not adequately pretreated with a P2Y12-receptor antagonist.994 Regarding the choice of GP IIb/IIIa-receptor inhibitor in patients undergoing PCI, abciximab, “double-bolus” eptifibatide (i.e., two 180-mcg/kg direct IV injections given 10 minutes apart), and high-dose tirofiban (25 mcg/kg given by direct IV injection) all have been shown to produce a high degree of platelet inhibition and reduce ischemic complications.994

Adjunctive Therapy During Thrombolysis to Prevent Reocclusion

Eptifibatide has been administered concomitantly with a thrombolytic agent (e.g., alteplase, tenecteplase) in a limited number of patients to prevent coronary artery reocclusion† after an acute MI.6,8,13,14,34,43 However, the appropriate dosage of adjunctive eptifibatide therapy in terms of efficacy and bleeding complications (see Drug Interactions: Thrombolytic Therapy) in such patients has not been established,13,20,34,43,60 and studies to date have not been of sufficient size to detect differences in clinical outcomes such as survival.8,13,14,20,43,60

Administration

Eptifibatide is administered by IV injection followed by IV infusion using a controlled-infusion device (e.g., pump).1 For IV injection, the appropriate dose of eptifibatide is withdrawn from the 10-mL vial containing the drug solution and administered undiluted IV over 1-2 minutes.1,71 The solution for continuous IV infusion should be administered directly from the 100-mL vial after spiking the vial with a vented infusion set.1,8,71 Care should be taken to center the spike within the circle on the stopper top.1 Any drug solution remaining after IV injection or infusion of the appropriate dose of eptifibatide should be discarded.1

Parenteral eptifibatide solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1

Dosage

In clinical trials of eptifibatide therapy, most patients received adjunctive antithrombotic therapy with aspirin (75-325 mg daily) and IV heparin sodium.1,4,8,10,12,13,14,19,40 The safety and efficacy of eptifibatide therapy without concomitant aspirin and heparin remains to be established.1

Non-ST-Segment-Elevation Acute Coronary Syndromes

For reducing the risk of death and/or myocardial infarction (MI) in patients with unstable angina or non-ST-segment-elevation myocardial infarction (NSTEMI) (i.e., non-ST-segment-elevation acute coronary syndromes [NSTE ACS]) who have normal renal function, the recommended initial adult dosage of eptifibatide is 180 mcg/kg given as an IV loading dose over 1-2 minutes as soon as possible following diagnosis, followed by continuous IV infusion of 2 mcg/kg per minute until hospital discharge or initiation of coronary artery bypass grafting (CABG), or for up to 72 hours. 1,8,72 In the PURSUIT study, bleeding occurred more frequently in both the placebo and treatment groups in patients undergoing CABG, and the incidence of major bleeding was not different between the groups.1,8 However, the manufacturer states that eptifibatide therapy should be discontinued prior to CABG.1

The manufacturer states that if a patient with NSTE ACS is to undergo percutaneous coronary intervention (PCI) while receiving eptifibatide, the infusion should be continued at the same rate either up to hospital discharge or for up to 18-24 hours after the procedure, whichever comes first, for a maximum of 96 hours of therapy.1

Adjunctive Antithrombotic Therapy

Adjunctive antithrombotic therapy with aspirin and heparin was used in most patients with NSTE ACS receiving eptifibatide therapy in clinical trials.1,4,8,10,14,40 The manufacturer of eptifibatide recommends an initial aspirin dosage of 160-325 mg daily in patients with NSTE ACS.1 For additional details regarding aspirin dosage regimens in patients with ACS, see Non-ST-Segment-Elevation Acute Coronary Syndromes under Dosage: Thrombosis, in Dosage and Administration in Aspirin 28:08.04.24.

In patients not undergoing PCI, the initial dosage of heparin sodium is based on patient weight and subsequently adjusted to a target activated partial thromboplastin time (aPTT) of 50-70 seconds.1 The manufacturer states that if patient weight is 70 kg or greater, an IV loading dose of 5000 units of heparin sodium should be administered followed by continuous IV infusion of 1000 units per hour.1 In patients weighing less than 70 kg, an IV loading dose of heparin sodium 60 units/kg should be given followed by infusion of 12 units/kg per hour.1

In patients with NSTE ACS who undergo PCI, multiple IV injections of heparin sodium are administered based on activated clotting time (ACT) determinations during PCI to achieve and maintain an ACT of at least 200 seconds.1,117,118 Since eptifibatide and other GP IIb/IIIa-receptor inhibitors may have additive effects on ACT in patients receiving one of these drugs concomitantly with heparin, the dosage of heparin required to maintain an appropriate ACT during such concomitant therapy may be lower than with heparin monotherapy.19,113

Clinical experience from other studies with GP IIb/IIIa-receptor inhibitors (e.g., abciximab)16,89 and current American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) guidelines suggest that use of lower dosages of concomitant IV heparin sodium (e.g., 50-70 units/kg) given 6 hours prior to PCI and targeted to an ACT of at least 200 seconds may provide similar reductions in ischemic coronary events as dosages for higher target ACTs with less risk of major bleeding.8,16,19,61,72,89,117,118,994

Percutaneous Coronary Intervention

For reducing the risk of acute ischemic complications (death, MI, and/or the need for urgent revascularization procedures) in patients undergoing PCI, the manufacturer and some clinicians state that the initial adult dosage of eptifibatide in patients with normal renal function consists of an IV loading dose of 180 mcg/kg given immediately before PCI, followed in 10 minutes by a second 180-mcg/kg IV dose; in addition, a continuous IV infusion of 2 mcg/kg per minute should be initiated immediately after the first loading dose.1,117,118 The IV infusion should be continued until hospital discharge or for up to 18-24 hours, whichever comes first.1 A minimum infusion period of 12 hours is recommended in patients undergoing PCI.1 The manufacturer states that eptifibatide therapy should be discontinued prior to CABG.1

Adjunctive Antithrombotic Therapy

Adjunctive antithrombotic therapy with aspirin and heparin was used in most patients receiving eptifibatide in clinical trials.1,4,8,10,12,13,14,19,40 In the IMPACT-II study, aspirin was given in a dosage of 75-325 mg 1-24 hours prior to PCI.1,10 In patients undergoing PCI, ACCF/AHA/SCAI recommends that aspirin 325 mg be given prior to PCI in patients not already receiving maintenance therapy with aspirin.994 Patients already receiving maintenance therapy with aspirin should receive a dose of 81-325 mg of aspirin before the procedure.994 For additional details regarding aspirin dosage regimens in patients undergoing PCI, see Percutaneous Coronary Intervention and Revascularization Procedures under Dosage: Thrombosis, in Dosage and Administration, in Aspirin 28:08.04.24.

In patients undergoing PCI with stent placement, a loading dose of a P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) also is recommended.994

Since eptifibatide and other GP IIb/IIIa-receptor inhibitors may have additive effects on ACT in patients receiving one of these drugs concomitantly with heparin, the dosage of heparin sodium required to maintain an appropriate ACT during such concomitant therapy may be lower than with heparin monotherapy.72,994 The manufacturer recommends a heparin sodium dose of 60 units/kg given by direct (“bolus”) IV injection within 6 hours prior to PCI.1 Additional injections of heparin sodium should be given during PCI to maintain an ACT of 200-300 seconds.1 In patients who have received prior therapy with heparin before PCI, ACCF/AHA/SCAI states that additional heparin sodium injections should be administered during the procedure as needed.994

Postprocedural use of heparin generally is not recommended while GP IIb/IIIa-receptor inhibitor therapy is given.1,10,26

Dosage in Renal and Hepatic Impairment

Results of a small pilot study in patients with mild to moderate renal impairment (as determined by a reduction in creatinine clearance of 30 mL/minute from normal) revealed no apparent differences in mean pharmacokinetic parameters between renally impaired patients and healthy individuals.8 However, other data in patients with moderate to severe renal impairment (creatinine clearance less than 50 mL/minute) indicate a reduction of approximately 50% in eptifibatide clearance and a doubling of plasma drug concentrations.1 In vitro studies indicate that eptifibatide may be removed from plasma by dialysis.1,8

Dosage adjustment is not necessary in patients with mild to moderate renal impairment (i.e., those with creatinine clearance of at least 50 mL/minute).1 However, patients with NSTE ACS who have a creatinine clearance of less than 50 mL/minute (using Cockcroft-Gault equation) should receive a 180-mcg/kg IV loading dose of eptifibatide as soon as possible following diagnosis followed by IV infusion of 1 mcg/kg per minute.1

In patients undergoing PCI who have a creatinine clearance of less than 50 mL/minute, an IV loading dose of 180 mcg/kg of eptifibatide should be given immediately prior to PCI followed by IV infusion of the drug at 1 mcg/kg per minute; a second IV loading dose of 180 mcg/kg should be given 10 minutes after the first loading dose. 1

Information on the pharmacokinetics or use of eptifibatide in patients with hepatic impairment is not available, and the manufacturer currently makes no specific dosage recommendations for such patients.8 Patients with hepatic disease severe enough to produce alterations in the synthesis of coagulation factors were excluded from clinical trials of eptifibatide, and use of the drug is contraindicated in such patients.8

The incidence of adverse effects with eptifibatide therapy is based principally on data from 2 large, placebo-controlled studies, the PURSUIT study in patients with unstable angina or non-ST-segment-elevation myocardial infarction (NSTEMI) (i.e., non-ST-segment-elevation acute coronary syndromes [NSTE ACS])1,4,8,40 and the IMPACT-II study in patients undergoing percutaneous coronary intervention (PCI).1,4,8,10 Patients in the PURSUIT study received 180 mcg/kg of eptifibatide as an IV loading dose followed by either 1.3 or 2 mcg/kg per minute by continuous IV infusion for up to 72-96 hours;1,4,8,40 patients in the IMPACT-II study received 135 mcg/kg of the drug as an IV loading dose immediately before PCI, followed by either 0.5 or 0.75 mcg/kg per minute by continuous IV infusion for 20-24 hours.1,4,8,10 (See Uses.) Almost all patients receiving eptifibatide in clinical studies received concomitant therapy with heparin and/or aspirin;1 therefore, the incidence of bleeding complications attributable solely to eptifibatide is difficult to determine.1,8 Because of the different eptifibatide dosage regimens used in the PURSUIT and IMPACT-II studies, data from these studies were not pooled.1

The most frequent and severe adverse effect of eptifibatide therapy is bleeding.1,17 Bleeding complications, which usually are minor and develop at vascular access (e.g., femoral puncture) sites (e.g., in patients undergoing PCI), have been reported in 35-75% of patients receiving various dosages of eptifibatide in clinical studies.8,10,40,43 Bleeding is an extension of the pharmacologic action of eptifibatide8,72 and was classified in clinical trials principally according to criteria of the Thrombolysis in Myocardial Infarction (TIMI) study groups.1,4,8,10,17,40,43,85 Minor bleeding generally was defined as spontaneous gross hematuria or spontaneous hematemesis; observed blood loss with a decrease in hemoglobin concentration of 3-5 g/dL or a reduction in hematocrit of at least 10%;1,17 or a decrease of 4-5 g/dL or 12-15% in hemoglobin or hematocrit, respectively, with no identifiable bleeding site.1,8,17,72,85 Major bleeding was defined as intracranial hemorrhage or overt bleeding associated with a hemoglobin or hematocrit decrease of at least 5 g/dL or at least 15%, respectively.1,17,85

In clinical trials, administration of eptifibatide was associated with an increase in major and minor bleeding complications compared with placebo.1 The overall incidence of major and minor bleeding according to TIMI criteria in the PURSUIT study was 23.5% compared with an incidence of 40-70% in smaller studies.40,43 Bleeding of any severity was reported in about 15-60% of patients receiving placebo (i.e., heparin and aspirin therapy alone).43 Bleeding episodes resulted in discontinuance of eptifibatide in 8, 4.6, or 3.5% of patients receiving the drug in the PURSUIT, ESPRIT, or IMPACT-II study, respectively.1

Hematologic Effects

Major bleeding events occurred in 4.4 or 4.7% of evaluable patients receiving eptifibatide 0.5 or 0.75 mcg/kg per minute, respectively, by IV infusion following an IV loading dose of 135 mcg/kg in the IMPACT-II study;1,8,10,11 major bleeding occurred in 10.5 or 10.8% of those receiving 1.3 or 2 mcg/kg per minute, respectively, of eptifibatide following an IV loading dose of 180 mcg/kg in the PURSUIT study.1,40 Major bleeding occurred in 1.3 or 0.4% of those receiving eptifibatide (2 IV loading doses of 180 mcg/kg each given 10 minutes apart followed by continuous infusion of 2 mcg/kg per minute initiated after the first loading dose) or placebo in the ESPRIT study, respectively.1 The incidence of bleeding increased as the activated clotting time (ACT) increased (mean ACT of 284 seconds) in those receiving eptifibatide. 1,117 At the lower ACTs achieved in the ESPRIT trial, the incidence of bleeding was lower than that observed in the IMPACT-II and PURSUIT studies.1 The incidence of major bleeding with eptifibatide was similar to that with placebo in the IMPACT-II study and modestly increased compared with placebo in the PURSUIT study.1,8,10,33 The overall incidence of major bleeding was higher in the PURSUIT study than in the IMPACT-II study because coronary artery bypass grafting (CABG) was more commonly employed in the PURSUIT study (15.5% incidence within 30 days) than in the IMPACT-II study (4.3%); major bleeding was minimal (0.6%) in patients receiving medical management alone in the PURSUIT trial.1,8 However, bleeding episodes in patients who underwent CABG were not more frequent in patients receiving eptifibatide than in placebo recipients in either study.1,8

In the PURSUIT and ESPRIT studies, the greatest increase in major bleeding with eptifibatide therapy compared with placebo was bleeding at the femoral vascular access site (2.8 and 1.3%, respectively, in the PURSUIT study and 0.8 and 0.1%, respectively, in the ESPRIT study) associated with PCI; oropharyngeal (principally gingival), genitourinary, GI, and retroperitoneal bleeding also were more common with eptifibatide therapy than with placebo.1,8,71,117 GI, pulmonary, and retroperitoneal hemorrhage, including fatalities, have been reported during postmarketing experience with eptifibatide given concomitantly with heparin and aspirin.1 Among patients experiencing major bleeding in the IMPACT-II study, an increase in bleeding with eptifibatide versus placebo was demonstrated only for bleeding at the femoral vascular access site (3.2 versus 2.8%, respectively).1 In the PURSUIT and ESPRIT studies, patient weight was inversely related to the number of major bleeding episodes in patients receiving eptifibatide; this relationship was not found in the IMPACT-II study.1,8

Adverse hematologic effects with eptifibatide therapy have been severe enough to require blood or platelet transfusions.1,10,117 In the IMPACT-II study, the incidences of major bleeding events and transfusions (including whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion) were similar in patients receiving eptifibatide or placebo, while minor bleeding events were more common with eptifibatide therapy.1,8 Bleeding or thrombocytopenia requiring transfusions in the IMPACT-II study10 occurred in about 5.5 or 5.8% of patients receiving eptifibatide 0.5 or 0.75 mcg/kg per minute, respectively, following an IV loading dose of 135 mcg/kg, compared with about 5.1% of patients receiving placebo injection and infusion (based on treated-as-randomized analysis).1,8 In the PURSUIT study, transfusions were required in 12.8% of patients receiving eptifibatide and in 10.4% of patients receiving placebo.1 In the ESPRIT study, transfusions were required in 1.5% of patients receiving eptifibatide and in 1.1% of those receiving placebo.1

Minor bleeding episodes occurred in about 11.7 or 14.2% of patients receiving 0.5 or 0.75 mcg/kg per minute, respectively, of eptifibatide following an IV loading dose of 135 mcg/kg in the IMPACT-II study,1,10,11 and in 10.5 or 13.1% of those receiving 1.3 or 2 mcg/kg per minute, respectively, following an IV loading dose of 180 mcg/kg in the PURSUIT study.1 Minor bleeding episodes occurred in 3 or 2% of patients receiving eptifibatide or placebo, respectively, in the ESPRIT study.1,8

Decreases in platelet count or thrombocytopenia occur occasionally (2.3% overall) after therapy with GP IIb/IIIa-receptor inhibitors.110,111 Thrombocytopenia associated with administration of a GP IIb/IIIa-receptor inhibitor generally occurs within hours or days after administration of the drug.55,99,106,112 The incidence of thrombocytopenia (defined as a platelet count less than 100,000/mm³ or a decrease of at least 50% in platelet count from baseline) and the need for platelet transfusions were similar in patients receiving eptifibatide in several clinical trials (IMPACT-II,1,10 PURSUIT,1,40 pilot studies12,13,19 ) and in patients receiving placebo.1,32,71 In the ESPRIT study, the incidence of thrombocytopenia was 1.2 or 0.6% among patients receiving eptifibatide or placebo, respectively.1 A preliminary report based on pooled data from clinical trials indicates that the incidence of thrombocytopenia is not appreciably different among GP IIb/IIIa-receptor inhibitors (i.e., abciximab, eptifibatide, tirofiban), although the absolute risk of thrombocytopenia appears to increase (but not synergistically) with concomitant use of heparin.110 However, severe thrombocytopenia (i.e., platelet count less than 20,000 per mm³)55,72,93,99,111,112 has been reported more frequently with abciximab than with eptifibatide.8,26,40,55,72,93,99,111 In the large PURSUIT study, the incidence of profound thrombocytopenia (defined as a platelet count less than 20,000/mm³) was small (0.2%) in patients receiving eptifibatide, but greater than the incidence in those receiving placebo (less than 0.1%).8,40,72

Sensitivity Reactions

Anaphylaxis was reported in 7 patients (0.16%) receiving an eptifibatide infusion rate of 2 mcg/kg per minute, respectively, following an IV loading dose of 180 mcg/kg in the PURSUIT study and in 7 patients (0.15%) receiving placebo in this study; none of the patients receiving eptifibatide and one patient receiving placebo in the IMPACT-II study developed anaphylaxis.1 Allergic reactions were reported in 2 patients (0.19%) receiving eptifibatide and in one patient (0.1%) receiving placebo in the ESPRIT study.1 Of those who received eptifibatide in the PURSUIT study, the drug was discontinued in 3 patients (0.05%).1 In patients undergoing PCI and receiving the drug in the IMPACT-II study, eptifibatide therapy was discontinued in 2 patients (0.04%) because of allergic reactions.1

While therapy with some platelet-aggregation inhibitors (e.g., abciximab) has been associated with development of antibodies to the drug,2,6,7,10,11 development of antibodies against eptifibatide has not been reported to date.2,4,6,7,8,10,11,37 No evidence of delayed-type hypersensitivity or antigenicity with eptifibatide was noted in studies in mice and guinea pigs.4 The low molecular weight of eptifibatide may account for its lack of antigenicity.2,4 Some clinicians suggest that the lack of antigenicity of eptifibatide and the rapidly reversible binding of the drug to platelets compared with abciximab may account for the relative lack of thrombocytopenia observed with eptifibatide.10,11,16

Cardiovascular Effects

Most adverse effects of eptifibatide other than bleeding in clinical trials were cardiovascular in nature and were typical of patients with unstable angina; the incidence of most of these effects, with the exception of hypotension, was similar in patients receiving eptifibatide or placebo.1,8,43

Hypotension occurred in 7% of patients receiving eptifibatide and 6% of those receiving placebo in the PURSUIT study.1,8

Stroke, including primary hemorrhagic stroke, cerebral infarction, or infarction with hemorrhagic conversion, occurred in 0.5% of patients receiving an eptifibatide infusion rate of 1.3 mcg/kg per minute following an IV loading dose of 180 mcg/kg in the PURSUIT study and in 0.5% of patients receiving an infusion rate of 0.5 mcg/kg per minute following an IV loading dose of 135 mcg/kg in the IMPACT-II study.1,8,33 The overall incidence of stroke was 0.7% in patients receiving an eptifibatide infusion rate of 2 mcg/kg per minute following an IV loading dose of 180 mcg/kg in the PURSUIT study and in 0.7% of patients receiving an infusion rate of 0.75 mcg/kg per minute following an IV loading dose of 135 mcg/kg in the IMPACT-II study.1,8,40 Hemorrhagic stroke occurred in 2 patients (0.19%) receiving eptifibatide and in one patient (0.1%) receiving placebo in the ESPRIT study.1

Therapy with GP IIb/IIIa receptor inhibitors, including eptifibatide, has not been associated with an increased risk of intracranial hemorrhage.29,99 The incidence of stroke was similar among patients receiving eptifibatide or placebo in either the PURSUIT or IMPACT-II study.1,8,33,40,86,87 Most strokes occurring in these studies were nonhemorrhagic (thromboembolic) in nature (i.e., cerebral infarctions).8,40,87 Cerebral infarction occurred in one patient (0.1%) receiving eptifibatide in the ESPRIT study.1 The incidence of intracranial hemorrhage in the IMPACT-II study was low (0.1-0.2%) and also was similar in patients receiving eptifibatide or placebo.8 Cerebral hemorrhage, sometimes resulting in death, has been reported with eptifibatide, principally in combination with heparin and aspirin, during postmarketing experience.1 Adverse cardiovascular effects leading to discontinuance of eptifibatide therapy occurred in 0.3 or 1.4% of patients receiving the drug in the PURSUIT or IMPACT-II study, respectively.1

Other Adverse Effects

Serious adverse effects of eptifibatide other than bleeding occurred in 19% of patients receiving either eptifibatide or placebo, respectively, in the PURSUIT study and in 7 or 6% of patients receiving the drug or placebo, respectively, in the ESPRIT study.1,4,8 Other adverse effects in the PURSUIT study occurring in at least 0.1% of patients and leading to discontinuance of eptifibatide involved the digestive system (0.1%), hemic/lymphatic system (0.1%), nervous system (0.3%), urogenital system (0.1%), and whole body (0.2%); these adverse effects resulted in discontinuance of therapy in a similar percentage of placebo recipients.1 In patients undergoing PCI who received eptifibatide in the IMPACT-II study, adverse effects other than bleeding that resulted in discontinuance of drug therapy occurred in the following body systems: whole body (0.3% of patients), digestive system (0.2%), hemic/lymphatic system (0.2%), nervous system (0.3%), and respiratory system (0.1%).1

Precautions and Contraindications

The administration of eptifibatide in patients with NSTE ACS is associated with a small increase in the frequency of major bleeding compared with heparin and aspirin therapy alone.1,8 Bleeding with platelet glycoprotein (GP IIb/IIIa)-receptor inhibitors can be reduced by adherence to strict anticoagulation guidelines, the use of a short course of low-dose, weight-adjusted heparin, early arterial sheath removal, and careful patient and access site management.26,43,52 Prior to administration of eptifibatide, preexisting hemostatic and renal abnormalities should be identified by obtaining a prothrombin time (PT), serum creatinine, hematocrit or hemoglobin, and activated partial thromboplastin time (aPTT).1 In patients receiving heparin concomitantly with eptifibatide, the extent of heparin anticoagulation (as assessed by activated clotting time [ACT] or aPTT) should be monitored closely to minimize bleeding.1,35 The aPTT should be maintained at 50-70 seconds unless PCI is to be performed.1 In addition, the ACT should be measured in patients undergoing PCI. 1,12,35 Current guidelines of the ACCP, ACC, and AHA and risk-benefit analyses in trials with GP IIb/IIIa-receptor inhibitors suggest that heparin sodium dosing should be adjusted to maintain the ACT at 200 seconds or greater during PCI in patients receiving GP IIb/IIIa-receptor inhibitors.8,16,72,89 (See Dosage and Administration: Dosage.) Routine use of postprocedural heparin is not recommended while GP IIb/IIIa-receptor inhibitor therapy is given.10,26 After PCI, the aPTT should be checked prior to arterial sheath removal, and the sheath should not be removed unless the aPTT is less than 45 seconds or the ACT is less than 150-180 seconds.1,35 The manufacturer recommends that concomitant thrombolytic therapy be used with caution.1

Platelet counts should be determined prior to treatment with eptifibatide and periodically (e.g., daily)72 during concomitant eptifibatide and heparin therapy.8,72,88 The manufacturer states that there is no clinical experience with the use of eptifibatide in patients who have platelet counts less than 100,000/mm³ and that the drug should be used with caution in such patients.1 Abciximab, another GP IIb/IIIa-receptor inhibitor, has been associated with pseudothrombocytopenia caused by an in vitro anticoagulant (edetate disodium [EDTA]) interaction.26,53 Some clinicians suggest that a peripheral-blood smear be examined for the presence of platelet clumping or that blood for platelet counts be drawn into separate tubes containing EDTA, citrate, or heparin to exclude pseudothrombocytopenia in patients receiving eptifibatide.26,53 The possibility of heparin-induced thrombocytopenia also should be considered in the differential diagnosis of thrombocytopenia in patients receiving GP IIb/IIIa-receptor inhibitors concomitantly with heparin.29,55,93,107,111 If true thrombocytopenia (platelet count less than 100,000/mm³) is verified, eptifibatide should be discontinued and the condition appropriately monitored and treated.1 Thrombocytopenia is usually reversible following discontinuance of GP IIb/IIIa-receptor inhibitors and anticoagulant (heparin) therapy; however, platelet transfusions should be considered for the management of severe thrombocytopenia.55,93,106,111,112

To minimize the possibility of bleeding associated with the use of eptifibatide, particularly at the site of femoral artery sheath placement, precautions in the placement, maintenance, and removal of the vascular access sheath should be observed.1,26,44,52 Placement of a femoral venous sheath should be avoided if possible.1 When inserting the femoral artery sheath, care should be taken so that only the anterior wall of the femoral artery is punctured; a Seldinger (through and through) technique for puncture of the artery should be avoided.8,26,72 Appropriate precautions should be observed while the vascular access sheath is in place (e.g., complete bed rest, elevation of the head of the bed not exceeding 30°, restraint of the limb in which the vascular access sheath is inserted, frequent monitoring of the vascular access site and the distal pulse in the involved limb).26,27,72 The femoral artery sheath may be removed during treatment with eptifibatide, provided that at least 3-4 hours have elapsed since heparin therapy was discontinued and its effects largely reversed1,27 (as indicated by an aPTT of less than 45 seconds or an ACT of less than 150-180 seconds).1,26,27,35,44 Early removal of femoral sheaths (4-6 hours after PCI) was encouraged in patients receiving PCI in both the PURSUIT and IMPACT-II studies while the study drug was being infused.1,10,11

Both heparin and eptifibatide therapy should be discontinued and sheath hemostasis achieved with standard compressive techniques at least 4 hours before hospital discharge.1 Pressure (e.g., using manual compression or a mechanical hemostatic device) should be applied to the femoral artery for at least 20-30 minutes after sheath removal;26,27 after hemostasis, a pressure dressing should be applied.8,26,72 Any hematoma that forms should be measured and monitored for enlargement.8,26,72

Careful monitoring of all potential bleeding sites should be undertaken during and following treatment with platelet aggregation inhibitors.26,29,97,107,109 Needle punctures (e.g., arterial, IM, IV, lumbar, subcutaneous, intradermal), cutdown sites, and use of nasotracheal intubation, nasogastric tubes, urinary catheterization, and automatic blood pressure cuffs26 should be minimized during and following treatment with eptifibatide.1,8,72 Establishment of IV access at noncompressible sites (e.g., in subclavian or jugular veins) should be avoided;1 an indwelling venipuncture device (e.g., heparin lock) should be considered for drawing blood; documentation and monitoring of vascular puncture sites should occur; and dressings should be removed gently and carefully.8,26,72 The manufacturer states that any occurrence of serious bleeding that cannot be controlled by pressure on the bleeding site should result in discontinuance of eptifibatide and concomitantly administered heparin therapy.1

Because eptifibatide increases the risk of bleeding, the drug is contraindicated in patients with a history of bleeding diathesis1,10,13 or active abnormal bleeding (e.g., elevated hemostatic indices, recent noncompressible vascular punctures GI or genitourinary bleeding) within the previous 30 days.1,10,12,13 A low hematocrit value (less than 30%) at baseline could represent recent undetected bleeding, and patients with such values may not be able to tolerate additional bleeding episodes; eptifibatide should not be used in these patients.8,72 Eptifibatide also is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure exceeding 200 mm Hg or diastolic blood pressure exceeding 110 mm Hg with antihypertensive therapy);1,10,13 recent (within 6 weeks) major surgery;1,10,12,13 history of stroke within 30 days or any history of hemorrhagic stroke;1,10,12,13 current or planned therapy with another GP IIb/IIIa-receptor inhibitor;1 and patients receiving renal dialysis.1 No data are available on the use of eptifibatide in patients with serum creatinine concentrations of 4 mg/dL or greater; the dosage should be reduced in patients with serum creatinine concentrations between 2-4 mg/dL.1 (See Dosage in Renal and Hepatic Impairment under Dosage and Administration: Dosage.)

Eptifibatide also is contraindicated in patients with known hypersensitivity to any component of the commercially available preparation.1

Pediatric Precautions

Safety and efficacy of eptifibatide in pediatric patients have not been determined.1,8

Geriatric Precautions

Safety and efficacy of eptifibatide in geriatric patients have not been specifically studied to date; however, in clinical studies of eptifibatide involving over 14,000 patients up to 94 years of age, approximately 45% of the patients were 65 years of age or older, and 12% were 75 years of age or older.1 Clinical experience generally has not revealed age-related differences in efficacy with eptifibatide therapy.1 However, the incidence of bleeding complications in clinical trials was higher in geriatric than in younger patients receiving either placebo or eptifibatide in clinical trials.1 No dosage adjustment was made for geriatric patients in the principal clinical trials (PURSUIT, IMPACT II), but patients older than 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUIT study because of a concern for an increased risk of bleeding in those weighing less than that.1 (See Cautions: Hematologic Effects.)

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was seen at the chromosomal or gene level when eptifibatide was evaluated in several in vitro and in vivo test systems.1 The drug was not genotoxic in the Ames microbial mutagen test, mouse micronucleus test, or mouse lymphoma cell forward mutation assay.1 Eptifibatide did not demonstrate any potential to induce chromosomal aberrations in human lymphocytes.1

Since eptifibatide is designed to be used in acute-care settings, long-term studies in animals to evaluate the carcinogenic potential of eptifibatide have not been performed and are not planned.1,4

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies using continuous IV infusion of eptifibatide dosages at a total daily dosage of up to 72 mg/kg in pregnant rats and up to 36 mg/kg in pregnant rabbits (either dosage representing about 4 times the recommended maximum daily human dosage based on body surface area) have not revealed evidence of harm to the fetus.1 However, since animal reproduction studies are not always predictive of human response and there are no adequate or controlled studies to date using eptifibatide in pregnant women, eptifibatide should be used during pregnancy only when clearly needed.1

Fertility

Reproduction studies in male and female rats using eptifibatide dosages up to 72 mg/kg daily (about 4 times the maximum recommended human daily dosage) by continuous IV infusion have not revealed evidence of impaired fertility.1,4

Lactation

Since it is not known if eptifibatide is distributed into milk, the drug should be used with caution in nursing women.1

Drugs Affecting Platelet Function

Limited data from preclinical and clinical studies in patients receiving eptifibatide (0.5 mcg/kg per minute by IV infusion) alone or concomitantly with aspirin, heparin, or both drugs suggest no substantial pharmacokinetic or pharmacodynamic interactions (e.g., additive effects on platelet-aggregation inhibition) between eptifibatide and aspirin.4,8,41,42,72 While coadministration of eptifibatide and aspirin resulted in up to a fivefold increase in bleeding time compared with baseline values, similar increases in bleeding time were observed with aspirin and placebo.4,41 Nevertheless, since eptifibatide inhibits platelet aggregation, caution should be observed when the drug is used with other drugs that affect hemostasis, including thrombolytic agents, oral anticoagulants, nonsteroidal anti-inflammatory agents (NSAIAs), or dipyridamole.1 (See Drug Interactions: Thrombolytic Therapy and also see Drug Interactions: Anticoagulants.) However, clopidogrel or ticlopidine was used routinely with eptifibatide in a large clinical, multicenter study (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy [ESPRIT]) in patients undergoing coronary artery stent placement.1,117,118

To minimize potentially additive pharmacologic effects, the manufacturer of eptifibatide states that concomitant therapy with other platelet glycoprotein (GP IIb/IIIa)-receptor inhibitors (e.g., abciximab, tirofiban) should be avoided.1,4

Thrombolytic Therapy

Eptifibatide has been administered concomitantly with thrombolytic agents (e.g., alteplase, streptokinase, tenecteplase) in a limited number of patients with acute myocardial infarction (MI) to reduce the risk of reocclusion of the infarct-related artery.1,5,13 (See Uses: Adjunctive Therapy During Thrombolysis to Prevent Reocclusion.) Some clinicians suggest that use of short-acting platelet-aggregation inhibitors such as eptifibatide13 concomitantly with thrombolytic therapy may provide optimal benefit while minimizing the risk of bleeding.5,13 However, use after thrombolysis of drugs that affect platelet function may increase the risk of bleeding complications, including those requiring blood transfusions, associated with thrombolytic therapy1,5,34 and has not been shown to be unequivocally effective to date;13,20,43 therefore, use of eptifibatide with thrombolytic therapy should be considered investigational and should be undertaken with caution.1,4,34,43,72

In a small, placebo-controlled trial and dose-ranging study in patients with acute MI, combined therapy with eptifibatide (up to 180 mcg/kg as an IV loading dose followed by continuous infusion of 0.75 mcg/kg per minute for 24 hours) and alteplase (accelerated, weight-adjusted IV infusion up to 100 mg) was not associated with an increased incidence of major bleeding or transfusions compared with alteplase monotherapy.1,13,14 However, in another study in patients with acute MI receiving streptokinase (1.5 million units IV over 60 minutes) and eptifibatide (up to 180 mcg/kg as an IV loading dose followed by continuous infusion of 2 mcg/kg per minute for 72 hours), the higher infusion rates of eptifibatide (1.3 and 2 mcg/kg per minute) were associated with an increase in bleeding and the need for blood transfusion compared with streptokinase monotherapy.1,5,34 In the IMPACT-II study, 2 of 15 patients who received a thrombolytic agent concomitantly with eptifibatide (135 mcg/kg as an IV loading dose followed by 0.5 mcg/kg per minute by IV infusion) had a major bleeding episode, while 10 of 40 patients who received thrombolytic therapy and eptifibatide (180 mcg/kg as an IV loading dose followed by 2 mcg/kg per minute by IV infusion) in the PURSUIT study experienced major bleeding.1

Anticoagulants

Concomitant use of platelet-aggregation inhibitors and an anticoagulant (particularly in high dosages) may increase the risk of hemorrhage,26,43 and careful monitoring for bleeding is necessary, especially at arterial puncture sites.1,20,26,43 Eptifibatide and concomitant heparin therapy should be discontinued immediately1 and appropriate therapy (e.g., protamine sulfate in patients receiving heparin) 27 instituted as necessary if serious bleeding occurs (e.g., bleeding not controlled by pressure).1 In healthy individuals, enoxaparin sodium (1 mg/kg subcutaneously every 12 hours for 4 doses) did not alter the pharmacokinetics or pharmacodynamics (platelet aggregation) of eptifibatide.1 The manufacturer states that caution should be employed when using eptifibatide with oral anticoagulants.1

In almost all patients receiving eptifibatide for non-ST-segment-elevation acute coronary syndromes or in patients undergoing percutaneous coronary intervention (PCI), heparin (generally combined with aspirin) has been administered before and during eptifibatide therapy to reduce the risk of coronary artery occlusion or new thrombi formation.1,10,12,13 When eptifibatide was given alone or in combination with heparin in a limited number of healthy individuals at eptifibatide infusion rates exceeding 0.5 mcg/kg per minute or for durations exceeding 6 hours, bleeding time was prolonged approximately twofold or greater; smaller dosages infused over 90 minutes had minimal effects on bleeding time.41

Laboratory Test Interferences

In blood samples, binding of eptifibatide to the GP IIb/IIIa-receptor and the drug's subsequent inhibitory activity on platelet aggregation are dependent on the free calcium concentration, and therefore the type of anticoagulant used in the sample.3,8,61 In the IMPACT-II study, the assay used to determine inhibition of platelet aggregation involved anticoagulation with sodium citrate, which removes calcium bound to the GP IIb/IIIa receptor and results in enhanced binding of eptifibatide to the receptor.3,8,11,16,20,37,55 Therefore, the inhibitory activity of eptifibatide is overestimated in blood samples collected in citrate relative to that in samples anticoagulated with PPACK.2,3,8,11,16,20,37,55 (See Uses: Acute Ischemic Complications of Percutaneous Coronary Intervention.)

Acute Toxicity

Limited information is available on the acute toxicity of eptifibatide.1 In general, overdosage of eptifibatide in humans may be expected to produce effects that are extensions of the pharmacologic and adverse effects of the drug, predominantly bleeding.8,72 (See Cautions: Hematologic Effects.) A small number of patients in each of the major clinical studies (IMPACT-II, PURSUIT) received doses of eptifibatide by IV injection and/or infusion that were more than twice those recommended or that were identified by study investigators as an overdose; none of these individuals had intracranial hemorrhage or other major bleeding.1

In acute toxicity studies in animals (rats, rabbits, or monkeys) given 45 mg/kg of eptifibatide (about 2-5 times the maximum recommended daily human dose based on body surface area) over 90 minutes by continuous IV infusion, loss of righting reflex, dyspnea, ptosis, and decreased muscle tone were observed in rabbits, and petechial hemorrhages in the femoral and abdominal areas were observed in monkeys; no manifestations of toxicity were observed in rats given this dose of eptifibatide.1,4,8 In short-term toxicology studies (14-28 days) in monkeys, continuous IV infusion of eptifibatide in dosages exceeding 5 mcg/kg per minute produced contusions, hemorrhage, and petechial hemorrhages, resulting in anemia in some animals.4,71 At a dosage of 50 mcg/kg per minute, bleeding, decreased concentrations of plasma proteins, anemia, and death occurred.4 These effects were not observed in monkeys given eptifibatide 5 mcg/kg per minute (representing 1.1 times the mean steady-state plasma concentrations in patients undergoing PCI and receiving the recommended dosing regimen) in the IMPACT-II study.4

Pharmacology

Platelet Aggregation and Thrombosis

Eptifibatide is a selective, competitive, reversible inhibitor of platelet aggregation that is used to prevent acute ischemic complications associated with non-ST-segment-elevation acute coronary syndromes (NSTE ACS) and/or percutaneous coronary intervention (PCI).1,4,8,10,40 Because of its mechanism of action, eptifibatide, like abciximab and tirofiban, has been referred to as a platelet glycoprotein (GP) IIb/IIIa-receptor inhibitor.2,6,7,11,14,26,37,44,48,50 Platelet adhesion, activation, and aggregation are key processes leading to the formation of platelet-rich (“white”) coronary artery thrombi and the development of ACS and ischemic complications associated with PCI.2,10,12,13,72 White thrombus formation is triggered by vascular injury (e.g., from PCI procedures), plaque rupture, or denudation of endothelium that exposes the subendothelial matrix of the vessel to circulating platelets.2,6,7,11,12,16,19,37,48 Upon exposure of the vessel subendothelium, potent thrombogenic stimuli (e.g., thrombin, collagen) present in both subendothelium and plaque, and/or high-shear stress, stimulate platelet adhesion and activation.6,7

Activated platelets release intracellular granules consisting of vasoactive substances that are part of an autostimulatory loop for platelet aggregation;2,3,6,7,14,18,37 these vasoactive substances include thromboxane A₂,2,6 serotonin,6,7 and adenosine diphosphate (ADP);6,7,37 adhesive glycoproteins such as fibrinogen, fibronectin, and von Willebrand's factor;6,7 and plasminogen activator inhibitor-1 (PAI-1).14 Regardless of the initial stimulus for platelet activation, the final common pathway to platelet aggregation and thrombosis involves activation of the receptor function of the platelet glycoprotein (GP) IIb/IIIa complex (also known as α_IIbβ₃).2,4,7,8,9,10,11,16,37 GP IIb/IIIa receptors on the surface of activated platelets undergo a conformational change6,37 to accept soluble fibrinogen, von Willebrand's factor, and other ligands (e.g., fibronectin, vitronectin, thrombospondin).2,3,6,7,10,12,13,37 Some of these adhesive ligands form cross-links to GP IIb/IIIa receptors on the surface of adjacent activated platelets, causing aggregation and white thrombus formation.2,3,6,7,10,12,13,14,37 In addition, fibrinogen bound to the vessel wall or to other platelet aggregates can activate GP IIb/IIIa receptors on unstimulated platelets and recruit these platelets to growing white thrombi.2

Progression of unstable angina or non-ST-segment-elevation myocardial infarction (NSTEMI) to ST-segment-elevation myocardial infarction (STEMI) or sudden death occurs when obstructive platelet-rich thrombi grow to become occlusive thrombi in the absence of perfusion beyond the obstruction through collateral blood vessels.6,48,49,50,54,72,73,74 Fibrin and erythrocytes comprise the outer layer of occlusive red thrombi that are formed on the surface of the platelet-rich inner core of the thrombus.6,37,48,49,50,72 While thrombolytic therapy effectively dissolves the occluding fibrin-rich portion of the thrombus, this process releases clot-bound thrombin and re-exposes the underlying disrupted plaque, which releases potent thrombogenic stimuli.6,8,13,14,49 This newly released thrombin then activates platelets, leading to platelet aggregation.6,8,13,14,21,22,25,49,91 In addition, activated platelets secrete a variety of factors associated with rethrombosis and thrombin production (e.g., PAI-1, fibrinogen, factor V) and bind factors Xa, VIIIa, and IXa, which are involved in further thrombin production.13,14,18,23,49,51 Platelet reactivity also may increase after thrombolysis.92 Use of platelet-aggregation inhibitors such as eptifibatide concomitantly with thrombolytic therapy may counter the thrombogenic activity of these agents and minimize the risk of reocclusion.5,6,8,13,14,21,22,24,25

Inhibition of Platelet Aggregation

Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to resting and active GP IIb/IIIa receptors.1,2,3,4,7,8,16,37,71 Inhibition of platelet aggregation by eptifibatide occurs in a dose- and concentration-dependent manner via an increase in GP IIb/IIIa-receptor occupancy (as determined by ex vivo platelet aggregation assay with the direct thrombin inhibitor d-phenylalanyl-l-propyl-l-arginyl chloromethyl ketone [PPACK]).1,2,8,11,31,43,71 Some platelet-aggregation inhibitors such as aspirin, ticlopidine, and clopidogrel prevent platelet activation in response to one or more agonists (thromboxane A₂, adenosine diphosphate);20 agonists not affected by these drugs may continue to induce platelet aggregation.6,8,9,17,20,28 However, GP IIb/IIIa-receptor inhibitors such as abciximab, eptifibatide, and tirofiban prevent platelet aggregation regardless of the initial stimulus.6,8,29 In vitro studies indicate that eptifibatide is not effective in displacing fibrinogen cross-links from GP IIb/IIIa-receptors in platelet-rich thrombi when the bond between fibrinogen and GP IIb/IIIa becomes irreversible.18,72

Following a single 180-mcg/kg IV dose of eptifibatide in healthy individuals or patients with NSTE ACS and/or those undergoing PCI, platelet aggregation was inhibited by greater than 90% within 15 minutes at physiologic calcium concentrations based on ex vivo platelet-aggregation assays using PPACK as the anticoagulant.1,8 Inhibition of platelet aggregation by eptifibatide also may depend on the degree of initial platelet activation, which may be influenced by concurrent disease states.8,15 In an ex vivo study, the concentration of eptifibatide needed to inhibit 50% of ADP-induced platelet aggregation was lowest in healthy men, higher in patients undergoing PCI, and highest in patients with NSTE ACS, perhaps reflecting differences in existing platelet activation.8,15 The pharmacodynamics of eptifibatide do not appear to be affected by a differences in pharmacodynamic effects among ethnic groups have not been assessed.1

Hemostatic Effects

Since the effect of eptifibatide on platelet aggregation is rapidly reversible following cessation of the infusion, the drug has a modest effect on hemostatic indices (e.g., bleeding times) and platelet function. Normal hemostasis is restored more rapidly than with abciximab, a monoclonal antibody that dissociates very slowly from the GP IIb/IIIa-receptor.1,2,6,10,17,72

When eptifibatide was administered alone or in combination with heparin in clinical trials, bleeding time was prolonged approximately twofold.41 At steady-state plasma eptifibatide concentrations in patients with NSTE ACS (who received a 180-mcg/kg IV loading dose followed by IV infusion of 2 mcg/kg per minute) or who were undergoing PCI (who received a 135-mcg/kg IV loading dose followed by IV infusion of 0.5 mcg/kg per minute) and also were receiving concomitant aspirin and heparin, bleeding time was prolonged up to 5 times the control value.1,8,12,41,43 Ex vivo ADP-induced platelet aggregation using PPACK in patients with NSTE ACS was restored toward baseline values (i.e., to less than 50% inhibition) within 4 hours after cessation of an eptifibatide infusion (180-mcg/kg IV loading dose followed by IV infusion of 2 mcg/kg per minute for 72-96 hours); 6 hours after discontinuance of the eptifibatide infusion, bleeding time averaged 1.4 times the control value.1,2,4,8 Data from an ex vivo platelet aggregation assay in these patients indicated a GP IIb/IIIa-receptor occupancy of less than 60% 8 hours after discontinuance of the eptifibatide infusion.31

When administered alone, eptifibatide usually does not affect prothrombin time (PT) or activated partial thromboplastin time (aPTT).1

Effect of Calcium Concentration on Platelet-Aggregation Assays

The reported inhibitory effect of eptifibatide on platelet aggregation depends on the free calcium concentration (and therefore the type of anticoagulant used) in the samples to be assayed, which is negatively correlated with the inhibitory activity and can affect interpretation of results of platelet function tests. 3,8,61 (See Laboratory Test Interferences.)

Pharmacokinetics

The pharmacokinetics of eptifibatide in healthy individuals are linear, and plasma concentrations are proportional to dose following IV loading doses of 90-250 mcg/kg and IV infusion rates of 0.5-3 mcg/kg per minute.1,2,8,43 Concomitant administration of aspirin or heparin does not appear to affect the pharmacokinetics of eptifibatide, nor does gender.1,41

Absorption

With recommended IV loading and maintenance infusions of eptifibatide, peak plasma drug concentrations occur within 5 minutes of IV injection and steady-state drug concentrations are attained within 4-6 hours.1,4,9,41,43 Following IV administration of an eptifibatide loading dose of 135 mcg/kg and an IV infusion of 0.5 mcg/kg per minute for 20-24 hours, plasma drug concentrations at steady state averaged 291 ng/mL in patients undergoing percutaneous coronary intervention (PCI).10,41 In geriatric patients with coronary artery disease, plasma concentrations are increased compared with those in younger adults.1 Following IV administration of an eptifibatide loading dose of 180 mcg/kg and IV infusion of 2 mcg/kg per minute for 24 or 72 hours, steady-state plasma drug concentrations (as determined using population pharmacokinetic methods) in patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS) or those undergoing PCI reportedly averaged 2.2 or 1.5 mcg/mL, respectively.8 In healthy individuals receiving eptifibatide infusion rates of 0.5-2 mcg/kg per minute for 24 hours, steady-state plasma drug concentrations reportedly average approximately 0.3-1.1 mcg/mL.8 In patients with moderate to severe renal impairment (estimated Cl_cr less than 50 mL/minute), steady-state plasma concentrations double.1

Eptifibatide has a rapid onset and short duration of action; maximal inhibition of platelet aggregation occurs within 15 minutes after initiation of therapy and is rapidly reversible.1,8,12 Within 4 hours after cessation of drug infusion, platelet aggregation returned to greater than 50% of baseline in patients with NSTE ACS receiving recommended dosages of eptifibatide (180-mcg/kg IV loading dose followed by infusion of 2 mcg/kg per minute) and to less than 30% of peak values in patients undergoing PCI and receiving recommended dosages of the drug (135-mcg/kg IV loading dose followed by infusion of 0.5 mcg/kg per minute).1,4,11,12 Platelet aggregation usually returns toward normal within 4-8 hours after discontinuing eptifibatide in patients with NSTE ACS or ST-segment-elevation myocardial infarction (STEMI).8,13,31,41,43

Distribution

Eptifibatide is approximately 25% bound to plasma proteins, principally (9-16%) to albumin.1,8,41,43 The volume of distribution of eptifibatide in patients with coronary artery disease is about 185-260 mL/kg1,8 and is somewhat higher (220-270 mL/kg) in healthy individuals.8 It is not known whether eptifibatide is distributed into milk in humans.1

Elimination

Eptifibatide is eliminated by renal and nonrenal mechanisms.9,41,43,71 The drug appears to undergo rapid and nonmetabolic degradation in the urinary bladder after its elimination from plasma.1,9,71 Eptifibatide is metabolized principally through deamidation to a metabolite that has approximately 41% of the platelet-aggregation inhibitory activity of the parent compound, and through formation of other more polar metabolites.1,9,41,71 Approximately 27% of a dose of eptifibatide is broken down in plasma into naturally occurring amino acids;4,41 no major non-amino acid metabolites have been detected in plasma in humans.4,9 Following IV administration of a single, ¹⁴C-radiolabeled dose of eptifibatide (135 mcg/kg) in healthy men, 34, 19, and 13% of the radioactivity was recovered in urine within the first 24 hours as parent compound, deamidated metabolite, and polar metabolites (as detected by radiochromatography), respectively.9,71 In healthy men receiving a single, radiolabeled IV dose of the drug (135 mcg/kg), 98, 1.5, and 0.8% of the dose was recovered in urine, feces, and breath carbon dioxide, respectively.9 In vitro studies indicate that eptifibatide is not extensively bound to plasma proteins; therefore, the drug may be removed from plasma by hemodialysis.1

Plasma concentrations of eptifibatide decline in a biexponential manner following IV injection or infusion of the drug.8,41 The half-life of eptifibatide in patients with coronary artery disease averages 2.5-2.8 hours.1,8,19 In healthy individuals, half-life of the drug reportedly averages 0.83-2.4 hours.2,8,42,71 Clearance of eptifibatide in patients with coronary disease is 55-80 mL/kg per hour; clearance of the drug is twofold higher in healthy individuals.1,8,41,71 Plasma clearance of eptifibatide is proportional to body weight and estimated creatinine clearance and inversely proportional to age.9,41,43,70 Following a single IV dose of ¹⁴C-radiolabeled eptifibatide (135 mcg/kg) in healthy men, renal clearance averaged approximately 40-50% of total body clearance.1,8,9,71 Clearance is reduced by 50% in patients with moderate to severe renal impairment (estimated Cl_cr less than 50 mL/minute).1 Total body clearance in geriatric patients with coronary artery disease is lower than that in younger adults.1

Chemistry and Stability

Chemistry

Eptifibatide, a synthetic cyclic heptapeptide, is a selective platelet-aggregation inhibitor.1,2,3,10,11,71 Eptifibatide, like abciximab and tirofiban, has been referred to as a platelet glycoprotein (GP) IIb/IIIa-receptor inhibitor.2,6,7,11,14,26,37,44,48,50 The drug is similar in structure to barbourin, a peptide constituent of the venom of the southeastern pigmy rattlesnake, Sistrurus m. barbouri .2,9,10,43,71

Eptifibatide is composed of 6 amino acids and a mercaptopropionyl (desamino cysteinyl) residue with an interchain disulfide bridge between the cysteine amide and the mercaptopropionyl moieties.1 The active domain of eptifibatide contains a modified lysine-glycine-aspartate (KGD) amino acid sequence similar to the physiologic arginine-glycine-aspartate (RGD) sequence in von Willebrand's factor, vitronectin, fibrinogen, and fibronectin, adhesive ligands that bind to platelet glycoprotein (GP) IIb/IIIa receptors on activated platelets and cause platelet aggregation.2,4,7,8,10 The substitution of lysine for arginine on the binding site in eptifibatide increases the selectivity of binding to the GP IIb/IIIa receptor.2,10

Commercially available eptifibatide injection is a clear, colorless, sterile solution of the drug in sterile water for injection; sodium hydroxide and citric acid have been added to adjust the pH to 5.25.1,8,71 Eptifibatide is insoluble in nonpolar solvents such as hexane (0.02 mg/mL), but is freely soluble in polar aqueous solvents and in highly polar solvents such as dimethyl sulfoxide (exceeding 400 mg/mL).8,41 Eptifibatide has pK_as of 4 and exceeding 12.5.41

Stability

Eptifibatide should be refrigerated at between 2-8°C and protected from light until administration.1,8 Commercially available eptifibatide injection has an expiration date of 24 months following the date of manufacture when stored as directed.8 The injection may be transferred to room temperature storage (15-30°C) for a period not to exceed 2 months.1,8 When stored at room temperature, the injection container should be marked to indicate that any unused vials should be discarded after 2 months or by the manufacturer's labeled expiration date (whichever comes first).1,8 The manufacturer states that vials of the injection that have been left unrefrigerated only for a brief period (i.e., the vial is still cool to the touch) may be returned to refrigeration without the need to alter the expiration date.8

The manufacturer states that eptifibatide is chemically and physically compatible (i.e., no evidence of precipitation, color or pH change, or loss of potency) with, and may be administered in the same IV line as alteplase, atropine, dobutamine, heparin, lidocaine, meperidine, metoprolol, midazolam, morphine, nitroglycerin, or verapamil.1,8 Eptifibatide is chemically/physically incompatible with furosemide (i.e., precipitate formation within 1 hour of mixing, exceeding 40% loss of furosemide potency at 24 hours, and decrease in pH from about 8.9 to 5.4), and these drugs should not be administered through the same IV line.1,8 Eptifibatide may be administered in the same IV line with 0.9% sodium chloride injection or 0.9% sodium chloride and 5% dextrose injection.1 With either vehicle, the infusion may contain up to 60 mEq/L of potassium chloride.1 No incompatibilities have been observed between eptifibatide and IV administration sets, and no data are available concerning the compatibility of eptifibatide with polyvinyl chloride (PVC) bags.1

1. Schering. Integrilin^® (eptifibatide) injection prescribing information. Kenilworth, NJ; 2007 Mar.

2. Phillips DR, Scarborough RM. Clinical pharmacology of eptifibatide. Am J Cardiol . 1997; 80(Suppl 4A):11b-20b. [PubMed 9291241]

3. Phillips DR, Teng W, Arfsten A et al. Effect of Ca²⁺ on GP IIb-IIIa interactions with Integrilin: enhanced GP IIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate. Circulation . 1997; 96:1488-94. [PubMed 9315536]

4. Key Pharmaceuticals. Integrilin^® (eptifibatide) product monograph. Kenilworth, NJ; 1998 Aug.

5. Braunwald E, Maseri A, Armstrong PW et al. Rationale and clinical evidence for the use of GP IIb/IIIa inhibitors in acute coronary syndromes. Eur Heart J . 1998; 19(Suppl D):D22-30. [PubMed 9597519]

6. White H. Unmet therapeutic needs in the management of acute ischemia. Am J Cardiol . 1997; 80(Suppl 4A):2b-10b. [PubMed 9291240]

7. Le Breton H, Plow EF, Topol EJ et al. Role of platelets in restenosis after percutaneous coronary revascularization. J Am Coll Cardiol . 1996; 28:1643-51. [PubMed 8962547]

8. Cor Therapeutics, South San Francisco, CA, and Key Pharmaceuticals, Kenilworth, NJ: Personal communication.

9. Alton KB, Kosoglou T, Baker S et al. Disposition of ¹⁴C-eptifibatide after intravenous administration to healthy men. Clin Ther . 1998; 20: 307-323. [PubMed 9589822]

10. Anon. Randomised placebo-controlled trial of effect of eptifibatide on complication of percutaneous coronary intervention: IMPACT-II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II. Lancet . 1997; 349:1422-8. [PubMed 9164315]

11. Tcheng JE. Impact of eptifibatide on early ischemic events in acute ischemic coronary syndromes: a review of the IMPACT II trial. Am J Cardiol . 1997; 80(Suppl 4A):21B-8B. [PubMed 9291242]

12. Harrington RA, Kleiman NS, Kottke-Marchant K et al. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol . 1995; 76:1222-7. [PubMed 7503000]

13. Ohman EM, Kleiman NS, Gacioch G et al. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockage with Integrilin in acute myocardial infarction: results of a randomized, placebo-controlled, dose-ranging trial. Circulation . 1997; 98:846-54.

14. Moliterno DJ, Topol EJ. Conjunctive use of platelet glycoprotein IIb/IIIa antagonists and thrombolytic therapy for acute myocardial infarction. Thromb Haemost . 1997; 78:214-9. [PubMed 9198156]

15. Harrington RA, Ohman EM, Sigmon KN et al. Intensity of inhibition of the platelet glycoprotein IIb/IIIa receptor differs among disease states. Circulation . 1995; 92(Suppl 1):488-9.

16. Tcheng JE. Glycoprotein IIb/IIIa receptor inhibitors: putting the EPIC, IMPACT II, RESTORE, and EPILOG trials into perspective. Am J Cardiol . 1996; 78(Suppl 3A):35-40. [PubMed 8751845]

17. Kleiman NS. Primary and secondary safety endpoints from IMPACT II. Am J Cardiol . 1997; 80(Suppl 4A):29B-33B. [PubMed 9291243]

18. Plow EF, Ginsberg MH. Molecular basis of platelet function. In: Hoffman R, Benz EJ, Shattil SJ et al, eds. Hematology. 2nd ed. Churchill Livingstone. New York, NY. 1995:1524-35.

19. Tcheng JE, Harrington RA, Kottke-Marchant K et al. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrilin in elective coronary intervention. Circulation . 1995; 91:2151-7. [PubMed 7697843]

20. Catella-Lawson F, Fitzgerald GA. Confusion in reperfusion: problems in the clinical development of antithrombotic drugs. Circulation . 1997; 95: 793-5. [PubMedCentral]

21. Loscalzo J, Braunwald E. Tissue plasminogen activator. N Engl J Med . 1988; 319:925-31. [PubMed 3138537]

22. Ohlstein EH, Storer B, Fujita T et al. Tissue-type plasminogen activator and streptokinase induce platelet hyperaggregability in the rabbit. Thromb Res . 1987; 46:575-85. [PubMed 3112993]

23. Fitzgerald DJ, Catella F, Roy L et al. Marked platelet activation in vivo after IV streptokinase in patients with acute myocardial infarction. Circulation . 1988; 77:142-50. [PubMed 3275505]

24. Gold HK, Coller BS, Yashuda T et al. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIbIIIa antibody in a canine preparation. Circulation . 1988; 77:670-7. [PubMed 3124974]

25. Gold HK, Leinbach RC. Prevention of acute reocclusion after thrombolysis with IV recombinant tissue plasminogen activator. In: Sobel BE, Collen D, Grossbard EB, eds. Tissue plasminogen activator in thrombolytic therapy. New York: Marcel Dekker, Inc; 1987:115-30.

26. Eli Lilly and Company. ReoPro^® (abciximab) injection for intravenous administration prescribing information. Indianapolis, IN: 1998 Feb 12.

27. Bittl JA, Levin DC. Coronary arteriography. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 5th ed. Philadelphia: WB Saunders Company; 1997:240-72.

28. Sanofi. Plavix (clopidogrel bisulfate) tablets prescribing information. New York, NY: 1997 Nov.

29. Merck & Co. Aggrastat (tirofiban hydrochloride) injection prescribing information. West Point, PA; 1998 May.

30. Agency for Health Care Policy and Research. Diagnosing and managing unstable angina. 1994. (AHCPR publication no. 94-0603)

31. Jennings L, Tardiff B, Scarborough R et al. Comparison of receptor occupancy and platelet aggregation response of eptifibatide administered intravenously in patients with unstable angina or non-Q-wave myocardial infarction. J Am Coll Cardiol . 1998; 31(Suppl A): 93A.

32. McClure M, Kleiman NS, Berdan LG et al. Thrombocytopenia in a large, international trial of the GP IIb/IIIa inhibitor eptifibatide in patients with acute coronary syndromes. J Am Coll Cardiol . 1998; 31(Suppl A):93A.

33. Lincoff AM, Harrington RA, Califf RM et al. Clinical efficacy of Integrilin in unstable angina is accompanied by a modest increase in hemorrhagic risk: the PURSUIT trial. J Am Coll Cardiol . 1998; 31(Suppl A):185A.

34. Ronner E, van Kesteren HAM, Zijnen P et al. Combined therapy with streptokinase and Integrilin. J Am Coll Cardiol . 1998; 31(Suppl A):191A.

35. Simko RJ, Tsung FFW, Stamek EJ et al. Activated clotting time versus activated partial thromboplastin time for therapeutic monitoring of heparin. Ann Pharmacother . 1995; 29:1015-21. [PubMed 8845539]

37. Harrington RA. Design and methodology of the PURSUIT trial: evaluating eptifibatide for acute coronary syndromes. Am J Cardiol . 1997; 80(Suppl 4A):34b-8b. [PubMed 9291244]

40. PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med . 1998; 339:436-43. [PubMed 9705684]

41. Cor Therapeutics. Integrilin™ (eptifibatide). Summary basis of approval: clinical pharmacology/biopharmaceutics review. Reference No.: 20-718. Kenilworth, NJ. 1998.

42. Charo IF, Scarborough RM, du Mee CP et al. Pharmacodynamics of the GPIIb-IIIa antagonist integrilin: phase I clinical studies in normal healthy volunteers. Circulation . 1992; 86(Suppl I):I-260.

43. Goa KL, Noble S. Eptifibatide. A review of its use in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention. Drugs . 1999; 57:439-62. [PubMed 10193692]

44. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med . 1994; 330:956-61. [PubMed 8121459]

46. Levin T. Eptifibatide in acute coronary syndromes. N Engl J Med . 1999; 340:60. [PubMed 9882213]

47. Harrington RA, Simoons ML, Topol EJ. Eptifibatide in acute coronary syndromes. N Engl J Med . 1999; 340:61. [PubMed 9882216]

48. Davies MJ. The role of plaque pathology in coronary thrombosis. Clin Cardiol . 1997; 20(Suppl I):I-2-7. [PubMed 9377822]

49. Topol EJ. Targeted approaches to thrombus formation: an end to the shotgun approach. Clin Cardiol . 1997; 20(Suppl I):I-22-6.

50. de Feyter PJ. The benefits and risks of coronary intervention—-balancing the equation. Clin Cardiol . 1997; 20(Suppl I):I-14-21.

51. Merlini PA, Bauer KA, Oltrona L et al. Thrombin generation and activity during thrombolysis and concomitant heparin therapy in patients with acute myocardial infarction. J Am Coll Cardiol . 1995; 25:203-9. [PubMed 7798503]

52. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med . 1995; 332:1553-9. [PubMed 7739710]

53. Moll S. Eptifibatide in acute coronary syndromes. N Engl J Med . 1999; 340:60-1. [PubMed 9882215]

54. Alexander JH, Harrington RA, Tuttle RH et al. Prior aspirin use predicts worse outcomes in patients with non-ST elevation acute coronary syndromes. Am J Cardiol . 1999; 83:1147-51. [PubMed 10215274]

55. Lincoff AM. Trials of platelet glycoprotein IIb/IIIa receptor antagonists during percutaneous coronary revascularization. Am J Cardiol . 1998; 82:36P-42P. [PubMed 9809890]

56. Alexander JH, Harrington RA. Recent antiplatelet drug trials in the acute coronary syndromes. Clinical interpretation of PRISM, PRISM-PLUS, PARAGON A, and PURSUIT. Drugs . 1998; 56:965-76. [PubMed 9878986]

57. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ . 1994; 308:81-106. [PubMedCentral][PubMed 8298418]

58. Théroux P. Antiplatelet therapy: do the new platelet inhibitors add significantly to the clinical benefits of aspirin? Am Heart J . 1997; 134:S62-70.

59. Théroux P, Ouimet H, McCans J et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med . 1988; 319:1105-11. [PubMed 3050522]

60. Catella-Lawson F, FitzGerald GA. Trials in myocardial infarction. Circulation . 1997; 96:3815.

61. Kleiman NS. A risk-benefit assessment of abciximab in angioplasty. Drug Saf . 1999; 20:43-57. [PubMed 9935276]

62. Detre KM, Holmes DR Jr, Holubkov R et al. Incidence and consequences of periprocedural occlusion: the 1985-1986 National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation . 1990; 82:739-50. [PubMed 2394000]

63. Cairns JA, Gent M, Singer J et al. Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med . 1985; 313:1369-75. [PubMed 3903504]

64. Lewis HD, Davies JW, Archibald DG et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med . 1983; 309:396-403. [PubMed 6135989]

65. The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet . 1990; 336:827-30. [PubMed 1976875]

66. Cohen M, Adams PC, Gareth P et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users: Primary end points analysis for the ATACS trial. Circulation . 1994; 89:81-8. [PubMed 8281698]

67. Oler A, Whooley MA, Oler J et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA . 1996; 276:811-5. [PubMed 8769591]

68. Théroux P, Waters D, Qiu S et al. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation . 1993; 88(5 Pt 1):2045-8. [PubMed 8222097]

69. Cairns J, Théroux P, Armstrong P et al. Unstable angina—Report from a Canadian expert round table. Can J Cardiol . 1996; 12:1279-92. [PubMed 8987969]

70. Sambol NC, Tcheng JE, Kitt M et al. Population pharmacokinetics (PK) and pharmacodynamics (PD) of integrelin, a platelet aggregation inhibitor. Clin Pharmacol Ther . 1996; 59:150.

71. Anon. Eptifibatide. Drugs Future . 1998; 23:585-90.

72. Reviewers' comments (personal observations).

73. Freedman SB, Dunn RF, Bernstein L et al. Influence of coronary collateral blood flow on the development of exertional ismchemia and Q wave infarction in patients with severe single-vessel disease. Circulation . 1985; 71:681-6. [PubMed 3971537]

74. Théroux P, Fuster V. Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction. Circulation . 1998; 97:1195-1206. [PubMed 9537346]

75. Tonkin AM, Aroney CN. Guidelines for managing patients with unstable angina: rating the evidence and rationale for treatment. Med J Aust . 1997; 16:644-7.

76. Cohen M, Demers C, Gurfinkel EP et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med . 1997; 337: 447-52. [PubMed 9250846]

77. Armstrong PW. Heparin in acute coronary disease-requiem for a heavyweight? N Engl J Med . 1997; 337:492-4. (IDIS 389821)

78. Swahn E, Wallentin L for the FRISC study group. Low-molecular weight heparin (fragmin) during instability in coronary artery disease (FRISC). Am J Cardiol . 1997; 80(Suppl. 5A):25E-9E. [PubMed 9296466]

79. Berdan L, Weatherly BD, Widimsky P et al. Global gender variations in the care of patients with acute coronary syndromes. Circulation . 1998; 98(Suppl. 1):I-560.

80. Holmes DR, White HD, Hasdai D et al. Relationship between age and outcome in patients with acute ischemic syndromes randomized to eptifibatide or placebo: a report from the PURSUIT trial. Circulation . 1998; 98(Suppl. 1):I-359. [PubMed 9769316]

81. Greenbaum AB, Hudson MP, MacAulay CM et al. Timing of events after hospitalization for acute coronary syndromes. Circulation . 1998; 98(Suppl. 1):I-630.

82. Berdan LG, Kleiman NS, Guerci A et al. Unstable angina in the US: patients and management. Circulation . 1998; 98(Suppl. 1):I-359.

83. Gilchrist IC, Thel MC, Joseph D et al. Enhanced platelet Iib/IIIa inhibition with eptifibatide via high-dose, double-bolus dosing: final results of the PRIDE study. Circulation . 1998; 98(Suppl.1):I-844-5.

84. Akkerhuis M, Boersma E, Harrington RA et al. Eptifibatide protects against adverse cardiac complications both before and during percutaneous intervention in patients with acute coronary syndromes without Stelevation. J Am Coll Cardiol . 1999; 33(Suppl. A):40A.

85. Rao AK, Pratt C, Berke A et al. Thrombolysis in myocardial infarction (TIMI) trial-phase I: hemorrhagic manifestations and changes in plasma fibrinogen and fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol . 1988; 11:1-11. [PubMed 3121710]

86. Vorchheimer DA, Guzman IC, Greenberg S et al. Safety and efficacy of eptifibatide therapy in patients with previous stroke or transient ischemic attack. J Am Coll Cardiol . 1999; 33(Suppl. A):330A.

87. Mahaffey KW, Harrington RA, Simoons ML et al. Stroke in patients with acute coronary syndromes: incidence and outcomes in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. Circulation . 1999; 99:2371-7. [PubMed 10318656]

88. Wyeth-Ayerst Laboratories. Heparin sodium injection prescribing information. In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:3305-7.

89. The EPILOG Investigators. Platelet glycoprotein Iib/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med . 1997; 336:1689-96. [PubMed 9182212]

90. Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet . 1996; 347:561-8. [PubMed 8596317]

91. Scarborough RM, Kleiman NS, Phillips DR. Platelet glycoprotein IIb/IIIa antagonists: what are the relevant issues concerning their pharmacology and clinical use? Circulation . 1999; 100:437-44.

92. Kleiman NS, Lincoff AM, Ohman EM et al. Glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: pathophysiologic foundation and clinical findings. Am Heart J . 1998; 136:532-42.

93. Madan M, Berkowitz SD, Tcheng JE. Glycoprotein IIb/IIIa integrin blockade. Circulation . 1998; 98:2629-35. [PubMed 9843473]

94. Zaacks SM, Liebson PR, Calvin JE et al. Unstable angina and non-Q wave myocardial infarction: does the clinical diagnosis have therapeutic implications? J Am Coll Cardiol . 1999; 33:107-18.

95. Chesebro JH, Badimon JJ. Platelet glycoprotein IIb/IIIa receptor blockade in unstable coronary disease. N Engl J Med . 1998; 338:1539-41. [PubMed 9593795]

96. Kong DF, Califf RM, Miller DP et al. Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ishemic heart disease. Circulation . 1998; 98:2829-35. [PubMed 9860783]

97. Reviewers' comments (personal observations) on tirofiban.

98. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med . 1998; 338:1488-97. [PubMed 9599103]

99. Vorchheimer DA, Badimon JJ, Fuster V. Platelet glycoprotein IIb/IIIa receptor antagonists in cardiovascular disease. JAMA . 1999; 281:1407-14. [PubMed 10217057]

100. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation . 1997; 96:1445-53. [PubMed 9315530]

101. Gibson CM, Goel M, Cohen DJ et al. Six-month angiographic and clinical follow-up of patients prospectively randomized to receive either tirofiban or placebo during angioplasty in the RESTORE trial. J Am Coll Cardiol . 1998; 32:28-34. [PubMed 9669245]

102. Dobesh PP, Latham KA. Advancing the battle against ischemic syndromes: a focus on the GP-IIb/IIIa inhibitors. Pharmacotherapy . 1998; 18:663-85. [PubMed 9692642]

104. Antman EM, Fox KM for the International Cardiology Forum. Guidelines for the diagnosis and management of unstable angina and non-Q-wave myocardial infarction: proposed revisions. Am Heart J . 2000; 139:461-75. [PubMed 10689261]

105. Kaul S, Shah PK. Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin? J Am Coll Cardiol . 2000; 35:1699-702.

106. Quinn M, Fitzgerald DJ. Long-term administration of glycoprotein IIb/IIIa antagonists. Am Heart J . 1998; 135:S113-8. [PubMed 9588390]

107. Merck & Co. Product information form for American hospital formulary service: Aggrastat^® (tirofiban hydrochloride). West Point, PA; 1998.

108. Armstrong PW. Pursuing progress in acute coronary syndromes. Circulation . 1999; 100:1586-9. [PubMed 10517727]

109. Merck & Co., West Point, PA: Personal communication on tirofiban.

110. Giugliano RP, Hyatt RR. Thrombocytopenia with GP IIb/IIIa inhibitors: a meta-analysis. J Am Coll Cardiol . 1998; 31(Suppl 2A):185A.

111. Ferguson JJ, Kereiakes DJ, Adgey AAJ et al. Safe use of platelet GP IIb/IIIa inhibitors. Am Heart J . 1998; 135:S77-89.

112. Topol EJ, Byzova TV, Plow EF. Platelet GPIIb/IIIa blockers. Lancet . 1999; 353:227-31. [PubMed 9923894]

113. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol . 2000; 36:970-1062. [PubMed 10987629]

117. Enhanced Suppression of the Platelet IIb/IIIa receptor with Integrelin Therapy (ESPRIT) Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet . 2001; 356:2037-44.

118. O'Shea JC, Hafley GE, Greenberg S et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA . 2001; 285:2468-73. [PubMed 11368699]

124. Goodman S. Enoxaparin and glycoprotein IIb/IIIa inhibition in non-ST-segement-elevation acute coronary syndrome: insights for the INTERACT trial. Am Heart J . 2005; 149:S73-80.

125. James S, Armstrong P, Califf R et al. Safety and efficacy of abciximab combined with dalteparin in the treatment of acute coronary syndromes. Eur Heart J . 2002; 23:1538-45. [PubMed 12242074]

126. Goodman SG, Fitchett D, Armstrong P et al. Randomized evaluation of the safety and efficacy of enoxaparin versus unfarctionated heparin in high-risk patients with non-ST-sgement elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation . 2003; 107:238-44. [PubMed 12538422]

128. Lansky AJ, Hochman JS, Ward PA et al. Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professional from the American Heart Association. Circulation . 2005; 111:940-3. [PubMed 15687113]

991. Anderson JL, Adams CD, Antman EM et al. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2011; 123:e426-579.

994. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol . 2011; 58:e44-122. [PubMed 22070834]

995. Hamm CW, Bassand JP, Agewall S et al, for The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST -segment elevation of the European Society of Cardiology (ESC). ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J . 2011; 32:2999-3054. [PubMed 21873419]

1016. Eikelboom JW, Hirsh J, Spencer FA et al. Antiplatelet drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest . 2012; 141(2 Suppl):e89S-119S.

1100. Amsterdam EA, Wenger NK, Brindis RG et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation . 2014; 130:e344-426. [PubMedCentral]