Continuing Education Activity

Eptifibatide is a glycoprotein IIb/IIIa class platelet inhibitor drug used to reduce ischemic cardiac events in specific patient populations. A protein found in the venom of a southeastern pygmy rattlesnake is used to make eptifibatide. FDA has approved this medicine for the medical management of unstable angina (UA) and non-ST elevation myocardial infarction (NSTEMI). FDA also approved eptifibatide for patients undergoing PCI, including intracoronary stenting. The IMPACT-II trial proved that eptifibatide use with heparin and aspirin reduces ischemic events following a percutaneous coronary intervention (PCI), especially in individuals with unstable angina. This activity outlines the indications, mechanism of action, administration, adverse effects, contraindications, warnings, precautions, monitoring, and toxicity of eptifibatide.

Objectives:

• Identify the mechanism of action of eptifibatide.
• Describe the adverse effects of eptifibatide.
• Explain the appropriate monitoring of eptifibatide.
• Summarize interprofessional team strategies for enhancing care coordination and communication to advance the use of eptifibatide and improve outcomes.

Indications

Eptifibatide is an antiplatelet drug that reversibly binds and inhibits platelets' glycoprotein IIb/IIIa receptors. A protein found in the venom of a southeastern pygmy rattlesnake is used to make eptifibatide. The PURSUIT and IMPACT-II account for the indications of eptifibatide by the Food and Drug Administration(FDA)as mentioned below:

• Acute Coronary Syndrome: FDA-approved eptifibatide for the medical management of unstable angina (UA) and non-ST elevation myocardial infarction (NSTEMI). In the PURSUIT trial, the eptifibatide showed favorable outcomes in reducing the composite end-point mortality and preventing nonfatal myocardial infarction in patients with non-ST elevation myocardial infarction and unstable angina.[1]
• Percutaneous Coronary Intervention (PCI): FDA also approved eptifibatide for patients undergoing PCI, including intracoronary stenting. The IMPACT-II trial proved that eptifibatide use with heparin and aspirin reduces ischemic events following a percutaneous coronary intervention (PCI), especially in individuals with unstable angina.[2]

Non-FDA-labeled Indications

• Eptifibatide is used to enhance myocardial perfusion in the ST-elevation myocardial infarction(STEMI) before PCI, as supported by evidence by the "Time to Integrefilin Therapy in Acute Myocardial Infarction (TITAN)-TIMI 34 trial.[3]
• Another possible use of eptifibatide is to enhance the incidence and speed of reperfusion when used in large doses in combination with heparin, aspirin, and tissue plasminogen activators in STEMI patients, as evidenced by the small group in the IMPACT-AMI trial. In the IMPACT-AMI trial, the use of eptifibatide showed complete reperfusion and an early ST-segment recovery on the electrocardiogram.[4]
• Eptifibatide can be used in combination with TPA in acute ischemic strokes to prevent progression to subacute intracerebral hemorrhage, as supported by the "Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke (CLEAR)" trial.[5]

Mechanism of Action

Rupture of atherosclerotic plaque or injury to the vessel wall exposes the subendothelial matrix of the coronary blood vessel to circulating platelets. This event triggers a platelet signaling cascade that leads to the activation of the glycoprotein IIb/IIIa receptor (GpIIb/IIIa). The activation of Gp IIb/IIIa receptors leads to cross-linking of fibrinogen to attach multiple platelets to form a durable secondary platelet plug. The secondary platelet plug is essential for the progression and stability of the clot. The glycoprotein IIb/IIIa receptor inhibitors, including abciximab, eptifibatide, sibrafiban, and tirofiban, block the activation of Gp IIb/IIIa receptors, ultimately preventing clot formation/progression.[6][7]

GP IIb/IIIa heterodimer contains a large extracellular region, a transmembrane domain, and a short intracellular cytoplasmic tail. The Gp IIb/IIIa receptor is a calcium and manganese-dependent heterodimer protein with an alpha- and a beta-subunit. The alpha-subunit is characterized by three or four divalent Ca- or Mn-binding domains crucial in the GP IIb/IIIa heterodimer. The beta-subunit comprises disulfide bonds, binding sites including lysine-glycine-aspartic acid (KGD) bindings binding sites, or arginine-glycine-aspartic acid (RGD) for attachment of fibrinogen, von Willebrand factor (vWF) and prothrombin. The binding sites of GP IIb/IIIa are hidden as latent and become active on the surface by undergoing a conformational change via inside-out signaling.[8]

The eptifibatide is a natural disintegrin from snake venom. It has a highly specific binding to the Gp IIb/IIIa receptor because of the structural resemblance of the KGD (Lys-Gly-Asp) sequence. Eptifibatide binds to the KGD binding sites on Gp IIb/IIIa receptor and competitively fights against the receptor's binding with fibrinogen, von Willebrand factor (vWF), and prothrombin. Higher plasma levels of eptifibatide are needed to competitively inhibit the target of over 80% block of KGD binding sites. Eptifibatide can competitively inhibit the KGD (Lys-Gly-Asp) sequence binding site in active and inactive states. The low affinity for direct binding with GP IIb/IIIa is responsible for rapid states. Furthermore, high doses of eptifibatide provide additional antithrombotic benefits by blocking the vitronectin binding site, the ligand for alpha-beta in vascular cells, which may offer other antithrombotic benefits.[9] Glanzmann thrombasthenia is an autosomal recessive disease with platelet receptor deficiency similar to the site of action of eptifibatide.

Pharmacokinetics

• Eptifibatide has linear pharmacokinetics, proportional to the bolus drug for bolus doses ranging from 90 to 250 mcg/kg with an infusion rate from 0.5 to 3 mcg/kg/min. Therefore, administration of a 180-mcg/kg bolus dose combined with an infusion produces an early peak, followed by a slight decline before attaining steady-state (within 4 to 6 hours). Clinicians can prevent this by administering a second 180-mcg/kg bolus dose 10 minutes after the first dose.
• The onset of action is rapid (inhibition of platelet aggregation 15 min after bolus 84%)
• Plasma elimination half-life is 2.5 hours. The plasma protein binding is about 25%.
• In healthy patients, renal clearance is approximately 50% of total body clearances because most of the drug is excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites.

Administration

Eptifibatide is intravenously administered and is available in strengths of 0.75 mg/ml and 2 mg/ml. The dose of eptifibatide is different in patients diagnosed with the acute coronary syndrome (ACS) and in patients undergoing percutaneous coronary intervention (PCI). In patients with ACS, it is given immediately after the diagnosis at a loading dose of 180 mcg/kg IV, followed by a continuous IV infusion of 2 mcg/kg/min. The infusion continues up to 72 hours. Pre-PCI, eptifibatide is given as a loading dose of 180 mcg/kg IV, followed by a continuous infusion of 2 mcg/kg/min with another 180 mcg/kg IV bolus (double bolus regimen) given 10 minutes after the first one. Status post-PCI eptifibatide infusion continued up to 18 hours. 

• Eptifibatide injection is provided as a sterile solution in 10-mL single-dose vials containing 20 mg of eptifibatide and 100-mL single-dose vials containing 75 mg of eptifibatide. Discard unused portions. Eptifibatide vials should be refrigerated at 2° to 8°C (36° to 46°F). Upon transfer, the hospital pharmacist must mark the vial with a "DISCARD BY" time (Two months from the transfer date or the expiration date, whichever comes first). In addition, Eptifibatide should be Protected from light until administration.
• In ACS, eptifibatide is a therapeutic option, and other medications include alteplase, heparin, metoprolol, nitroglycerin, morphine, or furosemide. However, Eptifibatide is chemically incompatible with furosemide, and thus they should not be administered in the same intravenous line.
• Eptifibatide may be administered as eptifibatide injection in the same IV line with 0.9% NaCl or 0.9% NaCl/5% dextrose[10]

Specific Patient Population

• Patients with Renal Impairment: Total drug clearance is reduced by almost 50%, and the steady-state plasma eptifibatide concentrations are doubled in patients with an estimated CrCl less than 50 mL/min. Consequently, clinicians should reduce the infusion dose to 1 mcg/kg/min in such patients and keep the loading dose similar to that of a normal kidney function. Eptifibatide is contraindicated in patients with serum creatinine greater than 4 mg/dL or patients requiring hemodialysis.[11] 

• Patients with Hepatic Impairment:  Information regarding hepatic impairment is not provided in the manufacturer's labeling (no clinical studies have been conducted on patients with hepatic impairment).

• Pregnancy Considerations: Published literature and the pharmacovigilance database are insufficient to establish an eptifibatide associated with major congenital disability or adverse maternal or fetal outcomes. There were no adverse developmental effects in animal reproduction studies when eptifibatide was administered intravenously to pregnant rats and rabbits at approximately four times the recommended maximum daily human dose. However, myocardial infarction is a medical emergency that can be fatal to the pregnant woman and fetus if left untreated. Hence, the clinician should not withhold therapy for the pregnant woman because of potential concerns regarding the effects of eptifibatide on the fetus.

• Breastfeeding Considerations: No published information is available on the use of eptifibatide during breastfeeding. Eptifibatide is a small cyclic peptide; hence absorption by the infant is unlikely because it is likely destroyed in the infant's gastrointestinal tract.[12]

Adverse Effects

The significant side effect of eptifibatide described in the PURSUIT trial was bleeding. In most cases, bleeding was mild and occurred at femoral access sites. More red cell transfusions were required in the eptifibatide group than placebo to counteract anemia.[1] However, there is increased bleeding following abciximab administration compared to eptifibatide or tirofiban because of the rapid reversibility of these latter two agents.

Thrombocytopenia is another side effect of eptifibatide reported in several case reports.[13][14] Thrombocytopenia infrequently occurs with Gp IIb/IIIa inhibitors but sometimes may be profound. The risk of thrombocytopenia associated with eptifibatide (0.1 to 0.2%) and tirofiban (0.1 to 0.3%) is lesser compared to abciximab (0.4 to 1.1%). Tirofiban-induced thrombocytopenia (secondary to eptifibatide) occurs because the naturally occurring drug-dependent antibodies specific for eptifibatide occupy Gp IIb/IIIa receptor site. It is also clinically relevant to distinguish eptifibatide-induced thrombocytopenia from other etiologies. Pseudothrombocytopenia is detectable using complete blood cell analysis when blood samples are collected in EDTA- containing tubes. The absence of platelet clumping on peripheral smear rules out pseudo-thrombocytopenia. Among the Gp IIb/IIIa inhibitors, only abciximab has reportedly shown an association with pseudo-thrombocytopenia.[15] Heparin and eptifibatide are administered simultaneously during PCI and in ACS treatment. Compared to heparin-induced thrombocytopenia (HIT), eptifibatide usually causes a steep decline in platelet count (less than 30000 cells/ uL). HIT-1 occurs within one and five days, whereas HIT-2 occurs within 4 to 20 days following heparin administration.[16] Thus thrombocytopenia develops within the first day, or severe thrombocytopenia favors thrombocytopenia secondary to eptifibatide. Also, detecting platelet factor-4 (PF-4) assay in HIT can help differentiate it from eptifibatide-induced thrombocytopenia. Eptifibatide can inhibit new platelets in both active and inactive states. Thrombocytopenia due to eptifibatide responds better after discontinuation of medication, and the addition of a platelet bag is not helpful if the patient has a high concentration of eptifibatide in plasma. Other side effects reported include hypotension, heart failure, arrhythmias (ventricular fibrillation, atrial fibrillation), hypersensitivity reactions, gastrointestinal, genitourinary, or pulmonary alveolar hemorrhage.[13]

Contraindications

The contraindications to using eptifibatide are mentioned below[17]:

• Thrombocytopenia: eptifibatide is contraindicated in patients with a platelet count of less than 100000/microliter
• Renal failure: eptifibatide is contraindicated in patients with serum creatinine higher than 4 mg/dL or patients requiring hemodialysis because of its renal elimination. In such patients, abciximab is an alternative.
• Hypersensitivity to eptifibatide
• Severe, uncontrolled hypertension
• History of bleeding diathesis within 30 days
• Major surgery or trauma within the prior six weeks
• Active internal bleeding or recent significant gastrointestinal or genitourinary bleed within the past six months
• History of stroke within 30 days or hemorrhagic stroke at any time
• Intracranial neoplasm, arteriovenous malformations, aneurysms, or aortic dissection
• Use of another parenteral glycoprotein IIb/IIIa inhibitor
• Eptifibatide is a pregnancy category B drug. However, therapy for acute coronary syndrome should not be delayed due to maternal risk-benefit considerations. Clinicians should only use it cautiously in lactating mothers. Also, The drug is not recommended for use in the pediatric population.

Monitoring

• Monitor complete blood count (CBC), serum creatinine, and PT/aPTT. In patients undergoing PCI, measure activated clotting time (ACT).[17]
• Attach cardiac monitoring to detect dynamic EKG changes.
• Monitor for reperfusion arrhythmias during and after the percutaneous coronary intervention (PCI).[18]
• Check arterial line insertion site for evidence of bleeding manifestations.
• Troponin I rises after 4 hours (peaks at 24 hr) and is elevated for 7–10 days, more specific than other protein markers.
• CBC: look for thrombocytopenia and anemia due to bleeding. It is strongly recommended to measure platelet count within 2 to 6 hours of administering eptifibatide to detect thrombocytopenia.
• Serum creatinine: Since eptifibatide gets cleared renally, it is essential to monitor renal function tests.
• PT/aPTT: to monitor the risk of bleeding
• ACT: eptifibatide has an additive effect on activated clotting time (ACT) when used together with heparin. Therefore, aPTT and ACT require close monitoring when administering these agents concurrently.[19]

Toxicity

There is limited knowledge of the overdosage of eptifibatide in literature. In preclinical studies, eptifibatide was not lethal to experimental animals in a dosage of two to five times the recommended MRHD(maximum daily human dose). However, symptoms of acute toxicity were evident such as loss of righting reflex, dyspnea, ptosis and decreased muscle tone in rabbits, and petechial hemorrhages in monkeys' femoral and abdominal areas. From in vitro studies, eptifibatide has limited protein binding; consequently, it may be removed from the plasma by dialysis( according to the manufacturer's labeling). 

Bleeding at intravenous sites is the most common adverse effect. Simultaneous use of NSAIDs or other antiplatelet drugs and renal insufficiency would increase the risk of bleeding. There is no specific antidote for eptifibatide toxicity. Clinicians should discontinue eptifibatide when platelet counts are under 50000 cells/microliter. A platelet transfusion should be ordered when platelet counts are less than 20000 cells/microliter or significant bleeding.[13]

Enhancing Healthcare Team Outcomes

Eptifibatide is useful in treating acute coronary syndrome (ACS) and following percutaneous coronary intervention (PCI). Healthcare workers, including nurses, pharmacists, clinicians, specialists, and cardiologists, should know that bleeding and thrombocytopenia are major complications following the administration of eptifibatide. They should work together to identify these complications. Nursing should be first in line to monitor for adverse events, especially bleeding. Pharmacists should conduct thorough medication reconciliation and verify dosing since medication errors in either area can lead to therapeutic failure or severe bleeding. Any concerns in these areas require immediate communication with the physician in charge and the rest of the team involved in care. Eptibitaide is a high-risk medication, according to ISMP (Institute for Safe Medication Practices). Also, since heparin is used in conjunction with eptifibatide in ACS treatment and during PCI, it is imperative to learn how to differentiate heparin-induced thrombocytopenia from eptifibatide-induced thrombocytopenia. Only through this type of interprofessional collaboration can patients achieve optimal therapeutic outcomes with eptifibatide. [Level 5]