Eptifibatide is an antiplatelet drug that reversibly binds and inhibits glycoprotein IIb/IIIa receptor of platelets. 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 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 prevented 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 are:

• Eptifibatide 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 incidence and speed of reperfusion when used in large doses in combination with heparin, aspirin, tissue plasminogen activators in STEMI patients, as evidenced by the small group 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 possibly used in combination of 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]

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, which block the activation of Gp IIb/IIIa receptors, ultimately preventing clot formation/progression.[6] 

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 consisting of an alpha- and a beta-subunit. The alpha-subunit characterized by three or four divalent Ca- or Mn-binding domains that are crucial in the GP IIb/IIIa heterodimer. The beta-subunit comprises of 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.[7]

The eptifibatide is a natural disintegrin from snake venom and have highly specific binding to the Gp IIb/IIIa receptor because of the structural resemblance of KGD (Lys-Gly-Asp) sequence. Eptifibatide binds to the KGD binding sites on Gp IIb/IIIa receptor and competitively fights against the binding of the receptor 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 both active and inactive states. Eptifibatide has a half-life of 2 to 2.5 hrs and cleared by the kidney. 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.[8][9][10][11]

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 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.  Kidney clears eptifibatide; a maintenance dose is cut down to 50% in patients with serum creatinine greater than 2 mg/dL and keeping loading dose the same as that of a normal kidney function. Contraindications to eptifibatide in patients with serum creatinine greater than 4 mg/dL or patients requiring hemodialysis.[12] 

In ACS, eptifibatide is a therapeutic option along with other medications, including alteplase, heparin, metoprolol, nitroglycerin, morphine, or furosemide. Eptifibatide is chemically incompatible with furosemide, and thus they should not be administered in the same intravenous line.[13][14]

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. There were more red cell transfusions required in the eptifibatide group compared to 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.[15][16] 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 of the naturally occurring drug-dependent antibodies specific for eptifibatide occupied 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.[17] Heparin and eptifibatide are administered simultaneously during PCI and in the treatment of ACS. In comparison 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.[18] Thus thrombocytopenia developing within the first day or severe thrombocytopenia favor thrombocytopenia secondary to eptifibatide. Also, the detection of 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.[15]

The contraindications to using eptifibatide mentioned below[19]:

• 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. It should only be used cautiously in lactating mothers. Also, the drug is not recommended for use in the pediatric population.