Platelets are responsible for the formation of thrombus after endothelial injury, which is vital in maintaining normal hemostasis. Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors prevent platelet aggregation by blocking glycoprotein IIb/IIIa receptors; thus they found application in the management of coronary artery disease (CAD). The available GP IIb/IIIa inhibitors include abciximab, tirofiban, and eptifibatide. These agents, along with aspirin, are used in patients with unstable angina with PCI within 24 hrs. Among them, abciximab is a monoclonal antibody receptor inhibitor, and the other two are non-antibody receptor inhibitors. The Food and Drug Administration (FDA) had approved GP IIb/IIIa inhibitors for the management of acute coronary syndromes (ACS) such as unstable angina and non-ST elevation myocardial infarction requiring percutaneous coronary interventions (PCI) within 24 hrs. GP IIb/IIIa inhibitors were the drug of choice in ACS patients during the plain balloon angioplasty era when complications secondary to post-procedure acute thrombosis were frequent. However, after the introduction of oral P2Y12 inhibitors, the role of GP IIb/IIIa inhibitors in ACS is decreased. Currently, American College of Cardiology/American Heart Association has recommends the use of GP IIb/IIIa inhibitors in ACS when patient is allergic or cannot tolerate to P2Y12 inhibitors (Class I) or in patients who are undergoing PCI has received P2Y12 inhibitors but at higher risk for thrombus and in those who are allergic to aspirin (Class IIa). Before the advent of stents and the use of dual antiplatelets, a prolonged infusion (12 to 24 hours) of GP IIb/IIIa inhibitor was the recommendation for ACS patients. However, currently, a short duration infusion or bolus only methods are recommended to avoid bleeding complications. Intracoronary infusion of GP IIb/IIIa inhibitors in multiple trials had shown improvement in epicardial and myocardial perfusion with fewer adverse events. However, clinical trials did not find a significant improvement in outcomes or recurrent MI. In a major trial, AIDA-STEMI involving 2065 patients, researchers studied intracoronary infusion of abciximab, but there was no difference in the primary endpoint of death and new MI. Currently, the use of intracoronary GP IIb/IIIa inhibitors is a Class II b recommendation in PCI during STEMI.
In the coagulation cascade, glycoprotein receptors have two subunits α and β, which are responsible for platelet aggregation and adhesion. They are present on the platelet plasma membrane, undergo a conformational change upon platelet activation allowing the platelets to adhere to each other. These GP IIb/IIIa inhibitors bind to the receptor and prevent fibrinogen and von Willebrand factor (vWF) from binding to the receptors.
Abciximab is a chimeric human-murine monoclonal antibody and can reduce platelet aggregation by 80%. Its half-life is 30 mins, and its onset of action is at 10 min (less than 20% of baseline). Its duration of action is 72 hours; it undergoes metabolism through proteolytic cleavage. It remains bound to platelets for 15 days, and platelet inhibitory activity is maximum at approximately 30 min.
Integrillin has a half-life, elimination of 2.5 hours, the onset of action occurs in 1 hour with a duration of action of 4 hours. It is 25% protein-bound and has a Vd of 185 to 260 mL/kg. Its excretion is via the urinary system. It has a renal clearance of 55 to 58 mL/kg/hr.
Tirofiban has a half-life of 2 hours, and its duration of action is 4 hours. It is 65% protein-bound, and its Vd is 22 to 42. About 65% of tirofiban clearance is through urine and 25% through feces. Its clearance is 213 to 314 mL/min. It is dialyzable.
The GP IIb/IIIa inhibitors (abciximab, tirofiban, and eptifibatide) are only available as intravenous agents. Abciximab does not need any dosage adjustments for renal impairment. However, tirofiban and eptifibatide require a reduction in dosing for renal impaired patients.
Abciximab serves as an adjunct to PCI: 0.25 mg/kg IV bolus over at least 1 minute and then 0.125 mcg/kg/min IV continuous infusion for 18 to 24 hours concluding 1-hour after completion of PCI; not to exceed 10 mcg/minute. The clinician should discontinue continuous infusions of abciximab in patients with failed PCIs.
Integrillin in acute coronary syndromes: 180 mcg/kg IV bolus over 1 to 2 min, and then 2 mcg/kg/min IV for up to 72 hours. In patients undergoing PCI - 180 mcg/kg IV, and then continuous infusion 2 mcg/kg/min with another 180 mcg/kg IV bolus 10 minutes after 1st one, Continue infusion for at least 12 hours. The dosage of eptifibatide requires adjustment in patients with CrCl <50 mL/min; ACS: 180 mcg/kg IV, and then continuous infusion 1 mcg/kg/min; PCI: 180 mcg/kg IV, and then continuous infusion 1 mcg/kg/min with another 180 mcg/kg IV bolus 10 minutes after the first one. The safety and use during hemodialysis remain unestablished.
Tirofiban is available as a premixed IV infusion solution and IV solution vials. Premixed IV infusion solution: 5mg/100mL (50mcg/mL) and 12.5mg/250mL (50mcg/mL). IV solution vials 5mg/100mL vial (50mcg/mL), and 3.75mg/15mL bolus vial (250mcg/mL). In NSTEMI - loading dose: 25 mcg/kg IV infused within 5 min, and then post-loading dose infusion: 0.15 mcg/kg/min IV for up to 18 hr. In patients with CrCl ≤60 mL/min: Decrease post-loading dose infusion by 50% to 0.075 mcg/kg/min IV.
GP IIb/IIIa receptor inhibitors are used together with other antiplatelet and anticoagulants, increasing the risk of bleeding. Major and minor bleeding contributes to the majority of adverse events ranging from 1 to 10%. Cardiovascular side effects such as hypotension and bradycardia reported as well. Thrombocytopenia contributes to about 1 to 5% of adverse reactions. Hypersensitivity and local injection site complications are less frequent.
Absolute contraindications: Major bleeding diathesis and active major internal bleeding and a history of hemorrhagic stroke within 30 days. Relative contraindications: History of thrombocytopenia, stroke, major surgery within six weeks, and severe hypertension. Intracranial disease and renal impairment require review on a case-to-case basis.
Reports exist of acute thrombocytopenia within 24 hours. If platelet count drops below 100,000/mm during the infusion, discontinue the GP IIb/IIIa inhibitor. Usually, platelet count normalizes between 1 to 2 weeks. The clinician should have the patient's coagulation parameters and platelet count checked before and during infusion. Platelet count should be checked 2 to 4 hours after the beginning of infusion and at 24 hours. These patients require careful monitoring for signs and symptoms of bleeding along with other possible adverse events. The glycoprotein IIb/IIIa inhibitors may need to be continued after the procedure in patients at high risk for thrombus burden. Such patients should be monitored closely in an intensive care unit.
Glycoprotein IIb/IIIa inhibitor is used in combination with another antiplatelet agent such as aspirin during PCI increasing the bleeding risk. The following steps are necessary before the administration of glycoprotein IIb/IIIa inhibitors
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