Continuing Education Activity

Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors prevent platelet aggregation by blocking glycoprotein IIb/IIIa receptors on their platelet's plasma membrane and inhibiting fibrinogen binding. The available GP IIb/IIIa inhibitors include tirofiban and eptifibatide. These agents, along with aspirin, are used in patients with unstable angina with PCI within 24 hours.

Objectives:

• Review the risks associated with initiating intravenous glycoprotein IIb/IIIa inhibitors and identify the critical patient counseling points.
• Describe the mechanism of action and outline the administration of glycoprotein IIb/IIIa inhibitors.
• Identify the adverse events of glycoprotein IIb/IIIa inhibitors.
• Outline the measures to enhance the outcomes of the health care team when taking care of patients receiving anticoagulation with glycoprotein IIb/IIIa inhibitors.

Indications

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 tirofiban and eptifibatide. These agents, along with aspirin, are used in patients with unstable angina with PCI within 24 hrs. Tirofiban and eptifibatide 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.[1] However, after the introduction of oral P2Y12 inhibitors, the role of GP IIb/IIIa inhibitors in ACS is decreased.

Currently, the American College of Cardiology/American Heart Association recommends the use of GP IIb/IIIa inhibitors in ACS when the patient is allergic or cannot tolerate P2Y12 inhibitors (Class I) or in patients who are undergoing PCI have 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 antiplatelet therapy, 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.[2][3][4] 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. Currently, intracoronary GP IIb/IIIa inhibitors are a Class II b recommendation in PCI during STEMI.[5]

Mechanism of Action

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 and undergo a conformational change upon platelet activation, allowing them 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. 

Integrillin has a half-life, elimination of 2.5 hours, and 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. 

Administration

The GP IIb/IIIa inhibitors (tirofiban and eptifibatide) are only available as intravenous agents. However, tirofiban and eptifibatide require a reduction in dosing for renal impaired patients.

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 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/100 mL (50 mcg/mL) and 12.5mg/250 mL (50mcg/mL). IV solution vials 5mg/100 mL 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. 

Adverse Effects

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 were reported as well. Thrombocytopenia contributes to about 1 to 5% of adverse reactions.[6] Hypersensitivity and local injection site complications are less frequent.

Contraindications

Absolute contraindications: Major bleeding diathesis and active major internal bleeding, and 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.

Monitoring

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. 

Enhancing Healthcare Team Outcomes

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.

1. Check coagulation labs such as the international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT).
2. Make sure the patient is not allergic to the agent before its administration.
3. Confirm the dosage of the antiplatelets and anticoagulants that the patient is receiving.
4. Check for any absolute and relative contraindications. 
5. Perform post-administration labs. 
6. Monitor the patient for signs and symptoms of bleeding after its administration.
7. The patients require monitoring for adverse events.
8. 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. 

Given the above, the entire interprofessional healthcare team, including clinicians, specialists, mid-level practitioners, nurses, and pharmacists, all must understand the indications, adverse events, and monitoring of glycoprotein IIb/IIIa inhibitors so that patients can derive maximum therapeutic results when these drugs are indicated, and avoid adverse events, leading to optimal outcomes. [Level 5]