Antiplatelet Therapy: Glycoprotein IIb/IIIa Inhibitors

General

Glycoprotein IIb/IIIa inhibitors—generalities

The glycoprotein (GP) IIb/IIIa receptor is an integrin that mediates the final common pathway of platelet aggregation. In particular, the GP IIb/IIIa receptor is a heterodimer consisting of the alpha IIb and beta₃-subunits.

By competing with fibrinogen and von Willebrand factor (vWF) for GP IIb/IIIa binding, GP IIb/IIIa antagonists interfere with platelet cross-linking and platelet-derived thrombus formation. Therefore agents blocking the GP IIb/IIIa receptor are very potent platelet inhibitors.

Numerous clinical trials have been conducted to define the optimal use of GP IIb/IIIa inhibitors. Currently, GP IIb/IIIa inhibitors are mostly indicated for patients undergoing percutaneous coronary interventions (PCI) in the setting of acute coronary syndrome (ACS).

In fact, clinical trials have shown limited benefit of GP IIb/IIIa inhibitors in medically managed ACS patients or in the setting of stable coronary artery disease (CAD) patients undergoing PCI. Moreover, recent clinical trial data have failed to show any benefit with routine use of upstream compared to ad hoc GP IIb/IIIa inhibition in ACS patients undergoing PCI.

In addition, clinical trials have for the most part failed to show any benefit of upstream GP IIb/IIIa inhibitor use in the setting of facilitated primary PCI and thus their upstream treatment in STEMI patients is generally not recommended. The lack of benefit, including increased mortality, in patients with ACS or undergoing PCI showed by the oral GP IIb/IIIa inhibitors stopped their investigations, and therefore only parenteral forms are available for clinical use.

There are three parenteral GP IIb/IIIa antagonists approved for clinical use: abciximab, eptifibatide, and tirofiban. Eptifibatide and tirofiban, also known as “small molecule agents,” do not induce immune response and have lower affinity for the GP IIb/IIIa receptor than abciximab.

Differences between drugs within the class

Abciximab is a large chimeric monoclonal antibody with a high-binding affinity that results in a prolonged pharmacologic effect. In particular, it is a monoclonal antibody that is a Fab (fragment antigen binding) fragment of a chimeric human-mouse genetic reconstruction of 7E3.

The specific binding site of abciximab is the beta₃-subunit. Its plasma half-life is biphasic, with an initial half-life of less than 10 minutes and a second-phase half-life of approximately 30 minutes.

However, because of its high affinity for the GP IIb/IIIa receptor, it has a biologic half-life of 12 to 24 hours, and because of its slow clearance from the body, it has a functional half-life up to 7 days. Of note, platelet-associated abciximab can be detected for more than 14 days after treatment discontinuation.

Eptifibatide is a reversible and highly selective heptapeptide, which has a rapid onset and a short plasma half-life of 2 to 2.5 hours. After discontinuation of the infusion, the recovery of platelet aggregation occurs within 4 hours.

Tirofiban is a tyrosine-derived nonpeptide inhibitor and is highly specific for the GP IIb/IIIa receptor. Tirofiban has a rapid onset and short duration of action, with a plasma half-life of approximately 2 hours. Similarly to eptifibatide, tirofiban has significant recovery of platelet aggregation within 4 hours of completion of infusion.

Administration

• Abciximab: 0.25 mg/kg IV; 0.125 µg/kg/min IV for 12 hours (max 10 µg/min).

• Eptifibatide: 180 µg/kg IV bolus; 2 µg/kg/min for 18 to 24 hours.

• Tirofiban: 0.4 µg/kg IV bolus; 0.1µg/kg/min for 18 to 24 hours.

The approved route of administration is intravenous, even though in clinical practice the bolus of these agents is frequently given intracoronary. There are no studies supporting the superiority of an intracoronary versus an intravenous route of administration, although anecdotal experience shows that intracoronary administration may impact thrombus resolution in patients with a high thrombotic burden.

While no renal adjustments are required for abciximab, eptifibatide and tirofiban are renally excreted, and therefore require dose adjustments in patients with renal dysfunction (eptifibatide 1 µg/kg/min if creatinine clearance is less than 50 ml/min; tirofiban dose reduction by 50% if creatinine clearance is less than 30 mL/min).

Indications and contraindications

GP IIb/IIIa inhibitors have shown to be of benefit in the setting of ACS patients undergoing PCI. Among unstable angina (UA)/non-ST elevation myocardial infarction (NSTEMI) patients undergoing PCI, guidelines advise that high-risk patients, especially with positive cardiac biomarkers, should receive a GP IIb/IIIa antagonist. The small-molecule agents, eptifibatide and tirofiban, may be started 1 to 2 days before and continued during the procedure, while abciximab is typically recommended only in the setting of PCI.

However, recent clinical trial data have failed to show any benefit with routine use of upstream compared to ad hoc GP IIb/IIIa inhibition in ACS patients undergoing PCI, and therefore this strategy is no longer recommended. GP IIb/IIIa inhibitors should not be used in patients with an active bleeding or at high risk for bleeding.

They should also be used with caution in the elderly and in patients with chronic kidney disease, and dose adjustments should be made based on renal function to avoid overdosing and to reduce bleeding risk. ACS and PCI guidelines for use of GP IIb/IIIa receptor inhibitors are summarized in Table 1.

Table 1.n

Undesirable effects

The primary adverse effect to GP IIb/IIIa receptor antagonists is bleeding. The risk of bleeding complications has limited the use of GP IIb/IIIa receptor antagonists, which are now reserved for high thrombotic risk settings.

Bleeding complications with GP IIb/IIIa receptor antagonists are increased in elderly patients and in those with chronic kidney disease. This has been frequently attributed to overdosing, underscoring the need for dose adjustments in these settings.

In addition, adjusting heparin dosing (50 to 70 IU/kg) is pivotal to reduce bleeding complications in patients treated with GP IIb/IIIa receptor antagonists undergoing PCI. Thrombocytopenia is also an undesired side effect of GP IIb/IIIa receptor antagonists, in particular abciximab.

Although the overall incidence is relatively low, the effects may be life threatening. Thrombocytopenia with abciximab (as defined by a platelet count <100,000/L) occurs in 2.5% to 6% of patients, and severe thrombocytopenia (platelet count <50,000/L) occurs in 0.4% to 1.6% of patients in reported clinical trials.

This complication is less common with eptifibatide and tirofiban. In cases of severe thrombocytopenia, the immediate cessation of therapy is the main approach. Thrombocytopenia in patients undergoing PCI is associated with more ischemic events, bleeding complications, and transfusions.

The platelet count typically falls within hours of GP IIb/IIIa administration. Readministration of abciximab, but not eptifibatide and tirofiban, is associated with a slightly increased risk of thrombocytopenia, and thus its use should be avoided or changed for other small molecules.

Treatment with GP IIb/IIIa inhibitors can also cause pseudothrombocytopenia, which occurs as a result of artifactual platelet clumping in vitro, with an incidence as high as 2.1% with the use of abciximab. A smear to directly examine for the presence of clumped platelets may be required for an accurate diagnosis.

Alternative approaches

A large number of studies have examined strategies to minimize bleeding risk without affecting ischemic outcomes. Among these, bivalirudin has shown to have similar efficacy with reduced bleeding. Details are described in the Anticoagulation Therapy chapter.

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