Platelet+glycoprotein+IIb+IIIa+inhibitors

Platelet glycoprotein IIb/IIIa inhibitors
 * History:** The platelet glycoprotein (GP) IIb/IIIa inhibitors potently reduce platelet aggregation. The role of platelet activation in ischemic events, particularly acute coronary syndromes, is critical. The first GP IIb/IIIa inhibitors were monoclonal antibodies that were effective in preventing thrombosis in animal models but were very immunogenic. Replacing the murine constant region with a human sequence formed a chimeric antibody that resulted in decreased immunogenicity. The Fab fragment of this antibody (c7E3 Fab) is known as abciximab. Abciximab (ReoPro®) was the first GP IIb/IIIa inhibitor to be FDA-approved in December 1994. Competitive GP IIb/IIIa inhibitors include eptifibatide (Integrilin®) and tirofiban (Aggrastat®), both drugs were FDA-approved in May 1998. Lamifiban has been evaluated in a clinical trial but did not show a statistically significant benefit; further development of this agent has been suspended. Other GP IIb/IIIa inhibitors include xemilofiban, lotrafiban, and sibrafiban; these drugs are prodrugs of peptidomimetric compounds and are administered orally. Results of clinical trials of these orally administered agents have been disappointing.

The use of GP IIb/IIIa inhibitors in acute coronary syndromes (ACS) significantly reduces the 30-day mortality rate or incidence of secondary events (e.g., MI) as compared to placebo in high-risk patients with unstable angina or non-Q-wave myocardial infarction.[2989] Current ACC/AHS guidelines recommend the use of GP IIb/IIIa inhibitors, in addition to aspirin and heparin, in those patients with continuing ischemia or with other high-risk features (e.g., elevated CK-MB, myoglobin, or cardiac troponins) and also in those patients in whom percutaneous coronary intervention (PCI) is planned.[2998] Eptifibatide and tirofiban are FDA-approved for this use. However, abciximab is not recommended in patients in whom a PCI is not planned due to the lack of benefit of abciximab during the GUSTO-IV ACS trial. Abciximab may be used for 12—24 hours duration in patients with unstable angina or non-Q-wave myocardial infarction in whom PCI is planned within the next 24 hours.


 * Mechanism of Action:** During platelet activation, the GP IIb/IIIa receptor becomes activated on the surface of the platelet. The GP IIb/IIIa receptor is critical to platelet thrombus formation as it serves as the final common pathway of platelet aggregation. The GP IIb/IIIa receptor is a member of the integrins, a family of adhesion molecules found on virtually all cell types. Unlike many of the other integrins, the GP IIb/IIIa receptor is platelet specific; GP IIb/IIIa receptors are found abundantly on activated platelets, with about 50,000—80,000 copies/cell. Fibrinogen is the principal ligand to bind to the GP IIb/IIIa receptor. The binding of fibrinogen and, other ligands such as von Willebrand factor (vWF), to the GP IIb/IIIa receptor results in cross-linking between platelets.[2990]

Abciximab has a strong affinity for the GP IIb/IIIa receptor and appears to be involved with steric hindrance and/or conformational changes that block the access of fibrinogen and von Willebrand factor to the GP IIb/IIIa receptor sites. Eptifibatide and tirofiban are competitive inhibitors of GP IIb/IIIa receptors that mimic the binding sequences found on fibrinogen. In contrast to abciximab, the efficacy of competitive inhibitors of GP IIb/IIIa is dependent upon maintaining high plasma concentrations to successfully compete with fibrinogen for GP IIb/IIIa receptor binding. In addition, competitive inhibitors are specific for GP IIb/IIIa receptor while abciximab may bind to other integrin family receptors including the vitronectin and Mac-1 receptors.[2990] The vitronectin receptor has a regulatory role in the processes of cell adhesion, migration, and proliferation; it is upregulated under conditions of rapid vascular growth, such as angiogenesis. Inhibition of vitronectin-induced cell proliferation may have a role in the prevention of restenosis; however, the long-term benefits of vitronectin inhibition by abciximab have not been proven. Abciximab can act as an anticoagulant. Abciximab anticoagulant activity may be due to potent GP IIb/IIIa activity or the vitronectin receptor may be involved.[2990]


 * Distinguishing Features:** Abciximab is a chimeric monoclonal antibody Fab fragment which nonspecificly binds to the GP IIb/IIIa receptor. While, eptifibatide is a cyclic peptide and tirofiban is a peptidomimetric (nonpeptide), both bind selectively to the GP IIb/IIIa receptor. Eptifibatide contains the KGD (Lys-Gly-Asp) sequence of fibrinogen; tirofiban contains the RGD (Arg-Gly-Asp) sequence of fibrinogen.

Cyclic peptides (i.e., eptifibatide) are more resistant to degradation than linear peptides, but still have short half-lives because they are broken down in the body. Peptidomimetric inhibitors (i.e., tirofiban) do not have peptide bonds, which allows for longer survival time in circulation as compared to peptide compounds. Both eptifibatide and tirofiban are relatively short acting; platelet function returns to 50% of baseline within 4 hours of discontinuing the infusions. Although abciximab has a short plasma half-life, abciximab remains bound to GP IIb/IIIa receptors for weeks; platelet aggregation gradually returns to normal roughly 24—48 hours after stopping abciximab.

The cost of platelet glycoprotein IIb/IIIa inhibitors is substantial. Abciximab is considerably more expensive than eptifibatide or tirofiban, which are similarly priced. Because the various agents have not been compared directly, their relative efficacy is not known. Although tirofiban is approved for use during PCI; one trial (TARGET trial) reported inferior efficacy (composite endpoint of death, nonfatal MI, or urgent target-vessel revascularization at 30 days) of tirofiban compared to abciximab in patients undergoing percutaneous coronary revascularization, with the intent to perform stenting.[2882]


 * Adverse Reactions:** Bleeding is the major adverse effect of platelet glycoprotein IIb/IIIa inhibitors. In the EPIC trial, the incidence of major bleeding was 11% in the group that received abciximab and full-dose heparin.[756] However, in subsequent studies with lower-dose heparin and early post-procedural sheath removal the incidence of major bleeding has decreased and is similar to those seen with heparin therapy alone. Recommendations to decrease bleeding complications include reducing the dose of heparin to 70 IU/kg, targeting procedural ACTs to between 200—250 seconds, early sheath removal, avoidance of routine venous sheaths, meticulous groin care, and avoiding use of post-procedural heparin. Use of low-molecular weight heparins (LMWHs) also decreases the risk of bleeding. Platelet GP IIb/IIIa inhibitors do not increase the risk of intracranial hemorrhage, unlike fibrinolytic therapy. Eptifibatide was not associated with an increased risk of stroke during the PURSUIT trial.[1729]

Thrombocytopenia is uncommon with platelet GP IIb/IIIa inhibitors. Platelet counts < 20,000/mm3 have been reported in <= 1% of patients. Following readministration of abciximab the incidence of thrombocytopenia is slightly higher (i.e., 1.5—2%) than with initial administration. Thrombocytopenia is usually noted within 1—24 hours of receiving the drugs, and the most severe form usually occurs within 1 hour of initiation of an infusion.

Abciximab is an antibody and may be expected to be immunogenic; however, on initial administration severe allergic reactions are not problematic. Information regarding hypersensitivity risk on readministration of abciximab is pending. Severe allergic reactions have been reported with eptifibatide and tirofiban.