Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: Bleeding, reversal, thrombocytopenia, and retreatment
Section snippets
Background: Pharmacodynamics of the GP IIb/IIIa inhibitors
Three GP IIb/IIIa inhibitors have been approved for clinical use in the United States: abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). From the perspective of pharmacodynamics, the agents can be divided into 2 categories: those that exhibit avid receptor binding (and a low dissociation constant) and those that have competitive, dose-dependent pharmacodynamics.3 Abciximab is a long-acting, high-affinity receptor blocker and is the prototypic example of an agent with
Prevention of bleeding
In the Evaluation of 7E3 in Preventing Ischemic Complications (EPIC) trial,8 treatment with abciximab was associated with a doubling of rates of Thrombolysis in Myocardial Infarction (TIMI) grade major bleeding (from 7% to 14%) and transfusion of blood products (from 10% to 21%) compared to placebo.9 Among several factors, bleeding correlated the most strongly with the inverse of body weight. Because all patients received a similar initial bolus dose of heparin (10,000 to 12,000 U), in effect
Emergency reversal
Although the use of GP IIb/IIIa inhibition with PCI substantially reduces the need for urgent or emergency surgical coronary revascularization (Figure 4), a small percentage of patients still requires immediate coronary artery bypass graft surgery.Other patients may develop an untoward bleeding diathesis. In these settings, understanding how to reverse GP IIb/IIIa inhibition rapidly may be critical.
Knowledge of the pharmacodynamics of the individual drugs will help tailor the management
Thrombocytopenia
Across the clinical trials of GP IIb/IIIa inhibition, rates of mild thrombocytopenia (to less than 100,000 platelets/mm3) observed in the active treatment arms have been approximately 5%.15 This is a rate comparable to that seen with unfractionated heparin alone.16 However, in these same trials rates of severe thrombocytopenia (<50,000 platelets/mm3) were approximately 2% in the abciximab trials, a value somewhat higher than that seen (<1%) in the trials of eptifibatide and tirofiban (Figure 5).
Readministration
Because 10% to 20% of patients undergoing PCI will require repeat revascularization within 1 year of the initial intervention, it can be anticipated that retreatment with GP IIb/IIIa inhibitors will be frequent. Initial administration of abciximab has been associated with development of a human antichimeric antibody response in approximately 6% to 7% of patients. The titers have generally been low, and the antibody response has been an immunoglobulin G antibody rather than the immunoglobulin E
Conclusion
The concerns surrounding the use of GP IIb/IIIa inhibitors are several and need to be considered when these agents are used in practice. Concerns include the potential for enhanced bleeding, algorithms for reversal, the development of thrombocytopenia, and issues concerning readministration. Interpretation of clinical trial results, coupled with the evolution of practice, dictates that lower dose, judicious heparin administration and careful patient selection remain critical to success when
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