Unstable angina non ST elevation myocardial infarction direct thrombin inhibitors therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.; Smita Kohli, M.D.

Overview

Hirudin which is the prototype of direct thrombin inhibitors class of drugs has been studied in multiple trials with mixed results. Other drugs in this class include bivalirudin, argatroban, efegatran and inogatran. Bivalirudin is a synthetic analog of hirudin that binds reversibly to thrombin and inhibits clot-bound thrombin.

Direct Thrombin Inhibitors

Indications

• Hirudin (lepirudin) is presently indicated by the 'US Food and Drug Administration' only for anticoagulation in patients with heparin-induced thrombocytopenia and for the prophylaxis of deep vein thrombosis in patients undergoing hip replacement surgery.

• Argatroban is another direct thrombin inhibitor that is approved for the management of patients with heparin-induced thrombocytopenia.

Clinical Trial Data

• The relative benefits of hirudin versus UFH in ACS patients was evaluated in the 12,142 patient in GUSTO-IIb trial . A reduction in risk for nonfatal MI was seen without increased risk of major bleeding.

• TIMI 9B study failed to show any difference in outcomes in Hirudin verus heparin treated patients getting TPA.

• The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial randomized 13,819 patients with unstable angina/NSTEMI to one of three treatments: UFH, or enoxaparin plus a GP IIb/IIIa inhibitor, or bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. Patients were managed with an early invasive strategy and the primary endpoint was the composite of death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days. No differences were observed in the direct comparison of the anticoagulants i.e., between bivalirudin plus GP IIb/IIIa inhibitor and UFH/enoxaparin plus a GP IIb/IIIa inhibitor or bivalirudin alone. But for the bivalirudin alone group, when compared with the group receiving UFH/enoxaparin plus a GP IIb/IIIa inhibitor, there was decrease risk for bleeding.

Disadvantage of Direct Thrombin Inhibitors

• Direct thrombin inhibitors lack a protamine-binding domain, hence it is not possible to reverse the effect with protamine. In the event of bleeding, discontinuation of their administration and, if needed, transfusion of coagulation factors (e.g., fresh frozen plasma) is required.

• In ACS, the monovalent direct thrombin inhibitors (including argatroban) are ineffective anti-thrombotic agents compared with UFH, and thus, argatroban should generally not be used in management of ACS.