Direct thrombin inhibitors for treatment of heparin induced thrombocytopenia, deep vein thrombosis and atrial fibrillation.
Thrombin is a central enzyme in hemostasis, exerting potent procoagulant effects and activating platelets. Recently, several small molecule direct thrombin inhibitors (DTI's) with important clinical applications have been developed. Both lepirudin and argatroban are effective in treatment of heparin-induced thrombocytopenia resulting in rapid normalization of platelet counts and a reduction in thrombotic events. Because of differences in clearance mechanisms, argatroban is preferable in patients with renal insufficiency and lepirudin if there is hepatic impairment. DTI's have also been evaluated in treatment of venous thromboembolism. Small studies with recombinant hirudin have shown promise. Ximelagatran is a new DTI in late-stage clinical trials with advantages for treatment of venous thromboembolism including oral administration and fixed dosing, making it convenient for long-term treatment. A Phase III trial demonstrated that ximelagatran was superior to placebo for preventing recurrent thrombosis in patients who had undergone six months of standard anticoagulant therapy for venous thromboembolism. Another large trial compared ximelagatran to standard treatment with enoxaparin and warfarin for treatment of symptomatic deep vein thrombosis in a Phase III trial of 2,528 patients. The results showed that ximelagatran administered twice daily was as effective as standard treatment in preventing recurrence with no increase in bleeding complications. Ximelagatran has also been evaluated in two Phase III trials in patients with atrial fibrillation. The primary analysis of both showed that ximelagatran was non-inferior to warfarin for preventing stroke and other embolic events with no increase in bleeding complications. Unexpectedly, elevated serum transaminase levels were observed in 5-10% of patients receiving ximelagatran for over 1 month, and routine monitoring may be necessary. The introduction of DTIs represents an important advance in treatment of heparin-induced thrombocytopenia. The oral direct thrombin inhibitor, ximelagatran, shows promise in providing simplified, effective therapy for venous thromboembolism and atrial fibrillation.
Francis
C W
CW
Hematology-Oncology Unit, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA. charles_francis@urmc.rochester.edu
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects*; D001281:Atrial Fibrillation / Q000139:chemically induced* / Q000188:drug therapy*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000188:drug therapy*; D020246:Venous Thrombosis / Q000139:chemically induced* / Q000188:drug therapy*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006493:Heparin; D013917:Thrombin