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.