New approaches to anticoagulation in atrial fibrillation

Oral direct thrombin inhibitors (DTIs) are a potential alternative to vitamin K antagonists, such as warfarin, for anticoagulant therapy. The oral DTI at the most advanced stage of clinical development is ximelagatran, which is rapidly absorbed and bioconverted to the active form melagatran. Oral ximelagatran has been evaluated in randomized, controlled trials for several indications, including stroke prevention in atrial fibrillation (AF). Recently, two pivotal phase III trials demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular AF as effectively as well-controlled, adjusted-dose warfarin. Oral ximelagatran was generally well tolerated and caused less total (major plus minor) bleeding than warfarin. In a minority of ximelagatran-treated patients, elevated serum alanine aminotransferase levels were reported, but were typically not associated with specific symptoms, and returned toward the pretreatment baseline whether treatment was continued or discontinued. In AF, oral ximelagatran promises a better benefit to risk ratio than warfarin.