New issues in oral anticoagulants

Polymorphisms in CYP2C9, a critical cytochrome P-450 enzyme in the metabolism of warfarin, alters its clearance and affects dosing. CYP*1 has higher activity than either the *2 or *3 variants, and patients with the *2 or *3 variants require a lower dose. VKORC1 is the enzyme inhibited by warfarin, and its levels are affected by several polymorphisms that can be divided into high or low level haplotypes, and patients with high level haplotypes require higher warfarin doses. The use of algorithms for dosing that incorporate pharmacogenomic information perform better than those using clinical data alone. Considerable effort is ongoing to develop new oral anticoagulants as alternatives to warfarin, and three agents are in advanced development. Dabigatran is an oral direct thrombin inhibitor that has been compared with enoxaparin for prevention of VTE following hip or knee replacement. Based on non-inferiority results in European trials, it has now been approved for marketing in Europe. Phase III trials with a new oral Xa inhibitor, rivaroxaban, have been completed in hip or knee replacement, and rivaroxaban was superior to enoxaparin in prevention of VTE with no increase in bleeding complications. Phase III studies with apixaban, another oral Xa inhibitor, are in progress. These agents are also being evaluated in large studies for prevention of stroke in atrial fibrillation and for VTE treatment.