d B, and THRIVE II and III. Ximelagatran was also evaluated for the prevention of stroke and systemic embolism in patients with AF in the SPORTIF III and V trials. Based on the results of phase III trials, ximelagatran was launched in Europe in 2004 for the prevention of VTE after major orthopaedic surgery. However, it was withdrawn in 2006 PXD101 Belinostat due to concerns regarding liver toxicity and rebound cardiovascular effects. In the orthopedic development program, cardiovascular events and total mortality were signifi cantly increased in the ximelagatran group compared with the control groups. Because of liver toxicity concerns, the US Food and Drug Administration never approved ximelagatran. Figure 1 The coagulation cascade. Abbreviations: VKAs, vitamin K antagonists, AT, antithrombin.
FV Fibrinogen Fibrinunstable Prothrombin Thrombin FXa FVa F X FVIIa FIXa FIX Tissue Factor / FVII FXIa FVIIIa FXIIa FXII Contact activation FXI Prothrombinase Extrinsic Tenase Intrinsic Tenase Fibrinstable FXIIIa FXIII Heparinoids VKAs Fondaparinux Rivaroxaban Dabigatran Apixaban 1376 Vascular Health and Risk Management 2008:4 Lassen and Laux WZ4002 FXa is another rational target for the development of antithrombotics. FXa promotes both coagulation and infl ammation, and is at the point where the intrinsic and extrinsic coagulation cascade pathways meet. Inhibition of FXa is potentially more effective than targeting downstream thrombin, because the amount of activated coagulation factor generated from its inactive precursor increases at each level of the cascade.
FXa is the primary site of amplifi cation in the coagulation cascade: one molecule of FXa can facilitate the generation of more than 1000 thrombin molecules. Proof of principal for pure FXa inhibition was provided by fondaparinux, which selectively but indirectly inhibits FXa by binding to antithrombin and potentiating its inhibition of FXa. Razaxaban was one of the fi rst direct FXa inhibitors developed. The antithrombotic potential of razaxaban was investigated in a phase II VTE prevention study after TKR. Four doses of razaxaban were evaluated. The study showed a highly signifi cant reduction of thromboembolic events with increased doses of razaxaban. However, the three higher dose arms of the study were stopped prematurely because of increased rates of major bleeding.
Further development of razaxaban was halted and was replaced by development of another FXa inhibitor, apixaban. There are several promising oral anticoagulants currently in clinical development, including the DTI dabigatran etexilate and the direct FXa inhibitors rivaroxaban and apixaban. This review will provide a critical appraisal of the clinical potential of these agents. Dabigatran Dabigatran is a specifi c, competitive, and reversible DTI that is administered as the oral prodrug dabigatran etexilate. Dabigatran is formed by the rapid esterase catalyzed conversion of dabigatran etexilate via two intermediary prodrugs. Dabigatran binds to the active site of thrombin by hydrophobic interaction, thereby inhibiting the cleavage of fi brinogen to fi brin, and blocking the fi nal step of the coagulation cascade, and thus thrombus formation. Dabigatran inhibits both free and fi brin bound thrombin. The prodrug dabigatran etexilate is absorbed rapidly, but has low oral bioavailability . Peak plasma concentrations of dabigatran occur approximately 2 hours after administration, and steady state conditions are reached within 3 days after multiple dos