**5. Newer agents**

There are several new oral anticoagulants in various stages of clinical development. These new classes target the inhibition of either thrombin or factor Xa. Most of the clinical trial data have demonstrated equal or even superior efficacy in comparison to LMWH. However, bleeding complications remain the primary concern. There are several other potential complications that have been reported.

### **5.1 Newer agents of historic importance**

Ximelagatran was the first direct-thrombin inhibitor, and was approved initially by the European regulatory agencies. The initial trials showed no signs of liver toxicity in shortterm use of up to 11 days (Eriksson et al., 2003). However, extended treatment (greater than 35 fays) was found to be associated with an increased risk of liver toxicity in one study (Agnelli et al., 2009). The liver toxicity was unpredictable, and the product was later withdrawn from the market (Vaughan, 2005).

Razaxaban was the first oral Factor Xa inhibitor to be developed. Data from phase I clinical trials demonstrated adequate efficacy and safety (Spyropoulos, 2007). A phase II trial involving TKA patients demonstrated significantly higher bleeding complication rates when compared with enoxaparin (Lassen et al., 2003). The trial was terminated prematurely and the drug development was discontinued.
