**5.2 Current oral anticoagulants**

Dabaigatran etexilate is a pro-drug of the direct thrombin inhibitor, dabigatran (Eriksson et al., 2004). There have been four phase III clinical trials comparing this drug to enoxaparin. In addition, a meta-analysis of three of these has been conducted (Wolowacz et al., 2009). It demonstrated non-inferiority to once-daily enoxaparin 40mg dose in one clinical trial involving THA, but failed to do so when compared to twice-daily enoxaparin dosing with 30mg Additionally, it demonstrated non-inferiority to once-daily enoxaparin 40mg dose in two clinical trials involving THA patients (Eriksson et al., 2007a; Eriksson et al., 2007b). It was approved in the European Union and in Canada in 2008 for use in total joint arthroplasty patients as VTE prophylaxis. In the United States, it was approved for use in certain atria fibrillation patients for stroke prevention (Huo, 2011b).

unfractionated heparin alone in total joint arthroplasty or hip fracture patients due to inadequate evidence-based data to support its efficacy in these patient populations (Geerts

In contrast to warfarin, LMWHs have a predictable dose response with few interactions. Self-administration is generally well-tolerated and acceptable patient compliance has been documented in several studies. Additionally, there is no need for monitoring (Noble & Finlay, 2005). Dose adjustment may be necessary in the elderly, in particular in those with compromised renal clearance. LMWHs have considered to be the standard-of-care in many

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

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

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

Dabaigatran etexilate is a pro-drug of the direct thrombin inhibitor, dabigatran (Eriksson et al., 2004). There have been four phase III clinical trials comparing this drug to enoxaparin. In addition, a meta-analysis of three of these has been conducted (Wolowacz et al., 2009). It demonstrated non-inferiority to once-daily enoxaparin 40mg dose in one clinical trial involving THA, but failed to do so when compared to twice-daily enoxaparin dosing with 30mg Additionally, it demonstrated non-inferiority to once-daily enoxaparin 40mg dose in two clinical trials involving THA patients (Eriksson et al., 2007a; Eriksson et al., 2007b). It was approved in the European Union and in Canada in 2008 for use in total joint arthroplasty patients as VTE prophylaxis. In the United States, it was approved for use in

certain atria fibrillation patients for stroke prevention (Huo, 2011b).

et al., 2008).

**5. Newer agents** 

**4.3.5 Low-molecular-weight heparin** 

medical communities (Geerts et al., 2008).

complications that have been reported.

**5.1 Newer agents of historic importance** 

withdrawn from the market (Vaughan, 2005).

the drug development was discontinued.

**5.2 Current oral anticoagulants** 

Rivaroxaban and apixabab are both inhibitors of factor Xa. Their mechanism involves the inhibition of circulating factor Xa as well as bound factor Xa within the prothrombinase complex (Weitz, 2006). There have been four phase III clinical trials comparing rivaroxaban to enoxaparin (Eriksson et al., 2008). It also is approved in the European Union and Canada for VTE prophylaxis in patients undergoing THAs and TKAs. It has recently been approved in the United States.

Apixaban has been evaluated in several phase III clinical trials as well. It has not been approved for use anywhere (Lassen et al., 2010a). It was found to be more efficacious than once-daily dosing of enoxaparin, but failed to demonstrate non-inferiority to twice daily dosing of enoxaparin (Lassen et al., 2009; Lassen et al 2010b).
