**4.3.3 Aspirin**

The ACCP guidelines do not recommend using aspirin alone in any of the high-risk orthopedic patient populations. The AAOS guidelines do sanction its use in patients with standard risk profile for pulmonary embolism prevention (Geerts et al., 2008).

#### **4.3.4 Unfractionated heparin**

This has been included in the ACCP guidelines for patients undergoing general surgery procedures. However, the ACCP guidelines have recommended against using

Venous Thromboembolism in Orthopaedic Surgery 165

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

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

Bleeding events are the most important complication. A recent survey reported that 50% or more orthopaedic surgeons in the United States stated that they were more concerned with bleeding than the risk of VTE (Anderson et al., 2009). Major bleeding has occurred with all of these agents as it has with other pharmacological agents. LMWHs have been studied for over 20 years, and the incidents of significant bleeding complications ranges from 0.9% to 9.3% (Leizorovicz et al., 1992). A major difference between LMWH and the newer agents is that enoxaparin can be at least partially reversed using protamine in certain situations (Crowther et al., 2002). The thrombin and factor Xa inhibitors have no such reversal agents yet (Ng & Crowther, 2006). An overview of the bleeding in clinical trials involving new agents is included in Table 3. It is also important to note the effect of drug-drug interactions. There have been trials showing prolonged bleeding when rivaroxaban was taken with clopidogrel or aspirin (Perzborn et al., 2007). Though there may be a relationship between bleeding and infection, the use of anticoagulation has not specifically been associated with a higher infection rate (Parvizi et al., 2007; Saleh et al.,

Aside from bleeding risk, there are other adverse effects that have been documented with the thrombin and factor Xa inhibitors. Drug-induced liver toxicity is the most common reason cited for the withdrawal of a drug from the market (Lee, 2003). The exact mechanism has not been identified. There have been several trials with dabigatran that reported elevated liver enzymes, but all returned to baseline within 2 months (Eriksson et al., 2007b). Dabigatran is a substrate for the cellular transporter P-glycoprotein which could be a mechanism of drug interaction (Aszalos, 2007). CYP240 enzymes are involved in the metabolism of both factor Xa inhibitors (Bayer Inc, 2010). Both factor Xa and thrombin inhibitors are excreted through the renal system, so this could potentially lead to

Both types of drugs are promising alternatives due to several characteristics. They have predictable pharmacokinetics, few drug interactions, and no monitoring is required (Weitz et al., 2008). It is important to note that a perfect anticoagulant does not exist at this point. The thrombin and facto Xa inhibitors have been shown to be effective and safe in multiple

trials, but there still is a lack of data from community practice.

dosing of enoxaparin (Lassen et al., 2009; Lassen et al 2010b).

**5.2.1 Potential problems with the newer agents** 

in the United States.

2002).

complications.

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 et al., 2008).
