**5.2.1 Potential problems with the newer agents**

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., 2002).

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 complications.

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.

Venous Thromboembolism in Orthopaedic Surgery 167

VTE remains a challenging problem that complicates many orthopaedic procedures. The incidence has been found to be particularly high following TKA and THA. Governmental and consumer governing bodies are beginning to recognize it as a "never-event" indicating that increased emphasis will be placed on prophylaxis in the years to come. Recommendations have been released by both the ACCP and the AAOS and there remains some disagreement as to the optimal management of VTE. Warfarin and LMWH remain the

The authors have several recommendations regarding the duration and type of therapy. Patients should be anticoagulated for 25-30 days postoperatively following total hip arthroplasty and for 14 days following a total knee arthroplasty. Certain patients with high risk of VTE (obese, low mobility, prior VTE, family history of VTE, or protein C/S deficiency) should be treated for 25-30 days as well following hip or knee replacement. At our institution, we generally use enoxaparin for postoperative anticoagulation. For inpatients, either 30mg twice daily or 40mg daily may be used following total hip arthroplasty. The FDA has approved only the twice daily dosing after total knee

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American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons

Amin A, Spyropoulos AC, Dobesh P *et al*. Are hospitals delivering appropriate VTE

Aszalos A. Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) II. Clinical aspects. *Drug Discov Today* 2007;12:838–843. Bergqvist D, Agnelli G, Cohen AT, et al., for the ENOXACAN II Investigators. Duration of

Burnett RS, Clohisy JC, Wright RW, et al. Failure of the American College of Chest

thromboprophylaxis (VTE start). *J Thromb Thrombolysis* 2010;29:326–339. Anderson FA, Lieberman J, Pellegrini VD, et al. Practices in prevention of venous

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prevention? The venous thromboembolism study to assess the rate of

thromboembolism in primary hip and knee arthroplasty vary with surgeon operative volume: findings from a survey of US orthopedic surgeons. *J Thromb* 

prophylaxis against venous thromboembolism with enoxaparin after surgery for

Physicians-1A protocol for Lovenox in clinical outcomes for thromboembolic

standard of care in many practices, but newer agents show increasing promise.

arthroplasty. For outpatients, enoxaparin 40mg daily is our regimen of choice.

Agency for Healthcare Research and Quality. 2007.

*www.aaos.org/Research/guidelines/PE\_guideline pdf* 2007.

undergoing total hip or knee arthroplasty.

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**6. Conclusion** 

**7. References** 


Table 3. Major bleeding rates in VTE prophylaxis clinical trails in THA and TKA. (Reference: Huo, M. New oral anticoagulants in venous thromboembolism prophylaxis in orthopaedic patients: Are they really better? *Thromb Haemost* 2011;106:45-57.
