tients undergoing total joint arthroplasty, ASA may be one of the prophylactic drugs considered, along with warfarin, LMWH, and fondaparinux. The guidelines do not address other venous thromboembolic events, such GDC-0941 as DVT, and do not define standard or increased risk of bleeding or PE. ASA has been shown to reduce venous thromboembolic events by 26% and 13% in patients undergoing THA and TKA, respectively , which is less than the reduction with other prophylactic agents. 2.3. New Oral Anticoagulants. The ideal anticoagulant needs to be more effective without increasing bleeding risk, safe, convenient to use, administered orally once daily and have fixed dosing factors that could potentially improve patient compliance.
The most promising new oral anticoagulants are the direct thrombin inhibitors and the direct Factor Xa inhibitors agents that directly target a single coagulation factor in the coagulation cascade. Dabigatran is approved in the EU and Canada for VTE prophylaxis after elective THA/TKA in adults. Rivaroxaban is approved in the EU and Barasertib numerous other countries for the prevention of VTE in adult patients after elective hip or knee arthroplasty. These two drugs represent the first new oral agents for VTE prophylaxis in THA and TKA in over 50 years. 2.3.1. Apixaban. Apixaban is an oral, direct Factor Xa inhibitor with predictable pharmacokinetics and pharmacodynamics. Gender has no clinically relevant effect on apixaban. Data are lacking for the effects of body weight or old age on apixaban. Approximately half of administered apixaban is absorbed and half is recovered in faeces.
Of the total dose, approximately one third is recovered in urine, of which over 80% is apixaban. Digoxin and inhibitors or substrates of P450 enzymes do not have clinically relevant interactions with apixaban. Absorption of apixaban is not affected after a highcalorie meal. A phase II study of apixaban was used to establish the dose to be used for the phase III clinical development programme. In this study, 1,238 patients were randomized to one of six double blind apixaban doses, enoxaparin or open label warfarin, for 10 14 days. The primary efficacy outcome decreased with increasing apixaban dose. There was a significant dose related increase of total adjudicated bleeding events for the oncedaily and twice daily regimens. The authors concluded that apixaban 2.
5mg twice daily and 5 mg once daily might have a promising risk benefit profile compared with enoxaparin 30 mg twice daily and warfarin. The ADVANCE 1 phase III study compared apixaban 2.5mg twice daily with the enoxaparin regimen commonly used in North America of 30 mg twice daily, for the prevention of VTE after TKA . The primary efficacy outcome occurred in 9.0% of patients receiving apixaban and 8.8% of patients receiving enoxaparin during the treatment period. The rates of PE were 1.0% in the apixaban group and 0.4% in the enoxaparin group, two PEs were fatal in the apixaban group and none were fatal in the enoxaparin group. Major or clinically relevant nonmajor bleeding occurred in 2.9% and 4.3% of patients receiving apixaban and enoxaparin, respectively. Major bleeding occurred in 0.7% and 1.4% of patients receiving apixaban and enoxaparin, respectively. One patient in the enoxaparin group died from bleeding, none of the apixaban group died from bleeding. In the ADVANCE 2 study, which compared apixaban 2.5mg twice daily with enoxaparin 40 mg once daily, the hypothesis was that apixaban would be