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Orthopedic procedures, total hip replacements (THR) and total knee replacements (TKR), are common surgeries performed in the U.S. and are associated with a risk of post-operative deep venous thrombosis (DVT) and/or pulmonary embolism (PE).1 The American College of Chest Physician (ACCP) guidelines recommends low molecular weight heparin (LWMH) therapy, preferentially, in the post-operative period for a minimum of 10-14 days with extended therapy up to 35 days in high risk patients. LMWH therapy is considered standard therapy and reduces the risk of venous thromboembolism (VTE) by approximately 50%. Other antithrombotic therapies recommended if LMWH is not an option, include fondaparinux, adjusted-dose warfarin, low dose unfractioned heparin (UFH) and the newer oral anticoagulants (apixaban, dabigatran, and rivaroxaban). These agents are also effective prophylactic methods for prevention of VTE in high-risk patients undergoing elective THR or TKR.1 While LMWH, low dose UFH and adjusted dose warfarin therapy are effective and commonly used, they have practical disadvantages of either requiring an injection or dose-adjustments. In addition, evidence shows that subclinical VTE can still develop in up to 20% of patients who undergo THR and 30-40% in TKR, as well as up to 4% of patients undergoing THR and TKR will develop symptomatic VTE within 3 months of surgery, despite prophylaxis.2-4 Therefore, the new oral anticoagulants may offer a more convenient, and perhaps a more effective and safe option, to the older therapies.

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The Apixaban Dose orally vs. Anticoagulation with Enoxaparin or ADVANCE trials provide clinical evidence surrounding the usage of apixaban for venous thromboembolism (VTE) prophylaxis in orthopedic surgery. In the ADVANCE clinical trial series apixaban was compared to enoxaparin for thromboprophylaxis in patients undergoing total hip or knee replacement.5-7 In the first randomized trial (ADVANCE-1), Lassen and colleagues evaluated apixaban 2.5 mg orally twice daily compared to enoxaparin 30 mg subcutaneously (SC) every 12 hours for VTE prophylaxis in patients undergoing TKR.5 Therapy was started within 12-14 hours and continued for 10-14 days. The primary endpoint was symptomatic and asymptomatic VTE and death from any cause. The study sought to determine non-inferiority and the authors needed 3058 patients to meet a power of 99% for non-interiority and 90% for superiority. Unfortunately, statistical criterion for non-inferiority was not met. The primary endpoint occurred in 9% of apixaban patients and 8.8% of enoxaparin patients. Symptomatic VTE only occurred in 1.2% of apixaban and 0.81% of enoxaparin with a higher rate of PE in the apixaban group (1% vs. 0.4% with enoxaparin). While there was no significant difference in major bleeding (enoxaparin 1.4% vs. apixaban 0.7%, p=0.053), there was a significantly higher rate of major and clinically relevant nonmajor bleeding with enoxaparin (4.3% vs. 2.9% with apixaban, p=0.03).5

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In the ADVANCE-2 study, the safety and efficacy of apixaban 2.5 mg orally twice daily was compared to enoxaparin 40 mg SC daily for the prevention of VTE in patients undergoing TKR using a non-inferiority analysis (with the same parameters as the ...

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