Background: Apixaban is an orally active, highly selective, reversible inhibitor of Factor Xa. It binds directly to the active site of Factor Xa without requiring anti-thrombin. Antithrombotic activity was evaluated in a dose-ranging study in patients undergoing total knee replacement.Methods: Patients were allocated randomly to 1 of 6 double-blind doses of apixaban (5, 10, or 20 mg) given as a single or a twice-daily divided dose, or enoxaparin 30 mg bid, or open-label warfarin titrated to an INR of 1.8–3.0. Apixaban and enoxaparin were started 12 to 24 hours after completing surgery; warfarin the evening of the day of surgery. Treatment continued for 10–14 days. Mandatory bilateral venography was performed at the end of treatment. Patients could then be treated with non-study drug prophylaxis according to the attending physician's discretion. All patients were seen at follow-up on day 42. The primary efficacy outcome was a composite of all venous thromboembolic events (VTE) comprising asymptomatic and symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) and all-cause death during the treatment period. A central independent committee whose members were unaware of treatment assignments adjudicated all efficacy outcomes and bleeding events.Results: Of 1217 subjects treated and included in the safety analysis, 856 were eligible for the efficacy analysis. The composite VTE plus all cause death rate in the apixaban groups combined was significantly lower than the rate in the enoxaparin (p<.02) and warfarin (<.001) groups (8.6%; 15.6%; 26.6%, respectively). A trend for a dose-related decrease (p=.09) in the composite VTE plus all cause death rates of 10.6%, 8.6%, and 6.8% was apparent when QD and BID apixaban doses were combined as total daily doses of 5, 10, and 20 mg, respectively. When QD and BID apixaban doses were assessed separately, dose-dependent decreases in the composite VTE plus all cause death rates were observed for each but did not reach statistical significance. The composite VTE plus all cause death rates for apixaban 2.5 mg BID and 5 mg QD were 9.9% (95% CI:5.1–17.0) and 11.3% (95% CI:5.8–19.4) respectively, compared with a rate of 15.6% (95% CI: 9.4–23.8) in the enoxaparin group. For the composite outcome of proximal DVT+PE+all-cause death, each apixaban group had a lower event rate (0–2.7%) than the enoxaparin rate (4.6%). The incidence of major bleeding for apixaban ranged from 0.0% (2.5 mg BID) to 3.3% (20 mg QD); no major bleeding was observed in either the enoxaparin or warfarin groupsConclusions: Apixaban, an oral Factor Xa inhibitor, demonstrates a favorable efficacy and an acceptable bleeding safety profile at doses of 5 to 20 mg per day in the prevention of VTE after knee replacement surgery.