Oral Anticoagulation

 Apixaban Versus Enoxaparin for Thromboprophylaxis After Knee Replacement (ADVANCE-2): A Randomized Double-Blind Trial

 The study was coordinated by the ADVANCE-2 steering committee, chaired by M.R. Lassen, MD, from the University of Copenhagen.

 Bristol-Myers Squibb and Pfizer

 NCT00452530

 This is an international study that includes medical centers in North America, Europe, Latin America, South Africa, and Asia.

 The investigators enrolled 3,221 patients. The total number of patients eligible for primary efficacy analysis was 1,973.

 A multicenter, randomized, double-blind study was performed to compare the efficacy and safety of oral apixaban to that of subcutaneous enoxaparin in patients undergoing knee replacement. Patients received twice-daily dosing of 2.5 mg oral of apixaban beginning 12 to 24 hours after knee surgery or 40 mg subcutaneous of enoxaparin starting 12 hours before surgery. Both drugs were continued for 10 to 14 days. All participants had venography following treatment. The primary endpoint was a composite that included asymptomatic and symptomatic deep-vein thrombosis, non-fatal pulmonary embolism, and death from any cause during treatment.

 The last orally active anticoagulant to receive FDA approval was warfarin in 1954. Warfarin has a very slow onset of action, and its narrow therapeutic window necessitates frequent monitoring. Low-molecular-weight heparins, such as enoxaparin, are effective anticoagulants but require subcutaneous administration. These shortcomings have fostered the development of orally active direct thrombin inhibitors and factor Xa (fXa) inhibitors, such as apixaban. Venous thromboembolism is a common complication following total knee replacement and is an established clinical setting for the evaluation of antithrombotics. The objectives of this study were to determine whether apixaban was non-inferior to enoxaparin in preventing thrombosis following knee replacement and to compare the bleeding risk of the two regimens.

 Several direct thrombin inhibitors and fXa inhibitors are in advanced clinical development. Ximelagatran was approved in Europe but subsequently withdrawn owing to concerns about hepatoxicity. Rivaroxaban and dabigatran have been approved in Europe and Canada, and rivaroxaban is awaiting a decision from the U.S. FDA. The ADVANCE-2 trial represents the second phase III trial for apixaban. The primary efficacy analysis of 1,973 patients demonstrates that 2.5 mg BID apixaban is superior to 40 mg of enoxaparin QD in preventing thrombosis following knee replacement without causing increased bleeding or transaminitis. Event rates (15 percent for apixaban and 24 percent for enoxaparin) in this study were considerably higher than the 9 percent event rates observed in ADVANCE-1 for both 2.5 mg BID apixaban and 30 mg enoxaparin BID. However, the event rates in ADVANCE-2 were more consistent with anticipated results. The ADVANCE studies provide further evidence that orally active fXa inhibitors are promising agents for thrombosis prophylaxis. Which inhibitors find their way into clinical practice and the degree to which they replace warfarin and low-molecular-weight heparins remain intriguing questions.