Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement
Patients undergoing hip-replacement surgery require effective thromboprophylaxis, and low-molecular-weight heparins, vitamin K antagonists, and mechanical methods are now standard therapies. Despite prophylaxis, however, subclinical deep-vein thrombosis develops in approximately 15 to 20% of patients soon after surgery, and symptomatic venous thromboembolism develops in 2 to 4% during the first 3 months after surgery.1
Practical limitations of current prophylactic techniques have stimulated a search for simpler methods. Low-molecular-weight heparins and fondaparinux require subcutaneous injection. Warfarin has a delayed onset of action and is relatively ineffective soon after surgery. Mechanical methods are cumbersome and relatively ineffective after hip surgery.
The development of new oral anticoagulant agents has raised hopes that they will combine greater convenience with efficacy and safety profiles that are similar to or better than those of other methods. The use of rivaroxaban, a factor Xa inhibitor, and dabigatran etexilate, a direct thrombin inhibitor, for the prevention of venous thromboembolism after joint-replacement surgery has been evaluated in several phase 3 clinical trials.2-8
Apixaban is a highly specific factor Xa inhibitor that is administered in a fixed dose twice a day and does not require routine laboratory monitoring. 9 Clinical trials of apixaban involving patients who have undergone elective knee-replacement surgery showed that, as compared with enoxaparin, apixaban had better efficacy, with a similar or lower risk of bleeding.10-12 We conducted a randomized, phase 3 study, the Apixaban Dosed Orally Versus Anticoagulation with Injectable Enoxaparin to Prevent Venous Thromboembolism 3 (ADVANCE-3) trial, to compare apixaban with enoxaparin in patients undergoing elective total hip replacement. Both drugs were continued for 35 days after surgery.
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Methods
Patients
Patients were eligible if they were scheduled to undergo elective total hip replacement or revision of a previously inserted hip prosthesis. Major exclusion criteria were active bleeding, a contraindication to anticoagulant prophylaxis, or the need for ongoing anticoagulant or antiplatelet treatment. (A complete list of exclusion criteria is provided in the Supplementary Appendix, available with the full text of this article at NEJM. org.)
Study Design and Oversight
The study was a randomized, double-blind, double-dummy clinical trial. Potentially eligible patients were identified during a screening period of up to 14 days before surgery and were randomly assigned, with the use of an interactive telephone system, to receive apixaban at a dose of 2.5 mg orally twice daily plus placebo injections once daily or enoxaparin at a dose of 40 mg subcutaneously once daily plus placebo tablets twice daily. The randomization schedule was generated at the randomization center of Bristol-Myers Squibb with the use of SAS software and was stratified according to study site, with a block size of four. The study protocol, including the statistical analysis plan, is available at NEJM. org.
The study was designed and supervised by the ADVANCE-3 trial steering committee (see the Supplementary Appendix for a list of committee members) and was funded by Bristol-Myers Squibb and Pfizer. The protocol was approved by the ethics committee or institutional review board at each participating center.
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