Apixaban Versus Enoxaparin for Thromboprophylaxis After Joint Replacement Surgery: Pooled Analysis of Major Venous Thromboembolism and Bleeding In 8,464 Patients From the ADVANCE 2 and 3 Trials
Authors: Raskob Gary E. , Gallus Alexander S. , Pineo Graham F. , Chen Dalei , Ramirez Luz Margarita , Lassen Michael Rud 
Published: October 2019

Abstract
Abstract 192
Thromboprophylaxis after joint replacement surgery is evidence-based standard care. Usually, when thromboprophylaxis regimens with new anticoagulants have been more effective than existing standard practice they have also caused increased bleeding. Apixaban, a novel orally administered factor Xa inhibitor, has been evaluated in three phase 3 randomized, double-blind, double-dummy clinical trials (the ADVANCE studies) for the prevention of venous thromboembolism (VTE) after hip or knee replacement. A pre-specified aim of this program, in order to provide more precise estimates of the incidences of major VTE, bleeding, and the additional safety outcomes of myocardial infarction, stroke, and liver function, was to combine data from the two trials comparing apixaban 2.5 mg twice daily with the same enoxaparin regimen of 40 mg once daily (ADVANCE-2 and 3). Major VTE was defined a priori as the composite of adjudicated symptomatic or asymptomatic proximal deep-vein thrombosis (popliteal, femoral, or iliac vein thrombosis), non-fatal pulmonary embolism, and VTE-related death, counted if they occurred during the intended treatment period for each trial or within 2 days after the last dose of study medication, whichever was longer. The bleeding outcomes of major bleeding (adapted from ISTH criteria), clinically relevant non-major bleeding, and the composite of major and clinically relevant non-major bleeding, were counted if they occurred during the treatment period or within 2 days after the last dose of study medication. In both studies, subcutaneous enoxaparin (or placebo) was started 12±3 hours before operation, and resumed after surgery according to the investigator's standard of care, and oral apixaban (or placebo) was initiated 12 to 24 hours after wound closure (typically on the morning after surgery). Study medications were continued for 10 to 14 days after knee arthroplasty in ADVANCE- 2, and for 32 to 38 days after hip replacement in ADVANCE- 3. In both studies, mandatory bilateral venography was done at the end of the intended treatment period to assess the presence or absence of asymptomatic deep-vein thrombosis, and clinically suspected VTE was confirmed or excluded by objective testing. Patients were followed-up 30±5 and 60±5 days after the last dose of study medication. All venograms and all episodes of suspected VTE, bleeding, myocardial infarction, stroke, or death were adjudicated without knowledge of assigned treatment by an independent central adjudication committee. The site of bleeding was analysed as reported by the investigator. The pooled analysis was stratified by the type of joint replacement (hip or knee) for statistical calculations. A total of 8,564 patients were randomized in the ADVANCE-2 and 3 trials. Major VTE occurred in 23 of 3,394 evaluable patients (0.68%) in the apixaban group and in 51 of 3,394 (1.50%) evaluable patients in the enoxaparin group (absolute risk difference, -0.76%, 95% CI, -1.23% to -0.30%). Major bleeding occurred in 31 of 4,174 patients (0.74%) who received apixaban (18 occurred before the first dose) and in 32 of 4,167 patients (0.77%) given enoxaparin (absolute risk difference -0.02%, 95% CI, -0.40% to 0.35%). Major bleeding at the surgical site occurred in 26 apixaban and 27 enoxaparin patients (absolute risk difference -0.02%, 95% CI, -0.37% to 0.32%). The composite of major or clinically relevant non-major bleeding occurred in 182 patients (4.36%) given apixaban, compared with 206 patients (4.94%) given enoxaparin (absolute risk difference -0.58%, 95% CI, -1.49% to 0.32%); these bleeding events occurred at the surgical site in 135 (3.23%) apixaban patients, and in 155 (3.72%) enoxaparin patients (absolute risk difference -0.49%, 95% CI, -1.27% to 0.30%). Myocardial infarction or stroke during treatment or follow-up occurred in 13 patients (0.31%) in the apixaban group and in 10 patients (0.24%) in the enoxaparin group (absolute risk difference 0.07%, 95% CI, -0.15% to 0.30%). Elevated levels (>3 times upper normal limit) of enzymes ALT or AST occurred in 2.2% and 2.8% of apixaban patients respectively, and in 3.0% and 2.8% of enoxaparin patients respectively. The apixaban regimen was more effective than enoxaparin 40 mg once daily for preventing major VTE, without increased bleeding, and has the clinical advantages of oral administration and later initiation 12 to 24 hours post-operatively.

Disclosures:
Raskob: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda R and D: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy. Off Label Use: Apixaban is an experimental drug being evaluated in phase 3 clinical trials for the prevention and treatment of thromboembolic disease. Research reults will be discussed. Gallus:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Progen: Membership on an entity's Board of Directors or advisory committees. Pineo:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chen:BMS: Employment. Ramirez:BMS: Employment. Lassen:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Speakers Bureau; Sanofi Aventis: Consultancy; Astellas Pharma: Consultancy; GSK: Consultancy.