Randomized Double-Blind Comparison of Apixaban with Enoxaparin for Thromboprophylaxis after Knee Replacement: The ADVANCE-1 Trial
Authors: Lassen Michael Rud , Gallus Alexander S , Pineo Graham F , Raskob Gary E ,   the ADVANCE-1 Investigators
Published: April 2020

Abstract
Thromboprophylaxis with enoxaparin after total knee replacement is an evidence-based recommended standard of care. The ADVANCE-1 clinical trial was a phase III randomized double-blind multicenter study that evaluated the efficacy and safety of apixaban, an oral direct factor Xa inhibitor, 2.5 mg orally bid compared with enoxaparin 30 mg subcutaneously every 12 hours for preventing venous thromboembolism after total knee replacement. Apixaban (or oral placebo) and enoxaparin (or subcutaneous placebo) were begun 12 to 24 hours post-operatively (mean 20 hours) and continued until mandatory bilateral venography was completed at 12± 2 days. The primary efficacy outcome was the composite of deep-vein thrombosis (DVT) by venography; symptomatic, objectively confirmed DVT or pulmonary embolism (PE); or death from any cause during the treatment period. The secondary efficacy outcome was the composite of objectively confirmed proximal DVT or PE, or death. The primary safety outcome was bleeding, including major bleeding (defined by ISTH criteria), clinically relevant non-major bleeding, and minor bleeding. All outcome events were interpreted by a central independent adjudication committee without knowledge of treatment. The study hypothesis was that apixaban would be as effective as enoxaparin based on a pre-specified non-inferiority margin in which the upper limit of the two-sided 95% CI is &lt; 1.25 for relative risk and &lt; 5.6% for the absolute risk difference for the primary efficacy outcome. A total of 3195 patients from 129 sites in 14 countries were randomized. The primary efficacy outcome occurred in 104 of 1157 patients (8.99%) given apixaban and in 100 of 1130 (8.85%) given enoxaparin (relative risk 1.02, 95% CI 0.78 to 1.32, one-sided p= 0.064 for non-inferiority, statistical criteria not met). The secondary efficacy outcome occurred in 26 patients (2.05%) given apixaban and in 20 patients (1.64%) given enoxaparin. Symptomatic PE occurred in 16 patients (1.0%) who received apixaban (2 fatal) and in 7 patients (0.44%) given enoxaparin (0 fatal); the majority of the PE in apixaban patients occurred within 48 hours postoperatively. Major or clinically relevant non-major bleeding occurred in 46 of 1596 patients (2.88%) given apixaban, compared with 68 patients (4.28%) given enoxaparin (absolute difference 1.46%, two-sided p=0.034). Major bleeding occurred in 11patients (0.69%) who received apixaban and in 22 patients (1.39%) who received enoxaparin (two-sided p=0.053). Elevated levels of liver transaminase enzymes were uncommon (2% to 3%) in both groups; no patient given apixaban met Hy’s criteria. Myocardial infarction or stroke occurred in only one patient who received apixaban (0.06%) and in 5 patients (0.31%) given enoxaparin. The lower-than-expected incidence of the primary efficacy outcome in the enoxaparin group resulted in an undersized study to meet the pre-defined statistical criteria for non-inferiority in spite of a similar incidence with the apixaban regimen. This is the first phase III trial to demonstrate a potential advantage of the new oral anticoagulants for bleeding. The apixaban regimen resulted in less clinically relevant bleeding than enoxaparin 30 mg given every 12 hours. Maintaining this advantage while optimizing efficacy with an altered dosing regimen, either by earlier postoperative dosing or by a slightly increased dose, would be an important advance in patient care.