ADVANCE-3

Apixaban Dose Orally Vs. ANtiCoagulation with Enoxaparin 3 (2010)

Condition

Prophylaxis for VTE after hip replacement

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Objective

Evaluate the safety and efficacy of apixaban versus enoxaparin after total hip replacement

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Trial design

Randomized, double-blind phase III study
Active treatment: apixaban 2.5 mg p.o. twice daily, starting 12–24 hours after wound closure, continued for 35 days; placebo injections as in control treatment (n=2708)
Control treatment: enoxaparin 40 mg s.c., first dose 12±3 hours preoperatively and then every 24 hours starting 12–24 hours after wound closure, continued for 35 days; placebo tablets as in active treatment (n=2699)

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Endpoints

Primary efficacy endpoint: composite of asymptomatic and symptomatic DVT, non-fatal PE, and all-cause death during treatment period
Secondary efficacy endpoint: major VTE (composite of proximal DVT, non-fatal PE, and VTE-related death during treatment period)
Primary safety endpoint: bleeding during treatment period or until 2 days after last study medication, assessed for discrete predefined categories of severity (major, clinically relevant non-major, minor, and the composite of major and clinically relevant non-major bleeding according to ISTH criteria)
Secondary safety endpoints: elevated aminotransferase or bilirubin levels, thrombocytopenia and arterial thromboembolic events (myocardial infarction, acute ischemic stroke, or other systemic thromboembolism) occurring during treatment and follow-up

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Trial participants

5407 patients scheduled for total hip replacement

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Results

Efficacy outcome: In the population with evaluable efficacy outcome (n=3866), the primary efficacy endpoint occurred in 27 of 1949 patients (1.4%) given apixaban and in 74 of 1917 patients (3.9%) given enoxaparin (absolute risk reduction 2.5%, relative risk reduction 64%; p<0.001 for non-inferiority and superiority). Major VTE were registered in 0.5% of the patients treated with apixaban and in 1.1% treated with enoxaparin (p<0.001 for non-inferiority and <0.01 for superiority). Symptomatic VTE or death related to VTE during the 60-day follow-up period occurred in none of 2598 patients in the apixaban group and in 6 of 2577 patients (0.2%) in the enoxaparin group
Safety outcome: In the safety population (n=3009), major bleeding and clinically relevant non-major bleeding occurred in 129 of 2673 patients (4.8%) receiving apixaban and in 134 of 2659 patients (5.0%) receiving enoxaparin (p=0.72). Major bleeding occurred in 22 patients in the apixaban group (0.8%) and 18 patients in the enoxaparin group (0.7%). The incidence of drug-related adverse events was similar in both groups

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Summary

Efficacy: Oral apixaban (2.5 mg twice daily) was superior to subcutaneous enoxaparin (40 mg once daily) for prevention of all VTE, all-cause death, and major VTE in patients after total hip replacement
Safety: The incidence of major or clinically relevant non-major bleeding was similar in both groups

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Reference

Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM for the ADVANCE-3 investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-2498

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Corresponding author

Lassen MR, Hørsholm Hospital, Department of Orthopedics, Spine Clinic, Clinical Trial Unit, Usserod Kongevej 102, DK-2970 Hørsholm, Denmark,
e-mail: mirula@noh.regionh.dk

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