ADVANCE-2

Apixaban Dose Orally Vs. ANtiCoagulation with Enoxaparin 2 (2010)

Condition

Prophylaxis for VTE after total knee arthroplasty

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Objective

To prove non-inferiority of apixaban compared to enoxaparin in the prevention of venous thromboembolism after total knee 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 10–14 days; placebo injections as in control treatment (n=1528)
Control treatment: enoxaparin 40 mg s.c., first dose 12±3 hours preoperatively and then once daily starting 12–24 hours after surgery, continued for 10–14 days; placebo tablets as in active treatment (n=1529)

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Endpoints

Primary efficacy endpoint: composite of asymptomatic and symptomatic DVT,  non-fatal PE, or death from any cause during treatment period
Secondary efficacy endpoints: during treatment phase: major VTE (composite of symptomatic DVT, non-fatal PE and VTE-related death); during follow-up: symptomatic DVT, the composite of PE and VTE-related death, and all-cause death
Primary safety endpoint: bleeding reported during treatment, 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

3057 patients scheduled for elective total knee replacement

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Results

Efficacy outcome: In the population with evaluable efficacy outcome (n=1973), the primary efficacy endpoint (total VTE events) occurred in 147 of 976 patients (15.1%) given apixaban and in 243 of 997 patients (24.4%) given enoxaparin (absolute risk reduction 9.3%, relative risk reduction 38%; p<0.001). Major VTE were registered in 1.1% of the patients treated with apixaban and in 2.2% treated with enoxaparin
Safety outcome: In the safety population (all patients receiving at least one dose of the study medication; n=3009) major bleeding and clinically relevant non-major bleeding occurred in 53 of 1501 patients (3.5%) receiving apixaban and in 72 of 1508 patients (4.8%) receiving enoxaparin (p=0.0881). Major bleeding occurred in 9 patients in the apixaban group (0.6%) and 14 patients in the enoxaparin group (0.9%). The incidence of drug-related adverse events was 14% 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 total VTE and major VTE
Safety: The incidence of major bleeding events was low and comparable between both groups. There was no difference in clinically relevant non-major bleeding and adverse events

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Reference

Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P and the ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:807-15

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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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