ADVANCE-1

Apixaban Dose Orally Vs. ANtiCoagulation with Enoxaparin 1 (2009)

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 surgery, continued for 10–14 days; placebo injections as in control treatment (n=1599)
Control treatment: enoxaparin 30 mg s.c. every 12 hours, starting 12–24 hours after surgery, continued for 10–14 days; placebo tablets as in active treatment (n=1596)

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Endpoints

Primary efficacy endpoint: composite of asymptomatic and symptomatic DVT, non-fatal PE, and death from any cause during treatment
Secondary efficacy endpoints: composite of major thromboembolism (the composite of adjudicated proximal DVT, non-fatal PE and VTE-related death) and death from any cause during treatment; symptomatic thromboembolism (the composite of adjudicated symptomatic DVT and non-fatal or fatal PE) during treatment
Primary safety endpoint: composite incidence of major bleeding and clinically relevant non-major bleeding during treatment and within 2 days after the last dose
Secondary safety endpoints: elevated aminotransferase or bilirubin levels and arterial thromboembolic events (myocardial infarction, acute ischemic stroke, or other systemic thromboembolism) occurring during treatment and the 60-day follow-up

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Trial participants

3195 patients scheduled for elective total knee replacement

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Results

Efficacy outcome: In the population with evaluable efficacy outcome (n=2287), the primary efficacy endpoint (all VTE and death from any cause) occurred in 104 of 1157 patients (9.0%) given apixaban and in 100 of 1130 patients (8.8%) given enoxaparin (relative risk 1.02; p=0.06 for non-inferiority; difference in risk 0.11%)
Safety outcome: In the safety population (n=3184) major bleeding and clinically relevant non-major bleeding occurred in 46 of 1596 patients (2.9%) receiving apixaban and in 68 of 1588 patients (4.3%) receiving enoxaparin (p=0.03). Major bleeding occurred in 11 (0.7%) patients in the apixaban group and in 22 (1,4%) in the enoxaparin group (p=0.053). The incidence of serious adverse events was similar in the two groups: 8.5% with apixaban and 8.6% with enoxaparin

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Summary

Efficacy: Apixaban was similarly effective in preventing VTE after total knee arthroplasty. The prespecified statistical criteria for the non-inferiority of oral apixaban as compared with twice-daily administration of enoxaparin were not met for the primary efficacy outcome (composite of any VTE plus death from any cause during treatment)
Safety: Apixaban was superior to enoxaparin for major and clinically relevant bleeding episodes

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Reference

Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009;361:594-604

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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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