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Previous Volume 361:594-604 August 6, 2009 Number 6 Next

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ABSTRACT

Background The optimal strategy for thromboprophylaxis after major joint replacement has not been established. Low-molecular-weight heparins such as enoxaparin predominantly target factor Xa but to some extent also inhibit thrombin. Apixaban, a specific factor Xa inhibitor, may provide effective thromboprophylaxis with a low risk of bleeding and improved ease of use.

Methods In a double-blind, double-dummy study, we randomly assigned patients undergoing total knee replacement to receive 2.5 mg of apixaban orally twice daily or 30 mg of enoxaparin subcutaneously every 12 hours. Both medications were started 12 to 24 hours after surgery and continued for 10 to 14 days. Bilateral venography was then performed. The primary efficacy outcome was a composite of asymptomatic and symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, and death from any cause during treatment. Patients were followed for 60 days after anticoagulation therapy was stopped.

Results A total of 3195 patients underwent randomization, with 1599 assigned to the apixaban group and 1596 to the enoxaparin group; 908 subjects were not eligible for the efficacy analysis. The overall rate of primary events was much lower than anticipated. The rate of the primary efficacy outcome was 9.0% with apixaban as compared with 8.8% with enoxaparin (relative risk, 1.02; 95% confidence interval, 0.78 to 1.32). The composite incidence of major bleeding and clinically relevant nonmajor bleeding was 2.9% with apixaban and 4.3% with enoxaparin (P=0.03).

Conclusions As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse-event profile. (ClinicalTrials.gov number, NCT00371683 [ClinicalTrials.gov] .)

Source Information

From the Department of Orthopedics, Spine Clinic, Clinical Trial Unit, Hørsholm Hospital, University of Copenhagen, Hørsholm, Denmark (M.R.L.); the College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City (G.E.R.); SA Pathology at Flinders Medical Centre, and Flinders University, Adelaide, Australia (A.G.); the Department of Medicine and Oncology, University of Calgary, Calgary, AB, Canada (G.P.); and Research and Development, Bristol-Myers Squibb, Princeton, NJ (D.C., R.J.P.), for the Apixaban Dose Orally vs. Anticoagulant with Enoxaparin 2 (ADVANCE-1) Investigators.

This article (10.1056/NEJMoa0810773) was updated on October 28, 2009, at NEJM.org.

Address reprint requests to Dr. Lassen at Hørsholm Hospital, Department of Orthopedics, Spine Clinic, Clinical Trial Unit, Usserød Kongevej 102, DK-2970 Hørsholm, Denmark, or at mirula{at}noh.regionh.dk.

Full Text of this Article

Related Letters:

Apixaban or Enoxaparin for Thromboprophylaxis
Gómez-Outes A., Suárez-Gea M. L., Pozo-Hernández C., Lassen M. R., Raskob G. E., Gallus A.
Extract | Full Text | PDF  
N Engl J Med 2009; 361:2100-2101, Nov 19, 2009. Correspondence

This article has been cited by other articles:

• Gomez-Outes, A., Suarez-Gea, M. L., Pozo-Hernandez, C., Lassen, M. R., Raskob, G. E., Gallus, A. (2009). Apixaban or Enoxaparin for Thromboprophylaxis. NEJM 361: 2100-2101 [Full Text]  
• Levine, M. N. (2009). New Antithrombotic Drugs: Potential for Use in Oncology. JCO 27: 4912-4918 [Abstract] [Full Text]  
• (2009). Oral Drug to Prevent Venous Thrombosis After Knee Replacement. JWatch General 2009: 1-1 [Full Text]