Correspondence

Apixaban or Enoxaparin for Thromboprophylaxis

N Engl J Med 2009; 361:2100-2101November 19, 2009

Article

To the Editor:

Lassen and colleagues (Aug. 6 issue)1 state that apixaban and enoxaparin had similar efficacy, based on the point estimate for the relative risk of all types of venous thromboembolism; this end point was driven mainly by asymptomatic distal deep-vein thrombosis. However, according to established guidelines, noninferiority should be shown for major venous thromboembolism (the composite of proximal deep-vein thrombosis, nonfatal pulmonary embolism, and venous thromboembolism–related death).2 The relative risk of major venous thromboembolism was 1.25 (95% confidence interval [CI], 0.70 to 2.23). Therefore, a relative increase in the risk of major venous thromboembolism with apixaban of 123% cannot be ruled out. This conservative conclusion is consistent with the trend toward an increased risk of pulmonary embolism with apixaban; we calculate that the relative risk is 2.28 (95% CI, 0.97 to 5.39; P=0.06 by the chi-square test). The timing of the first apixaban administration (a mean [±SD] of 20.3±3.5 hours postoperatively in the Apixaban Dose Orally vs. Anticoagulation with Enoxaparin 2 [ADVANCE-1] study; ClinicalTrials.gov number, NCT00371683) or the total daily dose could affect the efficacy of apixaban as compared with the North American enoxaparin regimen.

Antonio Gómez-Outes, M.D.
Maria Luisa Suárez-Gea, Pharm.D., Ph.D.
Carmen Pozo-Hernández, Pharm.D.
Spanish Agency for Medicines and Medical Devices, Madrid, Spain
agomezo@agemed.es

2 References

1
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
Full Text | Web of Science | Medline

2
Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products for prophylaxis of high intra- and post-operative venous thromboembolic risk. London: European Medicines Agency, November 15, 2007. (Document no. CPMP/EWP/707/98 Rev.1 corr.) (Accessed October 30, 2009, at http://www.emea.europa.eu/pdfs/human/ewp/70798en_fin.pdf.)

Author/Editor Response

Our statement that “apixaban and enoxaparin have a similar efficacy that is within limits that should be acceptable to clinicians” was not based on the point estimate for the relative risk, but on 95% confidence intervals for absolute differences in risk in all types of venous thromboembolism, including major venous thromboembolism. Thus, it is unlikely that apixaban is less than 2.4% as effective as enoxaparin with respect to the risk of any venous thromboembolism plus death from any cause or less than 1.4% as effective with respect to the risk of major venous thromboembolism plus death from any cause. A relative increase in the risk of major venous thromboembolism plus death from any cause of 123% cannot be ruled out, but the low incidence of venous thromboembolism makes 95% confidence intervals for the difference in absolute risk the key result for clinical decisions and is evidence of the similar efficacy of the two anticoagulants. Another consideration is the lower risk of major and clinically relevant nonmajor bleeding with apixaban (a difference of −1.46%). Two further studies in patients who underwent joint replacement may clarify whether the trend toward an increased risk of pulmonary embolism with apixaban was a chance finding. The studies are the Randomized Double-Blind Comparison of Apixaban with Enoxaparin for Thromboprophylaxis after Knee Replacement (ADVANCE-2) (ClinicalTrials.gov number, NCT00452530) and A Phase 3 Randomized, Double-Blind, Active-Controlled, Parallel-Group, Multi-Center Study to Evaluate the Safety and Efficacy of Apixaban in Subjects Undergoing Elective Total Hip Replacement Surgery (ADVANCE-3) (NCT00423319).

Michael Rud Lassen, M.D.
Hørsholm Hospital, Hørsholm, Denmark
mirula@noh.regionh.dk

Gary E. Raskob, M.D.
University of Oklahoma Health Sciences Center, Oklahoma City, OK

Alexander Gallus, M.D.
Flinders University Medical Centre, Adelaide, SA, Australia

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