Early time courses of recurrent thromboembolism and bleeding during apixaban or enoxaparin/warfarin therapy

Summary

Risks of recurrence and bleeding are highest during the first weeks of anticoagulant therapy for venous thromboembolism (VTE). We therefore examined the early time course of recurrence and major bleeding in a pre-specified sub-analysis of the AMPLIFY trial, a randomised, double-blind, six-month comparison of oral apixaban with conventional therapy (enoxaparin followed by warfarin) in 5,395 patients with symptomatic proximal deep-vein thrombosis or pulmonary embolism. Early events were of particular interest because apixaban was given without initial heparin treatment. The primary efficacy and safety outcomes were the incidences of the adjudicated composite of recurrent symptomatic VTE or death related to VTE, and of adjudicated major bleeding, respectively. This analysis reports on recurrence and bleeding after 7, 21, and 90 days of therapy, in addition to the previously reported end-of-study results. These were the times specified before statistical analysis. Recurrent VTE after 7, 21, and 90 days, and six months had occurred in 18 (0.7%), 29 (1.1%), 46 (1.8%), and 59 patients (2.3%), respectively, given apixaban, and in 23 (0.9%), 35 (1.3%), 58 (2.2%), and 71 patients (2.7%), respectively, given conventional therapy. Major bleeding had occurred during these time intervals in 3 (0.1%), 5 (0.2%), 11 (0.4%), and 15 patients (0.6%), respectively, who received apixaban, and in 16 (0.6%), 26 (1.0%), 38 (1.4%), and 49 patients (1.8%), respectively, given conventional therapy. Efficacy of apixaban was non-inferior at each time point, with no excess of early recurrences. The reduced bleeding risk associated with apixaban began early during the course of treatment.

Keywords

Venous thrombosis - pulmonary embolism - anticoagulant therapy

• References

• 1 Douketis JD, Foster GA, Crowther MA. et al. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000; 160: 3431-3436.
• 2 Laliberte F, Coleman CI, Bookhart B. et al. Weekly risk of venous thromboembolism recurrence in patients receiving oral anticoagulants. Curr Med Res Opin 2014; 30: 1513-1520.
• 3 Agnelli G, Buller HR, Cohen A. et al. AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799-808.
• 4 Schulman S, Kearon C, Kakkar AK et al.. RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
• 5 Schulman S, Kakkar AK, Goldhaber SZ et al.. RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764-772.
• 6 Prins MH, Lensing AW, Bauersachs R et al.. EINSTEIN Investigators. Oral riva-roxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21.
• 7 Büller HR, Décousus H, Grosso MA et al.. Hokusai-VTE Investigators. Edox-aban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369: 1406-1415.
• 8 Brandjes DP, Heijboer H, Büller HR. et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327: 1485-1489.
• 9 Kearon C, Akl EA, Comerota AJ. et al. American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (02) Suppl e419S-e494S.
• 10 Rosendaal FR, Cannegieter SC, van der Meer FJ. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
• 11 Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 1990; 09: 1447-1454.
• 12 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719-748.
• 13 Fiessinger J-N, Huisman MV, Davidson BL. et al. for the THRIVE Treatment Study Investigators. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis. A randomized trial. J Am Med Assoc 2005; 293: 681-689.
• 14 Büller HR, Cohen AT, Davidson B. et al. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: 1094-1104.
• 15 Frost C, Wang J, Nepal S. et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 2013; 75: 476-487.
• 16 Buller H, Deitchman D, Prins M. et al. The Botticelli Writing Committee. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 06: 1313-1318.
• 17 Büller HR, Davidson BL, Decousus H. et al. Matisse Investigators. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004; 140: 867-873.
• 18 Büller HR, Davidson BL, Decousus H. et al. Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349: 1695-1702.
• 19 Erkens PM, ten Cate H, Büller HR. et al. Benchmark for time in therapeutic range in venous thromboembolism: a systematic review and meta-analysis. PLoS One 2012; 07: e42269.