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Thromb Haemost 2007; 97(06): 931-937
DOI: 10.1160/TH07-01-0055
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Rivaroxaban for thromboprophylaxis after orthopaedic surgery: Pooled analysis of two studies

William D. Fisher
1   McGill University Health Centre, Montreal, Canada
,
Bengt I. Eriksson
2   Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
,
Kenneth A. Bauer
3   Beth Israel Deaconess Medical Center, Boston, Massachussetts, USA
,
Lars Borris
4   Aarhus University Hospital, Aarhus, Denmark
,
Ola E. Dahl
5   Thrombosis Research Institute/International Surgical Thrombosis Forum, London, UK
,
Michael Gent
6   Department of Medicine, HHS-General Hospital, Hamilton, Canada
,
Sylvia Haas
7   Institute for Experimental Oncology and Therapy Research, Munich, Germany
,
Martin Homering
8   Bayer HealthCare AG, Wuppertal, Germany
,
Menno V. Huisman
9   Leiden University Medical Center, Leiden, The Netherlands
,
Ajay K. Kakkar
10   Thrombosis Research Institute and Barts and the London School of Medicine, London, UK
,
Peter Kälebo
2   Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
,
Louis M. Kwong
11   Harbor-UCLA Medical Center, Torrance, California, USA
,
Frank Misselwitz
8   Bayer HealthCare AG, Wuppertal, Germany
,
Alexander G. G. Turpie
6   Department of Medicine, HHS-General Hospital, Hamilton, Canada
› Author AffiliationsFinancial support: The original studies and the analysis reported in this manuscript were sponsored by Bayer HealthCare AG. F. Misselwitz and M. Homering are employees of Bayer Health-Care AG. W.D. Fisher, L. Kwong, and B.I. Eriksson were investigators in the studies and received grants for enrolling patients. P. Kälebo received honoraria for adjudication of the venograms during the studies. All steering committee members (A.G.G. Turpie, B.I. Eriksson, K.A. Bauer, L. Borris, O.E. Dahl, M. Gent, S. Haas, M.V. Huisman, A.K. Kakkar, L.M. Kwong, and W.D. Fisher) received honoraria for their participation. The steering committees had the final responsibility for the study protocol, the analyses, and the manuscript.
Further Information

Publication History

Received 25 January 2007

Accepted after revision 26 March 2007

Publication Date:
27 November 2017 (online)

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Summary

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of venous thromboembolism (VTE). This analysis of pooled results from two phase II studies of rivaroxaban for VTE prevention after major orthopaedic surgery aimed to strengthen the conclusions of the individual studies. One study was conducted in patients undergoing total hip replacement (THR; N=722), and one in patients undergoing total knee replacement (TKR; N=621). In both studies, patients were randomized, doubleblind, to oral, twice-daily (bid) rivaroxaban beginning after surgery, or subcutaneous enoxaparin (40 mg once daily beginning before THR, and 30 mg bid beginning after TKR). Treatment continued until mandatory bilateral venography was performed 5–9 days after surgery. Total VTE (deep vein thrombosis, pulmonary embolism, and all-cause mortality) occurred in 16.1–24.4% of per-protocol patients receiving rivaroxaban 5–60 mg, and 27.8% receiving enoxaparin (n=914). There was a flat dose response relationship between rivaroxaban and total VTE (p=0.39). Major bleeding (safety population, n=1,317) increased dose-dependently with rivaroxaban (p<0.001), occurring in 0.9%, 1.3%, 2.1%, 3.9%, and 7.0% of patients receiving rivaroxaban total daily doses of 5, 10, 20, 40, and 60 mg, respectively, versus 1.7% of patients receiving enoxaparin. No routine coagulation monitoring was performed, and there were no significant differences between dose response relationships with rivaroxaban after THR and TKR. Overall, rivaroxaban total daily doses of 5–20 mg had the most favorable balance of efficacy and safety, relative to enoxaparin, for the prevention of VTE after major orthopaedic surgery.

Keywords

Rivaroxaban - venous thromboembolism - orthopaedic surgery - total hip replacement - total knee replacement

Footnote: This paper was presented at the American Society of Hematology meeting, Atlanta, Georgia, December 12, 2005.


 

  • References

  • 1 Ansell J, Bergqvist D. Current options in the prevention of thromboembolic disease. Drugs 2004; 64: 1-5.
    PubMedSearch in Google Scholar
  • 2 Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005; 3: 1843-1853.
    CrossrefPubMedSearch in Google Scholar
  • 3 Becker RC, Alexander J, Dyke CK. et al. Development of DX-9065a, a novel direct factor Xa antagonist, in cardiovascular disease. Thromb Haemost 2004; 92: 1182-1193.
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 3: 514-521.
    CrossrefPubMedSearch in Google Scholar
  • 5 Biemond BJ, Perzborn E, Friederich PW. et al. Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 59-7939) – an oral, direct factor Xa inhibitor. Thromb Haemost 2007; 97: 471-477.
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Kubitza D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
    CrossrefPubMedSearch in Google Scholar
  • 7 Kubitza D, Becka M, Wensing G. et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939–an oral, direct Factor Xa inhibitor–after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: 873-880.
    CrossrefPubMedSearch in Google Scholar
  • 8 Kubitza D, Mueck W, Becka M. The oral, direct Factor Xa inhibitor BAY 59-7939 does not prolong the QTc interval. J Clin Pharmacol 2006; 46: 703 (Abstract 12).
    PubMedSearch in Google Scholar
  • 9 Kubitza D, Becka M, Mueck W. et al. Rivaroxaban (BAY 59-7939) – an oral, direct Factor Xa inhibitor – has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007; 63: 469-476.
    CrossrefPubMedSearch in Google Scholar
  • 10 Kubitza D, Becka M, Mueck W. et al. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban– an oral, direct Factor Xa inhibitor–are not affected by aspirin. J Clin Pharmacol 2006; 46: 981-990.
    CrossrefPubMedSearch in Google Scholar
  • 11 Kubitza D, Becka M, Zuehlsdorf M. et al. No interaction between the novel, oral direct Factor Xa inhibitor BAY 59-7939 and digoxin. J Clin Pharmacol 2006; 46: 702 (Abstract 11).
    PubMedSearch in Google Scholar
  • 12 Kubitza D, Becka M, Zuehlsdorf M. et al. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 2006; 46: 549-558.
    CrossrefPubMedSearch in Google Scholar
  • 13 Eriksson BI, Borris L, Dahl OE. et al. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: 121-128.
    PubMedSearch in Google Scholar
  • 14 Turpie AG, Fisher WD, Bauer KA. et al. BAY 59-7939: an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 3: 2479-2486.
    CrossrefPubMedSearch in Google Scholar
  • 15 Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134-144.
    CrossrefPubMedSearch in Google Scholar
  • 16 Kalebo P, Ekman S, Lindbratt S. et al. Percentage of inadequate phlebograms and observer agreement in thromboprophylactic multicenter trials using standardized methodology and central assessment. Thromb Haemost 1996; 76: 893-896.
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Eriksson BI, Borris LC, Dahl OE. et al. Dose-escalation study of rivaroxaban (BAY 59-7939) – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Res 2007;
    CrossrefPubMedSearch in Google Scholar
  • 18 Eriksson BI, Borris LC, Dahl OE. et al. A oncedaily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114: 2374-2381.
    CrossrefPubMedSearch in Google Scholar
  • 19 Agnelli G, Gallus A, Goldhaber S. et al. Treatment of acute, symptomatic, proximal deep vein thrombosis with the oral, direct Factor Xa inhibitor rivaroxaban (BAY 59-7939) – the ODIXa-DVT dose-ranging study. Eur Heart J 2006; 27 (Suppl) 761.
    CrossrefPubMedSearch in Google Scholar
  • 20 Buller HR. Once-daily treatment with an oral, direct factor Xa inhibitor – rivaroxaban (BAY 59-7939) – in patients with acute, symptomatic deep vein thrombosis. The EINSTEIN-DVT dose-finding study. Eur Heart J 2006; 27 (Suppl) 761.
    CrossrefPubMedSearch in Google Scholar
  • 21 Eriksson BI, Bergqvist D, Kalebo P. et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441-1447.
    CrossrefPubMedSearch in Google Scholar
  • 22 Eriksson BI, Dahl OE, Buller HR. et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005; 3: 103-111.
    CrossrefPubMedSearch in Google Scholar
  • 23 Geerts WH, Pineo GF, Heit JA. et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 338S-400S.
    CrossrefPubMedSearch in Google Scholar
  • 24 Gillespie W, Murray D, Gregg PJ. et al. Risks and benefits of prophylaxis against venous thromboembolism in orthopaedic surgery. J Bone Joint Surg Br 2000; 82: 475-479.
    CrossrefPubMedSearch in Google Scholar