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Postoperative Melagatran/ Ximelagatran for the Prevention of Venous Thromboembolism following Major Elective Orthopaedic Surgery

Effects of Timing of First Dose and Risk Factors for Thromboembolism and Bleeding Complications on Efficacy and Safety

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Abstract

Objectives: To examine the influence of timing of postoperative initiation of subcutaneous melagatran followed by oral ximelagatran, and of risk factors for venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and bleeding complications, on the efficacy and safety of this regimen, compared with preoperative enoxaparin sodium, following total hip replacement (THR) or total knee replacement (TKR) surgery.

Design: Statistical analyses of efficacy and safety in subgroups of the METHRO III intention-to-treat population.

Main outcome measures: Main efficacy outcome measures were major VTE (proximal DVT, PE or VTE-related death) and total VTE (distal or proximal DVT, fatal or non-fatal PE). The main safety outcome measures were blood transfusion, severe bleeding events, blood loss, bleeding-related adverse events and need for reoperation.

Results: In the combined THR and TKR population, melagatran initiated 4–<8 hours postoperatively was non-inferior to enoxaparin sodium with respect to the risks of total VTE (absolute risk reduction [ARR] 0; 95% confidence interval [CI] ∼-4.4, 4.4) and major VTE (ARR −0.63; 95% CI −2.94, 1.67). The rate of major VTE was unaffected by the different risk factors. In the combined THR and TKR population, blood transfusion requirements were lower with melagatran/ximela-gatran than enoxaparin sodium (odds ratio 0.83; 95% CI 0.71, 0.96; p = 0.016).

Conclusions: Melagatran/ximelagatran initiated 4–<8 hours postoperatively provided a comparable level of protection against total and major VTE to preoperative enoxaparin sodium. Major VTE rates and safety were consistent across different patient subgroups. Subcutaneous melagatran followed by fixed-dose oral ximelagatran offers an alternative to the standard European low molecular-weight heparin regimen in a wide range of patients.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

The original METHRO III study was initiated, designed and conducted by an eight-person steering committee, which included representatives of the sponsor (AstraZeneca). Study data are in an AstraZeneca database. The authors of these further analyses included three representatives of the sponsor (SP, MA, AB). All authors had full free access to all data.

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Authors and Affiliations

  1. Thrombosis Research Institute, Emmanuel Kaye Building, Manresa Road, London, SW3 6LR, UK

    Ola E. Dahl

  2. Sahlgrenska University Hospital/Östra, Göteborg, Sweden

    Bengt I. Eriksson

  3. University of Perugia, Perugia, Italy

    Giancarlo Agnelli

  4. Guy’s, King’s and St Thomas’ School of Medicine, London, UK

    Alexander T. Cohen

  5. Frankfurt-Höchst Clinic, Frankfurt, Germany

    Patrick Mouret

  6. Paris M 5 University and Cochin Hospital, Paris, France

    Nadia Rosencher

  7. AstraZeneca R&D Mölndal, Mölndal, Sweden

    Seva Panfilov, Anders Bylock & Magnus Andersson

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  1. Ola E. Dahl
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  2. Bengt I. Eriksson
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  3. Giancarlo Agnelli
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  4. Alexander T. Cohen
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Correspondence to Ola E. Dahl.

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Dahl, O.E., Eriksson, B.I., Agnelli, G. et al. Postoperative Melagatran/ Ximelagatran for the Prevention of Venous Thromboembolism following Major Elective Orthopaedic Surgery. Clin. Drug Investig. 25, 65–77 (2005). https://doi.org/10.2165/00044011-200525010-00006

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