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Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban

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Abstract

Dabigatran, apixaban, and rivaroxaban have been approved for primary and secondary stroke prevention in patients with atrial fibrillation. However, questions have arisen about how to manage emergency situations, such as when thrombolysis would be required for acute ischemic stroke or for the managing intracranial or gastrointestinal bleedings. We summarize the current literature and provide recommendations for the management of these situations. Peak plasma levels of the direct oral anticoagulants (DOACs) apixaban, dabigatran, or rivaroxaban are observed about 2–4 h after intake. Elimination of dabigatran is mainly dependent on renal function. Consequently, if renal function is impaired, there is a risk of drug accumulation that is highest for dabigatran followed by rivaroxaban and then apixaban and thus dosing recommendations are different. To date, no bedside tests are available that reliably assess the anticoagulatory effect of DOACs, nor are specific antidotes available. We recommend performing the following tests if DOAC intake is unknown: dabigatran-associated bleeding risk is minimized or can be neglected if thrombin time, Hemoclot test, or Ecarin clotting time is normal. Apixaban and rivaroxaban effects can be ruled out if findings from the anti-factor Xa activity test are normal. High plasma levels of DOAC are also mostly excluded if PTT and PTZ are normal four or more hours after DOAC intake. However, normal values of global coagulation tests are not sufficient if thrombolysis is indicated for treating acute stroke. The decision for or against thrombolysis is an individual decision; in these cases, thrombolysis use is off-label. In case of bleeding, prothrombin complex concentrates seems to be the most plausible treatment. For severe gastrointestinal bleeding with life-threatening blood loss, the bleeding source needs to be identified and treated by invasive measures. Use of procoagulant drugs (antifibrinolytics) might also be considered. However, there is very limited clinical experience with these products in conjunction with DOAC.

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Conflicts of interest

Prof. Dr. Thorsten Steiner: Speaker honoraria: Boehringer Ingelheim, Bristol-Myers Squipp, Pfizer, Bayer. Research Grant: Octapharma. Consultant fees: Boehringer.

Prof. Martin Dichgans: Speaker honoraria: Bayer, Boehringer Ingelheim, Lundbeck, Sanofi-Aventis, DZNE, George Thieme Verlag (publisher), UpToDate and W. Kohlhammer GmbH. Research Grant: Bayer, Eisai Medical Research, Eisai Ltd., Essex Pharma  and Ferrer Internacional. Consultant fees: Bayer Vital, Boehringer Ingelheim Pharma and Trommsdorff.

Prof. Dr. Hans-Christoph Diener: Speakers honoraria and consultant fees: Abbott, Allergan, AstraZeneca, Bayer Vital, BMS, Böhringer Ingelheim, CoAxia, Covidien, Daichii-Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, MSD, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Pain, Parke-Savis, Pfizer, Sanofi-Aventis, Servier, Solvay, Thrombogenics, Wyeth and Yamanouchi. Research Grant: AstraZeneca, GSK, Boehringer Ingelheim, Novartis, Janssen-Cilag and Sanofi-Aventis, DFG, BMBF, EU, Bertelmann Stiftung and Heinz-Nixdorf Stiftung.

Prof. Dr. Christian Ell: no conflicts of interest.

Prof. Dr. Matthias Endres: Speakers honoraria: Astra Zeneca, Bayer, Berlin Chemie, Bristol-Myers Squipp, Boehringer Ingelheim, Desitin, Eisei, Ever, GlaxoSmithKline, MSD, Novartis, Pfizer, Sanofi, Takeda, Trommsdorff. Research Grant: DFG (Exzellenzcluster NeuroCure; SFB TR 43, KFO 247, KFO 213), BMBF (Center for stroke research Berlin), EU (Eustroke, ARISE, WakeUp), Volkswagen (Lichtenberg program), Corona Stiftung. AstraZeneca, Sanofi. Consultant fees: Bayer, Boehringer Ingelheim, Bristol-Myers Squipp, MSD, Pfizer, Sanofi.

Corina Epple: no conflicts of interest.

Prof. Dr. Martin Grond: is member of the Pradaxa Advisory Board for Boehringer Ingelheim.

Prof. Dr. Hanno Riess: is member of the Pradaxa Advisory Board for Boehringer Ingelheim and the Rivaroxaban Advisory Board for Bayer.  Speakers honoraria: Bayer, Boehringer Ingelheim, GlaxoSmithKline, LeoPharma, Novartis, Pfizer, Roche Pharma, Sanofi-Aventis.

Prof. Dr. Joachim Röther: is member of the Pradaxa Advisory Board for Boehringer Ingelheim. Speaker honoraria: Boehringer Ingelheim, Bayer, BMS and Pfizer.

Prof. Dr. Peter Schellinger: is member of the Pradaxa Advisory Board for Boehringer Ingelheim and the Rivaroxaban Advisory Board for Bayer.

Prof. Dr. Roland Veltkamp: Speaker honoraria: Bayer, Boehringer Ingelheim, Sanofi Aventis. Research Grant: Bayer, Boehringer Ingelheim, Sanofi, Daichyisankyo, Apoplextechnologies.  Consultant fees: Boehringer Ingelheim and Bayer.

Prof. Dr. M. Böhm: Speakers honoraria: Astra Zeneca, AWD Dresden, Bayer, Boehringer-Ingelheim, Berlin-Chemie, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi-Aventis, Servier. Study support: Astra Zeneca, Bayer AG, Boehringer-Ingelheim, Novartis, Pfizer, Sanofi-Aventis, Servier, Adrian-Medtronic. Advisory Boards: Astra Zeneca, Bayer AG, Boehringer-Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi-Aventis, Servier.

Prof. Dr. M. Spannagl: Speakers honoraria: Boehringer Ing, BAyer, BMS, Daiichi Sankyo, Pfizer, Sanofi, Novartis. Advisory Board: Boehringer Ingelheim, Bayer, BMS.

Prof. Dr. U. Laufs: speakers honoraria, research grant and consultant fees: Amgen, AstraZeneca, Bayer, Berlin-Chemie, Boehringer-Ingelheim, Daiichi-Sankyo, Medtronik, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier.

Prof. Dr. G. Nickenig: Speakers honoraria and advisory boards: Boehringer Ingelheim, Bayer, Pfizer, Daiichi Sankyo. Study support: Boehringer Ingelheim.

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Authors and Affiliations

  1. Neurologische Klinik, Klinikum Frankfurt Höchst, Frankfurt am Main, Germany

    T. Steiner & C. Epple

  2. Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg an der Saar, Germany

    M. Böhm & U. Laufs

  3. Neurologische Klinik, Universitätsklinikum Großhadern, Munich, Germany

    M. Dichgans

  4. Neurologische Klinik, Universitätsklinikum Essen, Essen, Germany

    H.-C. Diener

  5. Medizinische Klinik II, HSK Wiesbaden, Wiesbaden, Germany

    C. Ell

  6. Klinik und Hochschulambulanz für Neurologie sowie Centrum für Schlaganfallforschung Berlin Charité–Universitätsmedizin Berlin, Berlin, Germany

    M. Endres

  7. Neurologische Klinik, Kreisklinikum Siegen, Siegen, Germany

    M. Grond

  8. Klinik für Innere Medizin II, Universitätsklinikum Bonn, Bonn, Germany

    G. Nickenig

  9. Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Charité Campus Virchow Klinikum, Berlin, Germany

    H. Riess

  10. Neurologische Abteilung, Asklepios Klinik Altona, Hamburg, Germany

    J. Röther

  11. Neurologische Klinik und Neurogeriatrie, Klinikum Minden, Minden, Germany

    P. D. Schellinger

  12. Hämostasiologie, Klinikum der Universität München, Munich, Germany

    M. Spannagl

  13. Neurologische Klinik, Universität Heidelberg, Heidelberg, Germany

    R. Veltkamp

Authors
  1. T. Steiner
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  2. M. Böhm
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  3. M. Dichgans
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  4. H.-C. Diener
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  5. C. Ell
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  6. M. Endres
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  7. C. Epple
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  8. M. Grond
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  9. U. Laufs
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  10. G. Nickenig
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  11. H. Riess
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  12. J. Röther
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  13. P. D. Schellinger
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  14. M. Spannagl
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  15. R. Veltkamp
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Corresponding author

Correspondence to T. Steiner.

Additional information

For the: German Society of Cardiology (Deutsche Gesellschaft für Kardiologie, DGK), German Society of Hematology (Deutsche Gesellschaft Hämatologie (DGHO), German Society of Nephrology (Deutsche Gesellschaft für Nephrologie, DGN), German Society of Neurology (Deutsche Gesellschaft für Neurologie, DGN), German Society of Research in Thrombosis and Haemostasis (Gesellschaft für Thrombose-und Hämostaseforschung, GTH), German Society of Visceral and Metabolic diseases (Deutsche Gesellschaft für Verdauungs-und Stoffwechselkrankheiten, DGVS), and German Stroke Society (Deutsche Schlaganfall Gesellschaft, DSG).

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Steiner, T., Böhm, M., Dichgans, M. et al. Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol 102, 399–412 (2013). https://doi.org/10.1007/s00392-013-0560-7

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  • DOI: https://doi.org/10.1007/s00392-013-0560-7

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