Skip to main content

Advertisement

SpringerLink
Log in

Treatment of Bleeding Complications When Using Oral Anticoagulants for Prevention of Strokes

  • Cerebrovascular Disease and Stroke (C Helgason and M Alberts, Section Editors)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Opinion statement

Major bleeding in patients taking oral anticoagulants for stroke prevention can progress to catastrophic bleeding if it is not controlled. This is especially of concern if the bleeding is related to the use of a novel oral anticoagulant (NOAC) such as dabigatran or rivaroxaban, given the dearth of literature addressing the reversal of their anticoagulant effects. The goal of treatment is to prevent progression to catastrophic hemorrhage or exsanguination, and decrease bleeding-related morbidity and mortality. Clinical decisions in such instances should be made in a timely fashion to address the necessity for intervention. Animal models have shown potential for the use of 'fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) in reversing bleeding related to novel oral anticoagulants. However, there is paucity of clinical trials assessing the efficacy of these agents in humans in such clinical scenarios. Hence, there are no guidelines or ideal agents to use in such a scenario. We do not recommend the use of FFP for bleeding related to NOACs. In the setting of early overdose of dabigatran (within 3–4 hours), activated charcoal may be given, and hemodialysis may be used if there is evidence of critical organ bleeding. In our opinion, 4-factor PCC or 3-factor PCC at a dose of about 50 U/kg may be given in an emergency setting to manage bleeding related to factor Xa inhibitors such as rivaroxaban or apixaban, but not direct thrombin inhibitors such as dabigatran. We are also of the opinion that aPCC (FEIBA®) would not be helpful for management of direct thrombin inhibitor (dabigatran)-related bleeding, based on current available efficacy data in humans. We reserve the use of Novoseven® as a last resort, given the lack of pre-clinical or clinical data supporting its ability to reverse the anticoagulant effects of NOACs, except in one case report where it was used in combination with hemodialysis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Schulman S et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4.

    Article  PubMed  CAS  Google Scholar 

  2. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med. 2012;172(8):623–31. discussion 631–3.

    Article  PubMed  Google Scholar 

  3. Hylek EM et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115(21):2689–96.

    Article  PubMed  CAS  Google Scholar 

  4. Aguilar MI, Hart RG, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and. Mayo Clin Proc. 2007;82(1):82–92.

    PubMed  CAS  Google Scholar 

  5. Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. CHEST J. 2012;141(2_suppl):e120S–51S.

    Article  CAS  Google Scholar 

  6. Baker RI et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2004;181(9):492–7.

    PubMed  Google Scholar 

  7. Holbrook A et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e152S–84S.

    Article  PubMed  CAS  Google Scholar 

  8. Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–9. This is one of few trials in humans assessing the efficacy of PCC in reversing bleeding related to rivaroxaban and dabigatran.

    Article  PubMed  CAS  Google Scholar 

  9. van Ryn J, Stangier J, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor. Thromb Haemost. 2010;103(6):1116–27.

    Article  PubMed  Google Scholar 

  10. Kaatz S et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87 Suppl 1:S141–5. This article discusses suggestings put together by experts in the field of thrombosis and anticoagulaton for emergent management of bleeding related to novel oral anticoagulants, and discusses currently available in both animal models and human clinical trials.

    Article  PubMed  CAS  Google Scholar 

  11. Frank Peacock W, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol. 2012;35(12):730–7. This review article also discusses challenges and current data on how to manage bleeding in the setting of oral anticoagulant use.

    Article  PubMed  Google Scholar 

  12. Fareed J, Thethi I, Hoppensteadt D. Old versus new oral anticoagulants: focus on pharmacology. Annu Rev Pharmacol Toxicol. 2012;52:79–99. This article reviews the pharmacology, pharmacokinetics and pharmacodynamics of old and new anticoagulants, including approved and currently unapproved agents. It is a very good overview of most of the oral anticoagulants in advanced stages of development.

    Article  PubMed  CAS  Google Scholar 

  13. Lubetsky A, Yonath H, Olchovsky D, et al. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med. 2003;163:2469–73.

    Article  PubMed  CAS  Google Scholar 

  14. Zhou W et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42(12):3594–9.

    Article  PubMed  Google Scholar 

  15. Chowdary P et al. Anaphylactic reaction with prothrombin complex concentrate in a patient with IgA deficiency and anti-IgA antibodies. Blood Coagul Fibrinolysis. 2010;21(8):764–5.

    PubMed  Google Scholar 

  16. van Ryn J et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116–27. This article discusses some of changes seen in coagulation tests related to dabigatran, and discusses a pre-clinical model of acidic gastric environment and successful removal of darbigatran using charcoal.

    Article  PubMed  Google Scholar 

  17. Marlu R et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108(2):217–24.

    Article  PubMed  CAS  Google Scholar 

  18. Godier A et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102.

    Article  PubMed  CAS  Google Scholar 

  19. Escolar G et al. Coagulation factor concentrates restore alterations in hemostasis induced by a high dose of apixaban: studies in vitro with circulating human blood. ASH Annu Meet Abstr. 2012;120(21):2263.

    Google Scholar 

  20. Warkentin TE et al. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012;119(9):2172–4. This is a case report of dabigatran-related bleeding and how the authors successfully managed the bleeding.

    Article  PubMed  CAS  Google Scholar 

  21. Morgenstern LB et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41(9):2108–29.

    Article  PubMed  Google Scholar 

  22. Stangier J et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259–68.

    Article  PubMed  CAS  Google Scholar 

  23. van Ryn J et al. In vitro characterization, pharmacokinetics and reversal of supratherapeutic doses of dabigatran-induced bleeding in rats by a specific antibody fragment antidote to dabigatran. ASH Annu Meet Abstr. 2012;120(21):3418.

    Google Scholar 

  24. Hollenbach SJ et al. PRT064445 but not recombinant Fviia reverses rivaroxaban induced anticoagulation as measured by reduction in blood loss in a rabbit liver laceration model. ASH Annu Meet Abstr. 2012;120(21):3414.

    Google Scholar 

Download references

Conflict of Interest

Dr. Frank Akwaa reported no conflicts of interest relevant to this article.

Dr. Alex C. Spyropoulos is on the data safety monitoring board of a Portola study (Apex) where the FXa inhibitor antidote may be tested. Dr. Spyropoulos received consultancies from Eisai, BMS, Pfizer, Astellas, Boehringer-Ingelheim, Bayer, and Jansen.

Author information

Authors and Affiliations

  1. University of Rochester, Rochester, NY, 14611, USA

    Frank Akwaa MD

  2. Lenox Hill Hospital, 100 E 77th St, New York, NY, 10075, USA

    Alex C. Spyropoulos MD, FACP, FCCP, FRCPC

Authors
  1. Frank Akwaa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alex C. Spyropoulos MD, FACP, FCCP, FRCPC
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alex C. Spyropoulos MD, FACP, FCCP, FRCPC.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Akwaa, F., Spyropoulos, A.C. Treatment of Bleeding Complications When Using Oral Anticoagulants for Prevention of Strokes. Curr Treat Options Cardio Med 15, 288–298 (2013). https://doi.org/10.1007/s11936-013-0238-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11936-013-0238-5

Keywords

Search

Navigation