Major and life-threatening bleeding is expected to occur in some patients treated with Pradaxa® (=Dabigatran). The question will then urgently arise how to best treat such catastrophic bleeding. As there have been only very limited data published on this topic in the peer-reviewed medical literature, we don’t know how to best manage a patient with major and life-threatening bleeding on Pradaxa®, even though suggestions have been made in the absence of such data [ref 1,2]. There (a) is no direct reversal agent available for Pradaxa®, and (b) have not been reversal strategies (backed up by clinical study data). It is key that data will be published in peer-reviewed journals indicating how major bleedingwhile on these drugs can be treated effectively. In the event of bleeding complications in patients receiving Pradaxa®, management should, of course, be individualized according to the severity and location of the bleed.
- Activated charcoal to prevent residual drug in the stomach to be absorbed
- Consideration of 1-2 sessions of hemodialysis.
- Recombinant factor VIIa (NovoSeven®) i.v.
- Antifibrinolytic therapy (Amicar®=aminocaproic acid or Lysteda®=tranexamic acid)
- Activated prothrombin complex concentrates (aPCCs; FEIBA®) i.v.
- Possibly not effective are: Prothrombin complex concentrates (PCCs; in the U.S.: Bebulin®, Profilnine®) intravenously with or without additional fresh frozen plasma (FFP) [ref 3]
- Unlikely effective is: Fresh frozen plasma (FFP)
Published Data about management of bleeding on new oral anticoagulants
- Pradaxa® (Dabigatran): Treatment of 12 healthy volunteers with Pradaxa,150 mg twice daily, led to an expected prolongation of certain clotting tests (aPTT, Ecarin clotting time, thrombin clot time) and this prolongation was NOT reversed by giving an unactivated PCC (Prothrombin Complex Concentrate; Cofact; 4-factor concentrate; 50 U/kg x 1), suggesting that PCCs might also NOT be effective in patients who bleed on Pradaxa [ref 3].
- Xarelto® (Rivaroxaban): In the study just mentioned above [ref 3], treatment of the 12 healthy volunteers with Xarelto 20 mg twice daily, led to an expected prolongation of the PT and to an inhibition of the ETP (endogenous thrombin potential), and these abnormalities were reversed immediately by giving an unactivated PCC (Prothrombin Complex Concentrate; Cofact; 4-factor concentrate; 50 U/kg x 1), suggesting that PCCs might be effective in patients who bleed on Xarelto. However, a lot of additional (patient) data are still needed to understand how to manage Xarelto®-associated bleeding.
- Edoxaban (not FDA approved): this drug also does not have a reversal drug. A small, non-human ex vivo plasma-mixing study presented at the Dec 2010 annual meeting of the American Society of Hematology (ASH) shows that the anticoagulant effect of Edoxaban can be reversed by PCCs and by NovoSeven® (ref 2). The maximum recombinant factor VIIa dose used in this study was equivalent to 50 mcg/kg. A lot of additional data are still needed to understand how to manage Edoxaban-associated bleeding.
At this point, not knowing what the most effective and safest treatment is, I would give the patient who has a life-threatening bleed on Pradaxa®:
- Charcoal to prevent residual drug in the stomach to be absorbed.
- Consider hemodialysis.
- Recombinant factor VIIa (NovoSeven; 90 mcg/kg x1). It is important to realize that it is not clear (a) whether recombinant factor VIIa is effective in this situation and (b) what VIIa dose might be appropriate. In addition, rVIIa is prothrombotic, and that needs to be kept in mind when considering use of the drug.
- I would consider fibrinolytic drugs (Amicar or tranexamic acid) as adjuncts.
- One could consider FEIBA® (activated prothrombin complex concentrate). But I would worry some about its prothrombotic effect, if the patient had had a recent thrombotic event or was quite hypercoagulable by history.
- Based on reference 3, I would NOT give Prothrombin complex concentrate (PCC; in the U.S.: Bebulin® or Profilnine®.
- I would NOT give FFP.
Management of major bleeding on Pradaxa® and other treatment related issues may best be addressed in a health care system by the establishment of a structured treatment algorithm/guide/help for the whole hospital or medical practice. As an example, here is the document that we have established for our institution, the University of North Carolina (UNC) Health Care System. The reader is welcome to (a) take the document and modify it to fit his/her institution/practice’s need or (b) use as a clinical reference for management issues.
- van Ryn J. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116–1127.
- Crowther MA. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009; 7 (Suppl 1):107–110.
- 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: prepublished on the web.
- Morishima Y et al. Anti-Inhibitor Coagulant Complex, Prothrombin Complex Concentrate, and recombinant factor VIIa reverse prothrombin time prolonged by Edoxaban in human plasma (abstract 3319; ASH annual meeting Dec 4-7, 2010, Orlando, FL).
- A well balanced and well explained audio-powerpoint presentation on Dabigatran, its action and reversal option of bleeding can be found here. However, Dabigatran is consistently pronounced incorrectly (correct pronounciation is on 2nd syllable) and vitamin K is not a reversal option.
This same information, written for patients and other non health care professionals, can be found here.
Disclosure: I have consulted for OrthoMcNeil, the company developing Xarelto (Rivaroxaban) in the U.S.
Disclaimer: ClotConnect.org, its contributors, authors, advisors, members and affiliate organizations do not assume any liability for the content of the website, blog and educational materials. Medical information changes rapidly. While information is believed to be correct, no representation is made and no responsibility is assumed for the accuracy of information contained on or available through this web site and blog. Information is subject to change without notice.
Last updated: Oct 6th, 2011