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 no 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 the companies making these drugs and clinical investigators produce and publish data in peer-reviewed journals indicating how reversal of bleeding 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. Treatment options are: (a) activated charcoal to prevent residual drug in the stomach to be absorbed; (b) consideration of 1-2 sessions of hemodialysis trying to get Pradaxa® out of the blood system; (c) recombinant factor VIIa (NovoSeven®) intravenously; (d) Antifibrinolytic therapy (Amicar®=aminocaproic acid or Lysteda®=tranexamic acid); (e) activated prothrombin complex concentrates (aPCCs; FEIBA®) intravenously; (f) based on recent data [ref 3] from volunteers treated with Pradaxa, prothrombin complex concentrates (PCCs; in the U.S.: Bebulin®, Profilnine®) intravenously may not be effective; (g) Fresh Frozen Plasma (FFP) is not likely to help. A lot of additional data are still needed to know how to best handle major bleeding events on Pradaxa®.
Published data about management of bleeding on new oral “blood “thinners”
- 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), suggesting that PCCs might 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 influence on certain clotting tests (PT, endogenous thrombin potential), and these abnormalities were reversed immediately by giving an unactivated PCC (Prothrombin Complex Concentrate), 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 4). 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.
One Page Management Guide from New Zealand
A reasonable management guideline has also been published by the New Zealand Government Pharmaceutical Management Agency. However, it was produced before a recent publication [ref 3] suggested that PCCs may not be effective in reversing Dabigatran’s anticoagulant effect.
Government warning about bleeding on Pradaxa
Warnings about bleeding with Pradaxa are being published, such as the one from the Australian Government of Health and Ageing, but this is not a surprise, as Pradaxa is an anticoagulant and bleeding in some patients is expected to occur. Without knowing the denominator as to how many patients were being treated with Pradaxa, reports about numbers of patients bleeding are not very meaningful. However, they highlight that care needs to be taken that patients are dosed correctly, renal function is observed, concomitant anti-platelet therapy is given only when appropriate.
At this point, not knowing what the most effective and safest treatment is, I would likely give the patient who has a life-threatening bleed on Pradaxa®: (a) charcoal to prevent residual drug in the stomach to be absorbed, (b) consider dialysis, (c) consider a firinolytic drug (tranexamic acid, amino-carpoic acid), (d) consider recombinant factor VIIa to try to reverse the drug effect.
- 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).
For health care professionals
This same information, written for health care professionals, can be found here.
Disclosure: I have consulted for OrthoMcNeil, the company developing Xarelto (Rivaroxaban) in the U.S.
Last updated: Oct 7th, 2011