Bleeding Hell! Dabigatran is Here.

Imagine an oral anticoagulant that does not require INR monitoring or dose changing. Imagine that compared with warfarin, it would have a lower incidence of intracranial haemorrhage (though slightly higher GI haemorrhage incidence). Sounds ideal!

Now imagine that according to the manufacturers data, up to 16% of patients taking this ideal drug, may experience bleeding. Imagine that it would be FDA approved without any known antidote or method of reversal. Imagine that of those patients, those with significant bleeding, would all have poor outcomes.

Sounds impossible... Think again.

Dabigatran - coming soon to an emergency department near you!

Dabigatran (Pradaxa^®) – a new anticoagulant drug that is currently licensed for anticoagulation of selected patients with atrial fibrillation (AF) or for post-orthopaedic prophylaxis of venous thromboembolism¹. It has the advantage of not requiring dietary precautions, continuous INR monitoring, or frequent dose changes.

We are likely to be increasingly involved in management of patients with moderate, severe or life threatening bleeding who are on Dabigatran. Recent experience treating several injured patients receiving Dabigatran in the United States has demonstrated uniformly poor outcomes².

Dabigatran is a direct thrombin inhibitor. As such the anticoagulant effect is through direct clotting factor inhibition and not clotting factor depletion³. 

Unlike the other novel oral anticoagulant - the Factor Xa inhibitor Rivaroxaban, which is rapidly reversed by by Prothrombin Complex Concentrate (PCC - Prothrombinex)⁴, Dabigatran is not reversed by conventional therapies (PCC, FFP, Vit K, etc.). Also, there is no readily available means for assessing the degree of anticoagulation with Dabigatran^1-5.

Dabigatran is mostly cleared by the kidneys. The half-life is 12-17 hours. Administration in the setting of renal failure  may lead to a half-life in excess of 24 hours^{1, 3, 5}. 

• The primary means of reversing the effects of Dabigatran is through natural renal elimination.
• The only emergency reversal option for Dabigatran is haemodialysis^1-5 (as suggested in a single line in the package insert²). 
  • Will remove approximately 60% of Dabigatran. 
  • Performing rapid dialysis in unstable bleeding patients or in patients with large intracranial haemorrhages, presents an incredible challenge, even at level 1 trauma centres².
• Supportive care is all that is currently available in the emergency setting.

Key points for management are:

• All clotting times may be abnormal on Dabigatran: 
  • aPTT and INR are often abnormal but do not adequately reflect the level of anticoagulation. 
  • TT (Thrombin clotting Time) is sensitive, but may need to be specifically requested. 
    • A normal TT excludes presence of significant Dabigatran levels³.
• Bleeding site control and supportive care.
• If Dabigatran was consumed within two hours of presentation, activated charcoal should be given^{1, 5}.
• In life threatening bleeding, conventional therapies (PCC, FFP, Vit K) should be given – especially in a possibility of residual warfarin effect (i.e. patient in changeover  period from warfarin to Dabigatran)^{1, 3, 5}.
• Recombinant Factor VIIa (Novoseven) should be considered in consultation with a haematologist (does not reverse the drug and the correct dose is unknown)^{1, 3, 5}.
• Haemodilaysis is currently the only way to reduce plasma levels of the drug. Charcoal filtration¹ is suggested a possible option for drug removal (may be more feasible in unstable patients). However, this recommendation is based on limited non-clinical data¹.
• Surgical and interventional radiology consults to consider surgical haemorrhage control or embolisation⁵, where appropriate.
• Consult a haematologist as early as possible.

References:  

1. Hayes L, Maxwell E. Dabigatran (Pradaxa) Monitoring and Reversal. Melbourne Pathology Publication. November 2011 - www.mps.com.au
2. Cotton BA, McArthy JJ, Holcomb JB. Acutely Injured Patients on Dabigatran.  N Engl J Med 2011: 365;21, 2039.
3. University of Utah Health Care - Thrombosis Service: Dabigatran (Pradaxa®) Principles and Guidance for the Reversal of Effect and Management of Life Threatening or Major Bleeding. http://healthcare.utah.edu/Thrombosis/newagents/TS.Dabi_Bleeding.pdf and http://healthcare.utah.edu/Thrombosis/dabigatran.html 
4. Eerenberg ES et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate. Circulation. 2011;124:1573-1579.
5. Institute for Clinical Systems Improvement, Health Care Protocol. Dabigatran - Consensus - Based Statement on Emergency Care of Bleeding. September 2011. http://www.icsi.org/dabigatran__consensus-based_statement_on_emergency_care_of_bleeding_protocol/dabigatran__consensus-based_statement_on_emergency_care_of_bleeding__protocol_.html
6. EMCrit Blog. Bleeding Patients on Dabigatran aka Pradaxa. May 2011. http://emcrit.org/misc/bleeding-patients-on-dabigatran

Comments

[Driver]

Never fear, while we can't stop the bleeding, we at least have an assay to determine dabigatran levels. Stangier J., Feuner, M. (2012) Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinoolysis.

Strangely enough, this is from the same people that brought us dabigatran in the first place. Convenient...

Thanks to Ryan Radecki of EMLit for bringing this to light for me.

Dabigatran is making it's presence felt in NZ already, and of course it is being used for many more conditions than the one originally intended. I have no doubt we will start seeing the first trickles of what may well become a flood all too soon.