Reversal of Novel Anticoagulants in the Bleeding Patient

In the last two years, two new oral anticoagulants have been introduced to the market. Despite advantages over their predecessors, these new agents have no proven reversal agent and limited data exists on how to potentially counteract the effects of these new drugs.  This poses a significant challenge to the physician faced with a bleeding patient on these anticoagulants.

        

Dabigatran (Pradaxa, Boehringer Ingelheim, Ridgefield CT), a direct thrombin inhibitor, was approved by the FDA in October of 2010 for prevention of stroke in patients with atrial fibrillation. 

Rivaroxaban (Xarelto, Jannsen, Titusville NJ), is a direct factor Xa inhibitor, was approved by the FDA for DVT prophylaxis in July of 2011 and also for stroke prevention in atrial fibrillation patients in November of 2011.  

Both are taken orally and offer several advantages over warfarin including:  less food and drug interactions, predictable pharmacokinetics, and no need for routine laboratory testing or dose adjustment.  

While PTT and INR assess the anticoagulant effect of heparin and warfarin, respectively, no laboratory test has been shown to adequately assess the levels or anticoagulation effect of the new drugs.  

Activated partial thromboplastin time (aPTT) and thrombin time (TT) are prolonged with these drugs but these tests underestimate drug effects at higher blood concentrations.  Therefore, a prolonged aPTT or TT indicates only that the drug is present but provides no information on how much is present or the extent of anticoagulation -- limiting these tests to qualitative roles only.

While there is no specific reversal agent for these new medications, there are potential management options for bleeding patients on these anticoagulants.  

PCC & FFP

Prothrombin complex concentrate (PCC) contains clotting factors II, IX, X, and thrombin (some also contain VII).

Eerenberg et al. evaluated the effects of PCC on 12 healthy male subjects who were treated with rivaroxaban then given PCC.  The study concluded there was complete reversal of rivaroxaban based on normalization of aPTT and endogenous thrombin potential following administration of PCC.  

This was then repeated with dabigatran and similar rates of reversal were not seen, leading the authors to conclude PCC would be effective in the reversal of rivaroxaban but not dabigatran.  

FFP contains many of the clotting factors in PCCs at a lower concentration, and may be of utility should PCCs be unavailable.

NovoSeven

Recombinant Factor VIIa (NovoSeven, Novo Nordisk, Princeton NJ) directly activates thrombin on the surface of platelets and has been shown to improve laboratory measures of clotting in rats.  Though theoretically useful, no case report or study has confirmed its therapeutic use in reversal of dabigatran or rivaroxaban.

Hemodialysis

There may also be a role for hemodialysis for removal of dabigatran.  Dabigatran has low protein binding, a moderate volume of distribution, and is a small molecule -- all properties making it amenable to dialysis.  

In one study where dabigatran was given to 6 patients with ESRD  on hemodialysis, it was estimated that 62% of the drug was removed by 2 hours and 68% by 4 hours of hemodialysis.  

Dialysis would not be an option for rivaroxaban as it is 95% protein bound.  

A simplified algorithm to managing bleeding patients on these anticoagulants is shown below:

Management of Dabigatran and Rivaroxaban Related Bleeding

Bleeding Severity	Management Recommendations
Mild	Delay next dose or discontinue dabigatran
Moderate to Severe	Symptomatic treatment Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal (will adsorb drug if ingestion < 2 hours) Hemodialysis*
Life-threatening Bleeding	All the same treatment modalities as Moderate to Severe bleeding Consideration of PCC, rFVIIa, FFP Hemodialysis*

*Hemodialysis is not recommended for rivaroxaban

-- Megan Stultz MD

References:

Crowther MA. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009; 7 (Suppl 1):107–110.

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.

Eerenberg ES et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate. Circulation. 2011; 124: 1573-1579.

Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokineti. 2010; 49: 259-268.

Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2010; 123: 1436-1450.

Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W, Laux V. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol. 2010; 30: 376-381.

Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361: 1139-1151.