NOAC Reversal

Ok, we all know warfarin sucks.  Patients hate it because it has to be monitored, and if they eat too many collard greens or you prescribe bactrim or cipro they're going to bleed and die.  Invariably, we've all had the patient with hematuria and an INR of 10, but totally stable and with a normal hematocrit.  You consult "the chart" on uptodate and end up more confused.  So, you make something up...um...let's stop taking the warfarin for the next two days, and decrease your dose from 5 mg to 4 mg...and, um...here's 2.5 mg of vitamin K...now, go check in at your coumadin clinic...


Lucky for us, there are new oral anticoagulants (NOAC) that do not have said interactions and do not require monitoring as their metabolism is stable.  Specifically, there is dabigatran (Pradaxa) -- a direct thrombin inhibitor -- and the direct Xa inhibitors -- rivaroxaban (Xarelto), and apixaban (Eliquis).  Generally, these are the bane of surgeons' existence as they are not easily reversed...or are they?

Dabigatran was approved for use in stroke prevention for patients with atrial fibrillation in the US in November, 2010 based largely on a 2009 industry sponsored NEJM study proving non-inferiority with warfarin (1).  There is really no good way to monitor dabigatran.  PTT is a decent qualitative marker, but does not have a linear relationship.  TT and ecarin clotting time (ECT, assay based on viper spit), do have linear relationships but are not standardized tests, and ECT is not available in most hospitals.  About 1/3 of it is bound to plasma proteins, so most of it can be dialyzed if need be.  Activated charcoal may bind if administered within 2 hours (2).  Currently, Boehringer Ingelheim is developing the antidote using antibody fragments (you gotta love the corporate conspiracy -- create the drug, then create the need for an antidote).

Rivaroxaban was approved for DVT/PE in November, 2012, then subsequently approved for use in atrial fibrillation.  It was actually superior to warfarin in another industry sponsored NEJM study in 2010 with a NNT of 222 (3).  It prolongs both PT and PTT, and has some linearity with PT.  It is almost all protein bound, so it cannot be dialyzed.

Apixaban is the latest of the three to hit the market in December of 2012.  It's mechanism of action is the same as rivaroxaban - direct Xa inhibitor.  It's also approved for atrial fibrillation based on another NEJM study in 2011 (4).

There are no clinical trials with patient oriented outcomes regarding reversal of these agents.  There are some animal studies that probably aren't worth mentioning, and one human trial with 12 healthy patients from Amsterdam that suggested rivaroxaban can be reversed with 4 factor PCC, but not dabigatran (2).

Bottom line: These drugs to not have clear reversal mechanisms like warfarin, but PCC will probably work for the Xa inhibitors, but not dabigatran.  FFP is not helpful.  Most hospital protocols for reversal of the NOAC involve administration of PCC (50 U/kg) +/- rFVIIa (not proven to be useful, but suggested so in animal models).

References:
1. Connolly S, et al.  Dabigatran versus Warfarin in Patients with Atrial Fibrillation.  N Engl J Med. 2009 Sep 17;361,1140-51.
2. Eerenberg E, et al.  Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects.  Circulation. 2011 Sep 6;124:1573-1579.
3. Patel MR et al.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-­‐91.
4. Granger C, et al.  Apixaban versus Warfarin in Patients with Atrial Fibrillation.  N Engl J Med. 2011 Sep 15;365(11):981-92.