Novel Oral Anticoagulants and Their Reversal

This article discusses the use of dabigatran and Xa inhibitors for a.fib, DVT/PE and stroke prevention.  They discuss the efficacy of each medication, the benefits/adverse effects as compared to warfarin and potential reversal agents.  There is also a brief discussion of different froms of prothrombin complex concentrate (PCC) which I think warrants a look at due to some confusion as to what PCC is, how many factors it has and its usefulness.  So here is a brief summary of each agent, their benefits and potential reversal:

Mechanism:

1) Dabigatran - direct thrombin inhibitor, time to onset 2 hours, half life 12-15 hours, renal excretion 80%

i) There is a dose depenent superiority in CVA risk and a.fib but also dose dependent hemorrhagic stroke risk. Dabigatran is equivalent to warfarin in a.fib prevention with major bleeding being more frequently from a GI source (80%) rather than ICH as compared to warfarin. The benefits of dabigatran as compared to coumadin are NOT extrapolated well to CVA and mechanical valves with a ischemic CVA risk of 5% as compared to 0% on coumadin and hemorrhage of 4% vs 2%.

2) Rivaroxiban - Xa inhibitor, time to onset 3 hours, half life 6-9 hours, renal excretion 66%

i) Not inferior to warfarin in a.fib with similar rates of major bleeding but less intracranial bleeds and fetal bleeding than coumadin.

3) Apixiban - Xa inhibitor, time to onset 3 hours, half life 9-14 hours, renal excretion 66%

i) Shown to have a reduced ischemic stroke incidence as compared to coumadin 1.6% vs 1.27% and lower mortality 3.94% vs 3.54%.

Reversal agents:

1) 3 factor PCC (Factors II, IX, X) - (Bebulin/Profilnine) has shown faster reversal in ICH as compared to warfarin 41 min vs 115 min and is maintained well at 96hrs when given with Vit K (but can cause incomplate reversal). Please keep in mind that in a trial of 70 patients who received PCC 10% had a confirmed thrombotic or thromboembolic event with 3% having BOTH CVA and PE which were sometimes fatal. There are other studies showing an increased risk of thrombosis with the use of PCC at times theorized to have to do with unmasking of underlying coagulopathy. 

2) 4 factors PCC (Factors II, VII, IX, X, C/S) -  (Kcentra) has been shown to cause complete reversal of rivaroxiban but only theorized benefit in reversal of dabigatran! Also same risk of thrombosis as 3 factor PCC.

3) Activated PCC (Factor VII with less II, VII, IX and protein C)-  (FEIBA) is usually used to reverse hemophiliacs with antibodies to factor VIII. Should in theory have similar effectiveness as 4 factor PCC.

* Tranexemic acid - shown to reduce mortality in major bleeding if given within 3 hours of onset of bleeding.

** 3 factor PCC with Factor VIIa - recombinant factor VIIa causes activation of IX and X and therefore increases thrombin drastically. There has been reversal of lab values with its addition but no decrease in bleeding. Overall be afraid of using lots of factor VII because it can arterial thrombosis and has been associated with adverse outcomes in prior literature as well.

Dialysis and activated charcoal are discussed but I will let you explore those on your own if you are itnerested.  Overall the article is good.  Please take everything with a grain of salt because many of the "novel anticoagulats" initially had sketchy funding for the trials.

Takehome points are Xa can be reversed at least partially with PCC, direct thrombin inhibitors likely cannot, renal failure and age significantly increases bleeding risk on these medications, Xa protein binding is higher than thrombin inhibitors, factor VII has a risk of arterial thrombosis, dabigatran is as good for a.fib but not to be used for valves/CVA prevention and be afraid of thrombotic events with PCC.