The new oral anticoagulants (NOACs) are an appealing alternative to the burdensome vitamin K antagonists such as warfarin. These novel agents include direct thrombin inhibitors such as dabigatran (which inhibits thrombin) and factor Xa inhibitors such as rivaroxaban and apixaban (which prevent thrombin generation).  Compared to warfarin, NOACs have fewer food and drug interactions, as well as a more predictable pharmacodynamic profile that serves to obviate the need for the frequent outpatient monitoring in most patients. In addition to convenience, there is expanding evidence that NOACs are equally effective or better than warfarin for both prophylaxis and treatment of arterial and venous thromboembolism, while at the same time bleeding rates are comparable or even improved with the new agents. [2-6] However, despite impressive data and ease-of-use, the widespread implementation of the NOACs has been diminished out of concern for their lack of reversibility in patients who present with life-threatening bleeding or in need of emergency surgery.
There is currently no specific antidote for the NOACs. For comparison, warfarin is effectively reversed with vitamin K, though this may take 24 hours to fully manifest.  In the interim, both fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC) can be used to quickly replace the vitamin K–dependent clotting proteins; of note, four-factor PCC (Kcentra, Octaplex)contains significant amounts of factors II, VII, IX, and X, whereas three-factor PCC contains little or no factor VII and may require concomitant plasma administration for complete reversal.  When it comes to the NOACs, transfusions are unlikely to be effective since the problem is not a deficit of factors (as there is in warfarinized patients) but rather competitive blocking of activated factor X or thrombin. 
The following agents are currently being investigated as possible new anticoagulation antidotes:
This protein is catalytically inactive but works by mimicking the appearance of factor Xa and thereby binds the direct Xa inhibitors (such as rivaroxaban and apixaban) in a dose-dependent fashion.  PRT06445 is currently in a phase 2 trial in which healthy volunteers are given rivaroxaban.
This drug is an antibody fragment (Fab) against dabigatran (a direct thrombin inhibitor) intended to neutralize its activity. This potential antidote mimics thrombin and has an affinity for dabigatran that is ~350 times stronger than the affinity of dabigatran for thrombin. In a pre-clinical study released May 2013, aDabi-Fab successfully reversed the effect of dabigatran in vivo in a rat model examining clotting time.  The effect was immediate (within 1 minute of aDabi-Fab injection) and was maintained even in the setting of continual infusion of dabigatran over 25 minutes. Importantly, aDabi-Fab given alone did not show any procoagulant properties. Clinical trials are expected to begin in the near future.
PER977 is a synthetic molecule that has been shown in pre-clinical studies to be capable of binding both the direct thrombin and factor Xa inhibitors, without binding blood coagulation factors. These studies demonstrated anticoagulation reversal in vitro animal models (with reduction in blood loss in the rat tail injury model) and ex vivo in human blood using aPTT and anti-Xa level analysis.  Exciting properties of this molecule include rapid action (with complete reversal of rivaroxaban and apixaban in human plasma by 30 minutes) and stability at room temperature making for easier storage in emergency rooms and potentially even ambulances. Additionally, if this agent is ultimately proven able to reverse the activity of all NOACs, it can be given upfront to patients on NOACs that may not know exactly which agent they take. PER977 is currently in a phase 1 trial to assess safety and tolerability in which normal subjects will receive PER977 alone followed one week later by PER977 plus edoxaban.
Until these potential antidotes become available, current management for significant bleeding in the setting of NOAC use consists mainly of supportive measures until the drug effect wears off. There is evidence that hemodialysis may partially remove dabigatran,  though the risk involved in placing a dialysis catheter in a patient with a bleeding diathesis is an important consideration. Hemodialysis does not effectively eliminate rivaroxaban as this drug is almost completely bound to protein. 
In cases of overdose, activated charcoal is likely beneficial if given within 1-2 hours after intake of the drug, however this has not been tested clinically; an in vitro study involving dabigatran suspended in acidic water (intended to simulate the gastric environment) demonstrated 99.9% absorption of dabigatran by activated charcoal.  For apixaban, the window for activated charcoal administration may be as long as 3 hours after drug administration based on evidence in dogs that apixaban undergoes entero-enteric recirculation involving multiple rounds of intestinal absorption. 
Though critical bleeding events are rare with the NOACs, an antidote can be life-saving in those situations. The current reversal agents under investigation show promise and, if successful, would raise the comfort level for prescribing physicians and their patients.
Commentary by David Green, MD, PhD, Assistant Professor, Medical Director Anticoagulation Svc Tisch Hospital
Anticoagulants are narrow therapeutic index drugs and management of bleeding complications is a major concern to patients and providers alike. The newer anticoagulants offer several advantages when compared to vitamin K antagonists (VKAs). However, the major limitation of the novel anticoagulants is lack of reversal agent. Reversal agents are in clinical or pre-clinical development and if successful will significantly increase the adoption of newer anticoagulants. Another important consideration is commercial assay development to measure anticoagulant activity which is especially important in patients undergoing invasive procedure or surgery and in special populations such as cancer patients or those with organ dysfunction or those at the extremes of body weight.
The perfect anticoagulant is not yet in hand: oral, inexpensive, immediate acting, reversible, no off target effects, no drug-drug or drug-food interactions, easily measurable. Having a range of therapeutic options is clearly a major advance. In the current practice pattern in the US many stable Coumadin patients are being maintained on Coumadin while newly anticoagulated patients are often prescribed one of the newer agents. Coumadin with all of its associated problems is not likely to become obsolete anytime soon, after all it is inexpensive, fully reversible, easily measured and has virtually no off target effects.
Dr. Gabriel Schneider, Internal Medicine, NYU Langone Medical Center
Peer reviewed by David Green, MD, PhD, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
1. Weitz, J.I., New oral anticoagulants: a view from the laboratory. Am J Hematol, 2012. 87 Suppl 1: p. S133-6. http://www.ncbi.nlm.nih.gov/pubmed/22407747
2. Connolly, S.J., et al., Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med, 2009. 361(12): p. 1139-51. http://www.nejm.org/doi/full/10.1056/NEJMoa0905561
3. Patel, M.R., et al., Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 2011. 365(10): p. 883-91. http://www.nejm.org/doi/full/10.1056/NEJMoa1009638
4. Granger, C.B., et al., Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 2011. 365(11): p. 981-92. http://www.nejm.org/doi/full/10.1056/NEJMoa1107039
5. Schulman, S., et al., Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med, 2009. 361(24): p. 2342-52. http://www.ncbi.nlm.nih.gov/pubmed/19966341
6. Agnelli, G., et al., Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med, 2013. 369(9): p. 799-808. http://www.nejm.org/doi/full/10.1056/NEJMoa1302507
7. Lubetsky, A., et al., Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med, 2003. 163(20): p. 2469-73.
8. Holland, L., et al., Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion, 2009. 49(6): p. 1171-7. http://www.ncbi.nlm.nih.gov/pubmed/19210325
9. Majeed, A. and S. Schulman, Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol, 2013. 26(2): p. 191-202. http://www.ncbi.nlm.nih.gov/pubmed/23953907
10. Lu, G., et al., A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med, 2013. 19(4): p. 446-51. http://www.ncbi.nlm.nih.gov/pubmed/23455714
11. Schiele, F., et al., A specific antidote for dabigatran: functional and structural characterization. Blood, 2013. 121(18): p. 3554-62. http://www.ncbi.nlm.nih.gov/pubmed/23476049
12. Laulicht, B.B., Sasha, Small Molecule Antidote for Anticoagulants. Circulation, 2012. 126: p. A11395.
13. Stangier, J., et al., Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet, 2010. 49(4): p. 259-68. http://www.ncbi.nlm.nih.gov/pubmed/20214409
14. Battinelli, E.M., Reversal of new oral anticoagulants. Circulation, 2011. 124(14): p. 1508-10. http://www.ncbi.nlm.nih.gov/pubmed/21969317
15. van Ryn, J., et al., Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost, 2010. 103(6): p. 1116-27. http://www.ncbi.nlm.nih.gov/pubmed/20352166
16. Zhang, D., et al., Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. Drug Metab Dispos, 2013. 41(4): p. 906-15. http://www.unboundmedicine.com/evidence/ub/citation/23386703/Investigating_the_enteroenteric_recirculation_of_apixaban_a_factor_Xa_inhibitor:_administration_of_activated_charcoal_to_bile_duct_cannulated_rats_and_dogs_receiving_an_intravenous_dose_and_use_of_drug_transporter_knockout_rats_