Anesthesiology, V 122 • No 2 353 February 2015 P RADAXA ® (Boehringer Ingelheim, Biberach, Ger- many) is an oral anticoagulant that contains the pro- drug, dabigatran etexilate. 1 It is metabolized to dabigatran by esterases in the liver and elsewhere. Dabigatran is a spe- cifc high-afnity thrombin inhibitor. In clinical trials, it had less risk of bleeding than vitamin K antagonists. 2 In the United States, it is approved as an antithrombotic to prevent stroke in patients with “nonvalvular” atrial fbrillation. Dabigatran has a relatively short half-life (between 7 and 17 h) in patients with adequate renal function (creatinine clearance > 80 ml/min). 3,4 Tus, minor bleeding can be man- aged by withholding the drug until its efects are reversed by clearance. However, life-threatening bleeding or an urgently needed invasive procedure can be difcult to manage due to the lack of a validated antidote. 5 A humanized antibody antidote for dabigatran has been tested in animal models. 6 It is in clinical trials 7 but is not yet commercially available. Tus, other reversal strategies have been attempted. Dabigatran can be removed by dialysis, but this strategy is rarely used because of the need for large bore vascular access. More commonly, nonactivated prothrom- bin complex concentrates (PCCs), recombinant factor VIIa (FVIIa), or activated PCC (FEIBA ® , Baxter International, Deerfeld, IL) have been administered in attempts to reverse its anticoagulant efects. 8–10 No clinical trials of the ability of What We Already Know about This Topic • Prothrombin complex concentrates and recombinant factor VIIa are used as procoagulant therapies to treat life-threaten- ing bleeding with the new oral anticoagulation agents • New target-specifc reversal agents are being developed that will bind to either the oral direct thrombin inhibitors (dabiga- tran) or the oral direct Xa inhibitors What This Article Tells Us That Is New • Using a cell-based coagulation model, the ability of either pro- thrombin complex concentrate or recombinant factor VIIa to restore hemostasis in the presence of dabigatran depends on the dose of procoagulant used and the level of dabigatran present and may explain the inconsistency of effects in differ- ent models and when used off label for treating bleeding Copyright © 2014, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2015; 122:353-62 ABSTRACT Background: Te oral thrombin inhibitor dabigatran has the drawbacks that it does not have a validated antidote. Data from animal studies and plasma coagulation assays suggest that prothrombin complex concentrate (PCC) or recombinant factor VIIa (FVIIa) might reverse dabigatran anticoagulation. Methods: Cellular elements make a signifcant contribution to hemostasis. Our goals were to (1) test the hypothesis that both FVIIa and a 4-factor PCC improve parameters of thrombin generation in the presence of dabigatran in a cell-based model; and (2) determine whether results in a cell-based model correlate with hemostasis in vivo. Results: PCC reversed dabigatran efects on the rate, peak, and total amount of thrombin but did not shorten the lag (n = 6 experiments in triplicate). By contrast, FVIIa shortened the lag, increased the rate and peak, but did not improve total throm- bin (n = 6). Efects of PCC were seen at both therapeutic and markedly supratherapeutic dabigatran levels, whereas benefcial efects of FVIIa decreased as the dabigatran level increased. Te PCC efect was reproduced by adding prothrombin, factor X, and factor IX. At therapeutic dabigatran levels, both PCC and FVIIa normalized hemostasis time in a mouse saphenous vein bleeding model. Conclusions: A cell-based model refects the efects on thrombin generation of clinically relevant levels of FVIIa and PCC in the presence of dabigatran. Enhancing the rate of thrombin generation and peak thrombin level appear to correlate best with hemostasis in vivo. Te inefectiveness of FVIIa at supratherapeutic dabigatran levels may explain conficting reports of its efcacy in dabigatran reversal. (ANESTHESIOLOGY 2015; 122:353-62) This article is featured in “This Month in Anesthesiology,” page 1A. Corresponding article on page 236. Portions of this work were pre- sented as a talk at the International Society for Thrombosis and Haemostasis meeting, June 29–July 4, 2013, Amsterdam, The Netherlands, and as a poster at the American Society for Hematology meeting, December 7–10, 2013, New Orleans, Louisiana. Submitted for publication March 2, 2014. Accepted for publication July 31, 2014. From the Division of Hematology/Oncology, Department of Medicine, The University of North Carolina, Chapel Hill, North Carolina. Reversal of Dabigatran Effects in Models of Thrombin Generation and Hemostasis by Factor VIIa and Prothrombin Complex Concentrate Maureane Hoffman, M.D., Ph.D., Zoya Volovyk, Ph.D., Dougald M. Monroe, Ph.D. CRITICAL CARE MEDICINE Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/122/2/353/267879/20150200_0-00022.pdf by guest on 24 June 2022