Dabigatran etexilate is an oral direct thrombin (Factor IIa) inhibitor approved for patients with atrial fibrillation and for management of risk of deep vein thrombosis and pulmonary embolism. Dabigatran offers advantages over treatment with warfarin, including limited laboratory monitoring. It is equivalent in prevention of stroke and deep vein thrombosis with essentially equivalent complication rates. In contrast to warfarin, reversal of the anticoagulation is less well established. Idarucizumab is available for reversal, however supporting research is mixed; the agent also happens to be quite expensive making availability difficult. Hemodialysis has been proposed as a method of reversal, but this is difficult in patients with life threatening hemorrhage, and is not available at many hospitals. Intravenous fat emulsion (IFE) has been used for treatment of overdose of lipophilic drugs. Most toxicologists only recommend IFE for patients in extremis after ingestion of a lipid soluble substance. Dabigatran is lipid soluble, although the pro-drug more so than the active metabolite. The authors sought to see if dabigatran-induced coagulopathy of human in vitro blood samples could be reversed with IFE. Blood samples were spiked with dabigatran or dabigatran plus IFE. Values for Ecarin clot time (ECT—primary outcome), PT/INR, and aPTT, were compared across both study arms. A total of 18 healthy volunteers were included in our study. There were no significant differences in the ECT, PT/INR, and aPTT between the dabigatran arm and the dabigatran plus IFE arm. Based on these methods, IFE does not reverse dabigatran-induced coagulopathy.
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Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ (2001) Validation of clinical classification schemes for predicting stroke: results from the national registry of atrial fibrillation. JAMA 285:2864–2870
Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J et al (2011) Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 123:2363–2372
Ezekowitz MD, Reilly PA, Nehmix G, Simmers TA, Nagarakanti R et al (2007) Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study). Am J Cardiol 100:1419–1426
Schulman S, Kearon C, Kakkar AK, Mismetti P et al (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. NEJM 361:2342–2352
Stangier J (2008) Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 47:285–295
Van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A (2010) Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103:1116–1127
Baglin T, Hillarp A, Tripodi A et al (2013) Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 11:756–760
Lindahl TL, Baghaei F, Blixter IF, Gustafsson KM, Stigendal L, Sten-Linder M et al (2011) Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost 105:371–378
Skeppholm M, Hjemdahl P, Antovic JP et al (2014) On the monitoring of dabigatran treatment in “real life” patients with atrial fibrillation. Thromb Res 134:783–789
Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA (2017) Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest 151:127–138
Nowak G (2004) The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb 33:173–183
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151
Pollack CV, Reilly PA, Eikelboom J, Glund S et al (2015) Idarucizumab for dabigatran reversal. N Engl J Med 373:511–520
Bendel S, Bona R, Baker WL (2011) Dabigatran: an oral direct thrombin inhibitor for use in atrial fibrillation. Adv Ther 28:460–472
Van Ryn J, Sieger P, Kink Eiband M, Gansser D, Clemens A (2009) Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro. Blood 114:1065 (abstract)
Lindahl T, Wallstedt M, Gustafsson KM, Persson E, Hillarp A (2015) More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate. Thromb Res 135:544–547
Honickel M, Braunschweig T, Rossaint R, Stoppe C, Ten Cate H, Grottke O (2017) Reversing dabigatran anticoagulation with prothrombin complex concentrate versus idarucizumab as part of multimodal hemostatic intervention in an animal model of polytrauma. Anesthesiology 127:852–861
Levy JH, Ageno W, Chan NC et al (2016) When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 14:623–627
Keeling D, Tait RC, Watson H, British Committee of Standards for Haematology (2016) Peri-operative management of anticoagulation and antiplatelet therapy. Br J Haematol 175:602–613
Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ (1998) Pretreatment of resuscitation with a lipid infusion shift the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 88:1071–1075
Weinberg G, Ripper R, Feinstein DL, Hoffman W (2003) Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 28:198–202
Cave G, Harvey M (2009) Intravenous lipid emulsion therapy as antidote beyond anesthetic toxicity: a systematic review. Acad Emerg Med 16:815–824
Jamaty C, Bailey B, Laroque A, Notebaert E, Sanogo K, Chauny JM (2010) Lipid emulsion in the treatment of acute poisoning a systematic review of human and animal studies. Clin Toxicol 48:1–27
Geib AJ, Liebelt E, Manini AF, Toxicology Investigators Consortium (ToxIC) (2012) Clinical experience with intravenous lipid emulsion for drug induced cardiovascular collapse. J Med Toxicol 8:10–14
Levine M, Hoffman RS, Lavergne V, Stork CM, Graudins A, Chuang R, Stellpflug SJ et al (2016) Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clin Toxicol 54:194–221
Gosselin S, Morris M, Miller-Nesbitt A, Hoffman RS, Hayes BD, Turgeon AF et al (2015) Methodology for AACT evidence-based recommendations on the use of intravenous lipi emulsion therapy in poisoning. Clin Toxicol 53:557–564
Gosselin S, Hoegberg LC, Hoffman RS, Graudins A, Stork CM, Thomas SH, Stellpflug SJ et al (2016) Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning. Clin Toxicol 54:899–923
Stellpflug SJ, Fritzlar SJ, Cole JB, Engebretsen KM, Holger JS (2011) Cardiotoxic overdose treated with intravenous fat emulsion and high-dose insulin in the setting of hypertrophic cardiomyopathy. J Med Toxicol 7(2):151–153
Fettiplace MR, Weinberg G (2018) The mechanisms underlying lipid resuscitation therapy. Reg Anesth Pain Med 43:138–149
Stellpflug SJ, Harris CR, Engebretsen KM, Cole JB, Holger JS (2010) Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high dose insulin. Clin Toxicol 48(3):227–229
Moffat AC et al (eds) (2004) Clarke’s analysis of drugs and poisons, 3rd edn. Pharm Press, Grayslake
Rautio Jarkko (2010) Prodrugs and targeted delivery: towards better ADME properties. Wiley-VCH John Wiley Distributor, Weinheim
Blum J, Carreiro S, Hack JB (2013) Intravenous lipid emulsion does not reverse dabigatran-induced anticoagulation in a rat model. Acad Emerg Med 20:1022–1025
Levine M, Skolnik AB, Ruha AM, Bosak A, Menke N, Pizon AF (2014) Complications following antidotal use of intravenous lipid emulsion therapy. J Med Toxicol 10:10–14
Cole JB, Stellpflug SJ, Engebretsen KM (2014) Asystole immediately following intravenous fat emulsion for overdose. J Med Toxicol 10:307–310
Hayes BD, Gosselin S, Calello DP, Nacca N, Rollins CJ, Abourbih D et al (2016) Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clin Toxicol 54:365–404
Dr. Kristin Engebretsen, PharmD, passed away during the completion of this project. She was an exemplary pharmacist, toxicologist, clinician, researcher, and writer. She will be missed dearly.
This study was funded through a HealthPartners Research Institute Internal Discovery Grant No. A12-096.
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Stellpflug, S.J., Bond, M.E., Henry, K.D. et al. Intravenous Fat Emulsion Does Not Significantly Alter Clotting Markers in Dabigatran-Treated Blood. Indian J Hematol Blood Transfus (2020). https://doi.org/10.1007/s12288-020-01309-5