A Case of Liver Failure Due to Dabigatran Treated with Venovenous Hemodiafiltration and Idarucizumab

Author(s): Nicola Guglielmo, Daniele Orso*, Rosalba Mestroni, Giulia Montanari

Journal Name: Current Drug Safety

Volume 15 , Issue 3 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Dabigatran etexilate, a direct thrombin inhibitor, was recently introduced in clinical use to prevent thromboembolic events in patients with risk factors (such as non-valvular atrial fibrillation or deep vein thrombosis). Dabigatran is not recommended in patients with creatinine clearance below 30 mL/min. More than 85% of the drug is eliminated by the renal route while the remaining part via the enteral route. Acute renal failure can result in an unexpected increase in serum levels of Dabigatran. In elderly, renal dysfunction, co-morbidity, and concomitant intake of different drugs could make the dosage of Dabigatran challenging. We present a case of an elderly man who suffered a severe accidental dabigatran intoxication with acute liver toxicity recovered after dialytic treatment and Idarucizumab.

Keywords: Toxicity, direct thrombin inhibitor, dabigatran, idarucizumab, overdose, therapeutic drug monitoring.

Antonijevic NM, Zivkovic ID, Jovanovic LM, et al. Dabigatran – Metabolism, pharmacologic properties and drug interactions. Curr Drug Metab 2017; 18(7): 622-35.
[http://dx.doi.org/10.2174/1389200218666170427113504] [PMID: 28460624]
Blair HA, Keating GM. Dabigatran etixilate: a review in nonvalvular atrial fibrillation. Drugs 2017; 77(3): 331-44.
[http://dx.doi.org/10.1007/s40265-017-0699-z] [PMID: 28185082]
(accessed: 7 March, 2020). Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/pradax-a#authorisation-details-section (visited 07/03/2020)
Forsyth J. FDA Approves Pradaxa® (dabigatran etexilate mesylate) for prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism (pe) after hip replacement surgery 2015; (accessed: 7 March, 2020). Available from: https://www.boehringer-ingelheim.us/press-release/fda-approves-pradaxa-dabigatran-etexilate-mesylate-prophylaxis-deep-venous-thrombosis
January CT, Wann LS, Calkins H, et al. AHA/ACC/HRS focused upadate of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74(1): 104-32.
[http://dx.doi.org/10.1016/j.jacc.2019.01.011] [PMID: 30703431]
Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis.9th ed: e44S-e88S American College of Chest Physicians evidence-based clinical practice guidelines Chest. 2012; p. 141.
Kirchhof P, Benussi S, Kotecha D, et al. ESC scientific document group. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37: 2983-62.
Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47(5): 285-95.
[http://dx.doi.org/10.2165/00003088-200847050-00001] [PMID: 18399711]
Comin J, Kallmes DF. Dabigatran (Pradaxa). AJNR Am J Neuroradiol 2012; 33(3): 426-8.
[http://dx.doi.org/10.3174/ajnr.A3000] [PMID: 22345499]
Connolly SJ, Ezekowitz MD, Yusuf S, et al. RE-LY Steering committee and investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12): 1139-51.
[http://dx.doi.org/10.1056/NEJMoa0905561] [PMID: 19717844]
Ezekowitz MD, Nagarakanti R, Noack H, et al. Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: the RE-LY trial (randomized evaluation of long-term anticoagulant therapy). Circulation 2016; 134(8): 589-98.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020950] [PMID: 27496855]
Adeboyeje G, Sylwestrzak G, Barron JJ, et al. Major bleeding risk during anticoagulation with warfarin, dabigatran, apixaban, or rivaroxaban in patients with nonvalvular atrial fibrillation. J Manag Care Spec Pharm 2017; 23(9): 968-78.
[http://dx.doi.org/10.18553/jmcp.2017.23.9.968] [PMID: 28854073]
Calkins H, Willems S, Gerstenfeld EP, et al. RE-CIRCUIT investigators. re-circuit investigators. Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation. N Engl J Med 2017; 376(17): 1627-36.
[http://dx.doi.org/10.1056/NEJMoa1701005] [PMID: 28317415]
Wallentin L, Yusuf S, Ezekowitz MD, et al. RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376(9745): 975-83.
[http://dx.doi.org/10.1016/S0140-6736(10)61194-4] [PMID: 20801496]
Yu YB, Liu J, Fu GH, Fang RY, Gao F, Chu HM. Comparison of dabigatran and warfarin used in patients with non-valvular atrial fibrillation: meta-analysis of random control trial. Medicine (Baltimore) 2018; 97(46) e12841
[http://dx.doi.org/10.1097/MD.0000000000012841] [PMID: 30431565]
Bai Y, Deng H, Shantsila A, Lip GY. Rivaroxaban versus dabigatran or warfarin in real-world studies of stroke prevention in atrial fibrillation: systemic review and meta-analysis. Stroke 2017; 48(4): 970-6.
[http://dx.doi.org/10.1161/STROKEAHA.116.016275] [PMID: 28213573]
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383(9921): 955-62.
[http://dx.doi.org/10.1016/S0140-6736(13)62343-0] [PMID: 24315724]
Marino KK, Santiago RA, Dew RB III, et al. Management of dabigatran-associated bleeding with two doses of idarucizumab plus hemodialysis. Pharmacotherapy 2016; 36(10): e160-5.
[http://dx.doi.org/10.1002/phar.1830] [PMID: 27581709]
Donaldson M, Norbeck AO. Adverse events in patients initiated on dabigatran etexilate therapy in a pharmacist-managed anticoagulation clinic. Pharm Pract (Granada) 2013; 11(2): 90-5.
[http://dx.doi.org/10.4321/S1886-36552013000200005] [PMID: 24155855]
Porru M, Mameli A, Cianchetti ME, et al. Dabigatran overdose: a case report of acute hepatitis. Extracorporeal treatment. Int J Hematol 2017; 105(4): 532-5.
[http://dx.doi.org/10.1007/s12185-016-2158-0] [PMID: 27910004]
Steiner T, Böhm M, Dichgans M, et al. Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol 2013; 102(6): 399-412.
[http://dx.doi.org/10.1007/s00392-013-0560-7] [PMID: 23669868]
Yao X, Shah ND, Sangaralingham LR, Gersh BJ, Noseworthy PA. Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol 2017; 69(23): 2779-90.
[http://dx.doi.org/10.1016/j.jacc.2017.03.600] [PMID: 28595692]
Gage L. Dabigatran in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2011; 58(5): 551.
[http://dx.doi.org/10.1016/j.jacc.2011.04.016] [PMID: 21777759]
Nielsen PB, Skjøth F, Søgaard M, Kjældgaard JN, Lip GY, Larsen TB. Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2017; 356: j510.
[http://dx.doi.org/10.1136/bmj.j510] [PMID: 28188243]
Liakoni E, Rätz Bravo AE, Krähenbühl S. Hepatotoxicity of new oral anticoagulants (NOACs). Drug Saf 2015; 38(8): 711-20.
[http://dx.doi.org/10.1007/s40264-015-0317-5] [PMID: 26138527]
Comuth WJ, Haase AM, Henriksen LØ, Malczynski J, van de Kerkhof D, Münster AB. Cholestatic liver injury as a side-effect of dabigatran and the use of coagulation tests in dabigatran intoxication and after reversal by idarucizumab in bleeding and sepsis. Scand J Clin Lab Invest 2018; 78(1-2): 1-5.
[http://dx.doi.org/10.1080/00365513.2017.1402127] [PMID: 29148292]
Sarma A, Rossi JE, Connors JM, Giugliano RP. Dabigatran excess: case report and review of the literature. Cardiol Ther 2013; 2(1): 111-24.
[http://dx.doi.org/10.1007/s40119-013-0016-1] [PMID: 25135294]
Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory monitoring of non-vitamin K antagonist oral anticoagulation use in patients with atrial fibrillation: a review. JAMA Cardiol 2017; 2(5): 566-74.
[http://dx.doi.org/10.1001/jamacardio.2017.0364] [PMID: 28355459]
Du S, Weiss C, Christina G, et al. Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods. Clin Chem Lab Med 2015; 53(8): 1237-47.
[http://dx.doi.org/10.1515/cclm-2014-0991] [PMID: 25720084]
Conway SE, Hwang AY, Ponte CD, Gums JG. Laboratory and clinical monitoring of direct acting oral anticoagulants: what clinicians need to know. Pharmacotherapy 2017; 37(2): 236-48.
[http://dx.doi.org/10.1002/phar.1884] [PMID: 27983747]
Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest 2017; 151(1): 127-38.
[http://dx.doi.org/10.1016/j.chest.2016.08.1462] [PMID: 27637548]
Schneider KL, Kastenmüller K, Weckbecker K, Bleckwenn M, Böhme M, Stingl JC. Potential drug-drug interactions in a cohort of elderly, polymedicated primary care patients on antithrombotic treatment. Drugs Aging 2018; 35(6): 559-68.
[http://dx.doi.org/10.1007/s40266-018-0550-6] [PMID: 29737468]
Gui YY, Zou S, Yang WL, et al. The impact of renal function on efficacy and safety of new oral anticoagulant in atrial fibrillation patients: a systemic review and meta-analysis. Medicine (Baltimore) 2019; 98(48) e18205
[http://dx.doi.org/10.1097/MD.0000000000018205] [PMID: 31770278]
Fava JP, Starr KM, Ratz D, Clemente JL. Dosing challenges with direct oral anticoagulants in the elderly: a retrospective analysis. Ther Adv Drug Saf 2018; 9(8): 405-14.
[http://dx.doi.org/10.1177/2042098618774498] [PMID: 30364869]
Liakoni E, Rätz Bravo AE, Krähenbühl S. Hepatotoxicity of New Oral Anticoagulants (NOACs). Drug Saf 2015; 38(8): 711-20.
[http://dx.doi.org/10.1007/s40264-015-0317-5] [PMID: 26138527]
LiverTox: clinical and research information on drug-induced liver injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547852
Ghannoum M, Nolin TD. What is the role of renal replacement therapy in the setting of dabigatran toxicity? Semin Dial 2014; 27(3): 223-6.
[http://dx.doi.org/10.1111/sdi.12230] [PMID: 24620942]
Sheikh-Taha M. Reversal of dabigatran requiring hemodialysis, fresh frozen plasma, and 2 doses of idarucizumab in a patient with acute kidney injury. Am J Health Syst Pharm 2019; 76(1): 9-12.
[http://dx.doi.org/10.1093/ajhp/zxy008] [PMID: 31381100]
Camm AJ, Fox KAA. Strengths and weaknesses of ‘real-world’ studies involving non-vitamin K antagonist oral anticoagulants. Open Heart 2018; 5(1) e000788
[http://dx.doi.org/10.1136/openhrt-2018-000788] [PMID: 29713485]
Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - Full cohort analysis. N Engl J Med 2017; 377(5): 431-41.
[http://dx.doi.org/10.1056/NEJMoa1707278] [PMID: 28693366]
Thibault N, Morrill AM, Willett KC. Idarucizumab for reversing dabigatran-induced anticoagulation: a systematic review. Am J Ther 2018; 25(3): e333-8.
[http://dx.doi.org/10.1097/MJT.0000000000000460] [PMID: 27175894]
Yip L, Deng JF. Idarucizumab dosing in kidney failure. Am J Kidney Dis 2018; 71(1): 146.
[http://dx.doi.org/10.1053/j.ajkd.2017.08.012] [PMID: 28985980]
Parli SE, Thompson Bastin ML, Lewis DA. Use of continuous renal replacement therapy for removal of dabigatran in a patient in need of emergent surgery. Case Rep Crit Care 2016. 20169692568
[http://dx.doi.org/10.1155/2016/9692568] [PMID: 27313909]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 17 November, 2020
Page: [227 - 230]
Pages: 4
DOI: 10.2174/1574886315666200623162926
Price: $65

Article Metrics

PDF: 29
PRC: 1