Dabigatran is a recently developed antithrombin anticoagulant which is used for prevention of stroke and venous embolism in patients with chronic atrial fibrillation. Dabigatran therapy has been associated with a low rate of serum enzyme elevations and rare instances of liver enzyme elevations and jaundice.
Dabigatran (da" bi gat' ran) is a potent direct inhibitor of thrombin, the final intermediate in blood coagulation. Dabigatran binds to the active site of thrombin and inactivates both fibrin-bound and unbound thrombin, unlike heparin that binds to the unbound thrombin only. Inhibiting thrombin prevents the conversion of fibrinogen to fibrin and subsequent cross linking of fibrin monomers, platelet activation and amplification of coagulation activation. Dabigatran itself is not absorbed from the gastrointestinal tract, but the prodrug dabigatran etexillate mesylate is absorbed and then converted to the active form by gut and plasma esterases. Dabigatran provides a reliable anticoagulant effect and monitoring of effect is not needed. Dabigatran etexilate was approved for use in the United States in 2010 and indications are for prevention of stroke and thromboembolic complications in patients with chronic atrial fibrillation not related to valvular heart disease. Dabigatran is available in capsules of 75 and 150 mg under the brand name Pradaxa and the recommended dose in adults is 150 mg twice daily. Dabigatran, like other anticoagulants, is associated with bleeding adverse events, but these are not common and no more frequent than with low molecular weight heparins or warfarin. Side effects not directly attributable to the anticoagulant activity are not common but can include nausea, abdominal discomfort, diarrhea, anorexia, fever, and skin rash.
Chronic therapy with dabigatran is associated with moderate ALT elevations (greater than 3 times the upper limit of normal) in 1.5% to 3% of patients, an overall rate which is slightly lower than with low molecular weight heparin and similar to the rates with warfarin. While case reports of clinically apparent liver injury due to dabigatran have not been published, several instances of ALT elevations with jaundice occurred during the large, prelicensure clinical trials of dabigatran. These cases were mild and self-limited, resolving completely once therapy was stopped. However, other causes of liver injury could not always be identified and the relationship of the injury to dabigatran therapy remains unclear. The clinical features of these cases were not described. In one large clinical trial, these unexplained cases of liver injury with bilirubin elevations occurred in approximately 1 in 2000 patients treated. In a subsequent case report, liver injury with jaundice and a mixed pattern of serum enzyme elevations arose within 4 weeks of starting dabigatran and resolved rapidly with its discontinuation. Immunoallergic and autoimmune features were not present. Thus, clinically apparent liver injury with jaundice due to dabigatran may occur but is rare and typically mild and self-limited.
One reason why dabigatran was subjected to close scrutiny for evidence of hepatotoxicity was that the initial oral, direct thrombin inhibitor developed and evaluated in clinical trials was ximelagatran (zye" mel a gat' ran), which subsequently was found to be associated with rare but potentially severe cases of liver injury, typically arising after 1 to 6 months of treatment with a hepatocellular pattern of serum enzyme elevations and potentially severe and fatal course. Ximelagatran did not receive approval for use in the United States because of concerns about hepatotoxicity. After several further cases of clinically apparent hepatic injury were found in patients taking ximelagatran, it was also withdrawn from use in Europe. Risk of serum ALT elevations during ximelagatran therapy were later shown to be linked to HLA-DRB1*07 and DQA1*-02.
Mechanism of Injury
The cause of liver injury during dabigatran oral anticoagulant therapy is unknown but is likely to be idiosyncratic and perhaps immunologic. Dabigatran undergoes little hepatic metabolism and does not affect CYP 450 activity.
Outcome and Management
Liver injury attributed to dabigatran varies from mild serum ALT elevations to liver injury with jaundice, but is usually mild and self-limited, resolving within 4 weeks of stopping. Recurrence of liver injury with rechallenge has not been described. There is no reason to suspect that there is cross sensitivity to hepatic injury among the different anticoagulants.
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REPRESENTATIVE TRADE NAMES
Dabigatran – Pradaxa®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 12 April 2014
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Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, et al.; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949-56. PubMed Citation (Controlled trial of dabigatran vs enoxaparin in 3294 patients undergoing hip replacement found ALT elevations above 3 times ULN in 3% of dabigatran vs 5% of enoxaparin treated patients, all returning to baseline during follow up; 2 dabigatran treated patients had elevations in ALT and bilirubin, diagnosis being cholangitis in one and unknown in other, both resolving with discontinuation).
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P, et al.; RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5: 2178-85. PubMed Citation (Controlled trial of dabigatran vs enoxaparin in 2076 patients undergoing knee replacement surgery found ALT elevations above 3 times ULN in 2.8% to 3.7% of dabigatran vs 4.0% of enoxaparin treated subjects; one patient on dabigatran had a simultaneous elevation of bilirubin and ALT which was unexplained and resolved within 4 weeks of stopping).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver injury in the US collected from 2004 to 2008, none were attributed to warfarin or other anticoagulants).
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2010; 52 (1351): 89-90. PubMed Citation (Concise review of pharmacology, efficacy and safety of dabigatran shortly after its approval in the US; most common troublesome side effects are dyspepsia and gastritis; no mention of liver injury or hepatotoxicity).
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52: 2065-76. PubMed Citation (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury, but none were due to anticoagulants or platelet inhibitors).
Friedman RJ, Dahl OE, Rosencher N, Caprini JA, Kurth AA, Francis CW, Clemens A, et al.; RE-MOBILIZE, RE-MODEL, RE-NOVATE Steering Committees. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res 2010; 126: 175-82. PubMed Citation (Analysis of 3 trials of prevention of venous thrombosis after arthroplasty found ALT elevations >3 times ULN in 2.2 to 2.6% of dabigatran vs 3.6% of enoxaparin treated subjects, usually arising in first 10 days; 2 of 5270 [~1 per 2000] dabigatran treated patients had both jaundice and enzyme elevations without another obvious cause, both resolving on stopping dabigatran).
Tran A, Cheng-Lai A. Dabigatran etexilate: the first oral anticoagulant available in the United States since warfarin. Cardiol Rev 2011; 19: 154-61. PubMed Citation (Review of pharmacology, safety and efficacy of dabigatran; "unlike ximelagatran, dabigatran does not appear to have any hepatotoxic effects," ALT elevations greater than 3 times ULN occurred in 3% of treated patients).
Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011; 123: 1436-50. PubMed Citation (Review of the mechanism of action, pharmacokinetics, clinical efficacy and safety of dabigatran).
Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis 2011; 31: 326-43. PubMed Citation (Extensive review of the drug-drug and drug-food interactions of the oral anticoagulants; unlike with warfarin, there are few significant drug and dietary interactions with dabigatran).
Ma TK, Yan BP, Lam YY. Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data. Pharmacol Ther 2011; 129: 185-94. PubMed Citation (Review of trials of efficacy and safety of dabigatran mentions that ALT levels above 3 times ULN occurred in 1.5-3.1% of dabigatran vs 5-7.4% of enoxaparin treated patients).
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randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105: 721-9. PubMed Citation (Controlled trial of dabigatran vs enoxaparin in 2055 patients undergoing orthopedic surgery found similar efficacy and side effects of the 2 anticoagulants; ALT elevations above 3 times ULN occurred in 3.8% on dabigatran and 5.6% on enoxaparin, and no episodes of clinically apparent liver injury that could be linked to either).
Rochwerg B, Xenodemetropoulos T, Crowther M, Spyropoulos A. Dabigatran-induced acute hepatitis. Clin Appl Thromb Hemost 2012; 18: 549-50. PubMed Citation (71 year old man with atrial fibrillation developed jaundice 2-4 weeks after starting dabigatran [bilirubin 6.0 mg/dL, ALT 667 U/L, Alk P 680 U/L], resolving within 2 weeks of stopping).
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PubMed Citation (86 year old woman with atrial fibrillation was taking dabigatran for 6 months when she presented with renal failure and ALT elevations [100 times ULN; bilirubin and Alk P not mentioned], which fell to normal within days of stopping).
Caldeira D, Barra M, Santos AT, de Abreu D, Pinto FJ, Ferreira JJ, Costa J.
Risk of drug-induced liver injury with the new oral anticoagulants: systematic
review and meta-analysis. Heart 2014; 100: 550-6. PubMed Citation (Systemic review of controlled trials of newer anticoagulants identified 29 trials in 152,116 patients followed for an average of 16 months and found no increase in risk of ALT elevations above 3 times ULN compared to low molecular weight heparin or placebo arms; 2.1% taking dabigatran vs 2.7% in control groups).
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