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CLINICIAN UPDATE

CLINICIAN UPDATE

Anticoagulants and Transaminase Elevation


Nipun Arora, MD; Samuel Z. Goldhaber, MD

C
ase 1: Mr F., a 65-year-old randomized controlled trials that are and SPORTIF V; a 6 times higher rate
man with hypertension and required for drug approval.2 of serum transaminase abnormalities
atrial fibrillation, began long- Anticoagulant-induced liver injury was found in patients receiving ximel-
term anticoagulation with warfarin 1 has been infrequently reported. Case re- agatran compared with those receiving
year ago. He presented with a 1-week ports have described the association of warfarin.27–30 Among the 3700 patients
history of nausea, anorexia, jaundice, anticoagulants with asymptomatic eleva- randomized to ximelagatran, there was
and altered mental status. His labora- tion of serum transaminases, clinically 1 case of biopsy-documented drug-
tory workup showed elevated serum significant hepatitis, and fatal liver fail- induced liver failure leading to death
transaminases and direct bilirubin. ure.3–22 As an increasing number of pa- (Figure) and a second probable case of
Could warfarin be potentially tients receive long-term anticoagulation drug-induced liver failure leading to
responsible? for prevention of stroke and venous coagulopathy, massive hemorrhage,
Case 2: Mr S., a 75-year-old man thromboembolism, the rare adverse and death.31
with diabetes and coronary artery dis- event of anticoagulant-induced liver in-
ease, presented with an acute anterior jury is gaining attention. Clinical Significance of
myocardial infarction. Echocardiogra- Ximelagatran is an oral direct Transaminase Elevation
phy showed a left ventricular aneu- thrombin inhibitor that prevents the Levels of transaminases ALT and as-
rysm with apical akinesis and throm- conversion of fibrinogen to fibrin by partate aminotransferase (AST) are
bus. He was started on enoxaparin, and thrombin. This agent is a prodrug and sensitive indicators of drug-induced
3 days later, he developed a rise in is converted to its active form, mel- hepatocellular injury. Elevations in
alanine aminotransferase (ALT) ⬎5 agatran, via hepatic metabolism.23 It ALT and AST can occur from condi-
times the upper limit of normal (ULN). has a short half-life, requires twice tions other than liver injury, but ALT
Could this laboratory abnormality be daily administration, and produces a is relatively more specific because it is
related to enoxaparin? predictable response after oral admin- synthesized primarily by the liver. The
istration. It does not require normal range for any laboratory test is
Epidemiology anticoagulant-level or drug-level mon- mean⫾2 SD. By definition, 5% of
Drug-induced hepatotoxicity is the itoring, and it has virtually no drug- results fall outside the normal range,
most common cause of acute liver drug or drug-food interactions.24 –26 and 2.5% may be above the ULN.32
failure in the United States and is the The Federal Drug Administration Levels of ALT ⬎3 times the ULN are
most frequently cited reason for with- (FDA) did not approve ximelagatran often used as a possible signal for
drawal of an approved drug from the after review of 2 pivotal premarketing drug-induced hepatotoxicity.33,34
market.1 It occurs at rates of 1 in 1000 efficacy trials, Stroke Prevention Us- An elevation in transaminase levels
to 1 in 100 000 patients, making it ing an Oral Direct Thrombin Inhibitor in conjunction with a rise in bilirubin
difficult to detect in the premarketing in Atrial Fibrillation (SPORTIF) III level ⬎2 ULN is a more ominous

From the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Samuel Z. Goldhaber, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail
sgoldhaber@partners.org
(Circulation. 2006;113:e698-e702.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.603100

e698
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Arora and Goldhaber Anticoagulants and Transaminase Elevation e699

patients, repeat challenge with warfa-


rin resulted in recurrent deterioration
of liver function.
With short-term therapy (prophy-
laxis against venous thromboembolism
for ⬍12 days), ximelagatran was not
associated with abnormalities in liver
function.34 In trials evaluating long-
term use, however, it was associated
with a 7.9% incidence of transaminase
elevation ⬎3 ULN, 1.1% incidence of
hepatitis, and a 1 in 2000 risk of dying
from liver failure.34
Another oral direct thrombin inhib-
itor, dabigatran, underwent evaluation
in the Boehringer-Ingelheim Study in
Thrombosis (BISTRO) I and II trials
Liver biopsy in an 84-year-old man who had taken the anticoagulant ximelagatran to for prevention of venous thromboem-
prevent stroke from permanent atrial fibrillation. The biopsy shows acute massive bolism after orthopedic surgery. Use of
hepatic necrosis. There is extensive parenchymal architectural collapse with hemor- dabigatran for durations of 6 to 10
rhage (white arrows), mixed inflammation, and focal clusters of residual hepatocytes
(black arrows). There are darkly stained (resulting from nuclear collapse and apoptosis) days resulted in a 1.5% to 3.1% rise in
pyknotic hepatocytes (acidophil bodies) indicated by black arrowheads. No normal ALT ⬎3 ULN. Elevations in serum
hepatic parenchyma remains. On the day of the biopsy, the ALT was 1778 U, and the alkaline phosphatase were also re-
AST was 1630 U. The total bilirubin was 4.5 mg/dL. The biopsy findings are not etiolog-
ically specific but may be due to drug toxicity. He died 5 weeks after this biopsy. (Pre- ported in some patients.38,39
pared by Jason L. Hornick, MD, PhD, Department of Pathology, Brigham and Women’s
Hospital, Boston, Mass). Parenteral Anticoagulants
Unfractionated heparin (UFH) and
marker for drug-induced liver injury. long-term clinical outcomes of these low-molecular-weight heparins can
This combination was first noticed in patients.2 lead to transaminase elevation. UFH
1978 by Hyman Zimmerman (cited in has been associated with transaminase
Reuben 35). He described drug-induced Oral Anticoagulants elevation even with low subcutaneous
hepatic reactions that caused hepato- Warfarin is the most common oral prophylactic dosages, although at a
cyte injury sufficient to affect global anticoagulant used in the United lesser frequency than with higher ther-
liver function and, in particular, to States. There have been case reports apeutic dosages. Transaminase eleva-
cause jaundice as a result of impaired describing the association of warfarin tions ⬎3 ULN have been reported to
bilirubin transport by the liver. Hepa- with fatal liver failure. Warfarin is
occur in 5% of patients receiving UFH
totoxicity of such severity is likely to associated with a 0.8% to 1.2% risk of
and in 4.3% to 13% of patients receiv-
lead to patient death in 10% to 15% of transaminase elevation ⬎3 ULN.27,28,30
ing the currently FDA-approved low
cases, especially if the offending drug Although there have been no long-
molecular weight heparins (enoxapa-
is not stopped.35 This sequence of ad- term postmarketing trials or prospec-
rin, dalteparin, and tinzaparin).40 – 42
verse events is now called Hy’s Law. tive registries in the United States, a
The hepatotoxic effects remained con-
According to the Clinical White Paper large retrospective registry consisting
of 4390 patients from Germany de- fined to transaminase elevations, re-
on hepatotoxicity published by the
scribed the association of liver injury flecting possible hepatocellular injury,
FDA (November 2000), Hy’s Law has
been the basis for the rejection of with phenprocoumon, a structurally and were not associated with cholesta-
several new drugs.33 similar coumarin analogue of warfarin sis or jaundice.6,14,15
and the most commonly used oral an- Recombinant hirudins such as lepi-
Magnitude of the Problem ticoagulant in Europe.36 There was a rudin have been reported to be associ-
Transaminase elevation in patients tak- 2% incidence of hepatitis and 0.2% ated with a 6% risk of transaminase
ing anticoagulant agents might be un- incidence of liver failure.37 Another elevation, although there are no reports
derreported. There are no guidelines German study described 8 patients on associated with argatroban or bivaliru-
that require monitoring of liver func- phenprocoumon with hepatotoxic ad- din.43 The indirect factor Xa inhibitor
tion in patients who are prescribed verse effects, 3 of whom developed fondaparinux has been associated with
anticoagulants. We lack postmarketing liver failure, leading to 1 death and 2 ⬎3 ULN elevation of ALT in 2.6% of
studies and registries that assess the liver transplants.37 In some of these patients.44
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e700 Circulation April 18, 2006

Pattern of Liver Function Clinical Diagnostic Scale


Test Abnormalities and the Component Elements Score Attributed
Usual Course Temporal relation between drug intake and reaction
The most common abnormality is ele- Time from drug intake to onset of first clinical or laboratory manifestation
vation of serum transaminases (ALT 4 d to 8 wk (or ⬍4 d in case of reexposure) 3
and AST). Elevation of alkaline phos-
⬍4 d or ⬎8 wk 1
phatase has been reported with dabig-
Time from withdrawal of drug until onset of manifestations
atran, ximelagatran, and warfarin.
0 to 7 d 3
Jaundice has been reported only with
8 to 15 d 0
ximelagatran and warfarin. Prothrom-
⬎15 d (except in case of drugs that persist for a long time; eg, amiodarone) ⫺3
bin time and international normalized
Time from withdrawal of drug to decrease of ALT or AST ⬍2 ULN
ratio (INR) are usually normal in clin-
⬍6 mo (cholestatic or mixed pattern) or 2 mo (hepatocellular) 3
ically stable patients. Elevation in ALT
and AST levels occurs within the first ⬎6 mo (cholestatic or mixed pattern) or 2 mo (hepatocellular) 0
week of initiating therapy, although it Exclusion of alternative causes (viral hepatitis, alcoholic liver disease, biliary
obstruction, preexisting liver disease, ischemic hepatitis)
can occur at any time during the course
Complete exclusion 3
of treatment. After terminating the an-
Partial exclusion 0
ticoagulant agent, transaminases usu-
Possible alternative cause detected ⫺1
ally improve or return to normal within
2 weeks. Although these laboratory Probable alternative cause detected ⫺1
abnormalities are believed to represent Extrahepatic manifestations (rash, fever, arthralgia, eosinophilia, cytopenia)
true hepatocellular injury, they often 4 or more 3
reverse even when the drug is contin- 2 to 3 2
ued. It is not clear why some patients 1 1
adapt and others develop severe liver None 0
failure.45 Intentional or accidental reexposure
Positive repeat challenge test 3
Is There a Common Negative or absent repeat challenge test 0
Underlying Mechanism? Previous report in literature of cases of hepatotoxicity associated with drug
The specific mechanism of transami- Yes 2
nase elevation after anticoagulant use No (drugs marketed for up to 5 y) 0
has not been identified and requires No (drugs marketed for ⬎5 y) ⫺3
further research. Possible mechanisms CDS scoring for drug-induced hepatotoxicity46 is as follows: ⬎17, definitive; 14 to 17, probable; 10 to 13,
for heparin include direct toxicity, he- possible; 6 to 9, unlikely; and ⬍6, excluded.
patocyte membrane modification, and CDS score ⬎9 indicates sensitivity of 70% to 88% and specificity of 92% to 99%.
immune-mediated hypersensitivity re-
action.6 Phenprocoumon can be asso- standard for diagnosis is liver biopsy, tion, (3) exclusion of alternative rea-
ciated with direct damage of hepato- but it is an invasive and potentially sons for liver damage by using detailed
cytes by reactive metabolites, which risky procedure. investigations, including liver biopsy,
may result in augmented antigenicity The first step in the evaluation of an (4) positive response to reexposure,
and consequent immunoallergic reac- elevated ALT or AST level is to repeat and (5) previous reports of liver injury
tion. It can also be associated with the test. If still abnormal, try to rule out associated with the drug. Patients with
high-energy reactions involving cyto- conditions such as alcohol ingestion, a CDS score ⬎9 are considered to be
chrome P-450 enzymes, causing de- hepatotoxic co-medications, chronic at possible risk for drug hepatotoxicity.
cline of adenosine triphosphate levels, hepatitis B and C, autoimmune hepa- Healthcare providers under these cir-
loss of ionic gradients, cell swelling, titis, nonalcoholic fatty liver disease, cumstances should file adverse drug
and rupture.37 hemochromatosis, Wilson’s disease, reaction reports to relevant drug safety–
␣-1 antitrypsin deficiency, and celiac monitoring authorities.
How to Diagnose sprue.32
Anticoagulant-Induced A clinical diagnostic scale (CDS) Recommendations for
Liver Injury has been developed and validated for Patient Management
Encountering ALT or AST elevation causality assessment of drug-induced Screening for liver function test abnor-
in patients on anticoagulants can pose liver damage (Table).46,47 CDS covers malities before starting anticoagulants
difficulty regarding the establishment (1) time from intake to onset of reac- is not a routine recommendation but
of a diagnosis and causality. The gold tion, (2) course of reaction after cessa- may be considered if there is a known
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Arora and Goldhaber Anticoagulants and Transaminase Elevation e701

preexisting liver disorder. Although prevent patients from developing fatal Zeneca and is a consultant for Sanofi-
the traditional wisdom among the liver failure. Aventis. Dr Arora reports no conflicts.
hepatologists is that patients with pre-
existing liver disease do not have a Review of Cases References
1. Lee WM. Drug-induced hepatotoxicity.
higher risk for drug-induced hepato- Case 1 N Engl J Med. 2003;349:474 – 485.
toxicity, inasmuch as most reactions The patient presented with prodro- 2. Lee WM. Assessing causality in drug-
are idiosyncratic, recent controversies induced liver injury. J Hepatol. 2000;33:
mal symptoms suggestive of acute 1003–1005.
have challenged that assumption. If no hepatitis and had an ALT level of 3. Bamanikar A, Hiremath S. Hepatotoxic
other cause is apparent and if ALT or 992 U/L and direct serum bilirubin reaction to warfarin in a recovering hepatitis
AST is elevated to ⬎3 ULN in any level of 2.5 mg/dL. His mental status and patient with hypoalbuminemia. J Assoc Phy-
patient on anticoagulant therapy, close sicians India. 2002;50:1456.
liver functions showed further worsen- 4. Chaudhry S, Oelsner D. Cholestatic reaction
follow-up is recommended.48 If the ing over the next 3 to 4 days. There was to warfarin. Am J Gastroenterol. 1995;
trend shows a persistent rise, switch to no bleeding from any site, and the INR 90:853.
another class of anticoagulant agent. If 5. Bux-Gewehr I, Zotz RB, Scharf RE.
was in the therapeutic range of 1.5 to 2.5. Phenprocoumon-induced hepatitis in a
the bilirubin is elevated to ⬎2 ULN Warfarin was temporarily withheld dur- patient with a combined hereditary hemo-
and if there is a strong suspicion of the ing the inpatient stay, and liver functions static disorder. Thromb Haemost. 2000;83:
anticoagulant medication being the gradually improved. No cause of hepa- 799 – 800.
culprit, discontinue the anticoagulant 6. Carlson MK, Gleason PP, Sen S. Elevation
tocellular injury was apparent from the of hepatic transaminases after enoxaparin
immediately. history or laboratory workup. After he use: case report and review of unfractionated
Fulminant hepatic failure can de- was discharged, the patient was restarted and low molecular weight heparin induced
velop within 2 weeks of onset of hep- hepatotoxicity. Pharmacotherapy. 2001;21:
on warfarin and had a repeat hospitaliza- 108 –113.
atocellular injury. If there is evidence tion that was due to worsening of liver 7. de Man RA, Wilson JH, Schalm SW, ten
of encephalopathy with persistent function. A switch was finally made Kate FJ, van Leer E. Phenprocoumon-
jaundice and coagulopathy (as mea- from warfarin to enoxaparin as mono-
induced hepatitis mimicking non-A, non-B
hepatitis. J Hepatol. 1990;11:318 –321.
sured by an INR of 1.5 or greater) even therapy, and the patient has been doing 8. den Boer W, Loeliger EA. Phenprocoumon-
after discontinuation of the anticoagu- well since. induced jaundice. Lancet. 1976;1:912.
lant, consider transferring the patient Letter.
to a liver transplantation center.34 Cor- 9. Ehrenforth S, Schenk JF, Scharrer I. Liver
Case 2 damage induced by coumarin anticoagulants.
ticosteroid treatment may be used in Serum ALT levels start rising 6 to 8 Semin Thromb Hemost. 1999;25:79 – 83.
patients with evident hypersensitive hours after myocardial infarction, peak 10. Quintana MR, Iruin G, Chacon JM. Cholestatic
reactions, although controlled trials at 24 to 48 hours, and can remain hepatitis secondary to the use of aceno-
coumarin. Haematologica. 1997;82:732–733.
have not proven the efficacy of such elevated above normal levels for up to 11. Hautekeete M, Holvoet J, Hubens H.
treatment for the hepatotoxic adverse 6 days. Our patient was initially con- Cytolytic hepatitis related to the oral antico-
reactions of other drugs.49 A cautious sidered to have ALT elevation (lev- agulant phenprocoumon. Gastroenterol Clin
repeat challenge can be performed if Biol. 1995;19:223–224.
els⫽600 IU/L) that was due to acute 12. Hinrichsen H, Luttges J, Kloppel G, Folsch
the association is highly questionable myocardial infarction and was dis- UR, Schmidt WE. Idiosyncratic drug allergic
and if no other drug is available for the charged home. He continued enoxapa- phenprocoumon-induced hepatitis with sub-
treatment of a potentially life- acute liver failure initially misdiagnosed as
rin therapy at home because coronary
autoimmune hepatitis. Scand J Gastro-
threatening disorder. bypass graft surgery was planned enterol. 2001;36:780 –783.
within 2 weeks. At the time of admis- 13. Hohler T, Schnutgen M, Helmreich-Becker
Conclusion sion for coronary bypass graft surgery, I, Mayet WJ, Mayer KH. Drug-induced hep-
In summary, anticoagulant-induced atitis: a rare complication of oral antico-
the patient still had elevated serum agulants. J Hepatol. 1994;21:447– 449.
transaminase elevation is common and ALT level (650 IU/L), prompting a 14. Hui CK, Yuen MF, Ng IO, Tsang KW, Fong
can be the initial marker of toxic liver further workup. A thorough history, GC, Lai CL. Low molecular weight heparin-
injury ranging from mild acute hepati- examination, and extensive laboratory induced liver toxicity. J Clin Pharmacol.
tis to massive hepatocellular necrosis 2001;41:691– 694.
workup failed to identify any cause for 15. AL-Mekhaizeem KA, Sherker AH. Heparin-
with liver failure. Further research is hepatocellular injury. Enoxaparin was induced hepatotoxicity. Can J Gastro-
required to better understand the out- considered to be a possible cause and enterol. 2001;15:527–530.
comes and underlying mechanisms. 16. Matsukawa R, Uemura S, Fukuchi S,
was discontinued. The patient received Tsuruta Y, Murakami S. Thrombosed St.
There is a need to improve the recog- UFH and had improvement in ALT Jude Medical prosthesis with drug induced
nition of this entity by clinicians. In- levels within 48 hours. hepatitis due to warfarin potassium: a case
creased awareness will help achieve report. Nippon Kyobu Geka Gakkai Zasshi.
the correct diagnosis, prevent unneces- 1994;42:413– 415.
Disclosures 17. Mix H, Wagner S, Boker K, Gloger S,
sary procedures such as liver biopsy, Dr Goldhaber receives clinical research Oldhafer KJ, Behrend M, Flemming P,
minimize expensive evaluations, and funding from Sanofi-Aventis and Astra- Manns MP. Subacute liver failure induced

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e702 Circulation April 18, 2006

by phenprocoumon treatment. Digestion. V trials. Am J Manag Care. 2004;10: of a new oral direct thrombin inhibitor,
1999;60:579 –582. S462–S469. dabigatran etexilate, in patients undergoing
18. Neef M, Kerekes Z, Fischer HP, Sauerbruch T, 28. Olsson SB, Executive Steering Committee on total hip replacement: BISTRO I. J Thromb
Spengler U. Acenocoumarol is not a safe alter- Behalf of the SPORTIF III Investigators. Haemost. 2004;2:1573–1580.
native for anticoagulation in phenprocoumon- Stroke prevention with the oral direct thrombin 39. Eriksson BI, Dahl OE, Buller HR,
induced hepatic failure: report of two cases. inhibitor ximelagatran compared with warfarin Hettiarachchi R, Rosencher N, Bravo ML,
Digestion. 2003;67:100 –104. in patients with non-valvular atrial fibrillation Ahnfelt L, Piovella F, Stangier J, Kalebo P,
19. Rehnqvist N. Intrahepatic jaundice due to (SPORTIF III): randomised controlled trial. Reilly P. A new oral direct thrombin inhib-
warfarin therapy. Acta Med Scand. 1978; Lancet. 2003;362:1691–1698. itor, dabigatran etexilate, compared with
204:335–336. 29. Investigators SPORTIF V. Ximelagatran vs enoxaparin for prevention of thrombo-
20. Slagboom G, Loeliger EA. Coumarin- warfarin for stroke prevention in patients embolic events following total hip or knee
associated hepatitis: report of two cases. with nonvalvular atrial fibrillation: a ran- replacement: the BISTRO II randomized
Arch Intern Med. 1980;140:1028 –1029. domized trial. JAMA. 2005;293:690 – 698. trial. J Thromb Haemost. 2005;3:103–111.
21. Wuillemin WA, Zenhausern R, Bernhard 30. Lip GY. Preventing stroke in atrial fibril- 40. Christiansen HM, Lassen MR, Borris LC,
MC, Lammle B. Phenprocoumon-induced lation: the SPORTIF programme. Patho- Sorensen JV, Rahr HB, Jorgensen LN,
hepatitis delaying precise diagnosis in a physiol Haemost Thromb. 2005;34(suppl Jorgensen PW, Hauch O. Biologic tolerance
thrombophilic patient with activated protein 1):25–30. of two different low molecular weight
C resistance due to factor V R506Q 31. FDA Advisory Committee Briefing heparins. Semin Thromb Hemost. 1991;17:
mutation. Am J Med. 1997;103:437– 439. Document. EXANTA (ximelagatran) tablets 450 – 454.
22. de Man RA. Phenprocoumon-induced liver NDA 21-686: Cardiovascular and Renal 41. Guevara A, Labarca J, Gonzalez-Martin G.
failure. Neth J Med. 1993;43:91. Drugs Advisory Committee 10 September Heparin-induced transaminase elevations: a
23. Eriksson UG, Bredberg U, Hoffmann KJ, 2004. Available at: http://www.fda. prospective study. Int J Clin Pharmacol Ther
Thuresson A, Gabrielsson M, Ericsson H, gov/ohrms/dockets/ac/04/briefing/2004- Toxicol. 1993;31:137–141.
Ahnoff M, Gislen K, Fager G, Gustafsson D. 42. Fragmin (Dalteparin) [package insert].
4069B1_01_AstraZeneca-Backgrounder.pdf.
Kalamazoo, Mich; Pharmacia; 1998.
Absorption, distribution, metabolism, and Accessed October 28, 2005.
43. Greinacher A, Janssens U, Berg G, Bock M,
excretion of ximelagatran, an oral direct 32. Pratt DS, Kaplan MM. Evaluation of
Kwasny H, Kemkes-Matthes B, Eichler P,
thrombin inhibitor, in rats, dogs, and abnormal liver-enzyme results in asymptom-
Volpel H, Potzsch B, Luz M. Lepirudin
humans. Drug Metab Dispos. 2003;31: atic patients. N Engl J Med. 2000;342:
(recombinant hirudin) for parenteral antico-
294 –305. 1266 –1271.
agulation in patients with heparin-induced
24. Eriksson UG, Bredberg U, Gislen K, 33. FDA. Clinical white paper. November 2000.
thrombocytopenia. Circulation. 1999;100:
Johansson LC, Frison L, Ahnoff M, Available at: http://www.fda.gov/cder/
587–593.
Gustafsson D. Pharmacokinetics and phar- livertox/clinical.pdf. Accessed October 28, 44. Center for Drug Evaluation and Research.
macodynamics of ximelagatran, a novel oral 2005. Fondaparinux (Arixtra) labeling instructions.
direct thrombin inhibitor, in young healthy 34. Lee WM, Larrey D, Olsson R, Lewis JH, Available at: http://www.fda.gov/cder/foi/
male subjects. Eur J Clin Pharmacol. 2003; Keisu M, Auclert L, Sheth S. Hepatic nda/2001/21-345_Arixtra_prntlbl.pdf. Ac-
59:35– 43. findings in long-term clinical trials of ximel- cessed on October 28, 2005.
25. Wahlander K, Lapidus L, Olsson CG, agatran. Drug Saf. 2005;28:351–370. 45. Russo MW, Watkins PB. Are patients with
Thuresson A, Eriksson UG, Larson G, 35. Reuben A. Hy’s law. Hepatology. 2004;39: elevated liver tests at increased risk of drug-
Eriksson H. Pharmacokinetics, pharmacody- 574 –578. induced liver injury? Gastroenterology.
namics and clinical effects of the oral direct 36. Giannini DD, Chan KK, Roberts JD. Carbon-13 2004;126:1477–1480.
thrombin inhibitor ximelagatran in acute nuclear magnetic resonance spectroscopy: 46. Aithal GP, Rawlins MD, Day CP. Clinical
treatment of patients with pulmonary structure of the anticoagulant warfarin and related diagnostic scale: a useful tool in the eval-
embolism and deep vein thrombosis. Thromb compounds in solution. Proc Natl Acad Sci uation of suspected hepatotoxic adverse drug
Res. 2002;107:93–99. U S A. 1974;71:4221–4223. reactions. J Hepatol. 2000;33:949 –952.
26. Wolzt M, Wollbratt M, Svensson M, 37. Schimanski CC, Burg J, Mohler M, Hohler 47. Edwards IR, Aronson JK. Adverse drug
Wahlander K, Grind M, Eriksson UG. Con- T, Kanzler S, Otto G, Galle PR, Lohse AW. reactions: definitions, diagnosis, and man-
sistent pharmacokinetics of the oral direct Phenprocoumon-induced liver disease agement. Lancet. 2000;356:1255–1259.
thrombin inhibitor ximelagatran in patients ranges from mild acute hepatitis to (sub-) 48. Kaplowitz N. Drug-induced liver disorders:
with nonvalvular atrial fibrillation and in acute liver failure. J Hepatol. 2004;41: implications for drug development and reg-
healthy subjects. Eur J Clin Pharmacol. 67–74. ulation. Drug Saf. 2001;24:483– 490.
2003;59:537–543. 38. Eriksson BI, Dahl OE, Ahnfelt L, Kalebo P, 49. Lee WM. Medical progress: drug-induced
27. Albers GW. Stroke prevention in atrial fibril- Stangier J, Nehmiz G, Hermansson K, hepatotoxicity. N Engl J Med. 1995;333:
lation: pooled analysis of SPORTIF III and Kohlbrenner V. Dose escalating safety study 1118 –1127.

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