OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Edoxaban – Savaysa®

DRUG CLASS

Anticoagulants

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

ANNOTATED BIBLIOGRAPHY

References updated: 16 February 2023

• Zimmerman HJ. Antithrombotic agents. Drugs used in cardiovascular disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 639-42.

  (Textbook of hepatotoxicity published in 1999, well before the availability of edoxaban and the direct factor Xa inhibitors).
• De Marzio DH, Navarro VJ. Hepatotoxicity of cardiovascular and antidiabetic drugs: antihypertensives. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 519-53.

  (Review of hepatotoxicity of cardiovascular drugs does not discuss the anticoagulants).
• Weitz JI. Blood coagulation and anticoagulant, fibrinolytic, and antiplatelet drugs. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 849-76.

  (Textbook of pharmacology and therapeutics).
• Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were due to anticoagulants).
• Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, Kastrissios H, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost. 2010;104:633–41. [PubMed: 20694273]

  (Among 1,146 patients with atrial fibrillation and risk of stroke who were treated with edoxaban [varying regimens] or warfarin for 3 months, rates of stroke were similar in all groups and ALT elevations occurred in 15 of 866 [1.7%] on edoxaban and 4 of 245 [1.6%] on warfarin; concurrent ALT, Alk P and bilirubin elevations in 2 edoxaban treated subjects were attributed to other conditions [gallstones and heart failure]).
• Raskob G, Cohen AT, Eriksson BI, Puskas D, Shi M, Bocanegra T, Weitz JI. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study. Thromb Haemost. 2010;104:642–9. [PubMed: 20589317]

  (Among 903 patients undergoing hip replacement who received either edoxaban [15, 30, 60 or 90 mg daily] or dalteparin for 7 to 10 days, rates of venous thromboembolism was less with edoxaban [11-20%] than dalteparin [44%], while rates of ALT elevations above 3 times ULN were similar [2.4-4.3% vs 2.9%]).
• Treatment of atrial fibrillation. Treat Guidel Med Lett. 2010;8(97):65–70. [PubMed: 20733547]

  (Concise review of treatment of atrial fibrillation including use of apixaban and rivaroxaban; does not mention hepatotoxicity or ALT elevations).
• Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–15. Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, et al. [PubMed: 23991658]

  (Among 4921 patients with deep venous thrombosis and 3319 with pulmonary embolism treated with edoxaban [30 or 60 mg daily] of warfarin for 3 to 12 months, recurrent thromboembolism was similar with either agent [3.2% vs 3.5%], as were adverse events with ALT elevations above 3 times ULN in 2.1% vs 2.3%, concurrent ALT and bilirubin elevations in 0.2% vs 0.1%, and no instance of a serious hepatic adverse event).
• Fuji T, Wang CJ, Fujita S, Kawai Y, Nakamura M, Kimura T, Ibusuki K, et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thromb Res. 2014;134:1198–204. [PubMed: 25294589]

  (Among 594 patients undergoing hip replacement treated with either edoxaban or enoxaparin for 11-14 days, thromboembolism occurred in 7% vs 14%, while ALT elevations above 3 times ULN occurred in 0.6% vs 6%).
• New oral anticoagulants for acute venous thromboembolism. Med Lett Drugs Ther. 2014;56(1433):3–4. [PubMed: 24419296]

  (Brief comparison of warfarin, rivaroxaban, apixaban and dabigatran as anticoagulants for therapy of venous thromboembolism, all of which have similar efficacy, warfarin requiring regular monitoring of INR whereas the others do not).
• 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: 24476812]

  (Systematic review of 29 controlled trials of oral anticoagulants in 152,116 patients focusing on risk of drug induced liver injury [including 1 trial with 3878 patients on edoxaban] found no increase in rate of serum ALT or AST elevations above 3 times ULN [2.1% vs 2.3%] or combined enzyme and bilirubin elevations above 2 times ULN [0.2% vs 0.08%] with edoxaban therapy compared to control patients on warfarin, and concludes that the direct Factor Xa inhibitors "do not increase the risk of DILI").
• Fuji T, Fujita S, Kawai Y, Nakamura M, Kimura T, Fukuzawa M, Abe K, Tachibana S. Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V. Thromb J. 2015;13:27. [PMC free article: PMC4534125] [PubMed: 26269694]

  (Among 610 patients undergoing hip replacement who were treated with edoxaban [30 mg daily] or enoxaparin [subcutaneously twice daily] for 11-14 days, venous thromboembolism events occurred in 2.4% vs 6.9% with no increase in bleeding episodes, and ALT elevations in 12% vs 42%, being above 3 times ULN in 3.3% vs 13.7%).
• Liakoni E, Rätz Bravo AE, Krähenbühl S. Hepatotoxicity of new oral anticoagulants (NOACs). Drug Saf. 2015;38:711–20. [PubMed: 26138527]

  (Review of published literature and data from pharmacovigilance registries on liver injury due to new oral anticoagulants including edoxaban, apixaban and rivaroxaban concludes that hepatotoxicity is possible with these agents, but is rare and does not warrant routine monitoring).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, two were attributed to antithrombotic agents [prasugrel and dalteparin], but none to edoxaban or other direct factor Xa inhibitors).
• Edoxaban (Savaysa)--the fourth new oral anticoagulant. Med Lett Drugs Ther. 2015;57(1465):43–5. [PubMed: 25853577]

  (Concise review of efficacy and safety of edoxaban for prevention of stroke or systemic embolization in patients with nonvalvular atrial fibrillation, which is equivalent or better in efficacy than warfarin with a lower rate of bleeding; no mention of hepatotoxicity or ALT elevations).
• Kawai Y, Fuji T, Fujita S, Kimura T, Ibusuki K, Abe K, Tachibana S. Edoxaban versus enoxaparin for the prevention of venous thromboembolism after total knee or hip arthroplasty: pooled analysis of coagulation biomarkers and primary efficacy and safety endpoints from two phase 3 trials. Thromb J. 2016;14:48. [PMC free article: PMC5134224] [PubMed: 27980462]

  (Among 716 patients undergoing total knee replacement in two trials in Asia comparing edoxaban to enoxaparin given for 11-14 days, thromboembolic events were less common with edoxaban [5% vs 11] while bleeding and other adverse event rates were similar; no mention of ALT elevations or hepatotoxicity).
• Goette A, Merino JL, Ezekowitz MD, Zamoryakhin D, Melino M, Jin J, Mercuri MF, et al. ENSURE-AF investigators. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial. Lancet. 2016;388(10055):1995–2003. [PubMed: 27590218]

  (Among 2199 patients with atrial fibrillation undergoing cardioversion treated with edoxaban or enoxaparin-warfarin, major thrombotic events were rare [<1% vs 1%] as were major bleeding episodes [<1% vs <1%] and overall adverse event rates [30% vs 33%]; no mention of ALT elevations or hepatotoxicity).
• Conway SE, Hwang AY, Ponte CD, Gums JG. Laboratory and clinical monitoring of direct acting oral anticoagulants: What clinicians need to know. Pharmacotherapy. 2017;37:236–48. [PubMed: 27983747]

  (Review and recommendations largely on use of coagulation tests to monitor oral anticoagulant therapy, but also concludes: "Hepatic function in otherwise healthy individuals can be assessed yearly or more frequently in those with hepatic impairment").
• Alonso A, MacLehose RF, Chen LY, Bengtson LG, Chamberlain AM, Norby FL, Lutsey PL. Prospective study of oral anticoagulants and risk of liver injury in patients with atrial fibrillation. Heart. 2017;103:834–9. [PMC free article: PMC5429195] [PubMed: 28057799]

  (Analysis of a database on more than 1 million patients with nonvalvular atrial fibrillation on oral anticoagulants identified 960 hospitalizations with liver injury between 2011 and 2014, rates being highest for warfarin, intermediate for rivaroxaban, and lowest for apixaban and dabigatran; edoxaban was not included in the analyses having been approved for use in 2015).
• Nagaoki Y, Aikata H, Daijyo K, Teraoka Y, Shinohara F, Nakamura Y, Hatooka M, et al. Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis. Hepatol Res. 2018;48:51–8. [PubMed: 28342265]

  (Among 50 patients with cirrhosis and portal vein thrombosis treated with low molecular weight heparin followed by either warfarin or edoxaban for up to 6 months, portal vein thrombus reduction was greater with edoxaban and adverse event rates including gastrointestinal bleeding were similar; no mention of ALT elevations and there were no liver related severe adverse events).
• Qamar A, Antman EM, Ruff CT, Nordio F, Murphy SA, Grip LT, Greenberger NJ, et al. Edoxaban versus warfarin in patients with atrial fibrillation and history of liver disease. J Am Coll Cardiol. 2019;74:179–189. [PubMed: 31296289]

  (Among 21,105 adults enrolled in a randomized controlled trial of edoxaban [30 or 60 mg daily] versus warfarin, 1083 [5%] had a history of liver disease, and while rates of bleeding episodes were more frequent in those with than without liver disease, rates of stroke, myocardial infarction and suspected drug induced liver injury were similar in the two groups).
• Björnsson HK, Gudmundsson DO, Björnsson ES. Liver injury caused by oral anticoagulants: A population-based retrospective cohort study. Liver Int. 2020;40:1895–1900. [PubMed: 32511827]

  (Search of Icelandic National Prescription Databases and Health Records identified 3 cases of clinically apparent, acute liver injury in 3446 [0.1%] patients taking rivaroxaban, but in none of 9101 taking warfarin, or in 1903 taking apixaban, 1335 dabigatran or 34 edoxaban).
• Yang X, Li N, Guo T, Guan X, Tan J, Gao X, Wu Y, Jia L, et al. Comparison of the effects of low-molecular-weight heparin and fondaparinux on liver function in patients with pulmonary embolism. J Clin Pharmacol. 2020;60:1671–1678. [PubMed: 32639644]

  (Among 463 adults with pulmonary embolus treated with low molecular weight heparins or with fondaparinux, 79 [17%] developed evidence of liver injury that was generally mild and less than 3 times ULN in 98%, compared to 15% of 377 on edoxaban, 32% of 59 on nadroparin, and 7.4% of 27 on fondaparinux).
• Zhao J, Blais JE, Chui CSL, Suh IH, Chen EYH, Seto WK, Mok MT, et al. Association between nonvitamin K antagonist oral anticoagulants or warfarin and liver injury: a cohort study. Am J Gastroenterol. 2020;115:1513–1524. [PubMed: 32467502]

  (Among 13,698 patients with atrial fibrillation started on anticoagulant therapy and followed in the Hong Kong Clinical Database and Reporting system between 2010 and 2016, 513 [2.8%] developed evidence of liver injury and propensity matching indicated that liver injury was less frequent [2.1% vs 3.4%], although more severe with oral anticoagulants than with warfarin).
• Maura G, Bardou M, Billionnet C, Weill A, Drouin J, Neumann A. Oral anticoagulants and risk of liver injury in patients with nonvalvular atrial fibrillation: a propensity-weighted nationwide cohort study. Sci Rep. 2020;10:11624. [PMC free article: PMC7363898] [PubMed: 32669591]

  (Among 434,015 patients with atrial fibrillation started on anticoagulant therapy and followed in the French National Healthcare Database, 218 [0.6%] were subsequently hospitalized for acute liver injury, the rates being similar for those on dabigatran [26 of 51,737 patients], apixaban [29 of 62,503 patients] and rivaroxaban [46 of 99,408 patients]).
• Zhou J, Leung KSK, Kong D, Lee S, Liu T, Wai AKC, Chang C, et al. Low rates of liver injury in edoxaban users: Evidence from a territory-wide observational cohort study. Clin Cardiol. 2021;44:886–889. [PMC free article: PMC8259145] [PubMed: 33590891]

  (Among 1213 patients with atrial fibrillation started on edoxaban between 2016 and 2020 and followed in the Hong Kong Clinical Database and Reporting System, 19 [1.5%] developed evidence of liver injury, a rate below that previously reported for warfarin [3.7%], apixaban [2.5%], and rivaroxaban [2.1%]).
• De Caterina R, Kim YH, Koretsune Y, Wang CC, Yamashita T, Chen C, Reimitz PE, et al. Safety and effectiveness of edoxaban in atrial fibrillation patients in routine clinical practice: one-year follow-up from the Global Noninterventional ETNA-AF Program. J Clin Med. 2021;10:573. [PMC free article: PMC7913627] [PubMed: 33546442]

  (Among 26,823 adults from Europe and Asia with atrial fibrillation enrolled in a postmarketing study of edoxaban, major complications were uncommon including annualized event rates of major bleeding episodes of 1.1%, strokes of 1.1%, cardiovascular mortality in 1.2% and all-cause mortality in 3%; rates of liver injury were not provided).
• Ma J, Chalasani NP, Schwantes-An L, Björnsson ES. Review article: the safety of anticoagulants and antiplatelet agents in patients with cirrhosis. Aliment Pharmacol Ther. 2023;57:52–71. [PubMed: 36373544]

  (Review of the safety of anticoagulant use in patients with cirrhosis mentions that drug induced liver injury is uncommon in patients with preexisting cirrhosis, at least in those with compensated [Child’s Class A] or mildly compensated [Child’s Class B] cirrhosis).