Advertisement

Journal of Thrombosis and Thrombolysis

, Volume 39, Issue 3, pp 288–294 | Cite as

Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review

  • Adam CukerEmail author
  • Holleh Husseinzadeh
Article

Abstract

Edoxaban, an oral direct inhibitor of factor Xa, was recently approved in the United States and Japan for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for treatment of venous thromboembolism (VTE). It is also licensed in Japan for prevention of VTE after major orthopedic surgery. Although routine laboratory monitoring of edoxaban is not required, laboratory measurement may be desirable in special circumstances. Our objective was to provide a systematic review of current evidence on laboratory measurement of the anticoagulant activity of edoxaban. PubMed and the Cochrane Library were searched for studies that reported a relationship between coagulation tests and plasma edoxaban levels. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). We identified 9 eligible studies. Anti-Xa activity is linear across a broad range of drug levels (R 2 > 0.95) and may be used for edoxaban quantification. The assay shows greater variability at above on-therapy drug concentrations. The PT is less sensitive to edoxaban. A normal prothrombin time may not exclude clinically relevant on-therapy drug levels. The activated partial thromboplastin time has insufficient sensitivity to edoxaban for measurement of its anticoagulant activity. Edoxaban exhibits variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in edoxaban-treated patients. More data on the relationship between drug levels, coagulation test results, and clinical outcomes in patients are needed.

Keywords

Activated partial thromboplastin time (APTT) Anti-Xa Edoxaban Monitoring Prothrombin time (PT) 

Notes

Acknowledgments

This work was supported by HL112903 (National Heart Lung and Blood Institute, Bethesda, MD) to AC.

Conflict of interest

AC has provided consulting services for Bracco and Genzyme, has participated in an advisory board for CSL Behring, and has received research support from Stago and T2 Biosystems. HH has no conflicts to disclose.

References

  1. 1.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM, ENGAGE AF-TIMI 48 Investigators (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369:2093–2104CrossRefPubMedGoogle Scholar
  2. 2.
    Investigators Hokusai-VTE, Büller HR, Décousos H, Grosso MA, Mercuri M, Middledorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369:1406–1415CrossRefGoogle Scholar
  3. 3.
    Matsushima N, Lee F, Sato T, Weiss D, Mendell J (2013) Bioavailability and safety of the factor Xa inhibitor edoxaban and the effects of quinidine in healthy subjects. Clinical Pharm in Drug Dev 2:358–366CrossRefGoogle Scholar
  4. 4.
    Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, Kunitada S (2010) Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 50:743–753CrossRefPubMedGoogle Scholar
  5. 5.
    Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, Kastrissios H, Jin J, Kunitada S (2010) 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 104:633–641CrossRefPubMedGoogle Scholar
  6. 6.
    Chung N, Jeon HK, Lien LM, Lai WT, Tse HF, Chung WS, Lee TH, Chen SA (2010) Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation. Thromb Haemost 105:535–544CrossRefPubMedGoogle Scholar
  7. 7.
    Cuker A, Siegal DM, Crowther MA, Garcia DA (2014) Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 64:1128–1139CrossRefPubMedGoogle Scholar
  8. 8.
    Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM, QUADAS-2 Group (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155:529–536CrossRefPubMedGoogle Scholar
  9. 9.
    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269CrossRefPubMedGoogle Scholar
  10. 10.
    Zafar MU, Vorchheimer DA, Gaztanaga J, Velez M, Yadegar D, Moreno PR, Kunitada S, Pagan J, Fuster V, Badimon JJ (2007) Antithrombotic effects of factor Xa inhibition with DU-176b: phase-I study of an oral, direct factor Xa inhibitor using an ex vivo flow chamber. Thromb Haemost 98:883–888PubMedGoogle Scholar
  11. 11.
    Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T (2008) DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 6:1542–1549PubMedGoogle Scholar
  12. 12.
    Mendell J, Tachibana M, Shi M, Kunitada S (2011) Effects of food on the pharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers. J Clin Pharmacol 51:687–694CrossRefPubMedGoogle Scholar
  13. 13.
    Wolzt M, Samama MM, Kapiotis S, Ogata K, Mendell J, Kunitada S (2011) Effect of edoxaban on markers of coagulation in venous and she blood compared with fondaparinux. Thromb Haemost 105:1080–1090CrossRefPubMedGoogle Scholar
  14. 14.
    Fukada T, Honda Y, Kamisato C, Morishima Y, Shibano T (2012) Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost 107:253–259CrossRefGoogle Scholar
  15. 15.
    Samama MM, Mendell J, Guinet C, Le Flem L, Kunitada S (2012) In vitro study of the anticoagulant effects of edoxaban and its effect on thrombin generation in comparison to fondaparinux. Thromb Res 129:e77–e82CrossRefPubMedGoogle Scholar
  16. 16.
    Mendell J, Noveck RJ, Shi M (2013) A randomized trial of the safety, pharmacokinetics and pharmacodynamics of edoxaban, an oral factor Xa inhibitor, following a switch from warfarin. Br J Clin Pharmacol 75:966–978CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Noguchi K, Morishima Y, Takahashi S, Ishihara H, Shibano T, Murata M (2015) Impact of nonsynonymous mutations of factor X on the functions of factor X and anticoagulant activity of edoxaban. Blood Coagul Fibrinolysis 26:117–122Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Pathology & Laboratory Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Penn Comprehensive Hemophilia and Thrombosis ProgramHospital of the University of PennsylvaniaPhiladelphiaUSA

Personalised recommendations