Advertisement

Heart and Vessels

, Volume 34, Issue 12, pp 2011–2020 | Cite as

Responses of prothrombin time and activated partial thromboplastin time to edoxaban in Japanese patients with non-valvular atrial fibrillation: characteristics of representative reagents in Japan (CVI ARO 7)

  • Shinya SuzukiEmail author
  • Yoshiyuki Morishima
  • Atsushi Takita
  • Naoharu Yagi
  • Takayuki Otsuka
  • Takuto Arita
  • Takeshi Yamashita
Original Article

Abstract

The aims of this study were to determine the distribution of plasma concentration of edoxaban (PC-Ed) with their 90% interval (on therapy range) and its correlation with anticoagulation markers in patients with non-valvular atrial fibrillation (NVAF). Consecutive 97 NVAF patients under edoxaban therapy were evaluated (60/30 mg dose, n = 48/49; men/women, n = 71/26; age, 69 years). CHADS2 score 0, 1, and ≥ 2 were 27%, 44%, and 29%, respectively. The mean (90% interval) of PC-Ed by LC–MS/MS was 194.3 (49.4–345.3) and 17.0 (4.8–40.7) ng/mL at peak (2–4 h post-dose) and trough (pre-dose), respectively. Correlation of prothrombin time (PT) with PC-Ed was higher than that of activated partial thromboplastin time (aPTT). Among 6 PT reagents, Coagupia PT–N and Simplastin Excel S (both PT reagents) showed the highest predictive capability for the upper outlier of PC-Ed at peak and trough. Among 4 aPTT reagents, only Thrombocheck APTT measured at peak had a significant predictive capability. When using PT reagents, both peak and trough sampling showed a similar predictive capability for the upper outliers of PC-Ed with a high sensitivity, but a relatively low specificity. We demonstrated the distributions of plasma concentration, PT with 6 reagents, and aPTT with 4 reagents under edoxaban therapy in Japanese patients with NVAF, showing their 90% intervals. For predicting the upper outlier of PC-Ed, PT was more sensitive compared with aPTT, whereas predicting capability for the outliers of PC-Ed was mostly similar between peak and trough samplings among PT reagents (UMIN 000032492).

Keywords

Atrial fibrillation Anticoagulation Edoxaban 

Notes

Compliance with ethical standards

Conflict of interest

This work was financially supported by Daiichi Sankyo. Dr. Suzuki received research funding from Daiichi Sankyo and Mitsubishi-Tanabe. Dr. Yamashita received research funding from Boehringer Ingelheim and Daiichi Sankyo, and remuneration from Boehringer Ingelheim, Daiichi Sankyo, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Eisai and Ono Pharmaceutical. Dr. Morishima and Mr. Takita are employees of Daiichi Sankyo. The management of this work was supported by Cardiovascular Institute Academic Research Organization (CVI ARO) [25, 26, 27, 28, 29, 30, 31, 32, 33, 34].

References

  1. 1.
    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
  2. 2.
    Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF, Deenadayalu N, Jarolim P, Betcher J, Shi M, Brown K, Patel I, Mercuri M, Antman EM (2015) Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 385:2288–2295CrossRefGoogle Scholar
  3. 3.
    Cuker A, Husseinzadeh H (2015) Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis 39:288–294CrossRefGoogle Scholar
  4. 4.
    Douxfils J, Chatelain B, Chatelain C, Dogne JM, Mullier F (2016) Edoxaban: Impact on routine and specific coagulation assays. A practical laboratory guide. Thromb Haemost 115:368–381PubMedGoogle Scholar
  5. 5.
    Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Haeusler KG, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Collins R, Camm AJ, Heidbuchel H, ESC Scientific Document Group (2018) The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 39:1330–1393CrossRefGoogle Scholar
  6. 6.
    Cuker A (2016) Laboratory measurement of the non-vitamin K antagonist oral anticoagulants: selecting the optimal assay based on drug, assay availability, and clinical indication. J Thromb Thrombolysis 41:241–247CrossRefGoogle Scholar
  7. 7.
    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:e77–82CrossRefGoogle Scholar
  8. 8.
    Morishima Y, Kamisato C (2015) Laboratory measurements of the oral direct factor Xa inhibitor edoxaban: comparison of prothrombin time, activated partial thromboplastin time, and thrombin generation assay. Am J Clin Pathol 143:241–247CrossRefGoogle Scholar
  9. 9.
    Testa S, Dellanoce C, Paoletti O, Cancellieri E, Morandini R, Tala M, Zambelli S, Legnani C (2019) Edoxaban plasma levels in patients with non-valvular atrial fibrillation: Inter and intra-individual variability, correlation with coagulation screening test and renal function. Thromb Res 175:61–67CrossRefGoogle Scholar
  10. 10.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41CrossRefGoogle Scholar
  11. 11.
    Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J (2012) Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos 40:2250–2255CrossRefGoogle Scholar
  12. 12.
    Kodani E, Okumura K, Inoue H, Yamashita T, Atarashi H, Origasa H (2011) Present status and problems of international sensitivity index (ISI) on the measurement of international normalized ratio of prothrombin time (INR). Jpn J Electrocardiol 31:225–233 (Japanese) CrossRefGoogle Scholar
  13. 13.
    Metz CE (1986) ROC methodology in radiologic imaging. Invest Radiol 21:720–733CrossRefGoogle Scholar
  14. 14.
    Youden WJ (1950) Index for rating diagnostic tests. Cancer 3:32–35CrossRefGoogle Scholar
  15. 15.
    Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M (2015) Short-term safety and plasma concentrations of edoxaban in japanese patients with non-valvular atrial fibrillation and severe renal impairment. Circ J 79:1486–1495CrossRefGoogle Scholar
  16. 16.
    Song S, Kang D, Halim AB, Miller R (2014) Population pharmacokinetic-pharmacodynamic modeling analysis of intrinsic FXa and bleeding from edoxaban treatment. J Clin Pharmacol 54:910–916CrossRefGoogle Scholar
  17. 17.
    Yin OQ, Miller R (2014) Population pharmacokinetics and dose-exposure proportionality of edoxaban in healthy volunteers. Clin Drug Investig 34:743–752CrossRefGoogle Scholar
  18. 18.
    Yin OQ, Tetsuya K, Miller R (2014) Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation. Eur J Clin Pharmacol 70:1339–1351CrossRefGoogle Scholar
  19. 19.
    Jonsson S, Simonsson US, Miller R, Karlsson MO (2015) Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study. J Clin Pharmacol 55:1268–1279CrossRefGoogle Scholar
  20. 20.
    Parasrampuria DA, Truitt KE (2016) Pharmacokinetics and pharmacodynamics of edoxaban, a non-vitamin K antagonist oral anticoagulant that inhibits clotting factor Xa. Clin Pharmacokinet 55:641–655CrossRefGoogle Scholar
  21. 21.
    Shimizu T, Tachibana M, Kimura T, Kumakura T, Yoshihara K (2017) Population pharmacokinetics of edoxaban in Japanese atrial fibrillation patients with severe renal impairment. Clin Pharmacol Drug Dev 6:484–491CrossRefGoogle Scholar
  22. 22.
    Al-Aieshy F, Malmstrom RE, Antovic J, Pohanka A, Ronquist-Nii Y, Berndtsson M, Al-Khalili F, Skeppholm M (2016) Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation. Eur J Clin Pharmacol 72:671–679CrossRefGoogle Scholar
  23. 23.
    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 104:633–641CrossRefGoogle Scholar
  24. 24.
    He L, Kochan J, Lin M, Vandell A, Brown K, Depasse F (2017) Determination of edoxaban equivalent concentrations in human plasma by an automated anti-factor Xa chromogenic assay. Thromb Res 155:121–127CrossRefGoogle Scholar
  25. 25.
    J-ELD AF study investigators. Investigation on Efficacy and Safety of Apixaban in Japanese Elderly Patients: Investigator-Initiated Multicenter Prospective Cohort Study (J-ELD AF [CVI ARO 5] Study) [UMIN000017895]. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000020733. Accessed 15 May 2019
  26. 26.
    Akao M, Yamashita T, Okumura K, Investigators J-ELDAF (2016) Study design of J-ELD AF: a multicenter prospective cohort study to investigate the efficacy and safety of apixaban in Japanese elderly patients. J Cardiol 68:554–558CrossRefGoogle Scholar
  27. 27.
    CVI ARO 1 investigators. An analysis on distribution and inter-relationships of biomarkers under rivaroxaban in Japanese patients with non-valvular atrial fibrillation (CVI ARO 1 study) [UMIN000016424]. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000019074. Accessed 15 May 2019
  28. 28.
    Suzuki S, Yamashita T, Kasai H, Otsuka T, Sagara K (2017) Response of prothrombin time to rivaroxaban in Japanese patients with non-valvular atrial fibrillation: Characteristics of 5 representative reagents in Japan (CVI ARO 1). Thromb Res 150:73–75CrossRefGoogle Scholar
  29. 29.
    Suzuki S, Yamashita T, Kasai H, Otsuka T, Sagara K (2018) An analysis on distribution and inter-relationships of biomarkers under rivaroxaban in Japanese patients with non-valvular atrial fibrillation (CVI ARO 1). Drug Metab Pharmacokinet 33:188–193CrossRefGoogle Scholar
  30. 30.
    R-mark study investigators. An analysis on validity of distribution of biomarkers, exploration of correlation between biomarker outliers and adverse events under rivaroxaban in Japanese patients with non-valvular atrial fibrillation (R-mark [CVI ARO 2] study) [UMIN000022721]. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024525. Accessed 15 May 2019
  31. 31.
    CVI ARO 9 investigators. The effect of landiolol on rehospitalization for heart failure in patients with acute heart failure and atrial fibrillation (CVI ARO 9 study) [UMIN000020290]. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000020641. Accessed 15 May 2019
  32. 32.
    CVI ARO 3 investigators. An analysis on validity of monitoring by wristwatch-type sphygmograph in detecting of atrial fibrillation (CVI ARO 3a study) [UMIN000022722]. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025921. Accessed 15 May 2019
  33. 33.
    CVI ARO 3 investigators. An analysis on usefulness of monitoring by wristwatch-type sphygmograph in evaluation of recurrence of atrial fibrillation after catheter ablation (CVI ARO 3b study) [UMIN000022723]. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025937. Accessed 15 May 2019
  34. 34.
    CVI ARO 3 investigators. A pilot study of detection of asymptomatic atrial fibrillation using wristwatch-type sphygmograph among patients with sinus rhythm and high CHADS2 score (CVI ARO 3c study) [UMIN000022724]. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025940. Accessed 15 May 2019

Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cardiovascular MedicineThe Cardiovascular InstituteTokyoJapan
  2. 2.Medical Science DepartmentDaiichi Sankyo Co., LtdTokyoJapan
  3. 3.Safety and Risk Management DepartmentDaiichi Sankyo Co., LtdTokyoJapan

Personalised recommendations