Journal of Thrombosis and Thrombolysis

, Volume 45, Issue 4, pp 543–549 | Cite as

Direct-acting oral anticoagulant drug level monitoring in clinical patient management

  • Amihai Rottenstreich
  • Netanel Zacks
  • Geffen Kleinstern
  • Bruria Hirsh Raccah
  • Batia Roth
  • Nael Da’as
  • Yosef Kalish


The role of drug-level monitoring among patients using direct-acting oral anticoagulant (DOAC) is unclear. We aimed to investigate its ‘real-life’ utilization and effect on clinical management. A review of records of patients who underwent DOAC level testing during 2013–2017. Overall, 212 patients (median age 77 years) underwent 292 DOAC measurements [apixaban (n = 147), rivaroxaban (n = 102), dabigatran (n = 43)]. Monitoring volume increased by 460% during study period. DOAC level testing was performed during routine follow-up in 51 (17.5%) cases, whereas the remaining 241 (82.5%) measurements were performed due to selected clinical circumstances, most commonly: bleeding (n = 60), perioperative status (n = 45), breakthrough thrombosis (n = 37) and renal failure (n = 35). Drug levels were within the expected range in 210 (71.9%), above the expected range in 62 (21.2%) and lower than expected range in 20 (6.8%). In multivariate analysis, older age (P = 0.005), lower glomerular filtration rate (P = 0.001) and lower body mass index (P = 0.006) were associated with DOAC levels above the expected range. Clinical decisions were affected by DOAC monitoring following most (140/241, 58.1%) measurements for which we identified an indication for testing; yet only rarely when monitoring was performed during routine follow-up (7.8%, 4/51) (P < 0.0001). While no benefit of routine DOAC monitoring was observed, drug level measurement has an important role in the management of patients in selected circumstances. Age, body weight and creatinine clearance were found to be significant predictors of drug levels. Future studies are warranted to establish associations between drug levels and outcomes, and better delineate the role of DOAC monitoring.


Monitoring Direct-acting oral anticoagulants Drug levels Real life Management 



Body mass index


Direct acting oral anticoagulant


Estimated glomerular filtration rate



Netanel Zacks’s participation in this study was performed in fulfillment of research requirements toward the MD degree. We thank Ms. Cindy Cohen for her editorial assistance.

Author's Contributions

All authors-study concept, design, review and approval of the final manuscript. AR, NZ, BHR, GK, BR and YK reviewed the literature and wrote the paper. Authors AR, YK, ND and NZ collected the data.


No external funding was used in this conduct of this study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ehical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the local institutional review board of Hadassah Medical Center Helsinki Committee (IRB approval number No. HMO 0126-17).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11239_2018_1643_MOESM1_ESM.doc (40 kb)
Supplementary material 1 (DOC 40 KB)


  1. 1.
    Chan NC, Eikelboom JW, Weitz JI (2016) Evolving treatments for arterial and venous thrombosis: role of the direct oral anticoagulants. Circ Res 118(9):1409–1424CrossRefPubMedGoogle Scholar
  2. 2.
    Bauer KA (2013) Pros and cons of new oral anticoagulants. Hematol Am Soc Hematol Educ Progr Google Scholar
  3. 3.
    Desmaele S, Steurbaut S, Cornu P, Brouns R, Dupont AG (2016) Clinical trials with direct oral anticoagulants for stroke prevention in atrial fibrillation: how representative are they for real life patients? Eur J Clin Pharmacol 72(9):1125–1134CrossRefPubMedGoogle Scholar
  4. 4.
    Hagg L, Johansson C, Jansson JH, Johansson L (2014) External validity of the ARISTOTLE trial in real-life atrial fibrillation patients. Cardiovasc Ther 32(5):214–218CrossRefPubMedGoogle Scholar
  5. 5.
    Amiral J, Dunois C, Amiral C, Seghatchian J (2016) Anti-Xa bioassays for the laboratory measurement of direct factor Xa inhibitors in plasma, in selected patients. Transfus Apher Sci 55:249–261CrossRefPubMedGoogle Scholar
  6. 6.
    Baglin T, Hillarp A, Tripodi A, Elalamy I, Buller H, Ageno W (2013) Measuring oral direct inhibitors of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 11:756–760CrossRefGoogle Scholar
  7. 7.
    Tripodi A (2016) To measure or not to measure direct oral anticoagulants before surgery or invasive procedures. J Thromb Haemost 14:1325–1327CrossRefPubMedGoogle Scholar
  8. 8.
    Rottenstreich A, Barkai A, Arad A, Raccah BH, Kalish Y (2017) The effect of bariatric surgery on direct-acting oral anticoagulant drug levels. Thromb Res. Google Scholar
  9. 9.
    Testa S, Legnani C, Tripodi A et al (2016) Poor comparability of coagulation screening test with specific measurement in patients receiving direct oral anticoagulants: results from a multicenter/multiplatform study. J Thromb Haemost 14:2194–2201CrossRefPubMedGoogle Scholar
  10. 10.
    European Medicines Agency (2016) Summary of product characteristics: Eliquis Accessed 18 Nov 2017
  11. 11.
    Mueck W, Lensing AW, Agnelli G et al (2011) Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 50:675–686CrossRefPubMedGoogle Scholar
  12. 12.
    Mueck W, Borris LC, Dahl OE et al (2008) Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 100:453–461CrossRefPubMedGoogle Scholar
  13. 13.
    Mueck W, Stampfuss J, Kubitza D et al (2014) Clinical pharmacokinetic and pharmacodynamics profile of rivaroxaban. Clin Pharmacokinet 53(1):1–16CrossRefPubMedGoogle Scholar
  14. 14.
    Reilly PA, Lehr T, Haertter S et al (2014) The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 63:321–328CrossRefPubMedGoogle Scholar
  15. 15.
    Ezekowitz MD, Reilly PA, Nehmiz G et al (2007) Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 100:1419–1426CrossRefPubMedGoogle Scholar
  16. 16.
    Ruff CT, Giugliano RP, Braunwald E et al (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(9984):2288–2295CrossRefPubMedGoogle Scholar
  17. 17.
    Granger CB, Alexander JH, McMurray JJ et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992CrossRefPubMedGoogle Scholar
  18. 18.
    Patel MR, Mahaffey KW, Garg J et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891CrossRefPubMedGoogle Scholar
  19. 19.
    Connolly SJ, Ezekowitz MD, Yusuf S et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151CrossRefPubMedGoogle Scholar
  20. 20.
    FDA Advisory Committee Briefing Document (2009) Cardiovascular and Renal Drugs Advisory Committee, March 19, 2009. Accessed 30 Nov 2017
  21. 21.
    Frost CE, Song Y, Shenker A et al (2015) Effects of age and sex on the single-dose pharmacokinetics and pharmacodynamics of apixaban. Clin Pharmacokinet 54(6):651–662CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Halvorsen S, Atar D, Yang H et al (2014) Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 35(28):1864–1872CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    European Medicines Agency (2016) Summary of product characteristics: Xarelto. Accessed 18 Nov 2017
  24. 24.
    European Medicines Agency (2016) Summary of product characteristics: Pradaxa. Accessed 18 Nov 2017
  25. 25.
    Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S (2016) Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 14:1308–1313CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chan KE, Giugliano RP, Patel MR et al (2016) Nonvitamin K anticoagulant agents in patients with advanced chronic kidney disease or on dialysis with AF. J Am Coll Cardiol 67:2888–2899CrossRefPubMedGoogle Scholar
  27. 27.
    Tripodi A (2015) The laboratory and the direct oral anticoagulants. Blood 121:4032–4036CrossRefGoogle Scholar
  28. 28.
    Yates SG, Smith S, Tharpe W, Shen YM, Sarode R (2016) Can an anti-Xa assay for low-molecular-weight heparin be used to assess the presence of rivaroxaban? Transfus Apher Sci 55:212–215CrossRefPubMedGoogle Scholar
  29. 29.
    Beyer J, Trujillo T, Fisher S, Ko A, Lind SE, Kiser TH (2016) Evaluation of a heparin-calibrated antifactor Xa assay for measuring the anticoagulant effect of oral direct Xa inhibitors. Clin Appl Thromb Hemost 22:423–428CrossRefPubMedGoogle Scholar
  30. 30.
    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 155:121–127CrossRefPubMedGoogle Scholar
  31. 31.
    Becker RC, Yang H, Barrett Y et al (2011) Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban—an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis 32:183–187CrossRefPubMedGoogle Scholar
  32. 32.
    Douxfils J, Dogne JM, Mullier F et al (2013) Comparison of calibrated dilute thrombin time and aPTT tests with LC–MS/MS for the therapeutic monitoring of patients treated with dabigatran etexilate. Thromb Haemost 110:543–549CrossRefPubMedGoogle Scholar
  33. 33.
    Douxfils J, Tamigniau A, Chatelain B et al (2013) Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC–MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 110:723–731CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Hematology DepartmentHadassah-Hebrew University Medical CenterJerusalemIsrael
  2. 2.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  3. 3.Department of CardiologyHadassah University HospitalJerusalemIsrael
  4. 4.Division of Clinical Pharmacy, Faculty of Medicine, School of Pharmacy, Institute for Drug ResearchHebrew University of JerusalemJerusalemIsrael
  5. 5.Internal Medicine Division, Hematology UnitShaare Zedek Medical CenterJerusalemIsrael

Personalised recommendations