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CC BY 4.0 · Thromb Haemost 2025; 125(06): 563-573
DOI: 10.1055/a-2446-1348
Stroke, Systemic or Venous Thromboembolism

Usual On-therapy Ranges of Drug Concentrations in Patients with Atrial Fibrillation Treated with Direct Oral Anticoagulants: A Systematic Review and Meta-analysis

Autoren

  • Tim A.C. de Vries    *

    1   Department of Clinical and Experimental Cardiology and Cardiothoracic Surgery, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
    2   Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, The Netherlands
    3   Department of Cardiology, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, The Netherlands
    4   Department of Cardiology, Rijnstate Hospital, Arnhem, The Netherlands

  • Imaad U. Mallick    *

    5   School of Medicine, St. George's University, Grenada, West Indies
    6   Division of Hematology and Thromboembolism, Department of Medicine, Population Health Research Institute, Hamilton, Ontario, Canada

  • Vinai C. Bhagirath

    6   Division of Hematology and Thromboembolism, Department of Medicine, Population Health Research Institute, Hamilton, Ontario, Canada
    7   Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
    8   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

  • John W. Eikelboom

    6   Division of Hematology and Thromboembolism, Department of Medicine, Population Health Research Institute, Hamilton, Ontario, Canada
    7   Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
    8   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

  • Calvin Gomes

    9   School of Medicine, Poznan University of Medical Sciences, Poznan, Poland

  • Qilong Yi

    10   School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada

  • Sean McGrath 

    11   Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States

  • Jack Hirsh

    7   Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada

  • Noel C. Chan 

    6   Division of Hematology and Thromboembolism, Department of Medicine, Population Health Research Institute, Hamilton, Ontario, Canada
    7   Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
    8   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

Funding N.C.C. is supported by a Heart and Stroke of Canada New Investigator Award. S.M. was supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE2140743. None of the other authors or their institutions have received funding for this project.
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Graphical Abstract

Abstract

Background

Although most patients with atrial fibrillation (AF) receiving a direct oral anticoagulant (DOAC) do not require drug concentration measurements, there are situations where such information could be useful. Existing guidance documents provide usual on-therapy ranges for drug concentrations, but these have important limitations.

Methods

This is a systematic review and meta-analysis of studies reporting trough and peak levels of DOAC regimens approved for stroke prevention in AF. We used random effects models and the quantile estimation method to estimate the median and a usual on-therapy range (10th and 90th percentiles).

Results

Of 4,822 unique publications, 53 studies met eligibility (29,266 trough and 12,103 peak levels). Usual on-therapy ranges for trough levels were 38 to 155 and 58 to 206 ng/mL for apixaban 2.5 and 5 mg twice daily; 35 to 138 and 33 to 151 ng/mL for dabigatran 110 and 150 mg twice daily; 8 to 54 and 13 to 66 ng/mL for edoxaban 30 and 60 mg daily; and 16 to 74 and 19 to 72 ng/mL for rivaroxaban 15 and 20 mg daily. The corresponding range for peak levels were 96 to 251 and 132 to 343; 65 to 223 and 76 to 285; 57 to 219 and 127 to 407; 131 to 384, and 169 to 313 ng/mL, respectively.

Conclusion

This systematic review and meta-analysis provides updated and more representative usual on-therapy ranges of DOAC levels in patients with AF.

Keywords

direct oral anticoagulant - blood coagulation tests - drug monitoring - biological variation - population - factor Xa inhibitors - anticoagulants - hemorrhage

Data Availability Statement

The data underlying this article are provided in [Supporting Information File 6] [available in the online version] and the other Supporting Information Files. The R-syntax underlying this paper will be shared on reasonable request to the corresponding author.


Authors' Contribution

T.A.C.dV., I.U.M., J.H., V.C.B., J.W.E., Q.Y., and N.C.C. have contributed to the concept and design of the study. The protocol including its statistical analysis plan were developed by T.A.C.dV., I.U.M., J.H., V.C.B., J.W.E., N.C.C., and then revised by T.A.C.dV., N.C.C., Q.Y., and S.M. The study was coordinated by T.A.C.dV., I.U.M., and N.C.C. The search strategy was developed by I.U.M., C.G., and N.C.C. I.U.M tailored the search strategy, performed the literature searches, and extracted all data together with C.G. T.A.C.dV., N.C.C., V.C.B., and J.W.E. performed the risk of bias and indirectness assessments and T.A.C.dV. and N.C.C. all other quality assessments. Q.Y. performed all analysis to simulate nonreported values, and T.A.C.dV. all analyses hereafter with support from S.M. T.A.C.dV., I.U.M., J.H., and N.C.C. wrote the initial draft and first subsequent iterations. All the other authors reviewed the drafts, provided critical comments, and revised the initial draft to produce the final manuscript.


* These authors contributed as co-first authors.


Supplementary Material



Publikationsverlauf

Eingereicht: 16. März 2024

Angenommen: 12. Oktober 2024

Artikel online veröffentlicht:
21. November 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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