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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(04): 552-559
DOI: 10.1055/a-1549-6556
New Technologies, Diagnostic Tools and Drugs

Pharmacokinetics of Direct Oral Anticoagulants in Emergency Situations: Results of the Prospective Observational RADOA-Registry

Edelgard Lindhoff-Last‡   *
1   Coagulation Centre at the Cardiology Angiology Centre Bethanien Hospital (CCB), Frankfurt, Germany
2   Coagulation Research Centre Bethanien Hospital, Frankfurt, Germany
,
Ingvild Birschmann‡   *
3   Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Centre, Ruhr University, Bochum, Germany
,
Joachim Kuhn
3   Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Centre, Ruhr University, Bochum, Germany
,
Simone Lindau
4   Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany
,
Stavros Konstantinides 
5   Center for Thrombosis and Haemostasis (CTH), Johannes Gutenberg University, Mainz, Germany
,
Oliver Grottke
6   Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
,
Ulrike Nowak-Göttl
7   Institute of Clinical Chemistry, Thrombosis & Haemostasis Treatment Centre, University Hospital, Kiel-Lübeck, Germany
,
Jessica Lucks
2   Coagulation Research Centre Bethanien Hospital, Frankfurt, Germany
,
Barbara Zydek
2   Coagulation Research Centre Bethanien Hospital, Frankfurt, Germany
,
Christian von Heymann
8   Department of Anaesthesia, Intensive Care Medicine, Emergency Medicine and Pain Therapy, Vivantes Klinikum im Friedrichshain, Berlin, Germany
,
Ariane Sümnig
9   Department of Immunology and Transfusion Medicine, Universitätsmedizin, Greifswald, Germany
,
Jan Beyer-Westendorf
10   Thrombosis Research Unit, Department of Medicine 1, Dresden, Germany
11   Division of Haematology, Dresden University Clinic, Dresden, Germany
12   Department of Haematology and Oncology, Kings College, London, United Kingdom
,
Sebastian Schellong
13   Medical Department 2, Municipal Hospital, Dresden, Germany
,
Patrick Meybohm
4   Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany
14   Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Wuerzburg, Wuerzburg, Germany
,
Andreas Greinacher
9   Department of Immunology and Transfusion Medicine, Universitätsmedizin, Greifswald, Germany
,
Eva Herrmann
15   Institute of Biostatistics and Mathematical Modelling, Goethe University, Frankfurt, Germany
,
On behalf of the RADOA-Registry Investigators (Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists Registry) › Author Affiliations Funding This work was funded by Bayer, Bristol-Myers Squibb/Pfizer, DAIICHI Sankyo, and CSL Behring.
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Abstract

Background Direct oral anticoagulants (DOACs) are increasingly used worldwide. Little is known so far about their pharmacokinetics in emergency situations.

Methods A prospective, observational registry was performed to determine the clinical course in consecutive patients with major bleeding or urgent surgery treated with DOACs. In samples collected as part of routine care DOAC drug concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. Anticoagulant intensity at first presentation and drug half-life (t 1/2), tested in repeat samples, were evaluated.

Results A total of 140 patients were prospectively included. Pharmacokinetic data were available in 94% (132/140) of patients. Note that 67% (89/132) experienced life-threatening bleeding and 33% (43/132) needed an urgent surgery. For pharmacokinetic analysis a total of 605 blood samples was available. Median concentration on admission was 205 ng/mL for rivaroxaban and 108 ng/mL for apixaban. All treatment groups showed a high variation of drug concentrations at baseline. In rivaroxaban-treated patients t ½ was 17.3 hours (95% confidence interval [CI]: 15.4–19.7) without significant difference in both groups (major bleeding: t ½ 16.7 hours, 95% CI: 14.7–19.3; urgent surgery: t ½ 19.7 hours, 95% CI: 15.2–27.9; p = 0.292). In apixaban-treated patients t ½ was 25.0 hours (95% CI: 22.9–27.6) with a longer t ½ after urgent surgery (t 1/2: 30.8 hours; 95% CI: 26.9–36.4) compared with severe bleeding (t 1/2: 20.8 hours; 95% CI: 18.8–23.2; p < 0.001).

Conclusion Emergency patients under DOAC treatment show a high variation of anticoagulant concentrations at baseline. Compared with rivaroxaban, apixaban showed a lower median concentration on admission and a longer t ½.

Keywords

direct oral anticoagulants - pharmacokinetics - emergency - major bleeding - urgent surgery

Author Contributions

E.L.-L. was responsible for the conceptualization and the methodology of the RADOA-registry, organized funding acquisition, and wrote the original draft preparation. I.B. performed the mass spectrometry analysis of the DOAC-levels and reviewed major parts of the manuscript. J.K. performed the mass spectrometry analysis of the DOAC-levels. S.L., S.K., O.G., U.N.-G., B.Z., C.v.H., I.B., A.S., J.B.-W., S.S., P.M., and A.G. recruited patients and supported the writing of the manuscript. J.L. and B.Z. were responsible for the project administration. E.H. performed the statistical analysis and was responsible for the validation and visualization of the results. All the authors have read and agreed to the published version of the manuscript.


Institutional Review Board Statements

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Boards of all participating hospitals. For informed consent statements see Ethics as part of the Material and Methods section of the manuscript. ClinicalTrials.gov Identifier: NCT01722786 (URL: https://clinicaltrials.gov/ct2/show/NCT01722786?term=lindhoff-last&rank=9).


* Both the authors contributed equally to the study.


Supplementary Material



Publication History

Received: 19 March 2021

Accepted: 25 June 2021

Accepted Manuscript online:
13 July 2021

Article published online:
29 September 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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