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Monitoring of low dabigatran concentrations: diagnostic performance at clinically relevant decision thresholds

  • Florian Härtig
  • Sven PoliEmail author
  • Matthias Ebner
  • Ingvild Birschmann
  • Joachim Kuhn
  • Ulf Ziemann
  • Hans-Ulrich Häring
  • Rainer Lehmann
  • Andreas Peter
  • Sebastian Hörber
Article

Abstract

The direct oral anticoagulant dabigatran does not require therapeutic drug monitoring, however emergency measurements are gaining importance. Current assays feature good performance at intermediate and high dabigatran concentrations but show limited accuracy at low concentrations. This area requires more attention as clinical decision threshold values currently lie at 30 and 50 ng/ml. The objective of the study was to evaluate and compare diagnostic performance of dabigatran assays at these thresholds. Dabigatran concentrations of 293 plasma samples taken from 50 patients were measured with the INNOVANCE direct thrombin inhibitor assay (DTI) from Siemens, the Biophen direct thrombin inhibitor assay (BDTI), the BDTI using a low range calibrator (BDTI-low), the Hemoclot direct thrombin inhibitor assay (HTI) and an ecarin clotting time assay (ECT). Assay results were compared to ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and test characteristics were calculated for thresholds of 30 and 50 ng/ml. DTI, BDTI-low and ECT showed very strong correlation and high agreement with UPLC-MS/MS and an improved determination of low dabigatran concentrations. ROC curve analyses revealed very high accuracy at the 30/50 ng/ml thresholds for DTI (AUC = 0.989/0.995), BDTI-low (AUC = 0.980/0.991) and ECT (AUC = 0.990/0.996) measurements. Sensitivity and specificity in detecting were calculated for DTI (98/92%), BDTI-low (87/95%), ECT (97/96%), BDTI (99/82%) and HTI (86/89%) measurements. Compared to the previously available HTI and BDTI, both novel assays, DTI and BDTI-low, reliably determine low dabigatran plasma concentrations around the clinical decision thresholds with very high sensitivity and specificity.

Keywords

Dabigatran Direct thrombin inhibitor assays Monitoring Emergency situations Thresholds 

Notes

Acknowledgments

We thank S. Faix and I. Riedlinger from the University Hospital Tübingen for excellent technical assistance and all the participants that contributed in this study.

Author contributions

SP, ME and FH designed the study. IB, JK, AP and SH conducted all laboratory-based tests and UPLC-MS/MS. FH, SP, AP and SH analyzed and interpreted the data and wrote the manuscript. UZ, RL and HUH reviewed the data and supervised the preparation of the manuscript. All authors have reviewed and approved the final version of the manuscript.

Compliance with ethical standards

Conflict of interest

SP received speaker’s honoraria and consulting honoraria from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo and Werfen, reimbursement for congress traveling and accommodation from Bayer and Boehringer-Ingelheim, and research support from Bristol-Myers Squibb/Pfizer (significant), Boehringer-Ingelheim, Daiichi Sankyo (significant) and Helena Laboratories (all other contributions: modest). ME and FH received reimbursement for congress traveling and accommodation from Bayer (contributions: modest). IB received speaker’s honoraria from Aspen Germany GmbH, Bristol-Myers Squibb/Pfizer, Siemens Healthcare and CSL Behring and reimbursement for congress traveling and accommodation from Aspen and Bristol-Myers Squibb and performed contract research for Siemens Healthcare. IB is a member of the advisory board of LFB biomedicaments. UZ received personal fees from Biogen Idec GmbH, Bayer Vital GmbH, Bristol-Myers Squibb/Pfizer, CorTec GmbH, Medtronic GmbH, and grants from Biogen Idec GmbH, Servier, and Janssen Pharmaceuticals NV, outside of the submitted work (all contributions: modest). AP received speaker’s honoraria unrelated to the topic of this manuscript from Siemens Healthineers (modest) and research support unrelated to the topic of this manuscript from Siemens Healthineers (modest) and Boehringer-Ingelheim (significant). The remaining authors have disclosed that they do not have any conflicts of interest.

Ethical approval

Institutional review board approval was obtained from the ethics committee at the University Hospital Tübingen (Protocol Number 259/2013BO1 and 270/2015B01). All studies were performed in accordance with the ethical standards of the Declaration of Helsinki.

Informed consent

Written informed consent was obtained from all participants at the beginning of the study.

Supplementary material

11239_2019_1981_MOESM1_ESM.docx (22 kb)
Supplementary material 1 (DOCX 20.6 kb)
11239_2019_1981_MOESM2_ESM.tif (598 kb)
Supplementary material 2 (TIF 597.6 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Florian Härtig
    • 1
  • Sven Poli
    • 1
    Email author
  • Matthias Ebner
    • 2
  • Ingvild Birschmann
    • 3
  • Joachim Kuhn
    • 3
  • Ulf Ziemann
    • 1
  • Hans-Ulrich Häring
    • 4
    • 5
  • Rainer Lehmann
    • 4
    • 5
    • 6
  • Andreas Peter
    • 4
    • 5
    • 6
  • Sebastian Hörber
    • 4
    • 5
    • 6
  1. 1.Department of Neurology & Stroke, and Hertie Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
  2. 2.Department of Internal Medicine and CardiologyCharité University Medicine Berlin – Campus Virchow KlinikumBerlinGermany
  3. 3.Institute for Laboratory and Transfusion Medicine, Heart and Diabetes CenterRuhr UniversityBochumGermany
  4. 4.Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of TübingenTübingenGermany
  5. 5.German Center for Diabetes Research (DZD)München-NeuherbergGermany
  6. 6.Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and PathobiochemistryUniversity Hospital TübingenTübingenGermany

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