Real-time detection and differentiation of direct oral anticoagulants (rivaroxaban and dabigatran) using modified thromboelastometric reagents

Simon Thomas Schäfer; Tobias Wiederkehr; Tobias Kammerer; Alice-Christin Acevedo; Katharina Feil; Lars Kellert; Klaus Görlinger; Ludwig Christian Hinske; Philipp Groene

doi:10.1016/j.thromres.2020.04.019

Real-time detection and differentiation of direct oral anticoagulants (rivaroxaban and dabigatran) using modified thromboelastometric reagents

Thromb Res. 2020 Jun:190:103-111. doi: 10.1016/j.thromres.2020.04.019. Epub 2020 Apr 18.

Authors

Simon Thomas Schäfer¹, Tobias Wiederkehr¹, Tobias Kammerer², Alice-Christin Acevedo¹, Katharina Feil³, Lars Kellert³, Klaus Görlinger⁴, Ludwig Christian Hinske¹, Philipp Groene⁵

Affiliations

¹ Department of Anaesthesiology, University Hospital, LMU Munich, Germany.
² Department of Anaesthesiology, University Hospital, LMU Munich, Germany; Institute of Anaesthesiology, Heart and Diabetes Centre NRW, Ruhr University Bochum, Germany.
³ Department of Neurology, University Hospital, LMU Munich, Germany.
⁴ TEM Innovations, Munich, Germany.
⁵ Department of Anaesthesiology, University Hospital, LMU Munich, Germany. Electronic address: philipp.groene@med.uni-muenchen.de.

PMID: 32335421
DOI: 10.1016/j.thromres.2020.04.019

Abstract

Introduction: Timely measurement of direct oral anticoagulants (DOACs) is challenging, though clinically important. We tested the hypotheses, that thromboelastometry is able to detect dabigatran and rivaroxaban and discriminates between dabigatran and rivaroxaban as representatives of the two groups of DOACs.

Methods and materials: We conducted a prospective-observational study: In-vitro dose-effect-curves for rivaroxaban and dabigatran were performed (n = 10). Ex-vivo: Patients with indication of DOAC treatment (stroke; dabigatran/rivaroxaban) were included (n = 21). Blood samples were analyzed before first intake, at first estimated peak level and at 24 h after first but before following intake and 3 h after 24 h-intake. Standard and modified thromboelastometric-assays, using low tissue factor concentrations (TFTEM) or ecarin (ECATEM) were used. Receiver-operating-characteristics-curve-analysis (ROC), regression-analysis and two-way-ANOVA were performed.

Results: In-vitro: TFTEM detected dabigatran and rivaroxaban (ROC_AUC: 0.99; sensitivity/specificity: 100%/98%) but could not discriminate. Dabigatran prolongs CT_ECATEM whereas rivaroxaban did not. Clotting Time (CT)-ratio TFTEM/ECATEM discriminated highly sensitive (100%) and specific (100%) between dabigatran and rivaroxaban even at very low concentrations (ROC_AUC:1.0). CT_ECATEM correlated with dabigatran spiked concentrations (r = 0.9985; p < 0.001) and CT_TFTEM (r = 0.9363; p = 0.006) with rivaroxaban. Similarly results could be demonstrated with patient data: We confirmed the performance for the differentiation of CT-ratio TFTEM/ECATEM (sensitivity 100%/specificity 100%) at any time after first intake of either DOAC.

Conclusion: The thromboelastometric tests TFTEM and ECATEM detect and differentiate rivaroxaban and dabigatran. Further investigations evaluate the other DOACs and the differentiation to phenprocoumon. However, results need to be confirmed in a larger study, and especially cut off values for differentiation need to be calculated from a larger sample size.

Keywords: Dabigatran; Direct oral anticoagulants; Rivaroxaban; Thromboelastometry.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Anticoagulants / pharmacology
Anticoagulants / therapeutic use
Dabigatran* / pharmacology
Dabigatran* / therapeutic use
Humans
Indicators and Reagents
Prospective Studies
Pyrazoles
Pyridones
Rivaroxaban* / pharmacology
Rivaroxaban* / therapeutic use
Thrombelastography

Substances

Anticoagulants
Indicators and Reagents
Pyrazoles
Pyridones
Rivaroxaban
Dabigatran