Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants including edoxaban

Abstract

Background: Direct oral anticoagulants (DOAC) including edoxaban are increasingly used for stroke prevention in atrial fibrillation. Despite treatment, annual stroke rate in these patients remains 1-2%. Rapid assessment of coagulation would be useful to guide thrombolysis or reversal therapy in this growing population of DOAC/edoxaban-treated stroke patients. Employing the Hemochron™ Signature Elite point-of-care test system (HC-POCT), clinically relevant plasma concentrations of dabigatran and rivaroxaban can be excluded in a blood sample. However, no data exists on the effect of edoxaban on HC-POCT results. We evaluated whether edoxaban plasma concentrations above the current treatment thresholds for thrombolysis or anticoagulation reversal (i.e., 30 and 50 ng/mL) can be ruled out with the HC-POCT.

Methods: We prospectively studied patients receiving a first dose of edoxaban. Six blood samples were collected from each patient: before, 0.5, 1, 2, 8, and 24 h after drug intake. HC-POCT-based INR (HC-INR), activated clotting time (HC-ACT+ and HC-ACT-LR), activated partial thromboplastin time (HC-aPTT), and mass spectrometry for edoxaban plasma concentrations were performed at each time-point. We calculated correlations, receiver operating characteristics (ROC) and test-specific cut-offs for ruling out edoxaban concentrations > 30 and > 50 ng/mL in a blood sample.

Results: One hundred twenty blood samples from 20 edoxaban-treated patients were analyzed. Edoxaban plasma concentrations ranged from 0 to 512 ng/mL. HC-INR/HC-ACT+/HC-ACT-LR/HC-aPTT ranged from 0.7-8.3/78-310 s/65-215 s/19-93 s, and Pearson's correlation coefficients showed moderate to very strong correlations with edoxaban concentrations (r = 0.95/0.79/0.70/0.60). With areas under the ROC curve of 0.997 (95% confidence interval: 0.991-0.971) and 0.989 (0.975-1.000), HC-INR most reliably ruled out edoxaban concentrations > 30 and > 50 ng/mL, respectively, and HC-INR results ≤1.5 and ≤ 2.1 provided specificity/sensitivity of 98.6% (91.2-99.9)/98.0% (88.0-99.9) and 96.8% (88.0-99.4)/96.5% (86.8-99.4).

Conclusions: Our study represents the first systematic evaluation of the HC-POCT in edoxaban-treated patients. Applying sufficiently low assay-specific cut-offs, the HC-POCT may not only be used to reliably rule out dabigatran and rivaroxaban, but also very low edoxaban concentrations in a blood sample. Because the assay-specific cut-offs were retrospectively defined, further investigation is warranted.

Trial registration: ClinicalTrials.gov, registration number: NCT02825394 , registered on: 07/07/2016, URL.

Keywords: Anticoagulation reversal; DOAC; Direct oral anticoagulants; NOAC; Non-vitamin K antagonist oral anticoagulants; POCT; Point-of-care testing; Stroke; Thrombolysis.

Conflict of interest statement

Florian Härtig received reimbursement for congress traveling and accommodation from Bayer and Daiichi Sankyo. Ingvild Birschmann received speaker’s honoraria from 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. She is a member of the advisory board of LFB biomedicaments. Ulf Ziemann received has received personal fees from Biogen Idec, Bayer Vital, Bristol-Myers Squibb/Pfizer, CorTec, and grants from Biogen Idec, Janssen Pharmaceutica NV, and Takeda. Sven Poli 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, Boehringer-Ingelheim, Daiichi Sankyo. The remaining authors have declared that they do not have any conflicts of interest.

Figures

Fig. 1

Scatter plots visualizing the correlation of (a) laboratory-based calibrated anti-Xa activity and (b to e) the results of all four Hemochron™ Signature Elite point-of-care test system-based coagulation assays with edoxaban plasma concentrations determined by mass spectrometry. HC-INR, HC-ACT+, HC-ACT-LR, HC-aPTT = Hemochron™ Signature Elite point-of-care test system-based international normalized ratio, activated clotting time, and activated partial thromboplastin time

Fig. 2

Receiver operating characteristics curves found for laboratory-based calibrated anti-Xa activity all four Hemochron™ Signature Elite point-of-care test system-based coagulation assays when testing for ruling out samples containing > 30 ng/mL (solid line) and > 50 ng/mL (dashed line)

Fig. 3

Percentage of edoxaban concentrations up to 30 ng/mL (light gray), > 30 and ≤ 50 ng/mL (dark gray) and > 50 ng/mL (black) found at corresponding laboratory-based calibrated anti-Xa activity and the ‘ideal cut-offs’ for Hemochron™ Signature Elite point-of-care test system-based prothrombin time/INR (HC-INR) and activated clotting time (HC-ACT+)

Fig. 4

Proposed algorithm for emergency coagulation assessment using the Hemochron™ Signature Elite point-of-care test system (POCT) for rapid decision making in patients treated with direct oral anticoagulants (DOAC). Ideal assay- and DOAC-specific cut-offs are provided for the 30/50 ng/mL thresholds. ICH = intracranial hemorrhage; HC-INR and HC-ACT+ = Hemochron™ Signature Elite point-of-care test system-based international normalized ratio and activated clotting time