A New Test for the Detection of Direct Oral Anticoagulants (Rivaroxaban and Apixaban) in the Emergency Room Setting

Figures

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  Figure 1.. Comparative clotting curves. Clotting times were compared at various agonist concentrations for all the patient groups to construct clotting curves. A, Clotting curves with the mean and se bars of all patient groups are demonstrated on a single graph for comparison. All three FXa-I groups appear subjectively very different from the control group, with there being multiple concentrations where there are significant statistical differences between the controls and the total FXa-I, rivaroxaban, and apixaban groups. B, Principal component analysis (PCA) triplot of times to clot for control (blue), apixaban (red), and rivaroxaban (green) patient samples at three separate agonist concentration. Control and FXa groups demonstrate distinct clotting profiles over the agonist concentrations tested, and FXa patient samples demonstrate increased clotting variability relative to control samples. Statistical significance is defined as p value less than 0.05 (asterisk).

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  Figure 2.. Clotting time score (CTS) analysis. Evaluation of CTS utilization for the detection of FXa-I in patient samples. A, Scatter plot with mean and se bars for CTS comparison between patient groups. Dashed line at CTS 0 represents the chosen cutoff for the determination of whether there is FXa inhibition in the patient sample. B, Receiver operating characteristic curve of utilizing the CTS to determine whether a patient has an FXa-I in their system. AUROC = area under the receiver operating curve.

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  Figure 3.. Clotting time scores (CTS) for factor Xa and factor IIa inhibitors. CTS are plotted for each concentration of various direct FXa inhibitors in response to the FXa test, including rivaroxaban, apixaban, edoxaban, and betrixaban. A, A combined CTS plot of all four FXa-I tested. This graph shows the differences in the CTS results for these drugs, despite a reportedly similar mechanism of action (direct FXa inhibition). B, A table showing the expected limit of detection (LOD) for each drug tested based on the current CTS equation and setting the negative control reference range less than or equal to 0. C, An example of how the CTS curve equation may be used to predict the CTS for each drug at its proposed peak therapeutic plasma concentration. H and I, The CTS approach can detect the inhibitors tested at their respective therapeutic concentrations. Note: peak concentration varies based on publication evaluated, and values selected are representative.

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  Figure 4.. Current and future diagnostic paradigms for patients on direct oral anticoagulants. A, Flow summary of existing decision-making framework for coagulation testing in the emergency setting. Clinicians first decide whether to proceed with coagulation testing by determining if a patient is actively bleeding, at heightened risk of bleeding due to pre-existing medical condition, or warrants invasive medical/surgical intervention. The clinician then typically orders coagulation tests that are currently available in the emergency department setting (e.g., prothrombin time [PT], international normalized ratio [INR], activated partial thromboplastic time [aPTT], activated clotting time [ACT], and thromboelastoraphy [TEG]). If these tests demonstrate abnormal clotting profiles or prolonged clotting times, the clinician must next decide appropriate treatment. Pre-existing tests have variable sensitivity and specificity toward direct oral anticoagulants (DOACs), and the choice of appropriate treatments for DOAC patients (e.g., DOAC-specific reversal agent vs plasma vs clotting factors) can be challenging. As many of these tests are insensitive or nonspecific to DOACs, normal clotting results…