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Background: Direct oral anticoagulants (DOACs) are widely used as therapies for venous thromboembolism and other cardiovascular diseases. However, routine coagulation monitoring is not required, but may be clinically indicated in high risk populations including obese patients., Objectives: The aims of this study were two fold; to validate a chromogenic assay for anti-factor Xa measurement in patients taking apixaban, and correlate it with PT/INR and PTT, and to measure anti-factor Xa levels in patients who weighed >120 kg., Patients/methods: Patients who were taking apixaban had 3 blood samples drawn over a 4 h period. Apixaban levels were determined using an anti-factor Xa activity assay (STA-Liquid Anti-Xa) using STA-Apixaban Calibrator and STA-Apixaban Controls. The PT/INR was determined using standard methodology. Apix MS, using manufacturer provided apixaban standard, was performed on plasma., Results and Conclusions: 18 normal weight patients, 39 obese patients and 14 controls were enrolled. There was a strong correlation between apixaban anti-factor Xa activity compared to plasma Apix MS (r = 0.95). In patients >120 kg, there was a statistically significant decreased rate of change in anti-factor Xa levels after ingestion. Further, the area under the curve for apixaban anti-factor Xa levels was significantly lower in patients over 120 kg. While INR correlated with apixaban MS and apixaban anti-factor Xa activity in both normal weight and obese patients, the association was not sufficiently strong to clinically manage patients, normal weight or obese. Given these findings, research is necessary to investigate the clinical utility of apixaban anti-factor Xa activity measurement in selected populations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dabigatran etexilate, rivaroxaban and apixaban (DOACs) are widely used and measurement of their concentration is desirable in certain clinical situations. Target-specific assays are available but limited information exists on their performance especially in their ability to accurately measure low and high concentrations., Aims: To define, in a multicenter study, the precision and accuracy of DOAC measurements in daily practice., Methods: 15 plasma samples (kindly provided by Hyphen-Biomed) spiked with 5 blinded concentrations of dabigatran, rivaroxaban or apixaban (targeted 0-40-100-250-500ng/mL, actual concentrations measured by HPLC-MS/MS), were sent to 30 haemostasis laboratories. DOAC concentration, PT and aPTT were measured once in each sample using local reagents. Interlaboratory precision was determined by its coefficient of variation (CV) and accuracy by its bias., Results: 464 DOAC measurements were performed in the 30 laboratories using 4 dabigatran and 5 rivaroxaban/apixaban calibrated assays on 3 analysers. Inter-laboratory CVs were below 18% for concentrations ≥100ng/mL, and higher for concentrations ~40ng/mL; biases were below 8% for all drugs and concentrations. In DOAC-free samples, concentrations were all below the lower limit of quantification except for one value (dabigatran: 35ng/mL). Depending on the concentrations, significant differences were found between reagents in rivaroxaban and apixaban concentration values. PT and aPTT ratios displayed a low sensitivity to apixaban., Conclusion: Our results suggest that calibrated DOAC assays allow the reliable measurement of a wide range of drug concentrations, even though improvement of their performances is necessary, especially for measuring low concentrations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We performed a review of all direct oral anticoagulant (DOAC) levels - ecarin times for dabigatran and anti-Xa levels for rivaroxaban and apixaban - ordered at our institution with the purpose of evaluating DOAC levels from "real-world" (non-clinical trial) patients taking DOACs long-term, in order to assess levels obtained, reasons for checking levels, and actions taken based on the testing result. A total of 28 patients had 48 levels sent over a 36-month period. The majority of outpatient levels were within or close to the range of published values. The setting in which levels were sent influenced how results affected management decisions: in the outpatient setting, the majority of levels served to reassure clinicians that DOAC levels were within expected ranges resulting in continuation of chosen management, whereas in the inpatient setting, DOAC levels were used most frequently to detect DOAC presence in urgent clinical situations and influenced clinical decision-making in the peri-procedural and pre-operative periods. Our results demonstrate that while testing may be useful if immediately available in urgent clinical situations where assessment of drug presence is needed, DOAC level monitoring is infrequently used overall, and the lack of use combined with the paucity of available evidence to guide clinical decision-making based on the results suggests there is little urgency to make the tests widely available for routine use outside of acute settings in the emergency department and urgent surgical setting., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice. 5-HT2A receptor occupancy was determined in humans using positron emission tomography (PET). Tolerance development was examined in rats after chronic dosing. EEG oscillations and network connectivity were assessed using multi-channel EEG. In rats, JNJ-40411813 increased deep sleep time and latency of REM onset but reduced REM time when administered 2 h after 'lights on' (CT2): this was sustained after chronic dosing. At CT5 similar effects were elicited, at CT10 only deep sleep was enhanced. Withdrawal resulted in baseline values, while re-administration reinstated drug effects. Parieto-occipital cortical slow theta and gamma oscillations were correlated with low locomotion. The specificity of functional response was confirmed in WT but not mGluR2 (-/-) mice. A double-blind, placebo-controlled polysomnographic study in healthy, elderly subjects showed that 500 mg of JNJ-40411813 consistently increased deep sleep time, but had no effect on REM parameters. This deep sleep effect was not explained by 5-HT2A receptor binding, as in the PET study even 700 mg only marginally displaced the tracer. JNJ-40411813 elicited comparable functional responses in rodents and men if circadian time of dosing was taken into account. These findings underscore the translational potential of sleep mechanisms in evaluating mGluR2 therapeutics when administered at the appropriate circadian time., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: The direct factor-Xa inhibitor apixaban is approved e.g. for the prevention of stroke in patients with atrial fibrillation (AF). Although routine monitoring of apixaban therapy is currently not recommended, selective monitoring could be useful to optimize efficacy and safety in certain clinical situations. We studied the exposure and effect of apixaban using different laboratory methods in a clinical setting with a well-defined cohort of AF patients., Material and Methods: Seventy AF patients (72±7.4years, 64 % men, mean CHADS2 score 1.7) treated with apixaban 2.5 (n=10) or 5mg BID (n=60). Trough plasma apixaban concentrations determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to the coagulation assays Anti-factor Xa, PT-INR and aPTT., Results: The apixaban plasma concentration determined by LC-MS/MS varied more than 10-fold overall. The range was between 15-83 and 29-186ng/mL for the 2.5mg BID and 5mg BID respectively, with patients receiving 5mg BID having significantly higher apixaban concentrations (p<0.001). A strong correlation between LC-MS/MS and anti-FXa-assay was found (p<0.001), while aPTT and PT-INR were not sensitive enough. There were no significant correlations between gender, creatinine clearance, body weight or age and apixaban exposure., Conclusions: Anti-FXa-assay performed well upon apixaban concentrations in a normal exposure range. Still LC-MS/MS remains the "gold standard" method, covering also low concentrations. Compared to clinical trials, we observed relatively lower apixaban exposure and a more pronounced difference between high and low dose. Additional information regarding apixaban exposure and benefit-risk profile is needed in order to individualize treatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Routine drug monitoring is not required for the two novel direct factor Xa inhibitors apixaban and rivaroxaban. Rapidly available test results might be beneficial in case of bleeding or prior to urgent surgery., Objectives: The aim of this study was to evaluate the applicability of the two rotational thrombelastometry (ROTEM®) -modifications Low-tissue factor activated ROTEM® (LowTF-ROTEM®) and Prothrombinase induced clotting time - activated ROTEM® (PiCT®-ROTEM®) for determination of apixaban and rivaroxaban in vitro and ex vivo., Methods: Blood samples from 20 volunteers were spiked with apixaban / rivaroxaban to yield samples with ascending drug concentrations ranging from 50 - 400ng/mL. LowTF - and PiCT® modified ROTEM® tests and determination of the corresponding antifactor Xa activity were performed in duplicate in 280 samples. LowTF-ROTEM® tests were performed in samples from 20 patients on apixaban or rivaroxaban therapy and 20 controls., Results: There was a strong correlation between apixaban / rivaroxaban plasma concentrations and the LowTF-ROTEM® parameters Clotting time (CT; spearman correlation coefficient (SCC) 0.81 and 0.81, respectively) and Time to maximum velocity (t,MaxVel; SCC: 0.81 and 0.80, resp.) and a low to moderate correlation for the PiCT®-ROTEM® parameters CT (SCC: 0.38 and 0.59, resp.) and t,MaxVel. (0.51 and 0.69, resp.) in the in vitro experiments. LowTF-ROTEM CT was significantly prolonged in patients on apxiaban or rivaroxaban therapy compared to controls., Conclusions: LowTF-ROTEM® could be a valuable diagnostic tool for rapid determination of the effect of apixaban and rivaroxaban at the point of care., (Copyright © 2014 Elsevier Ltd. All rights reserved.)