Estimation of Rivaroxaban Plasma Concentrations in the Perioperative Setting in Patients With or Without Heparin Bridging

Lessire, Sarah; Douxfils, Jonathan; Pochet, Lionel; Dincq, Anne-Sophie; Larock, Anne-Sophie; Gourdin, Maximilien; Dogné, Jean‐Michel; Châtelain, Bernard; Mullier, François

doi:10.1177/1076029616675968

Cited by 24 publications

(32 citation statements)

References 37 publications

(38 reference statements)

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“…Not all the anti‐Xa assays tested in our study were previously evaluated in published works for quantification of apixaban or rivaroxaban concentrations. The six methods not supplemented with exogenous antithrombin showed LOD and LOQ values ranging from 3‐16 ng/mL and 8‐39 ng/mL, respectively, comparable to the available published data [LOD from 11 to 29 ng/mL (DiXaI‐HY, LRT‐HY, AntiXa‐STA) and LOQ from 6 to 52 ng/mL (DiXaI‐HY, LRT‐HY, AntiXa‐STA, AntiXa‐TC)] . The HPLC‐UV method showed good LOD and LOQ for apixaban and rivaroxaban (LOD from 5 to 9 ng/mL and LOQ from 16 to 29 ng/mL), comparable to values reported in literature (LOD from 4 to 5 ng/mL and LOQ from 10 to 19 ng/mL) …”

Section: Discussionsupporting

confidence: 77%

DOAC plasma levels measured by chromogenic anti‐Xa assays and HPLC‐UV in apixaban‐ and rivaroxaban‐treated patients from the START‐Register

Cini¹,

Legnani²,

Padrini

et al. 2020

Int J Lab Hematology

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Introduction To measure direct factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) concentrations, dedicated chromogenic anti‐Xa assays are recommended as suitable methods to provide rapid drug quantification. Moreover, the high‐performance liquid chromatography with ultraviolet detection (HPLC‐UV) is reported as a reliable quantitative technique. We investigated seven anti‐Xa assays and an HPLC‐UV method for measurement of apixaban and rivaroxaban levels in patients enrolled in the START‐Register. Methods A total of 127 apixaban and 124 rivaroxaban samples were tested by HPLC‐UV and the following anti‐Xa assays: Biophen DiXaI and Heparin LRT (Hyphen BioMed), Berichrom and Innovance Heparin (Siemens), STA‐Liquid Anti‐Xa (Stago Diagnostics), Technochrom anti‐Xa (Technoclone), and HemosIL Liquid Anti‐Xa (Werfen). Each method was performed in one of the participating laboratories: Bologna, Cremona, Florence, and Padua. Results Our data confirmed the overestimation of apixaban and rivaroxaban levels by the antithrombin‐supplemented anti‐Xa method (Berichrom). Performances and reproducibility of the six anti‐Xa assays not supplemented with antithrombin and the HPLC‐UV method were good, with limits of quantification from 8‐39 ng/mL (apixaban) and 15‐33 ng/mL (rivaroxaban). The six chromogenic methods showed good concordances with the quantitative HPLC‐UV [bias: −26.9‐22.3 ng/mL (apixaban), −11.3‐18.7 ng/mL (rivaroxaban)]. Higher bias and wider range between limits of agreement were observed at higher concentrations [<100 ng/mL: bias −21.3‐4.1 ng/mL (apixaban) and −6.2‐3.8 ng/mL (rivaroxaban); >200 ng/mL: bias −42.2‐36.8 ng/mL (apixaban) and −20.1‐68.9 ng/mL (rivaroxaban)]. Conclusion Overall, the anti‐Xa assays not supplemented with antithrombin and the HPLC‐UV method proved to be suitable for apixaban and rivaroxaban quantification.

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Section: Discussionsupporting

confidence: 77%

DOAC plasma levels measured by chromogenic anti‐Xa assays and HPLC‐UV in apixaban‐ and rivaroxaban‐treated patients from the START‐Register

Cini¹,

Legnani²,

Padrini

et al. 2020

Int J Lab Hematology

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“…It is possible to assess the impact of residual concentration of tinzaparin that may be found 24 hours after last administration (up to 0.25 IU/mL) by interpolating this concentration on the linear regression ( r 2 = 0.99). An increased sensitivity of the STA ® ‐Liquid Anti‐Xa and the HemosIL ® Liquid Anti‐Xa kits for heparins and fondaparinux is obtained which is consistent with previous reports . This may lead to measure a falsely elevated betrixaban level when residual plasma concentrations of betrixaban are measured in patient bridged with heparins.…”

Section: Discussionsupporting

confidence: 88%

“…The absence of sensitivity to heparins for Biophen ® DiXaI ® is due to its TRIS‐NaCl‐EDTA buffer at pH = 7.85 . As it has been reported, lower dilution of the sample may render inefficient the buffer of the Biophen ® DiXaI ® assay . However, despite lower dilutions of the samples in the buffer of the Biophen ® DiXaI ® , the buffer is still strong enough to inhibit the anticoagulant effect of heparins.…”

Section: Discussionmentioning

confidence: 94%

Development of new methodologies for the chromogenic estimation of betrixaban concentrations in plasma

Siriez

Evrard

Dogné

et al. 2019

Int J Lab Hematology

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Introduction Chromogenic anti‐Xa assays are the most appropriate tests to estimate the amount of betrixaban in plasma but the sensitivity of available tests is limited and improvements are needed to encompass the on‐therapy range. Methods Betrixaban was spiked at concentrations ranging from 0 to 500 ng/mL in plasma from healthy donors. Three commercial tests were used (Biophen®DiXaI®, STA®Liquid Anti‐Xa, and HemosIL®Liquid Anti‐Xa), and adaptation of their sample dilution scheme was performed. These new methodologies were also tested on plasma spiked with amounts of unfractionated heparin (UFH), low molecular weight heparins (LMWH), or fondaparinux covering the on‐therapy ranges to evaluate their sensitivity to indirect factor Xa inhibitors. Results Results showed concentration‐dependent decreases in OD/min inversely proportional to the dilutions. While modifications improve the sensitivity of these tests to betrixaban (eg, ½*OD/min of 502 ng/mL [95% CI: 495‐508 ng/mL] for Biophen®DiXaI® [1:50] is reduced to 51 ng/mL [95% CI: 50‐52 ng/mL] for improved Biophen®DiXaI® [1:5]), results also showed an increased sensitivity to indirect factor Xa inhibitors, except for Biophen®DiXaI® which remains insensitive to UFH and LMWH. Conclusions Results showed that the improvement of current chromogenic anti‐Xa methodologies enhances the sensitivity of these assays to betrixaban but also to indirect factor Xa inhibitors. This lack of specificity may lead to overestimation of betrixaban concentrations in patients bridged with heparins. To avoid this cross‐interference, the use of the Biophen®DiXaI® may be a solution except for fondaparinux which remains active even in the presence of the Biophen®DiXaI®’s specific buffer. For the other chromogenic assays, the conception and validation of specific buffer is required.

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“…Future research should investigate the cause of this overestimation and improve anti‐Xa assays. Of note, calibration curves should include low concentration calibrators as well (as done in our study) to appropriately determine low rivaroxaban concentrations .…”

Section: Discussionmentioning

confidence: 99%

Accuracy and consistency of anti‐Xa activity measurement for determination of rivaroxaban plasma levels

Studt

Alberio

Angelillo‐Scherrer

et al. 2017

Journal of Thrombosis and Haemostasis

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Background Determining the plasma level of direct oral anticoagulants reliably is important in the work-up of complex clinical situations. Objectives To study the accuracy and consistency of anti-Xa assays for rivaroxaban plasma concentration in a prospective, multicenter evaluation study employing different reagents and analytical platforms. Methods Rivaroxaban 20 mg was administered once daily to 20 healthy volunteers and blood samples were taken at peak and trough levels (clinicaltrials.gov NCT01710267). Anti-Xa activity was determined in 10 major laboratories using different reagents and analyzers; corresponding rivaroxaban plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Findings Overall Pearson's correlation coefficient of anti-Xa levels and HPLC-MS results was 0.99 for Biophen Heparin (95% CI, 0.99, 0.99), Biophen DiXaI (95% CI, 0.99, 0.99) and STA anti-Xa liquid (95% CI, 0.99, 1.00). Correlation was lower in rivaroxaban concentrations below 50 μg L and above 200 μg L . The overall bias of the Bland-Altman difference plot was 14.7 μg L for Biophen Heparin, 17.9 μg L for Biophen DiXal and 19.0 μg L for STA anti-Xa liquid. Agreement between laboratories was high at peak level but limited at trough level. Conclusions Anti-Xa activity correlated well with rivaroxaban plasma concentrations, especially in a range between 50 and 200 μg L . However, anti-Xa assays systematically overestimated rivaroxaban concentration as compared with HPLC-MS, particularly at higher concentrations. This overestimation, coupled with an apparent interindividual variation, might affect the interpretation of results in some situations.

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Estimation of Rivaroxaban Plasma Concentrations in the Perioperative Setting in Patients With or Without Heparin Bridging

Cited by 24 publications

References 37 publications

DOAC plasma levels measured by chromogenic anti‐Xa assays and HPLC‐UV in apixaban‐ and rivaroxaban‐treated patients from the START‐Register

DOAC plasma levels measured by chromogenic anti‐Xa assays and HPLC‐UV in apixaban‐ and rivaroxaban‐treated patients from the START‐Register

Development of new methodologies for the chromogenic estimation of betrixaban concentrations in plasma

Accuracy and consistency of anti‐Xa activity measurement for determination of rivaroxaban plasma levels

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