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

Studt, Jan‐Dirk; Alberio, Lorenzo; Angelillo‐Scherrer, Anne; Asmis, Lars M.; Fontana, Pierre; Korte, Wolfgang; Méndez, Adriana; Schmid, Pirmin; Stricker, Hans; Tsakiris, Dimitrios Α.; Wuillemin, Walter A.; Nagler, Michael

doi:10.1111/jth.13747

Cited by 26 publications

(34 citation statements)

References 38 publications

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“…Anti‐Xa assays, which are successfully used for the monitoring of heparin and low‐molecular‐weight heparin (LMWH) 13 were introduced and a nice linear relationship was demonstrated in samples spiked with rivaroxaban 14,15 . DOAC‐calibrated anti‐Xa activity correlated well with drug concentrations if measured in healthy volunteers and even patients 11,16–23 . However, widespread implementation in clinical practice is hampered by two major problems.…”

Section: Introductionmentioning

confidence: 99%

A universal anti‐Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation

et al. 2021

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Summary A universal anti‐Xa assay for the determination of rivaroxaban, apixaban and edoxaban drug concentrations would simplify laboratory procedures and facilitate widespread implementation. Following two pilot studies analysing spiked samples and material from 698 patients, we conducted a prospective multicentre cross‐sectional study, including 867 patients treated with rivaroxaban, apixaban or edoxaban in clinical practice to comprehensively evaluate a simple, readily available anti‐Xa assay that would accurately measure drug concentrations and correctly predict relevant levels in clinical practice. Anti‐Xa activity was measured by an assay calibrated with low‐molecular‐weight heparin (LMWH) in addition to ultra‐high performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). As an external validation, LMWH‐calibrated anti‐Xa activity was also determined in nine external laboratories. The LMWH‐calibrated anti‐Xa activity correlated strongly with rivaroxaban, apixaban or edoxaban drug levels [rs = 0·98, 95% confidence interval (CI) 0·98–0·98]. The sensitivity for the clinically relevant cut‐off levels of 30, 50 and 100 µg/l was 96·2% (95% CI 94·4–97·4), 96·4% (95% CI 94·4–97·7) and 96·7% (95% CI 94·3–98·1) respectively. Concordant results were obtained in the external validation study. In conclusion, a universal, LMWH‐calibrated anti‐Xa assay accurately measured rivaroxaban, apixaban and edoxaban concentrations and correctly predicted relevant drug concentrations in clinical practice.

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Section: Introductionmentioning

confidence: 99%

A universal anti‐Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation

et al. 2021

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“…Monitoring DOAC therapy using anti‐Xa assays is established in clinical practice and recommended e.g. in case of bleeding or unplanned surgery during therapy 38,39 …”

Section: Methodsmentioning

confidence: 99%

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans

Scholz

Liakoni

Hammann

et al. 2020

Brit J Clinical Pharma

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Aims To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P‐glycoprotein (P‐gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban. Methods Open‐label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P‐gp phenotyping using low‐dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks’ treatment with the H. perforatum extract. Results The geometric mean ratios for the area under the concentration–time curve and Cmax of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect–time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding Tmax (median 1.5 vs 1 h, P = .26) and terminal elimination half‐life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P‐gp activity, as evidenced by phenotyping. Conclusion The CYP3A4/P‐gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin‐containing H. perforatum extracts with rivaroxaban.

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“…RXA plasma concentration was determined by chromogenic anti-Xa assay calibrated for RXA (Studt et al 2017). During the daytime, the DiXaI assay (Hyphen Biomed, Neuville-sur-Oise, France) was used due to its insensitivity to heparin and at all other times a routine anti-Xa assay (Biophen Heparin LRT, Hyphen Biomed) with the same set of calibrators.…”

Section: Methodsmentioning

confidence: 99%

“…However, this method is time-consuming, expensive, and therefore not suitable for routine clinical use. In comparison, chromogenic anti-Xa assays calibrated for RXA are fast, affordable, and show a very good agreement with HPLC-MS (Studt et al 2017). While most university hospitals or other large hospitals have introduced anti-Xa assays for RXA, these are not readily available to smaller hospitals often relying on routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT).…”

Section: Introductionmentioning

confidence: 99%

Standard coagulation assays alone are not sufficient to exclude surgically relevant rivaroxaban plasma concentrations

et al. 2019

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BackgroundWhile mainly larger hospitals have introduced routine anti-Xa assays for rivaroxaban (RXA), these are not readily available to smaller hospitals often relying on routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT).The aim of our study was to investigate the effect of RXA plasma concentration on the standard coagulation tests PT (Quick test and INR) and aPTT in a large group of real-life patients. We further assessed whether normal results of these standard coagulation assays are sufficient to exclude surgically relevant RXA plasma concentration, defined as > 50 mcg/l.MethodsThis retrospective study included all patients between 2012 and 2016 where anti-Xa (calibrated for RXA), PT (Quick test and INR), and/or aPTT were determined from the same sample. PT is expressed as Quick value (% of normal plasma pool). In total, 1027 measurements in 622 patients were eligible for analysis: 752 measurements of 505 patients for Quick/INR and 594 measurements of 417 patients for aPTT.ResultsA moderate correlation of PT/Quick (Pearson's correlation coefficient − 0.59; p < 0.001), INR (Pearson's correlation coefficient 0.5; p < 0.001), and aPTT (Pearson's correlation coefficient 0.53; p < 0.001) with RXA plasma concentration was observed. However, in 50% of all samples with a normal PT/Quick, in 25% of all samples with a normal INR and in 80% of all samples with a normal aPTT residual RXA plasma concentration was surgically relevant.ConclusionAlthough a moderate correlation of RXA plasma concentration with PT/Quick, INR, and aPTT was observed, standard coagulation assays are not sufficient to exclude surgically relevant RXA plasma concentrations.

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

Cited by 26 publications

References 38 publications

A universal anti‐Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation

A universal anti‐Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans

Standard coagulation assays alone are not sufficient to exclude surgically relevant rivaroxaban plasma concentrations

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