A universal anti-Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation - Willekens, G.; Studt, J. D.; Mendez, A.; Alberio, L.; Fontana, P.; Wuillemin, W. A.; Schmidt, A.; Graf, L.; Gerber, B.; Bovet, C.; Sauter, T. C.; Nagler, M. (Br J Haematol, 2021)
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 [r(s) = 0.98, 95% confidence interval (CI) 0.98-0.98]. The sensitivity for the clinically relevant cut-off levels of 30, 50 and 100 microg/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.
Keywords: journalArticle; *Drug Monitoring; Adolescent; Adult; Aged; Aged, 80 and over; Bangerter-Rhyner Stiftung (applicant Ursula Amstutz). We thank the following; Bristol-Myers Squibb, and Daiichi Sankyo. These companies had no role in study; Cantonal Hospital Lucerne. Michael Nagler is supported by a research grant of the; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Cyclophosphamide/*pharmacokinetics; Daiichi Sankyo. Lorenzo Alberio reports research grants from Bayer, CSL-Behring,; Factor Xa Inhibitors/*blood; Female; Humans; Male; Middle Aged; Novartis, Novo Nordisk, Roche, Sobi, and Takeda. Walter A. Wuillemin reports; Pilot Projects; Pyrazoles/*pharmacokinetics; Pyridones/*pharmacokinetics; Retrospective Studies; Rivaroxaban/*pharmacokinetics; Siemens, and Sanofi; Swiss National Science Foundation (#179334). Lorenzo Alberio is supported by a; Tandem Mass Spectrometry; apixaban; companies for the provision of pure substances: Bayer Healthcare AG,; design, data collection and analysis, the decision to publish, or manuscript; drug monitoring; edoxaban; factor Xa inhibitors; from Alexion Pharma GmbH, all outside the submitted. Jan-Dirk Studt reports; grant of the Swiss National Science Foundation (#320030-197392). Implementation; heparin; honoraria for participating in scientific advisory boards from Bayer, Pfizer, and; lecture fees and advisory honoraria from Bayer Healthcare, Pfizer, Takeda,; low-molecular-weight; of the LC-MS/MS measurements was supported by the Gottfried & Julia; outside of the submitted work, lecture honoraria from Bayer Healthcare, and; preparation. Michael Nagler reports research grants from Bayer Healthcare,; research grants from Bayer Healthcare, BMS-Pfizer, Daiichi Sankyo and Sanofi, and; rivaroxaban