title: Determination of dabigatran and rivaroxaban by ultra-performance liquid chromatography-tandem mass spectrometry and coagulation assays after major orthopaedic surgery.
abstract: Major orthopaedic surgery is associated with an increased risk of venous thromboembolism. Direct oral anticoagulants (DOACs) are recommended as thromboprophylactic agents after orthopaedic surgery. Although routine monitoring of DOACs in general is not required, measuring DOAC concentration may be necessary in clinical settings. The effects of DOACs on routine coagulation assays in spiked material are studied extensively, however, few data are available on DOAC concentration in patients after major orthopaedic surgery. We measured trough and peak DOAC concentrations with UPLC-MS/MS and routine coagulation tests in a prospective study including 40 patients receiving thromboprophylactic treatment with dabigatran 220mg od and 40 patients receiving rivaroxaban 10mg od after major orthopaedic surgery. For rivaroxaban, the median trough concentration with UPLC-MS/MS was 17.1ng/mL and median peak concentration was 149ng/mL. The anti-Xa assay displayed a good correlation, but a positive bias in comparison to the reference method. Furthermore, trough levels were mostly below the LOD of the anti-Xa assay. For dabigatran, the median trough concentration with UPLC-MS/MS was 12.1ng/mL, and median peak level was 80.8ng/mL. A positive bias was found when results from coagulation assays were compared to UPLC-MS/MS data. However, the addition of glucuronidated metabolites to dabigatran concentration UPLC-MS/MS data generally resolved most of this bias. Age was found to have a significant influence on dabigatran pharmacokinetics, irrespective of kidney function, whereas no effect of age was found during rivaroxaban treatment. In both treatment groups, female subjects displayed faster pharmacokinetics in comparison to male subjects, although not reaching significance. We conclude that UPLC-MS/MS is the method of choice to measure trough concentrations of DOACs in patients after orthopaedic surgery. Current coagulation assays are not suited for this purpose. We found large heterogeneity in both peak and trough concentrations of DOACs, and showed that pharmacokinetics of novel oral anticoagulants may be influenced by age and gender. Whether patients with high or low trough concentrations are at increased risk for bleeding or thromboembolic events respectively remains to be established.
authors.affiliation: MaasstadLab, Clinical Laboratory, Maasstad Hospital, Rotterdam, The Netherlands; Clinical Laboratory, Máxima Medical Center, Eindhoven, The Netherlands.
authors.forename: M W M
authors.initials: MW
authors.lastname: Schellings
authors.affiliation: Clinical Laboratory, Amphia Hospital, Breda, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Boonen
authors.affiliation: Clinical Laboratory, Máxima Medical Center, Eindhoven, The Netherlands; Laboratory of Chemical Biology and Institute of Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Expert Center Clinical Chemistry Eindhoven, Eindhoven, The Netherlands; Clinical Laboratory, Catharina Hospital, Eindhoven, The Netherlands.
authors.forename: E M H
authors.initials: EM
authors.lastname: Schmitz
authors.affiliation: Department of Orthopaedic Surgery, Catharina Hospital, Eindhoven, The Netherlands; Department of Orthopaedic Surgery, Máxima Medical Center, Eindhoven, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Jonkers
authors.affiliation: Clinical Laboratory, Catharina Hospital, Eindhoven, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: van den Heuvel
authors.affiliation: Department of Orthopaedic Surgery, Catharina Hospital, Eindhoven, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Besselaar
authors.affiliation: Department of Orthopaedic Surgery, Máxima Medical Center, Eindhoven, The Netherlands.
authors.forename: J G E
authors.initials: JG
authors.lastname: Hendriks
authors.affiliation: Expert Center Clinical Chemistry Eindhoven, Eindhoven, The Netherlands; Clinical Laboratory, Catharina Hospital, Eindhoven, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: van de Kerkhof
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000097:blood* / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000069604:Dabigatran / Q000097:blood* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019637:Orthopedic Procedures / Q000009:adverse effects; D000069552:Rivaroxaban / Q000097:blood* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry / Q000379:methods; D054556:Venous Thromboembolism / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D000069552:Rivaroxaban; D000069604:Dabigatran
keywords: Direct oral anticoagulants ultra-performance liquid chromatography ‐ -tandem mass spectrometry coagulation assays orthopaedic surgery