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Inter-individual variability of peak and trough plasma concentrations of dabigatran, rivaroxaban and apixaban in patients with non-valvular atrial fibrillation

Scientific research question: Inter-individual variability of both peak and trough plasma concentrations of direct oral anticoagulants (DOACs), dabigatran, rivaroxaban and apixaban, is still insufficiently investigated. Therefore, the aim of our study was to assess inter-individual variability of peak and trough plasma levels of all three DOACs in patients with non valvular atrial fibrillation (NVAF). Methodology: The study included plasma samples from patients treated with dabigatran (N = 106, 150 mg twice-daily), rivaroxaban (N = 123, 20 mg once-daily) and apixaban (N = 69 ; 5 mg twice-daily). Blood samples were taken on the same day to obtain both trough (immediately prior the next drug dose) and peak (two hours after drug administration) DOACs concentrations. Both rivaroxaban and apixaban were measured using chromogenic anti-FXa assay (Innovance anti-FXa, Siemens Healthineers, Germany) calibrated with drug specific calibrators (Hyphen BioMed, France). Dabigatran was measured using commercial chromogenic method (Innovance DTI assay, Siemens Healthineers, Germany). All coagulation assays were performed on Behring Coagulation System XP (BCSXP) analyzer (Siemens Healthineers, Germany). Statistical analysis was done using Mann-Whitney test by MedCalc Statistical Software version 11.5.1. The inter-individual variability for trough and peak concentrations was assessed by calculating mean values and standard deviation (SD) for each DOAC concentration measured for all samples. The study was funded as an integral part of the Croatian Science Foundation research project IP-2016-06-8208, entitled New oral anticoagulants: relationship between drug concentration and anticoagulant effect. Findings: Concentrations for all three DOACs ranged as follows: dabigatran (peak 3 - 473 ng/mL ; trough 0 - 292 ng/mL) ; rivaroxaban (peak 13 - 468 ng/mL ; trough 1 - 311 ng/mL) and apixaban (peak 56 - 396 ng/mL ; trough 10 - 259 ng/mL) with significant differences between peak and trough concentrations (P<0.001) for all three DOACs (Table 1). Inter-individual variability expressed as coefficient of variation (CV%) for both peak and trough plasma concentrations of all three DOACs was as follows: dabigatran (peak 69.6% ; trough 95%), rivaroxaban (peak 50.3% ; trough 149%), apixaban (peak 40% ; trough 51%), as shown in Table 1. Conclusion: Our study showed a relatively high inter-individual variability for all three DOACs in NVAF patients. Our results demonstrated that the overall inter-individual variability for all three DOACs to be lower at peak than at trough plasma concentrations. Further, among all three DOACs, apixaban showed the lowest inter-individual variability for both peak and trough concentrations. Relatively high inter-individual variability of peak and especially for trough concentrations of all three DOACs suggests that single measurement of these drugs could not be sufficient for reliable estimation the level of anticoagulation.

dabigatran, rivaroxaban, apixaban, inter-individual variability

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