Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

Anne-Laure Sennesael, Anne-Sophie Larock, Jonathan Douxfils, Laure Elens, Gabriel Stillemans, Martin Wiesen, Max Taubert, Jean-Michel Dogné, Anne Spinewine, François Mullier, Anne-Laure Sennesael, Anne-Sophie Larock, Jonathan Douxfils, Laure Elens, Gabriel Stillemans, Martin Wiesen, Max Taubert, Jean-Michel Dogné, Anne Spinewine, François Mullier

Abstract

Background: Serious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.

Methods: This analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.

Results: Rivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP).

Conclusions: Rivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.

Keywords: Bleeding; Direct oral anticoagulants; Drug monitoring; Patient safety; Pharmacogenomics; Rivaroxaban.

Conflict of interest statement

The study was approved by the Ethics Committees of the Cliniques Universitaires Saint-Luc (Brussels, Belgium) and the CHU UCL Namur (Yvoir, Belgium), and registered with clinicaltrials.gov (NCT02720328). Written informed consent was obtained from each patient.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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