Universität zu Köln

Sennesael, Anne-Laure, Larock, Anne-Sophie, Douxfils, Jonathan ORCID: 0000-0002-7644-5298, Elens, Laure ORCID: 0000-0002-0039-3583, Stillemans, Gabriel ORCID: 0000-0002-2356-4891, Wiesen, Martin ORCID: 0000-0002-9669-446X, Taubert, Max ORCID: 0000-0001-8925-7782, Dogne, Jean-Michel, Spinewine, Anne and Mullier, Francois (2018). Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study. Thromb. J., 16. LONDON: BMC. ISSN 1477-9560

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Abstract

BackgroundSerious 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.MethodsThis 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.ResultsRivaroxaban measurements varied from 5 to 358ng/ml, with a post-intake delay ranging from 9 to 38h. At trough, estimated plasma concentrations were between 12 and 251ng/ml (median value 94ng/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).ConclusionsRivaroxaban 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sennesael, Anne-Laure UNSPECIFIED UNSPECIFIED UNSPECIFIED Larock, Anne-Sophie UNSPECIFIED UNSPECIFIED UNSPECIFIED Douxfils, Jonathan UNSPECIFIED orcid.org/0000-0002-7644-5298 UNSPECIFIED Elens, Laure UNSPECIFIED orcid.org/0000-0002-0039-3583 UNSPECIFIED Stillemans, Gabriel UNSPECIFIED orcid.org/0000-0002-2356-4891 UNSPECIFIED Wiesen, Martin UNSPECIFIED orcid.org/0000-0002-9669-446X UNSPECIFIED Taubert, Max UNSPECIFIED orcid.org/0000-0001-8925-7782 UNSPECIFIED Dogne, Jean-Michel UNSPECIFIED UNSPECIFIED UNSPECIFIED Spinewine, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Mullier, Francois UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-165816
DOI:	10.1186/s12959-018-0183-3
Journal or Publication Title:	Thromb. J.
Volume:	16
Date:	2018
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1477-9560
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DIRECT ORAL ANTICOAGULANTS; NONVALVULAR ATRIAL-FIBRILLATION; VITAMIN-K ANTAGONISTS; MAJOR HEMORRHAGE; DABIGATRAN; MANAGEMENT; RISK; POLYMORPHISMS; EXPOSURE; REVERSAL Multiple languages Hematology; Peripheral Vascular Disease Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16581