Risk Factors for Higher-than-Expected Residual Rivaroxaban Plasma Concentrations in Real-Life Patients

Abstract

Introduction Rivaroxaban (RXA) is a direct oral factor Xa (Xa) antagonist with a short half-life and a fast onset and offset of effect. Before elective surgery, discontinuation is recommended with an interval of at least > 24 hours. In clinical practice, this is, however, not always sufficient to achieve a residual RXA plasma concentration deemed appropriate for surgery, defined as ≤ 50 mcg/L. Our study aimed at identifying factors associated with a higher-than-expected residual RXA plasma concentration in a large group of real-life patients.

Materials and Methods This retrospective single-centre study included all patients taking RXA between 2012 and 2016 where RXA plasma concentration was determined by pharmacodynamic anti-Xa assay (518 measurements in 368 patients). Medical records were reviewed. Residual RXA plasma concentrations were then compared with expected values according to a pharmacokinetic model.

Results Residual RXA plasma concentration was significantly higher-than-expected in patients with atrial fibrillation, impaired kidney function (glomerular filtration rate [GFR] < 60 mL/min), CYP3A4-, CYP2J2- and PGP-inhibitory co-medication including amiodarone. Impaired kidney function (odds ratio [OR], 2.22, 95% confidence interval [CI], 1.30–3.78, p = 0.003) and concomitant amiodarone intake (OR, 1.97, 95% CI, 1.04–3.72, p = 0.036) were significantly associated with RXA plasma concentrations > 50 mcg/L at 24 to 48 hours after the last RXA intake.

Conclusion In our group of real-life patients, impaired kidney function (GFR < 60 mL/min) and co-medication with amiodarone were independently associated with higher-than-expected residual RXA plasma concentrations. In these patients, standard intervals of RXA discontinuation may not always be sufficient before elective surgery and routine pre-operative determination of the residual RXA concentration could be advisable.

Keywords

anticoagulation - elevated plasma concentrations - risk factors - rivaroxaban

Authors' Contributions

A.K. planned the study, contributed to data collection, data interpretation and wrote the manuscript. A.S. acquired the data, contributed to data interpretation and wrote the manuscript. A.K. and A.S. contributed equally to this manuscript. P.S. contributed to statistical analyses, data interpretation and corrected the manuscript. A.J. contributed to study planning, data interpretation and corrected the manuscript. B.S. analysed the data and contributed to data interpretation. D.S. planned the study, contributed to data interpretation and corrected the manuscript. J.S. contributed to study planning, data acquisition, data interpretation, writing and review of the manuscript.

Ethical Approval

This study was approved by the local ethics committee (Kantonale Ethikkommission Zurich, Switzerland, KEK-ZH-No: 2017–00164).

^* These authors contributed equally to this article.

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