Regular ArticleAssessment of the impact of rivaroxaban on coagulation assays: Laboratory recommendations for the monitoring of rivaroxaban and review of the literature
Introduction
Rivaroxaban (Xarelto®) is a direct, antithrombin independent and orally active FXa inhibitor that inhibits not only free FXa but also the prothrombinase complex and clot bound FXa [1]. It is approved by the European Medicine Agency (EMA) [2] and the Food and Drug Administration (FDA) [3] for the prevention of thromboembolism in total hip replacement (THR) or total knee replacement (TKR) and to prevent stroke in patients with non-valvular atrial fibrillation (AF). The treatment of acute deep-vein thrombosis (DVT) is an additional indication approved by the EMA [4]. It was also evaluated for secondary prevention after acute coronary syndrome [5] and for thromboprophylaxis in acutely ill medical patients [6]. Rivaroxaban was found statistically superior to enoxaparin (versus both European and North American regimen) in prevention of venous thromboembolism (VTE) and equivalent in term of bleedings in the orthopaedic indications [7]. In patients with non-valvular AF, rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism and showed a similar rate of major bleeding [8]. The net clinical benefit of rivaroxaban, and other NOACs, versus warfarin in patients with high risk of bleeding and stroke, suggests a wider use of these compounds in the near future [9].
The absolute bioavailability of rivaroxaban is high (80%– 100%). In patients undergoing total hip replacement receiving Xarelto® 10 mg qd, median Cmax reaches 125 μg/mL (5th – 95th percentile: 91 – 196 μg/mL) and median Ctrough was 9 μg/mL (5th – 95th percentile: 1 – 38 μg/mL) [10]. At the dose of 20 mg od in stroke prevention in a simulated population of patients with non-valvular atrial fibrillation, rivaroxaban has a Cmax of approximately 290 μg/L (5th – 95th percentile ≈ 177 – 409 ng/mL) and a Ctrough of approximately 32 μg/L (5th – 95th percentile ≈ 5 – 155 ng/mL) [11]. Similar drug levels were found in patients receiving rivaroxaban 20 mg od for the treatment of DVT [11].
Thanks to its predictable pharmacokinetic and pharmacodynamic profiles, monitoring is generally not recommended [12]. However, clinical surveillance is recommended throughout the treatment period in several subgroups of patients [13]. Thus, in patients with severe renal impairment (creatinine clearance < 30 mL/min) rivaroxaban plasma levels may be significantly increased that may lead to a moderate increased bleeding risk [14]. The use of rivaroxaban is not recommended in patients with creatinine clearance < 15 mL/min and is to be used with “caution” in patients with creatinine clearance between 15 to 29 mL/min. In addition, Xarelto® is a substrate of P-gp transporter and is partially metabolized by CYP3A4 resulting in some clinically relevant drug interactions [15]. Moreover, it should be used with caution in cirrhotic patients with hepatic impairment (classified as Child Pugh B) and is contraindicated in patients with hepatic disease associated with a coagulopathy [16]. Therefore, biological monitoring would be valuable in acute situations such as recurrent thrombosis, bleedings, before urgent surgery, in case of bridging and in case of at least two risk factors among the following: drug interactions with caution, moderate renal impairment and moderate hepatic impairment; Monitoring may also be useful in infants, pregnant women or in extreme body weights, although no relevant data on drug levels associated with approximate therapeutic and harmful ranges are currently available [17].
The primary aim of the present study is to assess which coagulation assay(s) could be proposed to measure the pharmacodynamic effects of rivaroxaban and to compare our results with those found in the literature. Secondly, we also provide laboratory recommendations for the accurate determination of plasma drug concentration in patients treated by rivaroxaban as well as a correct interpretation of routine lab tests influenced by the presence of rivaroxaban.
Section snippets
Materials and methods
Rivaroxaban was spiked at increasing concentrations in pooled citrated normal human platelet poor plasma (PPP) to measure Prothrombin Time (PT), dilute PT (dPT), Prothrombinase-induced Clotting Time (PiCT), Thrombin Generation Assay (TGA), Liquid anti-Xa® (LAX) and Biophen Direct Factor-Xa Inhibitor® (DiXaI). Activated Partial Thromboplastin Time (aPTT), activated clotting time (ACT), Thrombin Time (TT), Ecarin Clotting Time (ECT) and Reptilase Time (RT), Activated Protein C Resistance (APC-R),
Prothrombin time (PT)
Rivaroxaban showed a concentration-dependent prolongation of PT (Fig. 1) depending on on the thromboplastin reagent used. The relation was linear for each reagent. Two-fold CT was respectively 66 ng/mL for Triniclot PT Excel S®; 73 ng/mL for Recombiplastin®; 84 ng/mL for Neoplastin R®; 135 ng/mL for Neoplastin CI + ®; 161 ng/mL for Triniclot PT Excel®; 180 ng/mL for Triniclot PT HTF®; and 258 ng/mL for Innovin®. Results in terms of reproducibility are summarized in Supplementary material: Table 2. The
Discussion
Rivaroxaban (Xarelto®) is an orally, direct FXa inhibitor approved by the EMA [2] and FDA [3] in the prevention of DVT and pulmonary embolism in TKR or THR and in stroke prevention in patients with non-valvular atrial fibrillation. Moreover, it has received the market authorization in the treatment of acute DVT and prevention of symptomatic VTE, in Europe only [2], [3], [4]. Thanks to its predictable kinetics, therapeutic monitoring is generally not required. Nevertheless, this statement is
Limitation of the study
One limitation of this study is the fact that we used spiked plasma and that the study is mono-centric. These results should therefore be validated in patients receiving Xarelto®. Moreover, it is currently unknown how coagulation assays are predictive for the bleeding risk [45]. However, it is not ethically acceptable to expose patients to high-risk overdose of rivaroxaban to study the impact on coagulation tests. Freyburger et al. performed such analysis in patients undergoing THR or TKR and
Conclusion
In this study we showed that chromogenic anti-Xa assays and, to a lesser extent, PT are clearly the most appreciate assays to measure pharmacodynamic effects of rivaroxaban on the coagulation in routine practice. We therefore recommend performing calibrated PT as a screening test and if value exceeds specific cut-offs, calibrated anti-factor Xa chromogenic assays should be done. Rivaroxaban also influenced routine coagulation assays such as measurement of clotting factor, proteins C and S,
Conflict of interest disclosures
The authors declare no competing financial interests.
Acknowledgments
The authors would like to thank Anne Spinewine, Gaetane Remy, Séverine Robert, Nicolas Bailly, Justine Baudar, Françoise Biot, Philippe Devel, Marie-Christine Lambert, for their contribution to this work.
References (48)
- et al.
Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) Versus Warfarin in Patients With Atrial Fibrillation
Am J Cardiol
(2012) - et al.
New oral antithrombotics: a need for laboratory monitoring
Against J Thromb Haemost
(2010) - et al.
New oral antithrombotics: a need for laboratory monitoring
For J Thromb Haemost
(2010) - et al.
Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests A study in 9 Swiss laboratories
Thromb Res.
(2012) - et al.
In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939–an oral, direct Factor Xa inhibitor
J Thromb Haemost
(2005) - et al.
Interchangeability of Activated Clotting Time Values Across Different Point-of-Care Systems
Am J Cardiol
(2012) - et al.
Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs?
Pharmacol Res
(2009) - et al.
Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time
J Thromb Haemost
(2011) - et al.
Optimisation of the assays for the measurement of clotting factor activity in the presence of rivaroxaban
Thromb Res
(2012) - et al.
Pre-analytical factors that influence the interpretation of prothrombin time in the clinical laboratory: one year experience in a super speciality hospital in India
Clin Chim Acta
(2009)
Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement
Thromb Res
In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban
J Thromb Haemost
Rivaroxaban: an oral direct inhibitor of factor Xa
Am J Health Syst Pharm
Approval History
Xarelto-H-C-000944-X-0010 : EPAR - Assessment Report - Variation
Rivaroxaban in Patients with a Recent Acute Coronary Syndrome
N Engl J Med
Extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study protocol
J Thromb Thrombolysis
Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies
Thromb Haemost
Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial fibrillation population: A modelling analysis based on a nationwide cohort study
Thromb Haemost
Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement
Thromb Haemost
Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention
Clin Pharmacokinet
Population pharmacokinetics and pharmacodynamics of rivaroxaban–an oral, direct factor Xa inhibitor–in patients undergoing major orthopaedic surgery
Clin Pharmacokinet
Summary of Product Characteristic (SmPC)
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Contributed equally to this work.