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AOPXXX10.1177/1060028018811657Annals of PharmacotherapyBilloir et al

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Annals of Pharmacotherapy

Anti-Xa Oral Anticoagulant Plasma


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DOI: 10.1177/1060028018811657
https://doi.org/10.1177/1060028018811657

Rivaroxaban and Apixaban Quantification journals.sagepub.com/home/aop

in Emergency With LMWH Calibrator

Paul Billoir, PharmD1 , Virginie Barbay, MD, PhD1, Luc Marie Joly, MD1,
Marielle Fresel, PharmD1, Marie Hélène Chrétien, PharmD1,
and Véronique Le Cam Duchez, MD, PhD1

Abstract
Background: Oral anti-Xa inhibitors have demonstrated noninferiority to vitamin K antagonists (VKAs) for the
prevention of stroke in patients with atrial fibrillation and recurrent venous thromboembolism. They are associated with
a decrease in major bleeding. In contrast with VKA, no coagulation monitoring is required. However, in clinical practice,
determination of drug concentration is sometimes necessary. Objective: The objective of this study was to evaluate a
low-molecular-weight heparin (LMWH) calibrated anti-Xa assay for the quantification of rivaroxaban and apixaban plasma
concentration in emergency. Methods: The anti-Xa plasma concentration of rivaroxaban and apixaban were measured
in emergency in 210 patients using STA anti-Xa liquid assay. For each plasma concentration <150 ng/mL of rivaroxaban
or apixaban, an anti-Xa assay calibrated with LMWH was performed. Results: We demonstrated a significant correlation
between LMWH anti-Xa activity and rivaroxaban (R2 = 0.947) or apixaban (R2 = 0.959) concentration and a significant
correlation between rivaroxaban and apixaban plasma concentration (R2 = 0.972). A LMWH anti-Xa activity <0.50 IU/
mL could exclude a plasma concentration of rivaroxaban and apixaban >30 ng/mL and indicate the feasibility of invasive
procedure. Conclusion and Relevance: In the absence of a specific test, LMWH-calibrated anti-Xa assay could be used
to determine the presence and evaluate the plasma concentration of oral anti-Xa inhibitors. However, these initial findings
require confirmation using other chromogenic calibrated oral anti-Xa assays.

Keywords
factor Xa inhibitors, bleeding, drug screening, correlation between anticoagulant measurement, laboratory testing

Introduction international normalized ratio.7 Nevertheless, the labora-


tory testing of oral anti-Xa inhibitor plasma concentration
During the past 5 decades, vitamin K antagonists (VKAs) is recommended in bleeding situations, thrombotic recur-
have been the standard treatment for atrial fibrillation (AF) rence, and emergency surgery.8,9 Management of VKA-
and venous thromboembolic (VTE) disease. However, related bleeding is well standardized, with oral or
these treatments generate many adverse outcomes, such as intravenous administration of vitamin K110 associated with
major bleeding and particularly intracerebral haemor- prothrombin complex concentrate (PCC) in cases of severe
rhage.1,2 Recently, oral anti-Xa inhibitors have appeared as bleeding.11 The recommendations in cases of severe bleed-
an alternative, and their noninferiority, and sometimes their ing or emergency invasive procedures for patients treated
superiority, has been demonstrated with a reduction in with rivaroxaban, apixaban, or edoxaban are, if possible,
stroke, systemic thromboembolism, and intracranial hem- plasma concentration measurement and, if required, the
orrhage in AF and a decrease in major bleeding in VTE
patients.3,4 These drugs (rivaroxaban, apixaban, edoxaban)
inhibit activated factor X. Their predictable pharmacoki- 1
Rouen University Hospital, France
netic profiles and fewer drug interactions exempt them
Corresponding Author:
from coagulation monitoring; only kidney function has to Paul Billoir, Service d’Hématologie Biologique, Centre hospitalier
be evaluated before treatment initiation and sometimes fol- Universitaire Charles Nicolle, 1 rue de Germont, 76031 Rouen, France.
lowed.5,6 In contrast, VKAs require monitoring with the Email: paul.billoir@chu-rouen.fr
2 Annals of Pharmacotherapy 00(0)

use of nonspecific hemostatic agents (PCC: 50 U/kg).12,13 Assays


Antidotes to rivaroxaban and apixaban are currently being
evaluated, and first results from the ANNEXA-4 trial Whatever the indication for treatment, the dose, the fre-
were hemostasis restoration in 79% of cases, associated quency of drug intake, and the time of the last dose, blood
with 18% of thrombotic events during 30 days of follow- tests were carried out in the emergency department. Blood
up.14 Recently, the Food and Drug Administration (FDA) samples were taken by antecubital venepuncture and col-
approved andexanet alfa (AndexXa, Portola Pharmaceiticals) lected in vacutainer tubes containing buffered 0.109 M tri-
to reverse life-threatening or uncontrolled bleeding.15 The sodium citrate (1 part of citrate 3.2%/9 parts of blood).
usefulness of routine coagulation tests is limited. Normal Platelet-free plasma was prepared by centrifugation of
activated partial thrombin time (aPTT) and prothrombin citrate blood at 2500g for 15 minutes. For each sample, we
time (PT) are neither sensitive nor specific to determine measured the anti-Xa activity for LMWH, rivaroxaban, and
the presence of oral anti-Xa inhibitors or to evaluate their apixaban within 2 hours after sampling.
overdose plasma concentration.16 Even if the mechanism PT was measured with NEOPLASTINE CI (control time
of action of low-molecular-weight heparin (LMWH) and [CT]: 12.7 s, Diagnostica Stago, Asnières sur Seine,
anti-Xa inhibitors is different, the same laboratory assay France), and aPTT was realized with PTTA (CT: 32.8 s,
could be used to measure the anti-Xa concentration of Diagnostica Stago, Asnières sur Seine, France).
these drugs. Commercial assays based on the anti-Xa of Anti-Xa assays were done using a chromogenic method
rivaroxaban and apixaban have been developed to mea- with LIQUID ANTI-Xa kit (Diagnostica Stago, Asnières
sure plasma concentration.9,17 A drug plasma concentra- sur Seine, France). Specific calibrators were used for
tion of <50 ng/mL indicates the feasibility of surgery LMWH (Multi Hep Calibrator, Diagnostica Stago, Asnières
even in a context of high-risk bleeding.18-20 Two concerns sur Seine, France), for rivaroxaban (rivaroxaban calibrator,
are known to delay the laboratory measurement of plasma Diagnostica Stago, Asnières sur Seine, France), and for
concentration and the care of patients in the emergency apixaban (apixaban calibrator, Diagnostica Stago, Asnières
department: first, the lack of availability of specific sur Seine, France). Methodological differences between
assays20 and, second, the lack of data on the oral anti-Xa assays were represented by a higher plasma dilution for
inhibitor taken by the patient. A recent publication dem- rivaroxaban and apixaban (1/9) compared with LMWH
onstrated a good correlation between anti-Xa activity and (1/5) to reduce limited range linearity.
rivaroxaban by high-performance liquid chromatography Each measurement was done on the STA-R Max coagu-
determination in healthy volunteers.21 The recommenda- lation analyzer (Diagnostica Stago, Asnières sur Seine,
tion of the International Council of Standardization in France) and reported in international units per milliliter
Haematology is to use validated chromogenic anti-Xa (LMWH) or nanogram per milliliter (direct anti-Xa inhibi-
assay, if liquid chromatography-tandem mass spectrome- tor). Assays of edoxaban were not performed, because of
try is not available, for rapid quantification of anti-Xa the nonavailability of this drug in France. Creatinine mea-
plasma concentration.9 surement was performed with Crea Jaffé gen.2 (Roche,
The objective of this study was to evaluate a Boulogne Billancourt, France) on Cobas 8000 (Roche,
­L MWH-calibrated anti-Xa assay for the quantification Boulogne Billancourt, France).
of rivaroxaban and apixaban plasma concentrations in
emergency. Statistical Analysis
Data are expressed as mean  ± SD. The Pearson correlation
Methods test was performed to analyze the correlation between
LMWH, rivaroxaban, and apixaban anti-Xa activity in
Patients patients with plasma concentration <150 ng/mL (patient
trough plasma concentration and linearity limit of assay22).
This retrospective study was conducted between 2013 and
Correlations and linear regressions were performed using R
2017. Included patients had laboratory measurement of
software v3.4.3. A Bland-Altman plot was performed with
rivaroxaban and apixaban plasma concentrations for bleed-
Graphpad Prism 5.0.
ing or overdosage suspicion, emergency and nonemergency
procedures or recurrent thrombosis, and plasma creatinine
for glomerular filtration rate. Results
Clinical data, biological results, and treatment and clini- Clinical Characteristics and Indications of
cal outcomes were retrieved from hospital medical records.
The study has been approved by the local IRB (Comité
Dosage
d’Ethique pour la Recherche Non Interventionnelle) of The anti-Xa plasma concentration of rivaroxaban and
Rouen University Hospital. ­apixaban were measured for 235 patients who presented to
Billoir et al 3

Table 1.  Patient General Characteristics.a concentration (n = 37; r2 = 0.947, P < 0.001) or apixaban
Rivaroxaban Apixaban (n = 37; r2 = 0.959, P < 0.001) concentration (Figures 1A
and 1B, respectively). There was also a significant correla-
n 135 75 tion between rivaroxaban concentration and apixaban con-
Age (years) 67.3 ± 17.9 77.0 ± 12.6 centration (r2 = 0.972; Figure 1C).
Gender 70 F/65 M 28 F/47 M Using the correlation equation curve, we calculated riva-
Treatment indication  
roxaban concentration or apixaban concentration based on
 NVAF 102 70
LMWH-calibrated anti-Xa activity. Then, we compared
  Thromboembolic event 33 5
calculated, and measured concentration using the Bland-
Reduced dose 19 16
Altman representation. The overall bias of the Bland-
Chronic kidney disease  
  Stage 3 13 12
Altman difference plot is zero for rivaroxaban (Figure 2A)
  Stage 4 5 1 and apixaban (Figure 2B). Moreover, the Bland-Altman
Dosage indication   representation of rivaroxaban versus apixaban shows a bias
 Bleeding 35 16 equal to −5.7, with apixaban concentration higher than riva-
  Including major bleeding 25 15 roxaban (Figure 2C).
  Bleeding suspicion 15 9
  Urgent procedure 55 5
Recurrent thrombosis 9 10 Oral Anti-Xa Inhibitor Plasma Concentration
Including recurrent stroke 7 4 Using LMWH Anti-Xa Activity Calculation for
Thrombosis suspicion 5 9 Safe Emergency Procedures
Kidney or liver disease 13 5
Other 21 3 Then, because no bias was observed between the calcu-
Plasmatic concentration (ng/mL) 130 [15-580] 95 [9-580] lated and measured concentrations, we used the correla-
tion equation curve to calculate the LMWH activity
Abbreviations: F, female; M, male; NVAF, nonvalvular atrial fibrillation. corresponding to 30 ng/mL (arbitrarily defined as thresh-
a
Age is expressed as mean ± SD. Reduced dose corresponds to 15
old of nonbleeding risk for neurosurgical procedures19)
mg/d of rivaroxaban and 2 × 2.5 mg/d of apixaban. Stage 3 corresponds
to 30 to 44 mL/min of estimated glomerular filtration rate, and stage 4 and 50 ng/mL for the oral anti-Xa inhibitor plasma con-
corresponds to 15 to 29 mL/min with Cockcroft and Gault. Plasmatic centration (arbitrarily defined as threshold of nonbleed-
anti-Xa concentration is expressed as mean [Minimal concentration − ing risk for other surgeries20) for rivaroxaban and
Maximal concentration].
apixaban. For each plasma concentration and treatment,
we calculated the sensitivity, specificity, positive predic-
Rouen University Hospital’s emergency department tive value, and negative predictive value of these LMWH
between June 2013 and October 2017. A total of 25 mea- activities. LMWH anti-Xa activity <0.5 and <1 IU/mL
surements were excluded from analysis because of repeated exclude oral anti-Xa inhibitor plasma concentration >30
measurements during hospitalization or plasma hemolysis. and >50 ng/mL, respectively. All these results are
Among the 210 included patients, oral anti-Xa inhibitors reported in Table 2.
were administered in 41 for a thromboembolic event and in
169 for nonvalvular AF at full or reduced dose. Indications
of dosage were essentially recurrent thrombosis, bleeding, Discussion
and emergency procedures. Details are reported in Table 1. The findings of our retrospective study demonstrate that
oral anti-Xa inhibitor plasma concentration was mainly
Plasma Measurement of Oral Anti-Xa Inhibitors performed for emergency procedures or suspicion of
bleeding events. Obviously, the first adverse effect of all
Using LMWH-Calibrated Anti-Xa Concentration
anticoagulant treatment is a bleeding risk. Compared with
First, we confirmed that there was an association, but a VKA, oral anti-Xa inhibitors have been reported to reduce
very important dispersion, between PT, aPTT, and rivar- major bleeding, intracranial bleeding in stroke, and
oxaban (n = 135; ρ < 0.001, R2 = 0.7238; ρ < 0.001, R2 venous thromboembolism prevention3,4,23 but to increase
= 0.3558; respectively) or apixaban (n = 75; ρ < 0.001, r2 gastrointestinal bleeding.24 Expected peak and trough
= 0.6892; ρ < 0.001, r2 = 0.4815; respectively). Then, we plasma concentration in a stroke prevention study were
evaluated the possibility of detecting the presence of rivar- 249 ng/mL (184-343) and 44 ng/mL (12-137) for rivar-
oxaban and apixaban using LMWH-calibrated anti-Xa oxaban and 171 ng/mL (91-321) and 103 ng/mL (41-230)
activity. In 37 patients, plasma concentrations were mea- for apixaban, respectively.9 In our study, assays were per-
sured on the 3 different assays. We demonstrated a correla- formed in an emergency situation—therefore, neither at
tion between LMWH anti-Xa activity and rivaroxaban peak nor at trough systematically.
4 Annals of Pharmacotherapy 00(0)

Figure 1.  Correlation between low-molecular-weight heparin (LMWH), rivaroxaban (A), and apixaban (B) measurement; correlation
between rivaroxaban and apixaban measurement (C). P < 0.001 for each correlation.

Figure 2.  Bland Altman representation between the calculated versus the measured concentration of rivaroxaban (A) and apixaban
(B). C. Bland-Altman comparison of measured rivaroxaban concentration versus measured apixaban concentration.

Table 2.  Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value for a Safe Emergency Procedure.

Sensitivity Specificity Positive Predictive Value Negative Predictive Value


Rivaroxaban <30 ng/mL LMWH-calibrated anti-Xa activity = 0.46 U/mL
100% 100% 100% 100%
Apixaban <30 ng/mL LMWH-calibrated anti-Xa activity = 0.40 U/mL
100% 100% 100% 100%
Rivaroxaban <50 ng/mL LMWH-calibrated anti-Xa activity = 0.89 U/mL
95.6% 86.7% 91.7% 92.7%
Apixaban <50 ng/mL LMWH-calibrated anti-Xa activity = 0.79 U/mL
95.7% 100% 100% 93.3%

Abbreviation: LMWH, low-molecular-weight heparin.

The perioperative management of patients treated with Conversely, LMWH-calibrated anti-Xa assay is more often
an oral anti-Xa inhibitor is to administer a last dose 3 days available in routine laboratory practice, and we demon-
before surgery.25 For emergency procedures, the estimation strated that LMWH-calibrated anti-Xa could be used to
of the bleeding risk is based on the drug concentration at the determine the presence of rivaroxaban or apixaban. Our
time of the procedure.19,20 To our knowledge, oral anti-Xa results show the feasibility of using an LMWH-calibrated
assay is not readily available in all hospital laboratories. anti-Xa assay to quantify rivaroxaban and apixaban plasma
This could be related to the cost of the assay, which requires concentrations. A LMWH anti-Xa activity of <0.50 IU/mL
specific calibration and controls for each drug. For these corresponds to a rivaroxaban or apixaban plasma concen-
laboratories, aPTT and PT tests are not the solution. Normal tration <30 ng/mL, representing a cutoff for safe indication
PT and aPTT probably exclude excess levels of rivaroxa- of emergency procedures with 100% sensitivity and speci-
ban, but they have inadequate sensitivity for apixaban.16,26 ficity. Then, we confirmed the results of an in vitro study
Billoir et al 5

that showed a good correlation between LMWH anti-Xa patients treated with anti-Xa oral inhibitors to validate the
and oral anti-Xa inhibitor concentrations.27 safety concentration of the drug.
The reference method for measuring rivaroxaban and
apixaban plasma concentration is ultraperformance liquid
Conclusion and Relevance
chromatography tandem mass spectrometry.28,29 However,
this method is complex and cannot be used in all labora- In the absence of a specific test, LMWH-calibrated anti-Xa
tories and especially in emergency settings. Nevertheless, assay could be used to determine the presence of and evalu-
the chromogenic assay gives reproducible results. In a ate oral anti-Xa plasma concentration inhibitors before per-
multicenter study, interlaboratory and intralaboratory forming emergency surgical procedures. It could also be
precision were satisfactory with chromogenic assay, used for the indication for a reversal agent. However, these
except for the lower limit (20 ng/mL).30 The recommen- initial findings require confirmation using other chromo-
dations of the French Working Group on perioperative genic-calibrated anti-Xa assays.
hemostasis concluded that a DOAC plasma concentration
of 30 ng/mL indicates the feasibility of performing neuro- Acknowledgments
surgical procedures even in a context of high-risk bleed- The authors are grateful to N. Sabourin-Gibbs, Rouen University
ing19 and of 50 ng/mL for other surgeries.20 Indeed, the Hospital, for editing the article. We are indebted to T. Duflot,
possibility of estimating apixaban concentration or rivar- Pharm D, Rouen University Hospital for statistical analysis. We
oxaban concentration using LMWH-calibrated anti-Xa would like to thank Dr V. Brunel, Department of Biochemistry
assay could reduce the time delay for an emergency pro- from Rouen University Hospital, for his contribution.
cedure. On the other hand, even if specific dosages are
not available, the results of LMWH-calibrated anti-Xa Declaration of Conflicting Interests
assay could help limit the use of specific antidotes such as
The authors declared no potential conflicts of interest with respect
the FDA-approved but very expensive andex- to the research, authorship, and/or publication of this article.
anet alfa15($11 000 per 400 mg; 880 to 1800 mg recom-
mended administration). Another study evaluated the Funding
correlation between LMWH anti-Xa and rivaroxaban
plasma concentration.31 In this study, 3 different kits were The authors received no financial support for the research, author-
ship, and/or publication of this article.
tested for the measurement of LMWH anti-Xa activity.
An acceptable correlation was demonstrated with 2 of
ORCID iD
these 3 reagents, but the STA liquid anti-Xa method was
the most sensitive to the presence of rivaroxaban. We Paul Billoir https://orcid.org/0000-0001-5632-7713.
confirmed the results of the Gosselin et al31 study.
Moreover, in the systematic review of Samuelson et al,32 References
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