Rivaroxaban: A Practical Guide V1.0 – 6 July 2012 · Rivaroxaban: A Practical Guide V1.0 – 6 July 2012 2 Writing and Review Committee Christophe Beauloye, Cliniques Universitaires

Rivaroxaban: A Practical Guide V1.0 – 6 July 2012

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RIVAROXABAN A Practical Guide V1.0 – 06 July 2012


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Writing and Review Committee

Christophe Beauloye, Cliniques Universitaires St Luc, Woluwé-St-Lambert

Jean-Michel Dogné, FUNDP, Namur

Jonathan Douxfils, FUNDP, Namur

Marnix Goethals, H.-Hartziekenhuis, Roeselare-Menen

Philippe Hainaut, Cliniques Universitaires St Luc, Woluwé-St-Lambert

Hein Heidbuchel, Universitaire Ziekenhuizen, Leuven

Cédric Hermans, Cliniques Universitaires St Luc, Woluwé-St-Lambert

Brigitte Ickx, Hospital Erasme, ULB, Bruxelles

Kristin Jochmans, Universitaire Ziekenhuis, Brussel

Serge Motte, Hospital Erasme, ULB, Bruxelles

François Mullier, Centre Hospitalier Universitaire Mont-Godinne, Yvoir ; FUNDP, Namur

André Peeters, Cliniques Universitaires St Luc, Woluwé-St-Lambert

Christophe Scavée, Cliniques Universitaires St Luc, Woluwé-St-Lambert

Peter Sinnaeve, Universitaire Ziekenhuizen, Leuven

Muriel Sprynger, Centre Hospitalier Universitaire du Sart Tilman, Liège

Vincent Thijs, Universitaire Ziekenhuizen, Leuven

Chantal Vandenbroeck, Universitair Ziekenhuis Antwerpen, Edegem

Erik Vandermeulen,Universitaire Ziekenhuizen, Leuven

Peter Verhamme, Universitaire Ziekenhuizen, Leuven


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Table of Contents Writing and Review Committee ................................................................................................. 2

List of Figures .............................................................................................................................. 5

List of Tables ............................................................................................................................... 6

List of Abbreviations ................................................................................................................... 7

Disclaimer ................................................................................................................................... 9

Preamble .................................................................................................................................. 10

Guide to treatment with rivaroxaban ...................................................................................... 11

1. How to initiate and follow-up patients on rivaroxaban? ............................................. 11

1.1. Dosing schemes in the different indications.......................................................... 11

1.2. How to switch between different anticoagulant therapies? ................................. 12

1.2.1. Switch from another anti-thrombotic agent to rivaroxaban ......................... 12

Vitamin K antagonist to rivaroxaban ........................................................................ 12

Low molecular weight heparin to rivaroxaban ........................................................ 13

Intravenous unfractioned heparin to rivaroxaban ................................................... 14

Dabigatran to rivaroxaban ....................................................................................... 14

Low dose acetylsalicylic acid to rivaroxaban ............................................................ 15

1.2.2. Switch from rivaroxaban to another anti-thrombotic agent ......................... 15

Rivaroxaban to vitamin K antagonist ....................................................................... 15

Rivaroxaban to low molecular weight heparin ........................................................ 16

Rivaroxaban to intravenous unfractioned heparin .................................................. 17

Rivaroxaban to dabigatran ....................................................................................... 17

1.2.3. Summary switching schemes ......................................................................... 18

2. Is there a need for biological measurement of the anticoagulant effect of

rivaroxaban? ......................................................................................................................... 19

2.1. Is routine laboratory monitoring required for rivaroxaban? ................................. 19

2.2. Performing point measurements in specific clinical situations ............................. 19

2.2.1. Prothrombin time and international normalized ratio .................................. 20

2.2.2. Anti-Factor Xa chromogenic assays ................................................................ 21

2.3. Summary on the impact of rivaroxaban on standard coagulation tests ............... 22

3. Drug-drug interactions ................................................................................................. 23


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4. How to manage bleeding complications under rivaroxaban? ..................................... 26

5. What in case of an overdose without bleeding? ......................................................... 28

6. Patients undergoing an intervention or surgery .......................................................... 29

6.1. Elective procedures ................................................................................................ 29

6.1.1. Minor interventions without significant bleeding risk ................................... 29

When to interrupt rivaroxaban? .............................................................................. 29

When to restart rivaroxaban? .................................................................................. 30

6.1.2. Interventions with increased bleeding risk .................................................... 30

When to interrupt rivaroxaban therapy? ................................................................. 30

When to restart rivaroxaban? .................................................................................. 30

6.2. Urgent surgical interventions ................................................................................ 31

6.3. Specific situations .................................................................................................. 32

6.3.1. Neuraxial (spinal/epidural) anaesthesia ......................................................... 32

7. Patients with atrial fibrillation and coronary heart disease......................................... 33

7.1. Acute management of acute coronary syndrome ................................................. 33

7.2. Long-term treatment after acute coronary syndrome .......................................... 33

8. Cardioversion in a rivaroxaban treated patient ........................................................... 34

9. Patients presenting with non-hemorrhagic stroke while on rivaroxaban ................... 35

9.1. Acute phase ............................................................................................................ 35

9.2. Post-acute phase .................................................................................................... 35

9.3. Initiation of rivaroxaban following an ischaemic stroke or transient ischemic

attack 35

10. Renal and hepatic (dys)function .............................................................................. 36

10.1. Renal (dys)function ............................................................................................ 36

10.2. Hepatic (dys)function ......................................................................................... 37

11. Patient education ..................................................................................................... 37

References ................................................................................................................................ 38


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List of Figures FIGURE 1: HOW TO SWITCH FROM VKA TO RIVAROXABAN? ............................................................................... 13

FIGURE 2: HOW TO SWITCH FROM LMWH TO RIVAROXABAN? ........................................................................... 13

FIGURE 3: HOW TO SWITCH FROM INTRAVENOUS UFH TO RIVAROXABAN? ...................................................... 14

FIGURE 4: HOW TO SWITCH FROM DABIGATRAN TO RIVAROXABAN BASED ON PATIENT’S RENAL FUNCTION? 15

FIGURE 5: HOW TO SWITCH FROM RIVAROXABAN TO VKA? ............................................................................... 16

FIGURE 6: HOW TO SWITCH FROM RIVAROXABAN TO LMWH? ........................................................................... 16

FIGURE 7: HOW TO SWITCH FROM RIVAROXABAN TO INTRAVENOUS UFH? ...................................................... 17

FIGURE 8: HOW TO SWITCH FROM RIVAROXABAN TO DABIGATRAN? ................................................................ 17

FIGURE 9: PHARMACOKINETIC PROFILE RIVAROXABAN: INHIBITION OF FXA ACTIVITY IS DOSE DEPENDENT .... 19

FIGURE 10: INFLUENCE OF RIVAROXABAN ON PROTHROMBIN TIME .................................................................. 20

FIGURE 11: RELATIONSHIP BETWEEN THE RIVAROXABAN PLASMA CONCENTRATION AND THE TIME AFTER

ADMINISTRATION ........................................................................................................................................ 22

FIGURE 12: PHARMACODYNAMIC PROFILE OF RIVAROXABAN IN A ONE AND TWICE DAILY DOSING REGIMEN

RESPECTIVELY IN THE LOWER AND UPPER PICTURES ................................................................................. 26

FIGURE 13: ADDITIONAL MEASURES ARE ADDED STEPWISE DEPENDING ON THE SEVERITY OF BLEEDING ........ 28

FIGURE 14: INTERRUPTING RIVAROXABAN FOR INTERVENTIONS WITH A BLEEDING RISK .................................. 31


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List of Tables TABLE 1: PHARMACOKINETIC AND PHARMACODYNAMIC CHARACTERISTICS OF RIVAROXABAN 10

TABLE 2: DOSING SCHEMES IN THE DIFFERENT INDICATIONS OF RIVAROXABAN 11

TABLE 3: RELATION BETWEEN INR MEASURES UNDER VKA TREATMENT AND INITIATION OF RIVAROXABAN 12

TABLE 4: SUMMARY SWITCHING SCHEME BETWEEN THE DIFFERENT ANTICOAGULANTS 18

TABLE 5: SENSITIVITY OF DIFFERENT PT-REAGENTS TO RIVAROXABAN 21

TABLE 6: IMPACT OF RIVAROXABAN ON THE DIFFERENT STANDARD COAGULATION TESTS 22

TABLE 7: DRUG-DRUG INTERACTIONS BASED ON THE CYP3A4 AND P-GP INTERACTIONS 25

TABLE 8: RECOMMENDED A-SPECIFIC PRO-HEMOSTATIC AGENTS 27

TABLE 9: RECOMMENDATIONS IN CASE OF PROCEDURES AND SURGICAL INTERVENTIONS 32

TABLE 10: RECOMMENDED TREATMENT DOSES FOR PATIENTS WITH RENAL IMPAIRMENT 36


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List of Abbreviations

µg

microgram

ACS

acute coronary syndrome

AF

atrial fibrillation

aPTT

activated partial thromboplastin time

ASA

acetylsalicylic acid

AUC

area under the curve

bid

bis in die (twice daily)

CHD

coronary heart disease

CrCl CT

creatinine clearance computed tomography

CYP3A4

cytochrome P450 3A4

DVT DRVVT

deep vein thrombosis dilute Russell’s viper venom

EMA

European Medicines Agency

G

gram

H

hour

H2O

water

ICH

intracranial hemorrhage

INR IV

international normalized ratio intravenous

kg

kilogram

l

liter

LMWH

low molecular weight heparin

mg

milligram

min

minute

ml

milliliter

MRI

magnetic resonance image

ng

nanogram

NOAC

new oral anticoagulant

NSAIDs

non-steroidal anti-inflammatory drugs

OAC

oral anticoagulant

od

omne in die (once daily)

PCC

prothrombin complex concentrate

PCI

percutaneous coronary intervention

PD

pharmacodynamic

PE

pulmonary embolism

P-gp

P-glycoprotein

PK

pharmacokinetic

POC PT

point-of-care prothrombin time


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RBPA red blood loss per anum

sec

seconds

SmPC

summary of product characteristics

SPAF

stroke prevention in atrial fibrillation

T1/2

half-life

TEE TGA TIA

transesophagal echocardiogram thrombin generation assay transient ischemic attack

Tmax

time to reach maximum (peak) plasma concentration

U

Units

UFH

unfractionated heparin

VKA

vitamin K antagonist

VTE

venous thromboembolism


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Disclaimer

Current practical guide was developed to enhance the understanding on when and how to

prescribe rivaroxaban. It is based on available scientific literature, existing guidelines and/or

the Summary of Product Characteristics (SmPC) of rivaroxaban. Some advice also comes

from clinical experience and the extrapolation of existing knowledge about the concerned

indications, coagulation system and anticoagulant drugs. This guide should not be

considered as a formal recommendation but rather as an addition to the regular product

information, providing pragmatic advice for the use of rivaroxaban in daily practice. The

authors cannot be held liable for the management resulting from this guidance.

Please note that the guidance provided in this document reflects our current state of

knowledge about rivaroxaban but is likely to change in the future.


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Preamble

Rivaroxaban has been approved by the European Medicines Agency (EMA) for the

prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee

replacement surgery since 20081. In December 2011, rivaroxaban was approved for the

prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation

with at least one risk factor (congestive heart failure, hypertension, age ≥ 75 years, diabetes

mellitus, prior stroke or transient ischaemic attack). A third approval was granted by the

EMA for the treatment of deep vein thrombosis (DVT), and the prevention of recurrent DVT

and pulmonary embolism (PE) following an acute DVT1.

This new oral anticoagulant (NOAC) is the first available oral, direct and selective Factor Xa

inhibitor. It has a predictable pharmacokinetic profile across a wide spectrum of patients

(age, gender, weight and race). Its absolute bioavailability exceeds 80 %. Since at the higher

doses (15mg and 20mg), the absorption decreases somewhat, the intake of the drug with

food is preferred2. Rivaroxaban is rapidly absorbed with maximum concentrations appearing

2 to 4 hours after oral intake3. The half-life (T½) of rivaroxaban is 5 to 13 hours3, 8.

Parameter Rivaroxaban

Mode of action Inhibition of free, prothombinase bound and clot-associated Factor Xa4

Type of inhibition Direct, selective, competitive and reversible5

Oral bioavailability 80–100%

Plasma protein binding 92–95%

T½ (h) 5-9 (young healthy)

11–13 (elderly)6

Renal clearance 33%7

Tmax

(h) 2–43, 8

Table 1: Pharmacokinetic and pharmacodynamic characteristics of rivaroxaban9

About one-third of the drug is excreted unchanged in the urine while the remaining two-

thirds are metabolized to inactive metabolites in the liver which then become eliminated via

the kidney or the colon in an approximate 50% ratio9. Rivaroxaban has a low propensity for

drug-drug interactions with the frequently used medications (table 1)9.

http://www.thrombosisadviser.com/en/_global/glossary.php#glossary-venous_thromboembolism


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Guide to treatment with rivaroxaban

1. How to initiate and follow-up patients on rivaroxaban?

1.1. Dosing schemes in the different indications

Rivaroxaban may be used for the indications mentioned in table 2. The dose regimens are

presented as recommended in the summary of product characteristics (SmPC). In some

patient populations, the optimal dose for efficacy (prevention of thrombosis) and safety

(bleeding) may not be well-defined at this stage of clinical development (see also sections 7,

8 and 10 on acute coronary syndrome , cardioversion, kidney and liver function

respectively)9.

Indication Dose and regimen Duration of therapy

Prevention of VTE after elective

hip replacement surgery

10 mg od 5 weeks*

Prevention of VTE after elective

knee replacement surgery

10 mg od 2 weeks*

Acute treatment of proximal

DVT

Intensified regimen of 15 mg

bid

3 weeks

Continued treatment and

prevention of recurrent DVT

and PE

20 mg od

15 mg od for patients with

moderate to severe renal

impairment**

At least 3 months

3 months of therapy for VTE caused by

transient risk factors (recent surgery,

trauma, immobilization,…) or in case of

increased bleeding risk

For idiopathic VTE or when permanent risk

factors are present, the risks and benefits

of continued anticoagulant treatment

need to be evaluated

Prevention of stroke and

systemic embolism in patients

with non-valvular AF

20 mg od

15 mg od for patients with

moderate to severe renal

impairment**

Clinical judgment applies: rivaroxaban is

recommended for long term use, provided

the benefit of prevention of stroke and

systemic embolism outweighs the risk of

bleeding

* The registered duration of thromboprophylaxis with rivaroxaban for VTE prevention is 2 weeks after elective knee

replacement and 5 weeks after elective hip replacement. Individual patient management may differ from the registered

durations.

**Moderate renal impairment: CrCl: 30 - 49 ml/min, Severe renal impairment: CrCl: 15 - 29 ml/min, see further

considerations in section 11.

Table 2: Dosing schemes in the different indications of rivaroxaban9


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Taking into account the short half-life of all NOACs, compliance is of major importance for

these drugs. The intake at a similar time each day is therefore highly recommended (see also

section 11 on patient education).

1.2. How to switch between different anticoagulant therapies?

In certain situations, switching from one anticoagulant to another one will be needed. It is

important to safeguard the continuation of anticoagulant therapy while minimizing the risk

for bleeding during any transition to an alternate anticoagulant.

1.2.1. Switch from another anti-thrombotic agent to rivaroxaban

Vitamin K antagonist to rivaroxaban

Following discontinuation of a vitamin K antagonist (VKA), an international normalized ratio

(INR) determination is important for the timing of the initiation of rivaroxaban. Rivaroxaban

can safely be initiated once the INR is lower than 2.5. It is recommended to repeat an INR

measurement in case of an INR exceeding 2.5 before initiating rivaroxaban, though

individual patient management may vary depending on the INR and the half-life of the VKA

(table 3 and figure 1).

Switching recommendations

INR < 2 Start rivaroxaban immediately

INR 2.0 – 2.5 Start rivaroxaban the next day

INR > 2.5

Repeat the INR measurement after stopping VKA for 1 to 3 days, taking into account the INR and the half-life of the VKA

acenocoumarol (Sintrom®):

warfarin (Marevan®):

phenprocoumon (Marcoumar®) :

8-14 hours

38-42 hours

120-200 hours

Table 3: Relation between INR measures under VKA treatment and initiation of rivaroxaban


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Figure 1: How to switch from VKA to rivaroxaban?

Low molecular weight heparin to rivaroxaban

Rivaroxaban can be started at the time of the next planned administration of low molecular

weight heparin (LMWH) (figure 2).

Figure 2: How to switch from LMWH to rivaroxaban?


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Intravenous unfractioned heparin to rivaroxaban

Following the short half-life of intravenous unfractioned heparin (IV UFH) (T½ of ±2 hours),

rivaroxaban can be started once the IV UFH is discontinued (figure 3).

Figure 3: How to switch from intravenous UFH to rivaroxaban?

Dabigatran to rivaroxaban

When switching from dabigatran to rivaroxaban, renal function, dabigatran half-life and the

daily dose need to be taken into consideration. Renal clearance of dabigatran is

approximately 80%10. In patients with normal renal function (≥50ml/min CrCL) the half-life

equals 13-15 hours while for patients with a creatinine clearance of 30 to 50ml/min the T½

increases to approximately 18 hours10.

Currently, there is no clinical data available on how to switch from dabigatran to

rivaroxaban. The following guidance is based on expert consensus (figure 4).

For patients with a normal renal function (≥50ml/min CrCL), rivaroxaban 20 mg od

can be initiated 12 to 24 hours after the last intake of dabigatran.

For patients with moderate renal impairment (30-50ml/min CrCL), the time window

between the last intake of dabigatran and the initiation of rivaroxaban 15 mg od is

recommended to be at least 24 to 48 hours.

For patients with severe renal impairment (15-29ml/min CrCL) caution is advised.

When considering a treatment switch from dabigatran to rivaroxaban 15 mg od, a

longer delay (at least 48h) might be preferred.


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* Caution is advised when considering a treatment switch from dabigatran to rivaroxaban 15 mg od for patients with severe

renal impairment (15-29ml/min CrCL)

Figure 4: How to switch from dabigatran to rivaroxaban based on patient’s renal function?

Low dose acetylsalicylic acid to rivaroxaban

Considering the increased bleeding risk with combined therapy of acetylsalicylic acid (ASA)

and rivaroxaban, the need for concomitant low-dose ASA after initiating rivaroxaban needs

to be carefully evaluated. In the absence of a specific indication for continuing ASA, ASA

should no longer be administered after initiating rivaroxaban (see also sections 3 and 7 on

drug-drug interactions and Acute Coronary Syndrome respectively).

1.2.2. Switch from rivaroxaban to another anti-thrombotic agent

Rivaroxaban to vitamin K antagonist

The onset of action of VKAs generally is delayed. For this reason, rivaroxaban and the VKA

should be administered concomitantly until the INR reaches the therapeutic range (figure 5).

Because rivaroxaban may also increase the INR, INR testing should be performed just before

the next intake of rivaroxaban to minimize the impact of rivaroxaban on the INR

measurement (see also section 2 on measurement of anticoagulant effect).

A loading dose is not recommended for acenocoumarol (Sintrom®) and warfarin (Marevan®).


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Figure 5: How to switch from rivaroxaban to VKA?

Rivaroxaban to low molecular weight heparin

LMWH can be started at the time of the next planned administration of rivaroxaban (i.e. 24h

for the SPAF indication and the prevention and continued treatment of VTE and 12h in the

acute treatment of VTE) (Figure 6).

Figure 6: How to switch from rivaroxaban to LMWH?


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Rivaroxaban to intravenous unfractioned heparin

IV UFH can be started at the time of the next planned administration of rivaroxaban (i.e. 24h

for the SPAF and the prevention and continued treatment of VTE and 12h in the acute

treatment of VTE) (Figure 7).

Figure 7: How to switch from rivaroxaban to intravenous UFH?

Rivaroxaban to dabigatran

Dabigatran can be initiated at the time the next dose of rivaroxaban would normally have

been taken within the approved indications (figure 8).

Figure 8: How to switch from rivaroxaban to dabigatran?


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1.2.3. Summary switching schemes

TO RIVAROXABAN

VKA

Rivaroxaban can be initiated once the INR is lower than 2.5

FRO

M

INR < 2.0

INR 2.0 – 2.5

INR > 2.5

Start rivaroxaban immediately

Start rivaroxaban the next day

Repeat INR after 1-3 days, considering VKA half-life

LMWH Start rivaroxaban at planned next administration of LMWH

IV UFH Start rivaroxaban immediately after stopping IV UFH

Dabigatran

When switching from rivaroxaban to dabigatran the renal function is an important parameter

≥50ml/min CrCL

30-50ml/min CrCL

15-29ml/min CrCL

start rivaroxaban 20mg od 12-24 hours after last dabigatran intake

start rivaroxaban 15mg od 24-48 hours after last dabigatran intake

start rivaroxaban 15mg od at the earliest 48 hours after last dabigatran intake

ASA In the absence of a specific indication for continuing ASA, ASA should no longer be administered

after initiating rivaroxaban

TO

VKA LMWH DABIGATRAN IV UFH

FRO

M R

IVA

RO

XA

BA

NN

Rivaroxaban and the VKA

should be administered

concomitantly until the INR

exceeds 2.0

Important! INR testing to be

performed just before the next

intake of rivaroxaban)

Initiate LMWH at the

time the next

rivaroxaban would

have been taken

Initiate dabigatran at

the time the next

rivaroxaban would

have been taken

Initiate IV UFH at the

time the next

rivaroxaban would

have been taken

Table 4: Summary switching scheme between the different anticoagulants


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2. Is there a need for biological measurement of the

anticoagulant effect of rivaroxaban?

2.1. Is routine laboratory monitoring required for rivaroxaban?

Because of its predictable pharmacokinetic profile, rivaroxaban does not require routine

coagulation monitoring. Furthermore and importantly, in routine clinical practice neither

the rivaroxaban dose nor the dosing intervals need to be altered in response to changes in

laboratory coagulation parameters. Routine monitoring tests are not designed for the new

oral anticoagulants.

Nevertheless, in some clinical circumstances, a point measurement to assess the rivaroxaban

plasma concentration may still be useful and desired (see also section 2.3).

2.2. Performing point measurements in specific clinical situations

As expected based on rivaroxaban’s mode of action and its pharmacokinetic profile,

inhibition of Factor Xa activity is dose-dependent (Figure 9). This dose-dependency will

variably and inconsistently affect several clotting tests including the prothrombin time (PT),

International Normalized Ratio (INR) and the activated Partial Thromboplastin Time (aPTT)4,

5. Therefore, when interpreting a coagulation assay in a rivaroxaban treated patient, the

pharmacokinetic profile of rivaroxaban (i.e. Tmax at 2 to 4 hours post-dose and the T1/2 of 5

to 13 hours) should be taken into account. The results from a coagulation assay obtained in

a blood sample taken 2 to 4 hours after rivaroxaban intake (Tmax) will likely differ from those

in a sample taken at trough levels. In clinical practice, this implies that the time delay

between rivaroxaban intake and blood sampling needs to be carefully recorded when

biological monitoring is performed.

Figure 9: Pharmacokinetic profile rivaroxaban: inhibition of FXa activity is dose dependent

8


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2.2.1. Prothrombin time and international normalized ratio

Prothrombin time

There are several commercial assays available to measure the prothrombin time (PT). When

performing these tests, it can be concluded that rivaroxaban prolongs the PT in a

concentration-dependent manner11, 12. The sensitivity of these assays for rivaroxaban

measurement varies greatly while at the same time this sensitivity is generally rather low

(figure 10 and table 5). Furthermore, inter- and intra-variability of these PT assays is high.

The interpretation of a PT point measurement therefore highly depends upon which assay is

being used and where it is being performed. The most sensitive PT assays will be able to

measure the presence of rivaroxaban in the blood at the higher concentrations namely

within a fairly short time frame after the drug has been taken (from 1 – 7 hours post-dose).

Therefore, at best, a PT test will be able to provide information on whether or not

rivaroxaban has actually been taken.

Figure 10: Influence of rivaroxaban on prothrombin time

A linear concentration-dependent prolongation of the PT is observed. The sensitivity (represented by

the slope of the linear regression) depends on the reagent used11, 12

.

Up to this date, there is no data available that associate PT changes with bleeding risk.

Neither is there data suggesting that PT is a valid marker for the anticoagulant efficacy. In

emergency situations in patients on rivaroxaban, a prolonged PT therefore may at most

suggest the recent intake of the drug; prolonged PT would suggest the likely intake of

rivaroxaban in the last 7 hours. Conversely, a non-delayed PT will only suggest that

rivaroxaban was likely taken more than approximately 7 hours ago. Due to this limitation,

the planning of an urgent surgical/invasive procedure based on the results of the PT/aPTT


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(as for VKAs and unfractionated heparin) is not a validated strategy and cannot be

recommended at the current time

Reagent Sensitivity

Triniclot PT Excel S +++++

Neoplastin R ++++

Recombiplastin ++++

Neoplastin CI+ +++

Triniclot PT HTF ++

Triniclot PT Excel ++

Innovin +

Table 5: Sensitivity of different PT-reagents to rivaroxaban

International normalized ratio (INR)

Conversion from PT to INR was specifically developed for VKAs and is not valid for

measuring rivaroxaban.

2.2.2. Anti-Factor Xa chromogenic assays

The anti-Factor Xa chromogenic assays have been specifically developed for the quantitative

determination of rivaroxaban using standardized anti-Factor Xa method and rivaroxaban

calibrators and controls.

Rivaroxaban plasma concentration measurements using anti-Xa tests may be more accurate;

however they provide no information on the actual anticoagulant effect of rivaroxaban.

Furthermore no target drug concentration ranges have currently been defined for the

different indications.

In patients with a thrombotic event and/or a bleeding complication, a point measurement of

rivaroxaban may provide the clinician useful information on the anticoagulant status of the

patient at the moment the blood sample was obtained. Measuring rivaroxaban could be

considered before (semi-) urgent surgery, in patients with renal and/or hepatic impairment

or suspected drug-drug interactions.

As an example, figure 11 shows the rivaroxaban plasma concentration-time profiles for a

virtually simulated population with atrial fibrillation with-or without renal impairment (15mg

or 20mg respectively)12.


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Figure 11: Relationship between the rivaroxaban plasma concentration and the time after administration

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2.3. Summary on the impact of rivaroxaban on standard coagulation tests

Rivaroxaban interferes with many of the coagulation tests, as outlined in table 6.

Standard coagulation test Impact of rivaroxaban

PT Time prolonged ++ (may vary depending on the reagents used)

aPTT Time prolonged +

PT-based coagulation factors (II, V, VII, X) Limited decrease -

aPTT-based coagulation factors (VIII, IX,

XI)

Limited decrease -

POC test for INR measurement aPTT Unpredictable

Thrombin Generation Assay Decreased/Influenced (depending on the parameter used)

Activated Clotting Time Unpredictable

Thrombo-elastogram In vitro data only, all parameters influenced (R, K, Angle, MA)

Fibrinogen (Clauss method) Not influenced

D-Dimer Not influenced

Thrombin time Not influenced

Ecarin clotting time Not influenced

Lupus anticoagulants (DRVVT) False positive results expected

Antithrombin anti-Xa based Increase with appr.10%/100µg/L rivaroxaban

Antithrombin anti-IIa based Not affected

Table 6: Impact of rivaroxaban on the different standard coagulation tests11, 13, 14


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3. Drug-drug interactions

Rivaroxaban is metabolized via CYP3A4 and is a substrate of the transporter proteins P-gp (P-

glycoprotein). Consequently, drugs that are strong inhibitors or inducers of CYP3A4 and/or

P-gp may cause a clinically relevant effect on the pharmacokinetic and/or pharmacodynamic

properties of rivaroxaban and are not recommended for concomitant use. Apart from this,

rivaroxaban has a low propensity for drug-drug interactions with frequently used

medications.

Interactions with co-medications that have been noted along with effects on the

pharmacokinetic and pharmacodynamic properties of rivaroxaban are described in table 7.


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Concomitant

Medications

CYP 3A4 interaction

P-gp interaction

Mean X-fold change in AUC

Mean X-fold change in Cmax

Recommendation

Inhibitors of CYP3A4 and/or P-gp

Azole-antimycotics

Ketoconazole (400mg OD)

Strong Strong 2.6 1.7

It is not recommended to co-administer these drugs with rivaroxaban due to significant increases in pharmacodynamic

effects which may lead to an increased bleeding risk.

Fluconazole is expected to have a weak increase of rivaroxaban exposure. This increase is not considered clinically relevant.

Itraconazole

Voriconazole

Posaconazole

Fluconazole (400mg OD) Moderate - 1.4 1.3

HIV protease inhibitors

Ritonavir (600mg BID) Strong Strong 2.5 1.6 It is not recommended to co-administer these drugs with

rivaroxaban due to an increased bleeding risk.

Macrolide antibiotics

Clarithromycin (500mg BID) Strong Moderate 1.5 1.4 No clinically relevant interactions have been noted and

rivaroxaban can be used in patients taking these

medications4.

Nevertheless, caution should be exercised10

Erythromycin (500mg TID) Moderate Moderate 1.3 1.3

Inducers of CYP3A4

Rifampicin

Phenytoin

Carbamazepine

Phenobarbital

St. John’s Wort Strong Strong 0,5 NA

Medications in this class should be co-administered with caution.


25

Table 7: Drug-drug interactions based on the CYP3A4 and P-gP interactions2,9

Concomitant

Medications Recommendation

Antithrombotic agents

Acetylsalicylic acid

Clopidogrel

Enoxaparin

Warfarin

Acenocoumarol

Care is to be taken, due to the increased bleeding risk.

NSAID

NSAIDs

Acetylsalicylic acid (500mg)

There may be individuals with a more pronounced pharmacodynamic response.

Care is to be taken if patients that are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk

Other commonly used medications

Midazolam

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with rivaroxaban when these drugs were coadministered

Digoxin

Atorvastatin

Dronedarone Given the limited clinical data available with dronedarone, co-adminsitration with rivaroxaban should be avoided

Anti-acids (Aluminium-magnesium hydroxide) (Maalox

®) The change in gastric pH by pretreatment with ranitidine or Aluminium-magnesium hydroxide had no effect on the plasma-

concentration profiles of rivaroxaban. The absorption of rivaroxaban was unaltered by the concomitant administration of these 2 drugs that alter intestinal pH. Ranitidin


26

4. How to manage bleeding complications under

rivaroxaban?

The pharmacodynamic profile of rivaroxaban is important for the management of bleeding

complications. Rivaroxaban has a half-life of 5 to 9 hours in young healthy persons and 11 to

13 hours in elderly. Due to this short half-life discontinuation of the drug is usually

sufficient to reverse its impact on hemostasis. For this reason, determining the dose and

timing of the last intake of rivaroxaban will be crucial. With a peak plasma concentration of

2 to 4 hours after intake (figure 12) it is theoretically possible to reduce the absorption of

rivaroxaban when administering activated charcoal within the first 2 hours after intake. Due

to its high plasma binding capacities (92-95%), rivaroxaban cannot be removed by dialysis.

Figure 12: Pharmacodynamic profile of rivaroxaban in a one and twice daily dosing regimen respectively in the lower and upper pictures

3,8


27

Currently, there is no specific antidote available for rivaroxaban. The antidotes available for

LMWH and VKA, protamine sulfate and vitamin K respectively, do not impact the

anticoagulation activity of rivaroxaban. Amongst the non-specific pro-coagulants, thus far

only Prothrombin Complex Concentrate (PCC) has shown a potential to reverse the

anticoagulant effects of rivaroxaban as assessed with thrombin generation assay (TGA) and

PT in a phase I clinical trial with 12 healthy volunteers15, 16.

Patients presenting with bleeding complications while on rivaroxaban should receive

individualized care based on the dose regimen, time of intake, drug compliance, possible

changes in co-morbidity impacting the plasma levels (e.g. overdose, renal or hepatic

function, drug-drug interactions) and the severity, source and location of the bleeding.

Regardless of the time of intake, the patient with a (suspected) bleeding should delay the

next administration. It is also possible that the treatment needs to be interrupted after

appropriate evaluation of the patient. The patient needs to be evaluated for associated

factors that increase the bleeding risk including a potential overdose, concomitant use of

antiplatelet or other antithrombotic agents, the use of non-steroidal anti-inflammatory

drugs (NSAIDs), co-existing bleeding disorders, renal or hepatic impairment.

There is insufficient (pre)clinical experience on the management of severe bleedings and the

guidance provided in table 8 and figure 13 is based on expert consensus and are not

clinically validated.

Hemostatic agent Recommendations

PCC: 4 factor concentrate

PPSB S.D.®

(flacon 20 ml - FIX ≥ 400IE) Confidex

®

(flacon 20 ml - FIX 500IE) Octaplex

®

(flacon 20 ml - FIX 400 à 620IE)

The administration of Prothrombin Complex Concentrate (PCC) is suggested in case of life-threatening bleeding. After an initial administration of 25U/kg of the available PCC we recommend to clinically re-evaluate the need for a repeat administration of PCCs*.

Desmopressin

Minirin®

Amp (4 µg/ml) for iv. use

Desmopressin can be considered in case of associated coagulopathy or thrombopathy**.

A standard dose scheme for bleeding disorders is 0,03 µg/kg with a maximum of 20 µg.

Tranexamic Acid

Exacyl®

Tranexamic acid associated to direct anti-Xa (antithrombin-independent) oral anticoagulants was effective in reducing postoperative blood loss, improving hemoglobinemia at 5 days and reducing transfusion rates.

21

aPCC: activated prothrombin concentrate (Feiba S-Tim 4®)

This writing group does not recommend the use of Feiba S-Tim 4® for life-threatening bleedings in patients treated with rivaroxaban.

recombinant human FVIIa (Novoseven®)

There is no clinical experience with rhFVIIa in rivaroxaban treated subjects. Due to the short half-life of rhFVIIa, a repeat dose may be needed. This writing group does not recommend the use of Novoseven® for life-threatening bleedings in patients treated with rivaroxaban.

Table 8: Recommended a-specific pro-hemostatic agents


28

Figure 13: Additional measures are added stepwise depending on the severity of bleeding

5. What in case of an overdose without bleeding?

Due to limited absorption of rivaroxaban at higher concentrations, a ceiling effect with no

further increase in average plasma exposure is expected at supra-therapeutic doses of 50 mg

rivaroxaban and above. The use of activated charcoal to reduce the absorption in case of a

rivaroxaban overdose can be considered within the first 2 to 4 hours after intake. We


29

propose to use in this case a suspension of 20g active charcoal / 240 ml H20, with a standard

dosing scheme for adults of 30 to 50 g.

Coagulation tests may help to estimate the plasma levels of rivaroxaban (see section 2).

6. Patients undergoing an intervention or surgery

To decide what to do with rivaroxaban treatment in case of surgical procedures, both

patient characteristics and surgical factors need to be taken into account. Points of

consideration are patient’s stroke risk (CHADS2, CHA2DS2-VASc), renal function

(<50ml/min), age (>75years), history of bleeding complications, risk of bleeding,

concomitant antiplatelet medication, and the existence of liver impairment.

We recommend an institutional guideline and a hospital broad policy on how to interrupt

rivaroxaban for surgical/invasive interventions. This could include the post-operative use of

LMWH according to hospital policy (prophylactic/intermediate dose) until the NOAC in the

recommended dose for the indication can be resumed (in general not before 48 hours after

the surgery). Alternatively, a reduced dosing regimen of the NOAC in that time period could

be considered (Table 9).

6.1. Elective procedures

6.1.1. Minor interventions without significant bleeding risk

Among minor interventions without significant bleeding risk we understand procedures for

e.g. cataract or glaucoma as well as dental interventions such as extraction of 1 to 3 teeth,

paradontal surgery, incision of an abscess or positioning of implants. In each situation, the

bleeding risk needs to be balanced against the thrombo-embolic risk.

When to interrupt rivaroxaban?

Rivaroxaban interruption may not be required for superficial interventions18. It is advised to

respect a time window of at least 18 hours between the last intake of rivaroxaban and the

scheduled procedure. An alternative recommendation for minor interventions could be to

respect a time window of at least 24 hours between the last intake of rivaroxaban and the

intervention.


30

Specifically with regards to dental interventions; tooth extractions should avoid the least

possible trauma and the wounds need to be sutured. When bleeding has stopped

completely, the patient can return home with instructions regarding post procedural care

and the measures to be taken in case of bleeding. Rinsing the mouth gently with 10 ml of

tranexamic acid 5%21, 4 times a day for 5 days is recommended. The patient has to contact

his dentist in case of bleeding that does not stop spontaneously.

When to restart rivaroxaban?

The next intake of rivaroxaban should be delayed until hemostasis has been assured.

Alternatively, one could wait to resume the intake of rivaroxaban until 24 hours after the

intervention.

6.1.2. Interventions with increased bleeding risk

When to interrupt rivaroxaban therapy?

Generally, if an invasive procedure or surgical intervention is planned, rivaroxaban should be

stopped at least 24 hours before the intervention. For procedures with high risk of bleeding,

or for patients that have a higher risk for bleeding complications, we recommend a time

window of at least 48 hours between the last intake of rivaroxaban and the scheduled

intervention (table 9, figure 16).

When to restart rivaroxaban?

Antithrombotic therapy should be restarted after the invasive procedure or surgical

intervention as soon as hemostasis is achieved and the risk for bleeding complications is

considered to be low.

For most procedures, it is appropriate to initiate a prophylactic dose of LMWH or

rivaroxaban 10mg (in case of total knee or hip replacement surgery) 6 to 10 hours after

surgery, whereas therapeutic anticoagulation is deferred until at least 48 hours.

Nevertheless, some surgical/invasive interventions that carry a high delayed bleeding risk

might require a longer interval before restarting anticoagulation therapy (table 9, figure 16).

NOTE: Due to the increased bleeding risk, co-administration of LMWH and rivaroxaban is not

recommended.


31

*Thromboprophylaxis with rivaroxaban low dose (10mg OD) only recommended in case of THR and TKR

surgery9.

Figure 14: Interrupting rivaroxaban for interventions with a bleeding risk

6.2. Urgent surgical interventions

In an emergency situation, clinical judgment by the attending physician will be required to

assess the relative risk of deferring the procedure versus an increased risk of bleeding if the

procedure/surgery is performed in a patient with recent intake of rivaroxaban.

If the procedure can be postponed, it is recommended to defer until 24 hours after the last

intake of rivaroxaban. Caution is required if this is not possible. In case of an (anticipated)

serious bleeding, the bleeding management described in section 6.1 should be taken into

consideration.

When the timing of the last intake of rivaroxaban is not known, a sensitive PT can provide

semi-quantitative information with respect to rivaroxaban intake. It needs to be reminded

though that a non-delayed PT will only suggest that rivaroxaban was likely taken more than

approximately 7 hours ago (see also section 2). Due to this limitation, the planning of a

surgical/invasive procedure based on the results of the PT/aPTT (as for VKAs and

unfractionated heparin) is not a validated strategy and cannot be recommended at the

current time.


32

* Thromboprophylaxis with rivaroxaban low dose (10mg od) only recommended in case of THR and TKR

surgery9, 17

** When determining the time window between the last intake of rivaroxaban and the procedure several

factors need to be taken into account. Points of consideration are patient’s stroke risk (CHADS2, CHA2DS2-

VASc), renal function (<50ml/min), age (>75years), history of bleeding complications, risk of bleeding,

concomitant antiplatelet medication, and the existence of liver impairment.

Table 9: Recommendations in case of procedures and surgical interventions

6.3. Specific situations

6.3.1. Neuraxial (spinal/epidural) anesthesia

The risk of adverse events such as the development of an epidural or spinal hematoma is

increased by the postoperative use of indwelling epidural catheters and the concomitant use

of antithrombotic agents.

The use of rivaroxaban in the presence of neuraxial anesthesia is not recommended by this

working group.

Especially an ongoing treatment with high dose rivaroxaban (15mg, 20mg) is an absolute

contraindication to the use of neuraxial anesthesia and the presence of an indwelling

neuraxial catheter. In a number of patients, and similar to VKAs, the interrupted treatment

may have to be bridged temporarily with IV UFH or LMWH. If a neuraxial block is considered

in those patients, the recommendations concerning IV UFH and LMWH apply.

Time window between intake of rivaroxaban and the procedure**

Before surgery After surgery

ELEC

TIV

E

PR

OC

EDU

RES

Minor Interventions (without significant bleeding risk)

≥18h

(Alternatively ≥24h)

Hemostasis achieved

(Alternatively ≥24h)

Major intervention

(with increased bleeding risk)

Standard patient/procedure**

≥24h ≥24h

High risk patient/procedure**

≥48h

≥48h (Thromboprophylaxis with

LMWH can be initiated 6-10h after the surgery*)

URGENT PROCEDURES Preferably 24h

(See also section 4 on Bleeding management)

≥48h (Thromboprophylaxis with

LMWH can be initiated 6-10h after the surgery*)


33

When using low dose rivaroxaban (10mg) in the presence of neuraxial blocks, extreme

caution is mandatory. A minimum time interval of 22-26 hours should be respected before a

neuraxial catheter is removed.

Postoperatively, the next dose of rivaroxaban should only be given 6 hours after withdrawal

of the neuraxial catheter and taking into account the adequacy of surgical hemostasis. In

case of a bloody puncture the next administration of rivaroxaban should be postponed for at

least 24 hours19.

7. Patients with atrial fibrillation and coronary heart disease

7.1. Acute management of acute coronary syndrome

Patients with AF who develop an acute coronary syndrome (ACS) while on rivaroxaban

should be treated according to usual clinical practice. Consideration should be given to

temporarily suspend rivaroxaban treatment in the setting of ACS, should the treatment

involve invasive procedures, such as PCI or coronary artery bypass surgery, or if thrombolytic

therapy is to be initiated.

Please consider that rivaroxaban, relative to VKA, is a short acting agent, and that the timing

of the last dose might impact the level of anticoagulation prior to initiation of standard

parenteral anticoagulation as is used before and during (semi)urgent PCI. Recent intake of

rivaroxaban might increase the risk of bleeding when initiating standard (full-dose)

parenteral anticoagulant. The timing, choice and dose of standard anticoagulation needs to

be balanced against the last intake of rivaroxaban (timing and dose) and the bleeding risk.

Urgent/planned PCI with only anti-Xa drugs might carry a risk of stent thrombosis as

suggested by the Oasis V study with fondaparinux in monotherapy.

7.2. Long-term treatment after acute coronary syndrome

The addition of antiplatelet therapy to oral anticoagulants (OAC) therapy increases the risk

of bleeding. Following an ACS and/or PCI in patients with AF at moderate to high risk of

stroke (i.e. CHADS2 ≥2) triple therapy, OAC (i.e. VKA with a reduced target INR of 2.0 – 2.5 or

rivaroxaban), aspirin and a P2Y12-inhibitor (i.e. ticlopidine, clopidogrel, prasugrel, ticagrelor)

is often inevitable. This, however, exposes the patient to an increased risk of bleeding. As a

consequence, the duration of triple therapy should be limited to the absolute minimum,

based on patient and procedural characteristics. Drug-eluding stent are preferably avoided,

if possible, to reduce the duration of triple therapy. Once triple antiplatelet therapy can be


34

stopped after coronary stent implant, rivaroxaban 20 mg once daily (15 mg once daily for

patients with moderate or severe renal impairment) with aspirin (or clopidogrel) is the

recommended scheme after stent implanation and/or an ACS. No data exist on the safety

and efficacy of rivaroxban in monotherapy for patients with stable coronary heart disease

(i.e. ≥1 year after ACS): therefore, treatment decisions should be individualised, and guided

by the assessment of ischemic vs. bleeding risks.

There is currently very limited experience in combining full-dose rivaroxaban (20 mg once

daily) with dual antiplatelet therapy. To date, no dosing recommendation can be made for

rivaroxaban for stroke prevention in AF in patients requiring dual antiplatelet therapy after

ACS and/or PCI. The need for long term continuation of aspirin or the P2Y12-inhibitor on top

of full-dose rivaroxaban for stroke prevention needs to be balanced against an increased

bleeding risk. Physicians should ensure appropriate anticoagulation by following current

guideline recommendations.

8. Cardioversion in a rivaroxaban treated patient

There is limited clinical experience of using rivaroxaban with this type of patients since in the

ROCKET AF study planned cardioversion and/or ablation was an exclusion criterion20. No

standardized protocols were used for these procedures, and study medication may have

been paused for the intervention with the patient having potentially been bridged with

another anticoagulant. Based on data analyzed to date, no firm clinical recommendations

can be made. As with VKA and LMWH, the duration and level of anticoagulation need to be

evaluated before considering a cardioversion in a compliant patient, taking into account that

rivaroxaban is a short acting agent.

Anticoagulation should be maintained for at least 4 weeks after successful cardioversion,

regardless of the baseline risk of stroke. Beyond 4 weeks, decisions on anticoagulation

should be made in accordance with CHADS2 and CHA2DS2-VASC. For patients with AF of

duration of 48h or less undergoing electrical or pharmacological cardioversion,

anticoagulation should be started at presentation and maintained for at least 4 weeks after

successful cardioversion. A similar scheme can be proposed for rivaroxaban but a TEE-based

strategy, with exclusion of intra-cardiac thrombi immediately before cardioversion, ican be

considered given absence of data and limited experience.

Switching to appropriate treatment with VKA can be an alternative, until further prospective

safety and efficacy data become available.


35

9. Patients presenting with non-hemorrhagic stroke while on

rivaroxaban

9.1. Acute phase

If a stroke occurs in a patient taking rivaroxaban, the drug intake should be interrupted and

intracranial hemorrhage should be excluded (using a CT or MRI scan).

If intracranial hemorrhage (ICH) is present, consultation with a neurosurgeon is

recommended. Otherwise, ICH should be managed like any other serious or life-

threatening bleeding on rivaroxaban (see also section 4)

An ischemic stroke should be treated according to usual clinical practice. The safety

of the use of thrombolytic therapy after recent intake of rivaroxaban is unclear. The

use of thrombolytic therapy should be individualized based on the neurological

evaluation and the timing of the last intake of rivaroxaban, if known

9.2. Post-acute phase

As non-compliance to the prescribed dose might be the underlying cause of stroke

recurrence, patient compliance should be checked and re-education of the patient might be

preferred (see section 11).

Other possible causes for stroke (stenosis of the carotid artery or lacunar stroke)

need to be checked

Based on the recommendations for the use of VKA, rivaroxaban treatment can be

restored for secondary stroke prevention, or alternate anticoagulant therapy can be

considered.

9.3. Initiation of rivaroxaban following an ischaemic stroke or transient

ischemic attack

Rivaroxaban has not been studied within the first 3 days after a transient ischemic attack

(TIA), two weeks after a stroke and within 3 months after a disabling stroke (mRS 4-5).

Although currently there is no published experience, it is felt that doctors should follow the

same rules they currently apply to initiate VKA, with the difference that rivaroxaban has a

quicker onset of action. In case of a TIA, anticoagulation treatment with rivaroxaban should


36

begin as soon as possible. Bridging with LMW heparin is generally not required as

rivaroxaban has a quick onset of action.

Rivaroxaban should not be initiated as long as there is a risk for hemorrhagic transformation.

10. Renal and hepatic (dys)function

10.1. Renal (dys)function

Rivaroxaban is partially cleared through the kidneys (33%). Decreased renal function

increases plasma levels of rivaroxaban and this may lead to an increased bleeding risk. No

dose adjustments are necessary for mild renal impairment (Creatinine Clearance , CrCl 50–80

ml/min). For patients with severe renal impairment (CrCl <30ml/min), no clinical data is

available. The recommended dosing for patients with moderate (CrCl 30-49 ml/min) to

severe (15-29 ml/min) renal impairment is shown in the table 12 for each indication. The use

of rivaroxaban is not recommended in patients with a CrCl below 15ml/min (Table 12).

Level of renal impairment Indication Dose

Moderate (CrCl 30–49 ml/min)

To be used with special caution in patients with moderate renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations

Prevention of VTE after elective orthopedic (knee/hip) surgery

10 mg od (5 weeks)

Acute treatment of proximal DVT Intensified treatment of 15mg bid (3 weeks)

Continued treatment of DVT and PE

15 mg od for continuous treatment (≥3months)

Prevention of stroke in patients with non-valvular AF

15 mg od

Severe (CrCl 15–29 ml/min)*

Use with caution

Prevention of VTE after elective orthopedic (knee/hip) surgery

10 mg od (5 weeks)

Acute treatment of proximal DVT Intensified treatment of 15mg bid (3 weeks)

Continued treatment of DVT and PE

15 mg od for continuous treatment (≥3months)

Prevention of stroke in patients with non-valvular AF

15 mg od

Severe (CrCl <15 ml/min)

Contraindication

Use of rivaroxaban at the above doses is not recommended for patients with CrCl rates < 15 ml/min

*Although severe renal impairment defined as a CrCl of 15-29 ml/min was not included in the fase III clinical

trials, this specific group was included in the SmPC.

Table 10: Recommended treatment doses for patients with renal impairment9


37

10.1. Hepatic (dys)function

As per summary of product characteristics rivaroxaban can be used in patients with mild

hepatic impairment (Child-Pugh A; unless there is evidence of coagulopathy). Use of

rivaroxaban in patients with hepatic impairment associated with coagulopathy or a clinically

relevant bleeding risk (e.g. Child-Pugh B and C) is not recommended.

11. Patient education

Patient education will be a very important aspect when introducing rivaroxaban or other

new oral anticoagulants. Such an education can be an effective strategy to adequately use

the drug. It should ideally offer an understanding of the disease and the pharmacological

characteristics of rivaroxaban. More specifically, the need for compliance, signs of bleeding

and instructions on when to seek medical attention should be discussed with the patient.

A patient alert card, containing basic information and instructions on rivaroxaban, was

developed to inform the health care professionals about the patient‘s anticoagulation

treatment. Additionally, this document contains the contact information of the treating

physician in case of emergency. Preferably the patient should carry the patient alert card at

all times and present it to every health care professional.


38

References

1. European public assessment report (EPAR) FOR Xarelto EMA/44192/. 2012. 2. Kubitza D, Becka M, Zuehlsdorf M and Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006; 46: 549-58. 3. Kubitza D, Becka M, Voith B, Zuehlsdorf M and Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005; 78: 412-21. 4. Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W and Laux V. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol. 2010; 30: 376-81. 5. Perzborn E, Strassburger J, Wilmen A, 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; 3: 514-21. 6. Kubitza D, Becka M, Roth A and Mueck W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008; 24: 2757-65. 7. Weinz C, Schwarz T, Kubitza D, Mueck W and Lang D. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos. 2009; 37: 1056-64. 8. Kubitza D, Becka M, Wensing G, Voith B and Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005; 61: 873-80. 9. Xarelto - Summary of product characteristics. 10. Dabigatran - Summary of Product Characteristics. 11. Douxfils J, Mullier F and al e. Thromb Haemost. 2012 submitted. 12. Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P and Misselwitz F. 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. 2011; 50: 675-86. 13. Asmis LM, Alberio L, Angelillo-Scherrer A, et al. Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res. 2012; 129: 492-8. 14. Hillarp A, Baghaei F, Fagerberg Blixter I, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011; 9: 133-9. 15. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR and Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011; 124: 1573-9. 16. Levi M, Eerenberg E and Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011; 9: 1705-12. 17. Eikelboom JW and Weitz JI. New oral anticoagulants for thromboprophylaxis in patients having hip or knee arthroplasty. BMJ. 2011; 342: c7270.


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18. Beleid bij tandheelkundige ingrepen tijdens antitrombotische behandeling. Acta richtlijn. 2010. 19. Bayer. Xarelto: EPAR - Product Information. 2009. 20. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365: 883-91. 21. Clavé A, Fazilleau F, Dumser D, Lacroix J. Efficacy of tranexamic acid on blood loss after primary cementless total hip replacement with rivaroxaban thromboprophylaxis: A case-control study in 70 patients. Orthop Traumatol Surg Res. 2012

Documents

Rivaroxaban: A Practical Guide V1.0 – 6 July 2012 · Rivaroxaban: A Practical Guide V1.0 – 6 July 2012 2 Writing and Review Committee Christophe Beauloye, Cliniques Universitaires