Dabigatran -Rivaroxaban : Variability and monitoring Scientific... · 2012. 11. 8. · Parenteral anticoagulants Unfractionated heparin Low molecular weight heparins Indirect Factor

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1

DabigatranDabigatran -- RivaroxabanRivaroxaban: :

VariabilityVariability and monitoringand monitoring

Jean-Michel Dogné , Jonathan Douxfils, François Mullier, Christian Chatelain, Bernard Chatelain,

December 1st, 2011

2

Anticoagulant Anticoagulant

landscapelandscape

3Geerts WH et al. Chest 2008;133:381S–453S

Commonly used anticoagulantsCommonly used anticoagulants

�� ParenteralParenteral anticoagulantsanticoagulants

�� UnfractionatedUnfractionated heparinheparin

�� Low molecular weight heparinsLow molecular weight heparins

�� Indirect Factor Indirect Factor XaXa inhibitor (inhibitor (fondaparinuxfondaparinux))

�� Oral anticoagulantsOral anticoagulants

�� Vitamin K antagonistsVitamin K antagonists

4

Traditional anticoagulants: Traditional anticoagulants:

drawbacksdrawbacks

�� UFHUFH11

�� ParenteralParenteral administration administration

�� Monitoring and dose Monitoring and dose

adjustment requiredadjustment required

�� Risk of HIT Risk of HIT

�� LMWHLMWH11

�� ParenteralParenteral administrationadministration

�� WeightWeight--adjusted dosingadjusted dosing

�� Oral VKAsOral VKAs22

�� Narrow therapeutic Narrow therapeutic

windowwindow

�� Interaction with Interaction with food and food and

drugsdrugs

�� Frequent monitoring and Frequent monitoring and

dose adjustment requireddose adjustment required

1. Hirsh J et al. Chest 2008;133;141S–159S; 2. Ansell J et al. Chest 2008;133;160S–198S

5

The evolution of anticoagulant The evolution of anticoagulant

drugsdrugs

AT + Xa + IIa(1:1 ratio)

Heparin

1930s

AT + Xa

IndirectFactor Xainhibitor

2002

IIa

Oral direct thrombin inhibitors

2004

AT + Xa + IIa(Xa > IIa)

LMWHs

1980s

II, VII, IX, X(Protein C, S)

VKAs

1940s

Xa

Oral directFactor Xainhibitors

2008

IIa

Directthrombininhibitors

1990s

Perzborn E et al. Nat Rev Drug Discov 2011;10:61-75

6

VKAsVKAs target multiple factors in target multiple factors in

the coagulation pathwaythe coagulation pathway

Adapted from Spyropoulos AC. Expert Opin Investig Drugs 2007;16:431–440

VKA VKA

VKA

VKAs inhibit the synthesis of functional coagulation

Factors II, VII, IX and X

Clot formation

Initiation

Propagation

Thrombin

Fibrinogen Fibrin

Prothrombin

X IX

II

VIITF

IXa

IIa

VIIa

Xa

Inactive factor

Active factor

Transformation

Catalysis

7

UFH is an indirect inhibitor of UFH is an indirect inhibitor of

Factor Factor XaXa and thrombinand thrombin

Indirect inhibition

by UFH via AT


Clot formation

Initiation

Propagation

Thrombin

Fibrinogen Fibrin

Prothrombin

X IX

II

VIITF

IXa

IIa

VIIa

Xa

AT

Inactive factor

Active factor

Transformation

Catalysis

8

LMWH is an indirect inhibitor of LMWH is an indirect inhibitor of

Factor Factor XaXa and thrombinand thrombin


Indirect inhibitionby LMWH

via AT

Clot formation

Initiation

Propagation

Thrombin

Fibrinogen Fibrin

Prothrombin

X IX

II

VIITF

IXa

IIa

VIIa

Xa

AT

Inactive factor

Active factor

Transformation

Catalysis

9

FondaparinuxFondaparinux is an indirectis an indirect

Factor Factor XaXa inhibitorinhibitor

Indirect inhibition by fondaparinux

via AT


Clot formation

Initiation

Propagation

Thrombin

Fibrinogen Fibrin

Prothrombin

X IX

II

VIITF

IXa

IIa

VIIa

Xa

Inactive factor

Active factor

Transformation

Catalysis

AT

10

New oral New oral

anticoagulants for anticoagulants for

VTEVTE treatmenttreatment

11

Direct Factor Direct Factor XaXa inhibitorsinhibitors

Direct Factor Xainhibition

RivaroxabanApixabanEdoxabanBetrixabanDarexaban


Inactive factor

Active factor

Transformation

Catalysis

Clot formation

Initiation

Propagation

Thrombin

Fibrinogen Fibrin

Prothrombin

X IX

II

VIITF

IXa

IIa

VIIa

Xa

12

Direct thrombin inhibitorsDirect thrombin inhibitors

Direct Factor IIainhibition

Dabigatran etexilate


Inactive factor

Active factor

Transformation

Catalysis

Clot formation

Initiation

Propagation

Thrombin

Fibrinogen Fibrin

Prothrombin

X IX

II

VIITF

IXa

IIa

VIIa

Xa

13

((R)evolutionR)evolution in anticoagulant in anticoagulant

therapytherapy

AG Turpie; C Esmon. Thromb Haemost 2011; 105: 586–596

14

Main Main disadvantagesdisadvantages of of currentcurrent

anticoagulantsanticoagulants

T. Mavrakanas, H. Bounameaux / Pharmacology & Therapeutics 2011

15

Main Main disadvantagesdisadvantages of of currentcurrent


�� Many patients do not receive satisfactory Many patients do not receive satisfactory

anticoagulant therapy or stop it too early.anticoagulant therapy or stop it too early.

�� Medical need: Medical need:

�� ““ideal anticoagulantideal anticoagulant”…”…

16

PropertiesProperties of of «« idealideal »» anticoagulantanticoagulant

�� ProvenProven efficacyefficacy (non (non inferiorinferior to to currentcurrent anticoagulant anticoagulant therapytherapy))

�� Oral administrationOral administration

�� No No requirementrequirement for routine for routine bloodblood monitoring and dose monitoring and dose adjustmentadjustment

�� WideWide therapeutictherapeutic windowwindow

�� RapidRapid onsetonset of actionof action

�� PredictablePredictable pharmacokineticspharmacokinetics and and pharmacodynamicspharmacodynamics (good oral (good oral availabilityavailability))

�� Minimal interaction Minimal interaction withwith foodfood and and otherother drugsdrugs

�� AbilityAbility to to inhibitinhibit and and clotclot--boundbound coagulation coagulation factorsfactors

�� LowLow nonnon--specificspecific bindingbinding

�� ReversibilityReversibility

�� AvailabilityAvailability of an antidoteof an antidote

�� No No unexpectedunexpected toxicitiestoxicities ((lowlow bleedingbleeding riskrisk, no , no hepatichepatic toxicitytoxicity))

�� Acceptable Acceptable costscosts

Adapted from T. Mavrakanas, H. Bounameaux / Pharmacology & Therapeutics 2011 and J.Steffel and E.Braunwald European Heart Journal March 2011

17

PotentialPotential indications of new oral indications of new oral


�� PreventionPrevention of of venousvenous thromboembolismthromboembolism

--Total hip/Total hip/kneeknee replacementsreplacements

-- MedicalMedical illill patientspatients

�� Prevention of stroke and systemic embolism in adult patients Prevention of stroke and systemic embolism in adult patients

with with nonvalvularnonvalvular atrialatrial fibrillationfibrillation

�� TreatmentTreatment of of venousvenous thromboembolismthromboembolism

�� Acute Acute coronarycoronary syndromesyndrome

18

The promise of new oral anticoagulantsThe promise of new oral anticoagulants

Improved compliance

Improved efficacy

and safety

Less impact on patients’ daily life

Improvedquality of life

Less labour-intensive

Reduced administrative

costs

Reduced potential for food and drug

interactions

� Simplified dosing regimen� No dietary restrictions� Predictable anticoagulation and no

need for routine coagulation monitoring� Can be given at fixed doses

1. Raghaven N et al. Drugs Metab Dispos 2009;37:74–81; 2. Shantsila E & Lip GY. Curr Opin Investig Drugs2008;9:1020–1033; 3. Mueck W et al. Clin Pharmacokinet 2008;47:203–216; 4. Mueck W et al. ThrombHaemost 2008;100:453–461; 5. Mueck W et al. Int J Clin Pharmacol Ther 2007;45:335–344

19I.Ahrens et al.Thromb Haemost 2010; 104: 49–60

2020

First new anticoagulant agentsFirst new anticoagulant agents

Dabigatran etexilate Rivaroxaban

2121

Dabigatran etexilate Rivaroxaban

Pradaxa® Xarelto®

Competitive, reversible direct thrombin inhibitor

Highly selective direct factor Xa inhibitor

EMA authorized: 18/03/2008

EMA authorized: 30/09/2008

First new anticoagulant agentsFirst new anticoagulant agents

22

RivaroxabanRivaroxaban: total : total arthroplastyarthroplasty

T. Galanis et al. J Thromb Thrombolysis 2011; 31: 310:320

23

DabigatranDabigatran: total : total arthroplastyarthroplasty


24

DabigatranDabigatran: total : total arthroplastyarthroplasty


-The proposed therapeutic doses (150 or 220 mg q.d.) were found to be non-inferior to enoxaparin in terms of efficacy in the pivotal studies.

-There is a trend to higher efficacy of DAB 220mg compared with enoxaparin, associated with an increased bleeding risk.

- On the opposite, with DAB 150mg, there is a trend to lower efficacy compared with enoxaparin, associated with a lower bleeding risk risk, which might be useful for some at risk populations (patients with moderate renal impairment, elderly) which have increased DAB exposure.

25

RivaroxabanRivaroxaban

KneeKnee replacement replacement surgerysurgery Hip replacement Hip replacement surgerysurgery

10 mg10 mg rivaroxabanrivaroxaban taken taken orally once dailyorally once daily. .

The initial dose should be taken The initial dose should be taken 6 to 10 hours after 6 to 10 hours after

surgerysurgery

a treatment duration of a treatment duration of 2 2

weeksweeks is recommendedis recommendeda treatment duration of a treatment duration of 5 5

weeksweeks is recommendedis recommended

26

DabigatranDabigatran

Knee replacement surgery Hip replacement surgery

220 m g once daily taken as 2 capsules of 110 m g

Treatm ent should be in itia ted orally w ith in 1 – 4 hours of com pleted surgery with a single capsule and

continuing w ith 2 capsules once daily thereafter for

a total of 10 days

continuing w ith 2 capsules

once daily thereafter for a tota l of 28-35 days

Knee replacement surgery Hip replacement surgery

220 m g once daily taken as 2 capsules of 110 m g

Treatm ent should be in itia ted orally w ith in 1 – 4 hours of com pleted surgery with a single capsule and

continuing w ith 2 capsules once daily thereafter for

a total of 10 days

continuing w ith 2 capsules

once daily thereafter for a tota l of 28-35 days

27

RivaroxabanRivaroxaban

Jean-Michel Dogné , Jonathan Jonathan DouxfilsDouxfils,, François Mullier, Christian Chatelain, Bernard Chatelain,

28

PharmacodynamicsPharmacodynamics

�� Direct, specific, competitive Direct, specific, competitive Factor Xa inhibitor Factor Xa inhibitor

�� Inhibits free and fibrinInhibits free and fibrin--bound Factor Xa activity, bound Factor Xa activity, and prothrombinase activityand prothrombinase activity

�� Inhibits thrombin generation Inhibits thrombin generation –– acts earlier in the acts earlier in the coagulation cascadecoagulation cascade

�� No direct effect on No direct effect on thrombinthrombin--induced platelet induced platelet aggregation, and thus, on aggregation, and thus, on primary haemostasisprimary haemostasis

Perzborn et al., J Thromb Haemost 2005; Pathophysiol Haemost Thromb 2004; Depasse et al., J Thromb Hameost 2005; Kubitza et al., Clin Pharmacol Ther 2005; Br J Clin Pharmacol 2007; Eur J Clin Pharmacol 2005; Graff et al., J Clin Pharmacol 2007; Fareed et al., J Thromb Haemost 2005; Tinel et al., Blood 2006, Roehrig S et al. J Med Chem 2005;48:5900–8

Rivaroxaban

N NO

NH

O

SCl

O

O

O

29

Rivaroxaban: High Rivaroxaban: High specificityspecificity

forfor FactorFactor XaXa

ICIC5050 > 20 000> 20 000Factor Factor VIIaVIIa, Factor , Factor XIaXIa, thrombin, activated , thrombin, activated

protein C, protein C, plasminplasmin, , urokinaseurokinase, , trypsintrypsin

KKii = 0.4 = 0.4 ±± 0.020.02Factor Factor XaXa

Rivaroxaban Rivaroxaban

((nMnM))Inhibition of:Inhibition of:

• Rivaroxaban kon = 1.7 ×××× 107 M–1 s–1

• Rivaroxaban koff = 5 ×××× 10–3 s–1

E + I E Ikon

koff

Data from Data from PerzbornPerzborn E E et al. et al. J Thromb J Thromb HaemostHaemost 2005;3:5142005;3:514––21;21;

TersteegenTersteegen A A et al. J Thromb et al. J Thromb HaemostHaemost 2007;5(Suppl. 2):P2007;5(Suppl. 2):P--WW--651.651.

30

Time (hours)0 2 4 6 8 10 12 14 16 18 20 22 24

Ant

ithro

mbi

n ac

tivity

(med

ian

chan

ge fr

om b

asel

ine)

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

Placebo (n = 25)

1.25 mg rivaroxaban (n = 8)5 mg rivaroxaban (n = 6)10 mg rivaroxaban (n = 8)20 mg rivaroxaban (n = 7)40 mg rivaroxaban (n = 8)80 mg rivaroxaban (n = 6)

Single doseHealthy volunteers

Rivaroxaban does not require Rivaroxaban does not require

antithrombinantithrombin as a cofactoras a cofactor

Adapted from Kubitza D et al. Clin Pharmacol Ther 2005;78:412–21, with permission from the Nature Publishing Group.

31

Thr

ombi

n ac

tivity

(med

ian

chan

ge fr

om b

asel

ine)

Placebo (n = 25)

1.25 mg rivaroxaban (n = 8)5 mg rivaroxaban (n = 6)10 mg rivaroxaban (n = 8)20 mg rivaroxaban (n = 7)40 mg rivaroxaban (n = 8)80 mg rivaroxaban (n = 6)



Rivaroxaban has no significant Rivaroxaban has no significant

effect on thrombin activityeffect on thrombin activity

Time (hours)

0 2 4 6 8 10 12 14 16 18 20 22 240.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

32

In vitro rivaroxaban has no direct effectIn vitro rivaroxaban has no direct effect

on platelet aggregation Ion platelet aggregation I

ICIC5050 81 81 µµMMγγ--ThrombinThrombin

(human platelet(human platelet--rich plasma)rich plasma)11

>75% aggregation>75% aggregation

No difference from No difference from

controlcontrol

Collagen, ADP, epinephrine, arachidonic acidCollagen, ADP, epinephrine, arachidonic acid

(human platelet(human platelet--rich plasma, rivaroxaban 23 rich plasma, rivaroxaban 23

µµM)M)22

No change from No change from

baselinebaselineCollagenCollagen

(healthy male subjects given rivaroxaban 15 mg)(healthy male subjects given rivaroxaban 15 mg)33

ICIC5050 >200 >200 µµMMCollagen, U46619, ADP, TRAPCollagen, U46619, ADP, TRAP--66

(human platelet(human platelet--rich plasma)rich plasma)11

EffectEffectPlatelet aggregation assayPlatelet aggregation assay

1Perzborn et al., ICT 2004; 2Fareed et al., ISTH 2005; 3Kubitza et al., Br J Clin Pharmacol 2007

In vitro human studies

33E Nutescu et al. ; J Thromb Thrombolysis 2011; 31: 326 -343

PharmacokineticsPharmacokinetics propertiesproperties


PharmacokineticsPharmacokinetics propertiespropertiesContraindicated in patient with hepatic disease associated with coagulopathy and an increase of bleeding risks.

Is to be used with caution in cirrhotic patients with moderate hepatic impairment (Child Pugh B) if it is not associated with coagulopathy.

� Risk of hemorrhage.

354 8 12 16 20 24

24

Rivaroxaban in patients with hepatic impairmentRivaroxaban in patients with hepatic impairment

�� Mild hepatic impairmentMild hepatic impairment

�� No relevant differences in No relevant differences in

PK/PD compared with healthy PK/PD compared with healthy

individualsindividuals

�� Moderate hepatic impairment Moderate hepatic impairment

may be associated with may be associated with

coagulopathycoagulopathy

�� Prolonged PT at baselineProlonged PT at baseline

�� Increased Increased CCmaxmax and AUCand AUC

�� Effects on PK reflected in PDEffects on PK reflected in PD

�� Moderate prolongation of PTModerate prolongation of PT

Data from Halabi A et al. J Thromb Haemost 2007;5(Suppl. 2):P-M-635.

PT

(x-

fold

rela

tive

chan

ge fr

om b

asel

ine)

0

1.0

1.5

2.0

2.5

Riv

arox

aban

pla

sma

conc

entr

atio

n (µ

g/m

L)

0 4 8 12 16 200

50

100

150

200

250

300

350

Healthy (n = 16) Mild hepatic impairment (n = 8) Moderate hepatic impairment (n = 8)

Rivaroxaban 10 mg

Time (hours)

Time (hours)

36


Mild renal impairment:(ClCr between 50 to 79ml.min -1)AUC increase by 44%

Moderate renal impairment:(ClCr between 30 to 49ml.min -1)AUC increase by 52%

Severe renal impairment:(ClCr <30ml.min -1)AUC increase by 54%

No recommendation

No recommendation, but care is to be taken in patient concomitantly receiving medicinal products which increase rivaroxaban plasma concentration

Is to be used with caution

and not recommended in patient with ClCr<15mL/min

�� Risk of bleeding

37

0 4 8 12 16 20 240

50

100

150

200

250

Phase I: effects of renal impairment on rivaroxaban Phase I: effects of renal impairment on rivaroxaban

PK and PDPK and PD

�� Renal clearance declined Renal clearance declined

with increasing renal with increasing renal

impairmentimpairment

�� PD effects mirrored PK PD effects mirrored PK

effectseffects

�� Patients with mild and Patients with mild and

moderate renal moderate renal

impairment have been impairment have been

enrolled in phase II and enrolled in phase II and

III trialsIII trials

Data from Halabi A et al. Blood 2006;108(11):Abstract 913; Kubitza et al. Br J Clin Pharmacol. 2010; 70 (5):703-712.

Time (hours)

Riv

arox

aban

pla

sma

conc

entr

atio

n (µ

g/L) Healthy controls (CrCL ≥ 80 mL/min)

Mild impairment (CrCL 50–79 mL/min) Moderate impairment (CrCL 30–49 mL/min) Severe impairment (CrCL < 30 mL/min)

Time (hours)

Pro

thro

mbi

ntim

e(x

-fol

d ch

ange

from

bas

elin

e)

0 4 8 12 16 20 24

1.0

1.2

1.4

1.6

1.8

Rivaroxaban 10 mg



Not recommended in patient receiving concomitant systemic treatment with azole-anti-mycotics(ketoconazole, itraconazole, posaconazole and voriconazole) or protease inhibitor (e.g: ritonavir)



Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) are to be administrated with caution.

�Reduction of plasma concentration of rivaroxaban

�Risk of thrombosis

40

Influence of CYP3A4 and PInfluence of CYP3A4 and P--gpgp inhibitors on inhibitors on

rivaroxaban plasma concentrationrivaroxaban plasma concentration

1.31.3

1.41.4

1.61.6

1.71.7

CCmaxmax

xx--fold fold

increaseincrease

1.31.3

1.51.5

2.52.5

2.62.6

AUCAUC

xx--fold fold

increaseincrease

NoNoModerateModerateStrongStrongClarithromycinClarithromycin

500500 mgmg b.i.d.b.i.d.

NoNoModerateModerateModerateModerateErythromycin Erythromycin

500500 mg mg t.i.dt.i.d..

YES*YES*StrongStrongStrongStrongRitonavirRitonavir

600600 mg b.i.d.mg b.i.d.

YES*YES*StrongStrongStrongStrongKetoconazoleKetoconazole

400400 mg mg o.do.d..

Clinically Clinically

relevantrelevantPP--gpgp

inhibitioninhibitionCYP3A4 CYP3A4

inhibitioninhibitionRivaroxaban +Rivaroxaban +

Summary of Product Characteristics. http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-PI-en.pdfLast accessed: 16/09/09.

*For full details please see the rivaroxaban summary of product characteristics.


Pharmacokinetics properties: Interactions

42

0 5 10 15 20 251.0

1.2

1.4

1.6

1.8

Phase I: effects of age and gender on rivaroxaban PK Phase I: effects of age and gender on rivaroxaban PK

and PDand PD

�� No clinically No clinically significant effects on significant effects on exposure or exposure or maximum plasma maximum plasma concentrationsconcentrations11

�� No clinically relevant No clinically relevant differences in PDdifferences in PD1,21,2

�� PT closely correlated PT closely correlated with plasma with plasma concentrationconcentration22

Pro

long

atio

n of

PT

(r

elat

ive

chan

ge fr

om b

asel

ine)

Time (hours)

Young women n = 6Elderly women n = 6Young men n = 5Elderly men n = 6

Placebo (women) n = 4Placebo (men) n = 5

Pla

sma

conc

entr

atio

n (µ

g/L)

(geo

met

ric m

ean)

Time after baseline (hours)0 5 10 15 20 25

0

50

100

150

200

250

300 Young women n = 6Elderly women n = 6Young men n = 6Elderly men n = 6

Adapted from 1Kubitza D et al. Poster presented at EFORT 2007; Data from 2 Kubitza D et al. Blood 2006;108(11):Abstract 905.

Rivaroxaban 10 mg

43

Time (hours)

Body weight 70–80 kgBody weight ≤ 50 kg

Body weight > 120 kg

0

20

40

60

80

100

120

140

160

180

0 2 4 6 8 10 12 14 16 18 20 22 24

Riv

arox

aban

pla

sma

conc

entr

atio

n (µ

g/L)

Phase I: effects of body weight on rivaroxaban PK Phase I: effects of body weight on rivaroxaban PK

and PDand PD

�� No relevant differences No relevant differences

in PKin PK

�� AUC unaffectedAUC unaffected

�� CCmaxmax increased by increased by

~24% in subjects ~24% in subjects ≤≤ 50 50

kg, not considered kg, not considered

clinically relevantclinically relevant

�� Close correlation Close correlation

between PK and PDbetween PK and PD

Data from Kubitza D et al. J Clin Pharmacol 2007;47:218–26.

Rivaroxaban 10 mg

44

Rivaroxaban 10 mg Rivaroxaban 10 mg o.do.d.: SMPC EU.: SMPC EU

PopulationPopulation Fixed dose of rivaroxabanFixed dose of rivaroxaban

GenderGender 10 mg 10 mg o.do.d. No dose adjustment.. No dose adjustment.

Elderly peopleElderly people 10 mg 10 mg o.do.d. No dose adjustment.. No dose adjustment.

Body weightBody weight 10 mg 10 mg o.do.d. No dose adjustment.. No dose adjustment.

Mild/moderate renal Mild/moderate renal

impairmentimpairment10 mg o.d.10 mg o.d.

No dose adjustment in mild (No dose adjustment in mild (CrCLCrCL 5050––8080 mL/min) or moderate (mL/min) or moderate (CrCLCrCL

3030––4949 mL/min) renal impairmentmL/min) renal impairment

To be used with caution in patients with moderate (To be used with caution in patients with moderate (CrCLCrCL 3030––4949 mL/min) mL/min)

renal impairment concomitantly receiving other medicinal productrenal impairment concomitantly receiving other medicinal products which s which

increase rivaroxaban plasma concentrationsincrease rivaroxaban plasma concentrations

To be used with caution in patients with severe (To be used with caution in patients with severe (CrCLCrCL 1515––29 mL/min) 29 mL/min)

renal impairment renal impairment

Not recommended in patients with Not recommended in patients with CrCLCrCL << 1515 mL/minmL/min

Hepatic impairmentHepatic impairment 10 mg o.d.10 mg o.d.

Contraindicated in hepatic disease associated with Contraindicated in hepatic disease associated with coagulopathycoagulopathy and and

clinically relevant bleeding risk. clinically relevant bleeding risk.

To be used with caution in cirrhotic patients with moderate hepaTo be used with caution in cirrhotic patients with moderate hepatic tic

impairment (Child Pughimpairment (Child Pugh B) if it is not associated with B) if it is not associated with coagulopathycoagulopathy..

45

MonitoringMonitoring

�� Why? Situation at risk?Why? Situation at risk?

�� EMA (EMA (SmPCSmPC) recommendations:) recommendations:

�� ““cautioncaution”” �� what is the meaningwhat is the meaning??

�� ““closely monitor patients for decrease effect of closely monitor patients for decrease effect of rivaroxabanrivaroxaban””�� Lack of effectiveness is of major concernLack of effectiveness is of major concern

�� Risk of thrombosisRisk of thrombosis

�� How to How to ““closely monitorclosely monitor””??

�� What are the risk minimizations?What are the risk minimizations?

�� Educational material for Educational material for HCPsHCPs and patients?and patients?

46


�� Opinion of the regulator agenciesOpinion of the regulator agencies

�� EMA (CHMP Report EMA (CHMP Report EMEA/543519/2008)EMEA/543519/2008)

““There is a There is a needneed to develop a to develop a laboratory test for detecting increased exposurelaboratory test for detecting increased exposure or or pharmacodynamicpharmacodynamic

activity. The Applicant has, as a followactivity. The Applicant has, as a follow--up measure, undertaken to validate modified up measure, undertaken to validate modified

commercially available tests for estimations of the commercially available tests for estimations of the pharmacodynamicpharmacodynamic activity of activity of rivaroxabanrivaroxaban that that

could be used in routine clinical setting.could be used in routine clinical setting.””

47


�� Why? Situation at risk?Why? Situation at risk?

�� InterestInterest of of biologicalbiological monitoring of monitoring of rivaroxabanrivaroxaban

�� RiskRisk of of overdose overdose

�� BleedingsBleedings

�� RiskRisk of of underdoseunderdose

�� LackLack of of effectivenesseffectiveness!!!!!!

�� ThrombosisThrombosis

48

WhyWhy? Situation ? Situation atat riskrisk??

Moreover, the Food and Drug Administration mentioned the necessity of a lower strength tablet for the following patients:

• Child Pugh class B hepatic impairment without coagulopathy

• Concurrently taking rivaroxaban with a P-gp and strong CYP3A4 inhibitor

• Concurrently taking rivaroxaban with a P-gp and mild or moderate CYP3A4inhibitor with mild-moderate renal impairment

FDA. CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REV IEW(S). 30-12-2010

Need for a comprehensive assessment of the patient to evaluate the risk of bleeding

Need for a sensitive, specific and reproducible dru g monitoring to assess the impact of all possible interaction .

49

Situations requiring a biological Situations requiring a biological

monitoringmonitoring


Clinical trials

Safe and protectedenvironment

50




Clinical trials


Monitoring not necessary

51




Clinical trials



Real world…

52




Clinical trials



Real world…

Monitoring to minimize the risks of

bleedings and identifynon responders (lack

of effectiveness)

53


�� When?When?

�� At the instauration of the treatmentAt the instauration of the treatment

�� In the case of a switch from AVK to In the case of a switch from AVK to rivaroxabanrivaroxaban

�� Relapse of Relapse of ThombosisThombosis or Strokeor Stroke

�� Bleedings complicationsBleedings complications

�� To assess complianceTo assess compliance

54

Laboratory assaysLaboratory assays

�� Criteria for a goldCriteria for a gold--standardstandard

�� Linearity on a wide range of concentrationLinearity on a wide range of concentration

�� SensitiveSensitive

�� SpecificSpecific

�� Reproducible (CV in %)Reproducible (CV in %)

�� RapidRapid

�� InexpensiveInexpensive

�� AvailabilityAvailability

55

LaboratoryLaboratory assaysassays

�� Tests performed with Tests performed with rivaroxabanrivaroxaban::

�� Chronometric assaysChronometric assays

�� aPTTaPTT

�� PTTPTT--AA®®

�� CKPrestCKPrest®®

�� CephascreenCephascreen®®

�� ActinActin FSFS®®

�� SynthasilSynthasil®®

56



�� Chronometric assaysChronometric assays

�� PTPT

�� RecombiplastinRecombiplastin®®

�� InnovinInnovin®®

�� NeoplastinNeoplastin CI +CI +®®

�� NeoplastinNeoplastin RR®®

�� TriniclotTriniclot PT HTFPT HTF®®

�� TriniclotTriniclot PT Excel PT Excel ®®

�� TriniclotTriniclot PT Excel S PT Excel S ®®

57



�� ChromogenicChromogenic assaysassays

�� STASTA®®-- Liquid antiLiquid anti--XaXa®® (LAX)(LAX)

�� Hyphen BiomedHyphen Biomed®®-- BiophenBiophen Direct Direct factorXafactorXa InhibitorInhibitor®®

((BiophenBiophen DiXaIDiXaI))

58

ResultsResults: : aPTTaPTT

aPTT is not suitable to evaluate the pharmacodynamic effects of rivaroxabandue to a lack of sensitivity

Simulated therapeutic range in AF (32 – 290ng/mL)

59

ResultsResults: PT: PT

0 500 1000 1500 2000 25000

50

100

150Recombiplastin (ACLTOP)Innovin (BCS)Neoplastine R (STA)Neoplastine CI+ (STA)

Triniclot PT HTF (STA)Triniclot PT Excel (STA)

Triniclot PT Excel S (STA)

[rivaroxaban] (ng/mL)

Tim

e (s

ec)

PT shows a concentration dependent prolongation of clotting time depending on the reagent.

Simulated therapeutic range in AF(32 – 290ng/mL)

60

ResultsResults: PT: PT

16,2 16,2 12,9 12,9 12,512,5TriniclotTriniclot PT ExcelPT Excel®®

20,1 20,1 13,0 13,0 12,112,1RecombiplastinRecombiplastin®®

ReagentReagent PT value (sec) at PT value (sec) at

baselinebaselinePT value (sec) at PT value (sec) at

CCtroughtrough (32ng/mL)(32ng/mL) in in

simulated population simulated population

in AFin AF

PT value (sec) at PT value (sec) at

CCmaxmax (290ng/mL) in (290ng/mL) in

simulated population simulated population

in AFin AF

TriniclotTriniclot PT Excel SPT Excel S®® 16,216,2 17,517,5 28,0 28,0

NeoplastinNeoplastin RR®® 15,115,1 16,0 16,0 23,8 23,8

NeoplastinNeoplastin CI+CI+®® 15,715,7 16,3 16,3 21,4 21,4

TriniclotTriniclot PT HTFPT HTF®® 14,214,2 14,7 14,7 18,0 18,0

InnovinInnovin®® 10,410,4 10,6 10,6 12,4 12,4

61

Predictable pharmacodynamics in phase I and Predictable pharmacodynamics in phase I and

II studiesII studies

�� The relationship between rivaroxaban plasma concentration and prThe relationship between rivaroxaban plasma concentration and prothrombin time was othrombin time was

identical identical in both healthy subjects and in patients undergoing orthopaedic in both healthy subjects and in patients undergoing orthopaedic surgerysurgery

Healthy subjects (phase I) Patients undergoing majororthopaedic surgery (phase II)

Rivaroxaban plasma concentration (µg/l)

Pro

thro

mbi

n tim

e (s

)

0 100 200 300 400 500 600 700 8000

10

20

30

40

50

60Observed values Model predictions

Rivaroxaban plasma concentration (µg/l)

0 100 200 300 400 500 600

Pro

thro

mbi

n tim

e (s

)

0

10

20

30

40

50

Kubitza et al., Eur J Clin Pharmacol 2005; Graff et al. J Clin Pharmacol 2007; Mueck et al., Clin Pharmacokinet 2008

�� RivaroxabanRivaroxaban plasma concentrations correlate closely with its pharmacodynamiplasma concentrations correlate closely with its pharmacodynamic effects, i.e. c effects, i.e. prothrombin time (only with prothrombin time (only with NeoplastinNeoplastin®® as thromboplastin) and thrombin generationas thromboplastin) and thrombin generation

62

ResultsResults: : BiophenBiophen DiXaIDiXaI

0 500 1000 15000

1

2

3

[rivaroxaban] ng/mL

OD

/mn

Simulated therapeutic range in AF(32 – 290ng/mL)

Biophen DiXaI showed a concentration dependent decrease of the OD/min with a linear regression and a good sensitivity.

This test is more specific than other anti-Xa chromogenic assay because it is performed with a Tris-EDTA-NaCl buffer making it insensitive to the presence of

heparin or fondaparinux.

63

DiscussionDiscussion

�� PT, and PT, and BiophenBiophen DiXaIDiXaI are the most appropriate assays are the most appropriate assays

to evaluate the to evaluate the pharmacodynamicspharmacodynamics effects of effects of

rivaroxabanrivaroxaban on coagulation.on coagulation.

Nevertheless, some points are to be considered.Nevertheless, some points are to be considered.

64


�� There is a need for a There is a need for a widely availablewidely available test, giving test, giving rapid rapid

informationinformation (without the necessity of calibration curve (without the necessity of calibration curve

and control) about the anticoagulation in case of and control) about the anticoagulation in case of

emergency.emergency.

�� Thus, we propose:Thus, we propose:

�� 1. 1. A screening functionalA screening functional testtest with PT.with PT.

�� 2. If the value of PT exceed a cut2. If the value of PT exceed a cut--off (to be determined in off (to be determined in

each lab depending on the reagent used), a each lab depending on the reagent used), a confirmation testconfirmation test

based on specific based on specific chromogenicchromogenic antianti--XaXa assay should be assay should be

performedperformed

65


�� Importance of standardizing the Importance of standardizing the timetime between between

the intake of the intake of rivaroxabanrivaroxaban and and the time of blood the time of blood

collection.collection.

Mueck et al. Clin Pharmacokinet 2011; 50(10): 675-686

66

Rapidly absorbed: Rapidly absorbed: CCmaxmax within 2within 2––4 hours of oral 4 hours of oral

administrationadministration


0

Riv

arox

aban

pla

sma

conc

entr

atio

n (µ

g/L)

0

50

100

150

200

300

250

4 10 14 18 24

Time (hours)

20 221612862


1.25 rivaroxaban mg (n = 8)5 mg rivaroxaban (n = 6)10 mg rivaroxaban (n = 8)20 mg rivaroxaban (n = 7)40 mg rivaroxaban (n = 8)80 mg rivaroxaban (n = 6)

67

Rapidly absorbed without accumulationRapidly absorbed without accumulation

Adapted from Kubitza D et al. Eur J Clin Pharmacol 2005;61:873–80, with permission from Springer-Verlag.

0Riv

arox

aban

pla

sma

conc

entr

atio

n (µ

g/L)

0

100

200

400

300

2 7 9Time (days)

81

Multiple rivaroxaban dosesHealthy volunteers

5 mg rivaroxaban (n = 7)10 mg rivaroxaban (n = 7)20 mg rivaroxaban (n = 7)30 mg rivaroxaban (n = 8)

68


�� Importance of standardizing the Importance of standardizing the timetime between between

the intake of the intake of rivaroxabanrivaroxaban and and the time of blood the time of blood

collection.collection.

�� CCtroughtrough is preferable to is preferable to CCmaxmax

�� Concentration are lower, and more stabilized Concentration are lower, and more stabilized

in in comparison with the absorption phase where comparison with the absorption phase where

the the CmaxCmax is observed.is observed.

Mueck et al. Clin Pharmacokinet 2011; 50(10): 675-686

69


�� For PT:For PT:

�� Sensitivity depends on the reagentSensitivity depends on the reagent

�� Results expressed in Results expressed in INR are not applicableINR are not applicable (ISI is defined for VKA (ISI is defined for VKA

and are not suitable for and are not suitable for rivaroxabanrivaroxaban but an ISI may be defined specifically but an ISI may be defined specifically

for for rivaroxabanrivaroxaban to reduce interto reduce inter--reagent variability)reagent variability)

��Results have to be expressed in Results have to be expressed in ng/mLng/mL, using a specific calibration curve , using a specific calibration curve

for each lot (+ controls) (availability of lyophilized plasma cofor each lot (+ controls) (availability of lyophilized plasma containing ntaining

rivaroxabanrivaroxaban) )

OROR

�� Results may be expressed Results may be expressed in seconds but specific cutin seconds but specific cut--off depending on off depending on

the reagent should be definedthe reagent should be defined..

[1] Tripodi et al., J Thromb Haemost. 2010. 10.1111/j.1538-7836

70

DiscussionDiscussion�� For For chromogenicchromogenic assays:assays:

�� BiophenBiophen DiXaIDiXaI::

�� Sensitivity is high for all the tested concentrations with a linSensitivity is high for all the tested concentrations with a linear ear

correlationcorrelation

�� Requires calibration and controlRequires calibration and control

ChromogenicChromogenic assays may be used to evaluate more precisely the antiassays may be used to evaluate more precisely the anti--

XaXa effect of the therapy in the patient.effect of the therapy in the patient.

71

Conclusion on monitoringConclusion on monitoring�� A TwoA Two--step approach:step approach:

�� First: First: Screening with PTScreening with PT�� Define cutDefine cut--off value (in second; depending on the reagent) for risk of bleeoff value (in second; depending on the reagent) for risk of bleeding (overdose) ding (overdose)

and risk of thrombosis (lack of effectiveness)and risk of thrombosis (lack of effectiveness)

�� Measures variable depending on the time between the intake of Measures variable depending on the time between the intake of rivaroxabanrivaroxaban and the and the time of time of blood collectionblood collection => High variability=> High variability

�� INR not acceptableINR not acceptable

�� Second: Second: Confirmation with Confirmation with BiophenBiophen DiXaIDiXaI®®

�� Need for specific calibrator and control to express results in Need for specific calibrator and control to express results in ng/mLng/mL

�� Define cutDefine cut--off value (off value (ng/mLng/mL) for risk of bleeding (overdose) and risk of thrombosis (lack o) for risk of bleeding (overdose) and risk of thrombosis (lack of f effectiveness)effectiveness)

�� ProthrombinProthrombin Complex Concentrate may be administrated at the appropriate Complex Concentrate may be administrated at the appropriate concentration to counter the excessive anticoagulant activity ofconcentration to counter the excessive anticoagulant activity of rivaroxabanrivaroxaban in in case of overdosecase of overdose

72

Conclusion on monitoringConclusion on monitoring

� At the present time, neither directly measured plasma concentrations nor PT prolongation predict bleeding in an individual patient treated with rivaroxaban.

� There is no rationale (guideline) for changing the timing of administration or the dosing based on laboratory coagulation tests in the routine clinical setting.

73

Invasive Invasive proceduresprocedures and and

management of management of bleedingsbleedings

JW. Eikelboom, JI. Weitz. BMJ 2011;342:224-227

74

Neutralization of rivaroxabanNeutralization of rivaroxaban

�� A specific antidote that antagonizes the PD effect of rivaroxabaA specific antidote that antagonizes the PD effect of rivaroxaban is not n is not availableavailable

�� Activated charcoal to reduce absorption in case of overdose may Activated charcoal to reduce absorption in case of overdose may be be consideredconsidered

�� Should bleeding occur:Should bleeding occur:

�� delay next administration or discontinue treatment as appropriatdelay next administration or discontinue treatment as appropriatee

�� rivaroxaban has a mean terminal trivaroxaban has a mean terminal t1/2 1/2 of 7of 7––1111 hourshours

�� appropriate symptomatic treatment (e.g. mechanical compression, appropriate symptomatic treatment (e.g. mechanical compression, surgical interventions, fluid replacement and surgical interventions, fluid replacement and haemodynamichaemodynamic support, support, blood product or component transfusion)blood product or component transfusion)

�� If lifeIf life--threatening bleeding cannot be controlled by the above measures,threatening bleeding cannot be controlled by the above measures,administration of recombinant Factor administration of recombinant Factor VIIaVIIa may be considered (this may be considered (this recommendation is based on limited nonrecommendation is based on limited non--clinical data)clinical data)

Summary of Product Characteristics. http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-PI-en.pdfLast accessed: 16/09/09.

75

AvailabilityAvailability of an antidoteof an antidote

PCC contains:PCC contains:

�� Factor II, VII,IX and X + Factor II, VII,IX and X +

protein C and Sprotein C and S

�� Was used at 50 U PCC/kgWas used at 50 U PCC/kg

PCC may restore PT value at PCC may restore PT value at

baseline compared with baseline compared with

placebo. placebo.

Elise S. Eerenberg , et al. Circulation 2011: 124; 1573-1579

76

DabigatranDabigatran

François Mullier, Jonathan Douxfils, Bernard Chatelain, Christian Chatelain, Jean-Michel Dogné

TGG

November 23th, 2011

77

PharmacologyPharmacology -- PharmacodynamicPharmacodynamic

�� Primary Primary pharmacodynamicpharmacodynamic

�� Synthetic, nonSynthetic, non--peptide, competitive, rapidly acting and reversible inhibitor peptide, competitive, rapidly acting and reversible inhibitor

of active site of thrombin.of active site of thrombin.

�� InhibitsInhibits

�� Free thrombin (Free thrombin (KiKi of 4.5 of 4.5 nMnM) )

�� Fibrin bound thrombin (observed in a blood clot)Fibrin bound thrombin (observed in a blood clot)

�� Thrombin induced platelet aggregationThrombin induced platelet aggregation

�� SecondarySecondary pharmacodynamicpharmacodynamic

�� lowlow affinityaffinity ((KiKi>3.5 >3.5 µµMM) ) towardstowards the serine the serine proteasesproteases factor factor XaXa, factor , factor

XIaXIa, factor , factor VIIaVIIa/tissue factor /tissue factor complexcomplex, plasma , plasma kallikreinkallikrein, , plasminplasmin, ,

urokinase, tissueurokinase, tissue--type type plasminogenplasminogen activatoractivator, , activatedactivated proteinprotein C, C,

granulocyte granulocyte elastaseelastase and C1 and C1 esteraseesterase. .

�� inhibitsinhibits trypsintrypsin withwith a a KiKi of 50.3 of 50.3 nMnM,,

78Dabigatran

HN

NH2

NH

N

N

O

N

N

HO O

CH3

PRADAXA = Dabigatran etexilate

HN

NH2

N

N

N

O

N

N

O O

CH3

H3C

O

O CH3

Gastrointestinal absorption

Oral prodrug

Active metabolite in plasma

PharmacologyPharmacology -- PKPK

79E Nutescu et al. ; J Thromb Thrombolysis 2011; 31: 326-343


Low…

⇒ with a very large interindividual variability of PK parameters (Cmax, AUC).

⇒ the interindividual variability of Cmax and AUC expressed as CV was high i.e. approximately 80%.

⇒In healthy volunteers the intraindividual variability was close to 30%.



Low…

⇒ with a very large interindividual variability of PK parameters (Cmax, AUC).

⇒Risks of underdosage(thrombosis) or overdosage(bleeding)

⇒Importance of monitoring and individual follow-up



moderate renal insufficiency(CrCL between 30 – 50 ml/min): 2.7-fold AUC increase

⇒Pradaxa should be used with caution

⇒A close clinical surveillance(looking for signs of bleeding or anemia)

⇒recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (in stead of 220 mg: 2x110mg)



Severe renal deficiency

(CrCL between 10 – 30 ml/min): 6-fold AUC increase

=> CONTRA-INDICATED



Plasma concentrations of dabigatran might be elevated when co-administered with strong P-gp inhibitors: verapamil, amiodarone.

⇒This may increase the risk of bleeding and these patients should be closely Clinically monitored (looking for signs of bleeding and anaemia)

84


�� PP-- glycoproteinglycoprotein inhibitorsinhibitors::

Caution Caution shouldshould bebe exercisedexercised withwith strongstrong PP--glycoproteinglycoprotein inhibitorsinhibitors. The P. The P-- glycoproteinglycoprotein inhibitorinhibitorquinidinequinidine isis contraindicatedcontraindicated..

�� PP-- glycoproteinglycoprotein inducersinducers::

PotentPotent PP-- glycoproteinglycoprotein inducersinducers suchsuch as as rifampicinrifampicin or St or St JohnJohn’’s s wortwort ((HypericumHypericum perforatumperforatum), ), maymay reducereduce the the systemicsystemic exposureexposure of of dabigatrandabigatran. . Caution Caution isis advisedadvisedwhenwhen coco--administeringadministering thesethese medicinalmedicinal productsproducts..


86

WhoWho saidsaid no monitoring?no monitoring?

EMA public assessment report:EMA public assessment report:

PradaxaPradaxa in the prevention of Venous in the prevention of Venous ThromboembolismThromboembolism (VTE) in patients following elective (VTE) in patients following elective knee or hip replacement surgeryknee or hip replacement surgery

Conclusion on balance benefitConclusion on balance benefit--risk in the indicationrisk in the indication

““It is important to underline that the PK characteristics of DAB It is important to underline that the PK characteristics of DAB i.ei.e low low bioavailability (6.5%) with a very large bioavailability (6.5%) with a very large interindividualinterindividual variability, the variability, the concentrationconcentration--effect relationship and the bleeding risks strongly effect relationship and the bleeding risks strongly

suggest that drug monitoring is neededsuggest that drug monitoring is needed””..

Based on the above balance the benefits associated with the propBased on the above balance the benefits associated with the proposed use of DE osed use of DE are considered to outweigh the risks.are considered to outweigh the risks.

87

EMA public assessment report:EMA public assessment report:

PradaxaPradaxa in the prevention of Venous in the prevention of Venous ThromboembolismThromboembolism (VTE) in patients following elective knee or hip (VTE) in patients following elective knee or hip replacement surgeryreplacement surgery

FollowFollow--up measureup measure

““The possibility of drug monitoring would be valuable, especiallyThe possibility of drug monitoring would be valuable, especially for these for these patients at risk and commercially available TT test kits will bepatients at risk and commercially available TT test kits will be developed for developed for

measurement of TT following administration of measurement of TT following administration of DTIsDTIs””..

““A crossA cross--validation of chronometric TT measurements at localvalidation of chronometric TT measurements at local

laboratories will be performed as part of the FUM . Commerciallylaboratories will be performed as part of the FUM . Commercially available TT test available TT test kits developed for measurement of TT following administration ofkits developed for measurement of TT following administration of DTIsDTIs (i.e. (i.e.

hirudinhirudin) will be validated for measurement of TT of DAB) will be validated for measurement of TT of DAB””..

WhoWho saidsaid no monitoring?no monitoring?

88

[…] In patients at high risk of bleeding a reduction in dabigatran dose may be necessary. A diluted Thrombin

Time test (dTT) is commercially available and can be used to identify patients at increased risk because of excessive exposure to dabigatran, e.g. when renal function could be

impaired […].

8989

How to monitor?How to monitor?

�� APTT: APTT: ActivatedActivated Partial Partial ThromboplastinThromboplastin TimeTime

�� PT: PT: ProthrombinProthrombin TimeTime

�� dPT:DilutedPT:Dilute ProthrombinProthrombin TimeTime

�� TT: TT: ThrombinThrombin TimeTime

�� PiCTPiCT: : ProthrombinaseProthrombinase inducedinduced ClottingClotting TimeTime

�� ECT: ECT: EcarinEcarin ClottingClotting TimeTime

�� ECAECA--T: T: EcarinEcarin ChromogenChromogen AssayAssay

�� ACT: ACT: ActivatedActivated ClottingClotting TimeTime

�� HemoclotHemoclot®® Thrombin Inhibitor assay (Hyphen Thrombin Inhibitor assay (Hyphen BioMedBioMed))

�� HepTestHepTest

�� antiXaantiXa chromogenicchromogenic assays (assays (StaChromStaChrom and and RotachromRotachrom/ Liquid anti / Liquid anti XaXa))

�� Thrombin Generation test (TGT)Thrombin Generation test (TGT)

�� ThromboelastogramThromboelastogram (TEG)(TEG)

90

aPTTaPTT

�� As recently recommended by Australian As recently recommended by Australian

regulatory authorities, regulatory authorities, aPTTaPTT could be used as a could be used as a

screening test to exclude a bleeding risk screening test to exclude a bleeding risk

associated with DE administration. associated with DE administration.

Douxfils J. Mullier F et al. submitted

91

Dabigatran: APTT


Australianguideline

9292

�� Sensitive diluted TT assay which allows for quantitative Sensitive diluted TT assay which allows for quantitative

measurement of DTI activity in plasma, based on inhibition of a measurement of DTI activity in plasma, based on inhibition of a

constant and defined concentration of thrombin. Diluted test constant and defined concentration of thrombin. Diluted test

plasma (1:8 to 1:20) is mixed with normal pooled human plasma, plasma (1:8 to 1:20) is mixed with normal pooled human plasma,

and clotting is then initiated by adding a constant amount of and clotting is then initiated by adding a constant amount of

highly purified human highly purified human αα--thrombin. thrombin.

CalibratorsCalibrators and and controlscontrols availableavailable sincesince decemberdecember 2010.2010.

Hemoclot ® : Thrombin Inhibitor assay

9393

Hemoclot ® : Thrombin Inhibitor assay


9494

Hemoclot ® : Thrombin Inhibitorassay


�� HTI:HTI:

-- One of the most sensitive with a 2 x CT of 8ng/mLOne of the most sensitive with a 2 x CT of 8ng/mL

-- Reproducibility was quite good (1.0%). Reproducibility was quite good (1.0%).

-- Linear correlation coefficient (RLinear correlation coefficient (R22 =1.00)=1.00)

-- Addition of NPP (reagent 1) Addition of NPP (reagent 1) �� insensitive to fibrinogen. insensitive to fibrinogen.

-- In a patient taking 150mg of DE In a patient taking 150mg of DE bid,bid, a concentration higher than a concentration higher than 200ng/mL is correlated with an increased risk of bleeding while 200ng/mL is correlated with an increased risk of bleeding while this value is reduced to 67ng/mL for patient in primary this value is reduced to 67ng/mL for patient in primary prevention of venous prevention of venous thromboembolismthromboembolism..

95

PracticalPractical approachapproach

�� For patient taking 150mg DE For patient taking 150mg DE bidbid regimen, an regimen, an aPTTaPTT above 80 seconds above 80 seconds at trough (corresponding to a at trough (corresponding to a CtroughCtrough about 200ng/mL) is correlated about 200ng/mL) is correlated with an increased risk of bleeding. with an increased risk of bleeding.

�� This cutThis cut--off is reduced to 45 seconds (corresponding to a off is reduced to 45 seconds (corresponding to a CtroughCtrough of of 67ng/mL) for patients taking 220mg DE 67ng/mL) for patients taking 220mg DE qdqd as for primary prevention as for primary prevention of venous of venous thromboembolismthromboembolism..

�� Nevertheless, first, as illustrated in our study, these cutNevertheless, first, as illustrated in our study, these cut--offs have to be offs have to be adapted according to the adapted according to the aPTTaPTT reagent: The clotting time related to a reagent: The clotting time related to a concentration of 200ng/mL varies from 48.6 to 62.5 sec, accordinconcentration of 200ng/mL varies from 48.6 to 62.5 sec, according to g to the reagent. Accordingly, the the reagent. Accordingly, the aPTTaPTT ratio for this concentration ranges ratio for this concentration ranges from 1.74 to 2.06. from 1.74 to 2.06.

�� These differences may lead to a misinterpretation if inappropriaThese differences may lead to a misinterpretation if inappropriate cutte cut--offs are used. Australian regulatory authorities proposed an APToffs are used. Australian regulatory authorities proposed an APTT cutT cut--off of 80 sec based on a concentration of 200ng/mL.off of 80 sec based on a concentration of 200ng/mL.


96

DelayDelay

�� Standardization of the Standardization of the time between the last intake of time between the last intake of dabigatrandabigatran and the and the time of blood collection as these influence time of blood collection as these influence dabigatrandabigatran concentration concentration and thus the results of the coagulation assayand thus the results of the coagulation assay. .

�� Which?Which?

-- CtroughCtrough may be more interesting than may be more interesting than CmaxCmax since the absorption phase and since the absorption phase and CmaxCmax are more variable than are more variable than CtroughCtrough. .

-- Nevertheless, if Nevertheless, if CtroughCtrough could be used to measure a risk of bleeding with could be used to measure a risk of bleeding with accurate define cutaccurate define cut--off, it seems off, it seems unappropriateunappropriate to evaluate compliance.to evaluate compliance.

-- Indeed, the range of local normal values for different Indeed, the range of local normal values for different aPTTaPTT showed minor showed minor differences in comparison with differences in comparison with CtroughCtrough in AF. in AF. Moreover, in realMoreover, in real--life, life, the the baseline clotting time (before drug administration) will often nbaseline clotting time (before drug administration) will often not be ot be determined precluding to detect a relative change in determined precluding to detect a relative change in aPTTaPTT. Thus, in this case, . Thus, in this case, more specific and sensitive assays should be used. more specific and sensitive assays should be used.


97

Discussion:Discussion:

Stangier et al. Br J Clin Pharmacol. 2007;64(3):292-303.

98


ReagentLocal normal

values (sec)

Baseline time(sec)

Coagulation time of NPP

corresponding to mean Ctrough in

AF (i.e 80ng/mL)

Coagulation time corresponding to a risk a bleeding

in MOS (i.e67ng/mL)

Coagulation time corresponding to a risk a bleeding

in AF (i.e200ng/mL)

Sec RatioSec Ratio Sec Ratio

Actin FS® 25.8-33.2 30.3 46.3 1.53 44.3 1.48 62.5 2.06

Cephascreen® N.D 27.4 37.5 1.37 36.2 1.32 48.6 1.77

CKPrest® 26.7- 37.6 30.5 41.6 1.36 40.2 1.32 53.0 1.74

PTT-A® 28.0-39.0 33.2 45.2 1.36 44.0 1.32 58.6 1.77

Synthasil® 25.8- 33.2 27.5 38.0 1.39 36.7 1.33 49.0 1.78

Hemoclot® N.D 33.3 42.3 1.27 40.9 1.23 54.7 1.64

Douxfils J. Mullier F et al. resubmitted

99


�� However, using 5 different reagents, the However, using 5 different reagents, the aPTTaPTT was lower than 80 sec for this was lower than 80 sec for this concentration in concentration in dabigatrandabigatran. In addition, the response of an . In addition, the response of an aPTTaPTT reagent reagent varies according to the lot number and varies according to the lot number and coagulometerscoagulometers showed differences in showed differences in end point detection.end point detection.

�� Therefore, each laboratory should therefore calibrate each lot Therefore, each laboratory should therefore calibrate each lot of its of its aPTTaPTTreagent on one instrument by spiking a NPP with at least 6 reagent on one instrument by spiking a NPP with at least 6 dabigatrandabigatranconcentrations ranging from 0 to 1,000ng/ml. concentrations ranging from 0 to 1,000ng/ml.

�� In one particular lab, the In one particular lab, the aPTTaPTT is also affected by is also affected by preanalyticalpreanalytical (time of blood (time of blood sampling and sample transport) and biological variables (lupus asampling and sample transport) and biological variables (lupus anticoagulant, nticoagulant, hereditary or acquired factor deficiencies) (37) hereditary or acquired factor deficiencies) (37)


100


�� aPTTaPTT > cut> cut--off off �� HTIHTI. .

�� Ratio for HTI < Ratio for HTI < aPTTaPTT

but but

-- Highly reproducibleHighly reproducible

-- Linear on a broad range of concentrations in comparison with Linear on a broad range of concentrations in comparison with aPTTaPTT showing showing a loss of sensitivity for higher concentration. a loss of sensitivity for higher concentration.

-- Calibrators and specific methodologies available from Hyphen BioCalibrators and specific methodologies available from Hyphen Biomed to med to easily perform these measurements on BCSeasily perform these measurements on BCS®®, ACL 7000, ACL 7000®®, ACL Top, ACL Top®®, , STASTA--RR®® and and provisoryprovisory on on SysmexSysmex CA1500. CA1500.

-- As As aPTTaPTT and HTI are global assays, it is also necessary for the clinicaand HTI are global assays, it is also necessary for the clinical l biologist to know which anticoagulant is administrated to choosebiologist to know which anticoagulant is administrated to choose the the adequate assay with accurate normal ranges.adequate assay with accurate normal ranges.


101

CommentsComments

�� Validation in patients receiving Validation in patients receiving PradaxaPradaxa®®. Indeed, it is currently . Indeed, it is currently unknown how coagulation testsunknown how coagulation tests are predictive of the bleeding are predictive of the bleeding risks (risks (3939). ).

�� However, However, FreyburgerFreyburger et al.et al.

-- explored the impact of DE on patients undergoing THR or TKR explored the impact of DE on patients undergoing THR or TKR ((1616). ).

-- correlation with those obtained correlation with those obtained in vitroin vitro. .

-- used a dilute thrombin time based on the same principle than used a dilute thrombin time based on the same principle than HTI to assess the impact of HTI to assess the impact of dabigatrandabigatran on the coagulation. on the coagulation.

-- InterindividualInterindividual variability variability �� value of value of point measurement to point measurement to minimize the risk of the product. minimize the risk of the product.

102

RenalRenal functionfunction�� EMA recommendations following an evaluation of reports of 6 caseEMA recommendations following an evaluation of reports of 6 cases of fatal s of fatal

bleeding in Japan (October 2011)bleeding in Japan (October 2011)

�� Most patients that experienced fatal bleeding in Japan were eldeMost patients that experienced fatal bleeding in Japan were elderly with rly with

severe renal impairment. severe renal impairment.

�� In the current EU In the current EU SmPCSmPC for for PradaxaPradaxa it is stated that factors such as high it is stated that factors such as high

age, moderate renal impairment (30age, moderate renal impairment (30--50 ml/min 50 ml/min CrCLCrCL), low body weight, ), low body weight,

use of acetylsalicylic acid, use of acetylsalicylic acid, clopidogrelclopidogrel or NSAID, and presence of or NSAID, and presence of

esophagitis/gastritis/gastroesophagealesophagitis/gastritis/gastroesophageal reflux requiring treatment increase reflux requiring treatment increase

the risk of bleeding associated with the risk of bleeding associated with PradaxaPradaxa treatment. treatment.

�� Furthermore, patients at increased risk of bleeding should be Furthermore, patients at increased risk of bleeding should be closely closely

clinically monitored looking for signs of bleeding and clinically monitored looking for signs of bleeding and anaemiaanaemia. .

103

RenalRenal functionfunction�� EMA recommendations following an evaluation of reports of 6 caseEMA recommendations following an evaluation of reports of 6 cases of fatal s of fatal

bleeding in Japan (October 2011)bleeding in Japan (October 2011)

�� Prior to initiation of treatment Prior to initiation of treatment with with PradaxaPradaxa®® the renal function should be the renal function should be

assessed by calculating the assessed by calculating the creatininecreatinine clearance (clearance (CrClCrCl) to exclude patients ) to exclude patients

for treatment with severe renal impairment (i.e. for treatment with severe renal impairment (i.e. CrClCrCl < 30 ml/min). < 30 ml/min).

�� While on treatment renal function should be assessed in certain While on treatment renal function should be assessed in certain clinical clinical

situationssituations when it is suspected that the renal function could decline or when it is suspected that the renal function could decline or

deteriorate (e.g. deteriorate (e.g. hypovolemiahypovolemia, dehydration, and with certain , dehydration, and with certain

comedicationscomedications). ).

�� In patients above 75 years of age or in patients with renal impaIn patients above 75 years of age or in patients with renal impairment renal irment renal

function should be function should be evaluated at least yearlyevaluated at least yearly..

104104

�� New oral anticoagulants: Developed with the intent not to New oral anticoagulants: Developed with the intent not to

require monitoring due to their predictable pharmacologic require monitoring due to their predictable pharmacologic

effectseffects

�� However this will be required in some specific settings (liver,However this will be required in some specific settings (liver,

kidney, drug interactions, compliance, bleeding, recurrence)kidney, drug interactions, compliance, bleeding, recurrence)

�� Therapeutic ranges for coagulation not delineated Therapeutic ranges for coagulation not delineated �� evaluation evaluation

of a bleeding complication will be a challengeof a bleeding complication will be a challenge

Conclusions

105105

�� Widespread use, 24h/24 accessibility, low cost and relatively Widespread use, 24h/24 accessibility, low cost and relatively

good sensitivity good sensitivity �� aPTTaPTT could be used for point measurements could be used for point measurements

of of dabigatrandabigatran and as screening test for the risk of bleeding. and as screening test for the risk of bleeding.

�� HTI, ECT and TGA are the most sensitive tests. HTI, ECT and TGA are the most sensitive tests.

�� Besides, HTI showed good reproducibility, excellent linear Besides, HTI showed good reproducibility, excellent linear

correlation at all doses, simplicity of use, automation capabilicorrelation at all doses, simplicity of use, automation capabilities ties

and should therefore be seen today as the goldand should therefore be seen today as the gold--standard assay for standard assay for

point measurements of point measurements of dabigatrandabigatran after a positive screening test.after a positive screening test.

Conclusions

106106

�� StrategiesStrategies

-- APTT followed by APTT followed by HemoclotHemoclot

-- HemoclotHemoclot

�� Other drugsOther drugs

-- Which drugWhich drug

-- Delay: which one? Standardisation!Delay: which one? Standardisation!

�� All of these issues will be encountered in a near future All of these issues will be encountered in a near future ��””the the

implementation of these antithrombotic agents will require a implementation of these antithrombotic agents will require a

multimulti--modal team approach and diligent postmodal team approach and diligent post--approval approval

monitoring for effectiveness and safetymonitoring for effectiveness and safety””

Conclusions

107

Management of Management of bleedingsbleedings on on

dabigatrandabigatran

Van Ryn et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation o f coagulation assays and reversal of anticoagulant activity.Thromb.Haemost 2010; 104: 49–60

108

Management of Management of bleedingsbleedings on on

dabigatrandabigatran

Van Ryn et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation o f coagulation assays and reversal of anticoagulant activity.Thromb.Haemost 2010; 104: 49–60

109

ThankThank youyou for for youryour attention!attention!

Jean-Michel Dogné , Jonathan Douxfils, François Mullier, Christian Chatelain, Bernard Chatelain,

110

Back up Back up slideslide

Practical management: Practical management:

frequently asked frequently asked

questionsquestions

112

Practical management: laboratory Practical management: laboratory

monitoring monitoring

�� Rivaroxaban does not require routine coagulation monitoringRivaroxaban does not require routine coagulation monitoring

�� The following coagulation tests are influenced after The following coagulation tests are influenced after administration of rivaroxaban: PT, aPTT and calculated INRadministration of rivaroxaban: PT, aPTT and calculated INR

�� INR testing was developed for measuring VKA effects and INR testing was developed for measuring VKA effects and is, therefore, not appropriate to measure activity of is, therefore, not appropriate to measure activity of rivaroxabanrivaroxaban

�� If clinically indicated, haemostatic status can be assessed by PIf clinically indicated, haemostatic status can be assessed by PT T using Neoplastine as described in the Summary of Product using Neoplastine as described in the Summary of Product CharacteristicsCharacteristics

�� Rivaroxaban calibrators and controls are currently under Rivaroxaban calibrators and controls are currently under validation and developmentvalidation and development

�� AntiAnti--Factor Xa assays are also currently under development Factor Xa assays are also currently under development

Xarelto Summary of Product Characteristics

113

Practical management: switching Practical management: switching

drugsdrugs

�� Switching from Switching from VKAs to rivaroxabanVKAs to rivaroxaban

�� VKA treatment should be stopped and rivaroxaban should be initiaVKA treatment should be stopped and rivaroxaban should be initiated ted

when the INR is when the INR is ≤≤2.52.5

�� INR measurement is not appropriate to measure rivaroxaban and shINR measurement is not appropriate to measure rivaroxaban and should ould

not be used; treatment with rivaroxaban only does not require ronot be used; treatment with rivaroxaban only does not require routine utine

coagulation monitoringcoagulation monitoring

�� Switching from Switching from a a parenteral anticoagulant to rivaroxabanparenteral anticoagulant to rivaroxaban

�� Rivaroxaban should be started 0Rivaroxaban should be started 0––2 hours before the time of the next 2 hours before the time of the next

scheduled administration of the parenteral medicinal product scheduled administration of the parenteral medicinal product

(e.g.(e.g. LMWH) or at the time of discontinuation of a continuously LMWH) or at the time of discontinuation of a continuously

administered parenteral medicinal product (e.g. i.v. UFH)administered parenteral medicinal product (e.g. i.v. UFH)

�� SwitchingSwitching from from rivaroxaban to parenteral anticoagulantsrivaroxaban to parenteral anticoagulants

�� Give the first dose of parenteral anticoagulant at the time the Give the first dose of parenteral anticoagulant at the time the next next

rivaroxaban dose would be takenrivaroxaban dose would be taken


114

Practical management: dosing Practical management: dosing before before

and after invasive procedures and after invasive procedures

�� Rivaroxaban should be stopped at least 24Rivaroxaban should be stopped at least 24 hours before the hours before the

intervention, if possible, and based on the clinical judgement ointervention, if possible, and based on the clinical judgement of f

the physicianthe physician

�� If the procedure cannot be delayed the increased risk ofIf the procedure cannot be delayed the increased risk of bleeding bleeding

should be assessed against the urgency of theshould be assessed against the urgency of the interventionintervention

�� Rivaroxaban should be restarted after the invasive procedure or Rivaroxaban should be restarted after the invasive procedure or

surgical intervention as soon as possible, provided the clinicalsurgical intervention as soon as possible, provided the clinical

situation allows and adequate situation allows and adequate haemostasishaemostasis has been establishedhas been established


115

Clinical utility of rivaroxaban for Clinical utility of rivaroxaban for

treatment of DVT and secondary treatment of DVT and secondary

prevention of VTEprevention of VTE

�� Does not require injection or routine coagulation Does not require injection or routine coagulation


�� Rapid anticoagulant effects (within 2Rapid anticoagulant effects (within 2––4 hours)4 hours)

�� High oral bioavailabilityHigh oral bioavailability

�� Low potential for drugLow potential for drug––drug or fooddrug or food––drug interactionsdrug interactions

�� Enables singleEnables single--drug approach versus LMWH plus drug approach versus LMWH plus

warfarin/VKA for the initial treatment of VTE and a warfarin/VKA for the initial treatment of VTE and a

convenient onceconvenient once--daily dosing for longdaily dosing for long--term treatment term treatment

and prevention of VTE recurrenceand prevention of VTE recurrence

The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2500; Xarelto Summary of Product Characteristics

116

Need for monitoring according to Need for monitoring according to

guidelinesguidelines

VKAsVKAs

Unpredictable anticoagulation response that necessitates regularUnpredictable anticoagulation response that necessitates regular monitoringmonitoring1,21,2

PT/INR testing to ensure patients are within INR rangePT/INR testing to ensure patients are within INR range2,32,3

LMWHsLMWHs

Routine coagulation monitoring not normally needed, except for Routine coagulation monitoring not normally needed, except for

patients with severe renal failure and pregnant womenpatients with severe renal failure and pregnant women22

AntiAnti--Factor Xa assay can be usedFactor Xa assay can be used22

UFHUFH

Anticoagulant response varies among patients; Anticoagulant response varies among patients;

UFH (intravenous and subcutaneous) requires monitoring UFH (intravenous and subcutaneous) requires monitoring

(weight(weight--based subcutaneous UFH does not)based subcutaneous UFH does not)2,42,4

aPTT test to be used to maintain doses that correspond to therapaPTT test to be used to maintain doses that correspond to therapeutic heparin levelseutic heparin levels22

1. Merli G et al. Ann Surg 2009;250:219–228; 2. Kearon C et al. Chest 2008;133:454S–545S; 3. Ansell J et al. Chest 2008;133:160S–198S; 4. Hirsh J et al. Chest 2008;133:141S–159S

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Dabigatran -Rivaroxaban : Variability and monitoring Scientific... · 2012. 11. 8. · Parenteral anticoagulants Unfractionated heparin Low molecular weight heparins Indirect Factor