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Oral anticoagulant therapy :Oral anticoagulant therapy :

a look to the futurea look to the future

Alexander G. G. TurpieAlexander G. G. Turpie

Department of MedicineDepartment of Medicine

HHSHHS--General HospitalGeneral Hospital

Hamilton, CanadaHamilton, Canada

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Antithrombotics That HaveAntithrombotics That Have

Changed Clinical PracticeChanged Clinical PracticeAnticoagulantsAnticoagulants

LowLow--molecularmolecular--weight heparinweight heparin

Antiplatelet DrugsAntiplatelet Drugs

ThienopyridinesThienopyridines

Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors

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But..But..

for oral anticoagulation, Vitamin Kfor oral anticoagulation, Vitamin K

antagonists (warfarin) remain the onlyantagonists (warfarin) remain the only

available optionavailable option

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The ideal oral anticoagulantThe ideal oral anticoagulant

Oral, preferably once dailyOral, preferably once daily

Rapid onset and offset of actionRapid onset and offset of action

Predictable PK and PDPredictable PK and PD Low propensity for food and drugLow propensity for food and drug

interactionsinteractions

Fixed dosesFixed doses

Wide therapeutic windowWide therapeutic window

Easy to use with no need for monitoringEasy to use with no need for monitoring

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New AnticoagulantsNew Anticoagulants

TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

LY517717

YM150

DU-176b

Betrixaban

TAK 442

Dabigatran

ORAL PARENTERAL

DX-9065a

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)

sTM (ART-123)

Adapted from Weitz & Bates, JThromb Haemost2007

TTP889

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VIIa

Xa

IXa

XIaXIIa

Direct Thrombin inhibitionDirect Thrombin inhibitionTissue

factor

Factor IIa

(thrombin)Dabigatran

II

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Dabigatran for prevention of VTE after majorDabigatran for prevention of VTE after major

orthopaedic surgery: phase III studiesorthopaedic surgery: phase III studies

Dabigatran doses of 150 and 220 mg once daily (od)Dabigatran doses of 150 and 220 mg once daily (od)were investigated in all three studieswere investigated in all three studies

TKR: total knee replacement; THR: total hip replacementEriksson et al. Blood2006; Friedman et al. JThromb Haemost2007; Eriksson et al. JThromb Haemost2007

StudyStudy Type of Type of

surgerysurgery

ComparatorComparator Number ofNumber of

patientspatients

Time to 1stTime to 1st

administrationadministration

of dabigatranof dabigatran

TreatmentTreatment

durationduration

RERE--MODELMODEL TKRTKR EnoxaparinEnoxaparin4040 mg od, startingmg od, starting

evening beforeevening before

surgerysurgery

20102010 114 hours4 hours

postpost--surgerysurgery

6610 days10 days

RERE--MOBILIZEMOBILIZE TKRTKR EnoxaparinEnoxaparin3030 mg bid, startingmg bid, starting

121224 hours post24 hours post--surgerysurgery

26152615 6612 hours12 hours


121215 days15 days

RERE--NOVATENOVATE THRTHR EnoxaparinEnoxaparin4040 mg od, startingmg od, starting

evening beforeevening before

surgerysurgery

34943494 114 hours4 hours


282835 days35 days

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Dabigatran for prevention of VTE after majorDabigatran for prevention of VTE after major

orthopaedic surgery: resultsorthopaedic surgery: results

EnoxaparinEnoxaparin DabigatranDabigatran

(150 mg)(150 mg)

DabigatranDabigatran

(220 mg)(220 mg)

DVT, PE and allDVT, PE and all--cause mortality (%)cause mortality (%)

RERE--NOVATENOVATE 6.76.7 8.68.6

pp

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Dabigatran: phase III studiesDabigatran: phase III studies

RERE--LY (stroke prevention in patients with AF)LY (stroke prevention in patients with AF)

Planned enrolment 15,000 patientsPlanned enrolment 15,000 patients

Dabigatran 110 and 150 mg bid compared withDabigatran 110 and 150 mg bid compared withwarfarinwarfarin

Treatment duration up to 3 yearsTreatment duration up to 3 years

RERE--SOLVE, RESOLVE, RE--COVER and RECOVER and RE--MEDYMEDY

Ongoing studies in treatment and secondaryOngoing studies in treatment and secondary

prevention of VTEprevention of VTE

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New AnticoagulantsNew Anticoagulants

TFPI (tifacogin)

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

LY517717

YM150

DU-176b

Betrixaban

TAK 442

Dabigatran

ORAL PARENTERAL

DX-9065a

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)

sTM (ART-123)

Adapted from Weitz & Bates, JThromb Haemost2007

TTP889

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VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa inhibitionDirect Factor Xa inhibition

Tissue

factor

Fibrinogen Fibrin clot

Factor II(prothrombin)

RivaroxabanApixaban

YM150

DU-176b

LY517717

BetrixabanTAK 442

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ApixabanApixaban

Oral, direct, selective factor Xa inhibitorOral, direct, selective factor Xa inhibitor

Produces concentrationProduces concentration--dependentdependent

anticoagulationanticoagulation

No formation of reactive intermediatesNo formation of reactive intermediates

No organ toxicity orLFT abnormalities inNo organ toxicity orLFT abnormalities inchronic toxicology studieschronic toxicology studies

Low likelihood of drug interactions orLow likelihood of drug interactions or

QTc prolongationQTc prolongation

GoodGood oral bioavailabilityoral bioavailability

No food effectNo food effect Balanced elimination (~25% renal)Balanced elimination (~25% renal)

HalfHalf--life ~12 hrslife ~12 hrs

He et al., ASH, 2006, Lassen, et al ASH, 2006

N

N

NO

N O

NH2

O

O

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Apixaban :Phase IIApixaban :Phase II

AproposApropos orthopaedic surgeryorthopaedic surgery

BotticelliBotticelli treatmenttreatment

AdaptAdapt advanced canceradvanced cancer

Appraise 1Appraise 1 ACSACS

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Lassen et al. Blood2006

10.6

8.6 6.8

26.6

15.6

0

5

10

15

20

25

30

Total VTE and AllTotal VTE and All--Cause Mortality (%)Cause Mortality (%)Total VTE and AllTotal VTE and All--Cause Mortality (%)Cause Mortality (%) Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)

Enoxaparin(30mg bid)

Apixaban for Prevention of VTE AfterApixaban for Prevention of VTE After

Major Orthopaedic SurgeryMajor Orthopaedic SurgeryApixaban od and bid (total daily doses 5Apixaban od and bid (total daily doses 5--20mg) were assessed20mg) were assessed

relative to enoxaparin and warfarin, in 1,217 patientsrelative to enoxaparin and warfarin, in 1,217 patients

20mg

ApixabanApixaban

(Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin(INR

1.8-3.0)

1.3 1.63.0

0 0

0

5

10

15

20

25

30

Enoxaparin(30mg bid)

20mg

ApixabanApixaban(Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin(INR

1.8-3.0)

Percent

Percent

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Bller, Eur HeartJ2006

6.05.6

2.6

4.2

0

2

4

6

8

10

Composite of Symptomatic Recurrent VTEComposite of Symptomatic Recurrent VTE

and Deterioration of Thrombotic Burden (%)and Deterioration of Thrombotic Burden (%)

Composite of Symptomatic Recurrent VTEComposite of Symptomatic Recurrent VTE

and Deterioration of Thrombotic Burden (%)and Deterioration of Thrombotic Burden (%)Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)

Apixaban for the Treatment of DVT:Apixaban for the Treatment of DVT:

The BotticelliThe Botticelli--DVT StudyDVT StudyApixaban bid (5 and 10mg) and od (20mg) were assessed relative toApixaban bid (5 and 10mg) and od (20mg) were assessed relative to

low molecular weight heparin (LMWH) or fondaparinux followed bylow molecular weight heparin (LMWH) or fondaparinux followed by

VKA, in 520 patientsVKA, in 520 patients

20mg

bidApixabanApixaban

10mg

bid

5mg

bid

LMWH/

fondaparinux

+ VKA

0.8

0

0.8

0

0

2

4

6

8

10

20mg

bidApixabanApixaban

10mg

bid

5mg

bid

LMWH/

fondaparinux

+ VKA

P

ercent

P

ercent

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Apixaban : Phase IIIApixaban : Phase III

Advance 1,2,3Advance 1,2,3 orthopaedic surgeryorthopaedic surgery

AdoptAdopt medically illmedically ill

AristotleAristotle --atrial fibrillationatrial fibrillationAppraise 2Appraise 2 -- ACSACS

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Rivaroxaban: oral direct Factor Xa inhibitorRivaroxaban: oral direct Factor Xa inhibitor

PredictablePredictable

pharmacologypharmacology

High bioavailabilityHigh bioavailability

Low risk of drugLow risk of drugdrugdruginteractionsinteractions

Fixed doseFixed dose

No requirement forNo requirement for

monitoringmonitoring

Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Rivaroxaban rivaroxaban

N NO

NH

O

S

ClO

O

O

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RivaroxabanRivaroxaban

Specific, competitive, directSpecific, competitive, directFXa inhibitorFXa inhibitor

Inhibits free and clotInhibits free and clot--associated FXa activity,associated FXa activity,and prothrombinase activityand prothrombinase activity

Inhibits thrombinInhibits thrombin

generation via inhibition ofgeneration via inhibition ofFXa activityFXa activity

Prolongs time to thrombinProlongs time to thrombingenerationgeneration

Inhibits peak thrombinInhibits peak thrombin

generationgeneration Reduces the total amountReduces the total amount

of thrombin generatedof thrombin generated

Does not require a cofactorDoes not require a cofactor

Perzborn et al.J

Thromb Haemost2005; ICT2004; Depasse et al. ISTH2005; Kubitza et al. Clin Pharmacol Ther2005;BrJClin Pharmacol, 2007; Graffet al. In press

Rivaroxaban (nM)

0.01 0.1 1 10 100 1000

InhibitionofFactorXa

activity(%)

0

20

40

60

80

100

Free FXaProthrombinase activityClot-associated FXa

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Rivaroxaban 10 mg once dailyRivaroxaban 10 mg once daily

is the optimum doseis the optimum dose

0 5 10 20 40 Enoxaparin30

0

10

20

40

30

0

10

20

30

Incidenceefficacy(%) In

c

idencesafety(%

)

Rivaroxaban (mg total daily dose)

DVT, PE and all-cause mortality

Major post-operative bleeding

p=0.0852

p=0.039

Efficacy, n=618; safety, n=845

Eriksson et al. Circulation 2006

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Rivaroxaban: VTE Treatment TrialsRivaroxaban: VTE Treatment Trials

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Two large, phase II studies of rivaroxaban forTwo large, phase II studies of rivaroxaban for

33 months for the treatment and long-termmonths for the treatment and long-term

secondary prevention of VTE:secondary prevention of VTE:

ODIXaODIXa--DVT : Rivaroxaban 10DVT : Rivaroxaban 1030 mg bid30 mg bid

and 40and 40 mg odmg od

EINSTEIN DVT : Rivaroxaban 20EINSTEIN DVT : Rivaroxaban 2040 mg od40 mg od

LMWH followed by a VKA comparator in bothLMWH followed by a VKA comparator in both

studiesstudies

Agnelli et al. Circulation 2007; Bller. Eur HeartJ2006

Rivaroxaban for the treatment andRivaroxaban for the treatment and

secondary prevention of VTEsecondary prevention of VTE

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Phase III RECORD programme inPhase III RECORD programme in

VTE preventionVTE prevention Oral rivaroxaban 10 mg od is being compared with subcutaneousOral rivaroxaban 10 mg od is being compared with subcutaneous

enoxaparin in >11,000 patients worldwideenoxaparin in >11,000 patients worldwide

StudyStudy Duration ofDuration ofrivaroxabanrivaroxaban

therapytherapy

Duration ofDuration of

enoxaparinenoxaparin

therapytherapyRECORD1RECORD1 THRTHR 5 weeks5 weeks 5 weeks5 weeks

RECORD2RECORD2 THRTHR 5 weeks5 weeks 101014 days,14 days,followed by placebofollowed by placebo

RECORD3RECORD3 TKRTKR 101014 days14 days 101014 days14 days

RECORD4RECORD4 TKRTKR 101014 days14 days 101014 days14 days

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Efficacy endpointsEfficacy endpoints

PrimaryPrimary Total venous thromboembolism (VTE): anyTotal venous thromboembolism (VTE): any

deep vein thrombosis (DVT), nondeep vein thrombosis (DVT), non--fatalfatal

pulmonary embolism (PE

), and allpulmonary embolism (PE

), and all--causecausemortalitymortality

SecondarySecondary

Major VTE

: proximal DVT, nonMajor VTE

: proximal DVT, non--fatal PE

, andfatal PE

, andVTEVTE--related deathrelated death

DVT: any, proximal, distalDVT: any, proximal, distal

Symptomatic VTE

Symptomatic VTE

All endpoints were adjudicated centrally by independent, blinded committees

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Safety endpointsSafety endpointsMainMain

Major bleeding starting after the first blinded doseMajor bleeding starting after the first blinded doseandand

2 days after last dose2 days after last dose

Bleeding that was fatal, into a critical organ or requiredBleeding that was fatal, into a critical organ or required

rere--operationoperation ExtraExtra--surgicalsurgical--site bleeding associated with a drop insite bleeding associated with a drop in

hemoglobin 2 g/dL or requiring transfusion of 2 unitshemoglobin 2 g/dL or requiring transfusion of 2 units

bloodblood

OtherOther Any bleeding on treatment*Any bleeding on treatment* NonNon--major bleeding*major bleeding* Hemorrhagic wound complications*Hemorrhagic wound complications* Cardiovascular adverse eventsCardiovascular adverse events Liver enzyme levelsLiver enzyme levels

All endpoints were adjudicated centrally by independent, blinded committees*Up to 2 days after last dose of study medication

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Rivaroxaban an oral, direct Factor Xa inhibitor

for the prevention of venous thromboembolism in

total knee arthroplasty surgery

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Enoxaparin 40 mg od

Rivaroxaban 10 mg od

Mandatory

bilateral

venography

RECORD3: study designRECORD3: study design

Inclusion criteria

f Patients aged 18 years,

scheduled to undergo elective,

total knee replacement (TKR)

surgery

Day 42+5

R

SURGERY

FOLLOW

U

PEvening before surgery

68 hours post-surgery


Day 1 Day 13 2

Double blind

Last dose, 1 day

before venography

Major exclusion criteria

f Active bleeding or high risk of bleeding

f Significant liver disease

f Anticoagulant therapy that could not be stopped

f Use of HIV-protease inhibitors

R

SURGERY

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RECORD3: summaryRECORD3: summary

Total VTETotal VTE

Major bleedingMajor bleeding

20

Incidence(%)

0

Major VTEMajor VTE

5

10

15

NS

RRR 49%

RRR 62%

Symptomatic VTESymptomatic VTE


Enoxaparin 40 mg od

RRR 65%

0.5% 0.6%18.9% 9.6% 2.6% 1.0% 2.0% 0.7%

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Study backgroundStudy background

ACCP guidelines: grade 1AACCP guidelines: grade 1A

recommendation for up torecommendation for up to35 days prophylaxis after35 days prophylaxis after

elective hip replacementelective hip replacement

surgerysurgery

Geerts et al., 2004

20042004

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Oral rivaroxaban compared with

subcutaneous enoxaparin for extended

thromboprophylaxis after total hip

arthroplasty

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Enoxaparin 40 mg od


RECORD1 study designRECORD1 study design

Mandatory

bilateral

venographyR

SURGERY

FOLLOW

UP

Evening before surgery



Day 1 Day 36 4

Double blind

Last dose, day

before venography

Up to

Day 65

Inclusion criteriaf Patients aged 18 years, scheduled

to undergo elective THR

Major exclusion criteriaf Active bleeding or high risk of bleeding




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Incidence(%

)

Total VTETotal VTE

MajorMajor

bleedingbleeding

Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

0

1

2

3

4

5

0.5% 0.3% 0.1% 0.3%

SymptomaticSymptomaticVTEVTE

RRR 70%

2.0% 0.2%

Major VTEMajor VTERRR 88%

1.1%3.7%

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Extended thromboprophylaxis with rivaroxabancompared with short-term thromboprophylaxis

with low molecular weight heparin

after total hip arthroplasty

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Mandatory

bilateral

venography

RECORD2: study designRECORD2: study design

Inclusion criteriaf Patients aged 18 years, scheduled

to undergo elective THR

Day 65+5

R

SURGE

RY

FOLLOW

UP

Evening before surgery



Day 1

Double blind

Major exclusion criteriaf Active bleeding or high risk of bleeding




Day 36 4

Enoxaparin

40 mg od

Oral placebo

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Total VTETotal VTE

Major bleedingMajor bleeding

Major VTEMajor VTE

Incidence(%)

0

2

4

6

10

8

9.3%

RRR 78.9%

2.0% 5.1% 0.1% 0.1%0.6%

RRR 87.8%RRR 80.1%

1.2% 0.2%

SymptomaticSymptomatic

VTEVTE

Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

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Clinical programme overview:Clinical programme overview:

50,000 patients to be enrolled50,000 patients to be enrolled

VTE prevention inVTE prevention in

hospitalized medically illhospitalized medically ill

patientspatients

Secondary prevention ofSecondary prevention of

acute coronary syndromesacute coronary syndromes

Japanese Phase III studyJapanese Phase III study

Stroke prevention in atrialStroke prevention in atrial

fibrillationfibrillation

EINSTEINEINSTEIN--DVTDVT

EINSTEINEINSTEIN--PEPE

EINSTEINEINSTEIN--EXTEXT

ODIXaODIXa--DVTDVT

EINSTEINEINSTEIN--DVTDVT

VTE treatmentVTE treatment

RECORD1RECORD1

RECORD2RECORD2

RECORD3RECORD3

RECORD4RECORD4

ODIXaODIXa--HIP1HIP1

ODIXaODIXa--HIP2HIP2

ODIXaODIXa--KNEEKNEE

ODIXaODIXa--ODOD--HIPHIP

VTE prevention after majorVTE prevention after major

orthopaedic surgeryorthopaedic surgery

Phase IIIPhase IIIPhase IIPhase II

>42,000~8,000

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