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

HHS-General HospitalHHS-General Hospital

Hamilton, Canada Hamilton, Canada

Antithrombotics That Have Antithrombotics That Have Changed Clinical PracticeChanged Clinical Practice

AnticoagulantsAnticoagulants

Low-molecular-weight heparinLow-molecular-weight heparin

Antiplatelet DrugsAntiplatelet Drugs

ThienopyridinesThienopyridines

Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors

But……………………..But……………………..

for oral anticoagulation, Vitamin K for oral anticoagulation, Vitamin K antagonists (warfarin) remain the only antagonists (warfarin) remain the only available optionavailable option

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 drug Low 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

New AnticoagulantsNew Anticoagulants

TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150DU-176bBetrixabanTAK 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, J Thromb Haemost 2007

TTP889

VIIa

Xa

IXa

XIa

XIIa

Direct Thrombin inhibitionDirect Thrombin inhibitionTissue factor

Factor IIa(thrombin)

Dabigatran

II

×

Dabigatran for prevention of VTE after major Dabigatran 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) were Dabigatran doses of 150 and 220 mg once daily (od) were investigated in all three studiesinvestigated in all three studies

TKR: total knee replacement; THR: total hip replacement Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

StudyStudy Type of Type of surgerysurgery

ComparatorComparator Number of Number of patientspatients

Time to 1st Time to 1st administration administration of dabigatranof dabigatran

Treatment Treatment durationduration

RE-MODELRE-MODEL TKRTKR Enoxaparin Enoxaparin 40 mg od, starting 40 mg od, starting evening before evening before surgerysurgery

20102010 1–4 hours 1–4 hours post-surgerypost-surgery

6–10 days6–10 days

RE-MOBILIZERE-MOBILIZE TKRTKR Enoxaparin Enoxaparin 30 mg bid, starting 30 mg bid, starting 12–24 hours post-12–24 hours post-surgerysurgery

26152615 6–12 hours 6–12 hours post-surgerypost-surgery

12–15 days12–15 days

RE-NOVATERE-NOVATE THRTHR Enoxaparin Enoxaparin 40 mg od, starting 40 mg od, starting evening before evening before surgerysurgery

34943494 1–4 hours 1–4 hours post-surgerypost-surgery

28–35 days28–35 days

Dabigatran for prevention of VTE after major Dabigatran for prevention of VTE after major orthopaedic surgery: resultsorthopaedic surgery: results

EnoxaparinEnoxaparin Dabigatran Dabigatran (150 mg)(150 mg)

Dabigatran Dabigatran (220 mg)(220 mg)

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

RE-NOVATERE-NOVATE 6.76.7 8.6 8.6 pp<0.0001*<0.0001*

6.06.0pp<0.0001*<0.0001*

RE-MOBILIZERE-MOBILIZE 25.325.3 33.733.7pp=0.0009=0.0009††

31.131.1pp=0.02=0.02††

RE-MODELRE-MODEL 37.737.7 40.540.5pp=0.0005*=0.0005*

36.436.4pp=0.0345*=0.0345*

Major bleeding (%)Major bleeding (%)

RE-NOVATERE-NOVATE 1.61.6 1.31.3 2.02.0

RE-MOBILIZERE-MOBILIZE 1.41.4 0.60.6 0.60.6

RE-MODELRE-MODEL 1.31.3 1.31.3 1.51.5

*Non-inferior to enoxaparin; †inferior to enoxaparin Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

Dabigatran: phase III studiesDabigatran: phase III studies

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

– Planned enrolment 15,000 patientsPlanned enrolment 15,000 patients

– Dabigatran 110 and 150 mg bid compared with Dabigatran 110 and 150 mg bid compared with

warfarinwarfarin

– Treatment duration up to 3 yearsTreatment duration up to 3 years

RE-SOLVE, RE-COVER and RE-MEDYRE-SOLVE, RE-COVER and RE-MEDY

– Ongoing studies in treatment and secondary Ongoing studies in treatment and secondary

prevention of VTEprevention of VTE

New AnticoagulantsNew Anticoagulants

TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150DU-176bBetrixabanTAK 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, J Thromb Haemost 2007

TTP889

VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa inhibitionDirect Factor Xa inhibitionTissue factor

Fibrinogen Fibrin clot

Factor II(prothrombin)

RivaroxabanApixaban

YM150DU-176b LY517717

BetrixabanTAK 442

×

ApixabanApixaban

Oral, direct, selective factor Xa inhibitorOral, direct, selective factor Xa inhibitor Produces concentration-dependent Produces concentration-dependent

anticoagulationanticoagulation No formation of reactive intermediatesNo formation of reactive intermediates No organ toxicity or LFT abnormalities in No organ toxicity or LFT abnormalities in

chronic toxicology studies chronic toxicology studies Low likelihood of drug interactions or Low likelihood of drug interactions or

QTc prolongationQTc prolongation Good oral bioavailability Good oral bioavailability No food effect No food effect Balanced elimination (~25% renal) Balanced elimination (~25% renal) Half-life ~12 hrs Half-life ~12 hrs

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

N

N

NO

N O

NH2

O

O

Apixaban :Phase IIApixaban :Phase II

Apropos – orthopaedic surgeryApropos – orthopaedic surgery

Botticelli – treatment Botticelli – treatment

Adapt – advanced cancer Adapt – advanced cancer

Appraise 1 – ACS Appraise 1 – ACS

Lassen et al. Blood 2006

10.68.6

6.8

26.6

15.6

0

5

10

15

20

25

30

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

Enoxaparin(30mg bid)

Apixaban for Prevention of VTE After Apixaban for Prevention of VTE After Major Orthopaedic SurgeryMajor Orthopaedic Surgery

Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patientswarfarin, in 1,217 patients

20mgApixaban Apixaban

(Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin (INR

1.8-3.0)

1.3 1.63.0

0 00

5

10

15

20

25

30

Enoxaparin(30mg bid)

20mgApixaban Apixaban

(Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin (INR

1.8-3.0)

Per

cen

t

Per

cen

t

Büller, Eur Heart J 2006

6.05.6

2.6

4.2

0

2

4

6

8

10

Composite of Symptomatic Recurrent VTE Composite of Symptomatic Recurrent VTE and Deterioration of Thrombotic Burden (%)and Deterioration of Thrombotic Burden (%)

Composite of Symptomatic Recurrent VTE Composite 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 Botticelli-DVT StudyThe Botticelli-DVT Study

Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patientsheparin (LMWH) or fondaparinux followed by VKA, in 520 patients

20mg bid

Apixaban Apixaban

10mg bid

5mg bid

LMWH/ fondaparinux

+ VKA

0.80

0.80

0

2

4

6

8

10

20mg bid

Apixaban Apixaban

10mg bid

5mg bid

LMWH/ fondaparinux

+ VKA

Per

cen

t

Per

cen

t

Apixaban : Phase IIIApixaban : Phase III

Advance 1,2,3 – orthopaedic surgeryAdvance 1,2,3 – orthopaedic surgery

Adopt – medically illAdopt – medically ill

Aristotle -atrial fibrillation Aristotle -atrial fibrillation

Appraise 2 - ACSAppraise 2 - ACS

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

Predictable Predictable pharmacologypharmacology

High bioavailability High bioavailability Low risk of drug–drug Low risk of drug–drug

interactionsinteractions Fixed doseFixed dose No requirement for No requirement for

monitoringmonitoring

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

Rivaroxaban® – rivaroxaban

N NO

NH

O

SCl

O

O

O

RivaroxabanRivaroxaban Specific, competitive, direct Specific, competitive, direct

FXa inhibitor FXa inhibitor Inhibits free and clot-Inhibits free and clot-

associated FXa activity, associated FXa activity, and prothrombinase activityand prothrombinase activity

Inhibits thrombin generation Inhibits thrombin generation via inhibition of FXa activity via inhibition of FXa activity

– Prolongs time to thrombin Prolongs time to thrombin generationgeneration

– Inhibits peak thrombin Inhibits peak thrombin generationgeneration

– Reduces the total amount Reduces the total amount of thrombin generatedof thrombin generated

Does not require a cofactorDoes not require a cofactor

Perzborn et al. J Thromb Haemost 2005; ICT 2004; Depasse et al. ISTH 2005; Kubitza et al. Clin Pharmacol Ther 2005; Br J Clin Pharmacol, 2007; Graff et al. In press

Rivaroxaban (nM)0.01 0.1 1 10 100 1000

Inh

ibit

ion

of

Fa

cto

r X

a a

cti

vit

y (

%)

0

20

40

60

80

100

Free FXaProthrombinase activityClot-associated FXa

Rivaroxaban 10 mg once daily Rivaroxaban 10 mg once daily is the optimum doseis the optimum dose

0 5 10 20 40 Enoxaparin300

10

20

40

30

0

10

20

30

Inci

denc

e –

effic

acy

(%) Incidence – safety (%

)

Rivaroxaban (mg total daily dose)

DVT, PE and all-cause mortalityMajor post-operative bleeding

p=0.0852

p=0.039

Efficacy, n=618; safety, n=845 Eriksson et al. Circulation 2006

Rivaroxaban: VTE Treatment TrialsRivaroxaban: VTE Treatment Trials

Deep Vein Thrombosis Pulmonary Embolism

Treatment

Two large, phase II studies of rivaroxaban for Two large, phase II studies of rivaroxaban for 3 months for the treatment and long term 3 months for the treatment and long term secondary prevention of VTE:secondary prevention of VTE:

– ODIXa-DVT : Rivaroxaban 10–30 mg bid ODIXa-DVT : Rivaroxaban 10–30 mg bid

and 40 mg odand 40 mg od

– EINSTEIN DVT : Rivaroxaban 20–40 mg od EINSTEIN DVT : Rivaroxaban 20–40 mg od

– LMWH followed by a VKA comparator in both LMWH followed by a VKA comparator in both studiesstudies

Agnelli et al. Circulation 2007; Büller. Eur Heart J 2006

Rivaroxaban for the treatment and Rivaroxaban for the treatment and secondary prevention of VTEsecondary prevention of VTE

Phase III RECORD programme in Phase III RECORD programme in VTE preventionVTE prevention

Oral rivaroxaban 10 mg od is being compared with subcutaneous Oral rivaroxaban 10 mg od is being compared with subcutaneous enoxaparin in >11,000 patients worldwideenoxaparin in >11,000 patients worldwide

StudyStudy Duration of Duration of rivaroxaban rivaroxaban

therapytherapy

Duration of Duration of enoxaparinenoxaparin

therapy therapy

RECORD1RECORD1 THRTHR 5 weeks5 weeks 5 weeks5 weeks

RECORD2RECORD2 THRTHR 5 weeks5 weeks 10–14 days, 10–14 days, followed by placebofollowed by placebo

RECORD3RECORD3 TKRTKR 10–14 days10–14 days 10–14 days10–14 days

RECORD4RECORD4 TKRTKR 10–14 days10–14 days 10–14 days10–14 days

Efficacy endpointsEfficacy endpoints

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

vein thrombosis (DVT), non-fatal pulmonary vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortalityembolism (PE), and all-cause mortality

Secondary Secondary Major VTE: proximal DVT, non-fatal PE, and Major VTE: proximal DVT, non-fatal PE, and

VTE-related deathVTE-related death DVT: any, proximal, distalDVT: any, proximal, distal Symptomatic VTESymptomatic VTE

All endpoints were adjudicated centrally by independent, blinded committees

Safety endpointsSafety endpointsMainMain Major bleeding starting after the first blinded dose and Major bleeding starting after the first blinded dose and

≤2 days after last dose≤2 days after last dose– Bleeding that was fatal, into a critical organ or required re-Bleeding that was fatal, into a critical organ or required re-

operationoperation– Extra-surgical-site bleeding associated with a drop in Extra-surgical-site bleeding associated with a drop in

hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units bloodhemoglobin ≥2 g/dL or requiring transfusion of ≥2 units blood

OtherOther Any bleeding on treatment*Any bleeding on treatment* Non-major bleeding* Non-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

Rivaroxaban – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in total knee arthroplasty surgery

Enoxaparin 40 mg od

Rivaroxaban 10 mg odMandatory

bilateralvenography

RECORD3: study designRECORD3: study design

Inclusion criteria Patients aged ≥18 years,

scheduled to undergo elective, total knee replacement (TKR) surgery

Day 42+5

R

SURGERY

FOLLOW

UP

Evening before surgery

6–8 hours post-surgery

6–8 hours post-surgery

Day 1 Day 13±2

Double blind

Last dose, 1 daybefore venography

Major exclusion criteria Active bleeding or high risk of bleeding

Significant liver disease

Anticoagulant therapy that could not be stopped

Use of HIV-protease inhibitors

R

SURGERY

RECORD3: summaryRECORD3: summaryTotal VTETotal VTE

Major bleedingMajor bleeding

20

Inci

den

ce (

%)

0

Major VTEMajor VTE5

10

15

NS

RRR 49%

RRR 62%

Symptomatic VTESymptomatic VTE

Rivaroxaban 10 mg od

Enoxaparin 40 mg od

RRR 65%

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

Study backgroundStudy background

ACCP guidelines: grade 1A recommendation ACCP guidelines: grade 1A recommendation for up to 35 days’ prophylaxis after elective for up to 35 days’ prophylaxis after elective hip replacement surgery hip replacement surgery

Geerts et al., 2004

20042004

Oral rivaroxaban compared with subcutaneous enoxaparin for extended

thromboprophylaxis after total hip arthroplasty

Enoxaparin 40 mg od

Rivaroxaban 10 mg od

RECORD1 study designRECORD1 study design

Mandatorybilateral

venographyR

SURGERY

FOLLOW

UP

Evening before surgery

6–8 hours post-surgery

6–8 hours post-surgery

Day 1 Day 36±4

Double blind

Last dose, daybefore venography

Up to Day 65

Inclusion criteria Patients aged ≥18 years, scheduled

to undergo elective THR

Major exclusion criteria Active bleeding or high risk of bleeding

Significant liver disease

Anticoagulant therapy that could not be stopped

Use of HIV-protease inhibitors

RECORD1: summaryRECORD1: summaryIn

cide

nce

(%)

Total VTETotal VTE

Major bleedingMajor bleeding

Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

0

1

2

3

4

5

0.5% 0.3% 0.1% 0.3%

Symptomatic VTESymptomatic VTE

RRR 70%

2.0% 0.2%

Major VTEMajor VTERRR 88%

1.1%3.7%

Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis

with low molecular weight heparin after total hip arthroplasty

Rivaroxaban 10 mg odMandatory

bilateralvenography

RECORD2: study designRECORD2: study design

Inclusion criteria Patients aged ≥18 years, scheduled

to undergo elective THR

Day 65+5

R

SURGERY

FOLLOW

UP

Evening before surgery

6–8 hours post-surgery

6–8 hours post-surgery

Day 1

Double blind

Major exclusion criteria Active bleeding or high risk of bleeding

Significant liver disease

Anticoagulant therapy that could not be stopped

Use of HIV-protease inhibitors

Day 36±4

Enoxaparin40 mg od

Oral placebo

RECORD2: summaryRECORD2: summary

Total VTETotal VTE

Major bleedingMajor bleeding

Major VTEMajor VTE

Inci

denc

e (%

)

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%

Symptomatic VTESymptomatic VTE

Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

Clinical programme overview: Clinical programme overview: 50,000 patients to be enrolled50,000 patients to be enrolled

VTE prevention in VTE prevention in hospitalized medically ill hospitalized medically ill patientspatients

Secondary prevention of Secondary prevention of acute coronary syndromesacute coronary syndromes

Japanese Phase III study Japanese Phase III study

Stroke prevention in atrial Stroke prevention in atrial fibrillationfibrillation

EINSTEIN-DVT EINSTEIN-DVT EINSTEIN-PEEINSTEIN-PE EINSTEIN-EXTEINSTEIN-EXT

ODIXa-DVTODIXa-DVT EINSTEIN-DVTEINSTEIN-DVT

VTE treatmentVTE treatment

RECORD1 RECORD1 RECORD2RECORD2 RECORD3RECORD3 RECORD4RECORD4

ODIXa-HIP1 ODIXa-HIP1 ODIXa-HIP2ODIXa-HIP2 ODIXa-KNEEODIXa-KNEE ODIXa-OD-HIPODIXa-OD-HIP

VTE prevention after major VTE prevention after major orthopaedic surgeryorthopaedic surgery

Phase III Phase III Phase IIPhase II

>42,000~8,000