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Oral anticoagulant therapy : a look to the future. Alexander G. G. Turpie Department of Medicine HHS-General Hospital Hamilton, Canada . Antithrombotics That Have Changed Clinical Practice. Anticoagulants Low-molecular-weight heparin Antiplatelet Drugs Thienopyridines

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oral anticoagulant therapy a look to the future

Oral anticoagulant therapy :a look to the future

Alexander G. G. Turpie

Department of Medicine

HHS-General Hospital

Hamilton, Canada

antithrombotics that have changed clinical practice
Antithrombotics That Have Changed Clinical Practice

Anticoagulants

  • Low-molecular-weight heparin

Antiplatelet Drugs

  • Thienopyridines
  • Glycoprotein IIb/IIIa Inhibitors
slide3
But……………………..

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

the ideal oral anticoagulant
The ‘ideal’ oral anticoagulant
  • Oral, preferably once daily
  • Rapid onset and offset of action
  • Predictable PK and PD
  • Low propensity for food and drug interactions
  • Fixed doses
  • Wide therapeutic window
  •  Easy to use with no need for monitoring
new anticoagulants
New Anticoagulants

ORAL

PARENTERAL

TF/VIIa

TFPI (tifacogin)

TTP889

X

IX

APC (drotrecogin alfa)

sTM (ART-123)

RivaroxabanApixaban

LY517717

YM150

DU-176b

Betrixaban

TAK 442

IXa

VIIIa

Va

AT

Xa

FondaparinuxIdraparinux

II

DX-9065a

IIa

Dabigatran

Fibrinogen

Fibrin

Adapted from Weitz & Bates, J Thromb Haemost 2007

direct thrombin inhibition
Direct Thrombin inhibition

Tissue factor

XIIa

XIa

VIIa

IXa

Xa

II

×

Factor IIa(thrombin)

Dabigatran

dabigatran for prevention of vte after major orthopaedic surgery phase iii studies
Dabigatran for prevention of VTE after major orthopaedic surgery: phase III studies
  • Dabigatran doses of 150 and 220 mg once daily (od) were investigated 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

dabigatran for prevention of vte after major orthopaedic surgery results
Dabigatran for prevention of VTE after major orthopaedic surgery: results

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

dabigatran phase iii studies
Dabigatran: phase III studies
  • RE-LY (stroke prevention in patients with AF)
    • Planned enrolment 15,000 patients
    • Dabigatran 110 and 150 mg bid compared with warfarin
    • Treatment duration up to 3 years
  • RE-SOLVE, RE-COVER and RE-MEDY
    • Ongoing studies in treatment and secondary prevention of VTE
new anticoagulants10
New Anticoagulants

ORAL

PARENTERAL

TF/VIIa

TFPI (tifacogin)

TTP889

X

IX

APC (drotrecogin alfa)

sTM (ART-123)

RivaroxabanApixaban

LY517717

YM150

DU-176b

Betrixaban

TAK 442

IXa

VIIIa

Va

AT

Xa

FondaparinuxIdraparinux

II

DX-9065a

IIa

Dabigatran

Fibrinogen

Fibrin

Adapted from Weitz & Bates, J Thromb Haemost 2007

direct factor xa inhibition
Direct Factor Xa inhibition

XIIa

Tissue factor

×

XIa

VIIa

IXa

Xa

Rivaroxaban

Apixaban

YM150

DU-176b

LY517717

Betrixaban

TAK 442

Factor II(prothrombin)

Fibrinogen

Fibrin clot

apixaban
Apixaban
  • Oral, direct, selective factor Xa inhibitor
  • Produces concentration-dependent anticoagulation
  • No formation of reactive intermediates
  • No organ toxicity or LFT abnormalities in chronic toxicology studies
  • Low likelihood of drug interactions or QTc prolongation
  • Good oral bioavailability
  • No food effect
  • Balanced elimination (~25% renal)
  • Half-life ~12 hrs

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

apixaban phase ii

Apixaban :Phase II

Apropos – orthopaedic surgery

Botticelli – treatment

Adapt – advanced cancer

Appraise 1 – ACS

apixaban for prevention of vte after major orthopaedic surgery
Apixaban for Prevention of VTE After Major Orthopaedic Surgery
  • Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patients

Total VTE and All-Cause Mortality (%)

Major Bleeding (%)

Percent

Percent

5mg

10mg

20mg

Warfarin (INR 1.8-3.0)

Enoxaparin(30mg bid)

5mg

10mg

20mg

Warfarin (INR 1.8-3.0)

Enoxaparin(30mg bid)

Apixaban (Total Daily Dose)

Apixaban (Total Daily Dose)

Lassen et al. Blood 2006

apixaban for the treatment of dvt the botticelli dvt study
Apixaban for the Treatment of DVT: The Botticelli-DVT Study
  • Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patients

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

Major Bleeding (%)

Percent

Percent

LMWH/ fondaparinux + VKA

LMWH/ fondaparinux + VKA

5mg bid

10mg bid

20mg bid

5mg bid

10mg bid

20mg bid

Apixaban

Apixaban

Büller, Eur Heart J 2006

apixaban phase iii

Apixaban : Phase III

Advance 1,2,3 – orthopaedic surgery

Adopt – medically ill

Aristotle -atrial fibrillation

Appraise 2 - ACS

rivaroxaban oral direct factor xa inhibitor

Rivaroxaban® – rivaroxaban

Rivaroxaban: oral direct Factor Xa inhibitor
  • Predictable pharmacology
  • High bioavailability
  • Low risk of drug–drug interactions
  • Fixed dose
  • No requirement for monitoring

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

rivaroxaban

100

80

60

Inhibition of Factor Xa activity (%)

40

20

Free FXa

Prothrombinase activity

Clot-associated FXa

0

0.01

0.1

1

10

100

1000

Rivaroxaban (nM)

Rivaroxaban
  • Specific, competitive, direct FXa inhibitor
  • Inhibits free and clot-associated FXa activity, and prothrombinase activity
  • Inhibits thrombin generation via inhibition of FXa activity
    • Prolongs time to thrombin generation
    • Inhibits peak thrombin generation
    • Reduces the total amount of thrombin generated
  • Does 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 10 mg once daily is the optimum dose
Rivaroxaban 10 mg once daily is the optimum dose

30

40

DVT, PE and all-cause mortality

Major post-operative bleeding

30

20

Incidence – efficacy (%)

Incidence – safety (%)

20

p=0.0852

10

10

p=0.039

0

0

0

5

10

20

30

40

Enoxaparin

Rivaroxaban (mg total daily dose)

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

rivaroxaban vte treatment trials
Rivaroxaban: VTE Treatment Trials

Deep Vein Thrombosis

Pulmonary Embolism

Treatment

rivaroxaban for the treatment and secondary prevention of vte
Rivaroxaban for the treatment and secondary prevention of VTE
  • Two large, phase II studies of rivaroxaban for 3 months for the treatment and long­term secondary prevention of VTE:
    • ODIXa-DVT : Rivaroxaban 10–30 mg bid

and 40 mg od

    • EINSTEIN DVT : Rivaroxaban 20–40 mg od
    • LMWH followed by a VKA comparator in both studies

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

phase iii record programme in vte prevention
Phase III RECORD programme in VTE prevention
  • Oral rivaroxaban 10 mg od is being compared with subcutaneous enoxaparin in >11,000 patients worldwide
efficacy endpoints
Efficacy endpoints

Primary

  • Total venous thromboembolism (VTE): any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality

Secondary

  • Major VTE: proximal DVT, non-fatal PE, and VTE-related death
  • DVT: any, proximal, distal
  • Symptomatic VTE

All endpoints were adjudicated centrally by independent, blinded committees

safety endpoints
Safety endpoints

Main

  • Major bleeding starting after the first blinded dose and ≤2 days after last dose
    • Bleeding that was fatal, into a critical organ or required re-operation
    • Extra-surgical-site bleeding associated with a drop in hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units blood

Other

  • Any bleeding on treatment*
  • Non-major bleeding*
  • Hemorrhagic wound complications*
  • Cardiovascular adverse events
  • Liver enzyme levels

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

slide25

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

record3 study design

F

S

S

O

U

U

L

R

R

L

G

G

O

E

E

W

R

R

U

Y

Y

P

RECORD3: study design

Double blind

Rivaroxaban 10 mg od

Mandatory

bilateral

venography

6–8 hours post-surgery

R

R

6–8 hours post-surgery

Enoxaparin 40 mg od

Evening before surgery

Day 1

Day 42+5

Day 13±2

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

Inclusion criteria

  • Patients aged ≥18 years, scheduled to undergo elective, total knee replacement (TKR) surgery
record3 summary
Total VTE

Major bleeding

RECORD3: summary

20

RRR 49%

Enoxaparin 40 mg od

Rivaroxaban 10 mg od

15

10

Incidence (%)

Major VTE

Symptomatic VTE

5

RRR 62%

RRR 65%

NS

1.0%

18.9%

9.6%

2.6%

2.0%

0.7%

0.5%

0.6%

0

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

2004

Geerts et al., 2004

slide29

Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty

record1 study design

F

S

O

U

L

R

L

G

O

E

W

R

U

Y

P

RECORD1 study design

Double blind

Mandatory

bilateral

venography

Rivaroxaban 10 mg od

6–8 hours post-surgery

R

6–8 hours post-surgery

Enoxaparin 40 mg od

Evening before surgery

Up to Day 65

Day 36±4

Day 1

Last dose, 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

Inclusion criteria

  • Patients aged ≥18 years, scheduled to undergo elective THR
record1 summary

Enoxaparin 40 mg once daily

RECORD1: summary

5

Rivaroxaban 10 mg once daily

Total VTE

RRR 70%

4

3

Major VTE

Incidence (%)

RRR 88%

2

Symptomatic VTE

Major bleeding

1

0.2%

3.7%

1.1%

2.0%

0.5%

0.1%

0.3%

0.3%

0

slide32

Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with low molecular weight heparin

after total hip arthroplasty

record2 study design

F

S

O

U

L

R

L

G

O

E

W

R

U

Y

P

RECORD2: study design

Double blind

Rivaroxaban 10 mg od

Mandatory

bilateral

venography

6–8 hours post-surgery

R

6–8 hours post-surgery

Enoxaparin40 mg od

Oral placebo

Evening before surgery

Day 1

Day 36±4

Day 65+5

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
record2 summary
Total VTE

Major bleeding

Enoxaparin 40 mg once daily

RECORD2: summary

10

Rivaroxaban 10 mg once daily

8

6

Major VTE

Incidence (%)

4

Symptomatic VTE

RRR 78.9%

2

RRR 87.8%

RRR 80.1%

2.0%

9.3%

5.1%

0.6%

0.2%

0.1%

0.1%

1.2%

0

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

Phase II

Phase III

VTE prevention after major orthopaedic surgery

  • ODIXa-HIP1
  • ODIXa-HIP2
  • ODIXa-KNEE
  • ODIXa-OD-HIP
  • RECORD1
  • RECORD2
  • RECORD3
  • RECORD4

VTE prevention in hospitalized medically ill patients

  • EINSTEIN-DVT
  • EINSTEIN-PE
  • EINSTEIN-EXT

VTE treatment

  • ODIXa-DVT
  • EINSTEIN-DVT

Stroke prevention in atrial fibrillation

Japanese Phase III study

Secondary prevention of acute coronary syndromes

~8,000

>42,000