2009, 심장학회

Venous thromboembolism: Evolution of anticoagulation therapy: Evolution of anticoagulation therapy

원주의대 김장영

2009, 심장학회

Venous Thromboembolism (VTE)

• Third most common vascular disease

• 600,000 cases of VTE annually in USA

• 200,000 cases of pulmonary embolism

(PE) annually(PE) annually

• PE remains the leading preventable

cause of death in hospital

Cause of death # of annual death

Pulmonary embolism (PE) 200,000

AIDS 18,017

Breast cancer 40,870

2008, AHA

2009, 심장학회

Treatment guidelineDeep Vein Thrombosis (DVT) & pulmonary embolism (PE)

• For objectively confirmed DVT

or PE, recommend SC LMWH,

IV or SC UFH, SC

Fondaparinux [Grade 1]

• Overlap a VKA (warfarin) with

a parenteral anticoagulant a

minimum of 5 days and until

the INR is ≥2.0 for at least 24

hours [Grade 1]

LMWH: low molecular weight heparin, UFH: unfractionated heparin, VKA: vitamin K antagonist

ACCP guideline, 2008

2009, 심장학회

Anticoagulants for VTE prophylaxis

Geerts WH. et al. Chest 2001

Turple AGG. et al. Arch Intern Med 2002

2009, 심장학회

Anticoagulants

Venous thrombosis

� Prevention

– After orthopaedic

surgery

Arterial thrombosis

� Prevention

– Stroke in patients with

AFsurgery

– After general surgery

– In cancer patients

� treatment

– MI in patients with ACS

– Thrombotic Cx. of

prosthetic heart valve

2009, 심장학회

A Brief History of Anticoagulant Therapy

Parenteral

Vitamin K antagonists : indirectly affect synthesis of

multiple coagulation factors

Low-molecular-weight heparin:

AT-dependent inhibition of factor Xa > IIa

ParenteralUnfractionated heparins: antithrombin (AT)-dependent inhibition of

factor Xa and IIa in a 1:1 ratio1930s

Oral 1940s

1980s

Parenteral

Parenteral

Oral

Parenteral and Oral

Direct factor IIa inhibitors (bivalrirudin)

Indirect factor Xa inhibitors (fondaparinux)

Direct factor IIa

inhibitors

Direct factor Xa

inhibitors

1990s

2000s

2009

Alban s. Eur J Clin Invest 2005;111:2671

New anticoagulants

2009, 심장학회

Warfain or UFH are problematic

Warfarin

– too slow onset of action

– variable anticoagulant response ( PT INR)

– Numerous food- and drug-drug interaction

UFH

- Low bioavailability and short half life

- variable anticoagulant response ( aPTT)

- Heparin induced thrombocytopenia or osteoporosis

2009, 심장학회

UFH vs. LMWH for acute VTE

Outcomes UFH, No. (%) LMWH, No. (%) Risk Difference

(95% CI)

Efficacy analysis N=345 N=352

Recurrent VTE

(3 mo)

13(3.8) 12 (3.4) 0.4 (-2.6 to 3.3)

(3 mo)

Type of

recurrence

2 PE

11 DVT

4 PE

8 DVT

Major bleeding (3

mo)

6 (1.7) 12 (3.4) -1.7 (-4.3 to 0.8)

Minor bleeding

(3 mo)

29 (8.3) 30 (8.5) -0.2 (-4.4 to 4.0)

Deaths (3 mo) 18 (5.2) 22 (6.3) -1.1 (-4.6 to 2.5)

2009, 심장학회

Fondaparinux: Treatment of DVT

Matisse DVT Study

2009, 심장학회

Anticoagulants that Have Changed

Clinical Practice

Unfractionated heparin (UFH)

� Low-molecular-weight heparin

� Fondaparinux

But………………………….

for oral anticoagulation, Vitamin K

antagonists (warfarin) remain the only

available option

2009, 심장학회

Anticoagulants in Development

TFPI (tifacogin)

NAPc2

Oral

Apixaban

Rivaroxaban

APC (drotrecogin alfa)

sTM (ART-123)

TTP889TF/VIIa

Xa

VIIIa

IXa

IXX

Va

Oral

Dabigation

Rivaroxaban

DU-176b

Betrixaban

YM150

Parenteral

Fondaparinux

Idraparinux

Biotinylated idraparinux

Xa

IIa

II

Fibrin Fibrinogen

2009, 심장학회

Anticoagulants in Development

TFPI (tifacogin)

NAPc2

Oral

apixaban

Rivaroxaban

APC (drotrecogin alfa)

sTM (ART-123)

TTP889TF/VIIa

Xa

VIIIa

IXa

IXX

Va

Direct thrombin inhibitors

Oral

Dabigation

Rivaroxaban

DU-176b

Betrixaban

YM150

Parenteral

Fondaparinux

Idraparinux

Biotinylated idraparinux

Xa

IIa

II

Fibrin Fibrinogen

2009, 심장학회

Dabigatran

• The prodrug dabigatran etexilate is

converted completely to active

dabigatran

• Terminal elimination t1/2 of 14-17 hr• Terminal elimination t1/2 of 14-17 hr

• No food interactions

• Mainly by renal excretion (80%)

2009, 심장학회

RE-VOLUTION clinical trial programSecondary prevention of cardiac

events in patients with ACS*Primary VTE Prevention

Stroke Prevention in patients

with Atrial Fibrillation

Involving >38,000 patients worldwide

Acute VTE Treatment Secondary VTE Prevention

2009, 심장학회

Dabigatran Clinical Program: REVOLUTIONPhase III Studies in VTE Prophylaxis After THR/TKR

Start evening before surgery* of

12-24 hours post-operatively*

Start 1-4 hours* or

6-12 hours* post-operatively

R

Enoxaparin

40mg QD* OR

30 mg BID*

Dabigatran etexilate

75/ 150 mg QD

Dabigatran etexilate

110/ 220 mg QDVenography

Within 12 hours of last dose

Follow-up

12-14 weeks

*RE-MODEL and RE-NOVATE

*RE-MOBILIZE

Design: Non-Inferiority

Intention-To-Treat Population

Study

Therapy

Duration

Enoxaparin

Dose (mg)

RE-MODEL Knee 6-10 days 40 QD

RE-NOVATE Hip 28-35 days 40 QD

RE-MOBILIZE Knee 12-15 days 30 BID

Eriksson et al. Lancet, 2007, J Thromb Haemost 2007

2009, 심장학회

Meta-Analysis Major VTE & VTE-Related Mortality

Dabigatran etexilate

Study or

sub-category

220 mg QD

n/N

Enoxaparin

n/NRR RR [95% CI]

RE-MOBILIZE 21/618 15/658 1.51 [0.79, 2.91]

RE-MODEL 13/506 18/511 0.73 [0.36, 1.47]

RE-NOVATE 28/909 36/917 0.78 [0.48, 1.27]

Total events 62 (dabigatran etexilate), 69 (enoxaparin)

Test for

Random Effects Analysis

Total (95% CI) 2033 2096 0.94 [0.61, 1.44]

Test for overall effect: Z = 0.30 (P=0.76)

0.1 0.2 0.5 1 2 5 10

Favours

Enoxaparin

Favours

Dabigatran Etexilate

2009, 심장학회

Meta-AnalysisMajor Bleeding Events

Dabigatran etexilate

Study or

sub-category

220 mg QD

n/N

Enoxaparin

n/NRR RR [95% CI]

RE-MOBILIZE 5/857 12/868 0.42 [0.15, 1.19]

RE-MODEL 10/679 9/694 1.14 [0.46, 2.78]

RE-NOVATE 23/1145 18/1154 1.29 [0.70, 2.37]

Total events 62 (datigatran etexilate), 69 (enoxaparin)

Test for

Random Effects Analysis

Total (95% CI) 2682 2716 0.94 [0.51, 1.75]

Test for overall effect: Z = 0.30 (P=0.76)

0.1 0.2 0.5 1 2 5 10

Favours

Enoxaparin

Favours

Dabigatran Etexilate

2009, 심장학회

Anticoagulants in Development

TFPI (tifacogin)

NAPc2

Oral

apixaban

Rivaroxaban

APC (drotrecogin alfa)

sTM (ART-123)

TTP889TF/VIIa

Xa

VIIIa

IXa

IXX

Va

Factor Xa inhibitors

Oral

Dabigation

Rivaroxaban

DU-176b

Betrixaban

YM150

Parenteral

Fondaparinux

Idraparinux

Biotinylated idraparinux

Xa

IIa

II

Fibrin Fibrinogen

2009, 심장학회

Apixaban: oral direct Factor Xa inhibitor

• No organ toxicity or LFT abnormalities

• Low likelihood of drug interactions or

QTc prolongation

• Good oral bioavailability

• No food effect

• Balanced elimination (~25% renal)

• Half-life : 9-12 hrs

2009, 심장학회

Apixaban for Prevention of VTE After Major

Orthopaedic Surgery

• Apixaban od and bid (total daily doses 5-20mg) wre assessed relative to

enoxaparin and warfarin, in 1,217 patients

Total VTE and all-cause mortality (%) Major bleeding (%)

Apixaban

(total Daily Dose)

Apixaban

(total Daily Dose)

2009, 심장학회

Apixaban – phase III

• Advance 1 – knee replacement 3000

• Advance 2 – knee replacement 3000

• Advance 3 – hip replacement 4000

• Aristotle – atrial fibrillation (vs warfarin) 15000

• Averroes– atrial fibrillation (vs aspirin) 5600

• Appraise 2 – ACS 1800

• Advocate – VTE in cancer 1600

2009, 심장학회

Primary Efficacy Outcome: Total VTE or All-Cause Mortality

RR = 1.02 (0.78, 1.32)

P = 0.064

N Engl J Med 2009;361:594-604

2009, 심장학회

Safety Outcome: Major or Clinically Relevant Bleeding

P = 0.034

N Engl J Med 2009;361:594-604

2009, 심장학회

Rivaroxaban: oral direct Factor Xa inhibitor

• Predictable pharmacology

• High bioavailability

• Low risk of drug-drug

interactionsinteractions

• Fixed dose

• No requirement for

monitoring

2009, 심장학회

RECORD programMajor orthopaedic surgery

• Rivaroxaban 10 mg once-daily investigated

• Same study design and efficacy and safety outcomes

RECORD1 RECORD2 RECORD3 RECORD4RECORD1HIP replacement

Rivaroxaban 10 mg od

for 5 weeks

vs

enoxaparin 40 mg od

for 5 weeks

N=4,541

RECORD2HIP replacement

Rivaroxaban 10 mg od

for 5 weeks

vs

enoxaparin 40 mg od

for 10-14 days then

oral placebo

N=2,509

RECORD3Knee replacement

Rivaroxaban 10 mg od

for 10-14 weeks

vs

enoxaparin 40 mg od

for 10-14 weeks

N=2,531

RECORD4KNEE replacement

Rivaroxaban 10 mg od

for 10-14 weeks

vs

enoxaparin 30 mg bid

for 10-14 weeks

N=3,148

2009, 심장학회

RECORD in VTE Prophylaxis After THR/TKR

R

S

U

R

G

E

R

Y

Rivaroxaban 10 mg QD

Enoxaparin

Mandatory

Bilateral

venography

F

O

L

L

O

W

U

P

6-8 hours post-surgery

Evening before surgery*

*RECORD1, 2 and 3#RECORD4 12-24 hours post-surgery‡followed by oral placebo for 3 weeks

Study

Therapy Duration (weeks)Enoxaparin

Dose (mg)Rivaroxaban Enoxaparin

RECORD1 Hip 5 5 40 QD

RECORD2 Hip 5 2‡ 40 QD

RECORD3 Knee 2 2 40 QD

RECORD4 Knee 2 2 30 BID

P

Or 12-24 hours post-surgery#Day 1

Last dose day

before venography

2009, 심장학회

Primary Efficacy OutcomeTotal VTE or All-Cause Mortality

RRR=49%ARD = -9.2% (-12.4, -5.9)

p<0.001

RRR=31%ARD = -3.19% (-5.67, -0.71)

p<0.012RRR=70%

RRR=31%ARD = -7.3% (-9.4, -5.2)

p<0.0001

Enoxaparin

Rivaroxaban

p<0.012 ARD = -2.6% (-3.7, -1.5)

p<0.001

RECORD3 RECORD4 RECORD1 RECORD2

(knee) (Hip)

2009, 심장학회

Pooled Analysis of RECORD1-4:Symptomatic VTE & All-Cause Mortality

58% reduction

HR=0.42 (95% CI: 0.29-0.63)

p<0.001

2009, 심장학회

Major Bleeding Across the RECORD Program

Enoxaparin

Rivaroxaban

RECORD3 RECORD4RECORD1 RECORD2

2009, 심장학회

Property Rivaroxaban Apixaban Dabigatran

Target Factor Xa Factor Xa Thrombin

Route of administration Oral Oral Oral

Prodrug No No Yes

Bioavailability >80 >50 6

Summary

Time to peak drug level, h 3 3 2

Half-life, h 9 9 14-17

Drug interactions Potent CYP3A4 Potent CYP3A4 Proton pump inhibitors

Renal excretion, % 66 25 80

Antidote No No No

2009, 심장학회

Evolution of Anticoagulant Therapy

Parenteral

Parenteral

Unfractionated heparins

Vitamin K antagonists

Low-molecular-weight heparin

1930s

Oral 1940s

1980s

Parenteral

Parenteral

Oral

Parenteral and Oral

Direct factor IIa inhibitors ( bivalrirudin)

Indirect factor Xa inhibitors (fondararinux)

Direct factor IIa inhibitors

Direct factor Xa inhibitors

1990s

2000s

Dabigatran

ApixabanRivaroxaban

Alban s. Eur J Clin Invest 2005;111:2671

2009, 심장학회

2009, 심장학회

•EXTRA-SLIDE

2009, 심장학회

Oral Factor Xa inhibitors –

clinical development

Rivaroxaban (Bayer/J&J) Phase III

Apixaban (BMS/Pfizer)Phase III

YM150 (Astellas)Phase IIb

Edoxaban (Daiichi) Phase IIb

Betrixaban (Portola) Phase II

TAK 442 (Takeda) Phase II

813893 (GSK)Phase I/II

2009, 심장학회

Targets for ANTITHROMBOTICS

Anticoagulants Antiplatelets

Tissue factor

Plasma clotting

cascade

collagen

Thromboxane A2

ADP

TF/FVIIi

Aspirin

Clopidogrel

PrasugrelProthrombin

Factor

Xa

Thromboxane A2

LMWH

Heparin

Bivalirudin

Ximelagatran

dabigatran

Direct Xa inhibConformational

activation of GPIIb/IIIa

ThrombinPlatelet aggregation

Fibrinogen Fibrin

Thrombus

GPIIb/IIIa

inhibitors

Prasugrel

Ticagrelor

AT-III

2009, 심장학회

Factor X Inhibitors

• Indirect

– AT dependent

– Fondaparinux, Idraparinux

• Direct

– AT Independent

2009, 심장학회

Fondaparinux: synthetic Inhibitor

Factor Xa (pentasaccharide)

• Half life of 17-20 h

• No monitoring required

• Contraindicated if CrCI < 30 mL/min

• Prophylaxis dose: 2.5 mg/day/SC• Prophylaxis dose: 2.5 mg/day/SC

• Treatment dose:

– 5 mg < 50 kg

– 7.5 mg if 50-100 kg

– 10 mg if > 100 kg

2009, 심장학회

Fondaparinux for VTE prevention in OS

surgery: efficacy versus enoxaparin

Extra 95% CI

Hip replacement

(n=3411)[-58.9 to -27.4]

EPHESUS

(n=1827)[-72.8 to -37.2]

PENTATHLON 2000

(n=1548) [-52.2 to -7.6]

Fondaparinux

better

Enoxaparin

better

-28.1

-45.3

(n=1548) [-52.2 to -7.6]

Hip fracture

PENTHIFRA

(n=1250)[-73.4 to -45.0]

Major knee surgery

PENTAMAKS

(n=724)[-75.5 to -44.8]

Overall adds reduction

(n=5385) [6.31 to -45.8]

-100 -80 -60 0 20 40

% odds reduction

-40 -20 60 80 100

p<0.001-55.2

-63.1

-61.6

2009, 심장학회

Direct Factor Xa inhibition

Tissue

factor

XIIa

XIa

IXa

Xa

VIIa

Rivaroxaban

Apixaban

Factor II

(prothrombin)

Fibrin clot Fibrinogen

Apixaban

YM150

Edoxaban

Betrixaban

TAK442