Pharmacological thromboprophylaxis Professor Ajay Kakkar Barts and the London School of Medicine Thrombosis Research Institute, London, UK.

Professor Ajay Kakkar

Barts and the London School of Medicine Thrombosis Research Institute, London, UK

Research Support/P.I.Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai

Employee N/A

ConsultantBayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai

Major Stockholder N/A

Speakers Bureau N/A

HonorariaBayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai, GSK

Scientific Advisory BoardBayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai

N/A = not applicable (no conflicts)

4

9

26132 132 postoperative postoperative patientspatients

40

92 normal92 normal

Kakkar VV, et al. Lancet. 1969;2:230-232.

Pati

en

ts w

ith

DV

T (

%) 42

8

Control Low-dose UFH

.

Efficacy of low-dose unfractionated heparin (UFH) in prevention of DVT after major surgery

s.c., subcutaneous; b.i.d., twice a day

– s.c. low-dose UFH: pre-operative and b.i.d.post-operative

– 78 ‘high-risk’ patients

05

10

15202530354045

Kakkar et al. Lancet 1972;2:101–6

Kakkar V V et al, Lancet. 1975;2:45-51.

Nu

mb

er

of

pati

en

tsw

ith

fata

l PE

P < 0.005

16

2

02468

1012141618

Control UFH

Low-dose UFH saves 7 lives for every 1000 operated patients.

Kakkar VV et al, Lancet. 1975;2:45-51.

NS = not significant. Kakkar vv et al, Lancet. 1975;2:45-51.

Pre

vale

nce o

f P

roxim

al D

VT (

%)

Asymptomatic DVT

60.5

20.3

RR=67

%

Fatal PE

Fre

qu

en

cy o

f P

E (

%)

RR=68%

Control

UFH

1.9

0.6

Collins R, et al. N Engl J Med. 1988;318:1162-1173.

LMWH

UFH

DVT PE* Major bleeding

25

20

15

10

5

0

RR 0.68

RR 0.43

RR 0.75

Pro

port

ion

of

Pati

en

ts E

xp

eri

en

cin

g

Ou

tcom

e

Nurmohamed MT, et al. Lancet. 1992;340:152-156.

93/672

132/622

10/590

24/582

6/6728/622

0

5

10

15

20

25

Pre

vale

nce o

f D

VT (

%)

18.6

THR(NNT=9)

OR=0.39[0.28–0.54]

24.0

TKR(NNT=29)

OR = 0.82[0.49–1.40]

7.7

20.5

Eikelboom JW, et al. Lancet. 2001;358:9-15.

Placebo/ No treatment

LMWH

4.3

1.4

OR = 0.33[0.19–0.56]

1.41.0

OR = 0.74[0.26–2.15]

0.0

1.0

2.0

3.0

4.0

5.0

Pre

vale

nce o

f V

TE (

%)

THR(NNT=34)

TKR(NNT=250)

Eikelboom JW, et al. Lancet. 2001;358:9-15.

Placebo/ No treatment

In-hospital prophylaxis followed by: LMWH

Clinical thromboembolism Cancer

0 1.0 2.0 3.0 4.0

Major hemorrhage

Asymptomatic DVT

Clinical PE

Death

Total hemorrhage

Wound hematoma

Transfusion

Non-cancer

Mismetti P et al. Br J Surg 2001;88:913–30.

LMWH better UFH better

Thromboprophylaxis: general surgery

Au

top

sy c

on

firm

ed

fata

l PE

(%

)

Control(n=2,076)

Low-dose heparint.i.d. (n=2,045)

P< 0.005

0.16

0.80.16

Kakkar VV, et al. Lancet. 1975;2:45-51; Haas S, et al. Thromb Haem. 2005;94:814-9.

00.10.20.30.40.50.60.70.80.9

0.1

0.10.20.30.40.50.60.70.8

0

Au

top

sy p

roven

fata

l PE

(%

)0.15

P=NS

Low-dose heparin t.i.d (n=11,536)

LMWH o.d. (n=11,542)

Death (%)

Fatal PE (%)

Non-fatal PE (%)

192 (3.1)

20 (0.31)

5 (0.08)

120 (0.7)

15 (0.09)

4 (0.02)

0.0001

0.0001

Kakkar AK, et al. Thromb Haem 2005. In press

All patients (low-dose UFH or LMWH)

Cancer(n = 6124)

No cancer(n = 16,954)

P

Enoxaparin 40 mg od*(n = 332)1

1Bergqvist D, et al. N Engl J Med. 2002;346:975-80; 2Rasmussen MS, et al. J Thromb Haemost. 2006

Dalteparin 5000 IU od(n = 198)2

*od = once daily.

Tota

l D

VT (

%) 19.619.6

8.88.8

1 week 4 weeks

21/107 P < 0. 04

0

5

10

20

15

Tota

l D

VT (

%)

1 week 4 weeks

1212.0.0

4.84.8

20/167

8/165

P = 0.02

0

5

10

20

15

8/91

Prevention of VTE in Pts Receiving Chemotherapy

Th

rom

boem

bolic E

ven

t (%

) Th

rom

boem

bolic E

ven

t (%

)

16/76916/769 15/38115/381

P= 0.033P= 0.033

RRR = 47.2%

NNT = 54

RRR = 47.2%

NNT = 54

Agnelli G. et al. ASH

2008

Agnelli G. et al. ASH

2008

Geerts et al. Chest 2001; Turpie et al. Arch Intern Med 2002

64.3

56.0

46.8

30.6

12.5

4.87.9

54.2

40.2

22.1

16.1

48.0

34.0

24.027.0

0

10

20

30

40

50

60

70

Placebo/control ASA Warfarin LMWH Fondaparinux

Tota

l D

VT in

cid

en

ce (

%)

Total knee replacement

Total hip replacement

Hip fracture surgery

Hip replacement (n=3411)

EPHESUS (n=1827)

PENTATHLON 2000 (n=1584)

–58.9 to –27.4

–72.8 to –37.2

–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

Common odds reduction

(n=5385)–63.1 to –45.8

Exact 95% CIFondaparinux better Enoxaparin better

–100 –80 –60 –40 –20 200 40 60 80 100

–45.3%

–63.1%

–55.2%

–61.6%

p<0.001

% Odds reduction

–58.3%

–28.1%

Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.

Fondaparinux

(n=3,616)

Enoxaparin

(n=3,621)

Fatal, (n)(0) (1)

In a critical organ, (n)(0) (1)

Leading to re-operation, % (n)

0.3 (12) 0.2 (8)

Overt bleeding with index ≥2, % (n)

2.3 (84) 1.5

(53). Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.

MEDENOX1 63% Placebo

Enoxaparin

PREVENT2 49% Placebo

Dalteparin

ARTEMIS 47% Placebo

Fondaparinux

14.9*

5.5

Study RRR Thromboprophylaxis Patients with VTE (%)

5.0*

2.8

10.5†

5.6

*VTE at day 14; †VTE at day 15.1Samama MM, et al. N Engl J Med. 1999;341:793-800.

2Leizorovicz A, et al. Circulation. 2004;110:874-9.3Cohen AT, et al. J Thromb Haemost. 2003;1 (Suppl 1):P2046.

p < 0.001

p = 0.0015

p = 0.029

RRR = relative risk reduction

Studyor subcategory

Cohen 2006Leizorovicz 2004Fraisse 2000Samama 1999

Total (95% CI)

Placebon/N

13 / 42053 / 185010 / 11414 / 371

2755

Anticoagulantn/N

5 / 42927 / 18563 / 1095 / 367

2761

RR (random)95% CI

Weight%

13.0864.968.5713.39

100.00

RR (random)95% CI

0.38 [0.14, 1.05]0.51 [0.32, 0.80]0.31 [0.09, 1.11]0.36 [0.13, 0.99]

0.45 [0.31, 0.65]

0.10.2 0.5 1 2 5 10

FavorsAnticoagulant

FavorsPlacebo

Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414

Studyor subcategory

Cohen 2006Leizorovicz 2004Fraisse 2000Samama 1999

Total (95% CI)

Placebon/N

25 / 420103 / 1850

8 / 11450 / 371

2755

Anticoagulantn/N

14 / 429 107 / 1856

8 / 10941 / 367

2761

RR (random)95% CI

Weight%

12.8051.066.2229.91

100.00

RR (random)95% CI

0.55 [0.29, 1.04]1.04 [0.80, 1.35]1.05 [0.41, 2.69]0.83 [0.56, 1.22]

0.89 [0.70, 1.14]

0.10.2 0.5 1 2 5 10

FavorsAnticoagulant

FavorsPlacebo

Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414

Multicenter, Prospective, Randomized, Double-blind, Placebo-controlled

study to demonstrate superiority of enoxaparin 40 mg sc qd for 28 days +

4 days compared with placebo both following 10 + 4 days of initial

treatment with enoxaparin 40 mg sc qd

10 + 4

Mandatory ultrasonography

0

R

Enoxaparin 40 mg sc od*

Placebo

38 ± 4Day

Follow-up

Enoxaparin40 mg sc od

Open-label Double-blind

180 ± 10

*qd = once a day, SC = subcutaneous

4.9

2.8

3.7

2.5

VTE

Efficacy – VTE Events

Proximal DVT

Symptomatic VTE

1.1

0.3

Placebo

Enoxaparin

Incid

en

ce (%

)

RRR- 44%

RRR

-34%

RRR

-73%

0.20.0

PE

0.10.0

Fatal PE

p = 0.0011

p = 0.0319

p = 0.0044

p = 0.2498

p = 1.0000

3.80

5.70

0.150.60

Total Bleeding

Safety – Bleeding

Major Bleeding

Minor Bleeding

3.70

5.20

Placebo

Enoxaparin

p = 0.007

p = 0.019

p = 0.024

Incid

en

ce (%

)

Coagulation cascadeInitiation

Propagation

Thrombin activity

TF/VIIa

VIIIa

IXa

IXX

Xa

VaII

IIa

Fibrinogen Fibrin

TFPINAPc2

TF: Tissue factor, TFPI: Tissue factor pathway inhibitor. * anti Xa > anti IIaTF: Tissue factor, TFPI: Tissue factor pathway inhibitor. * anti Xa > anti IIaactivity.activity.

Fondaparinux

Idrabiotaparinux

Apixaban

Rivaroxaban

YM-150

AVE 5026*

Ximelagatran

Dabigatran

TTP889

0

10

20

30

40

50

RE-NOVATEHip†,1

Tota

l V

TE a

nd

All-c

au

se M

ort

ality

(%

)

150 mg once daily

RE-MODELKnee†,2

RE-MOBILZEKnee‡,3

8.66.06.7

40.536.437.7

33.731.1

25.7

1. Eriksson BI, et al. Lancet. 2007;370:949-956. 2. Eriksson BI, et al. J Thromb Haemost. 2007;5:2178-2185. 3. The RE-MOBILIZE Writing Committee. J Arthroplasty. 2008.

Enoxaparin

220 mg once daily

Enoxaparin

Dabigatran (150 mg)

Dabigatran (220

mg)

Major VTE, % 3.3 3.8 3.0

Absolute risk difference, %

(95% CI)–

0.5(−0.6−1.6)

−0.2(−1.3−0.9

)

Major bleeding, % 1.4 1.1 1.4

Caprini J, et al. J Thomb Haemost. 2007;5(suppl 2):AO-W-050.

Hip replacement

Rivaroxaban 10 mg o.d.for 35 ± 4 days

vs.

Enoxaparin 40 mg o.d.for 35 ± 4 days

N = 4541

Hip replacement

Rivaroxaban 10 mg o.d.for 35 ± 4 days

vs.

Enoxaparin 40 mg o.d.for 12 ± 2 days

then placebo

N = 2509

Knee replacement

Rivaroxaban 10 mg o.d.for 12 ± 2 days

vs.

Enoxaparin 40 mg o.d.for 12 ± 2 days

N = 2531

Knee replacement

Rivaroxaban 10 mg o.d.

for 12 ± 2 days

vs.

Enoxaparin 30 mg b.i.d.

for 12 ± 2 days

N = 3148 Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14.