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.