Transcript Welcome 18th March 2009

Pharmacological
thromboprophylaxis
Professor Ajay Kakkar
Barts and the London School of Medicine
Thrombosis Research Institute, London, UK
Register of interests for Ajay Kakkar
Research Support/P.I.
Bayer HealthCare, Sanofi-Aventis, Boehringer
Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai
Employee
N/A
Consultant
Bayer HealthCare, Sanofi-Aventis, Boehringer
Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai
Major Stockholder
N/A
Speakers Bureau
N/A
Honoraria
Bayer HealthCare, Sanofi-Aventis, Boehringer
Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai, GSK
Scientific Advisory Board
Bayer HealthCare, Sanofi-Aventis, Boehringer
Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai
N/A = not applicable (no conflicts)
4
92 normal
9
132 postoperative
patients
40
26
Kakkar VV, et al. Lancet. 1969;2:230-232.
Patients with DVT (%)
Efficacy of low-dose unfractionated heparin (UFH) in prevention
of DVT after major surgery
45
40
35
30
25
20
15
10
5
0
42
– s.c. low-dose UFH:
pre-operative and b.i.d.
post-operative
– 78 ‘high-risk’ patients
8
Control
Low-dose UFH
s.c., subcutaneous; b.i.d., twice a day
Kakkar et al. Lancet 1972;2:101–6.
Kakkar V V et al, Lancet. 1975;2:45-51.
Number of patients
with fatal PE
P < 0.005
18
16
14
12
10
8
6
4
2
0
16
2
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.
RR=67%
RR=68%
60.5
Control
UFH
20.3
Frequency of PE (%)
Prevalence of Proximal DVT (%)
1.9
0.6
Asymptomatic DVT
Fatal PE
Collins R, et al. N Engl J Med. 1988;318:1162-1173.
Proportion of Patients Experiencing Outcome
25
RR 0.68
132/622
LMWH
20
UFH
15
93/672
10
RR 0.43
5
24/582
10/590
RR 0.75
6/672
8/622
0
DVT
PE*
Major bleeding
Nurmohamed MT, et al. Lancet. 1992;340:152-156.
Placebo/
No treatment
Prevalence of DVT (%)
25
20
OR=0.39
[0.28–0.54]
LMWH
OR = 0.82
[0.49–1.40]
24.0
20.5
18.6
15
10
7.7
5
0
THR
(NNT=9)
TKR
(NNT=29)
Eikelboom JW, et al. Lancet. 2001;358:9-15.
In-hospital prophylaxis followed by:
Prevalence of VTE (%)
5.0
Placebo/
No treatment
LMWH
OR = 0.33
[0.19–0.56]
4.3
4.0
3.0
2.0
1.4
1.0
OR = 0.74
[0.26–2.15]
1.4
1.0
0.0
THR
(NNT=34)
TKR
(NNT=250)
Eikelboom JW, et al. Lancet. 2001;358:9-15.
Thromboprophylaxis: general surgery
LMWH better
UFH better
Asymptomatic DVT
Clinical PE
Clinical thromboembolism
Cancer
Death
Non-cancer
Major hemorrhage
Total hemorrhage
Wound hematoma
Transfusion
0
1.0
2.0
3.0
4.0
Mismetti P et al. Br J Surg 2001;88:913–30.
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0.16
0.8
0.1
Control
(n=2,076)
Low-dose heparin
t.i.d. (n=2,045)
Autopsy proven fatal PE (%)
Autopsy confirmed fatal PE (%)
P< 0.005
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
P=NS
0.16
Low-dose
heparin t.i.d
(n=11,536)
0.15
LMWH o.d.
(n=11,542)
Kakkar VV, et al. Lancet. 1975;2:45-51; Haas S, et al. Thromb Haem. 2005;94:814-9.
All patients (low-dose
UFH or LMWH)
Cancer
(n = 6124)
No cancer
(n = 16,954)
P
Death (%)
192 (3.1)
120 (0.7)
0.0001
Fatal PE (%)
20 (0.31)
15 (0.09)
0.0001
Non-fatal PE (%)
5 (0.08)
4 (0.02)
Kakkar AK, et al. Thromb Haem 2005. In press
20
Enoxaparin 40 mg od*
(n = 332)1
20
Dalteparin 5000 IU od
(n = 198)2
15
12.0
10
P = 0.02
20/167
4.8
5
Total DVT (%)
Total DVT (%)
19.6
15
21/107
10
P < 0. 04
8.8
8/91
5
8/165
0
1 week
4 weeks
0
1 week
1Bergqvist D, et
*od = once daily.
4 weeks
al. N Engl J Med. 2002;346:975-80;
2Rasmussen MS, et al. J Thromb Haemost. 2006
Prevention of VTE in Pts Receiving
Chemotherapy
P= 0.033
Thromboembolic Event (%)
RRR = 47.2%
NNT = 54
16/769
15/381
Agnelli G. et al. ASH 2008
70
Total DVT incidence (%)
60
50
64.3
Total knee replacement
Total hip replacement
56.0
54.2
Hip fracture surgery
48.0
46.8
40.2
40
34.0
30.6
30
27.0
24.0
22.1
20
16.1
12.5
7.9
10
4.8
0
Placebo/control
ASA
Warfarin
LMWH
Fondaparinux
Geerts et al. Chest 2001; Turpie et al. Arch Intern Med 2002
Fondaparinux better
(n=1250)
Major knee surgery
PENTAMAKS
–58.9 to –27.4
–58.3%
PENTATHLON 2000
(n=1584)
Hip fracture PENTHIFRA
Exact 95% CI
–45.3%
Hip replacement (n=3411)
EPHESUS (n=1827)
Enoxaparin better
–72.8 to –37.2
–28.1%
–52.2 to –7.6
–61.6%
–73.4 to –45.0
–63.1%
–75.5 to –44.8
(n=724)
–55.2%
Common odds reduction
p<0.001
–63.1 to –45.8
(n=5385)
–100
–80
–60 –40
–20
0
20
40
60
80
100
% Odds reduction
Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.
Fondaparinux
Enoxaparin
(n=3,616)
(n=3,621)
Fatal, (n)
In a critical organ, (n)
(0)
(1)
(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.
Study
RRR
Thromboprophylaxis
MEDENOX1 63%
49%
5.0*
Placebo
Dalteparin
47%
2.8
Placebo
p = 0.029
*VTE
5.5
Enoxaparin
p = 0.0015
ARTEMIS
14.9*
Placebo
p < 0.001
PREVENT2
Patients with VTE (%)
10.5†
Fondaparinux
5.6
at day 14; †VTE at day 15.
1Samama MM, et
al. N Engl J Med. 1999;341:793-800.
Circulation. 2004;110:874-9.
3Cohen AT, et al. J Thromb Haemost. 2003;1 (Suppl 1):P2046.
2Leizorovicz A, et al.
RRR = relative risk reduction
Study
or subcategory
Cohen 2006
Leizorovicz 2004
Fraisse 2000
Samama 1999
Total (95% CI)
Anticoagulant
n/N
Placebo
n/N
5 / 429
27 / 1856
3 / 109
5 / 367
2761
RR (random)
95% CI
Weight
%
RR (random)
95% CI
13 / 420
53 / 1850
10 / 114
14 / 371
13.08
64.96
8.57
13.39
0.38 [0.14, 1.05]
0.51 [0.32, 0.80]
0.31 [0.09, 1.11]
0.36 [0.13, 0.99]
2755
100.00
0.45 [0.31, 0.65]
0.1 0.2
0.5 1
Favors
Anticoagulant
2
5
10
Favors
Placebo
Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414
Study
or subcategory
Cohen 2006
Leizorovicz 2004
Fraisse 2000
Samama 1999
Total (95% CI)
Anticoagulant
n/N
Placebo
n/N
14 / 429
107 / 1856
8 / 109
41 / 367
2761
RR (random)
95% CI
Weight
%
RR (random)
95% CI
25 / 420
103 / 1850
8 / 114
50 / 371
12.80
51.06
6.22
29.91
0.55 [0.29, 1.04]
1.04 [0.80, 1.35]
1.05 [0.41, 2.69]
0.83 [0.56, 1.22]
2755
100.00
0.89 [0.70, 1.14]
0.1 0.2
0.5 1
Favors
Anticoagulant
2
5
10
Favors
Placebo
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
Enoxaparin 40 mg sc od*
Enoxaparin
40 mg sc od
R
Placebo
Open-label
Day 0
10 + 4
*qd = once a day, SC = subcutaneous
Double-blind
Follow-up
38 ± 4
180 ± 10
Mandatory ultrasonography
Efficacy – VTE Events
Placebo
Enoxaparin
p = 0.0011
p = 0.0319
4.9
RRR
- 44%
p = 0.0044
p = 1.0000
p = 0.2498
RRR
3.7
Incidence (%)
-34%
2.8
RRR
2.5
-73%
1.1
0.3
VTE
Proximal DVT
Symptomatic
VTE
0.2
0.0
PE
0.1
0.0
Fatal PE
Safety – Bleeding
Placebo
Enoxaparin
p = 0.007
p = 0.019
p = 0.024
5.70
5.20
Incidence (%)
3.80
3.70
0.15
Total Bleeding
0.60
Major Bleeding
Minor Bleeding
Coagulation cascade
Initiation
TF/VIIa
IX
X
TFPI
NAPc2
TTP889
Propagation
Xa
VIIIa
II
Thrombin activity
Fibrinogen
IXa
Fondaparinux
Idrabiotaparinux
Apixaban
Rivaroxaban
Va
YM-150
AVE 5026*
IIa
Ximelagatran
Fibrin
Dabigatran
TF: Tissue factor, TFPI: Tissue factor pathway inhibitor. * anti Xa > anti IIa
activity.
Total VTE and All-cause Mortality (%)
50
40
Enoxaparin
150 mg once daily
220 mg once daily
37.7
40.5
30
36.4
33.7
31.1
25.7
20
10
6.7
8.6
6.0
0
RE-NOVATE
Hip†,1
RE-MODEL
Knee†,2
RE-MOBILZE
Knee‡,3
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.
Major VTE, %
Absolute risk difference, %
(95% CI)
Major bleeding, %
Enoxaparin
Dabigatran
(150 mg)
Dabigatran
(220 mg)
3.3
3.8
3.0
–
0.5
(−0.6−1.6)
−0.2
(−1.3−0.9)
1.4
1.1
1.4
Caprini J, et al. J Thomb Haemost. 2007;5(suppl 2):AO-W-050.
Hip replacement
Hip replacement
Knee replacement
Knee replacement
Rivaroxaban 10 mg o.d.
for 35 ± 4 days
Rivaroxaban 10 mg o.d.
for 35 ± 4 days
Rivaroxaban 10 mg o.d.
for 12 ± 2 days
Rivaroxaban 10 mg o.d.
for 12 ± 2 days
vs.
vs.
vs.
vs.
Enoxaparin 40 mg o.d.
for 35 ± 4 days
Enoxaparin 40 mg o.d.
for 12 ± 2 days
then placebo
Enoxaparin 40 mg o.d.
for 12 ± 2 days
Enoxaparin 30 mg b.i.d.
for 12 ± 2 days
N = 4541
N = 2509
N = 2531
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.