Pharmacological thromboprophylaxis Professor Ajay Kakkar Barts and the London School of Medicine...
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Transcript of Pharmacological thromboprophylaxis Professor Ajay Kakkar Barts and the London School of Medicine...
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
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.
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.