Pharmacological thromboprophylaxis

1
Pharmacological thromboprophylaxis
Professor Ajay Kakkar Barts and the London
School of Medicine Thrombosis Research
Institute, London, UK
2
Register of interests for Ajay Kakkar
N/A not applicable (no conflicts)
3
My talk today

• Rationale for prophylaxis
• Established pharmacological methods
• New agents

4
Natural history of postoperative DVT
4
92 normal
9
132 postoperative patients
26
40
Kakkar VV, et al. Lancet. 19692230-232.
5
Pharmacological Prevention of Thrombosis
Efficacy of low-dose unfractionated heparin (UFH)
in prevention of DVT after major surgery
45
42

• s.c. low-dose UFH pre-operative and
  b.i.d.post-operative
• 78 high-risk patients

40
35
30
25
Patients with DVT ()
20
15
8
10
5
0
Control
Low-dose UFH
Kakkar et al. Lancet 197221016
s.c., subcutaneous b.i.d., twice a day
.
6
Prophylaxis of fatal, postoperative PE with
low-dose UFH

• International multicenter trial
• 4121 patients undergoing major surgery
• Primary end point fatal PE
• Randomized control or UFH (5000 IU 2 hours
  before surgery and every 8 hours
  postoperativelyfor 7 days)
• 180 patients died during the postoperative
  period 100 in the control group and 80 in the
  UFH group
• Rate of autopsy 70

Kakkar V V et al, Lancet. 1975245-51.
7
Prophylaxis of fatal, postoperative PE with
low-dose UFH
P lt 0.005
18
16
16
14
12
Number of patientswith fatal PE
10
8
6
4
2
2
0
Control
UFH
Low-dose UFH saves 7 lives for every 1000
operated patients.
Kakkar VV et al, Lancet. 1975245-51.
8
Bleeding complications

• Control
  Heparin
• Excessive blood loss 126 182 NS
• Wound hematoma 117 158 lt 0.01
• Mean transfusion requirements (mL) 1285 1316
  0.34
• Mean Hb fall (g/dl) 0.7 1.0 0.23

NS not significant.
Kakkar vv et al, Lancet. 1975245-51.
9
Reduction in Asymptomatic DVT and Fatal PE
RR67
RR68
60.5
1.9
Control
Frequency of PE ()
UFH
Prevalence of Proximal DVT ()
20.3
0.6
Collins R, et al. N Engl J Med.
19883181162-1173.
Asymptomatic DVT
Fatal PE
10
LMWH and UFH in Major Orthopaedic Surgery
25
RR 0.68
LMWH
20
132/622
UFH
15
93/672
Proportion of Patients Experiencing Outcome
10
5
RR 0.43
RR 0.75
24/582
0
10/590
8/622
6/672
DVT
PE
Major bleeding
Nurmohamed MT, et al. Lancet. 1992340152-156.
11
Extendedduration Prophylaxis and Asymptomatic
DVT
Placebo/ No treatment
LMWH
OR 0.82 0.491.40
OR0.39 0.280.54
24.0
25
20.5
18.6
20
Prevalence of DVT ()
15
7.7
10
5
0
THR (NNT9)
TKR (NNT29)

Eikelboom JW, et al. Lancet.
20013589-15.
12
Extended-duration Prophylaxis and Symptomatic VTE
Placebo/ No treatment
LMWH
In-hospital prophylaxis followed by
OR 0.33 0.190.56
5.0
4.3
4.0
Prevalence of VTE ()
3.0
OR 0.74 0.262.15
2.0
1.4
1.4
1.0
1.0
0.0
THR (NNT34)
TKR (NNT250)
Eikelboom JW, et al. Lancet. 20013589-15.
13
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 20018891330.
14
Prevention of fatal PE in surgical patients
Plt 0.005
0.16
0.8
0.9
0.8
0.8
0.7
0.7
0.6
0.6
Autopsy confirmed fatal PE ()
PNS
0.5
0.5
Autopsy proven fatal PE ()
0.4
0.4
0.3
0.3
0.16
0.1
0.2
0.15
0.2
0.1
0.1
0
0
Low-dose heparin t.i.d. (n2,045)
Low-dose heparin t.i.d (n11,536)
LMWH o.d. (n11,542)
Control (n2,076)
Kakkar VV, et al. Lancet. 1975245-51 Haas S,
et al. Thromb Haem. 200594814-9.
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PE and death cancer vs no cancer
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
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Prolonged thromboprophylaxis after cancer
operations
Enoxaparin 40 mg od(n 332)1
Dalteparin 5000 IU od(n 198)2
20
19.6
15
P lt 0. 04
21/107
Total DVT ()
10
8.8
8/91
5
0
1 week
4 weeks
1Bergqvist D, et al. N Engl J Med.
2002346975-80 2Rasmussen MS, et al. J Thromb
Haemost. 2006
od once daily.
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Prevention of VTE in Pts Receiving Chemotherapy
P 0.033
RRR 47.2 NNT 54
Thromboembolic Event ()
16/769
15/381
Agnelli G. et al. ASH 2008
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Efficacy of Current Anticoagulants
70
64.3
Total knee replacement
Total hip replacement
60
56.0
54.2
Hip fracture surgery
48.0
46.8
50
40.2
40
34.0
Total DVT incidence ()
30.6
27.0
30
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
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Fondaparinux Efficacy
Fondaparinux better
Enoxaparin better
Exact 95 CI
45.3
58.3
28.1
61.6
63.1
55.2
plt0.001
0
100
80
60
40
20
20
40
60
80
100
Odds reduction
Turpie AGG, et al. Arch Intern Med.
20021621833-1840.
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Fondaparinux Safety
. Turpie AGG, et al. Arch Intern Med.
20021621833-1840.
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Thromboprophylaxis in medical patients
Study RRR Thromboprophylaxis Patients with VTE ()
14.9
MEDENOX1 63 Placebo
Enoxaparin PREVENT2 49 Placebo
Dalteparin ARTEMIS
47 Placebo
Fondaparinux
5.5
p lt 0.001
5.0
p 0.0015
2.8
10.5
5.6
p 0.029
VTE at day 14 VTE at day 15.
1Samama MM, et al. N Engl J Med.
1999341793-800. 2Leizorovicz A, et al.
Circulation. 2004110874-9. 3Cohen AT, et al. J
Thromb Haemost. 20031 (Suppl 1)P2046.
RRR relative risk reduction
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Thromboprophylaxis proximal DVT
Study or subcategory Cohen 2006 Leizorovicz
2004 Fraisse 2000 Samama 1999 Total (95 CI)
Placebo n/N 13 / 420 53 / 1850 10 / 114 14 /
371 2755
Anticoagulant n/N 5 / 429 27 / 1856 3 / 109 5 /
367 2761
RR (random) 95 CI
Weight 13.08 64.96 8.57 13.39 100.00
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
0.1
0.2
0.5
1
2
5
10
Favors Anticoagulant
Favors Placebo
Lloyd NS, et al. J Thromb Haemost. 20086405414
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Thromboprophylaxis all-cause mortality
Placebo n/N 25 / 420 103 / 1850 8 / 114 50 /
371 2755
Anticoagulant n/N 14 / 429 107 / 1856 8 /
109 41 / 367 2761
RR (random) 95 CI
Weight 12.80 51.06 6.22 29.91 100.00
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
Study or subcategory Cohen 2006 Leizorovicz
2004 Fraisse 2000 Samama 1999 Total (95 CI)
0.1
0.2
0.5
1
2
5
10
Favors Anticoagulant
Favors Placebo
Lloyd NS, et al. J Thromb Haemost. 20086405414
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Exclaim study
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
Double-blind
Follow-up
0
Day
180 10
10 4
38 4
Mandatory ultrasonography
qd once a day, SC subcutaneous
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Efficacy VTE Events
Placebo
Enoxaparin
p 0.0044
p 0.0011
p 0.0319
p 1.0000
p 0.2498
RRR
4.9
RRR
Incidence ()
3.7
RRR
2.8
2.5
1.1
0.3
0.2
0.1
0.0
0.0
Proximal DVT
PE
Fatal PE
Symptomatic VTE
VTE
26
Safety Bleeding
Placebo
Enoxaparin
p 0.007
p 0.019
p 0.024
5.70
Incidence ()
5.20
3.80
3.70
0.60
0.15
Total Bleeding
Major Bleeding
Minor Bleeding
27
New anticoagulants
Coagulation cascade
Initiation
TF/VIIa
TFPINAPc2
IX
X
TTP889
Fondaparinux Idrabiotaparinux Apixaban Rivaroxaba
n YM-150 AVE 5026
IXa
Xa
VIIIa
Propagation
Va
II
Thrombin activity
IIa
Ximelagatran Dabigatran
Fibrinogen
Fibrin
TF Tissue factor, TFPI Tissue factor pathway
inhibitor. anti Xa gt anti IIaactivity.
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Dabigatran for VTE Prevention
50
Enoxaparin
150 mg once daily
40.5
37.7
40
36.4
220 mg once daily
33.7
31.1
30
25.7
Total VTE and All-cause Mortality ()
20
8.6
10
6.7
6.0
0
RE-NOVATEHip,1
RE-MODELKnee,2
RE-MOBILZEKnee,3
1. Eriksson BI, et al. Lancet. 2007370949-956.
2. Eriksson BI, et al. J Thromb Haemost.
200752178-2185. 3. The RE-MOBILIZE Writing
Committee. J Arthroplasty. 2008.
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Dabigatran for Prevention of Major VTE Pooled
Analysis

• Pooled analysis from the phase 3 programme of
  dabigatran etexilate (RE-MODEL, RE-MOBILIZE, and
  RE-NOVATE studies)

Caprini J, et al. J Thomb Haemost. 20075(suppl
2)AO-W-050.
30
RECORD phase III programme for VTE
prevention

• Rivaroxaban 10 mg o.d. compared with enoxaparin

Knee replacement Rivaroxaban 10 mg o.d. for 12
2 days vs. Enoxaparin 30 mg b.i.d. for 12 2
days N 3148
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
Hip replacement Rivaroxaban 10 mg o.d. for 35
4 days vs. Enoxaparin 40 mg o.d. for 35 4
days N 4541
Knee replacement Rivaroxaban 10 mg o.d. for 12
2 days vs. Enoxaparin 40 mg o.d. for 12 2
days N 2531
Eriksson BI et al. N Engl J Med
2008358276575 Kakkar AK et al. Lancet
2008372319 Lassen MR et al. N Engl J Med
2008358277686 Turpie AGG et al. Pathophysiol
Haemost Thromb 2007/200836A14.
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Conclusion

• LMWH validated for efficacy and safety
• Orthopaedic
• General surgical
• Cancer surgery
• Medical patients
• Duration of prophylaxis remains controversial
• Medical patients
• New agents available for VTE prevention
• hip and knee arthroplasty