LIFEBLOODTHE

ThrombosisCHARITY

Venous thromboembolism –Primary prevention after major orthopaedic surgery

LIFEBLOODTHE

ThrombosisCHARITY

No of n Prevalence trials % (95%Cl) RRR %

Effect of prophylaxis on total DVT rates after total hip replacement

Placebo/control 12 626 54 (50-58) -

Elastic stockings 4 290 42 (36-48) 23

Aspirin 6 473 40 (35-45) 26

Low-dose UFH 11 1016 30 (27-33) 45

Warfarin 13 1828 22 (20-24) 59

IPC 7 423 20 (17-24) 63

LMWH 30 6216 16 (15-17) 70

R-hirudin 3 1172 16 (14-19) 70

Geerts WH et al. Chest 2001;119:132S–175S

LIFEBLOODTHE

ThrombosisCHARITY 7th ACCP recommendations

Total hip, knee replacement or hip fracture surgery

• Thromboprophylaxis for at least 10 days [Grade 1A] with:

– LMWH (high-risk dose)

– Fondaparinux (2.5 mg daily)

– Vitamin K antagonist (VKA, target INR 2.5 [INR range 2–3])

– For TKR, intermittent pneumatic compression is an alternative [Grade 2B]

Geerts WH et al. Chest 2004;126:338S–400S

LIFEBLOODTHE

ThrombosisCHARITY

• Prophylaxis should be extended until 28–35 days after surgery

– THR: LMWH, VKA or fondaparinux [all Grade 1A)]

– HFS: Fondaparinux (Grade 1A), LMWH or VKA [both Grade 1C+]

– TKR: Benefits remain unclear

Geerts WH et al. Chest 2004; 126:338S–400S

7th ACCP recommendations Total hip, knee replacement or hip fracture surgery

LIFEBLOODTHE

ThrombosisCHARITY

Timing of anticoagulant therapy in orthopaedic surgery

In Europe, the first dose of LMWH is commonly administered the evening

(10-12 hours) before surgery

LIFEBLOODTHE

ThrombosisCHARITY

In North America the initial dose of warfarin,or less common, LMWH is not administered

until 12-24 hours after surgery

Timing of anticoagulant therapy in orthopaedic surgery

LIFEBLOODTHE

ThrombosisCHARITY

Prophylaxis most effective when initiated in close relation to surgery

Upper and lower dashed lines indicate the 95% confidence interval for the estimated odds ratio

Quadratic fit for study odds ratio for DVT vs. the number of hours from surgery for the

first dose of LMWH

10Hours from surgery

Odds ratio

-10

1.4

1.0

0.6

0.2

0 20

Hull R et al. Arch Intern Med 2001;160:2208-15

LIFEBLOODTHE

ThrombosisCHARITY

Thrombin activation at bone traumatisation during THR surgery

Prothrombin F1 + 2 (nmol/L)

0 0.5 1.0 1.5 2.0 2.5

4

3

5

1

2

Time (h)

Bone trauma

Thrombin-antithrombin (TAT) (ng/mL)

*p=0.0001

0 0.5 1.0 1.5 2.0 2.5

Time (h) (h)

100

0

80

60

40

20

*

*

**

Bone trauma

Sharrock NE et al. Clin Orthop 1995;319:16-27

Saline

UFH 10 units/kg

UFH 20 units/kg

LIFEBLOODTHE

ThrombosisCHARITY

Increasing thrombin generation and thrombus growth after one week

Mixed venous blood

876543210

20

15

10

5

Intraoperatively (h)

Arterial blood

Venography shows DVT ~1 week after surgery

F1+2*

* Thrombin generation factors

631

Days after Surgery

Scanning electron microscopy shows DVT ~1 hour after

THR surgery

Dahl OE et al. Thromb Res 1993;70:451-8 Dahl OE et al. Blood Coagul Fibrinolysis 1995;6:709-17

LIFEBLOODTHE

ThrombosisCHARITY

Onset of VTE after THR / TKR- cumulated risk within 3 months

White RH et al. Arch Intern Med. 1998;158:1525-1531

Thromboembolic events (%)

0.00 14 28 42 56 70 84

Days

0.5

1.0

1.5

2.0

2.5

3.0

3.5 Primary hipPrimary knee

Pulmonary embolism (%)

0.00 14 28 42 56 70 84

Days

0.3

0.5

0.8

1.0

1.3 Primary hipPrimary knee

All VTE PE

LIFEBLOODTHE

ThrombosisCHARITY

0

5

10

15

20

25

30

0 1 6 14 20 35

Thrombin activity(TAT; ng/mL)

Days after surgery

D-dimer (ng/mL)

0

2000

4000

6000

16%

32%

TAT complexes

D-dimer – LMWH

DVT at venography

Duration of thrombin generation in THR

Dahl OE et al. Thromb Res 1995;80:299-306 Dahl OE et al. Thromb Haemost 1997;77:26-31

LIFEBLOODTHE

ThrombosisCHARITY

0

10

20

30

40

Effect of continuing prophylaxis on asymptomatic DVT

Bergqvist 1996

Planes1996

Dahl1997

Spiro1997

Lassen1998

Hull2000

Total DVT

DVT %

Proximal DVT

0

5

10

15

20

25

30 7 days35 days

LIFEBLOODTHE

ThrombosisCHARITY

Extended Control OR (95% CI) n (N) n (N)

Cohen A et al. Thromb Haemost 2001;85:940-1

Extended LMWH reduces symptomatic VTE

Bergqvist 2 (131) 10 (131) 0.25 (0.08, 0.79)

Dahl 4 (117) 6 (110) 0.62 (0.17, 2.19)

Heit 7 (607) 10 (588) 0.68 (0.26, 1.76)

Hull 4 (291) 3 (133) 0.58 (0.12, 2.91)

Lassen 2 (140) 3 (141) 0.67 (0.11, 3.92)

Planes 3 (90) 7 (89) 0.43 (0.12, 1.52)

Total 22 (1376) 39 (1192) 0.50 (0.30, 0.83)

LIFEBLOODTHE

ThrombosisCHARITY

Relative risk for DVT out-of-hospital

No. patients with events Relative risk

Study Year LMWH group Control group Weight (95% CI fixed) p valuen/n (%) (%)

Bergqvist et al 1996 21/117 (17.9) 45/116 (38.8) 28.6 0.46 (0.30–0.73) 0.001

Planes et al 1996 6/85 (7.1) 17/88 (19.3) 10.6 0.37 (0.15–0.88) 0.025

Dahl et al 1997 11/93 (11.8) 23/89 (25.8) 14.9 0.46 (0.24–0.88) 0.020

Lassen et al 1998 5/113 (4.4) 12/102 (11.8) 8.0 0.38 (0.14–1.03) 0.057

Hull et al 2000 14/291 (4.8) 14/133 (10.5) 12.2 0.46 (0.22–0.93) 0.031

Comp et al 2001 15/152 (9.9) 39/138 (28.2) 25.9 0.35 (0.20–0.60) <0.001

Total 72/911 (7.9) 150/666 (22.5) 100.0 0.41 (0.32–0.54) <0.001

Hull RD et al. Ann Intern Med 2001;135:858-69

LIFEBLOODTHE

ThrombosisCHARITY

Relative risk for symptomatic VTE out-of-hospital

No. patients with events Relative risk

Study Year LMWH group Control group Weight (95% CI fixed) p valuen/n (%) (%)

Bergqvist et al 1996 2/131 (1.5)10/131 (7.6) 26.3 0.20 (0.04–0.90) 0.035

Planes et al 1996 3/90 (3.3) 7/89 (7.9) 18.5 0.42 (0.11–1.59) 0.2

Dahl et al 1997 4/117 (3.4) 6/110 (5.5) 16.3 0.63 (0.18–2.16) >0.2

Lassen et al 1998 2/140 (1.4) 3/141 (2.1) 7.9 0.67 (0.11–3.96) >0.2

Hull et al 2000 4/389 (1.0) 3/180 (1.7) 10.8 0.62 (0.14–2.73) >0.2

Comp et al 2001 0/224 (0.0) 7/211 (3.3) 20.3 0.06 (0.00–1.09) 0.058

Total 15/1,091 (1.4) 36/862 (4.2) 100.0 0.36 (0.02–0.67) <0.001

Hull RD et al. Ann Intern Med 2001;135:858-69