1

Prevention of Venous Thromboembolism (VTE)

Andrew Nicolaides

Emeritus Professor of Vascular Surgery

Imperial College, London UK

2

VTE mortality per year in 25 EU countries

1Cohen AT. Presented at the 5th Annual Congress of the European Federation of Internal Medicine; 2005.2Eurostat statistics on health and safety 2001. Available from: http://epp.eurostat.cec.eu.int.

Deaths due to VTE : 543,4541 More than double the combined deaths

due to: AIDS 5,8602

breast cancer 86,8312

prostate cancer 63,6362

transport accidents 53,5992

3

Risk by Patient Group in the Absence of Prophylaxis

Patient group Studies DVT incidence 95% CI

Stroke 8 56% 51-61%

THR 17 51% 48-54%

Multiple trauma 4 50% 46-55%

TKR 7 47% 42-51%

Hip fracture 15 44% 40-47%

Spinal cord inj. 9 35% 31-39%

Retrop. prostatectomy 8 32% 27-37%

Patients in ICU 3 25% 19-32%

General Surgery 20 25% 24-26%

Neurosurgery 5 22% 17-27%

Gynecol. (malignancy) 4 22% 17-26%

Gynecol. Surgery 4 15% 11-17%

General medical 10 8.1% 7-9.1%

Knee arthroscopy 7 8% 6-10%

Nicolaides A et al Intern Angiol 2013 (In Press)

4

ENDORSE Survey

Multinational, cross-sectional survey of:

(a) prevalence of VTE risk and

(b) prophylaxis use in hospital

5

Patient Enrollment Criteria

Inclusion Criteria

Acute medical patients age 40 or older

Surgical patients age 18 or older

Exclusion Criteria

Admitted for treatment of VTE

Not evaluable because of missing data

6

Criteria for VTE Risk and Recommendations for Prophylaxis

2004 American College of Chest Physicians Recommendations1

Patients at risk and appropriate types of prophylaxis

1 Geerts WH, et al. Chest. 2004; 126 (Suppl 3):338S-400S

7

ENDORSE : A worldwide study

32 countries - 358 hospitals32 countries - 358 hospitalsFirst patient enrolled August 2, 2006Last patient enrolled January 4, 2007

8

Patients at risk for VTE in 32 countries

N= 68,183

0

10

20

30

40

50

60

70

80

90

100

%

Mean = 52%

9

Patients at risk for VTE receiving recommended prophylaxis in 32 countries

0

10

20

30

40

50

60

70

80

90

100

Algeria

Austra

lia

Bangla

desh

Brazil

Bulgar

ia

Colombia

Czech

Rep

Egypt

Franc

e

Germ

any

Greec

e

Hungar

yIn

dia

Irelan

d

Kuwait

Mex

ico

Pakist

an

Poland

Portu

gal

Romania

Russia

Saudi

Arabia

Slovakia

Spain

Switzer

land

Thaila

nd

Tunisi

a

Turke

yUAE UK

USA

Venez

uela

%

Mean = 50%

N= 35,329

10

Surgical Patients at risk for VTE and receiving recommended prophylaxis

Primary objectives

52 % at Risk for VTE

50 % receiving ACCP

Rec. Px

Overall( N= 68,183 )

Secondary objectives

64 % at Risk for VTE

59 % receiving

ACCP Rec. Px

Surgical( n = 30,827 )

Medical( n = 37,356 )

42 % at Risk for VTE

40 % receiving

ACCP Rec. Px

11

Conclusions

ENDORSE demonstrates:

the high prevalence of patients at risk for VTE and

the need to improve the rate of prophylaxis use.

12

(a) Implement hospital-wide strategies

(b) Assess patient risk for VTE routinely

(c) Provide appropriate prophylaxis

(d) Educate the public to ask for prophylaxis when admitted to hospital

These data reinforce the rationale to :These data reinforce the rationale to :

13

14

The International Guidelines on Prevention of VTE (2013)

15

Developed under the auspices of the:

Cardiovascular Disease Educational and Research Trust (UK)European Venous ForumNorth American Thrombosis ForumInternational Union of Angiology andUnion Internationale du Phlebologie

PREVENTION AND TREATMENTPREVENTION AND TREATMENTOF VENOUS THROMBOEMBOLISMOF VENOUS THROMBOEMBOLISM

International Consensus Statement 2013Guidelines According to Scientific Evidence

16

Prevention and Treatment of Venous Thromboembolism Consensus Statement

Aim Provide a concise account of the evidence of efficacy or

harm for various methods available to prevent and treat venous thromboembolism (VTE)

Provide recommendations based on critical evaluation of the evidence

17

EDITORIAL COMMITTEE

 

Chairman: AN Nicolaides,

Cochairmen: J Fareed, AK Kakkar

Members: AJ Comerota, SZ Goldhaber, R Hull, K Myers, M Samama, J Fletcher

Editorial Secretary: E Kalodiki

18

Faculty

D Bergqvist (Sweden) J Bonnar (Ireland) JA Caprini (USA) C Carter (USA) AJ Comerota (USA) J Conard (France) B Eklof (Sweden) I Elalamy (France) J Fareed (USA) J Fletcher (Australia) G Gerotziafas (France) G Geroulakos (UK) A Giannoukas (Greece) SZ Goldhaber (USA) I Greer (UK) M Griffin (UK)

R Hull (USA) A K Kakkar (UK) S Kakkos (Greece) E Kalodiki (UK) MR Lassen (Denmark) GDO Lowe (UK) A Markel (Israel) K Myers (Australia) A Nicolaides (Cyprus) P Prandoni (Italy) G Raskob (USA) M Samama (France) AC Spyropoulos (USA) AG Turpie (Canada) JM Walenga (USA) D Warwick (UK)

19

20

Corresponding Faculty

C Allegra (Italy)

J Arcelus (Spain)

N Baekgaard (Denmark)

G Belcaro (Italy)

H Bjarnason (USA)

MA Cairols (Spain)

M Catalano (Italy)

D Christopoulos (Greece)

D Clement (Belgium)

F Corvalán (Chile)

E Diamantopoulos (Greece)

J Fernandes e Fernandes (Portugal)

C Fisher (Australia)

A Gasparis (USA)

H Gibbs (Australia)

V Hadjianastassiou (Cyprus)

K Ivancev (UK)

CP Hsien (Thaiwan)

JT Hobbs (UK)

D Hoppenstead (USA)

EA Hussein (Egypt)

O Iqbal (USA)

K Ivancev (Russia)

R Kistner (USA)

TK Kim (Korea)

M Kurtoglou (Turkey)

T Kölbel (Germany)

N Labropoulos (USA)

LH Lee (Singapore)

BB Lee (USA)

Y-J Li (China)

NC Liew (Malaysia)

A Llinas (Colombia)

M Nakamura (Japan)

P Neglen (Cyprus)

L Norgren (Sweden)

H Partsch (Austria)

N Ramakrishnan (India)

G Rao (USA)

J-B. Ricco (France)

N Rich (USA)

P Robless (Singapore)

W Schobersberger (Austria)

M Seed (UK)

S Schellong (Germany)

A Scuderi (Brazil)

R Sexana (India)

E Shaydakov (Russia)

A Shevela (Russia)

R Simkin (Argentina)

W Toff (UK)

JM Trabal (Puerto Rico)

M Vandendriessche (Belgium)

M Veller (South Africa)

L Villavincencio (USA)

R Wahi (USA)

C Wittens (TheNetherlands)

R Wong (Hong Kong)

21

Levels of Evidence

High level of evidence was considered to be provided by RCTs with consistent results, or

systematic reviews that were directly applicable to the target population

also, by single randomized trials which have been rigorously performed, methodologically reliable, and sufficiently large to give clear results that are applicable to most patients in most circumstances

22

Levels of Evidence

Moderate level of evidence was considered to be provided by RCT with less consistent results, limited power or other

methodological problems, which were directly applicable to the target population

Also, by RCT extrapolated to the target population from a different group of patients.

23

Levels of Evidence

Low level of evidence was considered to be provided by well-conducted observational studies with consistent results that

were directly applicable to the target population.

Lack of evidence ? Lack of evidence or low level evidence resulted in a number of key

questions that require to be addressed by future studies

These key questions are stated throughout the document and are summarised in the final section (Chapter 24).

24

Outcomes

Evidence is presented for the following outcomes asymptomatic DVT at screening

symptomatic DVT or PE,

fatal PE,

overall mortality and

development of the post-thrombotic syndrome (PTS) when available

25

Recommendations

Low risk patients (minor general surgery, no risk factors)

Graduated elastic compression

Avoid dehydration

Level of evidence (LE): low (extrapolation from moderate risk)

26

Effect of GEC (8 studies: moderate risk general surgery)

0

5

10

15

20

25

DVT (%)

Control (n=637) GEC (n=653)

Groups

68% Reduction in DVT Incidence

p < 0.001

27

Effect of LDUH: 32 Studies in General Surgery

0

5

10

15

20

25

DVT (%)

Control (n=2567) LDUH (n=2655)

Groups

68% Reduction in DVT Incidence

p < 0.001

28

LMWH vs Placebo in General Surgery (1 study)

0

2

4

6

8

10

12

14

16

DVT (%)

Placebo (n = 91) LMWH (n = 92)

74% Reduction in DVT Incidence

p < 0.025

29

LMWH vs LDUH in General Surgery (17 Studies)

0

1

2

3

4

5

6

7

DVT (%)

LDUH (n = 3411) LMWH (n = 3467)

21% Reduction in DVT Incidence

p < 0.025

30

LMWH vs LDUH in General Surgery (14 Studies)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

PE (%)

LDUH (n = 2644) LMWH (n = 2798)

56% Reduction in PE Incidence

p < 0.001

31

LMWH vs LDUH in General Surgery

LMWH

is more effective in preventing PE

has a lower risk of HIT than LDUH

requires one injection per day

32

Effect of IPC in General Surgery (11 studies)

0

5

10

15

20

25

30

DVT (%)

Control (n = 658) IPC (n=660)

69% Reduction in DVT Incidence

p < 0.001

33

Recommendations

Moderate risk patients (major general surgery, age >40, no additional risk factors)

(LDUH) or LMWH LE: high

IPC + GEC LE: high

34

Fondaparinux (Arixtra)

Dalteparin

% V

TE

Relative Risk Reduction= 25%

p = 0.14

6.1%4.6%

0

1

2

3

4

5

6

7

Fondaparinux (Arixtra) in prevention of VTE in General Surgery (n= 2858)

47/1027

62/1021

British Journal of Surgery 2005, G Agnelli et al

35

Relative Risk Reduction= 39% (95 %CI : 59.6; 6.7%)

p = 0.02

55/712

9

Fondaparinux (ARIXTRA)

Dalteparin0

1

2

3

4

5

6

7

8

7.7%

4.7%

33/696

% V

TE

Cancer Surgery (n= 1941)

British Journal of Surgery 2005, G Agnelli et al

36

Recommendations

High risk patients (major general surgery, age > 60 or age > 40 with at least one additional risk factor)

(LDUH) LMWH LE: high

IPC + GEC LE: high

Fondaparinux (one study) LE: moderate

IPC + GEC with LMWH LE: high

37

Orthopedics

38

Efficacy in Elective Hip Replacement(Historical progression)

Control vs LDUH 50% reduction in DVT (20 sudies)

Control vs IPC 52% reduction in DVT (4 studies)

LDUH vs LMWH 54% further red. in DVT (10 studies)

LMWH vs Fondaparinux 24% further red. In DVT (2 studies)

50% further red. In PE (2 studies)

LMWH vs LMWH+IPC 28% vs 0% DVT (1 study)

39

Fondaparinuxbetter

Enoxaparin better

Homogeneity test: ns

95% CI

-100 -80 -60 -40 -20 200 40 60 80 100

Hip replacementn=3,411 (2 studies)

-45.3% [-58.9; -27.4]

Knee replacementn=724 -63.1% [-75.5; -

44.8]

Hip fracturen=1,250 [-73.4; -

45.0]-61.6%

Overall odds reduction -55.2% [-63.1; -

45.8]p=10-17

Odds reduction (%)

Efficacy of Fondaparinux vs Enoxaparin

Turpie et al. Arch Intern Med 2002;162:1833-40

40

New Oral Anticoagulants

41

Figure 1: Site of Actions for Conventional and Newer Oral AnticoagulantsSite of Actions for Conventional and Newer Oral Anticoagulants

Antithrombin

Fibrinogen

Factor II(Prothrombin)

Fibrin

Factor IIa(Thrombin)

Factor X

Factor IX Factor VII

Anti-Xa drugs

Anti-IIa drugs

Factor Xa

Dabigatran

ApixabanBetrixabanEdoxabanRivaroxaban

VKA drugs

Warfarin

FVIIa

FIXa

42

43

Recommendationsfor Elective Hip Replacement (2013)

Fondaparinux LE: high (Most effective)

LMWH LE: high

IPC + GEC LE: high (Equivalent to LMWH)

IPC+GEC+LMWH LE: high (More effective than either)

Rivaroxaban, Dabigatran LE: high

Initiation

LMWH: before or after operation LE: high

Fondaparinux: at least 6 hours after operation

44

Recommendations

Neurosurgery

IPC + GEC LE: High

Acutely ill medical patients

(LDUH) or LMWH LE: High

IPC + GEC LE: Moderate

Fondaparinux LE: Moderate

45

Duration of thromboprophylaxis

Total hip replacement patients (Hull et al1)

‒ 4-5 weeks vs 1-2 weeks LMWH – 64% RRR for symptomatic VTE

Cancer surgery (ENOXACAN II) 2

‒ 4 weeks vs 1 week LMWH – 60% RRR for VTE

Major abdominal surgery (Rasmussen et al3)

‒ 4 weeks vs 1 week LMWH – 55% RRR for VTE

Medical patients ?

1 Hull RD, et al. Ann Intern Med. 2001; 135:858-69.2 Bergqvist D, et al. NEJM. 2002; 346:975-980. 3 Rasmussen MS, et al. J Thromb Haemost. 2006; 4:2384-2390.

46 46

Study design 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

47

Enrolment per country

Belgium0.6%

Argentina0.5%

Austria0.3%

Israel1.1%

India2.2%

Brazil1.6%

Tunisia2.6%

Italy2.7%

Colombia2.8%

Russia3.1%

Spain3.7%

Poland4.0%

Canada4.1%

Australia/NZ4.6%

U.K.6.5%

Germany7.4%

South Africa7.5%

Mexico7.9%

France8.7%

USA28.2%

48

Baseline: Primary enrolment diagnosis

Primary Primary enrollmentenrollment diagnosis diagnosis (%)(%)

Enoxaparin N = 2013

PlaceboN = 2027

Acute infection

Acute respiratory insufficiency

Heart failure

Acute ischemic stroke

Acute rheumatic disorder

Active cancer

Fractures (non surgical)

Active episode of infl. bowel disease

Multiple diagnosis

Other

30.5

26.6

21.2

8.3

2.7

2.3

1.0

0.2

0.9

6.3

31.0

27.6

21.5

7.8

2.8

2.1

0.8

0.1

0.4

5.8

49

Efficacy – all VTE until Day 90

Day 38 Day 90

Inci

den

ce (

%)

4.9

2.8

5.2

3.0

p = 0.0011 p = 0.0115

- 44%

RRR- 42%

RRR

Placebo

Enoxaparin

50

Safety – Bleeding

p = 0.007 p = 0.019

p = 0.024

Inci

den

ce

(%

)

3.80

5.70

0.150.60

5.20

3.70

Total Bleeding Major Bleeding Minor Bleeding

Placebo

Enoxaparin

51

Conclusions

Extended-duration prophylaxis reduced the rate of VTE by 44%

This benefit was for proximal DVT and symptomatic VTE, reducing the rate by 34% and 73%, respectively

The overall rate of major bleeding was higher in the active treatment arm.

The benefit of extended-duration prophylaxis translates in a NNT to avoid one VTE of 46, versus a NNT to cause major bleeding of 224

52

Combined Modalities

53

IPC + Heparin vs IPC or Anticoagulant alone (DVT) (14 Studies)

Combined IPC or Anticoag.

TOTAL 63/3074 200/3238

2.05% 6.18% p < 0.001

OR 0.31 (95% CI 0.23 to 0.43) or 69% reduction

Kakkos S et al Cochrane Database Syst Rev 2008:CD005258

54

IPC + Heparin vs IPC or Anticoagulant (Symptomatic PE) ( 16 Studies)

Combined IPC or Anticoag.

TOTAL 33/3838 122/4313

0.86% 2.83% p < 0.001

OR 0.34 (95% CI 0.23 to 0.50) or 67% reduction

Kakkos S et al Cochrane Database Syst Rev 2008:CD005258

55

Conclusion

Compared to single modalities, combined

prophylactic modalities significantly decrease the

incidence of both postoperative DVT and PE in a

variety of specialties, including orthopedic, general

and cardiac surgery.

The results support their use, especially in high risk

patients (e.g. thrombophilia or previous VTE)