Transcript Slide 1

Prevention of Venous
Thromboembolism (VTE)
Andrew Nicolaides
Emeritus Professor of Vascular Surgery
Imperial College, London UK
1
VTE mortality per year in 25 EU countries
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

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.
2
Risk by Patient Group in the Absence of Prophylaxis
Patient group
DVT incidence
95% CI
8
56%
51-61%
17
51%
48-54%
Multiple trauma
4
50%
46-55%
TKR
7
47%
42-51%
15
44%
40-47%
Spinal cord inj.
9
35%
31-39%
Retrop. prostatectomy
8
32%
27-37%
Patients in ICU
3
25%
19-32%
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
Stroke
THR
Hip fracture
General Surgery
Studies
8%
6-10%
Nicolaides A et al Intern Angiol 2013 (In Press)
3
ENDORSE Survey
Multinational, cross-sectional survey of:
(a) prevalence of VTE risk and
(b) prophylaxis use in hospital
4
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
5
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
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ENDORSE : A worldwide study
32 countries - 358 hospitals
First patient enrolled August 2, 2006
Last patient enrolled January 4, 2007
7
90
U
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Ve U
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ne A
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a
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e
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er e
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un
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ry
In
d
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la
Ku n d
w
M a it
e
Pa x ic o
ki
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rt
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om l
a
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u
u d ss
i A ia
r
Sl abi a
ov
ak
Sw S ia
i tz pa
er in
la
Th nd
ai
la
Tu nd
ni
Tu s ia
rk
ey
U
AE
%
Patients at risk for VTE in 32
countries
N= 68,183
100
Mean = 52%
80
70
60
50
40
30
20
10
0
8
60
50
U
Ve U K
ne SA
zu
el
a
A
Au lger
B a s ia
ng tra
la lia
de
s
Br h
Bu az
Co lga il
Cz lom r ia
ec b
h ia
R
Eg ep
F yp
G ra n t
er ce
m
G any
r
Hu e ec
ng e
ar
In y
Ire dia
l
Ku an d
w
M ai
ex t
Pa ic
kis o
Po ta n
Po lan
r d
Ro tug
m al
Sa R a ni
ud u s a
i A s ia
r
Sl abi
ov a
a
Sw S kia
itz pa
e in
Th r lan
ai d
l
Tu an d
n
Tu isia
rk
e
UA y
E
%
Patients at risk for VTE receiving
recommended prophylaxis in 32 countries
N= 35,329
100
90
80
70
Mean = 50%
40
30
20
10
0
9
Surgical Patients at risk for VTE and
receiving recommended prophylaxis
Primary
objectives
52 % at Risk for VTE
Overall
( N= 68,183 )
Secondary
Surgical
objectives ( n = 30,827 )
50 % receiving
ACCP
Rec. Px
Medical
( n = 37,356 )
64 % at Risk for VTE
42 % at Risk for VTE
59 % receiving
40 % receiving
ACCP Rec. Px
ACCP Rec. Px
10
Conclusions
ENDORSE demonstrates:
the high prevalence of patients at risk for VTE and
the need to improve the rate of prophylaxis use.
11
These data reinforce the rationale to :
(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
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13
The International Guidelines on
Prevention of VTE (2013)
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PREVENTION AND TREATMENT
OF VENOUS THROMBOEMBOLISM
International Consensus Statement 2013
Guidelines According to Scientific Evidence
Developed under the auspices of the:
Cardiovascular Disease Educational and Research Trust (UK)
European Venous Forum
North American Thrombosis Forum
International Union of Angiology and
Union Internationale du Phlebologie
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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
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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
17
Faculty

D Bergqvist (Sweden)

R Hull (USA)

J Bonnar (Ireland)

A K Kakkar (UK)

JA Caprini (USA)

S Kakkos (Greece)

C Carter (USA)

E Kalodiki (UK)

AJ Comerota (USA)

MR Lassen (Denmark)

J Conard (France)

GDO Lowe (UK)

B Eklof (Sweden)

A Markel (Israel)

I Elalamy (France)

K Myers (Australia)

J Fareed (USA)

A Nicolaides (Cyprus)

J Fletcher (Australia)

P Prandoni (Italy)

G Gerotziafas (France)

G Raskob (USA)

G Geroulakos (UK)

M Samama (France)

A Giannoukas (Greece)

AC Spyropoulos (USA)

SZ Goldhaber (USA)

AG Turpie (Canada)

I Greer (UK)

JM Walenga (USA)

M Griffin (UK)

D Warwick (UK)
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19
Corresponding Faculty
C Allegra (Italy)
D Hoppenstead (USA)
J-B. Ricco (France)
J Arcelus (Spain)
EA Hussein (Egypt)
N Rich (USA)
N Baekgaard (Denmark)
O Iqbal (USA)
P Robless (Singapore)
G Belcaro (Italy)
K Ivancev (Russia)
W Schobersberger (Austria)
H Bjarnason (USA)
R Kistner (USA)
M Seed (UK)
MA Cairols (Spain)
TK Kim (Korea)
S Schellong (Germany)
M Catalano (Italy)
M Kurtoglou (Turkey)
A Scuderi (Brazil)
D Christopoulos (Greece)
T Kölbel (Germany)
R Sexana (India)
D Clement (Belgium)
N Labropoulos (USA)
E Shaydakov (Russia)
F Corvalán (Chile)
LH Lee (Singapore)
A Shevela (Russia)
E Diamantopoulos (Greece)
BB Lee (USA)
R Simkin (Argentina)
J Fernandes e Fernandes
(Portugal)
Y-J Li (China)
W Toff (UK)
NC Liew (Malaysia)
JM Trabal (Puerto Rico)
C Fisher (Australia)
A Llinas (Colombia)
A Gasparis (USA)
M Nakamura (Japan)
M Vandendriessche
(Belgium)
H Gibbs (Australia)
P Neglen (Cyprus)
M Veller (South Africa)
V Hadjianastassiou (Cyprus)
L Norgren (Sweden)
L Villavincencio (USA)
K Ivancev (UK)
H Partsch (Austria)
R Wahi (USA)
CP Hsien (Thaiwan)
N Ramakrishnan (India)
C Wittens (TheNetherlands)
JT Hobbs (UK)
G Rao (USA)
R Wong (Hong Kong)
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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
21
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.
22
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).
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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
24
Recommendations
Low risk patients (minor general surgery, no risk
factors)
Graduated elastic compression
Avoid dehydration
Level of evidence (LE): low (extrapolation from moderate risk)
25
Effect of GEC
(8 studies: moderate risk general surgery)
25
20
68% Reduction
in DVT
Incidence
15
DVT (%)
10
p < 0.001
5
0
Control (n=637)
GEC (n=653)
Groups
26
Effect of LDUH: 32 Studies in General Surgery
25
68% Reduction
in DVT
Incidence
20
15
DVT (%)
10
p < 0.001
5
0
Control (n=2567)
LDUH (n=2655)
Groups
27
LMWH vs Placebo in General Surgery (1 study)
16
74% Reduction
in DVT
Incidence
14
12
10
DVT (%) 8
6
p < 0.025
4
2
0
Placebo (n = 91)
LMWH (n = 92)
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LMWH vs LDUH in General Surgery (17 Studies)
7
21% Reduction
in DVT
Incidence
6
5
DVT (%)
4
3
2
p < 0.025
1
0
LDUH (n = 3411)
LMWH (n = 3467)
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LMWH vs LDUH in General Surgery (14 Studies)
0.7
56% Reduction
in PE Incidence
0.6
0.5
PE (%)
0.4
0.3
p < 0.001
0.2
0.1
0
LDUH (n = 2644) LMWH (n = 2798)
30
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
31
Effect of IPC in General Surgery (11 studies)
30
69% Reduction
in DVT
Incidence
25
20
DVT (%) 15
10
p < 0.001
5
0
Control (n = 658)
IPC (n=660)
32
Recommendations
Moderate risk patients (major general surgery,
age >40, no additional risk factors)
(LDUH) or LMWH
LE: high
IPC + GEC
LE: high
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Fondaparinux (Arixtra) in prevention of VTE
in General Surgery (n= 2858)
Relative Risk Reduction= 25%
p = 0.14
7
% VTE
6
5
6.1%
4
3
2
4.6%
62/1021
47/1027
1
0
Fondaparinux
(Arixtra)
Dalteparin
British Journal of Surgery 2005, G Agnelli et al 34
Cancer Surgery (n= 1941)
Relative Risk Reduction= 39%
9
(95 %CI : 59.6; 6.7%)
p = 0.02
8
% VTE
7
6
5
7.7%
4
55/712
3
4.7%
2
33/696
1
0
Fondaparinux
(ARIXTRA)
Dalteparin
British Journal of Surgery 2005, G Agnelli et al35
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
36
Orthopedics
37
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)
38
Efficacy of Fondaparinux vs Enoxaparin
Fondaparinux
better
Hip replacement
n=3,411 (2 studies)
Enoxaparin
better
-45.3%
Hip fracture
n=1,250
[-58.9; -27.4]
-61.6%
Knee replacement
n=724
[-73.4; -45.0]
[-75.5; -44.8]
-63.1%
Overall odds
reduction
p=10-17
-55.2%
-100
Homogeneity test: ns
-80
-60
95% CI
-40
-20
0
20
40
[-63.1; -45.8]
60
80
100
Odds reduction (%)
39
Turpie et al. Arch Intern Med 2002;162:1833-40
New Oral Anticoagulants
40
Site
Actions
Conventional
and
Newer
Oral
Anticoagulants
Figure 1: Site
of of
Actions
forfor
Conventional
and
Newer
Oral
Anticoagulants
Factor IX
Factor VII
FVIIa
FIXa
Factor X
VKA drugs
Anti-Xa drugs
Warfarin
Apixaban
Betrixaban
Edoxaban
Rivaroxaban
Factor Xa
Antithrombin
Anti-IIa drugs
Factor II
(Prothrombin)
Fibrinogen
Factor IIa
(Thrombin)
Dabigatran
Fibrin
41
42
Recommendations
for Elective Hip Replacement (2013)
Fondaparinux
LMWH
IPC + GEC
IPC+GEC+LMWH
Rivaroxaban, Dabigatran
LE: high (Most effective)
LE: high
LE: high (Equivalent to LMWH)
LE: high (More effective than either)
LE: high
Initiation
LMWH: before or after operation
LE: high
Fondaparinux: at least 6 hours after operation
43
Recommendations
Neurosurgery
IPC + GEC
LE: High
Acutely ill medical patients
(LDUH) or LMWH
LE: High
IPC + GEC
LE: Moderate
Fondaparinux
LE: Moderate
44
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 ?
Hull RD, et al. Ann Intern Med. 2001; 135:858-69.
D, et al. NEJM. 2002; 346:975-980.
3 Rasmussen MS, et al. J Thromb Haemost. 2006; 4:2384-2390.
1
2 Bergqvist
45
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
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
46
46
Enrolment per country
Germany
7.4%
U.K.
6.5%
Australia/NZ
4.6%
Canada Poland
4.0%
4.1%
South Africa
7.5%
Mexico
7.9%
Spain
3.7% Russia
3.1%
Colombia
2.8%
Italy
2.7%
Tunisia India
2.6% 2.2%
Brazil
Israel 1.6%
1.1%
France
8.7%
USA
28.2%
Austria
0.3%
Argentina
0.5%
Belgium
0.6%
47
Baseline: Primary enrolment diagnosis
Primary enrollment diagnosis
(%)
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
Enoxaparin
N = 2013
Placebo
N = 2027
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
48
Efficacy – all VTE until Day 90
Placebo
Enoxaparin
p = 0.0011
p = 0.0115
5.2
4.9
RRR
RRR
- 42%
Incidence (%)
- 44%
3.0
2.8
Day 38
Day 90
49
Safety – Bleeding
Placebo
Enoxaparin
Incidence (%)
p = 0.007
p=
0.019
p = 0.024
5.70
5.20
3.80
3.70
0.15
Total Bleeding
0.60
Major Bleeding
Minor Bleeding
50
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
51
Combined Modalities
52
IPC + Heparin vs IPC or Anticoagulant alone (DVT)
(14 Studies)
TOTAL
Combined
IPC or Anticoag.
63/3074
200/3238
2.05%
6.18%
OR 0.31 (95% CI 0.23 to 0.43)
or
p < 0.001
69% reduction
Kakkos S et al Cochrane Database Syst Rev 2008:CD005258
53
IPC + Heparin vs IPC or Anticoagulant
(Symptomatic PE) ( 16 Studies)
TOTAL
Combined
IPC or Anticoag.
33/3838
122/4313
0.86%
2.83%
OR 0.34 (95% CI 0.23 to 0.50)
or
p < 0.001
67% reduction
Kakkos S et al Cochrane Database Syst Rev 2008:CD005258
54
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)
55