Prevention Of Venous
Thromboembolism In The
Cancer Surgical Patient
A K Kakkar
Barts and the London School of Medicine and
Thrombosis Research Institute, London UK
Incidence Of VTE In Cancer Surgical Patients
VTE no malignancy
(%)
VTE malignancy
(%)*
Neurosurgery
0.5–2.3
2.0–3.6
Head and neck
0.1–0.2
0.2–1.4
Gastrointestinal
0.2–1.6
0.9–2.6
Urological
0.3–1.0
0.4–3.7
0.3
1.2–2.3
0.2–2.4
0.9–3.1
Surgical procedure
Gynaecological
Orthopaedic
*Symptomatic VTE at 91 days in patients after surgery.
Adapted from White et al. Thromb Haemost. 2003;90:446-55.
Impact Of Cancer On PE Frequency
Cancer
No Cancer
OR
Surgical (%)
2.34
0.36
6.7
Non surgical (%)
0.73
0.10
7.3
Total
1.84
0.27
6.8
Adapted from Huber et al. Arch Surg 1992;127:310-3.
Prognostic Risk Factors For VTE In Cancer
Variable
Age
Previous
VTE
Anaesthesia
Stage
Bedrest
No. of patients
VTE / non-VTE
Effect
≥ 60 yrs: 42 / 1,516
≥ 60 vs < 60
years
< 60 yrs: 8 / 807
Yes: 5 / 36
Yes vs no
≥ 2 vs < 2 hours
Advanced vs
No: 45 / 2,287
≥ 2 hours: 48 / 1,762
< 2 hours: 2 / 561
OR
95 % CI
2.6
1.2–5.7
6.0
2.1–16.8
4.5
1.1–19.0
2.7
1.4–5.2
4.4
2.5–7.8
Advanced: 38 / 1,078
not advanced
≥ 4 vs < 4 days
Adapted from Agnelli et al. Ann Surg 2006; 243:89-95.
Non advanced: 12 /
1,245
≥ 4 days: 25 / 346
< 4 days: 25 / 1,977
Prophylaxis Against Fatal 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 postoperatively
for 7 days)
 180 patients died during the postoperative period: 100 in
the control group and 80 in the UFH group
 Rate of autopsy was 72 % in control group and 66% in
the heparin group
Adapted from Kakkar et al. Lancet 1975;2:45-51.
Prophylaxis Against Fatal PE With Low-dose UFH
P<0.005
18
16
Number of patients
with fatal PE
16
14
12
10
8
6
4
2
2
0
Control
Adapted from Kakkar et al., Lancet 1975;2:45-51.
UFH
Fatal Post-operative PE In Patients With Cancer

Patients with PE, %
23% (n = 953) underwent operation with malignant disease
Adapted from Kakkar et al. Lancet 1975;2:45-51.
Heparin Prevents Death After Surgery
 21% reduction in total surgical mortality
 68% reduction in fatal PE
 67% reduction in asymptomatic DVT
Reduction in fatal pulmonary embolism and venous thrombosis
by perioperative administration of subcutaneous heparin
Adapted from Collins et al. New Engl J Med 1988;318:1162-73.
Death From PE But Not From Bleeding
“Other” deaths
PE
191 (3.0%)
(1.7%) 109
Fatal
bleeds
(0.9%)
(0.3%)
7
Adapted from Collins et al. N Engl J Med 1988;318:1162-73.
6
Low Dose vs. LMW Heparin
Canadian Colorectal DVT Prophylaxis Trial
Incidence of Outcome Event
16.9%
P=0.05
N=234
13.9%
N=241
1.5% 2.7%
N=653
N=643
VTE
(Cancer)
Adapted from McLeod et al. Ann Surg 2001;233:438-44.
Major Bleeding
(All)
Thromboprophylaxis In Cancer Surgery
P=0.001
 LMWH once daily
– Dalteparin 2500 IU vs
5000 IU daily
– Total duration 7 days
 Therapy commenced
preoperatively
DVT in Patients With
Malignancy (%)
 Prospective, randomized, doubleblind multicenter trial
 2070 patients randomized
 67% (1303/1957) malignancy
Bleeding complications in patients operated on for malignant disease occurred in
3.6% of those receiving dalteparin 2500 IU and
4.6% of those receiving dalteparin 5000 IU (P=NS).
Adapted from Bergqvist et al. Br J Surg. 1995;82:496-501.
Thromboprophylaxis In The Cancer Surgical Patient
LMWH better
UFH better
Asymptomatic DVT
Clinical PE
Clinical thromboembolism
Cancer
Death
Non-cancer
Major hemorrhage
Total hemorrhage
Wound hematoma
Transfusion
0
Adapted from Mismetti et al. Br J Surg 2001;88:913–30.
1.0
2.0
3.0
4.0
Effects Of Compression Methods of
Thromboprophylaxis On DVT
Category
(a)
No. of
Deep venous
trials
thrombosis
with data Compression Control
Compression (monotherapy)
Graduated
9
compression stockings
Intermittent
19
pneumatic compression
Footpump
2
30
99% or
57/665
(8.6%)
112/1108
(10.1%)
11/61
(18.0%)
180/1834
(9.8%)
95% confidence intervals
133/627
(21.2%)
268/1147
(23.4%)
34/65
(52.3%)
Stratified
statistics
O–E Variance
Odds ratio and
confidence interval
(compression : control)
% odds
reduction
(SE)
–39.7
37.2
66% (10)
–76.3
71.0
66% (7)
–10.7
7.3
77% (19)
435/1839 –126.7 115.5
(23.7%)
67% (6)
2p < 0.00001
0.0
0.5
1.0
Compression
better
1.5
Compression
worse
Treatment effect 2p < 0.00001
Adapted from Roderick et al. Health Technology Assessment 2005; Vol. 9: No. 49.
2.0
Effects Of Compression Methods of
Thromboprophylaxis On PE
Category
No. of
Deep venous
trials
thrombosis
with data Compression Control
(a) Compression (monotherapy)
Graduated
3
compression stockings
Intermittent
8
pneumatic compression(2.4%)
Footpump
1
12
99% or
0/123
(0.0%)
14/590
(2.9%)
0/28
(0.0%)
4/90
(4.4%)
18/618
14/741
(1.9%)
22/740
(3.0%)
95% confidence intervals
Stratified
statistics
O–E Variance
–1.8
0.9
–1.6
7.6
–3.4
8.5
Odds ratio and
confidence interval
(compression : control)
% odds
reduction
(SE)
0/32
(0.0%)
0.0
33% (28)
2p > 0.1; NS
0.5
1.0
1.5
Compression
Compression
better
worse
Treatment effect 2p = 0.006
Adapted from Roderick et al. Health Technology Assessment 2005; Vol. 9: No. 49.
2.0
Combined Mechanical and
Pharmacological Prophylaxis
Intervention
6 studies
LDH
(n=451)
LDH+GCS
(n=439)
RR
(95%CI)
DVT n (%)
83 (18)
35 (%)
0.47
0.33-0.69
Adapted from IUA Consensus statement Int Angiol 2006.
Prevention Of Fatal PE In Surgical Patients
P=NS
Low-dose
heparin t.i.d.
Adapted from Haas et al. Thromb Haem. 2005;94:814-9.
LMWH o.d.
Cancer Patients Are At Higher Risk For PE
Surgical Population
All Patients*
Cancer
(n=6,124)
No Cancer
(n=16,954)
P
Value
Death (%)
192 (3.1)
120 (0.7)
0.0001
Fatal PE (%)
20 (0.33)
15 (0.09)
0.0001
Nonfatal PE (%)
5 (0.08)
4 (0.02)
*Receiving UFH or LMWH.
Adapted from Kakkar et al. Thromb Haemost. 2005;94:867-71.
PE Occurs After Hospital Discharge
In-hospital PE (n=80)
After-discharge PE (n=24)
0
4
8
12
16
Adapted from Huber et al. Arch Surg 1992;127:310-3.
20
24
28
32
36 Days
ENOXACAN II: Design
7 Days
Enoxaparin
(40mg sc od)*
®
21 Days
Enoxaparin (40mg sc od)
n= 165
Placebo
n=167
Major abdominal
surgery
* Pre-op dose
Adapted from Bergqvist et al., New Engl J Med 2002;346:97580.
Bilateral venography
ENOXACAN II: Results
 332 patients undergoing surgery for
abdominal or pelvic tumours
received enoxaparin (40 mg daily)
for 1 week followed by enoxaparin or
placebo for another 21 days
 Venography was performed at 30day and 3-month follow-up
 At each follow-up, prolonged TP was
associated with a 60% risk reduction
for DVT
20
RRR, 60%;
P=0.02
15
13.8%
12.0%
10
5
4.8%
5.5%
0
Day 30
3 month
Follow-up
Placebo
(n=167)
Adapted from Bergqvist et al., N Engl J Med 2002;346:97580.
RRR, 60%;
P=0.01
Enoxaparin
(n=165)
FAME: Design
7 Days
®
Dalteparin
(5000 IU sc od)*
+ TED
21 Days
Dalteparin (5000 IU sc od)
No further prophylaxis
Major abdominal
surgery
*Pre-Op dose
TED: graduated compression stockings
Adapted from Rasmussen et al., J Thromb Haemost 2006 4: 2384–90.
Bilateral venography
(assessor-blinded)
FAME: Results
 The ITT population consisted of
178 patients in the short-term
prophylaxis group and 165 in the
prolonged prophylaxis group
 Venography was performed
on day 28
 Prolonged TP was associated
with a 55% risk reduction for
VTE and 77% risk reduction for
proximal DVT
RRR, 55%
P=0.012
20
RRR, 77%;
P=0.009
16.3%
15
8.0%
10
7.3%
5
1.8%
0
VTE
Proximal DVT
Dalteparin
4 weeks
1 week
Adapted from Rasmussen et al., J Thromb Haemost 2006 4: 2384–90.
Extended Thromboprophylaxis:
Meta Analysis
 4 studies: 2 double-blind and 2 open
 1,037 patients
 Bilateral venography
7–10 days
DVT
15%
4–5 weeks
p
6.5%
< 0.0005
< 0.01
Proximal DVT
5%
1%
Symptomatic DVT
1%
0.3%
Adapted from Rasmussen et al. J Thromb Haemost 2005; 3 Suppl 1:P2213.
0.27
ESMO Clinical Recommendations
Should Patients With Cancer Undergoing
Surgery Receive Thromboprophylaxis?
1. Prophylaxis with LMWH (3400 - 5000 U once daily) or
UFH (5000 U three times daily) is recommended. [I, A]*.
2. Cancer patients undergoing elective major abdominal or
pelvic surgery should receive post-discharge prophylaxis
with LMWH for up to 1 month after surgery [I, A]*.
* Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American
Society of Clinical Oncology.
ASCO VTE Guideline
Should Patients With Cancer Undergoing
Surgery Receive Thromboprophylaxis?
1. All patients undergoing major surgical intervention for cancer
should be considered for thromboprophylaxis.
2. Patients undergoing laparotomy, laparoscopy, thoracotomy
lasting greater than 30 minutes should receive
pharmacological thromboprophylaxis with UFH or LMWH
unless contraindicated.
3. Commenced preoperatively.
ASCO VTE Guideline
Should Patients With Cancer Undergoing Surgery
Receive Thromboprophylaxis?
4. Mechanical methods may be added to pharmacological methods but
should not be used as monotherapy for VTE prevention unless
pharmacological methods are contraindicated because of active
bleeding
5. Combined pharmacological and mechanical prophylaxis may improve
efficacy especially in the highest risk patients
6. Prophylaxis should be continued for at least 7 - 10 days postoperatively.
Prolonged prophylaxis for up to 4 weeks after major abdominal and
pelvic surgery in patients with high risk features such as residual
disease, obesity, and previous history of VTE
Conclusions
 VTE common after cancer surgery.
 Prophylaxis with LMWH effective and safe.
 Extended prophylaxis should be considered for highest
risk populations.