Prevention Of Venous Thromboembolism In The Cancer Surgical Patient A K Kakkar Barts and the London...
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Prevention Of Venous Thromboembolism In The Cancer Surgical Patient
Prevention Of Venous Thromboembolism In The Cancer Surgical Patient
A K Kakkar
Barts and the London School of Medicine andThrombosis Research Institute, London UK
Incidence Of VTE In Cancer Surgical Patients Incidence Of VTE In Cancer Surgical Patients
Surgical procedureVTE 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
Gynaecological 0.3 1.2–2.3
Orthopaedic 0.2–2.4 0.9–3.1
Adapted from White et al. Thromb Haemost. 2003;90:446-55.
*Symptomatic VTE at 91 days in patients after surgery.
Impact Of Cancer On PE Frequency Impact Of Cancer On PE Frequency
Adapted from Huber et al. Arch Surg 1992;127:310-3.
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
Prognostic Risk Factors For VTE In CancerPrognostic Risk Factors For VTE In Cancer
Variable EffectNo. of patients VTE / non-VTE
OR 95 % CI
Age ≥ 60 vs < 60
years
≥ 60 yrs: 42 / 1,516
< 60 yrs: 8 / 8072.6 1.2–5.7
Previous VTE
Yes vs noYes: 5 / 36
No: 45 / 2,2876.0 2.1–16.8
Anaesthesia ≥ 2 vs < 2 hours≥ 2 hours: 48 / 1,762
< 2 hours: 2 / 5614.5 1.1–19.0
StageAdvanced vs
not advanced
Advanced: 38 / 1,078
Non advanced: 12 / 1,245
2.7 1.4–5.2
Bedrest ≥ 4 vs < 4 days≥ 4 days: 25 / 346
< 4 days: 25 / 1,9774.4 2.5–7.8
Adapted from Agnelli et al. Ann Surg 2006; 243:89-95.
Prophylaxis Against Fatal PE With Low-dose UFH 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 postoperativelyfor 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.
Num
ber
of p
atie
nts
with
fata
l PE
P<0.005
Prophylaxis Against Fatal PE With Low-dose UFH Prophylaxis Against Fatal PE With Low-dose UFH
16
2
0
2
4
6
8
10
12
14
16
18
Control UFH
Adapted from Kakkar et al., Lancet 1975;2:45-51.
Fatal Post-operative PE In Patients With CancerFatal Post-operative PE In Patients With CancerP
atie
nts
with
PE
, %
23% (n = 953) underwent operation with malignant disease
Adapted from Kakkar et al. Lancet 1975;2:45-51.
Heparin Prevents Death After SurgeryHeparin 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.
(1.7%) 109
(0.3%) 7
(0.9%)
191 (3.0%)
6
PE
Fatalbleeds
“Other” deaths
Death From PE But Not From BleedingDeath From PE But Not From Bleeding
Adapted from Collins et al. N Engl J Med 1988;318:1162-73.
Canadian Colorectal DVT Prophylaxis Trial
13.9%
1.5% 2.7%
16.9%N=234
N=241
Adapted from McLeod et al. Ann Surg 2001;233:438-44.
P=0.05
I
ncid
ence
of
Out
com
e E
vent
VTE Major Bleeding(Cancer) (All)
N=653
N=643
Low Dose vs. LMW Heparin
Thromboprophylaxis In Cancer Surgery Thromboprophylaxis In Cancer Surgery
Prospective, randomized, double-blind multicenter trial
LMWH once daily
– Dalteparin 2500 IU vs 5000 IU daily
– Total duration 7 days
Therapy commenced preoperatively
2070 patients randomized
67% (1303/1957) malignancy
P=0.001
Adapted from Bergqvist et al. Br J Surg. 1995;82:496-501.
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).
DVT
in P
atie
nts
With
Mal
igna
ncy
(%)
Adapted from Mismetti et al. Br J Surg 2001;88:913–30.
Clinical thromboembolism Cancer
0 1.0 2.0 3.0 4.0
Major hemorrhage
Asymptomatic DVT
Clinical PE
Death
Total hemorrhage
Wound hematoma
Transfusion
Non-cancer
LMWH better UFH better
Thromboprophylaxis In The Cancer Surgical PatientThromboprophylaxis In The Cancer Surgical Patient
(a) Compression (monotherapy)Graduated 9 57/665 133/627 –39.7 37.2
66% (10)compression stockings (8.6%) (21.2%)
Intermittent 19 112/1108 268/1147 –76.3 71.066% (7)pneumatic compression (10.1%) (23.4%)
Footpump 2 11/61 34/65 –10.7 7.377% (19)
(18.0%) (52.3%)
30 180/1834 435/1839 –126.7 115.567% (6)
(9.8%) (23.7%)2p < 0.00001
No. of Deep venous Stratified Odds ratio and % odds trials thrombosis statistics confidence intervalreductionCategory with data Compression Control O–E Variance (compression : control) (SE)
Effects Of Compression Methods of Thromboprophylaxis On DVT
99% or 95% confidence intervals 0.0 0.5 1.0 1.5 2.0
Compression Compressionbetter worse
Treatment effect 2p < 0.00001
Adapted from Roderick et al. Health Technology Assessment 2005; Vol. 9: No. 49.
(a) Compression (monotherapy)Graduated 3 0/123 4/90 –1.8 0.9
compression stockings (0.0%) (4.4%)Intermittent 8 14/590 18/618 –1.6 7.6
pneumatic compression(2.4%) (2.9%)Footpump 1 0/28 0/32
(0.0%) (0.0%)
12 14/741 22/740 –3.4 8.533% (28)
(1.9%) (3.0%)2p > 0.1; NS
No. of Deep venous Stratified Odds ratio and % odds trials thrombosis statistics confidence intervalreductionCategory with data Compression Control O–E Variance (compression : control) (SE)
Effects Of Compression Methods of Thromboprophylaxis On PE
99% or 95% confidence intervals 0.0 0.5 1.0 1.5 2.0
Compression Compressionbetter worse
Treatment effect 2p = 0.006
Adapted from Roderick et al. Health Technology Assessment 2005; Vol. 9: No. 49.
83 (18) 35 (%) 0.470.33-0.69
DVT n (%)
6 studiesLDH
(n=451)LDH+GCS
(n=439)RR
(95%CI)
Combined Mechanical and Pharmacological Prophylaxis Combined Mechanical and Pharmacological Prophylaxis
Intervention
Adapted from IUA Consensus statement Int Angiol 2006.
Prevention Of Fatal PE In Surgical PatientsPrevention Of Fatal PE In Surgical Patients
Adapted from Haas et al. Thromb Haem. 2005;94:814-9.
Low-dose heparin t.i.d.
LMWH o.d.
P=NS
192 (3.1)
20 (0.33)
5 (0.08)
120 (0.7)
15 (0.09)
4 (0.02)
0.0001
0.0001
Death (%)
Fatal PE (%)
Nonfatal PE (%)
All Patients*Cancer
(n=6,124)No Cancer(n=16,954)
P Value
Cancer Patients Are At Higher Risk For PE Cancer Patients Are At Higher Risk For PE
Adapted from Kakkar et al. Thromb Haemost. 2005;94:867-71.
*Receiving UFH or LMWH.
Surgical Population
PE Occurs After Hospital DischargePE Occurs After Hospital Discharge
Adapted from Huber et al. Arch Surg 1992;127:310-3.
Days0 4 8 12 16 20 24 28 32 36
In-hospital PE (n=80)
After-discharge PE (n=24)
ENOXACAN II: DesignENOXACAN II: Design
Bilateral venography
Major abdominal surgery
7 Days 21 Days
Enoxaparin(40mg sc od)*
Enoxaparin (40mg sc od)
n= 165
Placebo
n=167
®
Adapted from Bergqvist et al., New Engl J Med 2002;346:97580.
* Pre-op dose
Placebo (n=167)
Enoxaparin (n=165)
0
5
10
15
20
Inci
den
ce
of
DV
T (
% p
atie
nts
)
12.0%
4.8%
13.8%
5.5%
RRR, 60%;P=0.02
RRR, 60%;P=0.01
3 monthDay 30Follow-up
ENOXACAN II: ResultsENOXACAN 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 30-day and 3-month follow-up
At each follow-up, prolonged TP was associated with a 60% risk reduction for DVT
Adapted from Bergqvist et al., N Engl J Med 2002;346:97580.
FAME: DesignFAME: Design
Major abdominal surgery Bilateral venography
(assessor-blinded)
7 Days 21 Days
Dalteparin(5000 IU sc od)* + TED
Dalteparin (5000 IU sc od)
No further prophylaxis
®
*Pre-Op dose TED: graduated compression stockings
Adapted from Rasmussen et al., J Thromb Haemost 2006 4: 2384–90.
FAME: ResultsFAME: 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
Dalteparin
1 week 4 weeks
0
5
10
15
20
Inci
den
ce (
% p
atie
nts
)
16.3%
7.3%
8.0%
1.8%
RRR, 55%P=0.012
RRR, 77%;P=0.009
Proximal DVTVTE
Adapted from Rasmussen et al., J Thromb Haemost 2006 4: 2384–90.
Extended Thromboprophylaxis: Meta Analysis Extended Thromboprophylaxis: Meta Analysis
4 studies: 2 double-blind and 2 open
1,037 patients
Bilateral venography
Adapted from Rasmussen et al. J Thromb Haemost 2005; 3 Suppl 1:P2213.
7–10 days 4–5 weeks p DVT 15% 6.5% < 0.0005
Proximal DVT 5% 1% < 0.01
Symptomatic DVT 1% 0.3% 0.27
ESMO Clinical RecommendationsESMO Clinical Recommendations
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.
Should Patients With Cancer Undergoing Surgery Receive Thromboprophylaxis?
ASCO VTE GuidelineASCO VTE Guideline
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.
Should Patients With Cancer Undergoing Surgery Receive Thromboprophylaxis?
Should Patients With Cancer Undergoing Surgery Receive Thromboprophylaxis?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
ASCO VTE Guideline