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

ConclusionsConclusions

VTE common after cancer surgery.

Prophylaxis with LMWH effective and safe.

Extended prophylaxis should be considered for highest risk populations.