Prophylaxis and Treatment of Thrombosis in cancer

Iman Supandiman Departement of Internal Medicine Division of Hematology Medical Oncology Hasan Sadikin Hospital /Faculty of Medicine, Padjajaran University

THROMBOSIS

Formation and propagation of a blood clot within the vasculature in vivo

INTERACTION :

BLOOD VESSEL PLATELET COAGULATION FACTOR

OCCLUSION

BLOOD CLOT
FIBRINOLYSIS THROMBOEMBOLISM

Most hospitalised adults have multiple risk factors for VTE1,2

Advancing age
Immobilisation Cord injury Heart or lung failure Hyperviscosity Obesity Stroke

Surgery
Prior DVT Venous access Trauma Sepsis Vasculitis

Virchows triad
Circulatory stasis

Cancer
Oestrogen use Family history Sepsis Heparin-induced thrombocytopenia
2.

Protein C, S or ATIII deficiency

Activated protein C resistance Hyperhomocysteinaemia Antiphospholipid antibody
1. Adapted from Kyrie PA. Lancet 2005;365:1163-74. Adapted from Anderson FA, Spencer FA. Circulation 2003;107:I9-

Thrombosis :
Arterial : Vessel wall Venous : - Stasis - Hypercoagulation

Thrombosis in cancer
Patient with cancer is in hypercoagulable state - Cancer : F VII - Therapy : Hormonal therapy - Immobility

 Trombosis in cancer
- Common - Complex - Costly - Underdiagnose - Undertreatment

Cancer Patients
DVT/PE is the second leading cause of death in patients with overt malignant disease
The incidence of cancer-associated VTE is rising Cancer patients is with acut VTE are at increased risk of its recurrence compared with non cancer patients Cancer are also are at increased risk of anticoagulant associated bleeding compared with noncancer patients

Risk of Inpatient VTE by Site of Cancer

14 12 10

Rate (%)

8 6 4 2 0

Khorana et al. J Clin Oncol. 2006;24:484-490.

Incidence of thrombosis in early-stage breast cancer

Study Node Negative Fisher et al. Fisher et al. Node Positive Levine et al. Pritchard et al. Clahsen et al. Rivkin et al. CMFVP CMFVP + AT CMF + T T Perioperative FAC No Rx CMFVP + T CMFVP T ACT T CMFVP CMF 102 103 353 352 1292 1332 303 300 295 383 367 143 144 8.8 4.9 9.6 1.4 2.1 0.8 3.6 1.3 0 3.1 1.6 6.3 3.5 T Placebo CMFT T 1318 1326 768 771 0.9 0.15 4.2 0.8 Treatment Number of Patients % of Patients with thrombosis

Fisher et al. Weiss et al.

A, adriamycin; C, cyclophosphamide; F, fluorouracil; M, methotrexate; P, prednisone; T, tamoxifen; V, vincristine; FAC, fluorouracil

Deep Vein Thrombosis/Pulmonary Embolism (DVT/PE) and Cancer

Cancer patients exhibit a risk of recurrent DVT/PE that is approximately twice as high as that observed in patients without cancer3

3. Prandoni. Cancer Treat Rev. 2002;28:133-136. .

RISK OF RECURRENT VTE AND BLEEDING

UFH / LMWH + at least 3 month Warfarin

Non Cancer
VTE BLEEDING 9.0/100 patient/years 2.1/100 patient/years

Cancer
21.1/100 patient/years 13.3/100 patient/years

P
0.003 0.002

Hutten: JCUN ONCOL 2000,18.3078-3083

Pathogenesis bleeding and thrombosis in cancer Tumor cell

Cytokine IL-1, TNF, VEGF

Platelet activation

Cell-cell interpretation

compression

TF

Cancer procoagulant

Sticky Platelet

stasis endothelial cell

Coagulation activation

Platelet aggregation

Endothelial pertubation

Hypercoagulable state

Thrombosis
Deficiencies factors DIC Post necrotic Thrombocytopenia

Bleeding

Why is VTE prophylaxis underused or misused?

Perceived low risk of VTE Difficulty with assessing risk level of patients Uncertainty about efficacy, dosage, and LMWH specificities Fear of bleeding Most clinician see only a few cases of extensive VTE each year Clinically silent thrombosis

Prophylaxis of VTE in medical patients

RR of DVT in studies comparing heparins with no treatment
Heparins better
Surgery General medicine Stroke Acute MI

Heparins worse
n = 12,550 RR = 0.43 (95% CI, 0.370.50) n = 845 n = 791 n = 659 RR = 0.44 (95% CI, 0.290.64) RR = 0.43 (95% CI, 0.260.73) RR = 0.32 (95% CI, 0.200.61)

0
MI = myocardial infarction.

0.5

1.5

VTE prophylaxis in medical patients: heparins (UFH and LMWH) vs control

Heparins better
DVT

Control better
5 trials, N = 845, p < 0.001 6 trials, N = 14,483, p < 0.001

PE

Death Major haemorrhage

4 trials, N = 14,658, p = NS 6 trials, N = 12,603, p = NS

0.5

2.0 2.5 1.5 Relative risk

3.0

3.5

4.0

Adapted from Mismetti P, et al. Thromb Haemost. 2000;83:14-9.

Efficacious and safe thromboprophylaxis of medical patients: LMWH vs placebo

Study
MEDENOX1
p < 0.001

Prophylaxis
Placebo Enoxaparin 40 mg Placebo Dalteparin 5,000 IU Placebo

Patients with VTE, %

14.9* (n = 288) 5.5 (n = 291)

RRR 63%

NNT 10

PREVENT2
p = 0.0015

5.0 (n = 1,473) 2.8 (n = 1,518) 10.5 (n = 323) 5.6 (n = 321)

45%

45

ARTEMIS3
p = 0.029

47%

20

Fondaparinux 2.5 mg

*VTE at day 14; VTE at day 21; VTE at day 15.

1Samama 2Leizorovicz

MM, et al. N Engl J Med. 1999;341:793-800. A, et al. Circulation. 2004;110:874-9. 3Cohen AT, et al. BMJ. 2006;332:325-9.

Cochrane Review of VTE prophylaxis UFH vs LMWH: major bleed

Study
Harenberg, 1990

LMWH (n/N)
0/84

UFH (n/N)
1/82

RR (95% CI fixed)
0.33 (0.017.88)

Aquino, 1990
Forette, 1995 Lechler, 1996 EMSG, 1996 HEIM, 1996 Kleber, 1998 Total

0/49
0/146 2/477 2/216 5/810 1/332 10/2,114

2/50
4/149 9/482 4/223 4/780 1/333 25/2,099 0.001 0.02 Favours LMWH

0.20 (0.014.14)
0.11 (0.014.14) 0.22 (0.051.03) 0.52 (0.102.79) 1.20 (0.324.47) 1.00 (0.0615.97) 0.43 (0.220.87) 50 1,000 Favours UFH

Test for heterogeneity: chi-square = 4.52, df = 6, p = 0.61 Test for overall effect: z = 2.37, p = 0.02 Alikhan R, Cohen AT. Cochrane Review 2002.

2006 National Comprehensive Cancer Network (NCCN) Guidelines for DVT Prophylaxis and Treatment
Anticoagulation therapy
Unfractionated heparin (UFH)*
*

Anticoagulation therapy (immediate)

Low-molecular-weight heparin

5000 U q8h SCQ (not q12h)

(LMWH)

Low-molecular-weight heparin (LMWH) Enoxaparin 40 mg daily

Dalteparin 5000 U daily x 10d

Enoxaparin

Dalteparin

Tinzaparin

Unfractionated heparin

Tinzaperin 4500 U (fixed dose) SC daily or 75 U/kg SC daily

Pentasaccharide Fondaparinux

Pentasaccharide Fondaparinux 2.5 mg SC daily

*NCCN notes that a section should be added on heparin-induced thrombocytopenia (HIT). NCCN Practice Guidelines in Oncology v.12006

MEDENOX Study

Prevention of VTE in stage IV breast cancer

Thrombosis (%)

Dosage: warfarin 1 mg daily for the first 6 weeks followed by INRadjusted doses (INR 1.31.9) Primary endpoint: symptomatic, objectively confirmed thromboembolic events Patients: n = 311 Results: RRR of 85% in favour of warfarin (7 vs 1 events, p = 0.03) without increase in bleeding

5
4 3 2 1 0

4.4%

p = 0.03

0.7%

Placebo

Warfarin

Levine M, et al. Lancet. 1994;343:886-9.

Thromboprophylaxis in surgery
Low-molecular-weight heparin
16

14.9% P=0.001 8.5%

LMWH Dalteparin 2500 vs 5000 units once daily Therapy commenced pre-operatively 2097 patients 65% malignancy

14

Rate of DVT

12

10
8 6 4 2 0

2500 IU Bleeding complications

3.6%

5000 IU
4.6%

P=NS

Bergqvist et al, Br J Surg 1995

Efficacy and Safety of Enoxaparin Versus Unfractionated Heparin for Prevention of Deep Vein Thrombosis in Elective Cancer Surgery: A DoubleBlind Randomized Multicentre Trial With Venographic Assessment

ENOXACAN Study Group Br J Surg 1997;84:1099-1103

Study objective
To compare the effect of enoxaparin 40 mg once daily, started two hours before surgery, with low-dose unfractionated heparin three times a day, for thromboprophylaxis in patients undergoing planned curative abdominal or pelvic surgery for cancer

ENOXACAN Study Group Br J Surg 1997;84:1099-1103

Study design
UFH 5000 IU s.c. Surgery

UFH 5000 IU t.i.d. s.c.

Venography Day 10 2

3-month follow-up

Randomization

Enoxaparin 40 mg s.c.

Surgery

Enoxaparin 40 mg o.d. s.c.

Venography Day 10 2

3-month follow-up

2 hours before surgery

ENOXACAN Study Group Br J Surg 1997;84:1099-1103

Venous thromboembolism in evaluable patients

UFH (n=319) Enoxaparin (n=312)

DVT only
PE + DVT* Death Total

56(17.6)
2(0.6) 0(0) 58(18.2)

45(14.4)
0(0) 1(0.3) 46(14.7)

Values in parentheses are percentages. *Scintigraphic verification (high probability). Considered thromboembolic. 95% confidence interval of the difference -9.22.3. There was no significant difference between the two groups.
DVT, deep-vein thrombosis; PE, pulmonary embolism

ENOXACAN Study Group Br J Surg 1997;84:1099-1103

Deep-vein thrombosis in evaluable patients

60 Number of patients 50 40 30 20 10
3 6 42 57 51 45

Enoxaparin UFH

0
Distal Proximal Total There was no significant difference between the enoxaparin and UFH groups regarding the number of distal, proximal and total DVTs.
UFH, unfractionated heparin; DVT, deep-vein thrombosis

ENOXACAN Study Group Br J Surg 1997;84:1099-1103

Safety data in 1115 treated patients

Incidence of haemorrhage was similar in both groups
UFH (n=560) n (%) Major bleeding Minor bleeding Discontinuation of prophylaxis Injection-site haematoma 16 (2.9) 80 (14.3) 12 (2.1) 11 (2.0) Enoxaparin (n=555) n (%) 23 (4.1) 81 (14.6) 18 (3.2) 6 (1.1)

There was no significant difference between the two groups.

ENOXACAN Study Group Br J Surg 1997;84:1099-1103

Conclusions of Enoxacan
Enoxaparin 40 mg once daily is at least as effective and safe as UFH 5000 IU three times a day in preventing postoperative thromboembolism in patients undergoing abdominal or pelvic surgery for malignant disease Enoxaparin has a comparable safety profile to UFH
UFH, unfractionated heparin

ENOXACAN Study Group Br J Surg 1997;84:1099-1103

ENOXACAN II

Duration of Prophylaxis Against Venous Thromboembolism with Enoxaparin after Surgery for Cancer
Bergqvist D et al. N Engl J Med 2002;346:975980

Study Design
Enrolment (n=613) Enoxaparin (n=609) 40 mg o.d. for 610 days
Enoxaparin (n=253) 40 mg o.d. for up to 21 days Placebo (n=248) for up to 21 days
Open-label phase

Double-blind phase

Bilateral venography at 2531 days Enoxaparin (n=165) Placebo (n=167)

Clinical follow-up at 3 months

Prolonged thromboprophylaxis after cancer operations

Enoxaparin 40 mg o.d. (n = 332)1 20 Total DVT (%) 15 12.0 10 5 0 1 week 4 weeks
1Bergqvist 2Rasmussen

Dalteparin 5,000 IU o.d. (n = 343)2 20 Total DVT (%)

p = 0. 012
16.3

p = 0.02

15
29/178

20/167

10 5 0 1 week

7.3
12/165

4.8
8/165

4 weeks

D, et al. N Engl J Med. 2002;346:975-80. MS, et al. J Thromb Haemost. 2006;4:2384-90.

Conclusions of Enoxacan II
Thromboprophylaxis with enoxaparin for 4 weeks after abdominal surgery for cancer reduced the risk of VTE by 60% compared with prophylaxis for 1 week only This benefit was achieved without an increase in the incidence of haemorrhagic complications The reduction of VTE risk associated with prolonged thromboprophylaxis persisted at 3-month follow-up

Treatment VTE with antocoagulant in Cancer

Three times higher The overall incidence of recurent VTE The Major Bleeding

6,5 times higher among those with malignancy

Treatment VTE with anticoagulant in Cancer

In patient with malignancy The incidence of recurent VTE was 2,8 times highes what were not adequantely anticoagulated

Clot Trial : multicenter, international,

randomized clinical trial

Dalteparin 200 I./kg/day (1mo) : - 150 I. (5mo) - Warfarin (INR 2,0 -3,0) (6mo) 672 patient with cancer + acute symptomatic VTE

9% VTE 17% VTE

Take Home Message

 VTE in cancer : - common - complex - underdiagnose - undertreatment

DVT/PE : cancer patient exhibit a risk of recurent DVT/PE that is approximathy force as high as that observed in patients without cancer

 Prophylaxis of VTE in cancer reduced morbiduty and mortality heparin /LmwH has the same eficacy and risk of major bleeding Treatment of VTE with anticoagulant in cancer : - Warfarin 17%VTE -Dalteparin 9% VTE