3.prof.iman supandiman-prophylaxis and treatment thrombosis in cancer_new

7/30/2019 3.Prof.iman Supandiman-Prophylaxis and Treatment Thrombosis in Cancer_New

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Prophylaxis and Treatment ofThrombosis in cancer

Iman SupandimanDepartement of Internal Medicine

Division of Hematology Medical Oncology

Hasan Sadikin Hospital /Faculty of Medicine, Padjajaran University


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THROMBOSIS

Formation and propagation of a blood clotwithin the vasculature in vivo

INTERACTION :

BLOODVESSEL

PLATELETCOAGULATIONFACTOR

BLOOD CLOT

FIBRINOLYSIS

OCCLUSION

THROMBOEMBOLISM


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Virchows

triad

Circulatory stasis

Most hospitalised adults have multiple risk factors for

VTE1,2

1. Adapted from Kyrie PA. Lancet2005;365:1163-74.2. Adapted from Anderson FA, Spencer FA. Circulation 2003;107:I9-

Adv

ancing age

Immobilisation

Cord injury

Heart or lung failure

Hyperviscosity Obesity

Stroke

Surgery Prior DVT

Venous access

Trauma

Sepsis

Vasculitis

Protein C, S or ATIII deficiency Activated protein C resistance

Hyperhomocysteinaemia

Antiphospholipid antibody

Cancer Oestrogen use

Family history

Sepsis

Heparin-induced thrombocytopenia


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Thrombosis :

Arterial : Vessel wall

Venous : - Stasis

- Hypercoagulation


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Thrombosis in cancer

Patient with cancer is in hypercoagulable

state

- Cancer : F VII

- Therapy : Hormonal therapy

- Immobility


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Trombosis in cancer

- Common

- Complex

- Costly

- Underdiagnose

- Undertreatment


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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

i k f i b


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

0

2

4

6

8

10

12

14

Risk of Inpatient VTE by

Site of Cancer

Rate(%)

I id f h b i i l b


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Incidence of thrombosis in early-stage breast

cancer

Study Treatment Number of Patients % of Patients withthrombosis

Node Negative

Fisher et al.

Fisher et al.

T

Placebo

CMFT

T

1318

1326

768

771

0.9

0.15

4.2

0.8

Node Positive

Levine et al.

Pritchard et al.

Clahsen et al.

Rivkin et al.

Fisher et al.

Weiss 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

A, adriamycin; C, cyclophosphamide;

F, fluorouracil; M, methotrexate; P, prednisone;T, tamoxifen; V, vincristine; FAC, fluorouracil


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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. .


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Non Cancer Cancer P

VTE 9.0/100patient/years

21.1/100patient/years

0.003

BLEEDING 2.1/100

patient/years

13.3/100

patient/years

0.002

Hutten: JCUN ONCOL 2000,18.3078-3083

RISK OF RECURRENT VTE AND BLEEDING

UFH / LMWH + at least 3 month Warfarin


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Pathogenesis bleeding and thrombosis in cancer

Tumor cell

Platelet

activation

Cytokine

IL-1, TNF,

VEGF

Cell-cell

interpretationcompression TF Cancer

procoagulant

Sticky

Platelet

Platelet

aggregation

endothelial

cell

stasis

Coagulationactivation

Hypercoagulable

state

Thrombosis

DIC

Postnecrotic Bleeding

Deficiencies

factors

Thrombocytopenia

Endothelial

pertubation


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Why is VTE prophylaxis

underused or misused?

Perceived low risk of VTE

Difficulty with assessing risk level of patients

Uncertainty about efficacy, dosage, and LMWHspecificities

Fear of bleeding

Most clinician see only a few cases of extensive VTE each

year Clinically silent thrombosis


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Prophylaxis of VTE in

medical patients

RR = 0.43 (95% CI, 0.370.50)

RR of DVT in studies comparing heparins with no treatment

Surgery

General

medicine

Stroke

Acute MI

0 0.5 1 1.5

n = 12,550

n = 845 RR = 0.44 (95% CI, 0.290.64)

n = 791 RR = 0.43 (95% CI, 0.260.73)

n = 659 RR = 0.32 (95% CI, 0.200.61)

Heparins better Heparins worse

MI = myocardial infarction.


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VTE prophylaxis in medical patients:

heparins (UFH and LMWH) vs control

5 trials, N = 845, p< 0.001DVT

PE

Death

Major haemorrhage

Heparins better Control better

10.50 1.5 2.0 2.5 3.0 3.5

Relative risk

4 trials, N = 14,658, p= NS

6 trials, N = 12,603, p= NS

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

6 trials, N = 14,483, p < 0.001

4.0


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1Samama MM, et al. N Engl J Med. 1999;341:793-800.2Leizorovicz A, et al. Circulation. 2004;110:874-9.

3Cohen AT, et al. BMJ. 2006;332:325-9.

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

Study Prophylaxis Patients with VTE, % NNT

10

45

20

RRR

63%

45%

47%

MEDENOX1 Placebo

Enoxaparin 40 mg

PREVENT2 Placebo

Dalteparin 5,000 IU

ARTEMIS3

PlaceboFondaparinux 2.5 mg

p< 0.001

p = 0.0015

p = 0.029

14.9*(n = 288)

5

5.0 (n = 1,473)

2.8 (n = 1,518)

10.5

(n = 323)

5.6 (n = 321)

Efficacious and safe thromboprophylaxisof medical patients: LMWH vs placebo

.5 (n = 291)


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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.

Cochrane Review of VTE prophylaxis

UFH vs LMWH: major bleed

Study LMWH (n/N) UFH (n/N) RR (95% CI fixed)

Harenberg, 1990 0/84 1/82 0.33 (0.017.88)

Aquino, 1990 0/49 2/50 0.20 (0.014.14)

Forette, 1995 0/146 4/149 0.11 (0.014.14)

Lechler, 1996 2/477 9/482 0.22 (0.051.03)EMSG, 1996 2/216 4/223 0.52 (0.102.79)

HEIM, 1996 5/810 4/780 1.20 (0.324.47)

Kleber, 1998 1/332 1/333 1.00 (0.0615.97)

Total 10/2,114 25/2,099 0.43 (0.220.87)

0.001 0.02

Favours UFH

1,000

Favours LMWH

50

2006 N i l C h i C


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2006 National Comprehensive Cancer

Network (NCCN) Guidelines for DVT

Prophylaxis and Treatment

Anticoagulation therapy

Unfractionated heparin (UFH)*

* 5000 U q8h SCQ (not q12h)

*NCCN notes that a section should be added on heparin-induced thrombocytopenia (HIT).

NCCN Practice Guidelines in Oncology v.12006

Low-molecular-weight heparin

(LMWH)

Enoxaparin 40 mg daily

Dalteparin 5000 U daily x 10d

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

Anticoagulation therapy (immediate)

Low-molecular-weight heparin

(LMWH)

Dalteparin

Tinzaparin

Unfractionated heparin

Pentasaccharide

Fondaparinux

Enoxaparin

Pentasaccharide

Fondaparinux 2.5 mg SC daily


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MEDENOX Study


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Prevention of VTE in stage IV

breast cancer

Dosage: warfarin 1 mg daily for

the first 6 weeks followed by INR-

adjusted 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

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

Thrombosis

(%)

4.4%

0.7%

p = 0.03

Placebo Warfarin01

2

3

4

5


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Thromboprophylaxis in surgeryLow-molecular-weight hepar in

LMWH

Dalteparin 2500 vs 5000units once daily

Therapy commencedpre-operatively

2097 patients

65% malignancy

P=0.001

Bleeding complications 3.6% 4.6% P=NS

Bergqvist et al, Br J Surg1995

02

4

6

810

12

14

16

2500 IU 5000 IU

RateofD

VT

14.9%

8.5%


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Efficacy and Safety of Enoxaparin VersusUnfractionated Heparin for Prevention of Deep Vein

Thrombosis in Elective Cancer Surgery: A Double-Blind Randomized Multicentre Trial With VenographicAssessment

ENOXACAN Study Group Br J Surg1997;84:1099-1103


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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



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Study design


UFH

5000 IU s.c.

Enoxaparin

40 mg s.c.

Randomization

Surgery

Surgery

UFH

5000 IU

t.i.d. s.c.

Enoxaparin

40 mg

o.d. s.c.

Venography

Day 10 2

Venography

Day 10 2

2 hours before

surgery

3-month

follow-up

3-month

follow-up


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Venous thromboembolism

in evaluable patients


Values in parentheses are percentages. *Scintigraphicverification (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

UFH Enoxaparin

(n=319) (n=312)

DVT only 56(17.6) 45(14.4)PE + DVT* 2(0.6) 0(0)

Death 0(0) 1(0.3)

Total 58(18.2) 46(14.7)


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Deep-vein thrombosis

in evaluable patients


UFH, unfractionated heparin;

DVT, deep-vein thrombosis

Numberofp

atients

0

10

20

30

40

50

60

Distal Proximal Total

Enoxaparin

UFH

42

51

36

45

57

There was no significant difference between the enoxaparin and

UFH groups regarding the number of distal, proximal and total DVTs.


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Safety data in 1115 treated patientsIncidence of haemorrhage was similar in both

groupsUFH Enoxaparin

(n=560) (n=555)

n (%) n (%)

Major bleeding 16 (2.9) 23 (4.1)

Minor bleeding 80 (14.3) 81 (14.6)

Discontinuation of prophylaxis 12 (2.1) 18 (3.2)Injection-site haematoma 11 (2.0) 6 (1.1)


There was no significant difference between the two groups.


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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 Surg1997;84:1099-1103


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Bergqvist D et al. N Engl J Med2002;346:975980

ENOXACAN I I

Duration of Prophylaxis Against

Venous Thromboembolism

with Enoxaparin after

Surgery for Cancer


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Study Design

Enrolment(n=613)

Enoxaparin (n=609)40 mg o.d. for 610 days

Placebo (n=248)for up to 21 days

Bilateral venography at 25

31 daysEnoxaparin (n=165) Placebo (n=167)

Open-label

phase

Double-blind

phase

Clinical follow-up at 3 months

Enoxaparin (n=253)40 mg o.d. for up to 21 days


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Prolonged thromboprophylaxis

after cancer operationsEnoxaparin 40 mg o.d.

(n = 332)1

1Bergqvist D, et al. N Engl J Med. 2002;346:975-80.2Rasmussen MS, et al. J Thromb Haemost. 2006;4:2384-90.

Dalteparin 5,000 IU o.d.

(n = 343)2

1 week 4 weeks1 week 4 weeks

T

otalDVT(%) 16.3

7.3

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p= 0. 012

0

5

10

20

15

T

otalDVT(%)

12.0

4.8

20/167

8/165

p= 0.02

0

5

10

20

15

12/165


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Conclusions of Enoxacan II

Thromboprophylaxis with enoxaparin for4 weeks after abdominal surgery forcancer reduced the risk of VTE by 60%compared with prophylaxis for 1 week

only

This benefit was achieved without anincrease in the incidence of haemorrhagic

complications

The reduction of VTE risk associated withprolonged thromboprophylaxis persistedat

3-month follow-up


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Treatment VTE with antocoagulant

in Cancer

The overall incidence The Major

of recurent VTE Bleeding

Three times

higher

6,5 times

higher among

those withmalignancy


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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


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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


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Take Home Message


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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 thatobserved in patients without cancer


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Prophylaxis of VTE in cancer reduced

morbiduty and mortalityheparin /LmwH has the same eficacy and

risk of major bleeding

Treatment of VTE with anticoagulant in

cancer :

- Warfarin 17%VTE

-Dalteparin 9% VTE


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3.prof.iman supandiman-prophylaxis and treatment thrombosis in cancer_new

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