Cancer og trombose Tromboseprofylakse

Morten Schnack RasmussenOverlæge

Kirurgisk Gastroenterologisk KBispebjerg Hospital

DispositionDisposition

Primær profylakse Kemoterapi og anti-hormonel behandling Central Vene Katetre Stråle behandling Postoperative venøs tromboemboliske komplikationer

Sekundær profylakse Øger LMWH overlevelsen hos cancer patienter?

Concurrent VTE and cancer increases the risk of death

Probability of death within 183 days of initial hospital admission

Prob

abili

ty o

f dea

th

1.00

0.80

0.60

0.40

0.20

0.00 0 40 80 120 180Number of days

Malignant disease alone

DVT/PE and malignant disease

Levitan et al Medicine 1999

Kemoterapi og anti-hormonel behandlingKemoterapi og anti-hormonel behandling

Incidence of VTE in malignancy: Incidence of VTE in malignancy: Breast cancerBreast cancer

Prevention (1) Node –ve (2) Node +ve (3) Advanced (4)

0.2%0.2%0.1%0.1%

0.2%0.2%

0.9%0.9%

1.6%1.6%

9.6%9.6%

17.6%17.6%

VTE

inci

denc

e

1:Fischer et al J Natl Cancer Inst 1997;89:1673; 2:Fischer et al New Eng J Med 1989; 320: 479; 3: Pritchard J Clin Oncol 1996: 14; 4:Goodnough et al Cancer; 1984: 54

• 311 kvinder, stage 3 and 4 mamma cancer. Kemoterapi.

• 6 week 1mg Warfarin dagligt.

• INR 1.3–1.9

• Median behandlingstid 181 dage

Thro

mbo

sis

(%)

4.4 %

0.7%

p=0.03

Placebo Warfarin0

0.51

1.52

2.53

3.54

4.55

85% VTE reduction

Levine M et al. Lancet 1994;886:886–9

LAVDOSIS Warfarin BEHANDLING ved C. MAMMAELAVDOSIS Warfarin BEHANDLING ved C. MAMMAE

Kemo terapi og VTE komplikationerKemo terapi og VTE komplikationer

Mangler evidensbaserede rekommandationer Ingen fra ACCP

Kun et enkelt randomiseret studie med peroral AK behandling.

Central venøse katetre og venøse Central venøse katetre og venøse tromboemboliske komplikationertromboemboliske komplikationer

treatmentn/N

controln/N

5/125

8/13

VTE

n.s 6/130SympCouban et al 2002

n.sSympReitchard et al 2002

1/16VenoMonreal et al. 1996

P value

Author

Central Venous CatheterCentral Venous CatheterVTE complicationsVTE complications

LMWH=low-molecular-weight heparin

LMWH 0.002

15/40 < 0.001

LMWH

Warfarin

3.7% 3.4%

4/42Warfarin

Diagnosis

VenoBern et al. 1992

Stråle behandling ogStråle behandling og venøse tromboemboliske komplikationer venøse tromboemboliske komplikationer

Stråle-behandling

control

3.0%

VTE

Silvani et al 2003

13.0%Goldberg et al. 1994

Holm et al. 1996

P value

Author

VTE og strålebehandlingVTE og strålebehandling

<0.001

0.001

19.0%

7.5%

Rectum cancer

Malignt Glioma

3.6%Rectum cancer

Postoperative venøs Postoperative venøs tromboemboliske komplikationertromboemboliske komplikationer

Surgery Randomization Phlebography

Prophylaxis6-10 days

Day 30

control

prophylaxis

The ENOXACAN II study The ENOXACAN II study designdesign

Bergqvist et al. N Engl J Med 2002;346:975-80

Incidence of venous thromboembolic events:Incidence of venous thromboembolic events:The ENOXACAN II study The ENOXACAN II study

0

2

4

6

8

10

12

14

All VTE Proximal DVT PE

Placebo Enoxaparin

Bergqvist et al. N Engl J Med 2002;346:975-80

p p = 0.02= 0.02

1212

4.84.8

1.81.80.60.6 0.60.6Pe

rcen

tage

of

patie

nts

Perc

enta

ge o

f pa

tient

s

nsnsnsns

FAME study designFAME study design

Major abdominal surgery Bilateral venography

(assessor-blinded)

7 days 21 days

Dalteparin(5,000 IU sc od) + TED

Dalteparin (5,000 IU sc od)Dalteparin (5,000 IU sc od)

No further prophylaxisNo further prophylaxis

R

TED: graduated compression stockings

7.3%

16.2%

0

2

4

6

8

10

12

14

16

18

n=165 n=178

Inci

denc

e of

all

VTE

(%)

Prolonged TP (28 day) withdalteparin

Short-term TP (7 day) withdalteparin

RRR: 55% (95% CI: 15% - 76%)

NNT: 12 (7 – 44)

Incidence of all VTE 28 days after major Incidence of all VTE 28 days after major abdominal surgeryabdominal surgery

p = 0.01

1.8%

8.0%

0

2

4

6

8

10

n=165 n=175

Inci

denc

e of

pro

xim

al D

VT (%

)

Prolonged TP (28 day)with dalteparinShort-term TP (7 day)with dalteparin

Incidence of proximal DVT 28 days after major Incidence of proximal DVT 28 days after major abdominal surgeryabdominal surgery

p = 0.009RRR: 77% (95% CI: 22% – 93%)

NNT: 17 (10 – 59)

ConclusionsConclusions

Cancer patients undergoing surgery: High risk patients

TP: LMWH in combination with TED.

In selected high risk patients, including those operated for cancer, we suggest post hospital discharge prophylaxis with LMWHThe 7th ACCP Guidelines. Chest 2004; 126 (3 suppl): 410S

Anti-koagulations behandling Anti-koagulations behandling hos cancer patienterhos cancer patienter

6 6

Cum

ulat

ive

prop

ortio

n of

recu

rren

t VTE

(%)

30

20

10

0

Hazard ratio 3.2

Cancer

No cancer

0181661

1160631

2 3129602

4 5 692

161

7 8 973120

10 11 1264115

Time (months)CancerNo cancer

Prandoni P et al. Blood 2002;100:3484-3488

Cumulative incidence of recurrence in cancer patients

8 8

Cumulative incidence of clinically important bleeding in cancer patients

Cum

ulat

ive

prop

ortio

nw

ith m

ajor

ble

edin

g (%

)

30

20

10

0

Hazard ratio 2.2

Cancer

No cancer

Time (months)CancerNo cancer

0181661

1170636

2 3141615

4 5 6102170

7 8 981127

10 11 1268

124

Prandoni P et al. Blood 2002;100:3484-3488

Øget risiko for recidiv og blødning

VTE recidiv

Blødning *

* : Fatal, hjerne, retroperitoneum. ≥ 2 transfusioner, fald i Hb ≥ 2 mmol/L

Hutten BA, et al. J Clin Oncol 2000; 18: 3078-83

AK-behandling: Effekt, risiko

Lavmolekylært heparin ved VTE• Veldokumenteret til behandling og profylakse af VTE

• Bedre end UFH

• Pålidelig biotilgængelighed og kinetik, få interaktioner

• Vægtbaseret dosering. Ingen monitorering

• Bedre effekt, færre blødninger

• Sikkert i langtidsbehandling (HIT, osteoporose)

• Selvadministration, behandling i hjemmet

Long-term treatment of cancer patients with Long-term treatment of cancer patients with VTE: LMWH versus warfarinVTE: LMWH versus warfarin

Outcome Warfarin LMWH*3 months n=71 (%) n=67 (%)

Major bleed 12 (16.9) 5 (7.5)VTE 3 (4.2) 2 (3.0)Total 15 (21.1) 7 (10.5)†

*Enoxaparin 1.5 mg/kg; †P=0.09Meyer G et al. Arch Intern Med. 2002;162:1729–35.

14 14

LITE trial

Event Tinzaparin (n=369) OAC (n=368)

Recurrent VTE (%) 4.9 5.7Major bleeding (%) 3.3 4.6

Subgruppe-analyse:Cancer n=80 n=87Recurrent VTE (%) 6.3 11.5*

*P=0.03

LITE trial: Hull et al. ASH 2002

R

Dalteparin

Oral anticoagulant

CLOT in cancerCLOT in cancer

• Acute VTE

• 5-7 days

• Dalteparin

• 200 IU/kg

Lee A et al. N Engl J Med 2003;349:146-153

CLOT trialCLOT trial

Treatmentgroup

Initial treatment(5-7 days)

Long-term therapy(180 days)

OAC Dalteparin 200 IU/kgsc once-daily

Warfarin or acenocoumarol(target INR 2.5)

LMWH Dalteparin 200 IU/kgsc once-daily

Day 30: dalteparin 200 IU/kgDay 31 to 180: 75-80% of full dose

Recurrent VTERecurrent VTE

0

5

10

15

20

25

Days post-randomisation0 30 60 90 120 150 180 210

Prob

abili

ty o

f rec

urre

nt V

TE (%

)

Risk reduction=52%

p=0.0017

Dalteparin

OAC

Recidiv af VTE 8,0% 15,8%Absolut risikoreduktion 7,8%1 event sparet pr. 13 behandlede (NNT 13)

”For patients with DVT and cancer, we recommend LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade 1A)”.

”For these patients, we recommend anticoagulant therapy indefinitely or until the cancer is resolved (Grade 1C)”.

The 7th ACCP Guidelines. Chest 2004; 126 (3 suppl): 410S

Treatment Outcomes Results

Long-term LMWH

Recurrent VTE

Bleeding No increase

Quality of life

CLOT-studiet

             

LMWH AND SURVIVAL LMWH AND SURVIVAL

385 patients with solid tumour malignancy R

Dalteparin5000 units once dailyfor up to 1 year

PlaceboUp to 1 year

84 patients with Small cell lung cancer (SCLC)

Chemotherapy plus dalteparin 5000 IU od18 weeks

Chemotherapy (cyclophosphamide, epirubicin, vincristine)18 weeks

302 patients with solid tumor malignancy

Nadroparin2 weeks therapeutic dose4 weeks 1/2 therapeutic dose

Placebo6 weeks

FAMOUS

SCLC study

MALT

R

R

LMWH and LMWH and SSurvival urvival DDataata

Year LMWH

Survival (months)Median (95% CI)

Overall population Good prognosis population

FAMOUS 2002 Dalteparin D 10.80P 9.14

43.524.3

CLOT 2003 Dalteparin D 62%*OAC 61%* (HR 1.0)

80%* 64%* (HR 0.5)

SCLC study 2003 Dalteparin D 13.0 P 8.0

16.0 10.0

MALT 2003 Nadroparin N 8.0P 6.6 (HR 0.75)

15.4 9.4 (HR 0.64)

*% surviving at 1 year D = dalteparin; N = nadroparin; OAC = oral anticoagulant; P = placebo; HR = hazard ratio