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Cancer og trombose
Tromboseprofylakse
Morten Schnack Rasmussen
Overlæge
Kirurgisk Gastroenterologisk K
Bispebjerg Hospital
Cancer og trombose
Tromboseprofylakse
Morten Schnack Rasmussen
Overlæge
Kirurgisk Gastroenterologisk K
Bispebjerg Hospital
DispositionDispositionDispositionDisposition
Primær profylakse Kemoterapi og anti-hormonel behandling
Central Vene Katetre
Stråle behandling
Postoperative venøs tromboemboliske komplikationer
Sekundær profylakse
Øger LMWH overlevelsen hos cancer patienter?
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
Pro
bab
ilit
y o
f d
eath
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 behandlingKemoterapi og anti-hormonel behandlingKemoterapi og anti-hormonel behandling
Incidence of VTE in malignancy: Incidence of VTE in malignancy: Breast cancerBreast cancerIncidence 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%
VT
E in
cid
en
ce
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
Th
rom
bo
sis
(%)
4.4 %
0.7%
p=0.03
Placebo Warfarin
0
0.5
1
1.5
2
2.53
3.5
4
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 komplikationerKemo terapi og VTE komplikationerKemo terapi og VTE komplikationer
Mangler evidensbaserede rekommandationer Ingen fra ACCP
Kun et enkelt randomiseret studie med peroral AK behandling.
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 komplikationerCentral venøse katetre og venøse Central venøse katetre og venøse tromboemboliske komplikationertromboemboliske komplikationer
treatment
n/N
control
n/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 complicationsCentral 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 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 strålebehandlingVTE 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
Postoperative venøs Postoperative venøs tromboemboliske komplikationertromboemboliske komplikationer
Surgery Randomization Phlebography
Prophylaxis
6-10 days
Day 30
control
prophylaxis
The ENOXACAN II study The ENOXACAN II study designdesign 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 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
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 0.60.6P
erce
nta
ge
of
pat
ien
tsP
erce
nta
ge
of
pat
ien
ts
nsnsnsns
FAME study designFAME study designFAME 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
den
ce o
f al
l VT
E (
%)
Prolonged TP (28 day) withdalteparin
Short-term TP (7 day) withdalteparin
7.3%
16.2%
0
2
4
6
8
10
12
14
16
18
n=165 n=178
Inci
den
ce o
f al
l VT
E (
%)
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 surgeryIncidence 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
den
ce o
f p
roxi
mal
DV
T (
%)
Prolonged TP (28 day)with dalteparin
Short-term TP (7 day)with dalteparin
1.8%
8.0%
0
2
4
6
8
10
n=165 n=175
Inci
den
ce o
f p
roxi
mal
DV
T (
%)
Prolonged TP (28 day)with dalteparin
Short-term TP (7 day)with dalteparin
Incidence of proximal DVT 28 days after major Incidence of proximal DVT 28 days after major abdominal surgeryabdominal surgeryIncidence 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)
ConclusionsConclusionsConclusionsConclusions
Cancer patients undergoing surgery: High risk patients
TP: LMWH in combination with TED.
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
Anti-koagulations behandling Anti-koagulations behandling hos cancer patienterhos cancer patienter
6 6
Cu
mu
lati
ve p
rop
ort
ion
o
f re
curr
ent
VT
E (
%)
30
20
10
0
Hazard ratio 3.2
Cancer
No cancer
0181661
1160631
2 3129602
4 5 692161
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
6 6
Cu
mu
lati
ve p
rop
ort
ion
o
f re
curr
ent
VT
E (
%)
30
20
10
0
Hazard ratio 3.2
Cancer
No cancer
0181661
1160631
2 3129602
4 5 692161
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
Cu
mu
lati
ve p
rop
ort
ion
wit
h m
ajo
r b
leed
ing
(%
)
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 1268124
Prandoni P et al. Blood 2002;100:3484-34888 8
Cumulative incidence of clinically important bleeding in cancer patients
Cu
mu
lati
ve p
rop
ort
ion
wit
h m
ajo
r b
leed
ing
(%
)
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 1268124
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, risikoAK-behandling: Effekt, risiko
Lavmolekylært heparin ved VTELavmolekylært 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 warfarinLong-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)†
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=0.09
Meyer 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 5.7
Major bleeding (%) 3.3 4.6
Subgruppe-analyse:
Cancer n=80 n=87
Recurrent VTE (%) 6.3 11.5*
*P=0.03
LITE trial: Hull et al. ASH 2002
R
Dalteparin
Oral anticoagulant
CLOT in cancerCLOT in cancerCLOT 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 trialCLOT trialCLOT trial
Treatment
group
Initial treatment
(5-7 days)
Long-term therapy
(180 days)
OAC Dalteparin 200 IU/kg
sc once-daily
Warfarin or acenocoumarol
(target INR 2.5)
LMWH Dalteparin 200 IU/kg
sc once-daily
Day 30: dalteparin 200 IU/kg
Day 31 to 180: 75-80% of full dose
Recurrent VTERecurrent VTERecurrent VTERecurrent VTE
0
5
10
15
20
25
Days post-randomisation
0 30 60 90 120 150 180 210
Pro
bab
ility
of
rec
urr
en
t 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-studietCLOT-studiet
LMWH AND SURVIVAL LMWH AND SURVIVAL 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 DDataataLMWH and LMWH and SSurvival urvival DDataata
Year LMWH
Survival (months)
Median (95% CI)
Overall population Good prognosis population
FAMOUS 2002 Dalteparin D 10.80
P 9.14
43.5
24.3
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 8.0
P 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