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Cancer og trombose Tromboseprofylakse Morten Schnack Rasmussen Overlæge Kirurgisk Gastroenterologisk K Bispebjerg Hospital. Disposition. Primær profylakse Kemoterapi og anti-hormonel behandling Central Vene Katetre Stråle behandling Postoperative venøs tromboemboliske komplikationer - PowerPoint PPT Presentation
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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