Transcript Preventing VTE in cancer patients undergoing major surgery

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
 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
Probability of death
1.00
DVT/PE and
malignant disease
0.80
0.60
0.40
Malignant
disease alone
0.20
0.00
0
40
80
120
Number of days
180
Levitan et al Medicine 1999
Kemoterapi og anti-hormonel behandling
Incidence of VTE in malignancy:
Breast cancer
17.6%
9.6%
1.6%
0.9%
0.2%
0.1%
0.2%
Prevention (1) Node –ve (2) Node +ve (3) Advanced (4)
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
LAVDOSIS Warfarin BEHANDLING ved C. MAMMAE
5
4.5
• 6 week 1mg Warfarin dagligt.
• INR 1.3–1.9
• Median behandlingstid 181 dage
4
3.5
Thrombosis (%)
• 311 kvinder, stage 3 and 4
mamma cancer. Kemoterapi.
4.4 %
3
2.5
p=0.03
2
1.5
0.7%
1
0.5
0
Placebo
Warfarin
85% VTE reduction
Levine M et al. Lancet 1994;886:886–9
Kemo terapi og VTE komplikationer
 Mangler evidensbaserede rekommandationer
 Ingen fra ACCP
 Kun et enkelt randomiseret studie med peroral AK
behandling.
Central venøse katetre og venøse
tromboemboliske komplikationer
Central Venous Catheter
VTE complications
Author
VTE
Diagnosis
control
n/N
treatment
n/N
P
value
15/40
4/42
< 0.001
LMWH
8/13
1/16
0.002
Symp
LMWH
3.7%
3.4%
n.s
Symp
Warfarin
5/125
6/130
n.s
Bern et al. 1992
Veno
Warfarin
Monreal et al.
1996
Reitchard et al
2002
Couban et al
2002
Veno
LMWH=low-molecular-weight heparin
Stråle behandling og
venøse tromboemboliske komplikationer
VTE og strålebehandling
Author
VTE
control
Strålebehandling
P
value
Holm et al. 1996
Rectum cancer
3.6%
7.5%
0.001
Goldberg et al.
1994
Rectum cancer
3.0%
13.0%
<0.001
Silvani et al 2003
Malignt Glioma
19.0%
Postoperative venøs
tromboemboliske komplikationer
The ENOXACAN II study design
Surgery
Randomization
Phlebography
control
prophylaxis
Day 30
Prophylaxis
6-10 days
Bergqvist et al. N Engl J Med 2002;346:975-80
Incidence of venous thromboembolic events:
The ENOXACAN II study
p = 0.02
Placebo
Enoxaparin
Percentage of patients
14
12
12
10
8
6
ns
4.8
ns
4
1.8
2
0.6
0.6
0
All VTE
Proximal DVT
Bergqvist et al. N Engl J Med 2002;346:975-80
PE
FAME study design
7 days
R
Dalteparin
(5,000 IU sc od)
+ TED
21 days
Dalteparin (5,000 IU sc od)
No further prophylaxis
Major abdominal
surgery
TED: graduated compression stockings
Bilateral venography
(assessor-blinded)
Incidence of all VTE 28 days after major
abdominal surgery
p = 0.01
18
RRR: 55% (95% CI: 15% - 76%)
16.2%
NNT: 12 (7 – 44)
Incidence of all VTE (%)
16
14
12
10
8
7.3%
Prolonged TP (28 day) with
dalteparin
6
4
Short-term TP (7 day) with
dalteparin
2
0
n=165
n=178
Incidence of proximal DVT 28 days after major
abdominal surgery
10
Incidence of proximal DVT (%)
RRR: 77% (95% CI: 22% – 93%)
p = 0.009
NNT: 17 (10 – 59)
8.0%
8
6
4
2
Prolonged TP (28 day)
with dalteparin
1.8%
Short-term TP (7 day)
with dalteparin
0
n=165
n=175
Conclusions
 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
LMWH
The 7th ACCP Guidelines. Chest 2004; 126 (3 suppl): 410S
Anti-koagulations behandling
hos cancer patienter
Øget risiko for recidiv og blødning
Cumulative incidence of recurrence in
cancer patients
30
Cumulative proportion
of recurrent VTE (%)
Hazard ratio 3.2
20
Cancer
10
No cancer
Cumulative incidence of clinically
important bleeding in cancer patients
0
6
1
160
631
2
3
129
602
4
5
6
92
161
7
8
9
73
120
10
11
12
64
115
Time (months)
Cancer
No cancer
Prandoni P et al. Blood 2002;100:3484-3488
30
6
Hazard ratio 2.2
Cumulative proportion
with major bleeding (%)
0
181
661
20
Cancer
10
No cancer
0
0
181
661
8
1
170
636
2
3
141
615
4
5
6
102
170
7
8
9
81
127
10
11
12
68
124
Time (months)
Cancer
No cancer
Prandoni P et al. Blood 2002;100:3484-3488
8
AK-behandling: Effekt, risiko
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
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
VTE: LMWH versus warfarin
Outcome
3 months
Warfarin
n=71 (%)
LMWH*
n=67 (%)
Major bleed
VTE
Total
12 (16.9)
3 (4.2)
15 (21.1)
5 (7.5)
2 (3.0)
7 (10.5)†
*Enoxaparin 1.5 mg/kg; †P=0.09
Meyer G et al. Arch Intern Med. 2002;162:1729–35.
LITE trial
Event
Tinzaparin (n=369)
OAC (n=368)
Recurrent VTE (%)
Major bleeding (%)
4.9
3.3
5.7
4.6
Subgruppe-analyse:
Cancer
Recurrent VTE (%)
n=80
6.3
n=87
11.5 *
*P=0.03
LITE trial: Hull et al. ASH 2002
14
14
CLOT in cancer
Dalteparin
• Acute VTE
• 5-7 days
• Dalteparin
R
• 200 IU/kg
Oral
anticoagulant
Lee A et al. N Engl J Med 2003;349:146-153
CLOT 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
Probability of recurrent VTE (%)
Recurrent VTE
25
Risk reduction=52%
p=0.0017
20
15
OAC
10
Dalteparin
5
0
0
30
60
90
120
150
180
Days post-randomisation
210
Recidiv af VTE
8,0%
15,8%
Absolut risikoreduktion
7,8%
1 event sparet pr. 13 behandlede (NNT 13)
CLOT-studiet
Treatment
Outcomes
Results
Recurrent VTE
Long-term LMWH
Bleeding
Quality of life
”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
No increase
LMWH AND SURVIVAL
FAMOUS
385 patients with solid
tumour malignancy
R
Dalteparin
5000 units once daily
for up to 1 year
Placebo
Up to 1 year
SCLC study
84 patients with
Small cell lung
cancer (SCLC)
R
Chemotherapy (cyclophosphamide,
epirubicin, vincristine)
18 weeks
MALT
302 patients with
solid tumor
malignancy
Chemotherapy plus
dalteparin 5000 IU od
18 weeks
R
Nadroparin
2 weeks therapeutic dose
4 weeks 1/2 therapeutic dose
Placebo
6 weeks
LMWH and Survival Data
Survival (months)
Median (95% CI)
Year
LMWH
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