cancer associated thrombosis - tao-ctm meeting...2015/11/20 · verso m. et al. j thromb haemost...
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Cancer Associated Thrombosis
Guy MeyerUniversité Paris Descartes
Hopital Europeen Georges Pompidou, Paris, France
Disclosures G Meyer
• Investigator: Bayer, Daichi-Sankyo, Sanofi
Aventis, Leo Pharma
• Research Funding: Leo Pharma, Boehringer-
Ingelheim, Bayer
• Board membreship (uncompensated) : Sanofi
Aventis, Leo Pharma, Bayer, Boehringer-
Ingelheim, Pfizer
• Travel support: Leo Pharma, Boehringer-
Ingelheim, Bayer, Daichi-Sankyo
Incidence of venous thromboembolism in patients
with cancer
Study n Cancer VTE (% yrs)
Ay 20101 819 Unselected 7.7%
Khorana 20052 3003 New chemotherapy 4.4%
Kröger 20063 507 Unselected 18%
Prospective studies with various cancer types
1. Ay C et al. Blood 2010;116:5377–82
2. Khorana AA et al. Cancer 2005;104:2822–9
3. Kröger K et al. Ann Oncol 2006;17:297–303
115 US Centers ; 3,196 patients chemotherapy < 4 cycles
Characteristics Score
Site of cancerVery high risk (pancreas, stomach)
High risk (lymphoma, lung, gynecological, genito-urinary) 21
Platelet count > 350,000/mm3 1
Hemoglobin < 10g/dL 1
Leukocyte count > 11,000/mm3 1
BMI > 35 kg/m2 1
A predictive rule for Cancer Associated Thrombosis
Khorana AA et al. Blood 2008;111:4902–07
Ris
k of
VT
E o
ver
2.5
mon
ths
(%)
734 374 1627 842 340 149
n
Khorana AA et al. Blood 2008;111:4902–07
A predictive rule for Cancer Associated
Thrombosis
Prolonged prophylaxis: PROTECHT
Agnelli G. et al. Lancet Oncol 2009; 10: 943-49
Nadroparin 3800 IU (4 months) (n = 799) vs placebo (n = 387)
3.9% vs 2.0%; p = 0.02
SAVE-ONCO
Agnelli G. et al. N Engl J Med 2012; 366: 601-9
Metastatic or locally advanced cancer on chemotherapy Semuloparin, n = 1608 or placebo n = 1604; median FUP: 3.5 months
HR: 0,36 ; 0,21-0,60; p < 0,001
Pancreatic cancer
Gemcitabine
Gemcitabine +
Dalteparin
Maraveyas A. et al. Eur J cancer 2012 ;48:1283-92
Advanced Pancreatic cancer: gemcitabine +/-dalteparin: 200 IU/kg OD 4 weeks followed by 150 IU/kg 8 weeks.
All type VTE
17 (28%)
7 (12%) 0.42 (0.19–0.93)
ClinicalVTE
13 (22%)
5 (9%) 0.39 (0.15–1.0)
Major bleedings
2 (3%) 2 (3%)
Control(n = 60)
Dalteparin(n = 59)
RR (95% CI)
Enoxaparin in advanced pancreatic cancer
Pelzer U. et al. J Clin Oncol 2015; 33:2028-2034
Symptomatic VTE
Pelzer U. et al. J Clin Oncol 2015; 33:2028-2034
Major bleedings
Enoxaparin in advanced pancreatic cancer
Verso M. et al. J Thromb Haemost 2010; 8: 1649–51
LMWH
467
Placebo
344
RR
Symptomatic VTE 15 (3.2%) 19 (5.5%) 0.58 (95% CI 0.28–1.06)
All VTE 20 (4.3%) 27 (7.8%) 0.54 (95% CI 0.31–0.95)
Major bleeding 12 (2.5%) 6 (1.7%) 1.50 (95% CI 0.57–3.95)
•TOPIC 2 : NSCLC (n = 532); PROTECHT : Lung cancer (279)
• Certoparin 3000 U or placebo; 6 months
• Nadroparin 3800 IU or placebo 4 months
Long-term prophylaxis in lung cancer patients ?
• In patients receiving chemotherapy, prophylaxis is not
recommended routinely [Grade 1B].
• Primary pharmacological prophylaxis of VTE may be indicated
in patients with locally advanced or metastatic pancreatic
cancer treated with chemotherapy and having a low bleeding
risk [Grade 1B].
• Primary pharmacological prophylaxis of VTE may be indicated
in patients with locally advanced or metastatic lung cancer
treated with chemotherapy and having a low bleeding risk
[Grade 2B].
Farge D. et al. J Thromb Haemost 2013; 11: 56–70
Recommendations (ISTH)
Lee A. et al. N Engl J Med 2003; 349: 146-153
The CLOT Study
Recurrences* Major bleedings
Mortality
Dalteparin 8.8% 5.6% 39%
Warfarin 17.4% 3.6% 41%
*: p = 0.002
The CLOT Study
Lee A. et al. N Engl J Med 2003; 349: 146-153
CATCH. Recurrent VTE
0
2
4
6
10
12
Days post-randomization
0 30 60 90 120 150 180
Pro
ba
bil
ity
of
recu
rre
nt
VT
E (
%)
14
8
tinzaparin, n = 450: 7.2%
warfarin, n = 450: 10.5% (TTR 47%)
HR 0.65 (95% CI 0.41–1.03) p = 0.07
Lee A. et al. JAMA 2015; 314: 677-86
CATCH. Safety Outcomes
2.0
Major bleeding
Clinically relevant non-major bleeding
Overall mortality
13/449
50/449
150/449
12/451
73/451
138/451
0.89 [0.40, 1.99]
0.69 [0.49, 0.96]
1.08 [0.85, 1.36]
Favors T Favors W
0.0 0.5 1.0 1.5
Event Tinzaparinn/N
Warfarinn/N
HR [95% CI]HR
Lee A. et al. JAMA 2015; 314: 677-86
0.53 (0.36 – 0.76)
Louzada M. et al. Thromb Res 2009; 123: 837-844
Recurrences with LMWH and VKA in patients
with cancer-associated thrombosis
Louzada M. et al. Thromb Res 2009; 123: 837-844
0.98 (0.49 – 1.93)
Bleedings during LMWH and VKA in patients
with cancer-associated thrombosis
Limitations of prolonged LMWH
• Daily injections
• Platelet monitoring
• HIT
• Cost: 8.60 euros to 16.90 euros
• Nurse
• Bruising- hematomas
• Difficult to use over prolonged periods
• Recurrent VTE: 5% to 7% at 3 or 6 months
• Bleeding risk 5% to 7% not lower than VKA
Recurrent VTE: DOA vs VKA
Vedovati MC. et al. Chest. 2015; 147: 475-83
Major bleeding: DOA vs VKA
Vedovati MC. et al. Chest. 2015; 147: 475-83
Patients with cancer: EINSTEIN, CLOT and
CATCH
Einstein
(n = 655)
CLOT
(n = 672)
CATCH
(n = 900)
Recurrent or
metastatic cancer22% 67.3% 54.7%
Anticancer
treatment13%* 77.7%** 42.4%***
% INR 2-3 57%-59% 46% 47%
*: chemotherapy,
**: all anticancer treatments,
***: systemic treatment (chemo or targeted therapy or hormonal treatment)
Lee A. et al. N Engl J Med 2003; 349: 146-153
Prins M H. et al. Lancet Haematol. 2014; 1: e37–46
Lee A. et al. JAMA 2015; 314: 677-86
Conclusion
• Long-term prophylaxis: work in progress..
• LMWH remains the preferred therapeutic option for the
treatment of Cancer Associated Thrombosis.
• LMWH should be given for at least 3 to 6 months.
• These results are supported by the CATCH study.
• The optimal treatment option after 6 months of LMWH
treatment remains to be defined.
• Direct oral anticoagulants should not been used in
patients with CAT, yet