Transcript Cancer & VTE Educational Program

1
Awareness
Disease management
Pathogenesis
Cancer & VTE
Educational Program
Epidemiology
Cancer & VTE
Disease
Management
Awareness
Disease management
Pathogenesis
Awareness
Epidemiology
Pathogenesis
Epidemiology
2
« Ironically, Trousseau died of gastric carcinoma six months after
writing to his student, Peter, on January 1st, 1867:
“I am lost . . . the phlebitis that has just appeared tonight leaves
me no doubt as to the nature of my illness”
Hôtel Dieu
1855
Epidemiology
Pathogenesis
Armand Trousseau
(1801-1867)
« When you are undecided about the nature of the disease of
the stomach, when you hesitate among a chronic gastritis, a
simple ulcer, and a carcinoma, a phlegmatia alba dolens
occuring in the leg or arm will put an end to your indecision
and you will be able to assert positively that a cancer is
present. Further, this obliterative phlebitis does not pertain
exclusively to carcinoma of the stomach and it may occur with
cancer affecting any internal organ whatever ».
Disease management
From Phlegmatia Alba Dolens to Pulmonary embolism (1865)
Awareness
Trousseau Lecture at Hôtel-Dieu
Epidemiology
Pathogenesis
Epidemiology
2- Thrombosis has an influence on cancer
4
Awareness
Disease management
1- Cancer has an influence on thrombosis
VTE and Cancer
Epidemiology
5
– 15% will have symptomatic VTE
– As many as 50% have VTE at autopsy
• Compared to patients without cancer:
– Higher risk of first and recurrent VTE
– Higher risk of bleeding on anticoagulants
– Higher risk of dying
Lee AY et al. Circulation. 2003;107:23:I17-I21
Disease management
• Of all cancer patients:
Awareness
– About 20% occur in cancer patients
– Annual incidence of VTE in cancer patients ≈ 1/250
Pathogenesis
• Of all cases of VTE:
Disease management
1- Cancer has an influence on thrombosis
Awareness
Pathogenesis
Epidemiology
6
VTE in hospitalized cancer patients
Increase in the rate of VTE overtime
7.0
Epidemiology
7
6.0
Pathogenesis
VTE patients on chemotherapy
VTE all patients
DVT all patients
PE all patients
Disease management
4.0
3.0
2.0
1.0
0.0
1995
1996
1997
Khorana et al, Heit et al, Cancer. 2007 Nov 15;110(10):2339-46.
1998
@
1999
2000
2001
2002
2003
Years
Awareness
Rate of VTE (%)
5.0
8%
Adenocarcinoma
Large cell carcinoma
6%
Carcinoma NCS
4%
Squamous cell carcinoma
2%
0%
100
200
300
400
500
Days after cancer diagnosis
Chew et al J Thromb Haemost. 2008;6:601-608
@
600
700
800
Epidemiology
Pathogenesis
Incidence of VTE
10%
Disease management
…stratified by histology for non-small cell lung cancer
Awareness
Incidence of VTE
in patients with lung cancer…
8
Incidence of VTE
in patients with colon cancer…
...stratified by initial cancer stage
7%
5%
Local
Regional
Remote
Disease management
4%
3%
2%
1%
0
100
200
300
Days after cancer diagnosis
Alcalay et al, J Clin Oncol. 2006;24:1112-1118
@
400
Awareness
Incidence of VTE (%)
6%
91 933 eligible lung cancer cases
identified in the 6-year study period:
• 85% NSCLC histology
• 15% SCLC histology
Pathogenesis
Epidemiology
9
Wun T et al, Best Pract Clin Haematol 2009;22:9-23
@
Regional stage
5.3
3.9
3.9
2.7
1.6
2.3
2.3
1.0
2.1
3.5
1.0
Remote stage
19.7
12.9
8.0
7.6
6.2
5.2
4.6
4.6
3.8
2.9
2.8
Epidemiology
Pathogenesis
Pancreas
Stomach
Kidney
Bladder
Uterus
Lung
Colon / rectum
Melanoma
Ovary
Lymphoma
Breast
Local stage
4.3
2.7
1.2
0.7
0.9
1.1
0.9
0.2
0.6
2.0
0.6
Disease management
Cancer
Incidence rate of VTE in year after cancer diagnostic
(events / 100 patients)
Awareness
Comparison of the incidence of VTE based on
initial cancer stage
10
Cancer type
Prostate
Breast
Lung
Colon / rectum
Melanoma
Non - Hodgkin’s lymphoma
Uterus
Bladder
Pancreas
Stomach
Ovary
Kidney
Initial stage
Local
5.6 (3.8 - 8.5)§
6.6 (3.7 - 11.8)§
3.1 (2.1 - 4.5)§
3.2 (1.8 - 5.5)§
14.4 (4.6 - 45.2)§
3.2 (1.9 - 5.3)§
7.0 (3.4 - 14.2)§
3.2 (1.7 - 6.2)§
2.3 (1.2 - 4.6)*
2.4 (1.1 - 5.1)*
11.3 (2.5 - 51.7)†
3.2 (1.2 - 8.8)*
Data are adjusted for age, race and gender
*p<0.05; † p<0.01; § p<0.001
Wun T et al, Best Pract Clin Haematol 2009;22:9-23
@
Regional
4.7 (1.9 - 11.5)§
2.7 (1.3 - 4.5)†
2.9 (2.3 - 3.5)§
2.2 (1.7 - 3.0)§
N/A
2.0 (1.3 - 3.2)†
9.1 (4.8 - 17.2)§
3.3 (1.7 - 6.4)§
3.8 (2.8 – 5.1)§
1.5 (1.0 - 2.1)*
4.8 (1.1 – 20.4)*
1.4 (0.6 – 3.2)
Metastatic
2.8 (1.5 – 5.0)†
1.8 (1.1 – 2.9)*
2.5 (2.3 – 2.7)§
2.0 (1.7 – 2.4)§
2.8 (1.5 – 5.3)†
2.3 (1.7 – 3.1)§
1.7 (1.0 – 3.0)*
3.3 (1.8 – 6.2)§
2.3 (1.9 – 2.7)§
1.8 (1.4 – 2.3)§
2.3 (1.7 – 3.0)§
1.3 (0.9 – 2.0)
Epidemiology
Pathogenesis
Hazard ratio for death within 1 year among cases with VTE diagnosed in Year 1 vs no VTE (95%
confidence interval), adjusted for age race and genre
Disease management
…stratified by initial Surveillance, Epidemiology an End Results (SEER) cancer stage
Awareness
Effect of VTE on survival of patients with
different cancer types…
11
7.4 %
1.9% (532)
-
1.5% (2337)
0.9% (32 655)
1.3% (1040)
0.4% (14 742)
1.3% (1503)
0.8% (34 375)
1.4% (9336)
0.6% (232 764)
3.3% (1444)
1.2% (26 406)
0.7% (970)
0.7% (22 938)
2.0% (2470)
1.0% (52 042)
1.7% (524)
-
1.7% (168)
-
2.3% (32 611)
7.4%
5.8%
4.3%
4.3%
4.2%
4.1%
3.7%
3.1%
3.1%
2.7%
1.3% (6262)
0.8%
1.5% (951)
1.8%
0.6% (165)
-
1.5% (7138)
1.7%
1.7%
1.0%
0.9%
0.5%
1.3% (2250)
0.2% (168 832)
1.1% (1431)
0.4% (11 606)
0.9% (6013)
0.5% (218 743)
0.8% (10566)
0.2% (186 273)
0.3% (2236)
-
5.3% (6524)
Brain
Acute myelogenous
leukaemia
Stomach
6.9% (3775)
3.7% (2292)
4.5% (5766)
Oesophagus
3.6% (2491)
Renal cell
3.5% (4891)
Lung
2.4% (44 497)
Ovary
3.3% (5707)
Liver
1.7% (2312)
Lymphoma
2.8% (9003)
Chronic lymphocytic leukaemia
2.7% (2023)
Acute lymphocytic leukaemia
2.6% (1058)
Colon
Chronic myelogenous
leukaemia
Bladder
Uterus
1,6% (8721)
Prostate
0.9% (51 362)
Breast
0.9% (44 707)
Melanoma
0.5% (9 497)
Wun T et al, Best Pract Clin Haematol 2009;22:9-23
@
Epidemiology
1.2% (13 529)
Pancreas
Netherlands :
cumulative incidence
6 months (n)
Pathogenesis
3.2% (1058)
Cancer
California :
Rate of VTE
(/100 patient-years)
14.0%
11.1 %
Disease management
2.3% (1674)
USA :
hospitalized
Medicare patients,
prevalence 6 months (n)
1.2% (41 551)
California :
Cumulative incidence of VTE
(%) 1 year (n)
Awareness
Incidence of VTE in cancer patients may differ
according to regions /countries
12
Hospitalization
Surgery
Transient and permanent risk in
cancer patients
7
5
Chemotherapy
End of life
Metastasis
4
3
2
Epidemiology
Diagnosis
Disease management
Log Odds Ratio
6
Remission
Baseline risk of VTE
in cancer patients
1
0.5
Time
Baseline risk in
subjects without
RF of VTE
Khorana et al, Heit et al, Cancer. 2007 Nov 15;110(10):2339-46.
@
Awareness
8
Pathogenesis
Risk of VTE varies over cancer evolution
13
Pathogenesis
30
28
22.2
20
20.3
19.8
14.3
10
4.9
3.6
2.6
0
Type of cancer
Blom et al, JAMA. 2005 Feb 9;293(6):715-22.
@
Time since cancer diagnosis
1.1
Disease management
40
53.5
Awareness
Adjusted odds ratio
50
• Population-based MEGA study
• N=3 220 consecutive patients with 1st VTE
vs. n=2 131 control subjects
• Cancer patients = OR 7x VTE risk vs. nonCancer patients
Epidemiology
Cancer and VTE
14
Epidemiology
Cancer is an independent risk factor for VTE
• 5% - 60% of cancer patients present VTE disease
• In 50% of cancer patients, DVT and/or PE are found at necrotomy
• 15% of patients hospitalized for cancer with limited metastasis or
without metastasis have fatal PE
Disease management
• 7% of cancer patients undergoing staging CT scan for cancer are
diagnosed with asymptomatic VTE
Awareness
• 20% of all new cases of VTE are associated with underlying cancer
Pathogenesis
• x 7 the relative risk of VTE in patients with active cancer
15
Disease management
2- Thrombosis has an influence on cancer
Awareness
Pathogenesis
Epidemiology
16
Pathogenesis
DVT/PE and malignant disease
0.80
Malignant disease
0.40
DVT/PE only
0.20
Non-malignant disease
0
20
40
60
80
100
Number of days
Levitan N, et al. Medicine. 1999;78:285-91.
120
140
160
180
Disease management
0.60
Awareness
Probability of death
1.00
Epidemiology
Thrombosis and survival:
likelihood of death after hospitalization
17
cancer
Incidence of death in bladder cancer patients after the date of VTE and in a matched
cohort of patients without VTE
Localized bladder cancer
Sandhu et al, Cancer. 2010 ;116(11):2596-603.
@
Metastatic bladder cancer
Awareness
Regional bladder cancer
Disease management
Pathogenesis
Entire bladder cancer cohort
Epidemiology
Incidence of death in bladder cancer patients after the date of VTE and in a
VTE influence
patient
survival
in bladder
matchedon
cohort
of patients
without VTE
18
• During the first year of follow-up, the standardized incidence ratio for
cancer in patients with idiopathic VTE ranges from 2.1 to 4.6
• 40% of these patients are suffering from metastasis at the time of
diagnosis
Rance et al, Lancet. 1997;350(9089):1448-9.
@
Lee et al, Thromb Res. 2003;110(4):167-72.
@
Prandoni et al, Lancet Oncol. 2005 ;6(6):401-10.
@
Epidemiology
Pathogenesis
• 10% of patients suffering from idiopathic VTE are diagnosed with cancer
at follow-up
Disease management
• Idiopathic VTE occurring prior the diagnosis of cancer is a pejorative
factor for survival
Awareness
Cancer and DVT: reciprocal interaction
19
Epidemiology
1- Cancer related thrombotic factors
2- Treatment related thrombotic factors
20
Awareness
Disease management
Pathogenesis
Pathogenesis
1. Blood Stasis
 Adhesivity
+
 Thromboresistance
 Prothrombotic potential
+
 Antithrombotic Potential
Acquired +++
Proinflammatory Cytokines
APCR,...
1821-1902
Direct Invasion
Surgery
Venous Catheters (infection++)
Intravenous drugs (chemotherapy ++)
Anti-angiogenic drugs
Radiotherapy
Disease management
3. Hypercoagulability
2. Endothelial Damage
Awareness
Immobilization
Prolonged Bed Rest
Hyperviscosity
Dehydration
Extrinsic Compression
Pathogenesis
 Accumulation procoagulant factors
+
 Clearance activated factors
Epidemiology
Pathogenesis of Thrombosis in Cancer –
A Modification of Virchow’s Triad
21
Disease management
Pathogenesis
1- Cancer related thrombotic factors
Awareness
Epidemiology
22
Epidemiology
Prothrombotic State and Cancer
Extrinsic
Patients
HYPERCOAGULABLITY
Factors
Metastasis
Procoagulant Factors
Elalamy et al, Pathol Biol 2008;56(4):184-94
@
Tumors
Awareness
Angiogenesis
Disease management
Pathogenesis
Inflammation
23
Boccaccio et al, J Clin Oncol. 2009 ;27(29):4827-33
@
Epidemiology
Awareness
Disease management
Pathogenesis
Cancer, genes and thrombosis
24
TNFa
IL-1
VEGF
Lympho T
Hetero-Complexes
Microparticles
TNFa
Tumor
Cell
IL-1
TF
platelets
mucins
IIa
CPF
TF
Proliferation
+
Invasion
VIIa-TF
Xa
Monocyte
macrophage
X
Epidemiology
Pathogenesis
Endothelial Cell
Disease management
 Angiogenesis
 TF
 von Willebrand
 Adhesion Molecules
 PAI-1
Awareness
Thrombomodulin
PC System
t-PA
25
Awareness
Disease management
Pathogenesis
Epidemiology
Thrombin generation
26
Epidemiology
Multiple biological effects of TF
Thrombosis
Pathogenesis
Haemostasis
Clotting
PARs
Signaling
Pawlinski et al, Thromb Haemost. 2004 ;92(3):444-50.
PARs
Inflammation
@
Awareness
Angiogenesis
Disease management
Tissue Factor
27
TUMOR GROWTH
AND METASTASIS
Ruf et al, J Thromb Haemost. 2007;5(8):1584-7.
@
Epidemiology
Pathogenesis
COAGULATION
INDEPENDENT
ANGIOGENESIS
COAGULATION
DEPENDENT
PARs
Fibrin
Disease management
Thrombin
TF
Awareness
Angiogenesis and coagulation
28
Fribourg et al, Hématologie 2006;12(6):400-11
@
Epidemiology
Awareness
Disease management
Pathogenesis
Platelet multitargeted pro-tumoral impact
29
Disease management
2- Treatment related thrombotic factors
Awareness
Pathogenesis
Epidemiology
30
↓ physiological inhibitors (AT, PC, PS)
↓ fibrinolytic activity (PAI-1)
↓ protein C system and APCR
Epidemiology
Pathogenesis
 procoagulant factors and cytokines after cell lysis
 platelet activation
 endothelium leukocyte adhesion
 endothelium prothrombotic profile (free radicals…)
Disease management
• Chemotherapy and/or hormonal therapy
• Surgery and/or Radiotherapy
• Catheters and extrinsic venous compression
Awareness
Cancer and Extrinsic VTE risk factors
31
Recent surgery w/ institutionalization
21.72
Trauma
12.69
Institutionalization without recent surgery
7.98
Malignancy with chemotherapy
6.53
Prior central venous catheter or pacemaker
5.55
Prior superficial vein thrombosis
4.32
Malignancy without chemotherapy
4.05
Neurologic disease w/ extremity paresis
3.04
Serious liver disease
0.10
Heit et al, Thromb Haemost. 2001;86(1):452-63.
@
Epidemiology
Pathogenesis
Odss
Ratio
Disease management
RISK FACTOR / CHARACTERISTICS
Awareness
Cancer is an independent risk factors for VTE
32
Chemotherapy
Tumor cell
Cytokine secretion
VEGF
TNF-α
IL-1β
Decrease protein C and S
Decrease AT III
Monocyte/Macrophage
Expression of TF
Increase PAI-1
Alterations in coagulation
And fibrinolytic molecules
Direct vascular
Endothelial toxicity
Endothelial cell
Apoptosis and
Increase in TF
activity
TF
@
TF
Increase in
Endothelial
TF expression
TF
Awareness
TF
Disease management
Pathogenesis
TF
Platelet Activation
Haddad et al, Thromb Res. 2006;118(5):555-68.
Epidemiology
Prothrombotic effect of antineoplasic agents
33
@
Nalluri et al, JAMA. 2008;300(19):2277-85.
Disease management
• Erythropoiesis-stimulating agents (EPO)
=> OR 1.7 (IC95% 1.4-2.1)
• Red Blood cell or Platelet Transfusions
=> OR 1.6 (IC95% 1.5-1.7)
@
Epidemiology
Bevacizumab (Avastin®)
Arterial Thrombosis => 0R=2,0 (IC95% 1.1 -3.8)
Venous Thrombosis => OR=1.3 (IC95% 1.1-1.6)
Khorana et al, Arch Intern Med. 2008;168(21):2377-81.
Awareness
•
Pathogenesis
Treatment, cancer and thrombosis
34
Zangari et al, J Clin Oncol. 2010 ;28(1):132-5.
@
Awareness
Disease management
Pathogenesis
Multiple myeloma and thalidomide alone = VTE incidence 2-4%
Epidemiology
VTE and anti-angiogenic treatment
35
=> OR=5.5 (95% CI 1.2 to 24.6)
– Previous KT
=> OR=3.8 (95% CI 1.4 to 10.4)
– Left Insertion
=> OR=3.5 (95% CI 1.6 to 7.5)
– Superior Vena Cava
=> OR=2.7 (95% CI 1.1 to 6.6)
– Arm vs Thorax
=> OR=8.1 (95% CI 3.5 to 19.1)
Lee et al, J Clin Oncol. 2006;24(9):1404-8.
@
Epidemiology
Pathogenesis
– >1 insertion attempt
Disease management
• “Associated” risk factors:
Awareness
Catheter, cancer and thrombosis
36
=> OR=6.0 (95% CI 2.1 to 16.8)
– Anesthesia > 2 h
=> OR=4.5 (95% CI 1.1 to 19)
– Bed rest > 3 days
=> OR=4.4 (95% CI 2.5 to 7.8)
– Advanced stage
=> OR=2.7 (95% CI 1.4 to 5.2)
– Age > 60 y
=> OR=2.6 (95%CI 1.2 to 5.7)
Agnelli et al, Ann Surg. 2006;243(1):89-95.
@
Epidemiology
Pathogenesis
– Previous DVT
Disease management
• “Associated” risk factors:
Awareness
Surgery, cancer and thrombosis
37
Epidemiology
Pathogenesis
Disease Management
2- Anticoagulation
3- Management of patients
• Treatment of DVT/PE
• Prophylaxis in cancer surgery and medical patients
38
Awareness
Disease management
1- Assessment of risk factors
Disease management
1- Assessment of risk factors
Awareness
Pathogenesis
Epidemiology
39
40
Epidemiology
Risk Factors for VTE in
Medical Oncology Patients
– Metastatic disease, venous stasis due to bulky disease
• Type of antineoplastic treatment
– Multiagent regimens, hormones,
anti-VEGF, radiation
• Miscellaneous VTE risk factors
– Previous VTE, hospitalization, immobility, infection, thrombophilia
Disease management
• Stage, grade, and extent of cancer
Awareness
– Ovary, brain, pancreas, lung, colon
Pathogenesis
• Tumor type
46 (23)
Immobile in the last 30 days
BMI ≥25
Smoking
Previous VTE
Active CHF
COPD Exacerbation
Sepsis
104 (52)
Hormonal therapy
13 (6.5)
Abdel Razek et al. J Thromb Thrombolysis. 2011;31(1):107-12.
@
115 (57.5)
82 (41)
12 (6)
6 (3)
5 (2.5)
48 (24)
Epidemiology
Surgery in the past 3 months
Pathogenesis
No (%)
Disease management
Risk factor
Awareness
VTE Risk Factors
in 200 cancer patients in Middle East
41
Epidemiology
VTE according to number of risk factors
Pathogenesis
30
25
20
10
5
0
0
1
2
3
No. of risk factors
Abdel Razek et al. J Thromb Thrombolysis. 2011;31(1):107-12.
@
4
≥5
Disease management
15
Awareness
Percentage of Patients (%)
35
42
DVT
Epidemiology
26%
SVC thrombosis
6%
Internal jugular
thrombosis
Brain sinuses
thrombosis
Portal vein
thrombosis
IVC thrombosis
Abdel Razek et al. J Thromb Thrombolysis. 2011;31(1):107-12.
1.5%
5%
@
3.5%
3%
Pathogenesis
PE
Disease management
55.5%
Awareness
Sites of VTE
43
Khorana et al, Blood. 2008;111(10):4902-4907.
Epidemiology
Awareness
Disease management
Pathogenesis
VTE Predictive Models:
The Khorana’s model
44
Risk Score
1. Site of cancer
Very high risk ( stomach, pancreas )
2
High risk ( Lung, Lymphoma, Gynecologic, bladder, testicular )
1
2. Prechemotherapy platelet count 350 x 109/ L or more
1
3. Hemoglobin level less than 100g/l or use of red cell growth
factors
1
4. Prechemotherapy leukocyte count more than 11 x 109 / L
1
5. BMI: 35 kg/m2 or more
1
Khorana et al, Blood. 2008;111(10):4902-4907.
Disease management
Patient characteristic
Awareness
RISK SCORE BASED ON PRETREATMENT RISK FACTORS
Pathogenesis
Epidemiology
Predictive model
Chemotherapy-associated VTE
45
Epidemiology
Khorana’s Predictive Model
0
1-2
>3
Khorana et al, Blood. 2008;111(10):4902-4907.
Awareness
Disease management
– Low Risk
– Intermediate Risk
– High Risk
Pathogenesis
• Three Groups:
46
Epidemiology
Actual Incidence
Estimated Incidence
95 % Confidence Limits
Pathogenesis
18%
16%
14%
12%
8%
6%
4%
2%
0%
0
1
2
3
4
Risk Score
0
1
2
3
4
N
1,352
974
476
160
33
VTE(%) /2.4
mos.
0.8
1.8
2.7
6.3
13.2
Disease management
10%
Awareness
Incidence of VTE Over 2.4 Months
Predictive Model
7%
6%
7.1%
Development cohort
6.7%
Validation cohort
Disease management
5%
4%
3%
1.8% 2.0%
2%
1%
0.8%
0.3%
0%
Risk
n=734 n=374
Low (0)
Khorana et al, Blood. 2008;111(10):4902-4907.
n=1627 n=842
Intermediate(1-2)
n=340 n=149
High(>3)
Awareness
Rate of VTE over 2.5 mos (%)
8%
Epidemiology
• 4000 out-patients (derivation and validation), prospective
• Sub-analysis of larger study (chemotherapy & neutropenia)
Pathogenesis
Risk Model Validation
Thrombosis in 44 pts (6,4%)
↑ sP-selectin (> 53,1 ng/mL, 75th percentile)
HR = 2.6 , 95% CI 1.4-4.9 (p=0,003)
VTE at 6 months 11,9% vs 3,7% (p=0,002)
Ay et al, Blood. 2008;112(7):2703-2708
@
Epidemiology
Pathogenesis
Prospective Study (n=687)
Mean Follow-Up 415 d [221-722]
Breast (n=125), Lung (n=86), Stomach (n=130), Pancreas (n=42), Kidney
(n=19), Bladder (n=72), Brain (n=80), Haematological (n=91), Others
(n=42)
Disease management
Soluble P-selectin: VTE Risk Factor?
Awareness
Score Extension: including P-selectin?
49
↑F1+2
↑DDimers
DDimers and F1+2 NI
Ay C et al. J Clin Oncol 2009;27:4124-4129.
Epidemiology
Pathogenesis
HR
3,6 (1,4 – 9,5)
Disease management
↑F1+2
↑ DDimers
Awareness
Score extension: including D-Dimers?
50
Ay et al, Blood. 2010 .116(24):5377-82
@
Epidemiology
Awareness
Disease management
Pathogenesis
Cancer, Biomarkers and VTE
51
Disease management
2- Anticoagulation
Awareness
Pathogenesis
Epidemiology
52
• Pharmacological
–
–
–
–
Unfractionated heparin
Low-molecular-weight heparins
Vitamin K antagonists
Fondaparinux
Epidemiology
Pathogenesis
– Graduated compression stockings
– Intermittent pneumatic compression
– Foot pump
Disease management
• Mechanical
Awareness
Methods of thromboprophylaxis
53
VII
X
//
VIIa
FXI
IX
NAPC2
ASIS-rTFPI
FXIa
Xa
//
Intrinsic tenase
Anti-Xa
Pentasaccharide+AT
Heparins + AT
Rivaroxaban
Apixaban
DX-9065a
//
Prothrombinase
Va - Xa
Phospholipids
…
//
IXa
Anti-IXa
Aptamers, and
others
+ VIIIa
+ phospholipids
Va
V
Anti-IIa
VIII
VIIIa
amplification
Thrombin
//
Platelets
Fibrinogen
Activation
Fibrin
Heparins+AT
Hirudin
Argatroban
Dabigatran
…
Epidemiology
Tissue Factor
Pathogenesis
Atherosclerotic plaque
Disease management
Blood borne TF
Vascular lesion
Awareness
Mechanisms of action of mains anticoagulants
Pharmacological
17
UFH
0
LMWH
17
Non-Pharmacological
11
Pneumatic compression
3.5
Elastic Stocking
7.5
Total
Abdel Razek et al. J Thromb Thrombolysis. 2011;31(1):107-12.
28
@
Epidemiology
Pathogenesis
(%)
Disease management
Method of Prophylaxis
Awareness
Cancer patients
Type & rate of prophylaxis
55
Pharmacological
Prophylaxis
Non-pharmacological
Prophylaxis
Both Methods
30
25
20
15
10
5
IN PATIENTS
Abdel Razek et al. J Thromb Thrombolysis. 2011;31(1):107-12.
Epidemiology
OUT PATIENTS
@
Awareness
0
Pathogenesis
35
Disease management
Prophylaxis Rate
Inpatients vs. Outpatients
56
Disease management
LMWH
Awareness
Pathogenesis
Epidemiology
57
IIa
AT
UFH
%
Disease management
LMWH
Pathogenesis
AT
Xa
anti-Xa
activity
0
5000
10000
15000
20000
Molecular weight (daltons)
25000
30000
Awareness
Pentasaccharide :
PM = 1700 D
Epidemiology
Molecular weight distribution and mechanism
of action of heparins
58
Epidemiology
Profile of thrombin generation
250
thrombine (nM)
Antithrombotic treatment
150
Disease management
200
normal
100
50
0
Pathogenesis
Hypercoagulable state
0
10
time (min)
20
Awareness
hypocoagulability
59
In production method
In pharmacokinetics
In distribution of molecular weight
In anti-Xa/anti-IIa ratio per mg
In the inhibition of thrombin generation
Epidemiology
Pathogenesis
–
–
–
–
–
Disease management
• LMWHs belong to the same family of drugs but
they differ:
Awareness
LMWHs differences
60
Prandoni et al, Lancet Oncol. 2005;6(6):401-10.
@
Epidemiology
Awareness
Disease management
Pathogenesis
Multitargeted anticancer effect of LMWH
61
• > 200 known food, drug, and botanical interactions
• Frequent discontinuation 2/2 chemotherapy induced
thrombocytopenia and invasive procedures
– slow onset and offset of action
• GI disturbances (n/v/d, loss of appetite, dysphagia)
Epidemiology
Pathogenesis
• Patients with malignancy have a therapeutic INR ~43% of the
time as compare to 53% in non-cancer counterparts
62
Disease management
WARFARIN (VKA)
Limitations in Cancer
@
Awareness
• Need for therapeutic monitoring
 in cancer surgery
 in cancer medical patients
Disease management
• Practical approach: Clinical cases
• Treatment of DVT/PE
• VTE Prophylaxis
Awareness
3- Management of patients
Pathogenesis
Epidemiology
63
Disease management
• Practical approach: Clinical cases
Awareness
3- Management of patients
Pathogenesis
Epidemiology
64
Epidemiology
Pathogenesis
• John M, 59 year old man, 82 kg, 176 cm
• History of COPD (heavy smokers)
• Diagnosis: stage IV squamous cell carcinoma of
the lung with liver metastasis.
• Three courses of chemotherapy started.
• After the completion of the 3 cycles, the CT
scans of chest showed a bilateral pulmonary
emboli
Disease management
Clinical case 1
65
Awareness
65
2 - VKA
3 - LMWH followed by VKA
4 - LMWH only
5 - ASA
6 - Thrombolytics
7 - No treatment
Epidemiology
Pathogenesis
1 - UFH
Disease management
(multiple answers)
Awareness
Clinical case 1
Q1- Which curative treatment do you prescribe ?
66
2 - 3 to 6 months
3 - 1 year
4 - Indefinite
5 - Don't know
Epidemiology
Pathogenesis
1 - 1 to 3 months
Disease management
(1 answer)
Awareness
Clinical case 1
Q2-What length of treatment?
67
• Well controlled hypertension
• Diagnosis of colon adenocarcinoma with liver metastasis
• Chemotherapy (3 courses)
• Admitted with fever, cough, and dyspnea
• CXR: consolidation
• CBC with 105 000 platelets/ml and 700 neutrophils
• Oxygen saturation 90 % and results of blood cultures pending.
Pathogenesis
cardiovascular diseases.
Disease management
• Linda L , 67 yo woman, 70 kg and 160 cm with a family history of
Awareness
Clinical case 2
Epidemiology
68
2 - Gender
3 - History of hypertension
4 - Acute pneumonia
5 - Cancer
Epidemiology
Pathogenesis
1 - Age
Disease management
Clinical case 2
Q1- What are the risk factors of VTE?
69
Awareness
6 - Anti cancer chemotherapy
2 - Elastic Stockings
3 - UFH
4 - Fondaparinux
5 - VKA
6 - ASA
7 - LMWH
Pathogenesis
1 - Nothing
Disease management
(Multiple answers)
Awareness
Clinical case 2
Q2- What is your attitude in terms of prophylaxis of VTE?
Epidemiology
70
1 - Until discharge
2 - 7 days
3 - 15 days
4 - 5 weeks
5 - As long as the risk remains
Epidemiology
Pathogenesis
(1 answer)
Disease management
Q3- How long do you prescribe the prophylaxis treatment?
Awareness
Clinical case 2
71
Pathogenesis
• Scheduled to have surgery in 2 days for an adenocarcinoma
of the right ovary.
• Decision to perform an ovariectomy with lymphadenectomy
and a complete peritoneal examination with a possible
hysterectomy
• Blood tests normal in terms of red cells and white cells but
platelets count: 40 000 /ml on the last complete blood
count
Disease management
• Rose C, 42 year old, 65 kg, 170 cm
Awareness
Clinical case 3
Epidemiology
72
1 - No prophylaxis
2 - UFH
3 - ASA
4 - Intermittent Pneumatic Compression
5 - LMWH
Epidemiology
Pathogenesis
(1 answer)
Disease management
Q1- What is your attitude in terms of prophylaxis of VTE?
Awareness
Clinical case 3
73
• Treatment of DVT/PE
Disease management
Pathogenesis
3- Management of patients
Awareness
Epidemiology
74
Therapeutic strategy of VTE in cancer patients (1)
Epidemiology
75
Pathogenesis
Diagnosis of VTE
Treatment with VKA
Disease management
UFH or LMWH
Long term secondary prevention
Awareness
Acute phase
Therapeutic strategy of VTE in cancer patients (2)
Epidemiology
76
Enoxaparin : 150 anti-Xa IU/kg o.d.
Dalteparin : 150 anti-Xa IU/kg o.d.
Tinzaparin : 175 anti-Xa IU/kg o.d.
3 to 6 months
Disease management
Long term secondary prevention
Awareness
Acute phase
Pathogenesis
Diagnosis of VTE
Dalteparin
OAC
CANTHANOX
(Meyer 2002)
Enoxaparin
OAC
LITE
(Hull ISTH 2003)
Tinzaparin
OAC
ONCENOX
(Deitcher ISTH
2003)
Enox (Low)
Enox (High)
OAC
N
0.002
6
336
336
9
17
3
67
71
11
21
3
80
87
6
11
0.03
3.4
3.1
6.7
NS
6
32
36
34
0.09
6
4
7
16
6
8
NS
0.09
NS
NS
Epidemiology
Death
(%)
39
41
NS
11 0.03
23
23
22
NS
Pathogenesis
CLOT Trial
(Lee 2003)
Design
Recurrent
Major
VTE
Bleeding
(%)
(%)
NR
Awareness
Study
Length of
Therapy
(Months)
Disease management
Treatment of Cancer-Associated VTE
12 months
Disease management
Duration of treatment 12 weeks
Cancer/proximal
DVT and/or PE
UFH/VKA (INR 2-3); n=100
Primary outcome:
recurrent VTE or death
Hull et al. Am J Med 2006;119:1062-1072
@
recurrent VTE or
death
Awareness
R
Epidemiology
Tinzaparin 175 anti-Xa IU/kg o.d. ; n= 100
Pathogenesis
Long-term LMWH vs UFH/VKA in DVT Patients
with Cancer
78
Epidemiology
Cumulative incidence of recurrent VTE in the
cancer groups
79
Pathogenesis
LMWH
UFH/VKA
7%
7%
47%
47%
p=0,044
Major bleeding
during 3 months treatment interval
Deaths at 12 months
Hull et al. Am J Med 2006;119:1062-1072
@
Awareness
7%
Disease management
16%
Epidemiology
Cumulative incidence of recurrent VTE in the
cancer groups
80
LMWH
Major bleeding
Deaths
Hull et al. Am J Med 2006;119:1062-1072
@
7%
47%
UFH/VKA
7%
47%
Disease management
7%
Awareness
p=0,044
Pathogenesis
16%
Comparison of the efficacy of long term LMWH
vs VKA in secondary prevention of VTE
Pathogenesis
LMWH; dose o.d.
Enoxaparin 150
aXa IU/kg
Dalteparin 200
– 150 aXa IU/kg
Tinzaparin 175
aXa IU/kg
@
Awareness
Disease management
Enoxaparin 1
– 1,5 aXa IU/kg
Hull et al. Am J Med 2006;119:1062-1072
Fereti G et al. Chest 2006;130:1808-1816
Epidemiology
81
Anticoagulant treatment (VKA or LMWH or UFH) significantly decreases one
year overall mortality
– relative risk of 0.905 95% CI, 0.847–0.967; p=0.003
•
LMWHs are more effective than warfarin
– relative risk for mortality is 0.877 for patients treated with LMWH, and 0.942 for
those receiving warfarin, (absolute risk difference 8% for LMWH and 3% for
warfarin; p>0,05).
•
Among all anticoagulants only warfarin significantly increased the risk of major
and fatal bleeding.
•
In contrast, treatment with LMWHs is associated with a significantly less
important increase of bleeding risk compared to VKA
Kuderer et al; Cancer 2007;110:1149–1160.
Lazo-Langner A J Thromb Haemost 2007; 5: 729–737.
Epidemiology
Pathogenesis
•
Disease management
The meta-analysis of 11 studies which enrolled in total 3343 patients with cancer
showed that :
Awareness
Anticoagulant treatment and mortality
in cancer patients
82
1 month 200 IU/kg od
CANCER* PATIENTS WITH
ACUTE DVT or PE
5 months 160 IU/kg od
Randomization
*Solid tumor malignancy
[N = 677]
Dalteparin
5 to 7 days 200 IU/kg od
VKA (Oral Anticoagulant)
6 months
►
Primary Endpoints: Recurrent VTE and Bleeding
►
Secondary Endpoint: Survival
Lee A et al. N Engl J Med 2003;349:146-53.
Epidemiology
Pathogenesis
Dalteparin
Disease management
Dalteparin
Awareness
Treatment of DVT Trial
CLOT: Design
Epidemiology
Pathogenesis
25
Risk reduction = 52%
p-value = 0.0017
20
Disease management
VKA
15
10
Dalteparin
5
0
0
Lee A et al. N Engl J Med 2003;349:146-53.
30
60
90
120
150
Days Post Randomization
180
210
Awareness
Probability of Recurrent VTE, %
CLOT: Results
Reduction in Recurrent VTE
Enoxaparin
1.5mg/kg SQ daily
for 3 Months
Patients Cancer +
VTE
Enoxaparin
1.5mg/kg SQ daily
Warfarin sodium
daily for 3 Months
(INR 2.0-3.0)
Meyer et al. Arch Intern Med. 2002;162:1729-1735
Pathogenesis
3 Month
Treatment Period
Disease management
Initial
Awareness
CANTHANOX: Design
Epidemiology
85
Meyer et al. Arch Intern Med. 2002;162:1729-1735
Awareness
Major Bleeding @ 3 Months
• Warfarin: 6 cases were fatal
• Enoxaparin: 0 fatal cases
Disease management
Pathogenesis
CANTHANOX: Efficacy outcomes
Epidemiology
86
Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Epidemiology
Awareness
Disease management
Pathogenesis
VTE treatment in cancer patients
Comparison LMWH vs VKA
87
Disease management
Pathogenesis
Prophylaxis:
Cancer surgery
Awareness
Epidemiology
88
89
Neurosurgery
0.5–2.3
2–3.6
Head and neck
0.1–0.2
0.2–1.4
Gastrointestinal
0.2–1.6
0.9–2.6
0.3–1
0.4–3.7
0.3
1.2–2.3
0.2–2.4
0.9–3.1
Urological
Gynaecological
Orthopaedic
*Symptomatic VTE in patients at 91 days after surgery.
White RH, et al. Thromb Haemost. 2003;90:446-55.
@
Pathogenesis
VTE malignancy (%)*
Disease management
VTE no malignancy (%)
Awareness
Surgical procedure
Epidemiology
Incidence of VTE in cancer
surgical patients
Venography
Day 10 ± 2
3-month
follow-up
Surgery
Enoxaparin
40 mg
o.d. s.c.
Venography
Day 10 ± 2
3-month
follow-up
Randomization
Enoxaparin
40 mg s.c.
Primary endpoint: documented venographic DVT
Secondary endpoint: major hemorrhage
Bergqvist et al, Br J Surg. 1996;83(11):1548-52.
@
Epidemiology
Surgery
UFH
5000 IU
t.i.d. s.c.
Pathogenesis
UFH
5000 IU s.c.
Disease management
2 hours before surgery
Awareness
Efficacy of LMWH in elective cancer surgery
ENOXACAN Study: Design
90
Incidence of Outcome Event
14.7%
4.1%
2.9%
@
Major Bleeding
Awareness
N=312
Disease management
N=319
VTE
Bergqvist et al, Br J Surg. 1996;83(11):1548-52.
P>0.05
Pathogenesis
18.2%
Epidemiology
ENOXACAN study: Results
91
Bergqvist et al, Br J Surg. 1996;83(11):1548-52.
@
Epidemiology
Awareness
Disease management
Pathogenesis
LMWH vs. UFH in general cancer surgery
92
14
VTE
Bleeding
Incidence (%)
12
10
8
6
4
2
0
2500 IU
o.d.
5000 IU
o.d.
Total cases (n=2097)
Bergqvist et al, Br J Surg. 1996;83(11):1548-52.
@
2500 IU
o.d.
5000 IU
o.d.
Cancer (n=1364)
Disease management
p < 0.001
Pathogenesis
p < 0.001
Awareness
16
Epidemiology
Elective abdominal surgery Higher LMWH
doses are required in cancer patients
93
•
Had greater postoperative drain losses (p = 0.0001)
•
Had higher transfusion of packed cells (p = 0.006) or whole
blood (p = 0.001)
•
More frequently underwent re-operation for bleeding
(p = 0.003)
•
and suffered more wound hematomas (p = 0.001)
Kakkar et al. ISTH 2001
@
Epidemiology
Pathogenesis
Cancer patients
Disease management
Comparison of cancer (6124) and non-cancer (16,954) patients
undergoing major surgery, receiving UFH or LMWH
Awareness
Higher complications in cancer surgery patients
despite prophylaxis
94
Just in time post-op: 4-6h
Pathogenesis
operation
1
0,8
0,6
0,4
increased bleeding risk
0,2
0
-16
-12
-8
-4
0
4
8
12
16
20
24
Disease management
odds ratio for DVT
1,2
Epidemiology
Timing of initial administration of DVT prophylaxis
with LMWH in elective hip arthroplasty
Hull et al, Arch Intern Med. 2001;161(16):1952-60.
@
Awareness
time from surgery (h)
95
Epidemiology
Duration of prophylaxis
Time course of post-operative VTE
Risk of VTE
Disease management
Pathogenesis
Prophylaxis
~1 week
?
Surgery
From Agnelli ISTH 2003
@
Discharge
Awareness
Time
96
up to 40% of VTE occur post-discharge
• Persisting risk factors in cancer are often present
• Benefit of therapy seen in similar risk orthopedic
patients
Epidemiology
Pathogenesis
•
Disease management
• Autopsy and clinical series
Awareness
Rationale for prolonged prophylaxis in cancer
patients
97
Enoxaparin 40 mg o.d. (n = 164)
Enoxaparin
40 mg o.d.
8±2
days
4 - 5 weeks
Bilateral
phlebography
Randomization
Bergqvist et al, N Engl J Med. 2002 Mar 28;346(13):975-80.
http://www.nejm.org/doi/pdf/10.1056/NEJMoa012385
Disease management
Placebo (n = 167)
Awareness
Planned curative surgery
for pelvic or abdominal cancer
(>45 min)
Pathogenesis
Prolonged LMWH thromboprophylaxis following cancer surgery
Epidemiology
ENOXACAN II: Design
98
Epidemiology
ENOXACAN II: Results
Primary endpoint: VTE at day 28
12.0
Placebo
10
8
p<0,05
6
4.8
Enoxaparin 40mg
4
1.8
2
0.6
Disease management
Frequency (%)
12
Pathogenesis
14
All VTE
Bergqvist et al, N Engl J Med. 2002 Mar 28;346(13):975-80.
Proximal DVT
Awareness
0
99
Epidemiology
100
FAME: design
(5,000 IU s.c. q.d.)*
+ TED
Dalteparin (5,000 IU s.c. q.d.)
No further prophylaxis
Major abdominal
surgery
* Pre-op dose.
TED = graduated compression stockings.
Rasmussen MS, et al. J Thromb Haemost. 2006;4:2384-90.
Bilateral venography
(assessor-blinded)
Disease management
Dalteparin
Pathogenesis
21 Days
Awareness
7 Days
Epidemiology
101
FAME: results
RRR = 77%
p = 0.009
16.3%
15
10
7.3%
8.0%
5
1.8%
0
VTE
Proximal DVT
Dalteparin
1 week
Rasmussen MS, et al. J Thromb Haemost. 2006;4:2384-90.
4 weeks
Disease management
Pathogenesis
RRR = 55%
p = 0.012
Awareness
20
CANBESURE: design
N/Saline placebo
Major abdominal
surgery
Bilateral venography
* Pre-op dose.
@
TED = graduated compression stockings.
Kakkar VV, et al. J. Thromb Haemost. 2010;8(6):1223-1229
Pathogenesis
bemiparin (3500 IU s.c. q.d.)
Disease management
bemiparin
(3500 IU s.c. q.d.)*
20 ± 2 days
Awareness
8 ± 2 days
Epidemiology
102
Placebo
(n = 240)
RRR
n (%; 95% CI)
p value
25 (10.1)
32 (13.3)
24.4 (53.8 to -23.7)
0.2634
Death (all causes)
6 (2.4)
3 (1.3)
-93.6 (51.0 to -665.1)
0.5043
Major VTE **
2 (0.8)
11 (4.6)
82.4 (96.1 to 21.5)
0.0096
Major VTE plus symptomatic DVT
3 (1.2)
11 (4.6)
73.6 (92.5 to 6.6)
0.0256
DVT
19 (7.7)
29 (12.1)
36.6 (63.4 to -10.0)
0.1010
proximal
1 (0.4)
8 (3.3)
87.9 (98.5 to 4.0)
0.0186
distal only
18 (7.3)
21 (8.8)
17.1 (54.7 to -51.8)
0.5434
Non-fatal PE
0 (0.0)
0 (0.0)
–
–
Primary efficacy end-point*
*Primary efficacy end-point: any DVT, non-fatal PE and deaths from all causes.
**Major VTE: proximal DVT, non-fatal PE and VTE-related deaths.
Kakkar VV, et al. J. Thromb Haemost. 2010;8(6):1223-1229
@
Disease management
Bemiparin
(n = 248)
Awareness
CANBESURE: efficacy
Pathogenesis
Epidemiology
103
Bemiparin
(n = 315)
Placebo
(n = 310)
Major bleeding
2 (0.6)
1 (0.3)
Minor bleeding*
1 (0.3)
1 (0.3)
Major bleeding
2 (0.6)
2 (0.6)
Minor bleeding*
1 (0.3)
1 (0.3)
During double-blind period
During double-blind plus follow-up periods
Disease management
CANBESURE: safety
Pathogenesis
Epidemiology
104
Kakkar VV, et al. J. Thromb Haemost. 2010;8(6):1223-1229
@
Awareness
*Clinically relevant.
•
•
No available data for new antithrombotic agents
Epidemiology
Pathogenesis
•
Dosage: higher dose of LMWH than in non cancer
patients
Timing of the first injection
 preoperative, early postoperative ?
 just in time’ (R. Hull)
Optimal prophylactic treatment
 Extended Grade 2A (for how long?)
Disease management
•
Awareness
Optimal thromboprophylaxis in
cancer patients undergoing surgery
105
Disease management
Pathogenesis
Prophylaxis:
Medical patient
Awareness
Epidemiology
106
Kakkar AK, et al. Oncologist 2003, 8:381–388
Epidemiology
Pathogenesis
<5% of medical oncologists
use antithrombotic
prophylaxis in nonsurgical
cancer patients
Disease management
The Frontline Survey
Awareness
Thromboprophylaxis
in non-surgical cancer patients
107
70
60
Cancer:
Surgical
Major
Abdominothoracic
Surgery (Elderly)3 Medical
Inpatients4
52
50
38
40
Confirmed DVT
(Inpatients)5
42
33
30
Cancer:
Medical
20
5
10
0
FRONTLINE FRONTLINE:
Surgical
Medical
Stratton
Bratzler
Rahim
1. Kakkar AK, et al. Oncologist 2003, 8:381–388
4.Rahim SA et al. Thromb Res. 2003;111:215-219
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340
5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912
@
@
Pathogenesis
80
89
DVT FREE
Disease management
Rate of Appropriate Prophylaxis, %
90
Major
Surgery2
Awareness
100
Cancer:
FRONTLINE Survey1—
3891 Clinician
Respondents
Epidemiology
VTE Prophylaxis Is Underused
in Patients With Cancer
Cohen et al, Semin Hematol. 2001 Apr;38(2 Suppl 5):31-8.
@
19.5 %
Enoxaparin 20 mg
(n=56)
15.4 %
Enoxaparin 40 mg
(n=45)
9.7 %
Epidemiology
Pathogenesis
Overall
157 patients
14.27 %
(1102 total
randomized
patients)
Placebo
(n=56)
Disease management
Results in the patient subgroups, history of cancer
or current cancer
Awareness
MEDENOX Study
Cancer subgroup
109
RESULTS
• Symptomatic VTE: 2.0% nadroparin vs 3.9% placebo
(p=0.02)
• Bleeding: Major bleeding = 0.7% nadroparin vs 0% placebo
(p=0.18) - Minor bleeding: 7.4% nadroparin vs 7.9%
placebo
Agnelli G et al. Lancet Oncol 2009; 10: 943-949.
@
Epidemiology
Pathogenesis
Disease management
• 1150 ambulatory patients with lung, gastrointestinal,
pancreatic, breast, ovarian, or head and neck cancer were
randomised to nadroparin (3800 IU od, n=779) or placebo
(n=387), in a 2:1 ratio for the duration of chemotherapy up to
a maximum of 4 months.
Awareness
Nadroparin for thromboprophylaxis:
PROTECHT
P=0.6
VTE
Riess et al. ASCO May 2009 and ISTH July 2009.
bleeding
Disease management
• Enoxaparin 1 mg/kg once
daily x 12 weeks then 40 mg
once daily
Awareness
P<0.01
• Randomized to gemcitabine
+ enoxaparin or gemcitabine
• Primary outcome:
symptomatic VTE and fatal
PE at 12 weeks
Pathogenesis
• 312 patients receiving
chemotherapy for APC
Epidemiology
Prophylaxis in Pancreatic Cancer:
CONKO 004 Trial
111
Prophylaxis in Medical Outpatients
Efficacy outcome: VTE
Upper
limit
p-Value
FAMOUS
0.77
0.21
2.84
0.70
TOPIC-1
1.01
0.36
2.81
0.99
TOPIC-2
0.53
0.25
1.11
0.09
PRODIGE
0.66
0.29
1.49
0.32
PROTECHT
0.50
0.22
1.13
0.10
SIDERAS
0.82
0.23
2.94
0.76
0.64
0.44
0.94
0.02
CONKO004
0.35
0.16
0.75
0.01
FRAGEM
0.37
0.17
0.81
0.01
0.36
0.20
0.62
<.001
Other Cancers
Pancreas
0.1
0.2
0.5
LMWH
Kuderer et al. Presented at ASH 2009.
Epidemiology
Disease management
Lower
limit
1
2
5
Control
10
Awareness
MH risk
ratio
MH risk ratio and 95% CI
Pathogenesis
Statistics for each study
112
Prophylaxis in Medical Outpatients
Safety outcome: major bleeding
Upper
limit
p-Value
FAMOUS
2.906
0.119
70.874
0.513
TOPIC-1
7.040
0.366 135.290
0.196
TOPIC-2
1.607
0.534
4.837
0.399
PRODIGE
4.394
0.523
36.887
0.173
PROTECHT
5.457
0.303
98.434
0.250
Sideras
0.412
0.083
2.051
0.279
1.846
0.927
3.675
0.081
CONKO004
1.425
0.410
4.952
0.577
FRAGEM
1.050
0.153
7.218
0.960
1.304
0.459
3.703
0.618
Other Cancers
Pancreas
0.01
Kuderer et al. Presented at ASH 2009.
Epidemiology
Disease management
Lower
limit
0.1
LMWH
1
10
Control
100
Awareness
MH risk
ratio
MH risk ratio and 95% CI
Pathogenesis
Statistics for each study
113
Epidemiology
Pathogenesis
Disease management
A limited number of studies have suggested possible effect
of heparins on cancer progression and survival
– MALT
– FAMOUS (Advanced cancer subgroup)
– TOPIC1-2
Two recent studies have shown significant decrease in
symptomatic VTE but no significant effect on survival
– PROTECHT
– CONKO-04
Other studies are ongoing
– SAVE-ONCO
Awareness
Antineoplasic activity of heparins?
No definite answer
114
Enoxaparin (40 mg o.d.)*
FUP visit
Day 35-42
Randomization
Stratification on:
AVE5026 (20 mg o.d.)*
- Cancer/non-cancer
- Geographic region
- CrCl < or ≥30 mL/min
*Dose adapted in case of SRI
EOT visit
Day 7-10
SURGERY
ENDPOINT:
• Any Confirmed VTE
(systematic bilateral venography D7-D11)
• All cause deaths
Epidemiology
Pathogenesis
Double-blind, superiority study
Disease management
N = 4,400
Awareness
SAVE ABDO:
study design
– different histological types of cancer,
– different stage of disease
– different life expectancy.
• Subgroups were not pre-specified rendering a bias in the post-hoc
analysis
• The duration of LMWH treatment varies from some weeks to life-long
Epidemiology
Pathogenesis
• Heterogeneous groups of patients were included
Disease management
Limitations of RCT assessing the influence of
antithrombotic treatment in patients with cancer
Awareness
• Patients who might have some benefit from antithrombotic treatment
were not systematically excluded (i.e. those with recent cardiovascular or
thrombo-embolic episodes)
116
• The efficacy of anticoagulation is not universal for all
histological types of cancer
• Cancer histology is a significant determinant for cancer
procoagulant activity on thrombin generation process and for
some types of cancer it depends at least on the expression of TF
Epidemiology
Pathogenesis
• Administration of LMWH in patients with cancer who do not
suffer VTE is effective and safer than treatment with VKA.
Disease management
• Anticoagulation with LMWH or VKA adjunct to the
recommended anticancer treatment has an antitumor effect
which is verified by the clinical trials.
Awareness
Conclusions
117
• Tailoring the LMWH dose according to the histological type
of cancer might be an attractive issue for clinical studies
aiming the optimisation of the antithrombotic prophylaxis
or treatment in this context.…
Epidemiology
Pathogenesis
• The impact of each LMWH is modified by the histological
type of cancer
Disease management
• LMWHs have a variable inhibitory effect on cancer induced
thrombin generation based on their anti-Xa activity
Awareness
Perspectives
118
Epidemiology
Pathogenesis
1- Lessons from registries
2- Guidelines
119
Awareness
Disease management
Awareness
Disease management
1- Lessons from registries
Awareness
Pathogenesis
Epidemiology
120
Are we properly prophylaxing cancer patients at risk of
VTE ???
Epidemiology
Pathogenesis
is actually implemented within our Department??
Disease management
Did we ever check whether DVT prophylaxis in cancer patients
Awareness
Questions
121
(N =37,356)
Assessable
Surgical
patients
(N =30,827)
51.8 % at Risk for VTE
10 objectives
recommended prophylaxis
41.5 % at Risk for VTE
64.4 % at Risk for VTE
39.5 % receiving ACCP-
58.5 % receiving ACCP-
recommended prophylaxis
recommended prophylaxis
~ 40% unprophylaxed
~ 60% unprophylaxed
@
Awareness
50.2 % receiving ACCP-
Disease management
(N=35,329)
20 objectives
Cohen et al, Lancet. 2008 ;371(9610):387-94.
Epidemiology
68,183 assessable patients
Assessable
Medical
patients
Pathogenesis
ENDORSE global study results
122
Pre-specified analysis of
ENDORSE data within Medical
patients (N=37,356 patients)
At risk receiving ACCP prophylaxis
2,984
Active non-infectious respiratory disease
44%
1,005
3,259
41%
1,329
4,384
1,939
1,649
Ischemic stroke
37%
612
1,072
Active malignancy
Epidemiology
37%
397
0
500
1,000
1,500
40%
2,000
2,500
3,000
3,500
4,000
4,500
Awareness
Pulmonary infection
Disease management
2,298
Acute Heart Failure
@
45%
1,335
Infection (non-respiratory)
ENDORSE. Thromb Haemost 2010
% at-risk
receiving
ACCP
prophylaxis
At risk for VTE
Pathogenesis
A basic fact:
Cancer patients are clearly under-prophylaxed!
123
@
Bergmann et al, Thromb Haemost. 2010 ;103(4):736-48
Epidemiology
Awareness
Disease management
Factors associated with the use of
ACCP-recommended prophylaxis
Pathogenesis
Pre-specified analysis of ENDORSE data within
Medical patients (N=37,356 patients)
124
N=2266
Countries
Total
N=2266
Lebanon
453
Syria
220
Kazakhstan
348
Iran
355
Georgia
400
KSA
200
Gulf
290
Primary
objectives
90.8% at Risk for VTE
7.9% have Cl to
VTE prophylaxis
9.2% do not need
prophylaxis
92.1% eligible for
prophylaxis
55.6% received prophylaxis
31.3% received
prophylaxis
39.9% received ACCP
Recommended prophylaxis
26.8% received
prophylaxis
Awaiting subgroup analysis of Cancer patients!
Taher et al, J Thromb Thrombolysis. 2011;31(1):47-56.
@
Epidemiology
Pathogenesis
Objectives: 1- % of hospitalized patients at risk of VTE
2- % of at-risk patients who are actually receiving prophylaxis
Disease management
Design: Multinational, cross-sectional survey of the prevalence of VTE risk and prophylaxis use in hospital patients.
Awareness
Registry from Middle East
125
Existence of a VTE protocole
Epidemiology
Who received ANY prophylaxis among those who
should have VTE prophylaxis?
3.77
Surgical patient
Immobile on admission/indep
Pathogenesis
2.15
2.08
Contraceptives
2.03
Acute respiratory failure
1.76
Varicose veins
Central venous catheter
1.55
Immobile during hospitalization/indep
1.54
Chronic heart failure
1.52
Active cancer
Disease management
1.59
1.25
Male gender
0.8
Cancer therapy
0
0.5
1
Adjusted Odds Ratio (ORa)
Taher et al, J Thromb Thrombolysis. 2011;31(1):47-56.
@
1.5
2
2.5
3
3.5
4
Awareness
0.79
126
• Median length of hospital stay: 8 days.
• VTE Prophylaxis Compliance rate:
– USA:
– Non-USA:
Tapson et al, Chest. 2007;132(3):936-45.
@
38%
54%
Epidemiology
Pathogenesis
• Median age: 71 years
Disease management
• 15,156 high-risk medically ill patients enrolled at 52
hospitals.
Awareness
The IMPROVE Study
127
Primary-admission Category and rate of prophylaxis
Pathogenesis
46
40
24
20
0
Cardiac
Pulmonary
Neurological
Primary-admission category
Tapson et al, Chest. 2007;132(3):936-45.
@
Cancer
Awareness
45
Disease management
50
thromboprophylaxis (%)
Patients receiving
60
Epidemiology
IMPROVE Study:
128
Disease management
2- Guidelines
Awareness
Pathogenesis
Epidemiology
129
VTE treatment in cancer pts:↑
hemorrhage and therapeutic failures
•
Heterogeneity in clinical practices
•
Practices in France inspired by Italian
(2006) and North American (2007)
recommendations
•
Foreseeable increase of venous
thrombosis in cancer patients: ↑ nb
of cancers + ↑ use of KT and
implanted chambers
Prandoni et al, Blood. 2002;100(10):3484-8.
@
Pathogenesis
•
Disease management
VTE independent risk factor for
death in cancer pts
(842 pts VTE, LMWH + Warfarin 3 months)
130
Awareness
•
Epidemiology
WHY Clinical Practice Guidelines
for “Treatment established VTE in cancer pts?”
Epidemiology
Pathogenesis
Khorana et al, J Clin Oncol. 2009 ;27(29):4919-26
@
Disease management
Recommendation. Hospitalized patients with cancers should be considered candidates for VTE
prophylaxis with anticoagulants in the absence of bleeding or other contraindications to
anticoagulation.
Awareness
1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR
VTE PROPHYLAXIS
131
Surgical cancer
patients
Ambulatory
cancer patients
Central venous
catheters
FNCLCC
For all (unless contraindications)
Hospitalized cancer patients,
immobilized, with acute medical
illness
NA
Low-dose UFH, LMWH, or fondaparinux
Laparotomy, laparoscopy, or
thoracotomy > 30 min
Prolonged prophylaxis: High risk
major abdominal or pelvic
surgery
Recommended
Major cancer surgery
Prolonged prophylaxis:
For high risk abdominal or pelvic
cancer surgery
Prolonged prophylaxis: after
major abdominal or pelvic
surgery
LMWH or UFH;
highest risk: + mechanical
methods
LMWH, UFH, or fondaparinux
(± pneumatic compression)
LMWH or UFH
Not recommended
except multiple myeloma w.
thalidomide / lenalidomide
Not recommended
except multiple myeloma w.
thalidomide / lenalidomide
Not recommended
except multiple myeloma w.
thalidomide / lenalidomide
NA
Not recommended
Not recommended
Not
recommended
NA
AIOM, Italian Association of Medical Oncology; FNCLCC, French National Federation of the League of Centers Against
Cancer; NA, not addressed
Adapted from: Khorana et al, J Clin Oncol. 2009 ;27(29):4919-26. @
Epidemiology
AIOM/ESMO
Pathogenesis
Hospitalized
cancer patients
Consider for all
(unless contraindications)
NCCN
Disease management
ASCO
Awareness
Recommendations for the Prevention of VTE in
Patients With Cancer
132
PRIMARY PREVENTION IN CANCER SURGERY
Epidemiology
133
• Start before surgery (or as soon as possible in the PO).
• Mechanical methods can be added in very high risk patients.
• Do not use only mechanical methods unless anticoagulants are
contraindicated because of active bleeding!!!
Lyman GH et al. J Clin Oncol 2007; 25:5490-5505.
Hirsh J et al. Chest. 2008 ;133(6):110S-112S.
Disease management
• Pharmacological prophylaxis with UFH, LMWH or fondaparinux
unless contraindicated.
Awareness
• Cancer patients undergoing surgery (›30 min) should receive
routine VTE prophylaxis (appropriate for the type of surgery)
(GRADE IA).
Pathogenesis
RECOMMENDATIONS:
PRIMARY PREVENTION IN CANCER SURGERY
Epidemiology
134
• Dosing is important as well as the duration of treatment.
UFH: TID. LMWH: e.g. dalteparin: 5000 U. Minimum: 7-10
days.
Pathogenesis
• Extended prophylaxis for up to 4 weeks in patients
undergoing abdominal or pelvic cancer surgery with high risk
features such as: residual malignant disease PO, obese pts,
Disease management
RECOMMENDATIONS (II):
or previous history of VTE.
Lyman GH et al. J Clin Oncol 2007; 25:5490-5505.
Hirsh J et al. Chest. 2008 ;133(6):110S-112S.
Awareness
• We need controlled trials for every type of surgery.
Disease management
Awareness
SHOULD HOSPITALIZED
PATIENTS WITH CANCER
RECEIVE ANTICOAGULATION
FOR VTE PROPHYLAXIS?
Pathogenesis
Epidemiology
135
HOSPITALIZED PATIENTS
Epidemiology
PRIMARY PREVENTION IN CANCER
136
Lyman GH et al. J Clin Oncol 2007; 25:5490-5505.
Hirsh J et al. Chest. 2008 ;133(6):110S-112S.
Disease management
Awareness
• HOSPITALIZED patients with cancer should be considered
candidates for VTE anticoagulation prophylaxis…ASCO. ACCP:
routine in bedridden with acute medical illness…. in the
absence of bleeding or other contraindication.
Pathogenesis
RECOMMENDATIONS:
HOSPITALIZED PATIENTS
Epidemiology
PRIMARY PREVENTION IN CANCER
137
• Fondaparinux: 2.5 mg/d
Lyman GH et al. J Clin Oncol 2007; 25:5490-5505.
Hirsh J et al. Chest. 2008 ;133(6):110S-112S.
Disease management
• UFH: 5 000 U TID
Awareness
• Enoxaparin: 40 mg/d
Pathogenesis
RECOMMENDATIONS:
Disease management
Awareness
SHOULD AMBULATORY
PATIENTS WITH CANCER
RECEIVE ANTICOAGULATION
FOR VTE PROPHYLAXIS
DURING SYSTEMIC CHEMO?
Pathogenesis
Epidemiology
138
AMBULATORY PATIENTS
Epidemiology
PRIMARY PREVENTION IN CANCER
139
• More data are needed (ASA for low risk pts?)
Lyman GH et al. J Clin Oncol 2007; 25:5490-5505.
Hirsh J et al. Chest. 2008 ;133(6):110S-112S.
Palumbo et al. Leukemia. 2009;23(10):1904-12.
@
Disease management
• Patients receiving thalidomide or lenalidomide +
dexametasone o QT should receive thromboprophylaxis
(ASCO). LMWH or warfarin is indicated.
Awareness
• For cancer patients receiving chemotherapy or hormonal
therapy we recommend against routine thromboprohylaxis
(Grade 1C).
Pathogenesis
RECOMMENDATIONS:
Epidemiology
Pathogenesis
Disease management
Awareness
WHAT IS THE BEST
TREATMENT FOR CANCER
PATIENTS WITH ESTABLISHED VTE
TO PREVENT RECURRENT VTE?
140
SECONDARY PREVENTION IN CANCER PATIENTS
Epidemiology
141
Lyman GH et al. J Clin Oncol 2007; 25:5490-5505.
Hirsh J et al. Chest. 2008 ;133(6):110S-112S.
Disease management
Awareness
• LMWH is the preferred approach for the initial 5-10 days of
anticoagulant treatment in cancer patient with established
VTE.
• LMWH given for at least 6 months is also the preferred
approach for long-term anticoagulant therapy. (Grade 1A).
• VKA (INR 2-3) are an option only when LMWH are not
available.
Pathogenesis
RECOMMENDATIONS
RECOMMENDATIONS (III)
• Bleeding should be considered mainly in high risk bleeding
patients: elderly, CNS malignancies. Careful monitoring and
dose adjustment if necessary.
Lecumberri R et al. Haematologica. 2005;90(9):1258-66
Lyman GH et al. J Clin Oncol 2007; 25:5490-5505.
Hirsh J et al. Chest. 2008 ;133(6):110S-112S.
Epidemiology
Pathogenesis
RECOMMENDATIONS (II)
• After 6 months, individualize therapy (risk/benefit). (Grade IC)
• Indefinite anticoagulation should be considered for selected
patients with active cancer such as those with metastases and
those receiving chemo (Grade 1C)
Disease management
(LONG-TERM)
Awareness
SECONDARY PREVENTION IN CANCER PATIENTS
142
Epidemiology
Pathogenesis
Disease management
Awareness
SHOULD PATIENTS WITH
CANCER RECEIVE ANTICOAGULANTS
IN THE ABSENCE OF ESTABLISHED
VTE TO IMPROVE SURVIVAL?
143
Klerk J et al. Clin Oncol 2005 Apr 1;23(10):2130-5
Kakkar AK et al. J Clin Oncol. 2004 May 15;22(10):1944-8.
Lecumberri R et al. Haematologica. 2005;90(9):1258-66
Pathogenesis
Disease management
RECOMMENDATIONS:
• Anticoagulants are not recommended to improve survival
in patients with cancer without VTE.
• Nevertheless, patients should be encouraged to participate
in clinical trials designed to evaluate LMWH as an adjunct
to standard anticancer therapy
Awareness
ANTINEOPLASIC EFFECT OF ANTITHROMBOTICS
Epidemiology
144
YES
ANTICOAG
YES
Contraindication?
Contraindication?
YES
MECHANICAL
NO
ANTICOAG +
MECHANICAL
Contraindication?
YES
MECHANICAL
NO
ASPIRIN
LMWH
VKA
YES
No
PROPHYLAXIS
NO
routine
prophylaxis
Pathogenesis
NO
Does person
have multiple
myeloma and
treatment?
Disease management
Undergoing
major
surgery?
YES
NO
NO
Awareness
NO
Hospitalized
for acute
medical
illness?
Epidemiology
PATIENT WITH
ACTIVE MALIGNANCY
145
146
Epidemiology
VTE AND CANCER
TAKE-HOME MESSAGES:
• Usually thrombosis occurs early (at diagnosis, first 3 months).
• Risk of thrombosis versus risk of bleeding.
• Evidence based approach (guidelines, stratification).
• Talk with your patient-Informed decision (risk vs benefit).
• Legal considerations.
Disease management
• Thrombosis influence in prognosis and survival.
Awareness
• Cancer is a high risk scenario for thrombosis.
Pathogenesis
• Increasing incidence of both.
Epidemiology
Pathogenesis
Recognizing cancer patients at risk for DVT and
identifying appropriate candidates for long-term
prophylaxis and/or treatment with approved and
indicated therapies are among the most important
challenges encountered in contemporary clinical
practice for oncologists.
Disease management
Implementation of VTE prophylaxis continues to be
problematic, despite detailed global guidelines
Awareness
MISSION AND CHALLENGES
147
Epidemiology
Pathogenesis
Khorana et al, Cancer. 2007 Nov 15;110(10):2339-46.
Khorana et al, Blood. 2008;111(10):4902-4907.
Khorana et al, J Clin Oncol. 2009 ;27(29):4919-26
Klerk J et al. Clin Oncol 2005 Apr 1;23(10):2130-5
Kuderer et al. Presented at ASH 2009.
Kuderer et al; Cancer 2007;110:1149–1160.
Lazo-Langner A J Thromb Haemost 2007; 5: 729–737.
Lecumberri R et al. Haematologica. 2005;90(9):1258-66
Lee A et al. N Engl J Med 2003;349:146-53.
Lee AY et al. Circulation. 2003;107:23:I17-I21
Lee et al, J Clin Oncol. 2006;24(9):1404-8.
Lee et al, Thromb Res. 2003;110(4):167-72.
Levitan N, et al. Medicine. 1999;78:285-91.
Lyman GH et al. J Clin Oncol 2007; 25:5490-5505.
Meyer et al. Arch Intern Med. 2002;162:1729-1735
Palumbo et al. Leukemia. 2009;23(10):1904-12.
Pawlinski et al, Thromb Haemost. 2004 ;92(3):444-50.
Prandoni et al, Blood. 2002;100(10):3484-8.
Prandoni et al, Lancet Oncol. 2005;6(6):401-10.
Rahim SA et al. Thromb Res. 2003;111:215-219
Rance et al, Lancet. 1997;350(9089):1448-9.
Rasmussen MS, et al. J Thromb Haemost. 2006;4:2384-90.
Riess et al. ASCO May 2009 and ISTH July 2009.
Ruf et al, J Thromb Haemost. 2007;5(8):1584-7.
Sandhu et al, Cancer. 2010 ;116(11):2596-603.
Stratton MA et al. Arch Intern Med. 2000;160:334-340
Taher et al, J Thromb Thrombolysis. 2011;31(1):47-56.
Tapson et al, Chest. 2007;132(3):936-45.
Wun T et al, Best Pract Clin Haematol 2009;22:9-23
Zangari et al, J Clin Oncol. 2010 ;28(1):132-5.
Disease management
Abdel Razek et al. J Thromb Thrombolysis. 2011;31(1):107-12.
Agnelli et al, Ann Surg. 2006;243(1):89-95.
Agnelli G et al. Lancet Oncol 2009; 10: 943-949.
Agnelli ISTH 2003
Alcalay et al, J Clin Oncol. 2006;24:1112-1118
Ay C et al. J Clin Oncol 2009;27:4124-4129.
Ay et al, Blood. 2010 .116(24):5377-82
Bergmann et al, Thromb Haemost. 2010 ;103(4):736-48
Bergqvist et al, Br J Surg. 1996;83(11):1548-52.
Bergqvist et al, N Engl J Med. 2002 Mar 28;346(13):975-80.
Bick et al. J Support Oncol 2006 ;
Blom et al, JAMA. 2005 Feb 9;293(6):715-22.
Boccaccio et al, J Clin Oncol. 2009 ;27(29):4827-33
Bona et al. Thromb Haemost 1995; 74(4):1055-1058.
Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912
Chew et al J Thromb Haemost. 2008;6:601-608
Cohen et al, Lancet. 2008 ;371(9610):387-94.
Cohen et al, Semin Hematol. 2001 Apr;38(2 Suppl 5):31-8.
Elalamy et al, Pathol Biol 2008;56(4):184-94
ENDORSE. Thromb Haemost 2010
Fereti G et al. Chest 2006;130:1808-1816
Fribourg et al, Hématologie 2006;12(6):400-11
Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
Haddad et al, Thromb Res. 2006;118(5):555-68.
Heit et al, Thromb Haemost. 2001;86(1):452-63.
Hirsh J et al. Chest. 2008 ;133(6):110S-112S.
Hull et al, Arch Intern Med. 2001;161(16):1952-60.
Hull et al. Am J Med 2006;119:1062-1072
Kakkar AK et al. J Clin Oncol. 2004 May 15;22(10):1944-8.
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Kakkar et al. ISTH 2001
Kakkar VV, et al. J Thromb Haemost. 2010;8(6):1223-1229
Awareness
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