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Welcome to this Science-to-Strategy Summit
Clotting, Cancer, and Controversies
Critical Challenges and Landmark
Advances in Thrombosis Management
The Evolving and Foundation Role of LMWHs in Cancer and
VTE Prophylaxis: Applying Science, Expert Analysis, and
Landmark Trials to the Front Lines of Oncology Practice
Program Chairman
Ajay Kakkar, MBBS, PhD, FRCS
Head of the Centre for Surgical Sciences
Barts and the London
Queen Mary’s School of
Medicine and Dentistry
The Thrombosis Research Institute
London, UK
Welcome and Program Overview
CME-accredited symposium jointly sponsored by the
Postgraduate Institute of Medicine and CMEducation Resources
Commercial Support: Sponsored by an independent educational
grant from Eisai, Inc.
Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies
COI: Full faculty disclosures provided in syllabus and at the
beginning of the program
Program Educational Objectives
As a result of this session, physicians will be able to:
► Review recent trials, research, and expert analysis of issues focused on
thrombosis and cancer.
► Specify strategies for risk-directed prophylaxis against DVT in at risk
patients with cancer.
► Explain how to assess and manage special needs of cancer patients at
risk for DVT, with a focus on protecting against recurrent DVT.
► Describe how to risk stratify patients undergoing cancer surgery, and
implement ACCP-mandated pharmacologic and non-pharmacologic
measures aimed at DVT prophylaxis.
► Review landmark clinical trials focusing on DVT prophylaxis in patients
with cancer.
► Explain how to appropriately use the range of pharmacologic options
available for thrombosis management in patients with malignancy.
Program Faculty
Program Chairman
Ajay Kakkar, MBBS, PhD, FRCS
Head of the Centre for Surgical
Sciences
Barts and the London
Queen Mary’s School of Medicine
and Dentistry
Thrombosis Research Institute
London, UK
Alex C. Spyropoulos, MD, FACP, FCCP
Chair, Department of Clinical
Thrombosis
Lovelace Medical Center
Clinical Associate Professor of
Medicine
University of New Mexico
Albuquerque, New Mexico
Distinguished Panel Member,
Consultant, and Visiting Professor
Craig M. Kessler, MD
Samuel Z. Goldhaber, MD
Professor of Medicine and
Professor of Medicine, Cardiovascular
Pathology
Division Harvard Medical School
Georgetown University Medical
Director, Venous Thromboembolism
Center
Research Group
Director of the Division of
Director, Anticoagulation Service
Coagulation
Department of Laboratory Medicine Brigham and Women’s Hospital
Boston, MA
Washington, DC
Faculty COI Financial Disclosures
Ajay Kakkar, MBBS, PhD, FRCS
Grants/research support: sanofi-aventis, AstraZeneca, Pfizer
Consultant: Pfizer, sanofi-aventis
Craig M. Kessler, MD
Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline,
Octapharma
Consultant: sanofi-aventis, Eisai, NovoNordisk
Alex C. Spyropoulos, MD, FACP, FCC
Consultant: sanofi-aventis, Eisai, Bayer, Boehringer-Ingelheim
Speaker’s Bureau: sanofi-aventis Eisai
Samuel Z. Goldhaber, MD
Grant/Research Support: sanofi-aventis, GSK, Eisai
Consultant: sanofi-aventis, BMS, Emisphere, Boehringer-Ingelheim
Introduction and Chairman’s Overview
Clotting, Cancer, And Controversies:
What The Cascade Of Evidence And
Current Thinking Tell Us
The Evolving Science, Epidemiology, and
Foundation Role of Low Molecular Weight Heparin
in the Setting of Cancer
Program Chairman
Ajay Kakkar, MBBS, PhD, FRCS
Head of the Centre for Surgical Sciences
Barts and the London
Queen Mary’s School of Medicine and Dentistry
The Thrombosis Research Institute
London, UK
Comorbidity Connection
COMORBIDITY
CONNECTION
SUBSPECIALIST
STAKEHOLDERS
CAP
UTI
Cancer
Heart Failure
ABE/COPD
Respiratory Failure
Myeloproliferative Disorder
Thrombophilia
Surgery
History of DVT
Other
Infectious diseases
Oncology
Cardiology
Pulmonary medicine
Hematology
Oncology/hematology
Interventional Radiology
Hospitalist
Surgeons
EM
PCP
Epidemiology of First-Time VTE
Variable
Finding
Seasonal Variation
Possibly more common in winter
and less common in summer
Risk Factors
25% to 50% “idiopathic”
15%–25% associated with cancer;
20% following surgery (3 mo.)
Recurrent VTE
6-month incidence: 7%;
higher rate in patients with cancer
Recurrent PE more likely after PE
than after DVT
Death After Treated VTE
30 day incidence 6% after
incident DVT
30 day incidence 12% after PE
Death strongly associated with
cancer, age, and cardiovascular
disease
White R. Circulation. 2003;107:I-4 –I-8.)
Epidemiology of VTE
► One major risk factor for VTE is ethnicity, with a
significantly higher incidence among
Caucasians and African Americans than among
Hispanic persons and Asian-Pacific Islanders.
► Overall, about 25% to 50% of patient with firsttime VTE have an idiopathic condition, without
a readily identifiable risk factor.
► Early mortality after VTE is strongly associated
with presentation as PE, advanced age, cancer,
and underlying cardiovascular disease.
White R. Circulation. 2003;107:I-4 –I-8.)
Comorbidity Connection
Overview
Comorbidity
Connection
Acute Medical Illness and VTE
Among Patients Receiving Placebo or
Ineffective Antithrombotic Therapy
Acute Medical
Illness
Heart failure
NYHA class III
NYHA class IV
Relative Risk
Risk
1.08 (0.72-1.62)
0.89 (0.55-1.43)
1.48 (0.84-2.6)
X2
0.05
0.12
1.23
P Value
.82
.72
.27
Acute
respiratory
disease
1.26 (0.85-1.87)
1.03
.31
Acute
infectious
disease
1.50 (1.00-2.26)
3.54
.06
Acute
rheumatic
disease
1.45 (0.84-2.50)
1.20
.27
Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
Acute Medical Illness and VTE
Multivariate Logistic Regression Model
for Definite Venous Thromboembolism (VTE)
Risk Factor
X2
Odds Ratio
(95% CI)
Age >75 y
Cancer
Previous VTE
1.03 (1.00-1.06)
1.62 (0.93-2.75)
2.06 (1.10-3.69)
0.0001
0.08
0.02
Acute
infectious
disease
1.74 (1.12-2.75)
0.02
Chronic
respiratory
disease
0.60 (0.38-0.92)
0.02
Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
Comorbid Condition and DVT Risk
► Hospitalization for surgery (24%) and for medical illness (22%)
accounted for a similar proportion of the cases, while nursing
home residence accounted for 13%.
► The individual attributable risk estimates for malignant
neoplasm, trauma, congestive heart failure, central venous
catheter or pacemaker placement, neurological disease with
extremity paresis, and superficial vein thrombosis were 18%,
12%, 10%, 9%, 7%, and 5%, respectively.
► Together, the 8 risk factors accounted for 74% of disease
occurrence
Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd.
Arch Intern Med. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein
thrombosis and pulmonary embolism: a population-based study
VTE Recurrence
Predictors of First Overall VTE Recurrence
Baseline
Characteristic
Hazard Ratio
(95% CI)
Age
1.17 (1.11-1.24)
Body Mass Index
1.24 (1.04-1.47)
Neurologic disease with
extremity paresis
1.87 (1.28-2.73)
Malignant neoplasm
None
With chemotherapy
Without chemotherapy
1.00
4.24 (2.58-6.95)
2.21 (1.60-3.06)
Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768
Clotting, Cancer, and Controversies
Cancer Surgery, Thrombosis, and the
Biology of Malignancy
A Science-to-Strategy Perspective—The
Foundation Role of LWMH at the Interface of
Thrombosis and Cancer
Program Chairman
Ajay Kakkar, MBBS, PhD, FRCS
Head of the Centre for Surgical Sciences
Barts and the London
Queen Mary’s School of
Medicine and Dentistry
The Thrombosis Research Institute
London, UK
Meta-analysis of
DVT Treatment Studies
Author
Year
No. of
studies
Cancer mortality
UFH
LMWH
Green
1992
2
21/67 (31%)
7/62 (11%)
Siragusa
1995
13
23/81 (28%)
10/74 (14%)
Famous: Trial Design
Dalteparin
5000 IU od
Advanced solid
tumour malignancy
R
N/Saline placebo
Treatment for 1 year or until death
1º Endpoint: 1 year mortality (50%  35%)
2º Endpoints: VTE and bleeding
Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
Kaplan–Meier survival distribution
function estimate
Kaplan–Meier survival curves for all ITT
patients in dalteparin and placebo groups
1.0
0.9
Dalteparin
Placebo
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
No. at risk: 190
184
12
24
36
48
60
72
Time from randomisation (months)
85
72
30
15
22
9
Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
12
8
5
5
4
2
84
Dalteparin
Placebo
Kaplan–Meier survival distribution
estimate
Survival Analysis:
Good Prognosis Patients
1.0
0.9
Dalteparin
Placebo
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.0
17 23
29
35
41 47
53
59 65
71
77
83
Time from randomisation (months)
No. at risk: 47 17 10
55 31
9 9
26 22 20
8
13
Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
8
8
5
5
3
5
2
5
0
3
Placebo
Dalteparin
LMWH and Survival:
Further Studies (2003)
CLOT
Solid tumor malignancy
and acute VTE
R
Oral anticoagulant
6 months
All patients received dalteparin
200 IU/kg od 5–7 days
SCLC study
Small cell lung
cancer (SCLC)
R
Patients with responsive limited
disease received thoracic radiotherapy
MALT
Solid tumor
malignancy
Dalteparin
1 month 200 IU/kg od
5 months 160 IU/kg od
R
Altinbas M, et al. J Thromb Haemost. 2004;2:1-6.
Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135.
Chemotherapy plus
dalteparin 5000 IU od
18 weeks
Chemotherapy (cyclophosphamide,
epirubicin, vincristine)
18 weeks
Nadroparin
2 weeks therapeutic dose
4 weeks 1/2 therapeutic dose
Placebo
6 weeks
Lee, et.al. N Engl J Med, 2003;349:146
SCLC Study Survival Curves
Overall population
Good prognosis population
0.8
Probability of survival
Probability of survival
1.0
p=0.01
0.6
Dalteparin
0.4
0.2
1.0
limited disease
0.8
p=0.007
0.6
Dalteparin
0.4
0.2
Placebo
Placebo
0.0
0.0
0
5
10
15
20
25
30
35
Months after randomization
Altinbas M, et al. J Thromb Haemost. 2004;2:1-6.
40
0
5
10
15
20
25
30
35
Months after randomization
40
CLOT Survival Curves
Good prognosis population
100
100
90
90
80
p=0.62
70
60
Dalteparin
50
OAC
40
30
20
Probability of survival (%)
Probability of survival (%)
Overall population
70
50
40
20
0
Lee, et.al. N Engl J Med, 2003;349:146
p=0.03
30
0
Days after randomization
OAC
60
10
30 60 90 120 150 180 210 240 270 300 330 360 390
Dalteparin
80
10
0
without metastases
0
30 60 90 120 150 180 210 240 270 300 330 360 390
Days after randomization
MALT Survival Curves
Overall population
Good prognosis population
>6 months survival
1.0
0.8
Probability of Survival
Probability of Survival
1.0
p=0.021
0.6
0.4
Nadroparin
0.2
0.8
p=0.010
0.6
0.4
0.2
Nadroparin
Placebo
Placebo
0.0
0.0
0
12
24
36
48
60
72
84
96
Months after randomization
Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135.
0
12
24
36
48
60
72
84
Months after randomization
96
LMWH and Prolonged Cancer Survival
Mechanistic explanations
VTE
Coagulation Protease
Direct Heparin
Other
Effect of Malignancy on Risk of
Venous Thromboembolism (VTE)
53.5
40
30
• Population-based case-control
(MEGA) study
• N=3220 consecutive patients with 1st
VTE vs. n=2131 control subjects
• CA patients = 7x OR for VTE vs.
non-CA patients
28
22.2
20.3
19.8
20
14.3
10
4.9
Type of cancer
1.1
> 15 years
2.6
5 to 10 years
1 to 3 years
3 to 12 months
0 to 3 months
Distant
metastases
Breast
Gastrointestinal
0
Lung
3.6
Hematological
Adjusted odds ratio
50
Time since cancer diagnosis
Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
Mechanisms of Cancer-Induced
Thrombosis: The Interface
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer therapy?
Interface of Biology and Cancer
Tumor cells
Angiogenesis,
Basement matrix
degradation.
Fibrinolytic
activities:
t-PA, u-PA, u-PAR,
PAI-1, PAI-2
Procoagulant Activities
IL-1,
TNF-a,
VEGF
PMN leukocyte
Activation of
coagulation
FIBRIN
Platelets
Monocyte
Endothelial cells
Falanga and Rickles, New Oncology:Thrombosis, 2005
Pathogenesis of Thrombosis in Cancer –
A Modification of Virchow’s Triad
1. Stasis


Prolonged bed rest
Extrinsic compression of blood vessels by tumor
2. Vascular Injury




Direct invasion by tumor
Prolonged use of central venous catheters
Endothelial damage by chemotherapy drugs
Effect of tumor cytokines on vascular endothelium
3. Hypercoagulability



Tumor-associated procoagulants and cytokines (tissue
factor, CP, TNFa, IL-1, VEGF, etc.)
Impaired endothelial cell defense mechanisms (APC
resistance; deficiencies of AT, Protein C and S)
Enhanced selectin/integrin-mediated, adhesive interactions
between tumor cells,vascular endothelial cells, platelets and
host macrophages
Mechanisms of Cancer-Induced
Thrombosis: Clot and Cancer Interface
►
Pathogenesis?
►
Biological significance?
►
Potential importance for cancer therapy?
Activation of Blood Coagulation in Cancer
Biological Significance?
►
Epiphenomenon?
Is this a generic secondary event (as in
inflammation, where clot formation is an
incidental finding)
Or, is clotting . . .
►
A Primary Event?
Linked to malignant transformation
Interface of Biology and Cancer
FVII/FVIIa
Tumor
Cell
TF
Blood Coagulation
Activation
VEGF
THROMBIN
FIBRIN
Angiogenesis
IL-8
PAR-2
Angiogenesis
TF
Endothelial cells
Falanga and Rickles, New Oncology:Thrombosis, 2005
Coagulation Cascade and Tumors
TF
Clottingindependent
Clottingdependent
Thrombin
Clottingdependent
Clottingindependent
PARs
ANGIOGENESIS
Tumor Growth And Metastasis
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31
Fibrin
Clottingdependent
Regulation of Vascular Endothelial Growth Factor Production
and Angiogenesis by the Cytoplasmic Tail of Tissue Factor
1.
TF regulates VEGF expression in human
melanoma cell lines
2.
Human cancer cells with increased TF are more
angiogenic (and, therefore, more “metastatic’) in
vivo due to high VEGF production
Abe et.al. Proc Nat Acad Sci 1999;96:8663-8668
Regulation of Vascular Endothelial Growth Factor Production
and Angiogenesis by the Cytoplasmic Tail of Tissue Factor
3.
The cytoplasmic tail of TF, which contains three
serine residues, appears to play a role in
regulating VEGF expression in human cancer
cells, perhaps by mediating signal transduction
4.
Data consistent with new mechanism(s) by
which TF signals VEGF synthesis in human
cancer cells; may provide insight into the
relationship between clotting and cancer
Abe et.al. Proc Nat Acad Sci 1999;96:8663-8668
Activation of Blood Coagulation
in Cancer: Malignant Transformation
►
Epiphenomenon?
►
Linked to malignant transformation?
1.
MET oncogene induction produces DIC in
human liver carcinoma
(Boccaccio et. al. Nature 2005;434:396-400)
2.
Pten loss produces TF activation and
pseudopalisading necrosis in human
glioblastoma
(Rong et.al. Ca Res 2005;65:1406-1413)
3.
K-ras oncogene, p53 inactivation and TF
induction in human colorectal carcinoma
(Yu et.al. Blood 2005;105:1734-1741)
Activation of Blood Coagulation
in Cancer: Malignant Transformation
“1. MET Oncogene Drives a Genetic Programme
Linking Cancer to Haemostasis”
►
MET encodes a tyrosine kinase receptor for
hepatocyte growth factor/scatter factor (HGF/SF) 

Drives physiological cellular program of

“invasive growth” (tissue morphogenesis,
angiogenesis and repair)
Aberrant execution (e.g. hypoxia-induced
transcription) is associated with neoplastic
transformation, invasion, and metastasis
Boccaccio et al Nature 2005;434:396-400
“MET Oncogene Drives a Genetic Programme
Linking Cancer to Haemostasis”
►
Mouse model of Trousseau’s Syndrome




Targeted activated human MET to the mouse
liver with lentiviral vector and liver-specific
promoter  slowly, progressive
hepatocarcinogenesis
Preceded and accompanied by a
thrombohemorrhagic syndrome
Venous thrombosis in tail vein occurred early
and was followed by fatal internal hemorrhage
Syndrome characterized by  d-dimer and PT
and  platelet count (DIC)
Blood Coagulation Parameters in Mice
Transduced with the MET Oncogene
Time after Transduction (days)
Transgene
Parameter
0
30
90
Platelets (x103)
968
656
800
D-dimer (µg/ml)
<0.05
<0.05
<0.05
PT (s)
12.4
11.6
11.4
_________
________________
_______________________________
MET
Platelets (x103)
974
350
150
D-dimer (µg/ml)
<0.05
0.11
0.22
PT (s)
12.9
11.8
25.1
GFP
Activation of Blood Coagulation
in Cancer: Malignant Transformation
2. “Pten and Hypoxia Regulate Tissue Factor
Expression and Plasma Coagulation By
Glioblastoma”
►
Pten = tumor suppressor with lipid and protein
phosphatase activity
►
Loss or inactivation of Pten (70-80% of
glioblastomas) leads to Akt activation and
upregulation of Ras/MEK/ERK signaling cascade
Rong, Brat et.al. Ca Res 2005;65:1406-1413
“Pten and Hypoxia Regulate Tissue Factor Expression
and Plasma Coagulation By Glioblastoma”
►
Glioblastomas characterized histologically by
“pseudopalisading necrosis”
►
Thought to be wave of tumor cells migrating
away from a central hypoxic zone, perhaps
created by thrombosis
►
Pseudopalisading cells produce VEGF and IL-8
and drive angiogenesis and rapid tumor growth
►
TF expressed by >90% of grade 3 and 4
malignant astrocytomas (but only 10% of
grades 1 and 2)
“Pten and Hypoxia Regulate Tissue Factor Expression
and Plasma Coagulation By Glioblastoma”
Results:
1. Hypoxia and PTEN loss  TF (mRNA, Ag
and procoagulant activity); partially reversed
with induction of PTEN
2. PTEN effect independent of lipid phosphatase
activity; dependent on protein phosphatase
3. Both Akt and Ras pathways modulated TF in
sequentially transformed astrocytes.
4. Ex vivo data:  TF by immunohistochemical
staining in pseudopalisades of 7 human
glioblastoma specimens
Activation of Blood Coagulation
in Cancer: Malignant Transformation
3. “Oncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells: Implications
For Tumor Progression And Angiogenesis”
►
►
►
►
►
Activation of K-ras oncogene and inactivation of p53 tumor
suppressor  TF expression in human colorectal cancer cells
Transforming events dependent on MEK/MAPK and PI3K
Cell-associated and MP-associated TF activity linked to genetic
status of cancer cells
TF siRNA reduced cell surface TF expression, tumor growth
and angiogenesis
TF may be required for K-ras-driven phenotype
Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
Activation of Blood Coagulation
in Cancer: Malignant Transformation
“Oncogenic Events Regulate Tissue Factor Expression In
Colorectal Cancer Cells: Implications For Tumor
Progression And Angiogenesis”
450
400
350
TF Activity (U/106 cells)
Mean Channel TF Flourescence
TF expression in cancer cells parallels genetic tumor progression
with an impact of K-ras and p53 status
300
250
200
150
100
50
0
HKh-2
HCT116
del/+
+/+
mut/+
+/+
379.2
mut/+
del/del
Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
160
140
120
100
80
60
40
20
0
HKh-2
HCT116
379.2
Activation of Blood Coagulation
in Cancer: Malignant Transformation
“Oncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells:
Implications For Tumor Progression And
Angiogenesis”
Effect of TF si mRNA on tumor growth in vitro and in vivo
Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
“Oncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells”
%VWF-Positive Area
Effect of TF si mRNA on new vessel formation in colon cancer
14
12
10
8
6
4
2
0
HCT116
SI-2
Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
SI-3
MG only
Activation of Blood Coagulation
in Cancer: Malignant Transformation
“Oncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells: Implications
For Tumor Progression And Angiogenesis”
Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology
Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
Mechanisms of Cancer-Induced
Thrombosis: Implications
1. Pathogenesis?
2. Biological significance?
3. Potential importance for
cancer therapy?
Clotting, Cancer, and Controversies
A Systematic Overview of VTE
Prophylaxis In The
Setting of Cancer
Linking Science to Clinical Practice
Craig M. Kessler, MD
Professor of Medicine and Pathology
Georgetown University Medical Center
Director of the Division of Coagulation
Department of Laboratory Medicine
Lombardi Comprehensive Cancer Center
Washington, DC
VTE and Cancer: Epidemiology
►
Of all cases of VTE:


►
Of all cancer patients:


►
About 20% occur in cancer patients
Annual incidence of VTE in cancer
patients ≈ 1/250
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, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
DVT and PE in Cancer
Facts, Findings, and Natural History
►
VTE is the second leading cause of death in
hospitalized cancer patients1,2
►
The risk of VTE in cancer patients undergoing
surgery is 3- to 5-fold higher than those without
cancer2
►
Up to 50% of cancer patients may have
evidence of asymptomatic DVT/PE3
►
Cancer patients with symptomatic DVT exhibit a
high risk for recurrent DVT/PE that persists for
many years4
1. Ambrus JL et al. J Med. 1975;6:61-64
2. Donati MB. Haemostasis. 1994;24:128-131
3. Johnson MJ et al. Clin Lab Haem. 1999;21:51-54
4. Prandoni P et al. Ann Intern Med. 1996;125:1-7
Clinical Features of VTE in Cancer
► VTE
has significant negative impact on
quality of life
► VTE
may be the presenting sign of occult
malignancy
• 10% with idiopathic VTE develop
cancer within 2 years
• 20% have recurrent idiopathic VTE
• 25% have bilateral DVT
Bura et. al., J Thromb Haemost 2004;2:445-51
Risk Factors for Cancer-Associated VTE
► Cancer

Type
• Men: prostate, colon, brain, lung
• Women: breast, ovary, lung

►
Stage
Treatments

Surgery
• 10-20% proximal DVT
• 4-10% clinically evident PE
• 0.2-5% fatal PE


Systemic
Central venous catheters (~4% generate
clinically relevant VTE)
Thrombosis and Survival:
Likelihood of Death After Hospitalization
1.00
Probability of
Death
DVT/PE and Malignant Disease
0.80
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0
20 40
60
80 100 120140 160 180
Number of Days
Levitan N, et al. Medicine 1999;78:285
As Number Of Cancer Survivors
Increases, VTE Rates Increase
4
Cancer Patients
3
2.5
2
1.5
1
Noncancer Patients
0.5
YEAR
99
97
95
93
91
89
87
85
83
81
0
79
VTE in Hospitalized Cancer
And Noncancer Patients (%)
3.5
Stein PD, et al. Am J Med 2006; 119: 60-68
Bladder
Cervix
Breast
Leukemia
Liver
Ovary
Colon
Kidney
Rectal
Prostate
Esophagus
Lung
Uterus
Lymphoma
Stomach
Myeloprol
Brain
Pancreas
Relative Risk of VTE in
Cancer Patients
VTE Risk And Cancer Type:
“Solid And Liquid”
Relative Risk of VTE Ranged From 1.02 to 4.34
4.5
4
3.5
3
2.5
2
1.5
1
0.5
Thrombosis Risk In Cancer
Primary Prophylaxis
►
Surgery
►
Chemotherapy
►
Radiotherapy
►
Central Venous Catheters
►
Acute Illness (immobilization)
Prevention and Management
of VTE in Cancer
►
Sparse data specifically related to cancer
patients was available until recently
►
Cancer patients are a small subset (< 20%) in
most of the largest trials of antithrombotic
therapy
►
Therefore, until the last two or three years, we
needed to extrapolate from non-cancer
patients, bearing in mind that cancer patients
are in the highest risk groups
Antithrombotic Therapy: Choices
Nonpharmacologic
(Prophylaxis)
Intermittent
Pneumatic
Compression
Elastic
Stockings
Inferior
Vena Cava
Filter
Pharmacologic
(Prophylaxis & Treatment)
Unfractionated
Heparin (UH)
Low Molecular
Weight Heparin
(LMWH)
Oral
Anticoagulants
New Agents: e.g.
Fondaparinux,
Direct anti-Xa inhibitors,
Direct anti-IIa, etc.?
Incidence of VTE in Surgical Patients
►
Cancer patients have 2-fold risk of postoperative DVT/PE and >3-fold risk of fatal
PE despite prophylaxis:
No Cancer
Cancer
N=16,954
N=6124
Post-op VTE
0.61%
1.26%
<0.0001
Non-fatal PE
0.27%
0.54%
<0.0003
Autopsy PE
0.11%
0.41%
<0.0001
Death
0.71%
3.14%
<0.0001
Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
P-value
Natural History of VTE in Cancer
Surgery: The @RISTOS Registry
►
Web-Based Registry of Cancer Surgery
Tracked 30-day incidence of VTE in 2373 patients
Type of surgery
• 52% General
• 29% Urological
• 19% Gynecologic
82% received in-hospital thromboprophylaxis
31% received post-discharge thromboprophylaxis
Findings
►
2.1% incidence of clinically overt VTE (0.8% fatal)
►
Most events occur after hospital discharge
►
Most common cause of 30-day post-op death
Agnelli, abstract OC191, ISTH 2003
Colorectal Cancer Resection
Overall, 1% incidence of VTE with 3.8 fold mortality
Transfused women 1.8-fold more likely to develop
VTE than non-transfused women
Association Between Transfusion and Venous Thromboembolism Stratified by Sex
in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 1994-2000
Variable
Incidence of VTE, %
Male Sex
No Transfusion (n = 5683)
Transfusion (n = 1156)
0.7
0.8
Female Sex
No Transfusion (n = 5565)
Transfusion (n = 1610)
0.9
2.1
Nilsson: Arch Surg, 142;2007:126–132
P Value
Stratified OR
(95% CI)*
Adjusted
P Value
.84
Referent
0.9 (0.5-1.9)
.85
<.001
Referent
1.8 (1.2-2.6)
.004
VTE Risk Factors in Surgical
Oncology Patients
►
Age >40 years
►
Cancer procoagulants
►
Thrombophilias
►
Adjuvant chemotherapy or hormonal
treatment
►
Complicated, lengthy surgery (tissue
trauma, immobilization)
►
Debilitation and slower recovery
►
Indwelling venous access
Surgical Prophylaxis
UFH better
LMWH better
Asymptomatic DVT
Clinical PE
Clinical thromboembolism
Cancer
Death
Non-cancer
Major hemorrhage
Total hemorrhage
Wound hematoma
Transfusion
0
Mismetti P et al. Br J Surg 2001;88:913–30
1.0
2.0
3.0
4.0
Prophylaxis in Surgical Patients
LMWH vs. UFH
►
Abdominal or pelvic surgery for cancer (mostly
colorectal)
►
LMWH once daily vs. UFH tid for 7–10 days post-op
►
DVT on venography at day 7–10 and symptomatic VTE
Study
ENOXACAN
1
Canadian Colorectal
DVT Prophylaxis 2
N
Design
Regimens
631
double-blind
enoxaparin vs. UFH
475
double-blind
enoxaparin vs. UFH
1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103
2. McLeod R, et al. Ann Surg 2001;233:438-444
Prophylaxis in Surgical Patients
Incidence of Outcome Event
20%
18.2%
P>0.05
ENOXACAN
14.7%
15%
UFH 5000 U tid
N=319
10%
2.9%
4.1%
5%
0%
VTE
Major Bleeding
ENOXACAN Study Group. Br J Surg 1997;84:1099–103
enoxaparin 40 mg
N=312
Prophylaxis in Surgical Patients
Incidence of Outcome Event
20%
16.9%
15%
P=0.052
13.9%
Canadian
Colorectal DVT
Prophylaxis Trial
UFH 5000 U tid
N=234
10%
enoxaparin 40 mg
N=241
5%
0%
1.5% 2.7%
VTE
(Cancer)
McLeod R, et al. Ann Surg 2001;233:438-444
Major Bleeding
(All)
Prophylaxis in Surgical Patients
Extended prophylaxis
►
Abdominal or pelvic surgery for cancer
►
LMWH for ~ 7 days vs. 28 days post-op
►
Routine bilateral venography at ~day 28
Study
N
Design
Regimens
ENOXACAN II
332
Double-blind
Enoxaparin vs. placebo
FAME
(subgroup)
198
Open-label
Dalteparin vs. no
prophylaxis
1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
2. Rasmussen M, et al (FAME) Blood 2003;102:56a
Incidence of Outcome Event
Extended Prophylaxis in
Surgical Patients
15%
12.0%
ENOXACAN II
10%
P=0.02
placebo
N=167
5.1%
4.8%
enoxaparin 40 mg
N=165
3.6%
5%
1.8%
0.6%
0%
VTE
Prox
DVT
0% 0.4%
NNT = 14
Any
Major
Bleeding Bleeding
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
Major Abdominal Surgery: FAME
Investigators—Dalteparin Extended
►
A multicenter, prospective, assessor-blinded, openlabel, randomized trial: Dalteparin administered for
28 days after major abdominal surgery compared to 7
days of treatment
►
RESULTS: Cumulative incidence of VTE was reduced
from 16.3% with short-term thromboprophylaxis
(29/178 patients) to 7.3% after prolonged
thromboprophylaxis (12/165) (relative risk reduction
55%; 95% confidence interval 15-76; P=0.012).
►
CONCLUSIONS: 4-week administration of dalteparin,
5000 IU once daily, after major abdominal surgery
significantly reduces the rate of VTE, without
increasing the risk of bleeding, compared with 1
week of thromboprophylaxis.
Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.
Gynecological Cancer Surgery
►
Paucity of level I/II studies in this population
►
Based on small historical studies:

Postoperative risk of DVT/PE varies 12%–35%

LDUH (5000 u bid) ineffective

LDUH 5000 u tid reduces risk by 50%–60%

Once-daily LMWH comparable to LDUH for efficacy
and safety
Gynecological Surgery
Cochrane Systematic Review
►
Meta-analysis of 8 randomized controlled trials
►
Heparin reduces risk of DVT by 70% (95% CI
0.10–0.89)
►
No evidence that anticoagulation reduces risk
of PE
►
No statistical difference between LDUH and
LMWH in efficacy and bleeding
Oates-Whitehead et al. Cochrane Database Syst Rev 2003;4:CD003679
Urological Cancer Surgery
Poorly studied population
Risk of VTE varies with type of surgery and diagnosis
DVT
PE
Fatal PE
1–3%
1–3%
0.6%
Cystectomy
8%
2–4%
2%
Radiological studies
51%
22%
Radical retropubic
prostatectomy
►
Small studies have suggested prophylaxis with either LDUH or
LMWH is effective and safe
►
Possible increased risk of pelvic hematoma and lymphocele
formation
Kibel, Loughlin. J Urol. 1995;153:1763-1774
Neurosurgery and VTE
OBSERVATIONS
►
Majority of patients undergoing
neurosurgery for malignancy
►
Risk of venographic VTE ~30%-40%
►
High risk of intracranial or intraspinal
hemorrhage
►
Mechanical prophylaxis preferred method
►
Use of anticoagulant prophylaxis remains
controversial in this setting
Neurosurgery and VTE Prophylaxis
Meta-analysis of three (3) RCTs evaluating
LMWH prophylaxis
►
ES
LMWH
RR
NNT/NNH
P
VTE
28.3%
17.5%
0.6
9
0.001
Proximal DVT
12.5%
6.2%
0.5
16
<0.01
Total bleeding
3.0%
6.1%
2.0
33
0.02
Major bleeding
1.3%
2.2%
1.7
115
0.30
One major bleeding event observed for every 7 proximal
DVTs prevented with LMWH
Iorio A, Agnelli G. Arch Intern Med. 2000;160:2327-2332
7th ACCP Consensus Guidelines
Grade
Recommendations for Cancer Patients
1A
Patients undergoing surgery should receive LDUH 5000
U tid or LMWH > 3400 U daily
2A
Patients undergoing surgery may receive post-hospital
discharge prophylaxis with LMWH
2A
No routine prophylaxis to prevent thrombosis secondary
to central venous catheters, including LMWH (2B) and
fixed-dose warfarin (1B)
1A
Patients hospitalized with an acute medical illness
should receive LDUH or LMWH
Geerts W, et al. Chest 2004; 126: 338S-400S
Central Venous Catheters
Thrombosis is a potential complication of central
venous catheters, including these events:
–Fibrin sheath formation
–Superficial phlebitis
–Ball-valve clot
–Deep vein thrombosis (DVT)
• Incidence up to 60% from historical data
• ACCP guidelines recommended routine prophylaxis
with low dose warfarin or LMWH
Geerts W, et al. Chest 2001;119:132S-175S
Prophylaxis for Venous Catheters
Placebo-Controlled Trials
Study
Regimen
N
CRT (%)
Reichardt*
2002
Dalteparin 5000 U od
285
11 (3.7)
placebo
140
5 (3.4)
Couban*
Warfarin 1mg od
130
6 (4.6)
2002
placebo
125
5 (4.0)
ETHICS†
Enoxaparin 40 mg od
155
22 (14.2)
2004
placebo
155
28 (18.1)
*symptomatic outcomes; †routine venography at 6 weeks
Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G,
et al. Proc ASCO 2004;23:730
Central Venous Catheters: Warfarin
Tolerability of Low-Dose Warfarin
►
95 cancer patients receiving FU-based infusion
chemotherapy and 1 mg warfarin daily
►
INR measured at baseline and four time points
►
10% of all recorded INRs >1.5
►
Patients with elevated INR
2.0–2.9
6%
3.0–4.9
19%
>5.0
7%
Masci et al. J Clin Oncol. 2003;21:736-739
Prophylaxis for Central
Venous Access Devices
Summary
►
Recent studies demonstrate a low
incidence of symptomatic catheterrelated thrombosis (~4%)
►
Routine prophylaxis is not warranted to
prevent catheter-related thrombosis,
but catheter patency rates/infections
have not been studied
►
Low-dose LMWH and fixed-dose
warfarin have not been shown to be
effective for preventing symptomatic
and asymptomatic thrombosis
7th ACCP Consensus Guidelines
Grade
Recommendations for Cancer Patients
1A
Patients undergoing surgery should receive LDUH 5000 U
tid or LMWH > 3400 U daily
2A
Patients undergoing surgery may receive post-hospital
discharge prophylaxis with LMWH
2A
No routine prophylaxis to prevent thrombosis secondary to
central venous catheters, including LMWH (2B) and fixeddose warfarin (1B)
1A
Patients hospitalized with an acute medical illness should
receive LDUH or LMWH
Geerts W, et al. Chest 2004; 126: 338S-400S
Primary Prophylaxis in Cancer
Radiotherapy in the Ambulatory Patient
►
No recommendations from ACCP
►
No data from randomized trials (RCTs)
►
Weak data from observational studies
in high risk tumors (e.g. brain tumors;
mucin-secreting adenocarcinomascolorectal, pancreatic, lung, renal cell,
ovarian)
►
Recommendations extrapolated from
other groups of patients if additional
risk factors present (e.g. hemiparesis
in brain tumors, etc.)
Risk Factors for VTE in
Medical Oncology Patients
► Tumor

Ovary, brain, pancreas, lung, colon
► Stage,

►
grade, and extent of cancer
Metastatic disease, venous stasis due
to bulky disease
Type of antineoplastic treatment

►
type
Multiagent regimens, hormones,
anti-VEGF, radiation
Miscellaneous VTE risk factors

Previous VTE, hospitalization,
immobility, infection, thrombophilia
Independent Risk Factors for DVT/PE
Risk Factor/Characteristic
O.R.
Recent surgery w/ institutionalization
21.72
Trauma
12.69
Institutionalization without recent surgery
7.98
Malignancy with chemotherapy
6.53
Prior CVAD 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 JA et al. Thromb Haemost. 2001;86:452-463
VTE Incidence In Various Tumors
Oncology Setting
Breast cancer (Stage I & II) w/o further treatment
VTE
Incidence
0.2%
Breast cancer (Stage I & II) w/ chemo
2%
Breast cancer (Stage IV) w/ chemo
8%
Non-Hodgkin’s lymphomas w/ chemo
3%
Hodgkin’s disease w/ chemo
6%
Advanced cancer (1-year survival=12%)
9%
High-grade glioma
26%
Multiple myeloma (thalidomide + chemo)
28%
Renal cell carcinoma
43%
Solid tumors (anti-VEGF + chemo)
47%
Wilms tumor (cavoatrial extension)
4%
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
Strategies for Thromboprophylaxis in
Thalidomide Treated MM Patients
Therapy
T+ D in newly
diagnosed
patients
No prophylaxis
26% Cavo, 2002
(19 pts)
18% Rajkumar, 2004
(102 pts)
T+ dox in
newly
diagnosed
patients
34.5% Zangari, 2004
(87 pts)
T+dox at
relapse
16% Zangari, 2002
(192 pts)
Warfarin
1mg/daily
25% Weber, 2002
(24 pts)
13% Cavo, 2004
(52 pts)
31.4% Zangari,
2004 (35 pts)
Warfarin
(INR 2 – 3)
LMWH
Aspirin
(81
mg/d)
7% Weber,
2002
(46 pts)
14.7%
Zangari, 2004
(68pts)
7% Minnema,
2004 (412 pts)
17.8%
Baz,
2004
(103 pts)
MM-009/010: Thromboembolic Events
16
14
12
10
8
DVT
6
PE
4
2
0
Len + D(%)
D (%)
MM-009
Weber D. ASCO 2005 Annual Meeting
Len + D(%)
MM-010
D (%)
Incidence of VTE: USA and Canada
>Israel, Australia, and Europe
Multivariate Analysis of the Risk of Thrombosis Associated
with Lenalidomide plus High-Dose Dexamethasone and
Concomitant Erythropoietin for the Treatment of Multiple
Myeloma
Treatment
Odds Ratio
(95% CI)
P Value
Lenalidomide plus
High-dose dexamethasone
3.51 (1.77-6.97)
<0.001
Concomitant erythropoietin
3.21 (1.72-6.01)
<0.001
Knight: N Engl J Med.2006,354:2079
►
rEPO used
more in USA
and Canada
►
L+Dex: 23%
VTE with EPO
vs 5% w/o
EPO
►
Placebo +
Dex: 7% VTE
with EPO vs
1% without
EPO
Thrombotic Outcomes from rEPO or
Darbopoietin Use in Cancer Patients
Among 6,769
pts with cancer,
RR for DVT with
rEPO/Darbepo
was increased
by 67%
(RR=1.67; 95%
CI 1.35 to 2.06)
Bohlius: The Cochrane Library, Volume (4).2006
Standard Treatment of VTE
Can We Do Better Than This?
Initial treatment
5 to 7 days
LMWH or UFH
Long-term therapy
Vitamin K antagonist (INR 2.0 - 3.0)
> 3 months
Recurrent VTE in Cancer – Subset Analysis of
the Home Rx Studies (UH/VKA vs. LMWH/VKA)
Recurrent VTE
Events per 100 patient years
Malignant
Non- Malignant
P value
27.1
Hutten et.al. J Clin Oncol 2000;18:3078
9.0
0.003
Recurrent VTE in Cancer – Subset
Analysis of the Home Rx Studies
Major Bleeding
Events per 100 patient years
Malignant
13.3
Hutten et.al. J Clin Oncol 2000;18:3078
Nonmalignant
2.1
P-value
0.002
Oral Anticoagulant Therapy
in Cancer Patients: Problematic
► Warfarin
(Coumadin®) therapy is
complicated by:




►
Difficulty maintaining tight therapeutic control,
due to anorexia, vomiting, drug interactions, etc.
Frequent interruptions for thrombocytopenia
and procedures
Difficulty in venous access for monitoring
Increased risk of both recurrence and bleeding
Is it reasonable to substitute long-term
LMWH for warfarin ? When? How? Why?
CLOT: Landmark Cancer/VTE Trial
Dalteparin
Dalteparin
CANCER PATIENTS WITH
Randomization
ACUTE DVT or PE
[N = 677]
Dalteparin Oral Anticoagulant
►
Primary Endpoints: Recurrent VTE and Bleeding
►
Secondary Endpoint: Survival
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Landmark CLOT Cancer Trial
Probability of Recurrent VTE, %
Reduction in Recurrent VTE
25
Recurrent VTE
20
Risk reduction =
52%
p-value = 0.0017
OAC
15
10
Dalteparin
5
0
0
Lee, Levine, Kakkar, Rickles et.al.
N Engl J Med, 2003;349:146
30
60
90
120
150
Days Post Randomization
180
210
Bleeding Events in CLOT
Dalteparin
OAC
N=338
N=335
Pvalue*
Major bleed
19 ( 5.6%)
12 ( 3.6%)
0.27
Any bleed
46 (13.6%)
62 (18.5%)
0.093
* Fisher’s exact test
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Treatment of Cancer-Associated VTE
Study
Design
Length
of
Therapy
N
Recurrent
Major
VTE (%) Bleeding
Dalteparin
(Lee 2003)
OAC
CANTHENOX
Enoxaparin
(Meyer 2002)
OAC
LITE
Tinzaparin
(Hull ISTH 2003)
OAC
ONCENOX
Enox (Low)
(Deitcher ISTH
2003)
6
336
9
336
17
67
11
71
21
80
6
87
11
32
3.4
Enox (High)
36
3.1
OAC
34
6.7
3
3
6
(%)
(%)
(Months)
CLOT Trial
Death
0.002
0.09
6
NS
4
41
7
0.09 11
16
0.03
6
NS
0.03
23
NS
8
NS
39
23
NS
22
NS
NR
Treatment and 2° Prevention of VTE
in Cancer – Bottom Line
New Development
►
New standard of care is LMWH at
therapeutic doses for a minimum of 3-6
months (Grade 1A recommendation—ACCP)
►
Oral anticoagulant therapy to follow for as
long as cancer is active (Grade 1C
recommendation—ACCP)
Buller et.al. Chest Suppl 2004;126:401S-428S
CLOT 12-month Mortality
All Patients
Probability of Survival, %
100
90
80
70
Dalteparin
60
OAC
50
40
30
20
10
0
HR 0.94 P-value = 0.40
0
30 60 90 120
180
240
300
Days Post Randomization
Lee A,
et al. ASCO. 2003
360
Anti-Tumor Effects of LMWH
CLOT 12-month Mortality
Patients Without Metastases (N=150)
Probability of Survival, %
100
Dalteparin
90
80
70
OAC
60
50
40
30
20
10
HR = 0.50 P-value = 0.03
0
0
30 60 90 120 150 180
240
300
Days Post Randomization
Lee A, et al. ASCO. 2003
360
LMWH for Small Cell Lung Cancer
Turkish Study
►
84 patients randomized: CEV +/- LMWH (18 weeks)
►
Patients balanced for age, gender, stage, smoking
history, ECOG performance status
Chemo +
Dalteparin
Chemo alone
P-value
1-y overall survival, %
51.3
29.5
0.01
2-y overall survival, %
17.2
0.0
0.01
Median survival, m
13.0
8.0
0.01
CEV = cyclophosphamide, epirubicin, vincristine;
LMWH = Dalteparin, 5000 units daily
Altinbas et al. J Thromb Haemost 2004;2:1266.
Rate of Appropriate Prophylaxis, %
VTE Prophylaxis Is Underused
in Patients With Cancer
100
90
Cancer:
FRONTLINE Survey1—
3891 Clinician
Respondents
Major
Surgery2
89
80
70
60
Cancer:
Surgical
Major
Abdominothoracic
Surgery (Elderly)3
52
50
38
40
30
Medical
Inpatients4
Confirmed DVT
(Inpatients)5
42
33
Cancer:
Medical
20
10
5
0
FRONTLINE FRONTLINE:
Surgical
Medical
Stratton
1. Kakkar AK et al. Oncologist. 2003;8:381-388
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912
Bratzler
Rahim
DVT FREE
4. Rahim SA et al. Thromb Res. 2003;111:215-219
5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
Clotting, Cancer, and Controversies
Venous Thromboembolism (VTE)
Prophylaxis in the Cancer Patient
Guidelines and Implications for
Clinical Practice
Alex C Spyropoulos, MD, FACP, FCCP
Chair, Department of Clinical Thrombosis
Lovelace Medical Center
Clinical Associate Professor of Medicine
Associate Professor of Pharmacy
University of New Mexico Health Sciences Center
Albuquerque, NM, USA
Outline of Presentation
► VTE
prophylaxis in cancer
 Surgical, CVC, medical
► Guidelines
for VTE prophylaxis
in the cancer patient
 ACCP, NCCN
► Performance
to date
► Opportunities
for improvement
Thromboprophylaxis in Cancer vs NonCancer Surgical patients
Cancer patients have a 2-fold increased risk
Of VTE and 3-fold increased risk of fatal PE
despite prophylaxis
Non-Cancer (%)
N=16,954
Cancer (%)
N=6124
P
Post-op VTE
0.61
1.26
<0.0001
Non-fatal PE
0.27
0.54
<0.0003
Autopsy PE
0.11
0.41
0.0001
Death
0.71
3.14
0.0001
Haas S et al Thromb Haemost 2005;94:814-819
Kakkar AJ et al Thromb Haemost 2005;94:867-71
Thromboprophylaxis in Surgical Patients
►
ARISTOS
 Prospective cohort of 2373 patients
►
Overall symptomatic VTE 2.1% and
death 1.7%
►
Advanced tumor
 OR 4.4 (95% CI 1.4 – 5.2)
Agnelli G Ann Surg 2006; 243:85-89
In-hospital Thromboprophylaxis in
Cancer Surgery
14
12
10
8
6
4
2
0
P=NS
P=0.05
NNT=29
NNT=33
VTE
Major
Bleed
VTE
Major
Bleed
UFH 5000 Enox 40 mg
ENOXACAN
Canadian Colorectal Study
ENOXACAN Study Group Br J Surg 1997;84:1099-1103
Mcleod R et al Ann Surg 2001;233:436-44
Extended Thromboprophylaxis in
Cancer Surgery
40
35
30
25
20
15
10
5
0
P= 0.02
P<0.03
NNT=14
NNT= 9
VTE
Placebo
Prox DVT
Enox 40 mg
ENOXACAN II
Berquvist D et al NEJM 2002;346:975-80
Rasmusan M et al Blood 2003;102;52a
VTE
Placebo 2
FAME
Prox DVT
Dalteparin
Systematic Review of DVT Prophylaxis of
Surgical Cancer Patients
►
26 RCTs of 7,639 patients




Overall DVT of pharmacological Px
vs controls - 12.7% vs 35.2%
High dose vs Low dose LMWH for
DVT 7.9% vs 14.5% (p<0.01)
No differences in LMWH vs UFH in
efficacy, DVT location, or bleeding
Overall bleeding complications 3%
Leonardi MJ et al Ann Surg Oncol 2007;14(2):929-36
Thromboprophylaxis for CVC
►
Prior studies with ~ 5% incidence of
symptomatic catheter-related thrombosis
Regimen
N
Cath
Thrombosis (%)
Kathaus
2006
dalteparin 5000U qd
placebo
285
140
11 (3.7)
5 (3.4)
Couban
2005
warfarin 1mg QD
Placebo
130
125
6 (4.6)
5 (4.0)
Verso 2005
enoxaparin 40mg qd
placebo
155
155
22 (14.2)
28 (18.1)
Karthaus et al Oncol 2006;17:286-296
Couban et al JCO 2006: 23:4063-8
Verso et al JCO 2006;23:4057-62
Thromboprophylaxis in Hospitalized
Medical Cancer Patients
►
There are no randomized trials in hospitalzed medical
oncology patients
►
Randomized, placebo controlled trials in acutely ill
hospitalized medical patients (of which cancer patients
area percentage)
16
14
12
10
8
6
4
2
0
E nox aparin 40mg
P lac ebo
Dalteparin 5000IU
P lac ebo2
F onda 2.5mg QD
P lac ebo3
ME DE NOX P R E VE NT AR T E MIS
Pt no
866
2991
644
Cancer (%)
14
5
5
Fatal Pulmonary Embolism During
Anticoagulant Prophylaxis
Study,
Prophylaxis
Year
(Reference)
n/n
Placebo
n/n
RR Fixed
RR Fixed
(95% CI)
(95% CI)
Dahan et al, 1986 (41)
1/132
3/131
0.33 (0.03 to 3.14)
Garlund at al, 1996 (35)
3/5776
12/5917
0.26 (0.07 to 0.91)
Leizorovic et al, 2004 (23) 0/1829
2/1807
0.20 (0.01 to 4.11)
17/1244
0.59 (0.27 to 1.29)
Mahe et al, 2005 (22)
Cohen at, 2006 (42)
10/1230
0/321
5/323
Total (95% CI)
Total events
0.09 (0.01 to 1.65)
0.38 (0.21 to 0.69)
14 39
0.001 0.01 0.1 1.0 10 100 1000
Favors Treatment
Dentali, F. et. al. Ann Intern Med 2007;146:278-288
Favors Placebo
Unfractionated Heparin Prophylaxis:
BID vs TID—What Works, What Doesn’t?
Meta-analysis: 12
RCTs
► DVT,
PE, all VTE events, Bleeding
► Proximal


DVT plus PE
BID VTE event rate:
2.34 events per 1,000
patient days
TID event rate:
0.86 events per 1,000
patient days
P=0.05
► NNT


676 hospital prophylaxis days
with UFH TID to prevent
1 major bleed with 1,649
hospital prophylaxis days of
TID dosing
King CS et al. CHEST 2007;131:507-516
Incidence and Economic
Implications of HIT
N = 10,121
60,000
Incidence of HIT (%)
0.51
0.5
0.4
0.3
P = 0.037
0.2
0.084
0.1
0
Cost of admission ($)
0.6
56,364
50,000
40,000
30,000
P < 0.001
20,000
15,231
10,000
0
UFH
LWMH
Creekmore FM, et al. Pharmacotherapy. 2006;26:1438-1445.
With HIT
Without HIT
2004 ACCP Recommendations
Cancer patients undergoing surgical procedures receive prophylaxis that is
appropriate for their current risk state (Grade 1A)
 General, Gynecologic, Urologic Surgery
• Low Dose Unfractionated Heparin 5,000 units TID
• LMWH > 3,400 units Daily
– Dalteparin 5,000 units
– Enoxaparin 40 mg
– Tinzaparin 4,500 units
• GCS and/or IPC
Surgical patients may receive post-discharge prophylaxis with LMWH (Grade 2A)
No routine prophylaxis for central venous catheters, including LMWH (Grade 2B)
and fixed-dose warfarin (Grade 1B)
Cancer patients with an acute medical illness receive prophylaxis
that is appropriate for their current risk state (Grade 1A)
• Low Dose Unfractionated Heparin
• LMWH
Contraindication to anticoagulant prophylaxis (Grade 1C+)
• GCS or IPC
Geerts WH et al. Chest. 2004;126(suppl):338S-400S
NCCN Practice Guidelines in VTE Disease
At Risk Population
►
►
►
►
►
►
►
►
►
►
►
►
►
►
Adult patient
Diagnosis or
clinical
suspicion of
cancer
Inpatient
Initial Prophylaxis
Prophylactic anticoagulation
therapy (category 1) + sequential
compression device (SCD)
Relative contraindication to
anticoagulation
treatment
Mechanical prophylaxis (options)
- SCD
- Graduated compression stockings
RISK FACTOR ASSESSMENT
Age
Prior VTE
Familial thrombophilia
Active cancer
Trauma
Major surgical procedures
Acute or chronic medical illness requiring
hospitalization or prolonged bed rest
Central venous catheter/IV catheter
Congestive heart failure
Pregnancy
Regional bulky lymphadenopathy with
extrinsic vascular compression
Modifiable risk factors: Lifestyle,
smoking, tobacco, obesity,
activity level/exercise
►
►
►
AGENTS ASSOCIATED
WITH INCREASED RISK
Chemotherapy
Exogenous estrogen
compounds
- HRT
- Oral contraceptives
- Tamoxifen/Raloxifene
- Diethystilbestrol
Thalidomide/lenalidomide
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
NCCN Practice Guidelines
in VTE Disease
Inpatient Prophylactic Anticoagulation Therapy
►
LMWH
- Dalteparin 5,000 units subcutaneous daily
- Enoxaparin 40 mg subcutaneous daily
- Tinzaparin 4,500 units (fixed dose) subcutaneous daily or 75
units/kg cubcutaneous daily
►
Pentasaccharide
- Fondaparinux 2.5 mg subcutaneous daily
►
Unfractioned heparin 5,000 units subcutaneous 3 times daily
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
NCCN Practice Guidelines
in VTE Disease
►
►
►
►
►
►
►
►
►
Relative Contraindications to Prophylactic or
Therapeutic Anticoagulation
Recent CNS bleed, intracranial or spinal lesion at high risk for
bleeding
Active bleeding (major): more than 2 units transfused in 24 hours
Chronic, clinically significant measurable bleeding > 48 hours
Thrombocytopenia (platelets < 50,000/mcL)
Severe platelet dysfunction (uremia, medications, dysplastic
hematopoiesis)
Recent major operation at high risk for bleeding
Underlying coagulopathy
Clotting factor abnormalities
- Elevated PT or aPTT (excluding lupus inhibitors)
- Spinal anesthesia/lumbar puncture
High risk for falls
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
Compliance With ACCP VTE
Prophylaxis Guidelines Is Poor
Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group
62,012
70,000
At risk for DVT/PE
35,124
Received compliant care
Number of patients
10,000
9175
5,000
2324
1388
0
52.4%
Orthopedic
Surgery
15.3%
12.7%
At-risk Medical
Conditions
General
Surgery
9.9%
Urologic
Surgery
6.7%
Gynecologic
Surgery
Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based
on the 6th American College of Chest Physicians (ACCP) guidelines.
HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76
In-Hospital Prophylaxis by Medical Condition –
IMPROVE Registry
Heart failure (CHF)
64%
Stroke
63%
COPD or Resp. failure
60%
Ischemic heart disease
59%
57%
Hypertension
Severe Infection
55%
Diabetes
55%
Renal failure
49%
Other disease
49%
45%
Malignancy
0%
Tapson V et al Chest 2007 (in press)
20%
40%
60%
80%
100%
Predictors of the Use of
Thromboprophylaxis
Effect
Odds Ratio (95% CI)
Malignancy
0.40
Others
0.58
Infection
0.83
Bleeding Risk
0.91
Gender
0.92
Hospital Size
0.93
Age
1.00
LOS
1.05
Cardiovascular Disease
1.06
Internal Medicine
1.33
Respiratory
1.35
AMC
1.46
Duration of Immobility
1.60
VTE Risk Factors
1.78
Kahn SR et Al. Thromb Res 2007; 119:145-155
0.0 0.5 1.0
1.5 2.0 2.5
Odds Ratio
3.0 3.5 4.0
Independent factors present at admission for in-hospital
bleeding – multivariate analysis (IMPROVE Registry)
Adjusted Odds Ratio
Bleeding disorder
Active G-duodenal ulcer
Adm platelets<50 x 109
Hepatic failure
ICU/CCU stay
Current cancer
Central venous catheter
Age 85 years
S. creatinine ≥2.5 mg/dL
Decousus H et al Blood 2005
5.11
4.93
3.00
2.79
2.41
1.99
1.98
1.91
1.88
(95% CI)
(2.38, 10.98)
(2.86, 8.50)
(1.67, 5.41)
(1.57, 4.95)
(1.60, 3.63)
(1.39, 2.85)
(1.33, 2.95)
(1.29, 2.85)
(1.26, 2.79)
Computer Reminder System
►
Computer program linked to patient database to identify
consecutive hospitalized patients at risk for VTE
►
Patients randomized to intervention group or control group
►
In the intervention group the physicians were alerted to the
VTE risk and offered the option to order VTE prophylaxis
►
Point scale for VTE risk
 Major risk: Cancer, prior VTE, hypercoagulability
(3 points)
 Intermediate risk: Major surgery (2 points)
 Minor risk: Advanced age, obesity, bedrest, HRT,
use of oral contraceptives (1 point)
►
VTE prophylaxis (graduated elastic stockings, IPC, UFH,
LMWH, warfarin)
Kucher N, et al. N Engl J Med. 2005;352:969-77
Electronic Alerts to Prevent VTE
Freedom from
DVT or PE (%)
100
98
96
Intervention group
94
92
Control group
90
P<0.001
88
0
Number at risk
Intervention group
Control group
30
1,255
1,251
60
Time (days)
977
876
Kucher N, et al. N Engl J Med. 2005;352:969-77
90
900
893
853
839
VTE Risk Assessment for
Hospitalized Medical Patients
Does
Does the
the patient
patient have
have one
one of
of the
the following
following
acute medical
illnesses/conditions?
risk factors?
All medical patients
should be routinely
assessed
and considered for
thromboprophylaxis
Is the patient > 40 years
old with acute medical
illness and reduced
mobility?
Evidence-based:
Evidence-based
in acutely ill medical patients:
■
■
■
■
■
■
■
■
■
YES
Cohen A et al Thromb Haemost 2005;94(4):750-9
■
■
■
■
■
■
■
■
■
■
■
■
■
■
■
Acute
HistoryMIof VTE
Acute
failure—NYHA III/IV
Historyheart
of malignancy
Active
cancer
requiring
therapy
Concurrent
acute
infectious
disease
Severe
infection/sepsis
Age > 75
years
Respiratory disease (respiratory failure
with/without
mechanical
ventilation,
Consensus
view
only:
exacerbations of chronic respiratory
Prolonged immobility
disease)
Age > 60 years
Rheumatic
disease (including acute
Varicoseofveins
arthritis
lower extremities and vertebral
Obesity
compression)
Hormone stroke
therapy
Ischemic
Pregnancy/postpartum
Paraplegia
Nephrotic syndrome
Dehydration
Consensus view only:
Thrombopilia
Inflammatory
disorder with immobility
Thrombocytosis
Inflammatory bowel disease
VTE Risk Assessment for
Hospitalized Medical Patients
YES
NO
Is pharmacological
No evidence
for the benefits of
thromboprophylaxis
thromboprophylaxis.
However,
patientscontraindicated?
should be considered for
thromboprophylaxis on a case-byNObasis
case
LMWH (enoxaparin 40 mg o.d. or
dalteparin 5000 IU o.d.) or
UFH (5000 IU t.i.d.)
(LMWH preferred due to
better safety profile)
.
Cohen A et al Thromb Haemost 2005;94(4):750-9
YES
Mechanical
thromboprophylaxis with
graduated compression
stockings or intermittent
pneumatic compression is
recommended
Conclusions
Current practices of VTE prophylaxis in the
cancer patient
►
►
►
►
►
Cancer surgical patients have an increased risk of
VTE and fatal PE despite prophylaxis
Prophylaxis with LMWH or UFH reduces
venographic VTE but not CVC-related thrombosis
Out-of-hospital prophylaxis with LMWH is
warranted in specific surgical cancer populations
Prophylaxis in hospitalized non-surgical cancer
patients is suboptimal
Compliance with ACCP and NCCN guidelines is
poor