Transcript VTE Prophylaxis in the Setting of Cancer

Welcome to this Science-to-Strategy Summit
Clotting, Cancer, and Clinical Strategies
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
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
Welcome and Program Overview
CME-accredited symposium jointly sponsored by University of
Massachusetts Medical Center, office of CME and CMEducation
Resources, LLC
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:
►
Specify strategies for risk-directed prophylaxis against DVT in at risk patients
with cancer, using FDA-indicated and approved agents
►
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
Craig M. Kessler, MD
Professor of Medicine and Pathology
Georgetown University Medical Center
Director of the Division of Coagulation
Department of Laboratory Medicine
Washington, DC
John Fanikos, RPh, MBA
Assistant Director of Pharmacy
Brigham and Women’s Hospital
Assistant Clinical Professor of Pharmacy
Northeastern University
Massachusetts College of Pharmacy
Boston, MA
Samuel Z. Goldhaber, MD
Professor of Medicine
Cardiovascular Division
Harvard Medical School
Director, Venous Thromboembolism Research Unit
Brigham and Women’s Hospital
Boston, MA
Faculty COI Financial Disclosures
Craig M. Kessler, MD
Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline,
Octapharma
Consultant: sanofi-aventis, Eisai, NovoNordisk
John Fanikos, RPh, MBA
Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca,
Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis,
The Medicines Company
Samuel Z. Goldhaber, MD
Grant/Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai;
GSK; Sanofi-Aventis;
Consultant: Boehringer-Ingelheim; BMS; Eisai; Merck; Pfizer; SanofiAventis
Clots and Cancer—A Looming
National Healthcare Crisis
MISSION AND CHALLENGES
Recognizing cancer patients at risk for DVT and identifying
patients who are appropriate candidates for long-term
prophylaxis and/or treatment with approved and indicated
therapies are among the most important and difficult
challenges encountered in contemporary oncology
practice.
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
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
Comorbidity Connection
COMORBIDITY
SUBSPECIALIST
CONNECTION
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 first-time
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
Relative Risk
X2
P value
Heart failure
1.08 (0.72-1.62)
0.05
.82
NYHA class III
0.89 (0.55-1.43)
0.12
.72
NYHA class IV
1.48 (0.84-2.60)
1.23
.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
Odds Ratio
(95% CI)
X2
Age > 75y
Cancer
Previous VTE
1.03 (1.00-1.06)
1.26 (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
Withot chemotherapy
Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768
1.00
4.24 (2.58-6.95)
2.21 (1.60-3.06)
Clotting, Cancer, and Clinical Strategies
Cancer, Thrombosis, and the
Biology of Malignancy
Scientific Foundations for the Role of
Low-Molecular-Weight Heparin
John Fanikos, RPh, MBA
Assistant Director of Pharmacy
Brigham and Women’s Hospital
Assistant Clinical Professor of Pharmacy
Northeastern University
Massachusetts College of Pharmacy
Boston, MA
Professor Armand Trousseau
Lectures in Clinical Medicine
“ I have always been struck with the
frequency with which cancerous patients
are affected with painful oedema of the
superior or inferior extremities….”
New Syndenham Society – 1865
Professor Armand Trousseau
More Observations About Cancer and Thrombosis
“In other cases, in which the absence of
appreciable tumor made me hesitate as to
the nature of the disease of the stomach, my
doubts were removed, and I knew the
disease to be cancerous when phlegmasia
alba dolens appeared in one of the limbs.”
Lectures in Clinical Medicine, 1865
Trousseau’s Syndrome
Ironically, Trousseau died of gastric carcinoma 6
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”
Trousseau’s Syndrome
►
Occult cancer in patients with idiopathic
venous thromboembolism
►
Thrombophlebitis in patients
with cancer
Effect of Malignancy on Risk of
Venous Thromboembolism (VTE)
53.5
Adjusted odds ratio
50
40
30
• Population-based case-control
(MEGA) study
• N=3220 consecutive patients with 1st
VTE vs. n=2131 control subjects
• CA patients = OR 7x VTE risk vs. nonCA patients
28
22.2
20.3
19.8
20
14.3
10
4.9
3.6
2.6
1.1
Type of cancer
Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
> 15 years
5 to 10 years
1 to 3 years
3 to 12 months
0 to 3 months
Distant
metastases
Breast
Gastrointestinal
Lung
Hematological
0
Time since cancer diagnosis
Cancer, Mortality, and VTE
Epidemiology and Risk
►
Patients with cancer have a 4- to 6-fold increased risk
for VTE vs. non-cancer patients
►
Patients with cancer have a 3-fold increased risk for
recurrence of VTE vs. non-cancer patients
►
Cancer patients undergoing surgery have a 2-fold
increased risk for postoperative VTE
►
Death rate from cancer is four-fold higher if patient has
concurrent VTE
►
VTE 2nd most common cause of death in ambulatory
cancer patients (tied with infection)
Heit et.al. Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et.al. Blood 2002;100:3484-3488;
White et.al. Thromb Haemost 2003;90:446-455; Sorensen et.al. New Engl J Med 2000;343:1846-1850); Levitan et.al.
Medicine 1999;78:285-291; Khorana et.al. J Thromb Haemost 2007;5:632-4
Mechanisms of Cancer-Induced Thrombosis
The Interface
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer therapy?
Trousseau’s Observations (continued)
“There appears in the cachexiae…a
particular condition of the blood that
predisposes it to spontaneous
coagulation.”
Lectures in Clinical Medicine, 1865
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; Hematology, 2007
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
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer therapy?
Activation of Blood Coagulation in Cancer
Biological Significance?
►
Epiphenomenon?
Is this a generic secondary event where
thrombosis is an incidental finding
or, is clotting activation . . .
►
A Primary Event?
Linked to malignant transformation
Interface of Clotting Activation
and Tumor Biology
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 Tumor Biology
TF
Clottingdependent
VIIa
Clottingindependent
Thrombin
Xa
Clottingdependent
Clottingindependent
PARs
Angiogenesis, Tumor
Growth and Metastasis
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
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 cancer
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; Ruf et.al. Nature Med 2004;10:502-509
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; Ruf et.al. Nature Med. 2004;10:502-509
Tissue Factor Expression, Angiogenesis, and
Thrombosis in Pancreatic Cancer
Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan, Charles W. Francis, Ralph H.
Hruban, Ying Chuan Hu, Galen Hostetter, Jennifer Harvey and Mark B.Taubman
(U Rochester, U Pitt, Johns Hopkins, Translational Genomics)
Clin Cancer Res 2007;13:2870
►
Retrospective IH and microarray study of TF, VEGF and MVD in:
●
●
●
●
Normal pancreas (10)
Intraductal papillary mucinous neoplasms (IPMN; 70)
Pancreatic intrepithelial neoplasia (PanIN; 40)
Resected or metastatic pancreatic adenoca(130)
►
Survival
►
VTE Rate
Correlation of Tissue Factor Expression with the
Expression of Other Angiogenesis Cariables in Resected
Pancreatic Cancer
High TF
Expression
Low TF
Expression
Negative
13
41
Positive
53
15
V6 per tissue core
27
33
>6 per tissue core
39
23
Median
8
6
P
VEGF expression
<0.0001
Microvessel density
Khorana et.al. Clin CA Res 2007:13:2870
0.47
0.01
Symptomatic VTE in Pancreatic Cancer
5/19
30%
26.3%
Rate of VTE
25%
20%
15%
10%
5%
1/22
4.5%
0%
Low TF
Khorana et.al. Clin CA Res 2007;13:2872
High TF
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
GFP
_________
MET
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
________________
_______________________________
Platelets (x103)
974
350
150
D-dimer (µg/ml)
<0.05
0.11
0.22
PT (s)
12.9
11.8
25.1
“MET Oncogene Drives a Genetic Programme
Linking Cancer to Haemostasis”
►
Mouse model of Trousseau’s Syndrome
●
Genome-wide expression profiling of hepatocytes
expressing MET upregulation of PAI-1 and COX-2
genes with 2-3x  circulating protein levels
●
Using either XR5118 (PAI-1 inhibitor) or Rofecoxib
(Vioxx; COX-2 inhibitor) resulted in inhibition of
clinical and laboratory evidence for DIC in mice
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. Both Akt and Ras pathways modulated TF in
sequentially transformed astrocytes.
3. Ex vivo data:  TF (by immunohistochemical
staining) in pseudopalisades of # 7 human
glioblastoma specimens
Both Akt and Ras Pathways Modulate TF
Expression By Transformed Astrocytes
N=Normoxia
H=hypoxia
Rong, Brat et.al. Ca Res 2005;65:1406-1413
“Pten and Hypoxia Regulate Tissue Factor Expression
and Plasma Coagulation By Glioblastoma”
pseudopalisading
necrosis
H&E
Vascular
Endothelium
TF Immunohistochemistry
Rong, Brat et.al. Ca Res 2005;65:1406-1413
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/+
+/+
Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
379.2
mut/+
del/del
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
Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
SI-2
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?
Cancer and Thrombosis
Year 2008 State-of-the-Science Update
Key Questions
1. Does activation of blood coagulation affect
the biology of cancer positively or negatively?
2. Can we treat tumors more effectively using coagulation
protein targets?
3. Can anticoagulation alter the biology of cancer?
Cancer and Thrombosis
Year 2008 State-of-the-Science Update
Tentative Answers
1.
Epidemiologic evidence is suggestive that VTE is a bad
prognostic sign in cancer
2.
Experimental evidence is supportive of the use of
antithrombotic strategies for both prevention of thrombosis
and inhibition of tumor growth
3.
Results of recent, randomized clinical trials of LMWH in
cancer patients indicate superiority in preventing recurrent
VTE and suggest increased survival (not due to just
preventing VTE)— “Titillating”
Coagulation Cascade and Tumor Biology
TF
Clottingdependent
VIIa
Clottingindependent
Thrombin
Xa
Clottingindependent
?
Clottingdependent
Fibrin
Clottingdependent
PARs
Angiogenesis, Tumor
Growth and Metastasis
LMWH (e.g. FRAGMIN)
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
Clotting, Cancer, and Clinical Strategies
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
1.
2.
3.
4.
►
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
Ambrus JL et al. J Med. 1975;6:61-64
Donati MB. Haemostasis. 1994;24:128-131
Johnson MJ et al. Clin Lab Haem. 1999;21:51-54
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
100 120
Number of Days
Levitan N, et al. Medicine 1999;78:285
140 160 180
As Number Of Cancer Survivors Increases, VTE
Rates Increase
4
VTE in Hospitalized Cancer
And Noncancer Patients (%)
3.5
Cancer Patients
3
2.5
2
1.5
1
Noncancer Patients
0.5
Year
Stein PD, et al. Am J Med 2006; 119: 60-68
99
97
95
93
91
89
87
85
83
81
79
0
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
Outcome
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
N
Design
Regimens
ENOXACAN 1
631
double-blind
enoxaparin vs. UFH
Canadian Colorectal
DVT Prophylaxis 2
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
20%
18.2%
Incidence of Outcome Event
P>0.05
15%
ENOXACAN
14.7%
UFH 5000 U tid
N=319
10%
enoxaparin 40 mg
2.9%
5%
0%
VTE
ENOXACAN Study Group. Br J Surg 1997;84:1099–103
4.1%
Major Bleeding
N=312
Prophylaxis in Surgical Patients
20%
Incidence of Outcome Event
16.9%
13.9%
15%
P=0.052
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 1
332
double-blind
Enoxaparin vs. placebo
FAME
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
Extended Prophylaxis in
Surgical Patients
Incidence of Outcome Event
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%
Any
Bleeding
Major
Bleeding
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
NNT = 14
Major Abdominal Surgery: FAME Investigators—
Dalteparin Extended
►
A multicenter, prospective, assessor-blinded, open-label,
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
Radical retropubic prostatectomy
1–3%
1–3%
0.6%
Cystectomy
8%
2–4%
2%
Radiological studies
51%
22%
►
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 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
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 catheter-related
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 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
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; mucinsecreting adenocarcinomas-colorectal,
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
VTE Incidence
Breast cancer (Stage I & II) w/o further
treatment
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(%)
MM-009
Weber D. ASCO 2005 Annual Meeting
D (%)
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
P value
Malignant
Non- Malignant
27.1
9.0
Hutten et.al. J Clin Oncol 2000;18:3078
0.003
Recurrent VTE in Cancer – Subset Analysis of
the Home Rx Studies
Major Bleeding
Events per 100 patient years
Malignant
Nonmalignant
13.3
2.1
Hutten et.al. J Clin Oncol 2000;18:3078
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
Risk reduction = 52%
p-value = 0.0017
20
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
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
P-value*
Treatment of Cancer-Associated VTE
Study
Design
CLOT Trial
Dalteparin
(Lee 2003)
OAC
CANTHENOX
Enoxaparin
(Meyer 2002)
OAC
LITE
Tinzaparin
(Hull ISTH 2003)
OAC
ONCENOX
Enox (Low)
(Deitcher ISTH
2003)
Enox (High)
OAC
Length
of
Therapy
(Months)
6
3
3
6
Major
Recurrent
Bleeding
VTE (%)
(%)
Death
(%)
336
9
39
336
17
67
11
71
21
80
6
87
11
32
3.4
36
3.1
34
6.7
N
0.002
6
NS
4
0.09
7
41
0.09
16
0.03
6
11 0.03
23
NS
8
NS
NS
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
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
Stratton
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
Cancer and Venous Thrombosis
VTE Prophylaxis in the Cancer Patient
and Beyond
Guidelines and Implications for Day-to-day Practice
Samuel Z. Goldhaber, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Learning Objectives
►
Scope of the problem
►
Tools in the toolkit: drugs, devices
►
Guidelines: ASCO, NCCN, ACCP
►
Implementation: voluntary or mandatory
Scope of the Problem
►
Epidemiology
►
Long-term sequelae
►
Failure to prophylax Medical Service patients,
especially Medical Oncology patients
Annual Patients At-Risk For VTE
U.S. Hospitals
►
7.7 million Medical Service inpatients
►
4.3 million Surgical Service inpatients
►
Based upon ACCP guidelines for VTE prophylaxis
Anderson FA Jr, et al. Am J Hematol 2007; 82: 777-782
Patients At-Risk For VTE
An 86-year-old man underwent successful
gastrectomy for newly diagnosed stomach cancer.
He was recovering uneventfully.
On POD #4, he had a witnessed cardiac arrest
while transferring from commode to bed. ACLS
yielded repeated PEA.
After 35 minutes, the code was “called.” An
autopsy was obtained.
ICOPER Cumulative Mortality
25
17.5%
Mortality (%)
20
15
10
5
0
7
14
30
Days From Diagnosis
Lancet 1999; 353: 1386-1389
60
90
Progression Of
Chronic Venous Insufficiency
VTE Prophylaxis: Underused
Implementation of VTE prophylaxis continues
to be problematic, despite detailed North
American and European Consensus
guidelines.
The Amin Report
VTE Prophylaxis Rates in USA
►
Studied 196,104 Medical Service discharges from
227 hospitals.
►
VTE prophylaxis rate was 62%.
►
ACCP-deemed appropriate prophylaxis rate was
34%.
J Thromb Haemostas 2007; 5: 1610-6)
The Amin Report
Medical Oncology Patients
►
Of 196,104 Medical Service discharges, 30,708
were medical oncology patients.
►
Only 56% received any VTE prophylaxis.
►
Only 28% received ACCP-deemed appropriate
prophylaxis
J Thromb Haemostas 2007; 5: 1610-6
Medical Patient
Prophylaxis In Canada
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Studied 1,894 Medical Service discharges from 29
hospitals.
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VTE prophylaxis was indicated in 90% of patients.
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ACCP-deemed appropriate prophylaxis rate was
16%.
Thrombosis Research 2007; 119: 145-155
Cancer: Medical Patient
Prophylaxis In Canada
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19% of the 1,894 Medical Service patients had
cancer, either as the admission diagnosis (9%) or
an active comorbid condition (19%).
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The most common cancers were: lung, breast,
prostate, and colon.
Thrombosis Research 2007; 119: 145-155
Cancer: Decreased Likelihood Of VTE
Prophylaxis In Canada
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Multivariable analysis: 60% less likely to prescribe
VTE prophylaxis (95% CI: 32% to 76% less likely;
p=0.0007).
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Perhaps MDs fear an increased risk of bleeding in
cancer patients?
Thrombosis Research 2007; 119: 145-155
VTE in Cancer Patients
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Prospective registry of 5,451 consecutive
ultrasound-confirmed DVT patients at 183 U.S.
institutions. (Am J Cardiol 2004; 93:259-262 )
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Cancer occurred in 1,768 (39%), of whom 1,096
(62%) had active cancer, of whom 599 (55%) were
receiving chemotherapy.
Thromb Haemost 2007; 98: 656-661
VTE in Cancer Patients
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Lung, colorectal, and breast cancer were the most
common cancers.
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Cancer patients less often received VTE prophylaxis
(28%) compared with the other DVT Registry
patients (35%) (p<0.0001).
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Cancer patients were more likely to receive IVC
filters (22% vs. 14%; p<0.0001) than non-cancer
patients.
Thromb Haemost 2007; 98: 656-661
Tools in the Toolkit
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LMWH, Unfractionated Heparin,
Fondaparinux, Warfarin
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IVC Filters
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Graduated Compression Stockings and
Intermittent Pneumatic Compression Devices
VTE Prophylaxis In 19,958 Medical
Patients/ 9 Studies (Meta-analysis)
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62% reduction in fatal PE
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57% reduction in fatal or nonfatal PE
►
53% reduction in DVT
Dentali F, et al. Ann Intern Med 2007; 146: 278-288
Dalteparin Prophylaxis in 3,706 Medical Patients
Cancer Subgroup
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Dalteparin 5,000 U/d vs. placebo
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6 of 72 placebo patients (8.3%) developed VTE,
compared with 2 of 65 dalteparin patients
(3.1%)
►
Dalteparin was effective in all subgroups.
Vascular Medicine 2007; 12: 123-128
Filters
Filter insertion has increased, especially retrievable
filters. Filters prevent PE but increase DVT rate
(and do not halt the thrombotic process).
Main indications:
1)
2)
3)
Severe bleeding that precludes anticoagulation
Recurrent PE despite therapeutic anticoagulation
Prophylaxis
Retrievable Filters
Prospective Series (N=228)
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Retrieval attempted in only 25%
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Filter tilting: 5.7%
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Puncture site hematoma: 4.2%
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Filter migration: 1.4%
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Infection: 0.9%
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DVT: 15%
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Fatal PE: 2.3%
Mismetti P et al. Chest 2007; 131: 223-229
Intermittent Pneumatic Compression
Meta-analysis In Postop Patients
►
2,270 patients in 15 randomized
trials
►
IPC devices reduced DVT risk by
60% (Relative Risk 0.40, 95% CI
0.29-0.56, p< 0.001)
Urbankova J. Thromb Haemost 2005; 94: 1181-5
Guidelines
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ASCO
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NCCN
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ACCP
National Comprehensive Cancer Network
(NCCN)
►
The NCCN “recommends prophylactic
anticoagulation for all inpatients with a diagnosis
of active cancer who do not have a
contraindication.”
►
“Anticoagulation should be administered
throughout hospitalization.”
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“VTE prophylaxis after hospital discharge should
be strongly considered.”
J NCCN 2006; 4: 838-869
American Society Of Clinical Oncology
(ASCO)
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“Consider all hospitalized cancer patients for VTE
prophylaxis with anticoagulants, in absence of
bleeding…”
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“Give routine prophylaxis to outpatients receiving
thalidomide or lenalidomide.”
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“LMWH represents the preferred agent.”
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“Impact of anticoagulants on cancer patient survival
requires additional study.”
JCO 2007; 25: 5490-5505
American College Of Chest Physicians
(ACCP)
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VTE prophylaxis while hospitalized
►
Treat acute DVT or PE with LMWH as monotherapy
without warfarin for at least 3-6 months
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Continue anticoagulant therapy indefinitely or until
the cancer resolves.
CHEST 2004; 126: 338S-400S
CHEST 2004; 126: 401S-428S
Implementation
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Electronic (computerized) alerts to physicians
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Human Alerts
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JCAHO
►
Medicare payments
►
“Opt out” strategies
Implementation
The high death rate from PE (exceeding acute
MI!) and the high frequency of undiagnosed PE
causing “sudden cardiac death” emphasize the
need for improved preventive efforts.
Failure to institute prophylaxis is a much bigger
problem with Medical Service patients,
especially medical oncology patients, than
Surgical Service patients.
Implementation
We have initiated trials to change MD
behavior and improve implementation of VTE
prophylaxis—not trials of specific types of
prophylaxis—eAlert RCT, eAlert cohort,
human Alert, 3-screen eAlert.
Quality Improvement Initiative to Improve
Clinical Practice
Randomized (“eAlert”) controlled trial to
issue or withhold electronic alerts to MDs
whose high-risk patients were not receiving
DVT prophylaxis.
Kucher N, et al. NEJM 2005;352:969-977
Definition of “High Risk”
VTE risk score ≥ 4 points:
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►
►
►
►
►
►
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Cancer
Prior VTE
Hypercoagulability
Major surgery
Bed rest
Advanced age
Obesity
HRT/OC
3
3
3
2
1
1
1
1
(ICD codes)
(ICD codes)
(Leiden, ACLA)
(> 60 minutes)
(“bed rest” order)
(> 70 years)
(BMI > 29 kg/m2)
(order entry)
DVT Prophylaxis at BWH
►
There were 13,922 patients with a VTE risk score
≥ 4 from September 2000 to January 2004
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11,416 (82%) patients received DVT prophylaxis
►
2506 (18%) patients did not receive DVT
prophylaxis
Kucher N, et al. NEJM 2005;352:969-977
Randomization
VTE risk score > 4
No prophylaxis
N = 2506
INTERVENTION
Single alert
n = 1255
Kucher N, et al. NEJM 2005;352:969-977
CONTROL
No alert
n = 1251
Baseline Characteristics
►
Median age = 62.5 years
►
Medical services: 83%
Surgical services: 17%
Comorbidities
►
►
●
●
●
●
Cancer:
Hypertension:
Infection:
Prior VTE:
Kucher N, et al. NEJM 2005;352:969-977
80%
34%
30%
20%
90-Day Primary Endpoint
Intervent. Control
Hazard Ratio p
N=1255 N=1251
(95% CI)
Total VTE
61 (4.9)
103 (8.2)
0.59 (0.43-0.81) 0.001
Acute PE
14 (1.1)
35 (2.8)
0.40 (0.21-0.74) 0.004
Proximal DVT
10 (0.8)
23 (1.8)
0.47 (0.20-1.09) 0.08
Distal DVT
5 (0.4)
12 (1.0)
UE DVT
32 (2.5)
Kucher N, et al. NEJM 2005;352:969-977
33 (2.6)
0.42 (0.15-1.18) 0.10
0.97 (0.60-1.58) 0.90
Primary End Point
%Freedom from DVT/ PE
100
98
Intervention
96
94
92
Control
90
0
Number at risk
Intervention
1255
Control
1251
Kucher N, et al. NEJM 2005;352:969-977
30
60
Time (days)
977
976
900
893
90
853
839
Conclusions
Electronic alerts
1. Facilitated the detection of patients at high risk of
DVT/PE
2. Increased the rate of DVT prophylaxis from 14.5%
to 33.5%
3. Reduced the incidence of DVT/PE by 41%, without
increasing bleeding
Kucher N, et al. NEJM 2005;352:969-977
JCAHO Performance Measures
Prophylaxis (Approved in May 2006)
►
►
Surgery patients with recommended VTE prophylaxis
ordered
Surgery patients who received appropriate VTE
prophylaxis within 24 hours preop to 24 hours after
surgery
Risk Assessment/Prophylaxis (Pending)
►
►
VTE risk assessment/ prophylaxis within 24 hours of
hospital admission
VTE risk assessment/ prophylaxis within 24 hours of
transfer to ICU
Quality Measures
►2
●
●
measures are in current use
SCIP VTE 1: Was DVT/PE prophylaxis
ordered?
SCIP VTE 2: Was DVT/PE prophylaxis
received?
►Implementation
●
●
by Medicare
Hospitals must report on the 2 measures
beginning January 2007 to receive full
payment in 2008
Medicare adjusted rate increase will be
reduced by 2.0% for noncompliance
Default (“Opt Out”) Options
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Flu, pneumonia vaccines.
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Remove urinary catheters within 72h.
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Head of bed at 30-45 angle in ICU.
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Interrupt sedatives daily: vented pts.
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Prophylax against VTE.
Halpern SD et al. NEJM 2007; 357: 1340
Summary
1.
Cancer and VTE is a disabling and at times deadly
combination.
2.
VTE prophylaxis is safe and effective.
3.
ASCO, NCCN, and ACCP endorse VTE
prophylaxis in cancer patients.
4.
For unclear reasons, VTE prophylaxis is
underutilized.
5.
VTE prophylaxis of cancer patients will increase,
through a combination of voluntary initiatives and
regulatory mandates.