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
Charles W. Francis, MD
Professor of Medicine and Pathology and
Laboratory Medicine
Department of Medicine
University of Rochester
School of Medicine and Dentistry
Rochester, New York
 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:

► Review recent trials, research, and expert analysis of issues focused on

thrombosis and cancer.

► Learn how national guidelines for thrombosis prevention should impact

management of patients with cancer.

► Be able to specify strategies for risk-directed prophylaxis against DVT in at risk

patients with cancer.

► Be able to explain how to assess and manage special needs of cancer patients
at risk for DVT, with a focus on protecting against recurrent DVT.

► Be able to describe how to risk stratify patients undergoing cancer surgery, and
implement ACCP-mandated pharmacologic and non-pharmacologic measures
aimed at DVT prophylaxis.
 Program Faculty
Program Chairman
Charles W. Francis, MD
Professor of Medicine and Pathology and Laboratory Medicine
Department of Medicine
University of Rochester
School of Medicine and Dentistry
Rochester, NY

Frederick Rickles, MD
Professor of Medicine, Pediatrics, Pharmacology and Physiology
Department of Medicine
Division of Hematology-Oncology
The George Washington University
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
 Faculty COI Financial Disclosures

Charles Francis, MD
Grants/research support: Boehringer-Ingelheim, Eisai, Consultant: Eisai,
Amgen, Pfizer

Frederick Rickles, MD
Consultant: Pfizer, Eisai, sanofi-aventis, and Bristol-Myers Squibb
Speakers Bureau: Eisai

John Fanikos, RPh, MBA

Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai
Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines
Company
 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
Charles W. Francis, MD
Professor of Medicine and Pathology and
Laboratory Medicine
Department of Medicine
University of Rochester
School of Medicine and Dentistry
Rochester, New York
 Comorbidity Connection

COMORBIDITY SUBSPECIALIST
CONNECTION STAKEHOLDERS
CAP Infectious diseases
UTI Oncology
Cancer Cardiology
Heart Failure Pulmonary medicine
ABE/COPD Hematology
Respiratory Failure Oncology/hematology
Myeloproliferative Disorder Interventional Radiology
Thrombophilia Hospitalist
Surgery Surgeons
History of DVT EM
Other PCP
 Epidemiology of First-Time VTE

Variable Finding
Possibly more common in winter and less
Seasonal Variation
common in summer
25% to 50% “idiopathic”
Risk Factors 15%-25% associated with cancer
20% following surgery (3 months)
6-month incidence, 7%;
Higher rate in patients with cancer
Recurrent VTE
Recurrent PE more likely after PE than
after DVT
30-day incidence 6% after incident DVT
30-day incidence 12% after PE
Death After Treated VTE
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
Relative Risk X2 P Value
Illness
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
1.26 (0.85-1.87) 1.03 .31
disease
Acute infectious
1.50 (1.00-2.26) 3.54 .06
disease
Acute rheumatic
1.45 (0.84-2.50) 1.20 .27
disease

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 X2

(95% CI)

Age > 75 years 1.03 (1.00-1.06) 0.0001

Cancer 1.62 (0.93-2.75) 0.08
Previous VTE 2.06 (1.10-3.69) 0.02

Acute infectious
1.74 (1.12-2.75) 0.02
disease

Chronic respiratory
0.60 (0.38-0.92) 0.02
disease

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 (1.04-1.7)

Neurologic disease with extremity

1.87 (1.28-2.73)
paresis
Malignant neoplasm
None 1.00
With chemotherapy 4.24 (2.58-6.95)
Without chemotherapy 2.21 (1.60-3.06)

Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768

 Clotting, Cancer, and Clinical Strategies

Cancer, Thrombosis, and the

Biology of Malignancy
Scientific Foundations for the Role of
Low-Molecular-Weight Heparin

Frederick R. Rickles, MD
Professor of Medicine, Pediatrics,
Pharmacology and Physiology
The George Washington University
Washington, DC
 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
50 • Population-based case-control
(MEGA) study
• N=3220 consecutive patients with 1st
40 VTE vs. n=2131 control subjects
Adjusted odds ratio

• CA patients = OR 7x VTE risk vs. non-

CA patients
30 28
22.2
20.3 19.8
20
14.3

10 4.9
3.6 2.6
1.1
0

> 15 years
Lung

Breast

Distant

1 to 3 years

5 to 10 years
metastases

0 to 3 months

3 to 12 months
Hematological

Gastrointestinal

Type of cancer Time since cancer diagnosis

Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
 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, Fibrinolytic Procoagulant Activities

Basement matrix activities:
degradation. t-PA, u-PA, u-PAR,
PAI-1, PAI-2

IL-1, Activation of
TNF-a, coagulation
VEGF

PMN leukocyte 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 Blood Coagulation
TF Activation
Cell

VEGF
THROMBIN

FIBRIN
Angiogenesis
IL-8
PAR-2 TF

Endothelial cells
Angiogenesis

Falanga and Rickles, New Oncology:Thrombosis, 2005

 Coagulation Cascade and Tumor Biology

Clotting- Clotting-
dependent dependent
TF Thrombin Fibrin

VIIa Xa Clotting-
independent
Clotting- Clotting-
independent dependent

PARs

Angiogenesis, Tumor
Growth and Metastasis

Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
 VEGF and Angiogenesis

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
 VEGF and Angiogenesis

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 Low TF
P
expression expression

VEGF expression
Negative 13 41 <0.0001
Positive 53 15

Microvessel density
V6 per tissue core 27 33 0.047
>6 per tissue core 39 23
Median 8 6 0.01

Khorana et.al. Clin CA Res 2007:13:2870

 Symptomatic VTE in Pancreatic Cancer

30
5/19; 26.3%
25
Rate of VTE (%)

20

15

10
1/22; 4.5%
5

0
Low TF High TF

Khorana et.al. Clin CA Res 2007:13:2870

 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
GFP 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

Boccaccio et al Nature 2005;434:396-400

 “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 Immuno-
histochemistry
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”
TF expression in cancer cells parallels genetic tumor progression
with an impact of K-ras and p53 status
Mean Channel TF Flourescence

450 160

TF Activity (U/106 cells)

400 140
350 120
300
100
250
80
200
60
150
100 40
50 20
0 0
HKh-2 HCT116 379.2 HKh-2 HCT116 379.2

del/+ mut/+ mut/+

+/+ +/+ del/del

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”
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”

Effect of TF si mRNA on new vessel formation in colon cancer

14
%VWF-Positive Area

12
10
8
6
4
2
0
HCT116 SI-2 SI-3 MG only

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”
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
Clotting- Clotting-
dependent dependent
TF Thrombin Fibrin

VIIa Xa
Clotting-
independent
Clotting- Clotting-
independent dependent
?
PARs

Angiogenesis, Tumor
Growth and Metastasis

LMWH (e.g. dalteparin)

Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
 Clotting, Cancer, and Controversies

A Systematic Overview of VTE Prophylaxis

in the Setting of Cancer

Linking Science to Clinical Practice

Program Chairman
Charles W. Francis, MD
Professor of Medicine and Pathology and
Laboratory Medicine
Department of Medicine
University of Rochester
School of Medicine and Dentistry
Rochester, New York
 VTE and Cancer: Epidemiology

► Of all cases of VTE:

● About 20% occur in cancer patients
● Annual incidence of VTE in cancer
patients ≈ 1/250
► Of all cancer patients:
● 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

 Thrombosis and Survival
Likelihood of Death After Hospitalization

1.00
DVT/PE and Malignant Disease
0.80
Probability of
Death

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

 Hospital Mortality With or Without VTE

No VTE VTE
18 16.13 16.41
16 14.85
14
Mortality (%)

12 10.59
10 7.98
8.67
8
6
4
2
0
All Non-metastatic Metastatic
N=66,016 N=20,591 N=17,360

Khorana, JCO, 2006

 Trends in VTE in Hospitalized Cancer Patients

7.0
6.5
6.0
5.5
5.0
Rate of VTE (%)

4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5 P<0.0001
0.0
1995 1996 1997 1998 1999 2000 2001 2002 2003

VTE- patients on chemotherapy VTE-all patients DVT-all patients

Khorana AA et al. Cancer. 2007.

PE-all patients
 Thrombosis Risk In Cancer

Primary Prophylaxis
► Medical Inpatients

► Surgery

► Radiotherapy

► Central Venous Catheters

 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 therapy
● Central venous catheters (~4% generate clinically
relevant VTE)
► Patient
● Prior VTE
● Co-morbities
● Genetic backgroud
 VTE Risk And Cancer Type
“Solid And Liquid Malignancies”
Relative Risk of VTE Ranged From 1.02 to 4.34
4.5
4
Relative Risk of VTE in

3.5
Cancer Patients

3
2.5
2
1.5
1
0.5

Kidney

Ovary

Bladder
Cervix
Stomach

Lung

Liver
Brain

Breast
Colon
Lymphoma
Uterus

Prostate

Leukemia
Myeloprol

Rectal
Esophagus
Pancreas

Stein PD, et al. Am J Med 2006; 119: 60-68

Cancer and Thrombosis

Medical Inpatients
 Thromboembolism in Hospitalized
Neutropenic Cancer Patients

►Retrospective cohort study of discharges using

the University Health System Consortium

►66,106 adult neutropenic cancer patients

between 1995 and 2002 at 115 centers

Khorana, JCO, 2006

 Neutropenic Patients: Results

►8% had thrombosis

►5.4% venous and 1.5% arterial in 1st hospitalization

►Predictors of thrombosis
● Age over 55
● Site (lung, GI, gynecologic, brain)
● Comorbidities (infection, pulmonary and renal
disease, obesity)

Khorana, JCO, 2006

 Predictors of VTE in
Hospitalized Cancer Patients

Characteristic OR P Value
Site of Cancer
Lung 1.3 <0.001
Stomach 1.6 0.0035
Pancreas 2.8 <0.001
Endometrium/cervix 2 <0.001
Brain 2.2 <0.001

Age 65 y 1.1 0.005

Arterial thromboembolism 1.4 0.008
Comorbidities (lung/renal disease,
1.3-1.6 <0.001
infection, obesity)

Khorana AA et al. J Clin Oncol. 2006;24:484-490.

 Antithrombotic Therapy: Choices

Nonpharmacologic Pharmacologic
(Prophylaxis) (Prophylaxis & Treatment)

Intermittent Elastic Unfractionated Low Molecular

Pneumatic Stockings Heparin (UH) Weight Heparin
Compression (LMWH)

Inferior
Vena Cava Oral
Filter Anticoagulants
New Agents: e.g.
Fondaparinux,
Direct anti-Xa inhibitors,
Direct anti-IIa, etc.?
 Prophylaxis Studies in Medical Patients

20

14.9
15
Rate of VTE (%)

Relative Relative
risk
10.5 risk
reduction
10 reduction Relative 47%
63% risk
reduction
5.5 5 44% 5.6
5
2.8

0
Placebo Enoxaparin Placebo Dalteparin Placebo Fondaparinux
MEDENOX Trial PREVENT ARTEMIS

Francis, NEJM, 2007

 ASCO Guidelines

1. SHOULD HOSPITALIZED PATIENTS WITH

CANCER RECEIVE ANTICOAGULATION FOR
VTE PROPHYLAXIS?

Recommendation. Hospitalized patients with cancer

should be considered candidates for VTE prophylaxis
with anticoagulants in the absence of bleeding or other
contraindications to anticoagulation.

Lyman, JCO, 2007

Cancer and Thrombosis

Surgical Patients
 Incidence of VTE in Surgical Patients

► Cancer patients have 2-fold risk of post-operative DVT/PE

and >3-fold risk of fatal PE despite prophylaxis:

No Cancer Cancer
P-value
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

 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

 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
475 double-blind enoxaparin vs. UFH
DVT Prophylaxis 2

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%
P>0.05
Incidence of Outcome Event

14.7% ENOXACAN
15%

UFH 5000 U tid

10% N=319
enoxaparin 40 mg
2.9% 4.1% N=312
5%

0%
VTE Major Bleeding

ENOXACAN Study Group. Br J Surg 1997;84:1099–103

 Prophylaxis in Surgical Patients

20%
16.9%
Canadian
Incidence of Outcome Event

P=0.052 Colorectal DVT

13.9%
15% Prophylaxis Trial
UFH 5000 U tid
N=234
10%
enoxaparin 40 mg
N=241
5%
1.5% 2.7%

0%
VTE Major Bleeding
(Cancer) (All)
McLeod R, et al. Ann Surg 2001;233:438-444
 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
198 Open-label Dalteparin vs. no prophylaxis
(subgroup)

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

15%
Incidence of Outcome Event

12.0%
ENOXACAN II
10%
P=0.02 placebo
N=167

4.8% 5.1% enoxaparin 40 mg

5% 3.6% N=165

1.8%
0.6% 0% 0.4% NNT = 14

0%
VTE Prox Any Major
DVT 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, 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.
 ASCO Guidelines: VTE Prophylaxis

► All patients undergoing major surgical intervention

for malignant disease should be considered for
prophylaxis.

► Patients undergoing laparotomy, laparoscopy, or

thoracotomy lasting > 30 min should receive
pharmacologic prophylaxis.

► Prophylaxis should be continued at least 7 – 10

days post-op. Prolonged prophylaxis for up to 4
weeks may be considered in patients undergoing
major surgery for cancer with high-risk features.

Lyman, JCO, 2007

 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* Dalteparin 5000 U od 285 11 (3.7)

2002 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

No routine prophylaxis to prevent

thrombosis secondary to central venous
catheters, including LMWH (2B) and fixed-
dose warfarin (1B)

Geerts W, et al. Chest 2004; 126: 338S-400S

 Primary Prophylaxis in Cancer Radiotherapy
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 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.)
 Cancer and Thrombosis

Ambulatory Chemotherapy Patients

 Risk Factors for VTE in
Medical Oncology Patients

► Tumor type
● Ovary, brain, pancreas, lung, colon
► Stage, grade, and extent of cancer
● Metastatic disease, venous stasis due to
bulky disease
► Type of antineoplastic treatment
● Multiagent regimens, hormones,
anti-VEGF, radiation
► Miscellaneous VTE risk factors
● Previous VTE, hospitalization, immobility,
infection, thrombophilia
 Independent Risk Factors for DVT/PE

Risk Factor/Characteristic O.R.

Recent surgery with 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

VTE
Oncology Setting 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
 Primary VTE Prophylaxis

►Recommended for hospitalized

cancer patients

►Not recommended or generally used

for outpatients
● Very little data
● Heterogeneous

Need for risk stratification

 Ambulatory Cancer plus Chemotherapy

Study Methods

► Prospective observational study of

ambulatory cancer patients initiating a new
chemotherapy regimen, and followed for a
maximum of 4 cycles

► 115 U.S. centers participated

► Patients enrolled between March, 2002 and

August, 2004 who had completed at least
one cycle of chemotherapy were included in
this analysis

Khorana, Cancer, 2005

 Ambulatory Cancer plus Chemotherapy

Study Methods
► VTE events were recorded during mid-cycle or new-cycle
visits

► Symptomatic VTE was a clinical diagnosis made by the

treating clinician

► Statistical analysis
● Odds ratios to estimate relative risk
● Multivariate logistic regression to adjust for other risk factors

Khorana, Cancer, 2005

 Patient Characteristics

Characteristic No. (%)

All patients 3,196

Age > 65 1,243 (39)

Female 2,136 (67)

Stage IV 1,150 (37)

Performance status 0-1 2,912 (91)

Pre-chemotherapy platelet count >

691 (22)
350,000/mm3

Khorana, Cancer, 2005

 Patient Characteristics (2)

Site of Cancer No. (%)

All patients 3,196

Breast 1,137 (36)

Lung 612 (19)

Colon 353 (11)
Ovary 225 (7)

Upper GI 91 (3)

Non-Hodgkin’s lymphoma 287 (9)

Hodgkin’s disease 53 (2)

Others 438 (14)

Khorana, Cancer, 2005

 Incidence of VTE

3.0%
2.5%
Rate of VTE (%)

2.0%
1.5%
1.0%
0.5%
0.0%
Baseline Cycle 1 Cycle 2 Cycle 3

Cumulative rate
VTE / 2.4 months VTE/month VTE /cycle
(95% CI)
1.93% 0.8% 0.7% 2.2% (1.7-2.8)

Khorana, Cancer, 2005

 Risk Factors: Site of Cancer

12
VTE (%) / 2.4 months

10
8
6
4
2
0

Site of Cancer Khorana, Cancer, 2005

 Incidence of Venous Thromboembolism By
Quartiles of Pre-chemotherapy Platelet Count

5.0%
p for trend=0.005
4.5%
Incidence Of VTE Over 2.4

4.0%
3.5%
Months(%)

3.0%
2.5%
2.0%
1.5%
1.0%
0.5%
0.0%
<217 217-270 270-337 >337
Pre-chemotherapy Platelet Count/mm 3 (x1000)
Khorana, Cancer, 2005
 Risk Factors: Multivariate Analysis

Characteristic OR P value
Site of Cancer 0.03
Upper GI 3.88 0.0076
Lung 1.86 0.05
Lymphoma 1.5 0.32
Pre-chemotherapy platelet count >
2.81 0.0002
350,000/mm3
Hgb < 10g/dL or use of red cell growth
1.83 0.03
factor
Use of white cell growth factor in high-
2.09 0.008
risk sites

Khorana, Cancer, 2005

 Predictive Model

Patient Characteristic Score

Site of Cancer
Very high risk (stomach, pancreas)
2
High risk (lung, lymphoma, gynecologic, GU
1
excluding prostate)

Platelet count > 350,000/mm3 1

Hgb < 10g/dL or use of ESA 1

Leukocyte count > 11,000/mm3 1

BMI > 35 1

Khorana AA et al. JTH Suppl Abs O-T-002

 Predictive Model
Actual Incidence
Estimated Incidence
Incidence of VTE Over 2.4 Months

18% 95 % Confidence Limits

16%
14%
12%
10%
8%
6%
4%
2%
0%
0 1 2 3 4

Risk Score 0 1 2 3 4
N 1,352 974 476 160 33
VTE(%) /2.4 mo.s 0.8 1.8 2.7 6.3 13.2
 Predictive Model Validation
8%
Rate of VTE over 2.5 mos (%)

7.1%
7% Development cohort 6.7%

6% Validation cohort

5%

4%

3%

2% 1.8% 2.0%

1% 0.8%
0.3%
0%
n=734 n=374 n=1627 n=842 n=340 n=149

Risk Low (0) Intermediate(1-2) High(>3)

Khorana AA et al. JTH Suppl Abs O-T-002

Cancer and Thrombosis

VTE Treatment
 Standard Treatment of VTE
Can We Do Better Than This?

Initial treatment 5 to 7 days

LMWH or UFH

Long-term therapy > 3 months

Vitamin K antagonist (INR 2.0 - 3.0)

 Recurrent VTE in Cancer

Subset Analysis of the Home Treatment Studies

(UH/VKA vs. LMWH/VKA)

Recurrent VTE
Events per 100 patient years
P value
Malignant Non- Malignant

27.1 9.0 0.003

Hutten et.al. J Clin Oncol 2000;18:3078

 Recurrent VTE in Cancer

Subset Analysis of the Home Treatment Studies

Major Bleeding
Events per 100 patient years
P-value
Non-
Malignant
malignant

13.3 2.1 0.002

Hutten et.al. J Clin Oncol 2000;18:3078

 Oral Anticoagulant Therapy
in Cancer Patients: Problematic

► Warfarin 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
Reduction in Recurrent VTE

Probability of Recurrent VTE, % 25 Risk reduction = 52%

Recurrent VTE
p-value = 0.0017
20

15 OAC

10
Dalteparin
5

0 30 60 90 120 150 180 210

Lee, Levine, Kakkar, Rickles et.al. N Engl Days Post Randomization
J Med, 2003;349:146
 Bleeding Events in CLOT

Dalteparin OAC P-value*

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

 Treatment of Cancer-Associated VTE

Length of Recurrent Major

Death
Study Design Therapy N VTE Bleeding
(%)
(Months) (%) (%)
CLOT Trial Dalteparin
(Lee 2003) OAC 336 9 0.002 6 NS 39 NS
6
336 17 4 41

CANTHENOX Enoxaparin
(Meyer 2002) OAC 67 11 0.09 7 0.09 11
3 0.03
71 21 16 23

LITE Tinzaparin
(Hull ISTH 2003) OAC 80 6 0.03 6 NS 23 NS
3
87 11 8 22

ONCENOX Enox (Low) 32 3.4

(Deitcher ISTH Enox (High) NS NS NR
6 36 3.1
2003) OAC
34 6.7
 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)
► NOTE: Dalteparin is only LMWH approved (May,
2007) for both the treatment and secondary
prevention of VTE in cancer
► 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

100
90
Probability of Survival, %

80
70
Dalteparin
60
50 OAC
40
30
20
10 HR 0.94 P-value = 0.40
0

0 30 60 90 120 180 240 300 360

Days Post Randomization
Lee A, et al. ASCO. 2003
 Anti-Tumor Effects of LMWH
CLOT 12-month Mortality
Patients Without Metastases (N=150)

100
90 Dalteparin
Probability of Survival, %

80
70
60 OAC
50
40
30
20
10
HR = 0.50 P-value = 0.03
0

0 30 60 90 120 150 180 240 300 360

Days Post Randomization

Lee A, et al. ASCO. 2003
 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

Chemotherapy
Chemo alone P-value
plus Dalteparin

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.

 VTE Prophylaxis Is Underused
in Patients With Cancer

Cancer: Major
FRONTLINE Survey1— Surgery2
Rate of Appropriate Prophylaxis, %

100
3891 Clinician 89
90 Respondents
80
Cancer:
70 Surgical Major Confirmed DVT
60 52
Abdominothoracic (Inpatients)5
Surgery (Elderly)3 Medical
50 Inpatients4
42
38
40 33
Cancer:
30 Medical
20
10 5
0
FRONTLINE FRONTLINE: Stratton Bratzler Rahim DVT FREE
Surgical Medical

1. Kakkar AK et al. Oncologist. 2003;8:381-388

2. Stratton MA et al. Arch Intern Med. 2000;160:334-340 4. Rahim SA et al. Thromb Res. 2003;111:215-219
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
 Clotting, Cancer, and Clinical Strategies

Venous Thromboembolism (VTE)

Prophylaxis in the
Cancer Patient and Beyond

Guidelines and Implications for Clinical Practice

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
 Outline of Presentation

► Guidelines for VTE prevention

► Performance to date
► Opportunities for improvement
► Guidelines for VTE Treatment
► Performance to date
• www.nccn.org
• NCCN Clinical Practice Guidelines in
Oncology™
• “…The panel of experts includes medical
and surgical oncologists, hematologists,
cardiologists, internists, radiologists. And a
pharmacist.”
• www.asco.org
•Recommendations for VTE Prophylaxis &
Treatment in Patients with Cancer
 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
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

1A is the highest possible grade

Indicates that benefits outweigh risks, burdens, and costs,
with consistent RCT level of evidence

Geerts WH et al. Chest. 2004;126(suppl):338S-400S

 NCCN Practice Guidelines in VTE Disease
At Risk Population Initial Prophylaxis
► Adult patient
Continue
Prophylactic anticoagulation
therapy (category 1) + sequential
► Diagnosis or
clinical
suspicion of
Relative contra-
indication to
Prophylaxis
compression device (SCD)

Mechanical prophylaxis (options)

cancer
► Inpatient
anticoagulation
treatment
- SCD
After
- Graduated compression stockings

► Age
RISK FACTOR ASSESSMENT Discharge
Modifiable
smoking, tobacco, obesity,
?
risk factors: Lifestyle,

► Prior VTE activity level/exercise

► Familial thrombophilia
► Active cancer AGENTS ASSOCIATED
► Trauma WITH INCREASED RISK
► Major surgical procedures ► Chemotherapy
► Acute or chronic medical illness requiring ► Exogenous estrogen
hospitalization or prolonged bed rest compounds
► Central venous catheter/IV catheter - HRT
► Congestive heart failure - Oral contraceptives
► Pregnancy - Tamoxifen/Raloxifene
► Regional bulky lymphadenopathy with - Diethystilbestrol
extrinsic vascular compression ► 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 subcutaneous daily

► Pentasaccharide
- Fondaparinux 2.5 mg subcutaneous daily

► Unfractionated 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
 ► Should hospitalized patients with cancer
receive anticoagulation for VTE
prophylaxis ?
● “Hospitalized patients with cancer should be
considered candidates for VTE prophylaxis in
the absence of bleeding or other
contraindications to anticoagulation”

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

 ► Should ambulatory patients with cancer
receive anticoagulation for VTE
prophylaxis during systemic
chemotherapy?
● “Routine prophylaxis is not recommended.”
● “Patients receiving thalidomide or lenalidomide
with chemotherapy or dexamethasone are at high
risk for thrombosis and warrant prophylaxis.”

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

 ► Should hospitalized patients with cancer
undergoing surgery receive perioperative VTE
prophylaxis ?
● All patients should be considered for
thromboprophylaxis.
● Procedures greater than 30 minutes should receive
pharmacologic prophylaxis.
● Mechanical methods should not be used as
monotherapy.
● Prophylaxis should continue for at least 7-10 days
post-op. Prolonged prophylaxis may be considered
for cancer with high risk features.

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

 Compliance With ACCP VTE
Prophylaxis Guidelines Is Poor
Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group

70,000 62,012
At risk for DVT/PE
35,124
Received compliant care

10,000
9175
Number of patients

5,000

2324

1388

15.3% 12.7% 9.9% 6.7%

52.4%
0
Orthopedic At-risk Medical General Urologic Gynecologic
Surgery Conditions Surgery Surgery 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
 Reasons for Inadequate Duration
of VTE Prophylaxis

Started late &

Started Late Ended Early
Ended Early
At-Risk Medical 1,347 (22.5) 2,961 (49.4) 1,686 (28.1)
(n=5,994)
Abdominal Surgery 824 (25.4) 1,764 (54.4) 652 (20.1)
(n=3,240)
Urologic surgery 18 (11.4) 73 (46.2) 67 (42.4)
(n=158)
Gynecologic surgery 13 (8.0) 43 (26.4) 107 (65.6)
(n=163)
Neurosurgery 66 (26.4) 125 (50.0) 59 (23.6)
(n=250)

HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76

 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

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Kahn SR et Al. Thromb Res 2007; 119:145-155 Odds Ratio
 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

MD Computer Alert
 Electronic Alerts to Prevent VTE

100
98
DVT or PE (%)
Freedom from

96 Intervention group
94
92 Control group
90 P<0.001

88
0 30 60 90
Time (days)
Number at risk
Intervention group 1,255 977 900 853
Control group 1,251 876 893 839

Kucher N, et al. N Engl J Med. 2005;352:969-77

 Mechanical Thromboprophylaxis In Critically Ill Patients:
Review And Meta-analysis
RESULTS: 21 relevant studies (5 randomized controlled trials, 13
observational studies, and 3 surveys) were found. A total of 811 patients
were randomized in the 5 randomized controlled trials; 3421 patients
participated in the observational studies.
Trauma patients only were enrolled in 4 randomized controlled trials and 4
observational studies. Meta-analysis of 2 randomized controlled trials with
similar populations and outcomes revealed that use of compression and
pneumatic devices did not reduce the incidence of venous
thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).
A range of methodological issues, including bias and confounding variables,
make meaningful interpretation of the observational studies difficult.

CONCLUSIONS: The role of mechanical approaches to

thromboprophylaxis for intensive care patients remains
uncertain

Limbus A et al. Am J Crit Care, 2006;15:402-10

 Fatal Pulmonary Embolism During
Anticoagulant Prophylaxis
Study,
Year Prophylaxis Placebo RR Fixed RR Fixed
(Reference) n/n n/n (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)

Mahe et al, 2005 (22) 10/1230 17/1244 0.59 (0.27 to 1.29)

Cohen at, 2006 (42) 0/321 5/323 0.09 (0.01 to 1.65)

Total (95% CI) 0.38 (0.21 to 0.69)

Total events 14 39

0.001 0.01 0.1 1.0 10 100 1000

Favors Treatment Favors Placebo

Dentali, F. et. al. Ann Intern Med 2007;146:278-288

 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

 Heparin, Low Molecular
Weight Heparin Prophylaxis
LMWH vs UFH
►Meta-analysis
DVT Risk
►36 randomized Study Reduction (95% CI) Weight %
controlled trials Harenberg et al, 1990 0.70 (0.16-3.03) 3.4

►23,000 hospitalized Turpie et al, 1992 0.29 (0.10-0.81) 11.4

medical patients Dumas et al, 1994 0.74 (0.38-1.43) 14.4

Bergmann & Neuhart 0.94 (0.39-2.26) 8.1
►UFH 5,000 units TID et al, 1996
is more effective in Harenberg et al, 1996 2.89 (0.30-27.71) 0.8
preventing DVT than Lechler et al, 1996 0.25 (0.03-2.23) 3.3
UFH BID Hillbom et al, 2002 0.55 (0.31-0.98) 20.5
Kleber, et al 2003 0.77 (0.43-1.38) 19.4
►Low molecular weight
Diener et al, 2006 0.76 (0.42-1.38) 18.9
heparin is 33% more
effective than Overall (95% CI) 0.68 (0.52-0.88)

unfractionated heparin
in preventing DVT 0.1 1.0 10
Risk Ratio
● RR for DVT 0.68
(p=0.004) LMWH Better LMWH Worse

Wein L et al. Arch Intern Med. 2007;167:1476-86.

 BWH/DFCI Partners
Cancer Care Experience
Compliance with UFH TID Reasons for Non-Compliance

100 95 80
90 82 68
70
80
70 60
Percent

60
50 50

Percent
40 29 40
30 28
20 30
10 20
0
<3 <3 4 doses 10 4
doses Doses 0
Day 1 Day 2+ Off Floor Refused Unknown

• Consecutive patients, < 60 days

• 2 Nursing units
• LOS ranged from 3 days to 31 days
• Number of days where doses were omitted ranged from
1 to 6 days
 VTE Incidence: More Common
in the Outpatient Setting
► Medical records of residents (n=477,800)
► 587 VTE events (104 per 100,000 population)
► 30 Day recurrence 4.8 %
Patients receiving prophylaxis
during high risk periods
VTE Event Location 52%
51%
25% 51%
50%
50%
75% 49%
49%
48%
Inpatient Outpatient Prophylaxis None

Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777

 DVT, PE Diagnosis and Treatment

http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
 Thrombosis in Malignancy
7TH ACCP Consensus Conference Recommendations

Initial Phase Chronic Phase

5-7 days Continue anticoagulation
(warfarin or LMWH) long-term or
Dalteparin 200/kg q24h
until malignancy resolves
(GRADE 1A) (GRADE 1C)

5 - 7 days 3 - 6 mos 6 mos - indefinite

Subacute Phase
3 - 6 months
PRESS RELEASE: May 2, 2007
Dalteparin 150 units/kg q24h
(GRADE
FDA Approves Dalteparin as First 1A) Weight Heparin for Extended
Low-Molecular
Treatment to Reduce the Recurrence of Blood Clots in Patients with Cancer

Buller HR, et al. Chest 2004; 126 (suppl 3): 401s-428s

 NCCN Practice Guidelines—Venous
Thromboembolic Disease
Therapeutic Anticoagulation Treatment for
DVT, PE, and Catheter-Associated Thrombosis

Immediate
► LMWH
- Dalteparin (200 units/kg subcutaneous daily)
- Enoxaparin (1 mg/kg subcutaneous every 12 hrs)
-Tinzaparin (175 units/kg subcutaneous daily)

► Pentasaccharide
- Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [50-100 lg]; 10 mg [>100 kg]
subcutaneous daily

► Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour,

target aPTT to 2.0-2.9 x control)

http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
 NCCN Practice Guidelines—Venous
Thromboembolic Disease
Therapeutic Anticoagulation Treatment for
DVT, PE, and Catheter-Associated Thrombosis

Long Term
► LMWH is preferred as monotherapy without warfarin in patients with
proximal DVT or PE and prevention of recurrent VTE in patients with
advanced or metastatic cancer
► Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR
value; target INR 2.0-3.0)

Duration of Long Term Therapy

► Minimum time of 3-6 mo for DVT and 6-12 mo for PE
► Consider indefinite anticoaugulation if active cancer or persistent risk
factors
► For catheter associated thrombosis, anticoagulate as long as catheter
is in place and for 1-3 mo after catheter removal
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
 ► What is the best treatment for patients with
cancer with established VTE to prevent recurrent
VTE ?
● LMWH is the preferred approach for the initial 5-10
days.
● LMWH, given for at least 6 months, is the preferred
for long-term anticoagulant therapy.
● After 6 months, anticoagulation therapy should be
considered for select patients.
● For CNS malignancies, elderly patients
anticoagulation is recommended with careful
monitoring and dose adjustment.

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

 ► Should patients with cancer receive
anticoagulants in the absence of
established VTE to improve survival?

● “Anticoagulants are not recommended to improve

survival in patients with cancer without VTE.”

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

 Antithrombotic Therapy Practices
in U.S. Hospitals
70%
►Survey of 38 U.S. 60% 50.7%

Percent (%)
Hospitals 50%
40%
26.6%
30%
►n=939 DVT or PE 20% 14.8%
7.9%
10%
►50% patients 0%
reached INR >2 for Acute (n=72) Bridge (n=241) Long Term
(n=460)
Other (n=134)

2 consecutive days Therapy

14 12.7
12
Therapy n (%)
LOS, Days

10
LMWH 527 (56.1%) 8.1
8
UFH 562 (59.8%) 6.1
6
UFH SC 78 (8.3%) 4
4
DTI 6 (0.6%)
2
0
Acute Bridge Long term Other
(n=72) (n=241) (n=460) (n=134)
Tapson V et al. Arch Intern Med 2005
 Self-Managed Long Term LMWH Therapy
2212 patients with proximal vein thrombosis assessed
for eligibility 1475 excluded for
anticoagulant violations
or inability to give
written consent
737
Randomized

369 assigned to LMWH 369 assigned to usual care with

heparin & warfarin

3 lost to follow=up 3 lost to follow-up

1 withdrew consent 5 withdrew consent

369 included in Analysis 369 included in Analysis

Hull R. Am Jour Med 2007; 120:72-82

 Self-Managed Long Term LMWH Therapy

Tinzaparin Usual Care Absolute Difference

Outcomes p-value
(n=369) (n=368) (95% CI)

New VTE at 3 Mos 18 (4.9) 21 (5.7) -0.8 (-4.2-2.4) NS

New VTE at 12 Mos 33 (8.9) 36 (9.8) -0.8 (-5.5-3.5) NS

All Bleeding 48 (13.0) 73 (19.8) -6.8 (-12.4--1.5) p=.011

Major Bleeding 12 (3.3) 17 (4.6) -1.4 (-4.3-1.4) NS
Minor Bleeding 36 (9.8) 56 (15.2) -5.5 (-10.4--0.6) p=.022

Stratified Bleeding-
31/144 (21.5) 39/146 (26.7) -5.2 (-15%-4.6%) NS
High Risk

Stratified Bleeding-Low
17/225 (7.6) 34/222 (15.3) -7.8 (-13.6--1.9%) p=.01
Risk

Thrombocytopenia
21 (5.7) 9 (2.4) 1.6 (-3.6-0.3) NS
(<150)
Bone Fracture 4 (1.1) 7 (1.9) -0.8 (-0.9-2.6) NS
Hull R. Am Jour Med 2007; 120:72-82
 LMWHs and Bleeding in Patients
with Renal Dysfunction

Dosage adjustments
for renal dysfunction

Lim W et al. Ann Intern Med 2006; 144:673-84

 Conclusions

Examine your current practices of VTE

prophylaxis and treatment

► Review available guidelines as a benchmark

► Consider the use of a pharmacologic or
mechanical intervention
► Evaluate use of Reminder or Risk Scoring
Systems
► Utilize the regimen providing the best efficacy in
reducing events and offering best compliance
► Follow-up with patients to monitor and avoid
adverse events and to ensure optimal outcomes