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Mechanisms ● Mortality ● Therapeutics
The Science and Medicine of
Thrombosis in Cancer
The Evolving and Foundation Role of LMWHs in Cancer and
Thrombosis: Applying Science, Expert Analysis, and
Landmark Trials to the Front Lines of Specialty 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 the University of
Massachusetts Medical Center, office of CME and CMEducation
Resources, LLC
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, participants will:
► Learn about recent trials, research, and expert analysis of issues
focused on thrombosis and cancer.
► Learn about mechanisms, morbidity, mortality, and therapeutic issues
focused on thrombosis and cancer.
► Learn about relationships among the clotting cascade, agents
affecting the coagulation system, and mortality outcomes in cancer
patients.
► Learn about strategies for risk-directed prophylaxis against VTE in at
risk patients with cancer.
► Learn how to assess and manage special needs of cancer patients atrisk for VTE, with a focus on protecting against recurrent DVT.
Program Faculty
Craig M. Kessler, MD—Program Chairman
Professor of Medicine and Pathology
Georgetown University Medical Center
Lombardi Comprehensive Cancer Center
Chief, Division of Coagulation
Washington, DC
Frederick R. Rickles, MD, FACP
Center for Health Innovation
Public Sector Healthcare, Noblis
Professor of Medicine, Pediatrics and Pharmacology and Physiology
The George Washington University
Washington, DC
Edith Nutescu, Pharm.D., FCCP
Clinical Associate Professor, Pharmacy Practice
Affiliate Faculty, Center for Pharmacoeconomic Research
Director, Antithrombosis Center
The University of Illinois at Chicago
College of Pharmacy & Medical Center
Chicago, Illinois
Faculty COI Financial Disclosures
Craig M. Kessler, MD - Co-Chairman
Grant/Research Support: GlaxoSmithKline
Consultant: sanofi-aventis, Eisai Pharmaceuticals
Speaker’s Bureau: sanofi-aventis, GlaxoSmithKline
Frederick R. Rickles, MD
Consultant: Eisai Pharmaceuticals, Genmab, Pharmacyclics
Speaker’s Bureau: Eisai Pharmaceuticals
Edith Nutescu, PharmD
Speakers Bureau: Eisai Inc., GlaxoSmithKline, sanofi-aventis U.S.
Advisory Committees or Review Panels, Board Membership, etc.:
Boehringer Ingelheim Pharmaceuticals, Inc., Scios Inc.
Innovation ● Investigation ● Application
Clotting, Cancer, and Controversies
What the Trials, Emerging Science, and Current Thinking
Tell Us About The Evolving Science and Foundation Role of
Anticoagulation in the Setting of Cancer
Program Chairman
Craig Kessler, MD MACP
Director, Division of Coagulation
Lombardi Comprehensive Cancer Center
Georgetown University Medical Center
Washington, DC
VTE and Cancer—A Looming
National Healthcare Crisis
MISSION AND CHALLENGES
Recognizing cancer patients at risk for DVT
and identifying appropriate candidates for
long-term prophylaxis and/or treatment with
approved and indicated therapies are among
the most important challenges encountered in
contemporary pharmacy and clinical practice.
Comorbidity Connection
COMORBIDITY
CONNECTION
SUBSPECIALIST
STAKEHOLDERS
CAP
UTI
Cancer
Heart Failure
ABE/COPD
Respiratory Failure
Myeloproliferative Disorder
Thrombophilia
Surgery
History of DVT
Other
Infectious diseases
Oncology
PHARMACISTS
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 months)
Recurrent VTE
6-month incidence, 7%;
Higher rate in patients with cancer
Recurrent PE more likely after PE than
after DVT
Death After Treated VTE
30-day incidence 6% after incident DVT
30-day incidence 12% after PE
Death strongly associated with cancer,
age, and cardiovascular disease
White R. Circulation. 2003;107:I-4 –I-8.)
Epidemiology of VTE
►One major risk factor for VTE is ethnicity, with a
significantly higher incidence among Caucasians
and African Americans than among Hispanic
persons and Asian-Pacific Islanders.
►Overall, about 25% to 50% of patient with firsttime VTE have an idiopathic condition, without a
readily identifiable risk factor.
►Early mortality after VTE is strongly associated
with presentation as PE, advanced age, cancer,
and underlying cardiovascular disease.
White R. Circulation. 2003;107:I-4–I-8.)
Thrombophilia Enhances Risks of
Thrombosis in Cancer Patients
Risk of thrombosis in cancer patients within the previous five years according
to the presence of factor V Leiden or G20210A prothrombin gene mutation
Mutation
Patients with
first venous
thrombosis
Control without
venous
thrombosis
(n=2706)
(n=1757)
Yes
2125
1635
1.00
Yes
162
26
5.1 (3.3-7.7)
No
403
95
3.3 (2.6-4.1)
Yes
16
1
12.1 (1.6-88.1)
No
2410
1693
1.00
Yes
164
27
4.5 (3.0-6.8)
No
118
36
2.3 (1.6-3.3)
Yes
14
0
Not determined
Cancer
Age- and sexadjusted odds
ratio (95% CI)
Factor V Leiden
No
Yes
Prothombin 20210A
No
Yes
H. Decousus et al. Thrombosis Research 120 Suppl. 2 (2007) S51-S61
Acute Medical Illness and VTE
Multivariate Logistic Regression Model
for Definite Venous Thromboembolism (VTE)
Risk Factor
Odds Ratio
(95% CI)
X2
Age > 75 years
Cancer
Previous VTE
1.03 (1.00-1.06)
1.62 (0.93-2.75)
2.06 (1.10-3.69)
0.0001
0.08
0.02
Acute infectious
disease
1.74 (1.12-2.75)
0.02
Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
VTE Recurrence
Predictors of First 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 paresis
1.87 (1.28-2.73)
Malignant neoplasm
With chemotherapy
Without chemotherapy
Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768
4.24 (2.58-6.95)
2.21 (1.60-3.06)
Progression of Chronic Venous Insufficiency
From UpToDate 2006
Rising VTE Incidence in Hospitalized Patients
2
VTE
1.5
DVT
%
1
0.5
PE
0
79
81
83
85
87
89
Year
Stein PD et al. Am J Cardiol 2005; 95: 1525-1526
91
93
95
97
99
DVT Registry (N=5,451)
Top 5 Medical Comorbidities
1. Hypertension
2. Immobility
3. Cancer
4. Obesity (BMI > 30)
5. Cigarette Smoking
Am J Cardiol 2004; 93: 259-262
Implementation of Guidelines
in Cancer Patients
Implementation of VTE prophylaxis
continues to be problematic, despite
detailed North American and European
Consensus guidelines.
Symposium Themes—Cancer/DVT
1.
Cancer rates are increasing as treatment for heart
disease and cancer improve
2.
Cancer increases VTE risk
3.
VTE is preventable (immunize!)
4.
VTE prophylaxis may slow cancer
5.
Increased emphasis on prophylaxis: OSG, NCCN,
ASCO, ACCP, NATF
6.
Facilitate prophylaxis with alerts
Clotting, Cancer, and Controversies
Cancer, Thrombosis, and the
Biology of Malignancy
Scientific Foundations for the Role of
Low-Molecular-Weight Heparin in Cancer Patients
Frederick R. Rickles, MD
Professor of Medicine, Pediatrics,
Pharmacology and Physiology
The George Washington University
Washington, DC
Cancer and Venous Thromboembolism
The Legacy of Armand Trousseau
(1801–1867)
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 tumour 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 six
months after writing to his student, Peter, on January
1st, 1867:
“I am lost . . . the phlebitis that has just
appeared tonight leaves me no doubt as to
the nature of my illness”
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)
• Population-based MEGA study
• N=3220 consecutive patients with 1st VTE
vs. n=2131 control subjects
• CA patients = OR 7x VTE risk vs. non-CA
patients
40
30
28
22.2
20.3
19.8
20
14.3
10
3.6
2.6
5 to 10 years
4.9
1 to 3 years
Adjusted odds ratio
50
53.5
1.1
Type of cancer
> 15 years
3 to 12 months
0 to 3 months
Distant
metastases
Breast
Gastrointestinal
Lung
Hematological
0
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
Critical Interfaces and Questions
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
Multiple Mechanisms in
Trousseau's Syndrome
Tissue Factor microparticles
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Varki, A. Blood 2007;110:1723-1729
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 Interfaces
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
TF
Tumor
Cell
Blood Coagulation
Activation
VEGF
THROMBIN
FIBRIN
Angiogenesis
IL-8
PAR-2
Angiogenesis
TF
Endothelial cells
Falanga and Rickles, New Oncology:Thrombosis, 2005;1:9-16
Coagulation Cascade and Tumor Biology
TF
Clottingdependent
VIIa
Clottingindependent
Thrombin
Xa
Clottingindependent
Clottingdependent
Fibrin
Clottingdependent
PARs
Angiogenesis, Tumor
Growth and Metastasis
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007;5:1584
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
Activation of Blood Coagulation
in Cancer and Malignant Transformation
►
Epiphenomenon vs. Linked to Malignant
Transformation?
1.
MET oncogene induction produces DIC in human liver
carcinoma (Boccaccio lab)
(Boccaccio et al Nature 2005;434:396-400)
2.
Pten loss and EGFR amplification produce TF activation
and pseudopalisading necrosis through JunD/Activator
Protein-1 in human glioblastoma
(Bratt lab)
(Rong et al Ca Res 2005;65:1406-1413; Ca Res 2009;69:2540-9)
3.
K-ras oncogene, p53 inactivation and TF induction in
human colorectal carcinoma; TF and angiogenesis
regulation in epithelial tumors by EGFR (ErbB1) –
relationship to EMTs (Rak lab)
(Yu et al Blood 2005;105:1734-1741; Milson et al Ca Res 2008;68:10068-76)
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

Thrombosis in tail vein occurs early and is 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
656
800
Platelets (x103)
968
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 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 IH-chemical staining) in
pseudopalisades of # 7 human glioblastoma
specimens
Both Akt and Ras Pathways Modulate TF
Expression By Transformed Astrocytes
N = Normoxia
H = Hypoxia
Similar data
for EGFR –
upregulation
of TF via JunD/
AP-1 transcription
(CA Res 2009;69:2540-9)
“Pten and Hypoxia Regulate Tissue Factor Expression
and Plasma Coagulation By Glioblastoma”
Pseudopalisading necrosis
H&E
TF IHC
Vascular
Endothelium
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 et al Blood 2005;105:1734-41
Activation of Blood Coagulation
in Cancer: Malignant Transformation
TF expression in cancer cells parallels genetic tumor progression
with an impact of K-ras and p53 status
450
400
350
160
TF Activity (U/106 cells)
Mean Channel TF Flourescence
“Oncogenic Events Regulate Tissue Factor Expression In
Colorectal Cancer Cells: Implications For Tumor Progression
And Angiogenesis”
300
250
200
150
100
50
0
HKh-2
HCT116
del/+
+/+
mut/+
+/+
379.2
mut/+
del/del
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
“Oncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells”
%VWF-Positive Area
Effect of TF si mRNA on new vessel formation in colon cancer
14
12
10
8
6
4
2
0
HCT116
SI-2
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
Similar amplification of TF with upregulated VEGF induced by mutated EGFR in glioblastoma and lung
cancer cells, accompanied by epithelial-to-mesenchymal transition (EMT)
Milsom et al CA Res 2008;68:10068-76
Class Effect of siRNA for Angiogenesis Inhibition
via Toll-Like Receptior 3 (TLR 3)
(21 nucleotides)*
* Kleinman et al Nature
2008;452:591
Kalluri and Kansaki Nature 2008;452:543
Mechanisms of Cancer-Induced Thrombosis
Clinical Implications
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer
therapy?
Activation of Blood Coagulation
in Cancer: Malignant Transformation
►
Q: What do all of these experiments in mice
have to do with real patients with cancer?
►
A: They suggest two things:
● Tumor cell-derived, TF-rich microparticles
(MPs) may be important as a predictive test
for VTE
● All patients with oncogene-driven cancer may
need prophylactic anticoagulation
Tissue Factor Expression, Angiogenesis, and
Thrombosis in Human Pancreatic Cancer
►
Retrospective study
►
Immunohistologic (IH) and microarray data on
expression of TF and VEGF, as well as microvascular
density (MVD) in:



Normal pancreas (10)
Pre-malignant pancreatic lesions:
• Intraductal papillary mucinous neoplasms (IPMN; 70)
• Pancreatic intrepithelial neoplasia (PanIN; 40)
Resected or metastatic pancreatic adenoca (130)
►
Survival
►
VTE Rate
Khorana et al Clin Cancer Res 2007;13:2870
Immunohistologic Correlation of TF with the Expression of
Other Angiogenesis Variables in Resected Pancreatic Cancer
High TF
Expression
Low TF
Expression
P Value
Negative
13
41
<0.0001
Positive
53
15
V6 per tissue core
27
33
>6 per tissue core
39
23
Median
8
6
VEGF Expression
Microvessel Density
Khorana et.al. Clin CA Res 2007:13:2870
0.047
0.01
Symptomatic VTE in Pancreatic Cancer
5/19;
26.3%
1/22;
4.5%
Khorana et al Clin CA Res 2007;13:2872
Median Survival of 122
Resected Pancreatic Cancer Patients
Months
17.9
Khorana et al Clin CA Res 2007;13:2872
P = 0.16
(HR 2.06;
0.74-5.7)
12.6
Cancer and Thrombosis
Year 2009 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 2009 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 LMWHs in
cancer patients indicate superiority to oral agents in
preventing recurrent VTE, as well as increasing survival
(not due to prevention of VTE)
LMWH and Prolongation
of Cancer Survival
Mechanistic Explanations
VTE
Coagulation
Proteases
Direct
Heparin
Other
Heparins and Tumour Biology
Multiple Potential Modes of Action
Angiogenesis
Apoptosis
Heparanase
Adhesion
Ex Vivo Angiogenesis:
Embryonic Chick Aortic Rings
Control Aortic Ring: Day 5
10U/ml Dalteparin-Treated Aortic Ring:
Day 5
Fernandez, Patierno and Rickles. Proc AACR 2003;44:698 (Abstr. #3055)
Effects of Low-Molecular Weight Heparin on
Lung Cancer Cell Apoptosis
P<0.05
• G1 arrest
• Decrease in
S phase
• 3-fold  in p21WAF1
and p27KIP1 (p <0.01)
• Reversed apoptosis
and G1 arrest with
p21 or p27 siRNA
Chen et al Cancer Invest 2008;26:718-24
Heparins Inhibit Cytokine–Induced
Capillary Tube Formation
Tube Length (mm/cm )
500
§
§
400
300
§
*
*
*
*
*
*
*
*
Control
*
200
100
2
0
VEGF
Cytokine
Marchetti et al. Thromb Res 2008;121:637-645
FGF-2
+UFH
TNF-a
+enoxaparin
+dalteparin
§ = p<0.05 vs control, * = p<0.05 vs cytokine
LMWH and VEGF Antisense Oligonucleotides Inhibit
Growth and Metastasis of 3LL Tumors in Mice
►
►
40 mice with Lewis Lung Cancer (3LL)
Rx qod x 15 with:
●
●
●
●
●
►
Control (saline)
VEGF antisense oligos (ASODN)
VEGF mismatch sense oligo (MSODN)
LMWH (dalteparin)
LMWH + ASODN
RESULTS:
Growth Inhibit*
Lung Mets*
●
ASODN
LMWH
47%
27%
38%
38%
●
Combined
59%
25%
●
* P < 0.05
Zhang YH et al Chinese Med J 2006;86:749-52
Inhibition of Binding of Selectins to
Human Colon Carcinoma by Heparins
Stevenson et al Clin Ca Res 2005;11:7003-11
Heparin Inhibition of B16 Melanoma
Lung Metastasis in Mice
Stevenson et al Clin Ca Res 2005;11:7003-11
Coagulation Cascade and Tumor Biology
Clottingdependent
TF
VIIa
Clottingindependent
Thrombin
Xa
Clottingdependent
Clottingindependent
?
PARs
?
Angiogenesis, Tumor
Growth and Metastasis
LMWHs (e.g. dalteparin); Non-anticoagulant heparins or inhibitors
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584;
Varki Blood 2007;110:1723-1729
Fibrin
Clottingdependent
Innovation ● Investigation ● Application
A Systematic Analysis of VTE
Prophylaxis in the Setting of Cancer
Linking Science and Evidence to Clinical Practice—
What Do Trials Teach?
Program Chairman
Craig Kessler, MD MACP
Director, Division of Coagulation
Lombardi Comprehensive Cancer Center
Georgetown University Medical Center
Washington, DC
VTE and Cancer: Epidemiology
►
Of all cases of VTE:
●
●
►
Of all cancer patients:
●
●
►
About 20% occur in cancer patients
Annual incidence of VTE in cancer
patients ≈ 1/250
15% will have symptomatic VTE
As many as 50% have VTE at autopsy
Compared to patients without cancer:
●
●
●
Higher risk of first and recurrent VTE
Higher risk of bleeding on anticoagulants
Higher risk of dying
Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
DVT and PE in Cancer
Facts, Findings, and Natural History
►
VTE is the second leading cause of death in hospitalized
cancer patients1,2
►
The risk of VTE in cancer patients undergoing surgery is 3to 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
Probability of Death
DVT/PE and Malignant Disease
0.80
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0
20 40
60
80 100 120140 160 180
Number of Days
Levitan N, et al. Medicine 1999;78:285
Incidence of VTE and Colon Cancer Stage
7%
Local
Regional
Remote
Incidence of VTE (%)
6%
5%
4%
3%
2%
1%
0%
0
50
100
150
200
250
300
Days after Cancer Diagnosis
White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40
350
400
Symptomatic VTE in Cancer Reduces Survival
Counterintuitively, Magnitude of Effect on Survival is Greatest with
Local Stage Disease
Cancer type
Hazard ratio (95% CI) for death within one year, cases
with VTE diagnosed in year 1 vs. no VTE, by stage
Local
Regional
Remote
Prostate
5.6 (3.8-8.5)‡
4.7 (1.9-11.5) ‡
2.8 (1.5-5.0) †
Breast
6.6 (3.7-11.8) ‡
2.4 (1.3-4.5) ‡
1.8 (1.1-2.9)*
Lung
3.1 (2.1-4.5) ‡
2.9 (2.3-3.5) ‡
2.5 (2.3-2.7) ‡
Colon/rectum
3.2 (1.8-5.5) ‡
2.2 (1.7-3.0) ‡
2.0 (1.7-2.4) ‡
Melanoma
14.4 (4.6-45.2) ‡
N/A
2.8 (1.5-5.3) †
Non-Hodgkin’s lymphoma
3.2 (1.9-5.3) ‡
2.0 (1.3-3.2) †
2.3 (1.7-3.1) ‡
Uterus
7.0 (3.4-14.2) ‡
9.1 (4.8-17.2) ‡
1.7 (1.0-3.0)*
Bladder
3.2 (1.7-6.2) ‡
3.3 (1.7-6.4) ‡
3.3 (1.8-6.2) ‡
Pancreas
2.3 (1.2-4.6)*
3.8 (2.8-5.1) ‡
2.3 (1.9-2.7) ‡
Stomach
2.4 (1.1-5.1)*
1.5 (1.0-2.1)*
1.8 (1.4-2.3) ‡
Ovary
11.3 (2.5-51.7) †
4.8 (1.1-20.4)*
2.3 (1.7-3.0) ‡
Kidney
3.2 (1.2-8.8)*
1.4 (0.6-3.2)
1.3 (0.9-2.0)
R.H. White et al. Thombosis Research 120 Suppl. 2 (2007) S29-S40
* p<0.05; †p<0.01); ‡ p<0.001)
VTE Associated with Accelerated Death in Breast Cancer
Does Symptomatic VTE Reflect Presence or Emergence
of Metastatic, Aggressive Cancer?
White, et al. Thromb Res,120 suppl. 2 (2007)
Recurrent Ovarian Cancer
• 7% symptomatic VTE (2.8-6.1% in primary ovarian Cancer)
• 78% of VTE in ROC occur within 2 months of second line chemo regimen:
cisplatin-related
• Ascites is the only independent risk factor for VTE (HR=2.2)
Fotopoulou C et al. Thromb Res 2009
Mortality (%)
Hospital Mortality With or Without VTE
N=66,016
Khorana, JCO, 2006
N=20,591
N=17,360
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
●
●
Chemotherapy
Central venous catheters (~4% generate clinically
relevant VTE)
►
Patient
●
●
●
Prior VTE
Comorbidities
Genetic background
Cancer and Thrombosis
Medical Inpatients
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.?
Rate of VTE (%)
Prophylaxis Studies in Medical Patients
Relative
risk
reduction
63%
Relative
risk
reduction
44%
Placebo Enoxaparin Placebo Dalteparin
MEDENOX Trial
PREVENT
Francis, NEJM, 2007
Relative
risk
reduction
47%
Placebo Fondaparinux
ARTEMIS
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 GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
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
N=16,954
N=6124
Post-op VTE
0.61%
1.26%
<0.0001
Non-fatal PE
0.27%
0.54%
<0.0003
Autopsy PE
0.11%
0.41%
<0.0001
Death
0.71%
3.14%
<0.0001
Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
P-value
Natural History of VTE in Cancer Surgery:
The @RISTOS Registry
►
Web-Based Registry of Cancer Surgery
Tracked 30-day incidence of VTE in 2373 patients
Type of surgery
• 52% General
• 29% Urological
• 19% Gynecologic
82% received in-hospital thromboprophylaxis
31% received post-discharge thromboprophylaxis
Findings
►
2.1% incidence of clinically overt VTE (0.8% fatal)
►
Most events occur after hospital discharge
►
Most common cause of 30-day post-op death
Agnelli, Ann Surg 2006; 243: 89-95
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
Incidence of Outcome Event
16.9%
P=0.052
13.9%
Canadian
Colorectal DVT
Prophylaxis Trial
N=234
N=241
1.5% 2.7%
VTE
(Cancer)
McLeod R, et al. Ann Surg 2001;233:438-444
Major Bleeding
(All)
Incidence of Outcome Event
Extended Prophylaxis in
Surgical Patients
12.0%
ENOXACAN II
P=0.02
N=167
5.1%
4.8%
N=165
3.6%
1.8%
0.6%
VTE
Prox
DVT
0% 0.4%
NNT = 14
Any
Major
Bleeding Bleeding
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
Major Abdominal Surgery: FAME
Investigators—Dalteparin Extended
►
A multicenter, prospective, assessor-blinded, 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 GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
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)
Geerts W, et al. Chest Jun 2008: 381S–453S
Prophylaxis for Venous Catheters
Placebo-Controlled Trials
Study
Regimen
N
CRT (%)
Reichardt*
2002
Dalteparin 5000 U daily
placebo
285
140
11 (3.7)
5 (3.4)
Couban*
2002
Warfarin 1mg daily
placebo
130
125
6 (4.6)
5 (4.0)
ETHICS†
2004
Enoxaparin 40 mg daily
placebo
155
155
22 (14.2)
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
WARP: Prophylactic Warfarin Does Not Reduce
Catheter-Associated Thrombosis in CA
Warfarin evaluation
Dose evaluation
Relative risk
(95% CI, p value)
Fixeddose
warfarin
(n=471)
Doseadjusted
warfarin
(n=473)
Relative risk
(95% CI, p value)
24
(6%)
0.99
(0.57-1.72, 0.98)
34
(7%)
13
(3%)
0.38
(0.20-0.71,0.002)
370
(92%)
372
(91%)
-
433
(92%)
448
(95%)
-
Not known
10
(2%)
12
(3%)
4
(<1%)
12
(3%)
All thrombotic
events
38
(9%)
30
(7%)
37
(8%)
26
(6%)
Thrombotic
Events
No
warfarin
(n=404)
Warfarin
(n=408)
Catheterrelated
thrombotic
events
24
(6%)
No catheterrelated event
Young AM et al. Lancet 2009;373:567
0.78
(0.50-1.24), 0.30
0.70
(0.43-1.14, 0.15)
WARP: Prophylactic Warfarin Does Not Reduce
Catheter-Associated Thrombosis in CA
Warfarin evaluation
Bleeding
and Raised
INR
Dose evaluation
Relative risk
(95% CI, p value)
Fixeddose
warfarin
(n=471)
Doseadjusted
warfarin
(n=473)
Relative risk
(95% CI, p value)
3 (<1%)
-
5 (1%)
7 (1%)
-
0
4 (<1%)
-
2 (<1%)
9 (2%)
-
Total major
bleeding
1 (<1%)
7 (2%)
6.93
(0.85-56.08, 0.07)
7 (1%)
16 (3%)
2.28
(0.95-5.48, 0.09)
Moderate and
severe raised
INR and no
major
bleeding
0
3 (<1%)
-
1 (<1%)
12 (3%)
-
Minor
bleeding
1 (<1%)
14 (3%)
-
21 (4%)
24 (5%)
-
No
warfarin
(n=404)
Warfarin
(n=408)
Major
bleeding and
no reported
raised INR
1 (<1%)
Major
bleeding and
raised INR
Young AM et al. Lancet 2009;373:567
WARP: Prophylactic Warfarin Does Not Reduce
Catheter-Associated Thrombosis in CA
Combined
thrombosis
and major
bleeding
events
Warfarin evaluation
Dose evaluation
Relative risk
(95% CI, p value)
Fixeddose
warfarin
(n=471)
Doseadjusted
warfarin
(n=473)
Relative risk
(95% CI, p value)
31 (8%)
1.23
(0.83-1.52, 0.51)
41 (9%)
29 (6%)
0.84
(0.74-2.04, 0.17)
37 (9%)
0.94
(0.61-1.44, 0.87)
44 (9%)
42 (9%)
0.95
(0.64-1.42, 0.89)
No
warfarin
(n=404)
Warfarin
(n=408)
Total
catheterrelated
thrombosis
and major
bleeding
events
25 (6%)
All thrombotic
and major
bleeding
events
39 (10%)
Young AM et al. Lancet 2009;373:567
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
Influence of Thrombophilia on Thrombotic
Complications of CVADs in Cancer
In 10 studies involving more than 1250 cancer patients with
CVADs vs CA controls:
CA + FVL
OR=5.18 (95% confidence interval: 3.0-8.8)
CA + G20210A
OR=3.95 (95% confidence interval: 1.5-10.6)
The attributable risk of catheter associated thrombosis
conferred by:
FVL
13.5%
G20210A
3.6%
Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564
8th ACCP Consensus Guidelines
No routine prophylaxis to prevent
thrombosis secondary to central
venous catheters, including LMWH
(2B) and fixed-dose warfarin (1B)
Revised 2009 NCCN guidelines
diverge from this philosophy
Chest Jun 2008: 454S–545S
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.)
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 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
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
Primary VTE Prophylaxis
►Recommended for hospitalized
cancer patients
►Not universally recommended for
outpatients, but there are exceptions
●
●
New data for certain agents
Heterogeneous population
Need for risk stratification
VTE Risk with Bevacizumab in Colorectal Cancer
Approaches Risk of Antiangiogenesis in Myeloma
All-Grade Venous
Thromboembolism,
No./Total No.
No. of
Studies
Bevacizumab
Control
Incidence
(95% CI), %
RR (95%
CI)
Overall
6
155/1196
107/1083
11.9
(6.8-19.9)
1.29
(1.03-1.63)
Colorectal
cancer
3
108/564
85/532
19.1
(16.1-22.6)
1.19
(0.92-1.55)
NSCLC
1
10/66
3/32
14.9
(8.2-25.5)
1.59
(0.47-5.37)
Breast
cancer
1
17/229
12/215
7.3
(4.6-11.5)
1.30
(0.64-2.67)
Renal cell
carcinoma
1
20/337
6/304
3.0
(1.6-5.5)
3.00
(1.23-7.33)
Tumor Type
Naluri SR et al. JAMA. 2008;300:2277
Bevacizumab Increases Risk of
Symptomatic VTE by 33% vs Controls
Naluri SR et al. JAMA. 2008;300:2277
Incidence of VTE: USA and Canada Greater
than 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
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
CANCER PATIENTS
WITH
ACUTE DVT or PE
[N = 677]
►
►
Dalteparin
Randomization
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
Risk reduction = 52%
p-value = 0.0017
Recurrent VTE
20
OAC
15
10
Dalteparin
5
0
0
30
60
90
120
150
Days Post Randomization
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
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
Length of
Therapy
(Months)
N
Recurrent
Major
Death
VTE
Bleeding
(%)
(%)
(%)
6
4
NS
39
41
0.09
7
16
0.09
11 0.03
23
0.03
6
8
CLOT Trial
(Lee 2003)
Dalteparin
OAC
6
336
336
9
17
0.002
CANTHENOX
(Meyer 2002)
Enoxaparin
OAC
3
67
71
11
21
LITE
(Hull ISTH 2003)
Tinzaparin
OAC
3
80
87
6
11
ONCENOX
(Deitcher ISTH
2003)
Enox (Low)
Enox (High)
OAC
6
32
36
34
3.4
3.1
6.7
NS
NS
NS
23
22
NS
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)
►
NOTE: Dalteparin is only LMWH approved (May,
2007) for both the treatment and secondary prevention
of VTE in cancer (NCCN preferred agent)
►
Oral anticoagulant therapy to follow for as long as
cancer is active (Grade 1C recommendation—ACCP)
Chest Jun 2008: 454S–545S
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 AY et al. J Clin Oncol. 2005; 23:2123-9.
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 AY et al. J Clin Oncol. 2005; 23:2123-9.
360
LMWH Influences Survival of Patients with
Advanced Solid Tumor Malignancies
6 wks LMWH immediately post diagnosis of CA-no initial chemo
<6 mos anticipated survival
Klerk, C. P.W. et al. J Clin Oncol; 23:2130-2135 2005
>6 mos anticipated survival
LMWH for Small Cell Lung Cancer
Turkish Study
►
84 patients randomized: Chemo +/- LMWH (18 weeks)
►
Patients balanced for age, gender, stage, smoking
history, ECOG performance status
Chemotherapy
plus 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
Cancer:
FRONTLINE Survey1—
3891 Clinician
Respondents
Cancer:
Surgical
Major
Surgery2
Major
Abdominothoracic
Surgery (Elderly)3
Medical
Inpatients4
Confirmed DVT
(Inpatients)5
Cancer:
Medical
1. Kakkar AK et al. Oncologist. 2003;8:381-388
4. Rahim SA et al. Thromb Res. 2003;111:215-219
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
Conclusions and Summary
► Risk factors for VTE in the setting of cancer have
been well characterized: solid tumors, chemotherapy,
surgery, thrombocytopenia
► Long-term secondary prevention with LMWH has
been shown to produce better outcomes than warfarin
► Guidelines and landmark trials support administration
of LMWH in at risk patients
► Cancer patients are under-prophylaxed for VTE
► Health system pharmacists can play a pivotal role in
improving clinical outcomes in this patient population
Mechanisms ● Mortality ● Therapeutics
Pharmacologic Prophylaxis of
DVT in Special Populations
Edith Nutescu, PharmD, FCCP
Clinical Associate Professor
Pharmacy Practice
Affiliate Faculty, Center for
Pharmacoeconomic Research
Director, Antithrombosis Center
The University of Illinois at Chicago
College of Pharmacy & Medical Center
Chicago, IL
Objectives
1. Differentiate data with various LMWHs in special
populations
2. Review appropriate dosing and monitoring of
LMWHs in patients with obesity and renal failure
Risk of Inadequate Therapy
in High Risk Patients
►
524 VTE Patients
●
Active Cancer in 26%
• Only 1/3rd on LMWH monotherapy
●
Weight > 100Kg in 15%
• Under-dosing of LMWH by > 10%
– 36% of > pts 100Kg
– 8% of pts < 100Kg (p < 0.001)
●
CrCL < 30mL/min in 5%
• LMWH tx in 67%
Cook LM, et.al. J Thromb Hemost 2007;5;937-41.
8th ACCP Conference on
Antithrombotic Therapy
Obese Patients
“In obese patients given LMWH prophylaxis or
treatment, we suggest weight-based dosing
(Grade 2C).”
►
What is this weight-based dosing and how does it differ
from typical dosing?
►
At what weight do we move away from standard dosing
and move to weight-based dosing?
Hirsh J et al. Chest. 2008;133(suppl):141S-159S.
Pharmacokinetic Characteristics of
Low Molecular Weight Heparins
Lipid solubility
LOW
Plasma protein binding
HIGH
Tissue binding
LOW
Volume of distribution
5-7 L
Logical conclusion:
IBW may be a better predictor of LMWH dosing than TBW
LMWH: Maximum Weights Studied
Kinetic
Studies
Clinical Trials
Dalteparin
190 kg
128 kg*
Enoxaparin
144 kg
194 kg
Tinzaparin
165 kg
88 kg
Fondaparinux
* max dose 18,000 - 20,000 IU/day
Duplaga BA et al. Pharmacotherapy 2001; 21:218-34.
Synergy Trial: Data on File
Davidson, et al. J Thromb Haem 2007;5:1191-4
175.5 kg
LMWH Pharmacokinetics in Obesity
Actual body weight correlates best with anticoagulant response to
LMWHs as measured by anti-factor Xa levels
Clin Pharmacol Ther 2002;72:308-18. Thromb Haemost 2002;87:817-23.
Dalteparin
Pharmacokinetics in Obesity
Dose: 200 U/kg qd
Duration: routine
Obese (BMI > 30)
Normal (BMI < 30)
10
10
TBW (mean +/- SD)
106.4 +/- 22.1
69.7 +/- 9.3
LBW (mean +/- SD)
64.1 +/- 12.3
66.1 +/- 8.7
Mean Vd (l)
12.39
8.36
Mean CI (l/hr)
1.30
1.11
N
Yee JYV, Duffull SB. Eur J Clin Pharmacol 2000; 56:293-7.
Dalteparin
Pharmacokinetics In Obesity
Correlation Coefficient Between Vd and:
LBW
0.05
ABW
0.52
TBW
0.55
Correlation Coefficient Between Cl and:
LBW
0.01
ABW
0.32
TBW
0.39
Conclusion:
TBW may be a better predictor of LMWH dose than IBW
Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7.
Dalteparin
Pharmacokinetics In Obesity
Dose: 200 U/kg qd
Duration: 5 Days
Max TBW: 190kg
<20% of
IBW
20-40% of
IBW
> 40% of
IBW
N
13
14
10
Mean Dose (U)
14,030
17,646
23,565
Day 3 Peak
1.01
0.97
1.12 NS
Day 3 Trough
0.12
0.11
0.11 NS
Ant-Xa Activity (u/ml)
Conclusion: Body mass does not appear to have an important effect on the
response to LMWH up to a weight of 190kg in patients with normal renal function.
Wilson SJ et al. Hemostasis 2001; 31:42-8.
LMWH Safety and Effectiveness Using TBW
Enoxaparin In ACS (ESSENCE/TIMI IIb)
P=0.39
16.1%
14.3%
P=0.13
1.6%
0.4%
Obese: BMI > 30mg/m2
Enoxaparin max weight 158 kg
Spinler SA et al. Am Heart J 2003; 146:33-41
Safety Of TBW-based Dosing of Dalteparin
for Treatment of Acute VTE in Obese Patients
N = 193 patients
> 90 kg
3 month outcomes: major bleeding = 1.0% (n=2)
recurrent VTE = 1.6% (n=3)
WEIGHT
(kg)
N
Mean
Dose
Full dose
+/- 5%
QD
Dosing
BID
Dosing
90-99
40
19,300
39
24
16
100-109
52
20,850
49
25
17
110-119
41
21,470
21
26
15
120-129
25
24,300
22
16
9
130-139
16
25,250
8
10
6
140-149
9
26,920
6
5
4
> 150
10
28,280
6
6
4
Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2.
Fondaparinux In Obesity
Results From the Matisse Trials
Fondaparinux:
< 50kg: 5mg qd
50-100kg: 7.5mg qd
> 100kg: 10mg qd
Enoxaparin:
(Matisse DVT)
1mg/kg q12h
Heparin:
(Matisse PE)
Adjusted per aPTT
Davidson BL et al. J Thrombosis Haemost 2007; 5:1191-4.
No weight-dependent
difference in
efficacy or safety
Body Weight and Anti-Xa Activity
for Prophylactic Doses of LMWH
Area under the curve for 10 h
N = 17 patients and 2 volunteers
Enoxaparin 40mg SQ x1 dose
AntiXa levels hourly x10 hours
Regression line
95% CI for line
95% CI for data points
200
150
100
50
0
40
60
80
100
120
Body Weight (kg)
Frederiksen SG et al. Br J Surgery 2003; 90:547-8
140
160
Dalteparin
Fixed Dosing For VTE Prevention
Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill)
BMI (kg/m2)
< 25
25-29.9
30-34.9
35-39.9
> 40
Patients %
Favors Dalteparin
Favor Placebo
37.5
33.1
18.9
7.1
3.3
Overall Prevent Trial
0.01
0.1
0.55 1.0
Relative Risk
10.0
Dalteparin 5,000 units daily was similarly effective in obese and non-obese patients (except
patients with BMI>40) with no observed difference in mortality or major bleeding
Kucher N et al. Arch Int Med 2005;165:341-5.
Enoxaparin VTE Prophylaxis in
TKA/THA/Trauma
31.8%
p<0.001
16.7%
N: 807
Dose: 40 mg qd
Samama MM et al. Thromb Haemost 1995; 73:977.
Obese : BMI>32kg/m2
Enoxaparin:
VTE Prophylaxis in Bariatric Surgery
5.4%
p<0.01
0.6%
30mg bid: n=92
BMI 51.7kg/m2
Scholten Obes Surg 2002; 12:19-24.
40mg bid: n=389
BMI 50.3kg/m2
Dalteparin in Morbid Obesity: Bariatric Surgery
N=135
Bariatric Surgery
Mean Weight: 148.8Kg
Mean BMI: 53.7
Dalteparin: 7,500 IU daily
Body Weight (kg)
200
180
P=0.052
P=0.444
160
140
120
0
Anti-factor Xa level
P=0.031
Under target value Target value Over target value
<>0.5 IU/mL
<0.2 IU/mL
<0.2-0.5 IU/mL
n=13
n-=41
n-=81
Number of patient (%) Body weight (kg)
Below target value (<0.2 UI/ml)
41 (30.4%)
159.4 ± 35.8
Target value (0.2–0.5 UI/ml)
81 (60.0%)
145.7 ± 28.4
Above target value (>0.5 UI/ml)
13 (9.6%)
134.6 ± 24.2
p value
Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print]
0.0152
LMWH in Obesity: Summary
►
Treatment: in controlled trials, LMWH dosing has been based on TBW
(max 160-190 kg)
●
Dalteparin
• Dose based on TBW
• PI recommends dose capping
• Recent clinical data supports TBW dosing
– QD or BID dosing
●
Enoxaparin
• Dose based on TBW
• Dose capping NOT recommended
• BID dosing preferred
●
Tinzaparin
• Dose based on TBW, NO dose adjustment or capping
●
►
Anti-Xa monitoring not necessary for TBW < 190kg
Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients)
Nutescu E, et.al. Ann Pharmacother; 2009; 43(6):1064-83.
8th ACCP Conference on Antithrombotic Therapy
Renal Impairment
►
For each of the antithrombotic agents, we recommend that
clinicians follow manufacturer-suggested dosing guidelines
(Grade 1C)
►
We recommend that renal function be considered when
making decisions about the use of and/or dose of LMWH or
fondaparinux (Grade 1A)
►
Options for patients with renal impairment (Grade 1B)
●
●
●
Avoid agents that renal accumulate
Use a lower dose
Monitor the drug level or anticoagulant effect
Geerts WH. Chest 2008;133(suppl):381S-453S.
LMWH in Renal Dysfunction
Manufacturer Recommendations
Dalteparin
●
“should be used with caution in patients with severe kidney
insufficiency.”
• Monitor anti-Factor Xa for dose guiding with therapeutic doses
Enoxaparin
●
“adjustment of dose is recommended for patients with severe
renal impairment (CrCL < 30 mL/min).”
Tinzaparin
●
“patients with severe renal impairment should be dosed with
caution.”
Fondaparinux
- Contraindicated in CrCL < 30mL/min
Recent Meta-Analysis of LMWHs and Bleeding
In Patients With Severe Renal Dysfunction
Patients w/
renal insuff.
(n/n)
Patients w/ no
renal insuff.
(n/n)
Collet, et al; 2001
Paulas, et al; 2002
Siguret, et al; 2000
0/28
0/51
0/17
1/83
3/149
0/13
Chow, et al; 2003
0/5
0/13
Khazan, et al. (adj.); 2003
(Prophylactic) 2003
(Therapeutic) 2003
Spinler, et al; 2003
0/10
3/36
2/17
5/69
3/42
3/47
3/61
74/3,432
4.78
14.77
8.62
15.93
0.28 (0.01 – 5.16)
1.33 (0.25 – 7.05)
3.09 (0.35 – 27.31)
10.05 (2.02 – 49.98)
Green, et al; 2005
1/18
0/20
2.66
8.26 (0.16 – 418.42)
Kruse & Lee; 2004
0/50
1/120
2.22
0.24 (0.00 – 17.90)
Macie, et al; 2004
2/7
6/201
2.68
977.78 (19.61 – 48,752.07)
Peng, et al; 2004
0/7
0/43
Thorevska, et al; 2004
7/65
11/171
35.56
1.85 (0.63 – 5.40)
Bazinet, et al; 2005
1/36
2/160
4.75
2.74 (0.15 – 51.73)
21/416
107/4,555
Study; year
Total (95%, CI)
Peto OR
(95%, CI)
2.01
6.02
Peto OR
(95%, CI)
0.26 (0.00 – 23.94)
0.26 (0.02 – 3.50)
Not estimable
Not estimable
Not estimable
0.01 0.1
Favors ↓’ed
Lim W, et al. Ann Intern Med. 2006;144:673-684.
Weight
(%)
100.00
1
10
100
Favors ↑’ed
bleeding
2.25 (1.19 – 4.27)
Dosage adjustments
for renal dysfunction
Enoxaparin PK and PD in Renal Impairment
Result:
Tmax: 3-4 hours
Amax: 10-35% higher in RI groups
CI/F linearly correlated with CrCl
CL/F
(L/h)
Half-life
(h)
Normals
0.98
6.87
Mild RI
0.87
9.94
20% ↑
Moderate RI
0.76
11.3
21% ↑
Severe RI
0.58
15.9
65% ↑
Day 4
Sanderink GJCM. Thromb Res 2002;105:225-31.
AUC (0-24)
(h●IU/mL)
LMWH Renal Dosing in NSTE ACS Patients
►
56 UA pts with CrCl <60
ml/min
►
Enoxaparin dose empirically
 and anti-Xa level
measured after 3rd dose
•
•
•
•
Dose may be  to 0.6mg/kg/ q12h if
CrCL <30mL/min; or 0.8 mg/kg/q12h if
CrCl 30-60 ml/min
Anti-Xa monitoring
Doses “appeared safe”
Further prospective evaluation needed
CrCl
(ml/min)
<30
(n = 28)
>30 and <60
(n =28)
Age
76+/-3
73+/-3
Enoxaparin (mg/kg/12h)
0.64
0.84
Anti-Xa (IU/ml)
0.95
0.95
Collet JP et al. International J Cardiol 2001;80:81-2.
Clinical Use Of Recommended
Enoxaparin Dosage in Renal Impairment
N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h
1.0.
6
0.9
TROUGH ANTI-Xa LEVELS
5
0.8
Number of Patients
Antifactor X1 Level (U/mL)
PEAK ANTI-Xa LEVELS
0.7
0.6
0.5
0.4
0.3
4
3
2
1
0.2
0.1
0
First dose
Median
Subsequent doses
(second and third)
25-75% interquartile range
Lachish T et al. Pharmacotherapy 2007; 27:1347-52.
0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55
Trough Antifactor Xa Level (U/mL)
Tinzaparin 175 U/kg
Peak Anti-Xa Levels According to Renal Function
No correlation between peak anti-Xa activity and Clcr
No accumulation of Anti-Xa activity after 10 days of therapy
Siguret V et al. Thromb Haemost 2000;84:800-4.
Pharmacokinetics of Prophylactic
Enoxaparin vs Tinzaparin
Enoxaparin 40mg qd
or
Tinazaparin 4500 IU qd
N = 52 patients
Mean age = 87.7 yrs
Mean wt = 52.3kg
Mean Clcr = 34.7ml/min
Mahe I et al. Thromb Haemost 2007; 97:581-6.
Pharmacokinetics of
Prophylactic Doses of Dalteparin
N = 115 elderly (age > 65) pts with acute medical illness and elevated SCr
Tx: dalteparin 5000 U or 2500 U SQ qd (risk-based) for VTE prophylaxis
Renal Failure
Mild
(n=12)
Moderate
(n=73)
Severe
(n=24)
CrCL (ml/min)
60-89
30-59
<30
Day 6 peak anti-Xa
0.030
0.033
0.048
Minor Bleeding
0
3
0
Major Bleeding
0
0
0
P=0.72
► No evidence of accumulation of anti-Xa activity
► No relationship between the degree of renal impairment and peak
anti-Xa level on Day 6
► No association between creatinine clearance and anti-Xa levels
Tincani E et al. Haematologica 2006; 91:976-9.
Dalteparin Thromboprophylaxis in Critically Ill Patients
with Severe Renal Insufficiency: The Direct Study
► N=138 critically ill patients
► CrCl < 30 ml/min
• Mean CrCL 18.9ml/min
► Dalteparin 5000 IU sc daily
► Serial anti Xa levels measured on days 3, 10, and 17
► Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mL
Results:
► The median duration of dalteparin exposure was 7 (4-12) days
► No patient had a trough anti Xa level > 0.4 IU/ml
► Based on serial measurements
• peak anti-Xa levels were 0.29 to 0.34 IU/mL
• trough levels were lower than 0.06 IU/mL
Douketis, et al. Arch Intern Med. 2008 Sep 8;168(16):1805-12.
Dosing of LMWHs In Renal Impairment
Recommendations
FOR CrCL < 30 ml/min
►
Enoxaparin:
●
●
►
Prophylaxis doses: 30 mg sq QD
Treatment doses: 1mg/Kg sq QD
Dalteparin and Tinzaparin:
●
●
●
no specific dosing guidelines
No or lower degree of accumulation expected
Anti-Factor Xa activity monitoring
FOR CrCL 30-50 mL/min
►
No specific recommendations
►
Concern with prolonged use > 10 days with enoxaparin (15-25%
dose decrease ?)
►
Monitoring anti-Xa ?
Nutescu E, et.al. Ann Pharmacother; 2009; 43(6):1064-83.
Unresolved Issues in
Renal Dosing of LMWHs
CrCl (mL/min)
Recommendations
< 30
Dose of enoxaparin should be adjusted; dalteparin and
tinzaparin no short term accumulation expected.
< 20-15
LMWHs have not been adequately studied as repeated
doses for prophylaxis and treatment indications; UFH is
preferred in these patients.
Issues with anti-factor Xa testing include:
true therapeutic range, standardization, availability, recommendations
for dose adjustment
Anti-Xa Activity Level Monitoring
Enoxaparin 1mg/kg SQ pharmacokinetic profile
Peak (goal ~ 0.5-1 U/ml) at 3-4 hrs
Trough (goal < 0.5 U/ml) at 11-12 hrs
Laposata et al. Arch Pathol Lab Med. 1998;122:799-807.
Fondaparinux Use in Patients
with Impaired Renal Function
► Total clearance lower than in patients
with normal renal function
Fondaparinux: PI
●
Mild impairment
~25%
●
Moderate impairment
~40%
●
Severe impairment
~55%
Mechanisms ● Mortality ● Therapeutics
Applying National Guidelines to
Clinical Practice
Current Status of ASCO and NCCN Guidelines for
VTE Prophylaxis in Cancer Patients
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
ASCO Guidelines
Hospitalized Patients with Cancer
Role of VTE Prophylaxis
Evidence
Patients with cancer should be
considered candidates for VTE
prophylaxis with anticoagulants
(UFH, LMWH, or fondaparinux) in
the absence of bleeding or other
contraindications to anticoagulation
Multiple RCTs of hospitalized
medical patients with subgroups of
patients with cancer. The 8th ACCP
guidelines strongly recommend
(1A) prophylaxis with either lowdose heparin or LMWH for
bedridden patients with active
cancer.
Ambulatory Patients with Cancer Without VTE
Receiving Systemic Chemotherapy
Role of VTE Prophylaxis
Evidence
Routine prophylaxis with an
antithrombotic agents is not
recommended except as noted below
Routine prophylaxis in ambulatory
patients receiving chemotherapy is not
recommended due to conflicting trials,
potential bleeding, the need for
laboratory monitoring and dose
adjustment, and the relatively low
incidence of VTE.
LMWH or adjusted dose warfarin (INR
~ 1.5) is recommended in myeloma
patients on thalidomide or
lenalidomide plus chemotherapy or
dexamethasone
This recommendation is based on
nonrandomized trial data and
extrapolation from studies of
postoperative prophylaxis in
orthopedic surgery and a trial of
adjusted-dose warfarin in breast
cancer
Patients with Cancer Undergoing Surgery
Role of VTE Prophylaxis
Evidence
All patients undergoing major surgical
intervention for malignant disease
should be considered for
thromboprophylaxis with low- dose
UFH, LMWH, or fondaparinux starting
as early as possible for at least 7-10
days unless contraindicated.
RCTs of UFH and those comparing
the effects of LMWH and UFH on DVT
rates on patients with cancer indicate
broadly similar prophylactic efficacies
for these two agents
Mechanical methods may be added to
anticoagulation in very high risk
patients but should not be used alone
unless anticoagulation in
contraindicated.
A Cochrane review of 19 studies
Patients with Cancer
Undergoing Surgery (continued)
Role of VTE Prophylaxis
Evidence
LMWH for up to 4 weeks may be
considered after major
abdominal/pelvic surgery with residual
malignant disease, obesity, and a
previous history of VTE
Recent RCTs suggest that prolonging
prophylaxis up to 4 weeks is more
effective than short-course
prophylaxis in reducing postoperative
VTE.
Treatment of Patients with Established
VTE to Prevent Recurrence
Role of VTE Prophylaxis
LMWH is the preferred approach for the initial
5-10 days in cancer patient with established
VTE.
LMWH for at least 6 months is preferred for
long-term anticoagulant therapy. Vitamin K
antagonists with a targeted INR of 2-3 are
acceptable when LMWH is not available. The
CLOT study demonstrated a relative risk
reduction of 49% with LMWH vs. a vitamin K
antagonist. Dalteparin sodium approved by the
FDA for extended treatment of symptomatic
VTE to reduce the risk of recurrence of VTE in
patients with cancer (FDA 2007)
Evidence
LMWH for 3-6 months is
more effective than vitamin K
antagonists given for a
similar duration for
preventing recurrent VTE.
Treatment of Patients with Established
VTE to Prevent Recurrence (continued)
Role of VTE Prophylaxis
Evidence
In the absence of clinical trials,
benefits and risks of continuing LMWH
Anticoagulation for an indefinite period
beyond 6 months is a clinical
should be considered for patients with
judgment in the individual patient.
active cancer (metastatic disease,
Caution is urged in elderly patients
continuing chemotherapy)
and those with intracranial
malignancy.
Inferior vena cava filters are reserved
for those with contraindications to
anticoagulation or PE despite
adequate long-term LMWH.
Consensus recommendations due to
lack of date in cancer-specific
populations
Anticoagulants in the Absence of
Established VTE to Improve Survival
Role of VTE Prophylaxis
Anticoagulants are not currently
recommended to improve survival in
patients with cancer without VTE.
Evidence
RCTs and meta-analysis of warfarin,
UFH and LMWH have reported
encouraging but variable results
generally showing clinical benefit only
in subgroup analyses.
Summary of NCCN Guidelines Updates
Summary of Major Changes in the
1.2009 Version of the NCCN Venous
Thromboembolic Disease Guidelines
Changes in 2009 NCCN Guidelines
►
Stage 1 Immediate:
“Stage 1 Immediate: Concomitant with diagnosis or while diagnosis
and risk assessment (heparin phase)” changed to “Stage 1
Immediate: At diagnosis or during diagnostic evaluation”
►
Low –molecular-weight-heparin: New footnote “6” was added that
states, “Although each of the low molecular weight heparins
(LMWH), have been studies in randomized control trials in cancer
patients, dalteparin’s efficacy in this population is supported by the
highest quality evidence and it is the only LMWH approved by the
FDA for this indication.”
►
Unfractionated heparin (IV): target aPTT range changed from “2.02.9 x control) to “2.0-2.5 x control…” (Also for VTE-H) in these
patients.
Changes in 2009 NCCN Guidelines
Stage 3 Chronic:
► “Third bullet: “Consider indefinite anticoagulation….”
changed to “Recommend indefinite anticoagulation….”
► Fourth bullet: “For catheter associated thrombosis,
anticoagulate as long as catheter is in place and for at
least 3 months after catheter removal”.
Changes in 2009 NCCN Guidelines
►
6Although
each of the low molecular weight heparins
(LMWH) have been studied in randomized controlled
trials in cancer patients, dalteparin’s efficacy in this
population is supported by the highest quality evidence
and is the only LMWH approved by the FDA for this
indication.
Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight
heparin versus a coumarin for the prevention of recurrent venous
thromboembolism on patients with cancer. New Eng J Med 2003;349(2):
146-153.
(VTE-D): Therapeutic Anticoagulation
Treatment for VenousThromboembolism
► The NCCN panel recommends VTE thromboprophylaxis for all
hospitalized patients with cancer who do not have
contraindications to such therapy, and the panel also
emphasized that an increased level of clinical suspicion of
VTE should be maintained for cancer patients. Following
hospital discharge, it is recommended that patients at high-risk
of VTE (e.g. cancer surgery patients) continue to receive VTE
prophylaxis for up to 4 weeks post-operation. Careful
evaluation and follow-up of cancer patients in whom VTE is
suspected and prompt treatment and follow-up for patients
diagnosed with VTE is recommended after the cancer status
of the patient is assessed and the risks and benefits of
treatment are considered.
(VTE-D): Therapeutic Anticoagulation
Treatment for VenousThromboembolism
Stage 1 Immediate: At diagnosis or during diagnostic
evaluation:
► Low-molecular-weight heparin (LMWH)
•
•
•
Dalteparin (200 units/kg subcutaneous daily)
Enoxaparin (1 mg/kg subcutaneous every 12 hours)
Tinzaparin (175 units/kg subcutaneous daily)
►
Fondaparinux (5 mg [<50 kg]; 7.5 mg [50-100 kg]; 10 mg [> 100 kg]
subcutaneous daily
► Unfractionated heparin (IV) (80 units/kg load, then 18
units/kg per hour, target aPTT of 2.0-2.5 x control or per
hospital SOP)
(VTE-D): Therapeutic Anticoagulation
Treatment for VenousThromboembolism
► Additional VTE risk factors for surgical oncology patients
with a previous episode of VTE include anesthesia times
longer than 2 hours, advanced stage disease, bed rest, >
4 days and patients age 60 years or older. Extended
prophylaxis out to 4 weeks post-surgery was associated
with a greater than 50% reduction in venographic VTE
(VTE-D): Therapeutic Anticoagulation
Treatment for VenousThromboembolism
Stage 2 Acute: Short term, during transition to chronic
phase:
► LMWH (category 1) 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
► If UFH or factor Xa antagonist, transition to LMWH or
warfarin
► Warfarin (2.5-5 mg every day initially, subsequent dosing
based on INR value; target INR 2.0-3.0)
Therapeutic Anticoagulation Failure
Therapeutic
INR
Patient
on
warfarin
Switch to heparin
(LMWH preferred)
or fondaparinux
Check
INR
Subtherapeutic
INR
Increase warfarin
dose and treat with
parenteral agent until
INR target achieved
or consider switching
to heparin (LMWH
preferred) or
fondaparinux
Therapeutic Anticoagulation Failure
Therapeutic
aPTT
Patient
on
heparin
Increase dose of heparin
or Switch to LMWH
or Switch to fondaparinux
and Consider placement
of IVC filter
and Consider HIT
Check
aPTT
levels
Subtherapeutic
aPTT
Increase dose of
heparin to reach
therapeutic level
Mechanisms ● Mortality ● Therapeutics
Thank You
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