Cancer and Thrombosis Management Focus on Thrombosis Assessment Prophylaxis and Management in the Setting of Cancer and Associated Conditions Program Chairman Craig M Kessler MD Professor of Medicine and Pathology ID: 778895
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Slide1
Slide2The Science and Medicine of
Cancer and Thrombosis Management
Focus on Thrombosis Assessment, Prophylaxis, and Management in the Setting of Cancer and Associated Conditions
Program ChairmanCraig M. Kessler, MDProfessor of Medicine and PathologyGeorgetown University Medical CenterDirector of the Division of CoagulationDepartment of Laboratory MedicineLombardi Comprehensive Cancer CenterWashington, DC
Innovation
●
Investigation
●
Application
Slide3CME-accredited symposium
jointly sponsored by
the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLCCommercial 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 managementProcesses: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studiesCOI: Full faculty disclosures provided in syllabus and at the beginning of the program
Welcome and Program Overview
Slide4Program Educational Objectives
As a result of this session, participants will:
Understand the scientific mechanisms, including the pathobiology of thrombosis-related complications, that explain the increased risk for thrombosis-related complications observed in patients with cancer.
Learn how national guidelines for thrombosis prevention issued by ASCO, NCCN, and ACCP should impact management of patients with cancer.Learn specific strategies for risk-directed prophylaxis against VTE in at-risk patients with cancer.Learn which tumor types and therapeutic strategies place patients at higher risk for acquiring thrombosis-related complications and institute appropriate measures to reduce these risks.Learn how to assess and manage special needs of cancer patients at risk for VTE and how national guidelines issued by cancer-focused organizations can improve patient care in this population.
Slide5Program Faculty
Craig M. Kessler, MD
Program Chairman
Professor of Medicine and PathologyGeorgetown University Medical CenterLombardi Comprehensive Cancer CenterChief, Division of CoagulationWashington, DC
Samuel Z. Goldhaber, MD
Professor of Medicine
Harvard Medical School
Director, Venous Thromboembolism
Research Group
Senior Staff Cardiologist
Brigham and Women’s Hospital
Boston, MA
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
Slide6Faculty COI Financial Disclosures
Craig M. Kessler, MD - Co-Chairman
Grant/Research Support:
GlaxoSmithKlineConsultant: sanofi-aventis, Eisai PharmaceuticalsSpeaker’s Bureau: sanofi-aventis, GlaxoSmithKlineFrederick R. Rickles, MDConsultant: Eisai Pharmaceuticals, Genmab
,
Pharmacyclics
Speaker’s Bureau:
Eisai Pharmaceuticals
Samuel Z. Goldhaber, MD
Research Support:
AstraZeneca, BMS,
Boehringer
-
Ingelheim
, Eisai,
sanofi
-
aventis
Consultant:
Boehringer
-
Ingelheim
, BMS, Eisai, Genentech,
Medscape
,
Possis
,
sanofi
-
aventis
Slide7Clotting, 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 MACPDirector, Division of CoagulationLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DCInnovation ● Investigation ● Application
Slide8VTE 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.
Slide9COMORBIDITY
CONNECTION CAPUTI Cancer
Heart Failure ABE/COPD Respiratory Failure Myeloproliferative DisorderThrombophilia Surgery History of DVTOther SUBSPECIALISTSTAKEHOLDERSInfectious diseasesOncology
PHARMACISTS
Cardiology
Pulmonary medicine
Hematology
Oncology/hematology
Interventional Radiology
Hospitalist
Surgeons
EM
PCP
Comorbidity
Connection
Slide10Epidemiology of First-Time VTE
White R.
Circulation. 2003;107:I-4 –I-8.)
VariableFinding
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
Slide11Epidemiology of VTE
White R.
Circulation. 2003;107:I-4–I-8.)
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.
Slide12Comorbidity
Connection
ComorbidityConnection
Overview
Slide13Acute Medical Illness and VTE
Multivariate Logistic Regression Model
for Definite Venous Thromboembolism
(VTE)Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968Risk FactorOdds Ratio
(95% CI)
X
2
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
Slide14Comorbid
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
Slide15VTE Recurrence
Predictors of First Overall VTE Recurrence
Heit
J, Mohr D, et al. Arch Intern Med. 2000;160:761-768Baseline CharacteristicHazard 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
4.24 (2.58-6.95)
2.21 (1.60-3.06)
Slide16Progression of Chronic Venous InsufficiencyFrom UpToDate 2006
Slide17Rising VTE Incidence in
Hospitalized Patients
Stein PD et al. Am J Cardiol 2005; 95: 1525-1526
Slide18DVT Registry (N=5,451):
Top 5 Medical
Comorbidities1. Hypertension
2. Immobility3. Cancer4. Obesity (BMI > 30)5. Cigarette SmokingAm J Cardiol 2004; 93: 259-262
Slide19Implementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines.
Implementation
Slide20Symposium Themes—Cancer/DVT
Cancer rates are increasing as heart disease Rx improves and as cancer Rx improves.
Cancer increases VTE risk.VTE is preventable (immunize!)VTE prophylaxis may slow cancer
Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATFFacilitate prophylaxis with alerts.
Slide21Cancer, Thrombosis, and the Biology of Malignancy
Scientific Foundations for the Role of
Low-Molecular-Weight Heparin
Frederick R. Rickles, MDProfessor of Medicine, Pediatrics, Pharmacology and PhysiologyThe George Washington UniversityWashington, DCClotting, Cancer, and Controversies
Slide22(1801–1867)
Cancer and Venous Thromboembolism
The Legacy of Armand Trousseau
Slide23Professor 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
Slide24Professor 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
Slide25Trousseau’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”
Slide26Trousseau’s Syndrome
Occult cancer
in patients with idiopathic venous thromboembolismThrombophlebitis in patients with cancer
Slide27Silver
In:
The Hematologist - modified from Blom et. al. JAMA 2005;293:715Population-based case-control (MEGA) studyN=3220 consecutive patients with 1st VTE vs. n=2131 control subjectsCA patients = OR 7x VTE risk vs. non-CA patients
Effect of Malignancy on Risk of Venous Thromboembolism (VTE)
0
10
20
30
40
50
Hematological
Lung
Gastrointestinal
Breast
Distant
metastases
0 to 3 months
3 to 12 months
1 to 3 years
5 to 10 years
> 15 years
Adjusted odds ratio
Type of cancer
Time since cancer diagnosis
28
22.2
20.3
4.9
19.8
53.5
14.3
2.6
1.1
3.6
Slide28Cancer, Mortality, and VTE
Epidemiology and Risk
Patients with cancer have a 4- to 6-fold increased risk for VTE vs. non-cancer patientsPatients with cancer have a 3-fold increased risk for recurrence of VTE vs. non-cancer patientsCancer patients undergoing surgery have a 2-fold increased risk for postoperative VTEDeath rate from cancer is four-fold higher if patient has concurrent VTEVTE 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
Slide29Mechanisms of Cancer-Induced Thrombosis: The Interface
Pathogenesis?
Biological significance?Potential importance for cancer therapy?
Slide30“There appears in the cachexiae…a
particular condition of the blood that
predisposes it to spontaneouscoagulation.”Lectures in Clinical Medicine, 1865Trousseau’s Observations (continued)
Slide31Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Varki, A. Blood 2007;110:1723-1729
Multiple Mechanisms in
Trousseau's Syndrome
Tissue Factor
microparticles
Slide32Fibrinolytic
activities
:t-PA, u-PA, u-PAR, PAI-1, PAI-2
Procoagulant Activities FIBRINEndothelial cells
IL-1, TNF-
a,
VEGF
Tumor cells
Monocyte
PMN leukocyte
Activation of coagulation
Platelets
Angiogenesis,
Basement matrix degradation
Falanga
and Rickles,
New Oncology: Thrombosis
, 2005;
Hematology,
2007
Interface of Biology and Cancer
Slide33Pathogenesis of Thrombosis in Cancer –
A Modification of Virchow’s Triad
StasisProlonged bed restExtrinsic compression of blood vessels by tumorVascular InjuryDirect invasion by tumorProlonged use of central venous catheters
Endothelial damage by chemotherapy drugsEffect of tumor cytokines on vascular endotheliumHypercoagulabilityTumor-associated procoagulants and cytokines (tissue factor, CP, TNF, 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
Slide34Mechanisms of Cancer-Induced Thrombosis: Clot and Cancer Interface
Pathogenesis?
Biological significance?Potential importance for cancer therapy?
Slide35Activation 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
Slide36TF
VEGF
Angiogenesis
Endothelial cellsIL-8Blood CoagulationActivation
FIBRIN
PAR-2
Angiogenesis
FVII/FVIIa
THROMBIN
Tumor
C
ell
TF
Falanga and Rickles,
New Oncology:Thrombosis
, 2005;1:9-16
Interface of Clotting Activation
and Tumor Biology
Slide37Coagulation Cascade and Tumor Biology
TF
Thrombin
Clotting-dependentClotting-dependentClotting-independentClotting-dependent
Fibrin
Clotting-independent
PARs
Fernandez, Patierno and Rickles.
Sem Hem Thromb
2004;30:31; Ruf.
J Thromb Haemost
2007;5:1584
VIIa
Xa
Angiogenesis, Tumor Growth and Metastasis
Slide38Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor
TF regulates VEGF expression in human cancer cell lines
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
Slide39The 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 cancerAbe 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
Slide40Activation
of Blood Coagulation
in Cancer and Malignant TransformationEpiphenomenon 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)
Slide41MET
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 metastasisBoccaccio et al Nature 2005;434:396-400
“1. MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis”
Activation of Blood Coagulation
in Cancer: Malignant Transformation
Slide42Mouse model of Trousseau’s Syndrome
Targeted activated human
MET to the mouse liver with lentiviral vector and liver-specific promoter slowly, progressive hepatocarcinogenesisPreceded and accompanied by a thrombo-hemorrhagic syndrome Thrombosis in tail vein occurrs early and is followed by fatal internal hemorrhage
Syndrome characterized by d-dimer and PT and platelet count (DIC)“MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis”
Slide43Blood Coagulation Parameters in Mice Transduced with the
MET
OncogeneTransgene
Parameter Time after Transduction (days)
0 30 90
GFP
_________
MET
Platelets (x10
3
)
D-
dimer
(
µg/ml)
PT (s)
________________
Platelets (x10
3
)
D-
dimer
(µg/ml)
PT (s)
968 656 800
<0.05 <0.05 <0.05
12.4 11.6 11.4
_______________________________
974 350 150
<0.05 0.11 0.22
12.9 11.8 25.1
Slide44Mouse 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“MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis”
Slide45Activation 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 activityLoss 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
Slide46Glioblastomas 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”
Slide47Results:
Hypoxia and
PTEN loss TF (mRNA, Ag and procoagulant activity); partially reversed with induction of PTEN 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“Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”
Slide48Both
Akt
and Ras Pathways Modulate TF Expression By Transformed AstrocytesN = Normoxia
H = HypoxiaSimilar data for EGFR – upregulationof TF via JunD/AP-1 transcription(CA Res 2009;69:2540-9)
Slide49Pseudopalisading necrosis
Vascular
Endothelium
H&ETF IHC“Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”
Slide50Activation 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 cellsTransforming events dependent on MEK/MAPK and PI3KCell-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
Slide51“
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 Activation of Blood Coagulation in Cancer: Malignant TransformationMean Channel TF FlourescenceTF Activity (U/106 cells)
del/+ mut/+ mut/+
+/+ +/+ del/del
Slide52“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 Activation of Blood Coagulation in Cancer: Malignant Transformation
Slide53Effect of TF
si
mRNA on new vessel formation in colon cancer
“Oncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells”
%VWF-Positive Area
Slide54“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
Activation of Blood Coagulation in Cancer: Malignant Transformation
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
Slide55Kalluri
and
Kansaki Nature 2008;452:543(21 nucleotides)*
* Kleinman et al Nature 2008;452:591Class Effect of siRNA for Angiogenesis Inhibition via Toll-Like Receptior 3 (TLR 3)
Slide56Mechanisms of Cancer-Induced Thrombosis: Implications
Pathogenesis?
Biological significance?Potential importance for cancer therapy?
Slide57Activation 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 VTEAll patients with oncogene-driven cancer may need prophylactic anticoagulation
Slide58Retrospective 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)
SurvivalVTE RateTissue Factor Expression, Angiogenesis, and Thrombosis in Human Pancreatic CancerKhorana et al Clin Cancer Res 2007;13:2870
Slide59Immunohistologic
Correlation of TF with the Expression of Other Angiogenesis Variables in
Resected Pancreatic Cancer High TF Low TF P expression expression____________________________________________________ VEGF expressionNegative 13 41 <0.0001Positive 53 15
Microvessel densityV6 per tissue core 27 33 0.047>6 per tissue core 39 23Median 8 6 0.01 ----------------------------------------------------------------------------------------Khorana et.al. Clin CA Res 2007:13:2870
Slide60Symptomatic VTE in Pancreatic Cancer
Khorana et al
Clin CA Res 2007;13:28725/19; 26.3%1/22; 4.5%
Slide61Median Survival of #122
Resected Pancreatic Cancer Patients
months17.912.6P = 0.16(HR 2.06; 0.74-5.7)
Khorana et al Clin CA Res 2007;13:2872
Slide621.
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 Key Questions
Slide631.
Epidemiologic evidence is
suggestive that VTE is a bad prognostic sign in cancer2. 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)
Cancer and Thrombosis: Year 2009 State-of-the-Science UpdateTentative Answers
Slide64LMWH and Prolongation
of Cancer Survival
Mechanistic Explanations
VTECoagulation ProteasesDirect HeparinOther
Slide65Heparins and
Tumour
BiologyMultiple Potential Modes of Action
AngiogenesisApoptosisHeparanaseAdhesion
Slide66Ex Vivo
Angiogenesis:
Embryonic Chick Aortic RingsControl Aortic Ring: Day 5
10U/ml Dalteparin-Treated Aortic Ring: Day 5Fernandez, Patierno and Rickles. Proc AACR 2003;44:698 (Abstr. #3055)
Slide67Effects of Low-Molecular Weight Heparin on Lung Cancer Cell Apoptosis
P<0.05
Chen et al
Cancer Invest 2008;26:718-24
G1 arrest
decrease in
S phase
3-fold
in p21
WAF1
and p27
KIP1
(
p
<0.01)
reversed apoptosis
and G1 arrest with
p21 or p27
siRNA
Slide680
100
200
300
400
500
VEGF
FGF-2
TNF-
*
*
*
*
*
*
Cytokine
+enoxaparin
+dalteparin
+UFH
§
§
§
Control
*
*
*
Marchetti et al.
Thromb Res
2008
;121:637-645
Heparins
Inhibit Cytokine–Induced
Capillary Tube Formation
§
= p<0.05 vs control,
*
= p<0.05 vs cytokine
Tube Length (mm/cm
2
)
Slide69LMWH and VEGF
Antisense
Oligonucleotides Inhibit Growth and Metastasis of 3LL Tumors in Mice40 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 + ASODNRESULTS: Growth Inhibit* Lung Mets*ASODN 47% 38%LMWH 27% 38%Combined 59% 25% * P < 0.05 Zhang YH et al Chinese Med J 2006;86:749-52
Slide70Inhibition of Binding of
Selectins
to Human Colon Carcinoma by Heparins Stevenson et al Clin Ca Res 2005;11:7003-11
Slide71Heparin Inhibition of B16 Melanoma
Lung
Metastasis in MiceStevenson et al Clin Ca Res 2005;11:7003-11
Slide72Coagulation Cascade and Tumor Biology
TF
Thrombin
Clotting-dependentClotting-dependentClotting-independentClotting-dependent
Fibrin
Clotting-independent
PARs
Fernandez, Patierno and Rickles.
Sem Hem Thromb
2004;30:31; Ruf.
J Thromb Haemost
2007; 5:1584
VIIa
Xa
Angiogenesis, Tumor Growth and Metastasis
?
LMWHs
(e.g.
dalteparin
); Non-anticoagulant heparins
Slide73A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer
Linking Science and Evidence to Clinical Practice—
What Do Trials Teach?
Program ChairmanCraig Kessler, MD MACPDirector, Division of CoagulationLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DCInnovation ● Investigation ● Application
Slide74VTE and Cancer: Epidemiology
Of all cases of VTE:
About 20% occur in cancer patientsAnnual incidence of VTE in cancer patients ≈ 1/250Of all cancer patients:15% will have symptomatic VTEAs many as 50% have VTE at autopsyCompared to patients without cancer:
Higher risk of first and recurrent VTEHigher risk of bleeding on anticoagulantsHigher risk of dying Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
Slide75Ambrus
JL et al.
J Med. 1975;6:61-64Donati MB.
Haemostasis. 1994;24:128-131Johnson MJ et al. Clin Lab Haem. 1999;21:51-54Prandoni P et al. Ann Intern Med. 1996;125:1-7DVT and PE in Cancer Facts, Findings, and Natural History
VTE is the second leading cause of death
in hospitalized cancer patients
1,2
The risk of VTE in cancer patients undergoing surgery is
3-
to 5-fold higher
than those without cancer
2
Up to
50% of cancer patients
may have evidence of
asymptomatic DVT/PE
3
Cancer patients with symptomatic DVT exhibit a
high risk for recurrent DVT/PE that persists for many years
4
Slide76Clinical Features of VTE in Cancer
VTE has significant negative impact on quality of life
VTE may be the presenting sign of occult malignancy10% with idiopathic VTE develop cancer within 2 years20% have recurrent idiopathic VTE25% have bilateral DVTBura
et. al., J Thromb Haemost 2004;2:445-51
Slide77Thrombosis and Survival
Likelihood of Death After Hospitalization
0 20 40 60 80 100 120 140 160 180
0.00
0.20
0.40
1.00
0.80
0.60
DVT/PE and Malignant Disease
Malignant Disease
DVT/PE Only
Nonmalignant Disease
Number of Days
Probability of Death
Levitan
N, et al. Medicine 1999;78:285
Slide78Incidence of VTE and Colon Cancer Stage
White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40
Days after Cancer Diagnosis
Incidence of VTE (%)
0 50 100 150 200 250 300 350 400
7%
6%
5%
4%
3%
2%
1%
0%
Local Regional Remote
Slide79Symptomatic VTE in Cancer Reduces Survival
Counterintuitively
, Magnitude of Effect on Survival is Greatest with Local Stage Disease
Slide80VTE 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)
Slide81Recurrent Ovarian Cancer
Fotopoulou C et al. Thromb Res 2009
•
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)
Slide82Hospital Mortality With or Without VTE
Khorana, JCO, 2006
Mortality (%)
N=66,016N=20,591N=17,360
Slide83Trends in VTE in Hospitalized Cancer Patients
VTE- patients on chemotherapy
VTE-all patients
DVT-all patients
PE-all patients
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
1995
1996
1997
1998
1999
2000
2001
2002
2003
Rate of VTE (%)
P<0.0001
Khorana AA et al.
Cancer.
2007.
Slide84Thrombosis Risk In Cancer
Primary Prophylaxis
Medical Inpatients
Surgery Radiotherapy Central Venous Catheters
Slide85Risk Factors for Cancer-Associated VTE
Cancer
Type Men: prostate, colon, brain, lungWomen: breast, ovary, lungStageTreatmentsSurgery10-20% proximal DVT4-10% clinically evident PE0.2-5% fatal PE
ChemotherapyCentral venous catheters (~4% generate clinically relevant VTE)PatientPrior VTEComorbiditiesGenetic background
Slide86Medical Inpatients
Cancer and Thrombosis
Slide87Pharmacologic
(Prophylaxis & Treatment)
Nonpharmacologic
(Prophylaxis)Antithrombotic Therapy: ChoicesIntermittentPneumaticCompression
Elastic
Stockings
Inferior
Vena Cava
Filter
Oral
Anticoagulants
Unfractionated
Heparin (UH)
Low Molecular Weight Heparin (LMWH)
New Agents: e.g.
Fondaparinux,
Direct anti-Xa inhibitors,
Direct anti-IIa, etc.?
Slide88Prophylaxis Studies in Medical Patients
Francis, NEJM, 2007
Placebo Enoxaparin
MEDENOX TrialPlacebo Dalteparin PREVENTPlacebo Fondaparinux ARTEMISRate of VTE (%)
Relative risk reduction 63%
Relative risk reduction 44%
Relative risk reduction 47%
Slide89ASCO Guidelines
1. SHOULD HOSPITALIZED PATIENTS WITH
CANCER RECEIVE ANTICOAGULATION FORVTE 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.
Slide90Surgical Patients
Cancer and Thrombosis
Slide91Cancer patients have
2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis
:Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl
1): OC1732Incidence of VTE in Surgical PatientsNo CancerN=16,954
Cancer
N=6124
P-value
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
Slide92Natural 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 Findings2.1% incidence of clinically overt VTE (0.8% fatal)Most events occur after hospital discharge Most common cause of 30-day post-op deathAgnelli, Ann Surg 2006; 243: 89-95
Slide93LMWH vs. UFH
Abdominal or pelvic surgery for cancer (mostly colorectal)
LMWH once daily vs. UFH tid for 7–10 days post-opDVT on venography at day 7–10 and symptomatic VTE1. ENOXACAN Study Group. Br J Surg
1997;84:1099–1032. McLeod R, et al. Ann Surg 2001;233:438-444Prophylaxis in Surgical PatientsStudy
N
Design
Regimens
ENOXACAN
1
631
double-blind
enoxaparin
vs. UFH
Canadian Colorectal DVT Prophylaxis
2
475
double-blind
enoxaparin
vs. UFH
Slide94Canadian Colorectal DVT Prophylaxis Trial
13.9%
1.5% 2.7%
16.9%N=234N=241McLeod R, et al. Ann Surg 2001;233:438-444
P=0.052
Incidence of Outcome Event
VTE Major Bleeding
(Cancer) (All)
Prophylaxis in Surgical Patients
Slide95VTE
Prox
Any Major DVT Bleeding Bleeding
P=0.025.1%1.8%Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
ENOXACAN II
Incidence of Outcome Event
N=167
N=165
0% 0.4%
12.0%
4.8%
NNT = 14
0.6%
3.6%
Extended Prophylaxis in
Surgical Patients
Slide96A multicenter, prospective, assessor-blinded, open-label, randomized trial:
Dalteparin
administered for 28 days after major abdominal surgery compared to 7 days of treatmentRESULTS: 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. Major Abdominal Surgery: FAME Investigators—Dalteparin Extended Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.
Slide97ASCO 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.
Slide98Thrombosis is a potential complication of central venous catheters, including these events:
Fibrin sheath formation
Superficial phlebitisBall-valve clotDeep vein thrombosis (DVT)Central Venous CathetersGeerts
W, et al. Chest Jun 2008: 381S–453S
Slide99Placebo-Controlled Trials
Study
RegimenN
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
Prophylaxis for Venous Catheters
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
Slide100Tolerability of Low-Dose
Warfarin95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailyINR measured at baseline and four time points10% of all recorded INRs >1.5Patients with elevated INR 2.0–2.9 6% 3.0–4.9 19% >5.0 7%
Central Venous Catheters: WarfarinMasci et al. J Clin Oncol. 2003;21:736-739
Slide1018
th
ACCP Consensus GuidelinesNo routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B)
Chest Jun 2008: 454S–545S
Slide102Primary Prophylaxis in Cancer Radiotherapy
The Ambulatory Patient
No recommendations from ACCPNo 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.)
Slide103Risk Factors for VTE in
Medical Oncology Patients
Tumor typeOvary, brain, pancreas, lung, colonStage, grade, and extent of cancerMetastatic disease, venous stasis due to bulky diseaseType of antineoplastic treatmentMultiagent regimens, hormones,anti-VEGF, radiationMiscellaneous VTE risk factorsPrevious VTE,
hospitalization, immobility, infection, thrombophilia
Slide104Independent Risk Factors for DVT/PE
Risk Factor/Characteristic
O.R.
Recent surgery with institutionalization21.72
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
Slide105VTE Incidence In Various Tumors
Otten
, et al.
Haemostasis
2000;30:72. Lee & Levine. Circulation 2003;107:I17
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%
Slide106Primary
VTE Prophylaxis
Recommended for hospitalized cancer patientsNot universally recommended for outpatients, but there are exceptionsNew data for certain agentsHeterogeneous population
Need for risk stratification
Slide107Naluri SR et al. JAMA.
2008;300:2277
VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in Myeloma
Slide108Naluri
SR et al. JAMA.
2008;300:2277Bevacizumab Increases Risk of Symptomatic VTE by 33%
vs Controls
Slide109Knight: N
Engl
J Med.2006,354:2079rEPO used more in USA and Canada
L+Dex: 23% VTE with EPO vs 5% w/o EPOPlacebo + Dex: 7% VTE with EPO vs 1% without EPOIncidence 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 P Value
(95% CI)
Lenalidomide plus 3.51 (1.77-6.97) <0.001
High-dose dexamethasone
Concomitant erythropoietin 3.21 (1.72-6.01) <0.001
Slide110Oral 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 proceduresDifficulty in venous access for monitoring Increased risk of both recurrence and bleedingIs it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?
Slide111CLOT: Landmark Cancer/VTE Trial
CANCER PATIENTS WITH ACUTE DVT or PE
Randomization
[N = 677] Primary Endpoints: Recurrent VTE and BleedingSecondary Endpoint: Survival Lee, Levine,
Kakkar
,
Rickles
et.al.
N
Engl
J Med,
2003;349:146
Dalteparin
Dalteparin
Dalteparin
Oral Anticoagulant
Slide112Landmark CLOT Cancer Trial
Reduction in Recurrent VTE
0
5 10 15
20
25
Days Post Randomization
0
30
60
90
120
150
180
210
Probability of Recurrent VTE, %
Risk reduction = 52%
p
-value = 0.0017
Dalteparin
OAC
Recurrent VTE
Lee, Levine,
Kakkar
,
Rickles
et.al.
N
Engl
J Med,
2003;349:146
Slide113Dalteparin
N=338
OACN=335
P-value*
Major bleed
19 ( 5.6%)
12 ( 3.6%)
0.27
Any bleed
46 (13.6%)
62 (18.5%)
0.093
* Fisher’s exact test
Bleeding Events in CLOT
Lee, Levine,
Kakkar
,
Rickles
et.al.
N
Engl
J Med,
2003;349:146
Slide114Treatment of Cancer-Associated VTE
Study
Design
Length of Therapy(Months)
N
Recurrent VTE
(%)
Major Bleeding
(%)
Death
(%)
CLOT Trial
(Lee 2003)
Dalteparin
OAC
6
336
336
9
17
6
4
39
41
CANTHENOX
(Meyer 2002)
Enoxaparin
OAC
3
67
71
11
21
7
16
11
23
LITE
(Hull ISTH 2003)
Tinzaparin
OAC
3
80
87
6
11
6
8
23
22
ONCENOX
(
Deitcher
ISTH 2003)
Enox (Low)
Enox (High)
OAC
6
32
36
34
3.4
3.1
6.7
NS
NS
0.03
NS
NS
0.002
NS
NS
NR
0.09
0.03
0.09
Slide115Treatment and 2
° Prevention of VTE
in Cancer – Bottom LineNew 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)Chest Jun 2008: 454S–545S New Development
Slide116CLOT 12-month Mortality
All Patients
0
10
20
30
40
50
60
70
80
90
100
0
30
60
90
120
180
240
300
360
Dalteparin
OAC
HR 0.94 P-value = 0.40
Days Post Randomization
Probability of Survival, %
Lee AY et al.
J
Clin
Oncol
.
2005; 23:2123-9.
Slide1170
10
20
3040506070
80
90
100
Days Post Randomization
0
30
60
90
120
150
180
240
300
360
Probability of Survival, %
OAC
Dalteparin
HR = 0.50 P-value = 0.03
Anti-Tumor Effects of LMWH
CLOT 12-month Mortality
Patients Without Metastases (N=150)
Lee AY et al.
J
Clin
Oncol
.
2005; 23:2123-9.
Slide11884 patients randomized: Chemo +/- LMWH (18 weeks)
Patients balanced for age, gender, stage, smoking history, ECOG performance status
LMWH for Small Cell Lung CancerTurkish Study Altinbas et al. J Thromb
Haemost 2004;2:1266.Chemotherapyplus 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
Slide119VTE Prophylaxis Is Underused
in Patients With Cancer
1. Kakkar AK et al. Oncologist. 2003;8:381-3882. Stratton MA et al. Arch Intern Med. 2000;160:334-3403. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912
Cancer:FRONTLINE Survey1— 3891 Clinician RespondentsRate of Appropriate Prophylaxis, %Major Surgery2Major Abdominothoracic Surgery (Elderly)3Medical Inpatients
4
Confirmed DVT (Inpatients)
5
Cancer: Surgical
Cancer: Medical
4. Rahim SA et al.
Thromb Res
. 2003;111:215-219
5. Goldhaber SZ et al.
Am J Cardiol
. 2004;93:259-262
Slide120Conclusions 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 warfarinGuidelines and landmark trials support administration of LMWH in at risk patients
Cancer patients are under-prophylaxed for VTEHealth system pharmacists can play a pivotal role in improving clinical outcomes in this patient population
Slide121VTE Prophylaxis
in the Cancer Patient
Scope, Trials, Guidelines and SolutionsThe Science and Medicine ofCancer and Thrombosis Management
Samuel Z. Goldhaber, MDProfessor of Medicine Harvard Medical SchoolCardiovascular Division Director, Venous Thromboembolism Research GroupBrigham and Women’s HospitalBoston, MA
Slide122Learning Objectives
Epidemiology/ Scope of the Problem
Prophylaxis Paradigm ShiftSurgeon General’s Call To ActionMedicare’s “Never Events”Prophylaxis ModalitiesElectronic, Computerized AlertsHuman, Physician-to-Physician AlertsGuidelines: NCCN, ASCO, ACCP
Slide123Epidemiology:
Scope of the Problem
Slide124ICOPER Cumulative Mortality
Mortality (%)
Days From Diagnosis
17.5%
0
5
10
15
20
25
7
14
30
60
90
Lancet 1999;353:1386-1389
Slide125The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing “sudden cardiac death” emphasize the need for
improved preventive efforts
.Failure to institute prophylaxis is a much bigger problem with Medical Service patients than Surgical Service patients.At-Risk for VTE
Slide126Two quality improvement initiatives show that among at-risk-for-VTE Medical Service patients, Medical Oncology patients are the least likely group to receive VTE prophylaxis
.
80% of omitted prophylaxis on Medical Services occurred in Medical Oncology patients. At-Risk for VTE
Slide127Annual At-Risk for VTE:
U.S. Hospitals
7.7 million Medical Service inpatients3.4 million Surgical Service inpatients Based upon ACCP guidelines for VTE prophylaxisAnderson FA Jr, et al. Am J Hematol
; 2007; 82: 777-782
Slide128Outpatient and Inpatient VTE Are Linked
74% of VTEs present in outpatients
.42% of outpatient VTE patients have had recent surgery or hospitalization. Only 40% had received VTE prophylaxis.Spencer FA, et al. Arch Intern Med 2007; 167: 1471-1475
Slide129ENDORSE : WORLDWIDE
(Lancet 2008; 371: 387-394)
68,183 patients; 32 countries; 358 sites
First patient enrolled August 2, 2006;Last patient enrolled January 4, 2007
Slide130Medical
Surgical
ENDORSE: 68,183 Patients
52% at risk for VTE(50% receive ACCPrecommended prophylaxis)64% at risk for VTE
59% receive ACCP recommended prophylaxis
42% at risk for VTE
40% receive ACCP recommended prophylaxis
Slide131VTE Prophylaxis Paradigm Shift
Cancer and Medical Conditions
in the Crosshairs
Slide132Ten Years Ago…
Most Americans had not heard of DVT (deep vein thrombosis) or PE (pulmonary embolism)
Virtually no awarenessMedia attention was limited to featuring a few celebrities who were strickenNo state or congressional resolutionsNo patient advocacyNo Medicare input
Slide133VTE
Awareness in 2009
Growing interest in VTE’s public health threatKnown as the most preventable illness in hospitalized patientsPublicity is increasing among health care professionals and the publicPatient advocacy is a realityCongress and most States have adopted months for “Thrombosis Awareness”Medicare has declared certain DVTs or PEs as “Never Events” and will not reimburse
Slide134Old Prophylaxis Paradigm
MD individualizes prophylaxis prescription and ultimately has complete “yes” or “no” authority to prescribe or withhold
prophylaxisHospital, government auditors, patients, and families do not challenge the MD’s decision to withhold prophylaxis. Instead, they “defer to the physician’s medical judgment”
Slide135New Prophylaxis Paradigm
Hospital monitors VTE prophylaxis prescribing and insists upon guideline-based practice
Electronic reminders and automated electronic orders ultimately ensure appropriate prophylaxis for at-risk patientsHospital’s financial and medicolegal penalty for failure to prophylax may be “passed on” to the responsible attending physicianCancer patients represent high-risk, “must prophylax” subgroup
Slide136SURGEON GENERAL:
CALL TO ACTION TO PREVENT DVT AND PE
September 15, 2008
Slide137Medicare’s
“Never Events”
Slide138Medicare’s most recent strategy to reduce medical errors is to withhold payment to hospitals for treatment of serious preventable illnesses or complications termed “never events.” The initial 3 were
:
Foreign object retained postopAir embolism removing CVCBlood transfusion incompatibilityMedicare’s “Never Events”
Slide139On October 1, 2008, Medicare added:
DVT or pulmonary embolism occurring after total knee or hip replacement.
Medicare will not pay the incremental cost to manage the complication. Nor will the patient be responsible. The hospital will bear the additional financial burden.
Medicare’s “Never Events”
Slide140Prophylaxis
Modalities
Slide141VTE Prophylaxis in 19,958 Medical Patients/
9 Studies (Meta-Analysis)
62% reduction in fatal PE57% reduction in fatal or nonfatal PE53% reduction in DVTDentali F, et al. Ann Intern Med 2007; 146: 278-288
Slide142VTE
Prophylaxis in
Medical Patients is Cost-Effective$1,264 per patient for LMWH$2,245 for No ProphylaxisDeitelzweig et al. Thromb
Haemostas 2008; 100: 810-820
Slide143Intermittent Pneumatic Compression
Meta-Analysis in
Postop Patients2,270 patients in 15 randomized trialsIPC devices reduced DVT risk by 60% (Relative Risk 0.40, 95% CI 0.29-0.56, p< 0.001)Urbankova J. Thromb
Haemost 2005; 94: 1181-5
Slide144Reversible Risk Factors
Nutrition: eat fruits, veggies, fish; less red meat (
Circulation 2007;115:188-195)Quit cigarettesLose weight/ exercisePrevent DM/ metabolic syndromeControl hypertension
Lower cholesterolAvoid air pollution Arch Intern Med 2008; 168: 920-927)
Slide145Statins
Prevent
PE and DVT!
Slide146JUPITER
Total Venous Thromboembolism
0
1
2
3
4
0.000
0.005
0.010
0.015
0.020
0.025
Cumulative Incidence
Number at Risk
Follow-up (years)
Rosuvastatin
Placebo
8,901
8,648
8,447
6,575
3,927
1,986
1,376
1,003
548
161
8,901
8,652
8,417
6,574
3,943
2,012
1,381
993
556
182
HR 0.57, 95%CI 0.37-0.86
P= 0.007
Placebo
60
/ 8901
Rosuvastatin
34 / 8901
- 43 %
Glynn et al NEJM 2009
Slide147JUPITER
Venous Thromboembolism – Unprovoked
vs ProvokedHR 0.52, 95% CI 0.28-0.96
P= 0.03
0
1
2
3
4
0.000
0.005
0.010
0.015
0.020
Cumulative Incidence
Follow-up (years)
0
1
2
3
4
0.000
0.005
0.010
0.015
0.020
Cumulative Incidence
Provoked Venous Thromboembolism
HR 0.61, 95% CI 0.35-1.09
P= 0.09
Unprovoked Venous Thromboembolism
Follow-up (years)
Clear clinical benefit in the absence of any bleeding hazard
(hemorrhagic events:
rosuvastatin
258, placebo 275, P=0.45)
Placebo
Placebo
Rosuvastatin
Rosuvastatin
Glynn et al NEJM 2009
Slide148Electronic and “Human” Prophylaxis Alerts
Implications for Cancer Patients
Slide149Randomization in ALERT Study
Kucher
N, et al. NEJM 2005;352:969-977VTE risk score
> 4No prophylaxisN = 2,506INTERVENTION:Single alertN = 1,255CONTROLNo computer alertN = 1,251
Slide150Slide151Primary End Point
Intervention
Control
Number at risk1255
977
900
853
1251
976
893
839
Intervention
Control
Time
(
days
)
0
30
60
90
%Freedom from DVT/
PE
90
92
94
96
98
100
Kucher
N, et al. NEJM 2005;352:969-977
Slide152Electronic Alerts
Halve Rate of PE and Maintain EffectivenessVTE Rate: Pre-Alert 2005—3.3/1000 Post-Alert 2006—1.7/1000Post-Alert 2007—1.7/1000
Thromb Haemost 2008; 100: 699-704
Slide153“Human” Physician Alert
As we planned a multicenter randomized trial applying the electronic alert strategy to a broad array of hospitals across the U.S., we learned that replication of our electronic alert was not feasible.
Therefore, we crafted a strategy that employed a “human” rather than electronic alerting system. The physician alert consisted of a direct page from a hospital staff member to the Attending Physician. The primary end point was reduction in symptomatic VTE within 90 days of randomization.
Slide154Physician Alert: Results
2493 patients (82% on Medical Services) from 25 study sites were randomized to the intervention (n=1238) versus the control group (n=1255).
Patients whose physicians were alerted were more than twice as likely to receive VTE prophylaxis (46.0% versus 20.6%, p<0.0001). The symptomatic VTE rate was lower in the intervention group (2.7% versus 3.4%; hazard ratio, 0.79; 95% confidence interval, 0.50 to 1.25), but the difference did not achieve statistical significance. Major bleeding at 30 days in the alert group was similar to the control group.
Slide155Physician Alert: Results
Piazza G.
Circulation 2009;119: 2196-2201
100%98%96%94%92%
90%
0 7 14 21 28 35 42 49 56 63 70 77 84 90
Time after initial enrollment (days)
Freedom from Primary Endpoint
Wilcoxon
P-value: 0.307; Long-Rank P-value: 0.309
Human Alert No Alert
Slide156Current Status of ASCO and NCCN Guidelines for VTE
Prophylaxis in Cancer Patients
Slide157ASCO Guidelines
Hospitalized Patients with Cancer
Role of VTE Prophylaxis
EvidencePatients 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 low-dose heparin or LMWH for bedridden patients with active cancer.
Slide158Ambulatory 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
Slide159Patients 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
Slide160Patients with Cancer
Undergoing Surgery
(continued)
Role of VTE ProphylaxisEvidenceLMWH 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.
Slide161Treatment of Patients with Established VTE to Prevent Recurrence
Role of VTE Prophylaxis
Evidence
LMWH is the preferred approach for the initial 5-10 days in cancer patient with established VTE.
LMWH for 3-6 months is more effective than vitamin K antagonists given for a similar duration for preventing recurrent 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)
Slide162Treatment of Patients with Established VTE to Prevent Recurrence
(continued)
Role of VTE Prophylaxis
EvidenceAnticoagulation for an indefinite period should be considered for patients with active cancer (metastatic disease, continuing chemotherapy)
In the absence of clinical trials, benefits and risks of
continuing LMWH beyond 6 months is a clinical judgment in the individual patient.
Caution is urged in elderly patients 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
Slide163Anticoagulants in the Absence of Established VTE to Improve Survival
Role of VTE Prophylaxis
Evidence
Anticoagulants are not currently recommended to improve survival in patients with cancer without VTE.
RCTs and meta-analysis
of warfarin, UFH and LMWH have reported encouraging but variable results generally showing clinical benefit only in subgroup analyses.
Slide164Summary of the Guidelines Updates
Summary of Major Changes in the 1.2009 Version of the Venous Thromboembolic Disease Guidelines
Slide165Changes 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 “2.0-2.9 x control) to “2.0-2.5 x control…” (Also for VTE-H) in these patients.
Slide166Changes 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”.
Slide167Changes in 2009 NCCN Guidelines
6
Although 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.
Slide168(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.
Slide169(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 dailyUnfractionated 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)
Slide170(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
Slide171(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 cancerIf UFH or factor Xa antagonist, transition to LMWH or warfarinWarfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR 2.0-3.0)
Slide172Therapeutic Anticoagulation Failure
Therapeutic
INRSwitch to heparin (LMWH preferred) or fondaparinuxIncrease warfarin dose and treat with parenteral agent until INR target achieved or consider switching to heparin (LMWH preferred) or fondaparinuxPatient onwarfarin
Check
INR
Sub-therapeutic
INR
Slide173Therapeutic Anticoagulation Failure
Therapeutic
aPTTIncrease dose of heparin or Switch to LMWH or Switch to fondaparinux and Consider placement of IVC filter and Consider HITIncrease dose of heparin to reach therapeutic levelPatient
on
heparin
Check
aPTT levels
Sub-therapeutic
aPTT
Slide174Improving VTE Prophylaxis in Cancer
“Immunize” cancer patients
with LMWH unless MD “opts out”—analogous to flu vaccine or pneumonia vaccinePay attention to the Continuum of Care and to VTE risk at the time of Discharge—Order discharge LMWHWithhold payments to hospitals when DVT/ PE develops after total hip or knee replacement—Medicare began this practice in October 2008
Slide175Conclusions
VTE prophylaxis has enjoyed a paradigm shift. Gone are the days when the imperial physician reigned unchallenged on VTE prophylaxis decisions. Hospitals and Medicare are scrutinizing implementation of prophylaxis.
Hospital-acquired VTE is not supposed to happen any longer. Medicare is declaring some VTEs “Never Events” and will not reimburse hospitals for additional treatment. Effective VTE prophylaxis in cancer patients usually requires anticoagulation with LMWH but when bleeding risk is too high, use mechanical measures. DVT prophylaxis in cancer patients is under-utilized and requires increased vigilance and prophylaxis-focused intervention
Slide176Conclusions
DVT prophylaxis following cancer surgery for four weeks is recommended; longer periods may be necessary depending on risk assessment
DVT prophylaxis following established DVT in cancer for at least 6 months is recommended and for longer, indefinite periods with active cancer and/or chemotherapy.Heart healthy lifestyle and statins reduce VTE riskElectronic, computerized alerts can reduce symptomatic VTE by at least 40%.When “human” alerts are used, symptomatic VTE is reduced by about 20%.
PE/ DVT patients with cancer warrant LMWH monotherapy.