The Science and Medicine of Thrombosis in Cancer

The Science and Medicine of Thrombosis in Cancer
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 at-risk 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.

Clotting, Cancer, and Controversies
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
CAP UTI Cancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder Thrombophilia Surgery History of DVT Other SUBSPECIALIST STAKEHOLDERS 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 first-time VTE have an idiopathic condition, without a readily identifiable risk factor. Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease. White R. Circulation. 2003;107:I-4–I-8.)

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 Cancer Patients with first venous thrombosis (n=2706) Control without venous thrombosis (n=1757) Age- and sex-adjusted odds ratio (95% CI) Factor V Leiden No Yes 2125 1635 1.00 162 26 5.1 ( ) 403 95 3.3 ( ) 16 1 12.1 ( ) Prothombin 20210A 2410 1693 164 27 4.5 ( ) 118 36 2.3 ( ) 14 Not determined 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 ( ) 1.62 ( ) 2.06 ( ) 0.0001 0.08 0.02 Acute infectious disease 1.74 ( ) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:

VTE Recurrence Hazard Ratio Baseline Characteristic
Predictors of First VTE/ Recurrence Baseline Characteristic Hazard Ratio (95% CI) Age 1.17 ( ) Body Mass Index 1.24 ( ) Neurologic disease with extremity paresis 1.87 ( ) Malignant neoplasm With chemotherapy Without chemotherapy 4.24 ( ) 2.21 ( ) Heit J, Mohr D, et al. Arch Intern Med. 2000;160:

Progression of Chronic Venous Insufficiency
From UpToDate 2006

Rising VTE Incidence in Hospitalized Patients
2 1.5 1 0.5 VTE DVT % PE Year Stein PD et al. Am J Cardiol 2005; 95:

DVT Registry (N=5,451) Top 5 Medical Comorbidities
Hypertension Immobility Cancer Obesity (BMI > 30) Cigarette Smoking Am J Cardiol 2004; 93:

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
Cancer rates are increasing as treatment for heart disease and cancer improve Cancer increases VTE risk VTE is preventable (immunize!) VTE prophylaxis may slow cancer Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATF Facilitate prophylaxis with alerts

Cancer, Thrombosis, and the Biology of Malignancy
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) 21

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 22

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 23

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” 24

Trousseau’s Syndrome Occult cancer in patients with idiopathic venous thromboembolism Thrombophlebitis in patients with cancer 25

Effect of Malignancy on Risk of Venous Thromboembolism (VTE)
53.5 50 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 28 30 22.2 Adjusted odds ratio 20.3 19.8 20 14.3 10 4.9 3.6 2.6 1.1 Lung Breast Distant > 15 years metastases 1 to 3 years Hematological 0 to 3 months 5 to 10 years Gastrointestinal 3 to 12 months Type of cancer Time since cancer diagnosis Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715 26

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: and 2002;162: ; Prandoni et al Blood 2002;100: ; White et al Thromb Haemost 2003;90: ; Sorensen et al New Engl J Med 2000;343: ); Levitan et al Medicine 1999;78: ; Khorana et al J Thromb Haemost 2007;5:632-4

Mechanisms of Cancer-Induced Thrombosis Critical Interfaces and Questions
Pathogenesis? Biological significance? 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 Figure 1. Multiple mechanisms in Trousseau’s syndrome. There are multiple overlapping and interacting mechanisms that can explain the increased incidence of thrombosis in patients with malignancies. In Trousseau’s syndrome, hypercoagulability manifests even before the diagnosis of the tumor and is probably the result of products arising from the tumor itself. The most common malignancies associated with this syndrome are carcinomas (cancers of epithelial origin) that are often, but not always, mucin producing. This cartoon depicts a mucin-producing carcinoma arising in a hollow organ, which secretes mucins with altered glycans inappropriately into the bloodstream. Although the bulk of these mucins are probably rapidly cleared by the liver, a small fraction are resistant to clearance and can interact with P- and L-selectins, inducing the formation of platelet-rich microthrombi by multiple pathways. Exposure of tissue factor (TF)–rich tumor cell surfaces to the bloodstream or the release of TF-rich microvesicles by the tumor is presumed to induce fibrin formation and platelet aggregation by thrombin production. There is some evidence for a cysteine proteinase secreted by carcinoma cells that can directly activate factor X to generate thrombin. Although interactions of platelet and endothelial P-selectin with P-selectin glycoprotein ligand-1 (PSGL-1) on monocytes may further contribute to these reactions, the exact mechanism by which mucins eventually generate thrombin and fibrin production is unknown. Hypoxic conditions within the tumor, the expression of the MET oncogene, or both might also enhance production of procoagulant factors such as TF and plasminogen activator inhibitor-1 (PAI-1), and tumor-derived inflammatory cytokines may serve to activate endothelial and platelet adhesion molecules. Various combinations of these mechanisms can help explain the unusual, migratory, and exaggerated thrombotic phenomena of Trousseau’s syndrome. As indicated in the figure, heparin has potential salutary effects on many of the relevant processes. This may explain why heparin preparations of various kinds are the preferred agent for the management of Trousseau’s syndrome. Tissue Factor microparticles Copyright ©2007 American Society of Hematology. Copyright restrictions may apply. Varki, A. Blood 2007;110:

Interface of Biology and Cancer
Tumor Cells Fibrinolytic activities: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities FIBRIN Endothelial cells IL-1, TNF-a, VEGF Monocyte PMN leukocyte Activation of coagulation Platelets Angiogenesis, Basement matrix degradation Falanga and Rickles, New Oncology: Thrombosis, 2005; Hematology, 2007

Pathogenesis of Thrombosis in Cancer – A Modification of Virchow’s Triad
Stasis Prolonged bed rest Extrinsic compression of blood vessels by tumor Vascular Injury Direct invasion by tumor Prolonged use of central venous catheters Endothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endothelium Hypercoagulability Tumor-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

Mechanisms of Cancer-Induced Thrombosis Clot and Cancer Interfaces

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 Blood Coagulation Activation Tumor Cell VEGF THROMBIN FIBRIN Angiogenesis IL-8 TF PAR-2 Endothelial cells Angiogenesis Falanga and Rickles, New Oncology:Thrombosis, 2005;1:9-16

Coagulation Cascade and Tumor Biology
Clotting-dependent Clotting-dependent TF Thrombin Fibrin Xa VIIa Clotting-independent Clotting-independent Clotting-dependent PARs Angiogenesis, Tumor Growth and Metastasis Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007;5:1584

TF regulates VEGF expression in human cancer cell lines
Regulation 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: ; Ruf et al Nature Med 2004;10:

Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor 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: ; Ruf et.al. Nature Med 2004;10:

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: ) 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: ; 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: ; Milson et al Ca Res 2008;68: )

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:

Mouse model of Trousseau’s Syndrome
“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 thrombo-hemorrhagic 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
Transgene Parameter Time after Transduction (days) GFP MET Platelets (x103) D-dimer (µg/ml) PT (s) < < <0.05 <

Mouse model of Trousseau’s Syndrome
“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

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:

“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: 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

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

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:

“Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” TF expression in cancer cells parallels genetic tumor progression with an impact of K-ras and p53 status Mean Channel TF Flourescence TF Activity (U/106 cells) del/+ mut/+ mut/+ +/+ +/+ del/del

“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

Effect of TF si mRNA on new vessel formation in colon cancer
“Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells” Effect of TF si mRNA on new vessel formation in colon cancer %VWF-Positive Area

“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:

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

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 VEGF Expression Negative 13 41 <0.0001 Positive 53 15 Microvessel Density V6 per tissue core 27 33 0.047 >6 per tissue core 39 23 Median 8 6 0.01 Khorana et.al. Clin CA Res 2007:13:2870

Symptomatic VTE in Pancreatic Cancer
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
17.9 P = 0.16 (HR 2.06; ) 12.6 Months Khorana et al Clin CA Res 2007;13:2872

Year 2009 State-of-the-Science Update
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?

Year 2009 State-of-the-Science Update
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

Embryonic Chick Aortic Rings
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
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/cm2) 500 * * 400 * * * * 300 * * Control * 200 100 VEGF FGF-2 TNF- Cytokine +UFH +enoxaparin +dalteparin § = p<0.05 vs control, * = p<0.05 vs cytokine Marchetti et al. Thromb Res 2008;121: 67

40 mice with Lewis Lung Cancer (3LL) Rx qod x 15 with:
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 47% 38% LMWH 27% 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:

Heparin Inhibition of B16 Melanoma Lung Metastasis in Mice
Stevenson et al Clin Ca Res 2005;11:

Angiogenesis, Tumor Growth and Metastasis
Coagulation Cascade and Tumor Biology Clotting-dependent Clotting-dependent TF Thrombin Fibrin Xa VIIa Clotting-independent Clotting-independent Clotting-dependent ? 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:

A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer
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: About 20% occur in cancer patients Annual incidence of VTE in cancer patients ≈ 1/250 Of all cancer patients: 15% will have symptomatic VTE As many as 50% have VTE at autopsy Compared to patients without cancer: Higher risk of first and recurrent VTE Higher risk of bleeding on anticoagulants Higher risk of dying Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21

DVT and PE in Cancer Facts, Findings, and Natural History
VTE is the second leading cause of death in hospitalized cancer patients1,2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4 Let’s continue examining the association between DVT/PE and cancer. Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE. As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer. Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer. Ambrus JL et al. J Med. 1975;6:61-64 Donati MB. Haemostasis. 1994;24: Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 Prandoni P et al. Ann Intern Med. 1996;125:1-7

Clinical Features of VTE in Cancer
VTE has significant negative impact on quality of life VTE may be the presenting sign of occult malignancy 10% with idiopathic VTE develop cancer within 2 years 20% have recurrent idiopathic VTE 25% have bilateral DVT Bura et. al., J Thromb Haemost 2004;2:445-51

Thrombosis and Survival Likelihood of Death After Hospitalization
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

Incidence of VTE and Colon Cancer Stage
Days after Cancer Diagnosis Incidence of VTE (%) 7% 6% 5% 4% 3% 2% 1% 0% Local Regional Remote White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40

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 ( )‡ 4.7 ( ) ‡ 2.8 ( ) † Breast 6.6 ( ) ‡ 2.4 ( ) ‡ 1.8 ( )* Lung 3.1 ( ) ‡ 2.9 ( ) ‡ 2.5 ( ) ‡ Colon/rectum 3.2 ( ) ‡ 2.2 ( ) ‡ 2.0 ( ) ‡ Melanoma 14.4 ( ) ‡ N/A 2.8 ( ) † Non-Hodgkin’s lymphoma 3.2 ( ) ‡ 2.0 ( ) † 2.3 ( ) ‡ Uterus 7.0 ( ) ‡ 9.1 ( ) ‡ 1.7 ( )* Bladder 3.2 ( ) ‡ 3.3 ( ) ‡ 3.3 ( ) ‡ Pancreas 2.3 ( )* 3.8 ( ) ‡ 2.3 ( ) ‡ Stomach 2.4 ( )* 1.5 ( )* 1.8 ( ) ‡ Ovary 11.3 ( ) † 4.8 ( )* 2.3 ( ) ‡ Kidney 3.2 ( )* 1.4 ( ) 1.3 ( ) 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 ( % 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

Hospital Mortality With or Without VTE
N=66,016 N=20,591 N=17,360 Khorana, JCO, 2006

Thrombosis Risk In Cancer
Primary Prophylaxis Medical Inpatients Surgery Radiotherapy Central Venous Catheters

Risk Factors for Cancer-Associated VTE
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
Pharmacologic (Prophylaxis & Treatment) Nonpharmacologic (Prophylaxis) Low Molecular Weight Heparin (LMWH) Intermittent Pneumatic Compression Elastic Stockings Unfractionated Heparin (UH) Inferior Vena Cava Filter Several classes of agents have been used for prophylaxis and treatment of VTE Nonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filter Most commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs) Oral Anticoagulants New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?

Prophylaxis Studies in Medical Patients
Relative risk reduction 47% Relative risk reduction 63% Rate of VTE (%) Relative risk reduction 44% Placebo Enoxaparin MEDENOX Trial Placebo Dalteparin PREVENT Placebo Fondaparinux ARTEMIS Francis, NEJM, 2007

ASCO Guidelines 1. SHOULD HOSPITALIZED PATIENTS WITH
CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS? Recommendation. Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation. Lyman GH et al. J Clin Oncol (25) 2007; 34:

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 N=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% Death 0.71% 3.14% Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732

Natural History of VTE in Cancer Surgery: The @RISTOS Registry
Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Type of surgery • 52% General • 29% Urological • 19% Gynecologic 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings 2.1% incidence of clinically overt VTE (0.8% fatal) Most events occur after hospital discharge Most common cause of 30-day post-op death Agnelli, 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 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:

Prophylaxis in Surgical Patients
Canadian Colorectal DVT Prophylaxis Trial 16.9% P=0.052 13.9% Incidence of Outcome Event N=234 N=241 1.5% 2.7% VTE Major Bleeding (Cancer) (All) McLeod R, et al. Ann Surg 2001;233:

Extended Prophylaxis in Surgical Patients
12.0% ENOXACAN II P=0.02 Incidence of Outcome Event N=167 4.8% 5.1% N=165 3.6% 1.8% NNT = 14 0.6% 0% 0.4% VTE Prox Any Major DVT Bleeding Bleeding Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:

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 Nov;4(11): 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:

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 130 125 6 (4.6) 5 (4.0) ETHICS† 2004 Enoxaparin 40 mg daily 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
Thrombotic Events Warfarin evaluation Dose evaluation No warfarin (n=404) Warfarin (n=408) Relative risk (95% CI, p value) Fixed-dose warfarin (n=471) Dose-adjusted warfarin (n=473) Relative risk (95% CI, p value) Catheter-related thrombotic events 24 (6%) 0.99 ( , 0.98) 34 (7%) 13 (3%) 0.38 ( ,0.002) No catheter-related event 370 (92%) 372 (91%) - 433 (92%) 448 (95%) Not known 10 (2%) 12 4 (<1%) All thrombotic events 38 (9%) 30 0.78 ( ), 0.30 37 (8%) 26 0.70 ( , 0.15) Young AM et al. Lancet 2009;373:567

Bleeding and Raised INR Warfarin evaluation Dose evaluation No warfarin (n=404) Warfarin (n=408) Relative risk (95% CI, p value) Fixed-dose warfarin (n=471) Dose-adjusted warfarin (n=473) Relative risk (95% CI, p value) Major bleeding and no reported raised INR 1 (<1%) 3 (<1%) - 5 (1%) 7 (1%) Major bleeding and raised INR 4 (<1%) 2 (<1%) 9 (2%) Total major bleeding 7 (2%) 6.93 ( , 0.07) 16 (3%) 2.28 ( , 0.09) Moderate and severe raised INR and no major bleeding 12 (3%) Minor bleeding 14 (3%) 21 (4%) 24 (5%) Young AM et al. Lancet 2009;373:567

Combined thrombosis and major bleeding events Warfarin evaluation Dose evaluation No warfarin (n=404) Warfarin (n=408) Relative risk (95% CI, p value) Fixed-dose warfarin (n=471) Dose-adjusted warfarin (n=473) Relative risk (95% CI, p value) Total catheter-related thrombosis and major bleeding events 25 (6%) 31 (8%) 1.23 ( , 0.51) 41 (9%) 29 (6%) 0.84 ( , 0.17) All thrombotic and major bleeding events 39 (10%) 37 (9%) 0.94 ( , 0.87) 44 (9%) 42 (9%) 0.95 ( , 0.89) 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– % 3.0– % > % Masci et al. J Clin Oncol. 2003;21:

Influence of Thrombophilia on Thrombotic Complications of CVADs in Cancer
In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls: The attributable risk of catheter associated thrombosis conferred by: CA + FVL OR=5.18 (95% confidence interval: ) CA + G20210A OR=3.95 (95% confidence interval: ) 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 type Ovary, brain, pancreas, lung, colon Stage, grade, and extent of cancer Metastatic disease, venous stasis due to bulky disease Type of antineoplastic treatment Multiagent regimens, hormones, anti-VEGF, radiation Miscellaneous VTE risk factors Previous VTE, hospitalization, immobility, infection, thrombophilia

Independent Risk Factors for DVT/PE
Risk Factor/Characteristic O.R. Recent surgery with institutionalization 21.72 Trauma 12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease w/ extremity paresis 3.04 Serious liver disease 0.10 Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study. This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data. Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included. What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE. Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE. Heit JA et al. Thromb Haemost. 2001;86:

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. Tumor Type No. of Studies Bevacizumab Control Incidence (95% CI), % RR (95% CI) Overall 6 155/1196 107/1083 11.9 ( ) 1.29 ( ) Colorectal cancer 3 108/564 85/532 19.1 ( ) 1.19 ( ) NSCLC 1 10/66 3/32 14.9 ( ) 1.59 ( ) Breast cancer 17/229 12/215 7.3 ( ) 1.30 ( ) Renal cell carcinoma 20/337 6/304 3.0 ( ) 3.00 ( ) 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
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 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 ( ) <0.001 High-dose dexamethasone Concomitant erythropoietin ( ) <0.001 Knight: N Engl J Med.2006,354:2079 111

Oral Anticoagulant Therapy in Cancer Patients: Problematic
Warfarin therapy is complicated by: Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia and procedures Difficulty in venous access for monitoring Increased risk of both recurrence and bleeding Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?

CLOT: Landmark Cancer/VTE Trial
Dalteparin Dalteparin CANCER PATIENTS WITH ACUTE DVT or PE Randomization Dalteparin Oral Anticoagulant [N = 677] Primary Endpoints: Recurrent VTE and Bleeding Secondary Endpoint: Survival Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Landmark CLOT Cancer Trial
Reduction in Recurrent VTE 5 10 15 20 25 Days Post Randomization 30 60 90 120 150 180 210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Bleeding Events in CLOT
Dalteparin N=338 OAC N=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 Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Treatment of Cancer-Associated VTE
Study Design Length of Therapy (Months) N Recurrent VTE (%) Major Bleeding Death CLOT Trial (Lee 2003) Dalteparin OAC 6 336 9 17 4 39 41 CANTHENOX (Meyer 2002) Enoxaparin 3 67 71 11 21 7 16 23 LITE (Hull ISTH 2003) Tinzaparin 80 87 8 22 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) 32 36 34 3.4 3.1 6.7 NS 0.002 NS 0.09 0.09 0.03 0.03 NS NS 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 Dalteparin
10 20 30 40 50 60 70 80 90 100 120 180 240 300 360 Dalteparin OAC HR 0.94 P-value = 0.40 Days Post Randomization Probability of Survival, % Lee AY et al. J Clin Oncol. 2005; 23:

Anti-Tumor Effects of LMWH
CLOT 12-month Mortality Patients Without Metastases (N=150) 10 20 30 40 50 60 70 80 90 100 Dalteparin OAC Probability of Survival, % HR = P-value = 0.03 30 60 90 120 150 180 240 300 360 Lee AY et al. J Clin Oncol. 2005; 23: Days Post Randomization

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 <6 mos anticipated survival Klerk, C. P.W. et al. J Clin Oncol; 23:

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 Chemotherapyplus Dalteparin Chemo alone P-value 1-y overall survival, % 51.3 29.5 0.01 2-y overall survival, % 17.2 0.0 Median survival, m 13.0 8.0 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J Thromb Haemost 2004;2:1266.

VTE Prophylaxis Is Underused in Patients With Cancer
[1/Kakkar. Oncologist.2003/ p381/c1/line A1-A24; p383/c1/line 44-46, c2/line 1-3] [2/Stratton. ArchInternMed. Feb.2000/ p336/c2/line 7-11] [3/Bratzler. ArchInternMed. Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3] [4/Rahim.ThrmbRes. 2003/p3/c2/line 1-5] [5/Goldhaber. AmJCardiol.Jan.2004/ p261/c2/line 6-8] Cancer: FRONTLINE Survey1— 3891 Clinician Respondents Major Surgery2 Cancer: Surgical Major Abdominothoracic Surgery (Elderly)3 Confirmed DVT (Inpatients)5 Rate of Appropriate Prophylaxis, % Medical Inpatients4 Cancer: Medical VTE prophylaxis is underused in patients with cancer The Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey was a questionnaire distributed globally to clinicians involved in cancer care and accessible on a dedicated Web site1 Data from 3891 completed questionnaires were available for analysis1 The results indicated that 52% of respondents would routinely utilize thromboprophylaxis for surgical oncology patients, and that most respondents only considered thromboprophlyaxis in approximately 5% of their medical oncology patients1 These results can be compared with prophylaxis rates in other patient groups as determined by other recent studies A retrospective record review in 10 US teaching or community-based hospitals of patients undergoing major surgeries (major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement) showed VTE prophylaxis was used in 89% of patients2 A retrospective record review of patients aged 65 and older in 20 Oklahoma hospitals undergoing major abdominothoracic surgery indicated that prophylaxis was used in 38% of patients3 A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4 In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis5 [1/Kakkar.Oncologist. 2003/p381/c1/ line A5-A22] [1/Kakkar/p381/c1/ line A23-A24] [1/Kakkar/p383/c1/ line 44-46, c2/line 1-3] [2/Stratton.ArchIntern Med.Feb.2000/ p334/c1/line A14-A19, c2/line A1-A2; p336/c2/line 7-11] [3/Bratzler.ArchIntern Med.Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3] [4/Rahim.ThrmbRes. 2003/p1/line A1-A12; p3/c2/line 1-5] [5/Goldhaber.AmJ Cardiol.Jan.2004/ p259/c1/line A1-A10; p261/c2/line 6-8] 1. Kakkar AK et al. Oncologist. 2003;8: 2. Stratton MA et al. Arch Intern Med. 2000;160: 3. Bratzler DW et al. Arch Intern Med. 1998;158: 4. Rahim SA et al. Thromb Res. 2003;111: 5. Goldhaber SZ et al. Am J Cardiol. 2004;93: 1. Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8: 2. Stratton MA, Anderson FA, Bussey HI, et al. Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients. Arch Intern Med. 2000;160: 3. Bratzler DW, Raskob GE, Murray CK, Bumpus LJ, Piatt DS. Underuse of venous thromboembolism prophylaxis for general surgery patients: physician practices in the community hospital setting. Arch Intern Med. 1998;158: 4. Rahim SA, Panju A, Pai M, Ginsberg J. Venous thromboembolism prophylaxis in medical inpatients: a retrospective chart review. Thromb Res. 2003;111: 5. Goldhaber SZ, Tapson VF, for the DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol. 2004;93:

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

Pharmacologic Prophylaxis of DVT in Special Populations
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 Differentiate data with various LMWHs in special populations 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;

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 175.5 kg * max dose 18, ,000 IU/day Duplaga BA et al. Pharmacotherapy 2001; 21: Synergy Trial: Data on File Davidson, et al. J Thromb Haem 2007;5:1191-4

LMWH Pharmacokinetics in Obesity
N= 30 (< 100kg) 35 ( kg) Tinzaparin 175 IU/kg SQ single dose Actual body weight correlates best with anticoagulant response to LMWHs as measured by anti-factor Xa levels Clin Pharmacol Ther 2002;72: Thromb Haemost 2002;87:

Dalteparin Pharmacokinetics in Obesity
Dose: 200 U/kg qd Duration: routine Obese (BMI > 30) Normal (BMI < 30) N 10 TBW (mean +/- SD) /- 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 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 N 13 14 10 Mean Dose (U) 14,030 17,646 23,565 Ant-Xa Activity (u/ml) Day 3 Peak 1.01 0.97 1.12 NS Day 3 Trough 0.12 0.11 0.11 NS 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)
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 3 month outcomes: major bleeding = 1.0% (n=2) > 90 kg 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 52 20,850 49 25 17 41 21,470 21 26 15 24,300 22 9 25,250 8 10 6 26,920 5 4 > 150 28,280 Failures defined as recurrent DVT. Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2.

Fondaparinux In Obesity Results From the Matisse Trials
< 50kg: 5mg qd 50-100kg: 7.5mg qd > 100kg: 10mg qd Enoxaparin: (Matisse DVT) 1mg/kg q12h Heparin: (Matisse PE) Adjusted per aPTT No weight-dependent difference in efficacy or safety Davidson BL et al. J Thrombosis Haemost 2007; 5:

Body Weight and Anti-Xa Activity for Prophylactic Doses of LMWH
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 Area under the curve for 10 h Body Weight (kg) Frederiksen SG et al. Br J Surgery 2003; 90:547-8

Fixed Dosing For VTE Prevention
Dalteparin Fixed Dosing For VTE Prevention Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill) BMI (kg/m2) Patients % Favors Dalteparin Favor Placebo < > Overall Prevent Trial 0.01 0.1 0.55 1.0 10.0 Relative Risk 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: Dose: 40 mg qd Obese : BMI>32kg/m2 Samama MM et al. Thromb Haemost 1995; 73:977.

Enoxaparin: VTE Prophylaxis in Bariatric Surgery
5.4% p<0.01 0.6% 30mg bid: n=92 BMI 51.7kg/m2 40mg bid: n=389 BMI 50.3kg/m2 Scholten Obes Surg 2002; 12:19-24.

Dalteparin in Morbid Obesity: Bariatric Surgery
200 180 160 140 120 P=0.031 P=0.052 N=135 Bariatric Surgery Mean Weight: 148.8Kg Mean BMI: 53.7 Dalteparin: 7,500 IU daily P=0.444 Body Weight (kg) Under target value <0.2 IU/mL n-=41 Target value < IU/mL n-=81 Over target value <>0.5 IU/mL n=13 Anti-factor Xa level 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 0.0152 Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print]

LMWH in Obesity: Summary
Treatment: in controlled trials, LMWH dosing has been based on TBW (max kg) Dalteparin Dose based on TBW PI recommends dose capping Recent clinical data supports TBW dosing QD or BID dosing Enoxaparin 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):

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

Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n)
Recent Meta-Analysis of LMWHs and Bleeding In Patients With Severe Renal Dysfunction Study; year Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n) Peto OR (95%, CI) Weight (%) Collet, et al; 2001 0/28 1/83 2.01 0.26 (0.00 – 23.94) Paulas, et al; 2002 0/51 3/149 6.02 0.26 (0.02 – 3.50) Siguret, et al; 2000 0/17 0/13 Not estimable Chow, et al; 2003 0/5 Khazan, et al. (adj.); 2003 0/10 3/42 4.78 0.28 (0.01 – 5.16) (Prophylactic) 2003 3/36 3/47 14.77 1.33 (0.25 – 7.05) (Therapeutic) 2003 2/17 3/61 8.62 3.09 (0.35 – 27.31) Spinler, et al; 2003 5/69 74/3,432 15.93 10.05 (2.02 – 49.98) Green, et al; 2005 1/18 0/20 2.66 8.26 (0.16 – ) 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 (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) Total (95%, CI) 21/416 107/4,555 100.00 2.25 (1.19 – 4.27) Dosage adjustments for renal dysfunction Favors ↓’ed Favors ↑’ed bleeding Lim W, et al. Ann Intern Med. 2006;144:

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 Day 4 CL/F (L/h) Half-life (h) AUC (0-24) (h●IU/mL) 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% ↑ Sanderink GJCM. Thromb Res 2002;105:

LMWH Renal Dosing in NSTE ACS Patients
Dose may be  to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl ml/min Anti-Xa monitoring Doses “appeared safe” Further prospective evaluation needed 56 UA pts with CrCl <60 ml/min Enoxaparin dose empirically  and anti-Xa level measured after 3rd dose 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 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. 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 6 5 4 3 2 1 PEAK ANTI-Xa LEVELS TROUGH ANTI-Xa LEVELS Antifactor X1 Level (U/mL) Number of Patients First dose Subsequent doses (second and third) Median % interquartile range Trough Antifactor Xa Level (U/mL) Trough Antifactor Xa Level (U/mL) Lachish T et al. Pharmacotherapy 2007; 27:

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.

Dalteparin 100 U/kg q12h Peak Anti-Xa Levels According to Renal Function
No difference in peak anti-Xa activity between normal patients and patients with renal impairment 1.5 1.0 0.5 Clcr > < 40 Mean peak anti-Xa level after 5-6 doses Antifactor Xa Level (U/mL) x x Subjects without Renal impairment Subjects with Renal impairment N=11 N=11 Shprecher AR et al. Pharmacotherapy 2005; 25:

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 3 Major Bleeding 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 Sep 8;168(16):

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 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):

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. < 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 ~ U/ml) at 3-4 hrs Trough (goal < 0.5 U/ml) at hrs Laposata et al. Arch Pathol Lab Med. 1998;122:

Fondaparinux Use in Patients with Impaired Renal Function
Total clearance lower than in patients with normal renal function Mild impairment ~25% Moderate impairment ~40% Severe impairment ~55% Fondaparinux: PI

Applying National Guidelines to Clinical Practice
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

Hospitalized Patients with Cancer
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 low-dose heparin or LMWH for bedridden patients with active cancer.

Role of VTE Prophylaxis
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

Undergoing Surgery (continued)
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 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)

Role of VTE Prophylaxis
Treatment of Patients with Established VTE to Prevent Recurrence (continued) Role of VTE Prophylaxis Evidence Anticoagulation 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

Anticoagulants 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.

Summary of NCCN Guidelines Updates
Summary of Major Changes in the 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 “ x control) to “ x control…” (Also for VTE-H) in these patients.

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”.

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):

(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.

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 [ kg]; 10 mg [> 100 kg] subcutaneous daily Unfractionated heparin (IV) (80 units/kg load, then 18 units/kg per hour, target aPTT of x control or per hospital SOP)

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

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 )

Therapeutic Anticoagulation Failure
INR Switch to heparin (LMWH preferred) or fondaparinux Increase warfarin dose and treat with parenteral agent until INR target achieved or consider switching to heparin (LMWH preferred) or fondaparinux Patient on warfarin Check Sub-therapeutic

Therapeutic Anticoagulation Failure
aPTT Increase dose of heparin or Switch to LMWH or Switch to fondaparinux and Consider placement of IVC filter and Consider HIT Increase dose of heparin to reach therapeutic level Patient on heparin Check aPTT levels Sub-therapeutic

Mechanisms ● Mortality ● Therapeutics
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The Science and Medicine of Thrombosis in Cancer

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