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Welcome to this Science-to-Strategy Summit Welcome to this Science-to-Strategy Summit

Clotting, Cancer, and Controversies Critical Challenges and Landmark Advances in Thrombosis Management The Evolving Clotting, Cancer, and Controversies Critical Challenges and Landmark Advances in Thrombosis Management The Evolving and Foundation Role of LMWHs in Cancer and VTE Prophylaxis: Applying Science, Expert Analysis, and Landmark Trials to the Front Lines of Oncology Practice Program Chairman Charles W. Francis, MD Professor of Medicine and Pathology and Laboratory Medicine Department of Medicine University of Rochester School of Medicine and Dentistry Rochester, New York

Welcome and Program Overview CME-accredited symposium jointly sponsored by University of Massachusetts Medical Center, Welcome and Program Overview CME-accredited symposium jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Eisai, Inc. Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program

Program Educational Objectives As a result of this session, physicians will: ► Review recent Program Educational Objectives As a result of this session, physicians will: ► Review recent trials, research, and expert analysis of issues focused on thrombosis and cancer. ► Learn how national guidelines for thrombosis prevention should impact management of patients with cancer. ► Be able to specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer. ► Be able to explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT. ► Be able to describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis.

Program Faculty Program Chairman Charles W. Francis, MD Professor of Medicine and Pathology and Program Faculty Program Chairman Charles W. Francis, MD Professor of Medicine and Pathology and Laboratory Medicine Department of Medicine University of Rochester School of Medicine and Dentistry Rochester, NY Frederick Rickles, MD Professor of Medicine, Pediatrics, Pharmacology and Physiology Department of Medicine Division of Hematology-Oncology The George Washington University Washington, DC John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA

Faculty COI Financial Disclosures Charles Francis, MD Grants/research support: Boehringer-Ingelheim, Eisai, Consultant: Eisai, Amgen, Faculty COI Financial Disclosures Charles Francis, MD Grants/research support: Boehringer-Ingelheim, Eisai, Consultant: Eisai, Amgen, Pfizer Frederick Rickles, MD Consultant: Pfizer, Eisai, sanofi-aventis, and Bristol-Myers Squibb Speakers Bureau: Eisai John Fanikos, RPh, MBA Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, Glaxo. Smith. Kline, sanofi-aventis, The Medicines Company

Introduction and Chairman’s Overview Clotting, Cancer, And Controversies: What The Cascade Of Evidence And Introduction and Chairman’s Overview Clotting, Cancer, And Controversies: What The Cascade Of Evidence And Current Thinking Tell Us The Evolving Science, Epidemiology, and Foundation Role of Low Molecular Weight Heparin in the Setting of Cancer Program Chairman Charles W. Francis, MD Professor of Medicine and Pathology and Laboratory Medicine Department of Medicine University of Rochester School of Medicine and Dentistry Rochester, New York

Comorbidity Connection COMORBIDITY CONNECTION SUBSPECIALIST STAKEHOLDERS CAP UTI Cancer Heart Failure ABE/COPD Respiratory Failure Comorbidity Connection COMORBIDITY CONNECTION SUBSPECIALIST STAKEHOLDERS CAP UTI Cancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder Thrombophilia Surgery History of DVT Other Infectious diseases Oncology 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 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 30 -day incidence 6% after incident DVT 30 -day incidence 12% after PE Death After Treated VTE Death strongly associated with cancer, age, and cardiovascular disease White R. Circulation. 2003; 107: I-4 –I-8. )

Epidemiology of VTE ► One major risk factor for VTE is ethnicity, with a Epidemiology of VTE ► One major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders. ► Overall, about 25% to 50% of patient with first-time VTE have an idiopathic condition, without a readily identifiable risk factor. ► Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease. White R. Circulation. 2003; 107: I-4 –I-8. )

Comorbidity Connection Overview Comorbidity Connection Comorbidity Connection Overview Comorbidity Connection

Acute Medical Illness and VTE Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Acute Acute Medical Illness and VTE Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Acute Medical Illness Relative Risk X 2 P Value Heart failure NYHA class III NYHA class IV 1. 08 (0. 72 -1. 62) 0. 89 (0. 55 -1. 43) 1. 48 (0. 84 -2. 60) 0. 05 0. 12 1. 23 . 82. 72. 27 Acute respiratory disease 1. 26 (0. 85 -1. 87) 1. 03 . 31 Acute infectious disease 1. 50 (1. 00 -2. 26) 3. 54 . 06 Acute rheumatic disease 1. 45 (0. 84 -2. 50) 1. 20 . 27 Alikhan R, Cohen A, et al. Arch Intern Med. 2004; 164: 963 -968 Alikhan R, Cohen A, et al. Arch Med. 2004; 164: 963 -968

Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Risk Factor Odds 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 Chronic respiratory disease 0. 60 (0. 38 -0. 92) 0. 02 Alikhan R, Cohen A, et al. Arch Intern Med. 2004; 164: 963 -968

Comorbid Condition and DVT Risk ► Hospitalization for surgery (24%) and for medical illness Comorbid Condition and DVT Risk ► Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%. ► The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively. ► Together, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3 rd. Arch Intern Med. 2002 Jun Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3 rd. Arch Med. 2002 Jun 10; 162(11): 1245 -8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

VTE Recurrence Predictors of First Overall VTE Recurrence Baseline Characteristic Hazard Ratio (95% CI) VTE Recurrence Predictors of First Overall VTE Recurrence Baseline Characteristic Hazard Ratio (95% CI) Age 1. 17 (1. 11 -1. 24) Body Mass Index 1. 24 (1. 04 -1. 7) Neurologic disease with extremity paresis 1. 87 (1. 28 -2. 73) Malignant neoplasm None With chemotherapy Without chemotherapy Heit J, Mohr D, et al. Arch Intern Med. 2000; 160: 761 -768 Heit J, Mohr D, et al. Arch Med. 2000; 160: 761 -768 1. 00 4. 24 (2. 58 -6. 95) 2. 21 (1. 60 -3. 06)

Clotting, Cancer, and Clinical Strategies Cancer, Thrombosis, and the Biology of Malignancy Scientific Foundations Clotting, Cancer, and Clinical Strategies Cancer, Thrombosis, and the Biology of Malignancy Scientific Foundations for the Role of Low-Molecular-Weight Heparin Frederick R. Rickles, MD Professor of Medicine, Pediatrics, Pharmacology and Physiology The George Washington University Washington, DC

Professor Armand Trousseau Lectures in Clinical Medicine “ I have always been struck with Professor Armand Trousseau Lectures in Clinical Medicine “ I have always been struck with the frequency with which cancerous patients are affected with painful oedema of the superior or inferior extremities…. ” New Syndenham Society – 1865

Professor Armand Trousseau More Observations About Cancer and Thrombosis “In other cases, in which Professor Armand Trousseau More Observations About Cancer and Thrombosis “In other cases, in which the absence of appreciable tumor made me hesitate as to the nature of the disease of the stomach, my doubts were removed, and I knew the disease to be cancerous when phlegmasia alba dolens appeared in one of the limbs. ” Lectures in Clinical Medicine, 1865

Trousseau’s Syndrome Ironically, Trousseau died of gastric carcinoma 6 months after writing to his Trousseau’s Syndrome Ironically, Trousseau died of gastric carcinoma 6 months after writing to his student, Peter, on January 1 st, 1867: “I am lost. . . the phlebitis that has just appeared tonight leaves me no doubt as to the nature of my illness”

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

Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 53. 5 Adjusted odds ratio Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 53. 5 Adjusted odds ratio 50 40 30 20 • Population-based case-control (MEGA) study • N=3220 consecutive patients with 1 st VTE vs. n=2131 control subjects • CA patients = OR 7 x VTE risk vs. non. CA patients 28 22. 2 20. 3 19. 8 14. 3 10 4. 9 3. 6 2. 6 1. 1 Type of cancer Silver In: The Hematologist - modified from Blom et. al. JAMA 2005; 293: 715 > 15 years 5 to 10 years 1 to 3 years 3 to 12 months 0 to 3 months Distant metastases Breast Gastrointestinal Lung Hematological 0 Time since cancer diagnosis

Cancer, Mortality, and VTE Epidemiology and Risk ► Patients with cancer have a 4 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 2 nd 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; Heit et. al. Arch 2000; 160: 809 -815 and 2002; 162: 1245 -1248; Prandoni et. al. Blood White et. al. Thromb Haemost 2003; 90: 446 -455; Sorensen et. al. New Engl J Med 2000; 343: 1846 -1850); Levitan et. al. White et. al. Thromb 2003; 90: 446 -455; Sorensen et. al. New 2000; 343: 1846 -1850); Levitan et. al. Medicine 1999; 78: 285 -291; Khorana et. al. J Thromb Haemost 2007; 5: 632 -4 1999; 78: 285 -291; Khorana et. al. Haemost 2007; 5: 632 -4

Mechanisms of Cancer-Induced Thrombosis: The Interface 1. Pathogenesis? 2. Biological significance? 3. Potential importance Mechanisms of Cancer-Induced Thrombosis: The Interface 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy?

Trousseau’s Observations (continued) “There appears in the cachexiae…a particular condition of the blood that Trousseau’s Observations (continued) “There appears in the cachexiae…a particular condition of the blood that predisposes it to spontaneous coagulation. ” Lectures in Clinical Medicine, 1865

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

Pathogenesis of Thrombosis in Cancer A Modification of Virchow’s Triad 1. Stasis ● ● Pathogenesis of Thrombosis in Cancer A Modification of Virchow’s Triad 1. Stasis ● ● Prolonged bed rest Extrinsic compression of blood vessels by tumor 2. Vascular Injury ● ● Direct invasion by tumor Prolonged use of central venous catheters Endothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endothelium 3. Hypercoagulability ● ● ● Tumor-associated procoagulants and cytokines (tissue factor, CP, 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 Interface 1. Pathogenesis? 2. Biological significance? 3. Mechanisms of Cancer-Induced Thrombosis: Clot and Cancer Interface 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy?

Activation of Blood Coagulation in Cancer Biological Significance? ► Epiphenomenon? Is this a generic 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 Tumor Cell FVII/FVIIa TF Blood Coagulation Activation Interface of Clotting Activation and Tumor Biology Tumor Cell FVII/FVIIa TF Blood Coagulation Activation VEGF THROMBIN FIBRIN Angiogenesis IL-8 PAR-2 Angiogenesis TF Endothelial cells Falanga and Rickles, New Oncology: Thrombosis, 2005

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

VEGF and Angiogenesis Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the VEGF and Angiogenesis Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor 1. TF regulates VEGF expression in human cancer cell lines 2. Human cancer cells with increased TF are more angiogenic (and, therefore, more “metastatic’) in vivo due to high VEGF production Abe et. al. Proc Nat Acad Sci 1999; 96: 8663 -8668; Ruf et. al. Nature Med 2004; 10: 502 -509 Abe et. al. Proc Sci 1999; 96: 8663 -8668; Ruf et. al. Nature Med 2004; 10: 502 -509

VEGF and Angiogenesis Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the VEGF and Angiogenesis Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor 3. The cytoplasmic tail of TF, which contains three serine residues, appears to play a role in regulating VEGF expression in human cancer cells, perhaps by mediating signal transduction 4. Data consistent with new mechanism(s) by which TF signals VEGF synthesis in human cancer cells may provide insight into the relationship between clotting and cancer Abe et. al. Proc Nat Acad Sci 1999; 96: 8663 -8668; Ruf et. al. Nature Med. 2004; 10: 502 -509 Abe et. al. Proc Sci 1999; 96: 8663 -8668; Ruf et. al. Nature Med. 2004; 10: 502 -509

Tissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic Cancer Alok A. Khorana, Steven A. Tissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic Cancer Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan, Charles W. Francis, Ralph H. Hruban, Ying Chuan Hu, Galen Hostetter, Jennifer Harvey and Mark B. Taubman (U Rochester, U Pitt, Johns Hopkins, Translational Genomics) Clin Cancer Res 2007; 13: 2870 ► Retrospective IH and microarray study of TF, VEGF and MVD in: ● ● Normal pancreas (10) Intraductal papillary mucinous neoplasms (IPMN; 70) Pancreatic intrepithelial neoplasia (Pan. IN; 40) Resected or metastatic pancreatic adenoca(130) ► Survival ► VTE Rate

Correlation of Tissue Factor Expression with the Expression of Other Angiogenesis Cariables in Resected Correlation of Tissue Factor Expression with the Expression of Other Angiogenesis Cariables in Resected Pancreatic Cancer High TF expression Low TF expression VEGF expression Negative Positive 13 53 41 15 <0. 0001 Microvessel density V 6 per tissue core >6 per tissue core Median 27 39 8 33 23 6 0. 047 Khorana et. al. Clin CA Res 2007: 13: 2870 P 0. 01

Symptomatic VTE in Pancreatic Cancer Rate of VTE (%) 5/19; 26. 3% 1/22; 4. Symptomatic VTE in Pancreatic Cancer Rate of VTE (%) 5/19; 26. 3% 1/22; 4. 5% Khorana et. al. Clin CA Res 2007: 13: 2870 Khorana et. al. Clin

Activation of Blood Coagulation in Cancer: Malignant Transformation ► Epiphenomenon? ► Linked to malignant Activation of Blood Coagulation in Cancer: Malignant Transformation ► Epiphenomenon? ► Linked to malignant transformation? 1. MET oncogene induction produces DIC in human liver carcinoma (Boccaccio et. al. Nature 2005; 434: 396 -400) 2. Pten loss produces TF activation and pseudopalisading necrosis in human glioblastoma (Rong et. al. Ca Res 2005; 65: 1406 -1413) 3. K-ras oncogene, p 53 inactivation and TF induction in human colorectal carcinoma (Yu et. al. Blood 2005; 105: 1734 -1741)

 Activation of Blood Coagulation in Cancer: Malignant Transformation “ 1. MET Oncogene Drives Activation of Blood Coagulation in Cancer: Malignant Transformation “ 1. MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” ► MET encodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) ● ● Drives physiological cellular program of “invasive growth” (tissue morphogenesis, angiogenesis and repair) Aberrant execution (e. g. hypoxia-induced transcription) is associated with neoplastic transformation, invasion, and metastasis Boccaccio et al Nature 2005; 434: 396 -400 Boccaccio et al Nature

“MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” ► Mouse model of “MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” ► Mouse model of Trousseau’s Syndrome ● Targeted activated human MET to the mouse liver with lentiviral vector and liver-specific promoter slowly, progressive hepatocarcinogenesis ● Preceded and accompanied by a thrombohemorrhagic syndrome ● Venous thrombosis in tail vein occurred early and was followed by fatal internal hemorrhage ● Syndrome characterized by d-dimer and PT and platelet count (DIC)

Blood Coagulation Parameters in Mice Transduced with the MET Oncogene Transgene Parameter Time after Blood Coagulation Parameters in Mice Transduced with the MET Oncogene Transgene Parameter Time after Transduction (days) GFP Platelets (x 103) 968 656 800 D-dimer (µg/ml) <0. 05 PT (s) 12. 4 11. 6 11. 4 ________________ MET Platelets (x 103) 974 350 150 D-dimer (µg/ml) <0. 05 0. 11 0. 22 PT (s) 12. 9 11. 8 25. 1 Boccaccio et al Nature 2005; 434: 396 -400 Boccaccio et al Nature 0 30 90

“MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” ► Mouse model of “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 -3 x circulating protein levels ● Using either XR 5118 (PAI-1 inhibitor) or Rofecoxib (Vioxx; COX-2 inhibitor) resulted in inhibition of clinical and laboratory evidence for DIC in mice

Activation of Blood Coagulation in Cancer: Malignant Transformation 2. “Pten and Hypoxia Regulate Tissue Activation of Blood Coagulation in Cancer: Malignant Transformation 2. “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” ► Pten = Tumor suppressor with lipid and protein phosphatase activity ► Loss or inactivation of Pten (70 -80% of glioblastomas) leads to Akt activation and upregulation of Ras/MEK/ERK signaling cascade Rong, Brat et. al. Ca Res 2005; 65: 1406 -1413

“Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” ► Glioblastomas “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” ► Glioblastomas characterized histologically by “pseudopalisading necrosis” ► Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by thrombosis ► Pseudopalisading cells produce VEGF and IL-8 and drive angiogenesis and rapid tumor growth ► TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2)

“Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” Results: 1. “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” Results: 1. Hypoxia and PTEN loss TF (m. RNA, Ag and procoagulant activity); partially reversed with induction of PTEN 2. Both Akt and Ras pathways modulated TF in sequentially transformed astrocytes. 3. Ex vivo data: TF (by immunohistochemical staining) in pseudopalisades of # 7 human glioblastoma specimens

Both Akt and Ras Pathways Modulate TF Expression By Transformed Astrocytes N=Normoxia H=hypoxia Rong, Both Akt and Ras Pathways Modulate TF Expression By Transformed Astrocytes N=Normoxia H=hypoxia Rong, Brat et. al. Ca Res 2005; 65: 1406 -1413

“Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” pseudopalisading necrosis “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” pseudopalisading necrosis H&E Vascular Endothelium TF Immunohistochemistry Rong, Brat et. al. Ca Res 2005; 65: 1406 -1413

 Activation of Blood Coagulation in Cancer: Malignant Transformation 3. “Oncogenic Events Regulate Tissue Activation of Blood Coagulation in Cancer: Malignant Transformation 3. “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications for Tumor Progression And Angiogenesis” ► ► ► Activation of K-ras oncogene and inactivation of p 53 tumor suppressor TF expression in human colorectal cancer cells Transforming events dependent on MEK/MAPK and PI 3 K Cell-associated and MP-associated TF activity linked to genetic status of cancer cells TF si. RNA reduced cell surface TF expression, tumor growth and angiogenesis TF may be required for K-ras-driven phenotype Yu, Mackman, Rak et. al. Blood 2005; 105: 1734 -41 Yu, Mackman, Rak et. al. Blood

 Activation of Blood Coagulation in Cancer: Malignant Transformation TF expression in cancer cells Activation of Blood Coagulation in Cancer: Malignant Transformation TF expression in cancer cells parallels genetic tumor progression with an impact of K-ras and p 53 status TF Activity (U/106 cells) Mean Channel TF Flourescence “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” del/+ +/+ mut/+ +/+ Yu, Mackman, Rak et. al. Blood 2005; 105: 1734 -41 Yu, Mackman, Rak et. al. Blood mut/+ del/del

 Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” Effect of TF si m. RNA on tumor growth in vitro and in vivo Yu, Mackman, Rak et. al. Blood 2005; 105: 1734 -41 Yu, Mackman, Rak et. al. Blood

 “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells” %VWF-Positive Area Effect “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells” %VWF-Positive Area Effect of TF si m. RNA on new vessel formation in colon cancer Yu, Mackman, Rak et. al. Blood 2005; 105: 1734 -41 Yu, Mackman, Rak et. al. Blood

 Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” Matrigel Assay: (D) HCT 116; (E) SI-3 cells – v. WF immunohistology Yu, Mackman, Rak et. al. Blood 2005; 105: 1734 -41 Yu, Mackman, Rak et. al. Blood

Mechanisms of Cancer-Induced Thrombosis: Implications 1. Pathogenesis? 2. Biological significance? 3. Potential importance for Mechanisms of Cancer-Induced Thrombosis: Implications 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy?

Cancer and Thrombosis Year 2008 State-of-the-Science Update Key Questions 1. Does activation of blood Cancer and Thrombosis Year 2008 State-of-the-Science Update Key Questions 1. Does activation of blood coagulation affect the biology of cancer positively or negatively? 2. Can we treat tumors more effectively using coagulation protein targets? 3. Can anticoagulation alter the biology of cancer?

Cancer and Thrombosis Year 2008 State-of-the-Science Update Tentative Answers 1. Epidemiologic evidence is suggestive Cancer and Thrombosis Year 2008 State-of-the-Science Update Tentative Answers 1. Epidemiologic evidence is suggestive that VTE is a bad prognostic sign in cancer 2. Experimental evidence is supportive of the use of antithrombotic strategies for both prevention of thrombosis and inhibition of tumor growth 3. Results of recent, randomized clinical trials of LMWH in cancer patients indicate superiority in preventing recurrent VTE and suggest increased survival (not due to just preventing VTE)— “Titillating”

Coagulation Cascade and Tumor Biology TF Clottingdependent §VIIa Clottingindependent Thrombin §Xa Clottingdependent Clottingindependent ? Coagulation Cascade and Tumor Biology TF Clottingdependent §VIIa Clottingindependent Thrombin §Xa Clottingdependent Clottingindependent ? Fibrin Clottingdependent PARs Angiogenesis, Tumor Growth and Metastasis LMWH (e. g. dalteparin) Fernandez, Patierno and Rickles. Sem Hem Thromb 2004; 30: 31; Ruf. J Thromb Haemost 2007; 5: 1584

Clotting, Cancer, and Controversies A Systematic Overview of VTE Prophylaxis in the Setting of Clotting, Cancer, and Controversies A Systematic Overview of VTE Prophylaxis in the Setting of Cancer Linking Science to Clinical Practice Program Chairman Charles W. Francis, MD Professor of Medicine and Pathology and Laboratory Medicine Department of Medicine University of Rochester School of Medicine and Dentistry Rochester, New York

VTE and Cancer: Epidemiology ► Of all cases of VTE: ● ● ► Of VTE and Cancer: Epidemiology ► Of all cases of VTE: ● ● ► Of all cancer patients: ● ● ► About 20% occur in cancer patients Annual incidence of VTE in cancer patients ≈ 1/250 15% will have symptomatic VTE As many as 50% have VTE at autopsy Compared to patients without cancer: ● ● ● Higher risk of first and recurrent VTE Higher risk of bleeding on anticoagulants Higher risk of dying Lee AY, Levine MN. Circulation. 2003; 107: 23 Suppl 1: I 17 -I 21 Circulation.

DVT and PE in Cancer Facts, Findings, and Natural History ► VTE is the DVT 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 1. Ambrus JL et al. J Med. 1975; 6: 61 -64 2. Donati MB. Haemostasis. 1994; 24: 128 -131 3. Johnson MJ et al. Clin Lab Haem. 1999; 21: 51 -54 Johnson MJ et al. Clin Haem. 1999; 21: 51 -54 4. Prandoni P et al. Ann Intern Med. 1996; 125: 1 -7 Prandoni P et al. Ann Med. 1996; 125: 1 -7

Clinical Features of VTE in Cancer ► VTE has significant negative impact on quality 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 Bura al. , Haemost 2004; 2: 445 -51

Thrombosis and Survival Likelihood of Death After Hospitalization 1. 00 Probability of Death DVT/PE Thrombosis and Survival Likelihood of Death After Hospitalization 1. 00 Probability of Death DVT/PE and Malignant Disease 0. 80 0. 60 Malignant Disease 0. 40 DVT/PE Only 0. 20 0. 00 Nonmalignant Disease 0 20 40 60 Levitan N, et al. Medicine 1999; 78: 285 80 100 120140 160 180 Number of Days

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

Rate of VTE (%) Trends in VTE in Hospitalized Cancer Patients 7. 0 6. Rate of VTE (%) Trends in VTE in Hospitalized Cancer Patients 7. 0 6. 5 6. 0 5. 5 5. 0 4. 5 4. 0 3. 5 3. 0 2. 5 2. 0 1. 5 1. 0 0. 5 0. 0 P<0. 0001 1995 1996 1997 VTE- patients on chemotherapy Khorana AA et al. Cancer. 2007. Khorana AA et al. Cancer. 1998 1999 2000 2001 VTE-all patients PE-all patients 2002 2003 DVT-all patients

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

Risk Factors for Cancer-Associated VTE ► Cancer ● ● ► Type Stage • Men: Risk Factors for Cancer-Associated VTE ► Cancer ● ● ► Type Stage • Men: prostate, colon, brain, lung • Women: breast, ovary, lung Treatments ● Surgery ● Systemic therapy Central venous catheters (~4% generate clinically ● ► • • • 10 -20% proximal DVT 4 -10% clinically evident PE 0. 2 -5% fatal PE relevant VTE) Patient ● ● ● Prior VTE Co-morbities Genetic backgroud

VTE Risk And Cancer Type “Solid And Liquid Malignancies” Relative Risk of VTE Ranged VTE Risk And Cancer Type “Solid And Liquid Malignancies” Relative Risk of VTE Ranged From 1. 02 to 4. 34 Relative Risk of VTE in Cancer Patients 4. 5 4 3. 5 3 2. 5 2 1. 5 1 Stein PD, et al. Am J Med 2006; 119: 60 -68 Bladder Cervix Breast Leukemia Liver Ovary Colon Kidney Rectal Prostate Esophagus Lung Uterus Lymphoma Stomach Myeloprol Brain Pancreas 0. 5

Cancer and Thrombosis Medical Inpatients Cancer and Thrombosis Medical Inpatients

Thromboembolism in Hospitalized Neutropenic Cancer Patients ►Retrospective cohort study of discharges using the University Thromboembolism in Hospitalized Neutropenic Cancer Patients ►Retrospective cohort study of discharges using the University Health System Consortium ► 66, 106 adult neutropenic cancer patients between 1995 and 2002 at 115 centers Khorana, JCO, 2006

Neutropenic Patients: Results ► 8% had thrombosis ► 5. 4% venous and 1. 5% Neutropenic Patients: Results ► 8% had thrombosis ► 5. 4% venous and 1. 5% arterial in 1 st hospitalization ►Predictors of thrombosis ● ● ● Age over 55 Site (lung, GI, gynecologic, brain) Comorbidities (infection, pulmonary and renal disease, obesity) Khorana, JCO, 2006

Predictors of VTE in Hospitalized Cancer Patients Characteristic OR P Value Site of Cancer Predictors of VTE in Hospitalized Cancer Patients Characteristic OR P Value Site of Cancer Lung Stomach Pancreas Endometrium/cervix Brain 1. 3 1. 6 2. 8 2 2. 2 <0. 001 0. 0035 <0. 001 Age 65 y 1. 1 0. 005 Arterial thromboembolism 1. 4 0. 008 Comorbidities (lung/renal disease, infection, obesity) 1. 3 -1. 6 <0. 001 Khorana AA et al. J Clin Oncol. 2006; 24: 484 -490. Khorana AA et al. J

Antithrombotic Therapy: Choices Nonpharmacologic (Prophylaxis) Intermittent Pneumatic Compression Elastic Stockings Inferior Vena Cava Filter Antithrombotic Therapy: Choices Nonpharmacologic (Prophylaxis) Intermittent Pneumatic Compression Elastic Stockings Inferior Vena Cava Filter Pharmacologic (Prophylaxis & Treatment) Unfractionated Heparin (UH) Low Molecular Weight Heparin (LMWH) Oral Anticoagulants New Agents: e. g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc. ?

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

ASCO Guidelines 1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS? Recommendation. ASCO Guidelines 1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS? Recommendation. Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation. Lyman, JCO, 2007

Cancer and Thrombosis Surgical Patients Cancer and Thrombosis Surgical Patients

Incidence of VTE in Surgical Patients ► Cancer patients have 2 -fold risk of 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 N=6124 Post-op VTE 0. 61% 1. 26% <0. 0001 Non-fatal PE 0. 27% 0. 54% <0. 0003 Autopsy PE 0. 11% 0. 41% <0. 0001 Death 0. 71% 3. 14% <0. 0001 Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC 1732 P-value

Natural History of VTE in Cancer Surgery: The @RISTOS Registry ► Web-Based Registry of Natural History of VTE in Cancer Surgery: The @RISTOS Registry ► Web-Based Registry of Cancer Surgery Tracked 30 -day incidence of VTE in 2373 patients Type of surgery • 52% General • 29% Urological • 19% Gynecologic 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings ► 2. 1% incidence of clinically overt VTE (0. 8% fatal) ► Most events occur after hospital discharge ► Most common cause of 30 -day post-op death Agnelli, abstract OC 191, ISTH 2003

Prophylaxis in Surgical Patients LMWH vs. UFH ► Abdominal or pelvic surgery for cancer Prophylaxis in Surgical Patients LMWH vs. UFH ► Abdominal or pelvic surgery for cancer (mostly colorectal) ► LMWH once daily vs. UFH tid for 7– 10 days post-op ► DVT on venography at day 7– 10 and symptomatic VTE Study N Design Regimens ENOXACAN 1 631 double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475 double-blind enoxaparin vs. UFH 1. ENOXACAN Study Group. Br J Surg 1997; 84: 1099– 103 1. ENOXACAN Study Group. Br Surg 1997; 84: 1099– 103 2. Mc. Leod R, et al. Ann Surg 2001; 233: 438 -444

Prophylaxis in Surgical Patients Incidence of Outcome Event 18. 2% 14. 7% P>0. 05 Prophylaxis in Surgical Patients Incidence of Outcome Event 18. 2% 14. 7% P>0. 05 ENOXACAN N=319 2. 9% VTE ENOXACAN Study Group. Br J Surg 1997; 84: 1099– 103 4. 1% Major Bleeding N=312

Incidence of Outcome Event Prophylaxis in Surgical Patients 16. 9% 13. 9% P=0. 052 Incidence of Outcome Event Prophylaxis in Surgical Patients 16. 9% 13. 9% P=0. 052 Canadian Colorectal DVT Prophylaxis Trial N=234 N=241 1. 5% 2. 7% VTE (Cancer) Mc. Leod R, et al. Ann Surg 2001; 233: 438 -444 Major Bleeding (All)

Prophylaxis in Surgical Patients Extended prophylaxis ► Abdominal or pelvic surgery for cancer ► Prophylaxis in Surgical Patients Extended prophylaxis ► Abdominal or pelvic surgery for cancer ► LMWH for ~ 7 days vs. 28 days post-op ► Routine bilateral venography at ~day 28 Study N Design Regimens ENOXACAN II 332 Double-blind Enoxaparin vs. placebo FAME (subgroup) 198 Open-label Dalteparin vs. no prophylaxis 1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002; 346: 975 -980 1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Med 2002; 346: 975 -980 2. Rasmussen M, et al (FAME) Blood 2003; 102: 56 a

 Incidence of Outcome Event Extended Prophylaxis in Surgical Patients 12. 0% ENOXACAN II Incidence of Outcome Event Extended Prophylaxis in Surgical Patients 12. 0% ENOXACAN II P=0. 02 N=167 5. 1% 4. 8% N=165 3. 6% 1. 8% 0. 6% 0% 0. 4% NNT = 14 VTE Prox Any Major DVT Bleeding Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002; 346: 975 -980

Major Abdominal Surgery: FAME Investigators— Dalteparin Extended ► A multicenter, prospective, assessor-blinded, open-label, randomized Major Abdominal Surgery: FAME Investigators— Dalteparin Extended ► A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment ► RESULTS: Cumulative incidence of VTE was reduced from 16. 3% with short-term thromboprophylaxis (29/178 patients) to 7. 3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15 -76; P=0. 012). ► CONCLUSIONS: 4 -week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis. Rasmussen, J Thromb Haemost. 2006 Nov; 4(11): 2384 -90. Epub 2006 Aug 1.

ASCO Guidelines: VTE Prophylaxis ► All patients undergoing major surgical intervention for malignant disease ASCO Guidelines: VTE Prophylaxis ► All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis. ► Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis. ► Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features. Lyman, JCO, 2007

Central Venous Catheters Thrombosis is a potential complication of central venous catheters, including these Central Venous Catheters Thrombosis is a potential complication of central venous catheters, including these events: –Fibrin sheath formation –Superficial phlebitis –Ball-valve clot –Deep vein thrombosis (DVT) • Incidence up to 60% from historical data • ACCP guidelines recommended routine prophylaxis with low dose warfarin or LMWH Geerts W, et al. Chest 2001; 119: 132 S-175 S

Prophylaxis for Venous Catheters Placebo-Controlled Trials Study Regimen N CRT (%) Reichardt* 2002 Dalteparin Prophylaxis for Venous Catheters Placebo-Controlled Trials Study Regimen N CRT (%) Reichardt* 2002 Dalteparin 5000 U od placebo 285 140 11 (3. 7) 5 (3. 4) Couban* 2002 Warfarin 1 mg od placebo 130 125 6 (4. 6) 5 (4. 0) ETHICS† 2004 Enoxaparin 40 mg od placebo 155 22 (14. 2) 28 (18. 1) *symptomatic outcomes; †routine venography at 6 weeks Reichardt P, et al. Proc ASCO 2002; 21: 369 a; Couban S, et al, Blood 2002; 100: 703 a; Agnelli G, et al. Proc ASCO 2004; 23: 730

Central Venous Catheters: Warfarin Tolerability of Low-Dose Warfarin ► 95 cancer patients receiving FU-based Central Venous Catheters: Warfarin Tolerability of Low-Dose Warfarin ► 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily ► INR measured at baseline and four time points ► 10% of all recorded INRs >1. 5 ► Patients with elevated INR 2. 0– 2. 9 6% 3. 0– 4. 9 19% >5. 0 7% Masci et al. J Clin Oncol. 2003; 21: 736 -739

Prophylaxis for Central Venous Access Devices Summary ► Recent studies demonstrate a low incidence Prophylaxis for Central Venous Access Devices Summary ► Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) ► Routine prophylaxis is not warranted to prevent catheter-related thrombosis, but catheter patency rates/infections have not been studied ► Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis

7 th ACCP Consensus Guidelines No routine prophylaxis to prevent thrombosis secondary to central 7 th ACCP Consensus Guidelines No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2 B) and fixeddose warfarin (1 B) Geerts W, et al. Chest 2004; 126: 338 S-400 S

Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient ► No recommendations from ACCP ► 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; mucinsecreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian) ► Recommendations extrapolated from other groups of patients if additional risk factors present (e. g. hemiparesis in brain tumors, etc. )

Cancer and Thrombosis Ambulatory Chemotherapy Patients Cancer and Thrombosis Ambulatory Chemotherapy Patients

Risk Factors for VTE in Medical Oncology Patients ► Tumor type ● Ovary, brain, Risk Factors for VTE in Medical Oncology Patients ► Tumor type ● Ovary, brain, pancreas, lung, colon ► Stage, grade, and extent of cancer ● ► Type of antineoplastic treatment ● ► Metastatic disease, venous stasis due to bulky disease 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. Independent Risk Factors for DVT/PE Risk Factor/Characteristic O. R. Recent surgery with institutionalization 21. 72 Trauma 12. 69 Institutionalization without recent surgery 7. 98 Malignancy with chemotherapy 6. 53 Prior CVAD or pacemaker 5. 55 Prior superficial vein thrombosis 4. 32 Malignancy without chemotherapy 4. 05 Neurologic disease w/ extremity paresis 3. 04 Serious liver disease 0. 10 Heit JA et al. Thromb Haemost. 2001; 86: 452 -463

VTE Incidence In Various Tumors Oncology Setting VTE Incidence Breast cancer (Stage I & 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: I 17

Primary VTE Prophylaxis ►Recommended for hospitalized cancer patients ►Not recommended or generally used for Primary VTE Prophylaxis ►Recommended for hospitalized cancer patients ►Not recommended or generally used for outpatients ● ● Very little data Heterogeneous Need for risk stratification

Ambulatory Cancer plus Chemotherapy Study Methods ► Prospective observational study of ambulatory cancer patients Ambulatory Cancer plus Chemotherapy Study Methods ► Prospective observational study of ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a maximum of 4 cycles ► 115 U. S. centers participated ► Patients enrolled between March, 2002 and August, 2004 who had completed at least one cycle of chemotherapy were included in this analysis Khorana, Cancer, 2005

Ambulatory Cancer plus Chemotherapy Study Methods ► VTE events were recorded during mid-cycle or Ambulatory Cancer plus Chemotherapy Study Methods ► VTE events were recorded during mid-cycle or new-cycle visits ► Symptomatic VTE was a clinical diagnosis made by the treating clinician ► Statistical analysis ● ● Odds ratios to estimate relative risk Multivariate logistic regression to adjust for other risk factors Khorana, Cancer, 2005

Patient Characteristics Characteristic No. (%) All patients 3, 196 Age > 65 1, 243 Patient Characteristics Characteristic No. (%) All patients 3, 196 Age > 65 1, 243 (39) Female 2, 136 (67) Stage IV 1, 150 (37) Performance status 0 -1 2, 912 (91) Pre-chemotherapy platelet count > 350, 000/mm 3 691 (22) Khorana, Cancer, 2005

Patient Characteristics (2) Site of Cancer No. (%) All patients 3, 196 Breast 1, Patient Characteristics (2) Site of Cancer No. (%) All patients 3, 196 Breast 1, 137 (36) Lung 612 (19) Colon 353 (11) Ovary 225 (7) Upper GI 91 (3) Non-Hodgkin’s lymphoma 287 (9) Hodgkin’s disease 53 (2) Others 438 (14) Khorana, Cancer, 2005

Incidence of VTE Rate of VTE (%) 3. 0% 2. 5% 2. 0% 1. Incidence of VTE Rate of VTE (%) 3. 0% 2. 5% 2. 0% 1. 5% 1. 0% 0. 5% 0. 0% Baseline Cycle 1 Cycle 2 Cycle 3 VTE / 2. 4 months VTE/month VTE /cycle Cumulative rate (95% CI) 1. 93% 0. 8% 0. 7% 2. 2% (1. 7 -2. 8) Khorana, Cancer, 2005

Site of Cancer O th er s N H L Lu ng U pp Site of Cancer O th er s N H L Lu ng U pp er G H I od gk in’ s C olo n Al l p at ie nt s Br ea st VTE (%) / 2. 4 months Risk Factors: Site of Cancer 12 10 8 6 4 2 0 Khorana, Cancer, 2005

Incidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet Count Incidence Of VTE Over Incidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet Count Incidence Of VTE Over 2. 4 Months(%) 5. 0% p for trend=0. 005 4. 5% 4. 0% 3. 5% 3. 0% 2. 5% 2. 0% 1. 5% 1. 0% 0. 5% 0. 0% <217 Khorana, Cancer, 2005 217 -270 270 -337 Pre-chemotherapy Platelet Count/mm >337 3 (x 1000)

Risk Factors: Multivariate Analysis Characteristic OR Site of Cancer P value 0. 03 Upper Risk Factors: Multivariate Analysis Characteristic OR Site of Cancer P value 0. 03 Upper GI 3. 88 0. 0076 Lung 1. 86 0. 05 Lymphoma Pre-chemotherapy platelet count > 350, 000/mm 3 Hgb < 10 g/d. L or use of red cell growth factor Use of white cell growth factor in highrisk sites 1. 5 0. 32 2. 81 0. 0002 1. 83 0. 03 2. 09 0. 008 Khorana, Cancer, 2005

Predictive Model Patient Characteristic Score Site of Cancer Very high risk (stomach, pancreas) High Predictive Model Patient Characteristic Score Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) 2 1 Platelet count > 350, 000/mm 3 1 Hgb < 10 g/d. L or use of ESA 1 Leukocyte count > 11, 000/mm 3 1 BMI > 35 1 Khorana AA et al. JTH Suppl Abs O-T-002

Incidence of VTE Over 2. 4 Months Predictive Model Actual Incidence Estimated Incidence 95 Incidence of VTE Over 2. 4 Months Predictive Model Actual Incidence Estimated Incidence 95 % Confidence Limits 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% 0 1 2 3 4 Risk Score 0 1 2 3 4 N 1, 352 974 476 160 33 VTE(%) /2. 4 mo. s 0. 8 1. 8 2. 7 6. 3 13. 2

Predictive Model Validation Rate of VTE over 2. 5 mos (%) 8% 7% Development Predictive Model Validation Rate of VTE over 2. 5 mos (%) 8% 7% Development cohort 6% 7. 1% 6. 7% Validation cohort 5% 4% 3% 1. 8% 2. 0% 2% 1% 0. 8% 0. 3% 0% n=734 n=374 n=1627 n=842 n=340 n=149 Risk Low (0) Intermediate(1 -2) High(>3) Khorana AA et al. JTH Suppl Abs O-T-002

Cancer and Thrombosis VTE Treatment Cancer and Thrombosis VTE Treatment

Standard Treatment of VTE Can We Do Better Than This? Initial treatment 5 to Standard Treatment of VTE Can We Do Better Than This? Initial treatment 5 to 7 days LMWH or UFH Long-term therapy Vitamin K antagonist (INR 2. 0 - 3. 0) > 3 months

Recurrent VTE in Cancer Subset Analysis of the Home Treatment Studies (UH/VKA vs. LMWH/VKA) Recurrent VTE in Cancer Subset Analysis of the Home Treatment Studies (UH/VKA vs. LMWH/VKA) Recurrent VTE Events per 100 patient years Malignant Non- Malignant 27. 1 9. 0 P value Hutten et. al. J Clin Oncol 2000; 18: 3078 0. 003

Recurrent VTE in Cancer Subset Analysis of the Home Treatment Studies Major Bleeding Events Recurrent VTE in Cancer Subset Analysis of the Home Treatment Studies Major Bleeding Events per 100 patient years Malignant Nonmalignant 13. 3 2. 1 Hutten et. al. J Clin Oncol 2000; 18: 3078 P-value 0. 002

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

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

Landmark CLOT Cancer Trial Probability of Recurrent VTE, % Reduction in Recurrent VTE 25 Landmark CLOT Cancer Trial Probability of Recurrent VTE, % Reduction in Recurrent VTE 25 Recurrent VTE Risk reduction = 52% p-value = 0. 0017 20 OAC 15 10 Dalteparin 5 0 0 Lee, Levine, Kakkar, Rickles et. al. N Engl Lee, Levine, Kakkar, Rickles et. al. N J Med, 2003; 349: 146 30 60 90 120 150 Days Post Randomization 180 210

Bleeding Events in CLOT Dalteparin N=338 OAC Major bleed 19 ( 5. 6%) 12 Bleeding Events in CLOT Dalteparin N=338 OAC 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 Lee, Levine, Kakkar, Rickles et. al. N N=335 P-value*

Treatment of Cancer-Associated VTE Study Design Length of Therapy (Months) N Recurrent Major VTE Treatment of Cancer-Associated VTE Study Design Length of Therapy (Months) N Recurrent Major VTE Bleeding (%) Death (%) CLOT Trial (Lee 2003) Dalteparin OAC 6 336 9 0. 002 17 6 4 NS 39 NS 41 CANTHENOX (Meyer 2002) Enoxaparin OAC 3 67 71 11 0. 09 21 7 16 0. 09 11 0. 03 23 3 80 87 6 0. 03 11 6 8 NS 23 NS 22 6 32 36 34 3. 4 NS 3. 1 6. 7 LITE Tinzaparin (Hull ISTH 2003) OAC ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC NS NR

Treatment and 2° Prevention of VTE in Cancer – Bottom Line New Development New 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 1 A 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 1 C recommendation—ACCP) ► Buller et. al. Chest Suppl 2004; 126: 401 S-428 S

CLOT 12 -month Mortality All Patients Probability of Survival, % 100 90 80 70 CLOT 12 -month Mortality All Patients Probability of Survival, % 100 90 80 70 Dalteparin 60 OAC 50 40 30 20 10 0 HR 0. 94 P-value = 0. 40 0 30 60 90 120 180 240 300 Days Post Randomization Lee A, et al. ASCO. 2003 360

Anti-Tumor Effects of LMWH CLOT 12 -month Mortality Patients Without Metastases (N=150) Probability of Anti-Tumor Effects of LMWH CLOT 12 -month Mortality Patients Without Metastases (N=150) Probability of Survival, % 100 Dalteparin 90 80 70 OAC 60 50 40 30 20 10 HR = 0. 50 P-value = 0. 03 0 0 30 60 90 120 150 180 240 300 Days Post Randomization Lee A, et al. ASCO. 2003 360

LMWH for Small Cell Lung Cancer Turkish Study ► 84 patients randomized: CEV +/- LMWH for Small Cell Lung Cancer Turkish Study ► 84 patients randomized: CEV +/- LMWH (18 weeks) ► Patients balanced for age, gender, stage, smoking history, ECOG performance status Chemotherapy plus Dalteparin Chemo alone P-value 1 -y overall survival, % 51. 3 29. 5 0. 01 2 -y overall survival, % 17. 2 0. 01 Median survival, m 13. 0 8. 0 0. 01 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J Thromb Haemost 2004; 2: 1266.

Rate of Appropriate Prophylaxis, % VTE Prophylaxis Is Underused in Patients With Cancer: FRONTLINE Rate of Appropriate Prophylaxis, % VTE Prophylaxis Is Underused in Patients With Cancer: FRONTLINE Survey 1— 3891 Clinician Respondents Cancer: Surgical Major Surgery 2 Major Abdominothoracic Surgery (Elderly)3 Medical Inpatients 4 Confirmed DVT (Inpatients) 5 Cancer: Medical 1. Kakkar AK et al. Oncologist. 2003; 8: 381 -388 2. Stratton MA et al. Arch Intern Med. 2000; 160: 334 -340 3. Bratzler DW et al. Arch Intern Med. 1998; 158: 1909 -1912 4. Rahim SA et al. Thromb Res. 2003; 111: 215 -219 5. Goldhaber SZ et al. Am J Cardiol. 2004; 93: 259 -262

Clotting, Cancer, and Clinical Strategies Venous Thromboembolism (VTE) Prophylaxis in the Cancer Patient and Clotting, Cancer, and Clinical Strategies Venous Thromboembolism (VTE) Prophylaxis in the Cancer Patient and Beyond Guidelines and Implications for Clinical Practice John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA

Outline of Presentation ► Guidelines for VTE prevention ► Performance to date ► Opportunities Outline of Presentation ► Guidelines for VTE prevention ► Performance to date ► Opportunities for improvement ► Guidelines for VTE Treatment ► Performance to date

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

2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for 2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1 A) ● General, Gynecologic, Urologic Surgery • Low Dose Unfractionated Heparin 5, 000 units TID • LMWH > 3, 400 units Daily – Dalteparin 5, 000 units – Enoxaparin 40 mg – Tinzaparin 4, 500 units • GCS and/or IPC Cancer patients with an acute medical illness receive prophylaxis that is appropriate for their current risk state (Grade 1 A) • Low Dose Unfractionated Heparin • LMWH Contraindication to anticoagulant prophylaxis (Grade 1 C+) • GCS or IPC 1 A is the highest possible grade Indicates that benefits outweigh risks, burdens, and costs, with consistent RCT level of evidence Geerts WH et al. Chest. 2004; 126(suppl): 338 S-400 S

NCCN Practice Guidelines in VTE Disease At Risk Population Initial Prophylaxis ► Adult patient NCCN Practice Guidelines in VTE Disease At Risk Population Initial Prophylaxis ► Adult patient ► Diagnosis or clinical suspicion of cancer ► Inpatient ► ► ► Relative contraindication to anticoagulation treatment RISK FACTOR ASSESSMENT NO YES Age Prior VTE Familial thrombophilia Active cancer Trauma Major surgical procedures Acute or chronic medical illness requiring hospitalization or prolonged bed rest Central venous catheter/IV catheter Congestive heart failure Pregnancy Regional bulky lymphadenopathy with extrinsic vascular compression http: //www. nccn. org/professionals/physician_gls/PDF/vte. pdf Continue Prophylaxis After Modifiable risk factors: Lifestyle, Discharge ? smoking, tobacco, obesity, Prophylactic anticoagulation therapy (category 1) + sequential compression device (SCD) Mechanical prophylaxis (options) - SCD - Graduated compression stockings activity level/exercise ► ► ► AGENTS ASSOCIATED WITH INCREASED RISK Chemotherapy Exogenous estrogen compounds - HRT - Oral contraceptives - Tamoxifen/Raloxifene - Diethystilbestrol Thalidomide/lenalidomide

NCCN Practice Guidelines in VTE Disease Inpatient Prophylactic Anticoagulation Therapy ► LMWH - Dalteparin NCCN Practice Guidelines in VTE Disease Inpatient Prophylactic Anticoagulation Therapy ► LMWH - Dalteparin 5, 000 units subcutaneous daily - Enoxaparin 40 mg subcutaneous daily - Tinzaparin 4, 500 units (fixed dose) subcutaneous daily or 75 units/kg subcutaneous daily ► Pentasaccharide - Fondaparinux 2. 5 mg subcutaneous daily ► Unfractionated heparin 5, 000 units subcutaneous 3 times daily http: //www. nccn. org/professionals/physician_gls/PDF/vte. pdf http: //www. nccn. org/professionals/physician_gls/PDF/vte.

NCCN Practice Guidelines in VTE Disease Relative Contraindications to Prophylactic or Therapeutic Anticoagulation ► NCCN Practice Guidelines in VTE Disease Relative Contraindications to Prophylactic or Therapeutic Anticoagulation ► ► ► ► ► Recent CNS bleed, intracranial or spinal lesion at high risk for bleeding Active bleeding (major): more than 2 units transfused in 24 hours Chronic, clinically significant measurable bleeding > 48 hours Thrombocytopenia (platelets < 50, 000/mc. L) Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis) Recent major operation at high risk for bleeding Underlying coagulopathy Clotting factor abnormalities - Elevated PT or a. PTT (excluding lupus inhibitors) - Spinal anesthesia/lumbar puncture High risk for falls http: //www. nccn. org/professionals/physician_gls/PDF/vte. pdf http: //www. nccn. org/professionals/physician_gls/PDF/vte.

► Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ? ● “Hospitalized ► Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ? ● “Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation” Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490 -5505.

► Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? ► Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? ● “Routine prophylaxis is not recommended. ” ● “Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. ” Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490 -5505.

► Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ? ● ► Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ? ● All patients should be considered for thromboprophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Mechanical methods should not be used as monotherapy. Prophylaxis should continue for at least 7 -10 days post-op. Prolonged prophylaxis may be considered for cancer with high risk features. ● ● ● Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490 -5505.

Compliance With ACCP VTE Prophylaxis Guidelines Is Poor Compliance With VTE Prophylaxis Guidelines in Compliance With ACCP VTE Prophylaxis Guidelines Is Poor Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group 62, 012 70, 000 At risk for DVT/PE 35, 124 Received compliant care Number of patients 10, 000 9175 5, 000 2324 1388 0 52. 4% Orthopedic Surgery 15. 3% At-risk Medical Conditions General Surgery 9. 9% 12. 7% Urologic Surgery 6. 7% Gynecologic Surgery Data collected January 2001 to March 2005; 123, 340 hospital admissions. Compliance assessment was based on the 6 th American College of Chest Physicians (ACCP) guidelines. HT Yu et al. Am J Health-Syst Pharm 2007; 64: 69 -76

Reasons for Inadequate Duration of VTE Prophylaxis Started Late At-Risk Medical (n=5, 994) Abdominal Reasons for Inadequate Duration of VTE Prophylaxis Started Late At-Risk Medical (n=5, 994) Abdominal Surgery (n=3, 240) Urologic surgery (n=158) Gynecologic surgery (n=163) Neurosurgery (n=250) Started late & Ended Early 1, 347 (22. 5) 2, 961 (49. 4) 1, 686 (28. 1) 824 (25. 4) 1, 764 (54. 4) 652 (20. 1) 18 (11. 4) 73 (46. 2) 67 (42. 4) 13 (8. 0) 43 (26. 4) 107 (65. 6) 66 (26. 4) 125 (50. 0) 59 (23. 6) HT Yu et al. Am J Health-Syst Pharm 2007; 64: 69 -76

Predictors of the Use of Thromboprophylaxis Effect Odds Ratio (95% CI) Malignancy 0. 40 Predictors of the Use of Thromboprophylaxis Effect Odds Ratio (95% CI) Malignancy 0. 40 Others 0. 58 Infection 0. 83 Bleeding Risk 0. 91 Gender 0. 92 Hospital Size 0. 93 Age 1. 00 LOS 1. 05 Cardiovascular Disease 1. 06 Internal Medicine 1. 33 Respiratory 1. 35 AMC 1. 46 Duration of Immobility 1. 60 VTE Risk Factors 1. 78 0. 0 0. 5 1. 0 Kahn SR et Al. Thromb Res 2007; 119: 145 -155 1. 5 2. 0 2. 5 Odds Ratio 3. 0 3. 5 4. 0

Computer Reminder System ► Computer program linked to patient database to identify consecutive hospitalized Computer Reminder System ► Computer program linked to patient database to identify consecutive hospitalized patients at risk for VTE ► Patients randomized to intervention group or control group ► In the intervention group the physicians were alerted to the VTE risk and offered the option to order VTE prophylaxis ► Point scale for VTE risk ● Major risk: Cancer, prior VTE, hypercoagulability (3 points) ● Intermediate risk: Major surgery (2 points) ● Minor risk: Advanced age, obesity, bedrest, HRT, use of oral contraceptives (1 point) ► VTE prophylaxis (graduated elastic stockings, IPC, UFH, LMWH, warfarin) Kucher N, et al. N Engl J Med. 2005; 352: 969 -77

MD Computer Alert MD Computer Alert

Freedom from DVT or PE (%) Electronic Alerts to Prevent VTE Intervention group Control Freedom from DVT or PE (%) Electronic Alerts to Prevent VTE Intervention group Control group P<0. 001 Time (days) Number at risk Intervention group Control group 1, 255 1, 251 Kucher N, et al. N Engl J Med. 2005; 352: 969 -77 977 876 900 893 853 839

Mechanical Thromboprophylaxis In Critically Ill Patients: Review And Meta-analysis RESULTS: 21 relevant studies (5 Mechanical Thromboprophylaxis In Critically Ill Patients: Review And Meta-analysis RESULTS: 21 relevant studies (5 randomized controlled trials, 13 observational studies, and 3 surveys) were found. A total of 811 patients were randomized in the 5 randomized controlled trials; 3421 patients participated in the observational studies. Trauma patients only were enrolled in 4 randomized controlled trials and 4 observational studies. Meta-analysis of 2 randomized controlled trials with similar populations and outcomes revealed that use of compression and pneumatic devices did not reduce the incidence of venous thromboembolism. The pooled risk ratio was 2. 37 (CI, 95% 0. 57 - 9. 90). A range of methodological issues, including bias and confounding variables, make meaningful interpretation of the observational studies difficult. CONCLUSIONS: The role of mechanical approaches to thromboprophylaxis for intensive care patients remains uncertain Limbus A et al. Am J Crit Care, 2006; 15: 402 -10

Fatal Pulmonary Embolism During Anticoagulant Prophylaxis Study, Year (Reference) Prophylaxis Placebo RR Fixed n/n Fatal Pulmonary Embolism During Anticoagulant Prophylaxis Study, Year (Reference) Prophylaxis Placebo RR Fixed n/n (95% CI) Dahan et al, 1986 (41) 1/132 3/131 0. 33 (0. 03 to 3. 14) Garlund at al, 1996 (35) 3/5776 12/5917 0. 26 (0. 07 to 0. 91) Leizorovic et al, 2004 (23) 0/1829 2/1807 0. 20 (0. 01 to 4. 11) Mahe et al, 2005 (22) 10/1230 17/1244 0. 59 (0. 27 to 1. 29) Cohen at, 2006 (42) 0/321 5/323 0. 09 (0. 01 to 1. 65) Total (95% CI) 0. 38 (0. 21 to 0. 69) Total events 14 39 0. 001 0. 1 1. 0 10 1000 Favors Treatment Favors Placebo Dentali, F. et. al. Ann Intern Med 2007; 146: 278 -288

Unfractionated Heparin Prophylaxis: BID vs TID—What Works, What Doesn’t? Meta-analysis: 12 RCTs ► DVT, Unfractionated Heparin Prophylaxis: BID vs TID—What Works, What Doesn’t? Meta-analysis: 12 RCTs ► DVT, PE, all VTE events, Bleeding ► Proximal DVT plus PE BID VTE event rate: 2. 34 events per 1, 000 patient days ● TID event rate: 0. 86 events per 1, 000 patient days P=0. 05 ● ► NNT ● ● 676 hospital prophylaxis days with UFH TID to prevent 1 major bleed with 1, 649 hospital prophylaxis days of TID dosing King CS et al. CHEST 2007; 131: 507 -516

Heparin, Low Molecular Weight Heparin Prophylaxis ►Meta-analysis ► 36 randomized controlled trials ► 23, Heparin, Low Molecular Weight Heparin Prophylaxis ►Meta-analysis ► 36 randomized controlled trials ► 23, 000 hospitalized medical patients ►UFH 5, 000 units TID is more effective in preventing DVT than UFH BID ►Low molecular weight heparin is 33% more effective than unfractionated heparin in preventing DVT ● RR for DVT 0. 68 (p=0. 004) LMWH vs UFH DVT Risk Study Reduction (95% CI) Weight % Harenberg et al, 1990 0. 70 (0. 16 -3. 03) 3. 4 Turpie et al, 1992 0. 29 (0. 10 -0. 81) 11. 4 Dumas et al, 1994 0. 74 (0. 38 -1. 43) 14. 4 Bergmann & Neuhart 0. 94 (0. 39 -2. 26) 8. 1 Harenberg et al, 1996 2. 89 (0. 30 -27. 71) 0. 8 Lechler et al, 1996 0. 25 (0. 03 -2. 23) 3. 3 Hillbom et al, 2002 0. 55 (0. 31 -0. 98) 20. 5 Kleber, et al 2003 0. 77 (0. 43 -1. 38) 19. 4 Diener et al, 2006 0. 76 (0. 42 -1. 38) 18. 9 Overall (95% CI) 0. 68 (0. 52 -0. 88) et al, 1996 Wein L et al. Arch Intern Med. 2007; 167: 1476 -86. Wein L et al. Arch Med. 2007; 167: 1476 -86. 0. 1 1. 0 10 Risk Ratio LMWH Better LMWH Worse

BWH/DFCI Partners Cancer Care Experience • Consecutive patients, < 60 days • 2 Nursing BWH/DFCI Partners Cancer Care Experience • Consecutive patients, < 60 days • 2 Nursing units • LOS ranged from 3 days to 31 days • Number of days where doses were omitted ranged from 1 to 6 days

VTE Incidence: More Common in the Outpatient Setting ► Medical records of residents (n=477, VTE Incidence: More Common in the Outpatient Setting ► Medical records of residents (n=477, 800) ► 587 VTE events (104 per 100, 000 population) ► 30 Day recurrence 4. 8 % VTE Event Location Spencer FA, et al. Jour Gen Int Med 2006; 21 (7): 722 -777 Patients receiving prophylaxis during high risk periods

DVT, PE Diagnosis and Treatment http: //www. nccn. org/professionals/physician_gls/PDF/vte. pdf DVT, PE Diagnosis and Treatment http: //www. nccn. org/professionals/physician_gls/PDF/vte. pdf

Thrombosis in Malignancy 7 TH ACCP Consensus Conference Recommendations Initial Phase Chronic Phase 5 Thrombosis in Malignancy 7 TH ACCP Consensus Conference Recommendations Initial Phase Chronic Phase 5 -7 days Dalteparin 200/kg q 24 h (GRADE 1 A) Continue anticoagulation (warfarin or LMWH) long-term or until malignancy resolves (GRADE 1 C) 5 - 7 days 3 - 6 mos - indefinite Subacute Phase 3 - 6 months Dalteparin 150 units/kg q 24 h (GRADE 1 A) FDA Approves Dalteparin as First Low-Molecular Weight Heparin for Extended PRESS RELEASE: May 2, 2007 Treatment to Reduce the Recurrence of Blood Clots in Patients with Cancer Buller HR, et al. Chest 2004; 126 (suppl 3): 401 s-428 s

NCCN Practice Guidelines—Venous Thromboembolic Disease Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis NCCN Practice Guidelines—Venous Thromboembolic Disease Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis Immediate ► LMWH - Dalteparin (200 units/kg subcutaneous daily) - Enoxaparin (1 mg/kg subcutaneous every 12 hrs) -Tinzaparin (175 units/kg subcutaneous daily) ► Pentasaccharide - Fondaparinux (5. 0 mg [<50 kg]; 7. 5 mg [50 -100 lg]; 10 mg [>100 kg] subcutaneous daily ► Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target a. PTT to 2. 0 -2. 9 x control) http: //www. nccn. org/professionals/physician_gls/PDF/vte. pdf http: //www. nccn. org/professionals/physician_gls/PDF/vte.

NCCN Practice Guidelines—Venous Thromboembolic Disease Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis NCCN Practice Guidelines—Venous Thromboembolic Disease Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis Long Term ► ► LMWH is preferred as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer Warfarin (2. 5 -5 mg every day initially, subsequent dosing based on INR value; target INR 2. 0 -3. 0) Duration of Long Term Therapy ► ► ► Minimum time of 3 -6 mo for DVT and 6 -12 mo for PE Consider indefinite anticoaugulation if active cancer or persistent risk factors For catheter associated thrombosis, anticoagulate as long as catheter is in place and for 1 -3 mo after catheter removal http: //www. nccn. org/professionals/physician_gls/PDF/vte. pdf http: //www. nccn. org/professionals/physician_gls/PDF/vte.

► What is the best treatment for patients with cancer with established VTE to ► What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE ? ● LMWH is the preferred approach for the initial 5 -10 days. LMWH, given for at least 6 months, is the preferred for long-term anticoagulant therapy. After 6 months, anticoagulation therapy should be considered for select patients. For CNS malignancies, elderly patients anticoagulation is recommended with careful monitoring and dose adjustment. ● ● ● Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490 -5505.

► Should patients with cancer receive anticoagulants in the absence of established VTE to ► Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? ● “Anticoagulants are not recommended to improve survival in patients with cancer without VTE. ” Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490 -5505.

Antithrombotic Therapy Practices in U. S. Hospitals ►Survey of 38 U. S. Hospitals ►n=939 Antithrombotic Therapy Practices in U. S. Hospitals ►Survey of 38 U. S. Hospitals ►n=939 DVT or PE ► 50% patients reached INR >2 for 2 consecutive days Therapy n (%) LMWH 527 (56. 1%) UFH 562 (59. 8%) UFH SC 78 (8. 3%) DTI 6 (0. 6%) Tapson V et al. Arch Intern Med 2005

Self-Managed Long Term LMWH Therapy 2212 patients with proximal vein thrombosis assessed for eligibility Self-Managed Long Term LMWH Therapy 2212 patients with proximal vein thrombosis assessed for eligibility 737 Randomized 369 assigned to LMWH 1475 excluded for anticoagulant violations or inability to give written consent 369 assigned to usual care with heparin & warfarin 3 lost to follow=up 3 lost to follow-up 1 withdrew consent 5 withdrew consent 369 included in Analysis Hull R. Am Jour Med 2007; 120: 72 -82 369 included in Analysis

Self-Managed Long Term LMWH Therapy Tinzaparin Usual Care Absolute Difference (n=369) (n=368) (95% CI) Self-Managed Long Term LMWH Therapy Tinzaparin Usual Care Absolute Difference (n=369) (n=368) (95% CI) New VTE at 3 Mos 18 (4. 9) 21 (5. 7) -0. 8 (-4. 2 -2. 4) NS New VTE at 12 Mos 33 (8. 9) 36 (9. 8) -0. 8 (-5. 5 -3. 5) NS All Bleeding 48 (13. 0) 73 (19. 8) -6. 8 (-12. 4 --1. 5) p=. 011 Major Bleeding 12 (3. 3) 17 (4. 6) -1. 4 (-4. 3 -1. 4) NS Minor Bleeding 36 (9. 8) 56 (15. 2) -5. 5 (-10. 4 --0. 6) p=. 022 Stratified Bleeding. High Risk 31/144 (21. 5) 39/146 (26. 7) -5. 2 (-15%-4. 6%) NS Stratified Bleeding-Low Risk 17/225 (7. 6) 34/222 (15. 3) -7. 8 (-13. 6 --1. 9%) p=. 01 Thrombocytopenia (<150) 21 (5. 7) 9 (2. 4) 1. 6 (-3. 6 -0. 3) NS Bone Fracture 4 (1. 1) 7 (1. 9) -0. 8 (-0. 9 -2. 6) NS Outcomes Hull R. Am Jour Med 2007; 120: 72 -82 p-value

LMWHs and Bleeding in Patients with Renal Dysfunction Dosage adjustments for renal dysfunction Lim LMWHs and Bleeding in Patients with Renal Dysfunction Dosage adjustments for renal dysfunction Lim W et al. Ann Intern Med 2006; 144: 673 -84

Conclusions Examine your current practices of VTE prophylaxis and treatment ► Review available guidelines Conclusions Examine your current practices of VTE prophylaxis and treatment ► Review available guidelines as a benchmark ► Consider the use of a pharmacologic or mechanical intervention ► Evaluate use of Reminder or Risk Scoring Systems ► Utilize the regimen providing the best efficacy in reducing events and offering best compliance ► Follow-up with patients to monitor and avoid adverse events and to ensure optimal outcomes