Welcome to this Science-to-Strategy Summit. Critical Challenges and Landmark Advances in Thrombosis Management The Evolving and Foundation Role of LMWHs.

Welcome to this Science-to-Strategy Summit

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 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 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 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 Clotting, Cancer, and Clinical Strategies

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 Welcome and Program Overview

Program Educational Objectives As a result of this session, physicians will be able to: Specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer, using FDA-indicated and approved agentsSpecify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer, using FDA-indicated and approved agents Explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT.Explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT. Describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis.Describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis. Review landmark clinical trials focusing on DVT prophylaxis in patients with cancer.Review landmark clinical trials focusing on DVT prophylaxis in patients with cancer. Explain how to appropriately use the range of pharmacologic options available for thrombosis management in patients with malignancy.Explain how to appropriately use the range of pharmacologic options available for thrombosis management in patients with malignancy. As a result of this session, physicians will be able to: Specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer, using FDA-indicated and approved agentsSpecify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer, using FDA-indicated and approved agents Explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT.Explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT. Describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis.Describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis. Review landmark clinical trials focusing on DVT prophylaxis in patients with cancer.Review landmark clinical trials focusing on DVT prophylaxis in patients with cancer. Explain how to appropriately use the range of pharmacologic options available for thrombosis management in patients with malignancy.Explain how to appropriately use the range of pharmacologic options available for thrombosis management in patients with malignancy.

Program Faculty Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Washington, DC 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 Womens Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Washington, DC 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 Womens Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA

Faculty COI Financial Disclosures Craig M. Kessler, MD Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline, Octapharma Consultant: sanofi-aventis, Eisai, NovoNordisk Frederick Rickles, MD Consultant for Pfizer, Eisai, sanofi-aventis, and Bristol-Myers Squibb Speakers Bureau: Eisai John Fanikos, RPh, MBA Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines Company Craig M. Kessler, MD Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline, Octapharma Consultant: sanofi-aventis, Eisai, NovoNordisk Frederick Rickles, MD Consultant for Pfizer, Eisai, sanofi-aventis, and Bristol-Myers Squibb Speakers Bureau: Eisai John Fanikos, RPh, MBA Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines Company

Clots and CancerA Looming National Healthcare Crisis MISSION AND CHALLENGES Recognizing cancer patients at risk for DVT and identifying patients who are appropriate candidates for long-term prophylaxis and/or treatment with approved and indicated therapies are among the most important and difficult challenges encountered in contemporary oncology practice. MISSION AND CHALLENGES Recognizing cancer patients at risk for DVT and identifying patients who are appropriate candidates for long-term prophylaxis and/or treatment with approved and indicated therapies are among the most important and difficult challenges encountered in contemporary oncology practice.

Introduction and Chairmans 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 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 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 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

COMORBIDITYCONNECTIONCAPUTICancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder ThrombophiliaSurgery History of DVT OtherCOMORBIDITYCONNECTIONCAPUTICancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder ThrombophiliaSurgery History of DVT OtherSUBSPECIALISTSTAKEHOLDERS Infectious diseases OncologyCardiology Pulmonary medicine HematologyOncology/hematology Interventional Radiology HospitalistSurgeonsEMPCPSUBSPECIALISTSTAKEHOLDERS Infectious diseases OncologyCardiology Pulmonary medicine HematologyOncology/hematology Interventional Radiology HospitalistSurgeonsEMPCP Comorbidity Connection

Epidemiology of First-Time VTE White R. Circulation. 2003;107:I-4 –I-8.) 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 mo.) 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 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 mo.) 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

Epidemiology of VTE White R. Circulation. 2003;107:I-4 –I-8.) One major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders.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.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.Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease. 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.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.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.Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease.

Comorbidity Connection ComorbidityConnection Overview Overview

Acute Medical Illness and VTE Acute MedicalRelative Risk Illness Risk X 2 P Value Illness Risk X 2 P Value Heart failure 1.08 (0.72-1.62) 0.05.82 NYHA class III 0.89 (0.55-1.43) 0.12.72 NYHA class IV 1.48 (0.84-2.6) 1.23.27 Acuterespiratory disease 1.26 (0.85-1.87) 1.03.31 Acuteinfectious disease 1.50 (1.00-2.26) 3.54.06 Acuterheumatic disease 1.45 (0.84-2.50) 1.20.27 Acute MedicalRelative Risk Illness Risk X 2 P Value Illness Risk X 2 P Value Heart failure 1.08 (0.72-1.62) 0.05.82 NYHA class III 0.89 (0.55-1.43) 0.12.72 NYHA class IV 1.48 (0.84-2.6) 1.23.27 Acuterespiratory disease 1.26 (0.85-1.87) 1.03.31 Acuteinfectious disease 1.50 (1.00-2.26) 3.54.06 Acuterheumatic disease 1.45 (0.84-2.50) 1.20.27 Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Ineffective Antithrombotic Therapy Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Ineffective Antithrombotic Therapy Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968

Acute Medical Illness and VTE Risk FactorOdds RatioX 2 (95% CI) Age >75 y 1.03 (1.00-1.06) 0.0001 Cancer 1.62 (0.93-2.75) 0.08 Previous VTE 2.06 (1.10-3.69) 0.02 Acuteinfectious disease 1.74 (1.12-2.75) 0.02 Chronicrespiratory disease 0.60 (0.38-0.92) 0.02 Risk FactorOdds RatioX 2 (95% CI) Age >75 y 1.03 (1.00-1.06) 0.0001 Cancer 1.62 (0.93-2.75) 0.08 Previous VTE 2.06 (1.10-3.69) 0.02 Acuteinfectious disease 1.74 (1.12-2.75) 0.02 Chronicrespiratory disease 0.60 (0.38-0.92) 0.02 Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968

Comorbid Condition and DVT Risk Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%.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.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 occurrenceTogether, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%.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.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 occurrenceTogether, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

VTE Recurrence BaselineHazard Ratio Characteristic (95% CI) Age1.17 (1.11-1.24) Body Mass Index1.24 (1.04-1.47) Neurologic disease with1.87 (1.28-2.73) extremity paresis Malignant neoplasm None 1.00 None 1.00 With chemotherapy4.24 (2.58-6.95) With chemotherapy4.24 (2.58-6.95) Without chemotherapy2.21 (1.60-3.06) Without chemotherapy2.21 (1.60-3.06) BaselineHazard Ratio Characteristic (95% CI) Age1.17 (1.11-1.24) Body Mass Index1.24 (1.04-1.47) Neurologic disease with1.87 (1.28-2.73) extremity paresis Malignant neoplasm None 1.00 None 1.00 With chemotherapy4.24 (2.58-6.95) With chemotherapy4.24 (2.58-6.95) Without chemotherapy2.21 (1.60-3.06) Without chemotherapy2.21 (1.60-3.06) Predictors of First Overall VTE Recurrence Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768

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 Frederick R. Rickles, MD Professor of Medicine, Pediatrics, Pharmacology and Physiology The George Washington University Washington, DC Clotting, Cancer, and Clinical Strategies

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…. 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 I have always been struck with the frequency with which cancerous patients are affected with painful oedema of the superior or inferior extremities…. I have always been struck with the frequency with which cancerous patients are affected with painful oedema of the superior or inferior extremities…. New Syndenham Society – 1865

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

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

Trousseaus Syndrome Occult cancer in patients with idiopathic venous thromboembolism Occult cancer in patients with idiopathic venous thromboembolism Thrombophlebitis in patients with cancer Thrombophlebitis in patients with cancer Occult cancer in patients with idiopathic venous thromboembolism Occult cancer in patients with idiopathic venous thromboembolism Thrombophlebitis in patients with cancer Thrombophlebitis in patients with cancer

Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715 Population-based case-control (MEGA) study N=3220 consecutive patients with 1 st VTE vs. n=2131 control subjects CA patients = OR 7x VTE risk vs. non- CA patients Population-based case-control (MEGA) study N=3220 consecutive patients with 1 st VTE vs. n=2131 control subjects CA patients = OR 7x VTE risk vs. non- CA patients Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 0 10 20 30 40 50 Hematological Lung Gastrointestinal Breast Distant metastases 0 to 3 months 3 to 12 months 1 to 3 years 5 to 10 years > 15 years Adjusted odds ratio Type of cancer Time since cancer diagnosis 28 22.2 20.3 4.9 19.8 53.5 14.3 2.6 1.1 3.6

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) 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; White et.al. Thromb Haemost 2003;90:446-455; Sorensen et.al. New Engl J Med 2000;343:1846-1850); Levitan et.al. Medicine 1999;78:285-291; Khorana et.al. Heit et.al. Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et.al. Blood 2002;100:3484-3488; White et.al. Thromb Haemost 2003;90:446-455; Sorensen et.al. New Engl J Med 2000;343:1846-1850); Levitan et.al. Medicine 1999;78:285-291; Khorana et.al. J Thromb Haemost 2007;5:632-4

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

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

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

Pathogenesis of Thrombosis in Cancer – A Modification of Virchows Triad 1.Stasis Prolonged bed rest Prolonged bed rest Extrinsic compression of blood vessels by tumor Extrinsic compression of blood vessels by tumor 2.Vascular Injury Direct invasion by tumor Direct invasion by tumor Prolonged use of central venous catheters Prolonged use of central venous catheters Endothelial damage by chemotherapy drugs Endothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endothelium Effect of tumor cytokines on vascular endothelium 3.Hypercoagulability Tumor-associated procoagulants and cytokines (tissue factor, CP, TNF, IL-1, VEGF, etc.) 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) 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 Enhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets and host macrophages 1.Stasis Prolonged bed rest Prolonged bed rest Extrinsic compression of blood vessels by tumor Extrinsic compression of blood vessels by tumor 2.Vascular Injury Direct invasion by tumor Direct invasion by tumor Prolonged use of central venous catheters Prolonged use of central venous catheters Endothelial damage by chemotherapy drugs Endothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endothelium Effect of tumor cytokines on vascular endothelium 3.Hypercoagulability Tumor-associated procoagulants and cytokines (tissue factor, CP, TNF, IL-1, VEGF, etc.) 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) 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 Enhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets and host macrophages

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

Activation of Blood Coagulation in Cancer Biological Significance? Epiphenomenon? Epiphenomenon? Is this a generic secondary event where thrombosis is an incidental finding Is this a generic secondary event where thrombosis is an incidental finding or, is clotting activation... or, is clotting activation... A Primary Event? A Primary Event? Linked to malignant transformation Linked to malignant transformation Epiphenomenon? Epiphenomenon? Is this a generic secondary event where thrombosis is an incidental finding Is this a generic secondary event where thrombosis is an incidental finding or, is clotting activation... or, is clotting activation... A Primary Event? A Primary Event? Linked to malignant transformation Linked to malignant transformation

TF VEGF Angiogenesis Endothelial cells IL-8 Blood Coagulation Activation FIBRIN PAR-2 Angiogenesis FVII/FVIIa THROMBIN Tumor Cell TF Falanga and Rickles, New Oncology:Thrombosis, 2005 Interface of Clotting Activation and Tumor Biology

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

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 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

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 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 Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor

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 : Retrospective IH and microarray study of TF, VEGF and MVD in : Normal pancreas (10) Normal pancreas (10) Intraductal papillary mucinous neoplasms (IPMN; 70) Intraductal papillary mucinous neoplasms (IPMN; 70) Pancreatic intrepithelial neoplasia (PanIN; 40) Pancreatic intrepithelial neoplasia (PanIN; 40) Resected or metastatic pancreatic adenoca(130) Resected or metastatic pancreatic adenoca(130) Survival Survival VTE Rate VTE Rate Retrospective IH and microarray study of TF, VEGF and MVD in : Retrospective IH and microarray study of TF, VEGF and MVD in : Normal pancreas (10) Normal pancreas (10) Intraductal papillary mucinous neoplasms (IPMN; 70) Intraductal papillary mucinous neoplasms (IPMN; 70) Pancreatic intrepithelial neoplasia (PanIN; 40) Pancreatic intrepithelial neoplasia (PanIN; 40) Resected or metastatic pancreatic adenoca(130) Resected or metastatic pancreatic adenoca(130) Survival Survival VTE Rate VTE Rate Tissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic Cancer

Correlation of Tissue Factor Expression with the Expression of Other Angiogenesis Cariables in Resected Pancreatic Cancer High TF Low TF P High TF Low TF P expression expression VEGF expression Negative 13 41 <0.0001 Negative 13 41 <0.0001 Positive 53 15 Positive 53 15 Microvessel density V6 per tissue core 27 33 0.047 V6 per tissue core 27 33 0.047 >6 per tissue core 39 23 >6 per tissue core 39 23 Median 8 6 0.01 Median 8 6 0.01 High TF Low TF P High TF Low TF P expression expression VEGF expression Negative 13 41 <0.0001 Negative 13 41 <0.0001 Positive 53 15 Positive 53 15 Microvessel density V6 per tissue core 27 33 0.047 V6 per tissue core 27 33 0.047 >6 per tissue core 39 23 >6 per tissue core 39 23 Median 8 6 0.01 Median 8 6 0.01 Khorana et.al. Clin CA Res 2007:13:2870

Symptomatic VTE in Pancreatic Cancer 1/22; 4.5% 5/19; 26.3% Khorana et.al. Clin CA Res 2007;13:2872 Khorana et.al. Clin CA Res 2007:13:2870

Activation of Blood Coagulation in Cancer: Malignant Transformation Epiphenomenon? Epiphenomenon? Linked to malignant transformation? Linked to malignant transformation? 1. MET oncogene induction produces DIC in human liver carcinoma (Boccaccio et. al. Nature 2005;434:396-400) (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) (Rong et.al. Ca Res 2005;65:1406-1413) 3. K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma (Yu et.al. Blood 2005;105:1734-1741) (Yu et.al. Blood 2005;105:1734-1741) Epiphenomenon? Epiphenomenon? Linked to malignant transformation? Linked to malignant transformation? 1. MET oncogene induction produces DIC in human liver carcinoma (Boccaccio et. al. Nature 2005;434:396-400) (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) (Rong et.al. Ca Res 2005;65:1406-1413) 3. K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma (Yu et.al. Blood 2005;105:1734-1741) (Yu et.al. Blood 2005;105:1734-1741)

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

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

Blood Coagulation Parameters in Mice Transduced with the MET Oncogene Transgene Parameter Time after Transduction (days) 0 30 90 GFP _________ MET Platelets (x10 3 ) D-dimer (µg/ml) PT (s) ________________ Platelets (x10 3 ) D-dimer (µg/ml) PT (s) 968 656 800 <0.05 <0.05 <0.05 12.4 11.6 11.4 _______________________________ 974 350 150 <0.05 0.11 0.22 12.9 11.8 25.1

Mouse model of Trousseaus Syndrome Mouse model of Trousseaus Syndrome Genome-wide expression profiling of hepatocytes expressing MET upregulation of PAI-1 and COX-2 genes with 2-3x circulating protein levels 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 Using either XR5118 (PAI-1 inhibitor) or Rofecoxib (Vioxx; COX-2 inhibitor) resulted in inhibition of clinical and laboratory evidence for DIC in mice Mouse model of Trousseaus Syndrome Mouse model of Trousseaus Syndrome Genome-wide expression profiling of hepatocytes expressing MET upregulation of PAI-1 and COX-2 genes with 2-3x circulating protein levels 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 Using either XR5118 (PAI-1 inhibitor) or Rofecoxib (Vioxx; COX-2 inhibitor) resulted in inhibition of clinical and laboratory evidence for DIC in mice MET Oncogene Drives a Genetic Programme Linking Cancer to HaemostasisMET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis

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 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 Loss or inactivation of Pten (70-80% of glioblastomas) leads to Akt activation and upregulation of Ras/MEK/ERK signaling cascade 2. Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma Pten = tumor suppressor with lipid and protein phosphatase activity 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 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

Glioblastomas characterized histologically by pseudopalisading necrosis Glioblastomas characterized histologically by pseudopalisading necrosis Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by thrombosis 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 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) TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2) Glioblastomas characterized histologically by pseudopalisading necrosis Glioblastomas characterized histologically by pseudopalisading necrosis Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by thrombosis 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 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) 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 GlioblastomaPten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma

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

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

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

Activation of Blood Coagulation in Cancer: Malignant Transformation 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 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 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 Transforming events dependent on MEK/MAPK and PI3K Cell-associated and MP-associated TF activity linked to genetic status of cancer cells 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 siRNA reduced cell surface TF expression, tumor growth and angiogenesis TF may be required for K-ras-driven phenotype TF may be required for K-ras-driven phenotype 3. Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis 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 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 Transforming events dependent on MEK/MAPK and PI3K Cell-associated and MP-associated TF activity linked to genetic status of cancer cells 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 siRNA reduced cell surface TF expression, tumor growth and angiogenesis TF may be required for K-ras-driven phenotype TF may be required for K-ras-driven phenotype Yu, Mackman, Rak et.al. Blood 2005;105:1734-41

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 Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis TF expression in cancer cells parallels genetic tumor progression with an impact of K-ras and p53 status Activation of Blood Coagulation in Cancer: Malignant Transformation Activation of Blood Coagulation in Cancer: Malignant Transformation Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 Mean Channel TF Flourescence TF Activity (U/10 6 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 Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis Effect of TF si mRNA on tumor growth in vitro and in vivo Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 Activation of Blood Coagulation in Cancer: Malignant Transformation Activation of Blood Coagulation in Cancer: Malignant Transformation

Effect of TF si mRNA on new vessel formation in colon cancer Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 %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 Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology Activation of Blood Coagulation in Cancer: Malignant Transformation Activation of Blood Coagulation in Cancer: Malignant Transformation Yu, Mackman, Rak et.al. Blood 2005;105:1734-41

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

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 Key Questions Key Questions

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 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 Cancer and Thrombosis: Year 2008 State- of-the-Science Update Tentative Answers

Coagulation Cascade and Tumor Biology TFThrombin Clotting- dependent Clotting- independent Clotting- dependent Fibrin Clotting- independent PARs Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584 VIIa VIIa Xa Xa Angiogenesis, Tumor Growth and Metastasis ? LMWH (e.g. FRAGMIN)

A Systematic Overview of VTE Prophylaxis In The Setting of Cancer Linking Science to Clinical Practice A Systematic Overview of VTE Prophylaxis In The Setting of Cancer Linking Science to Clinical Practice 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 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 Clotting, Cancer, and Clinical Strategies

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

1.Ambrus JL et al. J Med. 1975;6:61-64 2.Donati MB. Haemostasis. 1994;24:128-131 3.Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 4.Prandoni P et al. Ann Intern Med. 1996;125:1-7 DVT and PE in Cancer Facts, Findings, and Natural History VTE is the second leading cause of death in hospitalized cancer patients 1,2 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 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 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 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4

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

Risk Factors for Cancer-Associated VTE Cancer Cancer Type Type Men: prostate, colon, brain, lung Men: prostate, colon, brain, lung Women: breast, ovary, lung Women: breast, ovary, lung Stage Stage Treatments Treatments Surgery Surgery 10-20% proximal DVT 10-20% proximal DVT 4-10% clinically evident PE 4-10% clinically evident PE 0.2-5% fatal PE 0.2-5% fatal PE Systemic Systemic Central venous catheters (~4% generate clinically relevant VTE) Central venous catheters (~4% generate clinically relevant VTE)

Thrombosis and Survival: Likelihood of Death After Hospitalization 0 20 40 60 80 100 120140 160 180 0.00 0.20 0.40 1.00 0.80 0.60 DVT/PE and Malignant Disease Malignant Disease DVT/PE Only Nonmalignant Disease Number of Days Probability of Death Levitan N, et al. Medicine 1999;78:285

As Number Of Cancer Survivors Increases, VTE Rates Increase YEAR VTE in Hospitalized Cancer And Noncancer Patients (%) Stein PD, et al. Am J Med 2006; 119: 60-68 Cancer Patients Noncancer Patients

VTE Risk And Cancer Type: Solid And Liquid Stein PD, et al. Am J Med 2006; 119: 60-68 Relative Risk of VTE in Cancer Patients PancreasBrainMyeloprolStomachLymphomaUterusLungEsophagusProstateRectalKidneyColonOvaryLiverLeukemiaBreastCervixBladder 4.543.532.521.510.5 Relative Risk of VTE Ranged From 1.02 to 4.34

Thrombosis Risk In Cancer Primary Prophylaxis Surgery Surgery Chemotherapy Chemotherapy Radiotherapy Radiotherapy Central Venous Catheters Central Venous Catheters Acute Illness (immobilization) Acute Illness (immobilization) Primary Prophylaxis Surgery Surgery Chemotherapy Chemotherapy Radiotherapy Radiotherapy Central Venous Catheters Central Venous Catheters Acute Illness (immobilization) Acute Illness (immobilization)

Prevention and Management of VTE in Cancer Sparse data specifically related to cancer patients was available until recently Sparse data specifically related to cancer patients was available until recently Cancer patients are a small subset (< 20%) in most of the largest trials of antithrombotic therapy Cancer patients are a small subset (< 20%) in most of the largest trials of antithrombotic therapy Therefore, until the last two or three years, we needed to extrapolate from non-cancer patients, bearing in mind that cancer patients are in the highest risk groups Therefore, until the last two or three years, we needed to extrapolate from non-cancer patients, bearing in mind that cancer patients are in the highest risk groups

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

Cancer patients have 2-fold risk of postoperative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Cancer patients have 2-fold risk of postoperative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732 Incidence of VTE in Surgical Patients Outcome No Cancer N=16,954CancerN=6124P-value Post-op VTE 0.61%1.26%<0.0001 Non-fatal PE 0.27%0.54%<0.0003 Autopsy PE 0.11%0.41%<0.0001 Death0.71%3.14%<0.0001

Natural History of VTE in Cancer Surgery: The @RISTOS Registry Web-Based Registry of Cancer Surgery Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Tracked 30-day incidence of VTE in 2373 patients Type of surgery Type of surgery 52% General 52% General 29% Urological 29% Urological 19% Gynecologic 19% Gynecologic 82% received in-hospital thromboprophylaxis 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings Findings 2.1% incidence of clinically overt VTE (0.8% fatal) 2.1% incidence of clinically overt VTE (0.8% fatal) Most events occur after hospital discharge Most events occur after hospital discharge Most common cause of 30-day post-op death Most common cause of 30-day post-op death Agnelli, abstract OC191, ISTH 2003

Nilsson: Arch Surg, 142;2007:126–132 Colorectal Cancer Resection Association Between Transfusion and Venous Thromboembolism Stratified by Sex in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 1994-2000 VariableIncidence of VTE, %P ValueStratified ORAdjusted (95% CI)*P Value Male Sex No Transfusion (n = 5683)0.7Referent No Transfusion (n = 5683)0.7Referent Transfusion (n = 1156)0.8.840.9 (0.5-1.9).85 Transfusion (n = 1156)0.8.840.9 (0.5-1.9).85 Female Sex No Transfusion (n = 5565)0.9Referent No Transfusion (n = 5565)0.9Referent Transfusion (n = 1610)2.1<.0011.8 (1.2-2.6).004 Transfusion (n = 1610)2.1<.0011.8 (1.2-2.6).004 Association Between Transfusion and Venous Thromboembolism Stratified by Sex in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 1994-2000 VariableIncidence of VTE, %P ValueStratified ORAdjusted (95% CI)*P Value Male Sex No Transfusion (n = 5683)0.7Referent No Transfusion (n = 5683)0.7Referent Transfusion (n = 1156)0.8.840.9 (0.5-1.9).85 Transfusion (n = 1156)0.8.840.9 (0.5-1.9).85 Female Sex No Transfusion (n = 5565)0.9Referent No Transfusion (n = 5565)0.9Referent Transfusion (n = 1610)2.1<.0011.8 (1.2-2.6).004 Transfusion (n = 1610)2.1<.0011.8 (1.2-2.6).004 Overall, 1% incidence of VTE with 3.8 fold mortality Transfused women 1.8-fold more likely to develop VTE than non-transfused women

Age >40 years Age >40 years Cancer procoagulants Cancer procoagulants Thrombophilias Thrombophilias Adjuvant chemotherapy or hormonal treatment Adjuvant chemotherapy or hormonal treatment Complicated, lengthy surgery (tissue trauma, immobilization) Complicated, lengthy surgery (tissue trauma, immobilization) Debilitation and slower recovery Debilitation and slower recovery Indwelling venous access Indwelling venous access VTE Risk Factors in Surgical Oncology Patients

Clinical thromboembolism CancerCancer 0 1.0 2.0 3.0 4.0 0 1.0 2.0 3.0 4.0 Major hemorrhage Major hemorrhage Asymptomatic DVT Clinical PE DeathDeath Total hemorrhage Wound hematoma TransfusionTransfusion Non-cancerNon-cancer Mismetti P et al. Br J Surg 2001;88:913–30 Surgical Prophylaxis LMWH better UFH better

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

Prophylaxis in Surgical Patients VTE Major Bleeding Incidence of Outcome Event ENOXACAN 14.7% 2.9% 4.1% 18.2% N=319 N=312 ENOXACAN Study Group. Br J Surg 1997;84:1099–103 P>0.05

Canadian Colorectal DVT Prophylaxis Trial 13.9% 1.5% 2.7% 16.9% N=234 N=241 McLeod R, et al. Ann Surg 2001;233:438-444 P=0.052 Incidence of Outcome Event VTEMajor Bleeding VTEMajor Bleeding (Cancer) (All) Prophylaxis in Surgical Patients

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

VTE Prox Any Major VTE Prox Any Major DVT Bleeding Bleeding DVT Bleeding Bleeding P=0.02 5.1% 1.8% Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980 ENOXACAN II Incidence of Outcome Event Incidence of Outcome Event N=167 N=165 0% 0.4% 12.0% 4.8% NNT = 14 0.6% 3.6% Extended Prophylaxis in Surgical Patients

A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment 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). 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. CONCLUSIONS: 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis. Major Abdominal Surgery: FAME Investigators Dalteparin Extended Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.

Paucity of level I/II studies in this population Paucity of level I/II studies in this population Based on small historical studies: Based on small historical studies: Postoperative risk of DVT/PE varies 12%–35% Postoperative risk of DVT/PE varies 12%–35% LDUH (5000 u bid) ineffective LDUH (5000 u bid) ineffective LDUH 5000 u tid reduces risk by 50%–60% LDUH 5000 u tid reduces risk by 50%–60% Once-daily LMWH comparable to LDUH for efficacy and safety Once-daily LMWH comparable to LDUH for efficacy and safety Gynecological Cancer Surgery

Cochrane Systematic Review Meta-analysis of 8 randomized controlled trials Meta-analysis of 8 randomized controlled trials Heparin reduces risk of DVT by 70% (95% CI 0.10–0.89) Heparin reduces risk of DVT by 70% (95% CI 0.10–0.89) No evidence that anticoagulation reduces risk of PE No evidence that anticoagulation reduces risk of PE No statistical difference between LDUH and LMWH in efficacy and bleeding No statistical difference between LDUH and LMWH in efficacy and bleeding Gynecological Surgery Oates-Whitehead et al. Cochrane Database Syst Rev 2003;4:CD003679

Urological Cancer Surgery Poorly studied population Risk of VTE varies with type of surgery and diagnosis Risk of VTE varies with type of surgery and diagnosis Small studies have suggested prophylaxis with either LDUH or LMWH is effective and safe Small studies have suggested prophylaxis with either LDUH or LMWH is effective and safe Possible increased risk of pelvic hematoma and lymphocele formation Possible increased risk of pelvic hematoma and lymphocele formation Kibel, Loughlin. J Urol. 1995;153:1763-1774 DVTPE Fatal PE Radical retropubic prostatectomy 1–3% 0.6% Cystectomy 8% 2–4% 2% Radiological studies 51%22%

Majority of patients undergoing neurosurgery for malignancy Majority of patients undergoing neurosurgery for malignancy Risk of venographic VTE ~30%-40% Risk of venographic VTE ~30%-40% High risk of intracranial or intraspinal hemorrhage High risk of intracranial or intraspinal hemorrhage Mechanical prophylaxis preferred method Mechanical prophylaxis preferred method Use of anticoagulant prophylaxis remains controversial in this setting Use of anticoagulant prophylaxis remains controversial in this setting Neurosurgery and VTE OBSERVATIONS OBSERVATIONS

Meta-analysis of three (3) RCTs evaluating LMWH prophylaxis Meta-analysis of three (3) RCTs evaluating LMWH prophylaxis One major bleeding event observed for every 7 proximal DVTs prevented with LMWH One major bleeding event observed for every 7 proximal DVTs prevented with LMWH ESLMWHRRNNT/NNHP VTE28.3%17.5%0.6 9 0.001 0.001 Proximal DVT 12.5% 6.2% 6.2%0.5 16 16<0.01 Total bleeding 3.0% 3.0% 6.1% 6.1%2.0 33 33 0.02 0.02 Major bleeding 1.3% 1.3% 2.2% 2.2%1.7115 0.30 0.30 Iorio A, Agnelli G. Arch Intern Med. 2000;160:2327-2332 Neurosurgery and VTE Prophylaxis

7 th ACCP Consensus Guidelines Grade Recommendations for Cancer Patients 1A Patients undergoing surgery should receive LDUH 5000 U tid or LMWH > 3400 U daily 2A Patients undergoing surgery may receive post-hospital discharge prophylaxis with LMWH 2A No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed- dose warfarin (1B) 1A Patients hospitalized with an acute medical illness should receive LDUH or LMWH Geerts W, et al. Chest 2004; 126: 338S-400S

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 Incidence up to 60% from historical data ACCP guidelines recommended routine prophylaxis ACCP guidelines recommended routine prophylaxis with low dose warfarin or LMWH with low dose warfarin or LMWH Central Venous Catheters Geerts W, et al. Chest 2001;119:132S-175S

Placebo-Controlled Trials StudyRegimenN CRT (%) CRT (%) Reichardt* 2002 Dalteparin 5000 U od placebo285140 11 (3.7) 11 (3.7) 5 (3.4) 5 (3.4) Couban*2002 Warfarin 1mg od placebo130125 6 (4.6) 6 (4.6) 5 (4.0) 5 (4.0) ETHICS ETHICS 2004 Enoxaparin 40 mg od placebo155155 22 (14.2) 28 (18.1) * symptomatic outcomes ; routine venography at 6 weeks Prophylaxis for Venous Catheters Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730

Tolerability of Low-Dose Warfarin Tolerability of Low-Dose Warfarin 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily INR measured at baseline and four time points INR measured at baseline and four time points 10% of all recorded INRs >1.5 10% of all recorded INRs >1.5 Patients with elevated INR Patients with elevated INR 2.0–2.9 6% 3.0–4.919% >5.0 7% Central Venous Catheters: Warfarin Masci et al. J Clin Oncol. 2003;21:736-739

Summary Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) 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 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 Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis Prophylaxis for Central Venous Access Devices

7 th ACCP Consensus Guidelines Grade Recommendations for Cancer Patients Recommendations for Cancer Patients 1A Patients undergoing surgery should receive LDUH 5000 U tid or LMWH > 3400 U daily 2A Patients undergoing surgery may receive post-hospital discharge prophylaxis with LMWH 2A No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) 1A Patients hospitalized with an acute medical illness should receive LDUH or LMWH Geerts W, et al. Chest 2004; 126: 338S-400S

Primary Prophylaxis in Cancer Radiotherapy in the Ambulatory Patient No recommendations from ACCP No recommendations from ACCP No data from randomized trials (RCTs) 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) 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.) 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 Tumor type Ovary, brain, pancreas, lung, colon Ovary, brain, pancreas, lung, colon Stage, grade, and extent of cancer Stage, grade, and extent of cancer Metastatic disease, venous stasis due to bulky disease Metastatic disease, venous stasis due to bulky disease Type of antineoplastic treatment Type of antineoplastic treatment Multiagent regimens, hormones, anti-VEGF, radiation Multiagent regimens, hormones, anti-VEGF, radiation Miscellaneous VTE risk factors Miscellaneous VTE risk factors Previous VTE, hospitalization, immobility, infection, thrombophilia Previous VTE, hospitalization, immobility, infection, thrombophilia

Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery w/ institutionalization 21.72 Trauma12.69 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 47%47% Solid tumors (anti-VEGF + chemo) 43%43% Renal cell carcinoma 28%28% Multiple myeloma (thalidomide + chemo) 9% 9% Advanced cancer (1-year survival=12%) 6% 6% Hodgkins disease w/ chemo 3% 3% Non-Hodgkins lymphomas w/ chemo 8% 8% Breast cancer (Stage IV) w/ chemo 26%26% High-grade glioma 2% 2% Breast cancer (Stage I & II) w/ chemo 0.2% 0.2% Breast cancer (Stage I & II) w/o further treatment VTEIncidenceVTEIncidence Oncology Setting Wilms tumor (cavoatrial extension) 4% Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

16% Zangari, 2002 (192 pts) (192 pts) T+dox at relapse 17.8% Baz, 2004 (103 pts) 14.7% Zangari, 2004 (68pts) 7% Minnema, 2004 (412 pts) 31.4% Zangari, 2004 (35 pts) 34.5% Zangari, 2004 (87 pts) (87 pts) T+ dox in newly diagnosed patients 7% Weber, 2002 (46 pts) 25% Weber, 2002 (24 pts) 13% Cavo, 2004 (52 pts) 26% Cavo, 2002 (19 pts) (19 pts) 18% Rajkumar, 2004 (102 pts) T+ D in newly diagnosed patients Aspirin (81 mg/d) LMWH Warfarin (INR 2 – 3) Warfarin 1mg/daily No prophylaxis Therapy Strategies for Thromboprophylaxis in Thalidomide Treated MM Patients

DVT Len + D(%) D (%) Len + D(%) D (%) MM-009 MM-010 0 2 4 6 8 10 12 14 16 PE Weber D. ASCO 2005 Annual Meeting MM-009/010: Thromboembolic Events

Knight: N Engl J Med.2006,354:2079 rEPO used more in USA and Canada L+Dex: 23% VTE with EPO vs 5% w/o EPO Placebo + Dex: 7% VTE with EPO vs 1% without EPO Incidence of VTE: USA and Canada >Israel, Australia, and Europe Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma TreatmentOdds RatioP Value (95% CI) Lenalidomide plus3.51 (1.77-6.97)<0.001 High-dose dexamethasone Concomitant erythropoietin 3.21 (1.72-6.01)<0.001 Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma TreatmentOdds RatioP Value (95% CI) Lenalidomide plus3.51 (1.77-6.97)<0.001 High-dose dexamethasone Concomitant erythropoietin 3.21 (1.72-6.01)<0.001

Thrombotic Outcomes from rEPO or Darbopoietin Use in Cancer Patients Bohlius: The Cochrane Library, Volume (4).2006 Among 6,769 pts with cancer, RR for DVT with rEPO/Darbepo was increased by 67% (RR=1.67; 95% CI 1.35 to 2.06)

Vitamin K antagonist (INR 2.0 - 3.0) > 3 months LMWH or UFH 5 to 7 days Initial treatment Long-term therapy Standard Treatment of VTE Can We Do Better Than This?

Recurrent VTE in Cancer – Subset Analysis of the Home Rx Studies (UH/VKA vs. LMWH/VKA) Recurrent VTE Events per 100 patient years P value Malignant Non- Malignant 27.19.00.003 Hutten et.al. J Clin Oncol 2000;18:3078

Recurrent VTE in Cancer – Subset Analysis of the Home Rx Studies Major Bleeding Events per 100 patient years P-value Malignant Non- malignant 13.32.10.002 Hutten et.al. J Clin Oncol 2000;18:3078

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

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

Landmark CLOT Cancer Trial Reduction in Recurrent VTE 0 0 55 10 10 15 15 20 20 25 25 Days Post Randomization 00303060609090120120150150180180210210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = 0.0017 Risk reduction = 52% p-value = 0.0017 DalteparinDalteparin OACOAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Dalteparin N=338 N=338OACN=335 P- value* P- value* Major bleed 19 ( 5.6%) 19 ( 5.6%) 12 ( 3.6%) 12 ( 3.6%)0.27 Any bleed 46 (13.6%) 46 (13.6%) 62 (18.5%) 62 (18.5%)0.093 * Fishers exact test Bleeding Events in CLOT Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Treatment of Cancer-Associated VTE StudyDesign Length of Therapy (Months)N Recurrent VTE (%) Major Bleeding (%)Death(%) CLOT Trial (Lee 2003) DalteparinOAC6336336917643941 CANTHENOX (Meyer 2002) EnoxaparinOAC3677111217161123 LITE (Hull ISTH 2003) TinzaparinOAC38087611682322 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC63236343.43.16.7 NS 0.03 NS 0.002 NS NR 0.09 0.03 0.09

Treatment and 2° Prevention of VTE in Cancer – Bottom Line New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendationACCP) New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendationACCP) Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendationACCP) Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendationACCP) Buller et.al. Chest Suppl 2004;126:401S-428S New Development New Development

CLOT 12-month Mortality All Patients Lee A, et al. ASCO. 2003

0 10 20 30 40 50 60 70 80 90 100 Days Post Randomization 0306090120150180240300360 Probability of Survival, % OAC Dalteparin HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWH CLOT 12-month Mortality CLOT 12-month Mortality Lee A, et al. ASCO. 2003 Patients Without Metastases (N=150)

84 patients randomized: CEV +/- LMWH (18 weeks) 84 patients randomized: CEV +/- LMWH (18 weeks) Patients balanced for age, gender, stage, smoking history, ECOG performance status Patients balanced for age, gender, stage, smoking history, ECOG performance status LMWH for Small Cell Lung Cancer Turkish Study Altinbas et al. J Thromb Haemost 2004;2:1266. Chemo + Dalteparin Chemo alone P-value 1-y overall survival, % 51.329.50.01 2-y overall survival, % 17.2 0.0 0.00.01 Median survival, m 13.0 8.0 8.00.01 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily

VTE Prophylaxis Is Underused in Patients With Cancer 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 Cancer: FRONTLINE Survey 1 3891 Clinician Respondents Rate of Appropriate Prophylaxis, % Major Surgery 2 Major Abdominothoracic Surgery (Elderly) 3 Medical Inpatients 4 Confirmed DVT (Inpatients) 5 Cancer: Surgical Cancer: Medical 4.Rahim SA et al. Thromb Res. 2003;111:215-219 5.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262

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

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

Field Trip 2007 Plymouth Plantation

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

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

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

http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice Guidelines in VTE Disease Inpatient Prophylactic Anticoagulation Therapy LMWH 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 Pentasaccharide - Fondaparinux 2.5 mg subcutaneous daily Unfractionated heparin 5,000 units subcutaneous 3 times daily Unfractionated heparin 5,000 units subcutaneous 3 times daily Inpatient Prophylactic Anticoagulation Therapy LMWH 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 Pentasaccharide - Fondaparinux 2.5 mg subcutaneous daily Unfractionated heparin 5,000 units subcutaneous 3 times daily Unfractionated heparin 5,000 units subcutaneous 3 times daily

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

Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ? 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 Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ? 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 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. Routine prophylaxis is not recommended. Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. 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. Routine prophylaxis is not recommended. Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. 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. All patients should be considered for thromboprophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Mechanical methods should not be used as monotherapy. 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. Prophylaxis should continue for at least 7-10 days post-op. Prolonged prophylaxis may be considered for cancer with high risk features. 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. All patients should be considered for thromboprophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Mechanical methods should not be used as monotherapy. 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. 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 9.9% 6.7% 35,124 62,012 0 5,000 10,000 70,000 Number of patients At risk for DVT/PE Received compliant care 15.3% 12.7% 52.4% 2324 9175 1388 Orthopedic Surgery At-risk Medical Conditions General Surgery Urologic Surgery Gynecologic Surgery Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based on the 6th American College of Chest Physicians (ACCP) guidelines. HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group

HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 Started Late Started late & Ended Early Ended Early At-Risk Medical (n=5,994) 1,347 (22.5) 2,961 (49.4) 1,686 (28.1) Abdominal Surgery (n=3,240) 824 (25.4) 1,764 (54.4) 652 (20.1) Urologic surgery (n=158) 18 (11.4) 73 (46.2) 67 (42.4) Gynecologic surgery (n=163) 13 (8.0) 43 (26.4) 107 (65.6) Neurosurgery (n=250) 66 (26.4) 125 (50.0) 59 (23.6) Reasons for Inadequate Duration of VTE Prophylaxis

Odds Ratio Malignancy0.40 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 Malignancy0.40 Others 0.58 Infection 0.83 Bleeding Risk 0.91 Gender 0.92 Hospital Size 0.93 Age 1.00 LOS 1.05 Cardiovascular Disease 1.06 Internal Medicine 1.33 Respiratory 1.35 AMC 1.46 Duration of Immobility 1.60 VTE Risk Factors 1.78 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Effect Odds Ratio (95% CI) Predictors of the Use of Thromboprophylaxis Kahn SR et Al. Thromb Res 2007; 119:145-155

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

MD Computer Alert

Electronic Alerts to Prevent VTE Freedom from DVT or PE (%) Number at risk Intervention group1,255977900853 Control group1,251876893839 Control group Intervention group P<0.001 Time (days) Kucher N, et al. N Engl J Med. 2005;352:969-77

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

Dentali, F. et. al. Ann Intern Med 2007;146:278-288 Fatal Pulmonary Embolism During Anticoagulant Prophylaxis 0.001 0.01 0.1 1.0 10 100 1000 Favors Treatment Favors Placebo Study, Year (Reference) Study, Year (Reference) Prophylaxis n/n Prophylaxis n/n Placebo n/n Placebo n/n RR Fixed (95% CI) RR Fixed (95% CI) RR Fixed (95% CI) RR Fixed (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 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

Unfractionated Heparin Prophylaxis: BID vs TIDWhat Works, What Doesnt? Meta-analysis: 12 RCTs Meta-analysis: 12 RCTs DVT, PE, all VTE events, Bleeding DVT, PE, all VTE events, Bleeding Proximal DVT plus PE Proximal DVT plus PE BID VTE event rate: BID VTE event rate: 2.34 events per 1,000 patient days TID event rate: TID event rate: 0.86 events per 1,000 patient days P=0.05 P=0.05 NNT NNT 676 hospital prophylaxis days with UFH TID to prevent 676 hospital prophylaxis days with UFH TID to prevent 1 major bleed with 1,649 hospital prophylaxis days of TID dosing 1 major bleed with 1,649 hospital prophylaxis days of TID dosing Meta-analysis: 12 RCTs Meta-analysis: 12 RCTs DVT, PE, all VTE events, Bleeding DVT, PE, all VTE events, Bleeding Proximal DVT plus PE Proximal DVT plus PE BID VTE event rate: BID VTE event rate: 2.34 events per 1,000 patient days TID event rate: TID event rate: 0.86 events per 1,000 patient days P=0.05 P=0.05 NNT NNT 676 hospital prophylaxis days with UFH TID to prevent 676 hospital prophylaxis days with UFH TID to prevent 1 major bleed with 1,649 hospital prophylaxis days of TID dosing 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 Wein L et al. Arch Intern Med. 2007;167:1476-86. 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 et al, 1996 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) LMWH Better LMWH Worse 0.1 1.0 10 Risk Ratio Meta-analysis Meta-analysis 36 randomized controlled trials 36 randomized controlled trials 23,000 hospitalized medical patients 23,000 hospitalized medical patients UFH 5,000 units TID is more effective in preventing DVT than UFH BID 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 Low molecular weight heparin is 33% more effective than unfractionated heparin in preventing DVT RR for DVT 0.68 (p=0.004) RR for DVT 0.68 (p=0.004) Meta-analysis Meta-analysis 36 randomized controlled trials 36 randomized controlled trials 23,000 hospitalized medical patients 23,000 hospitalized medical patients UFH 5,000 units TID is more effective in preventing DVT than UFH BID 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 Low molecular weight heparin is 33% more effective than unfractionated heparin in preventing DVT RR for DVT 0.68 (p=0.004) RR for DVT 0.68 (p=0.004)

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

VTE Incidence: More Common in the Outpatient Setting Medical records of residents (n=477,800) Medical records of residents (n=477,800) 587 VTE events (104 per 100,000 population) 587 VTE events (104 per 100,000 population) 30 Day recurrence 4.8 % 30 Day recurrence 4.8 % VTE Event Location Patients receiving prophylaxis during high risk periods Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777

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

Thrombosis in Malignancy 7 TH ACCP Consensus Conference Recommendations Initial Phase 5-7 days Dalteparin 200/kg q24h (GRADE 1A) Subacute Phase 3 - 6 months Dalteparin 150 units/kg q24h (GRADE 1A) Chronic Phase Continue anticoagulation (warfarin or LMWH) long-term or until malignancy resolves (GRADE 1C) 5 - 7 days3 - 6 mos6 mos - indefinite Buller HR, et al. Chest 2004; 126 (suppl 3): 401s-428s Press Release: May 2, 2007

http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice GuidelinesVenous Thromboembolic Disease Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis Immediate LMWH LMWH - Dalteparin (200 units/kg subcutaneous daily) - Enoxaparin (1 mg/kg subcutaneous every 12 hrs) - Tinzaparin (175 units/kg subcutaneous daily) Pentasaccharide Pentasaccharide - Fondaparinux (5.0 mg [ 100 kg] subcutaneous daily - Fondaparinux (5.0 mg [ 100 kg] subcutaneous daily Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to 2.0-2.9 x control) Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to 2.0-2.9 x control) Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis Immediate LMWH LMWH - Dalteparin (200 units/kg subcutaneous daily) - Enoxaparin (1 mg/kg subcutaneous every 12 hrs) - Tinzaparin (175 units/kg subcutaneous daily) Pentasaccharide Pentasaccharide - Fondaparinux (5.0 mg [ 100 kg] subcutaneous daily - Fondaparinux (5.0 mg [ 100 kg] subcutaneous daily Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to 2.0-2.9 x control) Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to 2.0-2.9 x control)

http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice GuidelinesVenous 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 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) 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 Minimum time of 3-6 mo for DVT and 6-12 mo for PE Consider indefinite anticoaugulation if active cancer or persistent risk factors 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 For catheter associated thrombosis, anticoagulate as long as catheter is in place and for 1-3 mo after catheter removal 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 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) 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 Minimum time of 3-6 mo for DVT and 6-12 mo for PE Consider indefinite anticoaugulation if active cancer or persistent risk factors 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 For catheter associated thrombosis, anticoagulate as long as catheter is in place and for 1-3 mo after catheter removal

What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE ? 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 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. 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. 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. For CNS malignancies, elderly patients anticoagulation is recommended with careful monitoring and dose adjustment. What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE ? 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 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. 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. 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. For CNS malignancies, elderly patients anticoagulation is recommended with careful monitoring and dose adjustment. Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? 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. Anticoagulants are not recommended to improve survival in patients with cancer without VTE. Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? 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. 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.

Tapson V et al. Arch Intern Med 2005 Survey of 38 U.S. Hospitals n=939 DVT or PE 50% patients reached INR >2 for 2 consecutive days Survey of 38 U.S. Hospitals n=939 DVT or PE 50% patients reached INR >2 for 2 consecutive daysTherapy n (%) LMWH 527 (56.1%) UFH 562 (59.8%) UFH SC 78 (8.3%) DTI 6 (0.6%) Antithrombotic Therapy Practices in U.S. Hospitals

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

Self-Managed Long Term LMWH Therapy Outcomes Tinzaparin (n=369) Usual Care (n=368) Absolute Difference (95% CI) p-value 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 Hull R. Am Jour Med 2007; 120:72-82

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

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

Welcome to this Science-to-Strategy Summit. Critical Challenges and Landmark Advances in Thrombosis Management The Evolving and Foundation Role of LMWHs.

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Welcome to this Science-to-Strategy Summit. Critical Challenges and Landmark Advances in Thrombosis Management The Evolving and Foundation Role of LMWHs.

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Presentation on theme: "Welcome to this Science-to-Strategy Summit. Critical Challenges and Landmark Advances in Thrombosis Management The Evolving and Foundation Role of LMWHs."— Presentation transcript:

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